[Federal Register Volume 61, Number 231 (Friday, November 29, 1996)]
[Rules and Regulations]
[Pages 60533-60535]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-30510]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 177

[Docket No. 96F-0031]


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 1,2-
benzisothiazolin-3-one as a biocide in rubber latex for use in the 
manufacture of rubber articles intended for repeated use in contact 
with food. This action is in response to a petition filed by Reichhold 
Chemicals, Inc.

DATES: Effective November 29, 1996; written objections and requests for 
a hearing by December 30, 1996.

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-216), 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 February 8, 1996 (61 FR 4783), FDA announced that a food 
additive petition (FAP 3B4389) had been filed by Reichhold Chemicals, 
Inc., P.O. Box 13582, Research Triangle Park, NC 27709-3582. The 
petition proposed to amend the food additive regulations in 
Sec. 177.2600 Rubber articles intended for repeated use (21 CFR 
177.2600) to provide for the safe use of 1,2-benzisothiazolin-3-one as 
a biocide in rubber latex for use in the manufacture of rubber articles 
intended for repeated use in contact with 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 carcinogenic polychlorinated 
dibenzo-p-dioxins and dibenzofurans as residual impurities in 1,2-
benzisothiazolin-3-one. Residual amounts of reactants and manufacturing 
aids, such as polychlorinated dibenzo-p-dioxins and dibenzofurans, are 
commonly found as contaminants in chemical products, including food 
additives.

I. Determination of Safety

    Under section 409(c)(3)(A) of the Federal Food, Drug, and Cosmetic 
Act (the act) (21 U.S.C. 348(c)(3)(A)), ``the so-called general safety 
clause'' of the statute, 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 (section 
409(c)(3)(A) of the act) further 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 clause using risk assessment procedures to determine 
whether there is a reasonable certainty that no harm will result from 
the proposed 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 additive, 1,2-
benzisothiazolin-3-one, will result in exposure to the additive of no 
greater than 0.16 parts per billion (ppb), which equates to an

[[Page 60534]]

estimated daily intake (EDI) of 0.5 micrograms per person per day 
(g/p/d) (Ref. 1). The agency has also calculated the estimated 
daily intake of the migrating impurities associated with the additive 
under the most severe conditions of its intended use: bis(2-carbamoyl 
phenyl)disulfide, 5-chloro-1,2-benzisothiazolin-3-one, bis(2-
dimethylcarbamoylphenyl)disulfide, and 6-chloro-1,2-benzisothiazolin-3-
one, and the probable concentrations of these four migrants and the 
solvent impurity (dipropylene glycol) from the additive's use in 
contact with food. The agency estimated the potential daily intakes of 
the four impurities to be 0.4, 1.8, 1.4, and 1.8 nanograms/p/d, and the 
daily intake of the solvent impurity to be 9 g/p/d, 
respectively (Ref. 1). The additive may also contain small amounts of 
the carcinogenic impurities, polychlorinated dibenzo-p-dioxins and 
dibenzofurans.
    FDA does not ordinarily consider chronic toxicological testing to 
be necessary to determine the safety of an additive whose use will 
result in such 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 and subchronic 
studies in rat and dog on the additive. No adverse effects were 
reported in these studies.
    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 risk presented by the 
carcinogenic chemicals, polychlorinated dibenzo-p-dioxins and 
dibenzofurans, that may be present as impurities in the additive. This 
risk evaluation of these carcinogenic impurities has two aspects: (1) 
Assessment of the worst-case exposure to the impurities from the 
proposed use of the additive; and (2) extrapolation of the risk 
observed in the animal bioassays to the conditions of probable exposure 
to humans.

A. Polychlorinated Dibenzo-p-dioxins and Dibenzofurans

    FDA has estimated the worst-case exposure to polychlorinated 
dibenzo-p-dioxins and dibenzofurans from the petitioned use of the 
additive as discussed below. Because little is known about the toxicity 
of polychlorinated dibenzo-p-dioxins and dibenzofurans except 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD), the agency utilized the toxicity 
equivalency factor (TEF) method (Ref. 3) to relate the toxicity of the 
polychlorinated dibenzo-p-dioxins and dibenzofurans in terms of an 
equivalent amount of toxicologically well characterized TCDD, and used 
the TEF's adopted by the North Atlantic Treaty Organization (Ref. 4) 
(see 59 FR 17384, April 12, 1994). Summing the equivalent EDI's for 
each polychlorinated dibenzo-p-dioxin and dibenzofurans present as an 
impurity gives the total exposure to these polychlorinated compounds in 
terms of a total equivalent EDI for TCDD of 0.0039 picogram (pg)/p/d 
(Ref. 1).
    Using data from a 2-year chronic toxicity and carcinogenicity study 
by Kociba et. al., (Ref. 5) on TCDD fed to rats, the agency estimated 
the upper-bound level of lifetime human risk from exposure to TCDD 
toxic equivalents resulting from the use of 1,2-benzisothiazolin-3-one 
as a food contact biocide in repeat-use rubber articles intended for 
contact with food. The results of the bioassay on TCDD showed that the 
material was carcinogenic for rats under the conditions of the study in 
that the test material caused significantly increased incidences of 
hepatocellular carcinomas and adenomas as well as squamous cell 
carcinomas of the lung, hard palate, nasal turbinates, and tongue. FDA 
further concluded that given the paucity of TCDD bioassay data, the 
Kociba et. al., bioassay provided the appropriate basis on which to 
calculate an estimate of the upper-bound level of lifetime 
carcinogenesis risk from exposure to TCDD toxic equivalents stemming 
from the use of the subject additive (1,2-benzisothiazolin-3-one) as a 
biocide in repeat-use rubber articles.
    The agency used a linear-at-low-dose extrapolation method from the 
doses used in the Kociba et al., bioassay and the tumor incidence data 
based upon the original classification of tumors found in that study to 
estimate the upper-bound risk presented by the very low levels of TCDD 
toxic equivalents encountered under the actual conditions of use of the 
additive as a biocide in repeat-use rubber articles. This procedure is 
not likely to underestimate the actual risk from very low doses and may 
in fact exaggerate it because the extrapolation models used are 
designed to estimate the maximum risk consistent with the data. In so 
doing, FDA estimated a carcinogenic unit risk of 16 x 10-6 for an 
intake of 1 pg/kilogram (kg) body weight/d of TCDD toxic equivalents 
(Ref. 6).
    As noted, the carcinogenic unit risk assessed above by FDA was 
based on the original tumor incidence data from the Kociba bioassay 
(Ref. 5). Following FDA's risk assessment discussed above, however, a 
group of pathologists, the Pathology Working Group (PWG), reanalyzed 
the slides of the liver tumors observed in the Kociba bioassay using 
the National Toxicology Program's 1986 classification system for liver 
tumors (Ref. 7). FDA has reviewed the results of this reanalysis and 
agrees with the classification of the tumors made by PWG. Using the 
results of this revised reading of the Kociba study slides, FDA 
estimates a carcinogenic unit risk of 9 x 10-6 for an intake of 1 
pg TCDD equivalents/kg body weight/d (Ref. 8). Using this carcinogenic 
unit risk and an upper-bound total exposure to polychlorinated dibenzo-
p-dioxins and dibenzofurans present in the additive in terms of a total 
equivalent EDI for TCDD of 0.0039 pg/person/d, FDA estimates that the 
upper-bound limit of risk of cancer would be 5.9 x 10-10 from the 
proposed use of the subject additive (Ref. 9). Because of the numerous 
conservative assumptions used in calculating the exposure estimate, the 
actual lifetime averaged individual exposure to polychlorinated 
dibenzo-p-dioxins and dibenzofurans is expected to be substantially 
less than the worst-case exposure, and therefore, the calculated upper-
bound limit of risk would be less. Thus, the agency concludes that 
there is a reasonable certainty that no harm from exposure to 
polychlorinated dibenzo-p-dioxins and dibenzofurans would result from 
the proposed use of the additive.

B. Need for Specifications

    The agency has also considered whether specifications are necessary 
to control the amount of polychlorinated dibenzo-p-dioxins and 
dibenzofurans as impurities in the additive. The agency finds that 
specifications are not necessary for the following reasons: (1) Because 
low levels of polychlorinated dibenzo-p-dioxins and dibenzofurans 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 risk from exposure to these impurities, 
even under worst-case assumptions, are very low, less than 5.9 in 10 
billion for polychlorinated dibenzo-p-dioxins and dibenzofurans.

III. Conclusion

    FDA has evaluated data in the petition and other relevant material 
and concludes that the proposed use of the additive as a biocide in 
repeat-use rubber articles is safe, that the additive will have the 
intended technical effect, and therefore, that Sec. 177.2600 should be 
amended as set forth below.

[[Page 60535]]

    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.

V. 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 10, 1994, from the Chemistry Review 
Branch (HFS-247), to the Indirect Additives Branch (HFS-216), 
concerning FAP 3B4389--Reichhold Chemicals, Inc.--exposure to the 
food additive and its components (polychlorinated dibenzo-p-dioxins 
and dibenzofurans).
    2. Kokoski, C. J., ``Regulatory Food Additive Toxicology,'' in 
Chemical Safety Regulation and Compliance, edited by F. Homburger 
and J. K. Marquis, S. Karger, New York, pp. 24-33, 1985.
    3. EPA 560/5-90-014, Background Document to the Integrate Risk 
Assessment for Dioxins and Furans from Chlorine Bleaching in Pulp 
and Papermills, pp. 3-13, July, 1990.
    4. Pilot Study on International Information Exchange on Dioxins 
and Related Compounds, Report No. 178, December, 1988.
    5. Kociba, R. J., et al., ``Results of a Two Year Chronic 
Toxicity and Oncogenicity Study of 2,3,7,8-Tetrachlorodibenzo-p-
dioxin in Rats,'' Toxicology and Applied Pharmacology, 46:279-303, 
1978.
    6. Report of the Quantitative Risk Assessment Committee, 
``Carcinogenic Risk Assessment for Dioxins and Furans in Foods 
Contacting Bleached Paper Products,'' April 20, 1990.
    7. ``2,3,7,8-Tetrachlorodibenzo-p-dioxin in Sprague-Dawley 
Rats,'' Pathco, Inc., March 13, 1990.
    8. Report of the Quantitative Risk Assessment Committee, 
``Upper-Bound Lifetime Carcinogenic Risk From Exposure to Dioxin 
Congeners From Foods Contacting Paper Products With Dioxin Levels 
Not Exceeding 2 ppt,'' January 27, 1993.
    9. Memorandum, Report of the Quantitative Risk Assessment 
Committee, ``Estimation of Upper-Bound Lifetime Risk From 
Polychlorinated Dibenzo-p-dioxins and Dibenzofurans in 1,2-
benzisothiazolin-3-one,'' April 2, 1994.

VI. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before December 30, 1996, 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.

List of Subjects in 21 CFR Part 177

    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 
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: Secs. 201, 402, 409, 721 of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 321, 342, 348, 379e).
    2. Section 177.2600 is amended in paragraph (c)(4)(ix) by 
alphabetically adding a new entry for 1,2-benzisothiazolin-3-one to 
read as follows:


Sec. 177.2600  Rubber articles intended for repeated use.

* * * * *
    (c) * * *
    (4) * * *
    (ix) * * *
1,2-Benzisothiazolin-3-one (CAS Reg. No. 2634-33-5) for use as a 
biocide in uncured liquid rubber latex not to exceed 0.02 percent by 
weight of the latex solids, where the total of all items listed in 
paragraph (c)(4)(ix) of this section does not exceed 5 percent of the 
rubber product.
* * * * *

    Dated: November 15, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-30510 Filed 11-27-96; 8:45 am]
BILLING CODE 4160-01-F