Indirect Food Additives: Paper and Paperboard Components

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 176

[Docket No. 93F-0428]

Indirect Food Additives: Paper and Paperboard Components

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 -

(dinonylphenyl)--hydroxy-poly(oxy-1,2-ethanediyl), containing

7 to 24 moles of ethylene oxide per mole of dinonylphenol, as a

component of defoaming agents used in styrene-butadiene coatings for

paper and paperboard intended to contact food. This action is in

response to a food additive petition filed by PPG Industries, Inc.

DATES: Effective July 24, 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: 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 January 5, 1994

(59 FR 590), FDA announced that a food additive petition (FAP 3B4363)

had been filed by PPG Industries, Inc., One PPG Pl., Pittsburgh, PA

15272 (formerly 440 College Park Dr., Monroeville, PA 15146). The

petition proposed to amend the food additive regulations in

Sec. 176.200 Defoaming agents used in coatings (21 CFR 176.200) and

Sec. 176.210 Defoaming agents used in the manufacture of paper and

paperboard (21 CFR 176.210) to provide for the use of -

(dinonylphenyl)--hydroxy-poly(oxy-1,2-ethanediyl), containing

7 to 24 moles of ethylene oxide per mole of dinonylphenol, as a

defoaming agent used in the production of paper and paperboard and

coatings for paper and paperboard intended to contact food. The

petitioner has subsequently withdrawn the request for approval of the

use of the additive in the production of paper and paperboard and has

requested that approval of the additive be limited to use in styrene-

butadiene polymer coatings for paper and paperboard intended to contact

food.

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 ethylene oxide and

minute amounts of 1,4-dioxane 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

constitutents of chemical products, including food additives.

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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.''

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

clause 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).

III. Safety of Petitioned Use of the Additive

FDA estimates that the petitioned use of the additive, -

(dinonylphenyl)--hydroxy-poly(oxy-1,2-ethanediyl), containing

7 to 24 moles of ethylene oxide per mole of dinonylphenol, will result

in exposure to no greater than 25 parts per billion (ppb) of the

additive in the daily diet (3 kilogram (kg)) or an estimated daily

intake (EDI) of 75 micrograms per person per day (g/person/

day) (Refs. 1 and 2).

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. 3), 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 clause, considering all available data and using risk assessment

procedures to estimate the upper-bound limit of lifetime human risk

presented by ethylene oxide and 1,4-dioxane, the carcinogenic chemicals

that may be present as impurities in the additive. The risk evaluation

of ethylene oxide and 1,4-dioxane 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 the animal bioassays to the

conditions of exposure to humans.

A. Ethylene oxide

FDA has estimated the exposure to ethylene oxide from the

petitioned use of the additive as a component of defoaming agents used

in styrene-butadiene coatings for paper and paperboard to be no more

than 0.25 part per trillion (pptr) in the daily diet (3 kg), or 0.75

nanogram (ng)/person/day (Refs. 1 and 2). The agency used data from a

long-term rodent bioassay on ethylene oxide conducted for the Institute

of Hygiene, University of Mainz, Germany (Ref. 4), to estimate the

upper-bound limit of lifetime human risk from exposure to this chemical

resulting from the petitioned use of the additive. The author reported

that the test material caused significantly increased incidence of

squamous cell carcinomas in situ of the forestomach and carcinoma in

situ of the glandular stomach in female rats.

Based on the agency's estimate that exposure to ethylene oxide will

not exceed 0.75 ng/person/day, FDA estimates that the upper-bound limit

of lifetime human risk from the petitioned use of the subject additive

is 1.5 x 10-9, or 1.5 in a billion (Ref. 5). Because of the

numerous conservative assumptions used in calculating the exposure

estimate, the actual lifetime-averaged individual exposure to ethylene

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

ethylene oxide would result from the petitioned use of the additive.

B. 1,4-Dioxane

FDA has estimated the exposure to 1,4-dioxane from the petitioned

use of the additive as a component of defoaming agents used in styrene-

butadiene coatings for paper and paperboard to be no more than 0.13

pptr of the daily diet (3 kg), or 0.39 ng/person/day (Refs. 1 and 2).

The agency used data from a long-term rodent bioassay on 1,4-dioxane

conducted by the National Cancer Institute (Ref. 6), 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 significantly increased incidence of

squamous cell carcinomas in male and female rats and hepatocellular

tumors in female rats and male and female mice.

Based on the agency's estimate that exposure to 1,4-dioxane will

not exceed 0.39 ng/person/day, FDA estimates that the upper-bound limit

of lifetime human risk from the petitioned use of the subject additive

is 1.4 x 10-11, or 14 in a trillion (Ref. 5). Because of the

numerous conservative assumptions used in calculating the exposure

estimate, the actual lifetime-averaged individual exposure to 1,4-

dioxane 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 1,4-

dioxane would result from the petitioned use of the additive.

C. Need for Specifications

The agency has also considered whether specifications are necessary

to control the amount of 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 levels

at which 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 low levels; and (2) the upper-bound limits of lifetime human

risk from exposure to the impurities, even under worst-case

assumptions, are very low (less than 1.5 in 1 billion).

IV. Conclusion

FDA has evaluated the data in the petition and other relevant

material. Based on this information, the agency concludes that the

proposed use of the additive as a component of defoaming agents used in

styrene-butadiene coatings for paper and paperboard intended for

contact with food is safe, and that the additive will achieve its

intended technical effect. Therefore, the agency concludes that the

regulations in Sec. 176.200 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

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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. 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.

VI. 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 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.

VII. 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 June 19, 1995, from the Chemistry Review

Branch (HFS-247), to the Indirect Additives Branch (HFS-216)

entitled ``FAP 3B4363 (MATS No. 695; M 2.3 and M 2.4)-PPG

Industries, Inc. Dinonylphenol-ethylene oxide adduct for use as a

component of defoaming agents used in paper coatings and in the

manufacture of paper and paperboard. Submissions dated 7-12-94, 10-

4-94, and 11-1-94.''

2. Memorandum dated July 11, 1996, from the Chemistry Review

Branch (HFS-247), to the Indirect Additives Branch (HFS-216)

entitled ``FAP 3B4363 (MATS No. 695; M 2.4.1)-PPG Industries, Inc.

Dinonylphenol-ethylene oxide adduct for use as a component of

defoaming agents used in paper coatings. Telefax submissions dated

9-22-95 and 3-7-96.''

3. 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.

4. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-

Propylene Oxide Upon Intragastric Administration to Rats,'' British

Journal of Cancer, 46:924, 1982.

5. Memorandum dated July 24, 1996, from Indirect Additives

Branch (HFS-216), to Sara H. Henry, Executive Secretary,

Quantitative Risk Assessment Committee (HFS-308), entitled

``Estimation of the upper-bound lifetime risk from ethylene oxide

and 1,4-dioxane - FAP 3B4363.''

6. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,''

National Cancer Institute, NCI-CG-TR-80, 1978.

List of Subjects in 21 CFR Part 176

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

176 is amended as follows:

PART 176--INDIRECT FOOD ADDITIVES: PAPER AND PAPERBOARD COMPONENTS

1. The authority citation for 21 CFR part 176 continues to read as

follows:

Authority: Secs. 201, 402, 406, 409, 721 of the Federal Food,

Drug, and Cosmetic Act (21 U.S.C. 321, 342, 346, 348, 379e).

2. Section 176.200 is amended in the table in paragraph (d)(3) by

alphabetically adding a new entry under the headings ``List of

substances'' and ``Limitations'' to read as follows:

Sec. 176.200 Defoaming agents used in coatings.

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(d) * * *

(3) * * *

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List of substances Limitations

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-(Dinonylphenyl)--hydroxy-poly(oxy- For use only in defoaming agents for the production of

1,2-ethanediyl), containing 7 to 24 moles of ethylene styrene-butadiene coatings at a level not to exceed

oxide per mole of dinonylphenol (CAS Reg. No. 9014-93- 0.05 percent by weight of the finished coating.

1).

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Dated: June 10, 1997.

William K.Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 97-19428 Filed 7-23-97; 8:45 am]

BILLING CODE 4160-01-F