
[Federal Register: March 16, 2009 (Volume 74, Number 49)]
[Rules and Regulations]               
[Page 11019-11022]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr16mr09-10]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 172

[Docket No. FDA-2007-F-0274] (formerly Docket No. 2007F-0355)

 
Food Additives Permitted for Direct Addition to Food for Human 
Consumption; Vitamin D2

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 
D2 as a nutrient supplement in soy-based food products. This 
action is in response to a petition filed by Dean Foods Co. (Dean 
Foods).

DATES: This rule is effective March 16, 2009. Submit written or 
electronic objections and requests for a hearing by April 15, 2009. See 
section VII of this document for information on filing objections. The 
incorporation by reference of certain publications listed in the rule 
is approved by the Director of the Federal Register as of March 16, 
2009.

ADDRESSES: You may submit written or electronic objections and requests 
for a hearing, identified by Docket No. FDA-2007-F-0274 (formerly 
Docket No. 2007F-0355), by any of the following methods:
Electronic Submissions
    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of objections, FDA is no longer 
accepting objections submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic objections by using the Federal 
eRulemaking Portal, as described in the Electronic Submissions portion 
of this paragraph.
    Instructions: All submissions received must include the agency name 
and docket number for this rulemaking. All objections received will be 
posted without change to http://www.regulations.gov, including any 
personal information provided. For detailed instructions on submitting 
objections, see the ``Objections'' heading of the SUPPLEMENTARY 
INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Judith Kidwell, Center for Food Safety 
and Applied Nutrition (HFS-265), Food and Drug Administration, 5100 
Paint Branch Pkwy., College Park, MD 20740, 301-436-1071.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In a notice published in the Federal Register of October 4, 2007 
(72 FR 56768), FDA announced that a food additive petition (FAP 7A4769) 
had been filed by Dean Foods Co., c/o Hogan and Hartson LLP, 555 13th 
St., NW., Washington, DC 20004-1109. The petition proposed to amend the 
food additive regulations in part 172 (21 CFR part 172) Food Additives 
Permitted for Direct Addition to Food for Human Consumption to provide 
for the safe use of vitamin D2 as a nutrient supplement in 
soy-based food products. The petition pertains only to the use of 
crystalline vitamin D2 and not the resin form of the 
vitamin. Foods identified in the petition are soy beverages, soy 
beverage products, soy-based butter substitute spreads, soy-based 
cheese substitutes, and soy-based cheese substitute products. The 
petitioner requested that part 172 be amended to permit the use of 
crystalline vitamin D2 as a nutrient supplement at levels 
not to exceed 50 International Units (IU) per 100 grams (g) of soy 
beverages, 89 IU per 100 g of soy beverage products, 330 IU per 100 g 
of soy-based butter substitute spreads, and 270 IU per 100 g of soy-
based cheese substitutes and soy-based cheese substitute products.
    Vitamin D\1\, including vitamin D2, is affirmed as 
generally recognized as safe (GRAS) for use in food under 21 CFR 
184.1950 (Sec.  184.1950) with the following specific limitations:
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    \1\ 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. Section 184.1950 includes crystalline vitamin 
D2, crystalline vitamin D3, vitamin 
D2 resin, and vitamin D3 resin. Section 
172.379, which is established by this rule, includes only 
crystalline vitamin D2.


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          Category of Food            Maximum Levels in Food (as Served)
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Breakfast cereals                    350 International Units (IU)/100
                                      grams (g)
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[[Page 11020]]


Grain products and pasta             90 IU/100 g
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Milk                                 42 IU/100 g
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Milk products                        89 IU/100 g
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    Additionally, under Sec.  184.1950(c)(2) and (c)(3), vitamin D is 
affirmed as GRAS for use in infant formulas and margarine, 
respectively. Under Sec.  172.380, vitamin D3 also is 
approved for use as a nutrient supplement in calcium-fortified fruit 
juices and fruit juice drinks; meal replacement and other type bars, 
soy protein-based meal replacement beverages represented for special 
dietary use in reducing or maintaining body weight; and cheese and 
cheese products as defined therein.
    Vitamin D2, also known as ergocalciferol, is the 
chemical 9,10-seco(5Z,7E,22E)-5,7,10(19),22-ergostatetraen-3-ol. The 
additive that is the subject of this petition is vitamin D2 
that is produced by ultraviolet irradiation of ergosterol isolated from 
yeast and is purified by crystallization. In contrast to the 
description of vitamin D2 set forth in Sec.  184.1950, this 
petition does not cover vitamin D2 that may be produced from 
ergosterol isolated from fungi other than yeast.
    Vitamin D is essential for human health. 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. High levels of vitamin D may be toxic. Excessive intake of 
vitamin D elevates blood plasma calcium levels by increased intestinal 
absorption and/or mobilization from the bone.
    To ensure that vitamin D is not added to the U.S. food supply at 
levels that could raise safety concerns, FDA affirmed vitamin D as GRAS 
with specific limitations as listed in Sec.  184.1950. Under 21 CFR 
184.1(b)(2), an ingredient affirmed as GRAS with specific limitations 
may be used in food only within such limitations, including the 
category of food, functional use, and level of use. Any addition of 
vitamin D to food beyond those limitations set out in Sec.  184.1950 
requires either a food additive regulation or an amendment of Sec.  
184.1950.
    To support the safety of the proposed uses of vitamin 
D2, Dean Foods submitted dietary intake estimates from 
current and proposed uses and from naturally-occurring sources of 
vitamin D, and compared these intake estimates to the Tolerable Upper 
Intake Level (UL) for vitamin D established by the Institute of 
Medicine (IOM) of the National Academies. The petitioner also submitted 
a number of publications pertaining to human clinical studies on 
vitamin D. Based on this information, which is discussed in section II 
of this document, the petitioner concluded that the proposed use of 
vitamin D2 in soy-based food products is safe.

II. Evaluation of Safety

    To establish with reasonable certainty that a food additive is not 
harmful under its intended conditions of use, FDA considers the 
projected human dietary intake of the additive, the additive's 
toxicological data, and other relevant information (such as published 
literature) available to the agency. FDA compares an individual's 
estimated daily intake (EDI) of the additive from all food sources 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 amount 
consumed from all food sources of the additive. The agency commonly 
uses the EDI for the 90th percentile consumer of a food additive as a 
measure of high chronic dietary intake.

A. Estimated Daily Intake for Vitamin D

    The petitioner provided mean and 90th percentile vitamin D intake 
estimates for consumers of soy beverages, soy beverage products, soy-
based butter substitute spreads, soy-based cheese substitutes, and soy-
based cheese substitute products from the following: (1) The proposed 
food uses; (2) current food uses (including regulated uses, naturally-
occurring sources of vitamin D, and dietary supplements); and (3) 
combined current and proposed food uses. The petitioner provided intake 
estimates for the overall U.S. population and nine population 
subgroups. For the purpose of the estimate, Dean Foods assumed that 
current consumers of dairy products would substitute their consumption 
of milk and dairy products with the corresponding soy beverages and 
soy-based dairy alternative products. The agency has determined that 
the methodology used to calculate these estimates is appropriate.
    The petitioner's estimates of intake of vitamin D from all food 
sources include the proposed food uses, currently-regulated uses in 
conventional foods (under Sec. Sec.  184.1950 and 172.380), dietary 
supplements, and naturally-occurring sources of the vitamin. For the 
overall U.S. population, including consumers of the soy-based food 
products identified in the petition, the 90th percentile dietary intake 
of vitamin D was estimated to be 1,012 IU per person per day (IU/p/d). 
For the population subgroup of infants less than 12 months of age, 
including consumers of the soy-based food products identified in the 
petition, the 90th percentile dietary intake of vitamin D was estimated 
to be 907 IU/p/d. FDA concurs with these intake estimates.

B. Acceptable Intake Level for Vitamin D

    In 1997, the Standing Committee on the Scientific Evaluation of 
Dietary Reference Intakes of the Food and Nutrition Board at 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 UL for vitamin D for infants, children, and adults. The 
IOM UL for vitamin D for children 1 to 18 years of age and adults is 
2,000 IU/p/d. The UL for infants is 1,000 IU/p/d.
    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

[[Page 11021]]

substances: No-observed-adverse-effect level, lowest-observed-effect 
level, and an uncertainty factor.

C. Safety Assessment

    To support the safety of the proposed uses for vitamin 
D2, Dean Foods submitted 14 scientific articles published 
subsequent to the IOM report and issuance of the November 2005 final 
rule (70 FR 69435) for the use of vitamin D3 in cheese and 
cheese products. Dean Foods concluded that these recent publications 
continue to support vitamin D supplementation in humans. FDA concurs 
with Dean Foods' conclusions.
    FDA considered the ULs established by IOM relative to the intake 
estimates provided by the petitioner as the primary basis for assessing 
the safety of petitioned uses of vitamin D. FDA also reviewed the 
scientific articles submitted by the petitioner. Finally, FDA reviewed 
studies on vitamin D that have published since the IOM report in the 
agency's evaluation of three previous food additive petitions for 
fortifying a variety of foods with vitamin D3. The most 
recent petition resulted in FDA's amendment of the food additive 
regulations in Sec.  172.380 to allow for the safe use of vitamin 
D3 as a nutrient supplement in cheese and cheese products at 
levels above those allowed under Sec.  184.1950 (70 FR 69435). The two 
earlier food additive petitions also resulted in amendments of the food 
additive regulations to allow for the safe use of vitamin D3 
as a nutrient supplement in certain foods (70 FR 37255; June 29, 2005, 
70 FR 36021; June 22, 2005, and 68 FR 9000; February 27, 2003).
    The estimated intake of vitamin D from all food sources, including 
the proposed uses, at the 90th percentile for the overall U.S. 
population is 1,012 IU/p/d, which is below the IOM UL of 2,000 IU/p/d. 
For infants less than 12 months of age, the estimated intake of vitamin 
D from all food sources, including the proposed uses, at the 90th 
percentile is 907 IU/p/d, which is below the IOM UL of 1,000 IU/p/d. 
Because the 90th percentile EDI of vitamin D from all current and 
proposed food sources is less than the IOM UL in both cases, the agency 
concludes that dietary intake of vitamin D2 from its 
proposed use as a nutrient supplement in soy beverages, soy beverage 
products, soy-based butter substitute spreads, soy-based cheese 
substitutes, and soy-based cheese substitute products will not pose a 
safety concern.

III. Conclusion

    Based on all data relevant to vitamin D2 reviewed by the 
agency, FDA concludes that there is a reasonable certainty that no harm 
will result from the use of vitamin D2 as a nutrient 
supplement in soy beverages, soy beverage products, soy-based butter 
substitute spreads, soy-based cheese substitutes, and soy-based cheese 
substitute products within the limits proposed by the petitioner. Thus, 
vitamin D2 is safe for the 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 crystalline 
vitamin D2 is used in food under this rule, the additive 
must meet the specifications set forth in this document.
    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 will be made available for inspection 
at the Center for Food Safety and Applied Nutrition by appointment with 
the information contact person (see FOR FURTHER INFORMATION CONTACT). 
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 7A4769. 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. Section 301(ll) of the Federal Food, Drug, and Cosmetic Act

    FDA's review of this petition was limited to section 409 of the 
Federal Food, Drug, and Cosmetic Act (the act). This final rule is not 
a statement regarding compliance with other sections of the act. For 
example, the Food and Drug Administration Amendments Act of 2007, which 
was signed into law on September 27, 2007, amended the act to, among 
other things, add section 301(ll). Section 301(ll) of the act (21 
U.S.C. 301(ll)) prohibits the introduction or delivery for introduction 
into interstate commerce of any food that contains a drug approved 
under section 505 of the act (21 U.S.C. 355), a biological product 
licensed under section 351 of the Public Health Service Act (42 U.S.C. 
262), or a drug or biological product for which substantial clinical 
investigations have been instituted and their existence has been made 
public, unless one of the exemptions in section 301(ll)(1) through (4) 
applies. In our review of this petition, FDA did not consider whether 
section 301(ll) or any of its exemptions apply to food containing this 
additive. Accordingly, this final rule should not be construed to be a 
statement that a food containing this additive, if introduced or 
delivered for introduction into interstate commerce, would not violate 
section 301(ll). Furthermore, this language is included in all food 
additive final rules and therefore should not be construed to be a 
statement of the likelihood that section 301(ll) applies.

VII. Objections

    Any person who will be adversely affected by this regulation may 
file with the Division of Dockets Management (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 Division of Dockets Management 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.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under

[[Page 11022]]

authority delegated to the Commissioner of Food and Drugs and 
redelegated to the Director, Center for Food Safety and Applied 
Nutrition, 21 CFR part 172 is amended as follows:

PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR 
HUMAN CONSUMPTION

0
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.

0
2. Section 172.379 is added to subpart D to read as follows:


Sec.  172.379  Vitamin D2.

    Vitamin D2 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 D2, also known as ergocalciferol, is the 
chemical 9,10-seco(5Z,7E,22E)-5,7,10(19),22-ergostatetraen-3-ol. 
Vitamin D2 is produced by ultraviolet irradiation of 
ergosterol isolated from yeast and is purified by crystallization.
    (b) Vitamin D2 meets the specifications of the Food 
Chemicals Codex, 6th ed. (2008), pp. 1013 and 1014, which is 
incorporated by reference. The Director 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 a copy from the United States 
Pharmacopeial Convention, 12601 Twinbrook Pkwy., Rockville, MD 20852 
(Internet address: http://www.usp.org). You may inspect a copy at the 
Center for Food Safety and Applied Nutrition's Library, Food and Drug 
Administration, 5100 Paint Branch Pkwy., College Park, MD 20740, 301-
436-1071, or at the National Archives and Records Administration 
(NARA). For information on the availability of this material at NARA, 
call 202-741-6030, or go to: http://www.archives.gov/federal_register/
code_of_federal_regulations/ibr_locations.html.
    (c) The additive may be used as follows:


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                                           Maximum Levels in Food (as
           Category of Food                         Served)
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Soy beverages                          50 International Units (IU)/100
                                        grams (g)
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Soy beverage products                  89 IU/100 g
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Soy-based butter substitute spreads    330 IU/100 g
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Soy-based cheese substitutes and soy-  270 IU/100 g
 based cheese substitute products
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    Dated: February 23, 2009.
Leslye M. Fraser,
Director, Office of Regulations and Policy, Center for Food Safety and 
Applied Nutrition.
[FR Doc. E9-5549 Filed 3-13-09; 8:45 am]

BILLING CODE 4160-01-S
