68888 Federal Register / Vol. 65, No. 221 / Wednesday, November 15, 2000 / Rules and Regulations

PART 191—DRAWBACK

28. The general authority citation for

part 191 is revised to read as follows:

Authority: 5 U.S.C. 301; 19 U.S.C. 66, 1202

(General Note 22, Harmonized Tariff

Schedule of the United States), 1313, 1624.

* * * * *

Dated: November 8, 2000.

Stuart P. Seidel,

Assistant Commissioner, Office of

Regulations and Rulings.

[FR Doc. 00–29091 Filed 11–14–00; 8:45 am]

BILLING CODE 4820–02–P

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.

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

§ 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 acrylonitrilebutadiene 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

Federal Register / Vol. 65, No. 221 / Wednesday, November 15, 2000 / Rules and Regulations 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¥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 worstcase 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 × 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 foodcontact articles is safe, (2) the additive

will achieve its intended technical

effect, and therefore, (3) the regulations

in § 177.2600 should be amended as set

forth below.

In accordance with § 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 § 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.

68890 Federal Register / Vol. 65, No. 221 / Wednesday, November 15, 2000 / Rules and Regulations

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 foodcontact applications, and in several

petitioned food additives and premarket 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 UpperBound 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:

§ 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 α, β-olefinic

unsaturation as determined by a method

entitled ‘‘Determination of Residual α,

β-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 °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]

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