[Federal Register Volume 65, Number 50 (Tuesday, March 14, 2000)]
[Rules and Regulations]
[Pages 13675-13678]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-6116]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 176

[Docket No. 95F-0065]


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 polyamidoamine-
ethyleneimine-epichlorohydrin resin for use as a retention aid in the 
manufacture of paper and paperboard intended for use in contact with 
aqueous and fatty food. This action is in response to a petition filed 
by BASF Corp.

DATES: This rule is effective March 14, 2000. Submit written objections 
and requests for a hearing by April 13, 2000.

ADDRESSES: Submit written objections to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Vivian M. Gilliam, Center for Food 
Safety and Applied Nutrition (HFS-215), Food and Drug Administration, 
200 C St. SW., Washington, DC 20204, 202-418-3094.

SUPPLEMENTARY INFORMATION:

I. Background

    In a notice published in the Federal Register of April 13, 1995 (60 
FR 18845), FDA announced that a food additive petition (FAP 5B4452) had 
been filed by BASF Corp., 1609 Biddle Ave., Wyandotte, MI 48192. The 
petition proposed to amend the food additive regulations in 
Sec. 176.170 Components of paper and paperboard in contact with aqueous 
and fatty foods (21 CFR 176.170) to provide for the safe use of a 
polyamide-ethyleneimine-epichlorohydrin resin as a component of paper 
and paperboard in contact with aqueous and fatty food.
    Subsequent to the filing of the petition, the petitioner obtained a 
new Chemical Abstracts Service (CAS) Registry number for the additive 
under the following name: Polyamidoamine-ethyleneimine-epichlorohydrin 
resin prepared by reacting hexanedioic acid, N-(2-aminoethyl)-1,2-
ethanediamine, (chloromethyl)oxirane, ethyleneimine (aziridine), and 
polyethylene glycol, partly neutralized with sulfuric acid, CAS Reg. 
No. 167678-45-7. In this document, polyamidoamine-ethyleneimine-
epichlorohydrin resin will be referred to as the additive.
    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 ethylene oxide, 1,4-
dioxane,

[[Page 13676]]

epichlorohydrin, and ethyleneimine, which are carcinogenic impurities 
resulting from the manufacture of the additive. Residual amounts of 
reactants and manufacturing aids, such as ethylene oxide, 1,4-dioxane, 
epichlorohydrin, and ethyleneimine are commonly found as contaminants 
in chemical products, including food additives.

II. Determination of Safety

    Under the general safety standard of section 409(c)(3)(A) 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 section 
(409(c)(3)(A)) of the act 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 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).)

III. Safety of Petitioned Use of the Additive

    FDA estimates that the petitioned use of the additive, 
polyamidoamine-ethyleneimine-epichlorohydrin resin, will result in 
exposure to no greater than 650 parts per billion (ppb) of the additive 
in the daily diet (3 kilograms (kg)) or an estimated daily intake (EDI) 
of 2.0 milligrams per person per day (mg/p/d) (Ref. 1).
    FDA does not ordinarily consider chronic toxicological studies 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 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 ethylene oxide, 1,4-dioxane, epichlorohydrin, 
and ethyleneimine, the carcinogenic chemicals that may be present as 
impurities in the additive. The risk evaluation of ethylene oxide, 1,4-
dioxane, epichlorohydrin, and ethyleneimine 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 
bioassay to the conditions of exposure to humans.

A. Ethylene oxide

    FDA has estimated the exposure to ethylene oxide from the 
petitioned use of the additive as a component of paper and paperboard 
to be no more than 0.7 parts per trillion (pptr) of the daily diet (3 
kg), or 2 nanograms (ng)/p/d (Ref. 1). The agency used data from a 
carcinogenesis bioassay, in female rats, on ethylene oxide conducted by 
the Institute of Hygiene, University of Mainz, Germany (Ref. 3), to 
estimate the upper-bound limit of lifetime human risk from exposure to 
this chemical resulting from the petitioned use of the additive. The 
authors reported that the test material caused significantly increased 
incidence of squamous cell carcinomas of the forestomach and carcinomas 
in situ of the glandular stomach.
    Based on the agency's estimate that exposure to ethylene oxide will 
not exceed 2 ng/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the petitioned use of the subject additive is 
3.7  x  10-9, or 3.7 in a billion (Ref. 4). 
Because of the numerous conservative assumptions used in calculating 
the exposure estimate, the actual lifetime-averaged individual exposure 
to ethylene 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 ethylene oxide would result from the petitioned use of the additive.

B. 1,4-Dioxane

    FDA has estimated the exposure to 1,4-dioxane from the petitioned 
use of the additive as a component of paper and paperboard to be no 
more than 31 pptr of the daily diet (3 kg), or 94 ng/p/d (Ref. 1). The 
agency used data from a carcinogenesis bioassay, in mice and rats, on 
1,4-dioxane, conducted by the National Cancer Institute (Ref. 5), to 
estimate the upper-bound limit of lifetime human risk from exposure to 
this chemical resulting from the petitioned use of the additive. The 
authors reported that the test material induced squamous cell 
carcinomas of the nasal turbinates in male and female rats, 
hepatocellular adenomas in female rats, and hepatocellular carcinomas 
in male and female mice.
    Based on the agency's estimate that exposure to 1,4-dioxane will 
not exceed 94 ng/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the petitioned use of the subject additive is 
3.4  x  10-9, or 3.4 in a 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 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 1,4-dioxane would result from the petitioned use of the additive.

C. Epichlorohydrin

    FDA has estimated the exposure to epichlorohydrin from the 
petitioned use of the additive as a component of paper and paperboard 
to be no more than 1.3 pptr of the daily diet (3 kg), or 4 ng/p/d (Ref. 
1). The agency used data from a carcinogenesis bioassay, in male rats, 
on epichlorohydrin conducted by Konishi et al. (Ref. 6), to estimate 
the upper-bound limit of lifetime human risk from exposure to this 
chemical resulting from the petitioned use of the additive. The authors 
reported that the test material caused increased incidences of 
forestomach hyperplasia, papillomas, and carcinomas in the rats.
    Based on the agency's estimate that exposure to epichlorohydrin 
will not exceed 4 ng/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the petitioned use of the subject additive is 
1.9  x  10-10, or 1.9 in 10 billion (Ref. 4). 
Because of the numerous conservative assumptions used in calculating 
the exposure estimate, the actual lifetime-averaged individual exposure 
to epichlorohydrin 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

[[Page 13677]]

epichlorohydrin would result from the petitioned use of the additive.

D. Ethyleneimine

    FDA has estimated the exposure to ethyleneimine from the petitioned 
use of the additive as a component of paper and paperboard to be no 
more than 0.03 pptr of the daily diet (3 kg), or 0.1 ng/p/d (Ref. 1). 
The agency used data from a carcinogenesis bioassay, in mice, on 
ethyleneimine conducted by Innes et al. (Ref. 7), to estimate the 
upper-bound limit of lifetime human risk from exposure to ethyleneimine 
resulting from the petitioned use of the additive. The authors reported 
that the test material caused significantly increased incidence of lung 
and liver tumors in both male and female mice.
    Based on the agency's estimate that exposure to ethyleneimine will 
not exceed 0.1 ng/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the petitioned use of the subject additive is 
3.2  x  10-8, or 32 in a billion (Ref. 4). 
Because of the numerous conservative assumptions used in calculating 
the exposure estimate, the actual lifetime-averaged individual exposure 
to ethyleneimine 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 ethyleneimine would result from the petitioned use of the additive.

E. Need for Specifications

    The agency also has considered whether specifications are necessary 
to control the amount of ethylene oxide, 1,4-dioxane, epichlorohydrin, 
and ethyleneimine as impurities in the polyamidoamine-ethyleneimine-
epichlorohydrin resin. The agency finds that specifications are not 
necessary for the following reasons: (1) Because of the low level at 
which ethylene oxide, 1,4-dioxane, epichlorohydrin, and ethyleneimine 
may be expected to remain as impurities following production of the 
additive, the agency would not expect the impurities to become 
components of food at other than extremely low levels; and (2) the 
upper-bound limits of lifetime human risk from exposure to ethylene 
oxide, 1,4-dioxane, epichlorohydrin, and ethyleneimine are very low, 
3.7 in a billion, 3.4 in a billion, 1.9 in 10 billion, and 32 in a 
billion, respectively.

IV. Conclusion

    FDA has evaluated data in the petition and other relevant material. 
Based on this information, the agency concludes that the petitioned use 
of the additive as a retention aid in the manufacture of paper and 
paperboard intended for use in contact with aqueous and fatty food is 
safe, and that the additive will achieve its intended technical effect. 
Therefore, the agency concludes that the regulations in Sec. 176.170 
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.

V. 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.

VI. Paperwork Reduction Act of 1995

    This final rule contains no collection of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

VII. Objections

    Any person who will be adversely affected by this regulation may at 
any time file with the Dockets Management Branch (address above) 
written objections by April 13, 2000. 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 are to be 
submitted and are to 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.

VIII. 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 (HFS-246) to the 
Division of Petition Control (HFS-215) entitled ``FAP 5B4452, BASF 
Corp. Polyamide-ethyleneimine-epichlorohydrin resin, Polymin SKA, as 
a retention agent in the production of paper. Memorandum of 
correction,'' dated October 22, 1997.
    2. Kokoski, C. J., ``Regulatory Food Additive Toxicology,'' in 
Chemical Safety Regulation and Compliance, edited by F. Homburger, 
J. K. Marquis, and published by 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 Division of Petition Control (HFS-215) to 
the Executive Secretary, Quantitative Risk Assessment Committee 
(QRAC) (HFS-308) entitled ``Estimation of upper-bound limit of 
lifetime risk from ethyleneimine (EI), epichlorohydrin (ECH), 
ethylene oxide (EO), and 1,4-dioxane (DX), FAP 5B4452 (BASF 
Corp.),'' dated October 5, 1999.
    5. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,'' 
National Cancer Institute, NCI-CG-TR-80, 1978.
    6. Konishi, Y. et al., ``Forestomach Tumors Induced by Orally 
Administered Epichlorohydrin in Male Wistar Rats,'' Gann 71:922-923, 
1980.
    7. Innes, J. R. M. et al., ``Bioassay of Pesticide and 
Industrial Chemicals for Tumorigenicity in Mice: A Preliminary 
Note,'' Journal of the National Cancer Institute, 42, No. 6, 1101-
14, 1969.

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:

[[Page 13678]]

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

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

    Authority: 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 an 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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  *                    *                    *                        *                  *                  *
                                                              *
Polyamidoamine-ethyleneimine-epichlorohydrin resin       For use only as a retention aid employed prior to the
 prepared by reacting hexanedioic acid, N-(2-             sheet-forming operation in the manufacture of paper
 aminoethyl)-1,2-ethanediamine, (chloromethyl)oxirane,    and paperboard at a level not to exceed 0.12 percent
 ethyleneimine (aziridine), and polyethylene glycol,      resin by weight of the finished dry paper or
 partly neutralized with sulfuric acid (CAS Reg. No.      paperboard.
 167678-45-7).
  *                    *                    *                        *                  *                  *
                                                              *
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    Dated: March 3, 2000.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-6116 Filed 3-13-00; 8:45 am]
BILLING CODE 4160-01-F