Federal Register
                                Vol. 59, No. 2
                           Tuesday, January 4, 1994
                            Rules and Regulations

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration [Docket No. 93NÄ0481]

RIN 0905ÄAB67

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

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

SUMMARY: The Food and Drug Administration (FDA) is announcing that, in
accordance with the Nutrition Labeling and Education Act of 1990 (the 1990
amendments), as amended by the Dietary Supplement Act of 1992 (the DS act),
the regulation 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 (NTD's) is now considered a final regulation for dietary
supplements of vitamins, minerals, herbs, and other similar nutritional
substances (dietary supplements). The proposed regulation set out the
information that must be included in such a health claim to ensure that it is
an accurate representation of the effect of intake of folic acid on the risk
of NTD's, and that any claims that are made are understandable, informative,
and not misleading.

DATES: The final regulation will become effective on July 1, 1994.

FOR FURTHER INFORMATION CONTACT: Judith W. Riggins, Office of Policy (HFÄ23),
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,
301Ä443Ä2831.

or

Jeanne I. Rader, Center for Food Safety and Applied Nutrition (HFSÄ175), Food
and Drug Administration, 200 C St. SW., Washington, DC 20204, 202Ä205Ä5375.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing that, in accordance with section 3(b)(1)(A)(ii),
(b)(1)(A)(x), and (b)(2) of the 1990 amendments as amended by the DS act (Pub.
L. 102Ä571), the regulation 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 NTD's is now considered a final regulation for dietary supplements
of vitamins, minerals, herbs, and other similar nutritional substances
(dietary supplements).

II. Passage of 1990 Amendments

The 1990 amendments to the Federal Food, Drug, and Cosmetic Act (the act)
(Pub. L. 101Ä535) gave the Secretary of Health and Human Services (the
Secretary), and by delegation FDA, the authority to issue regulations
authorizing health claims on the labels and in the labeling of foods. 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 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 (21 U.S.C. 343(r)(3) and (r)(5)(D)).

The 1990 amendments also directed the Secretary to determine through
rulemaking whether claims regarding 10 nutrient-disease relationships met the
requirements of the act. The relationship of folic acid and NTD's was among
those 10 topics (section 3(b)(1)(A)(x) of the 1990 amendments).

III. Chronology of Regulatory and Other Activities Related To Folate and Ntd's

A. The 1991 Proposed Rule

In the Federal Register of November 27, 1991 (56 FR 60537), FDA proposed to
not authorize a health claim on folic acid and NTD's. The agency tentatively
concluded that the available evidence did not establish that the standard that
FDA had proposed for health claims for dietary supplements under section
403(r)(5)(D) of the act was met, that is, that there was not significant
scientific agreement, based on the totality of publicly available scientific
evidence, that the claim is valid.

B. The Public Health Service Recommendations

In September 1992, the Public Health Service (PHS) issued a recommendation
that all women of childbearing age in the United States who are capable of
becoming pregnant should consume 0.4 milligram (mg) of folic acid/day for the
purpose of reducing their risk of having a pregnancy affected with spina
bifida or other NTD's. The recommendation was based on data suggesting that
folic acid, when given at a high dose (4 mg), can reduce the risk of
recurrence of NTD's and on a synthesis of information from studies that used
multivitamins containing folic acid at dose levels from 0 to 1,000
micrograms/day. The PHS recommendation identified approaches and identified
outstanding issues, including the appropriate intake of folate, the potential
role of other nutrients in reduction of risk of NTD's, safety concerns, and
the "folate-preventable'' fraction of NTD's.

C. The Dietary Supplement Act of 1992

In October 1992, the DS act was enacted. This statute imposed a moratorium on
FDA's implementation of the 1990 amendments with respect to dietary
supplements until December 15, 1993. 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, section 3(b)(2) 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.

D. The 1993 Final Rules for Health Claims for Foods in Conventional Food Form

On January 6, 1993 (58 FR 2606), FDA published a final rule to not authorize a
health claim for folic acid and NTD's. However, the agency reaffirmed its
support of the PHS recommendation that all women of childbearing age in the
United States who are capable of becoming pregnant should consume 0.4 mg of
folic acid daily to reduce their risk of having a pregnancy affected with
spina bifida or other NTD's. The agency noted, however, that unresolved
questions about the safe use of folate remained. The agency concluded that it
could not authorize a health claim until these questions were resolved.
Because of the DS act, FDA took no final action with respect to the use of a
health claim on folic acid and NTD's on dietary supplements.

E. The 1993 Proposal to Authorize a Health Claim on Folic Acid and NTD's

On October 14, 1993, FDA published a proposed rule to authorize the use of a
health claim about the relationship of folate and NTD's on the labels of foods
in conventional food form and dietary supplements (58 FR 53254). FDA provided
60 days for comment on this proposed action. The comment period closed on
December 13, 1993.

Section 3(b)(2) of the 1990 amendments, as amended by section 202(a)(2)(B)(ii)
of the DS act, provides that if the Secretary does not promulgate final
regulations on any of the health claims applicable to dietary supplements in a
timely manner, the proposed regulations shall be considered final regulations
but not until December 31, 1993. FDA did not issue a final regulation on the
use of a health claim on folic acid and NTD's on dietary supplements by
December 31, 1993. Therefore, FDA is issuing this document announcing that by
operation of the law, the proposal to authorize a health claim about the
relationship of folate and NTD's published in the Federal Register of October
14, 1993, is now considered a final regulation applicable to the labels and
labeling of dietary supplements only. The agency proposed that 21 CFR part 101
be amended as follows:

PART 101 FOOD LABELING

2. Section 101.71 Health claims: claims not authorized is amended by removing
paragraph (c) and by redesignating paragraphs (d) through (f) as (c) through
(e), respectively.

3. New  101.79 is added to subpart E to read as follows:

 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 (g)) folic acid daily had a reduced risk of having a child
with a neural tube defect. (Products that contain this level of folic acid are
drugs.) In addition, based on its review of a Hungarian intervention trial
that used a multivitamin and multimineral preparation containing 800 g (0.8
mg) of folic acid, and its review of the observational studies that reported
use of multivitamins containing 0 to 1,000 g 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
occur in approximately 0.6 of 1,000 live births in the United States (i.e.,
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 the results of several
observational studies, the Public Health Service has estimated that about 50
percent of neural tube defect-affected pregnancies in the United States (e.g.,
about 1,250) may be averted annually if all women consume adequate amounts of
folate daily (i.e., 0.4 mg) throughout their childbearing years.

(c) Requirements. The label or labeling of food in conventional food form or
dietary supplements may contain a folate/neural tube defect health claim
provided that:

(1) General requirements. The health claim for a food or supplement meets all
of the general requirements of  101.14 for health claims, except that a food
or dietary supplement 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 foods in conventional food form or of
dietary supplements 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,'' or "spina bifida or anencephaly, birth
defects of the brain or spinal cord;''

(D) Multifactorial nature. The claim shall state that neural tube defects have
many causes and shall not imply that folate intake is the only recognized risk
factor for neural tube defects.

(E) Prevalence. In specifying the prevalence of neural tube defects among
women in the general population, the claim shall state that such birth defects
"which, while not widespread, are extremely significant'' or "* * * birth
defects * * * that, while not widespread, are extremely significant.''

(F) Reduction in risk. The claim shall not attribute any specific degree of
reduction in risk of neural tube defects, including mention of the Public
Health Service estimate that 50 percent of neural tube defects may be averted
annually, to 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 folic acid during
their childbearing years.

(G) Safe upper limit of daily intake. Claims on fortified foods in
conventional form and on dietary supplements that contain more than 25 percent
of the RDI for folate (100 g per serving or per unit) shall state that 1 mg
folate per day is the safe upper limit of intake (e.g., "Folate consumption
should be limited to 1,000 g per day from all sources.'')

(H) The claim. The claim shall not state that a specified amount of folate
(e.g., 400 g in a dietary supplement) is more effective in reducing the risk
of neural tube defects than a lower amount (e.g., 100 g in a breakfast cereal
or from diets rich in fruits and vegetables).

(ii) Nature of the food (A) Requirements. The food or supplement shall meet or
exceed the requirements for a good source of folate as defined in  101.54;

(B) Diets adequate in folate. The claim shall identify diets adequate in
folate by using phrases such as "* * * diets that include 2 to 4 servings per
day of fruits) including citrus fruits and juices), 3 to 5 servings of
vegetables (including dark green leafy vegetables and legumes), 6 to 11
servings of enriched grain products (such as breads, rice, and pasta) and
fortified cereals. Such diets provide many essential minerals and vitamins,
including folate. Women who do not eat well-balanced diets or who may be
concerned about their diets may choose to obtain folate from dietary
supplements.''; or "Adequate amounts of folate, a B vitamin, can be obtained
from diets rich in fruits, including citrus fruits and juices, vegetables,
including dark green leafy vegetables and legumes, enriched grain products,
including breads, rice, and pasta, fortified cereals, or a dietary
supplement.''; or "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.''

(C) Dietary supplements. Dietary supplements shall meet the United States
Pharmacopeia (U.S.P.) standards for disintegration and dissolution, except
that if there are no applicable U.S.P. 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 in conventional food
form or dietary supplements that contain more than 100 percent of the RDI for
vitamin A as retinol or preformed vitamin A or vitamin D.

(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  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;

(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.

(iv) Daily value. The claim may identify the daily value level of 400 g of
folate per day as the target intake goal.

(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) Example 1. Women who consume adequate amounts of folate, a B vitamin,
daily throughout their childbearing years may reduce their risk of having a
child with a neural tube birth defect. Such birth defects, while not
widespread, are very serious. They can have many causes. Adequate amounts of
folate can be obtained from diets rich in fruits, dark green leafy vegetables
and legumes, enriched grain products, fortified cereals, or a supplement.
Folate consumption should be limited to 1,000 g per day from all sources.

(2) Example 2. Women who consume adequate amounts of folate daily throughout
their childbearing years may reduce their risk of having a child with a birth
defect of the brain and spinal cord. Such birth defects, while not widespread,
are very serious. They can have many causes. 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 a
supplement. Women who have had a child with a spinal cord birth defect should
consult a physician before becoming pregnant. Folate consumption should be
limited to 1,000 g per day from all sources.

(3) Example 3. Women who take steps to ensure that their folate intake is
adequate throughout their childbearing years may reduce their risk of having a
child with a neural tube defect. Such birth defects, while not widespread, are
very serious. They can have many causes. Adequate amounts of folate, a B
vitamin, can be obtained from diets rich in citrus fruits and juices, dark
green leafy vegetables and legumes, enriched grain products such as breads,
rice, and pasta, fortified cereal, or a supplement. Folate consumption should
be limited to 1,000 g per day from all sources.

(4) Example 4. Women who take steps to ensure that their folate intake is at
least 400 g daily throughout their childbearing years may reduce their risk of
having a child with spina bifida or anencephaly, birth defects of the brain or
spinal cord that, while not widespread, are very serious. These birth defects
can have many causes. Adequate amounts of folate, a B vitamin, can be obtained
from diets rich in fruits, including citrus fruits and juices, vegetables,
including dark green leafy vegetables and legumes, enriched grain products,
including breads, rice, and pasta, fortified cereals, or from a supplement.
Women who have had a pregnancy affected with a neural tube defect should
consult a physician before becoming pregnant. Folate consumption should be
limited to 1,000 g per day from all sources.

(5) Example 5. Some women who consume the Daily Value of folate (400 g)
throughout their childbearing years may reduce their risk of having a child
affected with spina bifida or anencephaly, birth defects of the brain or
spinal cord that, while not widespread, are very serious. These birth defects
can have many causes. Women of childbearing age should choose well-balanced
diets that include 2 to 4 servings per day of fruits (including citrus fruits
and juices), 3 to 5 servings of vegetables (including dark green leafy
vegetables and legumes), 6 to 11 servings of enriched grain products (such as
breads, rice, and pasta) or fortified cereals throughout their childbearing
years. Such diets provide many essential minerals and vitamins, including
folate. Women who may be concerned about their diets may choose to obtain
folate from a supplement. Folate consumption should be limited to 1,000 g per
day from all sources.

(e) Effective date. For fortified foods, this regulation is effective on the
date the food additive regulation on the use of folic acid that was proposed
on October 14, 1993, becomes effective.

The 1990 amendments state that FDA is to promptly publish notice of the new
status of the proposed regulations in the Federal Register. This notice is
issued in response to that requirement. The agency emphasizes, however, that
this regulation is deemed to be a final regulation only with respect to
dietary supplements.

The agency notes that this document is part of a separate rulemaking
contemplated by Congress if the final regulation was not issued by December
31, 1993. This rulemaking bears a separate docket number from the one assigned
to the October 14, 1993 rulemaking to distinguish it from that rulemaking,
which is ongoing. The agency intends to continue its rulemaking with respect
to folic acid and neural tube defects and to issue a final rule as quickly as
possible.

In this regard, FDA recognizes that clarification with respect to the legal
status of claims about folic acid and NTD's on foods in conventional food form
is appropriate. FDA advises that, given the PHS recommendation and the results
of FDA's preliminary review of the evidence on this claim, at this time it has
no intention of taking action against foods in conventional food form 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 has become final for dietary supplements by operation of law.

However, for foods fortified with folic acid, the agency has more significant
concerns. As explained in the health claim proposal on folic acid and NTD's
(58 FR 53254 at 53288) and the proposal to amend the food additive regulation
on folic acid that published in the Federal Register on October 14, 1993 (58
FR 53312), there appears to be a rather narrow range of safe use of folic acid
in food. Based on this tentative view, FDA would be very concerned, at least
until it reached a final determination in those proceedings, if manufacturers
began adding folic acid to their products, or increasing the amount of folic
acid in their products, to qualify for a claim. Therefore, FDA strongly
discourages the use of a health claim about folic acid and NTD's on any such
fortified products pending the issuance of a final rule on this
nutrient-disease relationship.

As stated above, FDA intends to issue a final rule in the proceeding on a
health claim on folic acid and NTD's that it began on October 14, 1993, in the
near future. FDA is in the process of evaluating the comments that it has
received in that proceeding, including the results of an advisory committee
meeting held on October 14 and 15. FDA will attempt to resolve the issues in
that ongoing proceeding as soon as possible.

Dated: December 23, 1993.

David A. Kessler,

Commissioner of Food and Drugs.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 93Ä31817 Filed 12Ä29Ä93; 8:45 am]

BILLING CODE 4160Ä01ÄF