[Federal Register Volume 64, Number 208 (Thursday, October 28, 1999)]
[Rules and Regulations]
[Pages 57974-57976]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-28113]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 172

[Docket No. 84F-0050]


Food Additives Permitted for Direct Addition to Food for Human 
Consumption; Polysorbate 60

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 polysorbate 60 as 
an emulsifier in ice cream, frozen custard, fruit sherbet, and 
nonstandardized frozen desserts. This action is in response to a 
petition filed by ICI Americas, Inc.

DATES: This 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: Andrew D. Laumbach, Center for Food 
Safety and Applied Nutrition (HFS-215), Food and Drug Administration, 
200 C St. SW., Washington, DC 20204, 202-418-3071.

SUPPLEMENTARY INFORMATION: In a notice published in the Federal 
Register of March 20, 1984 (49 FR 10364), FDA announced that a food 
additive petition (FAP 4A3774) had been filed by ICI Americas, Inc., 
Wilmington, DE 19897 (now, Wilmington, DE 19850-5391). The petition 
proposed to amend the food additive regulations to provide for the safe 
use of polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) as 
an emulsifier in ice cream, frozen custard, ice milk, fruit sherbet, 
and nonstandardized frozen desserts when used alone or in combination 
with polysorbate 65 and/or polysorbate 80. The agency notes that the 
standard of identity for ice milk was removed from the Code of Federal 
Regulations in the final rule published in the Federal Register of 
September 14, 1994 (59 FR 47080). Therefore, the amendment to provide 
for the use of polysorbate 60 in ice milk will be included under the 
provisions for nonstandardized desserts in the regulation set forth 
below.
    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, which are 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 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 will result 
in an estimated mean daily intake of 39 milligrams per person per day 
(mg/p/d). The cumulative exposure to all ethoxylated direct additives 
from previously regulated uses is estimated to be 166 mg/p/d (Ref. 1).

[[Page 57975]]

    The agency has reviewed the available toxicological data on the 
additive and concludes that the estimated dietary exposure resulting 
from the petitioned use of the additive is safe. The calculated 
cumulative intake of ethoxylated direct food additives (166 mg/p/d) 
when added to the estimated intake of polysorbate 60 for use in frozen 
dairy desserts (39 mg/p/d) (i.e., 205 mg/p/d) is much lower than the 
current estimated acceptable daily intake of 1,500 mg/p/d for all 
regulated polysorbates, thus supporting the safety of the petitioned 
use (Ref. 2).
    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. The risk evaluation of 1,4-dioxane and ethylene oxide has two 
aspects as follows: (1) Assessment of 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 that exposure to 1,4-dioxane from the petitioned 
uses of the additive in frozen dairy desserts would not exceed 19 
nanograms (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 results of the bioassay on 1,4-dioxane demonstrated that 
the material was carcinogenic for female rats under the conditions of 
the study. 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 from 
the use of the additive in frozen dairy desserts will not exceed 19 ng/
p/d, FDA estimates that the upper-bound limit of lifetime human risk 
from the petitioned use of the subject additive in frozen dairy 
desserts is 6.7 x 10-10 or 6.7 in 10 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 that exposure to ethylene oxide from the 
petitioned use of the additive in the manufacture of frozen dairy 
desserts would not exceed 7.7 ng/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 
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 author 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 the exposure to ethylene oxide 
will not exceed 7.7 ng/p/d, FDA estimates that the upper-bound limit of 
lifetime human risk from the petitioned use of the subject additive in 
frozen dairy desserts is 1.5 x 10-8 or 1.5 in 100 million 
(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 polysorbate 60 for use in frozen dairy desserts (Ref. 6). 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 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 1,4-dioxane 
and ethylene oxide are very low, 6.7 in 10 billion and 1.5 in 100 
million, respectively.

III. Conclusion

    FDA has evaluated data in the petition and other relevant material. 
Based on this information, the agency concludes that the proposed use 
of the additive is safe, and that the additive will achieve its 
intended technical effect as an emulsifier in frozen dairy desserts. 
Therefore, the agency concludes that the regulations in 21 CFR 172.836 
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 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 collections 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 waiver of the right to a hearing on that objection. 
Each numbered objection for

[[Page 57976]]

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 CFSAN's Chemistry Review Branch (HFS-247) to 
CFSAN's Direct Additives Branch (HFS-217) concerning ``FAP 4A3774 & 
FAP 4A3824: Ethylene Oxide and 1,4-dioxane Residues in Polysorbate 
60, Direct Additives Branch Request of 9/3/93,'' dated September 28, 
1993.
    2. Memorandum from CFSAN's Additives Evaluation Branch No. 1 
(HFS-226) to CFSAN's Direct Additives Branch (HFS-217) concerning 
``Chemistry Review Branch (HFS-247) Memorandum of March 1, 1996, 
EDI's for Polyoxyethylene (20) Sorbitan Monostearate (Polysorbate 
60) in Frozen Dairy Desserts and Coconut Milk Drinks, and Risks 
Estimates for Residual Ethylene Oxide and 1,4-dioxane,'' dated March 
13, 1996.
    3. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,'' 
National Cancer Institute, NCI-CG-TR-80, 1978.
    4. Memorandum from CFSAN's Division of Petition Control (HFS-
215) to the Executive Secretary, Quantitative Risk Assessment 
Committee (HFS-308) concerning ``Estimation of Upper-bound Lifetime 
Risk from Ethylene Oxide (EO) and 1,4-dioxane (DX) Residues in 
Polysorbate 60: Subject of Food Additive Petition 4A3774 (ICI 
Americas, Inc.),'' dated December 14, 1998.
    5. 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.
    6. Memorandum to the Record from CFSAN's Division of Petition 
Control (HFS-215) concerning ``FAP 4A3774--Consideration of a Need 
for Specification for 1,4-dioxane in a Regulation for Polysorbate 60 
use in Frozen Dairy Desserts,'' dated December 14, 1998.

List of Subjects in 21 CFR Part 172

    Food additives, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
172 is amended as follows:

PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR 
HUMAN CONSUMPTION

    1. The authority citation for 21 CFR part 172 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 341, 342, 348, 371, 379e.

    2. Section 172.836 is amended by adding new paragraph (c)(16) to 
read as follows:


Sec. 172.836  Polysorbate 60.

* * * * *
    (c) * * *
    (16) As an emulsifier in ice cream, frozen custard, fruit sherbet, 
and nonstandardized frozen desserts when used alone or in combination 
with polysorbate 65 and/or polysorbate 80, whereby the maximum amount 
of the additives, alone or in combination, does not exceed 0.1 percent 
of the finished frozen dessert.
* * * * *

    Dated: October 19, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-28113 Filed 10-27-99; 8:45 am]
BILLING CODE 4160-01-F