[Federal Register Volume 64, Number 221 (Wednesday, November 17, 1999)]
[Rules and Regulations]
[Pages 62583-62585]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-29915]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 178

[Docket No. 98F-0492]


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 expanded safe use of N,N-bis 
(2-hydroxyethyl) alkyl (C13-C15) amine as an 
antistatic agent in polypropylene homo- and copolymers intended for 
contact with food. This action is in response to a petition filed by 
ICI PLC.

DATES: This regulation is effective November 17, 1999; written 
objections and requests for a hearing by December 17, 1999.

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: Ellen M. Waldron, Center for Food 
Safety and Applied Nutrition (HFS-215), Food and Drug Administration, 
200 C St. SW., Washington, DC 20204, 202-418-3089.

SUPPLEMENTARY INFORMATION: In a notice published in the Federal 
Register of July 7, 1998 (63 FR 36699), FDA announced that a food 
additive petition (FAP 8B4602) had been filed by ICI PLC, c/o ICI 
Surfactants, P.O. Box 8340, Wilmington, DE 19803-8340. The petition 
proposed to amend the food additive regulations in Sec. 178.3130 
Antistatic and/or antifogging agents in food-packaging materials (21 
CFR 178.3130) to provide for the expanded safe use of N,N-bis (2-
hydroxyethyl) alkyl (C13-C15) amine as an 
antistatic agent in polypropylene homo- and copolymers intended for 
contact with food.
     In its evaluation of the safety of this food additive, FDA has 
reviewed the safety of the additive itself, the starting materials 
used, 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 1,4-dioxane and ethylene oxide, which are 
carcinogenic impurities resulting from the manufacture of the additive. 
Residual amounts of impurities, such as 1,4-dioxane and ethylene oxide, 
are commonly found as contaminants in chemical products, including food 
additives.

 I. 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).

 II. Safety of Petitioned Use of the Additive

     FDA estimates that the petitioned use of the additive, N,N-bis (2-
hydroxyethyl) alkyl (C13-C15) amine, will result 
in exposure to no greater than 23 parts per billion (ppb) of the 
additive in the daily diet (3 kilograms (kg)) or an estimated daily 
intake of 69 micrograms per person per day (g/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 1,4-dioxane and ethylene oxide, the 
carcinogenic chemicals that may be present as impurities in the 
additive. This risk evaluation of 1,4-dioxane and ethylene oxide 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. 1,4-Dioxane

     FDA has estimated the exposure to 1,4-dioxane from the petitioned 
use of the additive as an antistatic agent in polypropylene homo- and 
copolymers intended for contact with food to be no more than 0.09 ppb 
in the daily diet (3 kg), or 0.28 g/p/d (Ref. 1). The agency 
used data from a carcinogenesis bioassay on 1,4-dioxane, conducted by 
the National Cancer Institute (Ref. 3), to estimate the upper-bound 
limit of lifetime human risk from exposure to this chemical resulting 
from the petitioned use of the additive. The results of the bioassay on 
1,4-dioxane

[[Page 62584]]

demonstrated that the material was carcinogenic for female rats under 
the conditions of the study. The authors reported that the test 
material caused significantly increased incidence of squamous cell 
carcinomas and hepatocellular tumors in female rats.
     Based on the agency's estimate that exposure to 1,4-dioxane will 
not exceed 0.28 g/p/d, FDA estimates that the upper-bound 
limit of lifetime human risk from the petitioned use of the subject 
additive is 9.8 x10-9, or 9.8 in one billion (Ref. 4). 
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 a reasonable certainty that no harm from 
exposure to 1,4-dioxane would result from the petitioned use of the 
additive.

 B. Ethylene Oxide

     FDA has estimated the exposure to ethylene oxide from the 
petitioned use of the additive as an antistatic agent in polypropylene 
homo- and copolymers intended for contact with food to be no more than 
2 parts per trillion in the daily diet (3 kg) or 6 nanograms (ng)/p/d 
(Ref. 1). The agency used data from a carcinogenesis bioassay on 
ethylene oxide, conducted for the Institute of Hygiene, University of 
Mainz, Germany (Ref. 5), to estimate the upper-bound limit of lifetime 
human risk from exposure to this chemical resulting from the petitioned 
use of the additive. The results of the bioassay on ethylene oxide 
demonstrated that the material was carcinogenic for female rats under 
the conditions of the study. The authors reported that the test 
material caused significantly increased incidence of squamous cell 
carcinomas of the forestomach and carcinomas in situ of the glandular 
stomach.
     Based on the agency's estimate that exposure to ethylene oxide 
will not exceed 6 ng/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the petitioned use of the subject additive is 
1.1 x 10-8, or 1.1 in 100 millon (Ref. 4). Because of the 
numerous conservative assumptions used in calculating the exposure 
estimate, 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 the exposure to 
ethylene oxide 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 amounts of 1,4-dioxane and ethylene oxide 
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 1,4-dioxane and ethylene oxide 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 small levels; and (2) the upper-bound 
limits of lifetime human risk from exposure to 1,4-dioxane and ethylene 
oxide, are very low, 9.8 in a billion and 1.1 in 100 million, 
respectively.

 III. 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 in food-contact articles is safe, that the 
additive will achieve its intended technical effect, and therefore, 
that the regulations in Sec. 178.3130 should be amended as set forth 
below in this document.
     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 previously considered the environmental effects of 
this rule as announced in the notice of filing for FAP 8B4602 (63 FR 
36699). No new information or comments have been received that would 
affect the agency's previous determination that there is no significant 
impact on the human environment and that an environmental impact 
statement is not required.

 V. Paperwork Reduction Act of 1995

     This final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

 VI. Objections

     Any person who will be adversely affected by this regulation may 
at any time on or before December 17, 1999, 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 from the Chemistry Review Team (HFS-246) to the 
Division of Petition Control (HFS-215) entitled ``FAP 8B4602 (MATS 
#976 M2.1): ICI Surfactants; Submission of 4/7/99.  N,N-Bis(2-
Hydroxyethyl) Alkyl (C13-C15) Amine as an 
Antistatic Agent in Polypropylene Used in Contact With Fatty Foods 
Hot Filled or Pasteurized Above 66  deg.C,'' dated May 28, 1999.
     2. 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.
     3. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,'' 
National Cancer Institute, NCI-CG-TR-80, 1978.
     4. Memorandum from the Division of Petition Control (HFS-215) 
to Executive Secretary, Quantitative Risk Assessment Committee (HFS-
308) entitled ``Estimate of the Upper bound Lifetime Risk From 
Residual 1,4-Dioxane (DO) and Ethylene

[[Page 62585]]

Oxide (EO) in N,N-bis (2-Hydroxyethyl) Alkyl (C13-
C15) Amine Intended for Use as an Antistatic Agent in 
Polypropylene Homo- and Copolymers Contacting Food: FAP 8B4602,'' 
dated June 8, 1999.
     5. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British 
Journal of Cancer, 46: 924-933, 1982.

 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 178.3130 is amended in the table in paragraph (b) by 
revising the entry for N,N-bis (2-hydroxyethyl) alkyl (C13-
C15) amine under the heading ``Limitations'' to read as 
follows:


Sec. 178.3130   Antistatic and/or antifogging agents in food-packaging 
materials.

* * * * *
     (b) * * *

 
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         List of substances                      Limitations
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  *                    *                    *                    *
                   *                    *                    *
N,N-bis(2-hydroxyethyl)alkyl (C13-    For use only:
 C15) amine (CAS Reg. No. 70955-14-   1. As an antistatic agent at
 5).                                  levels not to exceed 0.2 percent
                                      by weight in molded or extruded
                                      high-density polyethylene (having
                                      a density 0.95 g/cm3
                                      and polypropylene containers that
                                      contact food only of the types
                                      identified in Sec.  176.170(c) of
                                      this chapter, Table 1, under types
                                      I, VI-B, VII-B, and VIII, under
                                      the conditions of use E through G
                                      described in Table 2 of Sec.
                                      176.170(c) of this chapter,
                                      provided such foods have a pH
                                      above 5.0.
                                      2. As an antistatic agent at
                                      levels not to exceed 0.1 percent
                                      by weight in molded or extruded
                                      polypropylene homopolymers and
                                      copolymers that contact food only
                                      of the types identified in Sec.
                                      176.170(c) of this chapter, Table
                                      1, under Types II, III, IV, V, VII-
                                      A, and IX, under the conditions of
                                      use C through G described in Table
                                      2 of Sec.  176.170(c) of this
                                      chapter.
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    Dated: November 4, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-29915 Filed 11-16-99; 8:45 am]
BILLING CODE 4160-01-F