[Federal Register Volume 65, Number 29 (Friday, February 11, 2000)]
[Rules and Regulations]
[Pages 6889-6892]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-3195]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 175

[Docket No. 92F-0443]


Indirect Food Additives: Adhesives and Components of Coatings

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 1,2-dibromo-2,4-
dicyanobutane (DBDCB) and a mixture of 5-chloro-2-methyl-4-
isothiazolin-3-one (CMI) and 2-methyl-4-isothiazolin-3-one (MI), 
optionally containing magnesium nitrate, as antimicrobial agents in 
emulsion-based silicone coating formulations. This action responds to a 
petition filed by Dow Corning Corp.

DATES: This regulation is effective February 11, 2000. Submit written 
objections and requests for a hearing by March 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: Julius Smith, Center for Food Safety 
and Applied Nutrition (HFS-215), Food and Drug Administration, 200 C 
St. SW., Washington, DC 20204, 202-418-3091.

SUPPLEMENTARY INFORMATION: In a notice published in the Federal 
Register of February 12, 1993 (58 FR 8290), FDA announced that a 
petition (FAP 3B4346) had been filed by Dow Corning Corp., P.O. Box 
994, Midland, MI 48686-0994. The petition proposed to amend the food 
additive regulations in Sec. 175.300 Resinous and polymeric coatings 
(21 CFR 175.300), Sec. 175.320 Resinous and polymeric coatings for 
polyolefin films (21 CFR 175.320), and 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 dimethylpolysiloxane coatings produced 
by cross-linking a vinyl-containing dimethylpolysiloxane with 
methylhydrogen-containing polysiloxane and dimethylmethylhydrogen 
polysiloxane polymers using a platinum catalyst. It also proposed that 
the food additive regulations be amended to provide for the safe use of 
3,5-dimethyl-1-hexyne-3-ol, 1-ethynylcyclohexene, 
bis(methoxymethyl)ethyl maleate and methylvinyl cyclosiloxane as 
optional polymerization inhibitors. Additionally, the petition proposed 
that the regulations be amended to provide for the safe use of 5-
chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one 
mixture, optionally containing magnesium nitrate, as an antimicrobial 
agent for emulsion-based silicone coating formulations.
    However, subsequent to the filing of the petition, the petitioner 
requested that tetramethyltetravinylcyclotetrasiloxane be included in 
the petition. Therefore, in a notice published in the Federal Register 
of July 2, 1998 (63 FR 36246), FDA announced that it was amending the 
filing notice of February 12, 1993, to indicate that the petitioner was 
also proposing that the food additive regulations be amended to provide 
for the safe use of tetramethyltetravinylcyclotetrasiloxane as an 
optional polymerization inhibitor in the manufacture of 
dimethylpolysiloxane coatings produced by cross-linking a vinyl-
containing dimethylpolysiloxane with methylhydrogen-containing 
polysiloxane and dimethylmethylhydrogen polysiloxane polymers using a 
platinum catalyst.

[[Page 6890]]

    Also, subsequent to the filing of the petition, the petitioner 
requested that 1,2-dibromo-2,4-dicyanobutane be included in the 
petition. Therefore, in a notice published in the Federal Register of 
December 24, 1998 (63 FR 71294), FDA announced that it was amending the 
filing notice of July 2, 1998, to indicate that the petitioner was also 
proposing that the food additive regulations be amended to provide for 
the safe use of 1,2-dibromo-2,4-dicyanobutane as an antimicrobial agent 
in the manufacture of dimethylpolysiloxane coatings produced by cross-
linking a vinyl-containing dimethylpolysiloxane with methylhydrogen-
containing polysiloxane and dimethylmethylhydrogen polysiloxane 
polymers using a platinum catalyst.
    A partial response to the petition published in the Federal 
Register of December 23, 1998 (63 FR 71016). That document responded to 
the petitioner's request to amend the food additive regulations to 
provide for the safe use of dimethylpolysiloxane coatings produced by 
cross-linking a vinyl-containing dimethylpolysiloxane with 
methylhydrogen polysiloxane and dimethylmethylhydrogen polysiloxane 
using a platinum catalyst. In that document, FDA also amended the food 
additive regulations to provide for the safe use of 3,5-dimethyl-1-
hexyne-3-ol, 1-ethynylcyclohexene, bis(methoxymethyl)ethyl maleate, 
methylvinyl cyclosiloxane, and tetramethyltetravinylcyclotetrasiloxane 
as optional polymerization inhibitors.
    Also in the December 23, 1998, document, the agency stated that in 
1996, Congress enacted the Food Quality Protection Act (the FQPA). As a 
result of that law, antimicrobial formulations used in or on food 
contact articles became subject to regulation as pesticide chemicals by 
the U.S. Environmental Protection Agency (EPA). Thus, the petitioned 
antimicrobial use of 1,2-dibromo-2,4-dicyanobutane (DBDCB) and of 5-
chloro-2-methyl-4-isothiazolin-3-one (CMI) and 2-methyl-4-isothiazolin-
3-one (MI) mixture, optionally containing magnesium nitrate were, at 
that time, subject to regulation by EPA. Subsequently, Congress passed 
the Antimicrobial Regulation Technical Corrections Act of 1998 (the 
ARTCA) (Public Law 105-324) that returned some of the regulatory 
authority for regulating antimicrobials in or on food contact articles 
to FDA. As a result of ARTCA, these petitioned antimicrobial uses are 
once again subject to regulation by FDA under section 409 of the 
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 348) and are 
not subject to regulation as pesticide chemicals under section 408 of 
the act (21 U.S.C. 346a). Although these antimicrobial uses are 
regulated under section 409 of the act as food additives, nevertheless, 
the intended uses may be subject to regulation as pesticides under the 
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). Therefore, 
persons intending to market these food additives for such antimicrobial 
uses should contact the EPA to determine whether such uses require a 
pesticide registration under FIFRA.
    In this document, the agency is responding to the petitioner's 
request to amend the food additive regulations to provide for the safe 
use of: (1) DBDCB, and (2) a mixture of CMI and MI, optionally 
containing magnesium nitrate, as antimicrobial agents in emulsion-based 
silicone coating formulations.

I. Evaluation of the Additive DBDCB

    FDA has evaluated the data in the petition and other material 
relevant to the safety of DBDCB. The agency's conclusion on the safe 
use of DBDCB is contained in section III of this document.

II. Evaluation of the Mixture of CMI and MI

    In its evaluation of the safety of the mixture of CMI and MI, 
optionally containing magnesium nitrate, FDA has reviewed the safety of 
each component of the mixture and the chemical impurities that may be 
present in the mixture resulting from its manufacturing process. 
Although the components themselves have not been shown to cause cancer, 
the mixture of CMI and MI, optionally containing magnesium nitrate, has 
been found to contain residual amounts of dimethylnitrosamine (DMNA), a 
carcinogenic impurity resulting from the manufacture of the mixture. 
Residual amounts of reactants and manufacturing aids, such as DMNA, are 
commonly found as contaminants in chemical products, including food 
additives.

A. Determination of Safety

    Under the general safety standard of 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).

B. Safety of Petitioned Use of the Additive

    FDA estimates that the petitioned use of the CMI and MI mixture, 
optionally containing magnesium nitrate, as an antimicrobial agent in 
emulsion-based silicone coatings, will result in exposure to no greater 
than 0.2 parts per billion of the mixture in the daily diet (3 kilogram 
(kg)) or an estimated daily intake (EDI) of 600 nanograms per person 
per day (ng/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 mixture of CMI and MI and concludes 
that the estimated small dietary exposure resulting from the petitioned 
use of this mixture is safe.
    FDA has evaluated the safety of the CMI and MI mixture 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 DMNA, the carcinogenic chemical that may be 
present as an impurity in the mixture. The risk evaluation of DMNA has 
two aspects: (1) Assessment of exposure to the impurity from the 
petitioned use of the mixture, and (2) extrapolation of the risk 
observed in the animal bioassay to the conditions of exposure to 
humans.
1. Dimethylnitrosamine
    FDA has estimated the exposure to DMNA from the petitioned use of 
the mixture of CMI and MI, optionally containing magnesium nitrate, as 
an antimicrobial agent in emulsion-based silicone coating formulations, 
to be no more than 0.1 part per quintillion in the daily diet (3 kg), 
or 0.3 femtograms per

[[Page 6891]]

person per day (fg/p/d) (Ref. 1). The agency used data from a 
carcinogenesis bioassay on DMNA conducted by R. Peto et al. (Ref. 3), 
to estimate the upper-bound limit of lifetime human risk from exposure 
to this chemical resulting from the petitioned use of the mixture. The 
authors reported that DMNA was carcinogenic for male and female rats 
under the conditions of the study, causing liver tumors in the rats.
    Based on the agency's estimate that exposure to DMNA will not 
exceed 0.3 fg/p/d, FDA estimates that the upper-bound limit of lifetime 
human risk from the petitioned use of a mixture of CMI and MI, 
optionally containing magnesium nitrate, is 1  x  10-14 or 1 
in 100 trillion (Refs. 1 and 4). Because of the numerous conservative 
assumptions used in calculating the exposure estimate, the actual 
lifetime-averaged individual exposure to DMNA 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 DMNA would result 
from the petitioned use of the mixture of CMI and MI, optionally 
containing magnesium nitrate.
2. Need for Specifications
    The agency has also considered whether specifications are necessary 
to control the amount of DMNA present as an impurity in the mixture of 
CMI and MI. The agency finds that specifications are not necessary for 
the following reasons: (1) Because of the low level at which DMNA may 
be expected to remain as an impurity following production of the CMI 
and MI mixture, the agency would not expect this impurity to become a 
component of food at other than extremely low levels, and (2) the 
upper-bound limit of lifetime risk from exposure to this impurity from 
the petitioned use is very low, 1 in 100 trillion.

III. Conclusion on Safety

    FDA has evaluated the data in the petition and other relevant 
material. Based on this information, the agency concludes that: (1) The 
proposed uses of DBDCB, and of the mixture of CMI and MI, optionally 
containing magnesium nitrate, as antimicrobial agents in silicone 
coating formulations are safe, (2) each additive will achieve its 
intended technical effect, and therefore, that the regulations in 
Secs. 175.300 and 175.320 should be amended as set forth below.
    In the previous response to this petition (63 FR 71016, December 
23, 1998), the agency noted that the petition proposed to amend 
Sec. 176.170 to list the two antimicrobials; however, because the 
petitioned additives will be listed under Sec. 175.300(b)(3), by cross-
reference they may be used under Sec. 176.170(b)(1). Therefore, this 
action does not include an amendment that would establish a separate 
listing for the additives under Sec. 176.170(b)(1). (FDA inadvertently 
referred to Sec. 176.170(b)(2) in the earlier 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 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 action as announced in the amended notices of filing for FAP 
3B4346 published in the Federal Register of July 2, 1998 (63 FR 36246) 
and December 24, 1998 (63 FR 71294). 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 March 13, 2000 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.

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 dated March 10, 1999, from The Division of Product 
Manufacture and Use, Chemistry Review Team (HFS-246), to the 
Division of Petition Control (HFS-215) entitled ``FAP 3B4346 (MATS 
675, 2.8.1)--Dow Corning Corporation (DC). Request dated 2-10-99 
from Division of Petition Control (DPC) for an exposure estimate to 
nitrosamine impurities in 5-chloro-2-methyl-4-isothiazolin-3-one and 
2-methyl-4-isothiazolin-3-one.''
    2. Kokoski, C. J., ``Regulatory Food Additive Toxicology'' in 
Chemical Safety Regulation and Compliance, edited by F. Homburger, 
J. K. Marquis; published by S. Karger, New York, NY, pp. 24-33, 
1985.
    3. Peto, R. et al., ``Nitrosamine Carcinogenesis In 5120 
Rodents: Chronic Administration Of Sixteen Different Concentrations 
Of NDEA, NDMA, NPYR And NPIP In The Water of 4440 Inbred Rats, With 
Parallel Studies On NDEA Alone Of The Effect Of Age Of Starting (3, 
6 or 20 Weeks) And Of Species (Rats, Mice or Hamsters),'' IARC 
Science Publications, 57:627-665, 1984.
    4. Memorandum, dated March 25, 1999, from the Division of 
Petition Control (HFS-215), to Executive Secretary, Quantitative 
Risk Assessment Committee (QRAC), (HFS-308), entitled ``Estimation 
of upper-bound lifetime risk from dimethylnitrosamine, an impurity 
in 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-
isothiazolin-3-one, the subject of Food Additive Petition 3B4346 
(Dow Corning Corporation).''

List of Subjects in 21 CFR Part 175

    Adhesives, 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 
175 is amended as follows:

[[Page 6892]]

PART 175--INDIRECT FOOD ADDITIVES: ADHESIVES AND COMPONENTS OF 
COATINGS

    1. The authority citation for 21 CFR part 175 continues to read as 
follows:

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

    2. Section 175.300 is amended in paragraph (b)(3)(xxxiii), under 
the heading ``Miscellaneous materials'' by alphabetically adding two 
entries to read as follows:


Sec. 175.300  Resinous and polymeric coatings

* * * * *
    (b) * * *
    (3) * * *
    (xxxiii) * * *
    5-Chloro-2-methyl-4-isothiazolin-3-one (CAS Reg. No. 26172-55-4) 
and 2-methyl-4-isothiazolin-3-one (CAS Reg. No. 2628-20-4) mixture, at 
a ratio of 3 parts to 1 part, respectively, manufactured from methyl-3-
mercaptopropionate (CAS Reg. No. 2935-90-2) and optionally containing 
magnesium nitrate (CAS Reg. No. 10377-60-3) at a concentration 
equivalent to the isothiazolone active ingredients (weight/weight). For 
use only as an antimicrobial agent in emulsion-based silicone coatings 
at a level not to exceed 50 milligrams per kilogram (based on 
isothiazolone active ingredient) in the coating formulations.
* * * * *
    1,2-Dibromo-2,4-dicyanobutane (CAS Reg No. 35691-65-7). For use as 
an antimicrobial agent at levels not to exceed 500 milligrams per 
kilogram in emulsion-based silicone coatings.
* * * * *
    3. Section 175.320 is amended in the table in paragraph (b)(3) by 
alphabetically adding two entries in item (iii) under the headings 
``List of Substances'' and ``Limitations'' to read as follows:


Sec. 175.320  Resinous and polymeric coatings for polyolefin films.

* * * * *
    (b) * * *
    (3) * * *

 
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                   List of substances                                          Limitations
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(iii) * * *                                              .......................................................
5-Chloro-2-methyl-4-isothiazolin-3-one (CAS Reg. No.     For use only as an antimicrobial agent in emulsion-
 26172-55-4) and 2-methyl-4-isothiazolin-3-one (CAS       based silicone coatings at a level not to exceed 50
 Reg. No. 2628-20-4) mixture, at a ratio of 3 parts to    milligrams per kilogram (based on isothiazolone active
 1 part, respectively, manufactured from methyl-3-        ingredient) in the coating formulation.
 mercaptopropionate (CAS Reg. No. 2935-90-2) and
 optionally containing magnesium nitrate (CAS Reg. No.
 10377-60-3) at a concentration equivalent to the
 isothiazolone active ingredients (weight/weight).
1,2-Dibromo-2,4-dicyanobutane (CAS Reg. No. 35691-65-7)  For use as an antimicrobial agent at levels not to
                                                          exceed 500 milligrams per kilogram in emulsion-based
                                                          silicone coating.
*                  *                  *                  *                  *                  *
                                                         *
 
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    Dated: January 24, 2000.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-3195 Filed 2-10-00; 8:45 am]
BILLING CODE 4160-01-F