[Federal Register Volume 61, Number 44 (Tuesday, March 5, 1996)]
[Rules and Regulations]
[Pages 8752-8781]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 96-5013]




Federal Register / Vol. 61, No. 44 / Tuesday, March 5, 1996 / Rules 
and Regulations

[[Page 8752]]


DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 101

[Docket No. 91N-100H]
RIN 0910-AA19


Food Labeling: Health Claims and Label Statements; Folate and 
Neural Tube Defects

Agency: Food and Drug Administration, HHS.

Action: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is authorizing the use 
on the labels and in the labeling of food, including dietary 
supplements, of health claims on the association between adequate 
intake of folate and the risk of neural tube birth defects. This rule 
is issued in response to provisions of the Nutrition Labeling and 
Education Act of 1990 (the 1990 amendments) that bear on health claims. 
The agency has concluded that, based on the totality of the publicly 
available scientific evidence, there is significant scientific 
agreement among qualified experts that, among women of childbearing age 
in the general U.S. population, maintaining adequate folate intakes, 
particularly during the periconceptional interval, may reduce the risk 
of a neural tube birth defect-affected pregnancy.

EFFECTIVE DATE: April 19, 1996.

FOR FURTHER INFORMATION CONTACT: Jeanne I. Rader, Office of Food 
Labeling (HFS-175), Food and Drug Administration, 200 C St. SW., 
Washington, DC 20204, 202-205-5375.

SUPPLEMENTARY INFORMATION:

I. Background

A. Procedural History

1. The 1990 Amendments
    The 1990 amendments to the Federal Food, Drug, and Cosmetic Act 
(the act) provided for extensive changes in the way foods are labeled. 
Under these amendments, FDA can authorize the use, in the labeling of 
foods, of health claims that characterize the relationship of a 
nutrient to a disease or a health-related condition. Section 
403(r)(1)(B) of the act (21 U.S.C. 343(r)(1)(B)) provides that a 
product is misbranded if it bears a claim that characterizes the 
relationship of a nutrient to a disease or a health-related condition 
unless the claim is made in accordance with procedures and standards 
established under section 403(r)(3) and (r)(5)(D) of the act. The 1990 
amendments required that FDA evaluate 10 nutrient/disease relationships 
with respect to their appropriateness as the subjects of health claims. 
The topic of folic acid and neural tube defects was among those 10 
topics.
    In the Federal Register of November 27, 1991 (56 FR 60537), in 
conformity with the requirements of the 1990 amendments, the agency 
proposed to establish general principles that would govern the 
appropriateness and validity of health claims on dietary supplements as 
well as on foods in conventional food form. The agency also proposed to 
authorize four health claims and to not authorize six others, including 
a claim on folate and neural tube defects.
2. The Dietary Supplement Act of 1992 (DS Act)
    In October of 1992, the Dietary Supplement Act (DS Act; Title II of 
Pub. L. 102-571) was enacted. It imposed a moratorium until December 
15, 1993, on FDA implementation of the 1990 amendments with respect to 
dietary supplements. The DS Act directed FDA to issue proposed rules to 
implement the 1990 amendments with respect to dietary supplements by 
June 15, 1993, and to issue final rules based on these proposals by 
December 31, 1993.
    The DS Act also amended the so-called ``hammer'' provision of the 
1990 amendments to provide that, if the agency did not meet the 
established December 31, 1993, timeframe for issuance of final rules, 
the proposed regulations would be considered final regulations.
    Accordingly, when FDA issued its final rules on health claims in 
the Federal Register of January 6, 1993 (58 FR 2478), they did not 
cover dietary supplements.
3. The 1993 Final Rules
    On January 6, 1993, FDA published its final rules on general 
principles for health claims (58 FR 2478) and the 10 nutrient disease-
relationships (58 FR 2537 through 2849). The general principles 
regulation provides that FDA will issue regulations authorizing health 
claims only when it determines, based on the totality of publicly 
available scientific evidence (including evidence from well-designed 
studies conducted in a manner that is consistent with generally 
recognized scientific procedures and principles) that there is 
significant agreement, among experts qualified by training or 
experience to evaluate such claims, that the claim is supported by the 
scientific evidence.
    On January 6, 1993, the agency also issued regulations announcing 
its decisions with respect to conventional foods for each of the 10 
nutrient-disease relationships that the 1990 amendments directed it to 
consider. The agency authorized claims on all foods, including dietary 
supplements, on seven nutrient-disease relationships: Calcium and 
osteoporosis; sodium and hypertension; fat and cancer; saturated fat 
and cholesterol and coronary heart disease (CHD); fiber-containing 
grain products, fruits, and vegetables and cancer; fruits, vegetables, 
and grain products that contain fiber and risk of CHD; and fruits and 
vegetables and cancer.
    Because of the DS Act, FDA took no final action with respect to the 
use on dietary supplements of health claims on dietary fiber and 
cancer; dietary fiber and CHD; omega-3-fatty acids and CHD; zinc and 
immune function in the elderly; antioxidant vitamins and cancer; and 
folic acid and neural tube defects.
    With respect to folic acid, the agency explained that, while the 
Public Health Service (PHS) had recommended that all women of 
childbearing age in the United States consume 0.4 milligram (mg) of 
folic acid daily to reduce their risk of having a pregnancy affected 
with spina bifida or other neural tube defects, PHS had also identified 
several issues that remained outstanding, including the appropriate 
level of folic acid in food and safety concerns regarding increased 
intakes of folic acid. Sections 403(r)(3)(A)(ii), 402(a), and 409 of 
the act (21 U.S.C. 342(a) and 348) establish that the use of a 
substance in food must be safe. Questions raised in the PHS 
recommendation (see 58 FR 2606 at 2609) included the safety of high 
intakes of folate by the target population as well as by other segments 
of the population who may unintentionally be exposed to high intakes if 
overfortification of the food supply with folic acid were to occur as a 
result of the PHS recommendation. FDA concluded that it could not 
authorize a health claim on folic acid until the questions regarding 
the safety of the use of this nutrient, as well as other concerns 
raised by PHS, were satisfactorily resolved (58 FR 2606 at 2614).
4. The Dietary Supplement Proposals
    In the Federal Register of June 18, 1993 (58 FR 33700), FDA 
published a proposal on health claims on dietary supplements. FDA 
proposed to revise its food labeling regulations to make dietary 
supplements of vitamins, minerals, herbs, or other similar nutritional 
substances subject to the same general requirements that apply to 

[[Page 8753]]
all other types of food with respect to health claims.
    In the Federal Register of October 14, 1993 (58 FR 53296), FDA 
published a proposal not to authorize health claims on the labels of 
dietary supplements on five nutrient-disease relationships: Dietary 
fiber and cancer; dietary fiber and CHD; antioxidant vitamins and 
cancer; omega-3-fatty acids and CHD; and zinc and immune function in 
the elderly. However, in the same issue of the Federal Register (58 FR 
53254), the agency did propose to authorize the use on the labels and 
labeling of conventional foods and dietary supplements of a health 
claim on the relationship between folate and risk of neural tube 
defects and to provide for safe use of folic acid in foods by amending 
several of its regulations that permit use of folic acid in foods (see 
also 58 FR 53305 and 58 FR 53312).
5. The Dietary Supplement Health Claim Final Rule
    In the Federal Register of January 4, 1994 (59 FR 395), FDA 
announced that it was amending its food labeling regulations to make 
dietary supplements subject to the same general requirements that apply 
to all other types of food with respect to the use on the label or in 
labeling of health claims that characterize the relationship of a 
substance to a disease or health-related condition.
    Also in the Federal Register of January 4, 1994 (59 FR 433), the 
agency announced that, in accordance with the 1990 amendments, as 
amended by the DS Act, the regulation on folate and neural tube defects 
that it proposed on October 14, 1993 (58 FR 53254), was considered a 
final regulation for dietary supplements of vitamins, minerals, herbs, 
and other similar nutritional substances (dietary supplements). In its 
notice, the agency stated that the document was part of a separate 
rulemaking contemplated by Congress if a final regulation on the 
proposal issued on October 14, 1993, was not issued by December 31, 
1993, and noted that the notice bore a separate docket number (i.e., 
No. 93N-0481) to distinguish it from the one assigned to the October 
14, 1993 rulemaking (i.e., No. 91N-100H), which, the agency said, was 
ongoing.
    In this document, FDA is finalizing its October 14, 1993, proposal 
to authorize health claims on the relationship between folate and 
neural tube defects. This final rule pertains to conventional food as 
well as to dietary supplements. Elsewhere in this issue of the Federal 
Register, FDA is proposing to revoke the regulation on this nutrient-
disease relationship that became final by operation of law.
6. The Dietary Supplement Health and Education Act of 1994
    The President signed the Dietary Supplement Health and Education 
Act of 1994 (Pub. L. 103-417) (hereinafter referred to as the DSHEA) 
into law on October 25, 1994. Among other things, the DSHEA defines 
``dietary supplements'' (in section 3(a)).
    In the October 14, 1993, proposal, FDA used the terms ``dietary 
supplements of vitamins, minerals, herbs, and other nutritional 
substances'' and ``food in conventional food form.'' Under the changes 
effected by the DSHEA (see sections 3 (a) and (c) of the DSHEA), the 
form of a product is no longer determinative of whether the product is 
a dietary supplement. Accordingly, with the exception noted below, FDA 
will use the terms ``food'' or ``foods'' in this document to reflect 
this change and the act's definition of ``dietary supplements.'' FDA 
will use the terms ``conventional food'' and ``dietary supplement'' in 
response to comments dealing with the bioavailability of folate, for 
which a distinction needs to be made between foods and dietary 
supplements. Where other terminology was used in the regulatory 
language of the October 14, 1993, proposal, FDA has modified that 
language to conform to the changes effected by DSHEA.

B. Relationship Between Folate and Neural Tube Defects

    The agency reviewed and updated the scientific literature on the 
relationship between folate and neural tube defects in the Federal 
Register of November 27, 1991 (56 FR 60610), January 6, 1993 (58 FR 
2606), and October 14, 1993 (58 FR 53254), and provides only a brief 
summary here.
    Folate. The term ``folate,'' as used in this document, includes the 
entire group of folate vitamin forms: That is, folic acid 
(pteroylglutamic acid), the form of the vitamin added to dietary 
supplements and to fortified foods, and the naturally- occurring 
folylpolyglutamates (pteroylpolyglutamates) which are found in foods. 
``Folate'' is thus the general term used to include any form of the 
vitamin, without reference to the state of reduction, degree of 
substitution, or number of glutamates. As a vitamin, folate functions 
metabolically in the synthesis of amino acids and nucleic acids. 
Insufficient quantities of folate in the diet lead to impaired cell 
multiplication and alterations in protein synthesis (Ref. 1). These 
effects are most noticeable in rapidly growing or dividing cell 
populations (Ref. 1). Pregnancy increases the need for folate and many 
other nutrients because of the need of the mother to maintain adequate 
nutrition and to meet the nutritional requirements of the developing 
fetus.
    Neural tube defects. Neural tube defects are serious birth defects 
that can result in infant mortality or serious disability. The birth 
defects anencephaly and spina bifida are the most common forms of 
neural tube defects and account for about 90 percent of these defects. 
These defects result from failure of closure of the covering of the 
brain or spinal cord during early embryonic development. The neural 
tube forms between the 18th and 20th days of pregnancy and closes 
between the 24th and 27th days. Because the neural tube forms and 
closes during early pregnancy, the defect may occur before a woman 
realizes that she is pregnant.
    Each year, about 2,500 cases of neural tube defects occur among 
about 4 million births in the United States (i.e., in approximately 6 
of 10,000 births annually). Recent data from State-based birth defects 
surveillance systems show declining trends for neural tube defects in 
the United States for about the last 30 years (Ref. 2). The Maternal 
and Child Health Bureau of the Health Resources and Services 
Administration reported that the neural tube defect rate in the United 
States has declined from 1.3 per 1,000 live births in 1970 to 0.6 per 
1,000 live births in 1989 (Ref. 3).
    The majority of neural tube defects are isolated defects and are 
believed to be caused by multiple factors. About 90 percent of infants 
with a neural tube defect are born to women who do not have a family 
history of these defects. Neural tube defects have been reported to 
vary with a wide range of factors including genetics, geography, 
socioeconomic status, maternal birth cohort, month of conception, race, 
nutrition, and maternal health, including maternal age and reproductive 
history (Ref. 4). Women with a close relative (i.e., sibling, niece, 
nephew) with a neural tube defect, with insulin-dependent diabetes 
mellitus, and with seizure disorders who are being treated with 
valproic acid or carbamazepine are at significantly increased risk 
compared with women without these characteristics. Rates for neural 
tube defects also vary within the United States, with lower rates 
observed on the west coast than on the east coast.
    Several lines of evidence led to the hypothesis that nutritional 
factors might be associated with some human neural 

[[Page 8754]]
tube defects (see 56 FR 60610, 58 FR 2606, and 58 FR 53254). Among the 
nutrients that were hypothesized to play a role in reducing the risk of 
neural tube defects, folate, a B vitamin, received the greatest 
attention because of associations between folate intake and reduced 
risk of neural tube defects found in observational studies in humans 
and because of the well- recognized role of folate in cell division and 
growth. Because the neural tube forms early in embryonic development, 
interventions aimed at reducing the risk of these defects must occur 
periconceptionally (i.e., during the interval extending from at least 1 
month before conception and continuing through the first 6 weeks of 
pregnancy).
    In the folate health claim proposal (58 FR 53254), FDA tentatively 
concluded that the available data show that folate alone may reduce the 
risk of recurrence of neural tube defects when given periconceptionally 
at high-dose levels (i.e., 4 mg/day) to women at high risk of such a 
recurrence. Additionally, based on a synthesis of information from 
several observational studies that reported periconceptional use of 
multivitamins containing 0 to 1,000 micrograms (mcg or g) of 
folic acid, FDA inferred that folic acid intake at levels of 0.4 mg 
(400 mcg) per day may reduce the risk of occurrence of neural tube 
defects. Protective effects measured by reduction in incidence of 
neural tube defects have been found in several observational studies 
that reported periconceptional use of multivitamin supplements 
containing about 400 mcg folic acid.
    Public health significance. Reduction in adverse pregnancy outcomes 
such as birth defects is an important public health goal. Because most 
neural tube defects occur in women without a history of such outcomes, 
interest in reducing the risk of first occurrences has been very high. 
PHS has inferred that if all women of childbearing age consumed 0.4 mg 
(400 mcg) folic acid daily throughout their childbearing years, there 
might be a reduction in neural tube defects of about 50 percent (i.e., 
about 1,250 cases per year) (Ref. 5).

C. Regulatory and Other Activities Related to Folate and Neural Tube 
Defects

    Since the passage of the 1990 amendments in November 1990, the 
rapidly evolving nature of the science relative to folate and the risk 
of neural tube defects and a number of PHS activities have intertwined 
with the regulatory process on the question of whether a health claim 
should be authorized on this topic. These developments have resulted in 
a dynamic process that began with the publication of a proposed rule 
not to authorize a health claim on folic acid and neural tube defects 
(56 FR 60610); saw PHS issue a recommendation that all women of 
childbearing age in the United States should consume 0.4 mg of folic 
acid per day for the purpose of reducing their risk of having a 
pregnancy affected with spina bifida or other neural tube defect (Ref. 
5); included meetings of FDA's Folic Acid Subcommittee and Food 
Advisory Committee (Refs. 6 and 7); and was marked by FDA publishing a 
final rule that noted that, while the PHS recommendation evidenced that 
significant scientific agreement exists regarding the relationship 
between folate and neural tube defects, there were significant 
unresolved questions about the safe use of folic acid in food (58 FR 
2606). In its January 6, 1993, Federal Register document, the agency 
concluded that it could not authorize a health claim for folate until 
the questions regarding the safe use of this nutrient, as well as other 
concerns raised by PHS, were satisfactorily resolved.
    The process proceeded to the point where, in October 1993, FDA 
stated that it had tentatively concluded that the safety questions had 
been resolved, and that there is significant scientific agreement about 
the validity of the relationship between folate and neural tube defects 
(58 FR 53254). The agency also tentatively concluded that, based on its 
discussions with the Folic Acid Subcommittee and its analyses of food 
intake data, daily folate intakes can be maintained within safe ranges 
by allocating fortification with folic acid to specific foods in the 
food supply through an amendment to the food additive regulation for 
folic acid.
    The agency therefore proposed to authorize a health claim relating 
diets adequate in folate to a reduced risk of neural tube defect-
affected pregnancies (58 FR 53254). In companion documents published in 
the same issue of the Federal Register, the agency also proposed to 
provide for the safe use of folic acid in foods by amending the food 
additive regulations for folic acid (58 FR 53312) and to amend the 
standards of identity for specific enriched cereal-grain products to 
require the addition of folic acid (58 FR 53305).
    The agency convened the Folic Acid Subcommittee and the Food 
Advisory Committee on October 14 and 15, 1993 (Ref. 8). Members were 
asked to comprehensively review the October 14, 1993, proposals and to 
provide comments. The agency requested that the Folic Acid Subcommittee 
give priority to the health claim issue because the DS Act required 
that health claim regulations be finalized by December 31, 1993. The 
agency treated the discussions of the Folic Acid Subcommittee as 
comments. A summary of the discussions that occurred during the 
meetings is provided in the summary of comments below.
    As stated above, in January 1994, FDA announced (59 FR 433) that, 
by operation of law, the regulation that it proposed on October 14, 
1993 (58 FR 53254), to authorize the use of a health claim about the 
relationship between folate and the risk of neural tube defects was a 
final regulation applicable to the label and labeling of dietary 
supplements only. The agency also advised that, given the PHS 
recommendation and the results of the agency's review of the evidence 
on this claim, in addition to authorizing the claim on dietary 
supplements, it had no intention of taking action against conventional 
foods that are naturally high in folate that bear a claim on this 
nutrient-disease relationship, so long as the claim fully complies with 
the provisions of the regulation that became final for dietary 
supplements by operation of law.

D. Scope of This Document

    In the Federal Register of October 14, 1993 (58 FR 53254), the 
agency posed a series of questions for itself. These questions, and the 
agency's proposed answers, provided the outline for the October 14, 
1993 document. The questions were: (1) Is a health claim on the 
relationship between folate and neural tube defects appropriate on food 
labels? (2) If the agency concludes that a health claim can be safely 
implemented, what should such a claim say about folate and neural tube 
defects? (3) Should the food supply be fortified with folic acid to 
ensure that women have adequate folate intakes? If so, is it necessary 
to limit the foods to which folic acid can be added and the levels at 
which it can be added to those foods? (4) If there are to be 
limitations on the foods that can be fortified with folic acid, which 
foods are most appropriate for fortification, and at what levels should 
they be fortified?
    During the development of this final rule, data on the folate 
status of the U.S. population obtained during Phase 1 of the Third 
National Health and Nutrition Examination Survey (NHANES III, Phase 1, 
1988-1991) became available. The agency anticipated evaluating red 
blood cell (RBC) and serum folate data, and data on folate intake from 
foods and 

[[Page 8755]]
dietary supplements from this survey. Additionally, because the NHANES 
III folate consumption data are more current than the data used by the 
agency in developing its October 14, 1993, proposals for food 
fortification and for amending the agency's food additive regulation 
for folic acid (58 FR 53305 and 58 FR 53312, respectively), the agency 
considered delaying completion of these rulemakings until evaluation of 
the newer data was complete.
    However, in late 1993, FDA became aware of a methodological problem 
associated with the radioassay kits used in NHANES III (1988 to 1994) 
that affected serum folate and RBC folate values and, consequently, 
data interpretation. FDA's Center for Food Safety and Applied Nutrition 
requested that the Life Sciences Research Office (LSRO), Federation of 
American Societies for Experimental Biology (FASEB), review, under a 
contract with FDA, the issues and report its findings to the agency. 
FDA requested that LSRO/FASEB: (1) Examine the analytical bases of the 
discrepancies associated with serum folate and RBC folate values 
derived from use of certain analytical kits used in NHANES III (1988 to 
1991); (2) evaluate the scientific basis and validity of procedures 
proposed by the Centers for Disease Control and Prevention (CDC) to 
make corrections to serum folate and RBC folate values obtained in 
NHANES III Phase 1 (1988 to 1991); (3) reexamine current ``cutoff'' 
values used for estimation of ``deficient,'' ``low status,'' etc., in 
light of the need for application of a correction factor; and (4) 
determine whether these approaches are still useful for estimating the 
prevalence of inadequate folate nutriture in the U.S. population.
    A full description of the problem, the analytical issues involved, 
the issues that arose that are related to the interpretation of NHANES 
III Phase 1 (1988 to 1991) data, and LSRO/FASEB's conclusions are 
presented in ``Assessment of Folate Methodology Used in the Third 
National Health and Nutrition Examination Survey (NHANES III, 1988-
1991)'' (Ref. 9). A major conclusion of LSRO/FASEB was that neither 
adjustment of the serum folate or RBC folate data from NHANES III Phase 
1 (1988 to 1991) to correct for the analytical problem, the use of the 
data without adjustment, nor the use of either data set with adjusted 
criteria for normalcy and deficiency, by themselves, can predict the 
prevalence of inadequate folate nutriture of the U.S. population.
    Based on LSRO/FASEB's report and its own review of the data, the 
agency has concluded that while there is a need for further evaluation 
of the NHANES III (1988 to 1991) serum folate and RBC folate data set, 
the agency will not delay this rulemaking until such evaluation is 
complete.
    The complete data from NHANES III (1988 to 1994) on folate intake 
from food and dietary supplements are not yet publicly available. 
Therefore, the agency cannot evaluate total folate intakes from foods 
and from dietary supplements from this survey data. The agency has 
concluded that it will also not delay the fortification and food 
additive rulemakings until the expected availability of these data in 
1996.

II. Summary of Comments and the Agency's Responses

    The agency received nearly 100 comments in response to its October 
14, 1993, proposed rule on a health claim on folate and neural tube 
defects. In addition, as stated above, FDA submitted the transcript of 
the October 14 and 15, 1993, meetings of the Folic Acid Subcommittee 
and Food Advisory Committee, in which the proposed rule was discussed, 
to the docket 91N-100H as a comment (Ref. 8). Comments were received 
from individual members of FDA's Folic Acid Subcommittee and Food 
Advisory Committee and invited guest consultants; other Federal 
agencies; a foreign government; State departments of agriculture, 
consumer services, or health; health care professionals; consumers; 
consumer advocacy groups; national organizations of health care 
professionals; State and territorial public health nutrition directors; 
manufacturers and suppliers of vitamins to the conventional food 
industry and the dietary supplement industry; manufacturers of finished 
foods including breakfast cereals, frozen foods, and bakery products; 
and trade associations of dietary supplement manufacturers, bakers, 
millers, and food processors. A number of comments were received that 
were more appropriately answered in other dockets, and these were 
forwarded to the appropriate dockets for response.
    FDA has considered all of the comments on a health claim on folate 
and neural tube defects that it received. The agency reviewed all of 
the documents, including letters, press releases, scientific articles 
and data supporting these articles, review articles, and 
recommendations, that were included in the comments. A summary of the 
comments that the agency received and the agency's responses follow.

A. Advisability of Authorizing Health Claims

    1. Some comments endorsed health claims because of their potential 
educational benefits, while other comments stated that health claims on 
foods that focus on single nutrients are a bad idea because 
combinations of foods, not single nutrients, build health. The 
advisability of health claims was also discussed at the October 14 and 
15, 1993, meeting of the Folic Acid Subcommittee (Ref. 8).
    The agency notes that the issue of whether health claims should be 
permitted in food labeling is moot because the 1990 amendments 
authorized claims on the relationship between substances and diseases 
or health-related conditions if the scientific validity standard is 
met.

B. Advisability of Authorizing a Health Claim for Folate and Neural 
Tube Defects

    In Sec. 101.79(c)(2)(i)(A) (21 CFR 101.79(c)(2)(i)(A)), FDA 
proposed to authorize health claims on labels or in labeling of 
conventional foods and dietary supplements on the relationship between 
folate and neural tube defects in women of childbearing age.
1. Scientific Validity Standard: Adequacy of the Scientific Data
    2. Many comments supported FDA's tentative decision to authorize a 
health claim on the relationship between folate and neural tube defects 
but did not provide any specific reasons for their support. Several 
comments noted that the scientific basis for the claim was as strong as 
that used to authorize other claims (e.g., those relating calcium and 
osteoporosis and saturated fat and heart disease). Members of the Folic 
Acid Subcommittee who supported a health claim noted that such claims 
would provide information to the target population, and that such 
claims tend to be more effective than educational programs alone.
    Other comments opposed the health claim, identifying specific 
concerns with the quality and quantity of the data used to develop the 
PHS recommendation and to support the proposed health claim. Members of 
the Folic Acid Subcommittee who opposed a health claim cited the 
weakness of the data supporting the relationship, including the very 
small number, and observational nature, of studies relating intake of 
folate at levels attainable from usual diets to reduced risk of neural 
tube defects and the many issues associated with the interpretation of 
these studies (58 FR 53265). 

[[Page 8756]]

    Several comments noted that because of the variety of 
micronutrients in addition to folic acid contained in supplements whose 
use was reported in several case-control studies, and because foods 
high in folate are also important sources of other micronutrients, it 
is not possible to isolate an independent role for folate in reduction 
in risk of first occurrences of neural tube defects. Other comments 
also expressed concern regarding the lack of folate-specific data at 
intakes of 400 mcg daily and noted that studies showing a positive 
impact of use of multivitamins containing 400 to 1,000 mcg of folic 
acid may have been showing a combined effect of folic acid and vitamin 
B12 or of folic acid and other components of the multivitamin 
preparations.
    A comment noted that there is little knowledge about biological 
mechanisms that would explain the role of folate in reduction in risk 
of neural tube defects. The comment stated that it was inappropriate to 
conclude that, because folic acid alone at a supraphysiologic dose 
(i.e., 4,000 mcg/day; 4 mg/day) is effective in reducing the risk of 
neural tube defects among women at recurrent risk, it would also reduce 
the risk of such defects among women at much lower risk of a first 
occurrence when consumed at lower doses (i.e., at 400 mcg/day; 0.4 mg/
day). Another comment expressed the opinion that the agency should not 
authorize a claim because there is not significant scientific agreement 
that the evidence supports the claim.
    Section 101.14(c) (21 CFR 101.14(c)) states that the agency will 
issue a regulation authorizing a health claim when it determines, based 
on the totality of the publicly available scientific evidence, that 
there is significant scientific agreement, among experts qualified by 
scientific training and experience to evaluate such claims, that the 
claim is supported by such evidence.
    For folate and neural tube defects, the agency evaluated all of the 
available scientific evidence, consulted with the Folic Acid 
Subcommittee and Food Advisory Committee about this evidence, and 
considered all the information contained in the comments. Based on this 
review, FDA has concluded that there is significant scientific 
agreement that the data associating folate intake and reduced risk of 
neural tube defects support a health claim on this relationship.
    The strongest evidence for this relationship comes from the 
randomized controlled Medical Research Council intervention study (Ref. 
14) that showed that women at risk of a recurrence of a neural tube 
defect-affected pregnancy who consumed a supplement containing 4 mg 
(4,000 mcg; 10 times the reference daily intake (RDI) folic acid daily 
throughout the periconceptional period had a significantly reduced risk 
of having another child with a neural tube defect. This study 
demonstrated, for the first time, that there was a significant 
reduction in recurrence of neural tube defects with high levels of 
folic acid but not with other vitamins and minerals. This study 
identified a specific role for folic acid in reducing the risk of 
recurrence of neural tube defect-affected pregnancies in women with a 
history of this defect and thus established the scientific basis for a 
relationship between folate intake and the occurrence of neural tube 
defects.
    In addition, protective effects against occurrence of neural tube 
defects were found in a Hungarian randomized controlled trial that used 
a multivitamin/multimineral preparation containing 0.8 mg folic acid 
daily (Ref. 15). Four of five observational studies have also reported 
a reduced risk of neural tube defects among women who reported 
consuming 0.4 to 1.0 mg folate daily from multivitamin supplements 
(Refs. 10, 11, 13, and 16). Several of these studies (Refs. 11, 13, and 
16) have also reported beneficial effects against occurrence of neural 
tube defects of dietary folate intakes of 100 to 250 mcg or more daily.
    Based on its review of all of these studies, the agency has 
concluded that their results are consistent with the conclusion that 
folate, at levels attainable from usual diets, may reduce the risk of 
occurrence of neural tube defects.
    The agency agrees that there are still significant gaps in our 
knowledge about the etiology of neural tube defects; about how folate, 
either alone or in combination with other nutrients, reduces the risk 
of neural tube defects; about dose-response relationships between 
folate intake and reduction in risk of neural tube defect-affected 
pregnancies; and about the role of other essential nutrients in the 
etiology of neural tube defects. However, the randomized controlled 
Medical Research Council trial (Ref. 14) clearly established the 
specific effectiveness of increased folate intake in reducing the risk 
of recurrence of some neural tube defects, and the findings of most of 
the studies cited above (Refs. 9, 10, 11, 13, and 16) are consistent 
with the conclusions drawn from the results of the Medical Research 
Council trial.
    Because of the consistency between the results of the Medical 
Research Council trial and the results of the smaller observational 
studies, PHS has inferred that folate alone, at levels attainable in 
usual diets, may reduce the risk of neural tube defects (Ref. 5). FDA 
participated in the development of the PHS recommendation and noted in 
the folate health claim proposal (58 FR 53266) that the recommendation 
evidenced that significant scientific agreement exists regarding the 
validity of an association between folate intake and risk of neural 
tube defects.
    FDA has therefore concluded, based on its own review of the 
scientific literature, that there is significant scientific agreement 
regarding the validity of the relationship, and that the statutory 
requirements for authorizing a health claim in this topic area have 
thus been met. Therefore, the agency is adopting 
Sec. 101.79(c)(2)(i)(A) as proposed.
2. Appropriateness of Providing for a Claim
    In addition to comments addressing the scientific validity of a 
health claim on folate and neural tube defects, the agency received 
comments questioning the advisability of authorizing a claim on this 
topic.
    a. General comments.
    3. Some comments stated that it was advisable to provide for a 
folate/neural tube defects health claim because such a claim can serve 
to broaden public knowledge of the relationship between folate and 
neural tube defects. A comment noted that the folate/neural tube defect 
claim might be especially beneficial for women who had previously had a 
child with a neural tube defect. One comment suggested that a health 
claim for folate and neural tube defects would increase intake of 
folate by women of childbearing age.
    Others expressed concern by noting that consumers will find it 
difficult to understand the claim and will begin to associate folate-
containing foods with an effect on birth defects in general. A comment 
noted that, given that many occurrences of neural tube defects will not 
be affected by folate intake, the claim will give a false hope of 
avoidance of the defect. A comment expressed concern that publication 
of the claim might cause unnecessary alarm among women who are 
pregnant. Other comments noted that neural tube defects are not the 
result of folate deficiency per se or noted the lack of evidence that 
there is a need in the general U.S. population for an increase in 
folate intake. Another comment, in considering the agency's proposed 
model health claims, noted that FDA 

[[Page 8757]]
was trying to make the food label do more than it can.
    Another comment emphasized that the context in which data from the 
major controlled intervention trial of effects of folic acid at levels 
approaching those obtainable from diets (i.e., the Hungarian trial; 
Ref. 15) were obtained (e.g., women who volunteered for the trial gave 
up drinking and smoking, consumed healthful diets before pregnancy, and 
in general pursued good health practices in the periconceptional 
interval) is not the same context in which women in the general 
population will receive folate.
    The agency agrees with the comments above that a health claim for 
folate and neural tube defects may have an educational benefit and has 
the potential for increasing folate intake among women in the target 
population by informing them of the importance of folate intake during 
their childbearing years. The agency also recognizes the importance of 
informing women of childbearing age of the need to ensure that their 
diets include adequate folate throughout this time of their lives and 
notes that providing information at the point of purchase of food by 
means of health claims and nutrient content claims can be an effective 
means of getting the information to consumers and of helping consumers 
to maintain healthful diets. Given that about half of all pregnancies 
are unplanned, many women in the general population can benefit from 
the information provided in the health claim because it will motivate 
them to increase their folate intake, even if they are not anticipating 
a pregnancy in the near future.
    The agency recognizes that women in the Hungarian trial (Ref. 15) 
were advised to adopt specific health conscious practices before 
attempting to become pregnant, and that women in the general population 
may not adopt such practices before becoming pregnant. The agency 
notes, however, that there are no data to indicate that the outcome of 
the Hungarian trial was related to or dependent upon the adoption of 
those practices, and that all women in the trial were urged to adopt 
those practices, not only those receiving folate-containing 
supplements. The agency finds no basis to deny the claim based on such 
a consideration. In addition, although emphasis is frequently placed 
upon estimates that about half of all pregnancies in the United States 
are unplanned, the agency notes that the large numbers of women who do 
plan their pregnancies (i.e., about 50 percent) may be adopting health-
conscious practices before conception and thus may receive folate in a 
context similar to that employed in the Hungarian trial.
    The agency recognizes that there is the potential for the health 
claim to be misleading and has addressed that potential by requiring 
that all claims contain specific information that informs women about 
the effect that adequate intake of folate during their childbearing 
years may have on their risk of a specific type of birth defect, 
without implying that adequate folate intake will provide 100 percent 
protection against that, or any other, birth defect. The agency 
recognizes that many nutrients, as well as attention to overall diet 
and healthful lifestyles, are important for obtaining the best possible 
outcome of pregnancy and has incorporated these concepts into the 
language of the health claim.
    Specifically, in this health claim regulation, the agency 
identifies the target population for the claim as women during their 
childbearing years (Sec. 101.79(c)(2)(i)(A)); describes the effect of 
folate intake on the risk of neural tube defects, a very specific type 
of birth defect (Sec. 101.79(c)(2)(i)(C)); requires that claims not 
imply that folate intake is the only recognized risk factor for neural 
tube defects (Sec. 101.79(c)(2)(i)(D)); summarizes the significance of 
appropriate folate intake relative to reduction in risk of neural tube 
defects in the total dietary context by requiring that claims state 
that healthful diets are also needed (Sec. 101.79(c)(2)(i)(H)); and 
provides for optional (voluntary) identification of a variety of 
sources of folate in the claim (Sec. 101.79(c)(3)(vii)). In describing 
the requirements for foods to bear the claim, the agency has defined 
characteristics that will qualify a food for bearing the folate/neural 
tube defect health claim with an eye to ensuring that such foods will 
be good sources of folate (Sec. 101.79(c)(2)(ii)(A)).
    Provision of such information will assist women in understanding 
the relationship of folate intake to the risk of neural tube defects 
and the significance of the information in the context of the total 
daily diet. Thus, the claim includes facts essential for consumer 
understanding of the conditions and circumstances under which the 
claimed effect is more likely to be obtained.
    b. Small size of the population at risk.
    4. Some comments disagreed with the agency's proposal to authorize 
a health claim for folate and neural tube defects because other 
authorized claims are different from this one. They pointed out that 
the folate claim deals with a problem that affects a very small number 
of people, while other authorized claims deal with reducing the risk of 
long-developing conditions affecting very large segments of the 
population (e.g., calcium and osteoporosis; fat and heart disease). 
Another comment noted that there have been large unexplained declines 
in neural tube defects in the United States since the 1930's. Another 
comment noted that neural tube defects constitute only a small fraction 
of all birth defects and stated that the proposed claim could lead to a 
false sense of security regarding protection from risk of all birth 
defects. Another comment noted that despite their distressful nature, 
because neural tube defect-affected births are a relatively rare 
phenomena, they should be attacked at a medical level.
    The agency disagrees with comments that it should not authorize a 
folate/neural tube defect health claim on the basis that the affected 
population is small in number. The eligibility requirements for a 
health claim do not limit such claims solely to disease or health-
related conditions affecting significant portions of the population. 
Rather, the general eligibility requirements for health claims require 
that for a substance to be eligible for a health claim, the substance 
must be associated with a disease or health-related condition for which 
the general population or an identified U.S. population subgroup (e.g., 
the elderly) is at risk (see Sec. 101.14(b)(1)).
    As FDA explained in the final rule establishing Sec. 101.14(b)(1) 
(58 FR 2478 at 2499), the agency will interpret this provision flexibly 
and will disqualify few claims under it. However, the agency also 
advised that if the affected population is small in size or is not 
readily identifiable, information on prevalence in the U.S. population 
will be a material fact that must be disclosed to avoid misbranding the 
product.
    FDA agrees that the prevalence of pregnancies affected by neural 
tube defects in the United States is low. However, because it is not 
currently possible to predict when a pregnancy will be affected, the 
U.S. subpopulation potentially at risk is large (i.e., women capable of 
becoming pregnant). The agency, consequently, disagrees that this 
health claim should not be authorized because a large subpopulation is 
potentially at risk of a neural tube defect-affected pregnancy.
    c. Potential impact of new data.
    5. Several comments expressed concern that results of research in 
progress on the potential role of factors other than folate could lead 
to revisions of the current PHS recommendation that all women consume 
0.4 mg of folate daily throughout their childbearing 

[[Page 8758]]
years to reduce their risk of neural tube birth defects. A comment 
noted that, based on testimony presented at the April 15 and 16, 1993, 
meeting of the Folic Acid Subcommittee, data from ongoing studies in 
South Carolina and Texas will be available soon and should provide 
information on the effectiveness of folate-containing supplement 
intervention programs in these areas. Another comment noted that data 
reported at the recent meeting of the American Public Health 
Association suggested that while reported intake of folate-containing 
supplements appeared to be associated with a reduced incidence of 
neural tube defect-affected pregnancies overall, the association was 
not statistically significant for Hispanic women who have a higher risk 
for neural tube defects than many other women.
    Some members of the Folic Acid Subcommittee questioned whether new 
data on vitamin B12 (summarized in section II.E.6. of this 
document) should influence the agency's position on the relationship 
between folate and neural tube defects. Another Folic Acid Subcommittee 
member stated that regardless of the new findings, the agency should 
move ahead with the folate/neural tube defect health claim.
    The agency is aware that data from several ongoing studies have 
been discussed at national meetings, but until these data and detailed 
descriptions of study designs, methodologies, and full results are 
publicly available, the agency cannot act on them. New data that have 
become publicly available during this rulemaking are reviewed in 
Section II.E.6 of this document. The agency notes, however, that the 
validity of the relationship between folate and neural tube defects has 
been established by the Medical Research Council trial (Ref. 14). New 
findings are not likely to detract from the validity of that 
relationship.

C. Issues Regarding the Substance/Disease Relationship That Is the 
Basis of the Claim

1. Identifying the Substance (Folic Acid Versus Folate)
    In developing its proposed regulation, the agency considered how 
best to describe the relationship between folate and neural tube 
defects. In the proposed statement of the substance/disease 
relationship (Sec. 101.79(c)(2)(i)(A)), FDA described the substance 
that is the subject of the claim as ``folate.'' FDA also used this term 
in proposed Sec. 101.79(a)(2), (b)(1), (b)(3), (c)(2)(i)(B), 
(c)(2)(i)(F), (c)(2)(ii)(A), (c)(2)(ii)(B), (c)(2)(iv), (c)(3)(ii), and 
(d). The agency's use of this term differed from the wording of the 
1990 amendments which required that FDA evaluate the relationship 
between ``folic acid'' and neural tube defects.
    Based on its review of the available studies, the agency in its 
October 14, 1993, proposed rule (58 FR 53254 at 53280) described its 
rationale for broadening the topic by noting that the term ``folates'' 
is used broadly to represent the entire group of nutritionally active 
folate vitamin forms and includes both synthetic folic acid and the 
folylpolyglutamates that occur naturally in foods.
    In reviewing the scientific evidence on the relationship between 
folate and neural tube defects, the agency noted that some studies 
reported effects of use of supplements of folic acid in combination 
with intakes of food folates (Ref. 10), while other studies reported 
effects of dietary intakes of food folates alone (Refs. 11, 13, and 
16). Based on its review of these studies, the agency tentatively 
concluded that the diet/disease relationship is more accurately 
described as being related to all of the biologically active vitamin 
forms of folate rather than just to the synthetic form of the vitamin 
(i.e., folic acid). Thus, in its review of the substance/disease 
relationship, FDA considered the effect of all of the nutritionally 
active forms of this vitamin (i.e., folates) on neural tube defects and 
not just the effect of the form of the vitamin specified in the 1990 
amendments (i.e., folic acid). Use of the term ``folate'' in proposed 
Sec. 101.79(a)(2), (b)(1), (b)(3), (c)(2)(i)(B), (c)(2)(i)(F), 
(c)(2)(ii)(A), (c)(2)(ii)(B), (c)(2)(iv), (c)(3)(ii), and (d) was 
consistent with the scope of the agency's review.
    6. A comment stated that FDA had unjustifiably changed the 
demonstrated efficacious form of the vitamin from ``folic acid'' to 
``dietary folate,'' and that because dietary food folate has not been 
demonstrated to reduce the incidence of neural tube defects, such a 
change is not justified. Several comments stated that FDA, in its 
health claims proceedings, had departed from the PHS recommendation, 
which uses the term ``folic acid'' in its title and in describing 
dietary change associated with reduced risk of neural tube defects, and 
that FDA, instead, concentrated inappropriately on food folate.
    FDA does not agree with these comments and concludes that it was 
justified in expressing the food substance/disease relationship as 
``folate and neural tube defects'' rather than as ``folic acid and 
neural tube defects.'' FDA also disagrees with the comments that folic 
acid is the only substance that was appropriately the subject of FDA's 
review, and that dietary food folate has not been demonstrated to 
reduce the incidence of neural tube defects.
    a. Efficacy of food folate. In reviewing the scientific evidence on 
the relationship between folate and neural tube defects, the agency 
noted that one study attributed all observed effects to consumption of 
dietary supplements of undefined composition without quantifying 
contribution of folate either from the supplements or from food (Ref. 
10), while other studies attempted to specifically quantify intakes of 
folate from food as well as from dietary supplements (Refs. 11, 13, and 
16).
    Some studies reported protective effects of use of supplements 
containing folic acid in combination with intakes of food folates 
(Refs. 11, 13, and 16), while other studies reported protective effects 
from dietary improvement in general (Ref. 17) or from intakes of food 
folates alone (i.e., without supplement use) (Refs. 11 and 13).
    Milunsky et al. (Ref. 11), Bower and Stanley (Ref. 16), and Werler 
et al. (Ref. 13) presented data on the relationship of dietary folate 
to risk of neural tube defects among nonusers of dietary supplements. 
Each of these studies found reduced risk of neural tube defects 
associated with increasing dietary intake of food folate. In the 
prospective study of Milunsky et al. (Ref. 11), the relative risk of 
neural tube defects was 0.42 for those women ingesting more than 100 
mcg folate per day compared with those ingesting less than 100 mcg 
folate per day. Bower and Stanley (Ref. 16), in a study in Western 
Australia, found reduced risk of neural tube defects among women 
consuming more than 240 mcg food folate per day versus community 
controls. Werler et al. (Ref. 13) reported a significant trend of 
reduced occurrence of neural tube defects with increasing dietary food 
folate.
    Laurence et al. (Ref. 17) performed a trial of dietary education 
without prescribing supplements and found that improvement in women's 
diets from ``poor'' to ``good'' led to a 50 percent reduction in 
recurrence of neural tube defects in women at high risk of this 
complication. Dietary improvement is assumed to increase intake of 
folate and many other nutrients by unspecified amounts. Specifically, 
these authors reported no cases of neural tube defects among women who 
were judged to have eaten ``good'' or ``fair'' diets (Ref. 17). All 
recurrences occurred among the 30 of 186 women who were judged to have 
eaten ``poor'' diets. ``Poor'' diets were defined as those considered 
to be deficient in first-class protein, usually no fruits and 
vegetables, and generally 

[[Page 8759]]
with excessive amounts of carbohydrates. ``Good'' diets were defined as 
those providing good intakes of all essential foods, including protein, 
and with no excessive amounts of refined carbohydrates, sweets, and 
soft drinks (see 58 FR 53253, October 14, 1993).
    The studies of Milunsky et al. (Ref. 11), Bower and Stanley (Ref. 
16), Werler et al. (Ref. 13), and Laurence et al. (Ref. 17) have all 
demonstrated that food folates provide protective effects against risk 
of neural tube defects.
    b. Interchangeability of the terms ``folate'' and ``folic acid'' in 
common usage and in nutrition labeling. FDA notes that, in common 
usage, the terms ``folic acid'' and ``folate'' are frequently used 
interchangeably to describe the biologically active forms of the 
vitamin. Folates are ubiquitous in nature, being present in nearly all 
natural foods (Ref. 18), and occurring in a wide range of forms (Ref. 
19). Human nutritional requirements for folate can be met by a variety 
of naturally occurring forms of the vitamin from many sources as well 
as by pteroylglutamic acid, the form of the vitamin added as a 
fortificant to breakfast cereals and other foods, and the form present 
in dietary supplements.
    In nutrition labeling, ``folic acid,'' ``folate,'' and ``folacin'' 
are allowable synonyms (Sec. 101.9(c)(8)(iv) and (c)(7)(iv)). All of 
these terms provide a way to describe the nutritional value of folate 
vitamin forms, although the term ``folacin'' is now rarely used.
    c. Interchangeability of the terms ``folate'' and ``folic acid'' in 
the PHS recommendation. FDA disagrees that the PHS statement emphasizes 
synthetic folic acid, the form of the vitamin used as a fortificant in 
conventional foods and in dietary supplements. In point of fact, the 
PHS statement, consistent with lay information and with nutrition 
labeling regulations, uses the terms ``folic acid'' and ``folate'' 
interchangeably (Ref. 5). For example, the PHS recommendation states 
that ``folate intake  0.4 mg/day can be obtained from the 
diet through careful selection of foods,'' that improvement in dietary 
habits is one potential approach ``for the delivery of folic acid to 
the general population in the dosage recommended,'' and that ``women 
should be careful to keep their total daily folate consumption at < 1 
mg per day'' (Ref. 5).
    That some ambiguity with respect to use of the terms ``folic acid'' 
and ``folate'' was present in the PHS recommendation was recognized 
during finalization of the recommendation at a CDC-sponsored meeting 
held in Atlanta on July 27, 1992. At that meeting, CDC staff noted that 
the ambiguity was deliberate (Ref. 20):

    INVITED SPEAKER WALD: There is an ambiguity here over whether 
it's total or extra, unless you have a particularly kind of astute 
legal perspective on this. * * * I have a question, though. Was the 
ambiguity deliberate?
    CDC's ERICKSON: Yes.
    INVITED SPEAKER WALD: You see, I think I would have probably 
inserted the same ambiguity myself. Because the intention is to get 
something going. * * * And one has the 0.4 mg figure from the 
previous RDA * * * at least that is a psychological fixing point.

    Thus, there was some ambiguity in the PHS recommendation from the 
time of its development, and the recommendation does not identify 
synthetic folic acid as the sole active form of the vitamin.
    d. Conclusion. Based on its review of the available studies, the 
agency tentatively concluded in the proposed rule that the food 
substance/disease relationship is most accurately expressed as ``folate 
and neural tube defects'' rather than as ``folic acid and neural tube 
defects'' because the term ``folate'' encompasses all forms of the 
vitamin from any source. In addition, at intakes attainable from usual 
diets, both folate from foods and folic acid from fortified foods or 
dietary supplements are converted into the same functional, 
metabolically active, reduced coenzyme vitamin forms in the body (Ref. 
19). Thus, nutritional requirements are met by a variety of forms of 
folate, and, with respect to reduction in risk of neural tube defects, 
the utility of increased folate intake, whether achieved through 
improved food choices or through use of dietary supplements, has been 
shown.
    The comments summarized above do not provide a basis for the agency 
to change the relationship statement because they are inconsistent with 
the scientific data, and they do not provide data that demonstrate that 
``folic acid'' performs nutritional functions different from those 
performed by naturally occurring food folates. Thus, making a 
distinction between ``folate'' and ``folic acid'' when all forms of the 
vitamin are capable of conversion to active vitamin coenzymes and 
metabolic function is artificial and inappropriate.
    Therefore, in Sec. 101.79, FDA is authorizing a health claim on 
labels and in labeling of conventional foods and dietary supplements 
about the relationship between folate and neural tube defects in women 
of childbearing age. The agency is retaining this terminology 
throughout the codified language. However, Sec. 101.79(c)(2)(i)(B) 
states that any one of several synonyms may be used, including ``folic 
acid'' and ``folate,'' when specifying the nutrient in a health claim.
    FDA notes that in proposed Sec. 101.79(c)(2)(i)(F), the term 
``folic acid'' was used instead of the intended term ``folate,'' which 
was otherwise consistently used throughout the proposed codified 
language. FDA is correcting this terminology in the final codified 
language, which for other reasons described in this preamble is 
redesignated as Sec. 101.79(c)(2)(i)(E).
2. Issues of Source and Amount
    In Sec. 101.79(c)(2)(i)(H), the agency proposed to prohibit 
statements in the health claim that a specified amount of folate (e.g., 
400 mcg (100 percent of the Daily Value (DV)) in a dietary supplement) 
is more effective in reducing the risk of neural tube defects than a 
lower amount (e.g., 100 mcg (25 percent of the DV) in a breakfast 
cereal or from diets rich in fruits and vegetables). The agency 
proposed this limitation because it is consistent with scientific data 
showing that reduced risk of neural tube defects has been associated 
with general dietary improvement, which is assumed to increase folate 
intake by unspecified amounts. In response to this proposed limitation, 
the agency received comments addressing the separate issues of source 
of folate and amount of folate.
    a. Source.
    7. Several comments agreed with the agency's proposal, stating that 
health claims should not contain statements that adequate diets cannot 
provide sufficient folate, or that only fortified foods or supplements 
can provide adequate folate. Other comments disagreed, stating that FDA 
should require claims to state that the evidence that folate reduces 
the risk of neural tube defects is stronger for supplements than for 
food. Other comments stated that evidence that folate-rich diets reduce 
the risk of neural tube defects is only suggestive, while evidence that 
folic acid containing-supplements reduce the risk of neural tube 
defects is conclusive.
    The agency agrees with comments that health claims should not 
contain statements that diets cannot provide sufficient folate to 
affect the risk of a neural tube defect because such statements are 
inconsistent with the available scientific evidence.
    The studies of Milunsky et al. (Ref. 11), Bower and Stanley (Ref. 
16), Werler et al. (Ref. 13), and Laurence et al. (Ref. 17) were 
summarized in response to comment 6, above. Milunsky et al. (Ref.

[[Page 8760]]

11), Bower and Stanley (Ref. 16), and Werler et al. (Ref. 13) all 
presented data on the relationship of dietary folate to risk of neural 
tube defects among nonusers of dietary supplements. Each of these 
studies found reduced risk of neural tube defects associated with 
increasing intakes of dietary folate. Laurence et al. (Ref. 17) found 
fairly strong protection against recurrence of neural tube defects 
associated with improvement in overall diets.
    FDA concludes, based on its review of the scientific literature, 
that the proposed limitation in Sec. 101.79 on statements that specific 
sources are superior to others is appropriate because the scientific 
literature does not support the superiority of any one source over 
others. As noted above, both folate from conventional foods and folic 
acid from fortified foods or dietary supplements are converted into 
functional, metabolically active coenzyme forms for use in the body 
(Ref. 19). Thus, in the absence of the limitation, manufacturers would 
be free to put statements that would be false and misleading in their 
labeling. The agency's conclusion is consistent with PHS's 
recommendation that advises that careful selection of foods is one 
means by which women can increase their folate intakes.
    b. Amount.
    8. Several comments agreed with the agency that the claim should 
not state that a specific amount of folate is more effective than 
another amount. Several comments noted that dose/response data to 
justify such statements do not exist, and that scientists do not yet 
know the requisite folate level that will protect the fetus from a 
neural tube defect. Other comments disagreed, stating that claims 
should state that experts recommend 400 mcg per day or 100 percent of 
the DV when referring to adequate amounts of folate. Another comment 
stated that while the 400 mcg level is admittedly imprecise, it is the 
recommendation of PHS. Another comment stated that consumers need to be 
reminded that a reduction in neural tube defects will only occur if all 
women consume 400 mcg folate per day throughout their childbearing 
years.
    The agency agrees with comments that dose/response data are 
insufficient to provide a basis for stating that a specific amount of 
folate is more effective than another amount. The quantitative results 
from the studies of Milunsky et al. (Ref. 11), Bower and Stanley (Ref. 
16), and Werler et al. (Ref. 13) suggest that amounts lower than the 
current recommendation of 400 mcg may be protective.
    After reviewing the comments above and the available scientific 
literature, FDA concludes that the comments do not provide a basis for 
the agency to change its position regarding prohibition of statements 
in the claim that imply that specific amounts of folate are superior to 
other amounts because such statements are inconsistent with the 
scientific data. FDA's conclusion is consistent with information 
provided in the PHS recommendation that states that amounts of folate 
lower than 400 mcg may reduce the risk of neural tube defects, and that 
additional research is needed to establish the minimum effective dose 
(Ref. 5). Again, a contrary position by the agency would permit false 
statements to appear on the label.
    In the final codified language, the agency is redesignating 
proposed Sec. 101.79(c)(2)(i)(H) as Sec. 101.79(c)(2)(i)(G) and, for 
the reasons stated above, is prohibiting in Sec. 101.79(c)(2)(i)(G) 
claims that a specified amount of folate per serving from one source is 
more effective in reducing the risk of neural tube defects than a lower 
amount per serving from another source.
    c. Restriction of claims to specific products.
    9. Several comments stated that the health claim should be limited 
to supplements containing 400 or 800 mcg of folate or limited to 
dietary supplements or breakfast cereals containing 400 mcg of folate. 
Other comments stated that health claims should not be allowed for 
naturally occurring food folates. Another comment stated that to allow 
health claims solely on supplements or fortified foods would undermine 
the need for women to learn to eat more healthfully and to obtain a 
full array of nutrients found in a balanced diet.
    The agency disagrees with comments that recommended that it limit 
claims to dietary supplements or to dietary supplements and fortified 
breakfast cereals that contain 400 mcg or more of folate. The agency's 
review of the scientific literature, summarized in response to comments 
6 to 8 above, provides no basis for making a distinction in source or 
in amount between folate from conventional foods and folic acid from 
dietary supplements or fortified cereals because the available evidence 
shows that increased folate intake, rather than the source of the 
folate, is what is of importance in reducing the risk of neural tube 
defects (Ref. 5). Increasing total folate intake among women of 
childbearing age, rather than emphasis on one source versus another, is 
what is of importance. This conclusion is consistent with PHS's 
recommendation, which states that improvement in dietary habits and use 
of dietary supplements are both appropriate approaches by which women 
may increase their folate intake.
    d. Target intake goal. The agency proposed in Sec. 101.79(c)(3)(iv) 
to include as optional information in the health claim a statement that 
the DV level of 400 mcg of folate is the target intake goal.
    10. Several comments stated that all health claims should refer to 
the likely effectiveness of 400 mcg of folate, or that claims should be 
required to state that experts recommend 400 mcg per day. Other 
comments stated that 400 mcg is the PHS recommendation, and without 
this information, women may assume that lower amounts are adequate.
    The agency disagrees with these comments. FDA chose not to propose 
to require that claims identify 400 mcg as the target intake goal 
because it tentatively concluded that there is uncertainty as to the 
optimal intake of folate with respect to reduction in risk of neural 
tube defects (Ref. 5). As noted above, several studies (Refs. 11 and 
13) have found reductions in risk of neural tube defect-affected 
pregnancies at folate intakes below 400 mcg per day. None of the 
comments provided evidence that showed that these findings were not 
valid. Thus, FDA concludes that a requirement that claims state that 
women must consume 400 mcg folate per day to achieve a reduction in 
risk of a neural tube defect-affected pregnancy would be inconsistent 
with the available scientific data.
    However, because 400 mcg is the reference daily intake (RDI), 
because PHS recommends a 400 mcg/day intake, and because the Folic Acid 
Subcommittee supported the 400 mcg/day intake goal, the agency has 
concluded that it may be helpful to some consumers if the health claim 
were to include information that the RDI of 400 mcg per day is the 
target intake goal. Therefore, FDA is adopting Sec. 101.79(c)(3)(iv) to 
allow for optional inclusion of this information, with the target 
intake goal (400 mcg; 0.4 mg) expressed as 100 percent DV. Claims may 
identify 100 percent of the DV (400 mcg folate) as the target intake 
goal and may state the PHS recommended daily intake (400 mcg folate, 
0.4 mg).
3. Focusing on the Periconceptional Interval
    In proposed Sec. 101.79(a)(1), the agency defined neural tube 
defects as serious birth defects of the brain or spinal cord. The 
agency noted that these defects result from a failure of the covering 
of the brain or spinal cord to close during 

[[Page 8761]]
early embryonic development and further noted that, because the neural 
tube forms and closes during early pregnancy, the defect may occur 
before a woman realizes that she is pregnant. In proposed 
Sec. 101.79(a)(2), the agency described the relationship between 
adequate folate intake and reduced risk of a neural tube defect-
affected pregnancy and summarized the studies whose results provide the 
basis for the health claim.
    11. A number of comments stated that studies have shown that folic 
acid added to the diet before pregnancy reduces the risk of neural tube 
defects, and that the relationship statement should be corrected to 
reflect this fact.
    The agency agrees that the studies that provide the basis for the 
relationship between folate and neural tube defects focused on improved 
folate nutriture before conception and continuing into early pregnancy. 
Therefore, the agency is modifying several of the statements in 
Sec. 101.79(a)(2) to more precisely describe the results of these 
studies. Specifically, FDA is modifying the second sentence of 
Sec. 101.79(a)(2) to state that in the studies described, folic acid 
was consumed daily ``before conception and continuing into early 
pregnancy * * *,'' and the fourth sentence to state that the study 
involved reported periconceptional use of multivitamins that contained 
folic acid.
    12. A comment suggested that claims be allowed to be more precise 
in describing the period during which adequate folate is needed. The 
comment noted that the statement relating to daily consumption of 
folate throughout the childbearing years implies that body folate 
stores must be built up over decades, while studies have shown that it 
is sufficient to consume folate during the weeks before the neural tube 
closes. The comment proposed that a statement that women who consume 
adequate amounts of folate during the month before and after becoming 
pregnant may reduce their risk of a neural tube defect would convey 
this information. Another comment criticized the model health claims 
provided by the agency because they failed to alert women to the 
critical periconceptional period.
    The agency recognizes that the scientific data support the need for 
specific attention to folate intake in the periconceptional interval 
and has modified Sec. 101.79(a)(2) to reflect this fact by specifically 
mentioning periconceptional use.
    The agency notes that one of the purposes of health claims is to 
assist women in recognizing the importance of healthful diets, 
including adequate folate nutriture throughout their childbearing years 
(see H. Rept. 101-538, 101st Cong., 2d Sess. 9-10 (1990)). Given that 
about 50 percent of pregnancies are unplanned, and that many women may 
not recognize that they are pregnant until after the critical period of 
neural tube closure, it is important for women to maintain healthful 
diets throughout their childbearing years. While some women who plan 
their pregnancies might benefit from the more specific information 
suggested in the comment, the agency concludes that the more general 
wording in the model claims will reach a wider group of women and 
provide them with useful and important information.
    FDA is adopting Sec. 101.79(c)(3)(ii), which states that health 
claims may include statements from paragraphs Sec. 101.79 (a) and (b). 
Through the use of statements derived from Sec. 101.79(a)(2), 
manufacturers will be able to provide information that alerts women to 
the importance of the periconceptional period.
4. ``Will Reduce'' Versus ``May Reduce''
    13. One comment stated that proposed Sec. 101.79(a)(2), which 
stated that available data show that diets adequate in folate may 
reduce the risk of neural tube defects, was misleading and recommended 
that this section be reworded to state that ``studies have shown that 
folic acid added to the diet before a pregnancy occurs will reduce the 
risk of neural tube defects.''
    The agency disagrees with the assertion that adequate folate intake 
will reduce the risk of neural tube defects. The available data show 
that in an area of low prevalence of neural tube defects, folate intake 
from dietary supplements or from fortified cereals was not associated 
with reduced risk of neural tube defects (Ref. 12). The agency did not 
receive any data or information challenging this data.
    The agency notes that use of the term ``will reduce'' is overly 
promissory to the individual and is misleading because it is not 
consistent with the available data. Prevalence rates for neural tube 
defects vary with a wide range of factors including genetics, 
socioeconomic status, maternal health, and race. The agency has 
discussed the multifactorial nature of neural tube defects (and will do 
so again below (see comment 36 of this document)). It has concluded 
that claims need to reflect this aspect of the nature of these defects 
because folate intake is not the only risk factor for them. Use of the 
term ``will reduce'' in the claim is not consistent with the 
multifactorial nature of neural tube defects. Thus, FDA finds no basis 
to change the wording of Sec. 101.79(a)(2), and it is including the 
sentence ``The available data show that diets adequate in folate may 
reduce the risk of neural tube defects'' in the final regulation 
without change.
5. Need for Healthful Diets
    14. Some members of the Folic Acid Subcommittee expressed concern 
about a single nutrient approach to the problem of neural tube defects 
because nutrients function together in the body. Another comment felt 
that a health claim for folic acid could be misinterpreted to mean that 
folic acid could prevent all birth defects. One comment noted that, 
because nutrients function synergistically in the body, increasing a 
single nutrient is unwise. Another comment stated that by focusing on 
the relationship between a single nutrient and a single outcome, 
opportunities to improve overall health are missed. Another comment 
expressed concern about singling out one vitamin for a health claim 
when the major sources of the vitamin (e.g., fruits and vegetables) are 
being promoted for good health. Other comments noted that in pregnancy 
it is the total diet, not a single nutrient, that is related to health 
outcome.
    The agency agrees with the comments that expressed concern about 
the problems in focusing on a single-nutrient, particularly in women of 
childbearing age. Many nutrients affect healthy pregnancy, and the 
claim should not lead women to focus undue attention on one nutrient, 
or on a single dietary factor, instead of on overall healthful diets 
and health conscious behaviors.
    In addition, because healthy pregnancies and good pregnancy 
outcomes are dependent upon an overall good diet, adequate in protein, 
vitamins and minerals, and many other nutrients, women should not be 
misled into believing that folate is the only nutrient about which they 
need to be concerned in preparing for a pregnancy. With respect to 
neural tube defects, FDA in its proposed rule (58 FR 53254) reviewed 
evidence that nutrients other than folate (e.g., methionine, vitamin 
B12, pantothenic acid) have roles in reducing the risk of neural 
tube defects, and additional evidence is summarized in section II.E.6. 
of this document. Thus, normal fetal development requires many 
nutrients in addition to the nutrient that is the subject of the health 
claim.
    Based on these considerations, the agency has concluded that 
information regarding overall improvement in a woman's diet and 
nutrition in the 

[[Page 8762]]
periconceptional interval, as well as throughout her childbearing 
years, is of considerable importance because pregnancy outcome depends 
upon adequate intakes of a wide range of nutrients. This concern needs 
to be balanced against the fact that the available evidence provides 
the basis for significant scientific agreement that dietary intakes of 
folate may reduce the risk of neural tube defect-affected pregnancies.
    Therefore, in response to these comments, FDA is including in 
Sec. 101.79(c)(2)(i)(H) in the final regulation a requirement that the 
claim state that folate needs to be consumed as part of a healthy diet. 
This requirement will ensure that, while highlighting the role of 
adequate folate intake, the health claim will not cause women to place 
undue emphasis on consumption of this nutrient. Thus, this information 
is necessary to ensure that the claim is properly balanced.

D. Requirements for Foods Bearing the Claim

1. Qualifying Amounts
    In Sec. 101.79(c)(2)(ii)(A), FDA proposed that the food or dietary 
supplement meet or exceed the requirements for a ``good source'' of 
folate as defined in Sec. 101.54 (i.e., containing  10 
percent of the RDI). In proposing this eligibility requirement, FDA 
considered that folate is ubiquitously distributed in the U.S. food 
supply. While a number of foods (e.g., some legumes, okra, broccoli, 
spinach, turnip greens, asparagus, Brussels sprouts, endive, lentils) 
contain more than 80 mcg of folate/serving (the amount that is greater 
than or equal to 20 percent of the RDI (i.e., that amount that would be 
required for a claim of a ``rich'' source)), the great majority of 
foods contain folate at lower levels. For example, oranges, grapefruit, 
many berries, peas, many vegetable juices, beets, and parsnips contain 
folate at levels of 40 to 80 mcg/serving (i.e., at or above 10 percent 
of the RDI or at levels that meet the requirement of a claim of a 
``good'' source) (Ref. 22).
    a. General comments.
    15. Many comments and the Folic Acid Subcommittee and Food Advisory 
Committee were generally satisfied with the eligibility requirements 
and supported FDA's proposal to allow claims on foods that were at 
least a good source of folate. These comments supported the criterion 
because it would accommodate a wide variety of fruits and vegetables 
that would be excluded if the eligibility requirement was set at a 
higher level. One comment, however, suggested that the proposed amount 
was too high and might exclude some commonly consumed foods such as 
peas.
    A third group of comments thought that the proposed amount was too 
low. Some of the comments said that claims should not be permitted 
unless the food provides at least 20 percent of the RDI (i.e., 80 mcg 
folate/serving), arguing that it was poor policy to make exception to 
the general health claims requirements regulations, and that if the 
goal is to maximize intake of folate, then 20 percent of the RDI should 
be the minimum amount allowed for the claim. Others felt strongly that 
the claim should be limited to those foods or supplements that provide 
100 percent of the RDI per serving or per dose.
    The agency is concerned that if it required (in accord with 
Sec. 101.14(d)(2)(vii)) that the food contain 20 percent or more of the 
RDI for folate (i.e., 80 mcg or more folate per reference amount 
customarily consumed; an amount sufficient to qualify for a ``high'' or 
``excellent source of'' nutrient content claim) to bear a health claim, 
many good food sources of folate would not qualify without 
fortification.
    One of Congress' purposes in providing for health claims was to 
enable Americans to maintain a balanced and healthful diet (H. Rept. 
101-538, supra, pp. 9-10). Given this fact, and given that the evidence 
demonstrates that the risk of neural tube defects can be affected by 
consuming foods that, while good sources of this nutrient, do not 
provide the high level that is provided by supplements and highly 
fortified foods (see Refs. 11, 13, 16, and 17), FDA concludes that it 
would not be consistent with the intent of the 1990 amendments to set 
requirements that would limit eligibility to bear a health claim to the 
foods that are high in folate.
    Use of a qualifying criterion for the health claim that is 
consistent with the ``good source'' definition (i.e., 10 to 19 percent 
of the DV; 40 to 76 mcg folate/serving) provides for an amount of the 
nutrient that allows a wide variety of fruits, vegetables, and whole 
grain products to qualify to bear the health claim, is consistent with 
current Federal guidelines for general dietary patterns, and yet is 
still likely to result in a daily dietary intake of folate that the 
data show may reduce the risk of neural tube defects. For example, 
current Federal dietary guidelines recommend five or more servings of 
fruits and vegetables and six or more servings of grain products per 
day. Consumption of fruits, vegetables, and grain products in the 
recommended amounts would likely result in daily intakes of folate of 
0.4 mg (400 mcg) or more, even though individually many of the foods 
consumed contain less than 20 percent of the RDI for folate per 
reference serving (Ref. 22).
    Accordingly, FDA is adopting Sec. 101.79(c)(2)(ii)(A), which 
provides that conventional foods and dietary supplements can bear a 
folate/neural tube defect health claim if they contain 10 percent or 
more of the RDI for folate per reference amount customarily consumed 
(i.e., meet the definition for a ``good source'' claim in Sec. 101.54 
(21 CFR 101.54)). The availability of the claim for a wide variety of 
products will provide flexibility to women in deciding how to 
individually achieve the target intake by selecting from among foods 
that naturally contain folate, dietary supplements, and highly 
fortified foods.
    b. Higher qualifying amounts for dietary supplements than for 
foods. 
    16. Several comments stated that to qualify to bear the claim, each 
food should provide at least 25 percent of the RDI, and each supplement 
should provide 100 percent of the RDI. However, these comments did not 
provide any support for the levels that they suggested or for why 
supplements should have to have a higher level of the nutrient than a 
conventional food.
    Having dealt with the level necessary to qualify to bear the claim 
in response to the previous comment, the agency will deal here with the 
question of whether, to qualify for a claim, dietary supplements should 
be required to provide more folate than foods. The agency concludes 
that there is no reason why they should. In response to comment 7 of 
this document, the agency concluded that the available scientific 
evidence establishes that sources of folate are equivalent in their 
ability to provide folate. Thus, there is no basis for requiring that 
either dietary supplements or conventional foods provide more than 10 
percent of the RDI for folate per reference amount customarily consumed 
to qualify for the claim.
2. Disintegration and Dissolution of Dietary Supplements
    FDA proposed in Sec. 101.79(c)(2)(ii)(C) to disqualify dietary 
supplements from bearing a health claim if they fail to meet the United 
States Pharmacopeia (USP) standards for disintegration and dissolution. 
The agency tentatively concluded that the benefits of folate intake 
from food and dietary supplements can only be obtained if the folate is 
available for absorption and metabolism by the body. The agency noted 
that a dietary supplement that does not disintegrate and dissolve 

[[Page 8763]]
clearly does not provide the nutrient in an assimilable form, and that 
a claim for such a supplement would be misleading because the 
supplement would not provide the nutrient that is the subject of the 
health claim (58 FR 58283).
    17. Several comments agreed with the agency's proposed requirement 
and urged the agency to require all dietary supplements to meet such 
quality standards. Another comment proposed that the agency use the USP 
standards that are currently under development, and that the 
dissolution requirement become effective when the USP proposal becomes 
effective. The USP commented and proposed wording for use in 
Sec. 101.79(c)(2)(ii)(C): ``Folic acid present in dietary supplement 
dosage forms (e.g., tablets, capsules) shall meet the requirements of 
the United States Pharmacopeia as defined in Section 201(j) of the 
act.''
    Another comment stated that in making this proposed requirement 
effective for dietary supplements, the agency would accord the same 
claim to foods (i.e., conventional foods) without similar requirements 
for bioavailability, and that excluding foods from this requirement was 
scientifically unjustified. The comment did not identify conventional 
foods from which folate had been demonstrated to be unavailable or 
elaborate on the concern.
    The agency proposed that dietary supplements meet USP standards for 
dissolution and disintegration, and that bioavailability under 
conditions of use stated on the label be shown only if there are no 
applicable USP standards for disintegration and dissolution. Thus, the 
agency proposed that a demonstration of bioavailability would be 
required only if there were no USP method available to check for 
dissolution and disintegration.
    The comment that stated that in making the requirement proposed in 
Sec. 101.79(c)(2)(ii)(C) effective for dietary supplements, the agency 
would accord the same claim to conventional foods without similar 
requirements, may have misread the agency's proposed requirement. 
``Bioavailability'' includes, but is not limited to, dissolution and 
disintegration. Dissolution and disintegration are necessary 
preconditions for absorption and subsequent metabolism. Digestive 
processes ensure that conventional foods are digested, and that 
components are liberated for absorption. With respect to the 
bioavailability of folate from conventional foods, the agency is aware 
that the bioavailability of folate varies widely but is not aware of 
any foods from which folate has been shown to be unavailable.
    However, dietary supplements, including folate-containing 
supplements, can be manufactured in a manner that prevents dissolution 
and disintegration (e.g., extremely compressed preparations), and the 
digestive processes may be insufficient to ensure the liberation of the 
components for absorption. The components of such a supplement would 
not be available for absorption and utilization by the body. A claim on 
a dietary supplement that does not disintegrate or dissolve would be 
misleading because the supplement would not meet the preconditions 
necessary to ensure that the nutrient that is the subject of the claim 
is available for absorption.
    The agency did not receive other comments contending that dietary 
supplements should not meet USP standards for disintegration and 
dissolution, or that bioavailability should not be demonstrated when 
applicable USP disintegration and dissolution standards are not 
available. The agency is adopting Sec. 101.79(c)(2)(ii)(C) as proposed 
and is redesignating it as Sec. 101.79(c)(2)(ii)(B).
3. No Health Claim on Foods or Supplements Containing More Than 100 
Percent of the RDI for Preformed Vitamin A or Vitamin D
    In Sec. 101.79(c)(2)(iii), FDA proposed that a health claim for 
folate and neural tube defects be prohibited on conventional foods and 
on dietary supplements that contain more than 100 percent of the RDI 
for vitamin A as retinol or preformed vitamin A or vitamin D per 
serving or per unit. The agency proposed this limitation because of the 
recognized toxicity of high intakes of these vitamins for the fetus and 
the teratogenic effects of these nutrients at levels not greatly in 
excess of the RDI.
    18. Several comments agreed with FDA's proposal, noting that many 
dietary supplements currently contain more than 100 percent of the RDI 
for vitamin A, and that such levels are unnecessary and potentially 
harmful. Another comment misread the proposed requirement regarding 
vitamin A and noted that since manufacturers were now increasing the 
-carotene content of supplements because of health benefits, 
these supplements should not be excluded from carrying a folate/neural 
tube defect claim because of their high -carotene content.
    The agency is aware that folate is often combined with other 
nutrients, particularly vitamins and minerals, in dietary supplement 
formulations or in highly fortified foods. In light of the expectation 
that the presence of a health claim on the label of such products is 
likely to result in increased intake of these products, FDA is 
concerned that some consumers may try to increase their folate intake 
by consuming multiple doses of dietary supplements or multiple servings 
of highly fortified foods. The agency was concerned that, for some 
fortified foods and dietary supplements that contain both folate and 
preformed vitamin A or vitamin D, consumers could be exposed to 
excessive vitamin A or vitamin D intakes in their attempts to obtain 
increased amounts of folate. The agency, however, did not propose 
similar requirements for -carotene because the agency is not 
aware of data on potential teratogenic or other adverse effects of 
-carotene on the fetus.
    This limitation is consistent with other recent recommendations. In 
1991, the CDC recommendation for increased intake of folate by women 
with a history of a neural tube defect- affected pregnancy (Ref. 23) 
warned against overconsumption of multivitamins because of the 
potential for excessive intakes of vitamins A and D from such 
preparations and the known adverse effects of these vitamins on the 
health of the fetus. In addition, recent recommendations in Canada for 
women of childbearing age regarding folic acid and neural tube defects 
recognized the teratogenicity of high levels of vitamin A and cautioned 
against excessive intakes of this nutrient (Ref. 24).
    With the exception of the comment regarding -carotene 
discussed above, the agency received no comments objecting to this 
requirement. Thus, the agency is adopting Sec. 101.79(c)(2)(iii) as 
proposed. The agency advises that the limitation contained in this 
provision pertains only to conventional foods or to dietary supplements 
that contain more than 100 percent of the RDI for vitamin A as retinol 
or preformed vitamin A or vitamin D.

E. Label Information

1. Mandatory Nutrition Labeling
    In Sec. 101.79(c)(2)(iv), FDA proposed to require that the 
nutrition label of conventional foods or dietary supplements bearing 
the folate/neural tube defect health claim provide information about 
the amount of folate in the food or dietary supplement. This proposed 
requirement is consistent with Sec. 101.9(c)(8)(ii) (21 CFR 
101.9(c)(8)(i)), which states that the declaration of vitamins and 
minerals on the nutrition label shall include any of the vitamins

[[Page 8764]]

and minerals listed in Sec. 101.9(c)(8)(iv) when a claim is made about 
them.
    19. One comment agreed with the proposed requirement for mandatory 
nutrition labeling on products bearing the folate/neural tube defects 
health claim. Another comment noted that use of multiple terms such as 
``micrograms,'' milligrams,'' etc., would probably confuse lay persons.
    The agency agrees with the comments and is adopting, with the 
modifications noted below, the requirement in Sec. 101.79(c)(2)(iv) 
that products bearing the health claim include in the nutrition 
labeling information about the amount of folate in the food.
    FDA adopted the 1980 Recommended Dietary Allowance (RDA) values as 
RDI values, with folate values expressed on the label in milligrams 
(mg) and percent of the DV (58 FR 2206, January 6, 1993). In the 
Federal Register of January 4, 1994 (59 FR 427 at 431), FDA proposed to 
amend Sec. 101.9 by revising paragraph (c)(8)(iv) to state, among other 
things, the RDI for folate in micrograms (i.e., 400 micrograms; 400 
mcg). The agency stated that changing the current unit of measure for 
folate will facilitate consumer comprehension of quantitative nutrient 
information because consumers are more familiar with this nutrient 
being expressed in microgram units.
    In Sec. 101.79(c)(2)(i)(F) and (c)(3)(iv), FDA has modified the 
codified language so that all references to folate intake in the health 
claim will be required to be expressed as percent DV with the option of 
adding the microgram equivalent in parentheses. That is, values for 
folate will be expressed as percent of the DV (i.e., the percent of the 
RDI as established in Sec. 101.9(c)(8)(iv)). FDA has modified the 
codified language in Sec. 101.79(c)(2)(i)(F) so that reference to the 
safe upper limit of daily folate intake in the health claim will also 
be required to be expressed as percent DV with the option of adding the 
microgram equivalent in parentheses (see comment 32 of this document). 
Thus, in response to the comment's concern about the confusion that 
would result if multiple terms are used to describe the level of 
folate, FDA has modified the regulations to provide for consistent 
terminology.
2. Identifying the Nutrient
    In proposed Sec. 101.79(c)(2)(i)(B), FDA considered the use of 
synonyms for ``folate'' and the need to aid consumers in understanding 
this nutrient. The agency provided for the use of synonyms and for 
additional description of this term through phrases such as ``folate,'' 
``folic acid,'' ``folacin,'' ``folate, a B vitamin,'' ``folic acid, a B 
vitamin,'' and ``folacin, a B vitamin.''
    20. Several comments agreed that the agency's proposed synonyms are 
appropriate. Other comments urged that a single term, for example, 
``folic acid,'' ``folic acid, a B vitamin,'' ``folate,'' or ``folate, a 
B vitamin,'' be used throughout all claims. Other comments agreed with 
the use of the agency's proposed synonyms to encourage the consumption 
of healthy diets but recommended that claims be worded in such a way as 
to demonstrate that ``folic acid'' is the effective form. Several 
comments disagreed with use of the term ``folacin,'' noting that it was 
rarely used.
    The agency notes that the descriptive term ``a B vitamin'' in 
conjunction with ``folate,'' ``folacin,'' or ``folic acid'' is commonly 
used in lay information for consumers and may be useful for consumers 
in indicating the nutritive function of folate as a vitamin. FDA is 
thus retaining the provision for its optional use in 
Sec. 101.79(c)(2)(i)(B).
    FDA recognizes that current regulations for nutrition labeling in 
Secs. 101.9 and 101.36 do not include the term ``folic acid'' as an 
allowable synonym for folate. This omission was an oversight when the 
agency amended Sec. 101.9 (58 FR 2079 at 2178, January 6, 1993), and 
when it promulgated Sec. 101.36 (59 FR 373, January 4, 1994). Before it 
was amended, Sec. 101.9 had listed folic acid as the preferred term, 
with folacin as an allowable parenthetical synonym. When it proposed 
amendments to Sec. 101.9 in 1990 (55 FR 29847, July 19, 1990), the 
agency explained why the term ``folate'' was preferable to ``folacin''. 
However, an explanation for use of ``folic acid'' was inadvertently 
omitted in that document, as was inclusion of the term ``folic acid'' 
as an allowable synonym.
    The agency has advised firms that it would have no objection to the 
use of the term ``folic acid'' in nutrition labeling. In light of 
common usage and FDA policy, and for consistency among nutrition 
labeling and health claim regulations, the agency is making a technical 
amendment to Secs. 101.9 and 101.36 in this final rule to include 
``folic acid'' as an allowable synonym for folate.
    The agency notes that, as discussed in comment 6, above, the terms 
``folic acid'' and ``folate'' are both used in the PHS recommendation 
(Ref. 5). By allowing the use of these terms, the PHS recommendation 
can be quoted directly on the label if all other requirements for the 
health claim are met. The inappropriateness of limiting the term to 
``folic acid'' to describe the relationship has been discussed in 
response to comment 6 of this document. Therefore, FDA is adopting 
Sec. 101.79(c)(2)(i)(B) as proposed.
3. Identifying Diets Adequate in Folate
    In Sec. 101.79(c)(2)(ii)(B), the agency proposed to require that 
health claims relating folate to neural tube defects identify sources 
of folate by stating that adequate amounts of folate may be obtained by 
making specific dietary choices of folate-rich foods, as well as 
through use of dietary supplements or fortified breakfast cereals. The 
purpose of this proposed requirement was to assist women in obtaining 
adequate amounts of folate in their diets by providing information on 
sources of folate. In proposed Sec. 101.79(c)(2)(ii)(B), the agency 
provided examples of the types of phrases that could be used to meet 
this requirement (e.g., ``Adequate amounts of folate, a B vitamin, can 
be obtained from diets rich in fruits, dark green leafy vegetables and 
legumes, enriched grain products, fortified cereals, or from dietary 
supplements'').
    21. Many comments agreed with the proposal to require statements 
that dietary sources such as fruits, vegetables, and grains may 
contribute folate to the diet, although some comments disagreed with 
providing specific details, such as recommended numbers of servings. 
Other comments supported the agency's proposed approach, emphasizing 
that the health claim must help consumers understand that, in 
pregnancy, it is the total diet, not a single food, that is related to 
health outcome, and that there is good evidence for dietary claims 
regarding increased folate intake and reduced risk of neural tube 
defects. Another comment stated that health claims should not reveal a 
bias against food forms, fortificants, or dietary supplements.
    Other comments disagreed with the proposal to identify healthful 
dietary patterns on the basis that many women will not change their 
eating habits, and that it is therefore important to point out the 
importance of use of dietary supplements. Other comments noted that the 
statements regarding beneficial diets were overly focused on food and 
should be made optional, that adding dietary information to the health 
claim reduces its educational effectiveness, and that inclusion of such 
information was neither required by law nor consistent with other 
authorized health claims such as that for calcium and osteoporosis. 
Several comments recommended that statements regarding diets adequate 
in folate be made optional because such information is 

[[Page 8765]]
better presented in educational materials.
    The agency disagrees with the comments that stated that the 
proposed statements regarding sources of folate were overly focused on 
food. Such comments imply that FDA was biasing the statements against 
dietary supplements. In fact, each example included dietary supplements 
in the list of sources of folate (e.g., fruits, vegetables, enriched 
grain products, fortified cereals, and dietary supplements). The agency 
also disagrees that the educational effectiveness of the claim is 
reduced by inclusion of the proposed statement because statements of 
this type provide, in an abbreviated form, information on sources of 
folate about which a consumer may be unaware.
    In the context of a total diet, the consumer needs flexibility in 
deciding how to increase folate intake. Provision of this information 
is consistent with section 403(r)(3)(B)(iii) of the act, which states 
that the claim shall be stated in a way that enables the public to 
understand the relative significance of the claim in the context of the 
total daily diet. Awareness of the food sources of folate, including 
dietary supplements, will assist women in recognizing the significance 
of the claim in the context of the total diet. Provision of information 
on sources of folate in the health claim will assist consumers by 
making them aware that specific foods and dietary supplements contain 
folate.
    However, FDA recognizes that while there has been a noticeable 
increase in the use of health claims over the last 2 years, the number 
of products that bear health claims is not as great as the agency had 
anticipated. The agency is therefore interested in simplifying claims 
to facilitate their increased use. The agency is particularly 
interested in removing so-called ``required'' elements that are not 
necessary to ensure that the claims are truthful, not misleading, and 
scientifically valid. While the agency agrees with the comments that 
supported inclusion of information on the dietary sources of folate, 
and while it supports health claim statements that include examples of 
dietary sources of this nutrient, the agency is concerned that 
requiring such specific information will increase the length of the 
claim and may dissuade manufacturers from including it in their 
labeling.
    In comment 14 of this document, the agency concluded that 
information regarding overall improvement in a woman's diet and 
nutrition throughout her childbearing years is of considerable 
importance because pregnancy outcome depends upon adequate intake of a 
wide range of nutrients. The agency is adopting 
Sec. 101.79(c)(2)(i)(H), which requires that the health claim state 
that there is a need for a healthful diet as well as adequate folate 
intake. FDA has concluded that this information is necessary to ensure 
that the claims have proper balance.
    The agency is persuaded that shorter claims that state the need for 
a healthful diet, without reference to specific foods, will meet the 
objective of encouraging broader use of the claim while alerting women 
to the importance of overall diet during the childbearing years. 
Therefore, FDA is requiring that claims state that adequate folate 
needs to be consumed as part of a healthful diet (see section II.C.5. 
of this document, and new Sec. 101.79(c)(2)(i)(H)) without identifying 
specific sources. The appearance of the claim on a wide range of 
qualifying foods will itself convey information about the variety of 
sources of folate available to women as part of a healthful total diet.
    Therefore, the agency is removing proposed Sec. 101.79(c)(2)(ii)(B) 
in its entirety and is adding in the codified language a provision 
(Sec. 101.79(c)(3)(vii)) for optionally including in the claim 
information that identifies sources of folate. Because of these 
changes, FDA has adopted proposed Sec. 101.79(c)(2)(ii)(C) as 
Sec. 101.79(c)(2)(ii)(B).
4. Identifying the Health-Related Condition
    In developing proposed Sec. 101.79(c)(2)(i)(C), FDA considered 
whether women might be confused or not understand the term ``neural 
tube defect'' and provided for some qualification of this term through 
use of alternate phrases such as ``the birth defect spina bifida,'' 
``the birth defects spina bifida and anencephaly,'' ``spina bifida and 
anencephaly, birth defects of the brain or spinal cord,'' and ``birth 
defects of the brain or spinal cord, spina bifida and anencephaly.''
    22. The agency received several comments regarding these proposed 
synonyms. A comment agreed with the agency that the health-related 
condition must be specified and stated that the agency's proposed 
synonyms were appropriate. Another comment noted that ``anencephaly'' 
is not a familiar term, and that a phrase such as ``certain serious 
birth defects, neural tube defects'' is preferable. Another comment 
recommended that only the statement ``neural tube defect'' be allowed 
because it is the more appropriate and accurate term, and because 
consumers will benefit from seeing the same identifying statements in 
health claims on many products. Several comments, however, asserted 
that consumers will not understand ``neural tube defects'' and stated 
that a more understandable term might be ``birth defects of the brain 
and/or spinal cord.''
    The agency has considered these comments and concludes that the 
term and qualifiers provided in its proposed rule, i.e., ``neural tube 
defects,'' ``the birth defect spina bifida,'' ``birth defects spina 
bifida and anencephaly,'' ``spina bifida and anencephaly, birth defects 
of the brain or spinal cord,'' and ``birth defects of the brain or 
spinal cord anencephaly or spina bifida,'' will allow manufacturers 
considerable flexibility in crafting claims and in educating consumers. 
The agency is also persuaded to include the option of using the simpler 
terms ``birth defects of the brain or spinal cord'' or ``brain or 
spinal cord birth defects'' and has modified Sec. 101.79(c)(2)(i)(C) 
accordingly. The agency accepts the suggestion that use of the latter 
terms will make the claims simpler and more useful to consumers because 
the phrase may be more understandable than phrases that include medical 
terms such as ``neural tube defects'' or ``anencephaly''.
    The agency also considered whether use of the very general terms 
``some birth defects'' or ``some serious birth defects'' would be 
appropriate. As discussed in its January 1993 final rule on folate and 
neural tube defects (58 FR 2606 at 2610), the act requires that claims 
on foods be truthful and not misleading. The agency recognizes that, 
based on the results of the Medical Research Council trial, the 
association between folate intake and birth defects is limited to 
neural tube defects. The Medical Research Council trial found that 
folic acid, while significantly reducing the risk of neural tube 
defects in women at high risk of recurrence of this complication, did 
not significantly alter the incidences of a wide variety of other birth 
defects in the population studied (Ref. 14). Similarly, Czeizel et al. 
(Ref. 15) reported that the results of the Hungarian trial that studied 
use of a multivitamin/multimineral supplement containing 0.8 mg of 
folic acid showed no reduction in incidences of birth defects other 
than neural tube defects.
    FDA also points out that the prevalence of neural tube defects in 
the United States has been steadily declining in recent decades, and 
that the estimated incidence is presently about 1 in 1,600 births (Ref. 
25). Currently, estimated incidences of other serious birth defects are 
considerably higher than that for neural tube defects. For 

[[Page 8766]]
instance, estimated incidences are 1 in 115 for birth defects involving 
the heart and circulation, 1 in 130 for those involving the muscles and 
skeleton, 1 in 135 for those involving the genital and urinary tract, 1 
in 235 for those involving the nervous system and eye, 1 in 735 for 
club foot, and 1 in 635 for chromosomal syndromes (Ref. 25).
    Because neural tube defects constitute a relatively small fraction 
of all birth defects, women should not be misled into a false sense of 
security that they can affect their risk of all birth defects through 
diets adequate in folate. The agency has therefore decided not to 
include use of the more general terms ``some birth defects'' or ``some 
serious birth defects'' because use of such terms would fail to 
disclose the material fact that the food substance/disease relationship 
is specifically between folate and neural tube defects. Use of such 
general terms can create the impression that adequate folate intake 
will reduce a woman's risk of other serious birth defects, and women 
might, as a result, discount risk factors for other birth defects 
(e.g., alcohol use, drug abuse).
5. Safe Upper Limit of Daily Intake
    Sections 403(r)(3)(A)(ii), 402(a), and 409 of the act establish 
that the use of a substance in a food must be safe. Based on concerns 
discussed in the Federal Register of January 6, 1993 (58 FR 2606), the 
agency concluded that it could not authorize a health claim on folate 
and neural tube defects at that time. The agency was concerned that the 
possibility exists that folic acid itself could be a substance that 
increases the risk of a disease or a health-related condition in 
persons in the general population (see section 403(r)(3)(A)(ii) of the 
act).
    Recognizing the potential for adverse effects from high intakes of 
folate, PHS included a caution statement in its recommendation that 
``because the effects of higher intakes are not well known but include 
complicating the diagnosis of vitamin B12 deficiency, care should 
be taken to keep total folate consumption at <1 mg per day, except 
under the supervision of a physician'' (Ref. 5).
    In Sec. 101.79(c)(2)(i)(G), FDA proposed to require a statement as 
part of the health claim on fortified foods in conventional food form 
and on dietary supplements containing more than 25 percent of the RDI 
for folate per unit or per serving that 1 mg of folate per day is the 
safe upper limit of intake. The agency noted that the availability of 
the health claim would likely encourage increased intakes of health-
claim labeled foods, and that, if intakes of highly fortified foods and 
dietary supplements were increased, it could result in folate intakes 
above the level known to be safe.
    The agency received comments addressing two issues related to safe 
use of foods bearing health claims: (1) Is there a need for concern 
about a safe upper limit of daily intake? (2) If so, should a statement 
identifying a safe upper limit of intake be included in a health claim, 
and how should such a statement be worded?
    a. Need for concern about a safe upper limit of daily intake. FDA 
tentatively concluded that, under certain circumstances, there was a 
need to disclose the safe upper limit of intake in the health claim and 
tentatively decided to use 1 mg per day (1,000 mcg; 250 percent of the 
DV) of total folate as the upper limit for such intake (58 FR 53254 at 
53273).
    The agency noted in the final rule of January 6, 1993 (58 FR 2606 
at 2612), and the proposed rule of October 14, 1993 (58 FR 53254 at 
53266), that there is a general paucity of evidence on the safety of 
daily folate intakes above 1,000 mcg (1 mg). The agency noted that 
there may be risks attendant upon increased consumption of folate for 
some groups in the population. The agency stated that, at the present 
time, the potential adverse effect that has been most extensively 
documented is a masking of anemia in persons with vitamin B12 
deficiency, while irreversible neurologic damage progresses. Other 
groups at risk from excessive intakes of folate include pregnant women, 
persons on antiseizure (i.e., antiepileptic) medications, and those on 
antifolate medications. There were no data to identify the magnitude of 
other possible risks of increased folate intake or to establish safe 
use at daily intakes above 1,000 mcg.
    In its proposal of October 14, 1993 (58 FR 53254 at 53266), the 
agency described how it had reached its tentative decision that 1 mg of 
total folate per day was the safe upper limit of intake. Based on its 
review of the scientific literature and its discussions with the Folic 
Acid Subcommittee, the agency tentatively concluded that: (1) For those 
with vitamin B12 deficiency, there was little likelihood of 
problems at daily intakes lower than 1 mg (58 FR 53254 at 53268 to 
53270); (2) an upper limit of intake of 1 mg of folate per day was safe 
for pregnant women and for persons with epilepsy; (3) doses of folic 
acid of up to 1 mg per day have not been reported to reduce the 
effectiveness of medications that interfere with folate metabolism; (4) 
effects of long-term continuous exposures of body tissues to elevated 
blood levels of folic acid, which occur when the body's capacity to 
metabolize folic acid is exceeded, have not been evaluated; and (5) 
there have been no long-term studies to quantitate the effects, if any, 
of increased folate intake on the metabolism of other nutrients.
    The agency stated (58 FR 53254 at 53268) that it knew of no data 
that would support the long-term safety of continuous daily folate 
intakes of more than 1 mg. The agency, noting that the value of 1 mg 
for a safe upper limit of daily folate intake could be modified if data 
were available to support such a decision, solicited comments and data 
on this point.
    In addition, the agency described how it had reached its tentative 
decision that a statement that 1 mg of total folate per day was the 
safe upper limit of daily intake should be required on products bearing 
the health claim and fortified above 25 percent of the RDI for folate. 
The agency's tentative conclusion was based on, among other 
considerations: (1) The scientific evidence, and the view expressed by 
experts, that there are no data to ensure that adverse effects are not 
likely to occur at daily intakes above 1 mg (Refs. 6, 7, 8, and 26); 
(2) the PHS recommendation that folate intake of women of childbearing 
age should not exceed 1 mg per day (Ref. 5); and (3) the support by the 
Folic Acid Subcommittee of FDA's use of 1 mg of total folate per day as 
a safe upper limit guide when considering fortification strategies. The 
upper safe limit of intake that FDA proposed was based on its best 
scientific judgment at the time. The agency solicited comments and data 
on its tentative judgment.
    Some comments expressed uncertainty regarding an amount that would 
represent a safe upper limit of daily intake of folate, while other 
comments strongly agreed or strongly disagreed with FDA's proposal that 
1,000 mcg of total folate per day is the safe upper limit of intake.
    The agency did not receive any data relating to 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.
    23. Several comments noted that the agency should not misconstrue 
the absence of safety data on folate intakes of 1 to 4 mg (1,000 to 
4,000 mcg) per day as evidence of the absence of harm; that because 
daily intakes for the general population are well below 1 mg, it has 
never been established that 1 mg per day of folate from all sources is 
a safe daily upper limit; and that the upper safe limit of intake for 
African-Americans, and perhaps Hispanic 

[[Page 8767]]
Americans, is not known. Several comments noted that pernicious anemia 
has an earlier age-at-onset among African-Americans than among 
Caucasians, and that vitamin B12 deficiency is not rare in persons 
with sickle cell anemia. Another comment noted that the level of folate 
that will accelerate the neurologic disorders of vitamin B12 
deficiency is unknown, and that physicians see patients who have been 
taking folic acid supplements who present with neuropsychiatric 
disturbances. Another comment noted that there were uncertainties 
regarding effects of chronic exposures of children, whose requirements 
for folate are lower than those of adults, to increased intakes of 
folic acid. Uncertainties regarding safety of increased intakes of this 
nutrient were the major factor in the opposition in the Folic Acid 
Subcommittee/Food Advisory Committee to FDA's proposed rules (Ref. 8).
    Many comments agreed with FDA's estimate of 1 mg of folate as an 
upper safe limit of intake given the paucity of information concerning 
the possible risks of excess folate intakes. Other comments noted that 
the masking of pernicious anemia is real, but that there is no evidence 
for folate toxicity at daily intakes of 1 mg/day or less. The comments 
said that the value of 1 mg/day has, therefore, emerged as being safe. 
Other comments recognized that overconsumption of folate may complicate 
the diagnosis of vitamin B12 deficiency, but that there is limited 
evidence regarding effects of intakes of folic acid between 400 mcg and 
5,000 mcg per day.
    FDA notes that a major factor in both the Folic Acid Subcommittee's 
and the Food Advisory Committee's concern about FDA's proposals was the 
fundamental issue of lack of documentation of safety of long-term daily 
intakes at levels above 1,000 mcg (Ref. 8). The agency is also aware 
that the Committee members expressed considerable concern about the 
lack of information on the size of the population potentially at risk 
from increased intakes of folate. Specifically, the agency did not 
receive data regarding potential adverse effects of increased folate 
intakes in African-American women or in children. The agency notes that 
the absence of data on long-term effects of increased folate intakes 
does not allow the agency to adequately identify those potentially at 
risk.
    As stated above, the agency is not aware of any data that establish 
the safety of long-term intakes of folate above 1,000 mcg per day. The 
absence of any data that allow systematic evaluation of intakes above 
this level means that potential risks and at-risk groups cannot be 
adequately defined or described. FDA notes that some members of the 
Folic Acid Subcommittee and most folate and vitamin B12 experts 
submitting comments (Ref. 8) were concerned about the lack of 
documentation of safety of daily long-term intakes of folate above the 
level of 1 mg/day. In addition to concerns regarding those with low 
vitamin B12 status, other safety concerns included uncertainties 
of 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 proposed rule (58 FR 
53254 at 53269), 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. The agency also noted that 
no information is available to ascertain whether developing neural 
tissue is protected from the neurotoxic effects of very high 
circulating levels of free folic acid. None of these issues were 
addressed in comments that the agency received.
    Comments that disagreed with FDA's proposal to consider 1,000 mcg 
folate/day as the safe upper limit of intake raised several issues 
which are considered below:
    i. Basis for a safe upper limit: Synthetic folic acid versus total 
folate.
    24. A comment stated that the limit should be based on supplemental 
synthetic folic acid only because only this form has been associated 
with masking of the anemia of pernicious anemia. This issue of whether 
the upper limit should be based on total folate or on synthetic 
crystalline folic acid was raised in several comments, with some 
comments of the opinion that it was appropriate to use estimated 
consumption of folate from all sources in defining the safe upper limit 
of intake and others recommending use of ``crystalline folic acid'' 
only.
    The agency disagrees that the safe upper limit of daily intake 
should be based on ``crystalline folic acid'' rather than total folate 
from all sources. FDA notes that the distinction between ``synthetic 
folic acid,'' referring only to crystalline folic acid, and ``folate,'' 
referring only to naturally occurring food folates, with respect to the 
1,000 mg/day estimate of safe daily intake, is an artificial one and is 
not consistent with what is known about the nutritional 
interrelatedness of a variety of folate vitamin forms in providing 
coenzyme forms of the vitamin for meeting the body's needs for this 
essential nutrient. Issues relating to ``folic acid'' versus ``folate'' 
are discussed in response to comment 6 of this document.
    Metabolic needs for folate are met from body pools of reduced 
coenzymes, regardless of whether these coenzymes are derived from 
synthetic folic acid or from naturally occurring food folates. While it 
is true 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, such individuals were also consuming 
unknown quantities of folate from foods. Thus, total daily folate 
exposures associated with the masking have not been quantified, and the 
effect of food folates on adverse effects is not known. It is also not 
known whether the variable responses, in terms of masking effects, to 
low levels of folic acid in supplements are the result of differences 
in folate intakes from background diets or of other factors that are 
currently not understood. For these reasons, it is not possible to 
attribute all adverse effects solely to crystalline folic acid.
    In addition, high intakes of food folates can have adverse effects 
in persons with poor vitamin B12 status. With respect to 
nonpernicious anemia-related vitamin B12 deficiency, Sanders and 
Reddy (Ref. 27) noted that megaloblastic anemia is rarely encountered 
in Caucasian vegetarians and vegans because of their high intakes of 
folate. These authors reported that, for example, 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 (Ref. 27). Because the high 
folate intakes would at least temporarily improve the associated 
anemia, vitamin B12 deficiency usually presents with neurological 
signs and symptoms in infants (Ref. 27). Herbert reported that studies 
over several decades have all indicated that major myelin synthesis 
damage from vitamin B12 deficiency with only minor hematopoietic 
(i.e., hematologic) damage reflects better folate status because folate 
improves hematologic, but not neurologic, manifestations of the 
deficiency (Ref. 28). He also found generally higher red cell folate in 
persons with greater myelin damage (that only vitamin B12 
deficiency produces) than in persons with greater hematologic damage 
(which deficiency of either folate or vitamin B12 produces) (Ref. 
28).
    The observations above suggest that a safe upper limit of daily 
intake is more 

[[Page 8768]]
accurately based on total folate intake than on just intake of 
crystalline folic acid because under conditions in which vitamin 
B12 utilization or intake is limited (i.e., in pernicious anemia 
or in nonpernicious anemia-related vitamin B12 deficiency), either 
crystalline folic acid or food folate may cause adverse effects when 
consumed in excess.
    The agency noted in response to comment 6 of this document, that 
use of a distinction between ``folic acid'' and ``folate'' is 
inconsistent with the PHS recommendation, which uses these terms 
interchangeably (Ref. 5), and with advice provided by FDA's and CDC's 
advisory panels. Moreover, use of such a distinction is not supported 
by recent statements from experts on folate and vitamin B12 (Refs. 
7, 8, and 26). 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).
    ii. Lack of evidence of untoward effects of increased intakes.
    25. Several comments that disagreed with the agency's tentative 
conclusion that 1 mg folate per day from all sources is the safe upper 
limit of intake stated that there is no evidence that maximum intakes 
of 1,500 mcg to 2,000 mcg will result in any untoward effects. Another 
comment reviewed the literature describing the effects of intakes of 
1,000 to 5,000 mcg folic acid per day in persons with vitamin B12 
deficiency and concluded that the literature did not reveal any 
substantial safety concerns. Another comment stated that 5,000 mcg/day 
should replace 1,000 mcg/day as the upper limit of safe intake.
    The agency is aware that the literature describing the effects of 
intakes of folic acid between 1,000 and 5,000 mcg per day is very 
limited but disagrees that there is no evidence of untoward effects of 
daily folate intakes of 1,500 to 2,000 mcg per day, and that 5,000 mcg 
per day should be identified as the safe upper limit of intake.
    The literature describing the effects of daily intakes of 1,000 to 
5,000 mcg folic acid includes three uncontrolled intervention trials 
involving 15 persons (Refs. 29, 30, and 31) and 16 case reports (Refs. 
32, 33, 34, 35, 36, and 37). 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 1,000 to 5,000 mcg folic acid lasted for less than 30 
days (e.g., Refs. 30, 31, 32, and 33). Therefore, these reports are not 
useful in assessing the safety of life-long exposures. However, 
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 1,000 to 5,000 mcg and continued for 1 month or 
more (Refs. 29, 32, 33, 35, and 37). Thus, the limited scientific 
literature shows that approximately half of the patients with 
pernicious anemia associated with vitamin B12 deficiency will 
respond to folate at doses between 1,000 and 5,000 mcg per day when 
they are given the vitamin for relatively short periods of time (e.g., 
several months).
    In addition, in discussing safety issues in its proposed rule (58 
FR 53254 at 53267), the agency noted that, although there was a lack of 
systematic evaluation of the effect of folic acid on the anemia of 
vitamin B12 deficiency at intakes of less than 5,000 mcg per day, 
several case reports have described hematologic improvement in 
pernicious anemia patients with doses of folic acid lower than 1,000 
mcg/day (e.g., at 200 to 500 mcg/day; Refs. 38, 39, 40, 41, 42, 64 
through 65, and 72 through 74). Thus, adverse effects have been 
reported at daily doses of less than 1,000 mcg, at doses of 1,000 to 
5,000 mcg, and at doses greater than 5,000 mcg.
    iii. Lack of evidence of toxic effects of increased folate intakes 
in pregnant women.
    26. Another comment that disagreed with the agency's tentative 
conclusion noted that millions of pregnant women have taken prenatal 
vitamins containing 1,000 mcg folic acid, that folic acid at dosages of 
4,000 mcg per day has been extensively studied in pregnant women, and 
that no toxic effects have been shown in healthy individuals.
    The agency disagrees with the comment that folic acid at doses of 
4,000 mcg per day have been extensively studied in pregnant women and 
are without toxic effects. The agency recognizes that pregnant women 
take prenatal supplements which usually contain 800 mcg of folic acid, 
and that such supplements have been in use for many years. FDA notes 
that, while there is no evidence that 800 mcg of folic acid per day 
(i.e., the 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 physician supervision. The Institute of Medicine in Nutrition 
During Pregnancy stated that the safety of large doses of folic acid in 
pregnant women has not been systematically determined (Ref. 43).
    The agency notes also that the comment that folic acid at doses of 
4,000 mcg per day has been extensively studied in pregnant women, and 
that such doses are without toxic effects, is not substantiated by the 
scientific data. In the only study utilizing 4,000 mcg folic acid/day, 
the Medical Research Council (MRC) trial, about 910 women took 
supplements containing 4,000 mcg of folic acid from the time of 
randomization into the trial until the 12th week of pregnancy (Ref. 
14). At the conclusion of the study, the author stated that, although 
the MRC 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 
use of 4,000 mcg/day of folic acid by pregnant women is safe.
    Thus, the agency has not received any data or information that 
would persuade it that any level other than 1 mg (1,000 mcg) folate per 
day is the appropriate safe upper limit of intake for pregnant women.
    iv. Adverse effects in those with vitamin B12 deficiency can 
be detected with clinical care.
    27. Another comment disagreed with the proposed 1,000 mcg safe 
intake limit and noted that adverse effects of high intakes of folate 
with respect to vitamin B12 deficiency can be detected with 
clinical care. Other comments stated that the issue of masking of 
vitamin B12 deficiency was overstated and 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 this fact provides adequate justification for increasing 
the safe limit of daily intake. The agency notes that measurements of 
vitamin B12 status are not performed on a routine basis by 
physicians. Currently, there are no population-based data on how many 
people in the United States have undiagnosed vitamin B12 
deficiency and thus might be at risk from increased intakes of folate. 
The agency noted in the January 6, 1993 final rule (58 FR 2606 at 
2615), that significant percentages of the elderly, demented patients, 
acquired immune deficiency syndrome (AIDS) patients, and patients with 
malignant diseases have subnormal vitamin B12 levels without 
having any of the classical manifestations of vitamin B12 
deficiency. Lindenbaum et al. recently reported that the prevalence of 
vitamin B12 deficiency was greater than 

[[Page 8769]]
12 percent in a large study (n=548) of free-living elderly Americans 
(Ref. 44). 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). 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 subtle adverse effects were experienced. 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 increasing the safe upper limit of 
intake for such persons or for other persons in the general population 
for whom there are currently no data to establish the effects, if any, 
of high intakes of folate. In developing its proposed rule,
    FDA was aware of the contentious nature of a proposed upper limit 
and specifically asked for data on this issue. This topic was also 
extensively discussed by FDA's Folic Acid Advisory Committee and Food 
Advisory Committee (Refs. 7 and 8). No data were submitted in any of 
the comments that addressed the issue of the safety of intakes above 
1,000 mcg 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 1,000 mcg 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.
    Because there are inadequate data and information on the safety of 
consuming more than 1,000 mcg folate per day, the agency is unable to 
conclude that there is a reasonable certainty of no harm to persons 
consuming more than 1,000 mcg folate per day. In the absence of data on 
high intakes of folate, the agency is unable to adequately define the 
nature or magnitude of potential risk from increased folate intakes. At 
this time, the agency has no data to support a conclusion of safe use 
of folate above 1,000 mcg per day or data that would provide a basis 
for a change from the proposed upper limit of 1,000 mcg per day to an 
upper limit of 5,000 mcg per day. In addition, for the reasons 
explained above, the agency has not been persuaded by the comments that 
it should consider synthetic folic acid as the only active form of the 
vitamin and thus base its estimate of a safe upper limit of intake on 
this form of the vitamin only.
    The agency therefore concludes that, because of the lack of 
evidence of safe use at intakes greater than 1,000 mcg folate daily, 
and the potential for serious harm to some persons from such intakes, 
daily intakes above 1,000 mcg by the general population should not be 
encouraged.
    b. Including a safe upper limit of daily intake in the claim. In 
recognition of comments and safety concerns discussed in its proposal, 
FDA, in Sec. 101.79(c)(2)(i)(G), proposed to require a statement on 
fortified foods in conventional food form and on dietary supplements 
that contain more than 25 percent of the RDI (i.e., more than 100 mcg 
per reference amount customarily consumed or, for supplements, per 
unit) about the maximum safe daily limit for folate consumption. The 
agency proposed that such a statement (e.g., ``Folate consumption 
should be limited to 1,000 mcg per day from all sources.'') was 
necessary to prevent the health claim from being misleading regarding 
potential risks from excessive intakes.
    In the October 14, 1993 proposal (58 FR 53254 at 53282), the 
agency, noting that the safe upper limit of intake was 1 mg (1,000 
mcg), stated that a fortified food that contains more than 100 mcg 
folate per serving contributes more than 25 percent of the RDI and more 
than 10 percent of the daily limit. Therefore, it continued, 
consumption of such foods should be monitored by the consumer, so that 
he or she will not consistently or significantly exceed the upper 
limit.
    In its proposed rule (58 FR 53254 at 53282), the agency also noted 
that it was not proposing to require that this statement be included in 
claims on the relatively small number of conventional foods that 
contain more than 100 mcg of folate without fortification (e.g., dark 
green leafy vegetables, certain legumes). The agency stated that it 
believed that there is no need for the consumer to monitor intakes of 
these foods because their folate content consists of reduced 
pteroylpolyglutamates whose bioavailability is generally considered 
lower than that of the folic acid (i.e., pteroylmonoglutamate) added as 
a fortificant to foods. The agency received many comments on this 
aspect of the proposal.
    c. General comments.
    28. Comments supporting inclusion of a caution statement in health 
claims stated that an admonition regarding excessively high intakes is 
absolutely essential in the health claim, and that the agency must 
require a meaningful and useful disclosure regarding the risks of 
excess intake. One comment stated more specifically that health claims 
related to folate and neural tube defects should be balanced by a 
warning statement that increased intakes of folate may increase the 
frequency of irreversible neurologic damage from vitamin B12 
deficiency. A related comment stated that, among Black and Hispanic 
females, folic acid fortification or supplementation is likely to do 
more harm than good, and that a caution statement was important for 
such groups. One comment recognized the need to set upper limits of 
safe intake but noted that, in the absence of strong evidence, it is 
inappropriate to warn consumers about potential adverse effects and 
detract from the benefits of the health claim.
    Other comments supported the use of a statement of a safe upper 
limit of intake but found FDA's proposed language in 
Sec. 101.79(c)(2)(i)(G) and in the model health claims (Sec. 101.79(d)) 
unsatisfactory because the agency failed to provide specific 
information on the potential adverse effects of overconsumption and 
failed to identify the subpopulations at risk from high intakes (e.g., 
the elderly).
    The agency does not agree that it is inappropriate to warn 
consumers about the potential adverse effects of increased folate 
intake because adverse effects have been documented in the scientific 
literature. The agency's responses to comments 23, 25, and 27 of this 
document make clear that, for some population groups, there are risks 
attendant upon increased folate intake. Such groups include those with 
vitamin B12 deficiency and African-American women. As noted above, 
the agency did not receive data providing evidence rebutting the risks 
of folate intakes above 1 mg per day (1,000 mcg/day) for these and 
other at-risk groups, such as pregnant women, children, persons on 
antiseizure medications, or persons on antifolate medications.
    Therefore, the agency agrees with the comments that stated that it 
should require that a useful statement regarding risks of excessive 
intakes be included in the health claim. In response to the comment 
that the model health claims were unsatisfactory because they failed to 
identify specific subpopulations at risk from increased intakes (e.g., 
the elderly), the agency is advising that it will not require 
identification of specific 

[[Page 8770]]
at-risk groups in the caution statement because the limited data 
available from populations consuming folate at the level of 1 mg per 
day (1,000 mcg per day) and above do not allow an adequate 
identification of all such groups to be made. Identification in the 
claim of only some of the groups at risk (e.g., the elderly) would be 
misleading because persons in other at-risk groups that were not 
identified in the claim could conclude that because they were not 
mentioned, they were not at risk from high intakes.
    d. Inappropriate to include caution statement only on fortified 
foods and supplements.
    29. Other comments stated that it was inappropriate to single out 
only fortified foods or supplements that contain folate above 25 
percent of the DV for carrying a warning statement.
    The agency proposed not to require the caution statement in health 
claims on the relatively small number of conventional foods that 
contain more than 100 mcg of folate without fortification (e.g., dark 
green leafy vegetables, certain legumes) because many of these foods 
are not consumed on a daily basis, and even when consumed regularly, 
the bulk and energy value of such foods tends to limit their 
consumption.
    The agency has reevaluated whether foods that are naturally high in 
folate (e.g., those containing more than 25 percent of the DV) should 
carry the caution statement proposed for fortified foods or supplements 
containing more than 25 percent of the DV. The agency agrees with the 
comment that it is inappropriate to single out fortified foods and 
supplements for a caution statement because there is no justification 
for distinguishing between added and naturally-occurring nutrients. 
This decision is consistent with the agency's conclusion (see comment 
23 of this document) that total folate intake from all sources needs to 
be considered in arriving at a safe upper limit of daily intake. For 
this reason, FDA has decided to require that the modified caution 
statement described in comment 31 of this document appear on any 
conventional food or dietary supplement that meets the criteria set out 
in Sec. 101.79(c)(2)(i)(F).
    e. Optional caution statement.
    30. Another comment advised the agency to permit the identification 
of the 1,000 mcg per day limit as optional information.
    The agency rejects this comment. Given the point of the health 
claim message, it is unlikely that an optional caution statement would 
be included in most health claims. Therefore, most consumers would not 
be alerted to the potential adverse effects of high levels of folate or 
might assume that claim- bearing products without the caution statement 
were safer than products that bore a claim that included the caution 
statement. Consumption of products bearing the caution statement might 
come to be associated with potential adverse effects, while consumption 
of other products with an identical folate content that did not bear 
the caution statement would not be associated with such potential 
adverse effects. Because potential adverse effects are related to 
increased intakes of folate from any source, it would be illogical for 
the agency not to require the caution statement on all products that 
carry the health claim and that meet the criteria for the caution 
statement. Claims on products that meet the criteria and that fail to 
carry the caution statement would be misleading because they would fail 
to alert consumers to the material fact that there may be risks 
attendant upon excessive folate intakes.
    f. Upper limit of safe intake expressed as percent DV.
    31. Another comment agreed with the use of a caution statement but 
felt that the safe upper limit of intake should be expressed as percent 
of the DV.
    The agency agrees with this comment because this method of 
communicating the safe upper limit of intake will provide consistency 
with the nutrition label, thereby enhancing the comprehensibility of 
the information. The agency notes that, as stated in response to 
comment 19 of this document and in the codified language in 
Sec. 101.79(c)(2)(i)(F), the upper limit of daily intake is to be 
expressed in the claim as percent of the DV, with manufacturers having 
the option of including the microgram equivalent in parentheses (e.g., 
250 percent DV (1,000 mcg)).
    g. Limit caution statement to products with 100 percent DV.
    32. Several comments said that a warning statement should be 
limited to higher-dose foods or dietary supplements (those containing 
100 percent or more of the DV) unless further research and monitoring 
demonstrate that the risks of increased folate intakes from lower-dose 
foods or supplements are also significant. Other comments argued that 
there is no need to include a warning statement and noted that 
supplements and cereals with 100 percent of the DV have never carried 
such awarning statement. Other comments expressed the opinion that the 
warning statement would discourage increased consumption of folic acid 
supplements.
    The agency has considered whether requiring that the caution 
statement appear in claims on foods or dietary supplements that contain 
more than 25 percent of the DV is too restrictive. The agency 
recognizes that such a requirement would require that caution 
statements appear as part of health claims on a wide range of products 
that contain more than 100 mcg folate per serving (e.g., dietary 
supplements, breakfast cereals) that have not previously carried such a 
statement. The agency agrees with the comment that the result of such 
caution statements could well be to discourage consumption of such 
products. It was not the agency's intent to cause such a result because 
breakfast cereals and dietary supplements have traditionally been 
important sources of folate for consumers who use them. Additionally, 
in the case of many dietary supplements, a statement regarding daily 
consumption (e.g., ``consume one per day'') is already included in the 
labeling and serves to inform consumers as to the appropriate daily 
intake.
    The agency notes, however, that the health claim is intended to 
encourage women to increase their intakes of folate, and that the claim 
is likely to encourage some women to consume more of particular 
products, particularly those bearing the claim that are very high in 
folate, than they might otherwise consume. Thus, a caution statement 
regarding excessive intakes is appropriate on foods that contain very 
high levels of folate because the possibility is created by the claim 
itself that some women will achieve high folate intakes.
    The agency has concluded that a statement about high consumption of 
folate is necessary if a product contains more than 100 percent of the 
DV (i.e., 400 mcg when labeled for use by adults and children 4 or more 
years of age; 800 mcg when labeled for use by pregnant or lactating 
women; 58 FR 2206 at 2213, January 6, 1993; Food Labeling; Reference 
Daily Intakes and Daily Reference Values). Such an amount of folate 
would exceed not only the DV's but the PHS recommended folate intake 
for women of childbearing age. Thus, the caution statement is required 
only on products that contain more than current recommended daily 
intakes of folate per serving.
    The agency has redesignated proposed Sec. 101.79(c)(2)(i)(G) as 
Sec. 101.79(c)(2)(i)(F) and has modified this provision to read that:

    Claims on foods that contain more than 100 percent of the Daily 
Value (DV) (400 mcg) when labeled for use by adults and children 4 
or more years of age, or 800 mcg 

[[Page 8771]]
when labeled for use by pregnant or lactating women) shall identify the 
safe upper limit of daily intake with respect to the DV. The safe 
upper limit of daily intake value of 1,000 mcg (1 mg) may be 
included in parentheses.

    h. Upper limit useless without reference to intake goal.
    33. Other comments opposed including a reference to the upper limit 
of 1,000 mcg per day in any health claim because, they argued, 
consumers cannot determine their total daily intakes from all sources. 
These comments noted that stating an upper limit was useless unless all 
food types were labeled with their folate content. Another comment 
opposing the inclusion of a warning statement on foods or supplements 
containing more than 25 percent of the DV stated that inclusion of an 
upper limit was problematic if reference was not made to the 400 mcg/
day intake goal.
    The agency recognizes that there was an inconsistency in the way 
that proposed Sec. 101.79(c)(2)(i)(G) was worded in that the safe upper 
limit of daily intake was expressed as 1,000 mcg rather than as a 
percent of the DV. The agency has corrected this inconsistency, as 
noted above in response to comment 32 of this document.
    The agency disagrees that inclusion of the 400 mcg intake goal is 
necessary to make a caution statement understandable, and that a 
caution statement is useless unless all foods are labeled with their 
folate contents. The agency notes that diets that do not contain highly 
fortified foods and dietary supplements rarely provide daily folate 
intakes of more than 1,000 mcg. The likelihood of achieving daily 
intakes exceeding 1,000 mcg arises from consumption of highly fortified 
foods and dietary supplements, particularly those that contain more 
than the DV per unit or per serving. Under current labeling 
requirements, such foods and supplements must, or soon will have to, 
carry nutrition labeling. The safe upper limit of daily intake will 
thus appear on those products whose use provides the greatest potential 
for contributing to overconsumption (e.g., highly fortified foods and 
supplements whose label bears a health claim that explains a potential 
benefit of increased consumption). The agency concludes that it is 
necessary to require inclusion of the caution statement, with the safe 
upper limit of daily intake expressed as percent of the DV (percent 
DV), as part of the health claim on such products.
    The agency also notes that the availability of the health claim may 
result in increased consumption of foods with high folate content that 
carry the claim. The expression of the folate content as a percent of 
the DV will help consumers who select a health claim-labeled food that 
contains more than 100 percent of the DV and that is labeled with a 
statement that folate intakes should be limited to 250 percent of the 
DV, to recognize that the product provides more than the full amount of 
the DV while still leaving a considerable allowance for consumption of 
other foods of lower folate content. The percent DV labeling will also 
allow a consumer who selects four health claim-labeled foods that each 
contain more than 100 percent of the DV to quickly compute that these 
four products alone will provide more than 400 percent of the DV, an 
amount in excess of the safe upper limit of daily intake of 250 percent 
of the DV. Thus, the agency does not believe that explicit reference to 
the 400 mcg target intake goal is necessary to make the caution 
statement understandable. The agency advises, however, that 
manufacturers wishing to include reference to the 400 mcg intake goal 
may do so (Sec. 101.79(c)(3)(iv)).
    i. Caution statement on all products with >25 percent DV.
    34. One comment interpreted the proposed regulation to mean that 
the agency was proposing to require use of a caution statement on all 
products with more than 100 mcg folate/serving, whether or not they 
bore the health claim.
    This comment misunderstood the proposal. The agency advises that it 
is requiring that the caution statement be used only on conventional 
foods or dietary supplements that bear the folate/neural tube defects 
health claim and that contain more than 100 percent of the DV (400 mcg 
when labeled for use by the general population or 800 mcg when labeled 
for use by pregnant or lactating women).
    j. Warnings on supplements without adequate vitamin B12.
    35. One comment suggested that the agency should require warnings 
on supplements that do not provide amounts of vitamin B12 adequate to 
provide protection from the potential problem in nearly all cases.
    This comment was based on the assumption that the greatest 
potential for adverse effects of high folate intake is the masking of 
the anemia of vitamin B12 deficiency, with continued progression 
of neurologic damage, and that provision of oral vitamin B12 will 
negate this concern. The comment did not provide data or information 
identifying the amount of oral vitamin B12 that would protect 
nearly all persons from masking of a vitamin B12 deficiency and, 
thus, the level below which a warning statement would be required.
    The agency disagrees with this suggestion. The agency is aware that 
very high doses of vitamin B12 (e.g., about 1 mg; 500 times the 
RDI for this vitamin) without intrinsic factor (i.e., without the 
protein factor necessary for the absorption of vitamin B12 and the 
factor whose lack causes pernicious anemia) have provided adequate 
treatment for some persons with pernicious anemia (Ref. 45). It has 
been suggested, based in part on observations that some patients with 
pernicious anemia can be maintained on oral vitamin B12, that high 
doses of vitamin B12 be added to foods and dietary supplements 
fortified with folic acid to reduce the potential for adverse effects 
in persons with vitamin B12 deficiency.
    Several experts at a CDC meeting on surveillance for adverse 
effects of increased intakes of folate (Ref. 26) commented on this 
suggestion. One expert noted 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.
    In the 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, specifically data, 
on the appropriateness, potential effectiveness, and safety of such 
fortification. The agency did not receive data or other information on 
this issue.
    Given this lack of information, FDA finds no basis to require a 
warning statement on supplements based on their content of vitamin 
B12 because there are no data on the effects of various folate/
vitamin B12 combinations on which to base a warning. In addition, 
relating a caution statement only to the vitamin B12 content of a 
product would fail to recognize the potential adverse effects of 
increased folate intakes on other population groups, including, as 
discussed above, pregnant women, children, those on antiepileptic 
medications, and those on antifolate medications, because it would fail 
to recognize that potential adverse effects of increased intakes are 
not limited only to those with vitamin B12-related problems.
    Because data are not available that address for the general 
population on the issue of simultaneous fortification of foods or 
dietary supplements with both folate and vitamin B12, the agency 
cannot establish a level of oral vitamin 

[[Page 8772]]
B12 that is sufficient to protect most persons with vitamin 
B12-related problems from the adverse effects of increased intakes 
of folate. In addition, questions regarding the appropriateness, 
potential effectiveness, and safety of such an approach remain 
unanswered. Vitamin B12 deficiency, including pernicious anemia, 
is a serious condition, which, if untreated, can lead to irreversible 
neurological damage. Regardless of the widespread availability of oral 
vitamin B12 preparations, patients with pernicious anemia, and 
others at risk of vitamin B12 deficiency, should be diagnosed, 
treated, and monitored by a physician (Ref. 45).
6. Multifactorial Nature of Neural Tube Defects
    The general requirements for health claims for conventional foods 
(Sec. 101.14(d)(2)(iii)) provide that, where factors other than dietary 
intake of the substance affect the relationship between the substance 
and the disease or health-related condition, FDA may require that such 
factors be addressed in the health claim. FDA has decided that health 
claims on dietary supplements should be subject to the same requirement 
(see 59 FR 395 at 425).
    It is well-recognized that neural tube defects have many causes, 
some of which are not related to folate status. Genetic and 
environmental factors contribute to the multifactorial nature of neural 
tube defects. Environmental factors associated with neural tube defects 
include, for example, maternal health, maternal family history of 
neural tube defects, and maternal use of certain antiseizure 
medications (see 58 FR 53254 at 53258 for references).
    FDA discussed the multifactorial nature of neural tube defects in 
several sections of its proposed rule. In proposed Sec. 101.79(b)(1), 
FDA discussed the fact that neural tube defects are caused by many 
factors and also noted that a significant risk factor is a personal or 
family history of a pregnancy affected by a neural tube defect. In 
Sec. 101.79(c)(2)(i)(D), FDA proposed to require that claims state that 
neural tube defects have many causes, and that claims not imply that 
folate intake is the only recognized risk factor for neural tube 
defects. The agency included language to this effect in the agency's 
proposed model claims (Sec. 101.79(d)).
    The agency received several general comments and new data in 
response to the sections of the proposed codified language addressing 
the multifactorial nature of neural tube defects.
    a. General comments.
    36. Several comments agreed that the claim should include 
information on the multifactorial nature of neural tube defects to be 
consistent with claims for other diet-disease relationships. These 
comments asserted that the claims would be misleading if such 
information were not included. Other comments disagreed that the 
multifactorial nature of neural tube defects should be recognized in 
the claim because, for example: (1) Folate is the most important risk 
factor, or (2) there is no educational value in identifying the 
multifactorial nature of the condition. Another comment stated that 
only factors that can be controlled, or those on which women could take 
action, should be included in the claim.
    FDA is in the process of reconsidering the need to include in 
health claims the fact that the disease that is the subject of the 
claim has many causes. In the January 1993 final rules on health 
claims, FDA included this fact as a required element of the claim. 
However, as discussed below, FDA has come to tentatively conclude, at 
least in part in response to a petition from the National Food 
Processors Association (Docket No. 94P-0390), that, at least for most 
claims, a statement about their multifactorial etiology adds length to 
the claim without conveying information that would directly affect the 
dietary choices of the consumers.
    The agency is particularly concerned that manufacturers will be 
disinclined to use unnecessarily lengthy health claims on food labels, 
that additional verbiage may detract from the central consumer message 
of the claim, and that, as a result, health claims will be infrequently 
used, and the benefits of communicating information on diet-disease 
relationships to consumers through such claims will not be realized.
    The issue of manufacturers' reluctance to use lengthy health claims 
is particularly significant in the case of the folate/neural tube 
defects health claim because this topic has received much less 
attention than has been given to chronic illnesses such as 
osteoporosis, heart disease, and cancer. The lower level of public 
familiarity with this topic was confirmed in a recent survey conducted 
for the March of Dimes Birth Defects Foundation regarding knowledge and 
practices of women of childbearing age in the United States with 
respect to consumption of folic acid from supplements and breakfast 
cereals (Ref. 53).
    During January and February 1995, the Gallup Organization conducted 
for the March of Dimes a proportionate, stratified random-digit-dialed 
telephone survey of a national sample of 2,010 women aged 18 to 45 
years. The response rate was 50 percent. Estimates were statistically 
weighted to reflect the total population of women aged 18 to 45 years 
in the continental United States. In response to the question ``Have 
you ever heard or read anything about folic acid?'', 52 percent of 
women reported ever hearing of or reading about this nutrient. Of 
these, 9 percent answered that folic acid helps to prevent birth 
defects and 6 percent that folic acid helps to reduce the risk for 
spina bifida; 45 percent were unable to recall what they had heard or 
read. Fifteen percent of respondents reported having knowledge of the 
PHS recommendation regarding the use of folic acid; 4 percent reported 
that the recommendation was for prevention of birth defects and 1 
percent, for the prevention of spina bifida (Ref. 52).
    Respondents were also asked ``From what you know, is there anything 
a woman can do to reduce her risk of having a baby with birth 
defects?'' A total of 88 percent of respondents reported that a woman 
can help reduce the risk for having an infant with birth defects. The 
most common responses about how to reduce risk were avoiding alcohol 
and drugs (73 percent), and not smoking (63 percent); 1 percent of 
women reported that folic acid could reduce risk.
    This study found that while most women interviewed recognized that 
there were a number of factors that might affect their risk of having a 
baby with a birth defect, there was a low level of awareness that 
consumption of folate from supplements, breakfast cereals, and other 
foods may specifically help to reduce their risk of a neural tube 
defect-affected pregnancy.
    The results of the March of Dimes survey are consistent with recent 
findings by FDA. As part of FDA's ongoing review of its regulations 
governing health claims, the agency conducted six focus groups in May 
and June 1995 to evaluate consumer understanding of health claim 
messages. In a report on these focus groups, Levy (Ref. 54) noted that 
while almost all participants were aware of health effects of fat, 
calcium, and fruits and vegetables, very few had heard much about folic 
acid. Participants appreciated information provided in the folate/
neural tube defects model claims but considered it insufficient to 
inform them as adequately as they wished to be informed.
    Thus, recently available information suggests that there is a low 
level of awareness of the potential impact that 

[[Page 8773]]
increased folate intake may have on the risk of a serious type of birth 
defect.
    The agency has concluded, based in part on the studies mentioned 
above, that the need to provide a succinct health claim in this topic 
area is very important. Succinctness in the claim will increase the 
likelihood that firms will use it and thus will increase its 
educational value. To facilitate the use of such a claim by 
manufacturers, it needs to be no longer than necessary to convey the 
central consumer message.
    With respect to the issue of whether explicit identification of the 
multifactorial nature of neural tube defects is necessary to prevent 
the folate/neural tube defects health claim from being misleading, the 
agency notes that use of the term ``may reduce'' in the claim describes 
the potential of folate to affect the risk of neural tube defects and 
serves to reflect the multifactorial nature of this birth defect. In 
addition, data obtained in the March of Dimes survey described above 
indicate that many women already recognize that birth defects in 
general may have many causes. The agency has therefore concluded that 
explicit reference to ``may have many causes'' is redundant when 
included with the phrase ``may reduce.''
    The agency has concluded that it is not necessary to include 
explicit reference to the multifactorial nature of neural tube defects 
in the claim.
    The agency notes, however, that the fact remains that neural tube 
defects are multifactorial in nature. This fact is confirmed by new 
data of which FDA has become aware and that are discussed in the 
following section. Because of this fact, the claim must not imply that 
folate intake is the only risk factor for these birth defects.
    Therefore, the agency is modifying Sec. 101.79(c)(2)(i)(D) by 
deleting the requirement that the claim state that neural tube defects 
have many causes but is retaining the requirement that claims shall not 
imply that folate intake is the only recognized risk factor for neural 
tube defects.
    The agency is also advising that manufacturers who wish to do so 
may include, on an optional basis, information in the claim on 
additional risk factors for neural tube defects. Information that may 
be included is described in Sec. 101.79(c)(3)(i).
    b. Data received in comments. 1. The agency received new data from 
an Irish study that found that plasma levels of vitamin B12, as 
well as folate, were independent risk factors for neural tube defects 
(Ref. 51). These data were reviewed at the October 14 and 15, 1993, 
meeting of the Folic Acid Subcommittee and are summarized here because 
the agency did not have the data in sufficient time to include them in 
its October 14, 1993, proposed rule. Kirke et al. (1993) (Ref. 51) 
compared values for plasma folate, plasma vitamin B12, and red 
blood cell folate in 81 women who had a neural tube defect-affected 
pregnancy and 247 control women. Values for all three parameters were 
significantly lower in case mothers than in control mothers. Plasma 
vitamin B12 and red cell folate were both significantly positively 
correlated in case mothers but not in control mothers. Multiple 
regression analysis showed that plasma vitamin B12 and plasma 
folate were independent predictors of red cell folate in case mothers 
but not in control mothers.
    The authors concluded that plasma vitamin B12 and plasma 
folate were independent risk factors for neural tube defects and 
suggested that the enzyme methionine synthetase was involved directly 
or indirectly in the etiology of neural tube defects. They noted that 
the correlation between plasma vitamin B12 and red cell folate, 
observed in case mothers only, was difficult to explain on a purely 
nutritional basis and favored the etiology of neural tube defects as 
being the result of some metabolic abnormality in the mother, and 
possibly in the embryo, interacting with maternal plasma levels of 
folate and vitamin B12 (Ref. 50).
    Mooij et al. (Ref. 46) measured levels of seven vitamins in blood 
of women who had a neural tube defect-affected pregnancy and reported 
that such measurements were not suitable for identifying women at high 
risk of another affected pregnancy. The authors hypothesized that the 
effect of folic acid was attributable, at least in part, to its 
overriding a metabolic disorder.
    2. The agency received additional new data in a comment relating to 
a possible role of a deficiency of one or more antioxidant enzymes in 
the development of neural tube defects. The comment discussed the 
hypothesis that a genetic defect in antioxidant enzyme systems that 
protect neuronal membranes from excessive lipid peroxidation may play a 
role in the etiology of neural tube defects. The comment noted that 
abnormalities of the neural tube have been documented in cultured rat 
embryos exposed to oxygen radicals generated in vitro by xanthine plus 
xanthine oxidase. The severity of these abnormalities, which increases 
in a dose-responsive manner with exposure to xanthine oxidase, can be 
moderated by substances with known antioxidant activity such as 
glutathione, catalase, L-ascorbic acid (vitamin C), or DL-alpha 
tocopherol (vitamin E).
    This comment provided the results of a pilot study that tested the 
hypotheses in children with neural tube defects and their immediate 
families. In testing the hypothesis, the investigators assessed a 
number of red blood cell free radical- scavenging enzymes in eight 
families with one or more children with the neural tube defect 
meningomyelocele. Seventeen healthy adults without a history of neural 
tube defects served as controls. All meningomyelocele-affected children 
were found to be deficient in red blood cell glutathione peroxidase, 
with 5 in the range of moderately to severely deficient. At least one 
parent of seven of the eight affected children was deficient in red 
blood cell glutathione peroxidase activity, with four of seven in the 
moderately to severely deficient range. Nine additional children with 
meningomyelocele or other neural tube defects (specifically, 
encephalocele and iniencephaly) were also studied. Red blood cell 
glutathione peroxidase activities were low in all of the nine 
additional affected children, with values in six of the nine in the 
moderately to severely deficient range.
    The comment also noted that pterin aldehyde, a contaminant that may 
be present at a level of about 4 percent in commercially available 
folic acid preparations, may reduce exposure of the developing neural 
tube to toxic oxygen free radicals through its activity in inhibiting 
xanthine oxidase. The comment suggested (Comment 68H to docket 93N-
100H) that a combination of genetic factors, deficient antioxidant 
enzyme capacities, exogenous or endogenous teratogens, periconceptional 
diets with inadequate amounts of free radical scavenging substances, or 
suboptimal concentrations of pterin aldehyde-like agents may provide 
further explanations for tissue-specific injury in some pregnancies.
    The comment concluded that, while the mechanisms of neural tube 
defect formation likely fit into a complex ecogenetic model, a 
deficiency of one or more antioxidant enzymes may increase the risk for 
the development of neural tube defects. The comment recommended further 
study to determine whether reduced antioxidant activity predisposes the 
embryo to the development of neural tube defects.
    c. Data that were published after the close of the comment period. 
1. Mills et al. (1995) (Ref. 47) reported that women with neural tube 
defect-affected pregnancies had significantly higher levels of 
homocysteine than did vitamin B12-matched controls. Mills et al. 
(1995) 

[[Page 8774]]
(Ref. 47) noted that their study showed that an abnormality of 
homocysteine metabolism, apparently related to methionine synthase, is 
present in many pregnancies that resulted in neural tube defects.
    2. Mechanistic studies in cultured rat embryos have also provided 
insights into roles for nutrients in addition to folate in the etiology 
of neural tube defects. Chambers and coworkers identified 
autoantibodies (i.e., antibodies directed against tissue components of 
the same organism) to the extracellular basement membrane (i.e., the 
noncellular layer underlying the epithelium) protein laminin as an 
agent that caused neural tube defects in whole embryo cultures (see 
Ref. 48 for additional references). Such antibodies were found 
initially in the embryotoxic sera of monkeys with poor reproductive 
histories. Chambers et al. (1995) (Ref. 48) recently reported that 
methionine overcomes neural tube defects in rat embryos cultured on 
sera from monkeys immunized against laminin. The authors noted that the 
association of autoimmune diseases and fetal loss has received closer 
attention in recent years, but that neither the mechanisms of fetal 
loss nor treatments have been well defined (Ref. 48). The authors 
suggested that epidemiologic studies are needed to establish a possible 
role for autoantibodies in the etiology of neural tube defects and to 
determine the efficacy of methionine supplementation in overcoming such 
defects.
    3. Data addressing the etiologic heterogeneity of neural tube 
defects were also derived from observations that infants and fetuses 
with isolated neural tube defects have different risk factors than 
those with neural tube defects occurring with other birth defects and 
from reported differences in recurrence risks for neural tube defects 
based on the level of the affected infant's defect (Ref. 49; Shaw et 
al., 1994, for references). Shaw et al. (1994) (Ref. 49), used 
population-based case ascertainment by the California Birth Defects 
Monitoring Program in an ethnically diverse population of more than 
700,000 live births and fetal deaths to investigate whether 
heterogeneity existed among various anatomic and pathogenetic 
subclasses of neural tube defects for a variety of commonly collected 
child and parental characteristics. Among cases of anencephaly, 
increased risks were found for Hispanic white women with risk estimates 
highest for nonisolated cases. This population-based study showed 
increased risk for Hispanic women specifically among subclassifications 
of neural tube defects, and provides some evidence that further 
classification of neural tube defects may reveal subgroupings of cases 
with different etiologies.
    Shaw et al. (1995) (Ref. 50) used a case-control study design (549 
cases and 540 controls) to investigate whether intake of supplemental 
folic acid or dietary folate reduced the risk of a neural tube defect-
affected pregnancy (Ref. 50). The authors found that women with any use 
of a folic acid-containing vitamin in the 3 months prior to conception 
had a lower risk of having an NTD-affected pregnancy. Odds ratios were 
similar for average daily folic acid intakes of <400 mcg, 400 to 900 
mcg, and >900 mcg/day, and thus, no dose-response pattern was apparent. 
Use of 400 to 900 mcg folic acid/day in the 3 months after conception 
was also associated with reduced risk of a neural tube defect-affected 
pregnancy. The authors also observed that women who did not begin using 
a folic acid- containing vitamin until the second trimester of 
pregnancy also had a reduced risk of neural tube defects and suggested 
that although the finding may be indicative of errors in reporting 
vitamin use in general, it also weakens the attribution of a direct 
preventive effect of folate on neural tube defects in the study 
population (Ref. 50).
    When race/ethnicity were considered, nonHispanic white women who 
used a folic acid-containing vitamin in the 3 months before conception 
had a reduced risk of a neural tube defect-affected pregnancy. However, 
risk of a neural tube defect-affected pregnancy was not reduced in 
Hispanic women who consumed a folic acid-containing vitamin in the 3 
months before conception. The overall results of this study are 
consistent with other studies showing associations between folate 
intake and reduced risk of neural tube defects. However, the data also 
suggest that the folate-associated reduction in risk may be specific to 
subsets of the population, primarily nonHispanic women (Ref. 50).
    These recent studies are of significance for the insights that they 
provide into understanding the multifactorial etiology of neural tube 
defects. They support the hypothesis that neural tube defects are not 
the result of a wide-spread nutritional deficiency of folate in the 
U.S. population but may result from metabolic defects or other 
physiologic conditions affecting a small part of the population. These 
new data support FDA's decision to require that claims not imply that 
folate intake is the only recognized risk factor for neural tube 
defects.
7. Prevalence Statements
    In Sec. 101.79(c)(2)(i)(E), the agency proposed to require that the 
claim provide information that neural tube defects ``while not 
widespread, are extremely significant.'' Because the affected 
population is few in number and not readily identifiable, FDA proposed 
to require that this information be disclosed to prevent women from 
being misled into believing that neural tube defects are very common 
birth defects, or that, lacking a personal or family history of such 
defects or other recognized risk factors, their risk of having a 
pregnancy affected with such a birth defect is very high.
    37. The agency received a number of comments on the proposed 
prevalence statement. Some comments stated that the wording ``while not 
widespread'' was not clear, and one comment suggested use of 
``uncommon'' rather than ``while not widespread'' in describing the 
prevalence of neural tube defects. One comment noted that statements 
indicating that neural tube defects had a low prevalence in the United 
States would discourage women from taking folic acid supplements 
because women would believe that the health claim is not applicable to 
them, and they would be misled into not taking the health claim 
seriously. One comment noted that there is no standard for the proposed 
term ``not widespread.'' One comment noted that because the behavior 
intended to result from authorization of the health claim was to have 
women consume more folic acid, qualifiers regarding prevalence of the 
condition had no educational benefit. One comment, noting that 
statements regarding the extent of the disease-related conditions were 
optional in other approved health claims, and that the rarity of spina 
bifida and related birth defects is obvious to virtually all consumers, 
urged the agency to make prevalence statements optional in the folate/
neural tube defect claim.
    The Folic Acid Subcommittee also commented on issues of prevalence 
and demographics of neural tube defects at all of its meetings (e.g., 
Ref. 8). The Folic Acid Subcommittee discussed the decline in the rate 
of neural tube defects from a high in Boston in the 1930's of 5 per 
1,000 births to the current overall U.S. rate of about 0.6 per 1,000 
births (i.e., about 2,500 cases/year in the United States). In 
addressing the prevalence of neural tube defects among different ethnic 
groups, one Folic Acid Subcommittee member noted that African-American 
women have a rate lower than the overall U.S. rate, while Mexican-
American women have a rate 

[[Page 8775]]
about two and one-half times the national average. The participant also 
noted that there is about a two- fold higher rate among women in lower 
socio-economic groups than among those in higher socio-economic groups 
(Ref. 8).
    The agency has reviewed the comments that it received and agrees 
that use of the proposed wording ``while not widespread'' is not clear 
because it is not quantitative. The agency notes that even though the 
occurrence of neural tube defect-affected pregnancies is low, the 
population at risk may be quite large because about half of pregnancies 
are unplanned. Therefore, the agency concludes that a statement of 
prevalence is not a material fact in light of the other statements made 
in the claim. For this reason, the agency concludes that it is not 
necessary to require that the claim state that the prevalence of neural 
tube defects is low to ensure that the claim is not misleading. 
Therefore, the agency is deleting the requirement proposed in 
Sec. 101.79(c)(2)(i)(E) and redesignating subsequent sections as 
discussed below and as shown in the codified language.
    However, given the other comments cited above and its discussions 
with the Folic Acid Subcommittee, the agency does not agree that there 
would be no educational benefit from providing prevalence information 
in the health claim. The agency concludes, based on the comments above, 
that prevalence information can be useful to consumers because it can 
provide a context that increases understanding of how frequently neural 
tube defects actually occur among pregnancies in the U.S. population.
    The agency recognizes that it has provided for inclusion, on an 
optional rather than required basis, in other authorized health claims 
of information on the number of people in the United States who have 
the health-related condition (e.g., see saturated fat and 
cardiovascular disease claim and dietary fiber and cancer claims). 
Thus, in response to the comments above, and consistent with other 
authorized health claims, FDA, in Sec. 101.79(c)(3)(v), is authorizing 
the use of optional statements to provide the estimated numbers on an 
annual basis of neural tube defect births among live births to women in 
the general U.S. population. Currently, this estimate is 0.6 cases per 
1,000 live births, or 6 cases per 10,000 live births, or about 2,500 
cases among 4 million live births, or about 1 case per 1,600 live 
births. These estimates are based on information for the U.S. 
population from PHS. FDA finds, based on a review of how such 
statistics are generally presented, that expressing this information as 
the estimated annual number of neural tube defects per a specified 
number of births (e.g., per 1,000 live births or per 10,000 live 
births) will help to make this information as useful as possible. 
Section 101.79(c)(3)(v) provides for use of these estimates unless more 
current estimates from PHS become available, in which case, the newer 
estimates may be used.
8. Quantifying Risk Reduction
    In Sec. 101.79(c)(2)(i)(F), the agency proposed that the claim 
contain a statement that some women may reduce their risk of a neural 
tube defect-affected pregnancy by maintaining adequate folate intake 
during their childbearing years. Such a statement is consistent with 
the estimate provided in the PHS recommendation that about half of 
neural tube defects (i.e., about 1,250 annually) might be averted if 
all women of childbearing age in the United States who are capable of 
becoming pregnant consumed 0.4 mg of folate daily throughout their 
childbearing years. FDA tentatively concluded that such a statement is 
necessary to ensure that women do not conclude on the basis of the 
claim that adequate intake of folate will prevent all occurrences of 
neural tube defects. The agency also proposed in 
Sec. 101.79(c)(2)(i)(F) that the claim not attribute any specific 
degree of reduction in risk of neural tube defects to maintaining an 
adequate folate intake throughout the childbearing years.
    38. Several comments agreed with the agency that a specific degree 
of reduction in risk should not be stated in the health claim. Other 
comments noted that while occurrence of neural tube defects will be 
averted by only some women, the risk of occurrence will be reduced for 
the population. Other comments objected to the proposal to prohibit use 
of the PHS estimated percent risk reduction of 50 percent. Some 
comments argued that the 50 percent estimate should be stated because 
it was a scientific finding, and that failure to include this estimate 
could have a negative effect on how much effort women make to ensure 
that they have adequate folate intake. Another comment stated that the 
estimate of 50 percent reduction should be included because it is 
preferable for women to know the exact benefit of folic acid rather 
than to be informed that ``some but not all women may benefit.''
    The agency disagrees with comments that the PHS estimate of 50 
percent is a scientific finding and represents an exact benefit 
achievable by all women who consume adequate folate daily throughout 
their childbearing years. The PHS recommendation states that the 50 
percent estimate was derived from studies that associated recalled use 
of folic acid-containing multivitamins with reduced risk of neural tube 
defect-affected pregnancies and states that ``the protective effect 
found in the studies of lower-dose folic acid, measured by the 
reduction in neural tube defect incidence, ranged from none to 
substantial'' (Ref. 5) (emphasis added). The PHS recommendation also 
noted that:

    It is expected that consumption of adequate folic acid will 
avert some, but not all, neural tube defects. The underlying causes 
of neural tube defects are not known. Thus, it is not known what 
proportion of neural tube defects will be averted by adequate folic 
acid consumption. From the available evidence, CDC estimates that 
there is the potential for averting 50 percent of cases that now 
occur. However, until further research is done, no firm estimate of 
this proportion will be available (Ref. 5).

    The agency also notes that there may be minimal or no effect of 
periconceptional use of folate in areas of low prevalence or in areas 
where other factors are contributing to an increased prevalence. This 
observation is consistent with scientific evidence that shows that, in 
an area of low prevalence in the United States, women who consumed 
folate from multivitamins or fortified breakfast cereals did not have a 
lower risk of having a neural tube defect-affected pregnancy than did 
women who did not consume multivitamins or fortified breakfast cereals 
(Ref. 12; Mills et al.).
    Thus, the estimate of a potential for a 50 percent reduction in 
neural tube defect-affected pregnancies, if all women consumed adequate 
folate throughout their childbearing years, is not a scientific finding 
and may not be applicable to estimating potential risk reduction in 
areas of low prevalence. The agency notes further that the estimate of 
50 percent is not applicable to risk reduction that might be 
experienced by individual women, whose personal risk factors are not 
fully understood. In addition, the estimated proportion may change with 
the availability of new scientific data and information. The agency 
recognizes, however, that manufacturers may wish to use the PHS 
recommendation, including the estimate of the potential for a 50 
percent reduction in the incidence of neural tube defects, as labeling 
for folate-containing products. The agency also notes that there is 
considerable potential for making a misleading claim if such 
information is not presented in an accurate context. 

[[Page 8776]]

    The agency has concluded that an estimate of potential risk 
reduction can be included in the health claim because it may help some 
consumers better understand the potential population-based impact on 
neural tube defect-affected pregnancies if all women consumed adequate 
folate throughout their childbearing years. Therefore, FDA is providing 
in Sec. 101.79(c)(2)(i)(E) that population-based estimates of risk 
reduction may be included in the claim so long as the claim makes clear 
that the estimate does not reflect risk reduction that may be 
experienced by individual women. Provision of such information will 
reduce the likelihood of women being misled that adequate folate intake 
will prevent an occurrence of a neural tube defect-affected pregnancy.
    The agency has revised Sec. 101.79(b)(3) to provide information 
from the PHS recommendation that explains how the estimate of a 
potential for reduction in incidence of neural tube defects of 50 
percent was derived and provides the context in which the estimate can 
be understood by individual women.
    FDA has also redesignated proposed Sec. 101.79(c)(2)(i)(F) as 
Sec. 101.79(c)(2)(i)(E) and revised this section to remove the 
prohibition against use of the PHS estimate. Section 101.79(c)(2)(i)(E) 
includes reference to new Sec. 101.79(c)(3)(vi) which provides for 
optional inclusion of statements about population-based estimates of 
risk reduction. The requirement that claims state that some women may 
reduce their risk of a neural tube defect-affected pregnancy through 
adequate intake of folate throughout their childbearing years is 
retained in Sec. 101.79(c)(2)(i)(E).
    New Sec. 101.79(c)(3)(vi) states that an estimate of the reduction 
in the number of neural tube defect-affected births that might occur in 
the United States if all women consumed adequate folate throughout the 
childbearing years (i.e., 50 percent) may be included in the claim if 
such an estimate is accompanied by information that states that it is a 
population-based estimate and does not reflect reduction in risk that 
may be experienced by individual women. New Sec. 101.79(c)(3)(vi) also 
provides for use in the claim of information in revised 
Sec. 101.79(b)(3).
9. Optional Health Claim Information
    In Sec. 101.79(c)(3)(i), the agency proposed to permit 
manufacturers, in addition to including the fact that neural tube 
defects have many causes, to specifically identify risk factors for 
neural tube defects. The agency stated that specific examples of other 
risk factors include a personal history of such a defect, maternal 
diabetes mellitus, use of the antiepileptic drug valproic acid, 
maternal febrile illness, or a close relative with a neural tube defect 
(Sec. 101.79(b)(1) and (b)(2)). The agency requested comments on 
whether such additional information would be useful to consumers.
    a. Identifying other risk factors.
    39. Some comments expressed the opinion that most of the optional 
information was helpful, while others stated that there was no 
educational value in identifying the multifactorial nature of neural 
tube defects, and that women cannot control other risk factors.
    The agency disagrees with the comments that stated that 
identification of other risk factors would not be helpful to women. 
Certain conditions, such as diabetes mellitus, are known to increase a 
woman's risk of a neural tube defect-affected pregnancy. Identification 
of these risks in the claim may serve to alert some women to their 
higher risk and encourage them to seek advice from their health care 
providers before becoming pregnant.
    The agency is providing in Sec. 101.79(c)(3)(i) for the inclusion 
of optional information in the claim. Information in Sec. 101.79(b)(1) 
or (b)(2) or drawn from other parts of Sec. 101.79(c)(3) may be 
included in the claim. Use by manufacturers of factors listed in the 
regulation will ensure that claims will only include scientifically-
based information and will not include information that has not been 
well- documented (e.g., ``Birth defects of the brain or spinal cord may 
have many causes, such as exposure to pesticides * * *'').
    b. Consult a physician. In Sec. 101.79(c)(3)(iii), the agency 
proposed that a claim could include a statement that women with a 
history of a neural tube defect pregnancy should consult their 
physicians or health care providers before becoming pregnant. The 
agency tentatively concluded that such a statement would encourage such 
women to obtain medical guidance and thereby decrease their risk of a 
recurrence of a neural tube defect- affected pregnancy. The available 
data show that women with a history of a neural tube defect-affected 
pregnancy are at very high risk of another affected pregnancy (e.g., 
risk of a recurrence of a neural tube defect pregnancy is significantly 
greater than risk of an occurrence of this birth defect). The agency 
requested comments on whether provision of such information would be 
helpful to consumers.
    40. The agency received several comments on this proposed optional 
information. All comments that addressed this issue recommended that it 
be broadened to include all women rather than only those with a 
personal history of a neural tube defect- affected pregnancy. Comments 
stated that prenatal care was critical for all women and suggested that 
health claims should include a statement that all women planning a 
pregnancy should consult a physician or health care provider for 
information about adequate diets for their and their babies' health. 
Several comments suggested that such a statement be mandatory rather 
than optional.
    FDA does not believe that it is appropriate, in general, for health 
claims to bear statements concerning the need to seek medical advice 
for treating the disease or health-related condition mentioned in the 
claim. The agency is concerned that the appearance of a statement 
concerning the treatment of a disease on the label of a food could 
mislead some consumers to believe that the food possesses therapeutic 
value for an existing disease or health-related condition (58 FR 2478 
at 2514).
    The agency originally proposed such a statement regarding women at 
recurrent risk of a neural tube defect-affected pregnancy because their 
risk of recurrence is very high, and because a specific recommendation 
from PHS has been made to such women when they are planning a pregnancy 
(i.e., they are advised to take 4 mg folic acid daily under a 
physician's supervision; Ref. 52).
    Because all comments favored broadening the advice to include all 
women, and because the agency recognizes that it is important for all 
women to consult a health care provider before becoming pregnant, the 
agency is persuaded to modify Sec. 101.79(c)(3)(iii) as suggested in 
the comments and to provide for claims to include, in addition to a 
statement regarding women at recurrent risk of a neural tube defect, a 
statement that all women should consult a health care provider before 
becoming pregnant (e.g., ``Women, including those with a history of a 
neural tube defect pregnancy, should consult their health care provider 
when planning a pregnancy.'').
    However, because the length of claims has been consistently a 
concern of the comments, the agency is not persuaded that the 
information provided for in Sec. 101.79(c)(3)(iii) should be required 
in all health claims, as suggested by one comment above. 10. Model 
Health Claims
    FDA provided several model claims in the proposal that contained 
the elements described in its proposal. The agency included these model 
claims to 

[[Page 8777]]
assist manufacturers in formulating appropriate claims.
    a. Toll-free number, pregnancy information symbol.
    41. Several comments stated that less detailed model claims were 
needed and proposed that the agency establish a toll-free 800 number 
through which women could obtain more information or recommended that 
the agency devise a uniform pregnancy information symbol for food 
labels that would alert women to look for products that bear the 
symbol.
    The agency agrees that educational information is of great 
importance in increasing awareness among women of the need for adequate 
nutrition, including adequate folate intake, during their childbearing 
years. The agency is considering how best to evaluate consumer 
understanding of the health claim and is working with other PHS 
agencies to develop strategies to implement the PHS recommendation on 
folate intake.
    With respect to the use of a pregnancy information symbol, the 
agency noted above that many pregnancies are unplanned, and for this 
reason, women need to be informed of the need for adequate nutrition 
throughout their childbearing years. While a pregnancy symbol might 
draw the attention of women who are already pregnant or who might be 
planning a pregnancy, it may not be helpful to women whose pregnancies 
are unplanned or to women whose pregnancies are too far advanced for 
folate intake to alter their risk of giving birth to a neural tube 
defect-affected infant. Such a symbol may also discourage other women 
from using the product because they do not think they will become 
pregnant.
    The agency also notes that many of the foods that will bear the 
health claim will be consumed by the general population, and the 
appearance of a pregnancy symbol on the label might be incorrectly 
interpreted by some consumers to mean that the product is specifically 
intended for use in pregnancy.
    For these reasons, the agency is not persuaded to use a pregnancy 
symbol with the health claim.
    b. General comments.
    42. Many comments criticized the length of the model claims and 
their required components. Comments stated that the model messages were 
too lengthy and complex and unwieldy, and that therefore manufacturers 
would be disinclined to use them. Other comments noted that the claims 
included unnecessary disclosures and requested that FDA remove the 
requirements relating to the multifactorial nature of neural tube 
defects, sources of folate other than dietary supplements, and the 
caution statement. Several comments, stating that the model claims were 
overly focused on foods, urged the agency to develop a condensed claim 
for dietary supplements and suggested that such a claim should not need 
to identify other sources of folate or state a maximum daily limit on 
intake.
    Another comment noted that in formulating the claim, the agency 
should be guided by the need to communicate the benefits of increased 
folate intake from food sources or dietary supplements, and that the 
message must also convey proper cautions, including the fact that 
increased folate intake will not prevent all birth defects or even all 
neural tube defects. Several comments praised portions of the model 
claims that required disclosure of the multifactorial nature of neural 
tube defects and the inclusion of information regarding sources of 
folate. One comment recommended that claims use the information in the 
PHS recommendation, including the warning statement, as closely as 
possible. Several comments noted that the model claims were not 
educationally strong enough, while others recognized the problem of 
providing the guidance that needs to be included in the claim without 
having the claim become so long as to be unusable. Some comments 
provided examples of shorter claims that they proposed as more 
appropriate than the agency's model claims.
    As discussed in the proposal and elsewhere in this final rule, 
certain information is needed in the health claim, whether for 
conventional foods or for dietary supplements, for such claims to be 
truthful, scientifically valid, and not misleading to segments of the 
population that are not at high risk of having a neural tube defect-
affected pregnancy or for whom no link between folate intake and risk 
of neural tube defect-affected pregnancies has been established.
    The agency has addressed the issues of mandatory requirements 
relating to the multifactorial nature of neural tube defects, sources 
of folate other than dietary supplements, and the caution statement in 
response to comments 36, 21, and 32, respectively. The agency disagrees 
that all of these elements should be removed. Specifically, the agency 
has discussed in response to comment 36 why claims shall not imply that 
folate intake is the only risk factor for neural tube defects. In 
response to comments 28 through 34, the agency explained why a caution 
statement is necessary, as well as its reasoning in limiting the 
requirement for such a statement to very narrow circumstances. The 
agency in response to comments has dropped the requirement that sources 
of folate be identified in the claim and instead has provided for 
optional inclusion of such information.
    The agency also disagrees that its proposed model claims were 
overly focused on foods because each of the proposed claims 
specifically identified sources of folate as fruits, vegetables, whole 
grain products, fortified cereals, and dietary supplements.
    The agency rejects the comments that urged it to develop a 
condensed claim for dietary supplements and not identify a safe upper 
limit of daily intake. Throughout its responses to the comments it 
received, the agency has been even-handed in considering conventional 
foods and dietary supplements (comments 29 and 32, above). Since 
increased folate intake is what is of importance, and since a variety 
of dietary sources of folate are available, it would be inconsistent 
with the available evidence for the agency to set different 
requirements for claims on dietary supplements than for claims on 
conventional foods.
    Thus, the agency, in developing this final rule, has been guided by 
the need to communicate the effects on the risk of neural tube defects 
of increased folate intake while providing sufficient cautions to 
prevent claims from being misleading and to ensure that they are 
scientifically valid.
    FDA has modified the model claims to reflect the changes that it 
has made in Sec. 101.79 in response to the comments. The agency has 
sought to illustrate in the model claims that it is possible to fully 
comply with Sec. 101.79 and still produce a claim that uses less than 
30 words (see Examples 1 and 2 in Sec. 101.79(d)). The agency also 
notes that in response to the petition from the National Food 
Processors Association, mentioned above, it is exploring the 
possibility of permitting a shortened version of the claim to appear on 
the front panel of the food label as long as the full claim appears on 
the label. FDA is considering how this can be accomplished while still 
ensuring that there is full compliance with section 403 (a) and (r) of 
the act. FDA anticipates publishing a proposal on these matters in the 
near future.

III. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(11) that this 
action is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, 

[[Page 8778]]
neither an environmental assessment nor an environmental impact 
statement is required.

IV. Economic Impact

    FDA has examined the impacts of this final rule to authorize the 
use on the labels and in the labeling of conventional food and dietary 
supplements of health claims on the relationship between adequate 
folate intake and risk of neural tube birth defects as required by 
Executive Order 12866 and the Regulatory Flexibility Act. Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety effects; 
distributive impacts and equity). The Regulatory Flexibility Act (Pub. 
L. 96-654) requires analyzing options for regulatory relief for small 
businesses. FDA finds that this final rule is not a significant 
regulatory action as defined by Executive Order 12866. In compliance 
with the Regulatory Flexibility Act, the agency certifies that the 
final rule will not have a significant impact on a substantial number 
of small businesses.
    On October 14, 1993, FDA published an analysis of the economic 
impact of the proposed rule under the previous Executive Order (E.O. 
12291). In that analysis, the agency stated that folate health claims 
may result in increased demand for products containing folate, and that 
an increase in consumption of products containing folate is likely to 
result in health benefits in terms of fewer neural tube defects. The 
agency also stated that there would be no costs associated with folate 
health claims as use of these claims is voluntary.
    The agency concluded that it was not able to estimate the number of 
products that will bear health claims, or the effect that folate health 
claims will have on consumer demand for products containing folate, and 
requested comments. As mentioned previously, the agency received nearly 
100 comments in response to the proposed rule on health claims for 
folate and neural tube defects. None of the comments provided 
information that would alter the agency's economic impact conclusion.

V. Collection of Information

    This rule contains no collection of information requirements under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et. seq.).

VI. 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. Food and Nutrition Board, National Research Council, National 
Academy of Sciences, 1980, Recommended Dietary Allowances, 9th 
revised edition, 1980, Washington, DC, pp. 106-113.
2. Flood, T., M. Brewster, and J. Harris, et al., ``Spina Bifida 
Incidence at Birth--United States, 1983-1990,'' Morbidity and 
Mortality Weekly Report, 41(27); 497-500, 1992.
3. Maternal and Child Health Bureau, Health Resources and Services 
Administration, Public Health Service, Lin-Fu, J.S., and M.A. 
Anthony, ``Folic Acid and Neural Tube Defects: A Fact Sheet for 
Health Care Providers,'' May 1993.
4. Elwood, J.M., and J.H. Elwood, ``Epidemiology of Anencephalus and 
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6. Briefing Material, Folic Acid Subcommittee Meeting, April 15, 
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15-16, 1993, Transcript.
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and Editorial, ``Folic Acid and Neural Tube Defects,'' Lancet, 
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Occurrence of Neural-tube Defects by Periconceptional Vitamin 
Supplementation,'' New England Journal of Medicine, 327, 1832-1835, 
1992.
16. Bower, C., and F. J. Stanley, ``Dietary Folate as a Risk Factor 
for Neural Tube Defects: Evidence from a Case-control Study in 
Western Australia,'' Medical Journal of Australia, 150:1257-1261, 
1989.
17. Laurence, K. M., ``Dietary Approaches to the Prevention of 
Neural Tube Defects,'' Nutrition and Health, 2:181-189, 1983.
18. Shils, M. E., J. A. Olson, and M. Shike, In: Modern Nutrition in 
Health and Disease, pp. 412-413, Lea and Febiger, Philadelphia, 
1994.
19. Combs, G. F., In: The Vitamins: Fundamental Aspects in Nutrition 
and Health, pp. 359-360, Academic Press, New York, 1992.
20. Transcript of Meeting, July 27, 1992, CDC, Atlanta, GA, comment 
no. supp.1. to docket 91N-0100, August 8, 1992.
21. Seller, M. J., and N. C. Nevin, ``Vitamins and Neural Tube 
Defects, Letter to the Editor,'' Journal of the American Medical 
Association, 263:2749, 1990.
22. Memo to File from Nancy Crane ``Food Sources of Folate,'' August 
31, 1993.
23. Centers for Disease Control, ``Use of Folic Acid for Prevention 
of Spina Bifida and Other Neural Tube Defects,'' 1983-1991, 
Morbidity and Mortality Weekly Report, 40(30): 513-516, August 2, 
1991.
24. Health Protection Branch, Health and Welfare Canada, Ottawa, 
Ontario, Canada, ``Issues: Folic Acid, The Vitamin That Helps 
Protect Against Neural Tube (Birth) Defects,'' April 2, 1993.
25. March of Dimes, 1994.
26. Centers for Disease Control, Transcript of Meeting, Atlanta, GA, 
August 12, 1993; ``Surveillance for Possible Adverse Effects of 
Folic Acid Consumption.''
27. Sanders, T. A. B., and S. Reddy, ``Vegetarian Diets and 
Children,'' American Journal of Clinical Nutrition, 59:5(S):1176S-
1181S, 1994.
28. Herbert, V., ``Staging Vitamin B12 (Cobalamin) Status in 
Vegetarians,'' American Journal of Clinical Nutrition, 
59:5(S):1213S-1221S, 1994.
29. 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.
30. Davidson, L. S. P., and R. H. Girdwood, ``Folic Acid as 
Therapeutic Agent,'' British Medical Journal, 1:587-591, 1947.
31. Hansen, H. A., and A. Weinfeld, ``Metabolic Effects and 
Diagnostic Value of Small Doses of Folic Acid and B12 in 
Megaloblastic Anemias,'' Acta Medica Scandinavica, 172:427-443, 
1962. 

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32. 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.
33. Stambolian, D., and M. Behrens, ``Optic Neuropathy Associated 
with Vitamin B12 Deficiency,'' American Journal of 
Ophthalmology, 83:465-468, 1977.
34. 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.
35. Ellison, A. B. Curry, ``Pernicious Anemia Masked by 
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Medical Association, 173:240-243, 1960.
36. 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.
37. Victor, M., and A. A. Lear, ``Subacute Combined Degeneration of 
the Spinal Cord,'' American Journal of Medicine, 20:896- 911, 1956.
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of Medicine, 264:1339-1342, 1961.
39. 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.
40. Marshall, R. A., and J. H. Jandl, ``Responses to `Physiologic' 
Doses of Folic Acid in the Megaloblastic Anemias,'' Archives of 
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41. Chosy, J. J., D. V. Clatanoff, and R. F. Schilling, ``Responses 
to Small Doses of Folic Acid in Pernicious Anemia,'' American 
Journal of Clinical Nutrition, 10:349-350, 1962.
42. Hansen, H. A., and A. Weinfeld, ``Metabolic Effects and Diagno 
Stic Value of Small Doses of Folic Acid and B12 in 
Megaloblastic Anemias,'' Acta Medica Scandinavica, 172:427-443, 
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43. Institute of Medicine, National Academy of Sciences, ``Nutrition 
During Pregnancy,'' National Academy Press, Washington, DC, 1990.
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Stabler, and R. H. Allen, ``Prevalence of Cobalamin Deficiency in 
the Framingham Elderly Population,'' American Journal of Clinical 
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W. H. Doesburg, and T. K. A. B. Eskes, ``Periconceptional Vitamin 
Profiles Are Not Suitable for Identifying Women at Risk for Neural 
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47. Mills, J. L., J. M. McPartlin, P. N. Kirke, Y. J. Lee, M. R. 
Conley, D. G. Weir, and J. M. Scott, ``Impaired Homocysteine 
Metabolism in Pregnancies Complicated by Neural Tube Defects,'' 
Lancet, 345:149-151, 1995.
48. Chambers, J. B., Norman W. Klein, P. G. Nosel, L. H. Khairallah, 
and James S. Romanow, ``Methionine Overcomes Neural Tube Defects in 
Rat Embryos Cultured on Sera from Laminin-immunized Monkeys,'' 
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``Epidemiologic Characteristics of Phenotypically Distinct Neural 
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Teratology, 49:143-149, 1994.
50. Shaw, G. M., D. S. Schaffer, E. M. Velie, K. Morland, and J. A. 
Harris, ``Periconceptional Vitamin Use, Dietary Folate, and the 
Occurrence of Neural Tube Defects,'' Epidemiology, 6:219-226, 1995.
51. Kirke, P. N., A. M. Molloy, L. E. Daly, H. Burke, D. G. Weir, 
and J. M. Scott ``Maternal Plasma Folate and Vitamin B12 Are 
Independent Risk Factors for Neural Tube Defects,'' Quarterly 
Journal of Medicine, 86:703-708, 1993.
52. Centers for Disease Control, ``Use of Folic Acid for Prevention 
of Spina Bifida and Other Neural Tube Defects; 1983-1991,'' 
Morbidity and Mortality Weekly Report, 40(30):513-516, August 2, 
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``Knowledge and Use of Folic Acid by Women of Childbearing Age--
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1995.

List of Subjects in 21 CFR Part 101

    Food labeling, Nutrition, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
the authority delegated to the Commissioner of Food and Drugs, 21 CFR 
part 101 is amended as follows:

PART 101--FOOD LABELING

    1. The authority citation for 21 CFR part 101 continues to read as 
follows:

    Authority: Secs. 4, 5, 6 of the Fair Packaging and Labeling Act 
(15 U.S.C. 1453, 1454, 1455); secs. 201, 301, 402, 403, 409, 701 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 342, 
343, 348, 371).

    2. Section 101.9 Nutrition labeling of food is amended in paragraph 
(c)(8)(v) by revising the entry for folate to read as follows:


Sec. 101.9  Nutrition labeling of food.

* * * * *
    (c) * * *
    (8) * * *
    (v) * * *
    Folate--either Folic acid or Folacin may be used.
* * * * *


Sec. 101.36  [Amended]

    3. Section 101.36 Nutrition labeling of dietary supplements of 
vitamins and minerals is amended in paragraph (b)(3)(v) by removing the 
words ``folate (folacin),'' and by adding in their place the words 
``folate--either folic acid or folacin may be used.''
    4. Section 101.79 is revised to read as follows:


Sec. 101.79  Health claims: Folate and neural tube defects.

    (a) Relationship between folate and neural tube defects--(1) 
Definition. Neural tube defects are serious birth defects of the brain 
or spinal cord that can result in infant mortality or serious 
disability. The birth defects anencephaly and spina bifida are the most 
common forms of neural tube defects and account for about 90 percent of 
these defects. These defects result from failure of closure of the 
covering of the brain or spinal cord during early embryonic 
development. Because the neural tube forms and closes during early 
pregnancy, the defect may occur before a woman realizes that she is 
pregnant.
    (2) Relationship. The available data show that diets adequate in 
folate may reduce the risk of neural tube defects. The strongest 
evidence for this relationship comes from an intervention study by the 
Medical Research Council of the United Kingdom that showed that women 
at risk of recurrence of a neural tube defect pregnancy who consumed a 
supplement containing 4 milligrams (mg)(4,000 micrograms (mcg)) folic 
acid daily before conception and continuing into early pregnancy had a 
reduced risk of having a child with a neural tube defect. (Products 
containing this level of folic acid are drugs). In addition, based on 
its review of a Hungarian intervention trial that reported 
periconceptional use of a multivitamin and multimineral preparation 
containing 800 mcg (0.8 mg) of folic acid, and its review of the 
observational studies that reported periconceptional use of 
multivitamins containing 0 to 1,000 mcg of folic acid, the Food and 
Drug Administration concluded that most of these studies had results 
consistent with the conclusion that folate, at levels attainable in 
usual diets, may reduce the risk of neural tube defects.
    (b) Significance of folate--(1) Public health concern. Neural tube 
defects 

[[Page 8780]]
occur in approximately 0.6 of 1,000 live births in the United States 
(i.e., approximately 6 of 10,000 live births; about 2,500 cases among 4 
million live births annually). Neural tube defects are believed to be 
caused by many factors. The single greatest risk factor for a neural 
tube defect-affected pregnancy is a personal or family history of a 
pregnancy affected with a such a defect. However, about 90 percent of 
infants with a neural tube defect are born to women who do not have a 
family history of these defects. The available evidence shows that 
diets adequate in folate may reduce the risk of neural tube defects but 
not of other birth defects.
    (2) Populations at risk. Prevalence rates for neural tube defects 
have been reported to vary with a wide range of factors including 
genetics, geography, socioeconomic status, maternal birth cohort, month 
of conception, race, nutrition, and maternal health, including maternal 
age and reproductive history. Women with a close relative (i.e., 
sibling, niece, nephew) with a neural tube defect, those with insulin-
dependent diabetes mellitus, and women with seizure disorders who are 
being treated with valproic acid or carbamazepine are at significantly 
increased risk compared with women without these characteristics. Rates 
for neural tube defects vary within the United States, with lower rates 
observed on the west coast than on the east coast.
    (3) Those who may benefit. Based on a synthesis of information from 
several studies, including those which used multivitamins containing 
folic acid at a daily dose level of 400 mcg (0.4 
mg), the Public Health Service has inferred that folate alone at levels 
of 400 mcg (0.4 mg) per day may reduce the risk of neural tube defects. 
The protective effect found in studies of lower dose folate measured by 
the reduction in neural tube defect incidence, ranges from none to 
substantial; a reasonable estimate of the expected reduction in the 
United States is 50 percent. It is expected that consumption of 
adequate folate will avert some, but not all, neural tube defects. The 
underlying causes of neural tube defects are not known. Thus, it is not 
known what proportion of neural tube defects will be averted by 
adequate folate consumption. From the available evidence, the Public 
Health Service estimates that there is the potential for averting 50 
percent of cases that now occur (i.e., about 1,250 cases annually). 
However, until further research is done, no firm estimate of this 
proportion will be available.
    (c) Requirements. The label or labeling of food may contain a 
folate/neural tube defect health claim provided that:
    (1) General requirements. The health claim for a food meets all of 
the general requirements of Sec. 101.14 for health claims, except that 
a food may qualify to bear the health claim if it meets the definition 
of the term ``good source.''
    (2) Specific requirements--(i) Nature of the claim--(A) 
Relationship. A health claim that women who are capable of becoming 
pregnant and who consume adequate amounts of folate daily during their 
childbearing years may reduce their risk of having a pregnancy affected 
by spina bifida or other neural tube defects may be made on the label 
or labeling of food provided that:
    (B) Specifying the nutrient. In specifying the nutrient, the claim 
shall use the terms ``folate,'' ``folic acid,'' ``folacin,'' ``folate, 
a B vitamin,'' ``folic acid, a B vitamin,'' or ``folacin, a B 
vitamin.''
    (C) Specifying the condition. In specifying the health- related 
condition, the claim shall identify the birth defects as ``neural tube 
defects,'' ``birth defects spina bifida or anencephaly,'' ``birth 
defects of the brain or spinal cord anencephaly or spina bifida,'' 
``spina bifida and anencephaly, birth defects of the brain or spinal 
cord,'' ``birth defects of the brain or spinal cord;'' or ``brain or 
spinal cord birth defects.''
    (D) Multifactorial nature. The claim shall not imply that folate 
intake is the only recognized risk factor for neural tube defects.
    (E) Reduction in risk. The claim shall not attribute any specific 
degree of reduction in risk of neural tube defects from maintaining an 
adequate folate intake throughout the childbearing years. The claim 
shall state that some women may reduce their risk of a neural tube 
defect pregnancy by maintaining adequate intakes of folate during their 
childbearing years. Optional statements about population-based 
estimates of risk reduction may be made in accordance with paragraph 
(c)(3)(vi) of this section.
    (F) Safe upper limit of daily intake. Claims on foods that contain 
more than 100 percent of the Daily Value (DV) (400 mcg) when labeled 
for use by adults and children 4 or more years of age, or 800 mcg when 
labeled for use by pregnant or lactating women) shall identify the safe 
upper limit of daily intake with respect to the DV. The safe upper 
limit of daily intake value of 1,000 mcg (1 mg) may be included in 
parentheses.
    (G) The claim. The claim shall not state that a specified amount of 
folate per serving from one source is more effective in reducing the 
risk of neural tube defects than a lower amount per serving from 
another source.
    (H) The claim shall state that folate needs to be consumed as part 
of a healthful diet.
    (ii) Nature of the food--(A) Requirements. The food shall meet or 
exceed the requirements for a ``good source'' of folate as defined in 
Sec. 101.54;
    (B) Dietary supplements. Dietary supplements shall meet the United 
States Pharmacopeia (USP) standards for disintegration and dissolution, 
except that if there are no applicable USP standards, the folate in the 
dietary supplement shall be shown to be bioavailable under the 
conditions of use stated on the product label.
    (iii) Limitation. The claim shall not be made on foods that contain 
more than 100 percent of the RDI for vitamin A as retinol or preformed 
vitamin A or vitamin D per serving or per unit.
    (iv) Nutrition labeling. The nutrition label shall include 
information about the amount of folate in the food. This information 
shall be declared after the declaration for iron if only the levels of 
vitamin A, vitamin C, calcium, and iron are provided, or in accordance 
with Sec. 101.9 (c)(8) and (c)(9) if other optional vitamins or 
minerals are declared.
    (3) Optional information--(i) Risk factors. The claim may 
specifically identify risk factors for neural tube defects. Where such 
information is provided, it may consist of statements from 
Sec. 101.79(b)(1) or (b)(2) (e.g., Women at increased risk include 
those with a personal history of a neural tube defect-affected 
pregnancy, those with a close relative (i.e., sibling, niece, nephew) 
with a neural tube defect; those with insulin-dependent diabetes 
mellitus; those with seizure disorders who are being treated with 
valproic acid or carbamazepine) or from other parts of this paragraph 
(c)(3)(i).
    (ii) Relationship between folate and neural tube defects. The claim 
may include statements from paragraphs (a) and (b) of this section that 
summarize the relationship between folate and neural tube defects and 
the significance of the relationship except for information 
specifically prohibited from the claim.
    (iii) Personal history of a neural tube defect-affected pregnancy. 
The claim may state that women with a history of a neural tube defect 
pregnancy should consult their physicians or health care providers 
before becoming pregnant. If such a statement is provided, the claim 
shall also state that all women should consult a health care provider 
when planning a pregnancy.
    (iv) Daily value. The claim may identify 100 percent of the DV 
(100% DV; 400 mcg) for folate as the target intake goal. 

[[Page 8781]]

    (v) Prevalence. The claim may provide estimates, expressed on an 
annual basis, of the number of neural tube defect-affected births among 
live births in the United States. Current estimates are provided in 
Sec. 101.79(b)(1), and are approximately 6 of 10,000 live births 
annually (i.e., about 2,500 cases among 4 million live births 
annually). Data provided in Sec. 101.79(b)(1) shall be used, unless 
more current estimates from the U.S. Public Health Service are 
available, in which case the latter may be cited.
    (vi) Reduction in risk. An estimate of the reduction in the number 
of neural tube defect-affected births that might occur in the United 
States if all women consumed adequate folate throughout their 
childbearing years may be included in the claim. Information contained 
in paragraph (b)(3) of this section may be used. If such an estimate 
(i.e., 50 percent) is provided, the estimate shall be accompanied by 
additional information that states that the estimate is population-
based and that it does not reflect risk reduction that may be 
experienced by individual women.
    (vii) Diets adequate in folate. The claim may identify diets 
adequate in folate by using phrases such as ``Sources of folate include 
fruits, vegetables, whole grain products, fortified cereals, and 
dietary supplements.'' or ``Adequate amounts of folate can be obtained 
from diets rich in fruits, dark green leafy vegetables, legumes, whole 
grain products, fortified cereals, or dietary supplements.'' or 
``Adequate amounts of folate can be obtained from diets rich in fruits, 
including citrus fruits and juices, vegetables, including dark green 
leafy vegetables, legumes, whole grain products, including breads, 
rice, and pasta, fortified cereals, or a dietary supplement.''
    (d) Model health claims. The following are examples of model health 
claims that may be used in food labeling to describe the relationship 
between folate and neural tube defects:
    (1) Examples 1 and 2. Model health claims appropriate for foods 
containing 100 percent or less of the DV for folate per serving or per 
unit (general population). The examples contain only the required 
elements:
    (i) Healthful diets with adequate folate may reduce a woman's risk 
of having a child with a brain or spinal cord birth defect.
    (ii) Adequate folate in healthful diets may reduce a woman's risk 
of having a child with a brain or spinal cord birth defect.
    (2) Example 3. Model health claim appropriate for foods containing 
100 percent or less of the DV for folate per serving or per unit. The 
example contains all required elements plus optional information: Women 
who consume healthful diets with adequate folate throughout their 
childbearing years may reduce their risk of having a child with a birth 
defect of the brain or spinal cord. Sources of folate include fruits, 
vegetables, whole grain products, fortified cereals, and dietary 
supplements.
    (3) Example 4. Model health claim appropriate for foods intended 
for use by the general population and containing more than 100 percent 
of the DV of folate per serving or per unit: Women who consume 
healthful diets with adequate folate may reduce their risk of having a 
child with birth defects of the brain or spinal cord. Folate intake 
should not exceed 250% of the DV (1,000 mcg).

    Dated: February 26, 1996.
David A. Kessler,
Commissioner of Food and Drugs.

Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 96-5013 Filed 2-29-96; 1:12 pm]
BILLING CODE 4160-01-P