[Federal Register Volume 62, Number 143 (Friday, July 25, 1997)]
[Rules and Regulations]
[Pages 39935-39937]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-19567]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 175
[Docket No. 96F-0384]
Indirect Food Additives: Adhesives and Components of Coatings
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 epichlorohydrin-
dipropylene glycol and epichlorohydrin-polypropylene glycol as
reactants in the preparation of epoxy-based resins used as adhesives
for articles or components of articles intended for use in food-contact
applications. This action is in response to a petition filed by the Dow
Chemical Co.
DATES: Effective July 25, 1997; written objections and requests for a
hearing by August 25, 1997.
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: Vir D. Anand, Center for Food Safety
and Applied Nutrition (HFS-215), Food and Drug Administration, 200 C
St. SW., Washington, DC 20204, 202-418-3081.
SUPPLEMENTARY INFORMATION: In a notice published in the Federal
Register of October 22, 1996 (61 FR 54801), FDA announced that a food
additive petition (FAP 6B4523) had been filed by the Dow Chemical Co.,
2030 Dow Center, Midland, MI 48674. The petition proposed to amend the
food additive regulations in Sec. 175.105 Adhesives (21 CFR 175.105) to
provide for the safe use of epichlorohydrin-dipropylene glycol and
epichlorohydrin-polypropylene glycol as reactants in the preparation of
epoxy-based resins used as adhesives for articles or components of
articles intended for use in food-contact applications.
In FDA's evaluation of the safety of this additive, the agency
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
propylene oxide and epichlorohydrin, carcinogenic impurities resulting
from the manufacture of the additive. Residual amounts of reactants and
manufacturing aids, such as propylene oxide and epichlorohydrin, are
commonly found as contaminants in chemical products, including food
additives.
I. 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 the 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
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).
II. Safety of The Petitioned Use of The Additive
FDA estimates that the petitioned use of the additives, reaction
products of epichlorohydrin-dipropylene glycol and epichlorohydrin-
polypropylene glycol, will result in exposure to the additive of no
greater than 7 parts per billion 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
[[Page 39936]]
low exposure levels (Ref. 2), and the agency has not required such
testing here. However, the agency has reviewed the available
toxicological data from acute toxicity studies on the additive and
concludes that the estimated small dietary exposure resulting from the
petitioned use of the additive is safe.
FDA has evaluated the safety of this additive under the general
safety standard, considering all available data and using risk
assessment procedures to estimate the upper-bound limit of lifetime
human risk presented by propylene oxide and epichlorohydrin, the
carcinogenic chemicals that may be present as impurities in the
additive. This risk evaluation of propylene oxide and epichlorohydrin
has two aspects: (1) Assessment of the 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. Propylene Oxide
FDA has estimated the exposure to polypropylene oxide from the
petitioned use of each of the two additives in the manufacture of
adhesives to be 0.7 parts per quadrillion (ppq) of the daily diet or
2.1 picogram (pg)/person/day or a total of 4.2 pg/person/day (Ref. 1).
The agency used data from a carcinogenesis bioassay on propylene oxide,
conducted for the Institute of Hygiene, University of Mainz, Germany
(Ref. 3), to estimate the upper-bound lifetime human risk from exposure
to this chemical stemming from the petitioned use of the additive. The
results of the bioassay on propylene oxide demonstrated that the
material was carcinogenic for female rats under the conditions of the
study. The test material caused carcinomas and papillomas in the
squamous epithelium of the forestomach.
Based on the estimated worst-case exposure to propylene oxide of
4.2 pg/person/day, FDA estimates that the upper-bound limit of
individual lifetime risk from the use of the subject additives is in
the range of 6.5 x 10-13 (or 6.5 in 10 trillion) to 2.9 x
10-12 (or 2.9 in 1 trillion) (Ref. 4). FDA's estimate of the
upper-bound limit of individual lifetime risk has been stated as a
range because the agency evaluated complex tumor data in an oral
toxicity study using rats. Because of the numerous conservative
assumptions used in calculating the exposure estimate, the actual
lifetime-averaged individual exposure to propylene 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
reasonable certainty that no harm from exposure to propylene oxide
would result from the petitioned use of the additives.
B. Epichlorohydrin
FDA has estimated the exposure to epichlorohydrin from the
petitioned use of each of the two additives in the manufacture of
adhesives to be 0.7 ppq of the daily diet (3 kg), or 2.1 pg/person/day
or a total of 4.2 pg/person/day (Ref. 1). The agency used data from a
carcinogenesis bioassay conducted in Japan on epichlorohydrin fed to
rats via their drinking water (Ref. 5), to estimate the upper-bound
limit of lifetime human risk from exposure to this chemical resulting
from the petitioned use of the additives. The results of the bioassay
demonstrated that epichlorohydrin was carcinogenic under the conditions
of the study. The test material caused significantly increased
incidences of stomach papillomas and carcinomas in the rats.
Based on the agency's estimate that exposure to epichlorohydrin
will not exceed 4.2 pg/person/day, FDA estimates that the upper-bound
limit of individual lifetime human risk from the use of the subject
additives is 1.9 x 10-13 (or 1.9 in 10 trillion) (Ref. 4).
Because of the numerous conservative assumptions used in calculating
the exposure estimate, the actual lifetime-averaged individual exposure
to epichlorohydrin would 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 reasonable certainty that no harm from exposure
to epichlorohydrin would result from the petitioned use of the
additives.
C. Need for Specifications
The agency has also considered whether specifications are necessary
to control the amount of propylene oxide and epichlorohydrin 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 propylene oxide and epichlorohydrin may be expected to remain
as impurities following production of the additives, 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 propylene oxide and epichlorohydrin, even under worst-
case assumptions, is very low, in the range of less than 6.5 in 10
trillion to 2.9 in 1 trillion for propylene oxide and 1.9 in 10
trillion for epichlorohydrin.
III. Conclusion
FDA has evaluated data in the petition and other relevant material.
The agency concludes that: (1) The proposed use of the additive is
safe, (2) the additive will achieve its intended technical effect, and
(3) the regulations in Sec. 175.105 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.
IV. 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. No comments were received during the 30 day comment
period specified in the filing notice for comments on the environmental
assessment submitted with the petition.
V. Objections
Any person who will be adversely affected by this regulation may at
any time on or before August 25, 1997, file with the Dockets Management
Branch (address above) written objection 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
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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 objection 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.
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 from the Chemistry Review Team, FDA, to the file
concerning ``FAP 6B4523 (MATS #887, M2.0 & 2.1): Dow Chemical Co.,
dated September 18, 1996. Epichlorohydrin-dipropylene Glycol and
Epichlorohydrin-polypropylene Glycol as Reactants in the Preparation
of Epoxy Resins Used in Adhesives,'' dated October 29, 1996.
2. Kokoski, C. J., ``Regulatory Food Additive Toxicology,'' in
Chemical Safety Regulation and Compliance, edited by F. Homburger,
J. K. Marquis, and S. Karger, New York, NY, pp. 24-33, 1985.
3. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British
Journal of Cancer, 46: pp. 924-933, 1982.
4. Memorandum from the Indirect Additives Branch, FDA, to the
Executive Secretary, Quantitative Risk Assessment Committee, FDA,
concerning ``Estimation of Upper-bound Lifetime Risk from Propylene
Oxide and Epichlorohydrin Epoxy Resins Employed as Reactants in the
Preparation of Epoxy Resins Used in Adhesives: Subject of Food
Additive Petition No. 6B4523 (Dow Chemical Company),'' dated
November 12, 1996.
5. Konishi, Y. et al., ``Forestomach Tumors Induced by Orally
Administered Epichlorohydrin in Male Wistar Rats,'' Gann, 71: pp.
922-923, 1980.
List of Subjects in 21 CFR Part 175
Adhesives, 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
175 is amended as follows:
PART 175--INDIRECT FOOD ADDITIVES: ADHESIVES AND COMPONENTS OF
COATINGS
1. The authority citation for 21 CFR part 175 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 175.105 is amended in the table in paragraph (c)(5) by
alphabetically adding new entries under the headings ``Substances'' and
``Limitations'' to read as follows:
Sec. 175.105 Adhesives.
* * * * *
(c) * * *
(5) * * *
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Substances Limitations
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-(oxiranylmethyl)-- For use as a reactant in the
(oxiranylmethoxy)poly[oxy(methyl-1,2- preparation of epoxy-based
ethanediyl)], (alternative name: resins.
epichlorohydrin-polypropylene glycol)
(CAS Reg. No. 26142-30-3).
2,2'-[oxybis[(methyl-2,1-ethanediyl)- For use as a reactant in the
oxymethylene]]bisoxirane, preparation of epoxy-based
(alternative name: epichlorohydrin- resins.
dipropylene glycol) (CAS Reg. No.
41638-13-5).
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Dated: July 17, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-19567 Filed 7-24-97; 8:45 am]
BILLING CODE 4160-01-F
