[Federal Register Volume 61, Number 17 (Thursday, January 25, 1996)]
[Rules and Regulations]
[Pages 2111-2113]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-1143]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

 21 CFR Part 175

[Docket No. 94F-0381]


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 

[[Page 2112]]
food additive regulations to provide for the safe use of glyceryl 
polyoxypropylene triol;<greek-a>,<greek-a>',<greek-a>''-1,2,3-
propanetriyltris[<greek-oh>-hydroxypoly(oxypropylene)], minimum average 
molecular weight 250, as a reactant in the preparation of polyester and 
polyurethane resins used as components of adhesives for food-contact 
articles. This action is in response to a petition filed by the Dow 
Chemical Co.

DATES: Effective January 25, 1996; written objections and requests for 
a hearing by February 26, 1996.

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 23, 1994 (59 FR 60363), FDA announced that a food 
additive petition (FAP 4B4435) had been filed by the Dow Chemical Co., 
1803 Bldg., Midland, MI 48674-1803. 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 glyceryl polyoxypropylene 
triol;<greek-a>,<greek-a>',<greek-a>''-1,2,3-
propanetriyltris[<greek-oh>-hydroxypoly(oxypropylene)], minimum average 
molecular weight 250, as a reactant in the preparation of polyester and 
polyurethane resins used as components of adhesives for food-contact 
articles.
    The chemical, glyceryl polyoxypropylene 
triol;<greek-a>,<greek-a>',<greek-a>''-1,2,3-
propanetriyltris[<greek-oh>-hydroxypoly(oxypropylene)] is currently 
listed in 21 CFR 175.105 under the synonym, glyceryl polyoxypropylene 
triol. Therefore, for consistency, the subject additive is being listed 
by its synonym in this final rule.
    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 propylene oxide, a 
carcinogenic impurity, resulting from the manufacture of the additive. 
Residual amounts of reactants and manufacturing aids, such as propylene 
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, glyceryl 
polyoxypropylene triol (also known as glyceryl polyoxypropylene 
triol;<greek-a>,<greek-a>',<greek-a>''-1,2,3-
propanetriyltris[<greek-oh>-hydroxypoly(oxypropylene)], minimum average 
molecular weight 250, 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 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 chemical that may be present as an impurity in the 
additive, propylene oxide. This risk evaluation of propylene oxide has 
two aspects: (1) Assessment of the worst-case exposure to the impurity 
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. Propylene Oxide

    FDA has estimated the hypothetical worst-case exposure to propylene 
oxide from the petitioned use of the additive in the manufacture of 
adhesives to be 7 parts per quadrillion of the daily diet or 21 
picogram (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, 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 
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 of 21 pg/person/day, FDA 
estimates that the upper-bound limit of individual lifetime risk 
arising from likely exposure to propylene oxide resulting from the use 
of the subject additive is in the range of 3.2  x  10<SUP>-12 (or 3.2 
in 1 trillion) to 1.5  x  10<SUP>-11 (or 1.5 in 100 billion) (Ref. 4). 
The range in FDA's estimate results from the agency's evaluation of 
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 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 propylene oxide would result 
from the proposed use of the additive.

 B. Need for Specifications

    The agency has also considered whether specification are necessary 
to control the amount of propylene oxide 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 propylene 
oxide may be expected to remain as an impurity following production of 
the additive, the agency would not expect the impurity to become a 
component of food at other than extremely small levels; and (2) the 

[[Page 2113]]
upper-bound limits of lifetime risk from exposure to the impurity, even 
under worst-case assumptions, is very low, in the range of less than 
3.2 in 1 trillion to 1.5 in 100 billion.

III. Conclusion

    FDA has evaluated 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. 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), Center 
for Food Safety and Applied Nutrition (CFSAN), FDA, to the Indirect 
Additives Branch (HFS-216), CFSAN, FDA, concerning FAP 4B4435--Dow 
Chemical Co.--exposure to the food additive and its component, 
propylene oxide, dated March 1, 1995.-
    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. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British 
Journal of Cancer, 46: 924, 1982.
    4. Memorandum, ``Report of the Quantitative Risk Assessment 
Committee,'' CFSAN, FDA, dated April 20, 1995.

VI. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before February 26, 1996, 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.

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 paragraph (c)(5) in the table by 
alphabetically adding a new entry 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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*                    *                    *                    *        
                  *                    *                    *           
Glycerol polyoxypropylene triol,    For use only in the preparation of  
 minimum average molecular weight    polyester and polyurethane resins  
 250 (CAS Reg. No. 25791-96-2).      in adhesives.                      
  *                    *                    *                    *      
                   *                    *                    *          
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    Dated: January 17, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-1143 Filed 1-24-96; 8:45 am]
BILLING CODE 4160-01-F