Federal Register: March 5, 1996 (Volume 61, Number 44)
Rules and Regulations
Page 8797-8807
From the Federal Register Online via GPO Access wais.access.gpo.gov
DOCID:fr05mr96-17
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 172
Docket No. 91N-100F
Food Additives Permitted for Direct Addition to Food for Human
Consumption; Folic Acid (Folacin)
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the food
additive regulations to provide for the safe use of folic acid in foods
that are the subject of a standard of identity that requires the
addition of folic acid; to provide for its addition to breakfast
cereals on a per serving basis; to permit its use in infant formulas,
medical foods, and foods for special dietary use; and to incorporate
specifications for folic acid consistent with those in the Food
Chemicals Codex. This action is being taken to ensure that the amount
of folic acid that all segments of the population are reasonably
expected to consume is safe under the Federal Food, Drug, and Cosmetics
Act (the act) and to implement Public Health Service's (PHS)
recommendation to increase folic acid intake by women of childbearing
age, thereby reducing the risk of pregnancies affected by neural tube
defects (NTD's).
DATES: Effective March 5, 1996; written objections and requests for a
hearing by April 4, 1996. The Director of the Office of the Federal
Register approves the incorporation by reference in accordance with 5
U.S.C. 552(a) and 1 CFR part 51 of a certain publication in 21 CFR
103.35(d)(3)(v), effective March 5, 1996.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Dennis M. Keefe, Center for Food
Safety and Applied Nutrition (HFS-206), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-418-3090.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of October 14, 1993 (58 FR 53312), FDA
proposed to amend the regulation that establishes safe conditions of
food use for folic acid, Sec. 172.345 (21 CFR 172.345)). In the
proposed rule, which was entitled ``Food Additives Permitted for Direct
Addition to Food for Human Consumption; Folic Acid (Folacin),'' FDA
said that it intended to amend Sec. 172.345 to: (1) Set limitations on
the use of folic acid on a per serving basis, in accord with the
Nutrition Labeling and Education Act of 1990; (2) allow for the
addition of folic acid in foods for which standards of identity exist,
where such standards permit the addition of folic acid; (3) restrict to
breakfast cereals the foods for which standards of identity do not
exist, to which folic acid may be added; (4) continue to permit the use
of folic acid in infant formulas, dietary supplements, and foods for
special dietary use; and (5) incorporate specifications for folic acid
consistent with those in the Food Chemicals Codex.
Interested persons were given until December 13, 1993, to comment
on the proposal. FDA received 59 letters, each containing one or more
comments, from consumers, members of the Folic Acid Subcommittee of
FDA's Food Advisory Committee, the United States Pharmacopeial
Convention, Inc., consumer interest groups, food manufacturers, trade
associations, and dietary supplement manufacturers. Most comments
generally supported the proposed amendments. Some comments suggested
modifications of various provisions of the proposed rule or requested
clarification of certain issues. A number of comments were received
that were more appropriate to other dockets, and these were forwarded
to the appropriate dockets (Docket Nos. 91N-100H or 91N-100S) for
response. A summary of the comments and the agency's responses are
presented in section II of this document.
II. Comments to the Proposal
A. Safe Upper Limit
As part of FDA's implementation of the PHS recommendation that
women of childbearing age consume 400 micrograms (<greek-m>g) of folic
acid per day to reduce their risk of a pregnancy affected by an NTD
(Ref. 1), FDA initiated this proceeding, as well as a rulemaking to
authorize a health claim on the relationship between folate and NTD's
and a rulemaking to require the addition of folic acid to certain
standardized cereal-grains. As part of FDA's rulemaking to authorize a
folate health claim, the agency found it necessary to address the issue
of the safe upper limit of daily folate intake. In the health claim
proceeding, FDA was confronted with all of the issues related to a safe
upper limit that have been presented in this proceeding. Thus, FDA's
response to the comments that addressed the safe upper limit for folic
acid intake in the present rulemaking draws largely on the agency's
response to similar comments as laid out in a final rule authorizing a
Page 8798
health claim about the relationship of folate and neural tube defects
published elsewhere in this issue of the Federal Register.
The agency's overriding goal in this food additive rulemaking is to
ensure that the amount of folic acid that all segments of the
population are reasonably expected to consume is safe under section
409(c)(3)(A) and (c)(5)(A) of the act (21 U.S.C. 348(c)(3)(A) and
(c)(5)(A)), while concurrently aiding compliance with the PHS
recommendation on folate and NTD's by increasing the folate content of
the U.S. food supply.
The agency noted in the final folate health claim rule of January
6, 1993 (58 FR 2606 at 2612), and the folate health claim final rule
published elsewhere in this issue of the Federal Register, that there
may be risks attendant upon increased consumption of folate for some
groups in the population. At the present time, the potential adverse
effect for which there is the most evidence is a masking of anemia in
persons with vitamin B<INF>12 deficiency, while severe and irreversible
neurologic damage may progress. There is currently no way to determine
how many persons in the general U.S. population have undiagnosed
vitamin B<INF>12 deficiency, and thus, how many are potentially at risk
of developing pernicious anemia. However, marginal vitamin B<INF>12
nutritional status is not uncommon in the U.S. population (58 FR 53254
at 53266 to 53268), and it is observed not only in persons with
pernicious anemia from an inability to absorb dietary vitamin B<INF>12
but also in approximately 10 to 20 percent of elderly persons, more
than 25 percent of demented patients, 15 to 20 percent of acquired
immune deficiency syndrome (AIDS) patients, and 15 to 20 percent of
patients with malignant diseases.
The agency further noted that other groups may be at risk from
excessive intakes of folate. These other groups include pregnant women
(with the potential for high levels of free folic acid affecting the
embryo during early gestation) and persons on medications (the
effectiveness of which could be adversely affected by high dietary
folate intakes) used in the treatment of various cancers, psoriasis,
rheumatoid arthritis, and bronchial asthma). Throughout its folate
rulemaking proceedings, FDA evaluated the safety of high intakes of
folate for all of these potentially at-risk groups. In its folate
health claim final rule published elsewhere in this issue of the
Federal Register, the agency described how it had reached its decision
that 1 mg of total folate per day was the safe upper limit of intake.
In the folate health claim proposed rule (58 FR 53254, October 14,
1993), the agency provided data demonstrating the difficulty of
concurrently achieving the PHS recommended increase in folate intake
for all women of childbearing age without raising folate intakes of
other segments of the population to unsafe levels. Thus, the agency
recognized the significance of the proposed upper limit for daily
folate intake in limiting the ability of fortification of the food
supply alone to enable all women of child-bearing age to achieve the
PHS recommendation on folate intake. The agency also noted that there
is a general paucity of evidence on the safety of daily folate intakes
above 1,000 <greek-m>g (1 mg). Therefore, in the folate food additive
proposal, FDA specifically requested comments and data on the use of 1
mg per day total folate as a safe upper limit for establishing
restrictions on food additive uses of folic acid. FDA further noted
that the 1 mg daily safe upper limit for folate intake may need to be
modified if data became available to support such a decision. Several
comments supported FDA's tentative conclusion of 1 mg total dietary
folate per day as the safe upper limit because they felt that the 1 mg
per day limit is based on the best available data. As described below,
other comments felt that this level was either too high or too low.
1. Folate intakes of 1 mg or Less Daily
Several comments contended that current scientific knowledge is
insufficient to set the safe upper limit at 1 mg folate per day, and
that perhaps the safe upper limit may actually be lower than 1 mg
folate per day. These comments cited published studies suggesting that
500 <greek-m>g folic acid per day may mask the anemia of vitamin
B<INF>12 deficiency and urged that FDA set the safe upper limit below
500 <greek-m>g folic acid per day. None of the commenters provided any
new data to support their arguments.
FDA disagrees with those comments that contended that the safe
upper limit of intake of 1 mg folate daily is too high, and that the
limit should be set at a lower level. In its proposed folate health
claim rule (58 FR 53254 at 53266 to 53270, October 14, 1993), FDA
stated that it was aware that several published case reports suggest
that there is evidence of masking of pernicious anemia in patients who
consumed supplements that provided less than 1 mg folic acid daily. FDA
was also aware of limited reports of masking of the anemia of vitamin
B<INF>12 deficiency at levels as low as 250 <greek-m>g folic acid
daily. These reports were the basis for the agency's amendment, in the
Federal Register of October 17, 1980, to its drug regulation on the
therapeutic uses of folic acid (45 FR 69043 at 69044). In that
instance, the agency required that the labeling of oral and parenteral
preparations of folic acid include a ``Precautions'' statement that
``Folic acid in doses above 0.1 mg daily may obscure pernicious anemia
in that hematologic remission can occur while neurological
manifestations remain progressive'' (see discussion in proposed health
claims rule, 58 FR 53254 at 53257, October 14, 1993).
FDA, as part of its review of the scientific literature and its
discussions with the Folic Acid Subcommittee, carefully considered the
reports of masking at relatively low levels of folate. In its folate
health claim proposal, FDA noted that the effects of intakes of less
than 1 mg are infrequent, suboptimal, and less predictable than those
occurring at higher intakes (58 FR 53254 at 53267, October 14, 1993).
A safe upper limit of daily folate intake of 1 mg for persons with
vitamin B<INF>12 deficiency was discussed by experts during a Centers
for Disease Control and Prevention (CDC) workshop on surveillance for
adverse effects of increased folic acid intakes. Those experts stated
that there was little likelihood of problems at daily intakes lower
than 1 mg (Ref. 2).
Most commenters with expertise in folate and vitamin B<INF>12
metabolism and nutrition also supported a safe upper limit of 1 mg
folate daily based on their scientific knowledge and clinical
experiences (see folate health claim final rule published elsewhere in
this issue of the Federal Register). Moreover, a safe upper limit of 1
mg folate daily is consistent with the current Reference Daily Intakes
(RDI's) for folate (i.e., 400 <greek-m>g daily for the general
population and 800 <greek-m>g daily for pregnant women, levels that
were the same as the U.S. RDA's that were used as early standards for
nutrition labeling (Ref. 3)) and is consistent with the 1992 PHS
recommendation for women of child-bearing age (Ref. 1).
Therefore, FDA concludes that for those with vitamin B<INF>12
deficiency, there is little likelihood of problems if daily folate
intakes are 1 mg or less. Moreover, FDA received no comments that
disagreed with the agency's tentative conclusions that daily folate
intakes of 1 mg or less are safe for pregnant women and for persons on
medications whose effectiveness could be adversely affected by high
folate intakes. Thus, FDA concludes that there is a reasonable
certainty of no harm from a daily intake of up to 1 mg folate.
Page 8799
2. Folate Intakes Above 1 mg Daily
Other comments asserted that FDA's tentative conclusion of a safe
upper limit of intake of 1 mg daily was too low. These comments
contended that there is no evidence that folic acid intakes of 1.5 to 2
mg per day would result in any untoward effects and recommended that
FDA set the safe upper limit at 1.5 to 2 mg folic acid per day. Another
comment opined that setting the safe upper limit for folate intake at 1
mg per day is ``arbitrary'' and ``paranoid.'' One comment claimed that
the 1 mg limit is inappropriate because it is not based on substantive
medical data. Several comments claimed that there is no evidence to
suggest that folic acid doses at 1 mg per day are toxic. One comment
argued that ``there is no toxicity for folic acid per se,'' and that
``the fact one mg. is needed to treat megaloblastic anemia really
represents a floor. It does not speak to the intakes of Americans from
food and fortification and supplements. Because Americans are laggards
in their intake, a relative ceiling of 2 mgs. is not likely to be
reached.'' This comment argued that, because the food bioavailability
of folacin is fair but not excellent, fortificant and supplement
intakes of folic acid are not likely to exceed one mg. None of these
comments provided data to support their views.
Several comments focused on the safety of high folate intakes for
pregnant women. These comments suggested that concerns about the safety
of high intakes of folate in pregnant women were unfounded. In support
of this contention one comment claimed that ``* * * millions of
pregnant women have safely consumed prenatal vitamins with 1 mg of
folic acid in addition to their diet over the past 15-20 years.''
Several comments questioned why FDA set the safe upper limit at 1 mg
per day while the United Kingdom (UK) was recommending a much higher
limit of 5 mg folic acid per day.
Other comments focused on FDA's concern about the absence of data
on safe use for persons with marginal vitamin B<INF>12 nutritional
status. One comment asserted that FDA overstated the issue of the
masking of B<INF>12 deficiency by folate. Another comment claimed that
a hematologic response to folic acid in dosages between 1 mg and 5 mg
per day appears to occur in persons with clinical vitamin B<INF>12
deficiency, but the frequency, magnitude, and duration of this response
is unknown. The comment also stated that it is not known whether this
hematological response could lead to a delay in the diagnosis of
vitamin B<INF>12 deficiency. While agreeing that the masking of
pernicious anemia is a concern, these comments argued that there is
evidence that a substantial proportion of persons with pernicious
anemia do not present with anemia before neurological symptoms.
Therefore, these comments argued, these individuals would suffer the
effects of undiagnosed pernicious anemia with or without folic acid
supplementation. These comments did not provide any new data to support
their view.
In proposing the safe upper limit at 1 mg folate per day, FDA
carefully considered the available evidence on the safety for all
segments of the population that might be placed at risk if folate
intakes were to become excessively high. In response to the proposal,
the agency did not receive any comments that provided data relating to
the safety of long-term intakes of folate at levels above 1 mg per day
for any of the groups considered at potential risk from increased
intakes. FDA notes that both the Folic Acid Subcommittee and the Food
Advisory Committee expressed concerns about the lack of information to
support the safety of long-term daily intakes at levels above 1 mg
(Ref. 4). The Food Advisory Committee also expressed concern about the
lack of information on the size of the population potentially at risk
from increased intakes of folate.
The agency is not aware of data that establish the safety of long-
term intakes of folate above 1 mg per day. The absence of any data
allowing systematic evaluation of intakes above this level means that
potential risks and at-risk groups cannot be adequately defined or
described. FDA notes that most folate and vitamin B<INF>12 experts
submitting comments were concerned about the lack of documentation of
safety of long-term daily intakes of folate above the level of 1 mg per
day. In addition to expressing safety concerns regarding those with low
vitamin B<INF>12 status, experts cited uncertainties about the effects
of increased folate intakes by young children and the unknown
physiological significance of circulating free folic acid in the blood,
particularly in pregnant women. In its folate health claim proposed
rule (58 FR 53254 at 53269, October 14, 1993), the agency summarized
evidence from the scientific literature that high levels of free folic
acid are not normally found in the circulation, and that folic acid is
concentrated in crossing the placenta and accumulates in fetal tissues.
At that time, the agency noted that no information was available to
ascertain whether developing neural tissue is protected from the
neurotoxic effects of very high circulating levels of free folic acid.
Neither these issues nor issues related to long-term folate intakes of
greater than 1 mg daily by other risk groups were addressed in the
comments that the agency received.
The agency finds that the comments that suggested that there is
evidence of safe use of high intakes of folate by pregnant women are
misleading and erroneous. The agency disagrees with comments asserting
that folic acid at doses of 4 mg per day have been extensively studied
in pregnant women and are without toxic effects. The agency recognizes
that pregnant women take prenatal supplements that usually contain 800
<greek-m>g of folic acid, and that such supplements have been in use
for many years. FDA notes, however, that while there is no evidence
that 800 <greek-m>g of folic acid per day (i.e., the U.S. RDA level for
pregnant or lactating women) is unsafe for this group, such dosages are
usually taken only during the second and third trimesters of pregnancy,
or during lactation, to meet specific nutritional needs for limited
periods of time and are usually taken under a physician's supervision.
FDA further notes that the Institute of Medicine has stated that the
safety of large doses of folic acid in pregnant women has not been
systematically determined (Ref. 5).
FDA also disagrees with the comments that stated that the
recommendations of the government of the UK are directly relevant to
inferring that 5 mg daily is a safe level of intake for pregnant women.
FDA notes that these comments fail to reveal the full content of the UK
recommendations (Ref. 6). The UK government made two recommendations
relating daily folate intake to women of child-bearing age. The first
recommendation is for health care professionals to prescribe a dietary
supplement containing 4 or 5 mg (4,000 or 5,000 <greek-m>g) folic acid
daily until the 12th week of pregnancy to women who have already had a
pregnancy affected by a neural tube birth defect and, therefore, are at
a particularly high risk for another affected pregnancy. The second
recommendation is that women of child-bearing age, who have not had a
previous pregnancy affected by a neural tube defect and who are likely
to become pregnant, should increase their intakes of folate-rich foods
and take a dietary supplement containing 400 <greek-m>g folic acid
daily. The supplement use is recommended from the start of attempting
to conceive until the 12th week of pregnancy. Clearly, the UK
recommendation for women in the general population is the relevant
recommendation to this rulemaking
Page 8800
rather than the recommendation for the use of high potency supplements,
by prescription, for women at high risk of an affected pregnancy.
Moreover, the UK recommendation for women in the general population is
consistent with the PHS recommendation, to which FDA subscribes.
Finally, and most significant to this rulemaking, the UK
recommendations do not directly address the safety of fortification for
the entire food supply. FDA, therefore, finds that, contrary to the
suggestion in the comment, the UK's folate intake recommendations for
women anticipating pregnancy, but who have not had a history of a prior
affected pregnancy, are consistent with FDA's conclusions of safe
intakes for pregnant women.
FDA also disagrees with the comment that asserted that folic acid
at doses of 4 mg per day has been extensively studied in pregnant
women, and that such doses are without toxic effects. In the only study
utilizing 4 mg folic acid per day, the Medical Research Council trial,
about 910 women took supplements containing 4 mg of folic acid from the
time of randomization into the trial until the 12th week of pregnancy
(Ref. 7). The authors of this study concluded that, although this trial
had sufficient statistical power to demonstrate the efficacy of the
intervention, it did not have sufficient power to answer the question
of safety for public health purposes. Consequently, this study does not
provide a basis on which to determine whether the chronic use of 4 mg
per day of folic acid by pregnant women is safe. The agency is not
aware of any other studies on the effect of daily folate intakes of 4
mg in pregnant women, or of any other data or information that would
persuade the agency that 4 mg folate per day is the appropriate safe
upper limit of intake for pregnant women.
FDA is also not convinced by the comments on masking of the anemia
of vitamin B<INF>12 deficiency that a higher value for a safe upper
limit of folate intake is appropriate. As stated in the food additive
proposed rule (58 FR 53312, October 14, 1993), one of the safety
concerns associated with high intakes of folate is the potential for
masking the anemia associated with vitamin B<INF>12 deficiency which
may delay accurate diagnosis and prompt treatment of this problem while
neurologic damage progresses. The symptoms of vitamin B<INF>12
deficiency include both hematologic and neurologic effects. While the
hematologic effects of vitamin B<INF>12 deficiencies are reversible,
the associated neurologic effects may be irreversible depending on how
far they have progressed before detection and treatment. Any increase
in the potential for masking the hematologic effects of vitamin
B<INF>12 deficiency may compromise prompt and effective treatment,
thereby making irreversible neurologic damage more likely.
The scientific literature describing the effects of intakes of
folic acid between 1 and 5 mg per day is very limited. Nonetheless, FDA
disagrees with the comments that asserted that there is no evidence of
untoward effects of daily folate intakes of 1.5 to 2 mg per day, and
that 5 mg per day should be identified as the safe upper limit of
intake.
The literature describing the effects of daily intakes of 1 to 5 mg
folic acid includes three uncontrolled intervention trials involving 15
persons (Refs. 8, 9, and 10) and 16 case reports (Refs. 11, 12, 13, 14,
15, and 16). These reports represent a very small data base, with
information from a total of only 31 individuals. Moreover, the agency
notes that, among these data, exposures of 9 individuals to daily
intakes of 1 to 5 mg folic acid lasted for less than 30 days (e.g.,
Refs. 9, 11, 12, and 17). These short-term reports are inadequate for
assessing the safety of life-long exposures. FDA notes, however, that
hematological responses that could lead to a delay in the diagnosis of
vitamin B<INF>12 deficiency were observed in 9 of the 16 patients
(i.e., in more than 50 percent) whose daily oral intakes of folic acid
were in the range of 1 to 5 mg and continued for 1 month or more (Refs.
8, 11, 12, 14, and 16). Thus, the scientific literature, although
limited, shows that approximately half of the patients with pernicious
anemia associated with vitamin B<INF>12 deficiency responded to folate
at doses between 1 and 5 mg per day when they are given the vitamin for
relatively short periods of time (e.g., several months).
FDA also is not convinced by the comments that noted that adverse
effects of high intakes of folate with respect to vitamin B<INF>12
deficiency can be detected with clinical care and that the issue of
masking of vitamin B<INF>12 deficiency predated modern clinical
nutrition. FDA is aware that, in many instances, the adverse effects of
increased folate intake associated with the masking of the anemia of
vitamin B<INF>12 deficiency can be detected with clinical care but
disagrees that clinical care alone is sufficient to ensure a reasonable
certainty of no harm should the intake of folate exceed 1 mg folate per
day. The agency notes that measurements of vitamin B<INF>12 status are
not performed on a routine basis by physicians, and that there is no
way to systematically determine how many people in the United States
have undiagnosed vitamin B<INF>12 deficiency and thus might be at risk
from increased intake of folate. The agency noted in the January 6,
1993, folate health claim final rule (58 FR 2606 at 2615) that
significant percentages of the elderly, demented patients, AIDS
patients, and patients with malignant diseases have subnormal vitamin
B<INF>12 levels without having any of the classical manifestations of
vitamin B<INF>12 deficiency. It has been reported, in a large study (n
= 548) that the prevalence of vitamin B<INF>12 deficiency is greater
than 12 percent among free-living elderly Americans (Ref. 18). In
addition, 5 to 10 percent of all patients, regardless of age or
clinical status, are found to have low serum vitamin B<INF>12 levels
(58 FR 2606 at 2615, January 6, 1993). Little is known about whether
folate supplementation would have any adverse effect on such persons,
who are far more numerous in the U.S. population than are persons with
pernicious anemia.
The argument that adverse effects in persons with vitamin B<INF>12-
related problems can be identified with clinical care fails to consider
whether such persons, who may be unaware of their vitamin B<INF>12
status, would recognize an adverse effect as being the result of
increased folate intake, and whether they would seek medical attention
if such an effect occurred. There is no reason to conclude that they
would. Thus, the agency concludes that the argument that adverse
effects in persons with vitamin B<INF>12-related problems can be
identified with clinical care does not provide a sufficient basis for
the agency to conclude that increasing the safe upper limit of intake
provides a reasonable certainty of no harm.
In developing its proposed rules, FDA was aware of the contentious
nature of the proposed 1 mg folate per day upper limit and specifically
asked for data on this issue. This topic was also extensively discussed
by FDA's Folic Acid Subcommittee and the full Food Advisory Committee
(Refs. 4 and 19). No data were submitted in any of the comments that
addressed the issue of the safety of intakes above 1 mg per day either
for persons in the general population or for any of the groups
identified as potentially at risk from increased folate intakes. The
agency also notes that its position regarding use of 1 mg folate per
day as the safe upper limit of daily intake was supported by all
comments from individuals with known expertise in folate and vitamin
B<INF>12 metabolism and related diseases.
Page 8801
Because there are inadequate data and information on the safety of
consuming more than 1 mg folate per day, the agency finds that it
cannot conclude that there is a reasonable certainty of no harm to
persons who consume more than 1 mg folate per day. In the absence of
safety data on daily intakes of folate above 1 mg per day, the agency
is unable to adequately define the nature, or assess the magnitude, of
potential risk from increased folate intakes. Therefore, the agency
concludes that, because of the lack of evidence to support the safety
of intake at levels greater than 1 mg folate daily, and the potential
for serious harm to some persons from such intakes, the safe upper
limit for daily folate intakes is appropriately set at 1 mg, the
highest intake level that meets the safety standard for food additives
that there is a reasonable certainty of no harm from use of the
additive.
FDA finds that 1 mg per day as the safe upper limit for folate
intake is supported by: (1) The totality of the available scientific
evidence and the views expressed by experts with recognized expertise
in folate and vitamin B<INF>12 nutrition and metabolism, that there are
no data to ensure that adverse effects are not likely to occur at daily
intakes above 1 mg (Refs. 2, 4, 19, and 20); (2) the PHS recommendation
that folate intake of women of childbearing age should not exceed 1 mg
per day (Ref. 1); and (3) the Folic Acid Subcommittee's use of 1 mg of
total folate per day as a safe upper limit guide when considering
fortification strategies.
The agency also is aware, however, of the rapidly evolving and
potentially significant research suggesting a possible link between
folate intakes and reduced risk of heart disease. The agency notes that
a recent expert workshop sponsored by the National Heart, Lung, and
Blood Institute of the National Institutes of Health reviewed the
state-of-the art science in this area (Ref. 21). The expert working
group found that the currently available data, while highly suggestive
of a relationship, were insufficient to demonstrate the validity of
this hypothesis. Nonetheless, FDA intends to monitor and review new
data and information on both the safety of daily folate intakes at
levels above 1 mg daily and on the potential need for improving the
folate nutritional status of large segments of the U.S. population.
Should persuasive evidence emerge that provides a reasonable certainty
that daily intakes of folate at higher levels are safe, the agency will
take action to modify the 1 mg per day safe upper limit for daily
folate intake.
B. Concurrent Vitamin B<INF>12 Addition
One comment recommended requiring the addition of vitamin B<INF>12
to all foods containing added folic acid as a means to alleviate some
of the concerns about the masking of the effects of vitamin B<INF>12
deficiencies. Another comment claimed that many dietary supplements
contained 100 percent of the RDI for vitamin B<INF>12 as well as 100
percent of the RDI for folic acid and asserted that this level of
vitamin B<INF>12 should allay the concerns about masking vitamin
B<INF>12 deficiencies.
FDA is aware that very high oral doses of vitamin B<INF>12 (e.g.,
about 1 mg; 500-times the RDI for this vitamin) have provided effective
treatment for some persons with pernicious anemia (Ref. 22). These
findings have led some scientists to suggest that high doses of vitamin
B<INF>12 could be added to foods and dietary supplements fortified with
folic acid to reduce the potential for adverse effects in persons with
vitamin B<INF>12 deficiency.
This suggestion was discussed during a meeting on surveillance for
adverse effects of increased intakes of folate organized by CDC (Ref.
2). Several experts noted that even if an individual has pernicious
anemia because of vitamin B<INF>12 malabsorption, they are able to
absorb a small amount of oral vitamin B<INF>12 (about 1 to 2 percent).
Several experts, however, suggested that one possible question about
using foods or food products containing added vitamin B<INF>12 is that
in the presence of other nutrients (e.g., vitamin C, thiamin, iron),
vitamin B<INF>12 may be converted into analogs, some of which may have
antivitamin B<INF>12 activity. The participants in this meeting noted
the paucity of data about this matter. There were no conclusions or
recommendations by this expert group on these issues.
In the folate health claim proposal of October 14, 1993 (58 FR
53254 at 53280), the agency discussed the issue of whether high doses
of vitamin B<INF>12 should be added to foods or supplements fortified
with folic acid to reduce the potential for adverse effects in persons
with vitamin B<INF>12 deficiency. The agency requested comments, and
specifically data, on the appropriateness, potential effectiveness, and
safety of such fortification. The agency did not receive any data or
other information on this issue.
Because data are not available that address the safety of
simultaneous fortification of foods or dietary supplements with both
folate and vitamin B<INF>12, the agency cannot establish a level of
oral vitamin B<INF>12 that is safe for the general population, safe for
persons with vitamin B<INF>12-related problems, and sufficiently high
to protect persons with vitamin B<INF>12-related problems from the
adverse effects of increased intakes of folate. Furthermore, FDA notes
that, because difficulty in absorbing oral vitamin B<INF>12 is the
primary reason for inadequate vitamin B<INF>12 nutriture in many
persons, the amount of vitamin B<INF>12 to be added would likely need
to be very high, perhaps up to 500 times the RDI. Questions regarding
the appropriateness, potential effectiveness, and safety of such an
approach remain unanswered.
Given that vitamin B<INF>12 deficiency, including pernicious
anemia, is a serious condition, which if untreated can lead to
irreversible neurological damage, patients with pernicious anemia, and
others at risk of vitamin B<INF>12 deficiency, should be diagnosed,
treated, and monitored by a physician (Ref. 22). Moreover, the addition
of both vitamin B<INF>12 and folic acid to a food is not relevant to
other potential safety issues associated with high folate intakes
(e.g., high intakes in pregnant women and adverse interactions in
persons on some medications). Therefore, the agency rejects the
suggestion that it require the addition of vitamin B<INF>12 to all
foods containing added folic acid because there is not sufficient
information to demonstrate that the addition of vitamin B<INF>12
whenever folic acid is added will be effective for its intended purpose
and will ensure the safety of the use of folic acid.
C. Folate Versus Folic Acid
Several comments supported FDA's proposal to fortify certain
cereal-grain products based on a safe upper limit for total folate
rather than folic acid. Some comments stated that the use of total
folate as opposed to only added folic acid to set the safe upper limit
of intake was advisable because this approach provides an additional
safety factor. Other comments recommended that the safe upper limit
should be based solely on added folic acid and not total folate intake.
In support of establishing the safe upper limit based on folic acid
intakes, one comment claimed that the 1 mg limit should be based on
folic acid rather than folate because the bioavailability of folate is
fair but not excellent. One comment argued that using folic acid rather
than folate as the benchmark for measuring the safe upper limit of
total folate intake is consistent with FDA's historical treatment of
the
Page 8802
distinction between folic acid and folate. The comment pointed out that
in 1971, for example, FDA concluded that ``folic acid especially in
doses above 1.0 mg daily may obscure pernicious anemia * * *'' (36 FR
6843, April 7, 1971). According to this comment, in 1979, FDA warned
that for products containing 1 mg folic acid ``the use of folic acid
for treatment of anemia without the direction of a physician may be
dangerous.'' (44 FR 16126 at 16149, March 16, 1979.)
Several comments questioned why FDA proposed to establish the safe
upper limit on a folate basis, rather than on a folic acid basis, given
the fact that the human trials were run with folic acid, and there is
no evidence of food folate reducing the incidence of NTD's.
Another comment recommended that the safe upper limit be
established on a folic acid basis because:
* * * (1) all evidence relative to the delay in diagnosis of
vitamin B<INF>12 deficiency at consumption levels of 1,000 mcg and
above, however equivocal, derives from persons who took folic acid
supplements orally or received folic acid parenterally and who were
simultaneously consuming folates from their diets, and, (2) for
years, the cut point between 'over the counter' and prescription
folic acid supplements has been 1,000 mcg. FDA's 1971 drug use/
safety regulation governing oral and parenteral usage of folic acid
(36 FR 6843) stated that ``folic acid especially in doses above 1.0
mg daily may obscure pernicious anemia in that hematologic remission
may occur while neurological manifestations remain progressive.''
As discussed previously and in the proposed rule (58 FR 53312,
October 14, 1993), FDA is aware of the effect on the choice of a
fortification option if the safe upper limit were established based on
total folate rather than the added form of the vitamin, folic acid. FDA
notes that the distinction between ``synthetic folic acid,'' referring
only to folic acid, and ``folate,'' referring only to naturally
occurring food folates, with respect to the 1 mg estimate of safe daily
intake is an artificial one and is not consistent with what is known
about the metabolic interrelatedness and substitutability of a variety
of folate vitamin forms.
The agency acknowledges that evidence relative to the masking of
the anemia of vitamin B<INF>12 deficiency has been obtained from
persons who consumed or were treated with synthetic folic acid.
However, these individuals were also consuming unmeasured quantities of
folate from foods. Thus, total daily folate exposures were unknown. The
extent to which variations in background food folate intakes affected
the variable responses, in terms of masking effects, cannot be
determined. The absence of data on this issue means that it is not
possible to conclude that only added folic acid is responsible for any
masking effects.
Moreover, the agency notes that studies in vegetarians can provide
some insights into the question of whether high intakes of folates from
food sources alone can have adverse effects in persons with poor
vitamin B<INF>12 status. Vegetarians present a model group for
evaluating this question because their diets are very low in vitamin
B<INF>12 (because animal foods are the sole dietary source of vitamin
B<INF>12) and usually very high in foods rich in folate (e.g., fruits,
vegetables and legumes). Thus, vegetarians are at risk of developing
vitamin B<INF>12 deficiency in the presence of high folate intakes. In
one study of vegetarians, the authors reported that megaloblastic
anemia (i.e., the type of anemia associated with vitamin B<INF>12
deficiency) is rarely encountered in Caucasian vegetarians and vegans
(Ref. 23). This study also reported that the folate content of diets of
vegan children aged 6 to 13 years was twice as high as that of
omnivorous children aged 7 to 12 years. When infants of vegetarian
mothers developed vitamin B<INF>12 deficiency, they usually presented
first with neurological signs and symptoms rather than anemia. Another
article reported that studies conducted over several decades in
vegetarian populations have all indicated that major damage to myelin
synthesis (i.e., synthesis of the covering of nerves) occurs with only
minor hematopoietic damage (i.e., inability to synthesis red blood
cells, resulting in anemia) (Ref. 24). This report also found generally
higher red cell folate in persons with greater myelin damage of the
type that only vitamin B<INF>12 deficiency produces than in persons
with greater hematologic damage (i.e., anemia). These studies are
suggestive that high food folate intakes alone can mask early
hematologic symptoms of vitamin B<INF>12 deficiency in vegetarians,
thus, suggesting that food folates and synthetic folic acid are each
capable of causing masking effects.
These observations support the view that a safe upper limit of
daily intake is more accurately based on total folate intake than on
just intake of synthetic (or added) folic acid. Under conditions in
which vitamin B<INF>12 utilization or intake is limited, either
synthetic folic acid or food folate may cause masking of vitamin
B<INF>12-related anemia, and these two sources appear to be additive.
FDA also disagrees with the comments that the historical concern
with safety of folate intakes for drugs, as well as for FDA's food
additive regulations, was limited only to synthetic folic acid. The
agency notes that the commenters' references to FDA's 1971 drug
regulation in which intakes of synthetic folic acid above 1 mg daily
were stated to cause masking of anemia related to vitamin B<INF>12
deficiency are misleading in that they fail to note that in 1980, FDA
revised the 1971 drug regulation to require a warning statement that
intakes as low as 0.1 mg daily may obscure pernicious anemia (45 FR
69043 at 69044, October 17, 1980). Clearly, for the food supply, a safe
upper limit of intake of 0.1 mg would be inadequate to provide the
known folate nutritional requirements of the U.S. population. Thus,
considerations in drugs that are intended for the treatment of persons
with diagnosed diseases and health-related conditions are not
necessarily directly applicable to questions of food safety.
FDA further finds that suggestions that the historical examination
of food additive regulations dealt only with synthetic folic acid are
not helpful. Food additive regulations on folate addition to foods
necessarily specify that the added form is synthetic because that is
the only form that can be a food additive. On the other hand, it is
common practice when evaluating the safety of an added food ingredient
to consider the safety within the context of total dietary exposures,
regardless of source.
As to comments on possible differences in bioavailability between
food sources and synthetic sources of folic acid and the potential of
these differences to affect safety considerations, FDA discussed this
issue in its proposed health claim rule (58 FR 53254 at 53273 to
53274). FDA tentatively concluded that the issue of bioavailability is
complex, and that no systematic data are available on many of the
factors that affect bioavailability. FDA was not aware of any
meaningful way to factor bioavailability into fortification scenarios
or, by extension, into evaluations of safety. FDA received no new data
on this matter. Therefore, FDA has no basis on which to factor possible
differences in bioavailability of synthetic, as opposed to food,
folates into its determination of the safe upper limit of folate
intakes.
Significantly, the use of a distinction between folic acid and
folate for the purposes of establishing a safe upper limit of folate
intake was not supported by any expert group that the agency consulted
during this rulemaking proceeding or by comments from experts in folate
and B<INF>12 metabolism and related diseases (Refs. 2, 4, and 19).
Page 8803
Nor was it supported by any of the folate or vitamin B<INF>12 experts
who submitted written comments to the record. FDA received no new data
or compelling arguments in this regard. Therefore, the agency concludes
that the safe upper limit of daily intake should be based on total
folate intake (i.e., on consumption of folate from all sources).
D. Breakfast Cereals
Several comments supported the proposal to limit the fortification
of breakfast cereals to 100 <greek-m>g per serving. One comment
supported the proposed rule's distinction between the consumption of
dietary supplements and breakfast cereals, noting that:
The document appropriately makes the distinction between
breakfast cereal and vitamin supplements noting that some persons
may consume many more than one serving of breakfast cereal per day.
In contrast, however, another comment argued that:
* * * the potential for overconsumption of folic acid is greater
for dietary supplements in pill/tablet/capsule form than for
supplement cereals. Supplement cereal consumption is self-limiting
in light of volume and caloric considerations. In contrast, smaller
supplements have the potential to be consumed excessively, for
example, by adults using a multivitamin/mineral product to increase
vitamin C intake to combat a cold, or by children, with the
potential result of iron toxicity.
Several comments recommended that currently marketed breakfast
cereals containing 400 <greek-m>g per serving folic acid should be
allowed to continue to be formulated at this level. One breakfast
cereal manufacturer argued that allowing dietary supplements to contain
the full RDI level of folic acid while limiting the folic acid added to
breakfast cereal to 25 percent of the RDI did not seem to be based on
any scientific rationale:
If 100% RDI is a safe level for a vitamin supplement in tablet
form, it surely is a safe level in a food form. In fact, food is
potentially a safer alternative since the consumption is self-
limiting; whereas there is greater potential for over consuming
supplements in tablet form.
Several comments stated that they did not understand how FDA could
reduce the level of added folic acid in breakfast cereals and still
implement the PHS recommendation to have women of childbearing age
consume 400 <greek-m>g folic acid per day. Other comments argued that
FDA should allow some breakfast cereals to contain 100 percent of the
RDI for folic acid per serving as an alternative to taking dietary
supplement tablets.
Still other comments argued that FDA should not make a regulatory
distinction between dietary supplements in conventional and
unconventional food forms. The comments asserted that both should be
allowed to provide 100 percent of the daily value of folic acid.
One comment suggested that for breakfast cereals to contain 100
percent of the RDI for folic acid, they must contain 100 percent of the
RDI for at least 10 vitamins for which RDI's have been determined to
preserve their status as rationally balanced supplement products.
In the proposal, FDA tentatively concluded that if cereal-grain
products were fortified at 140 <greek-m>g folic acid per 100 g, the
addition of folic acid to breakfast cereals should be limited to 100
<greek-m>g folic acid per serving. FDA stated that fortification of all
breakfast cereals to 400 <greek-m>g folic acid per serving would result
in the estimated daily intake of folate among significant portions of
the population exceeding the safe upper limit of 1 mg folate per day.
FDA recognizes that fortification of some breakfast cereals at 400
<greek-m>g folic acid per serving provides women of child-bearing age
flexibility to meet the PHS recommendation that such women consume 400
<greek-m>g of folic acid per day as a means to reduce their risk of
having a pregnancy affected by an NTD. FDA emphasizes that the
estimates of folate consumption presented in the health claims proposal
(58 FR 53295, October 14, 1993) were based on calculations that assumed
all breakfast cereals would be fortified at 0, 100 <greek-m>g, or 400
<greek-m>g folic acid per serving. As discussed in the proposal, most
breakfast cereals are fortified at 100 <greek-m>g folic acid per
serving, and only 3 to 6 percent of breakfast cereals are fortified at
400 <greek-m>g folic acid per serving (Nielsen Scantrack Data, A.C.
Nielsen Marketing Research, Inc., Cherry Hill, New Jersey).
FDA has no basis to conclude that the current market distribution
of breakfast cereals fortified at 400 <greek-m>g folic acid per serving
will substantially change as the result of the authorization of a
health claim on the relationship of folate to NTD's. In fact, the
agency notes that the health claim on the relationship between folate
and NTD's may be included in the labeling of foods that are good
sources of folate (40 to 76 <greek-m>g folic acid per serving). Because
most breakfast cereals contain folic acid at levels (100 <greek-m>g
folic acid per serving) that permit them to bear this health claim,
there is no need for breakfast cereal manufacturers to increase their
level of folic acid fortification to qualify to bear the claim.
Moreover, FDA has provided in 21 CFR 101.79(c)(2)(i)(G) that the
health claim for folate and NTD's cannot state that a specified amount
of folate per serving from one source is more effective in reducing the
risk of NTD's than a lower amount per serving from another source.
Thus, the health claim regulation provides no incentive for increasing
the level of folic acid fortification in breakfast cereals.
Therefore, given the small number and limited market share of
breakfast cereals that are fortified with 400 <greek-m>g of folic acid
per serving, the lack of incentive for there to be any significant
increase in this number, and the fact that, if used appropriately,
breakfast cereals can contribute to a healthful diet and provide
flexibility for women in selecting foods to meet the PHS
recommendation, FDA has concluded that it is not necessary to limit the
addition of folic acid to breakfast cereals to 100 <greek-m>g folic
acid (25 percent of the RDI) per serving. FDA has determined that
addition of up to 400 <greek-m>g folic acid per serving in breakfast
cereals is safe as long as this practice does not become widespread.
FDA intends to monitor the marketplace, however, and should the
proportion of breakfast cereals fortified at 400 <greek-m>g folic acid
change substantially, FDA may find it necessary to reconsider this
conclusion.
E. Fruit Juice Replacements
One comment recommended that fruit juice replacements be permitted
to add folic acid at 20 percent of the RDI.
FDA has considered this recommendation in light of its efforts
towards implementation of the PHS recommendation and establishing safe
conditions of use for folic acid.
In examining options for providing folate to women of childbearing
age through food fortification, the agency considered various options
including allocation of folate to products such as cereal-grain
products, fruit juices, and dairy products.
In selecting foods to consider as vehicles for fortification, the
agency started with the basic principle that fortification of staple
products that are commonly consumed in significant amounts by virtually
all members of the target population is most likely to result in
increased intakes of a specific nutrient by the target population (Ref.
26). The agency notes that, based on this general principle, cereal-
grain products were the fortification vehicle recommended by the Food
and Nutrition Board (Ref. 26).
Recent food consumption data confirm that 90 percent of women of
childbearing age consume cereal-grain
Page 8804
products on a daily basis (Ref. 26). Therefore, all fortification
options that the agency considered included fortification of cereal-
grain products. Other commonly consumed food categories that may lend
themselves to fortification with nutrient additives, including juices
and dairy products, were also considered. Examples of dairy products
and fruit juices that the agency considered for fortification included:
Fluid cows' milk, reconstituted dry milk, condensed and evaporated
milks, yogurts, and fruit juices such as orange, grapefruit, lemon,
pineapple, apple, and grape.
FDA also included breakfast cereals in evaluating all fortification
strategies because these products represent a traditional source of
many nutrients, including folate, for those who consume them. Breakfast
cereals are also consumed by many women of childbearing age (Ref. 27).
Similarly, because approximately 30 to 40 percent of women of
childbearing age use dietary supplements (Ref. 28), the agency also
included the availability and continued use of dietary supplements in
all fortification options.
In the agency's analyses of potential intakes from fortified foods,
FDA applied different levels (70, 140, and 350 <greek-m>g per 100 unit)
of fortification to the broad range of food products under
consideration, including certain dairy products and fruit juices.
When fortification at the lowest level, (i.e., 70 <greek-m>g per
unit) included fruit juices and dairy products in addition to cereal-
grain products, intakes of high consumers exceeded the safe upper limit
of 1 mg folate per day for most age groups. For example, fortification
of cereal-grain products, fruit juices, and dairy products with 70
<greek-m>g folic acid per unit, in addition to usual patterns of
dietary supplement and breakfast cereal use, was estimated to result in
daily folate intakes of high consumers in many groups in excess of 1 mg
(58 FR 53254 at 53292, October 14, 1993).
On the other hand, as discussed more fully in the folate health
claim proposal, FDA examined the effects of not including fruit juices
and dairy products in its fortification model. As noted above, cereal-
grain products are more widely consumed than dairy products or fruit
juices by women of childbearing age. The agency examined the following
fortification levels: 70, 140, or 350 <greek-m>g folic acid per unit.
If cereal-grain products were fortified with 70 <greek-m>g folic acid
per 100 g, folate intakes by adult population groups of ``high
consumers'' would remain below 1 mg per day (58 FR 53254 at 53292,
October 14, 1993). If fortification of cereal-grain products was 140
<greek-m>g per 100 g, intakes by adults 51+ years who were ``high
consumers'' and who used supplements would approach but not exceed 1 mg
folate per day. Fortification of cereal-grain products at 350
<greek-m>g per 100 g could result in estimated daily intakes by ``high
consumers'' among several sex/age groups in excess of 1 mg folate per
day (58 FR 53254 at 53292, October 14, 1993).
As discussed above, FDA has concluded that 1 mg folate per day is
the safe upper limit for folate intake. To ensure that the safe upper
limit is not exceeded, FDA finds that folic acid fortification must be
limited to the cereal-grain products that are the subject of a standard
of identity that requires the addition of this substance at a level of
140 <greek-m>g per 100 g. Fortification of other standardized foods
with folic acid would cause the total daily folate intake of some
segments of the population to exceed the safe daily intake of folate.
Because fruit juices and fruit juice replacements are not as widely
consumed as cereal-grain products by women of childbearing age, they do
not provide as effective a means for addressing the PHS recommendation
that women of childbearing age consume 400 <greek-m>g folic acid per
day. Moreover, allowing their fortification in addition to the
fortification of cereal-grain products would cause some members of the
population to exceed the safe upper limit of intake. Therefore, FDA
rejects the comments recommending that fruit juice replacements be
permitted to add folic acid.
F. Infant Formula
One comment by a trade association representing infant formula
manufacturers supported proposed Sec. 172.345(e) which explicitly
permits the addition of folic acid to infant formula, consistent with
section 412(i) of the act (21 U.S.C. 350a(i)).
Another comment expressed concern that proposed Sec. 172.345(e)
would allow the addition of elevated levels of folic acid to infant
formula.
FDA notes that in accordance with section 412(i) of the act, infant
formulas are required to contain all essential nutrients, including
folic acid. This rulemaking amends the food additive regulations to
make clear that the use of folic acid in infant formula at a level
necessary to provide 4 <greek-m>g of folate is safe and meets the known
nutrient requirements of infants when used at the required level. This
level was set in accordance with the 1967 recommendations of the
Committee on Nutrition of the American Academy of Pediatrics (Ref. 29)
and was incorporated into the 1980 Infant Formula Act and the 1986
Amendments to the act. Therefore, FDA concludes that addition of folic
acid to infant formula at levels that comply with section 412 of the
act is safe.
G. Dietary Supplements
In the proposal, FDA tentatively concluded that it should continue
to provide for the use of folic acid in dietary supplements (58 FR
53312 at 53316, October 14, 1993). FDA received several comments
supporting this tentative conclusion. Since publication of the
proposal, however, the Dietary Supplement Health and Education Act of
1994 (DSHEA) was enacted. The DSHEA amended the act to exempt dietary
ingredients, including vitamins, used in dietary supplements from the
definition of a ``food additive'' (section 201(s)(6) of the act).
Therefore, there is no need to provide for the use of folic acid in
dietary supplements in the food additive regulations. Consequently, FDA
has modified the proposed revision of Sec. 172.345 by removing
paragraph (f) and redesignating paragraph (g) as paragraph (f).
H. Medical Foods
A comment from a trade association that represents manufacturers of
medical foods supported FDA's proposal to allow the addition of folic
acid to medical foods.
FDA recognizes that it is necessary and appropriate to provide for
the use of folic acid in foods that are formulated to be consumed or
administered enterally under the supervision of a physician and that
are intended for the specific dietary management of a disease condition
for which distinctive nutritional requirements, based on recognized
scientific principles, are established by medical evaluation (medical
foods). Therefore, FDA is providing for the use of folic acid in
medical foods in Sec. 172.345(f). In the proposal, FDA provided for
medical foods as a subset of foods for special dietary use (see
proposed Sec. 172.345(g)). However, FDA has reevaluated this approach
and concludes that it is more consistent with the act to provide for
medical foods as a separate class of products (see section 403(r)(5)(A)
of the act and compare section 411(c)(3) (21 U.S.C. 350(c)(3)) of the
act with section 5(b)(3) of the Orphan Drug Act (21 U.S.C.
360ee(b)(3)).
FDA has provided for the addition of folic acid to foods for
special dietary use in this final rule (Sec. 172.345(g)).
Page 8805
I. Meal-Replacements
Several comments recommended that FDA allow the fortification of
meal-replacement products with folic acid. These comments stated that
weight control meal-replacement products should be allowed to be
fortified with folic acid at a level based on the proportion of the
total daily caloric intake that the product is intended to provide. One
comment argued that meal-replacement products are unlikely to
contribute to excess folic acid in the diet because their use is self-
limiting. In addition, several comments argued that the addition of
folic acid to meal-replacement products is consistent with the
rationale used by FDA to justify the fortification of breakfast
cereals, because meal-replacement products are alternatives to
breakfast cereals, and like breakfast cereals, meal-replacement
products are consumed typically as a single serving at the beginning of
the day. In support of allowing addition of folic acid to meal-
replacement products, one comment argued that these products are often
consumed by women of childbearing age at breakfast in place of cereal,
or they are eaten as a mid-morning snack when breakfast is skipped.
Another comment recommended that any meal-replacement products be
permitted to contain up to 100 percent of the RDI per serving of folic
acid. The comment argued that this level was justified because these
products are usually promoted and knowingly purchased at a premium for
their nutrient properties.
FDA recognizes that meal-replacement products intended to be
consumed as the sole item of a meal or a diet provide persons consuming
such products with essential nutrients. Moreover, folic acid
fortification of such products provides an alternative to breakfast
cereals and dietary supplements for women of child-bearing age that
want to follow the PHS recommendation that they consume 400 <greek-m>g
of folic acid per day. Therefore, FDA concludes that meal-replacement
products represented as a sole item of a meal or a diet may contain
added folic acid.
To ensure that consumers of such meal-replacement products do not
exceed the safe upper limit for folate per day, FDA has concluded that
meal-replacement products that are intended to be consumed once per day
may contain up to 400 <greek-m>g folic acid per serving. However, to
ensure that consumption of meal-replacement products does not result in
folate intakes exceeding the safe upper limit of 1 mg folate per day,
FDA has concluded that meal-replacement products intended to be
consumed more than once per day may contain up to 200 <greek-m>g folic
acid per serving (Sec. 172.345(h)).
J. Foodstuff Premixes
One comment requested that the agency clarify whether folic acid
may be added to foodstuff premixes made with unenriched flour, but
whose labeling indicates that the product contains enriched flour.
FDA recognizes that current manufacturing practices can involve the
addition of nutrients, including folic acid, to premixes containing
unenriched cereal-grain. FDA advises that the addition of folic acid to
premixes made with unenriched cereal-grain flours, where a regulation
establishing a standard of identity exists and where the standard
specifically requires the addition of folic acid, is viewed by the
agency as use in accordance with Sec. 172.345(c).
K. Specifications
Several comments requested that the proposed specifications for
folic acid (Sec. 172.345(b)) be modified to include standards
established by the United States Pharmacopeia (USP) for the use of
folic acid in dietary supplements. These comments maintained that
current USP and Food Chemicals Codex standards for folic acid are
identical, and that including the USP requirements would help resolve
any differences should USP improve the standards for folic acid. The
comments noted that USP intends to establish new standards for folic
acid.
As discussed previously, in response to the DSHEA, FDA has removed
all references to the use of folic acid in dietary supplements from
Sec. 172.345. Establishing specifications for the use of folic acid in
dietary supplements, as recommended in the comments, is beyond the
scope of this rulemaking. Therefore, FDA concludes that new
Sec. 172.345(b) will specify FCC specifications for the food additive
use of folic acid.
L. Analytical Methodology
A comment noted that the current Association of Official Analytical
Chemists (AOAC) method for folate quantitation in food is inadequate,
and that there is a critical need for an improved method. Another
comment noted that the current AOAC method is subject to considerable
variability and requires 5 to 7 days to complete. The comment noted
that this length of time is not practical for in-plant quality control
purposes.
The agency recognizes that current methods for folate quantitation
in foods may present a problem. FDA notes that folate is one of the
most labile of the water-soluble vitamins, and the instability of the
numerous folate forms in food has proven to be an obstacle to their
quantitation.
Current methods to quantitate the level of folate in foods
generally involve a two-step process consisting of extraction of folate
from the food matrix followed by quantitation of folate levels.
Extraction of folate from the food matrix is the most technically
challenging step in the analysis. The AOAC has approved two methods for
folate quantitation in food (Ref. 30). Both are microbiological assays.
These assays can be completed within 72 hours after extraction of
folate from the food sample.
Attempts to improve the extraction of folate from food matrices
have focused on the use of a triple enzymatic digestion procedure using
a broad specificity protease, an <greek-a>-amylase, and chicken
pancreatic conjugase. Use of the triple enzyme procedure has been found
to increase measurable folate from a wide range of food matrices and
has been shown to be particularly effective on cereal-grain based foods
and milk and milk by-products. The triple enzyme procedure has been
adapted into analysis protocols at FDA's Atlanta Center for Nutrient
Analysis for the quantitation of folate in FDA's Total Diet samples
(Ref. 31).
FDA scientists are studying the triple enzyme extraction procedure
to identify foodstuffs for which the extraction method is most
applicable. The agency also notes that a number of high pressure liquid
chromatography (HPLC) methods for folate analysis and quantitation have
been described in the literature. Because such HPLC methods are more
rapid than the microbial methods currently in use, they offer the
potential for development of a rapid folate quantitation assay for
quality control purposes.
FDA will continue to work with AOAC to improve the methodology for
quantitation of folate in food. The agency anticipates that the use of
the triple enzyme extraction procedure and HPLC will result in advances
over the current folate assays by reducing variability and assay time.
III. Environmental Impact
The agency has carefully considered the potential environmental
effects of this action. FDA has concluded that the action will not have
a significant impact on the human environment and that an environmental
impact statement is not
Page 8806
required. The agency's finding of no significant impact and the
evidence supporting that finding, contained in an environmental
assessment, may be seen in the Dockets Management Branch (address
above) between 9 a.m. and 4 p.m., Monday through Friday.
IV. Objections
Any person who will be adversely affected by this regulation may at
any time on or before April 4, 1996 file with the Dockets Management
Branch (address above) written objections thereto. Each objection shall
be separately numbered, and each numbered objection shall specify with
particularity the provisions of the regulation to which objection is
made and the grounds for the objection. Each numbered objection on
which a hearing is requested shall specifically so state. Failure to
request a hearing for any particular objection shall constitute a
waiver of the right to a hearing on that objection. Each numbered
objection for which a hearing is requested shall include a detailed
description and analysis of the specific factual information intended
to be presented in support of the objection in the event that a hearing
is held. Failure to include such a description and analysis for any
particular objection shall constitute a waiver of the right to a
hearing on the objection. Three copies of all documents shall be
submitted and shall be identified with the docket number found in
brackets in the heading of this document. Any objections received in
response to the regulation may be seen in the Dockets Management Branch
between 9 a.m. and 4 p.m., Monday through Friday.
V. References
The following information has been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m. Monday through Friday.
1. Department of Health and Human Services, Public Health Service,
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/No. RR-14, pp. 1-7, September 11, 1992.
2. Center for Disease Control and Prevention, Transcript of Meeting,
Atlanta, GA, August 12, 1993; ``Surveillance for Possible Adverse
Effects of Folic Acid Consumption''.
3. DHHS, FDA, Nutrition Labeling, Federal Register 38 FR 2125-2132,
January 19, 1973.
4. Folic Acid Subcommittee/Food Advisory Committee, October 14-15,
1993, Transcript.
5. Institute of Medicine, National Academy of Sciences, ``Nutrition
During Pregnancy,'' Washington, DC, National Academy Press, 1990.
6. Department of Health, United Kingdom, Press Release and Letter to
all Drs. in England, Scotland, Wales, and North Ireland, ``Folic
Acid and Neural Tube Defects: Guidelines on Prevention,'' December
1992.
7. Wald, N., Prevention of NTD's: Results of the Medical Research
Council Vitamin Study, Lancet, 338:131-131, 1991; and editorial,
``Folic Acid and Neural Tube Defects,'' Lancet, 338:153-154, 1991.
8. Ross, F. J., H. Belding, and B. L. Paegel, ``The Development and
Progression of Subacute Combined Degeneration of the Spinal Cord in
Patients with Pernicious Anemia Treated with Synthetic
Pteroylglutamic (Folic) Acid.'' Blood, 3:68-90, 1948.
9. Hansen, H. A., and A. Weinfeld, ``Metabolic Effects and
Diagnostic Value of Small Doses of Folic Acid and B<INF>12 in
Megaloblastic Anemias,'' Acta Medica Scandinavia. 172:427-443, 1962.
10. Vilter, R. W., J. J. Will, T. Wright, and D. Rullman,
``Interrelationships of Vitamin B<INF>12, Folic Acid, and Ascorbic
Acid in the Megaloblastic Anemias,'' American Journal of Clinical
Nutrition, 12:130-144, 1963.
11. Allen, R. H., S. P. Stabler, D. G. Savage, and J. Lindenbaum,
``Diagnosis of Cobalamin Deficiency. I. Usefulness of Serum
Methylmalonic Acid and Total Homocysteine Concentrations,'' American
Journal of Hematology. 34:90-98, 1990.
12. Stambolian, D., and M. Behrens, ``Optic Neuropathy Associated
with Vitamin B<INF>12 Deficiency,'' American Journal of
Ophthalmology, 83:465-468, 1977.
13. Cooper, B. A., and T. Abe, ``Variable Response of Bone Marrow to
Feeding DL-5-formyltetrahydrofolate in Pernicious Anemia,'' British
Journal of Haematology, 32:387-394, 1976.
14. Ellison, A. B. Curry, ``Pernicious Anemia Masked by
Multivitamins Containing Folic Acid,'' Journal of the American
Medical Association, 173:240-243, 1960.
15. Challenger, W.A., and D.R. Korst, ``Pitfalls in the Diagnosis
and Treatment of Pernicious Anemia,'' American Journal of the
Medical Sciences, 134:226-231, 1960.
16. Victor, M., and A.A. Lear, ``Subacute Combined Degeneration of
the Spinal Cord,'' American Journal of Medicine, 20:896-911, 1956.
17. Davidson, L.S.P., and R.H. Girdwood, ``Folic Acid as Therapeutic
Agent,'' British Medical Journal, 1:587-591, 1947.
18. Lindenbaum, J., I.H. Rosenberg, Wilson, W.F. Peter, S.P.
Stabler, and R.H. Allen, ``Prevalence of Cobalamin Deficiency in the
Framingham Elderly Population,'' American Journal of Clinical
Nutrition, 60:2-11, 1994.
19. Transcript of meeting of Folic Acid Subcommittee/Food Advisory
Committee Meeting, Arlington, VA, April 15-16, 1993.
20. Briefing material, Folic Acid Subcommittee Meeting, April 15,
1993.
21. National Heart, Lung, and Blood Institute of the National
Institutes of Health Workshop.
22. Hathcock, J., and G. Troendle, ``Oral Cobalamin for Treatment of
Pernicious Anemia,'' Journal of the American Medical Association,
265:96-97, 1991.
23. Sanders, T.A.B., and S. Reddy, ``Vegetarian Diets and
Children,'' American Journal of Clinical Nutrition, 59:5(S):1176S-
1181S, 1994.
24. Herbert, V. ``Staging Vitamin B<INF>12 (Cobalamin) Status in
Vegetarians,'' American Journal of Clinical Nutrition,
59:5(S):1213S-1221S, 1994.
25. Food and Nutrition Board, National Research Council, National
Academy of Sciences, Proposed Fortification Policy for Cereal-Grain
Products, National Academy Printing and Publishing Office,
Washington, DC, p. 36, 1974.
26. Nationwide Food Consumption Survey, Continuing Survey of Food
Intakes by Individuals: Women 19-50 Years Old and Their Children 1-5
years, 1 day, 1985; United States Department of Agriculture,
Hyattsville, MD; NFCS, CSFII, Report No. 85-1, 1985.
27. Tippett, K.S., S.J. Mickle, J.D. Goldman, K.E. Sykes, D.A. Cook,
R.S. Sebastian, J.W. Wilson, and J. Smith, ``Food and Nutrient
Intakes by Individuals in the United States, 1 Day,'' 1989-91. U.S.
Department of Agriculture, p. 7.
28. Park, Y.M., I. Kim, E.A. Yetley, ``Characteristics of Vitamin
and Mineral Supplement Products in the United States,'' American
Journal of Clinical Nutrition, 54:750-759, 1991.
29. American Academy of Pediatrics' Committee on Nutrition,
Commentary on Breast-Feeding and Infant Formulas, Including Proposed
Standards for Formulas, Pediatrics, 57:278-285, 1976.
30. Association of Official Analytical Chemists Official Methods of
Analysis, 16th edition, Sections 944.12--Folic Acid (Pteroylglutamic
Acid) in Vitamin Preparations and 992.05--Folic Acid
(Pteroylglutamic Acid) in Infant Formula, 1995.
31. Martin, J, W.O. Landen, A.M. Soliman, and R.R. Eitenmiller,
``Application of a Tri-enzyme Extraction for Total Folate
Determination in Foods,'' Journal of the Association of Official
Analytical Chemists, 73:805-808, 1990.
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, 21 CFR part
172 is amended as follows:
Page 8807
PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR
HUMAN CONSUMPTION
1. The authority citation for 21 CFR 172 continues to read as
follows:
Authority: Secs. 201, 401, 402, 409, 701, 721 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 348, 371,
379e).
2. Section 172.345 is revised to read as follows:
Sec. 172.345 Folic acid (folacin).
Folic acid (CAS Reg. No. 59-30-3), also known as folacin or folate,
may be safely used in food as a nutrient in accordance with the
following prescribed conditions:
(a) Folic acid is the chemical N-4-(2-amino-1,4-dihydro-4-oxo-6-
pteridinyl)methylaminobenzoyl-L-glutamic acid.
(b) Folic acid meets the specifications of the ``Food Chemicals
Codex,'' 3d ed. (1981), pp. 125 to 126, which is incorporated by
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies
may be obtained from the National Academy Press, 2101 Constitution Ave.
NW., Washington, DC 20418, or may be examined at the Center for Food
Safety and Applied Nutrition's Library, 200 C St. SW., rm. 3321,
Washington, DC or at the Office of the Federal Register, 800 North
Capitol St. NW., suite 700, Washington, DC.
(c) Folic acid may be added to foods subject to a standard of
identity established under section 401 of the Federal Food, Drug, and
Cosmetic Act (the act) when the standard of identity specifically
provides for the addition of folic acid.
(d) Folic acid may be added, at levels not to exceed 400 micrograms
(<greek-m>g) per serving, to breakfast cereals, as defined under
Sec. 170.3(n)(4) of this chapter.
(e) Folic acid may be added to infant formula in accordance with
section 412(i)(1) of the act or with regulations issued under section
412(i)(2) of the act which are codified in Sec. 107.100 of this
chapter.
(f) Folic acid may be added to a medical food, as defined in
section 5(b)(3) of the Orphan Drug Act (21 U.S.C. 360ee(b)(3)), at
levels not to exceed the amount necessary to meet the distinctive
nutritional requirements of the disease or condition for which the food
is formulated.
(g) Folic acid may be added to food for special dietary use at
levels not to exceed the amount necessary to meet the special dietary
needs for which the food is formulated.
(h) Folic acid may be added to foods represented as meal-
replacement products, in amounts not to exceed:
(1) Four hundred <greek-m>g per serving if the food is a meal-
replacement that is represented for use once per day; or
(2) Two hundred <greek-m>g per serving if the food is a meal-
replacement that is represented for use more than once per day.
Dated: February 28, 1996.
David A. Kessler,
Commissioner of Food and Drugs.
FR Doc. 96-5012 Filed 2-29-96; 12:04 pm
BILLING CODE 4160-01-P