[Federal Register Volume 63, Number 219 (Friday, November 13, 1998)]
[Rules and Regulations]
[Pages 63406-63408]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-30296]



[[Page 63406]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 176

[Docket No. 96F-0401]


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

DATES: The regulation is effective November 13, 1998; written 
objections and requests for a hearing by December 14, 1998.

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: 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 31, 1996 (61 FR 56242), FDA announced that a food 
additive petition (FAP 6B4501) had been filed by BASF Corp., 11501 
Steele Creek Rd., Charlotte, NC 28273. The petition proposed to amend 
the food additive regulations in Sec. 176.180 Components of paper and 
paperboard in contact with dry food (21 CFR 176.180) to provide for the 
safe use of polyamide-ethyleneimine-epichlorohydrin resin for use as a 
retention aid in the manufacture of paper and paperboard intended for 
use in contact with dry food.
    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, epichlorohydrin, and ethyleneimine, 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.

I. Determination of Safety

    Under the general safety standard 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 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 Petitioned Use of the Additive

    FDA estimates that the petitioned use of the additive, polyamide-
ethyleneimine-epichlorohydrin resin will result in exposure to no 
greater than 50 parts per billion (ppb) of the additive in the daily 
diet (3 kilogram (kg)) or an estimated daily intake (EDI) of 0.15 
milligram 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 proposed 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, carcinogenic chemicals that may be present as 
impurities in the additive. This risk evaluation of ethylene oxide, 
1,4-dioxane, epichlorohydrin, and ethyleneimine has two aspects: (1) 
Assessment of the exposure to the impurities from the proposed use of 
the additive; and (2) extrapolation of the risk observed in animal 
bioassays 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 in the manufacture of paper and 
paperboard to be no greater than 50 parts per quadrillion (ppq) of the 
daily diet (3 kg) or no more than 150 picogram (pg)/p/d (Ref. 1). The 
agency used data from a carcinogenesis bioassay 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 results of the bioassay on ethylene oxide demonstrated 
that ethylene oxide 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 the agency's estimate that the exposure to ethylene oxide 
will not exceed 150 pg/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the proposed use of the subject additives 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, 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 proposed use of the additive.

B. 1,4-Dioxane

    FDA has estimated the exposure to 1,4-dioxane from the petitioned 
use of the additive in the manufacture of paper and paperboard to be no 
more than 55 parts per trillion (ppt) of the daily diet (3 kg) or 0.2 
microgram (g/p/d (Ref. 1)). The agency used data from a 
carcinogenesis bioassay on 1,4-dioxane, conducted by the National 
Cancer

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Institute (Ref. 5), to estimate the upper-bound limit of lifetime human 
risk from exposure to this chemical resulting from the proposed use of 
the additive. 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 agency's estimate that exposure to 1,4-dioxane will 
not exceed 0.2 g/p/d, FDA estimates that the upper-bound limit 
of lifetime human risk from the proposed use of the subject additive is 
6.9 x 10-9, or 6.9 in 1 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 proposed use of the additive.

C. Epichlorohydrin

    FDA has estimated the exposure to epichlorohydrin from the 
petitioned use of the additive in the manufacture of paper and 
paperboard to be no more than 100 ppq of the daily diet (3 kg) or no 
more than 300 pg/p/d (Ref. 1). The agency used data from a Japanese 
carcinogenesis bioassay (Ref. 6), on epichlorohydrin fed to rats via 
their drinking water to estimate the upper-bound limit of lifetime 
human risk from exposure to this chemical resulting from the proposed 
use of the additive. 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 300 pg/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the proposed use of the subject additive is 
1.4 x 10-11 (or 1.4 in 100 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 epichlorohydrin would result from the proposed use of the additive.

D. Ethyleneimine

    FDA has estimated the exposure to ethyleneimine from the petitioned 
use of the additive in the manufacture of paper and paperboard to be no 
greater than 2.5 ppq of the daily diet (3 kg) or no greater than 7.5 
pg/p/d (Ref. 1). The agency used data from a carcinogenesis bioassay on 
ethyleneimine conducted by the National Cancer Institute (Ref. 7), to 
estimate the upper-bound limit of lifetime human risk from exposure to 
ethyleneimine resulting from the proposed use of the additive. The 
results of the bioassay on ethyleneimine demonstrated that the material 
was carcinogenic for male and female mice under the conditions of the 
study. The test material caused significantly increased incidence of 
lung and liver neoplasia in both male and female mice.
    Based on the agency's estimate that exposure to ethyleneimine will 
not exceed 7.5 pg/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the proposed use of the subject additive is 
2.6 x 10-9 (or 2.6 in 1 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 proposed use of the additive.

E. Need for Specifications

    The agency has also considered whether specifications are necessary 
to control the amount of ethylene oxide, 1,4-dioxane, epichlorohydrin, 
and ethyleneimine present 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 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 risk 
from exposure to ethylene oxide, 1,4-dioxane, epichlorohydrin, and 
ethyleneimine are very low, 2.8 in 10 billion, 6.9 in 1 billion, 1.4 in 
100 billion, and 2.6 in 1 billion, respectively.

III. Conclusion

    FDA has evaluated the data in the petition and other relevant 
material. Based on this information, the agency concludes that the 
proposed use of the additive as a retention aid in the production of 
paper and paperboard is safe, and that the additive will achieve its 
intended technical effect. Therefore, the agency concludes that the 
regulations in Sec. 176.180 should be amended as set forth as follows.
    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.

V. 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.

VI. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before December 14, 1998, 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

[[Page 63408]]

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 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.

VII. 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, FDA, to the 
Indirect Additives Branch, FDA, concerning ``FAP 6B4501 (MATS M2.0 & 
2.1): BASF Corp., ``Safe Use of Polymin SB as a Retention Agent in 
the Manufacture of Paper and Paperboard to be Made Into Dry Food 
Containers,'' dated September 18, 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 
Ethyleneimine, Epichlorohydrin, Ethylene Oxide and 1,4-dioxane in an 
Aqueous Solution of Either One or a Mixture of the Following Two 
Polymers;
    Formate salt form: Hexanedioic acid with N-(2-aminoethyl)-1,3-
propanediamine, aziridine, (chloromethyl)oxirane, 1,2-ethanediamine, 
N,N''-1,2-ethanediylbis[1,3-propanediamine] formic acid and 
-hydro--hydroxypoly(oxy-1,2-ethanediyl) [CAS Reg. 
No. 114133-44-7].
    Sulfate salt form: Hexanedioic acid with N-(2-aminoethyl)-1,3-
propanediamine, aziridine, (chloromethyl)oxirane, 1,2-ethanediamine, 
N,N''-1,2-ethanediylbis[1,3-propanediamine] and -hydro-
-hydroxypoly(oxy-1,2-ethanediyl), sulfate salt [CAS Reg. 
No. 16768-43-5].''Subject of Food Additive Petition No. 6B4501 (BASF 
Corp.), dated October 17, 1996.
    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 Chemicals for 
Tumorigenicity in Mice: A Preliminary Note,'' Journal of National 
Cancer Institute, 42:1101, 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:

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 176.180 is amended in the table in paragraph (b)(2) by 
alphabetically adding an entry under the heading ``List of substances'' 
to read as follows:




Sec.  176.180   Components of paper and paperboard in contact with dry 
food.

* * * * *
    (b) * * *
    (2) * * *

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                   List of substances                                          Limitations
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Polyamide-ethyleneimine-epichlorohydrin resin is
 prepared by reacting equimolar amounts of adipic acid
 and three amines (21 mole percent of 1,2-
 ethanediamine, 51 mole percent of N-(2-aminoethyl)-1,3-
 propanediamine, and 28 mole percent of N, N'-1,2-
 ethanediylbis(1,3-propanediamine)) to form a basic
 polyamidoamine which is modified by reaction with
 ethyleneimine (5.5:1.0 ethyleneimine:polyamidoamine).
 The modified polyamidoamine is reacted with a
 crosslinking agent made by condensing approximately 34
 ethylene glycol units with (chloromethyl)oxirane,
 followed by pH adjustment with formic acid or sulfuric
 acid to provide a finished product as a formate (CAS
 Reg. No. 114133-44-7) or a sulfate (CAS Reg. No.
 167678-43-5), having a weight-average molecular weight
 of 1,300,000 and a number-average molecular weight of
 16,000.
  *                    *                    *                    *                    *                    *
                                                             *
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    Dated: November 2, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-30296 Filed 11-12-98; 8:45 am]
BILLING CODE 4160-01-F