[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