[Federal Register Volume 81, Number 73 (Friday, April 15, 2016)]
[Rules and Regulations]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-08792]
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,
ADDRESSES: You may submit objections and requests for a hearing as
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'').
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
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You should submit two copies total. One copy will include the
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will have the claimed confidential information redacted/blacked out,
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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.
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
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
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.
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
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
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
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
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
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).
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 -------------------------------
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
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;
Effects of prenatal exposure on childhood health outcomes;
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
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
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
Folic acid is a water-soluble vitamin. A significant
amount of folic
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
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.
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
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.
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
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
*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
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
*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,
*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:
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
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
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
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
1. The authority citation for 21 CFR part 172 continues to read as
Authority: 21 U.S.C. 321, 341, 342, 348, 371, 379e.
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.
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