[Federal Register: February 27, 2003 (Volume 68, Number 39)]
[Rules and Regulations]
[Page 9000-9003]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr27fe03-9]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 172
[Docket No. 02F-0160]
Food Additives Permitted for Direct Addition to Food for Human
Consumption; Vitamin D 3
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the food
additive regulations to provide for the safe use of vitamin
D 3 as a nutrient supplement in calcium-fortified fruit
juices and juice drinks, excluding fruit juices and juice drinks
specially formulated or processed for infants, at levels not to exceed
100 International Units (IU) per reference amount customarily consumed
(RACC). This action is in response to a petition filed by The Minute
Maid Co.
DATES: This rule is effective February 27, 2003. Submit written
objections and requests for a hearing by March 31, 2003. The Director
of the Office of the Federal Register approves the incorporation by
reference of certain publications in Sec. 172.380 (21 CFR 172.380) as
of February 27, 2003.
ADDRESSES: Submit written objections and requests for a hearing to the
Dockets Management Branch (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic
objections to http://www.fda.gov/dockets/ecomments.
FOR FURTHER INFORMATION CONTACT: Judith L. Kidwell, Center for Food
Safety and Applied Nutrition (HFS-265), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, 202-418-3354.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Introduction
II. Evaluation of Safety
A. Acceptable Daily Intake for Vitamin D for Adults, Children, and
Infants
B. Estimated Daily Intake for Vitamin D
C. Safety Assessment
III. Conclusion
IV. Environmental Effects
V. Paperwork Reduction Act of 1995
VI. References
VII. Objections
I. Introduction
In a notice published in the Federal Register of April 25, 2002 (67
FR 20533), FDA announced that a food additive petition (FAP 2A4734 ) had
been filed by The Minute Maid Co., c/o King and Spalding, 1700
Pennsylvania Ave. NW., Washington, DC 20006. The petition proposed that
the food additive regulations be amended in 21 CFR part 172 to provide
for the safe use of vitamin D 3 in calcium-fortified fruit
juices and juice drinks at levels not to exceed 100 IU per RACC\1\.
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\1\RACC values represent the amount of food typically consumed
per eating occasion. The RACC for fruit juices and juice drinks
intended for the general population is 240 milliliters (mL) (21 CFR
101.12).
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Vitamin D\2\ is affirmed as generally recognized as safe (GRAS) in
Sec. 184.1950(c)(1) (21 CFR 184.1950(c)(1)), in accordance with 21 CFR
184.1(b)(2), for use as a nutrient supplement, as defined in 21 CFR
170.3(o)(20), as the sole source of added Vitamin D in foods within the
limitations specified in the following table:
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\2\Vitamin D comprises a group of fat soluble seco-sterols and
comes in many forms. The two major physiologically relevant forms
are vitamin D 2 and vitamin D 3 . Vitamin D
without a subscript represents either D 2 or
D 3 . As used in Sec. 184.1950, the meaning of the term
vitamin D includes crystalline vitamin D 2 , crystalline
vitamin D 3 and vitamin D 2 resin, and vitamin
D 3 resin.
[[Page 9001]]
Table 1.
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Category of
Food Maximum Levels in Food (As Served)
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Breakfast 350 IU/100 grams (g)
cereals
Grain 90 IU/100 g
products and
pastas
Milk 42 IU/100 g
Milk products 89 IU/100 g
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Additionally, vitamin D is affirmed as GRAS for use in infant
formula (Sec. 184.1950(c)(2)) and as an optional ingredient in
margarine (Sec. 184.1950(c)(3)).
Vitamin D is essential for human health. Humans can synthesize
significant amounts of vitamin D 3 in skin from its
precursor, 7-dehydrocholesterol, under exposure to ultraviolet B
radiation in sunlight. Other sources of naturally occurring vitamin D
are foods such as butter, buttermilk, cheese, cream, eggs, fish, goat
milk, meat fats and organ meats, mushrooms, and sour cream.
The major function of vitamin D is the maintenance of blood serum
concentrations of calcium and phosphorus by enhancing the absorption of
these minerals in the small intestine. Vitamin D deficiency can lead to
abnormalities in calcium and bone metabolism such as rickets in
children or osteomalacia in adults. The elderly, who have significantly
decreased capacity for the production of vitamin D 3 in skin,
and patients with intestinal malabsorption syndromes are especially
prone to vitamin D deficiency. At high levels, vitamin D may be toxic.
Because it is metabolized to inactive forms in the skin, vitamin D does
not accumulate significantly in the body as a result of sun exposure.
Excessive dietary intake of vitamin D elevates blood plasma calcium
levels by increased intestinal absorption and/or mobilization from the
bone.
Vitamin D 3 , also known as cholecalciferol, is the
chemical 9,10-seco(5Z,7E)-5,7,10(19)-cholestatrien-3-ol. Vitamin
D 3 occurs in, and is isolated from fish liver oils. It also
is manufactured by ultraviolet irradiation of 7-dehydrocholesterol that
is derived synthetically from natural cholesterol. In both methods,
vitamin D 3 is purified by crystallization.
To support the safety of the proposed use of vitamin D 3 ,
The Minute Maid Co. submitted a summary of the metabolism of vitamin D,
a number of publications pertaining to human clinical studies,
bioavailability studies, and dietary intake estimates. Based on these
data, the petitioner concludes that the proposed use of vitamin
D 3 in calcium-fortified fruit juices and juice drinks is
safe.
II. Evaluation of Safety
In order to establish, with reasonable certainty, that a new food
additive is not harmful under its intended conditions of use, FDA
considers the projected human dietary exposure to the additive, the
additive's toxicological data, and other relevant information (such as
published literature) available to the agency.
In determining whether the proposed use of an additive is safe, FDA
compares an individual's estimated daily intake (EDI) of the additive
to an acceptable intake level established by toxicological data. The
EDI is determined by projections based on the amount of the additive
proposed for use in particular foods and on data regarding the
consumption levels of these particular foods. The agency commonly uses
the EDI for the 90th percentile consumer of a food additive as a
measure of high chronic dietary exposure.
A. Acceptable Daily Intake for Vitamin D for Adults, Children, and
Infants
In 1997, the Standing Committee on the Scientific Evaluation of
Dietary Reference Intakes of the Food and Nutrition Board at the
National Academy of Sciences Institute of Medicine (IOM) conducted an
extensive review of toxicology and metabolism studies on vitamin D
published through 1996. The IOM published a detailed report that
included a tolerable upper intake level (UL) for vitamin D (both
D 2 and D 3 ) for infants, children and adults (Ref.
1). The IOM UL for vitamin D for children 1 to 18 years of age and
adults is 2,000 IU/day and for infants is 1,000 IU/day.
The IOM considers the UL as the highest usual intake level of a
nutrient that poses no risk of adverse effects when the nutrient is
consumed over long periods of time. The UL is determined using a risk
assessment model developed specifically for nutrients and considers
intake from all sources: Food , water, nutrient supplements, and
pharmacological agents. The dose-response assessment, which concludes
with an estimate of the UL, is built upon three toxicological concepts
commonly used in assessing the risk of exposures to chemical
substances: No observed adverse effect level, lowest observed effect
level and an uncertainty factor.
B. Estimated Daily Intake for Vitamin D
The petitioner provided average and 90th percentile vitamin D
intake estimates for consumers of fruit juices and juice drinks from:
(1) The proposed use in calcium-fortified fruit juices and juice
drinks, (2) current uses in conventional foods (including naturally
occurring sources of vitamin D), (3) current and proposed uses in
conventional foods, and (4) current and proposed uses in both
conventional foods and dietary supplements. The petitioner presented
intake estimates for the general population, 2 years of age and older,
and for 15 population subgroups (including estimates for infants less
than 1 year old; children 1 year to 3 years old; and adults). The
agency has determined that the methodology used to calculate these
estimates is appropriate (Ref. 2).
For the proposed food use, dietary intake of vitamin D 3
for 90th percentile consumers of fruit juices and juice drinks, 2 years
of age and older, was estimated to be 211 IU per person per day (IU/p/
d). The corresponding mean intake was estimated to be 110 IU/p/d.
For currently regulated uses in conventional foods (including
naturally occurring sources), mean dietary exposure to vitamin D for
consumers of fruit juices and juice drinks was estimated to be 197 IU/
p/d for consumers 2 years of age and older. Intake at the 90th
percentile was estimated to be 368 IU/p/day. For consumers of fruit
juices and juice drinks 2 years of age and older, average and 90th
percentile dietary intakes from current (including naturally occurring
sources) and proposed food uses of vitamin D were estimated to be 306
IU/p/d and 519 IU/p/d, respectively.
The petitioner also considered the intake of vitamin D from dietary
supplements. The National Health and Nutrition Examination Survey III
(NHANES III) data indicate that approximately 40 percent of the U.S.
population 2 months of age and older take dietary supplements. The
NHANES
[[Page 9002]]
III data also show that, when vitamin D is taken as a dietary
supplement, the most frequent level is 400 IU/day. The petitioner
provided results from two Gallup polls that concluded that consumers of
vitamin D 3 -fortified fruit juices and fruit drinks also are
likely to take supplemental sources of vitamin D. As a conservative
estimate of intake of vitamin D from dietary supplements and food uses,
the petitioner assumed that all consumers of fruit juices and juice
drinks would take dietary supplements containing 400 IU of vitamin D.
They then added this value to the mean and 90th percentile intake
estimates from current and proposed food uses. For consumers of fruit
juices and juice drinks 2 years of age and older, mean and 90th
percentile dietary intake estimates from current and proposed food uses
and dietary supplements were 706 IU/p/d and 919 IU/p/d, respectively.
Although the petitioner has notified FDA that it does not intend to
fortify fruit juices and juice drinks specially formulated or processed
for infants with vitamin D 3 , the petitioner provided intake
estimates for breastfed and non-breastfed infants, 0 to 6 months of age
and 7 to 12 months of age. These estimates assumed that all fruit
juices and juice drinks, including those specially formulated or
processed for infants, would be fortified with vitamin D 3 .
Of these four infant population groups, intake estimates were the
highest for non-breastfed infants, 0 to 6 months of age. For non-
breastfed infants, 0 to 6 months of age, mean and 90th percentile
dietary intake from current and proposed food uses were 443 IU/p/d and
663 IU/p/d, respectively. When dietary supplements were considered in
the estimates for these consumers, mean and 90th percentile intakes
were 843 IU/p/d and 1,063 IU/p/d, respectively. Intake estimates for
the other infant population groups were below the UL for infants of
1,000 IU/day.
Due to the relatively small sample size of infants consuming fruit
juices and juice drinks, the agency does not consider the intake
estimates presented by the petitioner to be statistically robust enough
to make a quantitative safety assessment. For example, for infants 0 to
6 months of age, non-breastfed, intake estimates were based on data
from 49 consumers of fruit juice or juice drinks; for infants, 0 to 6
months, breastfed, 16 consumers; infants, 7 to 12 months, non-
breastfed, 75 consumers; and infants, 7 to 12 months, breastfed, 9
consumers. Intake estimates from these populations are not considered
to be statistically robust when compared, for example, to the numbers
of consumers in the sample populations for children 4 to 8 years of age
(1,194 consumers) and 9 to 13 years of age (717 consumers).
Because a quantitative safety assessment cannot be made with the
available data, we consider it appropriate to exclude fruit juices and
juice drinks specially formulated or processed for infants (ages 0 to
12 months) from the proposed use of vitamin D 3 . The agency
recognizes that some infants may consume fruit juices and juice drinks
that are not specially formulated or processed for infants (Ref. 3);
however, fruit juices and juice drinks are not major components of the
diets of infants. Further, in a May 2001 policy statement, the American
Academy of Pediatrics recommended that fruit juice should not be given
to infants before 6 months of age (Ref. 4).
C. Safety Assessment
The petitioner submitted over 80 published articles to support the
safety of the proposed use of vitamin D 3 in calcium-
fortified fruit juices and juice drinks. These articles included most
of the references considered by IOM in its evaluation and all of the
critical references that were the basis for the UL. The petitioner also
submitted publications on vitamin D that appeared in the literature
subsequent to the 1997 IOM report. New information since 1997 supports
that vitamin D intake is without adverse effects at the IOM UL for
adults (Ref. 5). No new studies in children on the effects of vitamin D
intake have been published since 1997.
We considered the UL established by IOM for children (ages 1 year
and older) and adults relative to the intake estimates provided by the
petitioner as the primary basis for assessing the safety of the
proposed use of vitamin D 3 in calcium-fortified fruit juices
and juice drinks. For all population groups of children and adults
evaluated, mean and 90th percentile intake estimates from current and
proposed food uses of vitamin D are well below the IOM UL of 2,000 IU/
p/day. Additionally, when dietary supplements are included in the
calculations, intake estimates remain below the UL. Because the EDI of
vitamin D from all sources is less than the UL, the agency believes
that dietary exposure of vitamin D 3 from its use as a
nutrient supplement in calcium-fortified fruit juices and juice drinks,
excluding juices and juice drinks specially formulated or processed for
infants, will not pose a safety concern (Ref. 5)
III. Conclusion
Based on all data relevant to vitamin D reviewed by the agency, FDA
concludes that there is a reasonable certainty that no harm will result
from the use of vitamin D 3 as a nutrient supplement at the
levels specified in calcium-fortified fruit juices and juice drinks,
excluding fruit juices and juice drinks specially formulated or
processed for infants. Thus, vitamin D 3 is safe for its
proposed use and the agency concludes that the food additive
regulations should be amended as set forth in this document. To ensure
that only food grade vitamin D 3 is used in food , the
additive must meet the specifications of the Food Chemicals Codex,
4\th\ ed.
In accordance with Sec. 171.1(h) (21 CFR 171.1(h)), the petition
and the documents that FDA considered and relied upon in reaching its
decision to approve the petition are available for inspection at the
Center for Food Safety and Applied Nutrition by appointment with the
information contact person listed previously. As provided in Sec.
171.1(h), the agency will delete from the documents any materials that
are not available for public disclosure before making the documents
available for inspection.
IV. Environmental Effects
The agency has previously considered the environmental effects of
this rule as announced in the notice of filing for FAP 2A4734 (67 FR
20533). No new information or comments have been received that would
affect the agency's previous determination that there is no significant
impact on the human environment and that an environmental impact
statement is not required.
V. Paperwork Reduction Act of 1995
This final rule contains no collection of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
VI. References
The following references have been placed on display in the Dockets
Management Branch (see ADDRESSES) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Standing Committee on the Scientific Evaluation of Dietary
Reference Intakes, Food and Nutrition Board, Institute of Medicine,
``Dietary Reference Intakes for Calcium, Phosphorus, Magnesium,
Vitamin D, and Fluoride,'' National Academy Press, Washington, DC,
1997.
2. Memorandum from Folmer, Division of Petition Review,
Chemistry Review Group, to
[[Page 9003]]
Kidwell, Division of Petition Review, May 21, 2002.
3. Meeting minutes from August 2 and August 28, 2002, Internal
meetings, Division of Petition Review.
4. American Academy of Pediatrics Policy Statement ``The Use and
Misuse of Fruit Juice in Pediatrics (RE0047),'' Pediatrics, 107(5):
1210-1213, 2001.
5. Memorandum from Park, Division of Petition Review, Toxicology
Review Group, to Kidwell, Division of Petition Review, September 17,
2002.
VII. Objections
Any person who will be adversely affected by this regulation may at
any time file with the Dockets Management Branch (see ADDRESSES)
written or electronic objections. Each objection shall be separately
numbered, and each numbered objection shall specify with particularity
the provisions of the regulation to which objection is made and the
grounds for the objection. Each numbered objection on which a hearing
is requested shall specifically so state. Failure to request a hearing
for any particular objection shall constitute a waiver of the right to
a hearing on that objection. Each numbered objection for which a
hearing is requested shall include a detailed description and analysis
of the specific factual information intended to be presented in support
of the objection in the event that a hearing is held. Failure to
include such a description and analysis for any particular objection
shall constitute a waiver of the right to a hearing on the objection.
Three copies of all documents are to be submitted and are to be
identified with the docket number found in brackets in the heading of
this document. Any objections received in response to the regulation
may be seen in the Dockets Management Branch between 9 a.m. and 4 p.m.,
Monday through Friday.
List of Subjects in 21 CFR Part 172
Food additives, Incorporation by reference, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food , Drug , and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
172 is amended as follows:
PART 172-- FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR
HUMAN CONSUMPTION
1. The authority citation for 21 CFR part 172 continues to read as
follows:
Authority: 21 U.S.C. 321, 341, 342, 348, 371, 379e.
2. Section 172.380 is added to subpart D to read as follows:
Sec. 172.380 Vitamin D 3 .
The food additive may be used safely in foods as a nutrient
supplement defined under Sec. 170.3(o)(20) of this chapter in
accordance with the following prescribed conditions:
(a) Vitamin D 3 , also known as cholecalciferol, is the
chemical 9,10-seco(5Z,7E)-5,7,10(19)-cholestatrien-3-ol. Vitamin
D 3 occurs in and is isolated from fish liver oils. It also
is manufactured by ultraviolet irradiation of 7-dehydrocholesterol
produced from cholesterol and is purified by crystallization.
(b) Vitamin D 3 meets the specifications of the Food
Chemicals Codex, 4\th\ ed. (1996), p. 434, which is incorporated by
reference. The Director of the Office of the Federal Register approves
this incorporation by reference in accordance with 5 U.S.C. 552(a) and
1 CFR part 51. You may obtain copies from the National Academy Press,
2101 Constitution Ave. NW., Washington, DC 20418 (Internet address
http://www.nap.edu. Copies may be examined at the Center for Food
Safety and Applied Nutrition's Library, Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, or the Office of the
Federal Register, 800 North Capitol St. NW., suite 700, Washington, DC.
(c) Vitamin D 3 may be added, at levels not to exceed 100
International Units (IU) per serving, to 100 percent fruit juices, as
defined under Sec. 170.3(n)(35) of this chapter, excluding fruit
juices that are specially formulated or processed for infants, that are
fortified with greater than 33 percent of the Recommended Daily Intake
(RDI) of calcium per Reference Amount Customarily Consumed (RACC).
(d) Vitamin D 3 may be added, at levels not to exceed 100
IU per serving, to fruit drinks, as defined under Sec. 170.3(n)(35) of
this chapter, excluding fruit drinks that are specially formulated or
processed for infants, that are fortified with greater than 10 percent
of the RDI of calcium per RACC.
Dated: February 21, 2003.
William K. Hubbard,
Associate Commissioner for Policy and Planning.
[FR Doc. 03-4604 Filed 2-24-03; 11:58 am]
BILLING CODE 4160-01-S
Food Ingredients and Packaging