[Federal Register Volume 64, Number 231 (Thursday, December 2, 1999)]
[Rules and Regulations]
[Pages 67483-67486]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-31228]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 178

[Docket No. 95F-0150]


Indirect Food Additives: Adjuvants, Production Aids, and 
Sanitizers

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 7-oxa-3,20-
diazadispiro-[5.1.11.2]-heneicosan-21-one,2,2,4,4-tetramethyl-
,hydrochloride, reaction products with epichlorohydrin, hydrolyzed, 
polymerized (CAS Reg. No. 202483-55-4) as an antioxidant and/or 
stabilizer for polyolefins intended for contact with food. This action 
is in response to a petition filed by Hoechst Aktiengesellschaft.

DATES: The regulation is effective December 2, 1999. Submit written 
objections and requests for a hearing by January 3, 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: Vivian M. Gilliam, Center for Food 
Safety and Applied Nutrition (HFS-215), Food and Drug Administration, 
200 C St. SW., Washington, DC 20204, 202-418-3094.

SUPPLEMENTARY INFORMATION: 

I. Background

    In a notice published in the Federal Register of July 12, 1995 (60 
FR 35914), FDA announced that a food additive petition (FAP 5B4461) had 
been filed by Hoechst Aktiengesellschaft, c/o 1001 G St. NW., suite 500 
West, Washington, DC 20001. The petition proposed that the food 
additive regulations in Sec. 178.2010 Antioxidants and/or stabilizers 
for polymers (21 CFR 178.2010) be amended to provide for the safe use 
of polymeric 2,2,4,4-tetramethyl-7-oxa-3,20-diaza-20-(2,3-epoxypropyl)-
dispiro-[5.1.11.2]-heneicosane-21-one (CAS Reg. No. 78301-43-6) as an 
antioxidant and/or stabilizer for polyolefins intended for contact with 
food.
    Subsequent to the filing of the petition, Hoechst 
Aktiengesellschaft sold its speciality business, including food 
additive petition 5B4461, to

[[Page 67484]]

Clariant AG, Switzerland. The petitioner also obtained a new Chemical 
Abstracts Service (CAS) Registry number for the additive under the 
following name: 7-oxa-3,20-diazadispiro-[5.1.11.2]-heneicosan-21-
one,2,2,4,4-tetramethyl-,hydrochloride, reaction products with 
epichlorohydrin, hydrolyzed, polymerized (CAS Reg. No. 202483-55-4).
    In FDA's evaluation of the safety of 7-oxa-3,20-diazadispiro-
[5.1.11.2]-heneicosan-21-one,2,2,4,4-tetramethyl-,hydrochloride, 
reaction products with epichlorohydrin, hydrolyzed, polymerized 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 minute amounts of 
epichlorohydrin, a carcinogenic impurity resulting from the manufacture 
of the additive. 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 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).

III. Safety of the Petitioned Use of the Additive

    FDA estimates that the petitioned use of the additive, 7-oxa-3,20-
diazadispiro-[5.1.11.2]-heneicosan-21-one,2,2,4,4-tetramethyl-
,hydrochloride, reaction products with epichlorohydrin, hydrolyzed, 
polymerized, will result in exposure to no greater than 224 parts per 
billion (ppb) of the additive in the daily diet (3 kilogram (kg)) or an 
estimated daily intake of 0.67 milligram per person per day (mg/p/d) 
(Ref.1).
    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. 2), 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 using risk 
assessment procedures to estimate the upper-bound limit of lifetime 
human risk presented by epichlorohydrin, the carcinogenic chemical that 
may be present as an impurity in the additive. The risk evaluation of 
epichlorohydrin has two aspects: (1) Assessment of exposure to the 
impurity 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. Epichlorohydrin

    FDA has estimated the exposure to epichlorohydrin from the 
petitioned use of the additive as an antioxidant and/or stabilizer for 
polyolefins to be no more than 0.011 ppb in the daily diet (3 kg) or 33 
nanograms (ng)/p/d (Ref.1). The agency used data from a carcinogenesis 
bioassay on epichlorohydrin conducted by Konishi et al. (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 
authors reported that the test material caused significantly increased 
incidence of stomach papillomas and carcinomas in male rats.
    Based on the agency's estimate that exposure to epichlorohydrin 
will not exceed 33 ng/p/d, 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. 3). Because of the 
numerous conservative assumptions used in calculating the exposure 
estimate, the actual lifetime-averaged individual exposure to 
epichlorohydrin 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 epichlorohydrin would result from the petitioned use of the 
additive.

B. Need for Specifications

    The agency has also considered whether specifications are necessary 
to control the amount of epichlorohydrin as an impurity in the 
additive. The agency finds that specifications are not necessary for 
the following reasons: (1) Because of the low level at which 
epichlorohydrin may be expected to remain as an impurity following 
production of the additive, the agency would not expect this impurity 
to become a component of food at other than extremely low levels; and 
(2) the upper-bound limit of lifetime human risk from exposure to 
epichlorohydrin is very low, 1.5 in a billion.

IV. Conclusion

    FDA has evaluated data in the petition and other relevant material. 
Based on this information, the agency concludes that the proposed use 
of the additive as an antioxidant and/or stabilizer for polyolefins 
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. 178.2010 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. 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.

VI. 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

[[Page 67485]]

in the Dockets Management Branch (address above) between 9 a.m. and 4 
p.m., Monday through Friday.

VII. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before January 3, 2000, 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.

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. Memorandum from A. B. Bailey, Chemistry and Environmental 
Review Team, to D. Harrison, Division of Petition Control, dated 
August 6, 1998.
    2. 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.
    3. Memo from Division of Petition Control (HFS-215) to Sara H. 
Henry, Quantitative Risk Assessment Committee (HFS-308), 
``Verification of upper bound risk calculation for epichlorohydrin 
(ECH) for petition No. FAP 5B4461,'' dated February 10, 1998.
    4. Konishi, Y. et al., ``Forestomach Tumors Induced by Orally 
Administered Epichlorohydin in Male Wistar Rats,'' Gann, 71:922-923, 
1980.

List of Subjects in 21 CFR Part 178

    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 
178 is amended as follows:

PART 178--INDIRECT FOOD ADDITIVES: ADJUVANTS, PRODUCTION AIDS, AND 
SANITIZERS

    1. The authority citation for 21 CFR part 178 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 342, 348, 379e.

    2. Section 178.2010 is amended in the table in paragraph (b) by 
alphabetically adding a new entry under the headings ``Substances'' and 
``Limitations'' to read as follows:


Sec. 178.2010  Antioxidants and/or stabilizers for polymers.

* * * * *
    (b) * * *

 
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                       Substances                                              Limitations
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  *                    *                    *                    *                    *                    *
                                                             *
 7-Oxa-3,20-diazadispiro-[5.1.11.2]-heneicosan-21-       For use only:
 one,2,2,4,4-tetramethyl-,hydrochloride, reaction        1. At levels not to exceed 0.5 percent by weight of
 products with epichlorohydrin, hydrolyzed, polymerized   olefin polymers complying with Sec.  177.1520 of this
 (CAS Reg. No. 202483-55-4).                              chapter, items 1.1, 3.1, and 3.2, where the copolymers
                                                          complying with items 3.1 and 3.2 contain not less than
                                                          85 weight percent of polymer units derived from
                                                          propylene; in contact with all types of food described
                                                          in Table 1 of Sec.  176.170 of this chapter, provided
                                                          that the finished food-contact article will have a
                                                          capacity of at least 18.9 liters (5 gallons) when in
                                                          contact with food of types III, IV-A, V, VII-A, and
                                                          IX, described in Table 1 of Sec.  176.170 of this
                                                          chapter.
                                                         2. At levels not to exceed 0.5 percent by weight of
                                                          olefin polymers complying with Sec.  177.1520 of this
                                                          chapter, items 2.1, 2.2, 3.1, and 3.2, having a
                                                          density of not less than 0.94 gram/milliliter, where
                                                          the copolymers complying with items 3.1 and 3.2
                                                          contain not less than 85 weight percent of polymer
                                                          units derived from ethylene; in contact with food only
                                                          under conditions of use C, D, E, F, and G, described
                                                          in Table 2 of Sec.  176.170 of this chapter, provided
                                                          that the finished food-contact article will have a
                                                          capacity of at least 18.9 liters (5 gallons) when in
                                                          contact with food of types III, IV-A, V, VII-A, and
                                                          IX, described in Table 1 of Sec.  176.170 of this
                                                          chapter.
                                                         3. At levels not to exceed 0.3 percent by weight of
                                                          olefin polymers complying with Sec.  177.1520 of this
                                                          chapter, items 2.1, 2.2, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,
                                                          and 4.0, having a density of less than 0.94 gram/
                                                          milliliter, in contact with food only under conditions
                                                          of use D, E, F, and G, described in Table 2 of Sec.
                                                          176.170 of this chapter, provided that the finished
                                                          food-contact article will have a capacity of at least
                                                          18.9 liters (5 gallons) except that, films and molded
                                                          articles containing not more than 0.2 percent by
                                                          weight of the stabilizer may contact aqueous food of
                                                          types I, II, IV-B, VI, and VIII, described in Table 1
                                                          of Sec.  176.170 of this chapter with no restrictions
                                                          on the amount of food contacted.
  *                    *                    *                    *                    *                    *
                                                             *
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[[Page 67486]]

    Dated: November 23, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-31228 Filed 12-1-99; 8:45 am]
BILLING CODE 4160-01-F