[Federal Register Volume 61, Number 44 (Tuesday, March 5, 1996)]
[Rules and Regulations]
[Pages 8752-8781]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-5013]
Federal Register / Vol. 61, No. 44 / Tuesday, March 5, 1996 / Rules
and Regulations
[[Page 8752]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 101
[Docket No. 91N-100H]
RIN 0910-AA19
Food Labeling: Health Claims and Label Statements; Folate and
Neural Tube Defects
Agency: Food and Drug Administration, HHS.
Action: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is authorizing the use
on the labels and in the labeling of food, including dietary
supplements, of health claims on the association between adequate
intake of folate and the risk of neural tube birth defects. This rule
is issued in response to provisions of the Nutrition Labeling and
Education Act of 1990 (the 1990 amendments) that bear on health claims.
The agency has concluded that, based on the totality of the publicly
available scientific evidence, there is significant scientific
agreement among qualified experts that, among women of childbearing age
in the general U.S. population, maintaining adequate folate intakes,
particularly during the periconceptional interval, may reduce the risk
of a neural tube birth defect-affected pregnancy.
EFFECTIVE DATE: April 19, 1996.
FOR FURTHER INFORMATION CONTACT: Jeanne I. Rader, Office of Food
Labeling (HFS-175), Food and Drug Administration, 200 C St. SW.,
Washington, DC 20204, 202-205-5375.
SUPPLEMENTARY INFORMATION:
I. Background
A. Procedural History
1. The 1990 Amendments
The 1990 amendments to the Federal Food, Drug, and Cosmetic Act
(the act) provided for extensive changes in the way foods are labeled.
Under these amendments, FDA can authorize the use, in the labeling of
foods, of health claims that characterize the relationship of a
nutrient to a disease or a health-related condition. Section
403(r)(1)(B) of the act (21 U.S.C. 343(r)(1)(B)) provides that a
product is misbranded if it bears a claim that characterizes the
relationship of a nutrient to a disease or a health-related condition
unless the claim is made in accordance with procedures and standards
established under section 403(r)(3) and (r)(5)(D) of the act. The 1990
amendments required that FDA evaluate 10 nutrient/disease relationships
with respect to their appropriateness as the subjects of health claims.
The topic of folic acid and neural tube defects was among those 10
topics.
In the Federal Register of November 27, 1991 (56 FR 60537), in
conformity with the requirements of the 1990 amendments, the agency
proposed to establish general principles that would govern the
appropriateness and validity of health claims on dietary supplements as
well as on foods in conventional food form. The agency also proposed to
authorize four health claims and to not authorize six others, including
a claim on folate and neural tube defects.
2. The Dietary Supplement Act of 1992 (DS Act)
In October of 1992, the Dietary Supplement Act (DS Act; Title II of
Pub. L. 102-571) was enacted. It imposed a moratorium until December
15, 1993, on FDA implementation of the 1990 amendments with respect to
dietary supplements. The DS Act directed FDA to issue proposed rules to
implement the 1990 amendments with respect to dietary supplements by
June 15, 1993, and to issue final rules based on these proposals by
December 31, 1993.
The DS Act also amended the so-called ``hammer'' provision of the
1990 amendments to provide that, if the agency did not meet the
established December 31, 1993, timeframe for issuance of final rules,
the proposed regulations would be considered final regulations.
Accordingly, when FDA issued its final rules on health claims in
the Federal Register of January 6, 1993 (58 FR 2478), they did not
cover dietary supplements.
3. The 1993 Final Rules
On January 6, 1993, FDA published its final rules on general
principles for health claims (58 FR 2478) and the 10 nutrient disease-
relationships (58 FR 2537 through 2849). The general principles
regulation provides that FDA will issue regulations authorizing health
claims only when it determines, based on the totality of publicly
available scientific evidence (including evidence from well-designed
studies conducted in a manner that is consistent with generally
recognized scientific procedures and principles) that there is
significant agreement, among experts qualified by training or
experience to evaluate such claims, that the claim is supported by the
scientific evidence.
On January 6, 1993, the agency also issued regulations announcing
its decisions with respect to conventional foods for each of the 10
nutrient-disease relationships that the 1990 amendments directed it to
consider. The agency authorized claims on all foods, including dietary
supplements, on seven nutrient-disease relationships: Calcium and
osteoporosis; sodium and hypertension; fat and cancer; saturated fat
and cholesterol and coronary heart disease (CHD); fiber-containing
grain products, fruits, and vegetables and cancer; fruits, vegetables,
and grain products that contain fiber and risk of CHD; and fruits and
vegetables and cancer.
Because of the DS Act, FDA took no final action with respect to the
use on dietary supplements of health claims on dietary fiber and
cancer; dietary fiber and CHD; omega-3-fatty acids and CHD; zinc and
immune function in the elderly; antioxidant vitamins and cancer; and
folic acid and neural tube defects.
With respect to folic acid, the agency explained that, while the
Public Health Service (PHS) had recommended that all women of
childbearing age in the United States consume 0.4 milligram (mg) of
folic acid daily to reduce their risk of having a pregnancy affected
with spina bifida or other neural tube defects, PHS had also identified
several issues that remained outstanding, including the appropriate
level of folic acid in food and safety concerns regarding increased
intakes of folic acid. Sections 403(r)(3)(A)(ii), 402(a), and 409 of
the act (21 U.S.C. 342(a) and 348) establish that the use of a
substance in food must be safe. Questions raised in the PHS
recommendation (see 58 FR 2606 at 2609) included the safety of high
intakes of folate by the target population as well as by other segments
of the population who may unintentionally be exposed to high intakes if
overfortification of the food supply with folic acid were to occur as a
result of the PHS recommendation. FDA concluded that it could not
authorize a health claim on folic acid until the questions regarding
the safety of the use of this nutrient, as well as other concerns
raised by PHS, were satisfactorily resolved (58 FR 2606 at 2614).
4. The Dietary Supplement Proposals
In the Federal Register of June 18, 1993 (58 FR 33700), FDA
published a proposal on health claims on dietary supplements. FDA
proposed to revise its food labeling regulations to make dietary
supplements of vitamins, minerals, herbs, or other similar nutritional
substances subject to the same general requirements that apply to
[[Page 8753]]
all other types of food with respect to health claims.
In the Federal Register of October 14, 1993 (58 FR 53296), FDA
published a proposal not to authorize health claims on the labels of
dietary supplements on five nutrient-disease relationships: Dietary
fiber and cancer; dietary fiber and CHD; antioxidant vitamins and
cancer; omega-3-fatty acids and CHD; and zinc and immune function in
the elderly. However, in the same issue of the Federal Register (58 FR
53254), the agency did propose to authorize the use on the labels and
labeling of conventional foods and dietary supplements of a health
claim on the relationship between folate and risk of neural tube
defects and to provide for safe use of folic acid in foods by amending
several of its regulations that permit use of folic acid in foods (see
also 58 FR 53305 and 58 FR 53312).
5. The Dietary Supplement Health Claim Final Rule
In the Federal Register of January 4, 1994 (59 FR 395), FDA
announced that it was amending its food labeling regulations to make
dietary supplements subject to the same general requirements that apply
to all other types of food with respect to the use on the label or in
labeling of health claims that characterize the relationship of a
substance to a disease or health-related condition.
Also in the Federal Register of January 4, 1994 (59 FR 433), the
agency announced that, in accordance with the 1990 amendments, as
amended by the DS Act, the regulation on folate and neural tube defects
that it proposed on October 14, 1993 (58 FR 53254), was considered a
final regulation for dietary supplements of vitamins, minerals, herbs,
and other similar nutritional substances (dietary supplements). In its
notice, the agency stated that the document was part of a separate
rulemaking contemplated by Congress if a final regulation on the
proposal issued on October 14, 1993, was not issued by December 31,
1993, and noted that the notice bore a separate docket number (i.e.,
No. 93N-0481) to distinguish it from the one assigned to the October
14, 1993 rulemaking (i.e., No. 91N-100H), which, the agency said, was
ongoing.
In this document, FDA is finalizing its October 14, 1993, proposal
to authorize health claims on the relationship between folate and
neural tube defects. This final rule pertains to conventional food as
well as to dietary supplements. Elsewhere in this issue of the Federal
Register, FDA is proposing to revoke the regulation on this nutrient-
disease relationship that became final by operation of law.
6. The Dietary Supplement Health and Education Act of 1994
The President signed the Dietary Supplement Health and Education
Act of 1994 (Pub. L. 103-417) (hereinafter referred to as the DSHEA)
into law on October 25, 1994. Among other things, the DSHEA defines
``dietary supplements'' (in section 3(a)).
In the October 14, 1993, proposal, FDA used the terms ``dietary
supplements of vitamins, minerals, herbs, and other nutritional
substances'' and ``food in conventional food form.'' Under the changes
effected by the DSHEA (see sections 3 (a) and (c) of the DSHEA), the
form of a product is no longer determinative of whether the product is
a dietary supplement. Accordingly, with the exception noted below, FDA
will use the terms ``food'' or ``foods'' in this document to reflect
this change and the act's definition of ``dietary supplements.'' FDA
will use the terms ``conventional food'' and ``dietary supplement'' in
response to comments dealing with the bioavailability of folate, for
which a distinction needs to be made between foods and dietary
supplements. Where other terminology was used in the regulatory
language of the October 14, 1993, proposal, FDA has modified that
language to conform to the changes effected by DSHEA.
B. Relationship Between Folate and Neural Tube Defects
The agency reviewed and updated the scientific literature on the
relationship between folate and neural tube defects in the Federal
Register of November 27, 1991 (56 FR 60610), January 6, 1993 (58 FR
2606), and October 14, 1993 (58 FR 53254), and provides only a brief
summary here.
Folate. The term ``folate,'' as used in this document, includes the
entire group of folate vitamin forms: That is, folic acid
(pteroylglutamic acid), the form of the vitamin added to dietary
supplements and to fortified foods, and the naturally- occurring
folylpolyglutamates (pteroylpolyglutamates) which are found in foods.
``Folate'' is thus the general term used to include any form of the
vitamin, without reference to the state of reduction, degree of
substitution, or number of glutamates. As a vitamin, folate functions
metabolically in the synthesis of amino acids and nucleic acids.
Insufficient quantities of folate in the diet lead to impaired cell
multiplication and alterations in protein synthesis (Ref. 1). These
effects are most noticeable in rapidly growing or dividing cell
populations (Ref. 1). Pregnancy increases the need for folate and many
other nutrients because of the need of the mother to maintain adequate
nutrition and to meet the nutritional requirements of the developing
fetus.
Neural tube defects. Neural tube defects are serious birth defects
that can result in infant mortality or serious disability. The birth
defects anencephaly and spina bifida are the most common forms of
neural tube defects and account for about 90 percent of these defects.
These defects result from failure of closure of the covering of the
brain or spinal cord during early embryonic development. The neural
tube forms between the 18th and 20th days of pregnancy and closes
between the 24th and 27th days. Because the neural tube forms and
closes during early pregnancy, the defect may occur before a woman
realizes that she is pregnant.
Each year, about 2,500 cases of neural tube defects occur among
about 4 million births in the United States (i.e., in approximately 6
of 10,000 births annually). Recent data from State-based birth defects
surveillance systems show declining trends for neural tube defects in
the United States for about the last 30 years (Ref. 2). The Maternal
and Child Health Bureau of the Health Resources and Services
Administration reported that the neural tube defect rate in the United
States has declined from 1.3 per 1,000 live births in 1970 to 0.6 per
1,000 live births in 1989 (Ref. 3).
The majority of neural tube defects are isolated defects and are
believed to be caused by multiple factors. About 90 percent of infants
with a neural tube defect are born to women who do not have a family
history of these defects. Neural tube defects have been reported to
vary with a wide range of factors including genetics, geography,
socioeconomic status, maternal birth cohort, month of conception, race,
nutrition, and maternal health, including maternal age and reproductive
history (Ref. 4). Women with a close relative (i.e., sibling, niece,
nephew) with a neural tube defect, with insulin-dependent diabetes
mellitus, and with seizure disorders who are being treated with
valproic acid or carbamazepine are at significantly increased risk
compared with women without these characteristics. Rates for neural
tube defects also vary within the United States, with lower rates
observed on the west coast than on the east coast.
Several lines of evidence led to the hypothesis that nutritional
factors might be associated with some human neural
[[Page 8754]]
tube defects (see 56 FR 60610, 58 FR 2606, and 58 FR 53254). Among the
nutrients that were hypothesized to play a role in reducing the risk of
neural tube defects, folate, a B vitamin, received the greatest
attention because of associations between folate intake and reduced
risk of neural tube defects found in observational studies in humans
and because of the well- recognized role of folate in cell division and
growth. Because the neural tube forms early in embryonic development,
interventions aimed at reducing the risk of these defects must occur
periconceptionally (i.e., during the interval extending from at least 1
month before conception and continuing through the first 6 weeks of
pregnancy).
In the folate health claim proposal (58 FR 53254), FDA tentatively
concluded that the available data show that folate alone may reduce the
risk of recurrence of neural tube defects when given periconceptionally
at high-dose levels (i.e., 4 mg/day) to women at high risk of such a
recurrence. Additionally, based on a synthesis of information from
several observational studies that reported periconceptional use of
multivitamins containing 0 to 1,000 micrograms (mcg or g) of
folic acid, FDA inferred that folic acid intake at levels of 0.4 mg
(400 mcg) per day may reduce the risk of occurrence of neural tube
defects. Protective effects measured by reduction in incidence of
neural tube defects have been found in several observational studies
that reported periconceptional use of multivitamin supplements
containing about 400 mcg folic acid.
Public health significance. Reduction in adverse pregnancy outcomes
such as birth defects is an important public health goal. Because most
neural tube defects occur in women without a history of such outcomes,
interest in reducing the risk of first occurrences has been very high.
PHS has inferred that if all women of childbearing age consumed 0.4 mg
(400 mcg) folic acid daily throughout their childbearing years, there
might be a reduction in neural tube defects of about 50 percent (i.e.,
about 1,250 cases per year) (Ref. 5).
C. Regulatory and Other Activities Related to Folate and Neural Tube
Defects
Since the passage of the 1990 amendments in November 1990, the
rapidly evolving nature of the science relative to folate and the risk
of neural tube defects and a number of PHS activities have intertwined
with the regulatory process on the question of whether a health claim
should be authorized on this topic. These developments have resulted in
a dynamic process that began with the publication of a proposed rule
not to authorize a health claim on folic acid and neural tube defects
(56 FR 60610); saw PHS issue a recommendation that all women of
childbearing age in the United States should consume 0.4 mg of folic
acid per day for the purpose of reducing their risk of having a
pregnancy affected with spina bifida or other neural tube defect (Ref.
5); included meetings of FDA's Folic Acid Subcommittee and Food
Advisory Committee (Refs. 6 and 7); and was marked by FDA publishing a
final rule that noted that, while the PHS recommendation evidenced that
significant scientific agreement exists regarding the relationship
between folate and neural tube defects, there were significant
unresolved questions about the safe use of folic acid in food (58 FR
2606). In its January 6, 1993, Federal Register document, the agency
concluded that it could not authorize a health claim for folate until
the questions regarding the safe use of this nutrient, as well as other
concerns raised by PHS, were satisfactorily resolved.
The process proceeded to the point where, in October 1993, FDA
stated that it had tentatively concluded that the safety questions had
been resolved, and that there is significant scientific agreement about
the validity of the relationship between folate and neural tube defects
(58 FR 53254). The agency also tentatively concluded that, based on its
discussions with the Folic Acid Subcommittee and its analyses of food
intake data, daily folate intakes can be maintained within safe ranges
by allocating fortification with folic acid to specific foods in the
food supply through an amendment to the food additive regulation for
folic acid.
The agency therefore proposed to authorize a health claim relating
diets adequate in folate to a reduced risk of neural tube defect-
affected pregnancies (58 FR 53254). In companion documents published in
the same issue of the Federal Register, the agency also proposed to
provide for the safe use of folic acid in foods by amending the food
additive regulations for folic acid (58 FR 53312) and to amend the
standards of identity for specific enriched cereal-grain products to
require the addition of folic acid (58 FR 53305).
The agency convened the Folic Acid Subcommittee and the Food
Advisory Committee on October 14 and 15, 1993 (Ref. 8). Members were
asked to comprehensively review the October 14, 1993, proposals and to
provide comments. The agency requested that the Folic Acid Subcommittee
give priority to the health claim issue because the DS Act required
that health claim regulations be finalized by December 31, 1993. The
agency treated the discussions of the Folic Acid Subcommittee as
comments. A summary of the discussions that occurred during the
meetings is provided in the summary of comments below.
As stated above, in January 1994, FDA announced (59 FR 433) that,
by operation of law, the regulation that it proposed on October 14,
1993 (58 FR 53254), to authorize the use of a health claim about the
relationship between folate and the risk of neural tube defects was a
final regulation applicable to the label and labeling of dietary
supplements only. The agency also advised that, given the PHS
recommendation and the results of the agency's review of the evidence
on this claim, in addition to authorizing the claim on dietary
supplements, it had no intention of taking action against conventional
foods that are naturally high in folate that bear a claim on this
nutrient-disease relationship, so long as the claim fully complies with
the provisions of the regulation that became final for dietary
supplements by operation of law.
D. Scope of This Document
In the Federal Register of October 14, 1993 (58 FR 53254), the
agency posed a series of questions for itself. These questions, and the
agency's proposed answers, provided the outline for the October 14,
1993 document. The questions were: (1) Is a health claim on the
relationship between folate and neural tube defects appropriate on food
labels? (2) If the agency concludes that a health claim can be safely
implemented, what should such a claim say about folate and neural tube
defects? (3) Should the food supply be fortified with folic acid to
ensure that women have adequate folate intakes? If so, is it necessary
to limit the foods to which folic acid can be added and the levels at
which it can be added to those foods? (4) If there are to be
limitations on the foods that can be fortified with folic acid, which
foods are most appropriate for fortification, and at what levels should
they be fortified?
During the development of this final rule, data on the folate
status of the U.S. population obtained during Phase 1 of the Third
National Health and Nutrition Examination Survey (NHANES III, Phase 1,
1988-1991) became available. The agency anticipated evaluating red
blood cell (RBC) and serum folate data, and data on folate intake from
foods and
[[Page 8755]]
dietary supplements from this survey. Additionally, because the NHANES
III folate consumption data are more current than the data used by the
agency in developing its October 14, 1993, proposals for food
fortification and for amending the agency's food additive regulation
for folic acid (58 FR 53305 and 58 FR 53312, respectively), the agency
considered delaying completion of these rulemakings until evaluation of
the newer data was complete.
However, in late 1993, FDA became aware of a methodological problem
associated with the radioassay kits used in NHANES III (1988 to 1994)
that affected serum folate and RBC folate values and, consequently,
data interpretation. FDA's Center for Food Safety and Applied Nutrition
requested that the Life Sciences Research Office (LSRO), Federation of
American Societies for Experimental Biology (FASEB), review, under a
contract with FDA, the issues and report its findings to the agency.
FDA requested that LSRO/FASEB: (1) Examine the analytical bases of the
discrepancies associated with serum folate and RBC folate values
derived from use of certain analytical kits used in NHANES III (1988 to
1991); (2) evaluate the scientific basis and validity of procedures
proposed by the Centers for Disease Control and Prevention (CDC) to
make corrections to serum folate and RBC folate values obtained in
NHANES III Phase 1 (1988 to 1991); (3) reexamine current ``cutoff''
values used for estimation of ``deficient,'' ``low status,'' etc., in
light of the need for application of a correction factor; and (4)
determine whether these approaches are still useful for estimating the
prevalence of inadequate folate nutriture in the U.S. population.
A full description of the problem, the analytical issues involved,
the issues that arose that are related to the interpretation of NHANES
III Phase 1 (1988 to 1991) data, and LSRO/FASEB's conclusions are
presented in ``Assessment of Folate Methodology Used in the Third
National Health and Nutrition Examination Survey (NHANES III, 1988-
1991)'' (Ref. 9). A major conclusion of LSRO/FASEB was that neither
adjustment of the serum folate or RBC folate data from NHANES III Phase
1 (1988 to 1991) to correct for the analytical problem, the use of the
data without adjustment, nor the use of either data set with adjusted
criteria for normalcy and deficiency, by themselves, can predict the
prevalence of inadequate folate nutriture of the U.S. population.
Based on LSRO/FASEB's report and its own review of the data, the
agency has concluded that while there is a need for further evaluation
of the NHANES III (1988 to 1991) serum folate and RBC folate data set,
the agency will not delay this rulemaking until such evaluation is
complete.
The complete data from NHANES III (1988 to 1994) on folate intake
from food and dietary supplements are not yet publicly available.
Therefore, the agency cannot evaluate total folate intakes from foods
and from dietary supplements from this survey data. The agency has
concluded that it will also not delay the fortification and food
additive rulemakings until the expected availability of these data in
1996.
II. Summary of Comments and the Agency's Responses
The agency received nearly 100 comments in response to its October
14, 1993, proposed rule on a health claim on folate and neural tube
defects. In addition, as stated above, FDA submitted the transcript of
the October 14 and 15, 1993, meetings of the Folic Acid Subcommittee
and Food Advisory Committee, in which the proposed rule was discussed,
to the docket 91N-100H as a comment (Ref. 8). Comments were received
from individual members of FDA's Folic Acid Subcommittee and Food
Advisory Committee and invited guest consultants; other Federal
agencies; a foreign government; State departments of agriculture,
consumer services, or health; health care professionals; consumers;
consumer advocacy groups; national organizations of health care
professionals; State and territorial public health nutrition directors;
manufacturers and suppliers of vitamins to the conventional food
industry and the dietary supplement industry; manufacturers of finished
foods including breakfast cereals, frozen foods, and bakery products;
and trade associations of dietary supplement manufacturers, bakers,
millers, and food processors. A number of comments were received that
were more appropriately answered in other dockets, and these were
forwarded to the appropriate dockets for response.
FDA has considered all of the comments on a health claim on folate
and neural tube defects that it received. The agency reviewed all of
the documents, including letters, press releases, scientific articles
and data supporting these articles, review articles, and
recommendations, that were included in the comments. A summary of the
comments that the agency received and the agency's responses follow.
A. Advisability of Authorizing Health Claims
1. Some comments endorsed health claims because of their potential
educational benefits, while other comments stated that health claims on
foods that focus on single nutrients are a bad idea because
combinations of foods, not single nutrients, build health. The
advisability of health claims was also discussed at the October 14 and
15, 1993, meeting of the Folic Acid Subcommittee (Ref. 8).
The agency notes that the issue of whether health claims should be
permitted in food labeling is moot because the 1990 amendments
authorized claims on the relationship between substances and diseases
or health-related conditions if the scientific validity standard is
met.
B. Advisability of Authorizing a Health Claim for Folate and Neural
Tube Defects
In Sec. 101.79(c)(2)(i)(A) (21 CFR 101.79(c)(2)(i)(A)), FDA
proposed to authorize health claims on labels or in labeling of
conventional foods and dietary supplements on the relationship between
folate and neural tube defects in women of childbearing age.
1. Scientific Validity Standard: Adequacy of the Scientific Data
2. Many comments supported FDA's tentative decision to authorize a
health claim on the relationship between folate and neural tube defects
but did not provide any specific reasons for their support. Several
comments noted that the scientific basis for the claim was as strong as
that used to authorize other claims (e.g., those relating calcium and
osteoporosis and saturated fat and heart disease). Members of the Folic
Acid Subcommittee who supported a health claim noted that such claims
would provide information to the target population, and that such
claims tend to be more effective than educational programs alone.
Other comments opposed the health claim, identifying specific
concerns with the quality and quantity of the data used to develop the
PHS recommendation and to support the proposed health claim. Members of
the Folic Acid Subcommittee who opposed a health claim cited the
weakness of the data supporting the relationship, including the very
small number, and observational nature, of studies relating intake of
folate at levels attainable from usual diets to reduced risk of neural
tube defects and the many issues associated with the interpretation of
these studies (58 FR 53265).
[[Page 8756]]
Several comments noted that because of the variety of
micronutrients in addition to folic acid contained in supplements whose
use was reported in several case-control studies, and because foods
high in folate are also important sources of other micronutrients, it
is not possible to isolate an independent role for folate in reduction
in risk of first occurrences of neural tube defects. Other comments
also expressed concern regarding the lack of folate-specific data at
intakes of 400 mcg daily and noted that studies showing a positive
impact of use of multivitamins containing 400 to 1,000 mcg of folic
acid may have been showing a combined effect of folic acid and vitamin
B12 or of folic acid and other components of the multivitamin
preparations.
A comment noted that there is little knowledge about biological
mechanisms that would explain the role of folate in reduction in risk
of neural tube defects. The comment stated that it was inappropriate to
conclude that, because folic acid alone at a supraphysiologic dose
(i.e., 4,000 mcg/day; 4 mg/day) is effective in reducing the risk of
neural tube defects among women at recurrent risk, it would also reduce
the risk of such defects among women at much lower risk of a first
occurrence when consumed at lower doses (i.e., at 400 mcg/day; 0.4 mg/
day). Another comment expressed the opinion that the agency should not
authorize a claim because there is not significant scientific agreement
that the evidence supports the claim.
Section 101.14(c) (21 CFR 101.14(c)) states that the agency will
issue a regulation authorizing a health claim when it determines, based
on the totality of the publicly available scientific evidence, that
there is significant scientific agreement, among experts qualified by
scientific training and experience to evaluate such claims, that the
claim is supported by such evidence.
For folate and neural tube defects, the agency evaluated all of the
available scientific evidence, consulted with the Folic Acid
Subcommittee and Food Advisory Committee about this evidence, and
considered all the information contained in the comments. Based on this
review, FDA has concluded that there is significant scientific
agreement that the data associating folate intake and reduced risk of
neural tube defects support a health claim on this relationship.
The strongest evidence for this relationship comes from the
randomized controlled Medical Research Council intervention study (Ref.
14) that showed that women at risk of a recurrence of a neural tube
defect-affected pregnancy who consumed a supplement containing 4 mg
(4,000 mcg; 10 times the reference daily intake (RDI) folic acid daily
throughout the periconceptional period had a significantly reduced risk
of having another child with a neural tube defect. This study
demonstrated, for the first time, that there was a significant
reduction in recurrence of neural tube defects with high levels of
folic acid but not with other vitamins and minerals. This study
identified a specific role for folic acid in reducing the risk of
recurrence of neural tube defect-affected pregnancies in women with a
history of this defect and thus established the scientific basis for a
relationship between folate intake and the occurrence of neural tube
defects.
In addition, protective effects against occurrence of neural tube
defects were found in a Hungarian randomized controlled trial that used
a multivitamin/multimineral preparation containing 0.8 mg folic acid
daily (Ref. 15). Four of five observational studies have also reported
a reduced risk of neural tube defects among women who reported
consuming 0.4 to 1.0 mg folate daily from multivitamin supplements
(Refs. 10, 11, 13, and 16). Several of these studies (Refs. 11, 13, and
16) have also reported beneficial effects against occurrence of neural
tube defects of dietary folate intakes of 100 to 250 mcg or more daily.
Based on its review of all of these studies, the agency has
concluded that their results are consistent with the conclusion that
folate, at levels attainable from usual diets, may reduce the risk of
occurrence of neural tube defects.
The agency agrees that there are still significant gaps in our
knowledge about the etiology of neural tube defects; about how folate,
either alone or in combination with other nutrients, reduces the risk
of neural tube defects; about dose-response relationships between
folate intake and reduction in risk of neural tube defect-affected
pregnancies; and about the role of other essential nutrients in the
etiology of neural tube defects. However, the randomized controlled
Medical Research Council trial (Ref. 14) clearly established the
specific effectiveness of increased folate intake in reducing the risk
of recurrence of some neural tube defects, and the findings of most of
the studies cited above (Refs. 9, 10, 11, 13, and 16) are consistent
with the conclusions drawn from the results of the Medical Research
Council trial.
Because of the consistency between the results of the Medical
Research Council trial and the results of the smaller observational
studies, PHS has inferred that folate alone, at levels attainable in
usual diets, may reduce the risk of neural tube defects (Ref. 5). FDA
participated in the development of the PHS recommendation and noted in
the folate health claim proposal (58 FR 53266) that the recommendation
evidenced that significant scientific agreement exists regarding the
validity of an association between folate intake and risk of neural
tube defects.
FDA has therefore concluded, based on its own review of the
scientific literature, that there is significant scientific agreement
regarding the validity of the relationship, and that the statutory
requirements for authorizing a health claim in this topic area have
thus been met. Therefore, the agency is adopting
Sec. 101.79(c)(2)(i)(A) as proposed.
2. Appropriateness of Providing for a Claim
In addition to comments addressing the scientific validity of a
health claim on folate and neural tube defects, the agency received
comments questioning the advisability of authorizing a claim on this
topic.
a. General comments.
3. Some comments stated that it was advisable to provide for a
folate/neural tube defects health claim because such a claim can serve
to broaden public knowledge of the relationship between folate and
neural tube defects. A comment noted that the folate/neural tube defect
claim might be especially beneficial for women who had previously had a
child with a neural tube defect. One comment suggested that a health
claim for folate and neural tube defects would increase intake of
folate by women of childbearing age.
Others expressed concern by noting that consumers will find it
difficult to understand the claim and will begin to associate folate-
containing foods with an effect on birth defects in general. A comment
noted that, given that many occurrences of neural tube defects will not
be affected by folate intake, the claim will give a false hope of
avoidance of the defect. A comment expressed concern that publication
of the claim might cause unnecessary alarm among women who are
pregnant. Other comments noted that neural tube defects are not the
result of folate deficiency per se or noted the lack of evidence that
there is a need in the general U.S. population for an increase in
folate intake. Another comment, in considering the agency's proposed
model health claims, noted that FDA
[[Page 8757]]
was trying to make the food label do more than it can.
Another comment emphasized that the context in which data from the
major controlled intervention trial of effects of folic acid at levels
approaching those obtainable from diets (i.e., the Hungarian trial;
Ref. 15) were obtained (e.g., women who volunteered for the trial gave
up drinking and smoking, consumed healthful diets before pregnancy, and
in general pursued good health practices in the periconceptional
interval) is not the same context in which women in the general
population will receive folate.
The agency agrees with the comments above that a health claim for
folate and neural tube defects may have an educational benefit and has
the potential for increasing folate intake among women in the target
population by informing them of the importance of folate intake during
their childbearing years. The agency also recognizes the importance of
informing women of childbearing age of the need to ensure that their
diets include adequate folate throughout this time of their lives and
notes that providing information at the point of purchase of food by
means of health claims and nutrient content claims can be an effective
means of getting the information to consumers and of helping consumers
to maintain healthful diets. Given that about half of all pregnancies
are unplanned, many women in the general population can benefit from
the information provided in the health claim because it will motivate
them to increase their folate intake, even if they are not anticipating
a pregnancy in the near future.
The agency recognizes that women in the Hungarian trial (Ref. 15)
were advised to adopt specific health conscious practices before
attempting to become pregnant, and that women in the general population
may not adopt such practices before becoming pregnant. The agency
notes, however, that there are no data to indicate that the outcome of
the Hungarian trial was related to or dependent upon the adoption of
those practices, and that all women in the trial were urged to adopt
those practices, not only those receiving folate-containing
supplements. The agency finds no basis to deny the claim based on such
a consideration. In addition, although emphasis is frequently placed
upon estimates that about half of all pregnancies in the United States
are unplanned, the agency notes that the large numbers of women who do
plan their pregnancies (i.e., about 50 percent) may be adopting health-
conscious practices before conception and thus may receive folate in a
context similar to that employed in the Hungarian trial.
The agency recognizes that there is the potential for the health
claim to be misleading and has addressed that potential by requiring
that all claims contain specific information that informs women about
the effect that adequate intake of folate during their childbearing
years may have on their risk of a specific type of birth defect,
without implying that adequate folate intake will provide 100 percent
protection against that, or any other, birth defect. The agency
recognizes that many nutrients, as well as attention to overall diet
and healthful lifestyles, are important for obtaining the best possible
outcome of pregnancy and has incorporated these concepts into the
language of the health claim.
Specifically, in this health claim regulation, the agency
identifies the target population for the claim as women during their
childbearing years (Sec. 101.79(c)(2)(i)(A)); describes the effect of
folate intake on the risk of neural tube defects, a very specific type
of birth defect (Sec. 101.79(c)(2)(i)(C)); requires that claims not
imply that folate intake is the only recognized risk factor for neural
tube defects (Sec. 101.79(c)(2)(i)(D)); summarizes the significance of
appropriate folate intake relative to reduction in risk of neural tube
defects in the total dietary context by requiring that claims state
that healthful diets are also needed (Sec. 101.79(c)(2)(i)(H)); and
provides for optional (voluntary) identification of a variety of
sources of folate in the claim (Sec. 101.79(c)(3)(vii)). In describing
the requirements for foods to bear the claim, the agency has defined
characteristics that will qualify a food for bearing the folate/neural
tube defect health claim with an eye to ensuring that such foods will
be good sources of folate (Sec. 101.79(c)(2)(ii)(A)).
Provision of such information will assist women in understanding
the relationship of folate intake to the risk of neural tube defects
and the significance of the information in the context of the total
daily diet. Thus, the claim includes facts essential for consumer
understanding of the conditions and circumstances under which the
claimed effect is more likely to be obtained.
b. Small size of the population at risk.
4. Some comments disagreed with the agency's proposal to authorize
a health claim for folate and neural tube defects because other
authorized claims are different from this one. They pointed out that
the folate claim deals with a problem that affects a very small number
of people, while other authorized claims deal with reducing the risk of
long-developing conditions affecting very large segments of the
population (e.g., calcium and osteoporosis; fat and heart disease).
Another comment noted that there have been large unexplained declines
in neural tube defects in the United States since the 1930's. Another
comment noted that neural tube defects constitute only a small fraction
of all birth defects and stated that the proposed claim could lead to a
false sense of security regarding protection from risk of all birth
defects. Another comment noted that despite their distressful nature,
because neural tube defect-affected births are a relatively rare
phenomena, they should be attacked at a medical level.
The agency disagrees with comments that it should not authorize a
folate/neural tube defect health claim on the basis that the affected
population is small in number. The eligibility requirements for a
health claim do not limit such claims solely to disease or health-
related conditions affecting significant portions of the population.
Rather, the general eligibility requirements for health claims require
that for a substance to be eligible for a health claim, the substance
must be associated with a disease or health-related condition for which
the general population or an identified U.S. population subgroup (e.g.,
the elderly) is at risk (see Sec. 101.14(b)(1)).
As FDA explained in the final rule establishing Sec. 101.14(b)(1)
(58 FR 2478 at 2499), the agency will interpret this provision flexibly
and will disqualify few claims under it. However, the agency also
advised that if the affected population is small in size or is not
readily identifiable, information on prevalence in the U.S. population
will be a material fact that must be disclosed to avoid misbranding the
product.
FDA agrees that the prevalence of pregnancies affected by neural
tube defects in the United States is low. However, because it is not
currently possible to predict when a pregnancy will be affected, the
U.S. subpopulation potentially at risk is large (i.e., women capable of
becoming pregnant). The agency, consequently, disagrees that this
health claim should not be authorized because a large subpopulation is
potentially at risk of a neural tube defect-affected pregnancy.
c. Potential impact of new data.
5. Several comments expressed concern that results of research in
progress on the potential role of factors other than folate could lead
to revisions of the current PHS recommendation that all women consume
0.4 mg of folate daily throughout their childbearing
[[Page 8758]]
years to reduce their risk of neural tube birth defects. A comment
noted that, based on testimony presented at the April 15 and 16, 1993,
meeting of the Folic Acid Subcommittee, data from ongoing studies in
South Carolina and Texas will be available soon and should provide
information on the effectiveness of folate-containing supplement
intervention programs in these areas. Another comment noted that data
reported at the recent meeting of the American Public Health
Association suggested that while reported intake of folate-containing
supplements appeared to be associated with a reduced incidence of
neural tube defect-affected pregnancies overall, the association was
not statistically significant for Hispanic women who have a higher risk
for neural tube defects than many other women.
Some members of the Folic Acid Subcommittee questioned whether new
data on vitamin B12 (summarized in section II.E.6. of this
document) should influence the agency's position on the relationship
between folate and neural tube defects. Another Folic Acid Subcommittee
member stated that regardless of the new findings, the agency should
move ahead with the folate/neural tube defect health claim.
The agency is aware that data from several ongoing studies have
been discussed at national meetings, but until these data and detailed
descriptions of study designs, methodologies, and full results are
publicly available, the agency cannot act on them. New data that have
become publicly available during this rulemaking are reviewed in
Section II.E.6 of this document. The agency notes, however, that the
validity of the relationship between folate and neural tube defects has
been established by the Medical Research Council trial (Ref. 14). New
findings are not likely to detract from the validity of that
relationship.
C. Issues Regarding the Substance/Disease Relationship That Is the
Basis of the Claim
1. Identifying the Substance (Folic Acid Versus Folate)
In developing its proposed regulation, the agency considered how
best to describe the relationship between folate and neural tube
defects. In the proposed statement of the substance/disease
relationship (Sec. 101.79(c)(2)(i)(A)), FDA described the substance
that is the subject of the claim as ``folate.'' FDA also used this term
in proposed Sec. 101.79(a)(2), (b)(1), (b)(3), (c)(2)(i)(B),
(c)(2)(i)(F), (c)(2)(ii)(A), (c)(2)(ii)(B), (c)(2)(iv), (c)(3)(ii), and
(d). The agency's use of this term differed from the wording of the
1990 amendments which required that FDA evaluate the relationship
between ``folic acid'' and neural tube defects.
Based on its review of the available studies, the agency in its
October 14, 1993, proposed rule (58 FR 53254 at 53280) described its
rationale for broadening the topic by noting that the term ``folates''
is used broadly to represent the entire group of nutritionally active
folate vitamin forms and includes both synthetic folic acid and the
folylpolyglutamates that occur naturally in foods.
In reviewing the scientific evidence on the relationship between
folate and neural tube defects, the agency noted that some studies
reported effects of use of supplements of folic acid in combination
with intakes of food folates (Ref. 10), while other studies reported
effects of dietary intakes of food folates alone (Refs. 11, 13, and
16). Based on its review of these studies, the agency tentatively
concluded that the diet/disease relationship is more accurately
described as being related to all of the biologically active vitamin
forms of folate rather than just to the synthetic form of the vitamin
(i.e., folic acid). Thus, in its review of the substance/disease
relationship, FDA considered the effect of all of the nutritionally
active forms of this vitamin (i.e., folates) on neural tube defects and
not just the effect of the form of the vitamin specified in the 1990
amendments (i.e., folic acid). Use of the term ``folate'' in proposed
Sec. 101.79(a)(2), (b)(1), (b)(3), (c)(2)(i)(B), (c)(2)(i)(F),
(c)(2)(ii)(A), (c)(2)(ii)(B), (c)(2)(iv), (c)(3)(ii), and (d) was
consistent with the scope of the agency's review.
6. A comment stated that FDA had unjustifiably changed the
demonstrated efficacious form of the vitamin from ``folic acid'' to
``dietary folate,'' and that because dietary food folate has not been
demonstrated to reduce the incidence of neural tube defects, such a
change is not justified. Several comments stated that FDA, in its
health claims proceedings, had departed from the PHS recommendation,
which uses the term ``folic acid'' in its title and in describing
dietary change associated with reduced risk of neural tube defects, and
that FDA, instead, concentrated inappropriately on food folate.
FDA does not agree with these comments and concludes that it was
justified in expressing the food substance/disease relationship as
``folate and neural tube defects'' rather than as ``folic acid and
neural tube defects.'' FDA also disagrees with the comments that folic
acid is the only substance that was appropriately the subject of FDA's
review, and that dietary food folate has not been demonstrated to
reduce the incidence of neural tube defects.
a. Efficacy of food folate. In reviewing the scientific evidence on
the relationship between folate and neural tube defects, the agency
noted that one study attributed all observed effects to consumption of
dietary supplements of undefined composition without quantifying
contribution of folate either from the supplements or from food (Ref.
10), while other studies attempted to specifically quantify intakes of
folate from food as well as from dietary supplements (Refs. 11, 13, and
16).
Some studies reported protective effects of use of supplements
containing folic acid in combination with intakes of food folates
(Refs. 11, 13, and 16), while other studies reported protective effects
from dietary improvement in general (Ref. 17) or from intakes of food
folates alone (i.e., without supplement use) (Refs. 11 and 13).
Milunsky et al. (Ref. 11), Bower and Stanley (Ref. 16), and Werler
et al. (Ref. 13) presented data on the relationship of dietary folate
to risk of neural tube defects among nonusers of dietary supplements.
Each of these studies found reduced risk of neural tube defects
associated with increasing dietary intake of food folate. In the
prospective study of Milunsky et al. (Ref. 11), the relative risk of
neural tube defects was 0.42 for those women ingesting more than 100
mcg folate per day compared with those ingesting less than 100 mcg
folate per day. Bower and Stanley (Ref. 16), in a study in Western
Australia, found reduced risk of neural tube defects among women
consuming more than 240 mcg food folate per day versus community
controls. Werler et al. (Ref. 13) reported a significant trend of
reduced occurrence of neural tube defects with increasing dietary food
folate.
Laurence et al. (Ref. 17) performed a trial of dietary education
without prescribing supplements and found that improvement in women's
diets from ``poor'' to ``good'' led to a 50 percent reduction in
recurrence of neural tube defects in women at high risk of this
complication. Dietary improvement is assumed to increase intake of
folate and many other nutrients by unspecified amounts. Specifically,
these authors reported no cases of neural tube defects among women who
were judged to have eaten ``good'' or ``fair'' diets (Ref. 17). All
recurrences occurred among the 30 of 186 women who were judged to have
eaten ``poor'' diets. ``Poor'' diets were defined as those considered
to be deficient in first-class protein, usually no fruits and
vegetables, and generally
[[Page 8759]]
with excessive amounts of carbohydrates. ``Good'' diets were defined as
those providing good intakes of all essential foods, including protein,
and with no excessive amounts of refined carbohydrates, sweets, and
soft drinks (see 58 FR 53253, October 14, 1993).
The studies of Milunsky et al. (Ref. 11), Bower and Stanley (Ref.
16), Werler et al. (Ref. 13), and Laurence et al. (Ref. 17) have all
demonstrated that food folates provide protective effects against risk
of neural tube defects.
b. Interchangeability of the terms ``folate'' and ``folic acid'' in
common usage and in nutrition labeling. FDA notes that, in common
usage, the terms ``folic acid'' and ``folate'' are frequently used
interchangeably to describe the biologically active forms of the
vitamin. Folates are ubiquitous in nature, being present in nearly all
natural foods (Ref. 18), and occurring in a wide range of forms (Ref.
19). Human nutritional requirements for folate can be met by a variety
of naturally occurring forms of the vitamin from many sources as well
as by pteroylglutamic acid, the form of the vitamin added as a
fortificant to breakfast cereals and other foods, and the form present
in dietary supplements.
In nutrition labeling, ``folic acid,'' ``folate,'' and ``folacin''
are allowable synonyms (Sec. 101.9(c)(8)(iv) and (c)(7)(iv)). All of
these terms provide a way to describe the nutritional value of folate
vitamin forms, although the term ``folacin'' is now rarely used.
c. Interchangeability of the terms ``folate'' and ``folic acid'' in
the PHS recommendation. FDA disagrees that the PHS statement emphasizes
synthetic folic acid, the form of the vitamin used as a fortificant in
conventional foods and in dietary supplements. In point of fact, the
PHS statement, consistent with lay information and with nutrition
labeling regulations, uses the terms ``folic acid'' and ``folate''
interchangeably (Ref. 5). For example, the PHS recommendation states
that ``folate intake 0.4 mg/day can be obtained from the
diet through careful selection of foods,'' that improvement in dietary
habits is one potential approach ``for the delivery of folic acid to
the general population in the dosage recommended,'' and that ``women
should be careful to keep their total daily folate consumption at < 1="" mg="" per="" day''="" (ref.="" 5).="" that="" some="" ambiguity="" with="" respect="" to="" use="" of="" the="" terms="" ``folic="" acid''="" and="" ``folate''="" was="" present="" in="" the="" phs="" recommendation="" was="" recognized="" during="" finalization="" of="" the="" recommendation="" at="" a="" cdc-sponsored="" meeting="" held="" in="" atlanta="" on="" july="" 27,="" 1992.="" at="" that="" meeting,="" cdc="" staff="" noted="" that="" the="" ambiguity="" was="" deliberate="" (ref.="" 20):="" invited="" speaker="" wald:="" there="" is="" an="" ambiguity="" here="" over="" whether="" it's="" total="" or="" extra,="" unless="" you="" have="" a="" particularly="" kind="" of="" astute="" legal="" perspective="" on="" this.="" *="" *="" *="" i="" have="" a="" question,="" though.="" was="" the="" ambiguity="" deliberate?="" cdc's="" erickson:="" yes.="" invited="" speaker="" wald:="" you="" see,="" i="" think="" i="" would="" have="" probably="" inserted="" the="" same="" ambiguity="" myself.="" because="" the="" intention="" is="" to="" get="" something="" going.="" *="" *="" *="" and="" one="" has="" the="" 0.4="" mg="" figure="" from="" the="" previous="" rda="" *="" *="" *="" at="" least="" that="" is="" a="" psychological="" fixing="" point.="" thus,="" there="" was="" some="" ambiguity="" in="" the="" phs="" recommendation="" from="" the="" time="" of="" its="" development,="" and="" the="" recommendation="" does="" not="" identify="" synthetic="" folic="" acid="" as="" the="" sole="" active="" form="" of="" the="" vitamin.="" d.="" conclusion.="" based="" on="" its="" review="" of="" the="" available="" studies,="" the="" agency="" tentatively="" concluded="" in="" the="" proposed="" rule="" that="" the="" food="" substance/disease="" relationship="" is="" most="" accurately="" expressed="" as="" ``folate="" and="" neural="" tube="" defects''="" rather="" than="" as="" ``folic="" acid="" and="" neural="" tube="" defects''="" because="" the="" term="" ``folate''="" encompasses="" all="" forms="" of="" the="" vitamin="" from="" any="" source.="" in="" addition,="" at="" intakes="" attainable="" from="" usual="" diets,="" both="" folate="" from="" foods="" and="" folic="" acid="" from="" fortified="" foods="" or="" dietary="" supplements="" are="" converted="" into="" the="" same="" functional,="" metabolically="" active,="" reduced="" coenzyme="" vitamin="" forms="" in="" the="" body="" (ref.="" 19).="" thus,="" nutritional="" requirements="" are="" met="" by="" a="" variety="" of="" forms="" of="" folate,="" and,="" with="" respect="" to="" reduction="" in="" risk="" of="" neural="" tube="" defects,="" the="" utility="" of="" increased="" folate="" intake,="" whether="" achieved="" through="" improved="" food="" choices="" or="" through="" use="" of="" dietary="" supplements,="" has="" been="" shown.="" the="" comments="" summarized="" above="" do="" not="" provide="" a="" basis="" for="" the="" agency="" to="" change="" the="" relationship="" statement="" because="" they="" are="" inconsistent="" with="" the="" scientific="" data,="" and="" they="" do="" not="" provide="" data="" that="" demonstrate="" that="" ``folic="" acid''="" performs="" nutritional="" functions="" different="" from="" those="" performed="" by="" naturally="" occurring="" food="" folates.="" thus,="" making="" a="" distinction="" between="" ``folate''="" and="" ``folic="" acid''="" when="" all="" forms="" of="" the="" vitamin="" are="" capable="" of="" conversion="" to="" active="" vitamin="" coenzymes="" and="" metabolic="" function="" is="" artificial="" and="" inappropriate.="" therefore,="" in="" sec.="" 101.79,="" fda="" is="" authorizing="" a="" health="" claim="" on="" labels="" and="" in="" labeling="" of="" conventional="" foods="" and="" dietary="" supplements="" about="" the="" relationship="" between="" folate="" and="" neural="" tube="" defects="" in="" women="" of="" childbearing="" age.="" the="" agency="" is="" retaining="" this="" terminology="" throughout="" the="" codified="" language.="" however,="" sec.="" 101.79(c)(2)(i)(b)="" states="" that="" any="" one="" of="" several="" synonyms="" may="" be="" used,="" including="" ``folic="" acid''="" and="" ``folate,''="" when="" specifying="" the="" nutrient="" in="" a="" health="" claim.="" fda="" notes="" that="" in="" proposed="" sec.="" 101.79(c)(2)(i)(f),="" the="" term="" ``folic="" acid''="" was="" used="" instead="" of="" the="" intended="" term="" ``folate,''="" which="" was="" otherwise="" consistently="" used="" throughout="" the="" proposed="" codified="" language.="" fda="" is="" correcting="" this="" terminology="" in="" the="" final="" codified="" language,="" which="" for="" other="" reasons="" described="" in="" this="" preamble="" is="" redesignated="" as="" sec.="" 101.79(c)(2)(i)(e).="" 2.="" issues="" of="" source="" and="" amount="" in="" sec.="" 101.79(c)(2)(i)(h),="" the="" agency="" proposed="" to="" prohibit="" statements="" in="" the="" health="" claim="" that="" a="" specified="" amount="" of="" folate="" (e.g.,="" 400="" mcg="" (100="" percent="" of="" the="" daily="" value="" (dv))="" in="" a="" dietary="" supplement)="" is="" more="" effective="" in="" reducing="" the="" risk="" of="" neural="" tube="" defects="" than="" a="" lower="" amount="" (e.g.,="" 100="" mcg="" (25="" percent="" of="" the="" dv)="" in="" a="" breakfast="" cereal="" or="" from="" diets="" rich="" in="" fruits="" and="" vegetables).="" the="" agency="" proposed="" this="" limitation="" because="" it="" is="" consistent="" with="" scientific="" data="" showing="" that="" reduced="" risk="" of="" neural="" tube="" defects="" has="" been="" associated="" with="" general="" dietary="" improvement,="" which="" is="" assumed="" to="" increase="" folate="" intake="" by="" unspecified="" amounts.="" in="" response="" to="" this="" proposed="" limitation,="" the="" agency="" received="" comments="" addressing="" the="" separate="" issues="" of="" source="" of="" folate="" and="" amount="" of="" folate.="" a.="" source.="" 7.="" several="" comments="" agreed="" with="" the="" agency's="" proposal,="" stating="" that="" health="" claims="" should="" not="" contain="" statements="" that="" adequate="" diets="" cannot="" provide="" sufficient="" folate,="" or="" that="" only="" fortified="" foods="" or="" supplements="" can="" provide="" adequate="" folate.="" other="" comments="" disagreed,="" stating="" that="" fda="" should="" require="" claims="" to="" state="" that="" the="" evidence="" that="" folate="" reduces="" the="" risk="" of="" neural="" tube="" defects="" is="" stronger="" for="" supplements="" than="" for="" food.="" other="" comments="" stated="" that="" evidence="" that="" folate-rich="" diets="" reduce="" the="" risk="" of="" neural="" tube="" defects="" is="" only="" suggestive,="" while="" evidence="" that="" folic="" acid="" containing-supplements="" reduce="" the="" risk="" of="" neural="" tube="" defects="" is="" conclusive.="" the="" agency="" agrees="" with="" comments="" that="" health="" claims="" should="" not="" contain="" statements="" that="" diets="" cannot="" provide="" sufficient="" folate="" to="" affect="" the="" risk="" of="" a="" neural="" tube="" defect="" because="" such="" statements="" are="" inconsistent="" with="" the="" available="" scientific="" evidence.="" the="" studies="" of="" milunsky="" et="" al.="" (ref.="" 11),="" bower="" and="" stanley="" (ref.="" 16),="" werler="" et="" al.="" (ref.="" 13),="" and="" laurence="" et="" al.="" (ref.="" 17)="" were="" summarized="" in="" response="" to="" comment="" 6,="" above.="" milunsky="" et="" al.="" (ref.="" [[page="" 8760]]="" 11),="" bower="" and="" stanley="" (ref.="" 16),="" and="" werler="" et="" al.="" (ref.="" 13)="" all="" presented="" data="" on="" the="" relationship="" of="" dietary="" folate="" to="" risk="" of="" neural="" tube="" defects="" among="" nonusers="" of="" dietary="" supplements.="" each="" of="" these="" studies="" found="" reduced="" risk="" of="" neural="" tube="" defects="" associated="" with="" increasing="" intakes="" of="" dietary="" folate.="" laurence="" et="" al.="" (ref.="" 17)="" found="" fairly="" strong="" protection="" against="" recurrence="" of="" neural="" tube="" defects="" associated="" with="" improvement="" in="" overall="" diets.="" fda="" concludes,="" based="" on="" its="" review="" of="" the="" scientific="" literature,="" that="" the="" proposed="" limitation="" in="" sec.="" 101.79="" on="" statements="" that="" specific="" sources="" are="" superior="" to="" others="" is="" appropriate="" because="" the="" scientific="" literature="" does="" not="" support="" the="" superiority="" of="" any="" one="" source="" over="" others.="" as="" noted="" above,="" both="" folate="" from="" conventional="" foods="" and="" folic="" acid="" from="" fortified="" foods="" or="" dietary="" supplements="" are="" converted="" into="" functional,="" metabolically="" active="" coenzyme="" forms="" for="" use="" in="" the="" body="" (ref.="" 19).="" thus,="" in="" the="" absence="" of="" the="" limitation,="" manufacturers="" would="" be="" free="" to="" put="" statements="" that="" would="" be="" false="" and="" misleading="" in="" their="" labeling.="" the="" agency's="" conclusion="" is="" consistent="" with="" phs's="" recommendation="" that="" advises="" that="" careful="" selection="" of="" foods="" is="" one="" means="" by="" which="" women="" can="" increase="" their="" folate="" intakes.="" b.="" amount.="" 8.="" several="" comments="" agreed="" with="" the="" agency="" that="" the="" claim="" should="" not="" state="" that="" a="" specific="" amount="" of="" folate="" is="" more="" effective="" than="" another="" amount.="" several="" comments="" noted="" that="" dose/response="" data="" to="" justify="" such="" statements="" do="" not="" exist,="" and="" that="" scientists="" do="" not="" yet="" know="" the="" requisite="" folate="" level="" that="" will="" protect="" the="" fetus="" from="" a="" neural="" tube="" defect.="" other="" comments="" disagreed,="" stating="" that="" claims="" should="" state="" that="" experts="" recommend="" 400="" mcg="" per="" day="" or="" 100="" percent="" of="" the="" dv="" when="" referring="" to="" adequate="" amounts="" of="" folate.="" another="" comment="" stated="" that="" while="" the="" 400="" mcg="" level="" is="" admittedly="" imprecise,="" it="" is="" the="" recommendation="" of="" phs.="" another="" comment="" stated="" that="" consumers="" need="" to="" be="" reminded="" that="" a="" reduction="" in="" neural="" tube="" defects="" will="" only="" occur="" if="" all="" women="" consume="" 400="" mcg="" folate="" per="" day="" throughout="" their="" childbearing="" years.="" the="" agency="" agrees="" with="" comments="" that="" dose/response="" data="" are="" insufficient="" to="" provide="" a="" basis="" for="" stating="" that="" a="" specific="" amount="" of="" folate="" is="" more="" effective="" than="" another="" amount.="" the="" quantitative="" results="" from="" the="" studies="" of="" milunsky="" et="" al.="" (ref.="" 11),="" bower="" and="" stanley="" (ref.="" 16),="" and="" werler="" et="" al.="" (ref.="" 13)="" suggest="" that="" amounts="" lower="" than="" the="" current="" recommendation="" of="" 400="" mcg="" may="" be="" protective.="" after="" reviewing="" the="" comments="" above="" and="" the="" available="" scientific="" literature,="" fda="" concludes="" that="" the="" comments="" do="" not="" provide="" a="" basis="" for="" the="" agency="" to="" change="" its="" position="" regarding="" prohibition="" of="" statements="" in="" the="" claim="" that="" imply="" that="" specific="" amounts="" of="" folate="" are="" superior="" to="" other="" amounts="" because="" such="" statements="" are="" inconsistent="" with="" the="" scientific="" data.="" fda's="" conclusion="" is="" consistent="" with="" information="" provided="" in="" the="" phs="" recommendation="" that="" states="" that="" amounts="" of="" folate="" lower="" than="" 400="" mcg="" may="" reduce="" the="" risk="" of="" neural="" tube="" defects,="" and="" that="" additional="" research="" is="" needed="" to="" establish="" the="" minimum="" effective="" dose="" (ref.="" 5).="" again,="" a="" contrary="" position="" by="" the="" agency="" would="" permit="" false="" statements="" to="" appear="" on="" the="" label.="" in="" the="" final="" codified="" language,="" the="" agency="" is="" redesignating="" proposed="" sec.="" 101.79(c)(2)(i)(h)="" as="" sec.="" 101.79(c)(2)(i)(g)="" and,="" for="" the="" reasons="" stated="" above,="" is="" prohibiting="" in="" sec.="" 101.79(c)(2)(i)(g)="" claims="" that="" a="" specified="" amount="" of="" folate="" per="" serving="" from="" one="" source="" is="" more="" effective="" in="" reducing="" the="" risk="" of="" neural="" tube="" defects="" than="" a="" lower="" amount="" per="" serving="" from="" another="" source.="" c.="" restriction="" of="" claims="" to="" specific="" products.="" 9.="" several="" comments="" stated="" that="" the="" health="" claim="" should="" be="" limited="" to="" supplements="" containing="" 400="" or="" 800="" mcg="" of="" folate="" or="" limited="" to="" dietary="" supplements="" or="" breakfast="" cereals="" containing="" 400="" mcg="" of="" folate.="" other="" comments="" stated="" that="" health="" claims="" should="" not="" be="" allowed="" for="" naturally="" occurring="" food="" folates.="" another="" comment="" stated="" that="" to="" allow="" health="" claims="" solely="" on="" supplements="" or="" fortified="" foods="" would="" undermine="" the="" need="" for="" women="" to="" learn="" to="" eat="" more="" healthfully="" and="" to="" obtain="" a="" full="" array="" of="" nutrients="" found="" in="" a="" balanced="" diet.="" the="" agency="" disagrees="" with="" comments="" that="" recommended="" that="" it="" limit="" claims="" to="" dietary="" supplements="" or="" to="" dietary="" supplements="" and="" fortified="" breakfast="" cereals="" that="" contain="" 400="" mcg="" or="" more="" of="" folate.="" the="" agency's="" review="" of="" the="" scientific="" literature,="" summarized="" in="" response="" to="" comments="" 6="" to="" 8="" above,="" provides="" no="" basis="" for="" making="" a="" distinction="" in="" source="" or="" in="" amount="" between="" folate="" from="" conventional="" foods="" and="" folic="" acid="" from="" dietary="" supplements="" or="" fortified="" cereals="" because="" the="" available="" evidence="" shows="" that="" increased="" folate="" intake,="" rather="" than="" the="" source="" of="" the="" folate,="" is="" what="" is="" of="" importance="" in="" reducing="" the="" risk="" of="" neural="" tube="" defects="" (ref.="" 5).="" increasing="" total="" folate="" intake="" among="" women="" of="" childbearing="" age,="" rather="" than="" emphasis="" on="" one="" source="" versus="" another,="" is="" what="" is="" of="" importance.="" this="" conclusion="" is="" consistent="" with="" phs's="" recommendation,="" which="" states="" that="" improvement="" in="" dietary="" habits="" and="" use="" of="" dietary="" supplements="" are="" both="" appropriate="" approaches="" by="" which="" women="" may="" increase="" their="" folate="" intake.="" d.="" target="" intake="" goal.="" the="" agency="" proposed="" in="" sec.="" 101.79(c)(3)(iv)="" to="" include="" as="" optional="" information="" in="" the="" health="" claim="" a="" statement="" that="" the="" dv="" level="" of="" 400="" mcg="" of="" folate="" is="" the="" target="" intake="" goal.="" 10.="" several="" comments="" stated="" that="" all="" health="" claims="" should="" refer="" to="" the="" likely="" effectiveness="" of="" 400="" mcg="" of="" folate,="" or="" that="" claims="" should="" be="" required="" to="" state="" that="" experts="" recommend="" 400="" mcg="" per="" day.="" other="" comments="" stated="" that="" 400="" mcg="" is="" the="" phs="" recommendation,="" and="" without="" this="" information,="" women="" may="" assume="" that="" lower="" amounts="" are="" adequate.="" the="" agency="" disagrees="" with="" these="" comments.="" fda="" chose="" not="" to="" propose="" to="" require="" that="" claims="" identify="" 400="" mcg="" as="" the="" target="" intake="" goal="" because="" it="" tentatively="" concluded="" that="" there="" is="" uncertainty="" as="" to="" the="" optimal="" intake="" of="" folate="" with="" respect="" to="" reduction="" in="" risk="" of="" neural="" tube="" defects="" (ref.="" 5).="" as="" noted="" above,="" several="" studies="" (refs.="" 11="" and="" 13)="" have="" found="" reductions="" in="" risk="" of="" neural="" tube="" defect-affected="" pregnancies="" at="" folate="" intakes="" below="" 400="" mcg="" per="" day.="" none="" of="" the="" comments="" provided="" evidence="" that="" showed="" that="" these="" findings="" were="" not="" valid.="" thus,="" fda="" concludes="" that="" a="" requirement="" that="" claims="" state="" that="" women="" must="" consume="" 400="" mcg="" folate="" per="" day="" to="" achieve="" a="" reduction="" in="" risk="" of="" a="" neural="" tube="" defect-affected="" pregnancy="" would="" be="" inconsistent="" with="" the="" available="" scientific="" data.="" however,="" because="" 400="" mcg="" is="" the="" reference="" daily="" intake="" (rdi),="" because="" phs="" recommends="" a="" 400="" mcg/day="" intake,="" and="" because="" the="" folic="" acid="" subcommittee="" supported="" the="" 400="" mcg/day="" intake="" goal,="" the="" agency="" has="" concluded="" that="" it="" may="" be="" helpful="" to="" some="" consumers="" if="" the="" health="" claim="" were="" to="" include="" information="" that="" the="" rdi="" of="" 400="" mcg="" per="" day="" is="" the="" target="" intake="" goal.="" therefore,="" fda="" is="" adopting="" sec.="" 101.79(c)(3)(iv)="" to="" allow="" for="" optional="" inclusion="" of="" this="" information,="" with="" the="" target="" intake="" goal="" (400="" mcg;="" 0.4="" mg)="" expressed="" as="" 100="" percent="" dv.="" claims="" may="" identify="" 100="" percent="" of="" the="" dv="" (400="" mcg="" folate)="" as="" the="" target="" intake="" goal="" and="" may="" state="" the="" phs="" recommended="" daily="" intake="" (400="" mcg="" folate,="" 0.4="" mg).="" 3.="" focusing="" on="" the="" periconceptional="" interval="" in="" proposed="" sec.="" 101.79(a)(1),="" the="" agency="" defined="" neural="" tube="" defects="" as="" serious="" birth="" defects="" of="" the="" brain="" or="" spinal="" cord.="" the="" agency="" noted="" that="" these="" defects="" result="" from="" a="" failure="" of="" the="" covering="" of="" the="" brain="" or="" spinal="" cord="" to="" close="" during="" [[page="" 8761]]="" early="" embryonic="" development="" and="" further="" noted="" that,="" because="" the="" neural="" tube="" forms="" and="" closes="" during="" early="" pregnancy,="" the="" defect="" may="" occur="" before="" a="" woman="" realizes="" that="" she="" is="" pregnant.="" in="" proposed="" sec.="" 101.79(a)(2),="" the="" agency="" described="" the="" relationship="" between="" adequate="" folate="" intake="" and="" reduced="" risk="" of="" a="" neural="" tube="" defect-="" affected="" pregnancy="" and="" summarized="" the="" studies="" whose="" results="" provide="" the="" basis="" for="" the="" health="" claim.="" 11.="" a="" number="" of="" comments="" stated="" that="" studies="" have="" shown="" that="" folic="" acid="" added="" to="" the="" diet="" before="" pregnancy="" reduces="" the="" risk="" of="" neural="" tube="" defects,="" and="" that="" the="" relationship="" statement="" should="" be="" corrected="" to="" reflect="" this="" fact.="" the="" agency="" agrees="" that="" the="" studies="" that="" provide="" the="" basis="" for="" the="" relationship="" between="" folate="" and="" neural="" tube="" defects="" focused="" on="" improved="" folate="" nutriture="" before="" conception="" and="" continuing="" into="" early="" pregnancy.="" therefore,="" the="" agency="" is="" modifying="" several="" of="" the="" statements="" in="" sec.="" 101.79(a)(2)="" to="" more="" precisely="" describe="" the="" results="" of="" these="" studies.="" specifically,="" fda="" is="" modifying="" the="" second="" sentence="" of="" sec.="" 101.79(a)(2)="" to="" state="" that="" in="" the="" studies="" described,="" folic="" acid="" was="" consumed="" daily="" ``before="" conception="" and="" continuing="" into="" early="" pregnancy="" *="" *="" *,''="" and="" the="" fourth="" sentence="" to="" state="" that="" the="" study="" involved="" reported="" periconceptional="" use="" of="" multivitamins="" that="" contained="" folic="" acid.="" 12.="" a="" comment="" suggested="" that="" claims="" be="" allowed="" to="" be="" more="" precise="" in="" describing="" the="" period="" during="" which="" adequate="" folate="" is="" needed.="" the="" comment="" noted="" that="" the="" statement="" relating="" to="" daily="" consumption="" of="" folate="" throughout="" the="" childbearing="" years="" implies="" that="" body="" folate="" stores="" must="" be="" built="" up="" over="" decades,="" while="" studies="" have="" shown="" that="" it="" is="" sufficient="" to="" consume="" folate="" during="" the="" weeks="" before="" the="" neural="" tube="" closes.="" the="" comment="" proposed="" that="" a="" statement="" that="" women="" who="" consume="" adequate="" amounts="" of="" folate="" during="" the="" month="" before="" and="" after="" becoming="" pregnant="" may="" reduce="" their="" risk="" of="" a="" neural="" tube="" defect="" would="" convey="" this="" information.="" another="" comment="" criticized="" the="" model="" health="" claims="" provided="" by="" the="" agency="" because="" they="" failed="" to="" alert="" women="" to="" the="" critical="" periconceptional="" period.="" the="" agency="" recognizes="" that="" the="" scientific="" data="" support="" the="" need="" for="" specific="" attention="" to="" folate="" intake="" in="" the="" periconceptional="" interval="" and="" has="" modified="" sec.="" 101.79(a)(2)="" to="" reflect="" this="" fact="" by="" specifically="" mentioning="" periconceptional="" use.="" the="" agency="" notes="" that="" one="" of="" the="" purposes="" of="" health="" claims="" is="" to="" assist="" women="" in="" recognizing="" the="" importance="" of="" healthful="" diets,="" including="" adequate="" folate="" nutriture="" throughout="" their="" childbearing="" years="" (see="" h.="" rept.="" 101-538,="" 101st="" cong.,="" 2d="" sess.="" 9-10="" (1990)).="" given="" that="" about="" 50="" percent="" of="" pregnancies="" are="" unplanned,="" and="" that="" many="" women="" may="" not="" recognize="" that="" they="" are="" pregnant="" until="" after="" the="" critical="" period="" of="" neural="" tube="" closure,="" it="" is="" important="" for="" women="" to="" maintain="" healthful="" diets="" throughout="" their="" childbearing="" years.="" while="" some="" women="" who="" plan="" their="" pregnancies="" might="" benefit="" from="" the="" more="" specific="" information="" suggested="" in="" the="" comment,="" the="" agency="" concludes="" that="" the="" more="" general="" wording="" in="" the="" model="" claims="" will="" reach="" a="" wider="" group="" of="" women="" and="" provide="" them="" with="" useful="" and="" important="" information.="" fda="" is="" adopting="" sec.="" 101.79(c)(3)(ii),="" which="" states="" that="" health="" claims="" may="" include="" statements="" from="" paragraphs="" sec.="" 101.79="" (a)="" and="" (b).="" through="" the="" use="" of="" statements="" derived="" from="" sec.="" 101.79(a)(2),="" manufacturers="" will="" be="" able="" to="" provide="" information="" that="" alerts="" women="" to="" the="" importance="" of="" the="" periconceptional="" period.="" 4.="" ``will="" reduce''="" versus="" ``may="" reduce''="" 13.="" one="" comment="" stated="" that="" proposed="" sec.="" 101.79(a)(2),="" which="" stated="" that="" available="" data="" show="" that="" diets="" adequate="" in="" folate="" may="" reduce="" the="" risk="" of="" neural="" tube="" defects,="" was="" misleading="" and="" recommended="" that="" this="" section="" be="" reworded="" to="" state="" that="" ``studies="" have="" shown="" that="" folic="" acid="" added="" to="" the="" diet="" before="" a="" pregnancy="" occurs="" will="" reduce="" the="" risk="" of="" neural="" tube="" defects.''="" the="" agency="" disagrees="" with="" the="" assertion="" that="" adequate="" folate="" intake="" will="" reduce="" the="" risk="" of="" neural="" tube="" defects.="" the="" available="" data="" show="" that="" in="" an="" area="" of="" low="" prevalence="" of="" neural="" tube="" defects,="" folate="" intake="" from="" dietary="" supplements="" or="" from="" fortified="" cereals="" was="" not="" associated="" with="" reduced="" risk="" of="" neural="" tube="" defects="" (ref.="" 12).="" the="" agency="" did="" not="" receive="" any="" data="" or="" information="" challenging="" this="" data.="" the="" agency="" notes="" that="" use="" of="" the="" term="" ``will="" reduce''="" is="" overly="" promissory="" to="" the="" individual="" and="" is="" misleading="" because="" it="" is="" not="" consistent="" with="" the="" available="" data.="" prevalence="" rates="" for="" neural="" tube="" defects="" vary="" with="" a="" wide="" range="" of="" factors="" including="" genetics,="" socioeconomic="" status,="" maternal="" health,="" and="" race.="" the="" agency="" has="" discussed="" the="" multifactorial="" nature="" of="" neural="" tube="" defects="" (and="" will="" do="" so="" again="" below="" (see="" comment="" 36="" of="" this="" document)).="" it="" has="" concluded="" that="" claims="" need="" to="" reflect="" this="" aspect="" of="" the="" nature="" of="" these="" defects="" because="" folate="" intake="" is="" not="" the="" only="" risk="" factor="" for="" them.="" use="" of="" the="" term="" ``will="" reduce''="" in="" the="" claim="" is="" not="" consistent="" with="" the="" multifactorial="" nature="" of="" neural="" tube="" defects.="" thus,="" fda="" finds="" no="" basis="" to="" change="" the="" wording="" of="" sec.="" 101.79(a)(2),="" and="" it="" is="" including="" the="" sentence="" ``the="" available="" data="" show="" that="" diets="" adequate="" in="" folate="" may="" reduce="" the="" risk="" of="" neural="" tube="" defects''="" in="" the="" final="" regulation="" without="" change.="" 5.="" need="" for="" healthful="" diets="" 14.="" some="" members="" of="" the="" folic="" acid="" subcommittee="" expressed="" concern="" about="" a="" single="" nutrient="" approach="" to="" the="" problem="" of="" neural="" tube="" defects="" because="" nutrients="" function="" together="" in="" the="" body.="" another="" comment="" felt="" that="" a="" health="" claim="" for="" folic="" acid="" could="" be="" misinterpreted="" to="" mean="" that="" folic="" acid="" could="" prevent="" all="" birth="" defects.="" one="" comment="" noted="" that,="" because="" nutrients="" function="" synergistically="" in="" the="" body,="" increasing="" a="" single="" nutrient="" is="" unwise.="" another="" comment="" stated="" that="" by="" focusing="" on="" the="" relationship="" between="" a="" single="" nutrient="" and="" a="" single="" outcome,="" opportunities="" to="" improve="" overall="" health="" are="" missed.="" another="" comment="" expressed="" concern="" about="" singling="" out="" one="" vitamin="" for="" a="" health="" claim="" when="" the="" major="" sources="" of="" the="" vitamin="" (e.g.,="" fruits="" and="" vegetables)="" are="" being="" promoted="" for="" good="" health.="" other="" comments="" noted="" that="" in="" pregnancy="" it="" is="" the="" total="" diet,="" not="" a="" single="" nutrient,="" that="" is="" related="" to="" health="" outcome.="" the="" agency="" agrees="" with="" the="" comments="" that="" expressed="" concern="" about="" the="" problems="" in="" focusing="" on="" a="" single-nutrient,="" particularly="" in="" women="" of="" childbearing="" age.="" many="" nutrients="" affect="" healthy="" pregnancy,="" and="" the="" claim="" should="" not="" lead="" women="" to="" focus="" undue="" attention="" on="" one="" nutrient,="" or="" on="" a="" single="" dietary="" factor,="" instead="" of="" on="" overall="" healthful="" diets="" and="" health="" conscious="" behaviors.="" in="" addition,="" because="" healthy="" pregnancies="" and="" good="" pregnancy="" outcomes="" are="" dependent="" upon="" an="" overall="" good="" diet,="" adequate="" in="" protein,="" vitamins="" and="" minerals,="" and="" many="" other="" nutrients,="" women="" should="" not="" be="" misled="" into="" believing="" that="" folate="" is="" the="" only="" nutrient="" about="" which="" they="" need="" to="" be="" concerned="" in="" preparing="" for="" a="" pregnancy.="" with="" respect="" to="" neural="" tube="" defects,="" fda="" in="" its="" proposed="" rule="" (58="" fr="" 53254)="" reviewed="" evidence="" that="" nutrients="" other="" than="" folate="" (e.g.,="" methionine,="" vitamin="">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 10
percent of the RDI). In proposing this eligibility requirement, FDA
considered that folate is ubiquitously distributed in the U.S. food
supply. While a number of foods (e.g., some legumes, okra, broccoli,
spinach, turnip greens, asparagus, Brussels sprouts, endive, lentils)
contain more than 80 mcg of folate/serving (the amount that is greater
than or equal to 20 percent of the RDI (i.e., that amount that would be
required for a claim of a ``rich'' source)), the great majority of
foods contain folate at lower levels. For example, oranges, grapefruit,
many berries, peas, many vegetable juices, beets, and parsnips contain
folate at levels of 40 to 80 mcg/serving (i.e., at or above 10 percent
of the RDI or at levels that meet the requirement of a claim of a
``good'' source) (Ref. 22).
a. General comments.
15. Many comments and the Folic Acid Subcommittee and Food Advisory
Committee were generally satisfied with the eligibility requirements
and supported FDA's proposal to allow claims on foods that were at
least a good source of folate. These comments supported the criterion
because it would accommodate a wide variety of fruits and vegetables
that would be excluded if the eligibility requirement was set at a
higher level. One comment, however, suggested that the proposed amount
was too high and might exclude some commonly consumed foods such as
peas.
A third group of comments thought that the proposed amount was too
low. Some of the comments said that claims should not be permitted
unless the food provides at least 20 percent of the RDI (i.e., 80 mcg
folate/serving), arguing that it was poor policy to make exception to
the general health claims requirements regulations, and that if the
goal is to maximize intake of folate, then 20 percent of the RDI should
be the minimum amount allowed for the claim. Others felt strongly that
the claim should be limited to those foods or supplements that provide
100 percent of the RDI per serving or per dose.
The agency is concerned that if it required (in accord with
Sec. 101.14(d)(2)(vii)) that the food contain 20 percent or more of the
RDI for folate (i.e., 80 mcg or more folate per reference amount
customarily consumed; an amount sufficient to qualify for a ``high'' or
``excellent source of'' nutrient content claim) to bear a health claim,
many good food sources of folate would not qualify without
fortification.
One of Congress' purposes in providing for health claims was to
enable Americans to maintain a balanced and healthful diet (H. Rept.
101-538, supra, pp. 9-10). Given this fact, and given that the evidence
demonstrates that the risk of neural tube defects can be affected by
consuming foods that, while good sources of this nutrient, do not
provide the high level that is provided by supplements and highly
fortified foods (see Refs. 11, 13, 16, and 17), FDA concludes that it
would not be consistent with the intent of the 1990 amendments to set
requirements that would limit eligibility to bear a health claim to the
foods that are high in folate.
Use of a qualifying criterion for the health claim that is
consistent with the ``good source'' definition (i.e., 10 to 19 percent
of the DV; 40 to 76 mcg folate/serving) provides for an amount of the
nutrient that allows a wide variety of fruits, vegetables, and whole
grain products to qualify to bear the health claim, is consistent with
current Federal guidelines for general dietary patterns, and yet is
still likely to result in a daily dietary intake of folate that the
data show may reduce the risk of neural tube defects. For example,
current Federal dietary guidelines recommend five or more servings of
fruits and vegetables and six or more servings of grain products per
day. Consumption of fruits, vegetables, and grain products in the
recommended amounts would likely result in daily intakes of folate of
0.4 mg (400 mcg) or more, even though individually many of the foods
consumed contain less than 20 percent of the RDI for folate per
reference serving (Ref. 22).
Accordingly, FDA is adopting Sec. 101.79(c)(2)(ii)(A), which
provides that conventional foods and dietary supplements can bear a
folate/neural tube defect health claim if they contain 10 percent or
more of the RDI for folate per reference amount customarily consumed
(i.e., meet the definition for a ``good source'' claim in Sec. 101.54
(21 CFR 101.54)). The availability of the claim for a wide variety of
products will provide flexibility to women in deciding how to
individually achieve the target intake by selecting from among foods
that naturally contain folate, dietary supplements, and highly
fortified foods.
b. Higher qualifying amounts for dietary supplements than for
foods.
16. Several comments stated that to qualify to bear the claim, each
food should provide at least 25 percent of the RDI, and each supplement
should provide 100 percent of the RDI. However, these comments did not
provide any support for the levels that they suggested or for why
supplements should have to have a higher level of the nutrient than a
conventional food.
Having dealt with the level necessary to qualify to bear the claim
in response to the previous comment, the agency will deal here with the
question of whether, to qualify for a claim, dietary supplements should
be required to provide more folate than foods. The agency concludes
that there is no reason why they should. In response to comment 7 of
this document, the agency concluded that the available scientific
evidence establishes that sources of folate are equivalent in their
ability to provide folate. Thus, there is no basis for requiring that
either dietary supplements or conventional foods provide more than 10
percent of the RDI for folate per reference amount customarily consumed
to qualify for the claim.
2. Disintegration and Dissolution of Dietary Supplements
FDA proposed in Sec. 101.79(c)(2)(ii)(C) to disqualify dietary
supplements from bearing a health claim if they fail to meet the United
States Pharmacopeia (USP) standards for disintegration and dissolution.
The agency tentatively concluded that the benefits of folate intake
from food and dietary supplements can only be obtained if the folate is
available for absorption and metabolism by the body. The agency noted
that a dietary supplement that does not disintegrate and dissolve
[[Page 8763]]
clearly does not provide the nutrient in an assimilable form, and that
a claim for such a supplement would be misleading because the
supplement would not provide the nutrient that is the subject of the
health claim (58 FR 58283).
17. Several comments agreed with the agency's proposed requirement
and urged the agency to require all dietary supplements to meet such
quality standards. Another comment proposed that the agency use the USP
standards that are currently under development, and that the
dissolution requirement become effective when the USP proposal becomes
effective. The USP commented and proposed wording for use in
Sec. 101.79(c)(2)(ii)(C): ``Folic acid present in dietary supplement
dosage forms (e.g., tablets, capsules) shall meet the requirements of
the United States Pharmacopeia as defined in Section 201(j) of the
act.''
Another comment stated that in making this proposed requirement
effective for dietary supplements, the agency would accord the same
claim to foods (i.e., conventional foods) without similar requirements
for bioavailability, and that excluding foods from this requirement was
scientifically unjustified. The comment did not identify conventional
foods from which folate had been demonstrated to be unavailable or
elaborate on the concern.
The agency proposed that dietary supplements meet USP standards for
dissolution and disintegration, and that bioavailability under
conditions of use stated on the label be shown only if there are no
applicable USP standards for disintegration and dissolution. Thus, the
agency proposed that a demonstration of bioavailability would be
required only if there were no USP method available to check for
dissolution and disintegration.
The comment that stated that in making the requirement proposed in
Sec. 101.79(c)(2)(ii)(C) effective for dietary supplements, the agency
would accord the same claim to conventional foods without similar
requirements, may have misread the agency's proposed requirement.
``Bioavailability'' includes, but is not limited to, dissolution and
disintegration. Dissolution and disintegration are necessary
preconditions for absorption and subsequent metabolism. Digestive
processes ensure that conventional foods are digested, and that
components are liberated for absorption. With respect to the
bioavailability of folate from conventional foods, the agency is aware
that the bioavailability of folate varies widely but is not aware of
any foods from which folate has been shown to be unavailable.
However, dietary supplements, including folate-containing
supplements, can be manufactured in a manner that prevents dissolution
and disintegration (e.g., extremely compressed preparations), and the
digestive processes may be insufficient to ensure the liberation of the
components for absorption. The components of such a supplement would
not be available for absorption and utilization by the body. A claim on
a dietary supplement that does not disintegrate or dissolve would be
misleading because the supplement would not meet the preconditions
necessary to ensure that the nutrient that is the subject of the claim
is available for absorption.
The agency did not receive other comments contending that dietary
supplements should not meet USP standards for disintegration and
dissolution, or that bioavailability should not be demonstrated when
applicable USP disintegration and dissolution standards are not
available. The agency is adopting Sec. 101.79(c)(2)(ii)(C) as proposed
and is redesignating it as Sec. 101.79(c)(2)(ii)(B).
3. No Health Claim on Foods or Supplements Containing More Than 100
Percent of the RDI for Preformed Vitamin A or Vitamin D
In Sec. 101.79(c)(2)(iii), FDA proposed that a health claim for
folate and neural tube defects be prohibited on conventional foods and
on dietary supplements that contain more than 100 percent of the RDI
for vitamin A as retinol or preformed vitamin A or vitamin D per
serving or per unit. The agency proposed this limitation because of the
recognized toxicity of high intakes of these vitamins for the fetus and
the teratogenic effects of these nutrients at levels not greatly in
excess of the RDI.
18. Several comments agreed with FDA's proposal, noting that many
dietary supplements currently contain more than 100 percent of the RDI
for vitamin A, and that such levels are unnecessary and potentially
harmful. Another comment misread the proposed requirement regarding
vitamin A and noted that since manufacturers were now increasing the
-carotene content of supplements because of health benefits,
these supplements should not be excluded from carrying a folate/neural
tube defect claim because of their high -carotene content.
The agency is aware that folate is often combined with other
nutrients, particularly vitamins and minerals, in dietary supplement
formulations or in highly fortified foods. In light of the expectation
that the presence of a health claim on the label of such products is
likely to result in increased intake of these products, FDA is
concerned that some consumers may try to increase their folate intake
by consuming multiple doses of dietary supplements or multiple servings
of highly fortified foods. The agency was concerned that, for some
fortified foods and dietary supplements that contain both folate and
preformed vitamin A or vitamin D, consumers could be exposed to
excessive vitamin A or vitamin D intakes in their attempts to obtain
increased amounts of folate. The agency, however, did not propose
similar requirements for -carotene because the agency is not
aware of data on potential teratogenic or other adverse effects of
-carotene on the fetus.
This limitation is consistent with other recent recommendations. In
1991, the CDC recommendation for increased intake of folate by women
with a history of a neural tube defect- affected pregnancy (Ref. 23)
warned against overconsumption of multivitamins because of the
potential for excessive intakes of vitamins A and D from such
preparations and the known adverse effects of these vitamins on the
health of the fetus. In addition, recent recommendations in Canada for
women of childbearing age regarding folic acid and neural tube defects
recognized the teratogenicity of high levels of vitamin A and cautioned
against excessive intakes of this nutrient (Ref. 24).
With the exception of the comment regarding -carotene
discussed above, the agency received no comments objecting to this
requirement. Thus, the agency is adopting Sec. 101.79(c)(2)(iii) as
proposed. The agency advises that the limitation contained in this
provision pertains only to conventional foods or to dietary supplements
that contain more than 100 percent of the RDI for vitamin A as retinol
or preformed vitamin A or vitamin D.
E. Label Information
1. Mandatory Nutrition Labeling
In Sec. 101.79(c)(2)(iv), FDA proposed to require that the
nutrition label of conventional foods or dietary supplements bearing
the folate/neural tube defect health claim provide information about
the amount of folate in the food or dietary supplement. This proposed
requirement is consistent with Sec. 101.9(c)(8)(ii) (21 CFR
101.9(c)(8)(i)), which states that the declaration of vitamins and
minerals on the nutrition label shall include any of the vitamins
[[Page 8764]]
and minerals listed in Sec. 101.9(c)(8)(iv) when a claim is made about
them.
19. One comment agreed with the proposed requirement for mandatory
nutrition labeling on products bearing the folate/neural tube defects
health claim. Another comment noted that use of multiple terms such as
``micrograms,'' milligrams,'' etc., would probably confuse lay persons.
The agency agrees with the comments and is adopting, with the
modifications noted below, the requirement in Sec. 101.79(c)(2)(iv)
that products bearing the health claim include in the nutrition
labeling information about the amount of folate in the food.
FDA adopted the 1980 Recommended Dietary Allowance (RDA) values as
RDI values, with folate values expressed on the label in milligrams
(mg) and percent of the DV (58 FR 2206, January 6, 1993). In the
Federal Register of January 4, 1994 (59 FR 427 at 431), FDA proposed to
amend Sec. 101.9 by revising paragraph (c)(8)(iv) to state, among other
things, the RDI for folate in micrograms (i.e., 400 micrograms; 400
mcg). The agency stated that changing the current unit of measure for
folate will facilitate consumer comprehension of quantitative nutrient
information because consumers are more familiar with this nutrient
being expressed in microgram units.
In Sec. 101.79(c)(2)(i)(F) and (c)(3)(iv), FDA has modified the
codified language so that all references to folate intake in the health
claim will be required to be expressed as percent DV with the option of
adding the microgram equivalent in parentheses. That is, values for
folate will be expressed as percent of the DV (i.e., the percent of the
RDI as established in Sec. 101.9(c)(8)(iv)). FDA has modified the
codified language in Sec. 101.79(c)(2)(i)(F) so that reference to the
safe upper limit of daily folate intake in the health claim will also
be required to be expressed as percent DV with the option of adding the
microgram equivalent in parentheses (see comment 32 of this document).
Thus, in response to the comment's concern about the confusion that
would result if multiple terms are used to describe the level of
folate, FDA has modified the regulations to provide for consistent
terminology.
2. Identifying the Nutrient
In proposed Sec. 101.79(c)(2)(i)(B), FDA considered the use of
synonyms for ``folate'' and the need to aid consumers in understanding
this nutrient. The agency provided for the use of synonyms and for
additional description of this term through phrases such as ``folate,''
``folic acid,'' ``folacin,'' ``folate, a B vitamin,'' ``folic acid, a B
vitamin,'' and ``folacin, a B vitamin.''
20. Several comments agreed that the agency's proposed synonyms are
appropriate. Other comments urged that a single term, for example,
``folic acid,'' ``folic acid, a B vitamin,'' ``folate,'' or ``folate, a
B vitamin,'' be used throughout all claims. Other comments agreed with
the use of the agency's proposed synonyms to encourage the consumption
of healthy diets but recommended that claims be worded in such a way as
to demonstrate that ``folic acid'' is the effective form. Several
comments disagreed with use of the term ``folacin,'' noting that it was
rarely used.
The agency notes that the descriptive term ``a B vitamin'' in
conjunction with ``folate,'' ``folacin,'' or ``folic acid'' is commonly
used in lay information for consumers and may be useful for consumers
in indicating the nutritive function of folate as a vitamin. FDA is
thus retaining the provision for its optional use in
Sec. 101.79(c)(2)(i)(B).
FDA recognizes that current regulations for nutrition labeling in
Secs. 101.9 and 101.36 do not include the term ``folic acid'' as an
allowable synonym for folate. This omission was an oversight when the
agency amended Sec. 101.9 (58 FR 2079 at 2178, January 6, 1993), and
when it promulgated Sec. 101.36 (59 FR 373, January 4, 1994). Before it
was amended, Sec. 101.9 had listed folic acid as the preferred term,
with folacin as an allowable parenthetical synonym. When it proposed
amendments to Sec. 101.9 in 1990 (55 FR 29847, July 19, 1990), the
agency explained why the term ``folate'' was preferable to ``folacin''.
However, an explanation for use of ``folic acid'' was inadvertently
omitted in that document, as was inclusion of the term ``folic acid''
as an allowable synonym.
The agency has advised firms that it would have no objection to the
use of the term ``folic acid'' in nutrition labeling. In light of
common usage and FDA policy, and for consistency among nutrition
labeling and health claim regulations, the agency is making a technical
amendment to Secs. 101.9 and 101.36 in this final rule to include
``folic acid'' as an allowable synonym for folate.
The agency notes that, as discussed in comment 6, above, the terms
``folic acid'' and ``folate'' are both used in the PHS recommendation
(Ref. 5). By allowing the use of these terms, the PHS recommendation
can be quoted directly on the label if all other requirements for the
health claim are met. The inappropriateness of limiting the term to
``folic acid'' to describe the relationship has been discussed in
response to comment 6 of this document. Therefore, FDA is adopting
Sec. 101.79(c)(2)(i)(B) as proposed.
3. Identifying Diets Adequate in Folate
In Sec. 101.79(c)(2)(ii)(B), the agency proposed to require that
health claims relating folate to neural tube defects identify sources
of folate by stating that adequate amounts of folate may be obtained by
making specific dietary choices of folate-rich foods, as well as
through use of dietary supplements or fortified breakfast cereals. The
purpose of this proposed requirement was to assist women in obtaining
adequate amounts of folate in their diets by providing information on
sources of folate. In proposed Sec. 101.79(c)(2)(ii)(B), the agency
provided examples of the types of phrases that could be used to meet
this requirement (e.g., ``Adequate amounts of folate, a B vitamin, can
be obtained from diets rich in fruits, dark green leafy vegetables and
legumes, enriched grain products, fortified cereals, or from dietary
supplements'').
21. Many comments agreed with the proposal to require statements
that dietary sources such as fruits, vegetables, and grains may
contribute folate to the diet, although some comments disagreed with
providing specific details, such as recommended numbers of servings.
Other comments supported the agency's proposed approach, emphasizing
that the health claim must help consumers understand that, in
pregnancy, it is the total diet, not a single food, that is related to
health outcome, and that there is good evidence for dietary claims
regarding increased folate intake and reduced risk of neural tube
defects. Another comment stated that health claims should not reveal a
bias against food forms, fortificants, or dietary supplements.
Other comments disagreed with the proposal to identify healthful
dietary patterns on the basis that many women will not change their
eating habits, and that it is therefore important to point out the
importance of use of dietary supplements. Other comments noted that the
statements regarding beneficial diets were overly focused on food and
should be made optional, that adding dietary information to the health
claim reduces its educational effectiveness, and that inclusion of such
information was neither required by law nor consistent with other
authorized health claims such as that for calcium and osteoporosis.
Several comments recommended that statements regarding diets adequate
in folate be made optional because such information is
[[Page 8765]]
better presented in educational materials.
The agency disagrees with the comments that stated that the
proposed statements regarding sources of folate were overly focused on
food. Such comments imply that FDA was biasing the statements against
dietary supplements. In fact, each example included dietary supplements
in the list of sources of folate (e.g., fruits, vegetables, enriched
grain products, fortified cereals, and dietary supplements). The agency
also disagrees that the educational effectiveness of the claim is
reduced by inclusion of the proposed statement because statements of
this type provide, in an abbreviated form, information on sources of
folate about which a consumer may be unaware.
In the context of a total diet, the consumer needs flexibility in
deciding how to increase folate intake. Provision of this information
is consistent with section 403(r)(3)(B)(iii) of the act, which states
that the claim shall be stated in a way that enables the public to
understand the relative significance of the claim in the context of the
total daily diet. Awareness of the food sources of folate, including
dietary supplements, will assist women in recognizing the significance
of the claim in the context of the total diet. Provision of information
on sources of folate in the health claim will assist consumers by
making them aware that specific foods and dietary supplements contain
folate.
However, FDA recognizes that while there has been a noticeable
increase in the use of health claims over the last 2 years, the number
of products that bear health claims is not as great as the agency had
anticipated. The agency is therefore interested in simplifying claims
to facilitate their increased use. The agency is particularly
interested in removing so-called ``required'' elements that are not
necessary to ensure that the claims are truthful, not misleading, and
scientifically valid. While the agency agrees with the comments that
supported inclusion of information on the dietary sources of folate,
and while it supports health claim statements that include examples of
dietary sources of this nutrient, the agency is concerned that
requiring such specific information will increase the length of the
claim and may dissuade manufacturers from including it in their
labeling.
In comment 14 of this document, the agency concluded that
information regarding overall improvement in a woman's diet and
nutrition throughout her childbearing years is of considerable
importance because pregnancy outcome depends upon adequate intake of a
wide range of nutrients. The agency is adopting
Sec. 101.79(c)(2)(i)(H), which requires that the health claim state
that there is a need for a healthful diet as well as adequate folate
intake. FDA has concluded that this information is necessary to ensure
that the claims have proper balance.
The agency is persuaded that shorter claims that state the need for
a healthful diet, without reference to specific foods, will meet the
objective of encouraging broader use of the claim while alerting women
to the importance of overall diet during the childbearing years.
Therefore, FDA is requiring that claims state that adequate folate
needs to be consumed as part of a healthful diet (see section II.C.5.
of this document, and new Sec. 101.79(c)(2)(i)(H)) without identifying
specific sources. The appearance of the claim on a wide range of
qualifying foods will itself convey information about the variety of
sources of folate available to women as part of a healthful total diet.
Therefore, the agency is removing proposed Sec. 101.79(c)(2)(ii)(B)
in its entirety and is adding in the codified language a provision
(Sec. 101.79(c)(3)(vii)) for optionally including in the claim
information that identifies sources of folate. Because of these
changes, FDA has adopted proposed Sec. 101.79(c)(2)(ii)(C) as
Sec. 101.79(c)(2)(ii)(B).
4. Identifying the Health-Related Condition
In developing proposed Sec. 101.79(c)(2)(i)(C), FDA considered
whether women might be confused or not understand the term ``neural
tube defect'' and provided for some qualification of this term through
use of alternate phrases such as ``the birth defect spina bifida,''
``the birth defects spina bifida and anencephaly,'' ``spina bifida and
anencephaly, birth defects of the brain or spinal cord,'' and ``birth
defects of the brain or spinal cord, spina bifida and anencephaly.''
22. The agency received several comments regarding these proposed
synonyms. A comment agreed with the agency that the health-related
condition must be specified and stated that the agency's proposed
synonyms were appropriate. Another comment noted that ``anencephaly''
is not a familiar term, and that a phrase such as ``certain serious
birth defects, neural tube defects'' is preferable. Another comment
recommended that only the statement ``neural tube defect'' be allowed
because it is the more appropriate and accurate term, and because
consumers will benefit from seeing the same identifying statements in
health claims on many products. Several comments, however, asserted
that consumers will not understand ``neural tube defects'' and stated
that a more understandable term might be ``birth defects of the brain
and/or spinal cord.''
The agency has considered these comments and concludes that the
term and qualifiers provided in its proposed rule, i.e., ``neural tube
defects,'' ``the birth defect spina bifida,'' ``birth defects spina
bifida and anencephaly,'' ``spina bifida and anencephaly, birth defects
of the brain or spinal cord,'' and ``birth defects of the brain or
spinal cord anencephaly or spina bifida,'' will allow manufacturers
considerable flexibility in crafting claims and in educating consumers.
The agency is also persuaded to include the option of using the simpler
terms ``birth defects of the brain or spinal cord'' or ``brain or
spinal cord birth defects'' and has modified Sec. 101.79(c)(2)(i)(C)
accordingly. The agency accepts the suggestion that use of the latter
terms will make the claims simpler and more useful to consumers because
the phrase may be more understandable than phrases that include medical
terms such as ``neural tube defects'' or ``anencephaly''.
The agency also considered whether use of the very general terms
``some birth defects'' or ``some serious birth defects'' would be
appropriate. As discussed in its January 1993 final rule on folate and
neural tube defects (58 FR 2606 at 2610), the act requires that claims
on foods be truthful and not misleading. The agency recognizes that,
based on the results of the Medical Research Council trial, the
association between folate intake and birth defects is limited to
neural tube defects. The Medical Research Council trial found that
folic acid, while significantly reducing the risk of neural tube
defects in women at high risk of recurrence of this complication, did
not significantly alter the incidences of a wide variety of other birth
defects in the population studied (Ref. 14). Similarly, Czeizel et al.
(Ref. 15) reported that the results of the Hungarian trial that studied
use of a multivitamin/multimineral supplement containing 0.8 mg of
folic acid showed no reduction in incidences of birth defects other
than neural tube defects.
FDA also points out that the prevalence of neural tube defects in
the United States has been steadily declining in recent decades, and
that the estimated incidence is presently about 1 in 1,600 births (Ref.
25). Currently, estimated incidences of other serious birth defects are
considerably higher than that for neural tube defects. For
[[Page 8766]]
instance, estimated incidences are 1 in 115 for birth defects involving
the heart and circulation, 1 in 130 for those involving the muscles and
skeleton, 1 in 135 for those involving the genital and urinary tract, 1
in 235 for those involving the nervous system and eye, 1 in 735 for
club foot, and 1 in 635 for chromosomal syndromes (Ref. 25).
Because neural tube defects constitute a relatively small fraction
of all birth defects, women should not be misled into a false sense of
security that they can affect their risk of all birth defects through
diets adequate in folate. The agency has therefore decided not to
include use of the more general terms ``some birth defects'' or ``some
serious birth defects'' because use of such terms would fail to
disclose the material fact that the food substance/disease relationship
is specifically between folate and neural tube defects. Use of such
general terms can create the impression that adequate folate intake
will reduce a woman's risk of other serious birth defects, and women
might, as a result, discount risk factors for other birth defects
(e.g., alcohol use, drug abuse).
5. Safe Upper Limit of Daily Intake
Sections 403(r)(3)(A)(ii), 402(a), and 409 of the act establish
that the use of a substance in a food must be safe. Based on concerns
discussed in the Federal Register of January 6, 1993 (58 FR 2606), the
agency concluded that it could not authorize a health claim on folate
and neural tube defects at that time. The agency was concerned that the
possibility exists that folic acid itself could be a substance that
increases the risk of a disease or a health-related condition in
persons in the general population (see section 403(r)(3)(A)(ii) of the
act).
Recognizing the potential for adverse effects from high intakes of
folate, PHS included a caution statement in its recommendation that
``because the effects of higher intakes are not well known but include
complicating the diagnosis of vitamin B12 deficiency, care should
be taken to keep total folate consumption at <1 mg="" per="" day,="" except="" under="" the="" supervision="" of="" a="" physician''="" (ref.="" 5).="" in="" sec.="" 101.79(c)(2)(i)(g),="" fda="" proposed="" to="" require="" a="" statement="" as="" part="" of="" the="" health="" claim="" on="" fortified="" foods="" in="" conventional="" food="" form="" and="" on="" dietary="" supplements="" containing="" more="" than="" 25="" percent="" of="" the="" rdi="" for="" folate="" per="" unit="" or="" per="" serving="" that="" 1="" mg="" of="" folate="" per="" day="" is="" the="" safe="" upper="" limit="" of="" intake.="" the="" agency="" noted="" that="" the="" availability="" of="" the="" health="" claim="" would="" likely="" encourage="" increased="" intakes="" of="" health-="" claim="" labeled="" foods,="" and="" that,="" if="" intakes="" of="" highly="" fortified="" foods="" and="" dietary="" supplements="" were="" increased,="" it="" could="" result="" in="" folate="" intakes="" above="" the="" level="" known="" to="" be="" safe.="" the="" agency="" received="" comments="" addressing="" two="" issues="" related="" to="" safe="" use="" of="" foods="" bearing="" health="" claims:="" (1)="" is="" there="" a="" need="" for="" concern="" about="" a="" safe="" upper="" limit="" of="" daily="" intake?="" (2)="" if="" so,="" should="" a="" statement="" identifying="" a="" safe="" upper="" limit="" of="" intake="" be="" included="" in="" a="" health="" claim,="" and="" how="" should="" such="" a="" statement="" be="" worded?="" a.="" need="" for="" concern="" about="" a="" safe="" upper="" limit="" of="" daily="" intake.="" fda="" tentatively="" concluded="" that,="" under="" certain="" circumstances,="" there="" was="" a="" need="" to="" disclose="" the="" safe="" upper="" limit="" of="" intake="" in="" the="" health="" claim="" and="" tentatively="" decided="" to="" use="" 1="" mg="" per="" day="" (1,000="" mcg;="" 250="" percent="" of="" the="" dv)="" of="" total="" folate="" as="" the="" upper="" limit="" for="" such="" intake="" (58="" fr="" 53254="" at="" 53273).="" the="" agency="" noted="" in="" the="" final="" rule="" of="" january="" 6,="" 1993="" (58="" fr="" 2606="" at="" 2612),="" and="" the="" proposed="" rule="" of="" october="" 14,="" 1993="" (58="" fr="" 53254="" at="" 53266),="" that="" there="" is="" a="" general="" paucity="" of="" evidence="" on="" the="" safety="" of="" daily="" folate="" intakes="" above="" 1,000="" mcg="" (1="" mg).="" the="" agency="" noted="" that="" there="" may="" be="" risks="" attendant="" upon="" increased="" consumption="" of="" folate="" for="" some="" groups="" in="" the="" population.="" the="" agency="" stated="" that,="" at="" the="" present="" time,="" the="" potential="" adverse="" effect="" that="" has="" been="" most="" extensively="" documented="" is="" a="" masking="" of="" anemia="" in="" persons="" with="" vitamin="">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 B12 deficiency, there was little likelihood of
problems at daily intakes lower than 1 mg (58 FR 53254 at 53268 to
53270); (2) an upper limit of intake of 1 mg of folate per day was safe
for pregnant women and for persons with epilepsy; (3) doses of folic
acid of up to 1 mg per day have not been reported to reduce the
effectiveness of medications that interfere with folate metabolism; (4)
effects of long-term continuous exposures of body tissues to elevated
blood levels of folic acid, which occur when the body's capacity to
metabolize folic acid is exceeded, have not been evaluated; and (5)
there have been no long-term studies to quantitate the effects, if any,
of increased folate intake on the metabolism of other nutrients.
The agency stated (58 FR 53254 at 53268) that it knew of no data
that would support the long-term safety of continuous daily folate
intakes of more than 1 mg. The agency, noting that the value of 1 mg
for a safe upper limit of daily folate intake could be modified if data
were available to support such a decision, solicited comments and data
on this point.
In addition, the agency described how it had reached its tentative
decision that a statement that 1 mg of total folate per day was the
safe upper limit of daily intake should be required on products bearing
the health claim and fortified above 25 percent of the RDI for folate.
The agency's tentative conclusion was based on, among other
considerations: (1) The scientific evidence, and the view expressed by
experts, that there are no data to ensure that adverse effects are not
likely to occur at daily intakes above 1 mg (Refs. 6, 7, 8, and 26);
(2) the PHS recommendation that folate intake of women of childbearing
age should not exceed 1 mg per day (Ref. 5); and (3) the support by the
Folic Acid Subcommittee of FDA's use of 1 mg of total folate per day as
a safe upper limit guide when considering fortification strategies. The
upper safe limit of intake that FDA proposed was based on its best
scientific judgment at the time. The agency solicited comments and data
on its tentative judgment.
Some comments expressed uncertainty regarding an amount that would
represent a safe upper limit of daily intake of folate, while other
comments strongly agreed or strongly disagreed with FDA's proposal that
1,000 mcg of total folate per day is the safe upper limit of intake.
The agency did not receive any data relating to safety of long-term
intakes of folate at levels above 1 mg per day for any of the groups
considered at potential risk from increased intakes.
23. Several comments noted that the agency should not misconstrue
the absence of safety data on folate intakes of 1 to 4 mg (1,000 to
4,000 mcg) per day as evidence of the absence of harm; that because
daily intakes for the general population are well below 1 mg, it has
never been established that 1 mg per day of folate from all sources is
a safe daily upper limit; and that the upper safe limit of intake for
African-Americans, and perhaps Hispanic
[[Page 8767]]
Americans, is not known. Several comments noted that pernicious anemia
has an earlier age-at-onset among African-Americans than among
Caucasians, and that vitamin B12 deficiency is not rare in persons
with sickle cell anemia. Another comment noted that the level of folate
that will accelerate the neurologic disorders of vitamin B12
deficiency is unknown, and that physicians see patients who have been
taking folic acid supplements who present with neuropsychiatric
disturbances. Another comment noted that there were uncertainties
regarding effects of chronic exposures of children, whose requirements
for folate are lower than those of adults, to increased intakes of
folic acid. Uncertainties regarding safety of increased intakes of this
nutrient were the major factor in the opposition in the Folic Acid
Subcommittee/Food Advisory Committee to FDA's proposed rules (Ref. 8).
Many comments agreed with FDA's estimate of 1 mg of folate as an
upper safe limit of intake given the paucity of information concerning
the possible risks of excess folate intakes. Other comments noted that
the masking of pernicious anemia is real, but that there is no evidence
for folate toxicity at daily intakes of 1 mg/day or less. The comments
said that the value of 1 mg/day has, therefore, emerged as being safe.
Other comments recognized that overconsumption of folate may complicate
the diagnosis of vitamin B12 deficiency, but that there is limited
evidence regarding effects of intakes of folic acid between 400 mcg and
5,000 mcg per day.
FDA notes that a major factor in both the Folic Acid Subcommittee's
and the Food Advisory Committee's concern about FDA's proposals was the
fundamental issue of lack of documentation of safety of long-term daily
intakes at levels above 1,000 mcg (Ref. 8). The agency is also aware
that the Committee members expressed considerable concern about the
lack of information on the size of the population potentially at risk
from increased intakes of folate. Specifically, the agency did not
receive data regarding potential adverse effects of increased folate
intakes in African-American women or in children. The agency notes that
the absence of data on long-term effects of increased folate intakes
does not allow the agency to adequately identify those potentially at
risk.
As stated above, the agency is not aware of any data that establish
the safety of long-term intakes of folate above 1,000 mcg per day. The
absence of any data that allow systematic evaluation of intakes above
this level means that potential risks and at-risk groups cannot be
adequately defined or described. FDA notes that some members of the
Folic Acid Subcommittee and most folate and vitamin B12 experts
submitting comments (Ref. 8) were concerned about the lack of
documentation of safety of daily long-term intakes of folate above the
level of 1 mg/day. In addition to concerns regarding those with low
vitamin B12 status, other safety concerns included uncertainties
of effects of increased folate intakes by young children and the
unknown physiological significance of circulating free folic acid in
the blood, particularly in pregnant women. In its proposed rule (58 FR
53254 at 53269), the agency summarized evidence from the scientific
literature that high levels of free folic acid are not normally found
in the circulation, and that folic acid is concentrated in crossing the
placenta and accumulates in fetal tissues. The agency also noted that
no information is available to ascertain whether developing neural
tissue is protected from the neurotoxic effects of very high
circulating levels of free folic acid. None of these issues were
addressed in comments that the agency received.
Comments that disagreed with FDA's proposal to consider 1,000 mcg
folate/day as the safe upper limit of intake raised several issues
which are considered below:
i. Basis for a safe upper limit: Synthetic folic acid versus total
folate.
24. A comment stated that the limit should be based on supplemental
synthetic folic acid only because only this form has been associated
with masking of the anemia of pernicious anemia. This issue of whether
the upper limit should be based on total folate or on synthetic
crystalline folic acid was raised in several comments, with some
comments of the opinion that it was appropriate to use estimated
consumption of folate from all sources in defining the safe upper limit
of intake and others recommending use of ``crystalline folic acid''
only.
The agency disagrees that the safe upper limit of daily intake
should be based on ``crystalline folic acid'' rather than total folate
from all sources. FDA notes that the distinction between ``synthetic
folic acid,'' referring only to crystalline folic acid, and ``folate,''
referring only to naturally occurring food folates, with respect to the
1,000 mg/day estimate of safe daily intake, is an artificial one and is
not consistent with what is known about the nutritional
interrelatedness of a variety of folate vitamin forms in providing
coenzyme forms of the vitamin for meeting the body's needs for this
essential nutrient. Issues relating to ``folic acid'' versus ``folate''
are discussed in response to comment 6 of this document.
Metabolic needs for folate are met from body pools of reduced
coenzymes, regardless of whether these coenzymes are derived from
synthetic folic acid or from naturally occurring food folates. While it
is true that evidence relative to the masking of the anemia of vitamin
B12 deficiency has been obtained from persons who consumed or were
treated with synthetic folic acid, such individuals were also consuming
unknown quantities of folate from foods. Thus, total daily folate
exposures associated with the masking have not been quantified, and the
effect of food folates on adverse effects is not known. It is also not
known whether the variable responses, in terms of masking effects, to
low levels of folic acid in supplements are the result of differences
in folate intakes from background diets or of other factors that are
currently not understood. For these reasons, it is not possible to
attribute all adverse effects solely to crystalline folic acid.
In addition, high intakes of food folates can have adverse effects
in persons with poor vitamin B12 status. With respect to
nonpernicious anemia-related vitamin B12 deficiency, Sanders and
Reddy (Ref. 27) noted that megaloblastic anemia is rarely encountered
in Caucasian vegetarians and vegans because of their high intakes of
folate. These authors reported that, for example, the folate content of
diets of vegan children aged 6 to 13 years was twice as high as that of
omnivorous children aged 7 to 12 years (Ref. 27). Because the high
folate intakes would at least temporarily improve the associated
anemia, vitamin B12 deficiency usually presents with neurological
signs and symptoms in infants (Ref. 27). Herbert reported that studies
over several decades have all indicated that major myelin synthesis
damage from vitamin B12 deficiency with only minor hematopoietic
(i.e., hematologic) damage reflects better folate status because folate
improves hematologic, but not neurologic, manifestations of the
deficiency (Ref. 28). He also found generally higher red cell folate in
persons with greater myelin damage (that only vitamin B12
deficiency produces) than in persons with greater hematologic damage
(which deficiency of either folate or vitamin B12 produces) (Ref.
28).
The observations above suggest that a safe upper limit of daily
intake is more
[[Page 8768]]
accurately based on total folate intake than on just intake of
crystalline folic acid because under conditions in which vitamin
B12 utilization or intake is limited (i.e., in pernicious anemia
or in nonpernicious anemia-related vitamin B12 deficiency), either
crystalline folic acid or food folate may cause adverse effects when
consumed in excess.
The agency noted in response to comment 6 of this document, that
use of a distinction between ``folic acid'' and ``folate'' is
inconsistent with the PHS recommendation, which uses these terms
interchangeably (Ref. 5), and with advice provided by FDA's and CDC's
advisory panels. Moreover, use of such a distinction is not supported
by recent statements from experts on folate and vitamin B12 (Refs.
7, 8, and 26). Therefore, the agency concludes that the safe upper
limit of daily intake should be based on total folate intake (i.e., on
consumption of folate from all sources).
ii. Lack of evidence of untoward effects of increased intakes.
25. Several comments that disagreed with the agency's tentative
conclusion that 1 mg folate per day from all sources is the safe upper
limit of intake stated that there is no evidence that maximum intakes
of 1,500 mcg to 2,000 mcg will result in any untoward effects. Another
comment reviewed the literature describing the effects of intakes of
1,000 to 5,000 mcg folic acid per day in persons with vitamin B12
deficiency and concluded that the literature did not reveal any
substantial safety concerns. Another comment stated that 5,000 mcg/day
should replace 1,000 mcg/day as the upper limit of safe intake.
The agency is aware that the literature describing the effects of
intakes of folic acid between 1,000 and 5,000 mcg per day is very
limited but disagrees that there is no evidence of untoward effects of
daily folate intakes of 1,500 to 2,000 mcg per day, and that 5,000 mcg
per day should be identified as the safe upper limit of intake.
The literature describing the effects of daily intakes of 1,000 to
5,000 mcg folic acid includes three uncontrolled intervention trials
involving 15 persons (Refs. 29, 30, and 31) and 16 case reports (Refs.
32, 33, 34, 35, 36, and 37). These reports represent a very small data
base, with information from a total of only 31 individuals. Moreover,
the agency notes that, among these data, exposures of 9 individuals to
daily intakes of 1,000 to 5,000 mcg folic acid lasted for less than 30
days (e.g., Refs. 30, 31, 32, and 33). Therefore, these reports are not
useful in assessing the safety of life-long exposures. However,
hematological responses that could lead to a delay in the diagnosis of
vitamin B12 deficiency were observed in 9 of the 16 patients
(i.e., in more than 50 percent) whose daily oral intakes of folic acid
were in the range of 1,000 to 5,000 mcg and continued for 1 month or
more (Refs. 29, 32, 33, 35, and 37). Thus, the limited scientific
literature shows that approximately half of the patients with
pernicious anemia associated with vitamin B12 deficiency will
respond to folate at doses between 1,000 and 5,000 mcg per day when
they are given the vitamin for relatively short periods of time (e.g.,
several months).
In addition, in discussing safety issues in its proposed rule (58
FR 53254 at 53267), the agency noted that, although there was a lack of
systematic evaluation of the effect of folic acid on the anemia of
vitamin B12 deficiency at intakes of less than 5,000 mcg per day,
several case reports have described hematologic improvement in
pernicious anemia patients with doses of folic acid lower than 1,000
mcg/day (e.g., at 200 to 500 mcg/day; Refs. 38, 39, 40, 41, 42, 64
through 65, and 72 through 74). Thus, adverse effects have been
reported at daily doses of less than 1,000 mcg, at doses of 1,000 to
5,000 mcg, and at doses greater than 5,000 mcg.
iii. Lack of evidence of toxic effects of increased folate intakes
in pregnant women.
26. Another comment that disagreed with the agency's tentative
conclusion noted that millions of pregnant women have taken prenatal
vitamins containing 1,000 mcg folic acid, that folic acid at dosages of
4,000 mcg per day has been extensively studied in pregnant women, and
that no toxic effects have been shown in healthy individuals.
The agency disagrees with the comment that folic acid at doses of
4,000 mcg per day have been extensively studied in pregnant women and
are without toxic effects. The agency recognizes that pregnant women
take prenatal supplements which usually contain 800 mcg of folic acid,
and that such supplements have been in use for many years. FDA notes
that, while there is no evidence that 800 mcg of folic acid per day
(i.e., the RDA level for pregnant or lactating women) is unsafe for
this group, such dosages are usually taken only during the second and
third trimesters of pregnancy or during lactation to meet specific
nutritional needs for limited periods of time and are usually taken
under physician supervision. The Institute of Medicine in Nutrition
During Pregnancy stated that the safety of large doses of folic acid in
pregnant women has not been systematically determined (Ref. 43).
The agency notes also that the comment that folic acid at doses of
4,000 mcg per day has been extensively studied in pregnant women, and
that such doses are without toxic effects, is not substantiated by the
scientific data. In the only study utilizing 4,000 mcg folic acid/day,
the Medical Research Council (MRC) trial, about 910 women took
supplements containing 4,000 mcg of folic acid from the time of
randomization into the trial until the 12th week of pregnancy (Ref.
14). At the conclusion of the study, the author stated that, although
the MRC trial had sufficient statistical power to demonstrate the
efficacy of the intervention, it did not have sufficient power to
answer the question of safety for public health purposes. Consequently,
this study does not provide a basis on which to determine whether the
use of 4,000 mcg/day of folic acid by pregnant women is safe.
Thus, the agency has not received any data or information that
would persuade it that any level other than 1 mg (1,000 mcg) folate per
day is the appropriate safe upper limit of intake for pregnant women.
iv. Adverse effects in those with vitamin B12 deficiency can
be detected with clinical care.
27. Another comment disagreed with the proposed 1,000 mcg safe
intake limit and noted that adverse effects of high intakes of folate
with respect to vitamin B12 deficiency can be detected with
clinical care. Other comments stated that the issue of masking of
vitamin B12 deficiency was overstated and predated modern clinical
nutrition.
FDA is aware that, in many instances, the adverse effects of
increased folate intake associated with the masking of the anemia of
vitamin B12 deficiency can be detected with clinical care but
disagrees that this fact provides adequate justification for increasing
the safe limit of daily intake. The agency notes that measurements of
vitamin B12 status are not performed on a routine basis by
physicians. Currently, there are no population-based data on how many
people in the United States have undiagnosed vitamin B12
deficiency and thus might be at risk from increased intakes of folate.
The agency noted in the January 6, 1993 final rule (58 FR 2606 at
2615), that significant percentages of the elderly, demented patients,
acquired immune deficiency syndrome (AIDS) patients, and patients with
malignant diseases have subnormal vitamin B12 levels without
having any of the classical manifestations of vitamin B12
deficiency. Lindenbaum et al. recently reported that the prevalence of
vitamin B12 deficiency was greater than
[[Page 8769]]
12 percent in a large study (n=548) of free-living elderly Americans
(Ref. 44). In addition, 5 to 10 percent of all patients, regardless of
age or clinical status, are found to have low serum vitamin B12
levels (58 FR 2606 at 2615). Little is known about whether folate
supplementation would have any adverse effect on such persons, who are
far more numerous in the U.S. population than are persons with
pernicious anemia.
The argument that adverse effects in persons with vitamin B12-
related problems can be identified with clinical care fails to consider
whether such persons, who may be unaware of their vitamin B12
status, would recognize an adverse effect as being the result of
increased folate intake, and whether they would seek medical attention
if subtle adverse effects were experienced. Thus, the agency concludes
that the argument that adverse effects in persons with vitamin
B12-related problems can be identified with clinical care does not
provide a sufficient basis for increasing the safe upper limit of
intake for such persons or for other persons in the general population
for whom there are currently no data to establish the effects, if any,
of high intakes of folate. In developing its proposed rule,
FDA was aware of the contentious nature of a proposed upper limit
and specifically asked for data on this issue. This topic was also
extensively discussed by FDA's Folic Acid Advisory Committee and Food
Advisory Committee (Refs. 7 and 8). No data were submitted in any of
the comments that addressed the issue of the safety of intakes above
1,000 mcg per day either for persons in the general population or for
any of the groups identified as potentially at risk from increased
folate intakes. The agency also notes that its position regarding use
of 1,000 mcg folate per day as the safe upper limit of daily intake was
supported by all comments from individuals with known expertise in
folate and vitamin B12 metabolism and related diseases.
Because there are inadequate data and information on the safety of
consuming more than 1,000 mcg folate per day, the agency is unable to
conclude that there is a reasonable certainty of no harm to persons
consuming more than 1,000 mcg folate per day. In the absence of data on
high intakes of folate, the agency is unable to adequately define the
nature or magnitude of potential risk from increased folate intakes. At
this time, the agency has no data to support a conclusion of safe use
of folate above 1,000 mcg per day or data that would provide a basis
for a change from the proposed upper limit of 1,000 mcg per day to an
upper limit of 5,000 mcg per day. In addition, for the reasons
explained above, the agency has not been persuaded by the comments that
it should consider synthetic folic acid as the only active form of the
vitamin and thus base its estimate of a safe upper limit of intake on
this form of the vitamin only.
The agency therefore concludes that, because of the lack of
evidence of safe use at intakes greater than 1,000 mcg folate daily,
and the potential for serious harm to some persons from such intakes,
daily intakes above 1,000 mcg by the general population should not be
encouraged.
b. Including a safe upper limit of daily intake in the claim. In
recognition of comments and safety concerns discussed in its proposal,
FDA, in Sec. 101.79(c)(2)(i)(G), proposed to require a statement on
fortified foods in conventional food form and on dietary supplements
that contain more than 25 percent of the RDI (i.e., more than 100 mcg
per reference amount customarily consumed or, for supplements, per
unit) about the maximum safe daily limit for folate consumption. The
agency proposed that such a statement (e.g., ``Folate consumption
should be limited to 1,000 mcg per day from all sources.'') was
necessary to prevent the health claim from being misleading regarding
potential risks from excessive intakes.
In the October 14, 1993 proposal (58 FR 53254 at 53282), the
agency, noting that the safe upper limit of intake was 1 mg (1,000
mcg), stated that a fortified food that contains more than 100 mcg
folate per serving contributes more than 25 percent of the RDI and more
than 10 percent of the daily limit. Therefore, it continued,
consumption of such foods should be monitored by the consumer, so that
he or she will not consistently or significantly exceed the upper
limit.
In its proposed rule (58 FR 53254 at 53282), the agency also noted
that it was not proposing to require that this statement be included in
claims on the relatively small number of conventional foods that
contain more than 100 mcg of folate without fortification (e.g., dark
green leafy vegetables, certain legumes). The agency stated that it
believed that there is no need for the consumer to monitor intakes of
these foods because their folate content consists of reduced
pteroylpolyglutamates whose bioavailability is generally considered
lower than that of the folic acid (i.e., pteroylmonoglutamate) added as
a fortificant to foods. The agency received many comments on this
aspect of the proposal.
c. General comments.
28. Comments supporting inclusion of a caution statement in health
claims stated that an admonition regarding excessively high intakes is
absolutely essential in the health claim, and that the agency must
require a meaningful and useful disclosure regarding the risks of
excess intake. One comment stated more specifically that health claims
related to folate and neural tube defects should be balanced by a
warning statement that increased intakes of folate may increase the
frequency of irreversible neurologic damage from vitamin B12
deficiency. A related comment stated that, among Black and Hispanic
females, folic acid fortification or supplementation is likely to do
more harm than good, and that a caution statement was important for
such groups. One comment recognized the need to set upper limits of
safe intake but noted that, in the absence of strong evidence, it is
inappropriate to warn consumers about potential adverse effects and
detract from the benefits of the health claim.
Other comments supported the use of a statement of a safe upper
limit of intake but found FDA's proposed language in
Sec. 101.79(c)(2)(i)(G) and in the model health claims (Sec. 101.79(d))
unsatisfactory because the agency failed to provide specific
information on the potential adverse effects of overconsumption and
failed to identify the subpopulations at risk from high intakes (e.g.,
the elderly).
The agency does not agree that it is inappropriate to warn
consumers about the potential adverse effects of increased folate
intake because adverse effects have been documented in the scientific
literature. The agency's responses to comments 23, 25, and 27 of this
document make clear that, for some population groups, there are risks
attendant upon increased folate intake. Such groups include those with
vitamin B12 deficiency and African-American women. As noted above,
the agency did not receive data providing evidence rebutting the risks
of folate intakes above 1 mg per day (1,000 mcg/day) for these and
other at-risk groups, such as pregnant women, children, persons on
antiseizure medications, or persons on antifolate medications.
Therefore, the agency agrees with the comments that stated that it
should require that a useful statement regarding risks of excessive
intakes be included in the health claim. In response to the comment
that the model health claims were unsatisfactory because they failed to
identify specific subpopulations at risk from increased intakes (e.g.,
the elderly), the agency is advising that it will not require
identification of specific
[[Page 8770]]
at-risk groups in the caution statement because the limited data
available from populations consuming folate at the level of 1 mg per
day (1,000 mcg per day) and above do not allow an adequate
identification of all such groups to be made. Identification in the
claim of only some of the groups at risk (e.g., the elderly) would be
misleading because persons in other at-risk groups that were not
identified in the claim could conclude that because they were not
mentioned, they were not at risk from high intakes.
d. Inappropriate to include caution statement only on fortified
foods and supplements.
29. Other comments stated that it was inappropriate to single out
only fortified foods or supplements that contain folate above 25
percent of the DV for carrying a warning statement.
The agency proposed not to require the caution statement in health
claims on the relatively small number of conventional foods that
contain more than 100 mcg of folate without fortification (e.g., dark
green leafy vegetables, certain legumes) because many of these foods
are not consumed on a daily basis, and even when consumed regularly,
the bulk and energy value of such foods tends to limit their
consumption.
The agency has reevaluated whether foods that are naturally high in
folate (e.g., those containing more than 25 percent of the DV) should
carry the caution statement proposed for fortified foods or supplements
containing more than 25 percent of the DV. The agency agrees with the
comment that it is inappropriate to single out fortified foods and
supplements for a caution statement because there is no justification
for distinguishing between added and naturally-occurring nutrients.
This decision is consistent with the agency's conclusion (see comment
23 of this document) that total folate intake from all sources needs to
be considered in arriving at a safe upper limit of daily intake. For
this reason, FDA has decided to require that the modified caution
statement described in comment 31 of this document appear on any
conventional food or dietary supplement that meets the criteria set out
in Sec. 101.79(c)(2)(i)(F).
e. Optional caution statement.
30. Another comment advised the agency to permit the identification
of the 1,000 mcg per day limit as optional information.
The agency rejects this comment. Given the point of the health
claim message, it is unlikely that an optional caution statement would
be included in most health claims. Therefore, most consumers would not
be alerted to the potential adverse effects of high levels of folate or
might assume that claim- bearing products without the caution statement
were safer than products that bore a claim that included the caution
statement. Consumption of products bearing the caution statement might
come to be associated with potential adverse effects, while consumption
of other products with an identical folate content that did not bear
the caution statement would not be associated with such potential
adverse effects. Because potential adverse effects are related to
increased intakes of folate from any source, it would be illogical for
the agency not to require the caution statement on all products that
carry the health claim and that meet the criteria for the caution
statement. Claims on products that meet the criteria and that fail to
carry the caution statement would be misleading because they would fail
to alert consumers to the material fact that there may be risks
attendant upon excessive folate intakes.
f. Upper limit of safe intake expressed as percent DV.
31. Another comment agreed with the use of a caution statement but
felt that the safe upper limit of intake should be expressed as percent
of the DV.
The agency agrees with this comment because this method of
communicating the safe upper limit of intake will provide consistency
with the nutrition label, thereby enhancing the comprehensibility of
the information. The agency notes that, as stated in response to
comment 19 of this document and in the codified language in
Sec. 101.79(c)(2)(i)(F), the upper limit of daily intake is to be
expressed in the claim as percent of the DV, with manufacturers having
the option of including the microgram equivalent in parentheses (e.g.,
250 percent DV (1,000 mcg)).
g. Limit caution statement to products with 100 percent DV.
32. Several comments said that a warning statement should be
limited to higher-dose foods or dietary supplements (those containing
100 percent or more of the DV) unless further research and monitoring
demonstrate that the risks of increased folate intakes from lower-dose
foods or supplements are also significant. Other comments argued that
there is no need to include a warning statement and noted that
supplements and cereals with 100 percent of the DV have never carried
such awarning statement. Other comments expressed the opinion that the
warning statement would discourage increased consumption of folic acid
supplements.
The agency has considered whether requiring that the caution
statement appear in claims on foods or dietary supplements that contain
more than 25 percent of the DV is too restrictive. The agency
recognizes that such a requirement would require that caution
statements appear as part of health claims on a wide range of products
that contain more than 100 mcg folate per serving (e.g., dietary
supplements, breakfast cereals) that have not previously carried such a
statement. The agency agrees with the comment that the result of such
caution statements could well be to discourage consumption of such
products. It was not the agency's intent to cause such a result because
breakfast cereals and dietary supplements have traditionally been
important sources of folate for consumers who use them. Additionally,
in the case of many dietary supplements, a statement regarding daily
consumption (e.g., ``consume one per day'') is already included in the
labeling and serves to inform consumers as to the appropriate daily
intake.
The agency notes, however, that the health claim is intended to
encourage women to increase their intakes of folate, and that the claim
is likely to encourage some women to consume more of particular
products, particularly those bearing the claim that are very high in
folate, than they might otherwise consume. Thus, a caution statement
regarding excessive intakes is appropriate on foods that contain very
high levels of folate because the possibility is created by the claim
itself that some women will achieve high folate intakes.
The agency has concluded that a statement about high consumption of
folate is necessary if a product contains more than 100 percent of the
DV (i.e., 400 mcg when labeled for use by adults and children 4 or more
years of age; 800 mcg when labeled for use by pregnant or lactating
women; 58 FR 2206 at 2213, January 6, 1993; Food Labeling; Reference
Daily Intakes and Daily Reference Values). Such an amount of folate
would exceed not only the DV's but the PHS recommended folate intake
for women of childbearing age. Thus, the caution statement is required
only on products that contain more than current recommended daily
intakes of folate per serving.
The agency has redesignated proposed Sec. 101.79(c)(2)(i)(G) as
Sec. 101.79(c)(2)(i)(F) and has modified this provision to read that:
Claims on foods that contain more than 100 percent of the Daily
Value (DV) (400 mcg) when labeled for use by adults and children 4
or more years of age, or 800 mcg
[[Page 8771]]
when labeled for use by pregnant or lactating women) shall identify the
safe upper limit of daily intake with respect to the DV. The safe
upper limit of daily intake value of 1,000 mcg (1 mg) may be
included in parentheses.
h. Upper limit useless without reference to intake goal.
33. Other comments opposed including a reference to the upper limit
of 1,000 mcg per day in any health claim because, they argued,
consumers cannot determine their total daily intakes from all sources.
These comments noted that stating an upper limit was useless unless all
food types were labeled with their folate content. Another comment
opposing the inclusion of a warning statement on foods or supplements
containing more than 25 percent of the DV stated that inclusion of an
upper limit was problematic if reference was not made to the 400 mcg/
day intake goal.
The agency recognizes that there was an inconsistency in the way
that proposed Sec. 101.79(c)(2)(i)(G) was worded in that the safe upper
limit of daily intake was expressed as 1,000 mcg rather than as a
percent of the DV. The agency has corrected this inconsistency, as
noted above in response to comment 32 of this document.
The agency disagrees that inclusion of the 400 mcg intake goal is
necessary to make a caution statement understandable, and that a
caution statement is useless unless all foods are labeled with their
folate contents. The agency notes that diets that do not contain highly
fortified foods and dietary supplements rarely provide daily folate
intakes of more than 1,000 mcg. The likelihood of achieving daily
intakes exceeding 1,000 mcg arises from consumption of highly fortified
foods and dietary supplements, particularly those that contain more
than the DV per unit or per serving. Under current labeling
requirements, such foods and supplements must, or soon will have to,
carry nutrition labeling. The safe upper limit of daily intake will
thus appear on those products whose use provides the greatest potential
for contributing to overconsumption (e.g., highly fortified foods and
supplements whose label bears a health claim that explains a potential
benefit of increased consumption). The agency concludes that it is
necessary to require inclusion of the caution statement, with the safe
upper limit of daily intake expressed as percent of the DV (percent
DV), as part of the health claim on such products.
The agency also notes that the availability of the health claim may
result in increased consumption of foods with high folate content that
carry the claim. The expression of the folate content as a percent of
the DV will help consumers who select a health claim-labeled food that
contains more than 100 percent of the DV and that is labeled with a
statement that folate intakes should be limited to 250 percent of the
DV, to recognize that the product provides more than the full amount of
the DV while still leaving a considerable allowance for consumption of
other foods of lower folate content. The percent DV labeling will also
allow a consumer who selects four health claim-labeled foods that each
contain more than 100 percent of the DV to quickly compute that these
four products alone will provide more than 400 percent of the DV, an
amount in excess of the safe upper limit of daily intake of 250 percent
of the DV. Thus, the agency does not believe that explicit reference to
the 400 mcg target intake goal is necessary to make the caution
statement understandable. The agency advises, however, that
manufacturers wishing to include reference to the 400 mcg intake goal
may do so (Sec. 101.79(c)(3)(iv)).
i. Caution statement on all products with >25 percent DV.
34. One comment interpreted the proposed regulation to mean that
the agency was proposing to require use of a caution statement on all
products with more than 100 mcg folate/serving, whether or not they
bore the health claim.
This comment misunderstood the proposal. The agency advises that it
is requiring that the caution statement be used only on conventional
foods or dietary supplements that bear the folate/neural tube defects
health claim and that contain more than 100 percent of the DV (400 mcg
when labeled for use by the general population or 800 mcg when labeled
for use by pregnant or lactating women).
j. Warnings on supplements without adequate vitamin B12.
35. One comment suggested that the agency should require warnings
on supplements that do not provide amounts of vitamin B12 adequate to
provide protection from the potential problem in nearly all cases.
This comment was based on the assumption that the greatest
potential for adverse effects of high folate intake is the masking of
the anemia of vitamin B12 deficiency, with continued progression
of neurologic damage, and that provision of oral vitamin B12 will
negate this concern. The comment did not provide data or information
identifying the amount of oral vitamin B12 that would protect
nearly all persons from masking of a vitamin B12 deficiency and,
thus, the level below which a warning statement would be required.
The agency disagrees with this suggestion. The agency is aware that
very high doses of vitamin B12 (e.g., about 1 mg; 500 times the
RDI for this vitamin) without intrinsic factor (i.e., without the
protein factor necessary for the absorption of vitamin B12 and the
factor whose lack causes pernicious anemia) have provided adequate
treatment for some persons with pernicious anemia (Ref. 45). It has
been suggested, based in part on observations that some patients with
pernicious anemia can be maintained on oral vitamin B12, that high
doses of vitamin B12 be added to foods and dietary supplements
fortified with folic acid to reduce the potential for adverse effects
in persons with vitamin B12 deficiency.
Several experts at a CDC meeting on surveillance for adverse
effects of increased intakes of folate (Ref. 26) commented on this
suggestion. One expert noted that in the presence of other nutrients
(e.g., vitamin C, thiamin, iron), vitamin B12 may be converted
into analogs, some of which may have antivitamin B12 activity.
In the proposal of October 14, 1993 (58 FR 53254 at 53280), the
agency discussed the issue of whether high doses of vitamin B12
should be added to foods or supplements fortified with folic acid to
reduce the potential for adverse effects in persons with vitamin
B12 deficiency. The agency requested comments, specifically data,
on the appropriateness, potential effectiveness, and safety of such
fortification. The agency did not receive data or other information on
this issue.
Given this lack of information, FDA finds no basis to require a
warning statement on supplements based on their content of vitamin
B12 because there are no data on the effects of various folate/
vitamin B12 combinations on which to base a warning. In addition,
relating a caution statement only to the vitamin B12 content of a
product would fail to recognize the potential adverse effects of
increased folate intakes on other population groups, including, as
discussed above, pregnant women, children, those on antiepileptic
medications, and those on antifolate medications, because it would fail
to recognize that potential adverse effects of increased intakes are
not limited only to those with vitamin B12-related problems.
Because data are not available that address for the general
population on the issue of simultaneous fortification of foods or
dietary supplements with both folate and vitamin B12, the agency
cannot establish a level of oral vitamin
[[Page 8772]]
B12 that is sufficient to protect most persons with vitamin
B12-related problems from the adverse effects of increased intakes
of folate. In addition, questions regarding the appropriateness,
potential effectiveness, and safety of such an approach remain
unanswered. Vitamin B12 deficiency, including pernicious anemia,
is a serious condition, which, if untreated, can lead to irreversible
neurological damage. Regardless of the widespread availability of oral
vitamin B12 preparations, patients with pernicious anemia, and
others at risk of vitamin B12 deficiency, should be diagnosed,
treated, and monitored by a physician (Ref. 45).
6. Multifactorial Nature of Neural Tube Defects
The general requirements for health claims for conventional foods
(Sec. 101.14(d)(2)(iii)) provide that, where factors other than dietary
intake of the substance affect the relationship between the substance
and the disease or health-related condition, FDA may require that such
factors be addressed in the health claim. FDA has decided that health
claims on dietary supplements should be subject to the same requirement
(see 59 FR 395 at 425).
It is well-recognized that neural tube defects have many causes,
some of which are not related to folate status. Genetic and
environmental factors contribute to the multifactorial nature of neural
tube defects. Environmental factors associated with neural tube defects
include, for example, maternal health, maternal family history of
neural tube defects, and maternal use of certain antiseizure
medications (see 58 FR 53254 at 53258 for references).
FDA discussed the multifactorial nature of neural tube defects in
several sections of its proposed rule. In proposed Sec. 101.79(b)(1),
FDA discussed the fact that neural tube defects are caused by many
factors and also noted that a significant risk factor is a personal or
family history of a pregnancy affected by a neural tube defect. In
Sec. 101.79(c)(2)(i)(D), FDA proposed to require that claims state that
neural tube defects have many causes, and that claims not imply that
folate intake is the only recognized risk factor for neural tube
defects. The agency included language to this effect in the agency's
proposed model claims (Sec. 101.79(d)).
The agency received several general comments and new data in
response to the sections of the proposed codified language addressing
the multifactorial nature of neural tube defects.
a. General comments.
36. Several comments agreed that the claim should include
information on the multifactorial nature of neural tube defects to be
consistent with claims for other diet-disease relationships. These
comments asserted that the claims would be misleading if such
information were not included. Other comments disagreed that the
multifactorial nature of neural tube defects should be recognized in
the claim because, for example: (1) Folate is the most important risk
factor, or (2) there is no educational value in identifying the
multifactorial nature of the condition. Another comment stated that
only factors that can be controlled, or those on which women could take
action, should be included in the claim.
FDA is in the process of reconsidering the need to include in
health claims the fact that the disease that is the subject of the
claim has many causes. In the January 1993 final rules on health
claims, FDA included this fact as a required element of the claim.
However, as discussed below, FDA has come to tentatively conclude, at
least in part in response to a petition from the National Food
Processors Association (Docket No. 94P-0390), that, at least for most
claims, a statement about their multifactorial etiology adds length to
the claim without conveying information that would directly affect the
dietary choices of the consumers.
The agency is particularly concerned that manufacturers will be
disinclined to use unnecessarily lengthy health claims on food labels,
that additional verbiage may detract from the central consumer message
of the claim, and that, as a result, health claims will be infrequently
used, and the benefits of communicating information on diet-disease
relationships to consumers through such claims will not be realized.
The issue of manufacturers' reluctance to use lengthy health claims
is particularly significant in the case of the folate/neural tube
defects health claim because this topic has received much less
attention than has been given to chronic illnesses such as
osteoporosis, heart disease, and cancer. The lower level of public
familiarity with this topic was confirmed in a recent survey conducted
for the March of Dimes Birth Defects Foundation regarding knowledge and
practices of women of childbearing age in the United States with
respect to consumption of folic acid from supplements and breakfast
cereals (Ref. 53).
During January and February 1995, the Gallup Organization conducted
for the March of Dimes a proportionate, stratified random-digit-dialed
telephone survey of a national sample of 2,010 women aged 18 to 45
years. The response rate was 50 percent. Estimates were statistically
weighted to reflect the total population of women aged 18 to 45 years
in the continental United States. In response to the question ``Have
you ever heard or read anything about folic acid?'', 52 percent of
women reported ever hearing of or reading about this nutrient. Of
these, 9 percent answered that folic acid helps to prevent birth
defects and 6 percent that folic acid helps to reduce the risk for
spina bifida; 45 percent were unable to recall what they had heard or
read. Fifteen percent of respondents reported having knowledge of the
PHS recommendation regarding the use of folic acid; 4 percent reported
that the recommendation was for prevention of birth defects and 1
percent, for the prevention of spina bifida (Ref. 52).
Respondents were also asked ``From what you know, is there anything
a woman can do to reduce her risk of having a baby with birth
defects?'' A total of 88 percent of respondents reported that a woman
can help reduce the risk for having an infant with birth defects. The
most common responses about how to reduce risk were avoiding alcohol
and drugs (73 percent), and not smoking (63 percent); 1 percent of
women reported that folic acid could reduce risk.
This study found that while most women interviewed recognized that
there were a number of factors that might affect their risk of having a
baby with a birth defect, there was a low level of awareness that
consumption of folate from supplements, breakfast cereals, and other
foods may specifically help to reduce their risk of a neural tube
defect-affected pregnancy.
The results of the March of Dimes survey are consistent with recent
findings by FDA. As part of FDA's ongoing review of its regulations
governing health claims, the agency conducted six focus groups in May
and June 1995 to evaluate consumer understanding of health claim
messages. In a report on these focus groups, Levy (Ref. 54) noted that
while almost all participants were aware of health effects of fat,
calcium, and fruits and vegetables, very few had heard much about folic
acid. Participants appreciated information provided in the folate/
neural tube defects model claims but considered it insufficient to
inform them as adequately as they wished to be informed.
Thus, recently available information suggests that there is a low
level of awareness of the potential impact that
[[Page 8773]]
increased folate intake may have on the risk of a serious type of birth
defect.
The agency has concluded, based in part on the studies mentioned
above, that the need to provide a succinct health claim in this topic
area is very important. Succinctness in the claim will increase the
likelihood that firms will use it and thus will increase its
educational value. To facilitate the use of such a claim by
manufacturers, it needs to be no longer than necessary to convey the
central consumer message.
With respect to the issue of whether explicit identification of the
multifactorial nature of neural tube defects is necessary to prevent
the folate/neural tube defects health claim from being misleading, the
agency notes that use of the term ``may reduce'' in the claim describes
the potential of folate to affect the risk of neural tube defects and
serves to reflect the multifactorial nature of this birth defect. In
addition, data obtained in the March of Dimes survey described above
indicate that many women already recognize that birth defects in
general may have many causes. The agency has therefore concluded that
explicit reference to ``may have many causes'' is redundant when
included with the phrase ``may reduce.''
The agency has concluded that it is not necessary to include
explicit reference to the multifactorial nature of neural tube defects
in the claim.
The agency notes, however, that the fact remains that neural tube
defects are multifactorial in nature. This fact is confirmed by new
data of which FDA has become aware and that are discussed in the
following section. Because of this fact, the claim must not imply that
folate intake is the only risk factor for these birth defects.
Therefore, the agency is modifying Sec. 101.79(c)(2)(i)(D) by
deleting the requirement that the claim state that neural tube defects
have many causes but is retaining the requirement that claims shall not
imply that folate intake is the only recognized risk factor for neural
tube defects.
The agency is also advising that manufacturers who wish to do so
may include, on an optional basis, information in the claim on
additional risk factors for neural tube defects. Information that may
be included is described in Sec. 101.79(c)(3)(i).
b. Data received in comments. 1. The agency received new data from
an Irish study that found that plasma levels of vitamin B12, as
well as folate, were independent risk factors for neural tube defects
(Ref. 51). These data were reviewed at the October 14 and 15, 1993,
meeting of the Folic Acid Subcommittee and are summarized here because
the agency did not have the data in sufficient time to include them in
its October 14, 1993, proposed rule. Kirke et al. (1993) (Ref. 51)
compared values for plasma folate, plasma vitamin B12, and red
blood cell folate in 81 women who had a neural tube defect-affected
pregnancy and 247 control women. Values for all three parameters were
significantly lower in case mothers than in control mothers. Plasma
vitamin B12 and red cell folate were both significantly positively
correlated in case mothers but not in control mothers. Multiple
regression analysis showed that plasma vitamin B12 and plasma
folate were independent predictors of red cell folate in case mothers
but not in control mothers.
The authors concluded that plasma vitamin B12 and plasma
folate were independent risk factors for neural tube defects and
suggested that the enzyme methionine synthetase was involved directly
or indirectly in the etiology of neural tube defects. They noted that
the correlation between plasma vitamin B12 and red cell folate,
observed in case mothers only, was difficult to explain on a purely
nutritional basis and favored the etiology of neural tube defects as
being the result of some metabolic abnormality in the mother, and
possibly in the embryo, interacting with maternal plasma levels of
folate and vitamin B12 (Ref. 50).
Mooij et al. (Ref. 46) measured levels of seven vitamins in blood
of women who had a neural tube defect-affected pregnancy and reported
that such measurements were not suitable for identifying women at high
risk of another affected pregnancy. The authors hypothesized that the
effect of folic acid was attributable, at least in part, to its
overriding a metabolic disorder.
2. The agency received additional new data in a comment relating to
a possible role of a deficiency of one or more antioxidant enzymes in
the development of neural tube defects. The comment discussed the
hypothesis that a genetic defect in antioxidant enzyme systems that
protect neuronal membranes from excessive lipid peroxidation may play a
role in the etiology of neural tube defects. The comment noted that
abnormalities of the neural tube have been documented in cultured rat
embryos exposed to oxygen radicals generated in vitro by xanthine plus
xanthine oxidase. The severity of these abnormalities, which increases
in a dose-responsive manner with exposure to xanthine oxidase, can be
moderated by substances with known antioxidant activity such as
glutathione, catalase, L-ascorbic acid (vitamin C), or DL-alpha
tocopherol (vitamin E).
This comment provided the results of a pilot study that tested the
hypotheses in children with neural tube defects and their immediate
families. In testing the hypothesis, the investigators assessed a
number of red blood cell free radical- scavenging enzymes in eight
families with one or more children with the neural tube defect
meningomyelocele. Seventeen healthy adults without a history of neural
tube defects served as controls. All meningomyelocele-affected children
were found to be deficient in red blood cell glutathione peroxidase,
with 5 in the range of moderately to severely deficient. At least one
parent of seven of the eight affected children was deficient in red
blood cell glutathione peroxidase activity, with four of seven in the
moderately to severely deficient range. Nine additional children with
meningomyelocele or other neural tube defects (specifically,
encephalocele and iniencephaly) were also studied. Red blood cell
glutathione peroxidase activities were low in all of the nine
additional affected children, with values in six of the nine in the
moderately to severely deficient range.
The comment also noted that pterin aldehyde, a contaminant that may
be present at a level of about 4 percent in commercially available
folic acid preparations, may reduce exposure of the developing neural
tube to toxic oxygen free radicals through its activity in inhibiting
xanthine oxidase. The comment suggested (Comment 68H to docket 93N-
100H) that a combination of genetic factors, deficient antioxidant
enzyme capacities, exogenous or endogenous teratogens, periconceptional
diets with inadequate amounts of free radical scavenging substances, or
suboptimal concentrations of pterin aldehyde-like agents may provide
further explanations for tissue-specific injury in some pregnancies.
The comment concluded that, while the mechanisms of neural tube
defect formation likely fit into a complex ecogenetic model, a
deficiency of one or more antioxidant enzymes may increase the risk for
the development of neural tube defects. The comment recommended further
study to determine whether reduced antioxidant activity predisposes the
embryo to the development of neural tube defects.
c. Data that were published after the close of the comment period.
1. Mills et al. (1995) (Ref. 47) reported that women with neural tube
defect-affected pregnancies had significantly higher levels of
homocysteine than did vitamin B12-matched controls. Mills et al.
(1995)
[[Page 8774]]
(Ref. 47) noted that their study showed that an abnormality of
homocysteine metabolism, apparently related to methionine synthase, is
present in many pregnancies that resulted in neural tube defects.
2. Mechanistic studies in cultured rat embryos have also provided
insights into roles for nutrients in addition to folate in the etiology
of neural tube defects. Chambers and coworkers identified
autoantibodies (i.e., antibodies directed against tissue components of
the same organism) to the extracellular basement membrane (i.e., the
noncellular layer underlying the epithelium) protein laminin as an
agent that caused neural tube defects in whole embryo cultures (see
Ref. 48 for additional references). Such antibodies were found
initially in the embryotoxic sera of monkeys with poor reproductive
histories. Chambers et al. (1995) (Ref. 48) recently reported that
methionine overcomes neural tube defects in rat embryos cultured on
sera from monkeys immunized against laminin. The authors noted that the
association of autoimmune diseases and fetal loss has received closer
attention in recent years, but that neither the mechanisms of fetal
loss nor treatments have been well defined (Ref. 48). The authors
suggested that epidemiologic studies are needed to establish a possible
role for autoantibodies in the etiology of neural tube defects and to
determine the efficacy of methionine supplementation in overcoming such
defects.
3. Data addressing the etiologic heterogeneity of neural tube
defects were also derived from observations that infants and fetuses
with isolated neural tube defects have different risk factors than
those with neural tube defects occurring with other birth defects and
from reported differences in recurrence risks for neural tube defects
based on the level of the affected infant's defect (Ref. 49; Shaw et
al., 1994, for references). Shaw et al. (1994) (Ref. 49), used
population-based case ascertainment by the California Birth Defects
Monitoring Program in an ethnically diverse population of more than
700,000 live births and fetal deaths to investigate whether
heterogeneity existed among various anatomic and pathogenetic
subclasses of neural tube defects for a variety of commonly collected
child and parental characteristics. Among cases of anencephaly,
increased risks were found for Hispanic white women with risk estimates
highest for nonisolated cases. This population-based study showed
increased risk for Hispanic women specifically among subclassifications
of neural tube defects, and provides some evidence that further
classification of neural tube defects may reveal subgroupings of cases
with different etiologies.
Shaw et al. (1995) (Ref. 50) used a case-control study design (549
cases and 540 controls) to investigate whether intake of supplemental
folic acid or dietary folate reduced the risk of a neural tube defect-
affected pregnancy (Ref. 50). The authors found that women with any use
of a folic acid-containing vitamin in the 3 months prior to conception
had a lower risk of having an NTD-affected pregnancy. Odds ratios were
similar for average daily folic acid intakes of <400 mcg,="" 400="" to="" 900="" mcg,="" and="">900 mcg/day, and thus, no dose-response pattern was apparent.
Use of 400 to 900 mcg folic acid/day in the 3 months after conception
was also associated with reduced risk of a neural tube defect-affected
pregnancy. The authors also observed that women who did not begin using
a folic acid- containing vitamin until the second trimester of
pregnancy also had a reduced risk of neural tube defects and suggested
that although the finding may be indicative of errors in reporting
vitamin use in general, it also weakens the attribution of a direct
preventive effect of folate on neural tube defects in the study
population (Ref. 50).
When race/ethnicity were considered, nonHispanic white women who
used a folic acid-containing vitamin in the 3 months before conception
had a reduced risk of a neural tube defect-affected pregnancy. However,
risk of a neural tube defect-affected pregnancy was not reduced in
Hispanic women who consumed a folic acid-containing vitamin in the 3
months before conception. The overall results of this study are
consistent with other studies showing associations between folate
intake and reduced risk of neural tube defects. However, the data also
suggest that the folate-associated reduction in risk may be specific to
subsets of the population, primarily nonHispanic women (Ref. 50).
These recent studies are of significance for the insights that they
provide into understanding the multifactorial etiology of neural tube
defects. They support the hypothesis that neural tube defects are not
the result of a wide-spread nutritional deficiency of folate in the
U.S. population but may result from metabolic defects or other
physiologic conditions affecting a small part of the population. These
new data support FDA's decision to require that claims not imply that
folate intake is the only recognized risk factor for neural tube
defects.
7. Prevalence Statements
In Sec. 101.79(c)(2)(i)(E), the agency proposed to require that the
claim provide information that neural tube defects ``while not
widespread, are extremely significant.'' Because the affected
population is few in number and not readily identifiable, FDA proposed
to require that this information be disclosed to prevent women from
being misled into believing that neural tube defects are very common
birth defects, or that, lacking a personal or family history of such
defects or other recognized risk factors, their risk of having a
pregnancy affected with such a birth defect is very high.
37. The agency received a number of comments on the proposed
prevalence statement. Some comments stated that the wording ``while not
widespread'' was not clear, and one comment suggested use of
``uncommon'' rather than ``while not widespread'' in describing the
prevalence of neural tube defects. One comment noted that statements
indicating that neural tube defects had a low prevalence in the United
States would discourage women from taking folic acid supplements
because women would believe that the health claim is not applicable to
them, and they would be misled into not taking the health claim
seriously. One comment noted that there is no standard for the proposed
term ``not widespread.'' One comment noted that because the behavior
intended to result from authorization of the health claim was to have
women consume more folic acid, qualifiers regarding prevalence of the
condition had no educational benefit. One comment, noting that
statements regarding the extent of the disease-related conditions were
optional in other approved health claims, and that the rarity of spina
bifida and related birth defects is obvious to virtually all consumers,
urged the agency to make prevalence statements optional in the folate/
neural tube defect claim.
The Folic Acid Subcommittee also commented on issues of prevalence
and demographics of neural tube defects at all of its meetings (e.g.,
Ref. 8). The Folic Acid Subcommittee discussed the decline in the rate
of neural tube defects from a high in Boston in the 1930's of 5 per
1,000 births to the current overall U.S. rate of about 0.6 per 1,000
births (i.e., about 2,500 cases/year in the United States). In
addressing the prevalence of neural tube defects among different ethnic
groups, one Folic Acid Subcommittee member noted that African-American
women have a rate lower than the overall U.S. rate, while Mexican-
American women have a rate
[[Page 8775]]
about two and one-half times the national average. The participant also
noted that there is about a two- fold higher rate among women in lower
socio-economic groups than among those in higher socio-economic groups
(Ref. 8).
The agency has reviewed the comments that it received and agrees
that use of the proposed wording ``while not widespread'' is not clear
because it is not quantitative. The agency notes that even though the
occurrence of neural tube defect-affected pregnancies is low, the
population at risk may be quite large because about half of pregnancies
are unplanned. Therefore, the agency concludes that a statement of
prevalence is not a material fact in light of the other statements made
in the claim. For this reason, the agency concludes that it is not
necessary to require that the claim state that the prevalence of neural
tube defects is low to ensure that the claim is not misleading.
Therefore, the agency is deleting the requirement proposed in
Sec. 101.79(c)(2)(i)(E) and redesignating subsequent sections as
discussed below and as shown in the codified language.
However, given the other comments cited above and its discussions
with the Folic Acid Subcommittee, the agency does not agree that there
would be no educational benefit from providing prevalence information
in the health claim. The agency concludes, based on the comments above,
that prevalence information can be useful to consumers because it can
provide a context that increases understanding of how frequently neural
tube defects actually occur among pregnancies in the U.S. population.
The agency recognizes that it has provided for inclusion, on an
optional rather than required basis, in other authorized health claims
of information on the number of people in the United States who have
the health-related condition (e.g., see saturated fat and
cardiovascular disease claim and dietary fiber and cancer claims).
Thus, in response to the comments above, and consistent with other
authorized health claims, FDA, in Sec. 101.79(c)(3)(v), is authorizing
the use of optional statements to provide the estimated numbers on an
annual basis of neural tube defect births among live births to women in
the general U.S. population. Currently, this estimate is 0.6 cases per
1,000 live births, or 6 cases per 10,000 live births, or about 2,500
cases among 4 million live births, or about 1 case per 1,600 live
births. These estimates are based on information for the U.S.
population from PHS. FDA finds, based on a review of how such
statistics are generally presented, that expressing this information as
the estimated annual number of neural tube defects per a specified
number of births (e.g., per 1,000 live births or per 10,000 live
births) will help to make this information as useful as possible.
Section 101.79(c)(3)(v) provides for use of these estimates unless more
current estimates from PHS become available, in which case, the newer
estimates may be used.
8. Quantifying Risk Reduction
In Sec. 101.79(c)(2)(i)(F), the agency proposed that the claim
contain a statement that some women may reduce their risk of a neural
tube defect-affected pregnancy by maintaining adequate folate intake
during their childbearing years. Such a statement is consistent with
the estimate provided in the PHS recommendation that about half of
neural tube defects (i.e., about 1,250 annually) might be averted if
all women of childbearing age in the United States who are capable of
becoming pregnant consumed 0.4 mg of folate daily throughout their
childbearing years. FDA tentatively concluded that such a statement is
necessary to ensure that women do not conclude on the basis of the
claim that adequate intake of folate will prevent all occurrences of
neural tube defects. The agency also proposed in
Sec. 101.79(c)(2)(i)(F) that the claim not attribute any specific
degree of reduction in risk of neural tube defects to maintaining an
adequate folate intake throughout the childbearing years.
38. Several comments agreed with the agency that a specific degree
of reduction in risk should not be stated in the health claim. Other
comments noted that while occurrence of neural tube defects will be
averted by only some women, the risk of occurrence will be reduced for
the population. Other comments objected to the proposal to prohibit use
of the PHS estimated percent risk reduction of 50 percent. Some
comments argued that the 50 percent estimate should be stated because
it was a scientific finding, and that failure to include this estimate
could have a negative effect on how much effort women make to ensure
that they have adequate folate intake. Another comment stated that the
estimate of 50 percent reduction should be included because it is
preferable for women to know the exact benefit of folic acid rather
than to be informed that ``some but not all women may benefit.''
The agency disagrees with comments that the PHS estimate of 50
percent is a scientific finding and represents an exact benefit
achievable by all women who consume adequate folate daily throughout
their childbearing years. The PHS recommendation states that the 50
percent estimate was derived from studies that associated recalled use
of folic acid-containing multivitamins with reduced risk of neural tube
defect-affected pregnancies and states that ``the protective effect
found in the studies of lower-dose folic acid, measured by the
reduction in neural tube defect incidence, ranged from none to
substantial'' (Ref. 5) (emphasis added). The PHS recommendation also
noted that:
It is expected that consumption of adequate folic acid will
avert some, but not all, neural tube defects. The underlying causes
of neural tube defects are not known. Thus, it is not known what
proportion of neural tube defects will be averted by adequate folic
acid consumption. From the available evidence, CDC estimates that
there is the potential for averting 50 percent of cases that now
occur. However, until further research is done, no firm estimate of
this proportion will be available (Ref. 5).
The agency also notes that there may be minimal or no effect of
periconceptional use of folate in areas of low prevalence or in areas
where other factors are contributing to an increased prevalence. This
observation is consistent with scientific evidence that shows that, in
an area of low prevalence in the United States, women who consumed
folate from multivitamins or fortified breakfast cereals did not have a
lower risk of having a neural tube defect-affected pregnancy than did
women who did not consume multivitamins or fortified breakfast cereals
(Ref. 12; Mills et al.).
Thus, the estimate of a potential for a 50 percent reduction in
neural tube defect-affected pregnancies, if all women consumed adequate
folate throughout their childbearing years, is not a scientific finding
and may not be applicable to estimating potential risk reduction in
areas of low prevalence. The agency notes further that the estimate of
50 percent is not applicable to risk reduction that might be
experienced by individual women, whose personal risk factors are not
fully understood. In addition, the estimated proportion may change with
the availability of new scientific data and information. The agency
recognizes, however, that manufacturers may wish to use the PHS
recommendation, including the estimate of the potential for a 50
percent reduction in the incidence of neural tube defects, as labeling
for folate-containing products. The agency also notes that there is
considerable potential for making a misleading claim if such
information is not presented in an accurate context.
[[Page 8776]]
The agency has concluded that an estimate of potential risk
reduction can be included in the health claim because it may help some
consumers better understand the potential population-based impact on
neural tube defect-affected pregnancies if all women consumed adequate
folate throughout their childbearing years. Therefore, FDA is providing
in Sec. 101.79(c)(2)(i)(E) that population-based estimates of risk
reduction may be included in the claim so long as the claim makes clear
that the estimate does not reflect risk reduction that may be
experienced by individual women. Provision of such information will
reduce the likelihood of women being misled that adequate folate intake
will prevent an occurrence of a neural tube defect-affected pregnancy.
The agency has revised Sec. 101.79(b)(3) to provide information
from the PHS recommendation that explains how the estimate of a
potential for reduction in incidence of neural tube defects of 50
percent was derived and provides the context in which the estimate can
be understood by individual women.
FDA has also redesignated proposed Sec. 101.79(c)(2)(i)(F) as
Sec. 101.79(c)(2)(i)(E) and revised this section to remove the
prohibition against use of the PHS estimate. Section 101.79(c)(2)(i)(E)
includes reference to new Sec. 101.79(c)(3)(vi) which provides for
optional inclusion of statements about population-based estimates of
risk reduction. The requirement that claims state that some women may
reduce their risk of a neural tube defect-affected pregnancy through
adequate intake of folate throughout their childbearing years is
retained in Sec. 101.79(c)(2)(i)(E).
New Sec. 101.79(c)(3)(vi) states that an estimate of the reduction
in the number of neural tube defect-affected births that might occur in
the United States if all women consumed adequate folate throughout the
childbearing years (i.e., 50 percent) may be included in the claim if
such an estimate is accompanied by information that states that it is a
population-based estimate and does not reflect reduction in risk that
may be experienced by individual women. New Sec. 101.79(c)(3)(vi) also
provides for use in the claim of information in revised
Sec. 101.79(b)(3).
9. Optional Health Claim Information
In Sec. 101.79(c)(3)(i), the agency proposed to permit
manufacturers, in addition to including the fact that neural tube
defects have many causes, to specifically identify risk factors for
neural tube defects. The agency stated that specific examples of other
risk factors include a personal history of such a defect, maternal
diabetes mellitus, use of the antiepileptic drug valproic acid,
maternal febrile illness, or a close relative with a neural tube defect
(Sec. 101.79(b)(1) and (b)(2)). The agency requested comments on
whether such additional information would be useful to consumers.
a. Identifying other risk factors.
39. Some comments expressed the opinion that most of the optional
information was helpful, while others stated that there was no
educational value in identifying the multifactorial nature of neural
tube defects, and that women cannot control other risk factors.
The agency disagrees with the comments that stated that
identification of other risk factors would not be helpful to women.
Certain conditions, such as diabetes mellitus, are known to increase a
woman's risk of a neural tube defect-affected pregnancy. Identification
of these risks in the claim may serve to alert some women to their
higher risk and encourage them to seek advice from their health care
providers before becoming pregnant.
The agency is providing in Sec. 101.79(c)(3)(i) for the inclusion
of optional information in the claim. Information in Sec. 101.79(b)(1)
or (b)(2) or drawn from other parts of Sec. 101.79(c)(3) may be
included in the claim. Use by manufacturers of factors listed in the
regulation will ensure that claims will only include scientifically-
based information and will not include information that has not been
well- documented (e.g., ``Birth defects of the brain or spinal cord may
have many causes, such as exposure to pesticides * * *'').
b. Consult a physician. In Sec. 101.79(c)(3)(iii), the agency
proposed that a claim could include a statement that women with a
history of a neural tube defect pregnancy should consult their
physicians or health care providers before becoming pregnant. The
agency tentatively concluded that such a statement would encourage such
women to obtain medical guidance and thereby decrease their risk of a
recurrence of a neural tube defect- affected pregnancy. The available
data show that women with a history of a neural tube defect-affected
pregnancy are at very high risk of another affected pregnancy (e.g.,
risk of a recurrence of a neural tube defect pregnancy is significantly
greater than risk of an occurrence of this birth defect). The agency
requested comments on whether provision of such information would be
helpful to consumers.
40. The agency received several comments on this proposed optional
information. All comments that addressed this issue recommended that it
be broadened to include all women rather than only those with a
personal history of a neural tube defect- affected pregnancy. Comments
stated that prenatal care was critical for all women and suggested that
health claims should include a statement that all women planning a
pregnancy should consult a physician or health care provider for
information about adequate diets for their and their babies' health.
Several comments suggested that such a statement be mandatory rather
than optional.
FDA does not believe that it is appropriate, in general, for health
claims to bear statements concerning the need to seek medical advice
for treating the disease or health-related condition mentioned in the
claim. The agency is concerned that the appearance of a statement
concerning the treatment of a disease on the label of a food could
mislead some consumers to believe that the food possesses therapeutic
value for an existing disease or health-related condition (58 FR 2478
at 2514).
The agency originally proposed such a statement regarding women at
recurrent risk of a neural tube defect-affected pregnancy because their
risk of recurrence is very high, and because a specific recommendation
from PHS has been made to such women when they are planning a pregnancy
(i.e., they are advised to take 4 mg folic acid daily under a
physician's supervision; Ref. 52).
Because all comments favored broadening the advice to include all
women, and because the agency recognizes that it is important for all
women to consult a health care provider before becoming pregnant, the
agency is persuaded to modify Sec. 101.79(c)(3)(iii) as suggested in
the comments and to provide for claims to include, in addition to a
statement regarding women at recurrent risk of a neural tube defect, a
statement that all women should consult a health care provider before
becoming pregnant (e.g., ``Women, including those with a history of a
neural tube defect pregnancy, should consult their health care provider
when planning a pregnancy.'').
However, because the length of claims has been consistently a
concern of the comments, the agency is not persuaded that the
information provided for in Sec. 101.79(c)(3)(iii) should be required
in all health claims, as suggested by one comment above. 10. Model
Health Claims
FDA provided several model claims in the proposal that contained
the elements described in its proposal. The agency included these model
claims to
[[Page 8777]]
assist manufacturers in formulating appropriate claims.
a. Toll-free number, pregnancy information symbol.
41. Several comments stated that less detailed model claims were
needed and proposed that the agency establish a toll-free 800 number
through which women could obtain more information or recommended that
the agency devise a uniform pregnancy information symbol for food
labels that would alert women to look for products that bear the
symbol.
The agency agrees that educational information is of great
importance in increasing awareness among women of the need for adequate
nutrition, including adequate folate intake, during their childbearing
years. The agency is considering how best to evaluate consumer
understanding of the health claim and is working with other PHS
agencies to develop strategies to implement the PHS recommendation on
folate intake.
With respect to the use of a pregnancy information symbol, the
agency noted above that many pregnancies are unplanned, and for this
reason, women need to be informed of the need for adequate nutrition
throughout their childbearing years. While a pregnancy symbol might
draw the attention of women who are already pregnant or who might be
planning a pregnancy, it may not be helpful to women whose pregnancies
are unplanned or to women whose pregnancies are too far advanced for
folate intake to alter their risk of giving birth to a neural tube
defect-affected infant. Such a symbol may also discourage other women
from using the product because they do not think they will become
pregnant.
The agency also notes that many of the foods that will bear the
health claim will be consumed by the general population, and the
appearance of a pregnancy symbol on the label might be incorrectly
interpreted by some consumers to mean that the product is specifically
intended for use in pregnancy.
For these reasons, the agency is not persuaded to use a pregnancy
symbol with the health claim.
b. General comments.
42. Many comments criticized the length of the model claims and
their required components. Comments stated that the model messages were
too lengthy and complex and unwieldy, and that therefore manufacturers
would be disinclined to use them. Other comments noted that the claims
included unnecessary disclosures and requested that FDA remove the
requirements relating to the multifactorial nature of neural tube
defects, sources of folate other than dietary supplements, and the
caution statement. Several comments, stating that the model claims were
overly focused on foods, urged the agency to develop a condensed claim
for dietary supplements and suggested that such a claim should not need
to identify other sources of folate or state a maximum daily limit on
intake.
Another comment noted that in formulating the claim, the agency
should be guided by the need to communicate the benefits of increased
folate intake from food sources or dietary supplements, and that the
message must also convey proper cautions, including the fact that
increased folate intake will not prevent all birth defects or even all
neural tube defects. Several comments praised portions of the model
claims that required disclosure of the multifactorial nature of neural
tube defects and the inclusion of information regarding sources of
folate. One comment recommended that claims use the information in the
PHS recommendation, including the warning statement, as closely as
possible. Several comments noted that the model claims were not
educationally strong enough, while others recognized the problem of
providing the guidance that needs to be included in the claim without
having the claim become so long as to be unusable. Some comments
provided examples of shorter claims that they proposed as more
appropriate than the agency's model claims.
As discussed in the proposal and elsewhere in this final rule,
certain information is needed in the health claim, whether for
conventional foods or for dietary supplements, for such claims to be
truthful, scientifically valid, and not misleading to segments of the
population that are not at high risk of having a neural tube defect-
affected pregnancy or for whom no link between folate intake and risk
of neural tube defect-affected pregnancies has been established.
The agency has addressed the issues of mandatory requirements
relating to the multifactorial nature of neural tube defects, sources
of folate other than dietary supplements, and the caution statement in
response to comments 36, 21, and 32, respectively. The agency disagrees
that all of these elements should be removed. Specifically, the agency
has discussed in response to comment 36 why claims shall not imply that
folate intake is the only risk factor for neural tube defects. In
response to comments 28 through 34, the agency explained why a caution
statement is necessary, as well as its reasoning in limiting the
requirement for such a statement to very narrow circumstances. The
agency in response to comments has dropped the requirement that sources
of folate be identified in the claim and instead has provided for
optional inclusion of such information.
The agency also disagrees that its proposed model claims were
overly focused on foods because each of the proposed claims
specifically identified sources of folate as fruits, vegetables, whole
grain products, fortified cereals, and dietary supplements.
The agency rejects the comments that urged it to develop a
condensed claim for dietary supplements and not identify a safe upper
limit of daily intake. Throughout its responses to the comments it
received, the agency has been even-handed in considering conventional
foods and dietary supplements (comments 29 and 32, above). Since
increased folate intake is what is of importance, and since a variety
of dietary sources of folate are available, it would be inconsistent
with the available evidence for the agency to set different
requirements for claims on dietary supplements than for claims on
conventional foods.
Thus, the agency, in developing this final rule, has been guided by
the need to communicate the effects on the risk of neural tube defects
of increased folate intake while providing sufficient cautions to
prevent claims from being misleading and to ensure that they are
scientifically valid.
FDA has modified the model claims to reflect the changes that it
has made in Sec. 101.79 in response to the comments. The agency has
sought to illustrate in the model claims that it is possible to fully
comply with Sec. 101.79 and still produce a claim that uses less than
30 words (see Examples 1 and 2 in Sec. 101.79(d)). The agency also
notes that in response to the petition from the National Food
Processors Association, mentioned above, it is exploring the
possibility of permitting a shortened version of the claim to appear on
the front panel of the food label as long as the full claim appears on
the label. FDA is considering how this can be accomplished while still
ensuring that there is full compliance with section 403 (a) and (r) of
the act. FDA anticipates publishing a proposal on these matters in the
near future.
III. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(11) that this
action is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore,
[[Page 8778]]
neither an environmental assessment nor an environmental impact
statement is required.
IV. Economic Impact
FDA has examined the impacts of this final rule to authorize the
use on the labels and in the labeling of conventional food and dietary
supplements of health claims on the relationship between adequate
folate intake and risk of neural tube birth defects as required by
Executive Order 12866 and the Regulatory Flexibility Act. Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety effects;
distributive impacts and equity). The Regulatory Flexibility Act (Pub.
L. 96-654) requires analyzing options for regulatory relief for small
businesses. FDA finds that this final rule is not a significant
regulatory action as defined by Executive Order 12866. In compliance
with the Regulatory Flexibility Act, the agency certifies that the
final rule will not have a significant impact on a substantial number
of small businesses.
On October 14, 1993, FDA published an analysis of the economic
impact of the proposed rule under the previous Executive Order (E.O.
12291). In that analysis, the agency stated that folate health claims
may result in increased demand for products containing folate, and that
an increase in consumption of products containing folate is likely to
result in health benefits in terms of fewer neural tube defects. The
agency also stated that there would be no costs associated with folate
health claims as use of these claims is voluntary.
The agency concluded that it was not able to estimate the number of
products that will bear health claims, or the effect that folate health
claims will have on consumer demand for products containing folate, and
requested comments. As mentioned previously, the agency received nearly
100 comments in response to the proposed rule on health claims for
folate and neural tube defects. None of the comments provided
information that would alter the agency's economic impact conclusion.
V. Collection of Information
This rule contains no collection of information requirements under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et. seq.).
VI. References
The following information has been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m. Monday through Friday.
1. Food and Nutrition Board, National Research Council, National
Academy of Sciences, 1980, Recommended Dietary Allowances, 9th
revised edition, 1980, Washington, DC, pp. 106-113.
2. Flood, T., M. Brewster, and J. Harris, et al., ``Spina Bifida
Incidence at Birth--United States, 1983-1990,'' Morbidity and
Mortality Weekly Report, 41(27); 497-500, 1992.
3. Maternal and Child Health Bureau, Health Resources and Services
Administration, Public Health Service, Lin-Fu, J.S., and M.A.
Anthony, ``Folic Acid and Neural Tube Defects: A Fact Sheet for
Health Care Providers,'' May 1993.
4. Elwood, J.M., and J.H. Elwood, ``Epidemiology of Anencephalus and
Spina Bifida,'' Oxford University Press, 1980.
5. Department of Health and Human Services, Public Health Service,
``Recommendations for the Use of Folic Acid to Reduce the Number of
Cases of Spina Bifida and Other Neural Tube Defects,'' Morbidity and
Mortality Weekly Report, 41/No. RR-14, pp. 1-7, September 11, 1992.
6. Briefing Material, Folic Acid Subcommittee Meeting, April 15,
1993.
7. Folic Acid Subcommittee/Food Advisory Committee Meeting, April
15-16, 1993, Transcript.
8. Folic Acid Subcommittee/Food Advisory Committee, October 14-15,
1993, Transcript.
9. LSRO/FASEB (1994), ``Assessment of Folate Methodology Used in the
Third National Health and Nutrition Examination Survey (NHANES III,
1988-1991),'' Bethesda, MD.
10. Mulinare, J., J.F. Cordero, J.D. Erickson, and R.J. Berry,
``Periconceptional Use of Multivitamins and the Occurrence of Neural
Tube Defects,'' Journal of the American Medical Association,
260:3141-3145, 1988.
11. Milunsky, A., H. Jick, S.S. Jick, et al., ``Multivitamin/Folic
Acid Supplementation in Early Pregnancy Reduces the Prevalence of
Neural Tube Defects,'' Journal of the American Medical Association,
262:2847-2852, 1989.
12. Mills, J.L., G.G. Rhoads, J.L. Simpson, et al., ``The Absence of
a Relation Between the Periconceptional use of Vitamins and Neural
Tube Defects,'' New England Journal of Medicine, 321:430-435, 1989.
13. Werler, M.M., S. Shapiro, and A.A. Mitchell, ``Periconceptional
Folic Acid Exposure and Risk of Occurrent Neural Tube Defects,''
Journal of the American Medical Association, 269:1257-1261, 1993.
14. Wald, N., ``Prevention of Neural Tube Defects: Results of the
Medical Research Council Vitamin Study,'' Lancet, 338:131-137, 1991;
and Editorial, ``Folic Acid and Neural Tube Defects,'' Lancet,
338:153-154, 1991.
15. Czeizel, A. E., and I. Dudas, ``Prevention of the First
Occurrence of Neural-tube Defects by Periconceptional Vitamin
Supplementation,'' New England Journal of Medicine, 327, 1832-1835,
1992.
16. Bower, C., and F. J. Stanley, ``Dietary Folate as a Risk Factor
for Neural Tube Defects: Evidence from a Case-control Study in
Western Australia,'' Medical Journal of Australia, 150:1257-1261,
1989.
17. Laurence, K. M., ``Dietary Approaches to the Prevention of
Neural Tube Defects,'' Nutrition and Health, 2:181-189, 1983.
18. Shils, M. E., J. A. Olson, and M. Shike, In: Modern Nutrition in
Health and Disease, pp. 412-413, Lea and Febiger, Philadelphia,
1994.
19. Combs, G. F., In: The Vitamins: Fundamental Aspects in Nutrition
and Health, pp. 359-360, Academic Press, New York, 1992.
20. Transcript of Meeting, July 27, 1992, CDC, Atlanta, GA, comment
no. supp.1. to docket 91N-0100, August 8, 1992.
21. Seller, M. J., and N. C. Nevin, ``Vitamins and Neural Tube
Defects, Letter to the Editor,'' Journal of the American Medical
Association, 263:2749, 1990.
22. Memo to File from Nancy Crane ``Food Sources of Folate,'' August
31, 1993.
23. Centers for Disease Control, ``Use of Folic Acid for Prevention
of Spina Bifida and Other Neural Tube Defects,'' 1983-1991,
Morbidity and Mortality Weekly Report, 40(30): 513-516, August 2,
1991.
24. Health Protection Branch, Health and Welfare Canada, Ottawa,
Ontario, Canada, ``Issues: Folic Acid, The Vitamin That Helps
Protect Against Neural Tube (Birth) Defects,'' April 2, 1993.
25. March of Dimes, 1994.
26. Centers for Disease Control, Transcript of Meeting, Atlanta, GA,
August 12, 1993; ``Surveillance for Possible Adverse Effects of
Folic Acid Consumption.''
27. Sanders, T. A. B., and S. Reddy, ``Vegetarian Diets and
Children,'' American Journal of Clinical Nutrition, 59:5(S):1176S-
1181S, 1994.
28. Herbert, V., ``Staging Vitamin B12 (Cobalamin) Status in
Vegetarians,'' American Journal of Clinical Nutrition,
59:5(S):1213S-1221S, 1994.
29. Ross, F. J., H. Belding, and B. L. Paegel, ``The Development and
Progression of Subacute Combined Degeneration of the Spinal Cord in
Patients with Pernicious Anemia Treated with Synthetic
Pteroylglutamic (Folic) Acid,'' Blood, 3:68-90, 1948.
30. Davidson, L. S. P., and R. H. Girdwood, ``Folic Acid as
Therapeutic Agent,'' British Medical Journal, 1:587-591, 1947.
31. Hansen, H. A., and A. Weinfeld, ``Metabolic Effects and
Diagnostic Value of Small Doses of Folic Acid and B12 in
Megaloblastic Anemias,'' Acta Medica Scandinavica, 172:427-443,
1962.
[[Page 8779]]
32. Allen, R. H., S. P. Stabler, D. G. Savage, and J. Lindenbaum,
``Diagnosis of Cobalamin Deficiency.I. Usefulness of Serum
Methylmalonic Acid and Total Homocysteine Concentrations,'' American
Journal of Hematology, 34:90-98, 1990.
33. Stambolian, D., and M. Behrens, ``Optic Neuropathy Associated
with Vitamin B12 Deficiency,'' American Journal of
Ophthalmology, 83:465-468, 1977.
34. Cooper B. A., and T. Abe, ``Variable Response of Bone Marrow to
Feeding DL-5- formyltetrahydrofolate in Pernicious Anemia,'' British
Journal of Haematology, 32:387-394, 1976.
35. Ellison, A. B. Curry, ``Pernicious Anemia Masked by
Multivitamins Containing Folic Acid,'' Journal of the American
Medical Association, 173:240-243, 1960.
36. Challenger, W. A., and D. R. Korst, ``Pitfalls in the Diagnosis
and Treatment of Pernicious Anemia,'' American Journal of the
Medical Sciences, 134:226-231, 1960.
37. Victor, M., and A. A. Lear, ``Subacute Combined Degeneration of
the Spinal Cord,'' American Journal of Medicine, 20:896- 911, 1956.
38. Baldwin, J. N., and D. J. Dalessio, ``Folic Acid Therapy and
Spinal-cord Degeneration in Pernicious Anemia,'' New England Journal
of Medicine, 264:1339-1342, 1961.
39. Vilter, R. W., J. J. Will, T. Wright, and D. Rullman,
``Interrelationships of Vitamin B12, Folic Acid, and Ascorbic
Acid in the Megaloblastic Anemias,'' American Journal of Clinical
Nutrition, 12:130-144, 1963.
40. Marshall, R. A., and J. H. Jandl, ``Responses to `Physiologic'
Doses of Folic Acid in the Megaloblastic Anemias,'' Archives of
Internal Medicine, 105:352-360, 1960.
41. Chosy, J. J., D. V. Clatanoff, and R. F. Schilling, ``Responses
to Small Doses of Folic Acid in Pernicious Anemia,'' American
Journal of Clinical Nutrition, 10:349-350, 1962.
42. Hansen, H. A., and A. Weinfeld, ``Metabolic Effects and Diagno
Stic Value of Small Doses of Folic Acid and B12 in
Megaloblastic Anemias,'' Acta Medica Scandinavica, 172:427-443,
1962.
43. Institute of Medicine, National Academy of Sciences, ``Nutrition
During Pregnancy,'' National Academy Press, Washington, DC, 1990.
44. Lindenbaum, J., I. H. Rosenberg, Peter W. F. Wilson, S. P.
Stabler, and R. H. Allen, ``Prevalence of Cobalamin Deficiency in
the Framingham Elderly Population,'' American Journal of Clinical
Nutrition, 60:2-11, 1994.
45. Hathcock, J., and G. Troendle, ``Oral Cobalamin for Treatment of
Pernicious Anemia,'' Journal of the American Medical Association,
265:96-97, 1991.
46. Mooij, P. N. M., R. P. M. Steegers- Theunissen, C. M. G. Thomas,
W. H. Doesburg, and T. K. A. B. Eskes, ``Periconceptional Vitamin
Profiles Are Not Suitable for Identifying Women at Risk for Neural
Tube Defects,'' Journal of Nutrition, 123:197-203, 1993.
47. Mills, J. L., J. M. McPartlin, P. N. Kirke, Y. J. Lee, M. R.
Conley, D. G. Weir, and J. M. Scott, ``Impaired Homocysteine
Metabolism in Pregnancies Complicated by Neural Tube Defects,''
Lancet, 345:149-151, 1995.
48. Chambers, J. B., Norman W. Klein, P. G. Nosel, L. H. Khairallah,
and James S. Romanow, ``Methionine Overcomes Neural Tube Defects in
Rat Embryos Cultured on Sera from Laminin-immunized Monkeys,''
Journal of Nutrition, 125:1587-1599, 1995.
49. Shaw, G. M., N. G. Jensvold, C. R. Wasserman, and E. J. Lammer,
``Epidemiologic Characteristics of Phenotypically Distinct Neural
Tube Defects Among 0.7 million California Births, 1983-1987,''
Teratology, 49:143-149, 1994.
50. Shaw, G. M., D. S. Schaffer, E. M. Velie, K. Morland, and J. A.
Harris, ``Periconceptional Vitamin Use, Dietary Folate, and the
Occurrence of Neural Tube Defects,'' Epidemiology, 6:219-226, 1995.
51. Kirke, P. N., A. M. Molloy, L. E. Daly, H. Burke, D. G. Weir,
and J. M. Scott ``Maternal Plasma Folate and Vitamin B12 Are
Independent Risk Factors for Neural Tube Defects,'' Quarterly
Journal of Medicine, 86:703-708, 1993.
52. Centers for Disease Control, ``Use of Folic Acid for Prevention
of Spina Bifida and Other Neural Tube Defects; 1983-1991,''
Morbidity and Mortality Weekly Report, 40(30):513-516, August 2,
1991.
53. Department of Health and Human Services, Public Health Service,
``Knowledge and Use of Folic Acid by Women of Childbearing Age--
United States, 1995,'' Morbidity and Mortality Weekly Report, 44/No.
R38, pp. 716-718, September 29, 1995.
54. Levy, A., ``Report on Health Claims Focus Groups,'' June 15,
1995.
List of Subjects in 21 CFR Part 101
Food labeling, Nutrition, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
the authority delegated to the Commissioner of Food and Drugs, 21 CFR
part 101 is amended as follows:
PART 101--FOOD LABELING
1. The authority citation for 21 CFR part 101 continues to read as
follows:
Authority: Secs. 4, 5, 6 of the Fair Packaging and Labeling Act
(15 U.S.C. 1453, 1454, 1455); secs. 201, 301, 402, 403, 409, 701 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 342,
343, 348, 371).
2. Section 101.9 Nutrition labeling of food is amended in paragraph
(c)(8)(v) by revising the entry for folate to read as follows:
Sec. 101.9 Nutrition labeling of food.
* * * * *
(c) * * *
(8) * * *
(v) * * *
Folate--either Folic acid or Folacin may be used.
* * * * *
Sec. 101.36 [Amended]
3. Section 101.36 Nutrition labeling of dietary supplements of
vitamins and minerals is amended in paragraph (b)(3)(v) by removing the
words ``folate (folacin),'' and by adding in their place the words
``folate--either folic acid or folacin may be used.''
4. Section 101.79 is revised to read as follows:
Sec. 101.79 Health claims: Folate and neural tube defects.
(a) Relationship between folate and neural tube defects--(1)
Definition. Neural tube defects are serious birth defects of the brain
or spinal cord that can result in infant mortality or serious
disability. The birth defects anencephaly and spina bifida are the most
common forms of neural tube defects and account for about 90 percent of
these defects. These defects result from failure of closure of the
covering of the brain or spinal cord during early embryonic
development. Because the neural tube forms and closes during early
pregnancy, the defect may occur before a woman realizes that she is
pregnant.
(2) Relationship. The available data show that diets adequate in
folate may reduce the risk of neural tube defects. The strongest
evidence for this relationship comes from an intervention study by the
Medical Research Council of the United Kingdom that showed that women
at risk of recurrence of a neural tube defect pregnancy who consumed a
supplement containing 4 milligrams (mg)(4,000 micrograms (mcg)) folic
acid daily before conception and continuing into early pregnancy had a
reduced risk of having a child with a neural tube defect. (Products
containing this level of folic acid are drugs). In addition, based on
its review of a Hungarian intervention trial that reported
periconceptional use of a multivitamin and multimineral preparation
containing 800 mcg (0.8 mg) of folic acid, and its review of the
observational studies that reported periconceptional use of
multivitamins containing 0 to 1,000 mcg of folic acid, the Food and
Drug Administration concluded that most of these studies had results
consistent with the conclusion that folate, at levels attainable in
usual diets, may reduce the risk of neural tube defects.
(b) Significance of folate--(1) Public health concern. Neural tube
defects
[[Page 8780]]
occur in approximately 0.6 of 1,000 live births in the United States
(i.e., approximately 6 of 10,000 live births; about 2,500 cases among 4
million live births annually). Neural tube defects are believed to be
caused by many factors. The single greatest risk factor for a neural
tube defect-affected pregnancy is a personal or family history of a
pregnancy affected with a such a defect. However, about 90 percent of
infants with a neural tube defect are born to women who do not have a
family history of these defects. The available evidence shows that
diets adequate in folate may reduce the risk of neural tube defects but
not of other birth defects.
(2) Populations at risk. Prevalence rates for neural tube defects
have been reported to vary with a wide range of factors including
genetics, geography, socioeconomic status, maternal birth cohort, month
of conception, race, nutrition, and maternal health, including maternal
age and reproductive history. Women with a close relative (i.e.,
sibling, niece, nephew) with a neural tube defect, those with insulin-
dependent diabetes mellitus, and women with seizure disorders who are
being treated with valproic acid or carbamazepine are at significantly
increased risk compared with women without these characteristics. Rates
for neural tube defects vary within the United States, with lower rates
observed on the west coast than on the east coast.
(3) Those who may benefit. Based on a synthesis of information from
several studies, including those which used multivitamins containing
folic acid at a daily dose level of 400 mcg (0.4
mg), the Public Health Service has inferred that folate alone at levels
of 400 mcg (0.4 mg) per day may reduce the risk of neural tube defects.
The protective effect found in studies of lower dose folate measured by
the reduction in neural tube defect incidence, ranges from none to
substantial; a reasonable estimate of the expected reduction in the
United States is 50 percent. It is expected that consumption of
adequate folate will avert some, but not all, neural tube defects. The
underlying causes of neural tube defects are not known. Thus, it is not
known what proportion of neural tube defects will be averted by
adequate folate consumption. From the available evidence, the Public
Health Service estimates that there is the potential for averting 50
percent of cases that now occur (i.e., about 1,250 cases annually).
However, until further research is done, no firm estimate of this
proportion will be available.
(c) Requirements. The label or labeling of food may contain a
folate/neural tube defect health claim provided that:
(1) General requirements. The health claim for a food meets all of
the general requirements of Sec. 101.14 for health claims, except that
a food may qualify to bear the health claim if it meets the definition
of the term ``good source.''
(2) Specific requirements--(i) Nature of the claim--(A)
Relationship. A health claim that women who are capable of becoming
pregnant and who consume adequate amounts of folate daily during their
childbearing years may reduce their risk of having a pregnancy affected
by spina bifida or other neural tube defects may be made on the label
or labeling of food provided that:
(B) Specifying the nutrient. In specifying the nutrient, the claim
shall use the terms ``folate,'' ``folic acid,'' ``folacin,'' ``folate,
a B vitamin,'' ``folic acid, a B vitamin,'' or ``folacin, a B
vitamin.''
(C) Specifying the condition. In specifying the health- related
condition, the claim shall identify the birth defects as ``neural tube
defects,'' ``birth defects spina bifida or anencephaly,'' ``birth
defects of the brain or spinal cord anencephaly or spina bifida,''
``spina bifida and anencephaly, birth defects of the brain or spinal
cord,'' ``birth defects of the brain or spinal cord;'' or ``brain or
spinal cord birth defects.''
(D) Multifactorial nature. The claim shall not imply that folate
intake is the only recognized risk factor for neural tube defects.
(E) Reduction in risk. The claim shall not attribute any specific
degree of reduction in risk of neural tube defects from maintaining an
adequate folate intake throughout the childbearing years. The claim
shall state that some women may reduce their risk of a neural tube
defect pregnancy by maintaining adequate intakes of folate during their
childbearing years. Optional statements about population-based
estimates of risk reduction may be made in accordance with paragraph
(c)(3)(vi) of this section.
(F) Safe upper limit of daily intake. Claims on foods that contain
more than 100 percent of the Daily Value (DV) (400 mcg) when labeled
for use by adults and children 4 or more years of age, or 800 mcg when
labeled for use by pregnant or lactating women) shall identify the safe
upper limit of daily intake with respect to the DV. The safe upper
limit of daily intake value of 1,000 mcg (1 mg) may be included in
parentheses.
(G) The claim. The claim shall not state that a specified amount of
folate per serving from one source is more effective in reducing the
risk of neural tube defects than a lower amount per serving from
another source.
(H) The claim shall state that folate needs to be consumed as part
of a healthful diet.
(ii) Nature of the food--(A) Requirements. The food shall meet or
exceed the requirements for a ``good source'' of folate as defined in
Sec. 101.54;
(B) Dietary supplements. Dietary supplements shall meet the United
States Pharmacopeia (USP) standards for disintegration and dissolution,
except that if there are no applicable USP standards, the folate in the
dietary supplement shall be shown to be bioavailable under the
conditions of use stated on the product label.
(iii) Limitation. The claim shall not be made on foods that contain
more than 100 percent of the RDI for vitamin A as retinol or preformed
vitamin A or vitamin D per serving or per unit.
(iv) Nutrition labeling. The nutrition label shall include
information about the amount of folate in the food. This information
shall be declared after the declaration for iron if only the levels of
vitamin A, vitamin C, calcium, and iron are provided, or in accordance
with Sec. 101.9 (c)(8) and (c)(9) if other optional vitamins or
minerals are declared.
(3) Optional information--(i) Risk factors. The claim may
specifically identify risk factors for neural tube defects. Where such
information is provided, it may consist of statements from
Sec. 101.79(b)(1) or (b)(2) (e.g., Women at increased risk include
those with a personal history of a neural tube defect-affected
pregnancy, those with a close relative (i.e., sibling, niece, nephew)
with a neural tube defect; those with insulin-dependent diabetes
mellitus; those with seizure disorders who are being treated with
valproic acid or carbamazepine) or from other parts of this paragraph
(c)(3)(i).
(ii) Relationship between folate and neural tube defects. The claim
may include statements from paragraphs (a) and (b) of this section that
summarize the relationship between folate and neural tube defects and
the significance of the relationship except for information
specifically prohibited from the claim.
(iii) Personal history of a neural tube defect-affected pregnancy.
The claim may state that women with a history of a neural tube defect
pregnancy should consult their physicians or health care providers
before becoming pregnant. If such a statement is provided, the claim
shall also state that all women should consult a health care provider
when planning a pregnancy.
(iv) Daily value. The claim may identify 100 percent of the DV
(100% DV; 400 mcg) for folate as the target intake goal.
[[Page 8781]]
(v) Prevalence. The claim may provide estimates, expressed on an
annual basis, of the number of neural tube defect-affected births among
live births in the United States. Current estimates are provided in
Sec. 101.79(b)(1), and are approximately 6 of 10,000 live births
annually (i.e., about 2,500 cases among 4 million live births
annually). Data provided in Sec. 101.79(b)(1) shall be used, unless
more current estimates from the U.S. Public Health Service are
available, in which case the latter may be cited.
(vi) Reduction in risk. An estimate of the reduction in the number
of neural tube defect-affected births that might occur in the United
States if all women consumed adequate folate throughout their
childbearing years may be included in the claim. Information contained
in paragraph (b)(3) of this section may be used. If such an estimate
(i.e., 50 percent) is provided, the estimate shall be accompanied by
additional information that states that the estimate is population-
based and that it does not reflect risk reduction that may be
experienced by individual women.
(vii) Diets adequate in folate. The claim may identify diets
adequate in folate by using phrases such as ``Sources of folate include
fruits, vegetables, whole grain products, fortified cereals, and
dietary supplements.'' or ``Adequate amounts of folate can be obtained
from diets rich in fruits, dark green leafy vegetables, legumes, whole
grain products, fortified cereals, or dietary supplements.'' or
``Adequate amounts of folate can be obtained from diets rich in fruits,
including citrus fruits and juices, vegetables, including dark green
leafy vegetables, legumes, whole grain products, including breads,
rice, and pasta, fortified cereals, or a dietary supplement.''
(d) Model health claims. The following are examples of model health
claims that may be used in food labeling to describe the relationship
between folate and neural tube defects:
(1) Examples 1 and 2. Model health claims appropriate for foods
containing 100 percent or less of the DV for folate per serving or per
unit (general population). The examples contain only the required
elements:
(i) Healthful diets with adequate folate may reduce a woman's risk
of having a child with a brain or spinal cord birth defect.
(ii) Adequate folate in healthful diets may reduce a woman's risk
of having a child with a brain or spinal cord birth defect.
(2) Example 3. Model health claim appropriate for foods containing
100 percent or less of the DV for folate per serving or per unit. The
example contains all required elements plus optional information: Women
who consume healthful diets with adequate folate throughout their
childbearing years may reduce their risk of having a child with a birth
defect of the brain or spinal cord. Sources of folate include fruits,
vegetables, whole grain products, fortified cereals, and dietary
supplements.
(3) Example 4. Model health claim appropriate for foods intended
for use by the general population and containing more than 100 percent
of the DV of folate per serving or per unit: Women who consume
healthful diets with adequate folate may reduce their risk of having a
child with birth defects of the brain or spinal cord. Folate intake
should not exceed 250% of the DV (1,000 mcg).
Dated: February 26, 1996.
David A. Kessler,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 96-5013 Filed 2-29-96; 1:12 pm]
BILLING CODE 4160-01-P
