81 FR 22176 - Food Additives Permitted for Direct Addition to Food for Human Consumption; Folic Acid
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration Federal Register Volume 81, Issue 73 (April 15, 2016)
Food and Drug Administration
Federal Register Volume 81, Issue 73 (April 15, 2016)
| Page Range | 22176-22183 | |
| FR Document | 2016-08792 |
[Federal Register Volume 81, Number 73 (Friday, April 15, 2016)] [Rules and Regulations] [Pages 22176-22183] From the Federal Register Online [www.thefederalregister.org] [FR Doc No: 2016-08792] [[Page 22176]] ----------------------------------------------------------------------- DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 172 [Docket No. FDA-2012-F-0480] Food Additives Permitted for Direct Addition to Food for Human Consumption; Folic Acid AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. ----------------------------------------------------------------------- SUMMARY: The Food and Drug Administration (FDA or we) is amending the food additive regulations to provide for the safe use of folic acid in corn masa flour. We are taking this action in response to a food additive petition filed jointly by Gruma Corporation, Spina Bifida Association, March of Dimes Foundation, American Academy of Pediatrics, Royal DSM N.V., and National Council of La Raza. DATES: This rule is effective April 15, 2016. See section VIII for further information on the filing of objections. Submit either electronic or written objections and requests for a hearing by May 16, 2016. The Director of the Federal Register approves the incorporation by reference of certain publications listed in the rule as of April 15, 2016. ADDRESSES: You may submit objections and requests for a hearing as follows: Electronic Submissions Submit electronic objections in the following way:Federal eRulemaking Portal: http://www.regulations.gov. Follow the instructions for submitting comments. Objections submitted electronically, including attachments, to http://www.regulations.gov will be posted to the docket unchanged. Because your objection will be made public, you are solely responsible for ensuring that your objection does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else's Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your objection, that information will be posted on http://www.regulations.gov. If you want to submit an objection with confidential information that you do not wish to be made available to the public, submit the objection as a written/paper submission and in the manner detailed (see ``Written/Paper Submissions'' and ``Instructions''). Written/Paper Submissions Submit written/paper submissions as follows: Mail/Hand delivery/Courier (for written/paper submissions): Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. For written/paper objections submitted to the Division of Dockets Management, FDA will post your objection, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in ``Instructions.'' Instructions: All submissions received must include the Docket No. FDA-2012-F-0480 for ``Food Additives Permitted for Direct Addition to Food for Human Consumption; Folic Acid.'' Received objections will be placed in the docket and, except for those submitted as ``Confidential Submissions,'' publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday. Confidential Submissions--To submit an objection with confidential information that you do not wish to be made publicly available, submit your objections only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states ``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on http://www.regulations.gov. Submit both copies to the Division of Dockets Management. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as ``confidential.'' Any information marked as ``confidential'' will not be disclosed except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA's posting of comments to public dockets, see 80 FR 56469, September 18, 2015, or access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm. Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the ``Search'' box and follow the prompts and/or go to the Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. FOR FURTHER INFORMATION CONTACT: Judith Kidwell, Center for Food Safety and Applied Nutrition (HFS-265), Food and Drug Administration, 5100 Paint Branch Pkwy., College Park, MD 20740-3835, 240-402-1071. SUPPLEMENTARY INFORMATION: I. Background In a document published in the Federal Register on June 13, 2012 (77 FR 35317), we announced that Gruma Corporation, Spina Bifida Association, March of Dimes Foundation, American Academy of Pediatrics, Royal DSM N.V., and National Council of La Raza (the petitioners), c/o Alston & Bird, LLP, 950 F Street NW., Washington, DC 20004-1404, had jointly filed a food additive petition (FAP 2A4796). Subsequently, the March of Dimes Foundation informed us that Alston & Bird, LLP, was no longer representing the petitioners and that the March of Dimes Foundation would be the main contact for the petition. The address of the March of Dimes Foundation is 1401 K. St. NW., Suite 900A, Washington, DC 20005. The March of Dimes Foundation also informed us that Royal DSM N.V. no longer was affiliated with this petition. The petition proposed that we amend the food additive regulations in Sec. 172.345 Folic acid (folacin) (21 CFR 172.345) to provide for the addition of folic acid to corn masa flour (CMF) at levels not to exceed 0.7 milligrams (mg) per pound (lb) (154 micrograms ([mu]g) folic acid/ 100 grams (g) CMF). The petition requested this fortification to increase the folic acid intake for U.S. women of childbearing age who regularly consume products made from CMF as a staple in their diet, including, in particular, women of Latin American descent (for example, Mexican Americans), to help reduce the incidence of neural tube defects (NTDs), which are birth defects affecting the spine, brain, and spinal cord. This final rule is a complete response to the petition. Folic acid is the synthetic form of folate, an important B vitamin essential to fetal development and other body functions. (Folate is the form of the vitamin found naturally in food.) It is [[Page 22177]] well recognized that pregnant women with folate deficiency have a higher risk of giving birth to infants affected with NTDs, specifically spina bifida and anencephaly. To reduce the incidence of NTDs, the U.S. Public Health Service (PHS) and Centers for Disease Control and Prevention (CDC) recommend that all women of childbearing age consume 0.4 mg (400 [mu]g) of folic acid daily, in addition to the consumption of naturally occurring folate from the diet. In response to this recommendation, FDA began a mandatory folic acid fortification program in 1998, requiring folic acid to be added to enriched cereal grains and cereal grain products that have a standard of identity under 21 CFR parts 136, 137, and 139 at levels ranging from 0.43 mg to 1.4 mg/lb of the finished product (61 FR 8781, March 5, 1996) (1996 final rule). Fortification with folic acid was required for enriched cereal- grain products that already had standards of identity at the time the 1996 final rule went into effect on January 1, 1998. (Standards of identity are FDA regulations that define a given food product, its name, and ingredients that must be used, or may be used, in the manufacture of the food. They were created to maintain the integrity of food products and to ensure that foods meet buyers' expectations.) Many foods do not have standards of identity, including CMF. The amounts of folic acid required in enriched cereal-grain products (bread, rolls, and buns; wheat flours; corn meals; farina; rice; and macaroni and noodle products) were specifically chosen to increase daily folic acid consumption for women of childbearing age without consumers in the general population exceeding established safe levels. In addition to mandatory fortification of these foods, folic acid may voluntarily be added at specified levels in breakfast cereal, corn grits, meal replacement products, infant formula, foods for special dietary uses, and medical foods (Sec. 172.345). To support the safety of the proposed uses of folic acid, the petitioners submitted dietary exposure estimates of folic acid from the proposed use in CMF, as well as all dietary sources from currently permitted uses of folic acid at levels reported in the U.S. Department of Agriculture's Food and Nutrient Database for Dietary Studies, which represents the most current database for nutrient composition in foods, including folic acid found in fortified foods. The petitioners included intake from dietary supplements reported in the National Health and Nutrition Examination Survey (NHANES) 2001-2008 datasets in their estimates. They reported exposure estimates at the median for several population groups stratified by gender, race/ethnicity, and age. The petitioners also reported estimates of the percentage of the different population groups whose intake estimates exceeded the Tolerable Upper Intake Levels (ULs) established by the Institute of Medicine (IOM) for folic acid. The IOM UL is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population. Generally, the UL represents total intake from conventional food, water and dietary supplements. Additionally, the petitioners included over 300 scientific literature reports on folic acid published through 2012. The majority of these references concern epidemiological studies that investigated associations between folate status or folic acid intake levels and health outcomes. The petitioners included some animal studies, most of which focused on the mechanisms of action of folic acid. The petitioners also provided safety information from the 1998 IOM Dietary Reference Intake (DRI) report on folic acid (Ref. 1). In the 1998 report, the IOM established Recommended Dietary Allowances (RDA) for folate and ULs for folic acid. The petitioners also presented safety reviews and data evaluations on folic acid that were conducted by various national health agencies: United Kingdom (UK) Scientific Advisory Committee on Nutrition (Refs. 2 and 3); Food Standards Australia New Zealand (Refs. 4 and 5); Food Safety Authority Ireland (Refs. 6 and 7); and Health Council of the Netherlands (Refs. 8 and 9). These health agencies conducted thorough reviews of scientific papers, published through 2009, on the potential health outcomes of folic acid intake. II. Evaluation of Safety To establish with reasonable certainty that a food additive is not harmful under its intended conditions of use, we consider the projected human dietary exposure to the additive, toxicological data on the additive, and other relevant information (such as published literature) available to us. We compare an individual's estimated daily intake (EDI) of the additive from all food sources, including dietary supplements, to an acceptable intake level established by toxicological data. The EDI is determined by projections based on the amount of the additive proposed for use in particular foods and on data regarding the amount consumed from all food sources of the additive. We chose the 95th percentile of exposure as a conservative representation of habitual intake of folic acid by ``high'' consumers. As part of our safety evaluation of folic acid fortification in CMF, we conducted an updated literature search for relevant scientific publications from 1998 through 2015. Results of our updated literature search confirmed that the petitioners adequately covered the available published relevant safety information on folic acid, and we found only a few additional relevant publications in our search. A. Acceptable Daily Intake Level for Folic Acid In the 1993 proposed rule (58 FR 53305, October 14, 1993) and the 1996 final rule for mandatory folic acid fortification in certain foods, we adopted a safe upper limit of 1 mg per day (d) of total folate intake for the general population. This decision was based on the recommendation of the PHS that all women of childbearing age consume 0.4 mg (400 [mu]g) of folic acid daily to reduce the risk of NTDs. The PHS further reported that total folate and folic acid consumption should be maintained at levels under 1 mg/d because high folic acid intakes could mask the signs of pernicious anemia thereby complicating the diagnosis of vitamin B 12 deficiency (Ref. 10). In its 1998 safety assessment, the IOM concluded that, based on the weight of the limited but suggestive evidence, excessive folic acid intake may precipitate or exacerbate neuropathy in vitamin B12 -deficient individuals and justifies the selection of this endpoint as the critical endpoint for the development of a UL (Ref. 1). In its dose-response analysis, the IOM evaluated case reports of patients with vitamin B12 deficiency who developed or demonstrated a progression of neurological complications and who had been treated with oral administrations of folic acid. The data from this analysis did not provide a no-observed-adverse-effect level. Instead, the IOM established a lowest-observed-adverse-effect level (LOAEL) at the 5 mg/d dose based on the number of reported cases of neurological deterioration at certain doses of folic acid. An uncertainty factor of 5 was applied to the LOAEL, establishing a UL of 1 mg/d for adults 19 years and older. This UL was adjusted for children and adolescents on the basis of relative metabolic body weights and the resulting values were rounded down. For children 1 to 3 years of age, the IOM established a UL of 300 [micro]g/p/d; for [[Page 22178]] children 4 to 8 years of age, the IOM established a UL of 400 [micro]g/ p/d; for children 9 to 13 years of age, the IOM established a UL of 600 [micro]g/p/d; for children 14 to 18 years of age; the IOM established a UL of 800 [micro]g/p/d. The IOM determined that a UL for infants could not be established because of a lack of data on adverse effects in this age group and concerns about the infant's ability to handle excess amounts of folic acid (Ref. 1). Folic acid intake of 1 mg/d is widely recognized by different international bodies as the safe or tolerable UL for adults. This UL has been used by different countries in the evaluation of their fortification policies, including Australia and New Zealand, the UK, Ireland, and the Netherlands. In a reevaluation in 2008, the European Food Safety Authority (EFSA) concluded that the evidence and dose- response information on other health endpoints were not sufficient to support establishing a different UL (Ref. 11). We reviewed available updated safety and epidemiological studies published after the publication of the 1998 IOM report and found no scientific concerns that would justify revision of the current IOM ULs (Ref. 12). B. Estimated Daily Intake for Folic Acid The petitioners provided dietary intake estimates for folic acid from the proposed use in CMF and from all current dietary sources, including dietary supplements. In calculating exposure to folic acid from foods, the petitioners used food consumption data from the NHANES 2001-2002 dataset, which is based on one 24-hour dietary recall survey, and from the NHANES 2003-2008 dataset, which is based on two 24-hour dietary recall surveys. We note that estimates of nutrient exposure based on a single day of consumption do not adequately account for within-person variation in intake and can lead to underestimation of population variance, thereby underestimating the exposure (Ref. 13). In modeling folic acid exposure from fortified CMF, the petitioners identified 103 foods as containing CMF. The petitioners considered CMF as a non-whole grain and used a proxy of non-whole grains to estimate the amount of CMF in each identified food item based on the number of ``ounce equivalents'' of non-whole grains present in each food item. The petitioners' estimate indirectly determined the proportion of CMF present in a grain product; however, we typically use the weight (e.g., gram, milligram) percentage of CMF in each food item for dietary exposure assessments. Based on our review, we identified 118 foods currently available on the market that contain CMF as an ingredient. For these reasons, we conducted our own exposure estimate to folic acid for the overall U.S. population 1 year of age and older, excluding pregnant women, and various population subgroups stratified by age, gender, and race/ethnicity, and for various percentiles of intake. Specifically, we calculated total dietary exposure estimates for folic acid that included exposure to folic acid from currently fortified foods, dietary supplements, and the proposed fortification in CMF. We used consumption data from the NHANES 2003-2008 database and a method for estimating usual dietary intakes of foods and nutrients developed by the National Cancer Institute (http://appliedresearch.cancer.gov/diet/usualintakes/method.html.). Naturally occurring food folate was not included in the total folic acid exposure estimates because the IOM ULs were established for synthetic folic acid only. The NHANES survey has five race/ethnicity codes in its demographic data file. According to NHANES, this race/ethnicity variable was derived from responses to the survey questions on race and Hispanic origin. Respondents who self-identified as ``Mexican American'' were coded as such (Mexican American) regardless of their other race- ethnicity identities. For respondents who self-identified as ``Hispanic'' but not as ``Mexican American'' the race/ethnicity was categorized as ``Other Hispanic.'' Non-Hispanic respondents were categorized based on their self-reported races: Non-Hispanic White, non-Hispanic Black, and other non-Hispanic races including non-Hispanic multiracial (Ref. 14). Using a statistical analysis software program (SAS[supreg]), we calculated exposure to folic acid from the proposed use in CMF by adding the daily exposure to folic acid from conventional foods to the average daily exposure of folic acid from dietary supplements. We used this software program to determine distributions of exposure (i.e., means, medians, percentiles) and the percentage of individuals with usual daily total folic acid whose exposure exceeded the UL (1,000 [micro]g or other age-specific ULs). We estimated exposure for the same population subgroups for which the petitioners reported exposure in their submission in 8 age groups (1 to 3 years, 4 to 8 years, 9 to 13 years, 14 to 18 years, 19 to 30 years, 31 to 50 years, 51 to 70 years, and 71+ years), 2 gender groups (male and female), and 3 race/ethnicity subgroups (Non-Hispanic (NH) White, NH Black, and Mexican American). We estimated exposure for two scenarios. The first estimate represented a background (current) cumulative exposure of folic acid that included currently permitted uses of folic acid in conventional foods and dietary supplement use. The second estimate represented a modeled cumulative exposure of folic acid that included currently permitted uses of folic acid in conventional food, dietary supplement use, and the proposed use in CMF and products made from CMF, such as tortillas and tortilla chips (modeled). For the second scenario, we assumed a fortification level of 140 [micro]g folic acid/100 g CMF. This fortification level was chosen to account for the petitioners' estimates of loss of folic acid during processing and storage (Ref. 13). Exposure estimates at the 95th percentile represent ``high'' consumers of folic acid and provide a conservative estimate of exposure. Table 1 summarizes our exposure estimates for the overall U.S. population for each of the scenarios at the median and 95th percentile of intake with the number of people represented in each age group in the NHANES survey indicated in the table: Table 1--Estimated Cumulative Folic Acid Intake for the U.S. Population -------------------------------------------------------------------------------------------------------------------------------------------------------- Median intake ([micro]g/d) 95th percentile intake IOM UL -------------------------------- ([micro]g/d) Age (years) NHANES (n) ([micro]g/d) ------------------------------- Current Modeled Current Modeled -------------------------------------------------------------------------------------------------------------------------------------------------------- All (1+ years).......................................... 22717 .............. 231 244 765 775 1-3..................................................... 1911 300 156 160 493 504 4-8..................................................... 2071 400 255 267 618 633 9-13.................................................... 2608 600 240 257 622 628 [[Page 22179]] 14-18................................................... 3038 800 239 252 646 658 19-30................................................... 2608 1000 229 247 744 758 31-50................................................... 4118 1000 219 237 769 783 51-70................................................... 3861 1000 266 271 919 927 71+..................................................... 2302 1000 255 258 836 840 -------------------------------------------------------------------------------------------------------------------------------------------------------- The median intakes for all age groups are well below the respective ULs. For children (1 to 13 years of age), the current 95th percentile folic acid intake estimates exceed their respective age-corresponding IOM ULs. We estimate that the addition of folic acid in CMF at the proposed level would result in a small additional increase of up to 15 [micro]g/d of folic acid intake for this population group. Our exposure estimates at the 95th percentile for the adult population 19 years of age and older and for children 14 to 18 years of age did not exceed the IOM UL for either exposure scenario. Results from our exposure assessment demonstrate that CMF fortification would result in a slight increase in total folic acid exposure among the U.S. population. Further, as shown in Table 2, the proposed CMF fortification would result in a greater proportional increase in the median usual total folic acid exposure among Mexican Americans than among the NH White and NH Black populations. The estimated current median usual total folic acid intake of Mexican Americans is lower than that of the NH White population. Intake estimates that include the proposed CMF fortification show a larger increase for the median usual total folic acid exposure of Mexican Americans compared to the other groups, but the median intake estimate for Mexican Americans remains lower than that of NH Whites. Table 2--Usual Total Folic Acid Intake Estimates for the U.S. Population by Race/Ethnicity ------------------------------------------------------------------------ Exposure (median/95th percentile) Race/Ethnicity ------------------------------- Current Modeled ([micro]g/d) ([micro]g/d) ------------------------------------------------------------------------ All..................................... 231/765 244/775 Non-Hispanic White...................... 253/820 261/834 Non-Hispanic Black...................... 181/597 191/608 Mexican American........................ 187/588 228/622 ------------------------------------------------------------------------ In addition, for non-pregnant women of childbearing age (15 to 44 years), our exposure estimates show an increase in the median usual total folic acid intake of Mexican American women from 164 [micro]g/d to 206 [micro]g/d when intake from fortified CMF was included in the analysis. Our exposure estimates also show an increase in folic acid intake among NH White women (214 [micro]g/d to 221 [micro]g/d) and NH Black women (168 [micro]g/d to 179 [micro]g/d) from the petitioned use of folic acid in CMF (Ref. 13). Dietary Supplements Because the use of supplements containing folic acid is a contributing factor to total exposure, we calculated usual folic acid intake for supplement non-users (i.e., those who did not report consuming supplements containing folic acid in the NHANES Dietary Supplement Questionnaire) and supplement users (i.e., those who reported consuming supplements containing folic acid). As shown in Table 3, among dietary supplement users who consume CMF products, the 95th percentile total folic acid intake estimates for all age groups exceeded the respective age-corresponding ULs, except for the population 71 years of age and older. Table 3--Estimated Total Folic Acid Intake Among Corn Masa Consumers Who Are Dietary Supplement Users and Non-Users -------------------------------------------------------------------------------------------------------------------------------------------------------- 95th percentile intake Amount of folic acid intake ([micro]g/d) exceeding the UL (95th IOM UL -------------------------------- percentile minus UL) ([micro]g/ Dietary supplement usage Age (years) NHANES (n) ([micro]g/d) d) Current Modeled ------------------------------- Current Modeled -------------------------------------------------------------------------------------------------------------------------------------------------------- Users................................... 1-3 362 300 552 575 252 275 4-8 626 400 774 811 374 411 9-13 444 600 699 724 99 124 14-18 361 800 998 1051 198 251 19-30 536 1000 1091 1135 91 135 31-50 1161 1000 1107 1130 107 130 51-70 1482 1000 1133 1148 133 148 71+ 947 1000 889 866 0 0 Non-users............................... 1-3 655 300 259 287 0 0 [[Page 22180]] 4-8 830 400 357 388 0 0 9-13 1086 600 450 489 0 0 14-18 1239 800 457 510 0 0 19-30 862 1000 344 400 0 0 31-50 1122 1000 329 389 0 0 51-70 675 1000 312 354 0 0 71+ 258 1000 413 419 0 0 -------------------------------------------------------------------------------------------------------------------------------------------------------- For the 51 to 70 year age group, exposure at the 95th percentile was estimated to be 1133 [micro]g/d, representing 113 [micro]g/d more than the adult UL of 1 mg/d (1000 [micro]g/d). CMF fortification would further increase the 95th percentile intake by 15 [micro]g/d, resulting in an intake estimated to be 1148 [micro]g/d, which is 148 [micro]g/d more than the UL. In contrast, CMF consumers who are not dietary supplement users had considerably lower folic acid exposure estimates compared to the supplement users. The 95th percentile folic acid intakes for all dietary supplement non-user age groups did not exceed their respective age-corresponding IOM ULs. While the proposed folic acid CMF fortification will increase folic acid intakes in these individuals, their modeled 95th percentile folic acid intakes remain below their respective age-corresponding ULs. The population group of users of dietary supplements with the highest percentile exceeding the UL for folic acid was children 1 to 8 years of age. For this population, exposure estimates exceed the age- specific ULs whether consumption of fortified CMF was included in the estimate or not (Ref. 13). Children are more likely than adults to exceed their age-specific UL because of their higher consumption of food and drink on a body weight basis as compared to adults. Another reason is the lower UL values established for children. We note that the ULs for children were not based on adverse effects, but extrapolated from the adult UL. C. Safety of the Petitioned Uses of Folic Acid In our safety review, we considered several potential health effects of folic acid intake that the petitioners reported in their submission. Specifically, these health effects include:Masking vitamin B 12 deficiency;Direct effects on vitamin B 12 deficiency- related neurological complications and cognitive decline;Cancer; Effects of prenatal exposure on childhood health outcomes; Hypersensitivity; Reproductive effects; and Folic acid-drug interaction. Of these health effects, our review found suggestive evidence for masking of vitamin B 12 deficiency and exacerbation of vitamin B12 deficiency-related neurological complications and cognitive decline. The most at-risk population for both of these potential health effects is the population 50 years of age and older. For the other health effects, the overall evidence is unclear and could not be substantiated based on the available evidence (Ref. 12). 1. Masking Effect of Folic Acid on Vitamin B12 Deficiency We reviewed data from clinical case reports from vitamin B12 deficient patients and found that masking cases were mostly associated with pharmacological doses of folic acid (greater than 5 mg/d). There was no information in the reports to identify the lowest level of folic acid associated with the masking effect. For populations with dietary exposure to folic acid, epidemiological studies have shown mixed results and study design limitations. In a recent study in which data from the NHANES 1991-1994 (pre-mandatory fortification in the United States) and 2001-2006 (post-mandatory fortification) surveys were compared, the prevalence of low vitamin B12 status in the absence of megaloblastic anemia or macrocytosis among adults 50 years of age and older did not increase after fortification (Ref. 15). The masking effect of folic acid has been reviewed by other regulatory authorities (Refs. 2 to 9). We agree with their conclusions that folic acid intake up to the UL of 1 mg/d is not likely to mask vitamin B12 deficiency. Additionally, current medical practice does not rely primarily on the hematological index to screen for vitamin B12 deficiency (Refs. 16 to 18). Currently, the recommended testing for vitamin B12 deficiency includes analyzing for serum levels of vitamin B12 and of the metabolites, methylmalonic acid and homocysteine. Based on our exposure estimates and the incremental increase in estimated exposure from the proposed use of folic acid in CMF, we conclude that the CMF fortification at the proposed level is not likely to increase the risk of masking vitamin B12 deficiency, and that the risk of the masking effect from current and proposed levels of dietary folic acid intake is low (Ref. 12). 2. Direct Effects of Folic Acid on Vitamin B12 Deficiency- Related Neurological Complications and Cognitive Decline a. Accelerating or exacerbating neurological complications. In addition to the indirect masking effect of folic acid, there have been concerns that excess folic acid also may directly accelerate or exacerbate B12 deficiency-related neurological complications such as neuropathy. These endpoints were evaluated by IOM to determine the folic acid UL. In reviewing the historical clinical cases of neuropathy related to vitamin B12 deficiency, we noted that the rate of disease progression varied significantly among vitamin B12 -deficient patients, regardless of folic acid treatment. Because of the limited number of recorded cases, the large variability among patients at clinical presentation, and no new evidence presented after the IOM evaluation, the evidence remains suggestive as IOM stated in 1998. A definitive conclusion cannot be determined in this review whether folic acid directly enhances or worsens B12 deficiency-related neuropathy. [[Page 22181]] The potential neurological effects of high folic acid intake in children and women of childbearing age have not been thoroughly studied. However, because vitamin B12 deficiency is rare in these two populations in the United States (Ref. 19), the public health risk of this effect associated with increased exposure from folic acid fortification of CMF is likely to be insignificant. b. Cognitive decline among the population group ages 50 years and older. Acceleration of cognitive decline among individuals who are vitamin B12 -deficient is a potential adverse health effect if undetected because of high folic acid intake. The most at-risk population for this adverse effect are consumers 50 years and older who have total folic acid intake higher than the UL. As described previously, people 50 years of age and older are unlikely to have total folic acid intake higher than the UL unless they use dietary supplements. According to an analysis in 2007, most multivitamins for seniors that contain folic acid also contain vitamin B12 (Ref. 20). Therefore, unless their vitamin B12 absorption is severely impaired due to certain diseases, individuals in this age group who have total folic acid higher than the UL are unlikely to have vitamin B12 deficiency, and thus are not at risk for this effect. Therefore, we conclude that cognitive health risks are not likely to be an issue for this sensitive population as a result of the petitioned use of folic acid in CMF (Ref. 12). 3. Metabolic Fate of Folic Acid Folic acid is a water soluble vitamin that is quickly absorbed by the body. In humans, the bioavailability of folic acid is about 85 percent in fortified foods (Ref. 1). To be used as a methyl group donor, it must first be converted to dihydrofolate (DHF) and then tetrahydrofolate (THF) by the liver enzyme dihydrofolate reductase (DHFR). Evidence has shown that the activity of DHFR in humans is extremely low in comparison to that in rats; highly variable due to genetic polymorphism; and may become saturated when folic acid is consumed at levels higher than the 1 mg/d (Ref. 21). In addition, unlike DHF, folic acid is a poor substrate of DHFR, making the first step of metabolism rate-limiting (Ref. 22). Upon conversion, THF is distributed in all body tissues. Excretion is the main elimination route of folic acid. In response to normal intake from food, the majority of folate is effectively reabsorbed in the kidney proximal tubules and little or no folate is lost in the urine (Ref. 22). Following oral administration of single 0.1 mg to 0.2 mg doses of folic acid in healthy adults, only a trace amount appears in urine. However, after doses of about 2.5 mg to 5 mg folic acid, about 50 percent is excreted in urine as a result of exceeded renal capacity for reabsorption (Refs. 22 and 23). Therefore, a significant amount of folic acid can be excreted from urine when the renal capacity for reabsorption is saturated by high intake, eliminating excess folic acid (Refs. 22 and 24). 4. Conclusions on the Potential Adverse Health Outcomes From High Intakes of Folic Acid There is some evidence linking two potential adverse health outcomes with high folic acid intake in adults: (1) Masking vitamin B12 deficiency and (2) accelerating or exacerbating neurological complications and cognitive decline among those who are vitamin B12 deficient. For both of these adverse health outcomes, the most at-risk population is individuals 50 years of age and older who have total folic acid intake higher than the UL. According to the results from our exposure assessment, these individuals primarily are dietary supplement users. The NHANES 1999-2002 data have established that, among the 60 years of age and older population in the United States, about 25 percent have low vitamin B12 status. Because about 10 to 30 percent of the population 50 years and older have decreased absorption of food-bound vitamin B12 , the IOM DRI report recommends that individuals 50 years of age and older obtain most of their vitamin B12 RDA, (2.4 [micro]g/d) from vitamin B12 - fortified foods or supplements (Ref. 1). Since most multivitamins for seniors contain both folic acid and vitamin B12 (Ref. 20), their risk for vitamin B12 deficiency should be low, unless their vitamin B12 absorption is severely impaired due to certain diseases. In addition, because the currently recommended medical practice in the United States does not rely primarily on the hematological index to screen for vitamin B12 deficiency but rather serum B12 metabolites, the masking effect is less likely. Therefore, we conclude that these health risks (vitamin B12 masking and exacerbating neurological deterioration) are not likely to be an issue for this population as a result of the petitioned use of folic acid in CMF. For other potential health outcomes, such as promoting the progression of established neoplasms, childhood hypersensitivity and reproductive outcomes, the evidence is not clear but suggests further study. There may be other, as-yet unidentified potential adverse effects of high folic acid intake in children and further study is warranted. However, as previously discussed, allowing folic acid in CMF is only projected to result in a slight increase for children 1 to 13 years and 14 to 18 years of age at the 95th percentile of folic acid intake, such that there is only a marginal increase in exposure beyond the current intake levels for children. 5. Safety and Risk Characterization for Folic Acid Based on the data reviewed in this safety and risk assessment on folic acid, there was no definitive association of adverse effects of folic acid at the noted levels of folic acid exposure. We do not consider that any of the intake estimates in excess of the UL in this evaluation would cause an adverse health impact on any of the population subgroups because of the following reasons:The increase in exposure to folic acid for the studied populations from CMF fortification is small other than for Mexican Americans. For Mexican Americans, the increase in exposure is significantly larger but the resultant exposure levels are still below the levels for the general population. The ULs were calculated using a five-fold uncertainty factor, which is approximately twice that used for other B vitamins, providing an additional margin of safety (Ref. 12). The risk of masking vitamin B 12 deficiency and related neurological complications from the estimated intake levels of folic acid is low because the most at-risk population to these health outcomes are individuals 50 years of age and older and most multivitamins for seniors that contain folic acid also contain vitamin B12. Additionally, current medical practice does not rely primarily on the hematological index to screen for vitamin B12 deficiency but rather serum testing for vitamin B12 and its metabolites, making the masking effect less likely.The metabolic activation of folic acid by the enzyme DHFR is slow in humans and may be saturated at doses higher than 1 mg/d. Unmetabolized folic acid (UMFA) has no known biological function as a methyl group donor in DNA synthesis and methylation. To become active, folic acid must be reduced to THF. Excess levels of folic acid are unable to completely convert to its active form resulting in circulating UMFA. Currently there is no consistent evidence of adverse health effects causatively associated with circulating UMFA. Folic acid is a water-soluble vitamin. A significant amount of folic [[Page 22182]] acid is excreted from urine when the renal capacity for reabsorption is saturated by high intake, eliminating excess folic acid. FDA's modeled intake estimates for folic acid in CMF are conservative in that they assume all CMF will be fortified with folic acid at the maximum permitted level and that manufacturing and storage losses would result in folic acid levels of 140 [micro]g/100 g in CMF as consumed. III. Incorporation by Reference FDA is incorporating by reference the Food Chemicals Codex (FCC), 9th ed. (updated through Third Supplement, effective December 1, 2015), pp. 495-496 (the most current edition), which was approved by the Office of the Federal Register. You may obtain a copy of the material from the United States Pharmacopeial Convention, 12601 Twinbrook Pkwy., Rockville, MD 20852, 1-800-227-8772, http://www.usp.org/. The FCC is a compendium of internationally recognized standards for the purity and identity of food ingredients. Because the current regulation for the use of folic acid in food (Sec. 172.345) indicates that the additive must meet the specifications in the FCC, we are amending the regulation to provide for the most current edition. IV. Conclusion Based on all data relevant to folic acid that we reviewed, we conclude that the petitioned use of folic acid in CMF at a level not to exceed 0.7 mg folic acid per lb. CMF is safe. Consequently, we are amending the food additive regulations as set forth in this document. Additionally, the current regulation for the use of folic acid in food (Sec. 172.345) indicates that the additive must meet the specifications in the FCC, 7th Edition (FCC 7). The more current FCC is the 9th Edition (FCC 9). Because the specifications for folic acid in FCC 9 are identical to those in FCC 7, we are amending Sec. 172.345 by adopting the specifications for folic acid in FCC 9 in place of FCC 7. V. Public Disclosure In accordance with Sec. 171.1(h) (21 CFR 171.1(h)), the petition and the documents that we considered and relied upon in reaching our decision to approve the petition will be made available for public disclosure (see FOR FURTHER INFORMATION CONTACT). As provided in Sec. 171.1(h), we will delete from the documents any materials that are not available for public disclosure. VI. Analysis of Environmental Impacts We previously considered the environmental effects of this rule, as stated in the June 13, 2012, Federal Register notice of petition for FAP 2A4796 (77 FR 35317). We stated that we had determined, under 21 CFR 25.32(k), that this action ``is of a type that does not individually or cumulatively have a significant effect on the human environment'' such that neither an environmental assessment nor an environmental impact statement is required. We have not received any new information or comments that would affect our previous determination. VII. Paperwork Reduction Act of 1995 This final rule contains no collection of information. Therefore, clearance by the Office of Management and Budget under the Paperwork Reduction Act of 1995 is not required. VIII. Objections If you will be adversely affected by one or more provisions of this regulation, you may file with the Division of Dockets Management (see ADDRESSES) either electronic or written objections. You must separately number each objection, and within each numbered objection you must specify with particularity the provision(s) to which you object, and the grounds for your objection. Within each numbered objection, you must specifically state whether you are requesting a hearing on the particular provision that you specify in that numbered objection. If you do not request a hearing for any particular objection, you waive the right to a hearing on that objection. If you request a hearing, your objection must include a detailed description and analysis of the specific factual information you intend to present in support of the objection in the event that a hearing is held. If you do not include such a description and analysis for any particular objection, you waive the right to a hearing on the objection. Any objections received in response to the regulation 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. IX. Section 301(ll) of the Federal Food, Drug, and Cosmetic Act Our review of this petition was limited to section 409 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 348). This final rule is not a statement regarding compliance with other sections of the FD&C Act. For example, section 301(ll) of the FD&C Act (21 U.S.C. 331(ll)) prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act (21 U.S.C. 355), a biological product licensed under section 351 of the Public Health Service Act (42 U.S.C. 262), or a drug or biological product for which substantial clinical investigations have been instituted and their existence has been made public, unless one of the exemptions in section 301(ll)(1) to (ll)(4) of the FD&C Act applies. In our review of this petition, FDA did not consider whether section 301(ll) of the FD&C Act or any of its exemptions apply to food containing this additive. Accordingly, this final rule should not be construed to be a statement that a food containing this additive, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll) of the FD&C Act. Furthermore, this language is included in all food additive final rules and therefore should not be construed to be a statement of the likelihood that section 301(ll) of the FD&C Act applies. X. References The following references marked with an asterisk (*) are on display at the Division of Dockets Management (see ADDRESSES), under Docket No. FDA-2012-F-0480, and are available for viewing by interested persons between 9 a.m. and 4 p.m., Monday through Friday, they also are available electronically at http://www.regulations.gov. References without asterisks are not on display; they are available as published articles and books. 1. IOM, 1998. ``Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B 6 , Folate, Vitamin B12 , Pantothenic Acid, Biotin, and Choline.'' Washington, DC: National Academy Press. Available at: http://www.ncbi.nlm.nih.gov/books/NBK114310/ (accessed April 1, 2016). *2. Scientific Advisory Committee on Nutrition (SACN), 2006. ``Folate and Disease Prevention,'' London. *3. SACN, 2009. ``Folic Acid and Colorectal Cancer Risk: Review of Recommendation for Mandatory Folic Acid Fortification.'' *4. Food Standards Australia New Zealand (FSANZ), 2007. ``Folic Acid and Colorectal Cancer Risk: Review of Recommendation for Mandatory Folic Acid Fortification.'' *5. FSANZ, 2009. ``Mandatory Folic Acid Fortification and Health Outcomes.'' *6. Food Safety Authority of Ireland (FSAI), 2006. ``Report of the National Committee on Folic Acid Food Fortification.'' *7. FSAI, 2008. ``Report of the Implementation Group on Folic Acid [[Page 22183]] Food Fortification to the Department of Health and Children.'' *8. GR Health Council of the Netherlands (HCN), 2000. ``Risks of Folic Acid Fortification.'' The Hague, Health Council of the Netherlands 2000/21. *9. GR HCN, 2008. ``Towards an Optimal Use of Folic Acid.'' The Hague, Health Council of the Netherlands 2008/02E. 10. CDC, 1992. ``Recommendations for the Use of Folic Acid to Reduce the Number of Cases of Spina Bifida and Other Neural Tube Defects.'' Morbidity and Mortality Weekly Report 41. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/00019479.htm (accessed April 1, 2016). *11. EFSA, 2009. Report prepared by the EFSA Scientific Cooperation Working Group on ``Analysis of Risks and Benefits of Fortification of Food with Folic A.'' *12. Memorandum from J. Zang, Toxicology Team, Division of Petition Review, to J. Kidwell, Division of Petition Review, March 23, 2016. *13. Memorandum from H. Lee, Chemistry Review Group, Division of Petition Review, to J. Kidwell, Regulatory Group I, Division of Petition Review, April 2, 2014. 14. National Health and Nutrition Examination Survey 2007-2008 Data Documentation, Codebook, and Frequencies, CDC, 2009. Available at: http://wwwn.cdc.gov/nchs/nhanes/search/nhanes07_08.aspx (accessed April 1, 2016). 15. Qi, Y.P., A.N. Do, H.C. Hamner, C.M. Pfeiffer, et al., 2014. ``The Prevalence of Low Serum Vitamin B-12 Status in the Absence of Anemia or Macrocytosis Did Not Increase Among Older U.S. Adults after Mandatory Folic Acid Fortification.'' The Journal of Nutrition 144, 170-176. 16. Oh, R. and D.L. Brown, 2003. ``Vitamin B12 Deficiency.'' American Family Physician 67, 979-986. 17. Stabler, S.P., 2013. ``Clinical Practice. Vitamin B12 Deficiency.'' New England Journal of Medicine 368(2): 149-160. 18. Hunt A., D. Harrington, and S. Robinson, 2014. ``Vitamin B12 Deficiency.'' British Medical Journal 349: g5226. 19. Wright J.D., K. Bialostosky, E.W. Gunter, M.D. Carroll, et al., 1998. ``Blood Folate and Vitamin B12 : United States, 1988-94.'' Vital Health and Statistics 11:1-78. 20. Berry, R.J., H.K. Carter, and Q. Yang, 2007. ``Cognitive Impairment in Older Americans in the Age of Folic Acid Fortification.'' American Journal of Clinical Nutrition 86, 265-267; author reply 267-269. 21. Bailey, S.W. and J.E. Ayling, 2009. ``The Extremely Slow and Variable Activity of Dihydrofolate Reductase in Human Liver and its Implications for High Folic Acid Intake.'' Proceedings of the National Academy of Sciences of the United States of America 106 (36), 15424-15429. 22. Shane, B., ``Folate Chemistry and Metabolism,'' in Folate in Health and Disease, L. B. Bailey, Ed. Marcel Dekker, Boca Raton, FL, USA, 2nd edition, 2009. 23. McEvoy, G.K. (ed.). ``American Hospital Formulary Service--Drug Information 2005.'' Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements). 24. Tamura, T. and E.L. Stokstad, 1973. ``The Availability of Food Folate in Man.'' British Journal of Haematology 25(4): 512-532. List of Subjects in 21 CFR Part 172 Food additives, Incorporation by reference, Reporting and recordkeeping requirements. Therefore, under the Federal Food, Drug, and Cosmetic Act and under authority delegated to the Commissioner of Food and Drugs and redelegated to the Director, Center for Food Safety and Applied Nutrition, 21 CFR part 172 is amended as follows: PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN CONSUMPTION 0 1. The authority citation for 21 CFR part 172 continues to read as follows: Authority: 21 U.S.C. 321, 341, 342, 348, 371, 379e. 0 2. Amend Sec. 172.345 by revising the first sentence of paragraph (b) and adding paragraph (i) to read as follows: Sec. 172.345 Folic acid (folacin). * * * * * (b) Folic acid meets the specifications of the Food Chemicals Codex, 9th ed., updated through Third Supplement, effective December 1, 2015, pp. 495-496, which is incorporated by reference. * * * * * * * * (i) Folic acid may be added to corn masa flour at a level not to exceed 0.7 milligrams of folic acid per pound of corn masa flour. Dated: April 12, 2016. Susan Bernard, Director, Office of Regulations, Policy and Social Sciences, Center for Food Safety and Applied Nutrition. [FR Doc. 2016-08792 Filed 4-14-16; 8:45 am] BILLING CODE 4164-01-P
![22176 Federal Register / Vol. 81, No. 73 / Friday, April 15, 2016 / Rules and Regulations
DEPARTMENT OF HEALTH AND manner detailed (see ‘‘Written/Paper Docket: For access to the docket to
HUMAN SERVICES Submissions’’ and ‘‘Instructions’’). read background documents or the
electronic and written/paper comments
Food and Drug Administration Written/Paper Submissions
received, go to http://
Submit written/paper submissions as www.regulations.gov and insert the
21 CFR Part 172 follows: docket number, found in brackets in the
• Mail/Hand delivery/Courier (for heading of this document, into the
[Docket No. FDA–2012–F–0480] written/paper submissions): Division of ‘‘Search’’ box and follow the prompts
Food Additives Permitted for Direct Dockets Management (HFA–305), Food and/or go to the Division of Dockets
Addition to Food for Human and Drug Administration, 5630 Fishers Management, 5630 Fishers Lane, Rm.
Consumption; Folic Acid Lane, Rm. 1061, Rockville, MD 20852. 1061, Rockville, MD 20852.
• For written/paper objections
FOR FURTHER INFORMATION CONTACT:
AGENCY: Food and Drug Administration, submitted to the Division of Dockets
HHS. Management, FDA will post your Judith Kidwell, Center for Food Safety
objection, as well as any attachments, and Applied Nutrition (HFS–265), Food
ACTION: Final rule.
except for information submitted, and Drug Administration, 5100 Paint
SUMMARY: The Food and Drug marked and identified, as confidential, Branch Pkwy., College Park, MD 20740–
Administration (FDA or we) is if submitted as detailed in 3835, 240–402–1071.
amending the food additive regulations ‘‘Instructions.’’ SUPPLEMENTARY INFORMATION:
to provide for the safe use of folic acid Instructions: All submissions received I. Background
in corn masa flour. We are taking this must include the Docket No. FDA–
action in response to a food additive 2012–F–0480 for ‘‘Food Additives In a document published in the
petition filed jointly by Gruma Permitted for Direct Addition to Food Federal Register on June 13, 2012 (77
Corporation, Spina Bifida Association, for Human Consumption; Folic Acid.’’ FR 35317), we announced that Gruma
March of Dimes Foundation, American Received objections will be placed in Corporation, Spina Bifida Association,
Academy of Pediatrics, Royal DSM N.V., the docket and, except for those March of Dimes Foundation, American
and National Council of La Raza. submitted as ‘‘Confidential Academy of Pediatrics, Royal DSM N.V.,
DATES: This rule is effective April 15, Submissions,’’ publicly viewable at and National Council of La Raza (the
2016. See section VIII for further http://www.regulations.gov or at the petitioners), c/o Alston & Bird, LLP, 950
information on the filing of objections. Division of Dockets Management F Street NW., Washington, DC 20004–
Submit either electronic or written between 9 a.m. and 4 p.m., Monday 1404, had jointly filed a food additive
objections and requests for a hearing by through Friday. petition (FAP 2A4796). Subsequently,
May 16, 2016. The Director of the • Confidential Submissions—To the March of Dimes Foundation
Federal Register approves the submit an objection with confidential informed us that Alston & Bird, LLP,
incorporation by reference of certain information that you do not wish to be was no longer representing the
publications listed in the rule as of made publicly available, submit your petitioners and that the March of Dimes
April 15, 2016. objections only as a written/paper Foundation would be the main contact
ADDRESSES: You may submit objections submission. You should submit two for the petition. The address of the
and requests for a hearing as follows: copies total. One copy will include the March of Dimes Foundation is 1401 K.
information you claim to be confidential St. NW., Suite 900A, Washington, DC
Electronic Submissions with a heading or cover note that states 20005. The March of Dimes Foundation
Submit electronic objections in the ‘‘THIS DOCUMENT CONTAINS also informed us that Royal DSM N.V.
following way: CONFIDENTIAL INFORMATION.’’ The no longer was affiliated with this
• Federal eRulemaking Portal: http:// Agency will review this copy, including petition. The petition proposed that we
www.regulations.gov. Follow the the claimed confidential information, in amend the food additive regulations in
instructions for submitting comments. its consideration of comments. The § 172.345 Folic acid (folacin) (21 CFR
Objections submitted electronically, second copy, which will have the 172.345) to provide for the addition of
including attachments, to http:// claimed confidential information folic acid to corn masa flour (CMF) at
www.regulations.gov will be posted to redacted/blacked out, will be available levels not to exceed 0.7 milligrams (mg)
the docket unchanged. Because your for public viewing and posted on http:// per pound (lb) (154 micrograms (mg)
objection will be made public, you are www.regulations.gov. Submit both folic acid/100 grams (g) CMF). The
solely responsible for ensuring that your copies to the Division of Dockets petition requested this fortification to
objection does not include any Management. If you do not wish your increase the folic acid intake for U.S.
confidential information that you or a name and contact information to be women of childbearing age who
third party may not wish to be posted, made publicly available, you can regularly consume products made from
such as medical information, your or provide this information on the cover CMF as a staple in their diet, including,
anyone else’s Social Security number, or sheet and not in the body of your in particular, women of Latin American
confidential business information, such comments and you must identify this descent (for example, Mexican
as a manufacturing process. Please note information as ‘‘confidential.’’ Any Americans), to help reduce the
that if you include your name, contact information marked as ‘‘confidential’’ incidence of neural tube defects (NTDs),
information, or other information that will not be disclosed except in which are birth defects affecting the
identifies you in the body of your accordance with 21 CFR 10.20 and other spine, brain, and spinal cord. This final
jstallworth on DSK7TPTVN1PROD with RULES
objection, that information will be applicable disclosure law. For more rule is a complete response to the
posted on http://www.regulations.gov. information about FDA’s posting of petition.
• If you want to submit an objection comments to public dockets, see 80 FR Folic acid is the synthetic form of
with confidential information that you 56469, September 18, 2015, or access folate, an important B vitamin essential
do not wish to be made available to the the information at: http://www.fda.gov/ to fetal development and other body
public, submit the objection as a regulatoryinformation/dockets/ functions. (Folate is the form of the
written/paper submission and in the default.htm. vitamin found naturally in food.) It is
VerDate Sep<11>2014 14:40 Apr 14, 2016 Jkt 238001 PO 00000 Frm 00004 Fmt 4700 Sfmt 4700 E:\FR\FM\15APR1.SGM 15APR1](https://thefederalregister.org/doc/81_FR_22249/page/1.svg)
![Federal Register / Vol. 81, No. 73 / Friday, April 15, 2016 / Rules and Regulations 22183
Food Fortification to the Department of 23. McEvoy, G.K. (ed.). ‘‘American Hospital DEPARTMENT OF THE INTERIOR
Health and Children.’’ Formulary Service—Drug Information
*8. GR Health Council of the Netherlands 2005.’’ Bethesda, MD: American Society Bureau of Indian Affairs
(HCN), 2000. ‘‘Risks of Folic Acid of Health-System Pharmacists, Inc. 2005
Fortification.’’ The Hague, Health (Plus Supplements). [167A2100DD/AAKC001030/
Council of the Netherlands 2000/21. A0A501010.999900 253G]
*9. GR HCN, 2008. ‘‘Towards an Optimal Use 24. Tamura, T. and E.L. Stokstad, 1973. ‘‘The
of Folic Acid.’’ The Hague, Health Availability of Food Folate in Man.’’
British Journal of Haematology 25(4):
25 CFR Part 151
Council of the Netherlands 2008/02E.
10. CDC, 1992. ‘‘Recommendations for the 512–532. RIN 1076–AF28
Use of Folic Acid to Reduce the Number
of Cases of Spina Bifida and Other List of Subjects in 21 CFR Part 172
Title Evidence for Trust Land
Neural Tube Defects.’’ Morbidity and
Food additives, Incorporation by Acquisitions
Mortality Weekly Report 41. Available at:
http://www.cdc.gov/mmwr/preview/ reference, Reporting and recordkeeping AGENCY: Bureau of Indian Affairs,
mmwrhtml/00019479.htm (accessed requirements. Interior.
April 1, 2016).
*11. EFSA, 2009. Report prepared by the Therefore, under the Federal Food, ACTION: Interim final rule; delay of
EFSA Scientific Cooperation Working Drug, and Cosmetic Act and under effective date.
Group on ‘‘Analysis of Risks and authority delegated to the Commissioner
Benefits of Fortification of Food with of Food and Drugs and redelegated to SUMMARY: The Bureau of Indian Affairs
Folic A.’’
the Director, Center for Food Safety and (BIA) published an interim final rule on
*12. Memorandum from J. Zang, Toxicology title evidence for trust land acquisitions
Team, Division of Petition Review, to J. Applied Nutrition, 21 CFR part 172 is
and received comments during the
Kidwell, Division of Petition Review, amended as follows:
public comment period. The BIA
March 23, 2016.
*13. Memorandum from H. Lee, Chemistry PART 172—FOOD ADDITIVES anticipates making technical revisions
Review Group, Division of Petition PERMITTED FOR DIRECT ADDITION to the rule in response to those
Review, to J. Kidwell, Regulatory Group TO FOOD FOR HUMAN comments. This notice delays the
I, Division of Petition Review, April 2, effective date of the interim final rule
2014.
CONSUMPTION
for 30 days, during which time BIA
14. National Health and Nutrition plans to publish a final rule with
Examination Survey 2007–2008 Data ■ 1. The authority citation for 21 CFR technical revisions.
Documentation, Codebook, and part 172 continues to read as follows:
Frequencies, CDC, 2009. Available at: DATES: The effective date of the interim
http://wwwn.cdc.gov/nchs/nhanes/ Authority: 21 U.S.C. 321, 341, 342, 348, final rule published March 1, 2016 (81
search/nhanes07_08.aspx (accessed 371, 379e. FR 10477) is delayed from April 15,
April 1, 2016). 2016 to May 16, 2016.
■ 2. Amend § 172.345 by revising the
15. Qi, Y.P., A.N. Do, H.C. Hamner, C.M.
first sentence of paragraph (b) and FOR FURTHER INFORMATION CONTACT: Ms.
Pfeiffer, et al., 2014. ‘‘The Prevalence of
Low Serum Vitamin B-12 Status in the adding paragraph (i) to read as follows: Elizabeth Appel, Director, Office of
Absence of Anemia or Macrocytosis Did Regulatory Affairs and Collaborative
Not Increase Among Older U.S. Adults § 172.345 Folic acid (folacin). Action, Office of the Assistant
after Mandatory Folic Acid * * * * * Secretary—Indian Affairs; telephone
Fortification.’’ The Journal of Nutrition (202) 273–4680, elizabeth.appel@
144, 170–176. (b) Folic acid meets the specifications
bia.gov.
16. Oh, R. and D.L. Brown, 2003. ‘‘Vitamin of the Food Chemicals Codex, 9th ed.,
B12 Deficiency.’’ American Family updated through Third Supplement, SUPPLEMENTARY INFORMATION: On March
Physician 67, 979–986. effective December 1, 2015, pp. 495– 1, 2016, BIA published an interim final
17. Stabler, S.P., 2013. ‘‘Clinical Practice. 496, which is incorporated by reference. rule with an effective date of April 15,
Vitamin B12 Deficiency.’’ New England 2016. 81 FR 10477. The interim final
* * *
Journal of Medicine 368(2): 149–160. rule deletes the requirement for fee-to-
18. Hunt A., D. Harrington, and S. Robinson, * * * * * trust applicants to furnish title evidence
2014. ‘‘Vitamin B12 Deficiency.’’ British (i) Folic acid may be added to corn
Medical Journal 349: g5226.
that meets the ‘‘Standards for the
19. Wright J.D., K. Bialostosky, E.W. Gunter, masa flour at a level not to exceed 0.7 Preparation of Title Evidence in Land
M.D. Carroll, et al., 1998. ‘‘Blood Folate milligrams of folic acid per pound of Acquisitions by the United States’’
and Vitamin B12: United States, 1988– corn masa flour. issued by the U.S. Department of Justice
94.’’ Vital Health and Statistics 11:1–78.
Dated: April 12, 2016. (DOJ), and replaces the requirement
20. Berry, R.J., H.K. Carter, and Q. Yang, with a more targeted requirement for
2007. ‘‘Cognitive Impairment in Older Susan Bernard,
title evidence, because adherence to the
Americans in the Age of Folic Acid Director, Office of Regulations, Policy and DOJ standards is not required for
Fortification.’’ American Journal of Social Sciences, Center for Food Safety and
Clinical Nutrition 86, 265–267; author
acquisitions of land in trust for
Applied Nutrition. individual Indians or Indian tribes. The
reply 267–269.
[FR Doc. 2016–08792 Filed 4–14–16; 8:45 am] BIA received 13 comments during the
21. Bailey, S.W. and J.E. Ayling, 2009. ‘‘The
Extremely Slow and Variable Activity of BILLING CODE 4164–01–P public comment period and anticipates
Dihydrofolate Reductase in Human Liver making technical changes in response to
and its Implications for High Folic Acid those comments. The interim final rule
jstallworth on DSK7TPTVN1PROD with RULES
Intake.’’ Proceedings of the National stated that BIA may withdraw, initiate
Academy of Sciences of the United a proposed rulemaking, or revise the
States of America 106 (36), 15424–
15429.
rule in response to comments. The BIA
22. Shane, B., ‘‘Folate Chemistry and has determined that technical revisions
Metabolism,’’ in Folate in Health and to the rule may be appropriate and is
Disease, L. B. Bailey, Ed. Marcel Dekker, therefore delaying the effective date of
Boca Raton, FL, USA, 2nd edition, 2009. the rule for 30 days, during which time
VerDate Sep<11>2014 14:40 Apr 14, 2016 Jkt 238001 PO 00000 Frm 00011 Fmt 4700 Sfmt 4700 E:\FR\FM\15APR1.SGM 15APR1](https://thefederalregister.org/doc/81_FR_22249/page/8.svg)
Document Created: 2016-04-15 00:55:45
Document Modified: 2016-04-15 00:55:45
| 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 | Rules and Regulations | |
| Action | Final rule. | |
| Dates | This rule is effective April 15, 2016. See section VIII for further information on the filing of objections. Submit either electronic or written objections and requests for a hearing by May 16, 2016. The Director of the Federal Register approves the incorporation by reference of certain publications listed in the rule as of April 15, 2016. | |
| Contact | Judith Kidwell, Center for Food Safety and Applied Nutrition (HFS-265), Food and Drug Administration, 5100 Paint Branch Pkwy., College Park, MD 20740-3835, 240-402-1071. | |
| FR Citation | 81 FR 22176 | |
| CFR Associated | Food Additives; Incorporation by Reference and Reporting and Recordkeeping Requirements |
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