96-5012. Food Additives Permitted for Direct Addition to Food for Human Consumption; Folic Acid (Folacin)  

  • [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]
    
    
    
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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 (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
    
    

Document Information

Effective Date:
3/5/1996
Published:
03/05/1996
Department:
Health and Human Services Department
Entry Type:
Rule
Action:
Final rule.
Document Number:
96-5012
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.
Pages:
8797-8807 (11 pages)
Docket Numbers:
Docket No. 91N-100F
PDF File:
96-5012.pdf
CFR: (3)
21 CFR 172.345(b)
21 CFR 170.3(n)(4)
21 CFR 172.345