[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
