[Federal Register Volume 63, Number 104 (Monday, June 1, 1998)]
[Rules and Regulations]
[Pages 29548-29551]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-14296]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 178
[Docket No. 87F-0162]
Indirect Food Additives: Adjuvants, Production Aids, and
Sanitizers
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 sulfosuccinic acid
4-ester with polyethylene glycol nonylphenyl ether, disodium salt
(alcohol moiety produced by the condensation of 1 mole of nonylphenol
and an average of 9 to 10 moles of ethylene oxide) for use as an
emulsifier in the manufacture of polyvinyl acetate and vinyl-acrylate
copolymers intended for use in coatings for paper and paperboard that
will contact food. This action responds to a petition filed by American
Cyanamid Co.
DATES: The regulation is effective June 1, 1998; written objections and
requests for a hearing by July 1, 1998.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Hortense S. Macon, Center for Food
Safety and Applied Nutrition (HFS-206), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-418-3086.
SUPPLEMENTARY INFORMATION:
I. Background
In a notice published in the Federal Register of June 4, 1987 (52
FR 21122), FDA announced that a food additive petition (FAP 6B3908) had
been filed by American Cyanamid Co., One Cyanamid Plaza, Wayne, NJ
07470. The petition proposed to amend the food additive regulations in
Sec. 178.3400 Emulsifiers and/or surface-active agents (21 CFR
178.3400) to provide for the safe use of sulfosuccinic acid 4-ester
with polyethylene glycol nonylphenyl ether, disodium salt for use as a
surfactant in contact with food.
The agency has determined that the data submitted in the food
additive petition provided information for a more specific
identification of the additive as sulfosuccinic acid 4-ester with
polyethylene glycol nonylphenyl ether, disodium salt (alcohol moiety
[[Page 29549]]
produced by the condensation of 1 mole of nonylphenol and an average of
9 to 10 moles of ethylene oxide). Therefore, FDA is using this
description of the additive in the codified section of the final rule.
The agency has also determined that the data submitted in the petition
are adequate to support its limited use as a surfactant in the
manufacture of polyvinyl acetate and vinyl-acrylate copolymers intended
for use in coatings for paper and paperboard food packaging.
Subsequent to the filing of the petition, American Cyanamid Co. was
acquired by Cytec Industries, Inc., Five Garret Mountain Plaza, West
Paterson, NJ 07424. As a result of this change in ownership, FDA was
informed in a letter dated September 20, 1995, that the petition and
all related records be amended to reflect this change in ownership for
this food additive petition.
In its evaluation of the safety of this additive, FDA has reviewed
the safety of the additive itself and the chemical impurities that may
be present in the additive resulting from its manufacturing process.
Although the additive itself has not been shown to cause cancer, it has
been found to contain minute amounts of unreacted ethylene oxide and
minute amounts of 1,4-dioxane as impurities resulting from its
manufacture. These chemicals have been shown to cause cancer in test
animals. Residual amounts of impurities are commonly found as
constituents of chemical products, including food additives.
II. Determination of Safety
Under the so-called ``general safety clause'' of the Federal Food,
Drug, and Cosmetic Act (the act) (21 U.S.C. 348(c)(3)(A)), 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 (21
U.S.C. 348(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.
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 properly evaluated under the general safety
clause using risk assessment procedures to determine whether there is a
reasonable certainty that no harm will result from the proposed 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,
sulfosuccinic acid 4-ester with polyethylene glycol nonylphenyl ether,
disodium salt (alcohol moiety produced by the condensation of 1 mole of
nonylphenol and an average of 9 to 10 moles of ethylene oxide) as an
emulsifier/surfactant in the manufacture of polyvinyl acetate and
vinyl-acrylate copolymers intended for use in coatings for paper and
paperboard food packaging, will result in exposure of no greater than
120 parts per billion (ppb) of the additive in the daily diet (3
kilograms (kg)), or an estimated daily intake (EDI) of 0.36 milligrams
per person per day (mg/p/d) (Refs. 1 and 2).
FDA concludes that the currently regulated use of the additive in
adhesives (21 CFR 175.105) and the petitioned use in polyvinyl acetate
and vinyl-acrylate copolymers intended for use as coatings for paper
and paperboard will result in a cumulative exposure no greater than 148
ppb, or an EDI of 0.44 mg/p/d.
FDA does not ordinarily consider chronic toxicological studies to
be necessary to determine the safety of an additive whose use will
result in such low exposure levels (Ref. 3), and the agency has not
required such testing here. However, the agency has reviewed the
available toxicological data on the additive and concludes that the
estimated small dietary exposure resulting from the proposed use of
this additive is safe.
FDA has evaluated the safety of this additive under the general
safety clause, considering all available data and using risk assessment
procedures to estimate the upper-bound limit of lifetime human risk
presented by ethylene oxide and 1,4-dioxane, the carcinogenic chemicals
that may be present as impurities in the additive. The risk evaluation
of ethylene oxide and 1,4-dioxane 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. Ethylene Oxide
FDA has estimated the cumulative exposure to ethylene oxide from
both the regulated use of the additive in adhesives and the petitioned
use of the additive as an emulsifier/surfactant in the manufacture of
polyvinyl acetate and vinyl-acrylate copolymers intended for use in
paper and paperboard coatings that will contact food to be no more than
1.5 parts per trillion (pptr) in the daily diet (3 kg) or 4.5 nanograms
(ng)/person/day (Ref. 2). The agency used data from a carcinogenesis
bioassay on ethylene oxide conducted by the Institute of Hygiene,
University of Mainz, Germany (Ref. 4) to estimate the upper-bound limit
of lifetime human risk from the cumulative exposure to this chemical
resulting from the currently regulated use and the proposed use of the
additive. The results of the bioassay on ethylene oxide demonstrated
that ethylene oxide was carcinogenic for female rats under the
conditions of the study. The author reported that the rodent bioassay
showed that the test material caused significantly increased incidence
of squamous cell carcinomas of the forestomach and carcinomas in situ
of the glandular stomach.
Based on the agency's estimate that the cumulative exposure to
ethylene oxide will not exceed 4.5 ng/person/day, FDA estimates that
the upper-bound limit of lifetime human risk from the regulated and
proposed uses of the subject additive is 8.4 x 10-9 or 8.4
in one billion (Refs. 2 and 5). 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 would be less than the upper-bound limit
of lifetime human risk. Thus, the agency concludes that there is a
reasonable certainty that no harm from exposure to ethylene oxide would
result from the proposed use of the additive.
B. 1,4-Dioxane
FDA has estimated the cumulative exposure to 1,4-dioxane from both
the regulated use of the additive in adhesives and the petitioned use
of the additive as an emulsifier/surfactant for paper and paperboard
coatings in contact with food to be no more than 0.15 pptr of the daily
diet (3 kg), or 0.45 ng/person/day (Refs. 2 and 5). The agency used
data from a carcinogenesis bioassay on 1,4-dioxane, conducted by the
National Cancer Institute (Ref. 6) to estimate the upper-bound limit of
lifetime human risk from exposure to this chemical resulting from the
regulated use of the additive in adhesives and the proposed use of the
additive. The results of the bioassay on
[[Page 29550]]
1,4-dioxane demonstrated that the material was carcinogenic for female
rats under the conditions of the study. The authors reported that the
rodent bioassay showed that the test material caused a 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 0.45 ng/person/day, FDA estimates that the upper-bound limit
of lifetime human risk from both the regulated and proposed uses of the
subject additive is 1.6 x 10-11, or 1.6 in 100 billion
(Refs. 2 and 5). 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 would be less than the 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 proposed use of
the additive.
C. Need for Specifications
The agency has also considered whether specifications are necessary
to control the amount of ethylene oxide and 1,4-dioxane present as
impurities in the food additive. The agency finds that specifications
are not necessary for the following reasons: (1) Because of the low
levels at which ethylene oxide and 1,4-dioxane may be expected to
remain as impurities following production of the additive, the agency
would not expect the impurities to become components of food at other
than extremely low levels; and (2) the upper-bound limits of lifetime
human risk from exposure to ethylene oxide and 1,4-dioxane are very
low, 8.4 in 1 billion and 1.6 in 100 billion, respectively.
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 additive as an emulsifier/surfactant for use in polyvinyl
acetate and vinyl-acrylate copolymers intended for use as coatings for
paper and paperboard food packaging is safe, and that the additive will
achieve its intended technical effect. Therefore, the agency concludes
that the regulations in Sec. 178.3400 should be amended as set forth
below.
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 above. 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 action. 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 Dockets
Management Branch (address above) between 9 a.m. and 4 p.m., Monday
through Friday.
VI. Objections
Any person who will be adversely affected by this regulation may at
any time on or before July 1, 1998, file with the Dockets Management
Branch (address above) written objections thereto. 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 shall be
submitted and shall 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.
VII. Paperwork Reduction Act of 1995
This final rule contains no collections of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
VIII. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Memorandum dated September 3, 1986, from the Regulatory Food
Chemistry Branch (HFF-458), to the Indirect Additives Branch (HFF-
335), entitled ``FAP 6B3908--American Cyanamid Co. Undated
submission received July 18, 1986. Sulfosuccinic acid 4-ester with
polyethylene glycol nonylphenyl ether disodium salt.''
2. Memorandum dated June 26, 1997, from the Division of Product
Policy, Scientific Support Branch (HFS-207), Chemistry and
Environmental Review Team (CERT), to the Regulatory Policy Branch
(HFS-206), entitled ``FAP 6B3908 (MATS #223, M2.10)-Cytec
Industries, Inc. (through Keller & Heckman). Update of exposure
estimates for Aerosol A-103. Regulatory Policy Branch (RPB) request
dated 3-31-97 and Division of Health Effects Evaluation (DHEE)
memorandum dated 3-27-97.''
3. Kokoski, C. J., ``Regulatory Food Additive Toxicology'' in
Chemical Safety Regulation and Compliance, edited by F. Homburger
and J. K. Marquis, published by S. Karger, New York, NY, pp. 24-33,
1985.
4. Dunkelburg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British
Journal of Cancer, 46, pp. 924-933, 1982.
5. Memorandum dated July 16, 1997, from the Regulatory Policy
Branch (HFS-206), to Sara H. Henry, Executive Secretary,
Quantitative Risk Assessment Committee (HFS-308), entitled ``Re-
evaluate Estimation of the Upper-Bound Lifetime Risk of Ethylene
Oxide and 1,4-Dioxane in Sulfosuccinic Acid 4-Ester With
Polyethylene Glycol Nonylphenyl Ether, Disodium Salt as an
Emulsifier for Latex Coatings for Food-Contact Applications: Subject
of Food Additive Petition FAP 6B3908 (Cytex Industries, Inc.)''.
6. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,''
National Cancer Institute, NCI-CG-TR-80, 1978.
List of Subjects in 21 CFR Part 178
Food additives, Food packaging.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
178 is amended as follows:
PART 178--INDIRECT FOOD ADDITIVES: ADJUVANTS, PRODUCTION AIDS, AND
SANITIZERS
1. The authority citation for 21 CFR part 178 continues to read as
follows:
Authority: 21 U.S.C. 321, 342, 348, 379e.
2. Section 178.3400 is amended in the table in paragraph (c) by
alphabetically adding a new entry under the headings
[[Page 29551]]
``List of substances'' and ``Limitations'' to read as follows:
Sec. 178.3400 Emulsifiers and/or surface active agents.
* * * * *
(c) * * *
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List of substances Limitations
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* * *
Sulfosuccinic acid 4-ester with For use only at levels not to
polyethylene glycol nonylphenyl exceed 5 percent by weight of the
ether, disodium salt (alcohol total coating monomers used in the
moiety produced by condensation of emulsion polymerization of
1 mole nonylphenol and an average polyvinyl acetate and vinyl-
of 9-10 moles of ethylene oxide) acrylate copolymers intended for
(CAS Reg. No. 9040-38-4). use as coatings for paper and
paperboard.
* * * *
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Dated: May 15, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-14296 Filed 5-29-98; 8:45 am]
BILLING CODE 4160-01-F