[Federal Register Volume 60, Number 205 (Tuesday, October 24, 1995)]
[Rules and Regulations]
[Pages 54428-54430]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-26359]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 178

[Docket No. 91F-0423]


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 N,N-bis(2-
hydroxyethyl)alkyl((C13-C15)amine as an antistatic agent in 
the manufacture of olefin polymer articles intended to contact food. 
This action is in response to a petition filed by ICI Americas, Inc.

DATES: Effective October 24, 1995; written objections and requests for 
a hearing by November 24, 1995.

ADDRESSES: Submit written objections to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
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 November 29, 1991 (56 FR 61022), FDA announced that a food 
additive petition (FAP 2B4297) had been filed by ICI Americas, Inc., 
Concord Pike and Murphy Rd., Wilmington, DE 19897. The petition 
proposed that the food additive regulations be amended in Sec. 178.3130 
Antistatic and/or antifogging agents in food-packaging materials (21 
CFR 178.3130) to provide for the safe use of N,N-bis(2-
hydroxyethyl)alkyl(C13-C15)amine as an antistatic agent in 
the manufacture of olefin polymer articles 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 1,4-dioxane and 
ethylene oxide, which are carcinogenic impurities resulting from the 
manufacture of the additive. Residual amounts of reactants and 
manufacturing aids, such as 1,4-dioxane and ethylene oxide, 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 anticancer or Delaney clause (section 409(c)(3)(A) (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 
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 proposed 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 
the additive of no greater than 0.26 part per million (ppm) in the 
daily diet (Ref. 1).
    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 subchronic rat and dog toxicity 
studies 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 that may be present as impurities in the 
additive, 1,4-dioxane and ethylene oxide. This risk evaluation of 1,4-
dioxane and ethylene oxide has two aspects: (1) Assessment of the 
worst-case exposure to the impurities from the proposed use of the 
additive; and (2) extrapolation of 

[[Page 54429]]
the risk observed in the animal bioassays to the conditions of probable 
exposure to humans.

A. 1,4-Dioxane

    FDA has estimated the hypothetical worst-case exposure to 1,4-
dioxane from the petitioned use of the additive in the manufacture of 
olefin polymer food-contact articles to be 3 parts per billion (ppb) of 
the daily diet or 9 micrograms per person per day (ug/person/day) (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 lifetime human risk from exposure to this chemical stemming 
from the proposed use of the additive (Ref. 3). The results of the 
bioassay on 1,4-dioxane demonstrated that the material was carcinogenic 
for female rats under the conditions of the study. The test material 
caused significantly increased incidence of squamous cell carcinomas 
and hepatocellular tumors in female rats.
    Based on the estimated worst-case exposure of 9 ug/ person/day, FDA 
estimates that the upper-bound limit of individual lifetime risk from 
the use of the subject additive is 3.15 x10-7, or 3.15 in 10 
million (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 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 1,4-dioxane would 
result from the proposed use of the additive.

B. Ethylene Oxide

    FDA estimated that the hypothetical worst-case exposure to ethylene 
oxide from the petitioned use of the additive in the manufacture of 
olefin polymer food-contact articles is 0.03 ppb of the daily diet or 
90 nanograms (ng)/person/day (Ref. 1). The agency used data from a 
carcinogenesis bioassay on ethylene oxide conducted for the Institute 
of Hygiene, University of Mainz, Germany, to estimate the upper-bound 
level of lifetime human risk from exposure to ethylene oxide stemming 
from the proposed use of the additive (Ref. 5). The results of the 
bioassay on ethylene oxide demonstrated that the material was 
carcinogenic for female rats under the conditions of the study. The 
test material caused significantly increased incidence of squamous cell 
carcinomas of the forestomach and carcinomas in situ of the glandular 
stomach.
    Based on a potential exposure of 90 ng/person/day, FDA estimates 
that the upper-bound limit of individual lifetime risk from the 
potential exposure to ethylene oxide from the use of the subject 
additive is 1.68 x 10-7, or 1.68 in 10 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 worst-case exposure, 
and therefore, the calculated upper-bound limit of risk would be less. 
Thus, the agency concludes that there is reasonable certainty that no 
harm from the exposure to ethylene oxide would result from the proposed 
use of the additive.

C. Need for Specifications

    The agency has also considered whether specifications are necessary 
to control the amount of 1,4-dioxane and ethylene oxide as impurities 
in the additive. The agency finds that specifications are not necessary 
for the following reasons: (1) Because of the low level 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 risk from exposure 
to these impurities, even under worst-case assumptions, are very low, 
less than 3.15 in 10 million for 1,4-dioxane and less than 1.68 in 10 
million for ethylene oxide, respectively.

III. Conclusion

    FDA has evaluated data in the petition and other relevant material 
and concludes that the proposed use of the additive in olefin polymer 
food-contact articles is safe. Based on this information, the agency 
has also concluded that the additive will have the intended technical 
effect. Therefore, Sec. 178.3130 should be amended as set forth below.
    In accordance with Sec. 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 (address above) by appointment with the 
information contact person listed above. As provided in 21 CFR 
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 August 30, 1993, from the Chemistry Review 
Branch (HFS-247), to the Indirect Additives Branch (HFS-216) 
concerning FAP 2B4297, ICI Americas, Inc., exposure to the food 
additive and its components (1,4-dioxane and ethylene oxide).
    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, NY, pp. 24-33, 1985.
    3. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,'' 
National Cancer Institute, NCI-CG-TR-80, 1978.
    4. Memorandum, ``Report of the Quantitative Risk Assessment 
Committee,'' October 7, 1993.
    5. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British 
Journal of Cancer, 46: 924, 1982.

VI. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before November 24, 1995, 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 

[[Page 54430]]
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 178

    Food additive, 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: Secs. 201, 402, 409, 721 of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 321, 342, 348, 379e).
    2. Section 178.3130 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. 178.3130  Antistatic and/or antifogging agents in food-packaging 
materials.

 * * * * *
     (b) * * *

                                                                        
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               Substances                          Limitations          
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  *                    *                    *                    *      
                   *                    *                    *          
N,N-Bis(2-hydroxyethyl)alkyl(C13-        For use only as an antistatic  
 C15)amine (CAS Reg. No. 70955-14-5)..    agent at 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.          
  *                    *                    *                    *      
                   *                    *                    *          
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    Dated: October 10, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-26359 Filed 10-23-95; 8:45 am]
BILLING CODE 4160-01-F