[Federal Register: November 15, 2000 (Volume 65, Number 221)]
[Rules and Regulations]
[Page 68888-68890]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr15no00-10]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 177
[Docket No. 93F-0319]
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 hydrogenated
butadiene/acrylonitrile copolymers, intended for contact with food in
repeated use applications. This action is in response to a petition
filed by Zeon Chemicals, Inc.
DATES: This rule is effective November 15, 2000. Submit written
objections and requests for a hearing by December 15, 2000. The
Director of the Office of the Federal Register approves the
incorporations by reference in accordance with 5 U.S.C. 552(a) and 1
CFR 51 of certain publications in Sec. 177.2600(c)(4)(i) (21 CFR
177.2600(c)(4)(i)), as of November 15, 2000.
ADDRESSES: Submit written objections to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Andrew J. Zajac, Center for Food
Safety and Applied Nutrition (HFS-215), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-418-3095.
SUPPLEMENTARY INFORMATION:
I. Background
In a notice published in the Federal Register of October 4, 1993
(58 FR 51632), FDA announced that a food additive petition (FAP 3B4377)
had been filed by Zeon Chemicals, Inc., Three Continental Towers, suite
1012, 1701 Golf Rd., Rolling Meadows, IL 60008 (now 4111 Bells Lane,
Louisville, KY 40211). The petition proposed to amend the food additive
regulations to provide for the safe use of acrylonitrile-butadiene
copolymer, hydrogenated, intended for contact with food in repeated use
applications. (The additive is currently listed in the regulation under
the nomenclature hydrogenated butadiene/acrylonitrile copolymers, and
this nomenclature will be retained.)
In FDA's evaluation of the safety of this food 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 residual amounts of acrylonitrile
and butadiene 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 general safety standard of section 409(c)(3)(A) 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
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.))
In evaluating the safety of a food additive, FDA customarily
reviews the available data on each relevant chemical impurity to
determine whether the chemical induces tumors in animals or humans. If
FDA concludes that the chemical impurity causes cancer in animals or
humans, the agency calculates the unit cancer risk for the chemical and
the upper bound limit of lifetime human cancer risk from the chemical's
presence in the additive (Ref. 1).
In some instances, the available data and information may not allow
the agency to determine whether a particular chemical impurity is a
carcinogen. However, the available data may suggest, but not establish
definitively, that the impurity poses a human cancer risk. In such
circumstances, the agency may perform a risk assessment based upon the
assumption that the impurity is carcinogenic. This approach permits the
agency to determine whether there is a reasonable certainty that no
harm will result from the petitioned use of the additive, even though
the carcinogenic status of the impurity is not clearly established.
FDA followed this approach to determine whether there is a
reasonable certainty that no harm will result from the use of
hydrogenated butadiene/acrylonitrile copolymers; in so doing, FDA
assumed that butadiene, an impurity in the additive, is a human
carcinogen. In inhalation studies, butadiene has been reported to
induce, in mice and rats, tumors at the site of exposure (lungs) as
well as a variety of tumors at numerous other sites (Refs. 2 to 4).
However, FDA does not believe that these inhalation studies are
necessarily determinative of the carcinogenic potential of butadiene
when administered orally, the most likely route of human exposure to
food additives. Because no long-term studies are available in which
butadiene was administered orally, the agency performed a risk
assessment for butadiene based on a twofold assumption: That butadiene
would induce tumors in animals and humans if administered orally and
that its potency by the oral route of exposure would be no greater than
its potency by the inhalation route of exposure. In FDA's view, this is
a conservative assumption (Ref. 5). Using this procedure, FDA estimated
the upper bound limit of lifetime human cancer risk from butadiene
under the proposed conditions of use of hydrogenated butadiene/
acrylonitrile copolymers.
III. Safety of the Petitioned Use of the Additive
FDA estimates that the petitioned use of the additive, hydrogenated
butadiene/acrylonitrile copolymers, will
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result in exposure to no greater than 5 parts per trillion of the
additive in the daily diet (3 kilograms (kg)) or an estimated daily
intake of 15 nanograms per person per day (ng/p/d) (Ref. 6).
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. 7), 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 petitioned use of
this additive is safe.
FDA has evaluated the safety of this additive under the general
safety standard, considering all available data and, as noted above,
using risk assessment procedures to estimate the upper-bound limit of
lifetime human risk presented by acrylonitrile and butadiene, the
carcinogenic chemicals that may be present as impurities in the
additive. The risk evaluation of acrylonitrile and butadiene 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 animal bioassays to the conditions of exposure to humans.
A. Acrylonitrile
FDA has estimated the exposure to acrylonitrile from the petitioned
use of the additive as a component of repeated use food-contact
articles to be no more than 0.095 parts per trillion in the daily diet
(3 kg), or 0.29 ng/p/d (Ref. 6). The agency used data from a long-term
rodent bioassay on acrylonitrile conducted by Quast et al. (Ref. 8) to
estimate the upper-bound limit of lifetime human risk from exposure to
this chemical resulting from the petitioned use of the additive. The
authors reported that the test material caused astrocytomas of the
nervous system, papillomas and carcinomas of the tongue, papillomas and
carcinomas of the stomach, and Zymbal's gland carcinomas in male and
female rats. The authors also reported carcinomas of the small
intestine and the mammary gland in female rats.
Based on the agency's estimate that exposure to acrylonitrile will
not exceed 0.29 ng/p/d, FDA estimates that the upper-bound limit of
lifetime human risk from the petitioned use of the subject additive is
5.45 x 10-10, or 0.5 in a billion (Ref. 9). Because of the
numerous conservative assumptions used in calculating the exposure
estimate, the actual lifetime-averaged individual exposure to
acrylonitrile 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 acrylonitrile would result from the petitioned use of the additive.
B. Butadiene
The scientific literature contains a variety of information
regarding the carcinogenic potential of butadiene. As noted, in a long-
term inhalation study butadiene has been reported to induce a variety
of tumors including in the hematopoietic system, heart, lung,
forestomach, liver, Harderian gland, brain, and kidney in male and
female mice and tumors of the ovaries and mammary gland in female mice
(Ref. 2). Butadiene also has been reported to induce tumors of the
pancreas and testis in male rats and tumors of the uterus, mammary
gland, and thyroid in female rats in a long-term inhalation study
(Refs. 3 and 4).
No long-term studies are available in which butadiene was
administered to test animals orally. Generally, FDA does not rely on
inhalation studies to assess the potential carcinogenicity and cancer
potency of substances in food, for which the most likely route of human
exposure is oral. However, in order to determine whether there is a
reasonable certainty that no harm would result from the presence of
butadiene as an impurity in the subject additive, the agency has
assumed that butadiene is an oral carcinogen and has performed a worst-
case risk assessment of the carcinogenic potential of butadiene using
data from the inhalation study on female mice. FDA has relied on this
study because it is the sex, species, and study that demonstrated the
highest unit cancer risk for butadiene.
FDA has estimated the exposure to butadiene from the petitioned use
of the subject additive would not exceed 0.0016 part per trillion in
the daily diet (3 kg), or 4.8 picogram per person per day (pg/p/d)
(Ref. 6). Based on this estimate and the assumption that butadiene
would induce tumors with the same potency in an oral study as it did in
the mice inhalation study, FDA estimates that the upper-bound limit of
lifetime human risk from butadiene exposure as a result of the
petitioned use of the subject additive would be 1.12 x
10-10, or 0.1 in a billion (Refs. 5 and 10). Because of the
numerous conservative assumptions used in calculating the exposure
estimate, the actual lifetime-averaged individual exposure to butadiene
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
butadiene would result from the petitioned use of the additive.
C. Need for Specifications
The agency also has considered whether specifications are necessary
to control the amount of acrylonitrile and butadiene 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 acrylonitrile and butadiene may be expected to remain as
impurities following production of the additive, the agency would not
expect these 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 acrylonitrile and butadiene are very low, 0.5 in
a billion and 0.1 in a billion, respectively.
IV. Conclusion
FDA has evaluated data in the petition and other relevant material.
Based on this information, the agency concludes that: (1) The proposed
use of the additive in repeated use food-contact articles is safe, (2)
the additive will achieve its intended technical effect, and therefore,
(3) the regulations in Sec. 177.2600 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.
[[Page 68890]]
VI. Paperwork Reduction Act of 1995
This final rule contains no collection of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
VII. Objections
Any person who will be adversely affected by this regulation may at
any time file with the Dockets Management Branch (address above)
written objections by December 15, 2000. 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.
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. Lorentzen, R., ``FDA Procedures for Carcinogenic Risk
Assessment,'' Food Technology, vol. 38, pp. 108-111, 1984.
2. ``Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS
No. 106-99-0) in B6C3F1 Mice (Inhalation Studies),'' National
Toxicology Program, Technical Report Series, No. 434.
3. Owen, P. E. et al., ``Inhalation Toxicity Studies with 1,3-
Butadiene. Two Year Toxicity/Carcinogenicity Study in Rats,'' American
Industrial Hygiene Association Journal, 48:407-413, 1987.
4. Owen, P. E. et al., ``Inhalation Toxicity and Carcinogenicity
Study of 1,3-Butadiene in Sprague-Dawley Rats,'' Environmental Health
Perspectives, 86:19-25, 1990.
5. Memorandum dated March 3, 2000, from the Division of Health
Effects Evaluation to the Chairman of the CFSAN Cancer Assessment
Committee and Quantitative Risk Assessment Committee, ``A worst-case
estimate of human cancer risk from exposure to 1,3-butadiene as an
impurity in all approved and petitioned uses of 1,3-butadiene-based
polymers in food-contact applications, and in several petitioned food
additives and pre-market notifications.''
6. Memorandum dated March 25, 1994, from Chemistry Review Branch to
Indirect Additives Branch, ``FAP 3B4377 (MATS# 711, M2.1)--Zeon
Chemicals, Inc. Submission dated 4-21-93. Hydrogenated acrylonitrile
butadiene elastomers (HNBR) as components of repeat-use articles.''
7. Kokoski, C. J., ``Regulatory Food Additive Toxicology,'' in
Chemical Safety Regulation and Compliance, edited by F. Homburger, and
J. K. Marquis, New York, NY, pp. 24-33, 1985.
8. Quast, J. F., C. E. Wade, C. G. Humiston, R. M. Carreon, E. A.
Hermann, C. N. Park, and B. A. Schwetz, ``A Two Year Toxicity and
Oncogenicity Study With Acrylonitrile Incorporated in the Drinking
Water of Rats,'' Toxicology Research Laboratory, Health and
Environmental Sciences, Dow Chemical USA, Midland, MI 48640, final
report dated January 22, 1980, corrections dated November 17, 1980.
9. Memorandum dated July 10, 2000, from the Division of Health
Effects Evaluation to the Division of Petition Control, ``FAP 3B4377:
Worst-Case Cancer Risk Assessment for Acrylonitrile.''
10. Memorandum dated April 3, 2000, from the Division of Petition
Control to the Quantitative Risk Assessment Committee, ``Estimation of
the Upper-Bound Lifetime Risk for Butadiene--FAP 3B4377.''
List of Subjects in 21 CFR Part 177
Food additives, Food packaging, Incorporation by reference.
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: 21 U.S.C. 321, 342, 348, 379e.
2. Section 177.2600 is amended in paragraph (c)(4)(i) by revising
the entry for ``Hydrogenated butadiene/acrylonitrile copolymers'' to
read as follows:
Sec. 177.2600 Rubber articles intended for repeated use.
* * * * *
(c) * * *
(4) * * *
(i) * * *
* * * * *
Hydrogenated butadiene/acrylonitrile copolymers (CAS Reg. No.
88254-10-8) produced when acrylonitrile/butadiene copolymers are
modified by hydrogenation of the olefinic unsaturation to leave either:
(1) Not more than 10 percent trans olefinic unsaturation and no
, -olefinic unsaturation as determined by a method
entitled ``Determination of Residual , -Olefinic and
Trans Olefinic Unsaturation Levels in HNBR,'' developed October 1,
1991, by Polysar Rubber Corp., 1256 South Vidal St., Sarnia, Ontario,
Canada N7T 7MI; or (2) 0.4 percent to 20 percent olefinic unsaturation
and Mooney viscosities greater than 45 (ML 1 + 4 @ 100 deg.C), as
determined by ASTM Standard Method D1646-92, ``Standard Test Method for
Rubber--Viscosity and Vulcanization Characteristics (Mooney
Viscometer),'' which are both incorporated by reference in accordance
with 5 U.S.C. 552(a) and 1 CFR part 51. Copies of these methods may be
obtained from the Division of Petition Control (HFS-215), Center for
Food Safety and Applied Nutrition, Food and Drug Administration, 200 C
St. SW., Washington, DC 20204, or may be examined at the Center for
Food Safety and Applied Nutrition's Library, 200 C St. SW., rm. 3321,
Washington, DC, or at the Office of the Federal Register, 800 North
Capitol St. NW., suite 700, Washington, DC. A copy of ASTM Standard
Method D1646-92 may also be obtained from the American Society for
Testing and Materials, 100 Barr Harbor Dr., West Conshohocken, PA
19428-2959.
* * * * *
Dated: November 6, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-29164 Filed 11-14-00; 8:45 am]
BILLING CODE 4160-01-F