[Federal Register Volume 71, Number 48 (Monday, March 13, 2006)]
[Rules and Regulations]
[Pages 12618-12621]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 06-2354]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 172

[Docket No. 1991F-0457] (formerly Docket No. 91F-0457)


Food Additives Permitted For Direct Addition to Food for Human 
Consumption; Glycerides and Polyglycides

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 a mixture of 
glycerides and polyethylene glycol mono- and di-esters of fatty acids 
of hydrogenated vegetable oils as an excipient in dietary supplement 
tablets, capsules, and liquid formulations that are intended for 
ingestion in daily quantities measured in drops or similar small units 
of measure. This action is in response to a petition filed by 
Gattefosse Corp.

DATES: This rule is effective March 13, 2006. Submit written or 
electronic objections and requests for a hearing by April 12, 2006. See 
section VII of this document for information on the filing of 
objections. The Director of the Office of the Federal Register approves 
the incorporation by reference of certain publications in accordance 
with 5 U.S.C. 552(a) and 1 CFR part 51 as of March 13, 2006.

ADDRESSES: You may submit comments, identified by Docket No. 1991F-
0457, by any of the following methods:
Electronic Submissions
    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
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 comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to http://www.fda.gov/ohrms/dockets/
default.htm, including any personal information provided. For 
additional information on submitting comments, 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.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), 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: Raphael A. Davy, Center for Food 
Safety and Applied Nutrition (HFS-265), Food and Drug Administration, 
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1272.

SUPPLEMENTARY INFORMATION:

I. Background

    In a notice published in the Federal Register of December 19, 1991 
(56 FR 65907), FDA announced that a food additive petition (FAP 9A4155) 
had been filed by Parexel International Corp., One Alewife Place, 
Cambridge, MA 02140 on behalf of Gattefosse S.A., Saint-Priest, France. 
The petition proposed to amend the food additive regulations to provide 
for the safe use of a mixture of glycerides and polyethylene glycol 
esters of fatty acids of vegetable origin as an excipient in vitamin 
tablets and liquid formulations. Subsequently, in a letter dated 
January 7, 1998, the petitioner informed the agency that the petition 
was being amended by narrowing the polyethylene glycol esters (commonly 
known as polyglycides) to one class of compounds, namely, the 
polyethylene glycol esters of fatty acids from hydrogenated vegetable 
oils. Further, under an e-mail dated October 5, 2005, the petitioner 
later clarified that the additive was intended for use as an excipient 
in all dietary supplement tablets, capsules, and liquid formulations 
that are intended for

[[Page 12619]]

ingestion in daily quantities measured in drops or similar small units 
of measure.
    In evaluating the safety of the petitioned substance, FDA has 
reviewed the safety of the additive (glycerides and polyglycides 
mixture) and the chemical impurities that may be present in the 
additive as a result of the manufacturing process. The mono-, di-, and 
tri-glycerides component of the additive are commonly found in food. In 
addition, mono-, and di-glycerides are affirmed as generally recognized 
as safe (GRAS) for use in food (Sec.  184.1505 (21 CFR 184.1505)). The 
``polyglycides,'' consist of mono- and di-esters of polyethylene 
glycol, made using fatty acids derived from hydrogenated oils of 
vegetable origin. Although the additive itself (glycerides and 
polyglycides mixture) has not been shown to cause cancer, it may 
contain minute amounts of carcinogenic residues resulting from the 
manufacture of the polyethylene glycol. In particular, the additive may 
contain traces of 1,4-dioxane and ethylene oxide, which have been shown 
to cause cancer in test animals.

II. Determination of Safety

    Under the general safety standard in section 409 of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 348), a food additive 
cannot be approved for a particular use unless a fair evaluation of the 
data available to FDA establishes that the additive is safe for that 
use. FDA's food additive regulations (21 CFR 170.3(i)) define safe as 
``a reasonable certainty in the minds of competent scientists that the 
substance is not harmful under the intended conditions of use.''
    The food additives anticancer, or Delaney, clause of the act 
(section 409(c)(3)(A)) provides that no food additive shall be deemed 
safe if it is found to induce cancer when ingested by man or animal, or 
if it is found, after tests which are appropriate for the evaluation of 
the safety of food additives, to induce cancer in man or animal. 
Importantly, however, the Delaney clause applies to the additive itself 
and not to impurities in the additive. That is, where an additive 
itself has not been shown to cause cancer, but contains a carcinogenic 
impurity, the additive is evaluated properly under the general safety 
standard using risk assessment procedures to determine whether there is 
a reasonable certainty that no harm will result from the intended use 
of the additive (Scott v. FDA, 728 F.2d 322 (6th Cir. 1984)).

III. Safety of the Petitioned Use of the Additive

    FDA estimates that the petitioned use of the additive as an 
excipient in dietary supplement tablets, capsules, and liquid 
formulations that are intended for ingestion in daily quantities 
measured in drops or similar small units of measure will result in an 
estimated average daily intake of no more than 720 milligrams per 
person per day (mg/p/d) of polyglycides, based on the consumption of 2 
dietary supplement doses per day and assuming that the polyglycide 
portion comprises 75 percent of the total excipient in the dose (Ref. 
1). Although the filing notice specifically referenced vitamin tablets 
and liquid formulations only, this estimate considered use of the 
additive in all dietary supplement tablets, capsules, and liquid 
formulations that are intended for ingestion in daily quantities 
measured in drops or similar small units of measure, due to the 
petitioner's clarification of the additive's intended use. The estimate 
is conservative as it assumes that all dietary supplements would be 
formulated with the additive. This estimate does not include the daily 
intake of the glycerides because glycerides are GRAS for use with no 
limit other than current good manufacturing practice (Sec.  184.1505).
    Based on the available toxicological data on this new food additive 
mixture, and considering the cumulative exposure of the components of 
the mixture from the use of other ingredients, the agency concludes 
that the estimated dietary exposure to polyglycides resulting from the 
petitioned use of this additive is well within an acceptable margin of 
safety.
    FDA has evaluated the safety of this additive under the general 
safety standard, considering all available toxicological data and using 
risk assessment procedures to estimate the upper-bound limit of 
lifetime human risk presented by 1,4-dioxane and ethylene oxide, the 
carcinogenic chemicals that may be present as impurities in the 
additive. The risk evaluation of 1,4-dioxane and ethylene oxide has two 
aspects: (1) Assessment of exposure to the impurities from the 
petitioned use of the additive and (2) extrapolation of the risk 
observed in the animal bioassays to the conditions of exposure to 
humans.

A. 1,4-Dioxane

    FDA has estimated the exposure to 1,4-dioxane from the petitioned 
use of the additive as an excipient in dietary supplement tablets, 
capsules, and liquid formulations that are intended for ingestion in 
daily quantities measured in drops or similar small units of measure to 
be 800 nanograms per person per day (ng/p/d) (Ref. 1). This estimate is 
conservative as it was based on the assumptions that the additive 
(glycerides and polyglycides mixture) would be the sole excipient in 
all dietary supplement tablets, capsules, and liquid formulations that 
are intended for ingestion in daily quantities measured in drops or 
similar small units of measure, and that the additive would be used in 
all dietary supplement tablets, capsules, and liquid formulations that 
are intended for ingestion in daily quantities measured in drops or 
similar small units of measure at a maximum practical 80 percent use 
level.
    The agency used data from a carcinogenesis bioassay on 1,4-dioxane, 
conducted by the National Cancer Institute, to estimate the upper-bound 
limit of lifetime human risk from exposure to this chemical resulting 
from the petitioned use of the additive. The results of the bioassay on 
1,4-dioxane demonstrated that the material was carcinogenic for female 
rats under the conditions of the study. The authors reported that the 
test material caused significantly increased incidence of squamous cell 
carcinomas and hepatocellular tumors in female rats.
    Based on the agency's estimate that exposure to 1,4-dioxane will 
not exceed 800 ng/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from exposure to 1,4-dioxane resulting from the 
petitioned use of the subject additive is 2.8 x 10-8 or 28 in 1 
billion. Because of the numerous conservative assumptions used in 
calculating the exposure estimate, the actual lifetime-averaged 
individual exposure to 1,4-dioxane is likely to be substantially less 
than the estimated exposure, and therefore, the probable lifetime human 
risk is also likely to be substantially less than the estimated upper-
bound limit of lifetime human risk. Thus, the agency concludes that 
there is a reasonable certainty that no harm from exposure to 1,4-
dioxane would result from the petitioned use of the additive.

B. Ethylene Oxide

    FDA has estimated the exposure to ethylene oxide from the 
petitioned use of the additive as an excipient in dietary supplement 
tablets, capsules, and liquid formulations that are intended for 
ingestion in daily quantities measured in drops or similar small units 
of measure to be 80 ng/p/d, using the same

[[Page 12620]]

additive exposure assumptions described above for 1,4-dioxane (Ref. 1).
    The agency used data from a carcinogenesis bioassay on ethylene 
oxide conducted by the Institute of Hygiene, University of Mainz, 
Germany, to estimate the upper-bound limit of lifetime human risk from 
exposure to ethylene oxide resulting from the petitioned use of the 
additive. The authors reported that the test material caused 
significantly increased incidence of squamous cell carcinomas of the 
forestomach and carcinomas in situ of the glandular stomach in female 
rats.
    Based on the agency's estimate that exposure to ethylene oxide will 
not exceed 80 ng/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from exposure to ethylene oxide resulting from the 
petitioned use of the subject additive is 15 x 10-8 or 150 in 1 
billion. Because of the numerous conservative assumptions used in 
calculating the exposure estimate, the actual lifetime-averaged 
individual exposure to ethylene oxide is likely to be substantially 
less than the estimated exposure, and therefore, the probable lifetime 
human risk is also likely to be substantially less than the estimated 
upper-bound limit of lifetime human risk. Therefore, FDA concludes that 
there is reasonable certainty that no harm from exposure to ethylene 
oxide would result from the petitioned use of the additive.

C. Need for Specifications

    Because 1,4-dioxane and ethylene oxide are animal carcinogens and 
because the additive is intended to be ingested in its entirety, the 
agency has concluded that specifications are necessary to ensure that 
safe levels of 1,4-dioxane and ethylene oxide impurities in the 
petitioned food additive are maintained in future batches. Thus, the 
agency is including in this regulation a specification limit of not 
greater than 10 parts per million (ppm) for 1,4-dioxane and not greater 
than 1 ppm for ethylene oxide. We are also including in this regulation 
specifications for total ester content, acid value, hydroxyl value, and 
lead in order to ensure that the product in the marketplace reflects 
the identity and purity of the material evaluated (Ref. 2).

IV. Conclusion

    FDA has evaluated data in the petition and other relevant material. 
Based on this information, the agency concludes that the proposed use 
of the food additive as an excipient in dietary supplement tablets, 
capsules, and liquid formulations that are intended for ingestion in 
daily quantities measured in drops or similar small units of measure is 
safe. Therefore, the regulations in 21 CFR part 172 should be amended 
as 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 are 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.

V. Environmental Impact

    The agency has carefully considered the potential environmental 
effects of this final rule. FDA has concluded that the action will not 
have a significant impact on the human environment, and that an 
environmental impact statement is not required. The agency's finding of 
no significant impact and the evidence supporting that finding, 
contained in an environmental assessment, may be seen in the Division 
of Dockets Management (see ADDRESSES) between 9 a.m. and 4 p.m., Monday 
through Friday.

VI. 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.

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.

VIII. References

    The following references have been placed on display in the 
Division of Dockets Management and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Memorandum dated January 22, 2004, from the Division of Biotech 
and GRAS Notice Review to Division of Petition Review, ``FAP 9A4155: 
Gattefosse Corp. Polyglycides From Hydrogenated Vegetable Oils. Revised 
Estimate of Exposure for 1,4-Dioxane and Ethylene Oxide.''
    2. Memorandum dated October 30, 1998, from Chemistry Review Branch 
to the Division of Product Policy, ``FAP 9A4155: (MATS Milestone 2.3) 
American Clinical Research Consultants, Inc., on behalf of Gattefosse 
S.A. Polyglycides for use as Tablet Excipients. Submission of 1-7-98.''

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 
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

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 172.736 is added to subpart H to read as follows:


Sec.  172.736  Glycerides and polyglycides of hydrogenated vegetable 
oils.

    The food additive glycerides and polyglycides of hydrogenated 
vegetable oils may be safely used in food in accordance with the 
following prescribed conditions:
    (a) The additive is manufactured by heating a mixture of 
hydrogenated oils of vegetable origin and polyethylene glycol in the 
presence of an alkaline catalyst followed by neutralization with any 
acid that is approved or is generally recognized as safe for this use 
to yield the finished product.

[[Page 12621]]

    (b) The additive consists of a mixture of mono-, di- and tri-
glycerides and polyethylene glycol mono- and di-esters of fatty acids 
(polyglycides) of hydrogenated vegetable oils and meets the following 
specifications:
    (1) Total ester content, greater than 90 percent as determined by a 
method entitled ``Determination of Esterified Glycerides and 
Polyoxyethylene Glycols,'' approved November 16, 2001, printed by 
Gattefosse S.A.S., and 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 a 
copy from the Office of Food Additive Safety, 5100 Paint Branch Pkwy., 
College Park, MD 20740 or you may examine 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, 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.
    (2) Acid value, not greater than 2, and hydroxyl value, not greater 
than 56 as determined by the methods entitled ``Acid Value,'' p. 934 
and ``Hydroxyl Value,'' p. 936, respectively, in the Food Chemicals 
Codex, 5th ed., effective January 1, 2004, and incorporated by 
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies 
are available from the National Academies Press, 500 Fifth St. NW., 
Washington, DC 20055 (Internet address http://www.nap.edu), or may be 
examined at the Center for Food Safety and Applied Nutrition's Library, 
5100 Paint Branch Pkwy., College Park, MD 20740, 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.
    (3) Lead, not greater than 0.1 mg/kg as determined by the American 
Oil Chemists' Society (A.O.C.S.) method Ca 18c-91, ``Determination of 
Lead by Direct Graphite Furnace Atomic Absorption Spectrophotometry,'' 
updated 1995, and incorporated by reference in accordance with 5 U.S.C. 
552(a) and 1 CFR part 51. Copies are available from American Oil 
Chemists' Society, P. O. Box 3489, Champaign, IL 61826-3489, or may be 
examined in the library at the Center for Food Safety and Applied 
Nutrition, 5100 Paint Branch Pkwy., College Park, MD 20740, 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.
    (4) 1,4-Dioxane, not greater than 10 milligrams per kilogram (mg/
kg), and ethylene oxide, not greater than 1 mg/kg, as determined by a 
gas chromatographic method entitled ``Determination of Ethylene Oxide 
and 1,4-Dioxane by Headspace Gas Chromatography,'' approved November 5, 
1998, printed by Gattefosse S.A.S., and incorporated by reference in 
accordance with 5 U.S.C. 552(a) and 1 CFR part 51; see paragraph (b)(1) 
of this section for availability of the incorporation by reference.
    (c) The additive is used or intended for use as an excipient in 
dietary supplement tablets, capsules, and liquid formulations that are 
intended for ingestion in daily quantities measured in drops or similar 
small units of measure.

    Dated: March 2, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 06-2354 Filed 3-10-06; 8:45 am]
BILLING CODE 4160-01-S