[Federal Register Volume 64, Number 104 (Tuesday, June 1, 1999)]
[Rules and Regulations]
[Pages 29224-29227]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-13670]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 173

[Docket No. 97F-0450]


Secondary Direct Food Additives Permitted in Food for Human 
Consumption; Boiler Water Additives

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending the food 
additive regulations to provide for the safe use of sorbitol anhydride 
esters, an emulsifier blend of sorbitan monostearate, polyoxyethylene 
(20) sorbitan monostearate (polysorbate 60), and polyoxyethylene (20) 
sorbitan monolaurate (polysorbate 20) as an anticorrosive agent in 
boilers where steam may contact food. This action is in response to a 
petition filed by Nalco Chemical Co.

DATES: This regulation is effective June 1, 1999; written objections 
and requests for a hearing by July 1, 1999. The Director of the Office 
of the Federal Register approves the incorporation by reference in 
accordance with 5 U.S.C. 552(a) and 1 CFR part 51 of a certain 
publication in Sec. 173.310 (21 CFR 173.310), effective June 1, 1999.

ADDRESSES: Submit written objections to the Dockets Management Branch 
(HFA-305), Food and Drug Administration,

[[Page 29225]]

5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Martha D. Peiperl, Center for Food 
Safety and Applied Nutrition (HFS-215), Food and Drug Administration, 
200 C St. SW., Washington, DC 20204, 202-418-3077.

SUPPLEMENTARY INFORMATION:

I. Background

    In a notice published in the Federal Register of November 13, 1997 
(62 FR 60903), FDA announced that a food additive petition (FAP 7A4540) 
had been filed by Nalco Chemical Co., One Nalco Center, Naperville, IL 
60568-1198. The petition proposed to amend the food additive 
regulations in Sec. 173.310 Boiler water additives to provide for the 
safe use of an emulsifier blend containing sorbitan monostearate, 
polyoxyethylene (20) sorbitan monostearate, and polyoxyethylene (20) 
sorbitan monolaurate as an anticorrosive agent in boilers where steam 
may contact food. The emulsifier blend is a simple mixture of these 
three substances, each of which is an ester of sorbitol anhydride. For 
convenience of listing of the mixture, the agency chooses to use the 
name sorbitol anhydride esters (SAHE) for this additive.
    Sorbitan monostearate is currently approved in Sec. 73.1001 (21 CFR 
73.1001) as a diluent in color additive mixtures for drug use exempt 
from certification; in Sec. 172.515 (21 CFR 172.515) as a synthetic 
flavoring substance and adjuvant; in 21 CFR 172.842 as an emulsifier; 
and in Sec. 173.340 (21 CFR 173.340) as a defoaming agent. 
Polyoxyethylene (20) sorbitan monostearate (polysorbate 60) is 
currently approved in Sec. 73.1001 as a diluent in color additive 
mixtures for drug use exempt from certification; in Sec. 172.515 as a 
synthetic flavoring substance and adjuvant; in 21 CFR 172.836 as an 
emulsifier, foaming agent, dough conditioner, dispersing agent, and 
surfactant and wetting agent; and in Sec. 173.340 as a defoaming agent. 
Polyoxyethylene (20) sorbitan monolaurate (polysorbate 20) is currently 
approved in Sec. 172.515 as a synthetic flavoring substance and 
adjuvant.
    In its evaluation of the safety of SAHE, FDA has reviewed the 
safety of the three esters and the chemical impurities that may be 
present in them resulting from their manufacturing process. Because 
these three esters have similar chemical structures, which do not react 
with each other, FDA has determined that its safety review for each of 
the three esters would be the same as that for the SAHE mixture. 
Therefore, FDA refers to each ester, rather than the additive as a 
whole, in its evaluation of the safety of SAHE in this final rule.
    Although none of the esters have been shown to cause cancer, two of 
them (polysorbate 20 and polysorbate 60) may contain minute amounts of 
unreacted 1,4-dioxane (DX) and ethylene oxide (EO), which are 
carcinogenic impurities resulting from their manufacture. Residual 
amounts of impurities are commonly found in chemical products, 
including food additives.

II. Determination of Safety

    Under the general safety standard section 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)).

III. Safety of Petitioned Use of the Additive

    FDA estimates that the petitioned use of SAHE will result in a 
maximum daily dietary exposure to each ester of approximately 0.8 part 
per million. This corresponds to an estimated daily intake (EDI) of 2.5 
milligrams per person per day (/p/d) of each ester (Ref. 1).
    The agency has reviewed the available toxicological data on the 
three sorbitol anhydride esters. Based on the available toxicology data 
for sorbitan monostearate and polysorbate 60 and the fact that their 
additional dietary exposure from the proposed use would be small 
compared to that from their currently regulated uses, the agency 
concludes that the estimated dietary exposure resulting from the 
petitioned use of these two esters is safe. The agency also finds that 
polysorbate 60 and polysorbate 20 would hydrolyze to similar breakdown 
products under the proposed conditions of use, the only difference 
being the chain length of the fatty acid residue (C12 for 
polysorbate 20 and C16 or C18 for polysorbate 
60). Based on the chemical similarities between polysorbate 60 and 
polysorbate 20, the agency concludes that the toxicology data for 
polysorbate 60 can be used to support the safety of polysorbate 20 
under their limited exposure anticipated from the petitioned use of 
SAHE. Moreover, based on the agency's review of the estimated dietary 
exposure from all three esters in SAHE, the agency concludes that the 
estimated small dietary exposure resulting from the proposed use of 
this additive is safe.
    Under the proposed conditions of use, any residual EO will 
quantitatively react with the boiler water to form ethylene glycol 
(Ref. 1). Thus, no EO will be present in the steam that contacts food. 
Consequently, the exposure to EO from the petitioned use of SAHE will 
be zero. Therefore, 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 DX, a carcinogenic chemical that may 
be present as an impurity in two of the components of the additive 
(polysorbate 20 and polysorbate 60). This risk evaluation of DX has two 
aspects: (1) Assessment of the exposure to the impurity 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. 1,4-Dioxane

    FDA has estimated the exposure to DX from the petitioned use of the 
additive as an anticorrosive agent in boilers where steam may contact 
food to be no more than 17 parts per trillion in the daily diet (3 
kilograms), or 50 nanograms (ng)/p/d (Ref. 1). The agency used data 
from a carcinogenesis bioassay on DX, conducted by the National Cancer 
Institute (Ref. 2), 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 DX demonstrated that 
the material was carcinogenic for female rats under the conditions of 
the study. The authors reported that the rodent bioassay showed that 
the test material caused a significantly increased incidence of

[[Page 29226]]

squamous cell carcinomas and hepatocellular tumors in female rats.
    Based on the agency's estimate that exposure to DX will not exceed 
50 ng/p/d, FDA estimates that the upper-bound limit of lifetime human 
risk from the petitioned use of the subject additive is 1.8 x 
10-9 or 1.8 in a billion (Ref. 3). Because of the numerous 
conservative assumptions used in calculating the exposure estimate, the 
actual lifetime-averaged individual exposure to DX 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 DX would result from 
the petitioned use of the additive.

B. Need for Specifications

    The agency has also considered whether specifications are necessary 
to control the amount of DX present as an impurity in SAHE. The agency 
finds that new specifications are not necessary for the following 
reasons: (1) Because of the low levels at which DX may be expected to 
remain as an impurity following production of SAHE, the agency would 
not expect the impurity to become a component of food at other than 
extremely low levels; and (2) the upper-bound limit of lifetime human 
risk from exposure to DX is very low, 1.8 in a billion.

IV. 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 as an anticorrosive agent in boilers where steam may 
contact food is safe, that the additive will achieve its intended 
technical effect, and therefore, that the regulations in Sec. 173.310 
should be amended as set forth below in this document.
    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 previously. 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 collections 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 on or before July 1, 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 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.

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, dated April 20, 1998, from the Division of 
Product Manufacture and Use (HFS-246) to the Division of Petition 
Control (HFS-215).
     2. ``Bioassay of 1,4-Dioxane for Possible Carcinogenicity,'' 
National Cancer Institute, NCI-CG-TR-80, 1978.
     3. Memorandum, dated June 19, 1998, from the Division of 
Petition Control (HFS-215) to Executive Secretary, Quantitative Risk 
Assessment Committee (QRAC) (HFS-308).

List of Subjects in 21 CFR Part 173

    Food additives, Incorporation by reference.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
173 is amended as follows:

PART 173--SECONDARY DIRECT FOOD ADDITIVES PERMITTED IN FOOD FOR 
HUMAN CONSUMPTION

    1. The authority citation for 21 CFR part 173 continues to read as 
follows:

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

    2. Section 173.310 is amended in the table in paragraph (c) by 
alphabetically adding an entry for ``sorbitol anhydride esters'' under 
the headings ``Substances'' and ``Limitations'' to read as follows:


Sec. 173.310  Boiler water additives.

* * * * *
    (c) * * *

[[Page 29227]]



 
----------------------------------------------------------------------------------------------------------------
                       Substances                                              Limitations
----------------------------------------------------------------------------------------------------------------
 
*                  *                  *                  *                  *                  *
                                                        *
Sorbitol anhydride esters: a mixture consisting of       The mixture is used as an anticorrosive agent in steam
 sorbitan monostearate as defined in Sec.  172.842 of     boiler distribution systems, with each component not
 this chapter; polysorbate 60 ((polyoxyethylene (20)      to exceed 15 parts per million in the steam.
 sorbitan monostearate)) as defined in Sec.  172.836 of
 this chapter; and polysorbate 20 ((polyoxyethylene
 (20) sorbitan monolaurate)), meeting the
 specifications of the Food Chemicals Codex, 4th ed.
 (1996), pp. 306-307, which is incorporated by
 reference in accordance with 5 U.S.C. 552(a) and 1 CFR
 part 51. Copies are available from the National
 Academy Press, 2101 Constitution Ave. NW., Box 285,
 Washington, DC 20055 (Internet http://www.nap.edu), or
 may be examined at the Center for Food Safety and
 Applied Nutrition's Library, Food and Drug
 Administration, 200 C St. SW., rm. 3321, Washington,
 DC, or at the Office of the Federal Register, 800
 North Capitol St. NW., suite 700, Washington, DC.
 
*                  *                  *                  *                  *                  *
                                                        *
----------------------------------------------------------------------------------------------------------------

* * * * *

    Dated: May 22, 1999.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 99-13670 Filed 5-28-99; 8:45 am]
BILLING CODE 4160-01-F