[Federal Register Volume 62, Number 143 (Friday, July 25, 1997)]
[Rules and Regulations]
[Pages 39935-39937]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-19567]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 175

[Docket No. 96F-0384]


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 epichlorohydrin-
dipropylene glycol and epichlorohydrin-polypropylene glycol as 
reactants in the preparation of epoxy-based resins used as adhesives 
for articles or components of articles intended for use in food-contact 
applications. This action is in response to a petition filed by the Dow 
Chemical Co.

DATES: Effective July 25, 1997; written objections and requests for a 
hearing by August 25, 1997.

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-215), 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 October 22, 1996 (61 FR 54801), FDA announced that a food 
additive petition (FAP 6B4523) had been filed by the Dow Chemical Co., 
2030 Dow Center, Midland, MI 48674. 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 epichlorohydrin-dipropylene glycol and 
epichlorohydrin-polypropylene glycol as reactants in the preparation of 
epoxy-based resins used as adhesives for articles or components of 
articles intended for use in food-contact applications.
    In FDA's evaluation of the safety of this additive, 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 unreacted 
propylene oxide and epichlorohydrin, carcinogenic impurities resulting 
from the manufacture of the additive. Residual amounts of reactants and 
manufacturing aids, such as propylene oxide and epichlorohydrin, are 
commonly found as contaminants in chemical products, including food 
additives.

I. Determination of Safety

    Under the so-called ``general safety clause'' 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 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 
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 The Petitioned Use of The Additive

    FDA estimates that the petitioned use of the additives, reaction 
products of epichlorohydrin-dipropylene glycol and epichlorohydrin-
polypropylene glycol, will result in exposure to the additive of no 
greater than 7 parts per billion 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

[[Page 39936]]

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 and 
concludes that the estimated small dietary exposure resulting from the 
petitioned use of the 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 propylene oxide and epichlorohydrin, the 
carcinogenic chemicals that may be present as impurities in the 
additive. This risk evaluation of propylene oxide and epichlorohydrin 
has two aspects: (1) Assessment of the 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. Propylene Oxide

    FDA has estimated the exposure to polypropylene oxide from the 
petitioned use of each of the two additives in the manufacture of 
adhesives to be 0.7 parts per quadrillion (ppq) of the daily diet or 
2.1 picogram (pg)/person/day or a total of 4.2 pg/person/day (Ref. 1). 
The agency used data from a carcinogenesis bioassay on propylene oxide, 
conducted for the Institute of Hygiene, University of Mainz, Germany 
(Ref. 3), to estimate the upper-bound lifetime human risk from exposure 
to this chemical stemming from the petitioned use of the additive. The 
results of the bioassay on propylene oxide demonstrated that the 
material was carcinogenic for female rats under the conditions of the 
study. The test material caused carcinomas and papillomas in the 
squamous epithelium of the forestomach.
    Based on the estimated worst-case exposure to propylene oxide of 
4.2 pg/person/day, FDA estimates that the upper-bound limit of 
individual lifetime risk from the use of the subject additives is in 
the range of 6.5 x 10-13 (or 6.5 in 10 trillion) to 2.9 x 
10-12 (or 2.9 in 1 trillion) (Ref. 4). FDA's estimate of the 
upper-bound limit of individual lifetime risk has been stated as a 
range because the agency evaluated complex tumor data in an oral 
toxicity study using rats. Because of the numerous conservative 
assumptions used in calculating the exposure estimate, the actual 
lifetime-averaged individual exposure to propylene 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 exposure to propylene oxide 
would result from the petitioned use of the additives.

B. Epichlorohydrin

    FDA has estimated the exposure to epichlorohydrin from the 
petitioned use of each of the two additives in the manufacture of 
adhesives to be 0.7 ppq of the daily diet (3 kg), or 2.1 pg/person/day 
or a total of 4.2 pg/person/day (Ref. 1). The agency used data from a 
carcinogenesis bioassay conducted in Japan on epichlorohydrin fed to 
rats via their drinking water (Ref. 5), to estimate the upper-bound 
limit of lifetime human risk from exposure to this chemical resulting 
from the petitioned use of the additives. The results of the bioassay 
demonstrated that epichlorohydrin was carcinogenic under the conditions 
of the study. The test material caused significantly increased 
incidences of stomach papillomas and carcinomas in the rats.
    Based on the agency's estimate that exposure to epichlorohydrin 
will not exceed 4.2 pg/person/day, FDA estimates that the upper-bound 
limit of individual lifetime human risk from the use of the subject 
additives is 1.9 x 10-13 (or 1.9 in 10 trillion) (Ref. 4). 
Because of the numerous conservative assumptions used in calculating 
the exposure estimate, the actual lifetime-averaged individual exposure 
to epichlorohydrin would 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 
additives.

C. Need for Specifications

    The agency has also considered whether specifications are necessary 
to control the amount of propylene oxide and epichlorohydrin 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 propylene oxide and epichlorohydrin may be expected to remain 
as impurities following production of the additives, the agency would 
not expect the impurities to become components of food at other than 
extremely small levels; and (2) the upper-bound limits of lifetime risk 
from exposure to propylene oxide and epichlorohydrin, even under worst-
case assumptions, is very low, in the range of less than 6.5 in 10 
trillion to 2.9 in 1 trillion for propylene oxide and 1.9 in 10 
trillion for epichlorohydrin.

III. Conclusion

    FDA has evaluated data in the petition and other relevant material. 
The agency concludes that: (1) The proposed use of the additive is 
safe, (2) the additive will achieve its intended technical effect, and 
(3) the regulations in 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 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. No comments were received during the 30 day comment 
period specified in the filing notice for comments on the environmental 
assessment submitted with the petition.

V. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before August 25, 1997, file with the Dockets Management 
Branch (address above) written objection 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

[[Page 39937]]

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 objection 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 Team, FDA, to the file 
concerning ``FAP 6B4523 (MATS #887, M2.0 & 2.1): Dow Chemical Co., 
dated September 18, 1996. Epichlorohydrin-dipropylene Glycol and 
Epichlorohydrin-polypropylene Glycol as Reactants in the Preparation 
of Epoxy Resins Used in Adhesives,'' dated October 29, 1996.
    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. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British 
Journal of Cancer, 46: pp. 924-933, 1982.
    4. Memorandum from the Indirect Additives Branch, FDA, to the 
Executive Secretary, Quantitative Risk Assessment Committee, FDA, 
concerning ``Estimation of Upper-bound Lifetime Risk from Propylene 
Oxide and Epichlorohydrin Epoxy Resins Employed as Reactants in the 
Preparation of Epoxy Resins Used in Adhesives: Subject of Food 
Additive Petition No. 6B4523 (Dow Chemical Company),'' dated 
November 12, 1996.
    5. Konishi, Y. et al., ``Forestomach Tumors Induced by Orally 
Administered Epichlorohydrin in Male Wistar Rats,'' Gann, 71: pp. 
922-923, 1980.

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 new entries under the headings ``Substances'' and 
``Limitations'' to read as follows:

Sec. 175.105  Adhesives.

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

                                                                        
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              Substances                           Limitations          
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  *                    *                    *                    *      
                   *                    *                    *          
-(oxiranylmethyl)--  For use as a reactant in the    
 (oxiranylmethoxy)poly[oxy(methyl-1,2-   preparation of epoxy-based     
 ethanediyl)], (alternative name:        resins.                        
 epichlorohydrin-polypropylene glycol)                                  
 (CAS Reg. No. 26142-30-3).                                             
2,2'-[oxybis[(methyl-2,1-ethanediyl)-   For use as a reactant in the    
 oxymethylene]]bisoxirane,               preparation of epoxy-based     
 (alternative name: epichlorohydrin-     resins.                        
 dipropylene glycol) (CAS Reg. No.                                      
 41638-13-5).                                                           
  *                    *                    *                    *      
                   *                    *                    *          
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    Dated: July 17, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-19567 Filed 7-24-97; 8:45 am]
BILLING CODE 4160-01-F