[Federal Register: March 5, 1996 (Volume 61, Number 44)]
[Rules and Regulations]
[Page 8752-8781]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr05mr96-15]
[[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 <greek-m>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
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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 B<INF>12 (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 <gr-thn-eq> 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
B<INF>12, 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 <gr-thn-eq> 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
<greek-b>-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 <greek-b>-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 <greek-b>-carotene because the agency is not
aware of data on potential teratogenic or other adverse effects of
<greek-b>-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 <greek-b>-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 B<INF>12 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 B<INF>12
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 B<INF>12 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 B<INF>12 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 B<INF>12
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 B<INF>12 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 B<INF>12 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 B<INF>12 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 B<INF>12 status. With respect to
nonpernicious anemia-related vitamin B<INF>12 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 B<INF>12 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 B<INF>12 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 B<INF>12
deficiency produces) than in persons with greater hematologic damage
(which deficiency of either folate or vitamin B<INF>12 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
B<INF>12 utilization or intake is limited (i.e., in pernicious anemia
or in nonpernicious anemia-related vitamin B<INF>12 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 B<INF>12 (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 m