[Federal Register Volume 61, Number 44 (Tuesday, March 5, 1996)]
[Rules and Regulations]
[Pages 8797-8807]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-5012]



-----------------------------------------------------------------------


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.

-----------------------------------------------------------------------

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 (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 B12 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 B12 deficiency, and thus, how many are potentially at risk 
of developing pernicious anemia. However, marginal vitamin B12 
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 B12 
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 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 g folic acid per day may mask the anemia of vitamin 
B12 deficiency and urged that FDA set the safe upper limit below 
500 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 
B12 deficiency at levels as low as 250 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 B12 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 B12 
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 g daily for the general 
population and 800 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 B12 
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 ``[t]here is no toxicity for folic acid per se,'' and that 
``[t]he 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 B12 nutritional 
status. One comment asserted that FDA overstated the issue of the 
masking of B12 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 B12 
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 B12 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 B12 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 B12 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 
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 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 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 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 B12 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 B12 deficiency which 
may delay accurate diagnosis and prompt treatment of this problem while 
neurologic damage progresses. The symptoms of vitamin B12 
deficiency include both hematologic and neurologic effects. While the 
hematologic effects of vitamin B12 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 
B12 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 B12 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 B12 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 B12 
deficiency can be detected with clinical care and that the issue of 
masking of vitamin B12 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 B12 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 B12 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 B12 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 
B12 levels without having any of the classical manifestations of 
vitamin B12 deficiency. It has been reported, in a large study (n 
= 548) that the prevalence of vitamin B12 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 B12 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 B12-
related problems can be identified with clinical care fails to consider 
whether such persons, who may be unaware of their vitamin B12 
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 B12-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 
B12 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 B12 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 B12 Addition

    One comment recommended requiring the addition of vitamin B12 
to all foods containing added folic acid as a means to alleviate some 
of the concerns about the masking of the effects of vitamin B12 
deficiencies. Another comment claimed that many dietary supplements 
contained 100 percent of the RDI for vitamin B12 as well as 100 
percent of the RDI for folic acid and asserted that this level of 
vitamin B12 should allay the concerns about masking vitamin 
B12 deficiencies.
    FDA is aware that very high oral doses of vitamin B12 (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 
B12 could be added to foods and dietary supplements fortified with 
folic acid to reduce the potential for adverse effects in persons with 
vitamin B12 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 B12 malabsorption, they are able to 
absorb a small amount of oral vitamin B12 (about 1 to 2 percent). 
Several experts, however, suggested that one possible question about 
using foods or food products containing added vitamin B12 is that 
in the presence of other nutrients (e.g., vitamin C, thiamin, iron), 
vitamin B12 may be converted into analogs, some of which may have 
antivitamin B12 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 B12 should be added to foods or supplements fortified 
with folic acid to reduce the potential for adverse effects in persons 
with vitamin B12 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 B12, the agency cannot establish a level of 
oral vitamin B12 that is safe for the general population, safe for 
persons with vitamin B12-related problems, and sufficiently high 
to protect persons with vitamin B12-related problems from the 
adverse effects of increased intakes of folate. Furthermore, FDA notes 
that, because difficulty in absorbing oral vitamin B12 is the 
primary reason for inadequate vitamin B12 nutriture in many 
persons, the amount of vitamin B12 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 B12 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 B12 deficiency, should be diagnosed, 
treated, and monitored by a physician (Ref. 22). Moreover, the addition 
of both vitamin B12 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 B12 to all 
foods containing added folic acid because there is not sufficient 
information to demonstrate that the addition of vitamin B12 
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 ``[f]olic 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 ``[t]he 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 B12 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 B12 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 B12 status. Vegetarians present a model group for 
evaluating this question because their diets are very low in vitamin 
B12 (because animal foods are the sole dietary source of vitamin 
B12) and usually very high in foods rich in folate (e.g., fruits, 
vegetables and legumes). Thus, vegetarians are at risk of developing 
vitamin B12 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 B12 
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 B12 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 B12 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 B12 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 B12 utilization or intake is limited, either 
synthetic folic acid or food folate may cause masking of vitamin 
B12-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 B12 
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 B12 metabolism and related diseases (Refs. 2, 4, and 19). 

[[Page 8803]]
Nor was it supported by any of the folate or vitamin B12 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 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 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 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 g folic acid per 100 g, the 
addition of folic acid to breakfast cereals should be limited to 100 
g folic acid per serving. FDA stated that fortification of all 
breakfast cereals to 400 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 
g folic acid per serving provides women of child-bearing age 
flexibility to meet the PHS recommendation that such women consume 400 
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 g, or 400 
g folic acid per serving. As discussed in the proposal, most 
breakfast cereals are fortified at 100 g folic acid per 
serving, and only 3 to 6 percent of breakfast cereals are fortified at 
400 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 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 g folic acid per serving). Because 
most breakfast cereals contain folic acid at levels (100 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 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 g folic 
acid (25 percent of the RDI) per serving. FDA has determined that 
addition of up to 400 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 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 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 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 
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 g folic acid per unit. 
If cereal-grain products were fortified with 70 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 
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 
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 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 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 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 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 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 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 -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 B12 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 B12, 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 B12 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 B12 (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)methyl]amino]benzoyl]-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 
(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 g per serving if the food is a meal-
replacement that is represented for use once per day; or
    (2) Two hundred 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