[Federal Register Volume 64, Number 208 (Thursday, October 28, 1999)]
[Rules and Regulations]
[Pages 57976-57978]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-28112]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 177

[Docket No. 99F-0345]


Indirect Food Additives: Polymers

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 mono- and bis-
(octadecyldiethylene oxide)phosphates as components of coatings on 
cellophane intended for use in contact with food. This action is in 
response to a petition filed by UCB Films PLC.

DATES: The regulation is effective October 28, 1999; written objections 
and requests for a hearing by November 29, 1999.

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 March 18, 1999 (64 FR 13431), FDA announced that a food 
additive petition (FAP 9B4642) had been filed by UCB Films PLC, c/o 
Keller and Heckman LLP, 1001 G St. NW., suite 500 West, Washington, DC 
20001. The petition proposed to amend the food additive regulations in 
Sec. 177.1200 Cellophane (21 CFR 177.1200) to provide for the safe use 
of mono- and bis-(octadecyldiethylene oxide)phosphates as component of 
coatings on cellophane intended for use in contact with 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 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 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

[[Page 57977]]

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, mono- and 
bis-(octadecyldiethylene oxide)phosphates as a component of coatings 
(as a release agent) on cellophane will result in exposure to no 
greater than 43.5 parts per billion of the additive in the daily diet 
(3 kilogram (kg)) or an estimated daily intake of 0.13 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 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 1,4-dioxane and ethylene oxide, the 
carcinogenic chemicals that may be present as impurities in the 
additive. This risk evaluation of 1,4-dioxane and ethylene oxide 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. 1,4-Dioxane

    FDA has estimated the exposure to 1,4-dioxane from the petitioned 
use of the additive in the coating on cellophane to be 0.22 part per 
trillion of the daily diet (3 kg) or 0.66 nanogram (ng)/p/d (Ref. 1). 
The agency used data from a carcinogenesis bioassay on 1,4-dioxane, 
conducted by the National Cancer Institute (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 and hepatocellular tumors in female rats.
    Based on the agency's estimate that exposure to 1,4-dioxane will 
not exceed 0.66 ng/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the petitioned use of the subject additive is 
2.3 x 10-11 (or 2.3 in 100 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.

B. Ethylene Oxide

    FDA has estimated the exposure to ethylene oxide from the 
petitioned use of the additive in coatings on cellophane to be 22 parts 
per quadrillion in the daily diet (3 kg) or 66 picograms (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. 5), to estimate the upper-bound limit of lifetime human 
risk from exposure to ethylene oxide 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 in female 
rats.
    Based on the agency's estimate exposure that to ethylene oxide of 
66 pg/p/d, FDA estimates that the upper-bound limit of lifetime human 
risk from the petitioned use of the subject additive is 1.2 x 
10-10 (or 1.2 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 petitioned use of the additive.

C. Need for Specifications

    The agency also has considered whether specifications are necessary 
to control the amount of 1,4-dioxane and ethylene oxide 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 1,4-
dioxane and ethylene oxide 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 1,4-dioxane and ethylene oxide is very low, 2.3 in 100 billion and 
1.2 in 10 billion, respectively.

III. Conclusion

    FDA has evaluated the data in the petition and other relevant 
material. Based on this information, the agency concludes that: (1) The 
proposed use of the additive is safe, (2) the additive will achieve its 
intended technical effect, and therefore, (3) the regulations in 
Sec. 177.1200 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 previously considered the environmental effects of 
this rule as announced in the notice of filing for FAP 9B4642 (64 FR 
13431). No new information or comments have been received that would 
affect the agency's previous determination that there is no significant 
impact on the human environment and that an environmental impact 
statement is not required.

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 November 29, 1999, 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

[[Page 57978]]

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.

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 Team, FDA, to the file 
concerning ``FAP 9B4642 (MATS #1025, M2.0 & 2.1): UCB Films PLC, 
dated March 30, 1999. Use of Mono- and Bis-(octadecyldiethylene 
oxide)phosphates as a Release Agent in Food-contact Coatings Applied 
to Cellophane.''
    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. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,'' 
National Cancer Institute, NCI-CG-TR-80, 1978.
    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 Ethylene 
Oxide and 1,4-dioxane in Mono- and Bis-(octadecyldiethylene 
oxide)phosphates as a Release Agent in Food-contact Coating Applied 
to Cellophane: Food Additive Petition No. 9B4642 (UCB Films PLC),'' 
dated June 10, 1999.
    5. Dunkelberg, H., ``Carcinogenicity of Ethylene Oxide and 1,2-
propylene Oxide Upon Intragastric Administration to Rats,'' British 
Journal of Cancer, 46:924-933, 1982.

List of Subjects in 21 CFR Part 177

    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 
177 is amended as follows:

PART 177--INDIRECT FOOD ADDITIVES: POLYMERS

    1. The authority citation for 21 CFR part 177 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 342, 348, 379e.

    2. Section 177.1200 is amended in the table in paragraph (c) by 
alphabetically adding an entry under the headings ``List of 
substances'' and ``Limitations'' to read as follows:


Sec. 177.1200  Cellophane.

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    (c) * * *

 
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                                      Limitations (residue and limits of
                                       addition expressed as percent by
         List of substances              weight of finished packaging
                                                 cellophane)
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*                    *                    *                    *
                  *                    *                    *
Mono- and bis-(octadecyldiethylene   For use only as a release agent at
 oxide) phosphates (CAS Reg. No.      a level not to exceed 0.6 percent
 62362-49-6).                         by weight of coatings for
                                      cellophane.
 
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    Dated: October 19, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-28112 Filed 10-27-99; 8:45 am]
BILLING CODE 4160-01-F