FR Doc 06-2354[Federal Register: March 13, 2006 (Volume 71, Number 48)]
[Rules and Regulations]
[Page 12618-12621]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr13mr06-4]
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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