[Federal Register Volume 59, Number 182 (Wednesday, September 21, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-23274]


[[Page Unknown]]

[Federal Register: September 21, 1994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 176

[Docket No. 89F-0453]

 

Indirect Food Additives: Paper and Paperboard Components

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,N',N',N'',N''-
hexakis(methoxymethyl)-1,3,5-triazine-2,4,6-triamine polymer with 
stearyl alcohol, -octadecenyl--hydroxypoly(oxy-1,2-
ethanediyl), and alkyl (C20+) alcohols as a component of paper and 
paperboard in contact with aqueous foods. This action responds to a 
petition filed by PPG Industries, Inc.

DATES: Effective September 21, 1994; written objections and requests 
for a hearing by October 21, 1994.

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: Julius Smith, Center for Food Safety 
and Applied Nutrition (HFS-216), Food and Drug Administration, 200 C 
St. SW., Washington, DC 20204, 202-418-3091.

SUPPLEMENTARY INFORMATION: In a notice published in the Federal 
Register of December 19, 1989 (54 FR 51946), FDA announced that a food 
additive petition (FAP 9B4172) had been filed by PPG Industries, Inc., 
Pittsburgh, PA 15146, proposing that Sec. 176.170 Components of paper 
and paperboard in contact with aqueous and fatty foods (21 CFR 176.170) 
be amended to provide for the safe use of N,N,N',N',N'',N''-
hexakis(methoxymethyl)-1,3,5-triazine-2,4,6-triamine polymer with 
stearyl alcohol, -octadecenyl->-hydroxypoly(oxy-1,2-
ethanediyl), and alkyl (C20+) alcohols as a component of paper and 
paperboard in contact with aqueous foods.
    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 may 
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 evidence 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) provides that no food additive shall be deemed 
to be 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 constituents of 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 the Petitioned Use

    FDA estimates that the petitioned use of the additive, 
N,N,N',N',N'',N''-hexakis(methoxymethyl)-1,3,5-triazine-2,4,6-triamine 
polymer with stearyl alcohol, -octadecenyl->-
hydroxypoly(oxy-1,2-ethanediyl), and alkyl (C20+) alcohols, will 
result in levels of exposure to the additive of no greater than 19 
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 limits 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 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 
paper and paperboard to be 11 nanograms per person per day (ng/person/
day) (Ref. 1). The agency used data from a carcinogenesis bioassay on 
1,4-dioxane, conducted for the National Cancer Institute (Ref. 3), to 
estimate the upper-bound limits of 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 a potential exposure of 11 ng/person/day, FDA estimates 
that the upper-bound limits of individual lifetime risk from the 
potential exposure to 1,4-dioxane from the use of the subject additive 
is 4x10-10, or less than 4 in 10 billion (Ref. 4). Because of the 
numerous conservative assumptions used in calculating the exposure 
estimate, actual lifetime averaged individual exposure to 1,4-dioxane 
is likely to be substantially less than the worst-case exposure, and 
therefore, the calculated upper-bound limits of risk would be less. 
Thus, the agency concludes that there is a reasonable certainty of no 
harm from the exposure to 1,4-dioxane that might 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 
paper and paperboard is 11 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 carcinoma in situ of 
the glandular stomach.
    Based on a potential exposure of 11 ng/person/day, FDA estimates 
that the upper-bound limits of individual lifetime risk from the 
potential exposure to ethylene oxide from the use of the subject 
additive is 2x10-8, or less than 2 in 100 million (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 limits of risk 
would be less. Thus, the agency concludes that there is a reasonable 
certainty of no harm from the exposure to ethylene oxide that might 
result from the proposed use of the additive.

C. Formaldehyde

    A review of the petition also indicates that the additive may 
contain formaldehyde as an impurity at a dietary concentration of 15 
micrograms/person/day. The potential carcinogenicity of formaldehyde 
was reviewed by the Cancer Assessment Committee (the committee) that 
has been formed by FDA's Center for Food Safety and Applied Nutrition. 
The committee noted that for many years formaldehyde has been known to 
be a carcinogen by the inhalation route, but it concluded that these 
inhalation studies are not appropriate for assessing the potential 
carcinogenicity of formaldehyde in food because of the inappropriate 
route administration and the fact that tumors were observed only 
locally at the portal of entry (nasal turbinates). The agency has 
received literature reports of two drinking water studies on 
formaldehyde: (1) A preliminary report of a carcinogenicity study 
purported to be positive by Soffritti et al. (1989), conducted in 
Bologna, Italy (Ref. 7), and (2) a negative study by Til, et al. 
(1989), conducted in The Netherlands (Ref. 8). The committee reviewed 
both studies and concluded in a ``Memorandum of Conference,'' dated 
April 24, 1991 and March 4, 1993, ``* * * that data concerning the 
Soffritti study reported were unreliable and could not be used in the 
assessment of the oral carcinogenicity of formaldehyde'' (Ref. 6). This 
conclusion is based on a lack of critical details in the study, 
questionable histopathologic conclusions, and the use of unusual 
nomenclature to describe the tumors. Thus, the committee concluded that 
there is no basis to find that formaldehyde is a carcinogen when 
ingested.

D. Need for Specifications

    The agency has also considered whether specifications are necessary 
to control the amount of 1,4-dioxane and ethylene oxide 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 low 
levels; and (2) the upper-bound limits of lifetime risk from exposure 
to these impurities, even under worst-case assumptions, is very low, 
less than 4 in 10 billion and less than 2 in 100 million for 1,4-
dioxane and ethylene oxide, respectively.

III. Conclusion

    FDA has evaluated the data in the petition and other relevant 
material and concludes that the proposed uses for the additive in paper 
and paperboard products in contact with aqueous food are safe. Based on 
this information, the agency has also concluded that the additive will 
have the intended technical effect. Accordingly, Sec. 176.170 is 
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 21, 1994, 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. FAP 9B4172--PPG Industries (Submission dated 9-8-89) ``Water-
Repellant Coating for Paper and Paperboard,'' Memorandum from the 
Food and Color Additives Review Section (HFF-415) to the Indirect 
Additives Branch (HFF-335), January 8, 1990.
    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,'' August 1, 1990.
    5. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
Propylene Oxide Upon Intragastric Administration to Rats,'' British 
Journal of Cancer, 46:924, 1982.
    6. Memorandum of Conference, ``Meeting of the Cancer Assessment 
Committee,'' April 24, 1991, and March 4, 1993.
    7. Soffritti, et al., ``Formaldehyde: An Experimental 
Multipotential Carcinogen,'' Toxicology and Industrial Health, Vol. 
5, No. 5: pp. 699-730, 1989.
    8. Til, et al., ``Two-Year Drinking-Water Study of Formaldehyde 
In Rats,'' Food Chemical Toxicology, Vol. 27, No. 2: pp. 77-87, 
1989.

List of Subjects in 21 CFR Part 176

    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 
176 is amended as follows:

PART 176--INDIRECT FOOD ADDITIVES: PAPER AND PAPERBOARD COMPONENTS

    1. The authority citation for 21 CFR part 176 continues to read as 
follows:

    Authority: Secs. 201, 402, 406, 409, 721 of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 321, 342, 346, 348, 379e).

    2. Section 176.170 is amended in the table in paragraph (a)(5) by 
alphabetically adding a new entry under the headings ``List of 
Substances'' and ``Limitations'' to read as follows:


Sec. 176.170  Components of paper and paperboard in contact with 
aqueous and fatty foods.

* * * * *
    (a) * * *
    (5) * * *

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        List of Substances                       Limitations            
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                                 *******                                
N,N,N',N',N'',N''-Hexakis            For use only as a water-repellent  
 (methoxymethyl)-1,3,5-triazine-      applied to the surface of paper   
 2,4,6-triamine polymer with          and paperboard at levels not to   
 stearyl alcohol, -          exceed 1 percent by weight of the 
 octadecenyl->-             finished dry paperboard fibers.   
 hydroxypoly(oxy-1,2-ethanediyl),     The finished paper and paperboard 
 and alkyl (C20+) alcohols (CAS       will be used in contact with      
 Reg. No. 130328-24-4).               aqueous foods under conditions of 
                                      use B through G as described in   
                                      Table 2 of paragraph (c) of this  
                                      section.                          
                                                                        
                                 *******                                
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* * * * *

    Dated: September 6, 1994.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 94-23274 Filed 9-20-94; 8:45 am]
BILLING CODE 4160-01-F