80 FR 10026 - Over-the-Counter Sunscreen Drug Products-Regulatory Status of Enzacamene

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 80, Issue 37 (February 25, 2015)

Page Range		10026-10035
FR Document		2015-03884

The Food and Drug Administration (FDA or the Agency) is issuing a proposed sunscreen order (proposed order) under the Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended by the Sunscreen Innovation Act (SIA). The proposed order announces FDA's tentative determination that enzacamene is not generally recognized as safe and effective (GRASE) and is misbranded when used in over-the- counter (OTC) sunscreen products because the currently available data are insufficient to classify it as GRASE and not misbranded, and additional information is needed to allow us to determine otherwise.

Federal Register, Volume 80 Issue 37 (Wednesday, February 25, 2015)

[Federal Register Volume 80, Number 37 (Wednesday, February 25, 2015)]
[Proposed Rules]
[Pages 10026-10035]
From the Federal Register Online [www.thefederalregister.org]
[FR Doc No: 2015-03884]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket Nos. FDA-2003-N-0196 (Formerly 2003N-0233), FDA-1978-N-0018
(Formerly 1978N-0038 and 78N-0038), and FDA-1996-N-0006 (Formerly 96N-
0277)]

Over-the-Counter Sunscreen Drug Products--Regulatory Status of
Enzacamene

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed order; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
issuing a proposed sunscreen order (proposed order) under the Federal
Food, Drug, and Cosmetic Act (the FD&C Act), as amended by the
Sunscreen Innovation Act (SIA). The proposed order announces FDA's
tentative determination that enzacamene is not generally recognized as
safe and effective (GRASE) and is misbranded when used in over-the-
counter (OTC) sunscreen products because the currently available data
are insufficient to classify it as GRASE and not misbranded, and
additional information is needed to allow us to determine otherwise.

DATES: Submit either electronic or written comments on this proposed
order by April 13, 2015. Sponsors may submit written requests for a
meeting with FDA to discuss this proposed order by March 27, 2015. See
section VI for the proposed effective date of a final order based on
this proposed order.

ADDRESSES: You may submit comments by any of the following methods:

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

Submit written submissions in the following ways:
Mail/Hand delivery/Courier (for paper submissions):
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

[[Page 10027]]

Instructions: All submissions received must clearly identify the
specific active ingredient (enzacamene) and the Docket Nos. FDA-2003-N-
0196, FDA-1978-N-0018, and FDA-1996-N-0006 for this rulemaking. All
comments received may be posted without change to http://www.regulations.gov, including any personal information provided. For
additional information on submitting comments, see the ``Comments''
heading of the SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket numbers, 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.
Submit requests for a meeting with FDA to discuss this proposed
order to Kristen Hardin (see FOR FURTHER INFORMATION CONTACT).

FOR FURTHER INFORMATION CONTACT: Kristen Hardin, Division of
Nonprescription Drug Products, Center for Drug Evaluation and Research,
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm.
5491, Silver Spring, MD 20993-0002, 240-402-4246.

SUPPLEMENTARY INFORMATION:

I. Regulatory Background

A. Regulatory and Statutory Framework

The data and information addressed in this proposed order were
originally submitted for review under FDA's Time and Extent Application
(TEA) regulation, Sec. 330.14 (21 CFR 330.14), a process that has
since been supplemented with new statutory procedures established in
the SIA (Pub. L. 113-195), enacted November 26, 2014. The discussion
that follows briefly describes and compares the pre- and post-SIA
processes as they apply to the regulatory status of enzacamene.
The TEA regulation established a process through which a sponsor
could request that an active ingredient or other OTC condition,\1\
particularly one not previously marketed in the United States, be added
to an OTC drug monograph to enable compliant OTC drug products
containing the condition to be marketed in the United States without an
approved new drug application (NDA) or abbreviated new drug application
(ANDA). Because this proposed order specifically addresses an OTC
sunscreen active ingredient (enzacamene), the remainder of this
discussion will refer only to ``active ingredients.''
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\1\ For purposes of OTC drug regulation, a ``condition'' is
defined as an active ingredient or botanical drug substance (or a
combination of active ingredients or botanical drug substances),
dosage form, dosage strength, or route of administration marketed
for a specific OTC use, with specific exclusions (see Sec.
330.14(a)(2)). This document will refer simply to new ``active
ingredients,'' since that is the condition under consideration.
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Critical steps in a proceeding under the TEA regulation include the
following: (1) FDA's determination that an active ingredient had been
marketed for the proposed OTC use for a material time and to a material
extent (eligibility determination), and public call for submission of
safety and efficacy data, followed by; (2) review of safety and
efficacy data submitted by the sponsor or other interested parties; and
(3) FDA's initial determination that the data show the active
ingredient to be either GRASE or not GRASE for OTC use under the
applicable monograph conditions (including any new conditions rising
from FDA's review) (GRASE determination). Under the TEA regulation,
FDA's GRASE determinations are effectuated through notice and comment
rulemaking to amend or establish the appropriate monograph.
The TEA process in FDA regulations was supplemented by Congress's
enactment of the SIA. Among other amendments it makes to the FD&C Act,
the SIA creates new procedures specifically for reviewing the safety
and effectiveness of nonprescription sunscreen active ingredients,
including those, such as enzacamene, that were the subject of pending
TEA proceedings at the time the SIA was enacted. Like the TEA
regulation, the SIA calls for an initial eligibility determination
phase for nonprescription sunscreen active ingredients, followed by
submissions of safety and efficacy data and a GRASE determination
phase. However, the SIA requires FDA to make proposed and final GRASE
determinations for nonprescription sunscreen active ingredients in the
form of administrative orders rather than the multistep public
rulemaking required by the TEA regulation, and establishes strict
timelines for the necessary administrative actions.
Among other requirements, no later than 90 days after the SIA was
enacted (i.e., no later than February 24, 2015), FDA must publish a
proposed sunscreen order in the Federal Register for any
nonprescription sunscreen active ingredient, including enzacamene, for
which, on the date of enactment, an eligibility determination had been
issued under the TEA regulation and submissions of safety and efficacy
data received, and for which a TEA feedback letter had not yet been
issued (section 586C(b)(4) of the FD&C Act (21 U.S.C. 360fff-3(b)(4)),
as amended by the SIA). Other provisions of the SIA that are not
discussed in this proposed order address procedures applicable to other
pending and future sunscreen active ingredient GRASE determinations,
pending and future GRASE determinations for OTC products other than
sunscreens, issuance of specified guidances and reports, and completion
of pending sunscreen rulemakings, among others.
A proposed sunscreen order under the SIA is an order containing
FDA's tentative determination proposing that a nonprescription
sunscreen active ingredient or combination of ingredients: (1) Is GRASE
and is not misbranded when marketed in accordance with the proposed
order; (2) is not GRASE and is misbranded; or (3) is not GRASE and is
misbranded because the data are insufficient to classify the active
ingredient or combination of ingredients as GRASE and not misbranded,
and additional information is necessary to allow FDA to determine
otherwise (section 586(7) of the FD&C Act, as amended by the SIA).
Publication of a proposed sunscreen order triggers several timelines
under the SIA, including a 45-day public comment period, and a 30-day
period in which a sponsor may request a meeting with FDA to discuss the
proposed order.

B. FDA's Review of Enzacamene

Buchanan Ingersoll submitted a TEA in 2002 on behalf of Merck KGaA
under Sec. 330.14(c) seeking OTC monograph status for the sunscreen
active ingredient enzacamene (also known as 4-Methylbenzylidene Camphor
(4-MBC) or Eusolex 6300) at concentrations up to 4 percent for use in
OTC sunscreen products (enzacamene TEA) (Note 1). FDA issued a TEA
notice of eligibility for enzacamene on July 11, 2003 (68 FR 41386),
stating that enzacamene at concentrations of up to 4 percent is
eligible to be considered for inclusion in the OTC sunscreen monograph
(21 CFR part 352, currently stayed) and calling for submission of
safety and effectiveness data for enzacamene. In response, a submission
of data dated October 9, 2003, was made to the docket on behalf of
Merck KGaA (enzacamene data submission) (Note 2), which referred to
materials previously submitted to other dockets.\2\ At the time

[[Page 10028]]

the SIA was enacted, FDA had not issued a TEA feedback letter or
otherwise responded to that submission.
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\2\ These include FDA-1978-N-0018-0744-0756 (Sup 24, 25, 26, 27
and 28), Request to Reopen Rulemaking Record Respect Sunscreen Drug
Products for OTC, submitted on April 12, 1999 (1999 enzacamene
submission); FDA-1978-N-0018-0766, Citizen Petition (CP1), submitted
on December 17, 1980; and Tracking number: 805596eb Legacy Doc. ID,
SUP 5, ``Supplement from Rona Pearle'' SUP5, submitted on August 15,
1985.
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In accordance with new section 586C(b)(4) of the FD&C Act as
amended by the SIA, we are issuing this notice as a proposed order for
enzacamene. Based on our review of the available safety and efficacy
data, we have made a tentative determination that enzacamene is not
GRASE and is misbranded because the data are insufficient to classify
it as GRASE and not misbranded for use in OTC sunscreens, and
additional information is necessary to allow us to determine otherwise.
The remainder of this proposed sunscreen order describes our review of
the available safety and efficacy data, identifies additional data
needed to demonstrate that enzacamene is GRASE for the requested use,
and explains our rationale for specific conclusions and data
requirements.
This proposed order will be open for public comment (see DATES).
The sponsor may request a meeting with FDA to discuss this proposed
order (see DATES). We also invite the sponsor to submit additional
safety and/or efficacy data to inform our further consideration, as
publication of a final sunscreen order under the SIA for enzacamene
will be contingent on receipt of such information. (See section
586C(b)(9)(ii) of the FD&C Act.) We specifically encourage the sponsor
to discuss any proposed study protocols with us before performing the
studies.

II. Safety Data Considerations for OTC Sunscreen Products Containing
Enzacamene

In evaluating the safety of a proposed monograph active ingredient,
FDA applies the following regulatory standard: Safety means a low
incidence of adverse reactions or significant side effects under
adequate directions for use and warnings against unsafe use as well as
low potential for harm which may result from abuse under conditions of
widespread availability. Proof of safety shall consist of adequate
tests by methods reasonably applicable to show the drug is safe under
the prescribed, recommended, or suggested conditions of use. This proof
shall include results of significant human experience during marketing.
General recognition of safety shall ordinarily be based upon published
studies which may be corroborated by unpublished studies and other data
(Sec. 330.10(a)(4)(i) (21 CFR 330.10(a)(4)(i))).
FDA's OTC drug regulations generally identify the types of
information that may be submitted as evidence that an active ingredient
or other OTC drug condition is safe, as part of the consideration of
whether an active ingredient or other condition is GRASE (Sec.
330.10(a)(2)). For convenience, this order uses the term ``generally
recognized as safe (GRAS)'' to refer to that aspect of the GRASE
determination. To apply the general OTC safety standard to each
potential new condition, FDA uses its scientific expertise to determine
what constitutes ``adequate tests by methods reasonably applicable to
show the drug is safe under the prescribed, recommended, or suggested
conditions of use.'' In assessing what specific testing or other data
are needed to adequately demonstrate the safety of enzacamene for use
in sunscreen, FDA considers the circumstances under which OTC sunscreen
products that could contain enzacamene would be used by consumers.
When used as directed with other sun protection measures, broad
spectrum OTC sunscreen products with a sun protection factor (SPF)
value of 15 or higher strongly benefit the public health by decreasing
the risk of skin cancer and premature skin aging associated with solar
ultraviolet (UV) radiation, as well as by helping to prevent sunburn.
(Sunscreens with lower SPF values, or without broad spectrum
protection, also help prevent sunburn.) When used as directed by the
required labeling, all OTC sunscreen products are applied liberally to
the skin and reapplied frequently throughout the day (Sec. 201.327(e)
(21 CFR 201.327(e))). Because the effects of UV exposure are
cumulative, to obtain the maximum benefit, users of broad spectrum
sunscreens with an SPF value of 15 or higher are directed to use such
products regularly--on a routine basis (id.). Given these conditions of
use, our safety evaluation of an OTC sunscreen active ingredient such
as enzacamene must consider both short-term safety concerns (such as
skin sensitization/irritation and photosafety) and potential concerns
related to long-term sunscreen use, including potential systemic
exposure via dermal absorption.
The purpose of the safety testing described in this section II is
to establish whether an OTC sunscreen product containing enzacamene and
otherwise marketed under the conditions described in a final sunscreen
order and in accordance with all requirements applicable to
nonprescription drugs would be GRAS for use as labeled. To demonstrate
that these requirements are met for enzacamene, initial safety testing
should be performed using enzacamene as the sole active ingredient up
to the highest concentration for which marketing status is sought and
eligibility has been established: 4 percent. If initial testing
suggests a particular safety concern associated with enzacamene (e.g.,
a hormonal activity), FDA may request additional studies to address
that concern.

A. Human Safety Data

1. Human Irritation, Sensitization, and Photosafety Studies
Studies of skin irritation, sensitization, and photosafety are
standard elements in the safety evaluation of topical drug products
that, like enzacamene-containing sunscreens, are applied to the skin
repeatedly over long periods of time. FDA recommends separate studies
for skin irritation and sensitization. Skin irritation studies should
generally include at least 30 evaluable subjects and should evaluate
the test formulation (i.e., enzacamene in an appropriate test vehicle),
the vehicle alone, and both negative and positive controls. Skin
sensitization studies generally should include at least 200 subjects
and should evaluate the test formulation containing enzacamene, the
vehicle, and a negative control. For both irritation and sensitization
studies, test site applications should be randomized and the test
observer blinded to the identities of the test formulations.
FDA recommends that photosafety evaluation generally involve
studies of skin photoirritation (phototoxicity) and skin
photosensitization (photoallergenicity). General principles for
designing and conducting photosafety studies are described in FDA
guidance (Ref. 1). Photosafety studies, like sensitization and
irritation studies, should be conducted using enzacamene 4 percent in
an appropriate test vehicle, the vehicle alone, and a negative control.
In addition, phototoxicity studies should include at least 30 evaluable
subjects and photoallerginicity studies should include at least 45
evaluable subjects.
Data Available for Enzacamene: Human Irritation, Sensitization, and
Photosafety Studies
We reviewed the submitted study reports for human safety studies,
including a skin irritation and sensitization study of enzacamene 5
percent in 30 subjects (Note 3); skin

[[Page 10029]]

irritation and sensitization study of enzacamene 5 percent in 10
subjects (Note 4); a photoirritation study of 4 percent enzacamene in 5
subjects (Note 5); and two photosensitization studies, one using 4
percent enzacamene in 5 subjects and the other using an unknown
concentration in 25 subjects (Notes 6 and 7). Although these studies
suggest that enzacamene may not be a primary irritant, sensitizer,
photosensitizer, or photoirritant, each of the submitted studies has
limitations, such as inadequate sample size, lack of blinding, and lack
of positive and negative controls, that prevent us from making
definitive conclusions. In addition, protocol information, such as the
inclusion and exclusion criteria used in subject selection, was not
consistently provided.
FDA concludes that the data submitted are not sufficient to assess
the dermal safety of enzacamene and specifically its potential to cause
irritation, sensitization, photoirritation, or photoallergenicity. We
recommend submission of additional data from human irritation,
sensitization, and photosafety studies to demonstrate that an OTC
sunscreen containing up to 4 percent enzacamene is not an irritant,
sensitizer, photosensitizer, or photoirritant.
2. Human Dermal Pharmacokinetic (Bioavailability) Studies
Because sunscreens are topically applied, another important safety
consideration for enzacamene for use in sunscreens is whether dermal
application may result in skin penetration and systemic exposure to
enzacamene, and if so, to what extent. A well-designed and -conducted
human dermal pharmacokinetic study can be expected to detect and
quantify the presence of enzacamene and/or any metabolites in blood or
other bodily fluids that may have a bearing on safety, using recognized
parameters such as bioavailability percentage, maximum plasma
concentration (Cmax), time to maximum plasma concentration (Tmax),
total area under the plasma concentration versus time curve (AUC),
half-life, clearance, and volume of distribution. This information can
help identify potential safety concerns and help determine whether an
adequate safety margin for sunscreens containing enzacamene exists. FDA
recommends that the pharmacokinetic studies performed on enzacamene
also collect additional safety-related data from regularly scheduled
physical examinations, collection of vital signs, and other measures,
which may help capture adverse skin events or other potential safety
signals. To ensure that maximum penetration of enzacamene has taken
place and chances of it being detected are optimal, studies should
continue until steady state is reached.
General information and recommendations on the design and conduct
of human pharmacokinetic studies can be found in FDA guidance (Ref. 2).
To support a GRAS determination for enzacamene (up to 4 percent), such
a study should be conducted under maximal use conditions using
enzacamene 4 percent in various vehicles, including vehicles that would
be expected to enhance absorption. We encourage study sponsors to
consult with us before conducting pharmacokinetic studies, because the
properties of enzacamene bear on the optimal design.
Data Available for Enzacamene: Human Dermal Pharmacokinetic
(Bioavailability) and Clinical Pharmacology Studies
We reviewed three submitted reports of dermal absorption studies in
humans in which percutaneous absorption was estimated using
radiolabeled (\14\C) formulations of enzacamene. In one study (Note 8)
a \14\C-labeled 5 percent formulation of enzacamene was applied to the
lower arms of six volunteers for 6 hours, followed by a 3-day
collection of urine and feces. Investigators reported that
approximately 54.6 percent of the \14\C-activity applied to the skin
was recovered. An average of 0.76 percent enzacamene was recovered in
urine and 0.14 percent in the feces. In a second study (Note 9),
investigators reported a total recovery of 98.2 percent and 90.7
percent overall recovery of the \14\C-activity applied to the skin from
two volunteers, respectively. The third study report (Note 10) was
similar to the previous two studies in terms of the general design.
Following the analysis of the data from the planned six volunteers, two
more volunteers were enrolled to evaluate the low observed recovery (54
to 69 percent) of the radiolabeled enzacamene. A different recovery
schema was applied to these last two patients with satisfactory results
in line with the previous studies. As to the utility of the aggregate
data, we cannot draw definitive conclusions regarding the dermal
absorption of enzacamene based on these studies. The overall number of
subjects was low, the studies were single-dose studies, a limited
surface area was exposed to the formulation, the recovery of
radioactivity was variable, and finally no blood or other body fluids
were sampled to provide direct information about systemic exposure. We
also note that these studies were conducted in the 1980s and the limit
of analytical detection for enzacamene was much higher than it is
today.
A review of the published literature identified more recent studies
related to the extent of absorption of enzacamene in humans after
dermal application. A 2004 article from Janjua et al. (Ref. 3) reports
on the absorption from a formulation containing 10 percent enzacamene
and 2 other active sunscreen ingredients after whole body application
for 4 days in 15 healthy males and 17 postmenopausal females. The
article provides only summary bioavailability information but claims
that the maximum plasma concentrations were 20 milligrams (mg)/
milliliter (mL) in both men and women and that increasing plasma levels
of enzacamene and metabolites were seen, suggesting the presence of
accumulation. It is noted that thyroid function was also assessed
during this study, but results are confounded by the simultaneous
application of three active sunscreen ingredients. A 2006 article from
Shauer et al. (Ref. 4) includes in vivo pharmacokinetic data from six
healthy volunteers exposed to 4 percent enzacamene applied over 90
percent body surface area for a 12-hour period. The data are limited by
the small number of subjects included; however, there was gender-
related difference observed in those males who had blood levels that
were approximately twice that of females. A 2008 article by Janjua et
al. contains a more complete analysis of in vivo absorption for
enzacamene in a 10 percent enzacamene formulation (Ref. 5). The levels
of absorption were generally low but accumulation was observed.
However, the age of the females enrolled in the study was 2 to 3 times
that of the males, confounding the interpretation of age or gender
effects.
Overall, the data available are incomplete for the assessment of
human bioavailability (dermal absorption) of enzacamene. Accordingly,
we request data from human pharmacokinetic studies to assess potential
for and extent of systemic absorption. These studies should be
performed under expected maximal-use conditions with the proposed
maximum concentration as discussed previously.
In addition to the bioavailability data described previously, three
reports of clinical pharmacology studies were submitted that evaluate
the potential effect of enzacamene on thyroid function. The first was a
pilot study in which a 5 percent enzacamene formulation was applied
twice, at 3-hour intervals, to the abdomen and back

[[Page 10030]]

of four adult subjects (two males and two females) (Note 11).
Subsequent increases in the thyroid analytes thyroid-stimulating
hormone (TSH), T3, and T4 were observed in some subjects. Blood and
urine levels of enzacamene were reported to have been measured but no
data were reported. We consider the number of subjects in this study
too small to draw conclusions about the safety of enzacamene. In
addition, there were missing data and the report lacked information
about whether subjects' thyroid analyte levels exceeded normal levels.
A second study evaluated the effect on thyroid function of topical
application of 5 percent enzacamene (6 grams (g) applied twice, at 3-
hour intervals) in nine healthy volunteers (Note 12). This was a
double-blind, placebo-controlled, crossover design study, and
investigators reported that there was a statistically significant
lowering of mean T3 and T4 values in the active treatment group at 24
hours after application. Although larger than the pilot study, this is
a small single-dose study and the changes reported were small relative
to placebo and were of questionable clinical significance.
Interpretation of the results is also hampered by the fact that some
analytes (TSH and free T4) were below normal levels at baseline.
A third study was a parallel-group, placebo-controlled design in
which 48 subjects received treatment with either enzacamene (5 g of a 6
percent enzacamene formulation per dose) or placebo twice daily for 14
days (Note 13). According to the investigators, the results of the
study did not reveal any significant differences in thyroid function
tests between enzacamene and placebo, although there was a small
between-group difference in thyroid volume gland decrease (a 1.7
percent reduction in the enzacamene arm and an increase of 3.1 percent
in the placebo group). The quality of the study report submitted is
inadequate to be used to verify the analyses, but no adverse events of
hypothyroidism or hyperthyroidism or abnormal thyroid function tests
were reported.
The three clinical pharmacology studies submitted are insufficient
either to substantiate or dismiss clinical concerns related to
potential thyroid effects from enzacamene. We request submission of any
additional clinical thyroid function data or analyses that have not yet
been submitted to us, including any provided to the European Scientific
Committee on Cosmetic Products and Nonfood Products (SCCNFP) to support
its 2008 conclusion that enzacamene at a concentration up to 4 percent
is safe for use in finished cosmetic products for whole body
application (Ref. 6). If, after full review of nonclinical toxicology
data (discussed in section I.B of this proposed order) and any
additional clinical data, concerns exist regarding enzacamene's thyroid
safety, we will recommend that additional clinical study be carried
out. It is recommended that we be consulted regarding the study
protocols prior to commencement of such investigations.
3. Human Safety Data To Establish Adverse Event Profile
An evaluation of safety information from adverse event reports and
other safety-related information derived from commercial marketing
experience of sunscreen products containing enzacamene, as well as from
other sources, is a critical aspect of FDA's safety review for
enzacamene. The TEA regulation under which the original request for
enzacamene was submitted specifically calls for submission of
information on all serious adverse drug experiences, as defined in 21
CFR 310.305(a) and 314.80(a), from each country where the active
ingredient or other condition has been or is currently marketed as
either a prescription or OTC drug; in addition, it calls for submission
of all data generally specified in Sec. 330.10(a)(2), which includes
documented case reports and identification of expected or frequently
reported side effects (Sec. 330.14(f)(1) and (f)(2)). To evaluate
enzacamene, FDA continues to seek individual adverse drug experience
reports, a summary of all serious adverse drug experiences, and
expected or frequently reported side effects of the condition (id.). To
assist in the Agency's safety evaluation of enzacamene, FDA emphasizes
our need for the following data:
A summary of all available reported adverse events
potentially associated with enzacamene;
All available documented case reports of serious side
effects
Any available safety information from studies of the
safety and effectiveness of enzacamene in humans; and
Relevant medical literature describing adverse events
associated with enzacamene. Submissions of adverse event data should
also include a description of how each country's system identifies and
collects adverse events, unless this information has been previously
submitted as part of enzacamene's TEA package.
Although we recognize that adverse event data from foreign
marketing experience may reflect patterns of use and regulatory
reporting requirements that differ from those in the United States, we
nonetheless consider such information to be strongly relevant both to
our overall GRASE assessment of enzacamene for use in sunscreens and to
our consideration of potential product labeling. FDA recognizes that
such information may not be available from all countries; where that is
the case, please provide a written explanation for the lack of data.
Overall, we seek sufficient data to characterize enzacamene's adverse
event profile.\3\
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\3\ See 67 FR 3060 at 3069 (January 23, 2002) (agreeing that the
absence of an adverse experience reporting system in a foreign
country for drugs or cosmetics does not necessarily mean that a
condition cannot be GRAS/E. The GRAS/E determination will be based
on the overall quality of the data and information presented to
substantiate safety and effectiveness).
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Data Available for Enzacamene: Human Safety Data To Establish Adverse
Event Profile
The 1999 enzacamene submission states that no complaints from
customers concerning tolerance or adverse reactions had been reported
for enzacamene by the cosmetic industry during the prior 10 years (Note
14). This information was referred to in the 2002 TEA submission and
the 2003 enzacamene data submission. The 1999 enzacamene submission
also included a literature search for adverse reactions to enzacamene
from the following databases: Medline (1966-1998), Derwent Drug File
(1983-1998), and CCSearch (week 3 1998-week 48 1998) (Note 15). There
were 17 articles reviewed which had been published or translated into
English. Of these, 10 articles describe contact dermatitis and
resultant positive photopatch testing in one or two patients. The 7
other articles are literature or case series reviews of up to 400
patients, describing dermatologic adverse reactions to sunscreen use
and subsequent photopatch testing. On the whole, these reports suggest
that enzacamene has the potential to cause contact allergy and
photocontact allergy. However, data from this literature have
limitations. In some cases, the testing methodology used to determine
that enzacamene is an allergen is not described. Also, some of the test
formulations used are not described. It is conceivable that the
observed reactions may have been specific to particular test
formulations, including formulations containing other active
ingredients.
The submitted information and literature do not fulfill the
criteria described previously. To support the evaluation of safety of
enzacamene for

[[Page 10031]]

use in OTC sunscreens, we request that the sponsor either supplement
the data already submitted, including more recent adverse drug
experience data, or explain why such data cannot be provided.

B. Nonclinical (Animal) Studies

Another important element of FDA's GRAS review of enzacamene for
use in sunscreens is an assessment of data from nonclinical (animal)
studies that characterize the potential long-term dermal and systemic
effects of exposure to enzacamene. Even if the bioavailability data
discussed in section II.A.2 suggest that dermal application is unlikely
to result in skin penetration and systemic exposure to enzacamene, FDA
still considers data on the effects of systemic exposure to be an
important aspect of our safety evaluation of enzacamene. A
determination that enzacamene up to 4 percent is GRASE for use in
sunscreens would permit its use in as-yet-unknown product formulations,
which might in turn alter the skin penetration of the active
ingredient. Therefore, an understanding of the effects of enzacamene,
were systemic exposure to occur, is critical to determine whether and
how regulatory parameters can be defined to assure that all conforming
enzacamene-containing sunscreens would be GRASE as labeled.
FDA recommends animal testing of the potential long-term dermal and
systemic effects of exposure to enzacamene because these effects cannot
be easily assessed from previous human use. Taken together, the
carcinogenicity studies, developmental and reproductive toxicity
studies, and toxicokinetic studies described in sections II.B.1 through
II.B.3 should provide the information needed to characterize both the
potential dermal and systemic toxic effects and the levels of exposure
at which they occur. These data, when viewed in the context of human
exposure data, can be used to determine a margin of safety for use of
enzacamene in OTC sunscreens.
Data Available for Enzacamene: Nonclinical (Animal) Studies Generally
The enzacamene submissions included data from the following types
of nonclinical safety studies:

Acute-dose toxicity studies
[cir] Oral toxicity (rats, dogs) (Note 16)
[cir] Dermal toxicity (rats) (Note 17)
[cir] Intraperitoneal toxicity (rats) (Note 18)
[cir] Mucosal irritation (rabbits) (Note 19)
[cir] Skin irritation and sensitization (guinea pigs) (Note 20)
[cir] Phototoxicity potential (mice) (Note 21)
[cir] Photosensitization (guinea pig) (Note 22)
Repeat-dose toxicity studies
[cir] 17 days oral (rat) (Note 23)
[cir] 4 weeks oral (rat) (Note 24)
[cir] 13 weeks oral (rat) (Note 25)
[cir] Liver enzyme induction study (rat) (Note 26)
Genotoxicity and mutagenicity assays
[cir] Chromosome aberration assay (Chinese hamster V79 cells) (Note
27)
[cir] Mutagenicity (Salmonella typhimurium) (Note 28)
[cir] Photomutagenicity (S. typhimurium, Escherichia coli) (Note
29)
Reproductive and developmental toxicity studies
[cir] Orienting tests for embryotoxicity (rabbit) (Note 30)
[cir] Toxicological investigation (incubated hen's egg) (Note 31)
[cir] Teratogenicity (rat) (Note 32)

Based on the submitted studies, acute toxicity was low. However,
the standard battery of tests detected findings that we will consider
further as additional data become available to inform our GRAS
assessment. Studies submitted by the sponsor showed an increase in
thyroid weight and changes in thyroid function that included an
increase in T3 and TSH, along with a decrease in T4. Other thyroid
findings included follicular epithelium hypertrophy and hyperplasia. A
decrease in adrenal and prostate weights, and alterations in ovarian
weights (an increase was seen in some studies while decreased weight
was noted in others), was documented with a no observed adverse effect
level (NOAEL) of 25-30 mg/kilograms (kg)/day (Note 33).
To followup on these findings, we identified published literature
that describes related enzacamene activity. A number of these articles
indicate that exposure to enzacamene at high doses has been associated
with hormonal changes. Among the in vitro findings (Refs. 7 through
16), a number of articles described the in vitro binding activity of
enzacamene to estrogen (ER) and androgen (AR) receptors where it was
able to bind to ER[szlig] but showed inconsistent binding activity at
ER[alpha] receptors. No androgenic activity and mixed results for
antiandrogenic activity were also documented.
Other effects of enzacamene included in vivo alterations of
reproductive tissues and behavior in rats (Refs. 17 through 25).
Findings include decreased testis weight; increased prostate volume and
altered duct development; delayed preputial separation; decreased
prostate weight in males; and increased uterine weight, decreased
ovarian weight, and altered sexual behavior in females. Overall, we
cannot arrive at a final determination about the findings described in
the literature until we receive a complete nonclinical assessment as
described in sections II.B.1 through II.B.3.
We did not receive data from toxicokinetic or dermal or systemic
carcinogenicity studies. Upon assessment of all available information
for enzacamene and based on the nonclinical studies currently
recommended to support sunscreen development, the following nonclinical
studies are recommended to support the safety of enzacamene:

Dermal and systemic carcinogenicity
Fertility
Prenatal/postnatal toxicity
Toxicokinetics

Additional discussion of study findings and data gaps are provided
in the following subsections.
1. Carcinogenicity Studies: Dermal and Systemic
FDA guidance recommends that carcinogenicity studies be performed
for any pharmaceutical that is expected to be clinically used
continuously for at least 6 months or ``repeatedly in an intermittent
manner'' (Refs. 26, 27, and 28). Because the proposed use of enzacamene
in OTC sunscreens falls within this category, these studies should be
conducted to help establish that enzacamene is GRAS for its proposed
use. Carcinogenicity studies assist in characterizing potential dermal
and systemic risks by identifying the type of toxicity observed, the
level of exposure at which toxicity occurs, and the highest level of
exposure at which no adverse effects occur (i.e., NOAEL). The NOAEL
would then be used in determining the safety margin for human exposure
to sunscreens containing enzacamene.
Systemic carcinogenicity studies can also help to identify other
systemic or organ toxicities that may be associated with enzacamene,
such as hormonal effects. For example, the effect of persistent
disruption of particular endocrine gland systems (e.g., hypothalamic-
pituitary-adrenal axis), if any, can be captured by these assays.
Data Available for Enzacamene: Genotoxicity Studies
Enzacamene showed no evidence of DNA mutations in one standard Ames
test. A chromosomal aberration assay using a Chinese hamster V79 cell
line

[[Page 10032]]

and a photomutagenicity assay were negative. Although these studies
somewhat ease concerns about potential genotoxicity and mutagenicity,
they were not definitive evaluations of potential toxic effects from
long-term systemic or dermal exposure.
Data Available for Enzacamene: Carcinogenicity Studies
We did not receive dermal or systemic carcinogenicity studies.
Assessments of both dermal and systemic carcinogenicity are recommended
because sunscreen products containing enzacamene are expected to be
applied over large portions of the body with multiple daily
applications. In addition, as discussed previously, marketing of this
product according to a final sunscreen order might permit its
formulation in a variety of as-yet-unknown vehicles that might have an
impact on systemic absorption. Consequently, FDA seeks information on
dermal and system carcinogenicity, in case of the possibility that
systemic absorption could occur.
2. Developmental and Reproductive Toxicity (DART) Studies (Ref. 29)
FDA recommends conducting DART studies to evaluate the potential
effects that exposure to enzacamene may have on developing offspring
throughout gestation and postnatally until sexual maturation, as well
as on the reproductive competence of sexually mature male and female
animals. Gestational and neonatal stages of development may also be
particularly sensitive to active ingredients with hormonal activity.
For this reason, we recommend that these studies include assessments of
endpoints such as vaginal patency, preputial separation, anogenital
distance, and nipple retention, which can be incorporated into
traditional DART study designs to assess potential hormonal effects of
enzacamene on the developing offspring. We also recommend conducting
behavioral assessments (e.g., mating behavior) of offspring, which may
also detect neuroendocrine effects.
Data Available for Enzacamene: DART Studies
Potential reproductive and developmental effects from enzacamene
were evaluated in two embryotoxicity studies and one teratogenicity
study. Enzacamene did not show evidence of embryotoxicity in a pilot
rabbit test and hen's egg assay. In a teratogenicity study in rats with
oral administration of single daily doses of 10, 30, and 100 mg/kg of
enzacamene administered on days 6 to 15 after conception, enzacamene
was not found to be teratogenic in any of the treated groups.
Additional DART testing is recommended to assess fertility and prenatal
and postnatal development in a rodent model.
3. Toxicokinetics (Ref. 30)
We recommend conducting animal toxicokinetic studies because they
provide an important bridge between toxic levels seen in animal studies
and potential human exposure. Data from these studies can be correlated
to potential human exposure via clinical dermal pharmacokinetic study
findings. Toxicokinetic data could be collected as part of animal
studies being conducted to assess one or more of the safety parameters
described previously.
Data Available for Enzacamene: Toxicokinetics
No toxicokinetic data were submitted as part of any of the
nonclinical studies, thus it is difficult to bridge from animal
findings to potential human exposure. Toxicokinetic data should be
collected as part of the animal studies to allow exposure comparisons
between animals and humans.
Toxicokinetic data are particularly important to the evaluation of
enzacamene's safety for use in sunscreens because enzacamene appears to
have the potential to affect some endocrine-responsive endpoints. We
need toxicokinetic data to develop more information about exposure
parameters, in order to understand whether a margin of safety exists
between the exposures that cause the effects in animals and estimated
human exposures. Should we find, after review of a more complete
nonclinical program, that additional clinical studies are warranted, we
will provide additional recommendations regarding the design of the
studies.

III. Effectiveness Data Considerations for OTC Sunscreen Products
Containing Enzacamene

FDA's evaluation of the effectiveness of active ingredients under
consideration for inclusion in an OTC drug monograph is governed by the
following regulatory standard: Effectiveness means a reasonable
expectation that, in a significant proportion of the target population,
the pharmacological effect of the drug, when used under adequate
directions for use and warnings against unsafe use, will provide
clinically significant relief of the type claimed. Proof of efficacy
shall consist of controlled clinical investigations as defined in 21
CFR 314.126(b). Investigations may be corroborated by partially
controlled or uncontrolled studies, documented clinical studies by
qualified experts, and reports of significant human experience during
marketing. Isolated case reports, random experience, and reports
lacking the details that permit scientific evaluation will not be
considered. General recognition of effectiveness shall ordinarily be
based upon published studies which may be corroborated by unpublished
studies and other data (Sec. 330.10(a)(4)(ii)). For convenience, this
order uses the term ``generally recognized as effective'' (GRAE) when
referring to this aspect of the GRASE determination.
To evaluate the efficacy of enzacamene for use in OTC sunscreen
products, FDA requests evidence from at least two adequate and well-
controlled SPF studies showing that enzacamene effectively prevents
sunburn. To determine that enzacamene is GRAE for use in OTC sunscreens
at concentrations in a range with the proposed maximum strength of 4
percent as requested, two adequate and well-controlled SPF studies of
enzacamene at a lower concentration should be conducted according to
established standards.\4\ These SPF studies should demonstrate that the
selected concentration (below 4 percent) provides an SPF of 2 or more.
---------------------------------------------------------------------------

\4\ The upper bound of any concentration of enzacamene
ultimately established in the OTC sunscreen monograph will be
governed by the safety data, as well as by efficacy.
---------------------------------------------------------------------------

The current standard procedure for SPF testing is described in
FDA's regulations in Sec. 201.327(i).\5\ Further SPF tests for
enzacamene should be performed as described in these regulations, using
a test formulation containing enzacamene as the only active ingredient
to identify its contribution to the overall SPF test results. (See the
following subsection Data Available for Enzacamene: Effectiveness for
further discussion of submitted SPF tests.) The study should also
include a vehicle control arm in order to rule out any contribution the
vehicle may have on the SPF test results. Finally, as described in
Sec. 201.327(i), an SPF standard formulation comparator arm should be
another component of the study design.
---------------------------------------------------------------------------

\5\ Although the SPF testing procedure is used primarily for
final formulation testing of finished products marketed without
approved NDAs, under the sunscreen monograph, it is equally
applicable for determining whether or not a sunscreen active
ingredient is GRAE.
---------------------------------------------------------------------------

Although current sunscreen testing and labeling regulations also
specify a ``broad spectrum'' testing procedure to support related
labeling claims for certain OTC sunscreen products marketed without
approved new drug

[[Page 10033]]

applications that contain specified active ingredients included in the
stayed sunscreen monograph, those additional claims are permitted, but
not required (Sec. 201.327(c)(2) and (j)). Under current regulations,
sunscreen active ingredients need only be effective for the labeled
indication of sunburn prevention, for which the SPF test can provide
sufficient evidence. Consistent with this approach, we here do not
request broad spectrum testing data for enzacamene. Broad spectrum
protection is often, although not always, the result of the combined
contribution of multiple active ingredients in a final sunscreen
formulation. Thus, under the current regulations applicable to other
sunscreens, the determination of whether an individual sunscreen
product may be labeled as broad spectrum and bear the related
additional claims is made on a product-specific basis, applying
standard testing methods set forth in those regulations. If enzacamene
is established to be GRASE for use in nonprescription sunscreens (based
in part on the efficacy data requested here), the final order can
likewise address broad-spectrum testing and related labeling conditions
for final sunscreen formulations containing enzacamene.

Data Available for Enzacamene: Effectiveness

A total of 11 efficacy studies were submitted. Two studies, an in
vitro assessment and a field study, both dated from the 1970s, did not
use study designs that we consider valid for SPF assessment for a GRASE
determination (Docket No. 78N-0038, OTC Volume 060083, submitted
December 18, 1973; Docket No. 78N-0038, OTC Volume 060130, submitted
November 1974). The other nine studies all tested enzacamene as the
only active ingredient. These included two studies of 1.25 percent
enzacamene and three studies of 2.5 percent enzacamene, concentrations
within the range found eligible for consideration of GRASE status in
the Agency's 2003 eligibility determination, and three studies of 5
percent enzacamene and one study of 10 percent enzacamene,
concentrations above the maximum established to be eligible for
consideration, which studies we do not further address in this proposed
order. (FDA-1978-N-0018-0766, Citizen Petition (CP1), submitted
December 17, 1980.) In each of the five studies addressing enzacamene
at concentrations of 1.25 percent and 2.5 percent, enzacamene achieved
a mean SPF of 2, but there is substantial variability in the data and
it cannot be confirmed that that efficacy was established at any of the
concentrations tested. In addition, none of these study reports
specified the use of appropriate standard controls to validate the test
results. Currently, there are insufficient data to support a finding
that enzacamene is GRAE at concentrations up to 4 percent.
To support a finding that enzacamene is GRAE at concentrations up
to 4 percent, we request data from two adequate and well-controlled SPF
studies conducted according to established standards to demonstrate
that the lowest selected concentration provides an SPF of 2 or more.
Because no study has been identified that establishes that enzacamene
is effective at a concentration of 4 percent, we also recommend that
such a study be conducted and submitted.

IV. Summary of Current Data Gaps for Enzacamene

Based on our review of the available safety and efficacy data as
discussed previously, we request the types of data listed in this
section of the proposed order, at minimum, for us to reverse our
tentative determination that enzacamene is not GRASE and is misbranded
because the data are insufficient to classify enzacamene as GRASE and
not misbranded, and additional data are necessary to allow us to
determine otherwise. For additional information about the purpose and
design of studies recommended to address these data gaps, please refer
to the earlier sections of this proposed order referenced in
parentheses. We welcome discussions on design of any of the studies
prior to their commencement. We request the following types of data:

Safety Data (see section II)

A. Human Clinical Studies

1. Skin irritation/sensitization and photosafety (see section II.A.1)
2. Human dermal pharmacokinetic (bioavailability) studies (see section
II.A.2)
The need for additional human safety studies (e.g., for evaluation
of hormonal disruption) will be based on review of the completed
nonclinical studies, as recommended in section IV.C.

B. Human Safety Data To Establish Adverse Event Profile (II.A.3)

1. A summary of all available reported adverse events potentially
associated with enzacamene
2. All available documented case reports of serious side effects
3. Any available safety information from studies of the safety and
effectiveness of sunscreen products containing enzacamene in humans
4. Relevant medical literature describing adverse events associated
with enzacamene
Alternatively, the results of a literature search that found no
reports of adverse events may be provided. In that case, detailed
information on how the search was conducted should be provided.

C. Nonclinical (Animal) Studies

1. Dermal and systemic carcinogenicity (see section II.B.1)
2. Fertility (see section II.B.2)
3. Prenatal/postnatal development (see section II.B.2)
4. Toxicokinetics (see section II.B.3)

Effectiveness Data (see section III)
In order for concentrations of enzacamene up to 4 percent to be
found to be GRASE for use in nonprescription sunscreen products as
requested, at least two SPF studies showing effectiveness of a selected
concentration lower than 4 percent should be conducted. An efficacy
study of enzacamene at 4 percent is also recommended.

V. Administrative Procedures

A copy of this proposed order will be filed in the Division of
Dockets Management in Docket Numbers FDA-2003-N-0196, FDA-1978-N-0018,
and FDA-1996-N-0006. To inform FDA's evaluation of whether this
ingredient is GRASE and not misbranded for use in sunscreen products,
we encourage the sponsor and other interested parties to submit
additional data regarding the safety and effectiveness of this
ingredient for use as an OTC sunscreen product. We also encourage the
sponsor and other interested parties to notify us in writing of their
intent to submit additional data. However, as noted previously, because
the data submitted to date are not sufficient to support a
determination that enzacamene is GRASE for use as an active ingredient
in OTC sunscreen drug products, at present, OTC sunscreen products
containing enzacamene may not be marketed without approval of an NDA
(see section 586C(e)(1)(A) of the FD&C Act, as amended by the SIA).
Data submissions relating to this proposed order should be submitted to
Docket Numbers FDA-2003-N-0196, FDA-1978-N-0018, and FDA-1996-N-0006 at
the Division of Dockets Management (see ADDRESSES). In addition, you
can submit the data through the Federal eRulemaking Portal at: http://www.regulations.gov. Follow the instructions for submitting comments.
Section 586C(b)(7) of the FD&C Act, as amended by the SIA, provides
that

[[Page 10034]]

the sponsor may, within 30 days of publication of a proposed order (see
DATES), submit a request to FDA for a meeting to discuss the proposed
order. Submit meeting requests electronically to http://www.regulations.gov or in writing to the Division of Dockets Management
(see ADDRESSES), identified with the active ingredient name enzacamene,
the docket numbers found in brackets in the heading of this proposed
order, and the heading ``Sponsor Meeting Request.'' To facilitate your
request, please also send a copy to Kristen Hardin (see FOR FURTHER
INFORMATION CONTACT).

VI. Proposed Effective Date

FDA proposes that any final administrative order based on this
proposal become effective on the date of publication of the final order
in the Federal Register.

VII. Comments

Similarly, section 586C(b)(6) of the FD&C Act, as amended by the
SIA, establishes that a proposed sunscreen order shall provide 45 days
for public comment. Interested persons wishing to comment on this
proposed order may submit either electronic comments to http://www.regulations.gov or written comments to the Division of Dockets
Management (see ADDRESSES). It is only necessary to send one set of
comments. Identify comments with the active ingredient name
(enzacamene) and the docket numbers found in brackets in the heading of
this proposed order. Received comments on this proposed order may be
seen in the Division of Dockets Management between 9 a.m. and 4 p.m.,
Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

VIII. Notes

1. FDA-2003-N-0196-0056, Time and Extent Application (TEA) Request
to Reopen the Rulemaking Record; submitted August 21, 2002.
2. FDA-2003-N-0196-0028, C1, dated October 9, 2003.
3. FDA-1978-N-0018-0759 (Sup 25), Volume 2, Report 10, dated
November 27, 1972.
4. FDA-1978-N-0018-0760 (Sup 26), Volume 3, Report 20, dated
September 8, 1982.
5. FDA-1978-N-0018-0759 (Sup 25), Volume 2, Report 11, dated
February 20, 1980.
6. FDA-1978-N-0018-0759 (Sup 25), Volume 2, Report 12, dated
February 20, 1980.
7. FDA-1978-N-0018-0760 (Sup 26), Volume 3, Report 21, dated June
5, 1985.
8. FDA-1978-N-0018-0759 (Sup 25), Volume 2, Report 14, dated
November 29, 1982.
9. FDA-1978-N-0018-0759 (Sup 25), Volume 2, Report 15, dated July
17, 1984.
10. FDA-1978-N-0018-0760 (Sup 26), Volume 3, Report 16, dated July
8, 1984.
11. FDA-1978-N-0018-0760 (Sup 26), Volume 3, Report 19, dated
August 1, 1981.
12. FDA-1978-N-0018-0760 (Sup 26), Volume 3, Report 18, dated July
2, 1982.
13. FDA-1978-N-0018-0762 (Sup 28), Volume 5, Report 29, Study no.
43/20792, dated October 18, 1995.
14. FDA-1978-N-0018-0754 (Sup 24), dated April 12, 1999.
15. FDA-1978-N-0018-0755 (Sup 24), Attachment 1, dated April 12,
1999.
16. FDA-1978-N-0018-0758 (Sup 24), Volume 1, Reports 1, 2, 3 and 4,
Study no. 4/83/71, 4/130/73, 4/131/73, 4/52/80.
17. FDA-1978-N-0018-0758 (Sup 24), Volume 1, Reports 2 and 3, Study
no. 4/130/73 and 4/131/73.
18. Id.
19. Id.
20. Id.
21. FDA-1978-N-0018-0759 (Sup 25), Volume 2, Report 8, dated
October 16, 1978.
22. FDA-1978-N-0018-0759 (Sup 25), Volume 2, Report 9, dated
October 16, 1978.
23. FDA-1978-N-0018-0758 (Sup 24), Volume 1, Report 5, dated May 5,
1983.
24. Id.
25. FDA-1978-N-0018-0759 (Sup 25), Volume 2, Report 7, dated April
26, 1984.
26. FDA-1978-N-0018-0760 (Sup 26), Volume 3, Report 17, dated May
1, 1984.
27. FDA-1978-N-0018-0760 (Sup 26), Volume 3, Report 22, Study no.
LMP166, dated April 25, 1986.
28. FDA-1978-N-0018-0759 (Sup 25), Volume 2, Report 13, Study no.
4/56/80, dated June 2, 1980.
29. FDA-1978-N-0018-0761 (Sup 27), Volume 4, Report 28, Study no.
40/13/93, dated April 14, 1993.
30. FDA-1978-N-0018-0760 (Sup 26), Volume 3, Report 23, Study no.
4/20/84, Experiment No. T9207.
31. FDA-1978-N-0018-0761 (Sup 27), Volume 4, Report 24 and 25,
dated October 23, 1987, and October 26, 1987.
32. FDA-1978-N-0018-0761 (Sup 27), Volume 4, Report 26, Study no.
4/43/88, Experiment No. T9305, dated September 14, 1983.
33. FDA-1978-N-0018-0759 (Sup 25), Volume 2, Report 7, dated April
26, 1984.

IX. References

The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday,
and are available electronically at http://www.regulations.gov. (FDA
has verified the Web site addresses in this reference section, but FDA
is not responsible for any subsequent changes to the Web sites after
this document publishes in the Federal Register.)

1. FDA, Guidance for industry, ``Photosafety Testing,'' May 2003
(available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079252.pdf).
2. FDA, Guidance for Industry, ``Guideline for the Format and
Content of the Human Pharmacokinetics and Bioavailability Section of
an Application,'' February 1987 (available at http://www.fda.gov/downloads/drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072112.pdf).
3. Janjua, N.R., et al., ``Systemic Absorption of the Sunscreens
Benzophenone-3, Octyl-Methoxycinnamate, and 3-(4-Methyl-Benzylidene)
Camphor After Whole Body Topical Application and Reproductive
Hormone Levels in Humans.'' Journal of Investigative Dermatology,
vol. 123, pp. 57-61, 2004.
4. Schauer, U.M., et al., ``Kinetics of 3-(methylbenzlidene) Camphor
in Rats and Humans After Dermal Application.'' Toxicology and
Applied Pharmacology, vol. 216(2), pp. 339-346, 2006.
5. Janjua, N.R., et al., ``Sunscreens in Human Plasma and Urine
After Repeated Whole-Body Topical Application.'' Journal of the
European Academy of Dermatology and Venereology, vol. 22, pp. 456-
461, 2008.
6. Scientific Committee on Consumer Products (SCCP)/1184/08--SCCNFP
opinion on 4-Methylbenzylidene camphor (4-MBC) Colipa n[deg] S60
adopted during the 16th plenary meeting of June 24, 2008 (available
at http://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_141.pdf).
7. Jim[eacute]nez-D[iacute]az, I., et al., ``Simultaneous
Determination of the UV-Filters Benzyl Salicylate, Phenyl
Salicylate, Octyl Salicylate, Homosalate, 3-(4-Methylbenzylidene)
Camphor and 3-Benzylidene Camphor in Human Placental Tissue by LC-
MS/MS. Assessment of Their In Vitro Endocrine Activity.'' Journal of
Chromatography. B, Analytical Technologies in the Biomedical and
Life Sciences, vol. 936, pp. 80-87, 2013.
8. Gomez, E., et al., ``Estrogenic Activity of Cosmetic Components
in Reporter Cell Lines: Parabens, UV Screens and Musks.'' Journal of
Toxicology and Environmental Health, Part A, vol. 68, pp. 239-251,
2005.

[[Page 10035]]

9. Ma, R., et al., ``UV Filters With Antagonistic Action at Androgen
Receptors in the MDA-kb2 Cell Transcriptional-Activation Assay.''
Toxicological Sciences, vol. 74(1), pp. 43-50, 2003.
10. Mueller, S.O., et al., ``Activation of Estrogen Receptor Alpha
and ERbeta by 4-Methylbenzylidene-Camphor in Human and Rat Cells:
Comparison With Phyto- and Xenoestrogens.'' Toxicology Letters, vol.
142(1-2), pp. 89-101, 2003.
11. Schlumpf, M., et al., ``Estrogenic Activity and Estrogen
Receptor Beta Binding of the UV Filter 3-Benzylidene Camphor.
Comparison With 4-Methylbenzylidene Camphor.'' Toxicology, vol.
199(2-3), pp. 109-120, 2004.
12. Schmutzler, C., et al., ``Endocrine Disruptors and the Thyroid
Gland--A Combined In Vitro and In Vivo Analysis of Potential New
Biomarkers.'' Environmental Health Perspectives, vol. 115
(Supplement 1), pp. 77-83, 2007.
13. Schreurs, R., et al., ``Estrogenic Activity of UV Filters
Determined by an In Vitro Reporter Gene Assay and an In Vivo
Transgenic Zebrafish Assay.'' Archives of Toxicology, vol. 76, pp.
257-261, 2002.
14. Seidlov[aacute]-Wuttke, D., et al., ``Comparison of Effects of
Estradiol With Those of Octylmethoxycinnamate and 4-
Methylbenzylidene Camphor on Fat Tissue, Lipids and Pituitary
Hormones.'' Toxicology and Applied Pharmacology, vol. 214(1), pp. 1-
7, 2006.
15. S[oslash]eborg, T., et al., ``Risk Assessment of Topically
Applied Products.'' Toxicology, vol. 236(1-2), pp. 140-148, 2007.
16. Tinwell, H., et al., ``Confirmation of Uterotrophic Activity of
3-(4-Methylbenzylidine) Camphor in the Immature Rat.'' Environmental
Health Perspectives, vol. 110(5), pp. 533-536, 2002.
17. Durrer, S., et al., ``Estrogen Sensitivity of Target Genes and
Expression of Nuclear Receptor Co-Regulators in Rat Prostate After
Pre- and Postnatal Exposure to the Ultraviolet Filter 4-
Methylbenzylidene Camphor.'' Environmental Health Perspectives, vol.
115 (Supplement 1), pp. 42-50, 2007.
18. Durrer, S., et al., ``Estrogen Target Gene Regulation and
Coactivator Expression in Rat Uterus After Developmental Exposure to
the Ultraviolet Filter 4-Methylbenzylidene Camphor.'' Endocrinology,
vol. 146(5), pp. 2130-2139, 2005.
19. Faass, O., et al., ``Female Sexual Behavior, Estrous Cycle and
Gene Expression in Sexually Dimorphic Brain Regions After Pre- and
Postnatal Exposure to Endocrine Active UV Filters.''
Neurotoxicology, vol. 30(2), pp. 249-260, 2009.
20. Hofkamp, L., et al., ``Region-Specific Growth Effects in the
Developing Rat Prostate Following Fetal Exposure to Estrogenic
Ultraviolet Filters.'' Environmental Health Perspectives, vol.
116(7), pp. 867-872, 2008.
21. Maerkel, K., et al., ``Sexually Dimorphic Gene Regulation in
Brain as a Target for Endocrine Disrupters: Developmental Exposure
of Rats to 4-Methylbenzylidene Camphor.'' Toxicology and Applied
Pharmacology, vol. 218(2), pp. 152-165, 2007.
22. Maerkel, K., et al., ``Sex- and Region-Specific Alterations of
Progesterone Receptor mRNA Levels and Estrogen Sensitivity in Rat
Brain Following Developmental Exposure to the Estrogenic UV Filter
4-Methylbenzylidene Camphor.'' Environmental Toxicology and
Pharmacology, vol. 19(3), pp. 761-765, 2005.
23. Schlumpf, M., et al., ``In Vitro and In Vivo Estrogenicity of UV
Screens.'' Environmental Health Perspectives, vol. 109(3), pp. 239-
244, 2001. Erratum in: Environmental Health Perspectives, vol.
109(11), p. A517, 2001.
24. Schlumpf, M., et al., ``Estrogenic Activity and Estrogen
Receptor Beta Binding of the UV Filter 3-Benzylidene Camphor.
Comparison With 4-Methylbenzylidene Camphor.'' Toxicology, vol.
199(2-3), pp. 109-120, 2004.
25. Schlumpf, M., et al. ``Endocrine Activity and Developmental
Toxicity of Cosmetic UV Filters--An Update.'' Toxicology, vol.
205(1-2), pp. 113-122, 2004.
26. International Conference on Harmonization (ICH), Guidance for
Industry, ``The Need for Long Term Rodent Carcinogenicity Studies of
Pharmaceuticals S1A,'' March 1996 (available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance/UCM074911.pdf).
27. ICH, Guidance for Industry, ``S1B Testing for Carcinogenicity of
Pharmaceuticals,'' July 1997 (available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074916.pdf).
28. ICH, ``S1C(R2) Dose Selection for Carcinogenicity Studies of
Pharmaceuticals SIC(R2)'' (Revision 1), September 2008 (available at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074919.pdf).
29. ICH Harmonized Tripartite Guideline for Industry, ``Detection of
Toxicity to Reproduction for Medicinal Products & Toxicity to Male
Fertility S5(R2),'' 2005 (available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S5_R2/Step4/S5_R2__Guideline.pdf).
30. ICH, Guideline for Industry, ``Toxicokinetics: The Assessment of
Systemic Exposure in Toxicity Studies S3A,'' March 1995 (available
at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074937.pdf).

Dated: February 20, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-03884 Filed 2-24-15; 8:45 am]
BILLING CODE 4164-01-P

10028 Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules

the SIA was enacted, FDA had not corroborated by unpublished studies all requirements applicable to
issued a TEA feedback letter or and other data (§ 330.10(a)(4)(i) (21 CFR nonprescription drugs would be GRAS
otherwise responded to that submission. 330.10(a)(4)(i))). for use as labeled. To demonstrate that
In accordance with new section FDA’s OTC drug regulations generally these requirements are met for
586C(b)(4) of the FD&C Act as amended identify the types of information that enzacamene, initial safety testing should
by the SIA, we are issuing this notice as may be submitted as evidence that an be performed using enzacamene as the
a proposed order for enzacamene. Based active ingredient or other OTC drug sole active ingredient up to the highest
on our review of the available safety and condition is safe, as part of the concentration for which marketing
efficacy data, we have made a tentative consideration of whether an active status is sought and eligibility has been
determination that enzacamene is not ingredient or other condition is GRASE established: 4 percent. If initial testing
GRASE and is misbranded because the (§ 330.10(a)(2)). For convenience, this suggests a particular safety concern
data are insufficient to classify it as order uses the term ‘‘generally associated with enzacamene (e.g., a
GRASE and not misbranded for use in recognized as safe (GRAS)’’ to refer to hormonal activity), FDA may request
OTC sunscreens, and additional that aspect of the GRASE determination. additional studies to address that
information is necessary to allow us to To apply the general OTC safety concern.
determine otherwise. The remainder of standard to each potential new
this proposed sunscreen order describes condition, FDA uses its scientific A. Human Safety Data
our review of the available safety and expertise to determine what constitutes 1. Human Irritation, Sensitization, and
efficacy data, identifies additional data ‘‘adequate tests by methods reasonably Photosafety Studies
needed to demonstrate that enzacamene applicable to show the drug is safe
under the prescribed, recommended, or Studies of skin irritation,
is GRASE for the requested use, and sensitization, and photosafety are
explains our rationale for specific suggested conditions of use.’’ In
assessing what specific testing or other standard elements in the safety
conclusions and data requirements. evaluation of topical drug products that,
This proposed order will be open for data are needed to adequately
demonstrate the safety of enzacamene like enzacamene-containing sunscreens,
public comment (see DATES). The
for use in sunscreen, FDA considers the are applied to the skin repeatedly over
sponsor may request a meeting with
circumstances under which OTC long periods of time. FDA recommends
FDA to discuss this proposed order (see
sunscreen products that could contain separate studies for skin irritation and
DATES). We also invite the sponsor to
enzacamene would be used by sensitization. Skin irritation studies
submit additional safety and/or efficacy
consumers. should generally include at least 30
data to inform our further consideration,
When used as directed with other sun evaluable subjects and should evaluate
as publication of a final sunscreen order
protection measures, broad spectrum the test formulation (i.e., enzacamene in
under the SIA for enzacamene will be
OTC sunscreen products with a sun an appropriate test vehicle), the vehicle
contingent on receipt of such
protection factor (SPF) value of 15 or alone, and both negative and positive
information. (See section 586C(b)(9)(ii)
higher strongly benefit the public health controls. Skin sensitization studies
of the FD&C Act.) We specifically
by decreasing the risk of skin cancer and generally should include at least 200
encourage the sponsor to discuss any
premature skin aging associated with subjects and should evaluate the test
proposed study protocols with us before
solar ultraviolet (UV) radiation, as well formulation containing enzacamene, the
performing the studies.
as by helping to prevent sunburn. vehicle, and a negative control. For both
II. Safety Data Considerations for OTC (Sunscreens with lower SPF values, or irritation and sensitization studies, test
Sunscreen Products Containing without broad spectrum protection, also site applications should be randomized
Enzacamene help prevent sunburn.) When used as and the test observer blinded to the
In evaluating the safety of a proposed directed by the required labeling, all identities of the test formulations.
monograph active ingredient, FDA OTC sunscreen products are applied FDA recommends that photosafety
applies the following regulatory liberally to the skin and reapplied evaluation generally involve studies of
standard: Safety means a low incidence frequently throughout the day skin photoirritation (phototoxicity) and
of adverse reactions or significant side (§ 201.327(e) (21 CFR 201.327(e))). skin photosensitization
effects under adequate directions for use Because the effects of UV exposure are (photoallergenicity). General principles
and warnings against unsafe use as well cumulative, to obtain the maximum for designing and conducting
as low potential for harm which may benefit, users of broad spectrum photosafety studies are described in
result from abuse under conditions of sunscreens with an SPF value of 15 or FDA guidance (Ref. 1). Photosafety
widespread availability. Proof of safety higher are directed to use such products studies, like sensitization and irritation
shall consist of adequate tests by regularly—on a routine basis (id.). Given studies, should be conducted using
methods reasonably applicable to show these conditions of use, our safety enzacamene 4 percent in an appropriate
the drug is safe under the prescribed, evaluation of an OTC sunscreen active test vehicle, the vehicle alone, and a
recommended, or suggested conditions ingredient such as enzacamene must negative control. In addition,
of use. This proof shall include results consider both short-term safety concerns phototoxicity studies should include at
of significant human experience during (such as skin sensitization/irritation and least 30 evaluable subjects and
marketing. General recognition of safety photosafety) and potential concerns photoallerginicity studies should
shall ordinarily be based upon related to long-term sunscreen use, include at least 45 evaluable subjects.
wreier-aviles on DSK5TPTVN1PROD with PROPOSALS

published studies which may be including potential systemic exposure
Data Available for Enzacamene: Human
via dermal absorption.
The purpose of the safety testing Irritation, Sensitization, and Photosafety
Rulemaking Record Respect Sunscreen Drug Studies
Products for OTC, submitted on April 12, 1999 described in this section II is to
(1999 enzacamene submission); FDA–1978–N– establish whether an OTC sunscreen We reviewed the submitted study
0018–0766, Citizen Petition (CP1), submitted on product containing enzacamene and reports for human safety studies,
December 17, 1980; and Tracking number:
805596eb Legacy Doc. ID, SUP 5, ‘‘Supplement
otherwise marketed under the including a skin irritation and
from Rona Pearle’’ SUP5, submitted on August 15, conditions described in a final sensitization study of enzacamene 5
1985. sunscreen order and in accordance with percent in 30 subjects (Note 3); skin

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Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules 10029

irritation and sensitization study of potential safety signals. To ensure that that these studies were conducted in the
enzacamene 5 percent in 10 subjects maximum penetration of enzacamene 1980s and the limit of analytical
(Note 4); a photoirritation study of 4 has taken place and chances of it being detection for enzacamene was much
percent enzacamene in 5 subjects (Note detected are optimal, studies should higher than it is today.
5); and two photosensitization studies, continue until steady state is reached. A review of the published literature
one using 4 percent enzacamene in 5 General information and identified more recent studies related to
subjects and the other using an recommendations on the design and the extent of absorption of enzacamene
unknown concentration in 25 subjects conduct of human pharmacokinetic in humans after dermal application. A
(Notes 6 and 7). Although these studies studies can be found in FDA guidance 2004 article from Janjua et al. (Ref. 3)
suggest that enzacamene may not be a (Ref. 2). To support a GRAS reports on the absorption from a
primary irritant, sensitizer, determination for enzacamene (up to 4 formulation containing 10 percent
photosensitizer, or photoirritant, each of percent), such a study should be enzacamene and 2 other active
the submitted studies has limitations, conducted under maximal use sunscreen ingredients after whole body
such as inadequate sample size, lack of conditions using enzacamene 4 percent application for 4 days in 15 healthy
blinding, and lack of positive and in various vehicles, including vehicles males and 17 postmenopausal females.
negative controls, that prevent us from that would be expected to enhance The article provides only summary
making definitive conclusions. In absorption. We encourage study bioavailability information but claims
addition, protocol information, such as sponsors to consult with us before that the maximum plasma
the inclusion and exclusion criteria conducting pharmacokinetic studies, concentrations were 20 milligrams (mg)/
used in subject selection, was not because the properties of enzacamene milliliter (mL) in both men and women
consistently provided. bear on the optimal design. and that increasing plasma levels of
FDA concludes that the data enzacamene and metabolites were seen,
Data Available for Enzacamene: Human
submitted are not sufficient to assess the suggesting the presence of
Dermal Pharmacokinetic
dermal safety of enzacamene and accumulation. It is noted that thyroid
(Bioavailability) and Clinical
specifically its potential to cause function was also assessed during this
Pharmacology Studies
irritation, sensitization, photoirritation, study, but results are confounded by the
or photoallergenicity. We recommend We reviewed three submitted reports simultaneous application of three active
submission of additional data from of dermal absorption studies in humans sunscreen ingredients. A 2006 article
human irritation, sensitization, and in which percutaneous absorption was from Shauer et al. (Ref. 4) includes in
photosafety studies to demonstrate that estimated using radiolabeled (14C) vivo pharmacokinetic data from six
an OTC sunscreen containing up to 4 formulations of enzacamene. In one healthy volunteers exposed to 4 percent
percent enzacamene is not an irritant, study (Note 8) a 14C-labeled 5 percent enzacamene applied over 90 percent
sensitizer, photosensitizer, or formulation of enzacamene was applied body surface area for a 12-hour period.
photoirritant. to the lower arms of six volunteers for The data are limited by the small
6 hours, followed by a 3-day collection number of subjects included; however,
2. Human Dermal Pharmacokinetic of urine and feces. Investigators there was gender-related difference
(Bioavailability) Studies reported that approximately 54.6 observed in those males who had blood
Because sunscreens are topically percent of the 14C-activity applied to the levels that were approximately twice
applied, another important safety skin was recovered. An average of 0.76 that of females. A 2008 article by Janjua
consideration for enzacamene for use in percent enzacamene was recovered in et al. contains a more complete analysis
sunscreens is whether dermal urine and 0.14 percent in the feces. In of in vivo absorption for enzacamene in
application may result in skin a second study (Note 9), investigators a 10 percent enzacamene formulation
penetration and systemic exposure to reported a total recovery of 98.2 percent (Ref. 5). The levels of absorption were
enzacamene, and if so, to what extent. and 90.7 percent overall recovery of the generally low but accumulation was
A well-designed and -conducted human 14C-activity applied to the skin from two
observed. However, the age of the
dermal pharmacokinetic study can be volunteers, respectively. The third study females enrolled in the study was 2 to
expected to detect and quantify the report (Note 10) was similar to the 3 times that of the males, confounding
presence of enzacamene and/or any previous two studies in terms of the the interpretation of age or gender
metabolites in blood or other bodily general design. Following the analysis effects.
fluids that may have a bearing on safety, of the data from the planned six Overall, the data available are
using recognized parameters such as volunteers, two more volunteers were incomplete for the assessment of human
bioavailability percentage, maximum enrolled to evaluate the low observed bioavailability (dermal absorption) of
plasma concentration (Cmax), time to recovery (54 to 69 percent) of the enzacamene. Accordingly, we request
maximum plasma concentration (Tmax), radiolabeled enzacamene. A different data from human pharmacokinetic
total area under the plasma recovery schema was applied to these studies to assess potential for and extent
concentration versus time curve (AUC), last two patients with satisfactory of systemic absorption. These studies
half-life, clearance, and volume of results in line with the previous studies. should be performed under expected
distribution. This information can help As to the utility of the aggregate data, maximal-use conditions with the
identify potential safety concerns and we cannot draw definitive conclusions proposed maximum concentration as
help determine whether an adequate regarding the dermal absorption of discussed previously.
wreier-aviles on DSK5TPTVN1PROD with PROPOSALS

safety margin for sunscreens containing enzacamene based on these studies. The In addition to the bioavailability data
enzacamene exists. FDA recommends overall number of subjects was low, the described previously, three reports of
that the pharmacokinetic studies studies were single-dose studies, a clinical pharmacology studies were
performed on enzacamene also collect limited surface area was exposed to the submitted that evaluate the potential
additional safety-related data from formulation, the recovery of effect of enzacamene on thyroid
regularly scheduled physical radioactivity was variable, and finally function. The first was a pilot study in
examinations, collection of vital signs, no blood or other body fluids were which a 5 percent enzacamene
and other measures, which may help sampled to provide direct information formulation was applied twice, at 3-
capture adverse skin events or other about systemic exposure. We also note hour intervals, to the abdomen and back

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Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules 10031

use in OTC sunscreens, we request that 21) weight in males; and increased uterine
the sponsor either supplement the data Æ Photosensitization (guinea pig) weight, decreased ovarian weight, and
already submitted, including more (Note 22) altered sexual behavior in females.
recent adverse drug experience data, or • Repeat-dose toxicity studies Overall, we cannot arrive at a final
explain why such data cannot be Æ 17 days oral (rat) (Note 23) determination about the findings
provided. Æ 4 weeks oral (rat) (Note 24) described in the literature until we
Æ 13 weeks oral (rat) (Note 25) receive a complete nonclinical
B. Nonclinical (Animal) Studies
Æ Liver enzyme induction study (rat) assessment as described in sections
Another important element of FDA’s (Note 26) II.B.1 through II.B.3.
GRAS review of enzacamene for use in • Genotoxicity and mutagenicity assays We did not receive data from
sunscreens is an assessment of data Æ Chromosome aberration assay toxicokinetic or dermal or systemic
from nonclinical (animal) studies that (Chinese hamster V79 cells) (Note carcinogenicity studies. Upon
characterize the potential long-term 27) assessment of all available information
dermal and systemic effects of exposure Æ Mutagenicity (Salmonella for enzacamene and based on the
to enzacamene. Even if the typhimurium) (Note 28) nonclinical studies currently
bioavailability data discussed in section Æ Photomutagenicity (S. recommended to support sunscreen
II.A.2 suggest that dermal application is typhimurium, Escherichia coli) development, the following nonclinical
unlikely to result in skin penetration (Note 29) studies are recommended to support the
and systemic exposure to enzacamene, • Reproductive and developmental safety of enzacamene:
FDA still considers data on the effects toxicity studies • Dermal and systemic
of systemic exposure to be an important Æ Orienting tests for embryotoxicity carcinogenicity
aspect of our safety evaluation of (rabbit) (Note 30) • Fertility
enzacamene. A determination that Æ Toxicological investigation • Prenatal/postnatal toxicity
enzacamene up to 4 percent is GRASE (incubated hen’s egg) (Note 31) • Toxicokinetics
for use in sunscreens would permit its Æ Teratogenicity (rat) (Note 32)
use in as-yet-unknown product Additional discussion of study
Based on the submitted studies, acute findings and data gaps are provided in
formulations, which might in turn alter toxicity was low. However, the standard
the skin penetration of the active the following subsections.
battery of tests detected findings that we
ingredient. Therefore, an understanding will consider further as additional data 1. Carcinogenicity Studies: Dermal and
of the effects of enzacamene, were become available to inform our GRAS Systemic
systemic exposure to occur, is critical to assessment. Studies submitted by the FDA guidance recommends that
determine whether and how regulatory sponsor showed an increase in thyroid carcinogenicity studies be performed for
parameters can be defined to assure that weight and changes in thyroid function any pharmaceutical that is expected to
all conforming enzacamene-containing that included an increase in T3 and be clinically used continuously for at
sunscreens would be GRASE as labeled. TSH, along with a decrease in T4. Other least 6 months or ‘‘repeatedly in an
FDA recommends animal testing of
thyroid findings included follicular intermittent manner’’ (Refs. 26, 27, and
the potential long-term dermal and
epithelium hypertrophy and 28). Because the proposed use of
systemic effects of exposure to
hyperplasia. A decrease in adrenal and enzacamene in OTC sunscreens falls
enzacamene because these effects
prostate weights, and alterations in within this category, these studies
cannot be easily assessed from previous
ovarian weights (an increase was seen in should be conducted to help establish
human use. Taken together, the
some studies while decreased weight that enzacamene is GRAS for its
carcinogenicity studies, developmental
was noted in others), was documented proposed use. Carcinogenicity studies
and reproductive toxicity studies, and
with a no observed adverse effect level assist in characterizing potential dermal
toxicokinetic studies described in
(NOAEL) of 25–30 mg/kilograms (kg)/ and systemic risks by identifying the
sections II.B.1 through II.B.3 should
day (Note 33). type of toxicity observed, the level of
provide the information needed to
To followup on these findings, we exposure at which toxicity occurs, and
characterize both the potential dermal
identified published literature that the highest level of exposure at which
and systemic toxic effects and the levels
describes related enzacamene activity. A no adverse effects occur (i.e., NOAEL).
of exposure at which they occur. These
number of these articles indicate that The NOAEL would then be used in
data, when viewed in the context of
exposure to enzacamene at high doses determining the safety margin for
human exposure data, can be used to
has been associated with hormonal human exposure to sunscreens
determine a margin of safety for use of
changes. Among the in vitro findings containing enzacamene.
enzacamene in OTC sunscreens.
(Refs. 7 through 16), a number of articles Systemic carcinogenicity studies can
Data Available for Enzacamene: described the in vitro binding activity of also help to identify other systemic or
Nonclinical (Animal) Studies Generally enzacamene to estrogen (ER) and organ toxicities that may be associated
The enzacamene submissions androgen (AR) receptors where it was with enzacamene, such as hormonal
included data from the following types able to bind to ER+ but showed effects. For example, the effect of
of nonclinical safety studies: inconsistent binding activity at ERa persistent disruption of particular
receptors. No androgenic activity and endocrine gland systems (e.g.,
• Acute-dose toxicity studies
wreier-aviles on DSK5TPTVN1PROD with PROPOSALS

Æ Oral toxicity (rats, dogs) (Note 16) mixed results for antiandrogenic activity hypothalamic-pituitary-adrenal axis), if
Æ Dermal toxicity (rats) (Note 17) were also documented. any, can be captured by these assays.
Æ Intraperitoneal toxicity (rats) (Note Other effects of enzacamene included
in vivo alterations of reproductive Data Available for Enzacamene:
18) Genotoxicity Studies
Æ Mucosal irritation (rabbits) (Note tissues and behavior in rats (Refs. 17
19) through 25). Findings include decreased Enzacamene showed no evidence of
Æ Skin irritation and sensitization testis weight; increased prostate volume DNA mutations in one standard Ames
(guinea pigs) (Note 20) and altered duct development; delayed test. A chromosomal aberration assay
Æ Phototoxicity potential (mice) (Note preputial separation; decreased prostate using a Chinese hamster V79 cell line

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10032 Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules

and a photomutagenicity assay were not found to be teratogenic in any of the clinical studies by qualified experts, and
negative. Although these studies treated groups. Additional DART testing reports of significant human experience
somewhat ease concerns about potential is recommended to assess fertility and during marketing. Isolated case reports,
genotoxicity and mutagenicity, they prenatal and postnatal development in a random experience, and reports lacking
were not definitive evaluations of rodent model. the details that permit scientific
potential toxic effects from long-term evaluation will not be considered.
3. Toxicokinetics (Ref. 30)
systemic or dermal exposure. General recognition of effectiveness
We recommend conducting animal shall ordinarily be based upon
Data Available for Enzacamene: toxicokinetic studies because they
Carcinogenicity Studies published studies which may be
provide an important bridge between corroborated by unpublished studies
We did not receive dermal or systemic toxic levels seen in animal studies and and other data (§ 330.10(a)(4)(ii)). For
carcinogenicity studies. Assessments of potential human exposure. Data from convenience, this order uses the term
both dermal and systemic these studies can be correlated to ‘‘generally recognized as effective’’
carcinogenicity are recommended potential human exposure via clinical (GRAE) when referring to this aspect of
because sunscreen products containing dermal pharmacokinetic study findings. the GRASE determination.
enzacamene are expected to be applied Toxicokinetic data could be collected as To evaluate the efficacy of
over large portions of the body with part of animal studies being conducted enzacamene for use in OTC sunscreen
multiple daily applications. In addition, to assess one or more of the safety products, FDA requests evidence from
as discussed previously, marketing of parameters described previously. at least two adequate and well-
this product according to a final controlled SPF studies showing that
Data Available for Enzacamene:
sunscreen order might permit its enzacamene effectively prevents
Toxicokinetics
formulation in a variety of as-yet- sunburn. To determine that enzacamene
unknown vehicles that might have an No toxicokinetic data were submitted
is GRAE for use in OTC sunscreens at
impact on systemic absorption. as part of any of the nonclinical studies,
concentrations in a range with the
Consequently, FDA seeks information thus it is difficult to bridge from animal
proposed maximum strength of 4
on dermal and system carcinogenicity, findings to potential human exposure.
percent as requested, two adequate and
in case of the possibility that systemic Toxicokinetic data should be collected
well-controlled SPF studies of
absorption could occur. as part of the animal studies to allow
enzacamene at a lower concentration
exposure comparisons between animals
2. Developmental and Reproductive should be conducted according to
and humans.
Toxicity (DART) Studies (Ref. 29) Toxicokinetic data are particularly established standards.4 These SPF
FDA recommends conducting DART important to the evaluation of studies should demonstrate that the
studies to evaluate the potential effects enzacamene’s safety for use in selected concentration (below 4 percent)
that exposure to enzacamene may have sunscreens because enzacamene appears provides an SPF of 2 or more.
on developing offspring throughout to have the potential to affect some The current standard procedure for
gestation and postnatally until sexual endocrine-responsive endpoints. We SPF testing is described in FDA’s
maturation, as well as on the need toxicokinetic data to develop more regulations in § 201.327(i).5 Further SPF
reproductive competence of sexually information about exposure parameters, tests for enzacamene should be
mature male and female animals. in order to understand whether a margin performed as described in these
Gestational and neonatal stages of of safety exists between the exposures regulations, using a test formulation
development may also be particularly that cause the effects in animals and containing enzacamene as the only
sensitive to active ingredients with estimated human exposures. Should we active ingredient to identify its
hormonal activity. For this reason, we find, after review of a more complete contribution to the overall SPF test
recommend that these studies include nonclinical program, that additional results. (See the following subsection
assessments of endpoints such as clinical studies are warranted, we will Data Available for Enzacamene:
vaginal patency, preputial separation, provide additional recommendations Effectiveness for further discussion of
anogenital distance, and nipple regarding the design of the studies. submitted SPF tests.) The study should
retention, which can be incorporated also include a vehicle control arm in
III. Effectiveness Data Considerations order to rule out any contribution the
into traditional DART study designs to
for OTC Sunscreen Products Containing vehicle may have on the SPF test
assess potential hormonal effects of
Enzacamene results. Finally, as described in
enzacamene on the developing
offspring. We also recommend FDA’s evaluation of the effectiveness § 201.327(i), an SPF standard
conducting behavioral assessments (e.g., of active ingredients under formulation comparator arm should be
mating behavior) of offspring, which consideration for inclusion in an OTC another component of the study design.
may also detect neuroendocrine effects. drug monograph is governed by the Although current sunscreen testing
following regulatory standard: and labeling regulations also specify a
Data Available for Enzacamene: DART Effectiveness means a reasonable ‘‘broad spectrum’’ testing procedure to
Studies expectation that, in a significant support related labeling claims for
Potential reproductive and proportion of the target population, the certain OTC sunscreen products
developmental effects from enzacamene pharmacological effect of the drug, marketed without approved new drug
wreier-aviles on DSK5TPTVN1PROD with PROPOSALS

were evaluated in two embryotoxicity when used under adequate directions
4 The upper bound of any concentration of
studies and one teratogenicity study. for use and warnings against unsafe use,
enzacamene ultimately established in the OTC
Enzacamene did not show evidence of will provide clinically significant relief sunscreen monograph will be governed by the
embryotoxicity in a pilot rabbit test and of the type claimed. Proof of efficacy safety data, as well as by efficacy.
hen’s egg assay. In a teratogenicity study shall consist of controlled clinical 5 Although the SPF testing procedure is used

in rats with oral administration of single investigations as defined in 21 CFR primarily for final formulation testing of finished
products marketed without approved NDAs, under
daily doses of 10, 30, and 100 mg/kg of 314.126(b). Investigations may be the sunscreen monograph, it is equally applicable
enzacamene administered on days 6 to corroborated by partially controlled or for determining whether or not a sunscreen active
15 after conception, enzacamene was uncontrolled studies, documented ingredient is GRAE.

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10034 Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules

the sponsor may, within 30 days of 8. FDA–1978–N–0018–0759 (Sup 25), IX. References
publication of a proposed order (see Volume 2, Report 14, dated November
DATES), submit a request to FDA for a 29, 1982. The following references have been
meeting to discuss the proposed order. 9. FDA–1978–N–0018–0759 (Sup 25), placed on display in the Division of
Submit meeting requests electronically Volume 2, Report 15, dated July 17, Dockets Management (see ADDRESSES)
to http://www.regulations.gov or in 1984. and may be seen by interested persons
writing to the Division of Dockets 10. FDA–1978–N–0018–0760 (Sup between 9 a.m. and 4 p.m., Monday
Management (see ADDRESSES), identified 26), Volume 3, Report 16, dated July 8, through Friday, and are available
with the active ingredient name 1984. electronically at http://
enzacamene, the docket numbers found 11. FDA–1978–N–0018–0760 (Sup www.regulations.gov. (FDA has verified
in brackets in the heading of this 26), Volume 3, Report 19, dated August the Web site addresses in this reference
proposed order, and the heading 1, 1981. section, but FDA is not responsible for
‘‘Sponsor Meeting Request.’’ To 12. FDA–1978–N–0018–0760 (Sup any subsequent changes to the Web sites
facilitate your request, please also send 26), Volume 3, Report 18, dated July 2, after this document publishes in the
a copy to Kristen Hardin (see FOR 1982. Federal Register.)
FURTHER INFORMATION CONTACT).
13. FDA–1978–N–0018–0762 (Sup 1. FDA, Guidance for industry, ‘‘Photosafety
28), Volume 5, Report 29, Study no. 43/ Testing,’’ May 2003 (available at http://
VI. Proposed Effective Date 20792, dated October 18, 1995. www.fda.gov/downloads/Drugs/
FDA proposes that any final 14. FDA–1978–N–0018–0754 (Sup GuidanceComplianceRegulatory
administrative order based on this 24), dated April 12, 1999. Information/Guidances/ucm079252.pdf).
proposal become effective on the date of 15. FDA–1978–N–0018–0755 (Sup 2. FDA, Guidance for Industry, ‘‘Guideline
publication of the final order in the 24), Attachment 1, dated April 12, 1999. for the Format and Content of the Human
16. FDA–1978–N–0018–0758 (Sup Pharmacokinetics and Bioavailability
Federal Register. Section of an Application,’’ February
24), Volume 1, Reports 1, 2, 3 and 4,
VII. Comments Study no. 4/83/71, 4/130/73, 4/131/73, 1987 (available at http://www.fda.gov/
4/52/80. downloads/drugs/GuidanceCompliance
Similarly, section 586C(b)(6) of the RegulatoryInformation/Guidances/
FD&C Act, as amended by the SIA, 17. FDA–1978–N–0018–0758 (Sup
ucm072112.pdf).
establishes that a proposed sunscreen 24), Volume 1, Reports 2 and 3, Study 3. Janjua, N.R., et al., ‘‘Systemic Absorption
order shall provide 45 days for public no. 4/130/73 and 4/131/73. of the Sunscreens Benzophenone-3,
comment. Interested persons wishing to 18. Id. Octyl-Methoxycinnamate, and 3-(4-
19. Id. Methyl-Benzylidene) Camphor After
comment on this proposed order may 20. Id.
submit either electronic comments to Whole Body Topical Application and
21. FDA–1978–N–0018–0759 (Sup Reproductive Hormone Levels in
http://www.regulations.gov or written 25), Volume 2, Report 8, dated October Humans.’’ Journal of Investigative
comments to the Division of Dockets 16, 1978. Dermatology, vol. 123, pp. 57–61, 2004.
Management (see ADDRESSES). It is only 22. FDA–1978–N–0018–0759 (Sup 4. Schauer, U.M., et al., ‘‘Kinetics of 3-
necessary to send one set of comments. 25), Volume 2, Report 9, dated October (methylbenzlidene) Camphor in Rats and
Identify comments with the active 16, 1978. Humans After Dermal Application.’’
ingredient name (enzacamene) and the 23. FDA–1978–N–0018–0758 (Sup Toxicology and Applied Pharmacology,
docket numbers found in brackets in the 24), Volume 1, Report 5, dated May 5, vol. 216(2), pp. 339–346, 2006.
heading of this proposed order. 5. Janjua, N.R., et al., ‘‘Sunscreens in Human
1983. Plasma and Urine After Repeated Whole-
Received comments on this proposed 24. Id. Body Topical Application.’’ Journal of
order may be seen in the Division of 25. FDA–1978–N–0018–0759 (Sup the European Academy of Dermatology
Dockets Management between 9 a.m. 25), Volume 2, Report 7, dated April 26, and Venereology, vol. 22, pp. 456–461,
and 4 p.m., Monday through Friday, and 1984. 2008.
will be posted to the docket at http:// 26. FDA–1978–N–0018–0760 (Sup 6. Scientific Committee on Consumer
www.regulations.gov. 26), Volume 3, Report 17, dated May 1, Products (SCCP)/1184/08—SCCNFP
1984. opinion on 4-Methylbenzylidene
VIII. Notes 27. FDA–1978–N–0018–0760 (Sup camphor (4–MBC) Colipa n° S60 adopted
1. FDA–2003–N–0196–0056, Time 26), Volume 3, Report 22, Study no. during the 16th plenary meeting of June
and Extent Application (TEA) Request LMP166, dated April 25, 1986. 24, 2008 (available at http://
to Reopen the Rulemaking Record; 28. FDA–1978–N–0018–0759 (Sup ec.europa.eu/health/ph_risk/
committees/04_sccp/docs/sccp_o_
submitted August 21, 2002. 25), Volume 2, Report 13, Study no. 4/
141.pdf).
2. FDA–2003–N–0196–0028, C1, 56/80, dated June 2, 1980. 7. Jiménez-Dı́az, I., et al., ‘‘Simultaneous
dated October 9, 2003. 29. FDA–1978–N–0018–0761 (Sup Determination of the UV-Filters Benzyl
3. FDA–1978–N–0018–0759 (Sup 25), 27), Volume 4, Report 28, Study no. 40/ Salicylate, Phenyl Salicylate, Octyl
Volume 2, Report 10, dated November 13/93, dated April 14, 1993. Salicylate, Homosalate, 3-(4-
27, 1972. 30. FDA–1978–N–0018–0760 (Sup Methylbenzylidene) Camphor and 3-
4. FDA–1978–N–0018–0760 (Sup 26), 26), Volume 3, Report 23, Study no. 4/ Benzylidene Camphor in Human
Volume 3, Report 20, dated September 20/84, Experiment No. T9207. Placental Tissue by LC–MS/MS.
8, 1982. 31. FDA–1978–N–0018–0761 (Sup Assessment of Their In Vitro Endocrine
wreier-aviles on DSK5TPTVN1PROD with PROPOSALS

5. FDA–1978–N–0018–0759 (Sup 25), 27), Volume 4, Report 24 and 25, dated Activity.’’ Journal of Chromatography. B,
Volume 2, Report 11, dated February 20, October 23, 1987, and October 26, 1987. Analytical Technologies in the
1980. 32. FDA–1978–N–0018–0761 (Sup Biomedical and Life Sciences, vol. 936,
pp. 80–87, 2013.
6. FDA–1978–N–0018–0759 (Sup 25), 27), Volume 4, Report 26, Study no. 4/ 8. Gomez, E., et al., ‘‘Estrogenic Activity of
Volume 2, Report 12, dated February 20, 43/88, Experiment No. T9305, dated Cosmetic Components in Reporter Cell
1980. September 14, 1983. Lines: Parabens, UV Screens and
7. FDA–1978–N–0018–0760 (Sup 26), 33. FDA–1978–N–0018–0759 (Sup Musks.’’ Journal of Toxicology and
Volume 3, Report 21, dated June 5, 25), Volume 2, Report 7, dated April 26, Environmental Health, Part A, vol. 68,
1985. 1984. pp. 239–251, 2005.

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Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules 10035

9. Ma, R., et al., ‘‘UV Filters With Endocrine Disrupters: Developmental DEPARTMENT OF HEALTH AND
Antagonistic Action at Androgen Exposure of Rats to 4-Methylbenzylidene HUMAN SERVICES
Receptors in the MDA–kb2 Cell Camphor.’’ Toxicology and Applied
Transcriptional-Activation Assay.’’ Pharmacology, vol. 218(2), pp. 152–165, Food and Drug Administration
Toxicological Sciences, vol. 74(1), pp. 2007.
43–50, 2003. 22. Maerkel, K., et al., ‘‘Sex- and Region-
10. Mueller, S.O., et al., ‘‘Activation of Specific Alterations of Progesterone 21 CFR Part 310
Estrogen Receptor Alpha and ERbeta by Receptor mRNA Levels and Estrogen
[Docket No. FDA–2008–N–0474]
4-Methylbenzylidene-Camphor in Sensitivity in Rat Brain Following
Human and Rat Cells: Comparison With Developmental Exposure to the
Estrogenic UV Filter 4-
Over-the-Counter Sunscreen Drug
Phyto- and Xenoestrogens.’’ Toxicology
Letters, vol. 142(1–2), pp. 89–101, 2003. Methylbenzylidene Camphor.’’ Products—Regulatory Status of
11. Schlumpf, M., et al., ‘‘Estrogenic Activity Environmental Toxicology and Ecamsule
and Estrogen Receptor Beta Binding of Pharmacology, vol. 19(3), pp. 761–765,
2005. AGENCY: Food and Drug Administration,
the UV Filter 3-Benzylidene Camphor.
Comparison With 4-Methylbenzylidene 23. Schlumpf, M., et al., ‘‘In Vitro and In HHS.
Camphor.’’ Toxicology, vol. 199(2–3), pp. Vivo Estrogenicity of UV Screens.’’ Proposed order; request for
ACTION:
109–120, 2004. Environmental Health Perspectives, vol. comments.
12. Schmutzler, C., et al., ‘‘Endocrine 109(3), pp. 239–244, 2001. Erratum in:
Disruptors and the Thyroid Gland—A Environmental Health Perspectives, vol. SUMMARY: The Food and Drug
Combined In Vitro and In Vivo Analysis 109(11), p. A517, 2001. Administration (FDA or the Agency) is
of Potential New Biomarkers.’’ 24. Schlumpf, M., et al., ‘‘Estrogenic Activity
issuing a proposed sunscreen order
Environmental Health Perspectives, vol. and Estrogen Receptor Beta Binding of
the UV Filter 3-Benzylidene Camphor. (proposed order) under the Federal
115 (Supplement 1), pp. 77–83, 2007.
Comparison With 4-Methylbenzylidene Food, Drug, and Cosmetic Act (the
13. Schreurs, R., et al., ‘‘Estrogenic Activity
of UV Filters Determined by an In Vitro Camphor.’’ Toxicology, vol. 199(2–3), pp. FD&C Act), as amended by the
Reporter Gene Assay and an In Vivo 109–120, 2004. Sunscreen Innovation Act (SIA). The
Transgenic Zebrafish Assay.’’ Archives of 25. Schlumpf, M., et al. ‘‘Endocrine Activity proposed order announces FDA’s
Toxicology, vol. 76, pp. 257–261, 2002. and Developmental Toxicity of Cosmetic tentative determination that ecamsule
14. Seidlová-Wuttke, D., et al., ‘‘Comparison UV Filters—An Update.’’ Toxicology, (also known as terephthalylidene
of Effects of Estradiol With Those of vol. 205(1–2), pp. 113–122, 2004.
26. International Conference on dicamphor sulfonic acid) at
Octylmethoxycinnamate and 4- concentrations up to 10 percent is not
Harmonization (ICH), Guidance for
Methylbenzylidene Camphor on Fat generally recognized as safe and
Industry, ‘‘The Need for Long Term
Tissue, Lipids and Pituitary Hormones.’’
Rodent Carcinogenicity Studies of effective (GRASE) and is misbranded
Toxicology and Applied Pharmacology,
Pharmaceuticals S1A,’’ March 1996 when used in over-the-counter (OTC)
vol. 214(1), pp. 1–7, 2006. (available at http://www.fda.gov/
15. S<eborg, T., et al., ‘‘Risk Assessment of sunscreen products because the
downloads/Drugs/GuidanceCompliance currently available data are insufficient
Topically Applied Products.’’ RegulatoryInformation/Guidance/
Toxicology, vol. 236(1–2), pp. 140–148, UCM074911.pdf).
to classify it as GRASE and not
2007. 27. ICH, Guidance for Industry, ‘‘S1B Testing misbranded, and additional information
16. Tinwell, H., et al., ‘‘Confirmation of for Carcinogenicity of Pharmaceuticals,’’ is needed to allow us to determine
Uterotrophic Activity of 3-(4- July 1997 (available at http:// otherwise.
Methylbenzylidine) Camphor in the www.fda.gov/downloads/Drugs/
Immature Rat.’’ Environmental Health GuidanceComplianceRegulatory
DATES: Submit either electronic or
Perspectives, vol. 110(5), pp. 533–536, Information/Guidances/ written comments on this proposed
2002. UCM074916.pdf). order by April 13, 2015. Sponsors may
17. Durrer, S., et al., ‘‘Estrogen Sensitivity of 28. ICH, ‘‘S1C(R2) Dose Selection for submit written requests for a meeting
Target Genes and Expression of Nuclear Carcinogenicity Studies of with FDA to discuss this proposed order
Receptor Co-Regulators in Rat Prostate Pharmaceuticals SIC(R2)’’ (Revision 1), by March 27, 2015. See section VI for
After Pre- and Postnatal Exposure to the September 2008 (available at http:// the proposed effective date of a final
Ultraviolet Filter 4-Methylbenzylidene www.fda.gov/downloads/Drugs/
Camphor.’’ Environmental Health order based on this proposed order.
GuidanceComplianceRegulatory
Perspectives, vol. 115 (Supplement 1), Information/Guidances/ ADDRESSES: You may submit comments
pp. 42–50, 2007. UCM074919.pdf). by any of the following methods:
18. Durrer, S., et al., ‘‘Estrogen Target Gene 29. ICH Harmonized Tripartite Guideline for
Regulation and Coactivator Expression in Industry, ‘‘Detection of Toxicity to Electronic Submissions
Rat Uterus After Developmental Reproduction for Medicinal Products & Submit electronic comments in the
Exposure to the Ultraviolet Filter 4- Toxicity to Male Fertility S5(R2),’’ 2005 following way:
Methylbenzylidene Camphor.’’ (available at http://www.ich.org/
fileadmin/Public_Web_Site/ICH_ • Federal eRulemaking Portal: http://
Endocrinology, vol. 146(5), pp. 2130–
2139, 2005. Products/Guidelines/Safety/S5_R2/ www.regulations.gov. Follow the
19. Faass, O., et al., ‘‘Female Sexual Step4/S5_R2__Guideline.pdf). instructions for submitting comments.
Behavior, Estrous Cycle and Gene 30. ICH, Guideline for Industry,
‘‘Toxicokinetics: The Assessment of
Written Submissions
Expression in Sexually Dimorphic Brain
Regions After Pre- and Postnatal Systemic Exposure in Toxicity Studies Submit written submissions in the
Exposure to Endocrine Active UV S3A,’’ March 1995 (available at http:// following ways:
wreier-aviles on DSK5TPTVN1PROD with PROPOSALS

Filters.’’ Neurotoxicology, vol. 30(2), pp. www.fda.gov/downloads/Drugs/ • Mail/Hand delivery/Courier (for
249–260, 2009. GuidanceComplianceRegulatory
Information/Guidances/
paper submissions): Division of Dockets
20. Hofkamp, L., et al., ‘‘Region-Specific Management (HFA–305), Food and Drug
Growth Effects in the Developing Rat UCM074937.pdf).
Administration, 5630 Fishers Lane, rm.
Prostate Following Fetal Exposure to Dated: February 20, 2015.
Estrogenic Ultraviolet Filters.’’ 1061, Rockville, MD 20852.
Leslie Kux, Instructions: All submissions received
Environmental Health Perspectives, vol.
116(7), pp. 867–872, 2008. Associate Commissioner for Policy. must clearly identify the specific active
21. Maerkel, K., et al., ‘‘Sexually Dimorphic [FR Doc. 2015–03884 Filed 2–24–15; 8:45 am] ingredient (ecamsule) and the Docket
Gene Regulation in Brain as a Target for BILLING CODE 4164–01–P No. FDA–2008–N–1474 for this

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Document Created: 2015-12-18 13:08:32
Document Modified: 2015-12-18 13:08:32

Category		Regulatory Information
Collection		Federal Register
sudoc Class		AE 2.7: GS 4.107: AE 2.106:
Publisher		Office of the Federal Register, National Archives and Records Administration
Section		Proposed Rules
Action		Proposed order; request for comments.
Dates		Submit either electronic or written comments on this proposed order by April 13, 2015. Sponsors may submit written requests for a meeting with FDA to discuss this proposed order by March 27, 2015. See section VI for the proposed effective date of a final order based on this proposed order.
Contact		Kristen Hardin, Division of Nonprescription Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 5491, Silver Spring, MD 20993-0002, 240-402-4246.
FR Citation		80 FR 10026

80 FR 10026 - Over-the-Counter Sunscreen Drug Products-Regulatory Status of Enzacamene

DEPARTMENT OF HEALTH AND HUMAN SERVICESFood and Drug Administration

Federal Register Volume 80, Issue 37 (February 25, 2015)

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration