[Federal Register Volume 61, Number 173 (Thursday, September 5, 1996)]
[Rules and Regulations]
[Pages 46716-46719]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-22695]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 177

[Docket No. 84F-0330]


Indirect Food Additives: Polymers

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 copolymer of 
ethyl acrylate, methyl methacrylate, and methacrylamide in combination 
with melamine-formaldehyde resin as a coating for polyethylene 
phthalate films intended for use in contact with food. This action is 
in response to a petition filed by ICI Americas, Inc.

DATES: Effective September 5, 1996; written objections and requests for 
a hearing by October 7, 1996.

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: Mitchell Cheeseman, Center for Food 
Safety and Applied Nutrition (HFS-217), Food and Drug Administration, 
200 C St. SW., Washington, DC 20204, 202-418-3083.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In a notice published in the Federal Register of October 26, 1984 
(49 FR 43111), FDA announced that a food additive petition (FAP 4B3786) 
had been filed by ICI Americas, Inc., Wilmington, DE 19897. The 
petition proposed that the food additive regulations be amended to 
provide for the safe use of a copolymer of ethyl acrylate, methyl 
methacrylate, and methacrylamide in combination with melamine-
formaldehyde resin for use in contact with food in coatings for 
polyethylene phthalate films as defined by Sec. 177.1630(a) (21 CFR 
177.1630(a)).
    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 ethyl acrylate, 1,4-
dioxane, and ethylene oxide, all of which are carcinogenic impurities 
resulting from the manufacture of the additive. Residual amounts of 
reactants and manufacturing aids, such as ethyl acrylate, 1,4-dioxane, 
and ethylene oxide, are commonly found as contaminants in 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.''

[[Page 46717]]

    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 Petitioned Use of the Additive

    FDA estimates that the petitioned use of the additive, a copolymer 
of ethyl acrylate, methyl methacrylate, and methacrylamide in 
combination with melamine-formaldehyde resin, will result in exposure 
to the additive of no greater than 50 parts per billion (ppb) in the 
daily diet (Ref. 1).
    FDA does not ordinarily consider chronic toxicological testing to 
be necessary to determine the safety of an additive whose use will 
result in such low exposure levels (Ref. 2), and the agency has not 
required such testing here. However, the agency has reviewed the 
available toxicological data on the additive and has determined that 
these data support the safety of the additive under the intended 
conditions of use.
    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 risk presented 
by the carcinogenic chemicals that may be present as impurities in the 
additive. This risk evaluation of the carcinogenic impurities has two 
aspects: (1) Assessment of the worst-case exposure to the impurities 
from the proposed use of the additive; and (2) extrapolation of the 
risk observed in the animal bioassays to the conditions of probable 
exposure to humans.

A. Ethyl Acrylate

    FDA has estimated the hypothetical worst-case exposure to ethyl 
acrylate from the petitioned use of the additive in coatings for 
polyethylene phthalate films to be 8 parts per trillion (ppt) of the 
daily diet or 24 nanograms per person per day (ng/person/day) (Refs. 1 
and 3). The agency used data from the National Toxicology Program 
report (No. 259:1986), a bioassay on ethyl acrylate, to estimate the 
upper-bound level of lifetime human risk from exposure to this chemical 
stemming from the proposed use of the additive (Ref. 4). The results of 
the bioassay demonstrated that ethyl acrylate was carcinogenic for rats 
and mice under the conditions of the study. The test material induced 
squamous cell neoplasms in both sexes of F344/N rats and B6C3F1 mice 
when administered by gavage in corn oil.
    Based on the estimated worst-case exposure to ethyl acrylate of 24 
ng/person/day, FDA estimates that the upper-bound limit of individual 
lifetime risk from exposure to ethyl acrylate from the use of the 
subject additive is 1.9 x 10-9 (or 2 in 1 billion) (Ref. 5). 
Because of the numerous conservative assumptions used in calculating 
the exposure, the actual lifetime-averaged individual exposure to ethyl 
acrylate is expected to be substantially less than the worst-case 
exposure, and therefore, the calculated upper-bound limit of risk would 
be less. Thus, the agency concludes that there is a reasonable 
certainty that no harm from exposure to ethyl acrylate would result 
from the proposed use of the additive.

B. Ethylene Oxide

    FDA has estimated the hypothetical worst-case exposure to ethylene 
oxide from the petitioned use of the additive in coatings for 
polyethylene phthalate films to be 0.04 ppt of the daily diet or 0.12 
ng/person/day (Refs. 1 and 3). The agency used data from a 
carcinogenesis bioassay on ethylene oxide, conducted for the Institute 
of Hygiene, University of Mainz, Germany, to estimate the upper-bound 
level of lifetime human risk from exposure to this chemical stemming 
from the proposed use of the additive (Ref. 6). The results of the 
bioassay on ethylene oxide demonstrated that the material was 
carcinogenic for female rats under the conditions of the study. The 
test material caused significantly increased incidence of squamous cell 
carcinomas of the forestomach and carcinoma in situ of the glandular 
stomach.
    Based on the estimated worst-case exposure to ethylene oxide of 
0.12 ng/person/day, FDA estimates that the upper-bound limit of 
individual lifetime risk from exposure to ethylene oxide from the use 
of the subject additive is 2.2 x 10-10 (or 2 in 10 billion) (Ref. 
5). Because of the numerous conservative assumptions used in 
calculating the exposure, the actual lifetime-averaged individual 
exposure to ethylene oxide is expected to be substantially less than 
the worst-case exposure, and therefore, the calculated upper-bound 
limit of risk would be less. 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.

C. 1,4-Dioxane

    FDA has estimated the hypothetical worst-case exposure to 1,4-
dioxane from the petitioned use of the additive in coatings for 
polyethylene phthalate films to be 0.04 ppt of the daily diet or 0.12 
ng/person/day (Refs. 1 and 3). The agency used data from a 
carcinogenesis bioassay on 1,4-dioxane, conducted by the National 
Cancer Institute, to estimate the upper-bound lifetime human risk from 
exposure to this chemical stemming from the proposed use of the 
additive (Ref. 7). 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 test material caused significantly 
increased incidence of squamous cell carcinomas and hepatocellular 
tumors in female rats.
    Based on the estimated worst-case exposure to 1,4-dioxane of 0.12 
ng/person/day, FDA estimates that the upper-bound limit of individual 
lifetime risk from exposure to 1,4-dioxane from the use of the subject 
additive is 4.2 x 10-12 (or 4 in 1 trillion) (Ref. 5). Because of 
the numerous conservative assumptions used in calculating the exposure, 
the actual lifetime-averaged individual exposure to 1,4-dioxane is 
expected to be substantially less than the worst-case exposure, and 
therefore, the calculated upper-bound limit of risk would be less. 
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.

D. Formaldehyde

    FDA's review of the subject petition indicates that the additive 
may contain trace amounts of formaldehyde as an impurity. The potential 
carcinogenicity of formaldehyde was reviewed by the Cancer Assessment 
Committee (the Committee) of FDA's Center for Food Safety and Applied 
Nutrition. The Committee noted that for many years formaldehyde has 
been known to be a carcinogen by the inhalation route, but it concluded 
that these inhalation studies are not appropriate for assessing the 
potential carcinogenicity of formaldehyde in food. The Committee's 
conclusion was based on the fact that the route of administration 
(inhalation) is not relevant to the safety of formaldehyde residues in 
food and the fact that tumors were observed only locally at the portal 
of entry (nasal

[[Page 46718]]

turbinates). In addition, the agency has received literature reports of 
two drinking water studies on formaldehyde: (1) A preliminary report of 
a carcinogenicity study purported to be positive by Soffritti et al. 
(1989), conducted in Bologna, Italy (Ref. 8) and a negative study by 
Til et al. (1989), conducted in The Netherlands (Ref. 9). The Committee 
reviewed both studies and concluded, concerning the Soffritti study, 
``* * * that data reported were unreliable and could not be used in the 
assessment of the oral carcinogenicity of formaldehyde'' (Ref. 10). 
This conclusion is based on a lack of critical detail in the study, 
questionable histopathologic conclusions, and the use of unusual 
nomenclature to describe the tumors. Based on the Committee's 
evaluation, the agency has determined that there is no basis to 
conclude that formaldehyde is a carcinogen when ingested.

E. Need for Specifications

    The agency has also considered whether specifications are necessary 
to control the amount of ethyl acrylate, ethylene oxide, and 1,4-
dioxane present as impurities in the additive. The agency finds that 
specifications are not necessary for the following reasons: (1) Because 
of the low level at which ethyl acrylate, 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 small levels; and (2) the 
upper-bound limits of lifetime risk from exposure to the impurities, 
even under worst-case assumptions, are very low, in the range of less 
than 4 in 1 trillion to 2 in 1 billion.

IV. Conclusion

    FDA has evaluated data in the petition and other relevant material. 
The agency concludes that the proposed use of the additive in coating 
polyethylene phthalate films is safe, that it will achieve its intended 
technical effect, and that the regulations in Sec. 177.1630 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. 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 20, 1984, from the Food Additive 
Chemistry Evaluation Branch (HFF-458), to the Petitions Control 
Branch (HFF-334), entitled ``FAP 4B3786-ICI Americas, Inc. Copolymer 
coating for polyethylene phthalate films complying with 
Sec. 177.1630(c). Submission dated 7/30/84 (Rohm & Haas).''
    2. Kokoski, C. J., ``Regulatory Food Additive Toxicology'' in 
``Chemical Safety Regulation and Compliance,'' edited by F. 
Homburger, and J. K. Marquis, S. Karger, New York, pp. 24-33, 1985.
    3. Memorandum dated October 30, 1992, from the Food and Color 
Additives Review Section (HFF-415), to the Indirect Additives Branch 
(HFF-335), concerning FAP 4B3786--ICI Americas, Inc.--exposures 
acrylamide and methacrylamide, ethyl acrylate, and formaldehyde.
    4. ``Carcinogenesis Studies of Ethyl Acrylate (CAS Reg. No. 140-
88-5) in F-344/N Rats and B6C3F1 Mice'' (gavage studies), 
National Toxicology Program, Technical Report Series, No. 259, 
December 1986.
    5. Memorandum, ``Report of the Quantitative Risk Assessment 
Committee,'' July 1, 1993.
    6. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British 
Journal of Cancer, 46:924-933, 1982.
    7. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,'' 
National Cancer Institute, NCI-CG-TR-80, 1978.
    8. Soffritti, M., C. Maltoni, F. Maffei, and R. Biagi, 
``Formaldehyde: An Experimental Multipotential Carcinogen,'' 
Toxicology and Industrial Health, vol. 5, No. 5:699-730, 1989.
    9. Til, H. P., R. A. Woutersen, V. J. Feron, V. H. M. 
Hollanders, H. E. Falke, and J. J. Clary, ``Two-Year Drinking-Water 
Study of Formaldehyde in Rats,'' Food Chemical Toxicology, vol. 27, 
No. 2, pp. 77-87, 1989.
    10. Memorandum of Conferences concerning ``Formaldehyde,'' 
Meeting of the Cancer Assessment Committee, FDA, April 24, 1991, and 
March 4, 1993.

VII. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before October 7, 1996, 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.

List of Subjects in 21 CFR Part 177

    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 
177 is amended as follows:

PART 177--INDIRECT FOOD ADDITIVES: POLYMERS

    1. The authority citation for 21 CFR part 177 continues to read as 
follows:

    Authority: Secs. 201, 402, 409, 721 of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 321, 342, 348, 379e).

    2. Section 177.1630 is amended in paragraph (e)(4) by 
alphabetically adding a new substance to paragraph (iii) in the ``List 
of Substances and Limitations'' to read as follows:

Sec. 177.1630  Polyethylene phthalate polymers.

* * * * *
    (e) * * *
    (4) * * *
List of Substances and Limitations
* * * * *
    (iii) * * *

[[Page 46719]]

Acrylic copolymers (CAS Reg. No. 30394-86-6): Prepared by reaction 
of ethyl acrylate (CAS Reg. No. 140-88-5), methyl methacrylate (CAS 
Reg. No. 80-62-6), and methyacrylamide (CAS Reg. No. 79-39-0) 
blended with melamine-formaldehyde resin (CAS Reg. No. 68002-20-0). 
For use in coatings for polyethylene phthalate films complying with 
paragraph (a) of this section.
* * * * *

    Dated: August 23, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-22695 Filed 9-4-96; 8:45 am]
BILLING CODE 4160-01-F