[Federal Register Volume 81, Number 73 (Friday, April 15, 2016)]
[Rules and Regulations]
[Pages 22176-22183]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-08792]



[[Page 22176]]

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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.

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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 B12 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

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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 B12 deficiency;
     Direct effects on vitamin B12 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 B12 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 B12 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 B6, 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