[Federal Register Volume 68, Number 39 (Thursday, February 27, 2003)]
[Rules and Regulations]
[Pages 9000-9003]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-4604]


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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 D3

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 
D3 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 D3 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 D2 and vitamin D3. Vitamin D 
without a subscript represents either D2 or 
D3. As used in Sec.  184.1950, the meaning of the term 
vitamin D includes crystalline vitamin D2, crystalline 
vitamin D3 and vitamin D2 resin, and vitamin 
D3 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 D3 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 D3 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 D3, also known as cholecalciferol, is the 
chemical 9,10-seco(5Z,7E)-5,7,10(19)-cholestatrien-3-ol. Vitamin 
D3 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 D3 is purified by crystallization.
    To support the safety of the proposed use of vitamin D3, 
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 
D3 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 
D2 and D3) 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 D3 
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 D3-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 D3, 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 D3. 
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 D3. 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 D3 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 D3 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 D3 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 D3 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 D3 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 D3 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 D3.

    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 D3, also known as cholecalciferol, is the 
chemical 9,10-seco(5Z,7E)-5,7,10(19)-cholestatrien-3-ol. Vitamin 
D3 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 D3 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 D3 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 D3 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