[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
