[Federal Register Volume 60, Number 177 (Wednesday, September 13, 1995)]
[Rules and Regulations]
[Pages 47478-47480]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-22637]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES
 21 CFR Part 175

[Docket No. 93F-0276]


Indirect Food Additives: Adhesives and Components of Coatings

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 ethoxylated primary 
linear alcohols of greater than 10 percent ethylene oxide by weight 
having molecular weights of 390 to 7,000 for use as components of food 
packaging adhesives. This action is in response to a petition filed by 
Petrolite Corp.

DATES: Effective September 13, 1995; written objections and requests 
for a hearing October 13, 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 September 17, 1993 (58 FR 48659), FDA announced that a food 
additive petition (FAP 3B4390) had been filed by Petrolite Corp., 369 
Marshall Ave., St. Louis, MO 63119-1897. The petition proposed to amend 
the food additive regulations in Sec. 175.105 Adhesives (21 CFR 
175.105) to provide for the safe use of ethoxylated primary linear 
alcohols of greater than 10 percent ethylene oxide by weight having 
molecular weights of 390 to 7,000 for use as components of food 
packaging adhesives.
     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, 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 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 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, ethoxylated 
primary linear alcohols of no greater than 10 percent ethylene oxide by 
weight having molecular weights of 390 to 7,000, will result in 
exposure to the additive of no greater than 50 parts per billion (ppb) 
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 acute 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, 

[[Page 47479]]
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 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 
adhesives to be 0.25 part per trillion of the daily diet or 750 
picogram (pg)/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 750 pg/ person/day, 
FDA estimates that the upper-bound limit of individual lifetime risk 
from the use of the subject additive is 2.7  x  10-11, or 2.7 in 
100 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 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 potential use of the additive in the 
manufacture of adhesives to be 0.05 part per trillion of the daily diet 
or 150 pg/person/day (Ref. 1). The agency used data from a 
carcinogenesis bioassay on ethylene oxide conducted by 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 150 pg/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 2.8  x  10-10, or 2.8 in 10 billion (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 a reasonable 
certainty that no harm from 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 2.7 in 100 billion for 1,4-dioxane and less 
than 2.8 in 10 billion for ethylene oxide, respectively.

 III. Conclusion

     FDA has evaluated the data in the petition and other relevant 
material and concludes that the proposed use of the additive in 
adhesives is safe. Based on this information, the agency has also 
concluded that the additive will have the intended technical effect. 
Therefore, Sec. 175.105 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 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. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before October 13, 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 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.

 VI. 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 Branch (HFS-247), to 
the Indirect Additives Branch (HFS-216), concerning FAP 3B4390--
Petrolite Corp.--exposure to the food additive and its component 
(1,4-dioxane and ethylene oxide), November 5, 1993. 

[[Page 47480]]

     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, June 30, 1994.
     5. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British 
Journal of Cancer, 46:924, 1982.

List of Subjects in 21 CFR Part 175

     Adhesives, 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 175 is amended as follows:

 PART 175--INDIRECT FOOD ADDITIVES: ADHESIVES AND COMPONENTS OF 
COATINGS

     1. The authority citation for 21 CFR part 175 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 175.105 is amended in the table in paragraph (c)(5) by 
alphabetically adding a new entry under the heading ``Substances'' to 
read as follows:


Sec. 175.105  Adhesives.

* * * * *
     (c) *  *  *
     (5) *  *  *

                                                                        
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             Substances                           Limitations           
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                      *      *      *      *      *                     
Ethoxylated primary linear alcohols                                     
 of greater than 10 percent                                             
 ethylene oxide by weight having                                        
 molecular weights of 390 to 7,000                                      
 (CAS Reg. No. 97953-22-5).                                             
                      *      *      *      *      *                     
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    Dated: September 1, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-22637 Filed 9-12-95; 8:45 am]
BILLING CODE 4160-01-F