[Federal Register Volume 65, Number 221 (Wednesday, November 15, 2000)]
[Rules and Regulations]
[Pages 68888-68890]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-29164]


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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

[[Page 68889]]

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<SUP>-10</SUP>, 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<SUP>-10</SUP>, 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 
<greek-a>, <greek-b>-olefinic unsaturation as determined by a method 
entitled ``Determination of Residual <greek-a>, <greek-b>-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