81_FR_43038 81 FR 42912 - Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record

81 FR 42912 - Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 81, Issue 126 (June 30, 2016)

Page Range42912-42937
FR Document2016-15410

The Food and Drug Administration (FDA or Agency) is issuing this proposed rule to amend the 1994 tentative final monograph or proposed rule (the 1994 TFM) for over-the-counter (OTC) antiseptic drug products. In this proposed rule, we are proposing to establish conditions under which OTC consumer antiseptic products intended for use without water (referred to throughout as consumer antiseptic rubs or consumer rubs) are generally recognized as safe and generally recognized as effective (GRAS/GRAE). In the 1994 TFM, certain antiseptic active ingredients were proposed as being GRAS for antiseptic rub use by consumers based on safety data evaluated by FDA as part of its ongoing review of OTC antiseptic drug products. However, in light of more recent scientific developments and changes in the use patterns of these products, we are now proposing that additional safety data are necessary to support the safety of antiseptic active ingredients for this use. We also are proposing that all consumer antiseptic rub active ingredients have in vitro data characterizing the ingredient's antimicrobial properties and in vivo clinical simulation studies showing that specified log reductions in the amount of certain bacteria are achieved using the ingredient.

Federal Register, Volume 81 Issue 126 (Thursday, June 30, 2016)
[Federal Register Volume 81, Number 126 (Thursday, June 30, 2016)]
[Proposed Rules]
[Pages 42912-42937]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2016-15410]



[[Page 42911]]

Vol. 81

Thursday,

No. 126

June 30, 2016

Part IV





Department of Health and Human Services





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 Food and Drug Administration





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21 CFR Part 310





Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial 
Drug Products for Over-the-Counter Human Use; Proposed Amendment of the 
Tentative Final Monograph; Reopening of Administrative Record; Proposed 
Rule

Federal Register / Vol. 81 , No. 126 / Thursday, June 30, 2016 / 
Proposed Rules

[[Page 42912]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. FDA-2016-N-0124 (Formerly Part of Docket No. FDA-1975-N-
0012)]
RIN 0910-AF69


Safety and Effectiveness of Consumer Antiseptics; Topical 
Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed 
Amendment of the Tentative Final Monograph; Reopening of Administrative 
Record

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is issuing 
this proposed rule to amend the 1994 tentative final monograph or 
proposed rule (the 1994 TFM) for over-the-counter (OTC) antiseptic drug 
products. In this proposed rule, we are proposing to establish 
conditions under which OTC consumer antiseptic products intended for 
use without water (referred to throughout as consumer antiseptic rubs 
or consumer rubs) are generally recognized as safe and generally 
recognized as effective (GRAS/GRAE). In the 1994 TFM, certain 
antiseptic active ingredients were proposed as being GRAS for 
antiseptic rub use by consumers based on safety data evaluated by FDA 
as part of its ongoing review of OTC antiseptic drug products. However, 
in light of more recent scientific developments and changes in the use 
patterns of these products, we are now proposing that additional safety 
data are necessary to support the safety of antiseptic active 
ingredients for this use. We also are proposing that all consumer 
antiseptic rub active ingredients have in vitro data characterizing the 
ingredient's antimicrobial properties and in vivo clinical simulation 
studies showing that specified log reductions in the amount of certain 
bacteria are achieved using the ingredient.

DATES: Submit electronic or written comments by December 27, 2016. See 
section IX of this document for the proposed effective date of a final 
rule based on this proposed rule.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on http://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions''). We 
note however, that the OTC drug monograph process is a public process; 
and, the Agency intends to consider only non-confidential material that 
is submitted to the docket for this rulemaking or that is otherwise 
publicly available in evaluating if a relevant ingredient is GRAS/GRAE.

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2016-N-0124 for ``Safety and Effectiveness of Consumer Antiseptics; 
Topical Antimicrobial Drug Products for Over-the-Counter Human Use; 
Proposed Amendment of the Tentative Final Monograph; Reopening of 
Administrative Record.'' Received comments will be placed in the docket 
and, except for those submitted as ``Confidential Submissions,'' 
publicly viewable at http://www.regulations.gov or at the Division of 
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Anita Kumar, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 5445, Silver Spring, MD 20993, 301-796-
1032.

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Executive Summary
    A. Purpose of the Regulatory Action
    B. Summary of the Major Provisions of the Regulatory Action in 
Question
    C. Effectiveness
    D. Safety
    E. Active Ingredients
    F. Costs and Benefits
II. Introduction
    A. Terminology Used in the OTC Drug Review Regulations
    B. Topical Antiseptics
    C. This Proposed Rule Covers Only Consumer Antiseptic Rubs

[[Page 42913]]

    D. Comment Period
III. Background
    A. Significant Rulemakings Relevant to This Proposed Rule
    B. Public Meetings Relevant to This Proposed Rule
    C. Comments Received by FDA
IV. Active Ingredients With Insufficient Evidence of Eligibility for 
the OTC Drug Review
    A. Eligibility for the OTC Drug Review
    B. Eligibility of Certain Active Ingredients for the OTC Drug 
Review
V. Ingredients Previously Proposed as Not Generally Recognized as 
Safe and Effective
VI. Summary of Proposed Classifications of OTC Consumer Antiseptic 
Rub Active Ingredients
VII. Effectiveness (Generally Recognized as Effective) Determination
    A. Evaluation of Effectiveness Data
    B. Current Standards: Studies Needed To Support a Generally 
Recognized as Effective Determination
    C. Impact of Application Parameters on Efficacy
VIII. Safety (Generally Recognized as Safe) Determination
    A. New Issues
    B. Antimicrobial Resistance
    C. Studies To Support a Generally Recognized as Safe 
Determination
    D. Review of Available Data for Each Antiseptic Active 
Ingredient
IX. Proposed Effective Date
X. Summary of Preliminary Regulatory Impact Analysis
A. Introduction
    B. Summary of Costs and Benefits
    XI. Paperwork Reduction Act of 1995
XII. Environmental Impact
XIII. Federalism
XIV. References

I. Executive Summary

A. Purpose of the Regulatory Action

    FDA is proposing to amend the 1994 TFM for OTC antiseptic drug 
products that published in the Federal Register of June 17, 1994 (59 FR 
31402). The 1994 TFM is part of FDA's ongoing rulemaking to evaluate 
the safety and effectiveness of OTC drug products marketed in the 
United States on or before May 1972 (OTC Drug Review).
    FDA is proposing to establish new conditions under which active 
ingredients used in OTC consumer antiseptic products intended to be 
used without water are GRAS/GRAE based on FDA's reevaluation of the 
safety and effectiveness data requirements proposed in the 1994 TFM for 
what were then referred to as antiseptic hand washes (which included 
the products we refer to in this document as consumer antiseptic rubs 
or consumer rubs). We are conducting this reevaluation based on the 
comments received, input from subsequent public meetings, and our 
independent evaluation of other relevant scientific information we have 
identified and placed in the docket. This proposed rule applies to 
active ingredients used in consumer antiseptic rub products that are 
sometimes referred to as rubs, leave-on products, or hand 
``sanitizers,'' as well as to consumer antiseptic wipes. These products 
are intended to be used when soap and water are not available, and are 
left on and not rinsed off with water. We will refer to them here as 
consumer antiseptic rubs or consumer rubs. In separate rulemakings (78 
FR 76444, December 17, 2013; 80 FR 25166, May 1, 2015), we proposed 
conditions under which OTC consumer antiseptic washes and OTC 
antiseptics intended for use by health care professionals in a hospital 
setting or other health care situation outside the hospital are GRAS/
GRAE. Those antiseptic products are not addressed in this proposed 
rule.

B. Summary of the Major Provisions of the Regulatory Action in Question

    We are proposing that additional safety and effectiveness data are 
necessary to support a GRAS/GRAE determination for OTC antiseptic rub 
active ingredients intended for use by consumers. The effectiveness 
data, the safety data, and the effect on the previously proposed 
classification of active ingredients are described briefly in this 
summary. Because no ingredients currently meet the criteria for a GRAS/
GRAE determination in this proposed rule, this rulemaking does not 
specifically address requirements for anticipated final formulation 
testing (i.e., testing the mixture of both active and inactive 
ingredients proposed for marketing) or labeling. Final formulation 
testing could potentially involve both efficacy testing and safety 
testing to determine absorption. It is anticipated that if a final rule 
includes any GRAS/GRAE ingredients, labeling will be addressed as part 
of the final rule and may include elements related to application 
volume and safety labeling for children, including a warning to keep 
out of reach of children. We anticipate that specific effectiveness 
claims in labeling will reflect the testing performed in support of 
these claims. Effectiveness testing using surrogate endpoints as 
described in this proposed rule is designed to support antibacterial 
claims.

C. Effectiveness

    A determination that a drug product containing a particular active 
ingredient would be GRAE for a particular intended use requires 
consideration of the benefit-to-risk ratio for the drug under the 
specified conditions of use. New information on potential risks posed 
by the use of certain consumer antiseptic products, as well as input 
from the Nonprescription Drugs Advisory Committee (NDAC) that met in 
March 2005 (the March 2005 NDAC) and October 2005 (the October 2005 
NDAC), has prompted us to reevaluate the data needed for classifying 
active ingredients used in consumer rubs as GRAE. The reevaluation of 
effectiveness will help to ensure that the level of effectiveness 
achieved is adequate to offset newly identified safety concerns (see 
new information described in the safety section of this executive 
summary). We continue to propose the use of surrogate endpoints 
(bacterial log reductions) as a demonstration of effectiveness for 
consumer antiseptic rubs combined with in vitro testing to characterize 
the antimicrobial activity of the ingredient. However, the log 
reductions required for the demonstration of effectiveness for consumer 
rubs have been revised based on the recommendations of the March 2005 
and October 2005 NDAC meetings, comments received after the 1994 TFM, 
and other information we reviewed.
    We have evaluated the available literature, the data, and other 
information that were submitted to the rulemaking on the effectiveness 
of consumer rub active ingredients, as well as the recommendations from 
the public meetings held by the Agency on antiseptics. We propose that 
the record contain additional log reduction data to demonstrate the 
effectiveness of consumer rub active ingredients. We are also asking 
for data and information to be submitted about the impact of product 
use factors (such as volume of product per application) on efficacy to 
help inform labeling and requirements for final formulation testing.

D. Safety

    Several important scientific developments that affect the safety 
evaluation of consumer rub active ingredients have occurred since FDA's 
1994 evaluation of the safety of these active ingredients under the OTC 
Drug Review. Improved analytical methods now exist that can detect and 
more accurately measure these active ingredients at lower levels in the 
bloodstream and tissue. Consequently, we now know that, at least for 
certain consumer antiseptic rub ingredients, systemic exposure is 
higher than previously thought (Refs. 1 through 5), and new information 
is available about the potential risks from systemic absorption and 
long-term exposure. These data are particularly important given the 
increased use of consumer antiseptic rubs since the publication of

[[Page 42914]]

the 1994 TFM. New safety information also suggests that widespread 
antiseptic use could have an impact on the development of bacterial 
resistance. Currently, the significance of this new information is not 
known and we are unaware of any information that would lead us to 
conclude that any consumer antiseptic rub active ingredient is unsafe 
(other than those that we proposed to be Category II in the 1994 TFM). 
The benefits of any active ingredient will need to be weighed against 
its risks once both the effectiveness and safety have been better 
characterized to determine GRAS/GRAE status.
    The previously proposed GRAS determinations were based on safety 
principles that have since evolved significantly because of advances in 
technology, development of new test methods, and experience with 
performing test methods. The standard battery of tests that were used 
to determine the safety of drugs has changed over time to incorporate 
improvements in safety testing. To ensure that consumer antiseptic rub 
active ingredients are GRAS, data that meet current safety standards 
are needed.
    Based on these developments, we are now proposing that additional 
safety data are needed for each consumer antiseptic rub active 
ingredient to support a GRAS classification. The data described in this 
proposed rule are the minimum data necessary to establish the safety of 
antiseptic active ingredients used in consumer antiseptic rub products 
in light of the new safety information. Consumers may use antiseptic 
rubs on a daily, long-term (i.e., chronic) basis. The data we propose, 
which are needed to demonstrate safety for all consumer antiseptic rub 
active ingredients, fall into two broad categories: (1) Human safety 
studies and (2) nonclinical safety studies. For one of the consumer 
antiseptic rub active ingredients (benzalkonium chloride), data to 
evaluate the development of antimicrobial resistance also is required 
to demonstrate its safety.

E. Active Ingredients

    Three active ingredients are being evaluated for use as a consumer 
antiseptic rub in this proposed rule: Alcohol (ethanol or ethyl 
alcohol), isopropyl alcohol, and benzalkonium chloride (sometimes 
referred to as ADBAC). As part of this proposed rule, FDA evaluated new 
data submitted after publication of the 1994 TFM for each of these 
three ingredients.
    In the 1994 TFM (59 FR 31402 at 31435), alcohol (60 to 95 percent) 
was proposed to be classified as GRAS/GRAE (59 FR 31402 at 31435 to 
31436) for use as what was then called an antiseptic hand wash (a use 
which included both products intended to be rinsed off (washes) and 
those intended to be left on (rubs)). Isopropyl alcohol (70 to 91.3 
percent) was proposed to be categorized in Category III in the 1994 TFM 
because of a lack of adequate effectiveness data for use as an 
antiseptic hand wash (59 FR 31402 at 31435 to 31436). However, we now 
propose that both alcohol and isopropyl alcohol need additional safety 
and effectiveness data to support a classification of GRAS/GRAE for 
consumer antiseptic rub use. Our detailed evaluation of the 
effectiveness and safety of the active ingredients for which data were 
submitted can be found in sections VII.A and VIII.D.
    In the 1994 TFM, FDA categorized benzalkonium chloride in Category 
III because of a lack of adequate safety and effectiveness data for its 
use as an antiseptic hand wash (59 FR 31402 at 31435). We have 
evaluated safety data received in response to the 1994 TFM and the 
consumer antiseptic wash proposed rule published in the Federal 
Register of December 17, 2013 (78 FR 76444) (2013 Consumer Wash 
Proposed Rule (PR)) (see section VIII.D). In this proposed rule, we 
propose that benzalkonium chloride needs additional safety and 
effectiveness data to support a classification of GRAS/GRAE for 
consumer antiseptic rub use.
    If we do not receive sufficient data to support monograph 
conditions for consumer antiseptic rub products containing these active 
ingredients, these active ingredients may not be included in the future 
OTC consumer antiseptic rub final monograph. Any consumer antiseptic 
rub product containing the active ingredients being considered under 
this rulemaking that are not included in a future final monograph could 
seek approval to market by submitting new drug applications (NDAs) 
under section 505 of the Federal Food, Drug, and Cosmetic Act (the FD&C 
Act) (21 U.S.C. 355). After a final monograph is established, NDA 
deviations might be submitted for these products in accordance with 21 
CFR 330.11, limiting the scope of review necessary to obtain approval.

F. Costs and Benefits

    The impact of the proposed rule on the OTC consumer antiseptic rub 
product industry will depend on the outcome of tests to determine 
whether three antiseptic ingredients--alcohol, isopropyl alcohol, and 
benzalkonium chloride--are GRAS/GRAE. It is possible that none, one, 
two, or all three of the ingredients will be determined to be GRAS/
GRAE. We consider two extreme scenarios to capture the entire range of 
total costs: (1) All three ingredients are deemed to be GRAS/GRAE or 
(2) none of the ingredients is deemed to be GRAS/GRAE.
    The range of estimated costs is wide because the number of products 
that would need to be reformulated and relabeled depends on whether or 
not an antiseptic ingredient is deemed to be GRAS/GRAE. A small number 
of products contain active ingredients which FDA has determined are not 
eligible for use in consumer antiseptic rubs and these products will 
need to be reformulated and relabeled (scenario 1). However, in 
scenario 2 (and intermediate scenarios), the resulting costs are higher 
because a greater number of products will need to be reformulated and 
relabeled as a result of tests failing to show GRAS/GRAE status.
    The total upfront costs of the proposed regulation--which include 
the expenditures to reformulate and relabel products that contain 
nonmonograph ingredients--are estimated to range from $0.34 million to 
$1.02 million for scenario 1 and from $15.99 million to $47.09 million 
for scenario 2. Annualizing upfront costs over a 10-year period at a 
discount rate of 3% for scenario 1, the costs of the proposed rule are 
estimated to be between $0.04 million and $0.12 million per year; the 
corresponding estimated cost at a discount rate of 7% is between $0.05 
million and $0.14 million per year. In scenario 2, none of the 
ingredients is determined to be GRAS/E and we expect that manufacturers 
will reformulate their products to be free of antiseptics and relabel 
them to reflect the change in ingredients. Annualizing upfront costs 
over a 10-year period at a discount rate of 3% for scenario 2, the 
costs of the proposed rule are estimated to be between $1.87 million 
and $5.52 million per year; the corresponding estimated cost at a 
discount rate of 7% is between $2.28 million and $6.70 million per 
year. We assume that health risk falls with reduced exposure to 
potentially unsafe or ineffective antiseptic ingredients in consumer 
antiseptic rubs. We estimate that the proposed rule will reduce 
exposure to potentially unsafe or ineffective antiseptic ingredients in 
consumer antiseptic rubs by between 110 and 67,272,847 pounds.\1\
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    \1\ As was the case with estimated costs, there is a great 
disparity in the estimated reductions in exposure to antiseptic 
ingredients. The lower bound (110 pounds) represents the estimated 
reduction in exposure to ingredients which FDA has determined are 
not GRAS/GRAE for use in consumer antiseptic rubs and few products 
contain such GRAS/GRAE ingredients.

[[Page 42915]]



----------------------------------------------------------------------------------------------------------------
                                  Total reduction in
 Summary of costs and benefits   antiseptic ingredient  Total costs annualized over    Total one-time costs (in
     of the proposed rule        exposure (in pounds)      10 years (in millions)             millions)
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Total.........................  110 and 67,272,847....  $0.04 to $5.52 (3%)........  $0.34 and $47.09.
                                                        $0.05 to $6.70 (7%)........
----------------------------------------------------------------------------------------------------------------

II. Introduction

    In the following sections, we provide a brief description of 
terminology used in the OTC Drug Review regulations and an overview of 
OTC topical antiseptic drug products, and then describe in more detail 
the OTC consumer antiseptic rubs that are the subject of this proposed 
rule.

A. Terminology Used in the OTC Drug Review Regulations

1. Proposed, Tentative Final, and Final Monographs
    To conform to terminology used in the OTC Drug Review regulations 
(Sec.  330.10 (21 CFR 330.10)), the September 1974 advance notice of 
proposed rulemaking (39 FR 33103, September 13, 1974) (1974 ANPR) was 
designated as a ``proposed monograph.'' Similarly, the notices of 
proposed rulemaking, which were published in the Federal Register of 
January 6, 1978 (43 FR 1210) (the 1978 TFM), and in the Federal 
Register of June 17, 1994 (59 FR 31402) (the 1994 TFM), were each 
designated as a ``tentative final monograph'' (see table 1 in section 
III.A). The present proposed rule, which is a proposal to amend the 
1994 TFM with respect to consumer antiseptic rub drug products, is also 
designated as a ``tentative final monograph.''
2. Category I, II, and III Classifications
    The OTC drug procedural regulations in Sec.  330.10 use the terms 
``Category I'' (generally recognized as safe and effective and not 
misbranded), ``Category II'' (not generally recognized as safe and 
effective or misbranded), and ``Category III'' (available data are 
insufficient to classify as safe and effective, and further testing is 
required). Section 330.10 provides that any testing necessary to 
resolve the safety or effectiveness issues that formerly resulted in a 
Category III classification, and submission to FDA of the results of 
that testing or any other data, must be done during the OTC drug 
rulemaking process before the establishment of a final monograph (i.e., 
a final rule or regulation). Therefore, this proposed rule (the 
tentative final monograph stage) retains the concepts of Categories I, 
II, and III.
    At the final monograph stage, FDA does not use the terms ``Category 
I,'' ``Category II,'' and ``Category III.'' In place of Category I, the 
term ``monograph conditions'' is used; in place of Categories II and 
III, the term ``nonmonograph conditions'' is used.

B. Topical Antiseptics

    The OTC topical antimicrobial rulemaking has had a broad scope, 
encompassing drug products that may contain the same active 
ingredients, but that are labeled and marketed for different intended 
uses. In 1974, the Agency published an ANPR for topical antimicrobial 
products that encompassed products for both health care and consumer 
use. The 1974 ANPR covered seven different intended uses for these 
products: (1) Antimicrobial soap; (2) health care personnel hand wash; 
(3) patient preoperative skin preparation; (4) skin antiseptic; (5) 
skin wound cleanser; (6) skin wound protectant; and (7) surgical hand 
scrub (39 FR 33103 at 33140). FDA subsequently identified skin 
antiseptics, skin wound cleansers, and skin wound protectants as 
antiseptics used primarily by consumers for first aid use and referred 
to them collectively as ``first aid antiseptics.'' We published a 
separate TFM covering the first aid antiseptics in the Federal Register 
of July 22, 1991 (56 FR 33644) (1991 First Aid TFM). Thus, first aid 
antiseptics are not discussed further in this document.
    The four remaining categories of topical antimicrobials were 
addressed in the 1994 TFM. The 1994 TFM covered: (1) Antiseptic hand 
wash (i.e., consumer hand wash); (2) health care personnel hand wash; 
(3) patient preoperative skin preparation; and (4) surgical hand scrub 
(59 FR 31402 at 31442). In the 1994 TFM, FDA also identified a new 
category of antiseptics for use by the food industry and requested 
relevant data and information (59 FR 31402 at 31440). Antiseptics for 
use by the food industry are not discussed further in this document.
    In the 1974 ANPR, we distinguished antimicrobial soaps used by 
consumers from professional use antiseptics, such as health care 
personnel hand washes. (See section II.C about the term ``antimicrobial 
soaps.'') In contrast, in the 1994 TFM, we proposed that both 
antiseptic hand washes (i.e., consumer antiseptic washes) and health 
care personnel hand washes should have the same effectiveness testing 
and performance criteria. In response to the 1994 TFM, we received 
submissions from the public arguing that consumer products serve a 
different purpose and should continue to be distinct from health care 
antiseptics. We agreed, and in the 2013 Consumer Wash PR and in the 
health care antiseptic proposed rule published in the Federal Register 
of May 1, 2015 (80 FR 25166) (2015 Health Care Antiseptic PR), our 
evaluation of OTC antiseptic drug products has been further subdivided 
into consumer antiseptics and health care antiseptics, which are used 
by health care professionals in a hospital setting or other health care 
situations outside the hospital. We believe that these categories are 
distinct based on the proposed-use setting, target population, and the 
fact that each setting presents a different level of risk for 
infection. For example, in health care settings, the patient population 
is generally more susceptible to infection than the general U.S. 
consumer population (i.e., the population who use consumer antiseptic 
rubs or washes). Furthermore, the purpose of use is generally 
different; health care antiseptics are primarily used to protect the 
patient (rather than just the user), whereas consumer antiseptics are 
generally applied to protect the user. In the health care setting, the 
potential for spread of infection and the potential for serious 
outcomes of infection may be relatively higher than in the U.S. 
consumer setting. Therefore, the safety and effectiveness should be 
evaluated separately for each intended use to support a GRAS/GRAE 
determination.
    As we did in the 2013 Consumer Wash PR, we refer to the group of 
products covered by this proposed rule as ``consumer antiseptics.'' 
Consumer antiseptic drug products addressed by this proposal include 
consumer antiseptic hand rubs (commonly called hand sanitizers) and 
antiseptic wipes.

[[Page 42916]]

These products may be used by consumers for personal use on a frequent 
basis, even multiple times per day. These products do not include 
personal care products intended to be used with water, such as 
antibacterial soaps, hand washes, and body washes.

C. This Proposed Rule Covers Only Consumer Antiseptic Rubs

    In this proposed rule, FDA proposes the establishment of a 
monograph for OTC consumer antiseptics that are intended for use as an 
antiseptic rub, but that are not identified as ``first aid 
antiseptics'' in the 1991 First Aid TFM. When the 1994 TFM was 
published, the term for daily consumer use antiseptics was changed to 
``antiseptic hand wash.'' In response to this change, we received 
comments that the term ``antiseptic hand wash'' did not include all of 
the consumer products on the market, such as hand rubs and body washes. 
Therefore, in this proposed rule, we use the term ``consumer 
antiseptic,'' which is a broad term and meant to include all of the 
types of antiseptic products used on a frequent or daily basis by 
consumers. However, this proposed rule covers only consumer antiseptic 
rubs and does not include consumer antiseptic hand washes or body 
washes.
    The 1994 TFM did not distinguish between products that we are now 
calling ``antiseptic washes'' and products we are now calling 
``antiseptic rubs.'' Washes are rinsed off with water, and include 
consumer hand washes and body washes, and health care personnel hand 
washes and surgical hand scrubs. Rubs are sometimes referred to as 
``leave-on products'' and are not rinsed off after use. They are 
intended to be used when soap and water are not available. Consumer 
antiseptic rubs include ``hand sanitizers'' and wipes. The 1994 TFM 
also did not distinguish between consumer antiseptic washes and rubs, 
and health care hand washes and rubs. This proposed rule covers only 
consumer antiseptic rubs. Completion of the monograph for consumer 
antiseptic rubs and certain other monographs for the active ingredient 
triclosan are subject to a Consent Decree entered by the U.S. District 
Court for the Southern District of New York on November 21, 2013, in 
Natural Resources Defense Council, Inc. v. United States Food and Drug 
Administration, et al., 10 Civ. 5690 (S.D.N.Y.).

D. Comment Period

    Because of the complexity of this proposed rule, we are providing a 
comment period of 180 days. Moreover, new data or information may be 
submitted to the docket via http://www.regulations.gov (see ADDRESSES) 
within 12 months of publication, and comments on any new data or 
information may then be submitted to the docket for an additional 60 
days (see Sec.  330.10(a)(7)(iii) and (iv)). In addition, FDA will also 
consider requests to defer further rulemaking with respect to a 
specific active ingredient for use as a consumer antiseptic rub to 
allow the submission of new safety or effectiveness data to the record 
if these requests are submitted to the docket within the initial 180-
day comment period. FDA will review all data and information submitted 
to the record in conjunction with all timely and complete requests to 
defer rulemaking. In assessing whether to defer further rulemaking for 
a particular active ingredient to allow for additional time for studies 
to generate new data and information, FDA will consider the data 
already in the docket, along with any information that is provided in 
any requests. FDA will determine whether the sum of the data, if 
submitted in a timely fashion, is likely to be adequate to provide all 
the data that are necessary to make a GRAS/GRAE determination.
    We note that the OTC Drug Review is a public process and any data 
submitted is public. There is no requirement or expectation that more 
than one set of data will be submitted to the docket for a particular 
active ingredient, and it does not matter who submits the data. In 
addition, data and other information for a single active ingredient may 
be submitted by any interested party and not all data for an ingredient 
must be submitted by a single party.

III. Background

    In this section, we describe the significant rulemakings and public 
meetings relevant to this proposed rule, and how we are responding to 
comments received in response to the 1994 TFM.

A. Significant Rulemakings Relevant to This Proposed Rule

    A summary of the significant Federal Register publications relevant 
to this proposed rule is provided in table 1. Other publications 
relevant to this proposed rule are available at http://www.regulations.gov in FDA Docket No. 1975-N-0012.

          Table 1--Significant Rulemaking Publications Related to Consumer Antiseptic Drug Products \1\
----------------------------------------------------------------------------------------------------------------
                     Federal Register Notice                                   Information in notice
----------------------------------------------------------------------------------------------------------------
1974 ANPR (September 13, 1974, 39 FR 33103)......................  We published an ANPR to establish a monograph
                                                                    for OTC topical antimicrobial drug products,
                                                                    together with the recommendations of the
                                                                    Advisory Review Panel on OTC Topical
                                                                    Antimicrobial I Drug Products (Antimicrobial
                                                                    I Panel or Panel), which was the advisory
                                                                    review panel responsible for evaluating data
                                                                    on the active ingredients in this drug
                                                                    class.
1978 Antimicrobial TFM (January 6, 1978, 43 FR 1210).............  We published our tentative conclusions and
                                                                    proposed effectiveness testing for the drug
                                                                    product categories evaluated by the Panel.
                                                                    The 1978 TFM reflects our evaluation of the
                                                                    recommendations of the Panel and comments
                                                                    and data submitted in response to the
                                                                    Panel's recommendations.
1982 Alcohol ANPR (May 21, 1982, 47 FR 22324)....................  We published an ANPR to establish a monograph
                                                                    for alcohol drug products for topical
                                                                    antimicrobial use, together with the
                                                                    recommendations of the Advisory Review Panel
                                                                    on OTC Miscellaneous External Drug Products,
                                                                    which was the advisory review panel
                                                                    responsible for evaluating data on the
                                                                    active ingredients in this drug class.
1991 First Aid TFM (July 22, 1991, 56 FR 33644)..................  We amended the 1978 TFM to establish a
                                                                    separate monograph for OTC first aid
                                                                    antiseptic products. In the 1991 First Aid
                                                                    TFM, we proposed that first aid antiseptic
                                                                    drug products be indicated for the
                                                                    prevention of skin infections in minor cuts,
                                                                    scrapes, and burns.
1994 Health Care Antiseptic TFM (June 17, 1994, 59 FR 31402).....  We amended the 1978 TFM to establish a
                                                                    separate monograph for the group of products
                                                                    that were referred to as OTC topical health
                                                                    care antiseptic drug products. These
                                                                    antiseptics are generally intended for use
                                                                    by health care professionals.
                                                                   In that proposed rule, we also recognized the
                                                                    need for antibacterial personal cleansing
                                                                    products for consumers to help prevent cross-
                                                                    contamination from one person to another and
                                                                    proposed a new antiseptic category for
                                                                    consumer use: Antiseptic hand wash.

[[Page 42917]]

 
2013 Consumer Antiseptic Wash TFM (December 17, 2013, 78 FR        We issued a proposed rule to amend the 1994
 76444).                                                            TFM and to establish data standards for
                                                                    determining whether OTC consumer antiseptic
                                                                    washes are GRAS/GRAE.
                                                                   In that proposed rule, we proposed that
                                                                    additional safety and effectiveness data are
                                                                    necessary to support the safety and
                                                                    effectiveness of consumer antiseptic wash
                                                                    active ingredients.
2015 Health Care Antiseptics TFM (May 1, 2015, 80 FR 25166 ).....  We issued a proposed rule to amend the 1994
                                                                    TFM and to establish data standards for
                                                                    determining whether OTC health care
                                                                    antiseptics are GRAS/GRAE.
                                                                   In that proposed rule, we proposed that
                                                                    additional safety and effectiveness data are
                                                                    necessary to support the safety and
                                                                    effectiveness of health care antiseptic
                                                                    active ingredients.
----------------------------------------------------------------------------------------------------------------
\1\ The publications listed in table 1 can be found at the FDA's ``Status of OTC Rulemakings'' Web site
  available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm070821.htm. The publications dated after 1993 can also be found in the Federal
  Register at https://www.federalregister.gov.

B. Public Meetings Relevant to This Proposed Rule

    In addition to the Federal Register publications listed in table 1, 
there have been four meetings of the NDAC and one public feedback 
meeting that are relevant to the discussion of consumer antiseptic rub 
safety and effectiveness. These meetings are summarized in table 2.

                                        Table 2--Relevant Public Meetings
----------------------------------------------------------------------------------------------------------------
                     Date and type of meeting                                   Topic of discussion
----------------------------------------------------------------------------------------------------------------
January 1997 NDAC Meeting (Joint meeting with the Anti-Infective   Antiseptic and antibiotic resistance in
 Drugs Advisory Committee) (January 6, 1997, 62 FR 764).            relation to an industry proposal for
                                                                    consumer and health care antiseptic
                                                                    effectiveness testing (Health Care Continuum
                                                                    Model) (Refs. 6, 7).
March 2005 NDAC Meeting (February 18, 2005, 70 FR 8376)..........  The use of surrogate endpoints and study
                                                                    design issues for the in vivo testing of
                                                                    health care antiseptics (Ref. 8).
October 2005 NDAC Meeting (September 15, 2005, 70 FR 54560)......  Benefits and risks of consumer antiseptics.
                                                                    NDAC expressed concern about the pervasive
                                                                    use of consumer antiseptic washes where
                                                                    there are potential risks and no
                                                                    demonstrable benefit. To demonstrate a
                                                                    clinical benefit, NDAC recommended clinical
                                                                    outcome studies to show that antiseptic
                                                                    washes are superior to nonantibacterial soap
                                                                    and water (Ref. 9).
November 2008 Public Feedback Meeting............................  Demonstration of the effectiveness of
                                                                    consumer antiseptics (Ref. 10).
September 2014 NDAC Meeting (July 29, 2014, 79 FR 44042).........  Safety testing framework for health care
                                                                    antiseptic active ingredients (Ref. 11).
----------------------------------------------------------------------------------------------------------------

C. Comments Received by FDA

    In response to the 1994 TFM, FDA received approximately 160 
comments from drug manufacturers, trade associations, academia, testing 
laboratories, consumers, health professionals, and law firms. In 
response to the 2013 Consumer Wash PR, we received safety data 
regarding benzalkonium chloride that is relevant to this ingredient's 
use in a consumer rub and these data are evaluated in section VIII.D.2. 
Copies of the comments received are on public display at http://www.regulations.gov (see ADDRESSES). Because only consumer antiseptic 
rubs are discussed in this proposed rule, only those comments and data 
received in response to the 1994 TFM that are related to consumer 
antiseptic rub active ingredients are addressed. We also received 
comments related to final formulation testing and labeling conditions 
proposed in the 1994 TFM. If in the future we determine that there are 
monograph consumer antiseptic rub active ingredients that are GRAS/
GRAE, we will address these comments. We invite further comment on the 
final formulation testing and labeling conditions proposed in the 1994 
TFM, particularly in light of the data proposed in this proposed rule 
as necessary to support a GRAS/GRAE determination. Comments that were 
received in response to the 1994 TFM regarding other intended uses of 
the active ingredients are addressed in the 2013 Consumer Wash PR (78 
FR 76444), or the 2015 Health Care Antiseptic PR (80 FR 25166), or will 
be addressed in future documents related to those other uses.
    This proposed rule constitutes FDA's evaluation of submissions made 
in response to the 1994 TFM to support the safety and effectiveness of 
OTC consumer antiseptic rub active ingredients (Ref. 12). We reviewed 
the available literature and data and the comments submitted to the 
rulemaking and are proposing that adequate data for a determination of 
safety and effectiveness are not yet available for the consumer 
antiseptic rub active ingredients.

IV. Active Ingredients With Insufficient Evidence of Eligibility for 
the OTC Drug Review

    In this section of the proposed rule, we describe the requirements 
for eligibility for the OTC Drug Review and the ingredients submitted 
to the OTC Drug Review that lack adequate evidence of eligibility for 
evaluation as consumer antiseptic rub products.

A. Eligibility for the OTC Drug Review

    An OTC drug is covered by the OTC Drug Review if its conditions of 
use existed in the OTC drug marketplace on or before May 11, 1972 (37 
FR 9464) (Ref. 13).\2\ Conditions of use include, among other things, 
active ingredient, dosage form and strength, route of administration, 
and specific OTC use or indication of the product (see Sec.  
330.14(a)). To determine eligibility for the OTC Drug Review, FDA 
typically

[[Page 42918]]

must have actual product labeling or a facsimile of labeling that 
documents the conditions of marketing of a product prior to May 1972 
(see Sec.  330.10(a)(2)). FDA considers a drug that is ineligible for 
inclusion in the OTC monograph system to be a new drug that will 
require FDA approval through the NDA process. Ineligibility for use as 
a consumer antiseptic rub does not affect eligibility under any other 
OTC drug monograph.
---------------------------------------------------------------------------

    \2\ Also, note that drugs initially marketed in the United 
States after the OTC Drug Review began in 1972 and drugs without any 
U.S. marketing experience can be considered in the OTC monograph 
system based on submission of a Time and Extent Application. (See 
Sec.  330.14).
---------------------------------------------------------------------------

B. Eligibility of Certain Active Ingredients for the OTC Drug Review

    The following list includes those active ingredients that were 
addressed in the 1994 TFM for use as an antiseptic hand wash or health 
care personnel hand wash, and which currently do not have adequate 
evidence of eligibility for evaluation under the OTC Drug Review for 
use in a consumer antiseptic rub. Our review of the labeling submitted 
to the Panel or to FDA at a later time did not identify evidence 
demonstrating eligibility for the following active ingredients:

 Benzethonium chloride
 Chloroxylenol
 Chlorhexidine gluconate \3\
---------------------------------------------------------------------------

    \3\ Chlorhexidine gluconate 4 percent aqueous solution was found 
to be ineligible for inclusion in the monograph for any health care 
antiseptic use and was not included in the 1994 TFM (59 FR 31402 at 
31413). We have not received any new information since the 1994 TFM 
demonstrating that this active ingredient is eligible for the 
topical antimicrobial monograph.
---------------------------------------------------------------------------

 Cloflucarban
 Fluorosalan
 Hexachlorophene
 Hexylresorcinol
 Iodine complex (ammonium ether sulfate and polyoxyethylene 
sorbitan monolaurate)
 Iodine complex (phosphate ester of alkylaryloxy polyethylene 
glycol)
 Methylbenzethonium chloride
 Nonylphenoxypoly (ethyleneoxy) ethanoliodine
 Phenol (less than 1.5 percent)
 Phenol (greater than 1.5 percent)
 Poloxamer iodine complex
 Povidone-iodine 5 to 10 percent
 Secondary amyltricresols
 Sodium oxychlorosene
 Tribromsalan
 Triclocarban
 Triclosan
 Triple dye
 Undecoylium chloride iodine complex

    Following the publication of the 1994 TFM, FDA received submissions 
for the first time requesting that the following compounds be added to 
the monograph (Refs. 14 through 20):

 Polyhexamethylene biguanide
 Benzalkonium cetyl phosphate
 Cetylpyridinium chloride
 Calicylic acid, sodium hypochlorite
 Tea tree oil
 Combination of potassium vegetable oil solution, phosphate 
sequestering agent, and triethanolamine

    These compounds were not addressed in prior FDA documents related 
to the monograph and were not evaluated for antiseptic hand wash use by 
the Antimicrobial I Panel. The submissions received by the Agency to 
date do not include documentation demonstrating the eligibility of any 
of these compounds for inclusion in the topical antimicrobial monograph 
(Ref. 21). Because of their lack of eligibility, effectiveness and 
safety information that has been submitted to the rulemaking for these 
consumer antiseptic rub active ingredients are not discussed in this 
proposed rule for such use. However, if documentation of the type 
described in section IV.A is submitted, these active ingredients could 
be determined to be eligible for evaluation for use as a consumer 
antiseptic rub.

V. Ingredients Previously Proposed as Not Generally Recognized as Safe 
and Effective

    FDA may determine that an active ingredient is not GRAS/GRAE for a 
given OTC use (i.e., nonmonograph) because of lack of evidence of 
effectiveness, lack of evidence of safety, or both. In the 1994 TFM (59 
FR 31402 at 31435), FDA proposed that the active ingredients 
fluorosalan, hexachlorophene, phenol (greater than 1.5 percent), and 
tribromsalan be found not GRAS/GRAE for the uses referred to in the 
1994 TFM as antiseptic hand wash and health care personnel hand wash. 
None of these ingredients currently have adequate evidence of 
eligibility for use in a consumer antiseptic rub (see section IV.B). 
Consequently, effectiveness and safety information that has been 
submitted to the rulemaking for these consumer antiseptic rub active 
ingredients are not discussed in this proposed rule for such use. 
However, if documentation of the type described in section IV.A is 
submitted, these active ingredients could be determined to be eligible 
for evaluation for use as a consumer antiseptic rub.

VI. Summary of Proposed Classifications of OTC Consumer Antiseptic Rub 
Active Ingredients

    Table 3 lists the OTC consumer antiseptic active ingredients 
eligible for evaluation under the OTC Drug Review for use in consumer 
rubs, the classification proposed in the 1994 TFM, and the 
classification being proposed in this rulemaking. For each active 
ingredient, data that have been submitted to the public docket (for the 
topical antimicrobial rulemaking) and evaluated by FDA and the 
description of data still lacking in the administrative record are 
described in detail in section VIII.

      Table 3--Classification of OTC Consumer Antiseptic Rub Active
          Ingredients in the 1994 TFM and in This Proposed Rule
------------------------------------------------------------------------
                                 1994 TFM proposal
       Active ingredient                \1\           This proposed rule
------------------------------------------------------------------------
Alcohol 60 to 95 percent......  I \2\..............  IIISE \3\
Isopropyl alcohol 70 to 91.3    IIIE...............  IIISE
 percent.
Benzalkonium chloride.........  IIISE..............  IIISE
------------------------------------------------------------------------
\1\ Because the 1994 TFM did not describe antiseptic hand washes and
  rubs separately, the 1994 TFM classification was for use as an
  antiseptic hand wash or health care antiseptic hand wash.
\2\ ``I'' denotes a classification that an active ingredient has been
  shown to be safe and effective.
\3\ ``III'' denotes a classification that additional data are needed.
  ``S'' denotes safety data needed. ``E'' denotes effectiveness data
  needed.

    In the 1994 TFM, alcohol was classified as Category I, isopropyl 
alcohol was classified as Category IIIE, and benzalkonium chloride was 
classified as Category IIISE for use as an antiseptic hand wash or 
health care

[[Page 42919]]

personnel hand wash. However, in this proposed rule, we are proposing 
to classify all three ingredients as Category IIISE for use as a 
consumer antiseptic rub because additional effectiveness and safety 
data are needed to classify each ingredient as GRAS/GRAE for this use.

VII. Effectiveness (Generally Recognized as Effective) Determination

    OTC regulations (Sec. Sec.  330.10(a)(4)(ii) and 314.126(b) (21 CFR 
330.10(a)(4)(ii) and 314.126(b))) define the standards for establishing 
that an OTC drug containing a particular active ingredient would be 
GRAE for its intended use. These regulations provide that supporting 
investigations must be adequate and well-controlled, and able to 
distinguish the effect of a drug from other influences such as a 
spontaneous change in the course of the disease, placebo effect, or 
biased observation. In general, such investigations include controls 
that are adequate to provide an assessment of drug effect, are adequate 
measures to minimize bias, and use adequate analytical methods to 
demonstrate effectiveness. For active ingredients being evaluated in 
the OTC Drug Review, this means that a demonstration of the 
contribution of the active ingredient to any effectiveness observed is 
required before an ingredient can be determined to be GRAE for OTC drug 
use.
    In the 1994 TFM, we continued to apply a log reduction standard (a 
clinical simulation standard) for establishing effectiveness of 
consumer antiseptics originally proposed in the 1978 TFM (59 FR 31402 
at 31412) for the proposed intended use of decreasing bacteria on the 
skin. The 1994 TFM log reduction standard for effectiveness is based on 
a surrogate endpoint (i.e., number of bacteria removed from the skin), 
rather than a clinical outcome (e.g., reduction in the number of 
infections). Although the test methods proposed in the 1994 TFM are 
intended to evaluate the effectiveness of antiseptic final 
formulations, this type of clinical simulation testing, when adequately 
controlled, can also be used to demonstrate that an active ingredient 
is GRAE for use in a consumer antiseptic rub product. As reflected by 
the recommendations of some public health agencies, FDA believes that 
consumer antiseptic rubs are generally used when hands are not visibly 
soiled, and soap and water are not readily available (Refs. 22, 23), 
for example, in settings such as school classrooms, childcare 
facilities, outdoors and various other public places (Ref. 24). 
However, as discussed in section VII.A, data from adequately controlled 
studies demonstrating the impact of consumer antiseptic rubs on 
infection rates are not available. In contrast to consumer washes, for 
which we are asking for clinical outcome data to support the benefit of 
these products, given the easily available alternative of washing with 
soap and water, there is no similar readily available alternative for 
consumer antiseptic rubs. A clinical outcome trial comparing the use of 
consumer antiseptic rubs to standard hand washing with soap and water 
has less applicability given that consumer antiseptic rubs are not 
generally used in situations in which soap and water are a readily 
available alternative. Therefore, we are currently recommending the use 
of clinical simulation studies because they are a practical means to 
assess the general effectiveness of consumer antiseptic rubs.
    FDA has already relied on clinical simulation studies as a standard 
for evaluating effectiveness of hand antiseptic drug products approved 
under NDAs, which are proven to be an effective measure to lower the 
surgical site infection rate (Refs. 25 through 27). In addition, in our 
recently revised standards for evaluating the effectiveness of health 
care antiseptics published in May 2015 (80 FR 25166), we relied on 
clinical simulation studies based on the recommendations of the March 
2005 NDAC. In contrast, in the 2013 Consumer Wash PR, we proposed an 
efficacy standard for consumer antiseptic washes that relies on 
clinical outcome trials, also based on NDAC recommendations. As noted 
previously, consumer antiseptic rub products are generally used when 
soap and water are not available, so consumers lack a readily available 
alternative. As such, we continue to propose a log reduction standard 
to demonstrate the general recognition of effectiveness for consumer 
antiseptic rubs in accordance with our standards for health care 
antiseptics, which contain the same active ingredients (i.e., alcohol, 
isopropyl alcohol, and benzalkonium chloride). Details of our current 
proposed log reduction standard are outlined in section VII.B.
    As discussed in section VII.A, we have evaluated the available 
effectiveness studies that were submitted to the OTC Drug Review or 
retrieved through the published literature to support the effectiveness 
for consumer antiseptic rubs using the log reduction criteria most 
recently proposed in the 1994 TFM (59 FR 31402 at 31448) (Refs. 28 and 
29). We found that the available studies are not adequate to support a 
GRAE determination for any consumer antiseptic rub active ingredient 
under either the final formulation effectiveness testing criteria 
proposed in the 1994 TFM or under the GRAE criteria proposed in this 
proposed rule (see table 4).
    We have also evaluated all the studies that were submitted to the 
OTC Drug Review and have searched the published literature for studies 
performed in consumer use settings that would provide the direct 
evidence of a clinical benefit from the use of consumer antiseptic rubs 
(Ref. 24). We are defining a clinical benefit here as a reduction in 
the number of infections in a population that uses the consumer 
antiseptic rubs. Although a definitive link between consumer antiseptic 
rubs and reduced infection rates has not been established, some public 
health agencies recommend the use of consumer antiseptic rubs when soap 
and water are not available (Refs. 22, 23).

A. Evaluation of Effectiveness Data

1. Clinical Simulation Studies
    Most of the available data to support the effectiveness of consumer 
antiseptic rubs are based on clinical simulation studies, such as the 
ones described in the 1994 TFM (59 FR 31402 at 31444). The premise 
behind these studies as described in the 1994 TFM is that bacterial 
reductions translate to a reduced risk for infection. However, 
currently, there are no clinical data that demonstrate that the 
specific bacterial log reductions that we have relied upon as a 
demonstration of effectiveness lead to a specific reduction in 
infections. In our view, although a lower number of bacteria on hands 
may not directly translate into a reduced chance of infection, a 
reduced bacterial load does decrease the opportunity for infection when 
used in situations with no other options for hand cleansing. In this 
case, rather than comparing using consumer antiseptic rubs to hand 
washing with soap and water, we are comparing them to the alternative 
of not cleaning the hands. In addition, because we believe that the 
consumer antiseptic rubs are intended to provide immediate reduction of 
bacteria rather than a persistent benefit, we are proposing that log 
reductions be measured after a single bacterial challenge (see table 
4), rather than after repeated contamination.
    We have evaluated all clinical simulation studies that were 
submitted to the OTC Drug Review for evidence of the effectiveness of 
consumer antiseptic rub active ingredients under the log reduction 
criteria proposed in the 1994

[[Page 42920]]

TFM (59 FR 31402 at 31448) (Refs. 28 through 30). We also searched the 
published literature for clinical simulation studies that assess 
consumer antiseptic rubs' effectiveness using the log reduction 
criteria in the 1994 TFM (Refs. 28 and 29).
    Overall, the studies used a variety of study designs, including 
nonstandard study designs. In some cases, data submitted to the OTC 
Drug Review were in the form of technical reports or published articles 
without any study details. There is insufficient information to 
evaluate the scientific merit of studies described in abstracts and 
technical reports. Most importantly, none of the evaluated studies were 
adequately controlled to demonstrate the contribution of the active 
ingredient to the effectiveness observed in the studies (43 FR 1210 at 
1240) and, therefore, cannot be used to demonstrate that the active 
ingredient tested is GRAE.
    In general, the evaluated studies also had at least one of the 
following deficiencies:
     Some studies that were described as using a standardized 
method (American Society for Testing and Materials (ASTM) \4\ or 1994 
TFM) varied from these methods without explanation or validation, and 
the majority of studies did not provide sufficient information about 
critical aspects of the study conduct.
---------------------------------------------------------------------------

    \4\ General information about ASTM can be found at https://www.astm.org/.
---------------------------------------------------------------------------

     Many studies did not include appropriate controls; for 
example, most studies did not include a vehicle control or an active 
control (59 FR 31402 at 31448), and some studies that included an 
active control failed to use the control product according to its 
labeled directions (59 FR 31402 at 31448).
     Many studies did not provide sufficient detail concerning 
neutralizer use (43 FR 1210 at 1244) or validation of neutralizer 
effectiveness.
     The studies evaluated a small number of subjects (59 FR 
31402 at 31449).
     Some studies did not sample all of the time points 
specified by the test method (59 FR 31402 at 31448).
    FDA's detailed evaluation of the data is filed in Docket No. FDA-
2016-N-0124, available at http://www.regulations.gov.
2. Clinical Outcome Studies
    Although we are not currently proposing to require clinical outcome 
studies to support a GRAE determination in this proposed rule, FDA 
identified and evaluated clinical outcome studies from the published 
literature that could potentially provide evidence of effectiveness for 
the use of consumer antiseptic rubs (Ref. 24). In our view, clinical 
outcome studies evaluating the effectiveness of consumer rubs should be 
adequately controlled and include a placebo or negative control arm to 
show the effect of an active ingredient. Among the reviewed studies and 
published literature, there are only a few studies that use these 
specified parameters for evaluating the effectiveness of consumer 
antiseptic rubs (Ref. 25). Overall, most of the studies were 
confounded, underpowered, and/or not properly controlled.
    Our detailed review of consumer hand rubs studies is available in 
Docket No. FDA-2016-N-0124 (Ref. 24). None of the alcohol-based hand 
rub studies demonstrating benefit were adequately controlled, thus they 
could not demonstrate the contribution of the antiseptic active 
ingredient to the observed clinical outcome of reduced infection rates. 
In general, the studies had the following design flaws:
     No comparison to vehicle.
     Small sample size.
     Lack of randomization, blinding, or both.
     Inadequate statistical power and, in some cases, a failure 
to analyze results for statistical significance.
     Inadequate description of methodology and data collection 
methods.
     Failure to observe and document hand rub application 
technique.
    One clinical outcome study was identified that was randomized, 
blinded, and placebo-controlled and was well designed to evaluate the 
effectiveness of a particular antiseptic active ingredient (Ref. 31). 
Although it had several significant limitations that prevent it from 
being sufficient to establish effectiveness for use of the active 
ingredient in a consumer antiseptic rub, this study is the best among 
the available studies that evaluate the impact of consumer antiseptic 
rubs on infections.
    This clinical outcome study performed in Sweden compared the 
effectiveness of a 70-percent alcohol-containing consumer antiseptic 
rub as an adjunct to hand washing with plain soap and water in 
childcare centers (Ref. 31). The study included 60 childcare centers 
(30 matched pairs) from 10 counties with a mean number of 50 children 
in each center. One childcare center from each matched pair was 
randomized to the intervention group, with the other serving as the 
control group. The intervention groups were provided instructions 
(verbal and written), and children and staff were asked to wash hands 
with plain soap and water, then rub with a 70-percent alcohol-
containing consumer antiseptic rub. Control groups followed the same 
hand-washing protocol without the hand rub. The primary outcome was the 
rate of illness absenteeism. Parents were asked to report every episode 
when the child was absent from childcare because of illness, including 
the dates of absence, symptoms, and any medical treatment. There were 
0.37 absences per 100 child hours in the control group, compared to 
0.33 in the intervention group. The effect of the intervention was a 
12-percent reduction in absenteeism. Based on the amount of hand rub 
used during the study, the estimated frequency of hand rub use by each 
child was two to six times per day. Although the study is well 
designed, there are several significant limitations, such as the 
following:
     No clinical or microbiological evaluation of illness.
     No specific infection was studied.
     Children kept home based on parent choice not addressed in 
the statistical analysis.
     Degree of illness and symptoms to keep child home varied 
among parents.

B. Current Standards: Studies Needed To Support a Generally Recognized 
as Effective Determination

    In the 1994 TFM, we proposed that the effectiveness of antiseptic 
active ingredients could be supported by a combination of in vitro 
studies and in vivo clinical simulation testing as described in 21 CFR 
333.470 (59 FR 31402 at 31444). In vitro studies are designed to 
demonstrate the product's spectrum and kinetics of antimicrobial 
activity, as well as the potential for the development of resistance 
associated with product use. In vivo test methods and evaluation 
criteria are based on the premise that bacterial reductions can be 
adequately demonstrated using tests that simulate conditions of actual 
use for OTC consumer antiseptic rub products and that those reductions 
are reflective of bacterial reductions that would be achieved during 
use. For the use of antiseptic rubs, some public health agencies (Ref. 
22) recommend their use when soap and water are not available, and when 
there is no other reasonably available alternative for the consumer.
    In addition to the standards described in section VII.B, the 
effectiveness of consumer antiseptic rubs can be affected by a variety 
of other factors related to product formulation and use. Section VII.C 
discusses these factors, which includes the number of times per day a

[[Page 42921]]

product is used and the volume used in each use.
1. In Vitro Studies
    The 1994 TFM proposed that the in vitro antimicrobial activity of 
an active ingredient could be demonstrated by a determination of the in 
vitro spectrum of antimicrobial activity, minimum inhibitory 
concentration (MIC) testing against 25 fresh clinical isolates and 25 
laboratory strains, and time-kill testing against 23 laboratory strains 
(59 FR 31402 at 31444). Comments received in response to the 1994 TFM 
objected to the proposed in vitro testing requirements, stating that 
they were overly burdensome (Ref. 32). Submissions of in vitro data 
submitted to support the effectiveness of antiseptic active ingredients 
were far less extensive than what was proposed in the 1994 TFM (Ref. 
33). Although we agree that the in vitro testing proposed in the 1994 
TFM is not warranted for testing every final formulation of an 
antiseptic product that contains a GRAE ingredient, we believe that a 
GRAE determination for a consumer antiseptic active ingredient should 
be supported by adequate in vitro characterization of the antimicrobial 
activity of the ingredient. In addition, we now propose the option of 
assessing the minimum bactericidal concentration (MBC) as an 
alternative to testing the MIC to demonstrate the broad spectrum 
activity of the antiseptic. The ability of an antiseptic to kill 
microorganisms, rather than inhibit them, is more relevant for a 
topical product. Because GRAE status is a very broad determination that 
can apply to many different formulations of an active ingredient, we 
continue to propose that an evaluation of the spectrum and kinetics of 
antimicrobial activity of a consumer antiseptic rub active ingredient 
should be evaluated by the following testing:
     A determination of the in vitro spectrum of antimicrobial 
activity against potential pathogens (listed in this section) that may 
be encountered in consumer use settings where soap and water are not 
readily available. MIC or MBC testing of 25 representative clinical 
isolates and 25 reference (e.g., American Type Culture Collection 
(ATCC)) strains of each of the microorganisms listed in this section.
     Time-kill testing of each of the following ATCC strains to 
assess how rapidly the antiseptic active ingredient produces its 
effect. The dilutions and time points tested should be relevant to the 
actual use pattern of the final product.
    Gram-negative organisms.
    [cir] Haemophilus influenzae.
    [cir] Bacteroides fragilis.
    [cir] Enterobacter species.
    [cir] Burkholderia cepacia (ATCC 25416 and ATCC 25608).
    [cir] Escherichia coli (ATCC 11775 and ATCC 25922).
    [cir] Klebsiella pneumoniae (ATCC 13883 and ATCC 27736).
    [cir] Pseudomonas aeruginosa (ATCC 15442 and ATCC 27853).
    [cir] Serratia marcescens (ATCC 8100 and ATCC 14756).
    [cir] Campylobacter jejuni (ATCC 33291 and ATCC 49943).
    [cir] Salmonella enterica Serovar Enteritidis (ATCC 13076) and 
Serovar Typhimurium (ATCC 14028). Serovar refers to the subspecies 
classification of a group of microorganisms based on cell surface 
antigens.
    [cir] Shigella sonnei (ATCC 9290 and ATCC 25931).
    Gram-positive organisms.
    [cir] Enterococcus faecalis (ATCC 19433 and ATCC 29212).
    [cir] Staphylococcus aureus (ATCC 6538 and ATCC 29213) and 
methicillin-resistant Staphylococcus aureus (ATCC 33591 and ATCC 
33592).
    [cir] Streptococcus pyogenes (ATCC 14289 and ATCC 19615).
    [cir] Listeria monocytogenes (ATCC 7644 and ATCC 19115).
    [cir] Streptococcus pneumoniae (ATCC 6303 and ATCC 49619).
    We propose that a consumer antiseptic rub active ingredient be 
considered bactericidal at the concentration and contact time that 
demonstrates a 3-log10 (99.9 percent) or greater reduction 
in bacterial viability for all the tested strains. This is the same 
performance criterion used by the Clinical and Laboratory Standards 
Institute (NCCLS, ``Methods for Determining Bactericidal Activity of 
Antimicrobial Agents; Approved Guideline,'' NCCLS document M26-A, 
1999).
    Despite the fact that the in vitro data submitted to support the 
effectiveness of antiseptic active ingredients were far less extensive 
than proposed in the 1994 TFM, manufacturers may have data of this type 
on file from their own product development programs that have not been 
submitted to the rulemaking. Furthermore, published data may be 
available that would satisfy some or all these data requirement. Data 
from these in vitro studies, as well as data from the literature, may 
be used to inform labeling, in particular, if there are specific 
organisms for which an active ingredient does not have significant 
activity. It is anticipated that if data supporting use of a consumer 
antiseptic demonstrate lack of activity against a particular organism 
that requires labeling, that labeling would also be relevant in the 
health care setting.
2. In Vivo Studies
    Based on the recommendations of the March 2005 NDAC meeting for 
health care antiseptic products, we continue to propose the use of 
bacterial log reductions as a means of demonstrating that consumer 
antiseptic rubs are GRAE (Ref. 8). The 1994 TFM also proposed final 
formulation testing for antiseptic hand washes (59 FR 31402 at 31448). 
We are not discussing the final formulation testing here because we are 
not proposing that any of the ingredients are GRAS/GRAE. Although, as 
previously noted, these proposed test methods are intended to evaluate 
the effectiveness of antiseptic final formulations, this type of 
clinical simulation testing when adequately controlled can also be used 
to demonstrate that an active ingredient is GRAE for use in a consumer 
antiseptic rub product. Based on our experience with the approval of 
NDA antiseptic products, and input from the March 2005 and October 2005 
NDAC meetings, we recommend that the bacterial log reduction studies 
used to demonstrate that an active ingredient is GRAE for use in 
consumer antiseptic rub drug products include the following:
     A vehicle control to show the contribution of the active 
ingredient to effectiveness. The test product should be statistically 
superior to the vehicle control for the clinical simulation to be 
considered successful at showing that the test product is effective for 
use in consumer antiseptic rub products. Products with vehicles that 
have antimicrobial activity should consider using a negative control, 
such as saline, rather than a vehicle control.
     An active control to validate the study conduct, to assure 
that the expected results are produced. For the results to be valid, 
the active control should meet the appropriate log reduction criteria.
     A sample size large enough to show statistically 
significant differences from the results achieved using the vehicle, 
and meeting the threshold of at least a 70-percent success rate for the 
test product, including justification that the number of subjects 
tested is adequate for the test.
     Use of an appropriate neutralizer in all recovery media 
(i.e., sampling solution, dilution fluid, and plating media) and a 
demonstration of neutralizer validation. The neutralizer is used to 
halt the antimicrobial activity of the antiseptic after product 
exposure so that a continued effect through subsequent dilution steps 
and culturing

[[Page 42922]]

thereby does not create inflated log reductions. The purpose of 
neutralizer validation is to show that the neutralizer used in the 
study is effective against the test and control products, and that it 
is not toxic to the test microorganisms. If a test product can be 
neutralized through dilution, this should be demonstrated in the 
neutralizer validation study.
     An analysis of the proportion of subjects who meet the log 
reduction criteria based on a two-sided statistical test for 
superiority to vehicle and a 95-percent confidence interval approach.
    To establish that a particular active ingredient is GRAE for use in 
consumer antiseptic rubs, clinical simulation studies using the 
parameters described in this section should be evaluated using log 
reduction criteria similar to those proposed in the 1994 TFM (59 FR 
31402 at 31448). Our current criteria are laid out in table 4. We have 
revised the log reduction criteria proposed for consumer antiseptic 
rubs based on the recommendations of the March 2005 NDAC and comments 
to the 1994 TFM, which argued that the demonstration of a cumulative 
antiseptic effect for these products is unnecessary. We agree that the 
critical element of the effectiveness is that a product must be 
effective after the first application because that represents the way 
in which consumer antiseptic rub products are used (59 FR 31402 at 
31442). For these reasons, log reduction criteria are proposed only for 
a single application of the test product rather than multiple 
applications. Given that we are no longer requiring a cumulative 
antiseptic effect, the log reduction criteria were revised to reflect 
this single application and fall between the log reductions previously 
proposed for the first and last applications. The GRAE criteria 
proposed for consumer antiseptic rubs are based on log reductions 
achieved by antiseptics as shown in the published literature (Refs. 28 
and 29) as well as those evaluated under the NDA process. Table 4 shows 
the log reductions that we would expect an effective consumer 
antiseptic rub active ingredient to meet to show that it is GRAE.

      Table 4--Clinical Simulation Testing Bacterial Log Reduction
    Effectiveness Criteria in This Proposed Rule and in the 1994 TFM
------------------------------------------------------------------------
         Indication                 1994 TFM         This proposed rule
------------------------------------------------------------------------
Antiseptic hand wash/         (1) Reduction of 2    (1) Reduction of 2.5
 Consumer antiseptic rub.      log10 on each hand    log10 on each hand
                               within 5 minutes      within 5 minutes
                               after the first       after a single rub.
                               wash and
                              (2) Reduction of 3
                               log10 on each hand
                               within 5 minutes
                               after the tenth
                               wash.
------------------------------------------------------------------------

C. Impact of Application Parameters on Efficacy

    Establishing GRAE status of active ingredients is one important 
aspect of ensuring the efficacy of OTC consumer antiseptic rub 
products. The standards for a GRAE determination for consumer 
antiseptic rubs have been described (see section VII.B). These 
standards will help determine final monograph active ingredients, as 
well as their permitted concentrations and the skin application time 
needed for the active ingredient to achieve adequate bacterial 
reduction. However, the efficacy of any particular final formulation of 
a consumer antiseptic rub appears to be affected by a variety of other 
factors related to product formulation and use.
    These factors include the number of times per day a product is used 
and the volume used in each use. The number of times per day that a 
consumer antiseptic rub product is applied has been shown to be 
positively correlated with a reduction in illness-related absenteeism 
in a kindergarten school (Ref. 34). In addition, more specific measures 
of application parameters have been assessed. The volume of product 
applied and the skin coverage achieved by the applied volume appear to 
have an impact on efficacy of antiseptic rub products containing 
alcohol. In comparing five different application volumes of 70 percent 
ethanol gel with 85 percent ethanol gel and 70 percent ethanol foam, 
Kampf et al. (2013) demonstrated that the label recommended volume of 
1.1 milliliters (mL) for the 70 percent ethanol products was not 
sufficient to achieve efficacy in in vivo efficacy testing according to 
ASTM methods (Ref. 35). The recommended application of 2 mL of 85 
percent gel, as well as higher than recommended volumes of the 70 
percent products, met efficacy criteria under ASTM E 2755-10 and ASTM E 
1174-06 methods used in this study. In the same study, insufficient 
skin coverage with lower application volumes (1.1 mL) was suggested as 
the reason for failure to achieve efficacy. Failure to achieve 
effectiveness with the lower volume was based on observation of gaps in 
skin coverage after volunteers applied products containing fluorescent 
dye to their hands. In a similar study, Kampf (2008) assessed the 
efficacy and coverage of four hand rub products (foam or gel 
formulation unspecified) containing 85 percent, 62 percent, 61 percent, 
or 60 percent ethanol (Ref. 36). At an application volume of 2.4 mL, 
the 60 percent and 61 percent ethanol formulations failed to meet in 
vivo ASTM efficacy criteria while 2.4 mL application volumes of 62 
percent and 85 percent ethanol formulations met the criteria. 
Application volumes of 3.6 mL met efficacy criteria for all ethanol 
concentrations tested (Ref. 36).
    Given that the applied volume of product may have consequences for 
product efficacy, the factors that may affect application volume are of 
interest. Variability has been demonstrated in the output of both gel 
and foam antiseptic rub dispensers. Macinga et al. (2013) measured 
output from a single wall-mounted dispenser and among wall-dispensers 
from different manufacturers (Ref. 37). In dispensing five different 
gel formulations containing varying percentages of ethanol or 
isopropanol, dispensers from five different manufacturers had outputs 
that ranged from 0.9 to 1.3 mL per actuation. In dispensing three 
different foam formulations each containing 70 percent ethanol, foam 
dispensers from three different manufacturers ranged from 0.6 to 1.1 mL 
per actuation. Furthermore, the volume of product that individuals 
choose to apply may be affected, independent of labeled instruction, by 
factors such as the time it takes hands to dry after application. Kampf 
et al. (2010) assessed four foam formulations, each containing 62 
percent ethanol, and found that the amount (weight) of foam applied was 
significantly correlated with the perceived drying time (Ref. 38). 
There is also evidence that final formulation affects efficacy. 
Different products containing the same concentration of active 
ingredient have been shown to perform differently when tested by in 
vivo bacterial reduction testing (ASTM 1174) (Ref. 39). One ``novel'' 
gel formulation and one ``novel'' foam formulation, each

[[Page 42923]]

containing 70 percent ethanol, were both shown to be statistically 
superior after both 1 and 10 applications compared to two marketed 
formulations, one gel and one foam, both containing 70 percent ethanol. 
All formulations were applied in equal volumes. The two ``novel'' 
formulations also demonstrated some evidence of improved performance 
relative to a marketed gel containing 90 percent ethanol.
    Understanding the impact of product-related parameters, such as 
formulation, dose applied, and application volume, to be used according 
to the labeling is imperative. We also need to understand the extent to 
which variability in product-related parameters must be reduced to 
ensure that products achieve the results expected based on their use of 
GRAE ingredients. Given the data demonstrating that efficacy varies 
with dose, application volume, and formulation, final formulation 
efficacy testing will be necessary for consumer antiseptic rub products 
in order to confirm effectiveness and label the product appropriately 
for use. However, because no ingredient has sufficient data to support 
GRAS/GRAE status in this rulemaking, we are not proposing specific 
final formulation testing or labeling at this time. Instead, we are 
requesting data to allow the assessment of the impact of various 
application parameters on efficacy and the interaction among them 
(e.g., how does formulation affect application volume requirements) to 
inform final formulation testing and labeling requirements.

VIII. Safety (Generally Recognized as Safe) Determination

    In the 1994 TFM, 11 active ingredients were proposed to be 
classified as GRAS for antiseptic hand wash use, which includes 2 
active ingredients (alcohol and isopropyl alcohol) that are eligible 
for consumer antiseptic rub use (59 FR 31402 at 31435). As described in 
section II.C, consumer antiseptic hand rubs were not addressed 
separately from antiseptic hand washes in the 1994 TFM. There have 
since been a number of important scientific developments affecting our 
evaluation of the safety of the active ingredients in consumer 
antiseptic rubs, causing us to reassess the data necessary to support a 
GRAS determination. There is now new information regarding systemic 
exposure to antiseptic active ingredients (Refs. 1 through 5). The 
potential for widespread antiseptic use to promote the development of 
antibiotic-resistant bacteria also needs to be evaluated. Furthermore, 
additional experience with, and knowledge about, safety testing has led 
to improved testing methods. Improvements include study designs that 
are more capable of detecting potential safety risks. Based on our 
reassessment, we are proposing new GRAS data standards for consumer 
antiseptic rub active ingredients. To fully address these new safety 
concerns, additional safety data will be necessary to support a GRAS 
determination for all consumer antiseptic rub active ingredients.
    Many of the safety considerations for consumer antiseptic rubs are 
based on FDA's view that the use of consumer antiseptic rubs is a 
``chronic'' use as that term is defined by the International Council on 
Harmonisation (ICH).\5\ As defined by the ICH, a use is considered 
chronic if the drug will be used for a period of at least 6 months over 
the user's lifetime, including repeated, intermittent use (Ref. 40). We 
believe that consumer antiseptic rubs are often used on a daily basis 
and sometimes repeatedly over the course of the day.
---------------------------------------------------------------------------

    \5\ FDA is a member of the ICH Steering Committee, the governing 
body that oversees the harmonization activities, and contributes to 
the development of ICH guidelines.
---------------------------------------------------------------------------

A. New Issues

    Since the 1994 TFM was published, new data have become available 
indicating that systemic exposure to topical antiseptic active 
ingredients may be greater than previously thought. Systemic exposure 
refers to the presence of antiseptic active ingredients inside and 
throughout the body. Because of advances in technology, our ability to 
detect antiseptic active ingredients in body fluids such as serum and 
urine is greater than it was in 1994. For example, studies have shown 
detectable blood alcohol levels after use of alcohol-containing hand 
rubs (Refs. 1, 4, and 5). We believe that any consequences of this 
systemic exposure should be identified and assessed to support our 
risk-benefit analysis for consumer antiseptic use.
    Given the frequent repeated use of consumer antiseptic rubs, 
systemic exposure may occur. Although some systemic exposure data exist 
for all three consumer antiseptic rub active ingredients, data on 
systemic absorption after maximal use are lacking. Currently, there is 
also a lack of data to assess the impact of important drug use factors 
that can influence systemic exposure such as dose, application 
frequency and method, duration of exposure, product formulation, skin 
condition, and age. Depending on the systemic absorption of the 
ingredient, variability in absorption anticipated between formulations, 
and the safety margin for toxic effects, final formulation safety 
testing for particular ingredients may be needed to assure that 
substantially different absorption that might significantly change the 
margin of safety is not anticipated for a new formulation. FDA does not 
address final formulation testing in this rulemaking because no 
ingredients have been proposed as GRAS/GRAE. However, FDA recently 
described final formulation safety testing for another class of OTC 
dermal products regulated under the OTC drug monograph (Ref. 41).
    The evaluation of the safety of drug products involves correlating 
findings from animal toxicity studies to the level of drug exposure 
obtained from pharmacokinetic studies in animals and humans. Our 
administrative record lacks the data necessary to define a margin of 
safety for the potential chronic use of consumer antiseptic rub active 
ingredients. Thus, we are continuing to propose that both animal and 
human pharmacokinetic (PK) data are necessary for consumer antiseptic 
rub active ingredients. This information will help identify any 
potential safety concerns and help determine the safety margin for OTC 
human use.
    One potential effect of systemic exposure to consumer antiseptic 
active ingredients that has come to our attention since publication of 
the 1994 TFM is data suggesting that some antiseptic active ingredients 
have hormonal effects. Ingredients in topical antiseptic products can 
cause alterations in the thyroid of neonatal and adolescent animals 
(Refs. 42 through 51). Hormonally active compounds have been shown to 
affect not only the exposed organism, but also subsequent generations 
(Ref. 52). These effects may not be related to direct deoxyribonucleic 
acid (DNA) mutation, but rather to alterations in factors that regulate 
gene expression (Ref. 53).
    A hormonally active compound that causes reproductive system 
disruption in the fetus or infant may have effects that are not 
apparent until many years after initial exposure. There are also 
critical times in fetal development when a change in hormonal balance 
that would not cause any lasting effect in an adult could cause a 
permanent developmental abnormality in a child. For example, untreated 
hypothyroidism during pregnancy has been associated with cognitive 
impairment in the offspring (Refs. 54 through 56).
    Because consumer antiseptic rubs are used chronically and are 
likely to be used by sensitive populations such as children and 
pregnant women,

[[Page 42924]]

evaluation of the potential for chronic toxicity and effects on 
reproduction and development should be included in the safety 
assessment. The designs of general toxicity and reproductive/
developmental studies are often sufficient to identify developmental 
effects that can be caused by hormonally active compounds through the 
use of currently accepted endpoints and standard good laboratory 
practice toxicology study designs. As followup in some cases, 
additional study endpoints may be needed to fully characterize the 
potential effects of drug exposure on the exposed individuals.

B. Antimicrobial Resistance

    In the 2013 Consumer Wash PR and 2015 Health Care Antiseptic PR, 
FDA raised the concern of the development of antiseptic resistance and 
its potential impact on the development of antibiotic resistance (78 FR 
76444 at 76454 and 80 FR 25166 at 25180). This concern was based on 
numerous reports of laboratory studies demonstrating the development of 
reduced susceptibility to certain antiseptic active ingredients and 
antibiotics after growth in nonlethal amounts of the antiseptic (i.e., 
low-to-moderate concentrations of antiseptic) and reports of the 
persistence of low levels of some antiseptic active ingredients in the 
environment (78 FR 76444 at 76454 and 80 FR 25166 at 25180). FDA 
concluded in both of these proposed rules that, given the increasing 
evidence of the magnitude of the antibiotic resistance problem and the 
speed with which new antibiotic resistant organisms are emerging, it is 
important to assess this potential consequence of antiseptic use and 
requested data to address the concern (78 FR 76444 at 76454 and 80 FR 
25166 at 25180). However, in its evaluation of the available data on 
the development of resistance to alcohol and isopropyl alcohol in the 
proposed rule for health care antiseptics, FDA cited a number of 
factors (speed of action, multiple nonspecific toxic effects, and lack 
of a residue) that made the development of resistance to these alcohols 
as a result of health care antiseptic use unlikely. Based on these 
factors, FDA concluded that no additional data relevant to this issue 
were necessary to support a GRAS determination for these ingredients 
for health care antiseptics (80 FR 25166 at 25184, 25187, and 25192). 
Consistent with FDA's findings for alcohol and isopropyl alcohol in its 
proposed rule for health care antiseptic, we have also tentatively 
concluded that no further data on the development of resistance to 
alcohol and isopropyl alcohol as a result of their use in consumer 
antiseptic rub products are needed. This is not the case for 
benzalkonium chloride for which additional laboratory studies will 
assist in more clearly defining the potential for the development of 
resistance. (See section VIII.D.2).

C. Studies To Support a Generally Recognized as Safe Determination

    A GRAS determination for consumer antiseptic rub active ingredients 
must be supported by both nonclinical (animal) and clinical (human) 
studies.\6\ To issue a final monograph for these products, this safety 
data must be in the docket.\7\
---------------------------------------------------------------------------

    \6\ We encourage sponsors to consult with us on non-animal 
testing methods they believe may be suitable, adequate, validated, 
and feasible. We are willing to consider if alternative methods 
could be assessed for equivalency to an animal test method.
    \7\ The Agency intends to consider only non-confidential 
material that is submitted to the docket for this rulemaking or that 
is otherwise publicly available in its evaluation of the GRAS/GRAE 
status of a relevant ingredient. Information about how to submit 
this data or information to the docket is set forth in this document 
in the ADDRESSES section.
---------------------------------------------------------------------------

    To assist manufacturers or others who wish to provide us with the 
information we expect will establish GRAS status for these active 
ingredients, we are including specific information, based in part on 
existing FDA guidance, about the other kinds of studies to consider 
conducting and submitting. We have published guidance documents 
describing the nonclinical safety studies that a manufacturer should 
perform when seeking to market a drug product under an NDA (Refs. 40, 
57 through 63). These guidance documents also provide relevant guidance 
for performing the nonclinical studies necessary to determine GRAS 
status for a consumer antiseptic rub active ingredient. Because 
consumer antiseptic rubs may be used repeatedly and in sensitive 
populations, we propose that consumer antiseptic rub active ingredients 
will need to be tested for carcinogenic potential, developmental and 
reproductive toxicity (DART), and other potential effects as described 
in more detail in this section.
1. FDA Guidances Describing Safety Studies
    The safety studies that are described in the existing FDA guidances 
(Refs. 40, 57 through 63) provide a framework for the types of studies 
that are needed for FDA to assess the safety of each consumer rub 
active ingredient according to modern scientific standards and make a 
GRAS determination. A description of each type of study and how we 
would use this information to improve our understanding of the safety 
of consumer antiseptic rub active ingredients is provided in table 5.

           Table 5--FDA Guidance Documents Related to Requested Safety Data and Rationale for Studies
----------------------------------------------------------------------------------------------------------------
           Type of study               Study conditions       What the data tell us      How the data are used
----------------------------------------------------------------------------------------------------------------
Animal pharmacokinetic absorption,  Both oral and dermal   Allows identification of    Used as a surrogate to
 distribution, metabolism, and       administration.        the dose at which the       identify toxic systemic
 excretion (ADME) (Refs. 58 and                             toxic effects of an         exposure levels that can
 64).                                                       active ingredient are       then be correlated to
                                                            observed as a result of     potential human exposure
                                                            systemic exposure of the    via dermal
                                                            drug. ADME data provide:    pharmacokinetic study
                                                            The rate and extent an      findings. Adverse event
                                                            active ingredient is        data related to
                                                            absorbed into the body      particular doses and
                                                            (e.g., AUC, Cmax, Tmax)     drug levels (exposure)
                                                            \1\; where the active       in animals are used to
                                                            ingredient is distributed   help formulate a safety
                                                            in the body; whether        picture of the possible
                                                            metabolism of the active    risk to humans.
                                                            ingredient by the body
                                                            has taken place;
                                                            information on the
                                                            presence of metabolites;
                                                            and how the body
                                                            eliminates the original
                                                            active ingredient
                                                            (parent) and its
                                                            metabolites (e.g., T\1/
                                                            2\)\2\.

[[Page 42925]]

 
Human pharmacokinetics (MUsT)       Dermal administration  Helps determine how much    Used to relate the
 (Ref. 62).                          using multiple         of the active ingredient    potential human exposure
                                     formulations under     penetrates the skin,        to toxic drug levels
                                     maximum use            leading to measurable       identified in animal
                                     conditions.            systemic exposure.          studies.
Carcinogenicity (ICH S1A, S1B, and  Minimum of one oral    Provides a direct measure   Identifies the systemic
 S1C) (Refs. 40, 57, and 60).        and one dermal study   of the potential for        and dermal risks
                                     for topical products   active ingredients to       associated with drug
                                     \3\.                   cause tumor formation       active ingredients.
                                                            (tumorogenesis) in the      Taken together, these
                                                            exposed animals.            studies are used to
                                                                                        identify the type(s) of
                                                                                        toxicity, the level of
                                                                                        exposure that produces
                                                                                        these toxicities, and
                                                                                        the highest level of
                                                                                        exposure at which no
                                                                                        adverse effects occur,
                                                                                        referred to as the ``no
                                                                                        observed adverse effect
                                                                                        level'' (NOAEL). The
                                                                                        NOAEL is used to
                                                                                        determine a safety
                                                                                        margin for human
                                                                                        exposure.
Developmental toxicity (ICH S5)     Oral administration..  Evaluates the effects of a
 (Ref. 59).                                                 drug on the developing
                                                            offspring throughout
                                                            gestation and postnatally
                                                            until sexual maturation.
Reproductive toxicity (ICH S5)      Oral administration..  Assesses the effects of a
 (Ref. 59).                                                 drug on the reproductive
                                                            competence of sexually
                                                            mature male and female
                                                            animals.
Hormonal effects (Ref. 63)........  Oral administration..  Assesses the drug's         Used in hazard assessment
                                                            potential to interfere      to determine whether the
                                                            with the endocrine system.  drug has the capacity to
                                                                                        induce a harmful effect
                                                                                        at any exposure level
                                                                                        without regard to actual
                                                                                        human exposures.
----------------------------------------------------------------------------------------------------------------
\1\ ``AUC'' denotes the area under the concentration-time curve, a measure of total exposure or the extent of
  absorption. ``Cmax'' denotes the maximum concentration, which is peak exposure. ``Tmax'' denotes the time to
  reach the maximum concentration, which aids in determining the rate of exposure.
\2\ ``T\1/2\'' denotes the half-life, which is the amount of time it takes to eliminate half the drug from the
  body or decrease the concentration of the drug in plasma by 50 percent.
\3\ Assessment of dermal carcinogenicity is considered important because the intended clinical route of
  administration of dermal, and skin exposure could be high. In addition, dermal exposure can result in systemic
  exposure to parent and metabolites that may differ from other routes. When substantial nonclinical information
  is already available for an active ingredient, the need for a dermal carcinogenicity study could be
  reconsidered based on available information such as negative systemic carcinogenicity information and lack of
  preneoplastic effects in chronic nonrodent dermal toxicity studies.

    These studies represent FDA's current thinking on the data needed 
to support a GRAS determination for an OTC antiseptic active ingredient 
and are similar to those recommended by the Antimicrobial I Panel 
(described in the ANPR (39 FR 33103 at 33135)) as updated by the 
recommendations of the 2014 NDAC. However, even before the September 
2014 NDAC meeting, the Panel's recommendations for data to support the 
safety of an OTC topical antimicrobial active ingredient included 
studies to characterize the following:
     Degree of absorption through intact and abraded skin and 
mucous membranes.
     Tissue distribution, metabolic rates, metabolic fates, and 
rates and routes of elimination.
     Teratogenic and reproductive effects.
     Mutagenic and carcinogenic effects.
2. Studies To Characterize Maximal Human Exposure
    Because the available data indicate that some dermal products, 
including at least some antiseptic active ingredients, are absorbed 
after topical application in humans and animals, it is necessary to 
assess the effects of long-term dermal and systemic exposure to these 
ingredients. This is particularly important for populations, such as 
pregnant women (and fetuses), lactating women, and children, who may 
have greater potential to experience deleterious developmental effects 
from drug exposure. Human exposure data can then be compared to drug 
levels in animals known to produce adverse effects in order to 
calculate a safety margin.
    Based on input from the September 2014 NDAC meeting, the Agency has 
also determined that results from a human PK maximal usage trial (MUsT) 
are needed to support a GRAS determination. This trial design is also 
referred to as a maximal use PK trial and is described in FDA's 2005 
draft guidance for industry on developing drugs for treatment of acne 
vulgaris (Ref. 62). The purpose of the MUsT is to evaluate systemic 
exposure under conditions that would maximize the potential for drug 
absorption in a manner consistent with possible ``worst-case'' real 
world use of the product. In a MUsT, the collected plasma samples are 
analyzed, and the resulting in vivo data could be used to estimate a 
safety margin based on animal toxicity studies.
    A MUsT to support a determination that an active ingredient is GRAS 
for use in consumer antiseptics is conducted by obtaining an adequate 
number of PK samples following administration of the active ingredient. 
For studies of active ingredients to be used in topically applied 
products like these, for which there is less information available and 
for which crossover designs are not feasible, a larger number of 
subjects are required compared to studies of orally administered drug 
products. A MUsT using 50 to 75 subjects per cohort should be 
sufficient to get estimates of the PK parameters from a topically 
applied consumer antiseptic.
    The MUsT should attempt to maximize the potential for drug 
absorption to occur by considering the following design elements (Ref. 
65):
     Adequate number of subjects (steps should be taken to 
ensure that the target population (for example, age, gender, race) is 
properly represented).
     Frequency of dosing (e.g., number of rub applications 
during the study).
     Duration of dosing.

[[Page 42926]]

     Use of highest proposed strength (e.g., 95 percent 
alcohol).
     Total involved surface area to be treated at one time 
(e.g., hands).
     Amount applied per square centimeter.
     Method of application (e.g., rub).
     Sensitive and validated analytical methods.
    It also is important that the MUsT reflect maximal use conditions 
of consumer antiseptic rubs using different formulations to fully 
characterize the active ingredient's potential for dermal penetration. 
There are very limited data on the maximal number of uses of antiseptic 
rubs in consumer settings. Consumer antiseptic rubs used in 
institutional settings, such as daycare centers, schools, and office 
buildings, would be used (as per label directions) at higher rates than 
in domestic households, and thus would represent maximal use. Kinnula 
et al. (2009) surveyed workers in child daycare centers in Finland to 
determine how commonly alcohol-containing hand rub gels were applied 
daily (Ref. 66). The respondents (n = 128) reported applying the 
alcohol hand rub gels up to 50 times per day. Using the upper limit of 
applications per day of antiseptic hand rubs from this study, FDA is 
considering 50 times per day as the maximal use of consumer hand rubs 
in a consumer setting.
    It should be noted that a systemic carcinogenicity study will not 
be required for an ingredient if a MUsT results in a steady state blood 
level less than 0.5 nanograms (ng)/mL, and an adequately conducted 
toxicology program demonstrates that there are no other signals for the 
ingredient or any known structurally similar compound indicating the 
potential for adverse effects at lower levels. The threshold value of 
0.5 ng/mL is based on the principle that the level would approximate 
the highest plasma level below which the carcinogenic risk of any 
unknown compound would be less than 1 in 100,000 after a single dose.
    The lack of absorption in a MuST does not alleviate the need to 
assess dermal carcinogenicity because the magnitude of exposure to the 
skin can be much higher than would be covered by systemic studies. In 
addition, systemic exposure to the parent compound and metabolites can 
differ significantly for a dermally applied product because the skin 
has metabolic capability and first-pass metabolism is bypassed via this 
route of administration.
    To fulfill the maximum human exposure requirement, the MUsT study 
should meet appropriate design standards using the highest 
concentration sought under this proposed rule in formulations expected 
to produce the highest in vivo absorption. The assay used in the MUsT 
should be properly validated according to current Good Laboratory 
Practices and consistent with FDA guidance for industry: 
``Bioanalytical Method Validation'' (Ref. 67).
    We expect that the 0.5 ng/mL concentration will be sufficiently 
above the assay's limit of quantitation-limit of detection to allow a 
signal: Noise ratio that assures confidence in the derived 
concentrations (in the case of ``exaggerated'' values) or lack of 
concentrations.
3. Studies To Characterize Hormonal Effects
    We propose that data are also needed to assess whether consumer 
antiseptic rub active ingredients have hormonal effects that could 
produce developmental or reproductive toxicity. There are several 
factors common to antiseptic products that make it necessary to assess 
their full safety profile prior to classifying an antiseptic active 
ingredient as GRAS for use in consumer antiseptic rub products. These 
factors are as follows:
     Evidence of systemic exposure to several of the antiseptic 
active ingredients.
     Exposure to multiple sources of antiseptic active 
ingredients that may be hormonally active compounds.
     Exposure to antiseptic active ingredients may be long term 
for some users.
    According to FDA's 2015 guidance on nonclinical evaluation of 
endocrine-related drug toxicity (Ref. 63), endocrine effects may be 
identified from the standard battery of toxicity tests conducted during 
drug development and may not require additional separate studies.
4. Studies To Evaluate the Potential Impact of Antiseptic Active 
Ingredients on the Development of Resistance
    Since the 1994 TFM published, the issue of antiseptic resistance 
and whether bacteria that exhibit antiseptic resistance have the 
potential for antibiotic cross-resistance has been the subject of much 
study and scrutiny. One of the major mechanisms of antiseptic and 
antibiotic cross-resistance is changes in bacterial efflux activity at 
nonlethal concentrations of the antiseptic (Refs. 68 through 73). 
Efflux pumps are an important nonspecific bacterial defense mechanism 
that can confer resistance to a number of substances toxic to the cell, 
including antibiotics (Refs. 74 and 75). The development of bacteria 
that are resistant to antibiotics is an important public health issue, 
and additional data may tell us whether use of antiseptics in consumer 
settings may contribute to the selection of bacteria that are less 
susceptible to both antiseptics and antibiotics. Therefore, we are 
requesting additional data and information to address this issue for 
ingredients other than alcohol or isopropyl alcohol (see section 
VIII.D).
    FDA believes that a tiered approach is an efficient means of 
developing data to address this issue. Laboratory studies in 
conjunction with a literature review are a feasible first step in 
evaluating the impact of exposure to nonlethal amounts of antiseptic 
active ingredients on antiseptic and antibiotic bacterial 
susceptibilities. However, only limited data exist on the effects of 
antiseptic exposure on the bacteria that are predominant in the oral 
cavity, gut, skin flora, and the environment (Ref. 76). These organisms 
represent pools of resistance determinants that are potentially 
transferable to human pathogens (Refs. 77 and 78). Thus, broader 
laboratory testing of consumer antiseptic active ingredients would more 
clearly define the scope of the impact of antiseptic active ingredients 
on the development of antibiotic resistance and may be able to identify 
those antiseptic active ingredients for which the development of 
resistance is not a concern. Laboratory studies evaluating the 
antiseptic and antibiotic susceptibilities of bacteria grown in the 
presence of sublethal concentrations of antiseptic active ingredients 
could help support a GRAS determination for antiseptic active 
ingredients intended for use in OTC consumer antiseptic drug products. 
The following types of organisms should be evaluated:
     Human bacterial pathogens.
     Nonpathogenic organisms, opportunistic pathogens, and 
obligate anaerobic bacteria that make up the resident microflora of the 
human skin, gut, and oral cavity.
     Food-related bacteria such as Listeria, Lactobacillus, and 
Enterococcus.
     Nonpathogenic organisms and opportunistic pathogens from 
relevant environmental sources (e.g., soil).

If the results of these studies show no evidence of changes in 
antiseptic or antibiotic susceptibility, no further studies addressing 
the development of resistance would be needed to support a GRAS 
determination.
    For antiseptic active ingredients that demonstrate an effect on 
antiseptic and

[[Page 42927]]

antibiotic susceptibilities, additional data will be necessary to help 
assess the likelihood that similar effects would occur in the consumer 
setting. Several types of data could be used to assess whether or not 
ingredients with positive laboratory findings pose a public health 
risk, and the type of data needed would depend on what is already known 
about the antiseptic active ingredient's mechanism of action and 
persistence in the environment. We do not anticipate that it will be 
necessary to obtain data from multiple types of studies for each active 
ingredient to adequately assess its potential to affect resistance. 
Such types of data could include, but are not limited to, the 
following:
     Information about the mechanism(s) of antiseptic action 
(for example, membrane destabilization or inhibition of fatty acid 
synthesis), and whether there is a change in the mechanism of action 
with changes in antiseptic concentration.
     Information clarifying the bacteria's mechanism(s) for the 
development of resistance or reduced susceptibility to the antiseptic 
active ingredient (for example, efflux mechanisms).
     Data characterizing the potential for reduced antiseptic 
susceptibility caused by the antiseptic active ingredient to be 
transferred to other bacteria that are still sensitive to the 
antiseptic.
     Data characterizing the concentrations and antimicrobial 
activity of the antiseptic active ingredient in biological and 
environmental compartments (for example, bacteria found on human skin, 
in the gut, and in environmental matrices).
     Data characterizing the antiseptic and antibiotic 
susceptibility levels of environmental isolates of bacteria in areas of 
prevalent antiseptic use, such as in the home or in schools.

Data from the types of testing described previously, as well as from 
testing of antiseptic and antibiotic susceptibilities of bacteria in 
settings where consumer topical antiseptic rub use is prevalent can 
help demonstrate whether or not changes in susceptibility are occurring 
with actual use. Because actual use concentrations of consumer 
antiseptics are much higher than the MICs for these active ingredients, 
data from compartments where sublethal concentrations of biologically 
active antiseptic active ingredients may occur (e.g., environmental 
compartments) can give us a sense of the potential for change in 
antimicrobial susceptibilities in these compartments (Refs. 79 through 
81). FDA recognizes, however, that methods of evaluating this issue are 
an evolving science and that there may be other data appropriate to 
evaluate the impact of consumer antiseptic active ingredients on the 
development of resistance. For this reason, FDA encourages interested 
parties to consult with the Agency on the specific studies appropriate 
to address this issue for a particular active ingredient.

D. Review of Available Data for Each Antiseptic Active Ingredient

    We have identified for each consumer antiseptic rub active 
ingredient whether the studies outlined in section VIII.C are publicly 
available. Table 6 lists the types of studies available for each 
antiseptic active ingredient eligible for use as a consumer rub 
proposed as Category I or Category III in the 1994 TFM and indicates 
whether the currently available data are adequate to serve as the basis 
of a GRAS determination. Although we have some data from submissions to 
the rulemaking and from information we have identified in the 
literature, our administrative record is incomplete for at least some 
types of safety studies for each of the active ingredients (see table 
6). As noted previously, only information that is part of the 
administrative record for this rulemaking can form the basis of a GRAS/
GRAE determination.
    We recognize that data and information submitted in response to the 
2013 Consumer Wash PR or 2015 Health Care Antiseptic PR may be relevant 
to this proposed rule. At the time of publication of this proposed 
rule, FDA's review of all submissions made to the 2015 Health Care 
Antiseptic PR has not been completed. FDA requests that any information 
relevant to consumer antiseptic rub active ingredients be resubmitted 
under this docket (FDA-2016-N-0124).

                                Table 6--Safety Studies Available for Consumer Antiseptic Hand Rub Active Ingredients \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                        Human            Animal                                                            Potential
        Active Ingredient          Pharmacokinetic  Pharmacokinetic        Oral            Dermal        Reproductive       Hormonal        Resistance
                                        (MUsT)           (ADME)      Carcinogenicity  Carcinogenicity  Toxicity (DART)      Effects         Potential
--------------------------------------------------------------------------------------------------------------------------------------------------------
Alcohol..........................           [cir]                                                      
Benzalkonium chloride............  ...............           [cir]            ...............                             [cir]
Isopropyl alcohol................           [cir]            [cir]   ...............           [cir]                     [cir]         
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Empty cell indicates no data available; ``[cir]'' indicates incomplete data available; ``'' indicates available data are sufficient to make
  a GRAS/GRAE determination.

    In the remainder of this section, we discuss the existing data and 
data gaps for alcohol, benzalkonium chloride and isopropyl alcohol, the 
consumer antiseptic rub active ingredients that were proposed as GRAS 
in the 1994 TFM, and explain why these active ingredients are no longer 
proposed as GRAS for use in consumer antiseptic hand rubs (i.e., why 
they are now proposed as Category III). We also discuss benzalkonium 
chloride, which was proposed as Category III in the 1994 TFM and for 
which there are some new data available and explain why this ingredient 
is still Category III. These three ingredients are also used in health 
care antiseptic products, and the safety data gaps identified in the 
2015 Health Care Antiseptic PR are similar to those discussed in this 
proposed rule for each ingredient. The requirements for a GRAS 
determination for an ingredient are generally the same for either a 
health care or consumer antiseptic product, with the exception of 
higher maximal use for health care antiseptic products. Therefore, it 
is anticipated that ingredients fulfilling the requirements for a 
health care antiseptic GRAS determination would also meet the criteria 
for GRAS as a consumer antiseptic, if eligible for that indication.
1. Alcohol
    In the 1994 TFM, FDA proposed to classify alcohol as GRAS for all 
health care antiseptic uses based on the recommendation of the Advisory 
Review Panel on OTC Miscellaneous External Drug Products (Miscellaneous 
External Panel), which concluded that the topical application of 
alcohol is safe (59 FR 31402 at 31412). In the 2013 Consumer Wash PR, 
FDA proposed to separately evaluate the safety and effectiveness of the 
OTC antiseptic drug products by use setting, specifically health care 
and consumer antiseptic products. As defined in the 2013 Consumer Wash 
PR, consumer

[[Page 42928]]

antiseptic products that are not rinsed off after use include hand rubs 
and antiseptic wipes. FDA is proposing to classify alcohol as Category 
III for use in consumer antiseptic rubs. Extensive studies have been 
conducted to characterize the metabolic and toxic effects of alcohol in 
animal models. Although the impetus for most of the studies has been to 
study the effects of alcohol exposure via the oral route of 
administration, some dermal toxicity studies are available and have 
shown that, although there is alcohol absorption through human skin, it 
is much lower than absorption via the oral route. Overall, there are 
adequate safety data to make a GRAS determination for alcohol, with the 
exception of human pharmacokinetic data under maximal use conditions.
    a. Summary of alcohol safety data.
    As discussed in more detail in the 2015 Health Care Antiseptic PR 
(80 FR 25166 at 25185 to 25187), FDA has reviewed the following and 
found them to be sufficient to characterize the safety of alcohol for 
use in consumer antiseptic rubs:
     Animal ADME data demonstrating absorption of alcohol both 
in vitro and in vivo (Refs. 82 through 86).
     Dermal and oral carcinogenicity data in animals and oral 
carcinogenicity data in humans (Refs. 87 through 93).
     DART human data (Refs. 94 and 95).
     Data on the hormonal effects of alcohol in animals and 
humans (Refs. 96 through 102).
     Data on the antimicrobial mechanism of alcohol (Refs. 103 
through 106). Alcohol readily evaporates from the skin after topical 
application, and the resulting lack of antiseptic residue on the skin 
suggests that the topical application of alcohol is not likely to 
contribute to the development of antimicrobial resistance (Refs. 103, 
105).
    Alcohol human pharmacokinetic data. The 2015 Health Care Antiseptic 
PR described data that characterize the level of dermal absorption and 
expected systemic exposure in adults as a result of topical use of 
alcohol-containing antiseptics (80 FR 25166 at 25185-25186). These data 
do not cover maximal use of these products as detailed in section 
VIII.D.1.a.
    A variety of alcohol-based hand rub product formulations and 
alcohol concentrations have been used in these studies. Based on the 
available data, which represents moderate hand rub use (7.5 to 40 hand 
rub applications per hour, studied for 30 to 240 minutes), the highest 
observed exposure was 1,500 milligrams (mg) of alcohol (Ref. 4), which 
is the equivalent of 10 percent of an alcohol-containing drink. See 
also the discussion of occupational exposure to alcohol via the dermal 
route (Ref. 107) in the alcohol carcinogenicity section of the 2015 
Health Care Antiseptic PR (80 FR 25166 at 25186).
    Although these data do indicate absorption of alcohol does occur 
after topical administration of alcohol-containing antiseptic rubs, we 
did not find the exposure conditions of these studies comparable to 
exposure that are required by our current MUsT standards specified in 
section VIII.C.2. Consequently, human pharmacokinetic data under 
maximal use conditions as determined by a MUsT are needed to make a 
GRAS determination for the alcohol-containing consumer antiseptic rubs.
    b. Alcohol safety data gap.
    In summary, our administrative record for the safety of alcohol is 
incomplete with respect to the following:
     Human pharmacokinetic studies under maximal use conditions 
when applied topically (MUsT), including documentation of validation of 
the methods used to measure alcohol and its metabolites.
2. Benzalkonium Chloride
    In the 1994 TFM, FDA categorized benzalkonium chloride as Category 
III because of a lack of adequate safety data for its use as both a 
health care antiseptic and consumer antiseptic product (59 FR 31402 at 
31435). FDA also is proposing to classify benzalkonium chloride as 
Category III for the indication of consumer antiseptic rubs. Thus, 
additional safety data are still needed to make a GRAS determination 
for benzalkonium chloride for use as a consumer antiseptic rub.
    In the 2013 Consumer Wash PR, FDA identified the safety data needed 
to make a GRAS determination for benzalkonium chloride as an ingredient 
in consumer antiseptic wash products. The safety gaps listed were human 
and animal pharmacokinetic data, reproductive toxicity studies, 
potential hormonal effects, carcinogenicity (oral and dermal) studies, 
and potential of the development of antimicrobial resistance to 
benzalkonium chloride. As was summarized in the 2015 Health Care 
Antiseptic PR, the safety of benzalkonium chloride has been reviewed 
and was determined to be safe for use in disinfectants and cosmetic 
products by the Environmental Protection Agency (EPA) and the Cosmetic 
Ingredient Review (an industry panel), respectively (Refs. 108 and 
109). The data cited in both of these evaluations are proprietary and 
only summaries of the data are publicly available. Consequently, these 
studies are not available to FDA and FDA cannot conduct a complete 
evaluation of them. Safety assessments with study summaries do not 
constitute an adequate record on which to base a GRAS classification 
(Sec.  330.10(a)(4)(i)). For FDA to evaluate this data with respect to 
the safety of benzalkonium chloride for this rulemaking, the full study 
reports and data sets must be submitted to the rulemaking docket or 
otherwise be publicly available.
    In response to the call for data in the 2013 Consumer Wash PR, a 
manufacturing consortium submitted the following studies to the 2013 
Consumer Wash PR docket (Refs. 110 through 121):
     An embryofetal toxicity study in the rabbit;
     an embryofetal toxicity study in the rat;
     a 2-generation study in the rat;
     a 90 day subchronic dietary study in rats;
     a 90 day subchronic dermal toxicity study in rats;
     a 1-year chronic dietary toxicity study in dogs;
     an ADME study in rats;
     a rat oral carcinogenicity study; and
     a mouse oral carcinogenicity study.
    All of these studies have been reviewed by FDA. Some of the data 
were found to be adequate to fill some of the safety data gaps for a 
GRAS determination for benzalkonium chloride. Data gaps remain for the 
following endpoints: Human pharmacokinetic data under maximal use 
condition, animal dermal carcinogenicity and animal ADME data, and data 
on antimicrobial resistance to benzalkonium chloride.
    a. Summary of benzalkonium chloride safety data.
    Benzalkonium chloride ADME data. ADME studies of ADBAC in rats of 
both sexes were conducted using the oral and the intravenous (IV) 
routes of administration. In the oral studies, rats were administered 
radiolabeled benzalkonium chloride using the following cohorts: A low-
dose single oral administration study (10 mg/kilogram (kg)), a low-dose 
repeated oral administration study (10 mg/kg) and a high-dose single 
oral administration study (50 mg/kg) (Ref. 115). For the low-dose 
repeated oral administration study, rats were treated via freely 
available feed containing 100 parts per million (ppm) of non-
radiolabeled benzalkonium chloride for 14 days, followed by 
administration of 10 mg/kg

[[Page 42929]]

benzalkonium chloride by oral gavage. Benzalkonium chloride was found 
to be excreted mainly via the feces in rats after oral administration. 
In all of the treated groups, the average amount of radioactivity 
recovered was 87 to 99 percent in the feces and 5 to 8 percent in the 
urine.
    In a separate group of animals tested in the same study, a single 
low-dose of 10 mg/kg benzalkonium chloride was administered to rats of 
both sexes. The average amount of radioactivity recovered following IV 
dosing was 45 to 55 percent in the feces and 20 to 30 percent in the 
urine. Tissue residues of radioactivity were less than 1 percent of the 
orally administered dose in all groups and 30 to 35 percent of the IV 
dose. No significant changes were noted when comparing the ADME profile 
of high dose versus low dose-treated rats. Although the available ADME 
data from nondermal routes of exposure are sufficient to characterize 
the ADME profile of benzalkonium chloride following nondermal exposure, 
they are not sufficient to characterize the ADME profile after dermal 
exposure. Studies on animal ADME after dermal exposure to benzalkonium 
chloride will need to be submitted to FDA for review, in order to 
complete a GRAS determination for benzalkonium chloride.
    Benzalkonium general toxicity data. Two subchronic 90-day toxicity 
studies in rats were submitted, one dermal and the other dietary 
(oral). A 1-year chronic oral toxicity study in dogs was also 
submitted. In the oral rat study, benzalkonium chloride was 
administered via feeding with concentrations ranging from 0 to 8,000 
ppm (Ref. 111) for 13 weeks. Among rats treated with 4,000 and 8,000 
ppm benzalkonium chloride, an increased incidence in mortality and 
overt toxicity was seen. A no adverse effect level (NOAEL) of 500 ppm 
was noted, which correlated with a mean daily dose of 31.2 mg/kg in 
males and 38.3 mg/kg in females.
    A 1-year chronic oral toxicity study in dogs was also submitted. 
Dogs were chronically administered benzalkonium chloride via feeding in 
concentrations ranging from 0 to 1,200 ppm for 1 year (Ref. 114). 
Changes in body weight included reduced absolute body weight and 
reduced body weight gain in males and females in the highest group 
tested (1,200 ppm), which correlated with a reduction in food 
consumption. At 1,200 ppm, cholesterol levels were reduced by about 10 
percent in both males and females (p <= 0.01). No specific organ 
toxicity was identified. Based on the changes in body weight and food 
consumption at 1,200 ppm, a NOAEL of 400 ppm was determined, which 
corresponds to 13.1 and 14.6 mg/kg/day in males and females, 
respectively.
    In the dermal toxicity study, rats were topically exposed to 
benzalkonium chloride in concentrations ranging from 0 (water) to 1.0 
percent (which correspond to 0 to 20 mg/kg/day) over a 13-week 
treatment period (Ref. 113). Slight local irritation and hyperkeratosis 
(thickening of the epidermis) were observed in all treatment groups 
(including control) in both sexes. All findings were limited to the 
treatment site. Under the conditions of this study, the NOAEL was 20 
mg/kg (1.0 percent). Toxicokinetic data were not collected; therefore, 
systemic exposure to benzalkonium chloride was not characterized. 
Consequently, dermal ADME (toxicokinetic) data is still needed to 
characterize benzalkonium chloride.
    Benzalkonium chloride carcinogenicity data. Two oral 
carcinogenicity studies, one in the rat and another in the mouse, were 
submitted (Refs. 117 through 121). Both studies were conducted in the 
1980's prior to the current ICH guidelines. They were conducted 
according to the OECD (Organisation for Economic Co-operation and 
Development) guidelines \8\ and designed to meet the requirements of 
EPA's regulations, which use a different type of exposure risk 
assessment analysis than is used by FDA for drug products.
---------------------------------------------------------------------------

    \8\ http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788.
---------------------------------------------------------------------------

    A 78-week dietary carcinogenicity study was conducted in mice with 
benzalkonium chloride concentrations of 500, 1,000, and 1,500 ppm, 
corresponding to approximately 15, 73, and 229 mg/kg/day in males and 
18, 92, 289 mg/kg/day in females (Refs. 120 and 121). Findings were 
limited to decreased body weight in both males and females treated with 
the highest dose compared to controls (7 percent and 5 percent at week 
78 in males and females, respectively). There were no treatment-related 
increases in the incidence of neoplasms at any of the doses tested.
    A 2-year oral carcinogenicity study was conducted in rats with 
benzalkonium chloride concentrations of 300, 1,000, and 2,000 ppm, 
corresponding to 13, 44, and 88 mg/kg/day, respectively, in males, and 
to 17, 57, and 116 mg/kg/day, respectively, in females (Refs. 117 
through 119). No treatment-related increases in the incidence of 
neoplasms were observed at any of the tested doses.
    There were no treatment-related neoplasms in either oral 
carcinogenicity study. Though the mouse study is suboptimal because of 
its relatively short duration (78 weeks), we believe these two studies 
are adequate to fill the oral carcinogenicity data gap for benzalkonium 
chloride.
    No dermal carcinogenicity studies of benzalkonium chloride have 
been submitted to FDA. The available data are not adequate to assess 
the carcinogenic potential of benzalkonium chloride. We propose that 
dermal carcinogenicity studies are still needed to complete a GRAS 
determination for benzalkonium chloride.
    Benzalkonium chloride DART data. A developmental toxicity study 
conducted in rabbits showed some increase (not dose-related) in the 
incidence of certain visceral and skeletal malformations among 
benzalkonium chloride-treated rabbits relative to concurrent controls 
(Ref. 110). None of the findings were considered significant. Some of 
the mated dams proved to be not pregnant; therefore, the total number 
of litters (13 to 15) is slightly less than the 16 to 20 recommended in 
the ICH S5 guideline, but further benzalkonium chloride DART data are 
not necessary to make a GRAS determination.
    In a developmental toxicity study in rats, the animals were 
administered benzalkonium chloride (10, 30, and 100 mg/kg/day) (Ref. 
112). There were no treatment-related differences in gestational 
parameters, including total number of embryonic implantations, number 
of viable and nonviable implants. There were also no treatment-related 
effects on fetal body weights per litter, or on the incidences of 
external, visceral, or skeletal malformations/variations. Based on 
these findings, a NOAEL for maternal toxicity was considered to be 10 
mg/kg/day and for developmental toxicity 100 mg/kg/day.
    A two-generation reproduction and development study in rats was 
submitted for review. Rats were exposed to benzalkonium chloride in the 
feed (Ref. 116). The exposure to benzalkonium chloride up to the 
highest dose tested of 2,000 mg/kg did not result in parental toxicity. 
No treatment-related reproductive effects were observed in any of the 
treatment groups. Findings were limited to decreases in body weight 
accompanied by a decrease in food consumption among treated females at 
2,000 mg/kg/day and a decrease in pup body weight. Based on these 
findings, a NOAEL for adults and offspring was considered to be 1000 
ppm (62.5 mg/kg/day).

[[Page 42930]]

    The submitted DART studies are adequate and no additional DART 
studies are needed for benzalkonium chloride.
    Hormonal effects. Based on the negative findings in the 
carcinogenicity studies and the two-generation DART studies, no signal 
for hormonal effects was detected and no further testing on hormonal 
effects will be required for benzalkonium chloride.
    Antimicrobial resistance. In addition to the summaries, as 
discussed in the 2013 Consumer Wash PR (78 FR 76444 at 76463), FDA has 
reviewed studies on resistance data and antibiotic susceptibility of 
certain bacteria related to the development of resistance to 
benzalkonium chloride (Refs. 122 through 129), and determined that the 
available studies have examined few bacterial species, provide no 
information on exposure levels, and are not adequate to define the 
potential for the development of resistance or cross resistance. 
Additional data are needed to more clearly define the potential for the 
development of resistance to benzalkonium chloride.
    b. Benzalkonium chloride safety data gaps.
    In summary, our administrative record for the safety of 
benzalkonium chloride is incomplete with respect to the following:
     Human pharmacokinetic studies under maximal use conditions 
when applied topically (MUsT), including documentation of validation of 
the methods used to measure benzalkonium chloride and its metabolites;
     Animal dermal ADME;
     Dermal carcinogenicity; and
     Data from laboratory studies that assess the potential for 
the development of resistance to benzalkonium chloride and cross-
resistance to antibiotics as discussed in section VIII.C.
3. Isopropyl Alcohol
    In the 1994 TFM, FDA proposed to classify isopropyl alcohol (70 to 
91.3 percent) as GRAS for all consumer antiseptic washes (59 FR 31402 
at 31435). FDA is now proposing to classify isopropyl alcohol as 
Category III for use in consumer antiseptic rubs. The GRAS 
determination in the 1994 TFM was based on the recommendations of the 
Miscellaneous External Panel, which based its recommendations on human 
absorption data and blood isopropyl alcohol levels (47 FR 22324 at 
22329). There was no comprehensive nonclinical review of the toxicity 
profile of isopropyl alcohol, nor was there a nonclinical safety 
evaluation of the topical use of isopropyl alcohol.
    a. Summary of isopropyl alcohol safety data.
    As discussed in more detail in the 2015 Health Care Antiseptic PR 
(80 FR 25166 at 25190-25193), FDA has reviewed the following data and 
found the data to be sufficient to characterize the safety of isopropyl 
alcohol:
     DART data (Refs. 130 through 135).
     Data on the antimicrobial mechanism of isopropyl alcohol 
(Refs. 103 through 106, 136 through 138). Isopropyl alcohol readily 
evaporates from the skin after topical application. The lack of 
antiseptic residue on the skin indicates that the topical application 
of isopropyl alcohol is not likely to contribute to the development of 
antimicrobial resistance (Refs. 103, 105). Additional data on the 
development of antimicrobial resistance are not needed to make a GRAS 
determination.
    No new data has been made available to FDA since publication of the 
1994 TFM that can fill any of the remaining safety data gaps for 
isopropyl alcohol. The following areas of safety assessment, which were 
identified in the 1994 TFM and discussed in detail in the 2015 Health 
Care Antiseptic PR (80 FR 25166 at 25190-25193), are being updated in 
this document:
     Human absorption data (Refs. 1, 139 through 142). However, 
the data submitted and found in the literature to date do not cover 
maximal use of these products in an institutional setting as detailed 
in section VIII.C.2.
     Animal ADME data following dermal and systemic exposure to 
isopropyl alcohol (Refs. 143 through 149). The available dermal 
exposure studies have demonstrated that there is some systemic exposure 
to isopropyl alcohol following dermal application. However, the extent 
of that exposure has not been fully characterized. Moreover, absorption 
data following dermal absorption in animals are still needed to 
determine the extent of systemic exposure following maximal dermal 
exposure to isopropyl alcohol-containing consumer antiseptic rub 
products.
     Systemic and dermal carcinogenicity data in animal models. 
Available data for chronic exposure to isopropyl alcohol include 
inhalation carcinogenicity data in rodents (Refs. 150 and 151) and a 
chronic 1-year dermal toxicity study in mice (Ref. 149). However, these 
data are not adequate to assess the systemic or dermal carcinogenic 
potential of isopropyl alcohol.
     Data on the hormonal effects of isopropyl alcohol. The 
existing data are not adequate to characterize the potential for 
hormonal effects of isopropyl alcohol. However, additional studies may 
not be needed to assess the potential hormonal effects of isopropyl 
alcohol if assessment of potential hormonal activity can be derived 
from existing (reproductive and developmental studies; chronic general 
toxicity data) and additional pending isopropyl alcohol (systemic and 
dermal carcinogenicity and ADME data) nonclinical studies, provided the 
appropriate endpoints are assessed.
    Thus, we believe the existing evaluations need to be supplemented 
to fully evaluate the safety of isopropyl alcohol. As described in more 
detail in the 2015 Health Care Antiseptic PR (80 FR 25166 at 25190-
25193), we propose that human pharmacokinetic studies under maximal use 
conditions when applied topically (MUsT), animal ADME studies (dermal 
absorption), systemic and dermal carcinogenicity studies, and data on 
hormonal effects are still needed to complete a GRAS determination for 
isopropyl alcohol.
    b. Isopropyl alcohol safety data gaps.
    In summary, our administrative record for the safety of isopropyl 
alcohol is incomplete with respect to the following:
     Human pharmacokinetic studies under maximal use conditions 
when applied topically (MUsT), including documentation of validation of 
the methods used to measure isopropyl alcohol and its metabolites;
     animal ADME (dermal absorption);
     dermal carcinogenicity;
     systemic carcinogenicity (may be waived if the MUsT data 
do not show absorption); and
     hormonal effects (could be derived from other endpoints).

IX. Proposed Effective Date

    Based on the currently available data, this proposed rule finds 
that additional data are necessary to establish the safety and 
effectiveness of consumer antiseptic rub active ingredients for use in 
OTC consumer antiseptic rub drug products. Accordingly, consumer 
antiseptic rub active ingredients would be nonmonograph in any final 
rule based on this proposed rule. We recognize, based on the scope of 
products subject to this monograph, that manufacturers will need time 
to comply with a final rule based on this proposed rule. However, 
because of the potential effectiveness and safety considerations raised 
by the data for some antiseptic active ingredients evaluated, we 
believe that an effective date later than 1 year after publication of 
the final rule would not be appropriate or necessary. Consequently, any 
final rule that results

[[Page 42931]]

from this proposed rule will be effective 1 year after the date of the 
final rule's publication in the Federal Register. On or after that 
date, any OTC consumer antiseptic rub drug product that is subject to 
the monograph and that contains a nonmonograph condition, i.e., a 
condition that would cause the drug to be not GRAS/GRAE or to be 
misbranded, could not be introduced or delivered for introduction into 
interstate commerce unless it is the subject of an approved new drug 
application or abbreviated new drug application. Any OTC consumer 
antiseptic rub drug product subject to the final rule that is 
repackaged or relabeled after the effective date of the final rule 
would be required to be in compliance with the final rule, regardless 
of the date the product was initially introduced or initially delivered 
for introduction into interstate commerce.

X. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). We have developed a comprehensive Economic Analysis of Impacts 
that assesses the impacts of the proposed rule. We believe that this 
proposed rule is a significant regulatory action as defined by 
Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because the consumer antiseptic rub product industry is 
mainly composed of establishments with 500 or fewer employees, we 
tentatively conclude that the proposed rule may have a significant 
economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any 1 year.'' The current threshold after adjustment for 
inflation is $146 million, using the most current (2015) Implicit Price 
Deflator for the Gross Domestic Product. This proposed rule would not 
result in an expenditure in any year that meets or exceeds this amount.

B. Summary of Costs and Benefits

    There are three active ingredients being evaluated for use as a 
consumer antiseptic rub in this proposed rule: Alcohol (ethanol or 
ethyl alcohol), isopropyl alcohol, and benzalkonium chloride. The 
impact of the proposed rule on OTC consumer antiseptic rub product 
industry will depend on the outcome of tests to determine whether these 
three active antiseptic ingredients are GRAS/GRAE. It is possible that 
none, one, two, or all three of the ingredients will be determined to 
be GRAS/GRAE. We consider two extreme scenarios to capture the entire 
range of total costs: (1) All three ingredients are deemed to be GRAS/
GRAE or (2) none of the ingredients is deemed to be GRAS/GRAE.
    In table 7, we provide a summary of the estimated costs of the 
proposed rule for the two scenarios. The costs of the proposed rule 
involve product reformulation and relabeling of products. It is 
important to note that, to demonstrate that an antiseptic active 
ingredient is GRAS/E, some manufacturers will also incur additional 
costs associated with safety and effectiveness testing. We note that 
the testing costs for this proposed rule are not attributed here 
because these costs will be realized if manufacturers conduct the 
testing discussed in the proposed rule for health care antiseptics (80 
FR 25166) and we do not count costs twice. However, we estimate these 
costs in this analysis to promote transparency in the event that this 
rule is finalized before the health care antiseptics proposed rule or 
manufacturers conduct the testing for the three ingredients discussed 
in this rule but do not conduct the testing for these ingredients for 
the health care antiseptic proposed rule or this rule is finalized but 
the health care antiseptics proposed rule is not.
    In scenario 1, all three ingredients are determined to be GRAS/E 
and manufacturers of products containing other ingredients will no 
longer be able to market these products under consumer antiseptic rub 
labels pursuant to the topical antimicrobial monograph. We expect that 
these manufacturers will reformulate their products to contain one of 
the monograph ingredients and relabel their products to reflect the 
change in ingredients. Annualizing upfront costs over a 10-year period 
at a discount rate of 3% for scenario 1, the costs of the proposed rule 
are estimated to be between $0.04 million and $0.12 million per year; 
the corresponding estimated cost at a discount rate of 7% is between 
$0.05 million and $0.14 million per year. In scenario 2, none of the 
ingredients is determined to be GRAS/E and we expect that manufacturers 
will reformulate their products to be free of antiseptics and relabel 
them to reflect the change in ingredients. Annualizing upfront costs 
over a 10-year period at a discount rate of 3% for scenario 2, the 
costs of the proposed rule are estimated to be between $1.87 million 
and $5.52 million per year; the corresponding estimated cost at a 
discount rate of 7% is between $2.28 million and $6.70 million per 
year.

                                          Table 7--Summary of Quantified Total Costs (in Millions), by Scenario
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                One-time costs                       Annualized costs over a 10-year period
                                                      --------------------------------------------------------------------------------------------------
                    Cost category                                                               3% Discount rate                 7% Discount rate
                                                          Low        Med.       High   -----------------------------------------------------------------
                                                                                           Low        Med.       High       Low        Med.       High
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                            Scenario 1: Assuming All Ingredients are Determined to be GRAS/E
--------------------------------------------------------------------------------------------------------------------------------------------------------
Relabeling Costs.....................................      $0.11      $0.19      $0.32      $0.01      $0.02      $0.04      $0.02      $0.03      $0.05
Reformulation Costs..................................       0.23       0.46       0.70       0.03       0.05       0.08       0.03       0.07       0.10
                                                      --------------------------------------------------------------------------------------------------
    Total Costs......................................       0.34       0.66       1.02       0.04       0.08       0.12       0.05       0.09       0.14
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 42932]]

 
                                         Scenario 2: Assuming None of the Ingredients is Determined to be GRAS/E
--------------------------------------------------------------------------------------------------------------------------------------------------------
Relabeling Costs.....................................       6.55      11.36      18.76       0.77       1.33       2.20       0.93       1.62       2.67
Reformulation Costs..................................       9.44      18.89      28.33       1.11       2.21       3.32       1.34       2.69       4.03
                                                      --------------------------------------------------------------------------------------------------
    Total Costs......................................      15.99      30.25      47.09       1.87       3.55       5.52       2.28       4.31       6.70
--------------------------------------------------------------------------------------------------------------------------------------------------------

    A potential benefit of the proposed rule is that the removal of 
potentially harmful antiseptic active ingredients in consumer 
antiseptic rub products will prevent health consequences associated 
with exposure to such ingredients. FDA lacks the necessary information 
to estimate the impact of exposure to antiseptic active ingredients in 
consumer antiseptic rub products on human health outcomes. We are, 
however, able to estimate the reduction in the aggregate exposure to 
antiseptic active ingredients found in currently marketed consumer 
antiseptic rub products. As with the total costs, the reduction in 
aggregate exposure to antiseptic active ingredients in consumer rub 
products depends on the outcome of testing and the determination of 
GRAS/E status of the three ingredients that require testing. The 
proposed rule will lead to an estimated reduction that ranges from 110 
pounds to 254 pounds per year in scenario 1 and from 13,080,963 and 
67,272,847 pounds per year in scenario 2. Absent information on the 
change in the short- and long-term health risks associated with a one 
pound increase in exposure to each antiseptic active ingredient in 
consumer antiseptic rub products, we are unable to translate the 
aggregate exposure figures into monetized benefits.
    FDA also examined the economic implications of the rule as required 
by the Regulatory Flexibility Act. If a rule will have a significant 
economic impact on a substantial number of small entities, the 
Regulatory Flexibility Act requires agencies to analyze regulatory 
options that would lessen the economic effect of the rule on small 
entities. This proposed rule could impose a significant economic impact 
on a substantial number of small entities. For small entities, we 
estimate the rule's one-time costs to roughly range between 0.001 and 
0.16 percent of average annual value of shipments for a small business. 
In the Initial Regulatory Flexibility Analysis, we assess regulatory 
options that would reduce the proposed rule's burden on small entities, 
such as extending relabeling compliance times to 18 months (rather than 
12 months).
    The full analysis of economic impacts is available in the docket 
for this proposed rule (Docket No. FDA-2016-N-0124) and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

XI. Paperwork Reduction Act of 1995

    This proposed rule contains no collections of information. 
Therefore, clearance by the Office of Management and Budget under the 
Paperwork Reduction Act of 1995 is not required.

XII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.31(a) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

XIII. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. Section 4(a) of the 
Executive order requires agencies to ``construe . . . a Federal statute 
to preempt State law only where the statute contains an express 
preemption provision or there is some other clear evidence that the 
Congress intended preemption of State law, or where the exercise of 
State authority conflicts with the exercise of Federal authority under 
the Federal statute.'' The sole statutory provision giving preemptive 
effect to this proposed rule is section 751 of the FD&C Act (21 U.S.C. 
379r). We have complied with all of the applicable requirements under 
the Executive order and have determined that the preemptive effect of 
this proposed rule, if finalized, would be consistent with Executive 
Order 13132. Through publication of this proposed rule, we are 
providing notice and an opportunity for State and local officials to 
comment on this rulemaking.

XIV. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m. Monday through Friday; they are also 
available electronically at http://www.regulations.gov. FDA has 
verified the Web site addresses, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

1. Brown, T.L. et al., ``Can Alcohol-Based Hand-Rub Solutions Cause 
You to Lose Your Driver's License? Comparative Cutaneous Absorption 
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Nonprescription Drugs and

[[Page 42933]]

Anti-Infective Drugs Advisory Committees, OTC Vol. 230002. Available 
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8. Transcript of the March 23, 2005, Nonprescription Drugs Advisory 
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10. Summary Minutes of the November 14, 2008, Feedback Meeting with 
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11. Transcript of the September 3, 2014, Meeting of the 
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FDA-1975-N-0012-0049, FDA-1975-N-0012-0068, FDA-1975-N-0012-0071, 
FDA-1975-N-0012-0073, FDA-1975-N-0012-0075, FDA-1975-N-0012-0081, 
FDA-1975-N-0012-0082, FDA-1975-N-0012-0085, FDA-1975-N-0012-0087, 
FDA-1975-N-0012-0088, FDA-1975-N-0012-0089, FDA-1975-N-0012-0090, 
FDA-1975-N-0012-0091, FDA-1975-N-0012-0093, FDA-1975-N-0012-0094, 
FDA-1975-N-0012-0095, FDA-1975-N-0012-0096, FDA-1975-N-0012-0097, 
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FDA-1975-N-0012-0105, FDA-1975-N-0012-0108, FDA-1975-N-0012-0109, 
FDA-1975-N-0012-0111, FDA-1975-N-0012-0110, FDA-1975-N-0012-0113, 
FDA-1975-N-0012-0116, FDA-1975-N-0012-0117, FDA-1975-N-0012-0118, 
FDA-1975-N-0012-0119, FDA-1975-N-0012-0121, FDA-1975-N-0012-0124, 
FDA-1975-N-0012-0126, FDA-1975-N-0012, FDA-1975-N-0012-0128, FDA-
1975-N-0012-0132, FDA-1975-N-0012-0134, FDA-1975-N-0012-0135, FDA-
1975-N-0012-0143, FDA-1975-N-0012-0148, FDA-1975-N-0012-0153, FDA-
1975-N-0012-0154, FDA-1975-N-0012-0155, FDA-1975-N-0012-0157, FDA-
1975-N-0012-0158, FDA-1975-N-0012-0161, FDA-1975-N-0012-0164, FDA-
1975-N-0012-0166, FDA-1975-N-0012-0176, FDA-1975-N-0012-0177, FDA-
1975-N-0012-0178, FDA-1975-N-0012-0184, FDA-1975-N-0012-0191, FDA-
1975-N-0012-0198, FDA-1975-N-0012-0199, FDA-1975-N-0012-0200, FDA-
1975-N-0012-0201, FDA-1975-N-0012-0202, FDA-1975-N-0012-0204, FDA-
1975-N-0012-0206, FDA-1975-N-0012-0208, FDA-1975-N-0012-0209, FDA-
1975-N-0012-0212, FDA-1975-N-0012-0213, FDA-1975-N-0012-0215, FDA-
1975-N-0012-0217, FDA-1975-N-0012-0218, FDA-1975-N-0012-0219, FDA-
1975-N-0012-0227, FDA-1975-N-0012-0233, FDA-1975-N-0012-0238, FDA-
1975-N-0012-0241, FDA-1975-N-0012-0243, FDA-1975-N-0012-0258, FDA-
1975-N-0012-0264, FDA-1975-N-0012-0266, FDA-1975-N-0012-0274, FDA-
1975-N-0012-0275, FDA-1975-N-0012-0276, FDA-1975-N-0012-0281, FDA-
1975-N-0012-0282, FDA-1975-N-0012-0284, FDA-1975-N-0012-0285, FDA-
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Toxicology, 23:407-420, 1994. Available at http://toxsci.oxfordjournals.org/content/23/3/407.full.pdf.
148. Kapp, R.W., Jr. et al., ``Isopropanol: Summary of TSCA Test 
Rule Studies and Relevance to Hazard Identification,'' Regulatory 
Toxicology and Pharmacology, 23:183-192, 1996. Available at http://www.sciencedirect.com/science/article/pii/S0273230096900422.
149. WHO International Program on Chemical Safety Working Group, 
``2-Propanol,'' Environmental Health Criteria, 103:132, 1990. 
Available at http://www.inchem.org/documents/ehc/ehc/ehc103.htm#SectionNumber:8.3.
150. World Health Organization International Agency for Research on 
Cancer, ``IARC Monographs on the Evaluation of Carcinogenic Risks to 
Humans: Re-evaluation of Some Organic Chemicals, Hydrazine and 
Hydrogen Peroxide,'' 71 (part 3):1027-1036, 1999, available at 
http://monographs.iarc.fr/ENG/Monographs/vol71/mono71.pdf.
151. Burleigh-Flayer, H. et al., ``Isopropanol Vapor Inhalation 
Oncogenicity Study in Fischer 344 Rats and CD-1 Mice,'' Fundamental 
and Applied Toxicology, 36:95-111, 1997. Available at http://www.sciencedirect.com/science/article/pii/S0272059096922848.

List of Subjects in 21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
310, as proposed to be amended December 17, 2013, at 78 FR 76444, and 
May 1, 2015, at 80 FR 25166, is proposed to be further amended as 
follows:

PART 310--NEW DRUGS

0
1. The authority citation for part 310 is revised to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 360hh-360ss, 361(a), 371, 374, 375, 379e, 379k-1; 42 U.S.C. 
216, 241, 242(a), 262.

0
2. In Sec.  310.545:
0
a. Add paragraph (a)(27)(v);
0
b. In paragraph (d) introductory text, remove ``(d)(42)'' and in its 
place add ``(d)(43)''; and
0
c. Add paragraph (d)(43).
    The additions to read as follows:


Sec.  310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (27) * * *
    (v) Consumer antiseptic rub drug products. Approved as of [DATE 1 
YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN THE Federal 
Register]:

Alcohol (ethanol and ethyl alcohol)
Benzalkonium chloride
Isopropyl alcohol

* * * * *
    (d) * * *
    (43) [DATE 1 YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN 
THE Federal Register], for products subject to paragraph (a)(27)(v) of 
this section.

    Dated: June 24, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-15410 Filed 6-29-16; 8:45 am]
 BILLING CODE 4164-01-P



                                                   42912                   Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules

                                                   DEPARTMENT OF HEALTH AND                                instructions for submitting comments.                  information that you do not wish to be
                                                   HUMAN SERVICES                                          Comments submitted electronically,                     made publicly available, submit your
                                                                                                           including attachments, to http://                      comments only as a written/paper
                                                   Food and Drug Administration                            www.regulations.gov will be posted to                  submission. You should submit two
                                                                                                           the docket unchanged. Because your                     copies total. One copy will include the
                                                   21 CFR Part 310                                         comment will be made public, you are                   information you claim to be confidential
                                                   [Docket No. FDA–2016–N–0124 (Formerly                   solely responsible for ensuring that your              with a heading or cover note that states
                                                   Part of Docket No. FDA–1975–N–0012)]                    comment does not include any                           ‘‘THIS DOCUMENT CONTAINS
                                                                                                           confidential information that you or a                 CONFIDENTIAL INFORMATION.’’ The
                                                   RIN 0910–AF69                                           third party may not wish to be posted,                 Agency will review this copy, including
                                                                                                           such as medical information, your or                   the claimed confidential information, in
                                                   Safety and Effectiveness of Consumer
                                                                                                           anyone else’s Social Security number, or               its consideration of comments. The
                                                   Antiseptics; Topical Antimicrobial
                                                                                                           confidential business information, such                second copy, which will have the
                                                   Drug Products for Over-the-Counter
                                                                                                           as a manufacturing process. Please note                claimed confidential information
                                                   Human Use; Proposed Amendment of
                                                                                                           that if you include your name, contact                 redacted/blacked out, will be available
                                                   the Tentative Final Monograph;
                                                                                                           information, or other information that                 for public viewing and posted on http://
                                                   Reopening of Administrative Record
                                                                                                           identifies you in the body of your                     www.regulations.gov. Submit both
                                                   AGENCY:    Food and Drug Administration,                comments, that information will be                     copies to the Division of Dockets
                                                   HHS.                                                    posted on http://www.regulations.gov.                  Management. If you do not wish your
                                                   ACTION:   Proposed rule.                                  • If you want to submit a comment                    name and contact information to be
                                                                                                           with confidential information that you                 made publicly available, you can
                                                   SUMMARY:   The Food and Drug                            do not wish to be made available to the                provide this information on the cover
                                                   Administration (FDA or Agency) is                       public, submit the comment as a                        sheet and not in the body of your
                                                   issuing this proposed rule to amend the                 written/paper submission and in the                    comments and you must identify this
                                                   1994 tentative final monograph or                       manner detailed (see ‘‘Written/Paper                   information as ‘‘confidential.’’ Any
                                                   proposed rule (the 1994 TFM) for over-                  Submissions’’ and ‘‘Instructions’’). We                information marked as ‘‘confidential’’
                                                   the-counter (OTC) antiseptic drug                       note however, that the OTC drug                        will not be disclosed except in
                                                   products. In this proposed rule, we are                 monograph process is a public process;                 accordance with 21 CFR 10.20 and other
                                                   proposing to establish conditions under                 and, the Agency intends to consider                    applicable disclosure law. For more
                                                   which OTC consumer antiseptic                           only non-confidential material that is                 information about FDA’s posting of
                                                   products intended for use without water                 submitted to the docket for this                       comments to public dockets, see 80 FR
                                                   (referred to throughout as consumer                     rulemaking or that is otherwise publicly               56469, September 18, 2015, or access
                                                   antiseptic rubs or consumer rubs) are                   available in evaluating if a relevant                  the information at: http://www.fda.gov/
                                                   generally recognized as safe and                        ingredient is GRAS/GRAE.                               regulatoryinformation/dockets/
                                                   generally recognized as effective (GRAS/                                                                       default.htm.
                                                   GRAE). In the 1994 TFM, certain                         Written/Paper Submissions                                 Docket: For access to the docket to
                                                   antiseptic active ingredients were                         Submit written/paper submissions as                 read background documents or the
                                                   proposed as being GRAS for antiseptic                   follows:                                               electronic and written/paper comments
                                                   rub use by consumers based on safety                       • Mail/Hand delivery/Courier (for                   received, go to http://
                                                   data evaluated by FDA as part of its                    written/paper submissions): Division of                www.regulations.gov and insert the
                                                   ongoing review of OTC antiseptic drug                   Dockets Management (HFA–305), Food                     docket number, found in brackets in the
                                                   products. However, in light of more                     and Drug Administration, 5630 Fishers                  heading of this document, into the
                                                   recent scientific developments and                      Lane, Rm. 1061, Rockville, MD 20852.                   ‘‘Search’’ box and follow the prompts
                                                   changes in the use patterns of these                       • For written/paper comments                        and/or go to the Division of Dockets
                                                   products, we are now proposing that                     submitted to the Division of Dockets                   Management, 5630 Fishers Lane, Rm.
                                                   additional safety data are necessary to                 Management, FDA will post your                         1061, Rockville, MD 20852.
                                                   support the safety of antiseptic active                 comment, as well as any attachments,                   FOR FURTHER INFORMATION CONTACT:
                                                   ingredients for this use. We also are                   except for information submitted,                      Anita Kumar, Center for Drug
                                                   proposing that all consumer antiseptic                  marked and identified, as confidential,                Evaluation and Research, Food and
                                                   rub active ingredients have in vitro data               if submitted as detailed in                            Drug Administration, 10903 New
                                                   characterizing the ingredient’s                         ‘‘Instructions.’’                                      Hampshire Ave., Bldg. 22, Rm. 5445,
                                                   antimicrobial properties and in vivo                       Instructions: All submissions received              Silver Spring, MD 20993, 301–796–
                                                   clinical simulation studies showing that                must include the Docket No. FDA–                       1032.
                                                   specified log reductions in the amount                  2016–N–0124 for ‘‘Safety and
                                                   of certain bacteria are achieved using                                                                         SUPPLEMENTARY INFORMATION:
                                                                                                           Effectiveness of Consumer Antiseptics;
                                                   the ingredient.                                         Topical Antimicrobial Drug Products for                Table of Contents
                                                   DATES: Submit electronic or written                     Over-the-Counter Human Use; Proposed
                                                                                                                                                                  I. Executive Summary
                                                   comments by December 27, 2016. See                      Amendment of the Tentative Final                          A. Purpose of the Regulatory Action
                                                   section IX of this document for the                     Monograph; Reopening of                                   B. Summary of the Major Provisions of the
                                                   proposed effective date of a final rule                 Administrative Record.’’ Received                            Regulatory Action in Question
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                   based on this proposed rule.                            comments will be placed in the docket                     C. Effectiveness
                                                   ADDRESSES: You may submit comments                      and, except for those submitted as                        D. Safety
                                                                                                           ‘‘Confidential Submissions,’’ publicly                    E. Active Ingredients
                                                   as follows:                                                                                                       F. Costs and Benefits
                                                                                                           viewable at http://www.regulations.gov
                                                   Electronic Submissions                                                                                         II. Introduction
                                                                                                           or at the Division of Dockets                             A. Terminology Used in the OTC Drug
                                                     Submit electronic comments in the                     Management between 9 a.m. and 4 p.m.,                        Review Regulations
                                                   following way:                                          Monday through Friday.                                    B. Topical Antiseptics
                                                     • Federal eRulemaking Portal: http://                    • Confidential Submissions—To                          C. This Proposed Rule Covers Only
                                                   www.regulations.gov. Follow the                         submit a comment with confidential                           Consumer Antiseptic Rubs



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                                                                           Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                           42913

                                                      D. Comment Period                                    information we have identified and                     posed by the use of certain consumer
                                                   III. Background                                         placed in the docket. This proposed rule               antiseptic products, as well as input
                                                      A. Significant Rulemakings Relevant to               applies to active ingredients used in                  from the Nonprescription Drugs
                                                         This Proposed Rule
                                                                                                           consumer antiseptic rub products that                  Advisory Committee (NDAC) that met in
                                                      B. Public Meetings Relevant to This
                                                         Proposed Rule                                     are sometimes referred to as rubs, leave-              March 2005 (the March 2005 NDAC)
                                                      C. Comments Received by FDA                          on products, or hand ‘‘sanitizers,’’ as                and October 2005 (the October 2005
                                                   IV. Active Ingredients With Insufficient                well as to consumer antiseptic wipes.                  NDAC), has prompted us to reevaluate
                                                         Evidence of Eligibility for the OTC Drug          These products are intended to be used                 the data needed for classifying active
                                                         Review                                            when soap and water are not available,                 ingredients used in consumer rubs as
                                                      A. Eligibility for the OTC Drug Review               and are left on and not rinsed off with                GRAE. The reevaluation of effectiveness
                                                      B. Eligibility of Certain Active Ingredients         water. We will refer to them here as                   will help to ensure that the level of
                                                         for the OTC Drug Review
                                                                                                           consumer antiseptic rubs or consumer                   effectiveness achieved is adequate to
                                                   V. Ingredients Previously Proposed as Not
                                                         Generally Recognized as Safe and                  rubs. In separate rulemakings (78 FR                   offset newly identified safety concerns
                                                         Effective                                         76444, December 17, 2013; 80 FR 25166,                 (see new information described in the
                                                   VI. Summary of Proposed Classifications of              May 1, 2015), we proposed conditions                   safety section of this executive
                                                         OTC Consumer Antiseptic Rub Active                under which OTC consumer antiseptic                    summary). We continue to propose the
                                                         Ingredients                                       washes and OTC antiseptics intended                    use of surrogate endpoints (bacterial log
                                                   VII. Effectiveness (Generally Recognized as             for use by health care professionals in                reductions) as a demonstration of
                                                         Effective) Determination                          a hospital setting or other health care                effectiveness for consumer antiseptic
                                                      A. Evaluation of Effectiveness Data
                                                                                                           situation outside the hospital are GRAS/               rubs combined with in vitro testing to
                                                      B. Current Standards: Studies Needed To
                                                         Support a Generally Recognized as                 GRAE. Those antiseptic products are not                characterize the antimicrobial activity of
                                                         Effective Determination                           addressed in this proposed rule.                       the ingredient. However, the log
                                                      C. Impact of Application Parameters on                                                                      reductions required for the
                                                                                                           B. Summary of the Major Provisions of
                                                         Efficacy                                                                                                 demonstration of effectiveness for
                                                                                                           the Regulatory Action in Question
                                                   VIII. Safety (Generally Recognized as Safe)                                                                    consumer rubs have been revised based
                                                         Determination                                        We are proposing that additional                    on the recommendations of the March
                                                      A. New Issues                                        safety and effectiveness data are                      2005 and October 2005 NDAC meetings,
                                                      B. Antimicrobial Resistance                          necessary to support a GRAS/GRAE                       comments received after the 1994 TFM,
                                                      C. Studies To Support a Generally                    determination for OTC antiseptic rub                   and other information we reviewed.
                                                         Recognized as Safe Determination                  active ingredients intended for use by
                                                      D. Review of Available Data for Each
                                                                                                                                                                     We have evaluated the available
                                                         Antiseptic Active Ingredient
                                                                                                           consumers. The effectiveness data, the                 literature, the data, and other
                                                   IX. Proposed Effective Date                             safety data, and the effect on the                     information that were submitted to the
                                                   X. Summary of Preliminary Regulatory                    previously proposed classification of                  rulemaking on the effectiveness of
                                                         Impact Analysis                                   active ingredients are described briefly               consumer rub active ingredients, as well
                                                   A. Introduction                                         in this summary. Because no ingredients                as the recommendations from the public
                                                      B. Summary of Costs and Benefits                     currently meet the criteria for a GRAS/                meetings held by the Agency on
                                                      XI. Paperwork Reduction Act of 1995                  GRAE determination in this proposed                    antiseptics. We propose that the record
                                                   XII. Environmental Impact                               rule, this rulemaking does not                         contain additional log reduction data to
                                                   XIII. Federalism                                        specifically address requirements for
                                                   XIV. References
                                                                                                                                                                  demonstrate the effectiveness of
                                                                                                           anticipated final formulation testing                  consumer rub active ingredients. We are
                                                   I. Executive Summary                                    (i.e., testing the mixture of both active              also asking for data and information to
                                                                                                           and inactive ingredients proposed for                  be submitted about the impact of
                                                   A. Purpose of the Regulatory Action                     marketing) or labeling. Final                          product use factors (such as volume of
                                                      FDA is proposing to amend the 1994                   formulation testing could potentially                  product per application) on efficacy to
                                                   TFM for OTC antiseptic drug products                    involve both efficacy testing and safety               help inform labeling and requirements
                                                   that published in the Federal Register of               testing to determine absorption. It is                 for final formulation testing.
                                                   June 17, 1994 (59 FR 31402). The 1994                   anticipated that if a final rule includes
                                                   TFM is part of FDA’s ongoing                            any GRAS/GRAE ingredients, labeling                    D. Safety
                                                   rulemaking to evaluate the safety and                   will be addressed as part of the final                   Several important scientific
                                                   effectiveness of OTC drug products                      rule and may include elements related                  developments that affect the safety
                                                   marketed in the United States on or                     to application volume and safety                       evaluation of consumer rub active
                                                   before May 1972 (OTC Drug Review).                      labeling for children, including a                     ingredients have occurred since FDA’s
                                                      FDA is proposing to establish new                    warning to keep out of reach of                        1994 evaluation of the safety of these
                                                   conditions under which active                           children. We anticipate that specific                  active ingredients under the OTC Drug
                                                   ingredients used in OTC consumer                        effectiveness claims in labeling will                  Review. Improved analytical methods
                                                   antiseptic products intended to be used                 reflect the testing performed in support               now exist that can detect and more
                                                   without water are GRAS/GRAE based on                    of these claims. Effectiveness testing                 accurately measure these active
                                                   FDA’s reevaluation of the safety and                    using surrogate endpoints as described                 ingredients at lower levels in the
                                                   effectiveness data requirements                         in this proposed rule is designed to                   bloodstream and tissue. Consequently,
                                                   proposed in the 1994 TFM for what                       support antibacterial claims.                          we now know that, at least for certain
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                   were then referred to as antiseptic hand                                                                       consumer antiseptic rub ingredients,
                                                   washes (which included the products                     C. Effectiveness                                       systemic exposure is higher than
                                                   we refer to in this document as                           A determination that a drug product                  previously thought (Refs. 1 through 5),
                                                   consumer antiseptic rubs or consumer                    containing a particular active ingredient              and new information is available about
                                                   rubs). We are conducting this                           would be GRAE for a particular                         the potential risks from systemic
                                                   reevaluation based on the comments                      intended use requires consideration of                 absorption and long-term exposure.
                                                   received, input from subsequent public                  the benefit-to-risk ratio for the drug                 These data are particularly important
                                                   meetings, and our independent                           under the specified conditions of use.                 given the increased use of consumer
                                                   evaluation of other relevant scientific                 New information on potential risks                     antiseptic rubs since the publication of


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                                                   42914                   Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules

                                                   the 1994 TFM. New safety information                    proposed to be classified as GRAS/                     possible that none, one, two, or all three
                                                   also suggests that widespread antiseptic                GRAE (59 FR 31402 at 31435 to 31436)                   of the ingredients will be determined to
                                                   use could have an impact on the                         for use as what was then called an                     be GRAS/GRAE. We consider two
                                                   development of bacterial resistance.                    antiseptic hand wash (a use which                      extreme scenarios to capture the entire
                                                   Currently, the significance of this new                 included both products intended to be                  range of total costs: (1) All three
                                                   information is not known and we are                     rinsed off (washes) and those intended                 ingredients are deemed to be GRAS/
                                                   unaware of any information that would                   to be left on (rubs)). Isopropyl alcohol               GRAE or (2) none of the ingredients is
                                                   lead us to conclude that any consumer                   (70 to 91.3 percent) was proposed to be                deemed to be GRAS/GRAE.
                                                   antiseptic rub active ingredient is unsafe              categorized in Category III in the 1994                   The range of estimated costs is wide
                                                   (other than those that we proposed to be                TFM because of a lack of adequate                      because the number of products that
                                                   Category II in the 1994 TFM). The                       effectiveness data for use as an                       would need to be reformulated and
                                                   benefits of any active ingredient will                  antiseptic hand wash (59 FR 31402 at                   relabeled depends on whether or not an
                                                   need to be weighed against its risks once               31435 to 31436). However, we now                       antiseptic ingredient is deemed to be
                                                   both the effectiveness and safety have                  propose that both alcohol and isopropyl                GRAS/GRAE. A small number of
                                                   been better characterized to determine                  alcohol need additional safety and                     products contain active ingredients
                                                   GRAS/GRAE status.                                       effectiveness data to support a                        which FDA has determined are not
                                                      The previously proposed GRAS                         classification of GRAS/GRAE for                        eligible for use in consumer antiseptic
                                                   determinations were based on safety                     consumer antiseptic rub use. Our                       rubs and these products will need to be
                                                   principles that have since evolved                      detailed evaluation of the effectiveness               reformulated and relabeled (scenario 1).
                                                   significantly because of advances in                    and safety of the active ingredients for               However, in scenario 2 (and
                                                   technology, development of new test                     which data were submitted can be                       intermediate scenarios), the resulting
                                                   methods, and experience with                            found in sections VII.A and VIII.D.                    costs are higher because a greater
                                                   performing test methods. The standard                      In the 1994 TFM, FDA categorized                    number of products will need to be
                                                   battery of tests that were used to                      benzalkonium chloride in Category III                  reformulated and relabeled as a result of
                                                   determine the safety of drugs has                       because of a lack of adequate safety and               tests failing to show GRAS/GRAE status.
                                                   changed over time to incorporate                        effectiveness data for its use as an                      The total upfront costs of the
                                                   improvements in safety testing. To                      antiseptic hand wash (59 FR 31402 at                   proposed regulation—which include the
                                                   ensure that consumer antiseptic rub                     31435). We have evaluated safety data                  expenditures to reformulate and relabel
                                                   active ingredients are GRAS, data that                  received in response to the 1994 TFM                   products that contain nonmonograph
                                                   meet current safety standards are                       and the consumer antiseptic wash                       ingredients—are estimated to range from
                                                   needed.                                                 proposed rule published in the Federal                 $0.34 million to $1.02 million for
                                                      Based on these developments, we are                  Register of December 17, 2013 (78 FR                   scenario 1 and from $15.99 million to
                                                   now proposing that additional safety                    76444) (2013 Consumer Wash Proposed                    $47.09 million for scenario 2.
                                                   data are needed for each consumer                       Rule (PR)) (see section VIII.D). In this               Annualizing upfront costs over a 10-
                                                   antiseptic rub active ingredient to                     proposed rule, we propose that                         year period at a discount rate of 3% for
                                                   support a GRAS classification. The data                 benzalkonium chloride needs additional                 scenario 1, the costs of the proposed
                                                   described in this proposed rule are the                 safety and effectiveness data to support               rule are estimated to be between $0.04
                                                   minimum data necessary to establish                     a classification of GRAS/GRAE for                      million and $0.12 million per year; the
                                                   the safety of antiseptic active                         consumer antiseptic rub use.                           corresponding estimated cost at a
                                                   ingredients used in consumer antiseptic                    If we do not receive sufficient data to             discount rate of 7% is between $0.05
                                                   rub products in light of the new safety                 support monograph conditions for                       million and $0.14 million per year. In
                                                   information. Consumers may use                          consumer antiseptic rub products                       scenario 2, none of the ingredients is
                                                   antiseptic rubs on a daily, long-term                   containing these active ingredients,
                                                                                                                                                                  determined to be GRAS/E and we
                                                   (i.e., chronic) basis. The data we                      these active ingredients may not be
                                                                                                                                                                  expect that manufacturers will
                                                   propose, which are needed to                            included in the future OTC consumer
                                                                                                                                                                  reformulate their products to be free of
                                                   demonstrate safety for all consumer                     antiseptic rub final monograph. Any
                                                                                                                                                                  antiseptics and relabel them to reflect
                                                   antiseptic rub active ingredients, fall                 consumer antiseptic rub product
                                                                                                                                                                  the change in ingredients. Annualizing
                                                   into two broad categories: (1) Human                    containing the active ingredients being
                                                                                                                                                                  upfront costs over a 10-year period at a
                                                   safety studies and (2) nonclinical safety               considered under this rulemaking that
                                                                                                                                                                  discount rate of 3% for scenario 2, the
                                                   studies. For one of the consumer                        are not included in a future final
                                                                                                                                                                  costs of the proposed rule are estimated
                                                   antiseptic rub active ingredients                       monograph could seek approval to
                                                                                                                                                                  to be between $1.87 million and $5.52
                                                   (benzalkonium chloride), data to                        market by submitting new drug
                                                                                                                                                                  million per year; the corresponding
                                                   evaluate the development of                             applications (NDAs) under section 505
                                                                                                                                                                  estimated cost at a discount rate of 7%
                                                   antimicrobial resistance also is required               of the Federal Food, Drug, and Cosmetic
                                                                                                                                                                  is between $2.28 million and $6.70
                                                   to demonstrate its safety.                              Act (the FD&C Act) (21 U.S.C. 355).
                                                                                                                                                                  million per year. We assume that health
                                                                                                           After a final monograph is established,
                                                   E. Active Ingredients                                                                                          risk falls with reduced exposure to
                                                                                                           NDA deviations might be submitted for
                                                     Three active ingredients are being                                                                           potentially unsafe or ineffective
                                                                                                           these products in accordance with 21
                                                   evaluated for use as a consumer                                                                                antiseptic ingredients in consumer
                                                                                                           CFR 330.11, limiting the scope of review
                                                   antiseptic rub in this proposed rule:                                                                          antiseptic rubs. We estimate that the
                                                                                                           necessary to obtain approval.
                                                                                                                                                                  proposed rule will reduce exposure to
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                   Alcohol (ethanol or ethyl alcohol),
                                                   isopropyl alcohol, and benzalkonium                     F. Costs and Benefits                                  potentially unsafe or ineffective
                                                   chloride (sometimes referred to as                        The impact of the proposed rule on                   antiseptic ingredients in consumer
                                                   ADBAC). As part of this proposed rule,                  the OTC consumer antiseptic rub                        antiseptic rubs by between 110 and
                                                   FDA evaluated new data submitted after                  product industry will depend on the                    67,272,847 pounds.1
                                                   publication of the 1994 TFM for each of                 outcome of tests to determine whether                    1 As was the case with estimated costs, there is
                                                   these three ingredients.                                three antiseptic ingredients—alcohol,                  a great disparity in the estimated reductions in
                                                     In the 1994 TFM (59 FR 31402 at                       isopropyl alcohol, and benzalkonium                    exposure to antiseptic ingredients. The lower bound
                                                   31435), alcohol (60 to 95 percent) was                  chloride—are GRAS/GRAE. It is                          (110 pounds) represents the estimated reduction in



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                                                                                    Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                                                42915

                                                                                                                                          Total reduction in antiseptic                      Total costs annualized
                                                               Summary of costs and benefits                                                                                                                          Total one-time costs
                                                                                                                                              ingredient exposure                                over 10 years
                                                                  of the proposed rule                                                                                                                                    (in millions)
                                                                                                                                                  (in pounds)                                      (in millions)

                                                   Total ..................................................................   110 and 67,272,847 .........................................   $0.04 to $5.52 (3%) ..   $0.34 and $47.09.
                                                                                                                                                                                             $0.05 to $6.70 (7%) ..



                                                   II. Introduction                                                           monograph stage) retains the concepts                          as health care personnel hand washes.
                                                                                                                              of Categories I, II, and III.                                  (See section II.C about the term
                                                     In the following sections, we provide                                       At the final monograph stage, FDA                           ‘‘antimicrobial soaps.’’) In contrast, in
                                                   a brief description of terminology used                                    does not use the terms ‘‘Category I,’’                         the 1994 TFM, we proposed that both
                                                   in the OTC Drug Review regulations and                                     ‘‘Category II,’’ and ‘‘Category III.’’ In                      antiseptic hand washes (i.e., consumer
                                                   an overview of OTC topical antiseptic                                      place of Category I, the term                                  antiseptic washes) and health care
                                                   drug products, and then describe in                                        ‘‘monograph conditions’’ is used; in                           personnel hand washes should have the
                                                   more detail the OTC consumer                                               place of Categories II and III, the term                       same effectiveness testing and
                                                   antiseptic rubs that are the subject of                                    ‘‘nonmonograph conditions’’ is used.                           performance criteria. In response to the
                                                   this proposed rule.                                                                                                                       1994 TFM, we received submissions
                                                                                                                              B. Topical Antiseptics                                         from the public arguing that consumer
                                                   A. Terminology Used in the OTC Drug
                                                   Review Regulations                                                            The OTC topical antimicrobial                               products serve a different purpose and
                                                                                                                              rulemaking has had a broad scope,                              should continue to be distinct from
                                                   1. Proposed, Tentative Final, and Final                                    encompassing drug products that may                            health care antiseptics. We agreed, and
                                                   Monographs                                                                 contain the same active ingredients, but                       in the 2013 Consumer Wash PR and in
                                                                                                                              that are labeled and marketed for                              the health care antiseptic proposed rule
                                                      To conform to terminology used in                                       different intended uses. In 1974, the                          published in the Federal Register of
                                                   the OTC Drug Review regulations                                            Agency published an ANPR for topical                           May 1, 2015 (80 FR 25166) (2015 Health
                                                   (§ 330.10 (21 CFR 330.10)), the                                            antimicrobial products that                                    Care Antiseptic PR), our evaluation of
                                                   September 1974 advance notice of                                           encompassed products for both health                           OTC antiseptic drug products has been
                                                   proposed rulemaking (39 FR 33103,                                          care and consumer use. The 1974 ANPR                           further subdivided into consumer
                                                   September 13, 1974) (1974 ANPR) was                                        covered seven different intended uses                          antiseptics and health care antiseptics,
                                                   designated as a ‘‘proposed monograph.’’                                    for these products: (1) Antimicrobial                          which are used by health care
                                                   Similarly, the notices of proposed                                         soap; (2) health care personnel hand                           professionals in a hospital setting or
                                                   rulemaking, which were published in                                        wash; (3) patient preoperative skin                            other health care situations outside the
                                                   the Federal Register of January 6, 1978                                    preparation; (4) skin antiseptic; (5) skin                     hospital. We believe that these
                                                   (43 FR 1210) (the 1978 TFM), and in the                                    wound cleanser; (6) skin wound                                 categories are distinct based on the
                                                   Federal Register of June 17, 1994 (59 FR                                   protectant; and (7) surgical hand scrub                        proposed-use setting, target population,
                                                   31402) (the 1994 TFM), were each                                           (39 FR 33103 at 33140). FDA                                    and the fact that each setting presents a
                                                   designated as a ‘‘tentative final                                          subsequently identified skin antiseptics,                      different level of risk for infection. For
                                                   monograph’’ (see table 1 in section                                        skin wound cleansers, and skin wound                           example, in health care settings, the
                                                   III.A). The present proposed rule, which                                   protectants as antiseptics used primarily                      patient population is generally more
                                                   is a proposal to amend the 1994 TFM                                        by consumers for first aid use and                             susceptible to infection than the general
                                                   with respect to consumer antiseptic rub                                    referred to them collectively as ‘‘first aid                   U.S. consumer population (i.e., the
                                                   drug products, is also designated as a                                     antiseptics.’’ We published a separate                         population who use consumer
                                                   ‘‘tentative final monograph.’’                                             TFM covering the first aid antiseptics in                      antiseptic rubs or washes). Furthermore,
                                                   2. Category I, II, and III Classifications                                 the Federal Register of July 22, 1991 (56                      the purpose of use is generally different;
                                                                                                                              FR 33644) (1991 First Aid TFM). Thus,                          health care antiseptics are primarily
                                                      The OTC drug procedural regulations                                     first aid antiseptics are not discussed                        used to protect the patient (rather than
                                                   in § 330.10 use the terms ‘‘Category I’’                                   further in this document.                                      just the user), whereas consumer
                                                   (generally recognized as safe and                                             The four remaining categories of                            antiseptics are generally applied to
                                                   effective and not misbranded),                                             topical antimicrobials were addressed in                       protect the user. In the health care
                                                   ‘‘Category II’’ (not generally recognized                                  the 1994 TFM. The 1994 TFM covered:                            setting, the potential for spread of
                                                   as safe and effective or misbranded),                                      (1) Antiseptic hand wash (i.e., consumer                       infection and the potential for serious
                                                   and ‘‘Category III’’ (available data are                                   hand wash); (2) health care personnel                          outcomes of infection may be relatively
                                                   insufficient to classify as safe and                                       hand wash; (3) patient preoperative skin                       higher than in the U.S. consumer
                                                   effective, and further testing is                                          preparation; and (4) surgical hand scrub                       setting. Therefore, the safety and
                                                   required). Section 330.10 provides that                                    (59 FR 31402 at 31442). In the 1994                            effectiveness should be evaluated
                                                   any testing necessary to resolve the                                       TFM, FDA also identified a new                                 separately for each intended use to
                                                   safety or effectiveness issues that                                        category of antiseptics for use by the                         support a GRAS/GRAE determination.
                                                   formerly resulted in a Category III                                        food industry and requested relevant                              As we did in the 2013 Consumer
                                                   classification, and submission to FDA of                                   data and information (59 FR 31402 at                           Wash PR, we refer to the group of
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                                                   the results of that testing or any other                                   31440). Antiseptics for use by the food                        products covered by this proposed rule
                                                   data, must be done during the OTC drug                                     industry are not discussed further in                          as ‘‘consumer antiseptics.’’ Consumer
                                                   rulemaking process before the                                              this document.                                                 antiseptic drug products addressed by
                                                   establishment of a final monograph (i.e.,                                     In the 1974 ANPR, we distinguished                          this proposal include consumer
                                                   a final rule or regulation). Therefore,                                    antimicrobial soaps used by consumers                          antiseptic hand rubs (commonly called
                                                   this proposed rule (the tentative final                                    from professional use antiseptics, such                        hand sanitizers) and antiseptic wipes.

                                                   exposure to ingredients which FDA has determined                           rubs and few products contain such GRAS/GRAE
                                                   are not GRAS/GRAE for use in consumer antiseptic                           ingredients.



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                                                   42916                   Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules

                                                   These products may be used by                           used when soap and water are not                       complete requests to defer rulemaking.
                                                   consumers for personal use on a                         available. Consumer antiseptic rubs                    In assessing whether to defer further
                                                   frequent basis, even multiple times per                 include ‘‘hand sanitizers’’ and wipes.                 rulemaking for a particular active
                                                   day. These products do not include                      The 1994 TFM also did not distinguish                  ingredient to allow for additional time
                                                   personal care products intended to be                   between consumer antiseptic washes                     for studies to generate new data and
                                                   used with water, such as antibacterial                  and rubs, and health care hand washes                  information, FDA will consider the data
                                                   soaps, hand washes, and body washes.                    and rubs. This proposed rule covers                    already in the docket, along with any
                                                   C. This Proposed Rule Covers Only                       only consumer antiseptic rubs.                         information that is provided in any
                                                   Consumer Antiseptic Rubs                                Completion of the monograph for                        requests. FDA will determine whether
                                                                                                           consumer antiseptic rubs and certain                   the sum of the data, if submitted in a
                                                      In this proposed rule, FDA proposes                  other monographs for the active                        timely fashion, is likely to be adequate
                                                   the establishment of a monograph for                    ingredient triclosan are subject to a                  to provide all the data that are necessary
                                                   OTC consumer antiseptics that are                       Consent Decree entered by the U.S.                     to make a GRAS/GRAE determination.
                                                   intended for use as an antiseptic rub,                  District Court for the Southern District                  We note that the OTC Drug Review is
                                                   but that are not identified as ‘‘first aid              of New York on November 21, 2013, in                   a public process and any data submitted
                                                   antiseptics’’ in the 1991 First Aid TFM.                Natural Resources Defense Council, Inc.                is public. There is no requirement or
                                                   When the 1994 TFM was published, the                    v. United States Food and Drug                         expectation that more than one set of
                                                   term for daily consumer use antiseptics                 Administration, et al., 10 Civ. 5690                   data will be submitted to the docket for
                                                   was changed to ‘‘antiseptic hand wash.’’                (S.D.N.Y.).                                            a particular active ingredient, and it
                                                   In response to this change, we received
                                                                                                           D. Comment Period                                      does not matter who submits the data.
                                                   comments that the term ‘‘antiseptic
                                                   hand wash’’ did not include all of the                                                                         In addition, data and other information
                                                   consumer products on the market, such                      Because of the complexity of this                   for a single active ingredient may be
                                                   as hand rubs and body washes.                           proposed rule, we are providing a                      submitted by any interested party and
                                                   Therefore, in this proposed rule, we use                comment period of 180 days. Moreover,                  not all data for an ingredient must be
                                                   the term ‘‘consumer antiseptic,’’ which                 new data or information may be                         submitted by a single party.
                                                   is a broad term and meant to include all                submitted to the docket via http://                    III. Background
                                                   of the types of antiseptic products used                www.regulations.gov (see ADDRESSES)
                                                   on a frequent or daily basis by                         within 12 months of publication, and                     In this section, we describe the
                                                   consumers. However, this proposed rule                  comments on any new data or                            significant rulemakings and public
                                                   covers only consumer antiseptic rubs                    information may then be submitted to                   meetings relevant to this proposed rule,
                                                   and does not include consumer                           the docket for an additional 60 days (see              and how we are responding to
                                                   antiseptic hand washes or body washes.                  § 330.10(a)(7)(iii) and (iv)). In addition,            comments received in response to the
                                                      The 1994 TFM did not distinguish                     FDA will also consider requests to defer               1994 TFM.
                                                   between products that we are now                        further rulemaking with respect to a                   A. Significant Rulemakings Relevant to
                                                   calling ‘‘antiseptic washes’’ and                       specific active ingredient for use as a                This Proposed Rule
                                                   products we are now calling ‘‘antiseptic                consumer antiseptic rub to allow the
                                                   rubs.’’ Washes are rinsed off with water,               submission of new safety or                              A summary of the significant Federal
                                                   and include consumer hand washes and                    effectiveness data to the record if these              Register publications relevant to this
                                                   body washes, and health care personnel                  requests are submitted to the docket                   proposed rule is provided in table 1.
                                                   hand washes and surgical hand scrubs.                   within the initial 180-day comment                     Other publications relevant to this
                                                   Rubs are sometimes referred to as                       period. FDA will review all data and                   proposed rule are available at http://
                                                   ‘‘leave-on products’’ and are not rinsed                information submitted to the record in                 www.regulations.gov in FDA Docket No.
                                                   off after use. They are intended to be                  conjunction with all timely and                        1975–N–0012.

                                                            TABLE 1—SIGNIFICANT RULEMAKING PUBLICATIONS RELATED TO CONSUMER ANTISEPTIC DRUG PRODUCTS 1
                                                            Federal Register Notice                                                                 Information in notice

                                                   1974 ANPR (September 13, 1974, 39 FR                We published an ANPR to establish a monograph for OTC topical antimicrobial drug products, to-
                                                     33103).                                             gether with the recommendations of the Advisory Review Panel on OTC Topical Antimicrobial I
                                                                                                         Drug Products (Antimicrobial I Panel or Panel), which was the advisory review panel responsible
                                                                                                         for evaluating data on the active ingredients in this drug class.
                                                   1978 Antimicrobial TFM (January 6, 1978,            We published our tentative conclusions and proposed effectiveness testing for the drug product cat-
                                                     43 FR 1210).                                        egories evaluated by the Panel. The 1978 TFM reflects our evaluation of the recommendations of
                                                                                                         the Panel and comments and data submitted in response to the Panel’s recommendations.
                                                   1982 Alcohol ANPR (May 21, 1982, 47                 We published an ANPR to establish a monograph for alcohol drug products for topical antimicrobial
                                                     FR 22324).                                          use, together with the recommendations of the Advisory Review Panel on OTC Miscellaneous Ex-
                                                                                                         ternal Drug Products, which was the advisory review panel responsible for evaluating data on the
                                                                                                         active ingredients in this drug class.
                                                   1991 First Aid TFM (July 22, 1991, 56 FR            We amended the 1978 TFM to establish a separate monograph for OTC first aid antiseptic prod-
                                                     33644).                                             ucts. In the 1991 First Aid TFM, we proposed that first aid antiseptic drug products be indicated
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                                                                                                         for the prevention of skin infections in minor cuts, scrapes, and burns.
                                                   1994 Health Care Antiseptic TFM (June               We amended the 1978 TFM to establish a separate monograph for the group of products that were
                                                     17, 1994, 59 FR 31402).                             referred to as OTC topical health care antiseptic drug products. These antiseptics are generally
                                                                                                         intended for use by health care professionals.
                                                                                                       In that proposed rule, we also recognized the need for antibacterial personal cleansing products for
                                                                                                         consumers to help prevent cross-contamination from one person to another and proposed a new
                                                                                                         antiseptic category for consumer use: Antiseptic hand wash.




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                                                                           Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                                    42917

                                                    TABLE 1—SIGNIFICANT RULEMAKING PUBLICATIONS RELATED TO CONSUMER ANTISEPTIC DRUG PRODUCTS 1—Continued
                                                            Federal Register Notice                                                                 Information in notice

                                                   2013 Consumer Antiseptic Wash TFM                   We issued a proposed rule to amend the 1994 TFM and to establish data standards for determining
                                                     (December 17, 2013, 78 FR 76444).                   whether OTC consumer antiseptic washes are GRAS/GRAE.
                                                                                                       In that proposed rule, we proposed that additional safety and effectiveness data are necessary to
                                                                                                         support the safety and effectiveness of consumer antiseptic wash active ingredients.
                                                   2015 Health Care Antiseptics TFM (May               We issued a proposed rule to amend the 1994 TFM and to establish data standards for determining
                                                     1, 2015, 80 FR 25166 ).                             whether OTC health care antiseptics are GRAS/GRAE.
                                                                                                       In that proposed rule, we proposed that additional safety and effectiveness data are necessary to
                                                                                                         support the safety and effectiveness of health care antiseptic active ingredients.
                                                     1 The publications listed in table 1 can be found at the FDA’s ‘‘Status of OTC Rulemakings’’ Web site available at http://www.fda.gov/Drugs/De-
                                                   velopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm070821.htm. The publications
                                                   dated after 1993 can also be found in the Federal Register at https://www.federalregister.gov.


                                                   B. Public Meetings Relevant to This                     been four meetings of the NDAC and                     These meetings are summarized in table
                                                   Proposed Rule                                           one public feedback meeting that are                   2.
                                                     In addition to the Federal Register                   relevant to the discussion of consumer
                                                   publications listed in table 1, there have              antiseptic rub safety and effectiveness.

                                                                                                           TABLE 2—RELEVANT PUBLIC MEETINGS
                                                            Date and type of meeting                                                                 Topic of discussion

                                                   January 1997 NDAC Meeting (Joint meet-              Antiseptic and antibiotic resistance in relation to an industry proposal for consumer and health care
                                                     ing with the Anti-Infective Drugs Advi-             antiseptic effectiveness testing (Health Care Continuum Model) (Refs. 6, 7).
                                                     sory Committee) (January 6, 1997, 62
                                                     FR 764).
                                                   March 2005 NDAC Meeting (February 18,               The use of surrogate endpoints and study design issues for the in vivo testing of health care
                                                     2005, 70 FR 8376).                                  antiseptics (Ref. 8).
                                                   October 2005 NDAC Meeting (September                Benefits and risks of consumer antiseptics. NDAC expressed concern about the pervasive use of
                                                     15, 2005, 70 FR 54560).                             consumer antiseptic washes where there are potential risks and no demonstrable benefit. To
                                                                                                         demonstrate a clinical benefit, NDAC recommended clinical outcome studies to show that anti-
                                                                                                         septic washes are superior to nonantibacterial soap and water (Ref. 9).
                                                   November 2008 Public Feedback Meeting               Demonstration of the effectiveness of consumer antiseptics (Ref. 10).
                                                   September 2014 NDAC Meeting (July 29,               Safety testing framework for health care antiseptic active ingredients (Ref. 11).
                                                     2014, 79 FR 44042).



                                                   C. Comments Received by FDA                             formulation testing and labeling                       IV. Active Ingredients With Insufficient
                                                      In response to the 1994 TFM, FDA                     conditions proposed in the 1994 TFM,                   Evidence of Eligibility for the OTC Drug
                                                   received approximately 160 comments                     particularly in light of the data proposed             Review
                                                   from drug manufacturers, trade                          in this proposed rule as necessary to                     In this section of the proposed rule,
                                                   associations, academia, testing                         support a GRAS/GRAE determination.                     we describe the requirements for
                                                   laboratories, consumers, health                         Comments that were received in                         eligibility for the OTC Drug Review and
                                                   professionals, and law firms. In                        response to the 1994 TFM regarding                     the ingredients submitted to the OTC
                                                   response to the 2013 Consumer Wash                      other intended uses of the active                      Drug Review that lack adequate
                                                   PR, we received safety data regarding                   ingredients are addressed in the 2013                  evidence of eligibility for evaluation as
                                                   benzalkonium chloride that is relevant                  Consumer Wash PR (78 FR 76444), or                     consumer antiseptic rub products.
                                                   to this ingredient’s use in a consumer                  the 2015 Health Care Antiseptic PR (80
                                                                                                                                                                  A. Eligibility for the OTC Drug Review
                                                   rub and these data are evaluated in                     FR 25166), or will be addressed in
                                                   section VIII.D.2. Copies of the comments                future documents related to those other                   An OTC drug is covered by the OTC
                                                   received are on public display at http://               uses.                                                  Drug Review if its conditions of use
                                                   www.regulations.gov (see ADDRESSES).                                                                           existed in the OTC drug marketplace on
                                                                                                              This proposed rule constitutes FDA’s
                                                   Because only consumer antiseptic rubs                                                                          or before May 11, 1972 (37 FR 9464)
                                                                                                           evaluation of submissions made in
                                                   are discussed in this proposed rule, only                                                                      (Ref. 13).2 Conditions of use include,
                                                                                                           response to the 1994 TFM to support the                among other things, active ingredient,
                                                   those comments and data received in
                                                                                                           safety and effectiveness of OTC                        dosage form and strength, route of
                                                   response to the 1994 TFM that are
                                                   related to consumer antiseptic rub                      consumer antiseptic rub active                         administration, and specific OTC use or
                                                                                                           ingredients (Ref. 12). We reviewed the                 indication of the product (see
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                                                   active ingredients are addressed. We
                                                   also received comments related to final                 available literature and data and the                  § 330.14(a)). To determine eligibility for
                                                   formulation testing and labeling                        comments submitted to the rulemaking                   the OTC Drug Review, FDA typically
                                                   conditions proposed in the 1994 TFM.                    and are proposing that adequate data for
                                                   If in the future we determine that there                a determination of safety and                            2 Also, note that drugs initially marketed in the

                                                   are monograph consumer antiseptic rub                   effectiveness are not yet available for the            United States after the OTC Drug Review began in
                                                                                                           consumer antiseptic rub active                         1972 and drugs without any U.S. marketing
                                                   active ingredients that are GRAS/GRAE,                                                                         experience can be considered in the OTC
                                                   we will address these comments. We                      ingredients.                                           monograph system based on submission of a Time
                                                   invite further comment on the final                                                                            and Extent Application. (See § 330.14).



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                                                   42918                          Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules

                                                   must have actual product labeling or a                                  •   Sodium oxychlorosene                                                given OTC use (i.e., nonmonograph)
                                                   facsimile of labeling that documents the                                •   Tribromsalan                                                        because of lack of evidence of
                                                   conditions of marketing of a product                                    •   Triclocarban                                                        effectiveness, lack of evidence of safety,
                                                   prior to May 1972 (see § 330.10(a)(2)).                                 •   Triclosan                                                           or both. In the 1994 TFM (59 FR 31402
                                                   FDA considers a drug that is ineligible                                 •   Triple dye                                                          at 31435), FDA proposed that the active
                                                   for inclusion in the OTC monograph                                      •   Undecoylium chloride iodine                                         ingredients fluorosalan,
                                                   system to be a new drug that will                                           complex                                                             hexachlorophene, phenol (greater than
                                                   require FDA approval through the NDA                                       Following the publication of the 1994                                1.5 percent), and tribromsalan be found
                                                   process. Ineligibility for use as a                                     TFM, FDA received submissions for the                                   not GRAS/GRAE for the uses referred to
                                                   consumer antiseptic rub does not affect                                 first time requesting that the following                                in the 1994 TFM as antiseptic hand
                                                   eligibility under any other OTC drug                                    compounds be added to the monograph                                     wash and health care personnel hand
                                                   monograph.                                                              (Refs. 14 through 20):                                                  wash. None of these ingredients
                                                   B. Eligibility of Certain Active                                        • Polyhexamethylene biguanide                                           currently have adequate evidence of
                                                   Ingredients for the OTC Drug Review                                     • Benzalkonium cetyl phosphate                                          eligibility for use in a consumer
                                                                                                                           • Cetylpyridinium chloride                                              antiseptic rub (see section IV.B).
                                                      The following list includes those                                    • Calicylic acid, sodium hypochlorite
                                                   active ingredients that were addressed                                                                                                          Consequently, effectiveness and safety
                                                                                                                           • Tea tree oil
                                                   in the 1994 TFM for use as an antiseptic                                                                                                        information that has been submitted to
                                                                                                                           • Combination of potassium vegetable
                                                   hand wash or health care personnel                                         oil solution, phosphate sequestering                                 the rulemaking for these consumer
                                                   hand wash, and which currently do not                                      agent, and triethanolamine                                           antiseptic rub active ingredients are not
                                                   have adequate evidence of eligibility for                                                                                                       discussed in this proposed rule for such
                                                                                                                              These compounds were not addressed
                                                   evaluation under the OTC Drug Review                                                                                                            use. However, if documentation of the
                                                                                                                           in prior FDA documents related to the
                                                   for use in a consumer antiseptic rub.                                                                                                           type described in section IV.A is
                                                                                                                           monograph and were not evaluated for
                                                   Our review of the labeling submitted to                                                                                                         submitted, these active ingredients
                                                                                                                           antiseptic hand wash use by the
                                                   the Panel or to FDA at a later time did                                                                                                         could be determined to be eligible for
                                                                                                                           Antimicrobial I Panel. The submissions
                                                   not identify evidence demonstrating                                                                                                             evaluation for use as a consumer
                                                                                                                           received by the Agency to date do not
                                                   eligibility for the following active                                                                                                            antiseptic rub.
                                                                                                                           include documentation demonstrating
                                                   ingredients:
                                                                                                                           the eligibility of any of these                                         VI. Summary of Proposed
                                                   • Benzethonium chloride                                                 compounds for inclusion in the topical
                                                   • Chloroxylenol                                                                                                                                 Classifications of OTC Consumer
                                                                                                                           antimicrobial monograph (Ref. 21).
                                                   • Chlorhexidine gluconate 3                                             Because of their lack of eligibility,
                                                                                                                                                                                                   Antiseptic Rub Active Ingredients
                                                   • Cloflucarban
                                                   • Fluorosalan                                                           effectiveness and safety information that                                 Table 3 lists the OTC consumer
                                                   • Hexachlorophene                                                       has been submitted to the rulemaking                                    antiseptic active ingredients eligible for
                                                   • Hexylresorcinol                                                       for these consumer antiseptic rub active                                evaluation under the OTC Drug Review
                                                   • Iodine complex (ammonium ether                                        ingredients are not discussed in this                                   for use in consumer rubs, the
                                                     sulfate and polyoxyethylene sorbitan                                  proposed rule for such use. However, if                                 classification proposed in the 1994
                                                     monolaurate)                                                          documentation of the type described in                                  TFM, and the classification being
                                                   • Iodine complex (phosphate ester of                                    section IV.A is submitted, these active                                 proposed in this rulemaking. For each
                                                     alkylaryloxy polyethylene glycol)                                     ingredients could be determined to be                                   active ingredient, data that have been
                                                   • Methylbenzethonium chloride                                           eligible for evaluation for use as a                                    submitted to the public docket (for the
                                                   • Nonylphenoxypoly (ethyleneoxy)                                        consumer antiseptic rub.
                                                                                                                                                                                                   topical antimicrobial rulemaking) and
                                                     ethanoliodine                                                         V. Ingredients Previously Proposed as                                   evaluated by FDA and the description of
                                                   • Phenol (less than 1.5 percent)                                        Not Generally Recognized as Safe and                                    data still lacking in the administrative
                                                   • Phenol (greater than 1.5 percent)
                                                                                                                           Effective                                                               record are described in detail in section
                                                   • Poloxamer iodine complex
                                                   • Povidone-iodine 5 to 10 percent                                         FDA may determine that an active                                      VIII.
                                                   • Secondary amyltricresols                                              ingredient is not GRAS/GRAE for a
                                                      TABLE 3—CLASSIFICATION OF OTC CONSUMER ANTISEPTIC RUB ACTIVE INGREDIENTS IN THE 1994 TFM AND IN THIS
                                                                                              PROPOSED RULE
                                                                                                                                                                                                                           1994 TFM                This proposed
                                                                                                                       Active ingredient                                                                                   proposal 1                   rule

                                                   Alcohol 60 to 95 percent .........................................................................................................................................   I 2 ....................   IIISE 3
                                                   Isopropyl alcohol 70 to 91.3 percent ......................................................................................................................          IIIE .................     IIISE
                                                   Benzalkonium chloride ............................................................................................................................................   IIISE ...............      IIISE
                                                     1 Because the 1994 TFM did not describe antiseptic hand washes and rubs separately, the 1994 TFM classification was for use as an anti-
                                                   septic hand wash or health care antiseptic hand wash.
                                                     2 ‘‘I’’ denotes a classification that an active ingredient has been shown to be safe and effective.
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                                                     3 ‘‘III’’ denotes a classification that additional data are needed. ‘‘S’’ denotes safety data needed. ‘‘E’’ denotes effectiveness data needed.




                                                     In the 1994 TFM, alcohol was                                          alcohol was classified as Category IIIE,                                classified as Category IIISE for use as an
                                                   classified as Category I, isopropyl                                     and benzalkonium chloride was                                           antiseptic hand wash or health care

                                                     3 Chlorhexidine gluconate 4 percent aqueous                           and was not included in the 1994 TFM (59 FR                             this active ingredient is eligible for the topical
                                                   solution was found to be ineligible for inclusion in                    31402 at 31413). We have not received any new                           antimicrobial monograph.
                                                   the monograph for any health care antiseptic use                        information since the 1994 TFM demonstrating that



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                                                                           Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                           42919

                                                   personnel hand wash. However, in this                   demonstrating the impact of consumer                   determination for any consumer
                                                   proposed rule, we are proposing to                      antiseptic rubs on infection rates are not             antiseptic rub active ingredient under
                                                   classify all three ingredients as Category              available. In contrast to consumer                     either the final formulation effectiveness
                                                   IIISE for use as a consumer antiseptic                  washes, for which we are asking for                    testing criteria proposed in the 1994
                                                   rub because additional effectiveness and                clinical outcome data to support the                   TFM or under the GRAE criteria
                                                   safety data are needed to classify each                 benefit of these products, given the                   proposed in this proposed rule (see
                                                   ingredient as GRAS/GRAE for this use.                   easily available alternative of washing                table 4).
                                                                                                           with soap and water, there is no similar                  We have also evaluated all the studies
                                                   VII. Effectiveness (Generally
                                                                                                           readily available alternative for                      that were submitted to the OTC Drug
                                                   Recognized as Effective) Determination
                                                                                                           consumer antiseptic rubs. A clinical                   Review and have searched the
                                                      OTC regulations (§§ 330.10(a)(4)(ii)                 outcome trial comparing the use of                     published literature for studies
                                                   and 314.126(b) (21 CFR 330.10(a)(4)(ii)                 consumer antiseptic rubs to standard                   performed in consumer use settings that
                                                   and 314.126(b))) define the standards for               hand washing with soap and water has                   would provide the direct evidence of a
                                                   establishing that an OTC drug                           less applicability given that consumer                 clinical benefit from the use of
                                                   containing a particular active ingredient               antiseptic rubs are not generally used in              consumer antiseptic rubs (Ref. 24). We
                                                   would be GRAE for its intended use.                     situations in which soap and water are                 are defining a clinical benefit here as a
                                                   These regulations provide that                          a readily available alternative.                       reduction in the number of infections in
                                                   supporting investigations must be                       Therefore, we are currently                            a population that uses the consumer
                                                   adequate and well-controlled, and able                  recommending the use of clinical                       antiseptic rubs. Although a definitive
                                                   to distinguish the effect of a drug from                simulation studies because they are a                  link between consumer antiseptic rubs
                                                   other influences such as a spontaneous                  practical means to assess the general                  and reduced infection rates has not been
                                                   change in the course of the disease,                    effectiveness of consumer antiseptic                   established, some public health agencies
                                                   placebo effect, or biased observation. In               rubs.                                                  recommend the use of consumer
                                                   general, such investigations include                       FDA has already relied on clinical                  antiseptic rubs when soap and water are
                                                   controls that are adequate to provide an                simulation studies as a standard for                   not available (Refs. 22, 23).
                                                   assessment of drug effect, are adequate                 evaluating effectiveness of hand
                                                   measures to minimize bias, and use                      antiseptic drug products approved                      A. Evaluation of Effectiveness Data
                                                   adequate analytical methods to                          under NDAs, which are proven to be an                  1. Clinical Simulation Studies
                                                   demonstrate effectiveness. For active                   effective measure to lower the surgical
                                                   ingredients being evaluated in the OTC                  site infection rate (Refs. 25 through 27).                Most of the available data to support
                                                   Drug Review, this means that a                          In addition, in our recently revised                   the effectiveness of consumer antiseptic
                                                   demonstration of the contribution of the                standards for evaluating the                           rubs are based on clinical simulation
                                                   active ingredient to any effectiveness                  effectiveness of health care antiseptics               studies, such as the ones described in
                                                   observed is required before an                          published in May 2015 (80 FR 25166),                   the 1994 TFM (59 FR 31402 at 31444).
                                                   ingredient can be determined to be                      we relied on clinical simulation studies               The premise behind these studies as
                                                   GRAE for OTC drug use.                                  based on the recommendations of the                    described in the 1994 TFM is that
                                                      In the 1994 TFM, we continued to                     March 2005 NDAC. In contrast, in the                   bacterial reductions translate to a
                                                   apply a log reduction standard (a                       2013 Consumer Wash PR, we proposed                     reduced risk for infection. However,
                                                   clinical simulation standard) for                       an efficacy standard for consumer                      currently, there are no clinical data that
                                                   establishing effectiveness of consumer                  antiseptic washes that relies on clinical              demonstrate that the specific bacterial
                                                   antiseptics originally proposed in the                  outcome trials, also based on NDAC                     log reductions that we have relied upon
                                                   1978 TFM (59 FR 31402 at 31412) for                     recommendations. As noted previously,                  as a demonstration of effectiveness lead
                                                   the proposed intended use of decreasing                 consumer antiseptic rub products are                   to a specific reduction in infections. In
                                                   bacteria on the skin. The 1994 TFM log                  generally used when soap and water are                 our view, although a lower number of
                                                   reduction standard for effectiveness is                 not available, so consumers lack a                     bacteria on hands may not directly
                                                   based on a surrogate endpoint (i.e.,                    readily available alternative. As such,                translate into a reduced chance of
                                                   number of bacteria removed from the                     we continue to propose a log reduction                 infection, a reduced bacterial load does
                                                   skin), rather than a clinical outcome                   standard to demonstrate the general                    decrease the opportunity for infection
                                                   (e.g., reduction in the number of                       recognition of effectiveness for                       when used in situations with no other
                                                   infections). Although the test methods                  consumer antiseptic rubs in accordance                 options for hand cleansing. In this case,
                                                   proposed in the 1994 TFM are intended                   with our standards for health care                     rather than comparing using consumer
                                                   to evaluate the effectiveness of                        antiseptics, which contain the same                    antiseptic rubs to hand washing with
                                                   antiseptic final formulations, this type                active ingredients (i.e., alcohol,                     soap and water, we are comparing them
                                                   of clinical simulation testing, when                    isopropyl alcohol, and benzalkonium                    to the alternative of not cleaning the
                                                   adequately controlled, can also be used                 chloride). Details of our current                      hands. In addition, because we believe
                                                   to demonstrate that an active ingredient                proposed log reduction standard are                    that the consumer antiseptic rubs are
                                                   is GRAE for use in a consumer                           outlined in section VII.B.                             intended to provide immediate
                                                   antiseptic rub product. As reflected by                    As discussed in section VII.A, we                   reduction of bacteria rather than a
                                                   the recommendations of some public                      have evaluated the available                           persistent benefit, we are proposing that
                                                   health agencies, FDA believes that                      effectiveness studies that were                        log reductions be measured after a
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                                                   consumer antiseptic rubs are generally                  submitted to the OTC Drug Review or                    single bacterial challenge (see table 4),
                                                   used when hands are not visibly soiled,                 retrieved through the published                        rather than after repeated
                                                   and soap and water are not readily                      literature to support the effectiveness for            contamination.
                                                   available (Refs. 22, 23), for example, in               consumer antiseptic rubs using the log                    We have evaluated all clinical
                                                   settings such as school classrooms,                     reduction criteria most recently                       simulation studies that were submitted
                                                   childcare facilities, outdoors and                      proposed in the 1994 TFM (59 FR 31402                  to the OTC Drug Review for evidence of
                                                   various other public places (Ref. 24).                  at 31448) (Refs. 28 and 29). We found                  the effectiveness of consumer antiseptic
                                                   However, as discussed in section VII.A,                 that the available studies are not                     rub active ingredients under the log
                                                   data from adequately controlled studies                 adequate to support a GRAE                             reduction criteria proposed in the 1994


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                                                   42920                   Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules

                                                   TFM (59 FR 31402 at 31448) (Refs. 28                    literature that could potentially provide              written), and children and staff were
                                                   through 30). We also searched the                       evidence of effectiveness for the use of               asked to wash hands with plain soap
                                                   published literature for clinical                       consumer antiseptic rubs (Ref. 24). In                 and water, then rub with a 70-percent
                                                   simulation studies that assess consumer                 our view, clinical outcome studies                     alcohol-containing consumer antiseptic
                                                   antiseptic rubs’ effectiveness using the                evaluating the effectiveness of consumer               rub. Control groups followed the same
                                                   log reduction criteria in the 1994 TFM                  rubs should be adequately controlled                   hand-washing protocol without the
                                                   (Refs. 28 and 29).                                      and include a placebo or negative                      hand rub. The primary outcome was the
                                                      Overall, the studies used a variety of               control arm to show the effect of an                   rate of illness absenteeism. Parents were
                                                   study designs, including nonstandard                    active ingredient. Among the reviewed                  asked to report every episode when the
                                                   study designs. In some cases, data                      studies and published literature, there                child was absent from childcare because
                                                   submitted to the OTC Drug Review were                   are only a few studies that use these                  of illness, including the dates of
                                                   in the form of technical reports or                     specified parameters for evaluating the                absence, symptoms, and any medical
                                                   published articles without any study                    effectiveness of consumer antiseptic                   treatment. There were 0.37 absences per
                                                   details. There is insufficient information              rubs (Ref. 25). Overall, most of the                   100 child hours in the control group,
                                                   to evaluate the scientific merit of studies             studies were confounded,                               compared to 0.33 in the intervention
                                                   described in abstracts and technical                    underpowered, and/or not properly                      group. The effect of the intervention was
                                                   reports. Most importantly, none of the                  controlled.                                            a 12-percent reduction in absenteeism.
                                                   evaluated studies were adequately                          Our detailed review of consumer                     Based on the amount of hand rub used
                                                   controlled to demonstrate the                           hand rubs studies is available in Docket               during the study, the estimated
                                                   contribution of the active ingredient to                No. FDA–2016–N–0124 (Ref. 24). None                    frequency of hand rub use by each child
                                                   the effectiveness observed in the studies               of the alcohol-based hand rub studies                  was two to six times per day. Although
                                                   (43 FR 1210 at 1240) and, therefore,                    demonstrating benefit were adequately                  the study is well designed, there are
                                                   cannot be used to demonstrate that the                  controlled, thus they could not                        several significant limitations, such as
                                                   active ingredient tested is GRAE.                       demonstrate the contribution of the                    the following:
                                                      In general, the evaluated studies also               antiseptic active ingredient to the                       • No clinical or microbiological
                                                   had at least one of the following                       observed clinical outcome of reduced                   evaluation of illness.
                                                   deficiencies:                                           infection rates. In general, the studies                  • No specific infection was studied.
                                                      • Some studies that were described as                had the following design flaws:                           • Children kept home based on
                                                   using a standardized method (American                      • No comparison to vehicle.                         parent choice not addressed in the
                                                   Society for Testing and Materials                          • Small sample size.                                statistical analysis.
                                                   (ASTM) 4 or 1994 TFM) varied from                          • Lack of randomization, blinding, or                  • Degree of illness and symptoms to
                                                   these methods without explanation or                    both.                                                  keep child home varied among parents.
                                                   validation, and the majority of studies                    • Inadequate statistical power and, in              B. Current Standards: Studies Needed
                                                   did not provide sufficient information                  some cases, a failure to analyze results               To Support a Generally Recognized as
                                                   about critical aspects of the study                     for statistical significance.                          Effective Determination
                                                   conduct.                                                   • Inadequate description of
                                                                                                           methodology and data collection                          In the 1994 TFM, we proposed that
                                                      • Many studies did not include
                                                                                                           methods.                                               the effectiveness of antiseptic active
                                                   appropriate controls; for example, most
                                                   studies did not include a vehicle control                  • Failure to observe and document                   ingredients could be supported by a
                                                                                                           hand rub application technique.                        combination of in vitro studies and in
                                                   or an active control (59 FR 31402 at
                                                                                                              One clinical outcome study was                      vivo clinical simulation testing as
                                                   31448), and some studies that included
                                                                                                           identified that was randomized,                        described in 21 CFR 333.470 (59 FR
                                                   an active control failed to use the
                                                                                                           blinded, and placebo-controlled and                    31402 at 31444). In vitro studies are
                                                   control product according to its labeled
                                                                                                           was well designed to evaluate the                      designed to demonstrate the product’s
                                                   directions (59 FR 31402 at 31448).
                                                                                                           effectiveness of a particular antiseptic               spectrum and kinetics of antimicrobial
                                                      • Many studies did not provide
                                                                                                           active ingredient (Ref. 31). Although it               activity, as well as the potential for the
                                                   sufficient detail concerning neutralizer
                                                                                                           had several significant limitations that               development of resistance associated
                                                   use (43 FR 1210 at 1244) or validation
                                                                                                           prevent it from being sufficient to                    with product use. In vivo test methods
                                                   of neutralizer effectiveness.
                                                      • The studies evaluated a small                      establish effectiveness for use of the                 and evaluation criteria are based on the
                                                   number of subjects (59 FR 31402 at                      active ingredient in a consumer                        premise that bacterial reductions can be
                                                   31449).                                                 antiseptic rub, this study is the best                 adequately demonstrated using tests
                                                      • Some studies did not sample all of                 among the available studies that                       that simulate conditions of actual use
                                                   the time points specified by the test                   evaluate the impact of consumer                        for OTC consumer antiseptic rub
                                                   method (59 FR 31402 at 31448).                          antiseptic rubs on infections.                         products and that those reductions are
                                                      FDA’s detailed evaluation of the data                   This clinical outcome study                         reflective of bacterial reductions that
                                                   is filed in Docket No. FDA–2016–N–                      performed in Sweden compared the                       would be achieved during use. For the
                                                   0124, available at http://                              effectiveness of a 70-percent alcohol-                 use of antiseptic rubs, some public
                                                   www.regulations.gov.                                    containing consumer antiseptic rub as                  health agencies (Ref. 22) recommend
                                                                                                           an adjunct to hand washing with plain                  their use when soap and water are not
                                                   2. Clinical Outcome Studies                             soap and water in childcare centers (Ref.              available, and when there is no other
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                                                      Although we are not currently                        31). The study included 60 childcare                   reasonably available alternative for the
                                                   proposing to require clinical outcome                   centers (30 matched pairs) from 10                     consumer.
                                                   studies to support a GRAE                               counties with a mean number of 50                        In addition to the standards described
                                                   determination in this proposed rule,                    children in each center. One childcare                 in section VII.B, the effectiveness of
                                                   FDA identified and evaluated clinical                   center from each matched pair was                      consumer antiseptic rubs can be affected
                                                   outcome studies from the published                      randomized to the intervention group,                  by a variety of other factors related to
                                                                                                           with the other serving as the control                  product formulation and use. Section
                                                      4 General information about ASTM can be found        group. The intervention groups were                    VII.C discusses these factors, which
                                                   at https://www.astm.org/.                               provided instructions (verbal and                      includes the number of times per day a


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                                                                           Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                           42921

                                                   product is used and the volume used in                     Æ Bacteroides fragilis.                             labeling, that labeling would also be
                                                   each use.                                                  Æ Enterobacter species.                             relevant in the health care setting.
                                                                                                              Æ Burkholderia cepacia (ATCC 25416
                                                   1. In Vitro Studies                                     and ATCC 25608).                                       2. In Vivo Studies
                                                      The 1994 TFM proposed that the in                       Æ Escherichia coli (ATCC 11775 and                     Based on the recommendations of the
                                                   vitro antimicrobial activity of an active               ATCC 25922).                                           March 2005 NDAC meeting for health
                                                   ingredient could be demonstrated by a                      Æ Klebsiella pneumoniae (ATCC                       care antiseptic products, we continue to
                                                   determination of the in vitro spectrum                  13883 and ATCC 27736).                                 propose the use of bacterial log
                                                   of antimicrobial activity, minimum                         Æ Pseudomonas aeruginosa (ATCC                      reductions as a means of demonstrating
                                                   inhibitory concentration (MIC) testing                  15442 and ATCC 27853).                                 that consumer antiseptic rubs are GRAE
                                                   against 25 fresh clinical isolates and 25                  Æ Serratia marcescens (ATCC 8100                    (Ref. 8). The 1994 TFM also proposed
                                                   laboratory strains, and time-kill testing               and ATCC 14756).                                       final formulation testing for antiseptic
                                                   against 23 laboratory strains (59 FR                       Æ Campylobacter jejuni (ATCC 33291                  hand washes (59 FR 31402 at 31448).
                                                   31402 at 31444). Comments received in                   and ATCC 49943).                                       We are not discussing the final
                                                   response to the 1994 TFM objected to                       Æ Salmonella enterica Serovar                       formulation testing here because we are
                                                   the proposed in vitro testing                           Enteritidis (ATCC 13076) and Serovar                   not proposing that any of the
                                                   requirements, stating that they were                    Typhimurium (ATCC 14028). Serovar                      ingredients are GRAS/GRAE. Although,
                                                   overly burdensome (Ref. 32).                            refers to the subspecies classification of             as previously noted, these proposed test
                                                   Submissions of in vitro data submitted                  a group of microorganisms based on cell                methods are intended to evaluate the
                                                   to support the effectiveness of antiseptic              surface antigens.                                      effectiveness of antiseptic final
                                                   active ingredients were far less                           Æ Shigella sonnei (ATCC 9290 and                    formulations, this type of clinical
                                                   extensive than what was proposed in                     ATCC 25931).                                           simulation testing when adequately
                                                   the 1994 TFM (Ref. 33). Although we                        Gram-positive organisms.                            controlled can also be used to
                                                   agree that the in vitro testing proposed                   Æ Enterococcus faecalis (ATCC 19433                 demonstrate that an active ingredient is
                                                   in the 1994 TFM is not warranted for                    and ATCC 29212).                                       GRAE for use in a consumer antiseptic
                                                   testing every final formulation of an                      Æ Staphylococcus aureus (ATCC 6538                  rub product. Based on our experience
                                                   antiseptic product that contains a GRAE                 and ATCC 29213) and methicillin-                       with the approval of NDA antiseptic
                                                   ingredient, we believe that a GRAE                      resistant Staphylococcus aureus (ATCC                  products, and input from the March
                                                   determination for a consumer antiseptic                 33591 and ATCC 33592).                                 2005 and October 2005 NDAC meetings,
                                                   active ingredient should be supported                      Æ Streptococcus pyogenes (ATCC                      we recommend that the bacterial log
                                                   by adequate in vitro characterization of                14289 and ATCC 19615).                                 reduction studies used to demonstrate
                                                   the antimicrobial activity of the                          Æ Listeria monocytogenes (ATCC 7644                 that an active ingredient is GRAE for use
                                                   ingredient. In addition, we now propose                 and ATCC 19115).                                       in consumer antiseptic rub drug
                                                   the option of assessing the minimum                        Æ Streptococcus pneumoniae (ATCC                    products include the following:
                                                   bactericidal concentration (MBC) as an                  6303 and ATCC 49619).                                     • A vehicle control to show the
                                                   alternative to testing the MIC to                          We propose that a consumer                          contribution of the active ingredient to
                                                   demonstrate the broad spectrum activity                 antiseptic rub active ingredient be                    effectiveness. The test product should
                                                   of the antiseptic. The ability of an                    considered bactericidal at the                         be statistically superior to the vehicle
                                                   antiseptic to kill microorganisms, rather               concentration and contact time that                    control for the clinical simulation to be
                                                   than inhibit them, is more relevant for                 demonstrates a 3-log10 (99.9 percent) or               considered successful at showing that
                                                   a topical product. Because GRAE status                  greater reduction in bacterial viability               the test product is effective for use in
                                                   is a very broad determination that can                  for all the tested strains. This is the                consumer antiseptic rub products.
                                                   apply to many different formulations of                 same performance criterion used by the                 Products with vehicles that have
                                                   an active ingredient, we continue to                    Clinical and Laboratory Standards                      antimicrobial activity should consider
                                                   propose that an evaluation of the                       Institute (NCCLS, ‘‘Methods for                        using a negative control, such as saline,
                                                   spectrum and kinetics of antimicrobial                  Determining Bactericidal Activity of                   rather than a vehicle control.
                                                   activity of a consumer antiseptic rub                   Antimicrobial Agents; Approved                            • An active control to validate the
                                                   active ingredient should be evaluated by                Guideline,’’ NCCLS document M26–A,                     study conduct, to assure that the
                                                   the following testing:                                  1999).                                                 expected results are produced. For the
                                                      • A determination of the in vitro                       Despite the fact that the in vitro data             results to be valid, the active control
                                                   spectrum of antimicrobial activity                      submitted to support the effectiveness of              should meet the appropriate log
                                                   against potential pathogens (listed in                  antiseptic active ingredients were far                 reduction criteria.
                                                   this section) that may be encountered in                less extensive than proposed in the 1994                  • A sample size large enough to show
                                                   consumer use settings where soap and                    TFM, manufacturers may have data of                    statistically significant differences from
                                                   water are not readily available. MIC or                 this type on file from their own product               the results achieved using the vehicle,
                                                   MBC testing of 25 representative clinical               development programs that have not                     and meeting the threshold of at least a
                                                   isolates and 25 reference (e.g., American               been submitted to the rulemaking.                      70-percent success rate for the test
                                                   Type Culture Collection (ATCC)) strains                 Furthermore, published data may be                     product, including justification that the
                                                   of each of the microorganisms listed in                 available that would satisfy some or all               number of subjects tested is adequate for
                                                   this section.                                           these data requirement. Data from these                the test.
                                                      • Time-kill testing of each of the                                                                             • Use of an appropriate neutralizer in
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                                                                                                           in vitro studies, as well as data from the
                                                   following ATCC strains to assess how                    literature, may be used to inform                      all recovery media (i.e., sampling
                                                   rapidly the antiseptic active ingredient                labeling, in particular, if there are                  solution, dilution fluid, and plating
                                                   produces its effect. The dilutions and                  specific organisms for which an active                 media) and a demonstration of
                                                   time points tested should be relevant to                ingredient does not have significant                   neutralizer validation. The neutralizer is
                                                   the actual use pattern of the final                     activity. It is anticipated that if data               used to halt the antimicrobial activity of
                                                   product.                                                supporting use of a consumer antiseptic                the antiseptic after product exposure so
                                                      Gram-negative organisms.                             demonstrate lack of activity against a                 that a continued effect through
                                                      Æ Haemophilus influenzae.                            particular organism that requires                      subsequent dilution steps and culturing


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                                                   42922                   Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules

                                                   thereby does not create inflated log                     in this section should be evaluated                    a single application of the test product
                                                   reductions. The purpose of neutralizer                   using log reduction criteria similar to                rather than multiple applications. Given
                                                   validation is to show that the neutralizer               those proposed in the 1994 TFM (59 FR                  that we are no longer requiring a
                                                   used in the study is effective against the               31402 at 31448). Our current criteria are              cumulative antiseptic effect, the log
                                                   test and control products, and that it is                laid out in table 4. We have revised the               reduction criteria were revised to reflect
                                                   not toxic to the test microorganisms. If                 log reduction criteria proposed for                    this single application and fall between
                                                   a test product can be neutralized                        consumer antiseptic rubs based on the                  the log reductions previously proposed
                                                   through dilution, this should be                         recommendations of the March 2005                      for the first and last applications. The
                                                   demonstrated in the neutralizer                          NDAC and comments to the 1994 TFM,                     GRAE criteria proposed for consumer
                                                   validation study.                                        which argued that the demonstration of
                                                                                                                                                                   antiseptic rubs are based on log
                                                      • An analysis of the proportion of                    a cumulative antiseptic effect for these
                                                                                                                                                                   reductions achieved by antiseptics as
                                                   subjects who meet the log reduction                      products is unnecessary. We agree that
                                                                                                            the critical element of the effectiveness              shown in the published literature (Refs.
                                                   criteria based on a two-sided statistical
                                                   test for superiority to vehicle and a 95-                is that a product must be effective after              28 and 29) as well as those evaluated
                                                   percent confidence interval approach.                    the first application because that                     under the NDA process. Table 4 shows
                                                      To establish that a particular active                 represents the way in which consumer                   the log reductions that we would expect
                                                   ingredient is GRAE for use in consumer                   antiseptic rub products are used (59 FR                an effective consumer antiseptic rub
                                                   antiseptic rubs, clinical simulation                     31402 at 31442). For these reasons, log                active ingredient to meet to show that it
                                                   studies using the parameters described                   reduction criteria are proposed only for               is GRAE.

                                                   TABLE 4—CLINICAL SIMULATION TESTING BACTERIAL LOG REDUCTION EFFECTIVENESS CRITERIA IN THIS PROPOSED RULE
                                                                                             AND IN THE 1994 TFM

                                                             Indication                                           1994 TFM                                                   This proposed rule

                                                   Antiseptic hand wash/Con-             (1) Reduction of 2 log10 on each hand within 5 minutes           (1) Reduction of 2.5 log10 on each hand within 5 min-
                                                     sumer antiseptic rub.                 after the first wash and                                         utes after a single rub.
                                                                                         (2) Reduction of 3 log10 on each hand within 5 minutes
                                                                                           after the tenth wash.



                                                   C. Impact of Application Parameters on                   and 70 percent ethanol foam, Kampf et                  product efficacy, the factors that may
                                                   Efficacy                                                 al. (2013) demonstrated that the label                 affect application volume are of interest.
                                                                                                            recommended volume of 1.1 milliliters                  Variability has been demonstrated in the
                                                      Establishing GRAE status of active                    (mL) for the 70 percent ethanol products               output of both gel and foam antiseptic
                                                   ingredients is one important aspect of                   was not sufficient to achieve efficacy in              rub dispensers. Macinga et al. (2013)
                                                   ensuring the efficacy of OTC consumer                    in vivo efficacy testing according to                  measured output from a single wall-
                                                   antiseptic rub products. The standards                   ASTM methods (Ref. 35). The                            mounted dispenser and among wall-
                                                   for a GRAE determination for consumer                    recommended application of 2 mL of 85                  dispensers from different manufacturers
                                                   antiseptic rubs have been described (see                 percent gel, as well as higher than                    (Ref. 37). In dispensing five different gel
                                                   section VII.B). These standards will help                recommended volumes of the 70                          formulations containing varying
                                                   determine final monograph active                         percent products, met efficacy criteria                percentages of ethanol or isopropanol,
                                                   ingredients, as well as their permitted                  under ASTM E 2755–10 and ASTM E                        dispensers from five different
                                                   concentrations and the skin application                  1174–06 methods used in this study. In                 manufacturers had outputs that ranged
                                                   time needed for the active ingredient to                 the same study, insufficient skin                      from 0.9 to 1.3 mL per actuation. In
                                                   achieve adequate bacterial reduction.                    coverage with lower application                        dispensing three different foam
                                                   However, the efficacy of any particular                  volumes (1.1 mL) was suggested as the                  formulations each containing 70 percent
                                                   final formulation of a consumer                          reason for failure to achieve efficacy.                ethanol, foam dispensers from three
                                                   antiseptic rub appears to be affected by                 Failure to achieve effectiveness with the              different manufacturers ranged from 0.6
                                                   a variety of other factors related to                    lower volume was based on observation                  to 1.1 mL per actuation. Furthermore,
                                                   product formulation and use.                             of gaps in skin coverage after volunteers              the volume of product that individuals
                                                      These factors include the number of                   applied products containing fluorescent                choose to apply may be affected,
                                                   times per day a product is used and the                  dye to their hands. In a similar study,                independent of labeled instruction, by
                                                   volume used in each use. The number                      Kampf (2008) assessed the efficacy and                 factors such as the time it takes hands
                                                   of times per day that a consumer                         coverage of four hand rub products                     to dry after application. Kampf et al.
                                                   antiseptic rub product is applied has                    (foam or gel formulation unspecified)                  (2010) assessed four foam formulations,
                                                   been shown to be positively correlated                   containing 85 percent, 62 percent, 61                  each containing 62 percent ethanol, and
                                                   with a reduction in illness-related                      percent, or 60 percent ethanol (Ref. 36).              found that the amount (weight) of foam
                                                   absenteeism in a kindergarten school                     At an application volume of 2.4 mL, the                applied was significantly correlated
                                                   (Ref. 34). In addition, more specific                    60 percent and 61 percent ethanol                      with the perceived drying time (Ref. 38).
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                   measures of application parameters                       formulations failed to meet in vivo                    There is also evidence that final
                                                   have been assessed. The volume of                        ASTM efficacy criteria while 2.4 mL                    formulation affects efficacy. Different
                                                   product applied and the skin coverage                    application volumes of 62 percent and                  products containing the same
                                                   achieved by the applied volume appear                    85 percent ethanol formulations met the                concentration of active ingredient have
                                                   to have an impact on efficacy of                         criteria. Application volumes of 3.6 mL                been shown to perform differently when
                                                   antiseptic rub products containing                       met efficacy criteria for all ethanol                  tested by in vivo bacterial reduction
                                                   alcohol. In comparing five different                     concentrations tested (Ref. 36).                       testing (ASTM 1174) (Ref. 39). One
                                                   application volumes of 70 percent                           Given that the applied volume of                    ‘‘novel’’ gel formulation and one
                                                   ethanol gel with 85 percent ethanol gel                  product may have consequences for                      ‘‘novel’’ foam formulation, each


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                                                                           Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                          42923

                                                   containing 70 percent ethanol, were                     experience with, and knowledge about,                  absorption anticipated between
                                                   both shown to be statistically superior                 safety testing has led to improved                     formulations, and the safety margin for
                                                   after both 1 and 10 applications                        testing methods. Improvements include                  toxic effects, final formulation safety
                                                   compared to two marketed                                study designs that are more capable of                 testing for particular ingredients may be
                                                   formulations, one gel and one foam,                     detecting potential safety risks. Based                needed to assure that substantially
                                                   both containing 70 percent ethanol. All                 on our reassessment, we are proposing                  different absorption that might
                                                   formulations were applied in equal                      new GRAS data standards for consumer                   significantly change the margin of safety
                                                   volumes. The two ‘‘novel’’ formulations                 antiseptic rub active ingredients. To                  is not anticipated for a new formulation.
                                                   also demonstrated some evidence of                      fully address these new safety concerns,               FDA does not address final formulation
                                                   improved performance relative to a                      additional safety data will be necessary               testing in this rulemaking because no
                                                   marketed gel containing 90 percent                      to support a GRAS determination for all                ingredients have been proposed as
                                                   ethanol.                                                consumer antiseptic rub active                         GRAS/GRAE. However, FDA recently
                                                      Understanding the impact of product-                 ingredients.                                           described final formulation safety
                                                   related parameters, such as formulation,                  Many of the safety considerations for                testing for another class of OTC dermal
                                                   dose applied, and application volume,                   consumer antiseptic rubs are based on                  products regulated under the OTC drug
                                                   to be used according to the labeling is                 FDA’s view that the use of consumer                    monograph (Ref. 41).
                                                   imperative. We also need to understand                  antiseptic rubs is a ‘‘chronic’’ use as that              The evaluation of the safety of drug
                                                   the extent to which variability in                      term is defined by the International                   products involves correlating findings
                                                   product-related parameters must be                      Council on Harmonisation (ICH).5 As                    from animal toxicity studies to the level
                                                   reduced to ensure that products achieve                 defined by the ICH, a use is considered                of drug exposure obtained from
                                                   the results expected based on their use                 chronic if the drug will be used for a                 pharmacokinetic studies in animals and
                                                   of GRAE ingredients. Given the data                     period of at least 6 months over the                   humans. Our administrative record
                                                   demonstrating that efficacy varies with                 user’s lifetime, including repeated,                   lacks the data necessary to define a
                                                   dose, application volume, and                           intermittent use (Ref. 40). We believe                 margin of safety for the potential
                                                   formulation, final formulation efficacy                 that consumer antiseptic rubs are often                chronic use of consumer antiseptic rub
                                                   testing will be necessary for consumer                  used on a daily basis and sometimes                    active ingredients. Thus, we are
                                                   antiseptic rub products in order to                     repeatedly over the course of the day.                 continuing to propose that both animal
                                                   confirm effectiveness and label the                                                                            and human pharmacokinetic (PK) data
                                                   product appropriately for use. However,                 A. New Issues                                          are necessary for consumer antiseptic
                                                   because no ingredient has sufficient                       Since the 1994 TFM was published,                   rub active ingredients. This information
                                                   data to support GRAS/GRAE status in                     new data have become available                         will help identify any potential safety
                                                   this rulemaking, we are not proposing                   indicating that systemic exposure to                   concerns and help determine the safety
                                                   specific final formulation testing or                   topical antiseptic active ingredients may              margin for OTC human use.
                                                   labeling at this time. Instead, we are                  be greater than previously thought.                       One potential effect of systemic
                                                   requesting data to allow the assessment                 Systemic exposure refers to the presence               exposure to consumer antiseptic active
                                                   of the impact of various application                    of antiseptic active ingredients inside                ingredients that has come to our
                                                   parameters on efficacy and the                          and throughout the body. Because of                    attention since publication of the 1994
                                                   interaction among them (e.g., how does                  advances in technology, our ability to                 TFM is data suggesting that some
                                                   formulation affect application volume                   detect antiseptic active ingredients in                antiseptic active ingredients have
                                                   requirements) to inform final                           body fluids such as serum and urine is                 hormonal effects. Ingredients in topical
                                                   formulation testing and labeling                        greater than it was in 1994. For                       antiseptic products can cause alterations
                                                   requirements.                                                                                                  in the thyroid of neonatal and
                                                                                                           example, studies have shown detectable
                                                                                                                                                                  adolescent animals (Refs. 42 through
                                                   VIII. Safety (Generally Recognized as                   blood alcohol levels after use of alcohol-
                                                                                                                                                                  51). Hormonally active compounds have
                                                   Safe) Determination                                     containing hand rubs (Refs. 1, 4, and 5).
                                                                                                                                                                  been shown to affect not only the
                                                      In the 1994 TFM, 11 active                           We believe that any consequences of
                                                                                                                                                                  exposed organism, but also subsequent
                                                   ingredients were proposed to be                         this systemic exposure should be
                                                                                                                                                                  generations (Ref. 52). These effects may
                                                   classified as GRAS for antiseptic hand                  identified and assessed to support our
                                                                                                                                                                  not be related to direct deoxyribonucleic
                                                   wash use, which includes 2 active                       risk-benefit analysis for consumer
                                                                                                                                                                  acid (DNA) mutation, but rather to
                                                   ingredients (alcohol and isopropyl                      antiseptic use.
                                                                                                                                                                  alterations in factors that regulate gene
                                                   alcohol) that are eligible for consumer                    Given the frequent repeated use of
                                                                                                                                                                  expression (Ref. 53).
                                                   antiseptic rub use (59 FR 31402 at                      consumer antiseptic rubs, systemic                        A hormonally active compound that
                                                   31435). As described in section II.C,                   exposure may occur. Although some                      causes reproductive system disruption
                                                   consumer antiseptic hand rubs were not                  systemic exposure data exist for all                   in the fetus or infant may have effects
                                                   addressed separately from antiseptic                    three consumer antiseptic rub active                   that are not apparent until many years
                                                   hand washes in the 1994 TFM. There                      ingredients, data on systemic absorption               after initial exposure. There are also
                                                   have since been a number of important                   after maximal use are lacking. Currently,              critical times in fetal development when
                                                   scientific developments affecting our                   there is also a lack of data to assess the             a change in hormonal balance that
                                                   evaluation of the safety of the active                  impact of important drug use factors                   would not cause any lasting effect in an
                                                   ingredients in consumer antiseptic rubs,                that can influence systemic exposure                   adult could cause a permanent
                                                                                                           such as dose, application frequency and
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                   causing us to reassess the data necessary                                                                      developmental abnormality in a child.
                                                   to support a GRAS determination. There                  method, duration of exposure, product                  For example, untreated hypothyroidism
                                                   is now new information regarding                        formulation, skin condition, and age.                  during pregnancy has been associated
                                                   systemic exposure to antiseptic active                  Depending on the systemic absorption                   with cognitive impairment in the
                                                   ingredients (Refs. 1 through 5). The                    of the ingredient, variability in                      offspring (Refs. 54 through 56).
                                                   potential for widespread antiseptic use                   5 FDA is a member of the ICH Steering
                                                                                                                                                                     Because consumer antiseptic rubs are
                                                   to promote the development of                           Committee, the governing body that oversees the
                                                                                                                                                                  used chronically and are likely to be
                                                   antibiotic-resistant bacteria also needs                harmonization activities, and contributes to the       used by sensitive populations such as
                                                   to be evaluated. Furthermore, additional                development of ICH guidelines.                         children and pregnant women,


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                                                   42924                   Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules

                                                   evaluation of the potential for chronic                 consequence of antiseptic use and                       we expect will establish GRAS status for
                                                   toxicity and effects on reproduction and                requested data to address the concern                   these active ingredients, we are
                                                   development should be included in the                   (78 FR 76444 at 76454 and 80 FR 25166                   including specific information, based in
                                                   safety assessment. The designs of                       at 25180). However, in its evaluation of                part on existing FDA guidance, about
                                                   general toxicity and reproductive/                      the available data on the development of                the other kinds of studies to consider
                                                   developmental studies are often                         resistance to alcohol and isopropyl                     conducting and submitting. We have
                                                   sufficient to identify developmental                    alcohol in the proposed rule for health                 published guidance documents
                                                   effects that can be caused by hormonally                care antiseptics, FDA cited a number of                 describing the nonclinical safety studies
                                                   active compounds through the use of                     factors (speed of action, multiple                      that a manufacturer should perform
                                                   currently accepted endpoints and                        nonspecific toxic effects, and lack of a                when seeking to market a drug product
                                                   standard good laboratory practice                       residue) that made the development of                   under an NDA (Refs. 40, 57 through 63).
                                                   toxicology study designs. As followup                   resistance to these alcohols as a result                These guidance documents also provide
                                                   in some cases, additional study                         of health care antiseptic use unlikely.                 relevant guidance for performing the
                                                   endpoints may be needed to fully                        Based on these factors, FDA concluded                   nonclinical studies necessary to
                                                   characterize the potential effects of drug              that no additional data relevant to this                determine GRAS status for a consumer
                                                   exposure on the exposed individuals.                    issue were necessary to support a GRAS                  antiseptic rub active ingredient. Because
                                                                                                           determination for these ingredients for                 consumer antiseptic rubs may be used
                                                   B. Antimicrobial Resistance
                                                                                                           health care antiseptics (80 FR 25166 at                 repeatedly and in sensitive populations,
                                                     In the 2013 Consumer Wash PR and                      25184, 25187, and 25192). Consistent                    we propose that consumer antiseptic
                                                   2015 Health Care Antiseptic PR, FDA                     with FDA’s findings for alcohol and
                                                   raised the concern of the development                                                                           rub active ingredients will need to be
                                                                                                           isopropyl alcohol in its proposed rule                  tested for carcinogenic potential,
                                                   of antiseptic resistance and its potential              for health care antiseptic, we have also
                                                   impact on the development of antibiotic                                                                         developmental and reproductive
                                                                                                           tentatively concluded that no further                   toxicity (DART), and other potential
                                                   resistance (78 FR 76444 at 76454 and 80                 data on the development of resistance to
                                                   FR 25166 at 25180). This concern was                                                                            effects as described in more detail in
                                                                                                           alcohol and isopropyl alcohol as a result               this section.
                                                   based on numerous reports of laboratory                 of their use in consumer antiseptic rub
                                                   studies demonstrating the development                   products are needed. This is not the                    1. FDA Guidances Describing Safety
                                                   of reduced susceptibility to certain                    case for benzalkonium chloride for                      Studies
                                                   antiseptic active ingredients and                       which additional laboratory studies will
                                                   antibiotics after growth in nonlethal                   assist in more clearly defining the                       The safety studies that are described
                                                   amounts of the antiseptic (i.e., low-to-                potential for the development of                        in the existing FDA guidances (Refs. 40,
                                                   moderate concentrations of antiseptic)                  resistance. (See section VIII.D.2).                     57 through 63) provide a framework for
                                                   and reports of the persistence of low                                                                           the types of studies that are needed for
                                                   levels of some antiseptic active                        C. Studies To Support a Generally                       FDA to assess the safety of each
                                                   ingredients in the environment (78 FR                   Recognized as Safe Determination                        consumer rub active ingredient
                                                   76444 at 76454 and 80 FR 25166 at                          A GRAS determination for consumer                    according to modern scientific
                                                   25180). FDA concluded in both of these                  antiseptic rub active ingredients must be               standards and make a GRAS
                                                   proposed rules that, given the increasing               supported by both nonclinical (animal)                  determination. A description of each
                                                   evidence of the magnitude of the                        and clinical (human) studies.6 To issue                 type of study and how we would use
                                                   antibiotic resistance problem and the                   a final monograph for these products,                   this information to improve our
                                                   speed with which new antibiotic                         this safety data must be in the docket.7                understanding of the safety of consumer
                                                   resistant organisms are emerging, it is                    To assist manufacturers or others who                antiseptic rub active ingredients is
                                                   important to assess this potential                      wish to provide us with the information                 provided in table 5.

                                                          TABLE 5—FDA GUIDANCE DOCUMENTS RELATED TO REQUESTED SAFETY DATA AND RATIONALE FOR STUDIES
                                                        Type of study               Study conditions                         What the data tell us                               How the data are used

                                                   Animal pharmaco-             Both oral and dermal         Allows identification of the dose at which the         Used as a surrogate to identify toxic systemic
                                                     kinetic absorption,          administration.              toxic effects of an active ingredient are ob-          exposure levels that can then be correlated
                                                     distribution, metabo-                                     served as a result of systemic exposure of             to potential human exposure via dermal
                                                     lism, and excretion                                       the drug. ADME data provide: The rate and              pharmacokinetic study findings. Adverse
                                                     (ADME) (Refs. 58                                          extent an active ingredient is absorbed into           event data related to particular doses and
                                                     and 64).                                                  the body (e.g., AUC, Cmax, Tmax) 1; where              drug levels (exposure) in animals are used
                                                                                                               the active ingredient is distributed in the            to help formulate a safety picture of the
                                                                                                               body; whether metabolism of the active in-             possible risk to humans.
                                                                                                               gredient by the body has taken place; infor-
                                                                                                               mation on the presence of metabolites; and
                                                                                                               how the body eliminates the original active
                                                                                                               ingredient (parent) and its metabolites
                                                                                                               (e.g., T1⁄2)2.
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                     6 We encourage sponsors to consult with us on           7 The Agency intends to consider only non-            submit this data or information to the docket is set
                                                   non-animal testing methods they believe may be          confidential material that is submitted to the docket   forth in this document in the ADDRESSES section.
                                                   suitable, adequate, validated, and feasible. We are     for this rulemaking or that is otherwise publicly
                                                   willing to consider if alternative methods could be     available in its evaluation of the GRAS/GRAE status
                                                   assessed for equivalency to an animal test method.      of a relevant ingredient. Information about how to



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                                                                           Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                                 42925

                                                         TABLE 5—FDA GUIDANCE DOCUMENTS RELATED TO REQUESTED SAFETY DATA AND RATIONALE FOR STUDIES—
                                                                                                 Continued
                                                        Type of study               Study conditions                         What the data tell us                             How the data are used

                                                   Human pharmaco-              Dermal administration        Helps determine how much of the active in-            Used to relate the potential human exposure
                                                     kinetics (MUsT) (Ref.        using multiple for-          gredient penetrates the skin, leading to              to toxic drug levels identified in animal
                                                     62).                         mulations under              measurable systemic exposure.                         studies.
                                                                                  maximum use con-
                                                                                  ditions.
                                                   Carcinogenicity (ICH         Minimum of one oral          Provides a direct measure of the potential for        Identifies the systemic and dermal risks asso-
                                                     S1A, S1B, and S1C)           and one dermal               active ingredients to cause tumor formation           ciated with drug active ingredients. Taken
                                                     (Refs. 40, 57, and           study for topical            (tumorogenesis) in the exposed animals.               together, these studies are used to identify
                                                     60).                         products 3.                                                                        the type(s) of toxicity, the level of exposure
                                                                                                                                                                     that produces these toxicities, and the
                                                                                                                                                                     highest level of exposure at which no ad-
                                                                                                                                                                     verse effects occur, referred to as the ‘‘no
                                                                                                                                                                     observed adverse effect level’’ (NOAEL).
                                                                                                                                                                     The NOAEL is used to determine a safety
                                                                                                                                                                     margin for human exposure.
                                                   Developmental toxicity       Oral administration .....    Evaluates the effects of a drug on the devel-
                                                     (ICH S5) (Ref. 59).                                       oping offspring throughout gestation and
                                                                                                               postnatally until sexual maturation.
                                                   Reproductive toxicity        Oral administration .....    Assesses the effects of a drug on the repro-
                                                     (ICH S5) (Ref. 59).                                       ductive competence of sexually mature
                                                                                                               male and female animals.
                                                   Hormonal effects (Ref.       Oral administration .....    Assesses the drug’s potential to interfere with       Used in hazard assessment to determine
                                                     63).                                                      the endocrine system.                                 whether the drug has the capacity to in-
                                                                                                                                                                     duce a harmful effect at any exposure level
                                                                                                                                                                     without regard to actual human exposures.
                                                      1 ‘‘AUC’’ denotes the area under the concentration-time curve, a measure of total exposure or the extent of absorption. ‘‘Cmax’’ denotes the
                                                   maximum concentration, which is peak exposure. ‘‘Tmax’’ denotes the time to reach the maximum concentration, which aids in determining the
                                                   rate of exposure.
                                                      2 ‘‘T1⁄2’’ denotes the half-life, which is the amount of time it takes to eliminate half the drug from the body or decrease the concentration of the
                                                   drug in plasma by 50 percent.
                                                      3 Assessment of dermal carcinogenicity is considered important because the intended clinical route of administration of dermal, and skin expo-
                                                   sure could be high. In addition, dermal exposure can result in systemic exposure to parent and metabolites that may differ from other routes.
                                                   When substantial nonclinical information is already available for an active ingredient, the need for a dermal carcinogenicity study could be recon-
                                                   sidered based on available information such as negative systemic carcinogenicity information and lack of preneoplastic effects in chronic non-
                                                   rodent dermal toxicity studies.


                                                      These studies represent FDA’s current                 assess the effects of long-term dermal                are analyzed, and the resulting in vivo
                                                   thinking on the data needed to support                   and systemic exposure to these                        data could be used to estimate a safety
                                                   a GRAS determination for an OTC                          ingredients. This is particularly                     margin based on animal toxicity studies.
                                                   antiseptic active ingredient and are                     important for populations, such as                      A MUsT to support a determination
                                                   similar to those recommended by the                      pregnant women (and fetuses), lactating               that an active ingredient is GRAS for use
                                                   Antimicrobial I Panel (described in the                  women, and children, who may have                     in consumer antiseptics is conducted by
                                                   ANPR (39 FR 33103 at 33135)) as                          greater potential to experience                       obtaining an adequate number of PK
                                                   updated by the recommendations of the                    deleterious developmental effects from                samples following administration of the
                                                   2014 NDAC. However, even before the                      drug exposure. Human exposure data                    active ingredient. For studies of active
                                                   September 2014 NDAC meeting, the                         can then be compared to drug levels in                ingredients to be used in topically
                                                   Panel’s recommendations for data to                      animals known to produce adverse                      applied products like these, for which
                                                   support the safety of an OTC topical                     effects in order to calculate a safety                there is less information available and
                                                   antimicrobial active ingredient included                 margin.                                               for which crossover designs are not
                                                   studies to characterize the following:                                                                         feasible, a larger number of subjects are
                                                      • Degree of absorption through intact                    Based on input from the September                  required compared to studies of orally
                                                   and abraded skin and mucous                              2014 NDAC meeting, the Agency has                     administered drug products. A MUsT
                                                   membranes.                                               also determined that results from a                   using 50 to 75 subjects per cohort
                                                      • Tissue distribution, metabolic rates,               human PK maximal usage trial (MUsT)                   should be sufficient to get estimates of
                                                   metabolic fates, and rates and routes of                 are needed to support a GRAS                          the PK parameters from a topically
                                                   elimination.                                             determination. This trial design is also              applied consumer antiseptic.
                                                      • Teratogenic and reproductive                        referred to as a maximal use PK trial and               The MUsT should attempt to
                                                   effects.                                                 is described in FDA’s 2005 draft                      maximize the potential for drug
                                                      • Mutagenic and carcinogenic effects.
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                                                                            guidance for industry on developing                   absorption to occur by considering the
                                                                                                            drugs for treatment of acne vulgaris (Ref.            following design elements (Ref. 65):
                                                   2. Studies To Characterize Maximal                       62). The purpose of the MUsT is to                      • Adequate number of subjects (steps
                                                   Human Exposure                                           evaluate systemic exposure under                      should be taken to ensure that the target
                                                      Because the available data indicate                   conditions that would maximize the                    population (for example, age, gender,
                                                   that some dermal products, including at                  potential for drug absorption in a                    race) is properly represented).
                                                   least some antiseptic active ingredients,                manner consistent with possible ‘‘worst-                • Frequency of dosing (e.g., number
                                                   are absorbed after topical application in                case’’ real world use of the product. In              of rub applications during the study).
                                                   humans and animals, it is necessary to                   a MUsT, the collected plasma samples                    • Duration of dosing.


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                                                   42926                   Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules

                                                      • Use of highest proposed strength                   standards using the highest                            antibiotics (Refs. 74 and 75). The
                                                   (e.g., 95 percent alcohol).                             concentration sought under this                        development of bacteria that are
                                                      • Total involved surface area to be                  proposed rule in formulations expected                 resistant to antibiotics is an important
                                                   treated at one time (e.g., hands).                      to produce the highest in vivo                         public health issue, and additional data
                                                      • Amount applied per square                          absorption. The assay used in the MUsT                 may tell us whether use of antiseptics in
                                                   centimeter.                                             should be properly validated according                 consumer settings may contribute to the
                                                      • Method of application (e.g., rub).                 to current Good Laboratory Practices                   selection of bacteria that are less
                                                      • Sensitive and validated analytical                 and consistent with FDA guidance for                   susceptible to both antiseptics and
                                                   methods.                                                industry: ‘‘Bioanalytical Method                       antibiotics. Therefore, we are requesting
                                                      It also is important that the MUsT                   Validation’’ (Ref. 67).                                additional data and information to
                                                   reflect maximal use conditions of                          We expect that the 0.5 ng/mL                        address this issue for ingredients other
                                                   consumer antiseptic rubs using different                concentration will be sufficiently above               than alcohol or isopropyl alcohol (see
                                                   formulations to fully characterize the                  the assay’s limit of quantitation-limit of             section VIII.D).
                                                   active ingredient’s potential for dermal                detection to allow a signal: Noise ratio                  FDA believes that a tiered approach is
                                                   penetration. There are very limited data                that assures confidence in the derived                 an efficient means of developing data to
                                                   on the maximal number of uses of                        concentrations (in the case of                         address this issue. Laboratory studies in
                                                   antiseptic rubs in consumer settings.                   ‘‘exaggerated’’ values) or lack of                     conjunction with a literature review are
                                                   Consumer antiseptic rubs used in                        concentrations.                                        a feasible first step in evaluating the
                                                   institutional settings, such as daycare
                                                                                                           3. Studies To Characterize Hormonal                    impact of exposure to nonlethal
                                                   centers, schools, and office buildings,
                                                                                                           Effects                                                amounts of antiseptic active ingredients
                                                   would be used (as per label directions)
                                                                                                                                                                  on antiseptic and antibiotic bacterial
                                                   at higher rates than in domestic                           We propose that data are also needed                susceptibilities. However, only limited
                                                   households, and thus would represent                    to assess whether consumer antiseptic                  data exist on the effects of antiseptic
                                                   maximal use. Kinnula et al. (2009)                      rub active ingredients have hormonal                   exposure on the bacteria that are
                                                   surveyed workers in child daycare                       effects that could produce                             predominant in the oral cavity, gut, skin
                                                   centers in Finland to determine how                     developmental or reproductive toxicity.                flora, and the environment (Ref. 76).
                                                   commonly alcohol-containing hand rub                    There are several factors common to                    These organisms represent pools of
                                                   gels were applied daily (Ref. 66). The                  antiseptic products that make it                       resistance determinants that are
                                                   respondents (n = 128) reported applying                 necessary to assess their full safety                  potentially transferable to human
                                                   the alcohol hand rub gels up to 50 times                profile prior to classifying an antiseptic             pathogens (Refs. 77 and 78). Thus,
                                                   per day. Using the upper limit of                       active ingredient as GRAS for use in                   broader laboratory testing of consumer
                                                   applications per day of antiseptic hand                 consumer antiseptic rub products.                      antiseptic active ingredients would
                                                   rubs from this study, FDA is considering                These factors are as follows:                          more clearly define the scope of the
                                                   50 times per day as the maximal use of                     • Evidence of systemic exposure to                  impact of antiseptic active ingredients
                                                   consumer hand rubs in a consumer                        several of the antiseptic active                       on the development of antibiotic
                                                   setting.                                                ingredients.                                           resistance and may be able to identify
                                                      It should be noted that a systemic                      • Exposure to multiple sources of                   those antiseptic active ingredients for
                                                   carcinogenicity study will not be                       antiseptic active ingredients that may be
                                                   required for an ingredient if a MUsT                                                                           which the development of resistance is
                                                                                                           hormonally active compounds.                           not a concern. Laboratory studies
                                                   results in a steady state blood level less                 • Exposure to antiseptic active
                                                   than 0.5 nanograms (ng)/mL, and an                                                                             evaluating the antiseptic and antibiotic
                                                                                                           ingredients may be long term for some
                                                   adequately conducted toxicology                                                                                susceptibilities of bacteria grown in the
                                                                                                           users.
                                                   program demonstrates that there are no                     According to FDA’s 2015 guidance on                 presence of sublethal concentrations of
                                                   other signals for the ingredient or any                 nonclinical evaluation of endocrine-                   antiseptic active ingredients could help
                                                   known structurally similar compound                     related drug toxicity (Ref. 63), endocrine             support a GRAS determination for
                                                   indicating the potential for adverse                    effects may be identified from the                     antiseptic active ingredients intended
                                                   effects at lower levels. The threshold                  standard battery of toxicity tests                     for use in OTC consumer antiseptic drug
                                                   value of 0.5 ng/mL is based on the                      conducted during drug development                      products. The following types of
                                                   principle that the level would                          and may not require additional separate                organisms should be evaluated:
                                                   approximate the highest plasma level                    studies.                                                  • Human bacterial pathogens.
                                                   below which the carcinogenic risk of                                                                              • Nonpathogenic organisms,
                                                                                                           4. Studies To Evaluate the Potential                   opportunistic pathogens, and obligate
                                                   any unknown compound would be less
                                                                                                           Impact of Antiseptic Active Ingredients                anaerobic bacteria that make up the
                                                   than 1 in 100,000 after a single dose.
                                                      The lack of absorption in a MuST                     on the Development of Resistance                       resident microflora of the human skin,
                                                   does not alleviate the need to assess                      Since the 1994 TFM published, the                   gut, and oral cavity.
                                                   dermal carcinogenicity because the                      issue of antiseptic resistance and                        • Food-related bacteria such as
                                                   magnitude of exposure to the skin can                   whether bacteria that exhibit antiseptic               Listeria, Lactobacillus, and
                                                   be much higher than would be covered                    resistance have the potential for                      Enterococcus.
                                                   by systemic studies. In addition,                       antibiotic cross-resistance has been the                  • Nonpathogenic organisms and
                                                   systemic exposure to the parent                         subject of much study and scrutiny. One                opportunistic pathogens from relevant
                                                                                                                                                                  environmental sources (e.g., soil).
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                   compound and metabolites can differ                     of the major mechanisms of antiseptic
                                                   significantly for a dermally applied                    and antibiotic cross-resistance is                     If the results of these studies show no
                                                   product because the skin has metabolic                  changes in bacterial efflux activity at                evidence of changes in antiseptic or
                                                   capability and first-pass metabolism is                 nonlethal concentrations of the                        antibiotic susceptibility, no further
                                                   bypassed via this route of                              antiseptic (Refs. 68 through 73). Efflux               studies addressing the development of
                                                   administration.                                         pumps are an important nonspecific                     resistance would be needed to support
                                                      To fulfill the maximum human                         bacterial defense mechanism that can                   a GRAS determination.
                                                   exposure requirement, the MUsT study                    confer resistance to a number of                          For antiseptic active ingredients that
                                                   should meet appropriate design                          substances toxic to the cell, including                demonstrate an effect on antiseptic and


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                                                                                        Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                                                               42927

                                                   antibiotic susceptibilities, additional                                             environmental compartments (for                                            D. Review of Available Data for Each
                                                   data will be necessary to help assess the                                           example, bacteria found on human skin,                                     Antiseptic Active Ingredient
                                                   likelihood that similar effects would                                               in the gut, and in environmental
                                                   occur in the consumer setting. Several                                              matrices).                                                                    We have identified for each consumer
                                                   types of data could be used to assess                                                                                                                          antiseptic rub active ingredient whether
                                                                                                                                         • Data characterizing the antiseptic                                     the studies outlined in section VIII.C are
                                                   whether or not ingredients with positive                                            and antibiotic susceptibility levels of
                                                   laboratory findings pose a public health                                                                                                                       publicly available. Table 6 lists the
                                                                                                                                       environmental isolates of bacteria in                                      types of studies available for each
                                                   risk, and the type of data needed would                                             areas of prevalent antiseptic use, such as
                                                   depend on what is already known about                                                                                                                          antiseptic active ingredient eligible for
                                                                                                                                       in the home or in schools.                                                 use as a consumer rub proposed as
                                                   the antiseptic active ingredient’s
                                                   mechanism of action and persistence in                                              Data from the types of testing described                                   Category I or Category III in the 1994
                                                   the environment. We do not anticipate                                               previously, as well as from testing of                                     TFM and indicates whether the
                                                   that it will be necessary to obtain data                                            antiseptic and antibiotic susceptibilities                                 currently available data are adequate to
                                                   from multiple types of studies for each                                             of bacteria in settings where consumer                                     serve as the basis of a GRAS
                                                   active ingredient to adequately assess its                                          topical antiseptic rub use is prevalent                                    determination. Although we have some
                                                   potential to affect resistance. Such types                                          can help demonstrate whether or not                                        data from submissions to the
                                                   of data could include, but are not                                                  changes in susceptibility are occurring                                    rulemaking and from information we
                                                   limited to, the following:                                                          with actual use. Because actual use                                        have identified in the literature, our
                                                      • Information about the mechanism(s)                                             concentrations of consumer antiseptics                                     administrative record is incomplete for
                                                   of antiseptic action (for example,                                                  are much higher than the MICs for these                                    at least some types of safety studies for
                                                   membrane destabilization or inhibition                                              active ingredients, data from                                              each of the active ingredients (see table
                                                   of fatty acid synthesis), and whether                                               compartments where sublethal                                               6). As noted previously, only
                                                   there is a change in the mechanism of                                               concentrations of biologically active                                      information that is part of the
                                                   action with changes in antiseptic                                                   antiseptic active ingredients may occur                                    administrative record for this
                                                   concentration.                                                                      (e.g., environmental compartments) can                                     rulemaking can form the basis of a
                                                      • Information clarifying the bacteria’s                                          give us a sense of the potential for                                       GRAS/GRAE determination.
                                                   mechanism(s) for the development of                                                 change in antimicrobial susceptibilities                                      We recognize that data and
                                                   resistance or reduced susceptibility to                                             in these compartments (Refs. 79 through                                    information submitted in response to
                                                   the antiseptic active ingredient (for                                               81). FDA recognizes, however, that                                         the 2013 Consumer Wash PR or 2015
                                                   example, efflux mechanisms).                                                        methods of evaluating this issue are an                                    Health Care Antiseptic PR may be
                                                      • Data characterizing the potential for                                          evolving science and that there may be                                     relevant to this proposed rule. At the
                                                   reduced antiseptic susceptibility caused                                            other data appropriate to evaluate the                                     time of publication of this proposed
                                                   by the antiseptic active ingredient to be                                           impact of consumer antiseptic active                                       rule, FDA’s review of all submissions
                                                   transferred to other bacteria that are still                                        ingredients on the development of                                          made to the 2015 Health Care Antiseptic
                                                   sensitive to the antiseptic.                                                        resistance. For this reason, FDA                                           PR has not been completed. FDA
                                                      • Data characterizing the                                                        encourages interested parties to consult                                   requests that any information relevant to
                                                   concentrations and antimicrobial                                                    with the Agency on the specific studies                                    consumer antiseptic rub active
                                                   activity of the antiseptic active                                                   appropriate to address this issue for a                                    ingredients be resubmitted under this
                                                   ingredient in biological and                                                        particular active ingredient.                                              docket (FDA–2016–N–0124).
                                                                       TABLE 6—SAFETY STUDIES AVAILABLE FOR CONSUMER ANTISEPTIC HAND RUB ACTIVE INGREDIENTS 1
                                                                                                                             Human                    Animal            Oral                      Dermal                Reproductive   Potential
                                                                                                                            Pharmaco-               Pharmaco-                                                                                      Resistance
                                                                       Active Ingredient                                                                               Carcino-                   Carcino-                Toxicity     Hormonal
                                                                                                                              kinetic                 kinetic                                                                                       Potential
                                                                                                                                                                       genicity                   genicity                (DART)        Effects
                                                                                                                             (MUsT)                  (ADME)

                                                   Alcohol ...........................................................              Æ                  •                     •                          •                    •            •            •
                                                   Benzalkonium chloride ..................................              ........................      Æ                     •               ........................        •            •            Æ
                                                   Isopropyl alcohol ...........................................                    Æ                  Æ          ........................              Æ                    •            Æ            •
                                                      1 Empty     cell indicates no data available; ‘‘Æ’’ indicates incomplete data available; ‘‘•’’ indicates available data are sufficient to make a GRAS/GRAE determination.


                                                     In the remainder of this section, we                                              data gaps identified in the 2015 Health                                    1. Alcohol
                                                   discuss the existing data and data gaps                                             Care Antiseptic PR are similar to those
                                                   for alcohol, benzalkonium chloride and                                              discussed in this proposed rule for each                                      In the 1994 TFM, FDA proposed to
                                                   isopropyl alcohol, the consumer                                                     ingredient. The requirements for a                                         classify alcohol as GRAS for all health
                                                   antiseptic rub active ingredients that                                              GRAS determination for an ingredient                                       care antiseptic uses based on the
                                                   were proposed as GRAS in the 1994                                                   are generally the same for either a health                                 recommendation of the Advisory
                                                   TFM, and explain why these active                                                                                                                              Review Panel on OTC Miscellaneous
                                                                                                                                       care or consumer antiseptic product,
                                                   ingredients are no longer proposed as                                                                                                                          External Drug Products (Miscellaneous
                                                                                                                                       with the exception of higher maximal
                                                   GRAS for use in consumer antiseptic                                                                                                                            External Panel), which concluded that
                                                                                                                                       use for health care antiseptic products.
                                                                                                                                                                                                                  the topical application of alcohol is safe
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                   hand rubs (i.e., why they are now
                                                                                                                                       Therefore, it is anticipated that                                          (59 FR 31402 at 31412). In the 2013
                                                   proposed as Category III). We also
                                                                                                                                       ingredients fulfilling the requirements                                    Consumer Wash PR, FDA proposed to
                                                   discuss benzalkonium chloride, which
                                                   was proposed as Category III in the 1994                                            for a health care antiseptic GRAS                                          separately evaluate the safety and
                                                   TFM and for which there are some new                                                determination would also meet the                                          effectiveness of the OTC antiseptic drug
                                                   data available and explain why this                                                 criteria for GRAS as a consumer                                            products by use setting, specifically
                                                   ingredient is still Category III. These                                             antiseptic, if eligible for that indication.                               health care and consumer antiseptic
                                                   three ingredients are also used in health                                                                                                                      products. As defined in the 2013
                                                   care antiseptic products, and the safety                                                                                                                       Consumer Wash PR, consumer


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                                                   42928                   Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules

                                                   antiseptic products that are not rinsed                 which is the equivalent of 10 percent of               and 109). The data cited in both of these
                                                   off after use include hand rubs and                     an alcohol-containing drink. See also                  evaluations are proprietary and only
                                                   antiseptic wipes. FDA is proposing to                   the discussion of occupational exposure                summaries of the data are publicly
                                                   classify alcohol as Category III for use in             to alcohol via the dermal route (Ref.                  available. Consequently, these studies
                                                   consumer antiseptic rubs. Extensive                     107) in the alcohol carcinogenicity                    are not available to FDA and FDA
                                                   studies have been conducted to                          section of the 2015 Health Care                        cannot conduct a complete evaluation of
                                                   characterize the metabolic and toxic                    Antiseptic PR (80 FR 25166 at 25186).                  them. Safety assessments with study
                                                   effects of alcohol in animal models.                       Although these data do indicate                     summaries do not constitute an
                                                   Although the impetus for most of the                    absorption of alcohol does occur after                 adequate record on which to base a
                                                   studies has been to study the effects of                topical administration of alcohol-                     GRAS classification (§ 330.10(a)(4)(i)).
                                                   alcohol exposure via the oral route of                  containing antiseptic rubs, we did not                 For FDA to evaluate this data with
                                                   administration, some dermal toxicity                    find the exposure conditions of these                  respect to the safety of benzalkonium
                                                   studies are available and have shown                    studies comparable to exposure that are                chloride for this rulemaking, the full
                                                   that, although there is alcohol                         required by our current MUsT standards                 study reports and data sets must be
                                                   absorption through human skin, it is                    specified in section VIII.C.2.                         submitted to the rulemaking docket or
                                                   much lower than absorption via the oral                 Consequently, human pharmacokinetic                    otherwise be publicly available.
                                                   route. Overall, there are adequate safety               data under maximal use conditions as                     In response to the call for data in the
                                                   data to make a GRAS determination for                   determined by a MUsT are needed to                     2013 Consumer Wash PR, a
                                                   alcohol, with the exception of human                    make a GRAS determination for the                      manufacturing consortium submitted
                                                   pharmacokinetic data under maximal                      alcohol-containing consumer antiseptic                 the following studies to the 2013
                                                   use conditions.                                         rubs.                                                  Consumer Wash PR docket (Refs. 110
                                                      a. Summary of alcohol safety data.                      b. Alcohol safety data gap.                         through 121):
                                                      As discussed in more detail in the                      In summary, our administrative                        • An embryofetal toxicity study in the
                                                   2015 Health Care Antiseptic PR (80 FR                   record for the safety of alcohol is                    rabbit;
                                                   25166 at 25185 to 25187), FDA has                       incomplete with respect to the                           • an embryofetal toxicity study in the
                                                   reviewed the following and found them                   following:                                             rat;
                                                   to be sufficient to characterize the safety                • Human pharmacokinetic studies                       • a 2-generation study in the rat;
                                                   of alcohol for use in consumer                          under maximal use conditions when                        • a 90 day subchronic dietary study
                                                   antiseptic rubs:                                        applied topically (MUsT), including                    in rats;
                                                      • Animal ADME data demonstrating                     documentation of validation of the                       • a 90 day subchronic dermal toxicity
                                                   absorption of alcohol both in vitro and                 methods used to measure alcohol and                    study in rats;
                                                   in vivo (Refs. 82 through 86).                          its metabolites.                                         • a 1-year chronic dietary toxicity
                                                      • Dermal and oral carcinogenicity                    2. Benzalkonium Chloride                               study in dogs;
                                                   data in animals and oral carcinogenicity                                                                         • an ADME study in rats;
                                                   data in humans (Refs. 87 through 93).                      In the 1994 TFM, FDA categorized                      • a rat oral carcinogenicity study; and
                                                      • DART human data (Refs. 94 and                      benzalkonium chloride as Category III                    • a mouse oral carcinogenicity study.
                                                   95).                                                    because of a lack of adequate safety data                All of these studies have been
                                                      • Data on the hormonal effects of                    for its use as both a health care                      reviewed by FDA. Some of the data
                                                   alcohol in animals and humans (Refs. 96                 antiseptic and consumer antiseptic                     were found to be adequate to fill some
                                                   through 102).                                           product (59 FR 31402 at 31435). FDA                    of the safety data gaps for a GRAS
                                                      • Data on the antimicrobial                          also is proposing to classify                          determination for benzalkonium
                                                   mechanism of alcohol (Refs. 103                         benzalkonium chloride as Category III                  chloride. Data gaps remain for the
                                                   through 106). Alcohol readily                           for the indication of consumer                         following endpoints: Human
                                                   evaporates from the skin after topical                  antiseptic rubs. Thus, additional safety               pharmacokinetic data under maximal
                                                   application, and the resulting lack of                  data are still needed to make a GRAS                   use condition, animal dermal
                                                   antiseptic residue on the skin suggests                 determination for benzalkonium                         carcinogenicity and animal ADME data,
                                                   that the topical application of alcohol is              chloride for use as a consumer                         and data on antimicrobial resistance to
                                                   not likely to contribute to the                         antiseptic rub.                                        benzalkonium chloride.
                                                   development of antimicrobial resistance                    In the 2013 Consumer Wash PR, FDA                     a. Summary of benzalkonium chloride
                                                   (Refs. 103, 105).                                       identified the safety data needed to                   safety data.
                                                      Alcohol human pharmacokinetic                        make a GRAS determination for                            Benzalkonium chloride ADME data.
                                                   data. The 2015 Health Care Antiseptic                   benzalkonium chloride as an ingredient                 ADME studies of ADBAC in rats of both
                                                   PR described data that characterize the                 in consumer antiseptic wash products.                  sexes were conducted using the oral and
                                                   level of dermal absorption and expected                 The safety gaps listed were human and                  the intravenous (IV) routes of
                                                   systemic exposure in adults as a result                 animal pharmacokinetic data,                           administration. In the oral studies, rats
                                                   of topical use of alcohol-containing                    reproductive toxicity studies, potential               were administered radiolabeled
                                                   antiseptics (80 FR 25166 at 25185–                      hormonal effects, carcinogenicity (oral                benzalkonium chloride using the
                                                   25186). These data do not cover                         and dermal) studies, and potential of the              following cohorts: A low-dose single
                                                   maximal use of these products as                        development of antimicrobial resistance                oral administration study (10 mg/
                                                   detailed in section VIII.D.1.a.                         to benzalkonium chloride. As was                       kilogram (kg)), a low-dose repeated oral
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                      A variety of alcohol-based hand rub                  summarized in the 2015 Health Care                     administration study (10 mg/kg) and a
                                                   product formulations and alcohol                        Antiseptic PR, the safety of                           high-dose single oral administration
                                                   concentrations have been used in these                  benzalkonium chloride has been                         study (50 mg/kg) (Ref. 115). For the low-
                                                   studies. Based on the available data,                   reviewed and was determined to be safe                 dose repeated oral administration study,
                                                   which represents moderate hand rub                      for use in disinfectants and cosmetic                  rats were treated via freely available
                                                   use (7.5 to 40 hand rub applications per                products by the Environmental                          feed containing 100 parts per million
                                                   hour, studied for 30 to 240 minutes), the               Protection Agency (EPA) and the                        (ppm) of non-radiolabeled
                                                   highest observed exposure was 1,500                     Cosmetic Ingredient Review (an                         benzalkonium chloride for 14 days,
                                                   milligrams (mg) of alcohol (Ref. 4),                    industry panel), respectively (Refs. 108               followed by administration of 10 mg/kg


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                                                                           Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                           42929

                                                   benzalkonium chloride by oral gavage.                   NOAEL of 400 ppm was determined,                       incidence of neoplasms were observed
                                                   Benzalkonium chloride was found to be                   which corresponds to 13.1 and 14.6 mg/                 at any of the tested doses.
                                                   excreted mainly via the feces in rats                   kg/day in males and females,                              There were no treatment-related
                                                   after oral administration. In all of the                respectively.                                          neoplasms in either oral carcinogenicity
                                                   treated groups, the average amount of                      In the dermal toxicity study, rats were             study. Though the mouse study is
                                                   radioactivity recovered was 87 to 99                    topically exposed to benzalkonium                      suboptimal because of its relatively
                                                   percent in the feces and 5 to 8 percent                 chloride in concentrations ranging from                short duration (78 weeks), we believe
                                                   in the urine.                                           0 (water) to 1.0 percent (which                        these two studies are adequate to fill the
                                                      In a separate group of animals tested                correspond to 0 to 20 mg/kg/day) over                  oral carcinogenicity data gap for
                                                   in the same study, a single low-dose of                 a 13-week treatment period (Ref. 113).                 benzalkonium chloride.
                                                   10 mg/kg benzalkonium chloride was                      Slight local irritation and hyperkeratosis                No dermal carcinogenicity studies of
                                                   administered to rats of both sexes. The                 (thickening of the epidermis) were                     benzalkonium chloride have been
                                                   average amount of radioactivity                         observed in all treatment groups                       submitted to FDA. The available data
                                                   recovered following IV dosing was 45 to                 (including control) in both sexes. All                 are not adequate to assess the
                                                   55 percent in the feces and 20 to 30                    findings were limited to the treatment                 carcinogenic potential of benzalkonium
                                                   percent in the urine. Tissue residues of                site. Under the conditions of this study,              chloride. We propose that dermal
                                                   radioactivity were less than 1 percent of               the NOAEL was 20 mg/kg (1.0 percent).                  carcinogenicity studies are still needed
                                                   the orally administered dose in all                     Toxicokinetic data were not collected;                 to complete a GRAS determination for
                                                   groups and 30 to 35 percent of the IV                                                                          benzalkonium chloride.
                                                                                                           therefore, systemic exposure to
                                                   dose. No significant changes were noted                                                                           Benzalkonium chloride DART data. A
                                                                                                           benzalkonium chloride was not
                                                   when comparing the ADME profile of                                                                             developmental toxicity study conducted
                                                                                                           characterized. Consequently, dermal                    in rabbits showed some increase (not
                                                   high dose versus low dose-treated rats.                 ADME (toxicokinetic) data is still
                                                   Although the available ADME data from                                                                          dose-related) in the incidence of certain
                                                                                                           needed to characterize benzalkonium                    visceral and skeletal malformations
                                                   nondermal routes of exposure are                        chloride.
                                                   sufficient to characterize the ADME                                                                            among benzalkonium chloride-treated
                                                   profile of benzalkonium chloride                           Benzalkonium chloride                               rabbits relative to concurrent controls
                                                   following nondermal exposure, they are                  carcinogenicity data. Two oral                         (Ref. 110). None of the findings were
                                                   not sufficient to characterize the ADME                 carcinogenicity studies, one in the rat                considered significant. Some of the
                                                   profile after dermal exposure. Studies                  and another in the mouse, were                         mated dams proved to be not pregnant;
                                                   on animal ADME after dermal exposure                    submitted (Refs. 117 through 121). Both                therefore, the total number of litters (13
                                                   to benzalkonium chloride will need to                   studies were conducted in the 1980’s                   to 15) is slightly less than the 16 to 20
                                                   be submitted to FDA for review, in order                prior to the current ICH guidelines.                   recommended in the ICH S5 guideline,
                                                   to complete a GRAS determination for                    They were conducted according to the                   but further benzalkonium chloride
                                                   benzalkonium chloride.                                  OECD (Organisation for Economic Co-                    DART data are not necessary to make a
                                                      Benzalkonium general toxicity data.                  operation and Development)                             GRAS determination.
                                                   Two subchronic 90-day toxicity studies                  guidelines 8 and designed to meet the                     In a developmental toxicity study in
                                                   in rats were submitted, one dermal and                  requirements of EPA’s regulations,                     rats, the animals were administered
                                                   the other dietary (oral). A 1-year chronic              which use a different type of exposure                 benzalkonium chloride (10, 30, and 100
                                                   oral toxicity study in dogs was also                    risk assessment analysis than is used by               mg/kg/day) (Ref. 112). There were no
                                                   submitted. In the oral rat study,                       FDA for drug products.                                 treatment-related differences in
                                                   benzalkonium chloride was                                  A 78-week dietary carcinogenicity                   gestational parameters, including total
                                                   administered via feeding with                           study was conducted in mice with                       number of embryonic implantations,
                                                   concentrations ranging from 0 to 8,000                  benzalkonium chloride concentrations                   number of viable and nonviable
                                                   ppm (Ref. 111) for 13 weeks. Among rats                 of 500, 1,000, and 1,500 ppm,                          implants. There were also no treatment-
                                                   treated with 4,000 and 8,000 ppm                        corresponding to approximately 15, 73,                 related effects on fetal body weights per
                                                   benzalkonium chloride, an increased                     and 229 mg/kg/day in males and 18, 92,                 litter, or on the incidences of external,
                                                   incidence in mortality and overt toxicity               289 mg/kg/day in females (Refs. 120 and                visceral, or skeletal malformations/
                                                   was seen. A no adverse effect level                     121). Findings were limited to                         variations. Based on these findings, a
                                                   (NOAEL) of 500 ppm was noted, which                     decreased body weight in both males                    NOAEL for maternal toxicity was
                                                   correlated with a mean daily dose of                    and females treated with the highest                   considered to be 10 mg/kg/day and for
                                                   31.2 mg/kg in males and 38.3 mg/kg in                   dose compared to controls (7 percent                   developmental toxicity 100 mg/kg/day.
                                                   females.                                                and 5 percent at week 78 in males and                     A two-generation reproduction and
                                                      A 1-year chronic oral toxicity study in              females, respectively). There were no                  development study in rats was
                                                   dogs was also submitted. Dogs were                      treatment-related increases in the                     submitted for review. Rats were exposed
                                                   chronically administered benzalkonium                   incidence of neoplasms at any of the                   to benzalkonium chloride in the feed
                                                   chloride via feeding in concentrations                  doses tested.                                          (Ref. 116). The exposure to
                                                   ranging from 0 to 1,200 ppm for 1 year                     A 2-year oral carcinogenicity study                 benzalkonium chloride up to the highest
                                                   (Ref. 114). Changes in body weight                      was conducted in rats with                             dose tested of 2,000 mg/kg did not result
                                                   included reduced absolute body weight                   benzalkonium chloride concentrations                   in parental toxicity. No treatment-
                                                   and reduced body weight gain in males                   of 300, 1,000, and 2,000 ppm,                          related reproductive effects were
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                                                   and females in the highest group tested                 corresponding to 13, 44, and 88 mg/kg/                 observed in any of the treatment groups.
                                                   (1,200 ppm), which correlated with a                    day, respectively, in males, and to 17,                Findings were limited to decreases in
                                                   reduction in food consumption. At                       57, and 116 mg/kg/day, respectively, in                body weight accompanied by a decrease
                                                   1,200 ppm, cholesterol levels were                      females (Refs. 117 through 119). No                    in food consumption among treated
                                                   reduced by about 10 percent in both                     treatment-related increases in the                     females at 2,000 mg/kg/day and a
                                                   males and females (p ≤ 0.01). No                                                                               decrease in pup body weight. Based on
                                                   specific organ toxicity was identified.                   8 http://www.oecd-ilibrary.org/environment/oecd-     these findings, a NOAEL for adults and
                                                   Based on the changes in body weight                     guidelines-for-the-testing-of-chemicals-section-4-     offspring was considered to be 1000
                                                   and food consumption at 1,200 ppm, a                    health-effects_20745788.                               ppm (62.5 mg/kg/day).


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                                                   42930                   Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules

                                                      The submitted DART studies are                          a. Summary of isopropyl alcohol                     potential for hormonal effects of
                                                   adequate and no additional DART                         safety data.                                           isopropyl alcohol. However, additional
                                                   studies are needed for benzalkonium                        As discussed in more detail in the                  studies may not be needed to assess the
                                                   chloride.                                               2015 Health Care Antiseptic PR (80 FR                  potential hormonal effects of isopropyl
                                                      Hormonal effects. Based on the                       25166 at 25190–25193), FDA has                         alcohol if assessment of potential
                                                   negative findings in the carcinogenicity                reviewed the following data and found                  hormonal activity can be derived from
                                                   studies and the two-generation DART                     the data to be sufficient to characterize              existing (reproductive and
                                                   studies, no signal for hormonal effects                 the safety of isopropyl alcohol:                       developmental studies; chronic general
                                                   was detected and no further testing on                     • DART data (Refs. 130 through 135).                toxicity data) and additional pending
                                                   hormonal effects will be required for                      • Data on the antimicrobial                         isopropyl alcohol (systemic and dermal
                                                   benzalkonium chloride.                                  mechanism of isopropyl alcohol (Refs.                  carcinogenicity and ADME data)
                                                      Antimicrobial resistance. In addition                103 through 106, 136 through 138).                     nonclinical studies, provided the
                                                   to the summaries, as discussed in the                   Isopropyl alcohol readily evaporates                   appropriate endpoints are assessed.
                                                   2013 Consumer Wash PR (78 FR 76444                      from the skin after topical application.                  Thus, we believe the existing
                                                   at 76463), FDA has reviewed studies on                  The lack of antiseptic residue on the                  evaluations need to be supplemented to
                                                   resistance data and antibiotic                          skin indicates that the topical                        fully evaluate the safety of isopropyl
                                                                                                           application of isopropyl alcohol is not                alcohol. As described in more detail in
                                                   susceptibility of certain bacteria related
                                                                                                           likely to contribute to the development                the 2015 Health Care Antiseptic PR (80
                                                   to the development of resistance to
                                                                                                           of antimicrobial resistance (Refs. 103,                FR 25166 at 25190–25193), we propose
                                                   benzalkonium chloride (Refs. 122
                                                                                                           105). Additional data on the                           that human pharmacokinetic studies
                                                   through 129), and determined that the
                                                                                                           development of antimicrobial resistance                under maximal use conditions when
                                                   available studies have examined few
                                                                                                           are not needed to make a GRAS                          applied topically (MUsT), animal ADME
                                                   bacterial species, provide no
                                                                                                           determination.                                         studies (dermal absorption), systemic
                                                   information on exposure levels, and are                    No new data has been made available
                                                   not adequate to define the potential for                                                                       and dermal carcinogenicity studies, and
                                                                                                           to FDA since publication of the 1994                   data on hormonal effects are still needed
                                                   the development of resistance or cross                  TFM that can fill any of the remaining
                                                   resistance. Additional data are needed                                                                         to complete a GRAS determination for
                                                                                                           safety data gaps for isopropyl alcohol.                isopropyl alcohol.
                                                   to more clearly define the potential for                The following areas of safety
                                                   the development of resistance to                                                                                  b. Isopropyl alcohol safety data gaps.
                                                                                                           assessment, which were identified in                      In summary, our administrative
                                                   benzalkonium chloride.                                  the 1994 TFM and discussed in detail in
                                                      b. Benzalkonium chloride safety data                                                                        record for the safety of isopropyl alcohol
                                                                                                           the 2015 Health Care Antiseptic PR (80                 is incomplete with respect to the
                                                   gaps.                                                   FR 25166 at 25190–25193), are being
                                                      In summary, our administrative                                                                              following:
                                                                                                           updated in this document:                                 • Human pharmacokinetic studies
                                                   record for the safety of benzalkonium                      • Human absorption data (Refs. 1, 139               under maximal use conditions when
                                                   chloride is incomplete with respect to                  through 142). However, the data                        applied topically (MUsT), including
                                                   the following:                                          submitted and found in the literature to               documentation of validation of the
                                                      • Human pharmacokinetic studies                      date do not cover maximal use of these                 methods used to measure isopropyl
                                                   under maximal use conditions when                       products in an institutional setting as                alcohol and its metabolites;
                                                   applied topically (MUsT), including                     detailed in section VIII.C.2.                             • animal ADME (dermal absorption);
                                                   documentation of validation of the                         • Animal ADME data following                           • dermal carcinogenicity;
                                                   methods used to measure benzalkonium                    dermal and systemic exposure to                           • systemic carcinogenicity (may be
                                                   chloride and its metabolites;                           isopropyl alcohol (Refs. 143 through                   waived if the MUsT data do not show
                                                      • Animal dermal ADME;                                149). The available dermal exposure                    absorption); and
                                                      • Dermal carcinogenicity; and                        studies have demonstrated that there is                   • hormonal effects (could be derived
                                                      • Data from laboratory studies that                  some systemic exposure to isopropyl                    from other endpoints).
                                                   assess the potential for the development                alcohol following dermal application.
                                                   of resistance to benzalkonium chloride                                                                         IX. Proposed Effective Date
                                                                                                           However, the extent of that exposure
                                                   and cross-resistance to antibiotics as                  has not been fully characterized.                         Based on the currently available data,
                                                   discussed in section VIII.C.                            Moreover, absorption data following                    this proposed rule finds that additional
                                                                                                           dermal absorption in animals are still                 data are necessary to establish the safety
                                                   3. Isopropyl Alcohol                                                                                           and effectiveness of consumer antiseptic
                                                                                                           needed to determine the extent of
                                                     In the 1994 TFM, FDA proposed to                      systemic exposure following maximal                    rub active ingredients for use in OTC
                                                   classify isopropyl alcohol (70 to 91.3                  dermal exposure to isopropyl alcohol-                  consumer antiseptic rub drug products.
                                                   percent) as GRAS for all consumer                       containing consumer antiseptic rub                     Accordingly, consumer antiseptic rub
                                                   antiseptic washes (59 FR 31402 at                       products.                                              active ingredients would be
                                                   31435). FDA is now proposing to                            • Systemic and dermal                               nonmonograph in any final rule based
                                                   classify isopropyl alcohol as Category III              carcinogenicity data in animal models.                 on this proposed rule. We recognize,
                                                   for use in consumer antiseptic rubs. The                Available data for chronic exposure to                 based on the scope of products subject
                                                   GRAS determination in the 1994 TFM                      isopropyl alcohol include inhalation                   to this monograph, that manufacturers
                                                   was based on the recommendations of                     carcinogenicity data in rodents (Refs.                 will need time to comply with a final
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                   the Miscellaneous External Panel,                       150 and 151) and a chronic 1-year                      rule based on this proposed rule.
                                                   which based its recommendations on                      dermal toxicity study in mice (Ref. 149).              However, because of the potential
                                                   human absorption data and blood                         However, these data are not adequate to                effectiveness and safety considerations
                                                   isopropyl alcohol levels (47 FR 22324 at                assess the systemic or dermal                          raised by the data for some antiseptic
                                                   22329). There was no comprehensive                      carcinogenic potential of isopropyl                    active ingredients evaluated, we believe
                                                   nonclinical review of the toxicity profile              alcohol.                                               that an effective date later than 1 year
                                                   of isopropyl alcohol, nor was there a                      • Data on the hormonal effects of                   after publication of the final rule would
                                                   nonclinical safety evaluation of the                    isopropyl alcohol. The existing data are               not be appropriate or necessary.
                                                   topical use of isopropyl alcohol.                       not adequate to characterize the                       Consequently, any final rule that results


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                                                                               Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                                       42931

                                                   from this proposed rule will be effective                      product industry is mainly composed of                 costs associated with safety and
                                                   1 year after the date of the final rule’s                      establishments with 500 or fewer                       effectiveness testing. We note that the
                                                   publication in the Federal Register. On                        employees, we tentatively conclude that                testing costs for this proposed rule are
                                                   or after that date, any OTC consumer                           the proposed rule may have a significant               not attributed here because these costs
                                                   antiseptic rub drug product that is                            economic impact on a substantial                       will be realized if manufacturers
                                                   subject to the monograph and that                              number of small entities.                              conduct the testing discussed in the
                                                   contains a nonmonograph condition,                                The Unfunded Mandates Reform Act                    proposed rule for health care antiseptics
                                                   i.e., a condition that would cause the                         of 1995 (section 202(a)) requires us to                (80 FR 25166) and we do not count costs
                                                   drug to be not GRAS/GRAE or to be                              prepare a written statement, which                     twice. However, we estimate these costs
                                                   misbranded, could not be introduced or                         includes an assessment of anticipated                  in this analysis to promote transparency
                                                   delivered for introduction into interstate                     costs and benefits, before proposing                   in the event that this rule is finalized
                                                   commerce unless it is the subject of an                        ‘‘any rule that includes any Federal                   before the health care antiseptics
                                                   approved new drug application or                               mandate that may result in the                         proposed rule or manufacturers conduct
                                                   abbreviated new drug application. Any                          expenditure by State, local, and tribal                the testing for the three ingredients
                                                   OTC consumer antiseptic rub drug                               governments, in the aggregate, or by the               discussed in this rule but do not
                                                   product subject to the final rule that is                      private sector, of $100,000,000 or more                conduct the testing for these ingredients
                                                   repackaged or relabeled after the                              (adjusted annually for inflation) in any               for the health care antiseptic proposed
                                                   effective date of the final rule would be                      1 year.’’ The current threshold after                  rule or this rule is finalized but the health
                                                   required to be in compliance with the                          adjustment for inflation is $146 million,              care antiseptics proposed rule is not.
                                                   final rule, regardless of the date the                         using the most current (2015) Implicit
                                                                                                                  Price Deflator for the Gross Domestic                     In scenario 1, all three ingredients are
                                                   product was initially introduced or                                                                                   determined to be GRAS/E and
                                                   initially delivered for introduction into                      Product. This proposed rule would not
                                                                                                                  result in an expenditure in any year that              manufacturers of products containing
                                                   interstate commerce.                                                                                                  other ingredients will no longer be able
                                                                                                                  meets or exceeds this amount.
                                                   X. Economic Analysis of Impacts                                                                                       to market these products under
                                                                                                                  B. Summary of Costs and Benefits                       consumer antiseptic rub labels pursuant
                                                   A. Introduction                                                                                                       to the topical antimicrobial monograph.
                                                                                                                    There are three active ingredients
                                                      We have examined the impacts of the                         being evaluated for use as a consumer                  We expect that these manufacturers will
                                                   proposed rule under Executive Order                            antiseptic rub in this proposed rule:                  reformulate their products to contain
                                                   12866, Executive Order 13563, the                              Alcohol (ethanol or ethyl alcohol),                    one of the monograph ingredients and
                                                   Regulatory Flexibility Act (5 U.S.C.                           isopropyl alcohol, and benzalkonium                    relabel their products to reflect the
                                                   601–612), and the Unfunded Mandates                            chloride. The impact of the proposed                   change in ingredients. Annualizing
                                                   Reform Act of 1995 (Pub. L. 104–4).                            rule on OTC consumer antiseptic rub                    upfront costs over a 10-year period at a
                                                   Executive Orders 12866 and 13563                               product industry will depend on the                    discount rate of 3% for scenario 1, the
                                                   direct Agencies to assess all costs and                        outcome of tests to determine whether                  costs of the proposed rule are estimated
                                                   benefits of available regulatory                               these three active antiseptic ingredients              to be between $0.04 million and $0.12
                                                   alternatives and, when regulation is                           are GRAS/GRAE. It is possible that                     million per year; the corresponding
                                                   necessary, to select regulatory                                none, one, two, or all three of the                    estimated cost at a discount rate of 7%
                                                   approaches that maximize net benefits                          ingredients will be determined to be                   is between $0.05 million and $0.14
                                                   (including potential economic,                                 GRAS/GRAE. We consider two extreme                     million per year. In scenario 2, none of
                                                   environmental, public health and safety,                       scenarios to capture the entire range of               the ingredients is determined to be
                                                   and other advantages; distributive                             total costs: (1) All three ingredients are             GRAS/E and we expect that
                                                   impacts; and equity). We have                                  deemed to be GRAS/GRAE or (2) none                     manufacturers will reformulate their
                                                   developed a comprehensive Economic                             of the ingredients is deemed to be                     products to be free of antiseptics and
                                                   Analysis of Impacts that assesses the                          GRAS/GRAE.                                             relabel them to reflect the change in
                                                   impacts of the proposed rule. We                                 In table 7, we provide a summary of                  ingredients. Annualizing upfront costs
                                                   believe that this proposed rule is a                           the estimated costs of the proposed rule               over a 10-year period at a discount rate
                                                   significant regulatory action as defined                       for the two scenarios. The costs of the                of 3% for scenario 2, the costs of the
                                                   by Executive Order 12866.                                      proposed rule involve product                          proposed rule are estimated to be
                                                      The Regulatory Flexibility Act                              reformulation and relabeling of                        between $1.87 million and $5.52
                                                   requires us to analyze regulatory options                      products. It is important to note that, to             million per year; the corresponding
                                                   that would minimize any significant                            demonstrate that an antiseptic active                  estimated cost at a discount rate of 7%
                                                   impact of a rule on small entities.                            ingredient is GRAS/E, some                             is between $2.28 million and $6.70
                                                   Because the consumer antiseptic rub                            manufacturers will also incur additional               million per year.

                                                                                   TABLE 7—SUMMARY OF QUANTIFIED TOTAL COSTS (IN MILLIONS), BY SCENARIO
                                                                                                              One-time costs                                    Annualized costs over a 10-year period

                                                               Cost category                                                                              3% Discount rate                       7% Discount rate
                                                                                                     Low           Med.            High
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                                                                                                                                                Low            Med.          High          Low         Med.         High

                                                                                                   Scenario 1: Assuming All Ingredients are Determined to be GRAS/E

                                                   Relabeling Costs ..........................         $0.11           $0.19        $0.32         $0.01          $0.02        $0.04         $0.02        $0.03       $0.05
                                                   Reformulation Costs ....................             0.23            0.46         0.70          0.03           0.05         0.08          0.03         0.07        0.10

                                                        Total Costs ............................           0.34         0.66         1.02          0.04           0.08           0.12        0.05         0.09        0.14




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                                                   42932                       Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules

                                                                         TABLE 7—SUMMARY OF QUANTIFIED TOTAL COSTS (IN MILLIONS), BY SCENARIO—Continued
                                                                                                              One-time costs                                    Annualized costs over a 10-year period

                                                               Cost category                                                                              3% Discount rate                       7% Discount rate
                                                                                                     Low           Med.            High
                                                                                                                                                Low            Med.          High          Low         Med.         High

                                                                                             Scenario 2: Assuming None of the Ingredients is Determined to be GRAS/E

                                                   Relabeling Costs ..........................             6.55        11.36        18.76          0.77           1.33           2.20        0.93         1.62        2.67
                                                   Reformulation Costs ....................                9.44        18.89        28.33          1.11           2.21           3.32        1.34         2.69        4.03

                                                        Total Costs ............................       15.99           30.25        47.09          1.87           3.55           5.52        2.28         4.31        6.70



                                                      A potential benefit of the proposed                         the proposed rule’s burden on small                    and an opportunity for State and local
                                                   rule is that the removal of potentially                        entities, such as extending relabeling                 officials to comment on this rulemaking.
                                                   harmful antiseptic active ingredients in                       compliance times to 18 months (rather
                                                                                                                                                                         XIV. References
                                                   consumer antiseptic rub products will                          than 12 months).
                                                   prevent health consequences associated                            The full analysis of economic impacts                 The following references are on
                                                   with exposure to such ingredients. FDA                         is available in the docket for this                    display in the Division of Dockets
                                                   lacks the necessary information to                             proposed rule (Docket No. FDA–2016–                    Management (see ADDRESSES) and are
                                                   estimate the impact of exposure to                             N–0124) and at http://www.fda.gov/                     available for viewing by interested
                                                   antiseptic active ingredients in                               AboutFDA/ReportsManualsForms/                          persons between 9 a.m. and 4 p.m.
                                                   consumer antiseptic rub products on                            Reports/EconomicAnalyses/default.htm.                  Monday through Friday; they are also
                                                   human health outcomes. We are,                                                                                        available electronically at http://
                                                   however, able to estimate the reduction                        XI. Paperwork Reduction Act of 1995                    www.regulations.gov. FDA has verified
                                                   in the aggregate exposure to antiseptic                                                                               the Web site addresses, as of the date
                                                                                                                    This proposed rule contains no
                                                   active ingredients found in currently                                                                                 this document publishes in the Federal
                                                                                                                  collections of information. Therefore,
                                                   marketed consumer antiseptic rub                                                                                      Register, but Web sites are subject to
                                                                                                                  clearance by the Office of Management
                                                   products. As with the total costs, the                                                                                change over time.
                                                                                                                  and Budget under the Paperwork
                                                   reduction in aggregate exposure to                                                                                    1. Brown, T.L. et al., ‘‘Can Alcohol-Based
                                                                                                                  Reduction Act of 1995 is not required.
                                                   antiseptic active ingredients in                                                                                           Hand-Rub Solutions Cause You to Lose
                                                   consumer rub products depends on the                           XII. Analysis of Environmental Impact                       Your Driver’s License? Comparative
                                                   outcome of testing and the                                                                                                 Cutaneous Absorption of Various
                                                   determination of GRAS/E status of the                            We have determined under 21 CFR                           Alcohols,’’ Antimicrobial Agents and
                                                   three ingredients that require testing.                        25.31(a) that this action is of a type that                 Chemotherapy, 51:1107–1108, 2007.
                                                   The proposed rule will lead to an                              does not individually or cumulatively                       Available at http://
                                                                                                                  have a significant effect on the human                      www.ncbi.nlm.nih.gov/pmc/articles/
                                                   estimated reduction that ranges from                                                                                       PMC1803104/.
                                                   110 pounds to 254 pounds per year in                           environment. Therefore, neither an
                                                                                                                  environmental assessment nor an                        2. Calafat, A.M. et al., ‘‘Urinary
                                                   scenario 1 and from 13,080,963 and                                                                                         Concentrations of Triclosan in the U.S.
                                                   67,272,847 pounds per year in scenario                         environmental impact statement is                           Population: 2003–2004,’’ Environmental
                                                   2. Absent information on the change in                         required.                                                   Health Perspective, 116:303–307, 2008.
                                                   the short- and long-term health risks                          XIII. Federalism                                            Available at http://
                                                   associated with a one pound increase in                                                                                    www.ncbi.nlm.nih.gov/pmc/articles/
                                                   exposure to each antiseptic active                                We have analyzed this proposed rule                      PMC2265044/.
                                                   ingredient in consumer antiseptic rub                          in accordance with the principles set                  3. Centers for Disease Control and
                                                                                                                  forth in Executive Order 13132. Section                     Prevention, ‘‘Fourth National Report on
                                                   products, we are unable to translate the                                                                                   Human Exposure to Environmental
                                                   aggregate exposure figures into                                4(a) of the Executive order requires                        Chemicals, Updated Tables, July 2010,’’
                                                   monetized benefits.                                            agencies to ‘‘construe . . . a Federal                      2010. Available at http://www.cdc.gov/
                                                      FDA also examined the economic                              statute to preempt State law only where                     exposurereport/.
                                                   implications of the rule as required by                        the statute contains an express                        4. Kramer, A. et al., ‘‘Quantity of Ethanol
                                                   the Regulatory Flexibility Act. If a rule                      preemption provision or there is some                       Absorption After Excessive Hand
                                                   will have a significant economic impact                        other clear evidence that the Congress                      Disinfection Using Three Commercially
                                                   on a substantial number of small                               intended preemption of State law, or                        Available Hand Rubs Is Minimal and
                                                   entities, the Regulatory Flexibility Act                       where the exercise of State authority                       Below Toxic Levels for Humans,’’
                                                                                                                                                                              BioMed Central Infectious Diseases,
                                                   requires agencies to analyze regulatory                        conflicts with the exercise of Federal                      7:117, 2007. Available at http://
                                                   options that would lessen the economic                         authority under the Federal statute.’’                      www.pubfacts.com/detail/17927841/
                                                   effect of the rule on small entities. This                     The sole statutory provision giving                         Quantity-of-ethanol-absorption-after-
                                                   proposed rule could impose a                                   preemptive effect to this proposed rule                     excessive-hand-disinfection-using-three-
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                   significant economic impact on a                               is section 751 of the FD&C Act (21                          commercially-available-.
                                                   substantial number of small entities. For                      U.S.C. 379r). We have complied with all                5. Miller, M.A. et al., ‘‘Does the Clinical Use
                                                   small entities, we estimate the rule’s                         of the applicable requirements under                        of Ethanol-Based Hand Sanitizer Elevate
                                                   one-time costs to roughly range between                        the Executive order and have                                Blood Alcohol Levels? A Prospective
                                                                                                                                                                              Study,’’ American Journal of Emergency
                                                   0.001 and 0.16 percent of average                              determined that the preemptive effect of                    Medicine, 24:815–817, 2006. Available at
                                                   annual value of shipments for a small                          this proposed rule, if finalized, would                     http://www.ajemjournal.com/article/
                                                   business. In the Initial Regulatory                            be consistent with Executive Order                          S0735-6757(06)00131-8/pdf.
                                                   Flexibility Analysis, we assess                                13132. Through publication of this                     6. Transcript of the January 22, 1997, Meeting
                                                   regulatory options that would reduce                           proposed rule, we are providing notice                      of the Joint Nonprescription Drugs and



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                                                                           Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                               42933

                                                        Anti-Infective Drugs Advisory                           FDA–1975–N–0012–0204, FDA–1975–                        ajph.aphapublications.org/doi/pdf/
                                                        Committees, OTC Vol. 230002. Available                  N–0012–0206, FDA–1975–N–0012–0208,                     10.2105/AJPH.79.1.92.
                                                        in Docket No. FDA 2015–N–0101 at                        FDA–1975–N–0012–0209, FDA–1975–                   28. FDA Review of Health Care Personnel
                                                        http://www.regulations.gov.                             N–0012–0212, FDA–1975–N–0012–0213,                     Hand Wash Effectiveness Data, OTC Vol.
                                                   7. Comment submitted in Docket No. FDA–                      FDA–1975–N–0012–0215, FDA–1975–                        03HCATFM, available at http://
                                                        1975–N–0012 available at http://                        N–0012–0217, FDA–1975–N–0012–0218,                     www.regulations.gov in Docket No.
                                                        www.regulations.gov with Comment No.                    FDA–1975–N–0012–0219, FDA–1975–                        FDA–2016–N–0101.
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                                                   8. Transcript of the March 23, 2005,                         FDA–1975–N–0012–0238, FDA–1975–                        Hand Rubs Clinical Simulation Data,’’
                                                        Nonprescription Drugs Advisory                          N–0012–0241, FDA–1975–N–0012–0243,                     2015, available at http://
                                                        Committee. Available in Docket No. FDA                  FDA–1975–N–0012–0258, FDA–1975–                        www.regulations.gov in Docket No.
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                                                   9. Transcript of the October 20, 2005,                       N–0012–0275, FDA–1975–N–0012–0276,                     Meeting of the Nonprescription Drugs
                                                        Meeting of the Nonprescription Drugs                    FDA–1975–N–0012–0281, FDA–1975–                        Advisory Committee,’’ available at
                                                        Advisory Committee, available at http://                N–0012–0282, FDA–1975–N–0012–0284,                     http://www.fda.gov/ohrms/dockets/ac/
                                                        www.fda.gov/ohrms/dockets/ac/05/                        FDA–1975–N–0012–0285, FDA–1975–                        05/briefing/2005-4098B1_02_01-FDA-
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                                                        Available in Docket No. FDA 2015–N–                     available at http://www.regulations.gov.               1680, 2008. Available at http://
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                                                        Meeting of the Nonprescription Drugs               16. Comment No. FDA–1975–N–0012–0091                   32. Comments submitted in Docket No. FDA–
                                                        Advisory Committee, available at http://                available at http://www.regulations.gov.               1975–N–0012 available at http://
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                                                                                                                available at http://www.regulations.gov.               FDA–1975–N–0012–0082, FDA–1975–
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                                                                                                                                                                  33. Comments submitted in Docket No. FDA–
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                                                                                                                                                                       1975–N–0012 available at http://
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                                                        FDA–1975–N–0012–0037, FDA–1975–                         available at http://www.regulations.gov.               FDA–1975–N–0012–0073, FDA–1975–
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                                                        FDA–1975–N–0012–0071, FDA–1975–                         Prevention, ‘‘Clean Hands Save Lives:                  FDA–1975–N–0012–0081, FDA–1975–
                                                        N–0012–0073, FDA–1975–N–0012–0075,                      Emergency Situations,’’ available at                   N–0012–0085, FDA–1975–N–0012–0089,
                                                        FDA–1975–N–0012–0081, FDA–1975–                         http://emergency.cdc.gov/disasters/                    FDA–1975–N–0012–0093, FDA–1975–
                                                        N–0012–0082, FDA–1975–N–0012–0085,                      handhygienefacts.asp.                                  N–0012–0096, FDA–1975–N–0012–0105,
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                                                        N–0012–0088, FDA–1975–N–0012–0089,                      Infectious Diseases, ‘‘Common Colds:                   N–0012–0108, FDA–1975–N–0012–0109,
                                                        FDA–1975–N–0012–0090, FDA–1975–                         Protect Yourself and Others,’’ available               FDA–1975–N–0012–0113, FDA–1975–
                                                        N–0012–0091, FDA–1975–N–0012–0093,                      at http://www.niaid.nih.gov/topics/                    N–0012–0116, FDA–1975–N–0012–0117,
                                                        FDA–1975–N–0012–0094, FDA–1975–                         commoncold/Pages/default.aspx.                         FDA–1975–N–0012–0119, FDA–1975–
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                                                        FDA–1975–N–0012–0097, FDA–1975–                         Studies in Consumer Use Settings,’’                    FDA–1975–N–0012–0153, FDA–1975–
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                                                        FDA–1975–N–0012–0118, FDA–1975–                         Infection Control Practices Advisory                   FDA–1975–N–0012–0286, FDA–1975–
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                                                        FDA–1975–N–0012–0124, FDA–1975–                         APIC/IDSA Hand Hygiene Task Force,’’                   FDA–1975–N–0012–0266, FDA–1975–
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                                                        FDA–1975–N–0012–0157, FDA–1975–                         Prevention (CDC) Hospital Infection
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                                                                                                                                       FDA–1975–N–0012–0172, FDA–1975–
                                                        N–0012–0158, FDA–1975–N–0012–0161,                      Control Practices Advisory Committee,’’                N–0012–0264, FDA–1975–N–0012–0178,
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                                                                           Federal Register / Vol. 81, No. 126 / Thursday, June 30, 2016 / Proposed Rules                                                 42937

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                                                       Propanol and Isopropanol Administered                   Avilable at http://www.ajicjournal.org/               Administrative practice and
                                                       at High Inhalation Concentrations to                    article/S0196–6553(11)00227-6/pdf.
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                                                       toxsci.oxfordjournals.org/content/22/1/                 Safety, ‘‘2-Propanol,’’ 1990, available at         2013, at 78 FR 76444, and May 1, 2015,
                                                       139.full.pdf+html.                                      http://www.inchem.org/documents/ehc/               at 80 FR 25166, is proposed to be further
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                                                       Reproductive Toxicity Study with                        ehc103.htm#SectionNumber%3A8.3.
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                                                   136. McEvoy, E.M., P.C. Wright, and M.T.                    Metabolism and Disposition, 26:197–
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                                                       Growth of a Solvent-Tolerant Strain of                  197.full.pdf+html.                                 361(a), 371, 374, 375, 379e, 379k–1; 42 U.S.C.
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                                                                                                                                                                  ■  2. In § 310.545:
                                                       Available at http://ac.els-cdn.com/                     Isopropyl Alcohol by Oral, Dermal and
                                                       S0141022904001085/1-s2.0-S014102290                     Inhalation Routes,’’ Veterinary and                ■  a. Add paragraph (a)(27)(v);
                                                       4001085-main.pdf?_tid=b24dcd2a-2b59-                    Human Toxicology, 28:233–236, 1986.                ■ b. In paragraph (d) introductory text,
                                                       11e6-9e77-00000aa                                       Available at http://europepmc.org/                 remove ‘‘(d)(42)’’ and in its place add
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                                                       Isopropanol by a Solvent-Tolerant                       344 Rats and B6C3F1 Mice,’’
                                                       Paracoccus denitrificans Strain,’’                      Fundamental and Applied Toxicology,                § 310.545 Drug products containing
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                                                       Available at http://                                    407.full.pdf.
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                                                   138. Bustard, M.T. et al., ‘‘Biodegradation of              Relevance to Hazard Identification,’’                (v) Consumer antiseptic rub drug
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                                                       Solvent-Tolerant Thermophile, Bacillus                  Pharmacology, 23:183–192, 1996.                    YEAR AFTER DATE OF PUBLICATION
                                                       pallidus,’’ Extremophiles, 6:319–323,                   Available at http://
                                                                                                                                                                  OF THE FINAL RULE IN THE Federal
                                                       2002. Available at https://                             www.sciencedirect.com/science/article/
                                                       www.researchgate.net/publication/                       pii/S0273230096900422.                             Register]:
                                                       11173057_Biodegradation_of_high-                    149. WHO International Program on                      Alcohol (ethanol and ethyl alcohol)
                                                       concentration_isopropanol_by_a_                         Chemical Safety Working Group,                     Benzalkonium chloride
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                                                       Propanol-Containing Skin Disinfectant,’’            150. World Health Organization International             (43) [DATE 1 YEAR AFTER DATE OF
                                                       Langenbeck’s Archives of Surgery.,                      Agency for Research on Cancer, ‘‘IARC              PUBLICATION OF THE FINAL RULE
                                                       394:151–157, 2009. Available at http://                 Monographs on the Evaluation of
                                                                                                                                                                  IN THE Federal Register], for products
                                                       www.springer.com/medicine/surgery/                      Carcinogenic Risks to Humans: Re-
                                                       journal/423.                                            evaluation of Some Organic Chemicals,              subject to paragraph (a)(27)(v) of this
                                                   140. Turner, P., B. Saeed, and M.C. Kelsey,                 Hydrazine and Hydrogen Peroxide,’’ 71              section.
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                                                       Decontamination,’’ The Journal of                   151. Burleigh-Flayer, H. et al., ‘‘Isopropanol         Associate Commissioner for Policy.
sradovich on DSK3GDR082PROD with PROPOSALS3




                                                       Hospital Infection, 56:287–290, 2004.                   Vapor Inhalation Oncogenicity Study in             [FR Doc. 2016–15410 Filed 6–29–16; 8:45 am]
                                                       Available at http://                                    Fischer 344 Rats and CD–1 Mice,’’                  BILLING CODE 4164–01–P




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Document Created: 2018-02-08 07:44:58
Document Modified: 2018-02-08 07:44:58
CategoryRegulatory Information
CollectionFederal Register
sudoc ClassAE 2.7:
GS 4.107:
AE 2.106:
PublisherOffice of the Federal Register, National Archives and Records Administration
SectionProposed Rules
ActionProposed rule.
DatesSubmit electronic or written comments by December 27, 2016. See section IX of this document for the proposed effective date of a final rule based on this proposed rule.
ContactAnita Kumar, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 5445, Silver Spring, MD 20993, 301-796- 1032.
FR Citation81 FR 42912 
RIN Number0910-AF69
CFR AssociatedAdministrative Practice and Procedure; Drugs; Labeling; Medical Devices and Reporting and Recordkeeping Requirements

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