[Federal Register Volume 62, Number 24 (Wednesday, February 5, 1997)]
[Notices]
[Pages 5399-5403]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-2466]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-697; FRL-5584-4]
American Cyanamid Company; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
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SUMMARY: This notice announces the filing of a pesticide petition
proposing regulations establishing tolerances for residues of 4-bromo-
2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1-pyrrole-3-
carbonitrile, (chlorfenapyr) in or on cottonseed. This notice includes
a summary of the petition that was prepared by the petitioner, American
Cyanamid Company.
DATES: Comments, identified by the docket control number [PF-697], must
be received on or before March 7, 1997.
ADDRESSES: By mail, submit written comments to: Public Response and
Program Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In person, bring comments to: Crystal Mall #2,
Room 1132, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by sending
electronic mail (e-mail) to: [email protected] or by
submitting disks. Electronic comments must be submitted either in ASCII
format (avoiding the use of special characters and any form of
encryption) or in WordPerfect in 5.1 file format. All comments and data
in electronic form must be identified by the docket control number [PF-
697]. Electronic comments on this notice may be filed online at many
Federal Depository Libraries. The official record for this notice, as
well as the public version described above, will be kept in paper form.
Accordingly, EPA will transfer all comments received electronically
into printed, paper form as they are received and will place the paper
copies in the official record, which will also include all comments
submitted directly in writing.
Information submitted as comments concerning this notice may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). The CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Room 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: Dennis Edwards (PM 19), Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location, telephone number, and e-mail address: Crystal Mall #2, Room
207, 1921 Jefferson Davis Highway, Arlington, VA, 703-305-6386,
[[Page 5400]]
e-mail: [email protected].
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition from
American Cyanamid Company. The petition proposes, pursuant to section
408 of the Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C. 346a,
to amend 40 CFR part 180 to establish tolerances for the insecticide,
4-bromo-2-(4-chlorophenyl)-1(ethoxymethyl)-5-(trifluoromethyl)-1-
pyrrole-3-carbonitrile, (chlorfenapyr), in or on the raw agricultural
commodity cottonseed.
The proposed analytical method is capillary gas chromatography
using an electron capture detector.
As required by section 408(d) of the FFDCA, as recently amended by
the Food Quality Protection Act (FQPA) Pub. L. 104-170, American
Cyanamid Company included in the petition a summary of the petition and
authorization for the summary to be published in the Federal Register
in a notice of receipt of the petition. The summary represents the
views of American Cyanamid; EPA is in the process of evaluating the
petition. As required by section 408(d)(3) of the FFDCA, EPA is
including the summary as a part of this notice of filing. EPA may have
made minor edits to the summary for the purpose of clarity.
I. Petition Summary
The American Cyanamid Company has petitioned EPA, under pesticide
petition number PP-5F4456, for a permanent tolerance of 0.5 parts per
million (ppm) for the residues of chlorfenapyr in or on cottonseed. As
cottonseed processed commodities fed to food animals may be transferred
to milk and edible tissues, tolerances are also proposed for the
following ruminant food items:
Milk: 0.01 ppm
Milk fat: 0.15 ppm
Meat: 0.01 ppm
Meat by-products (including fat): 0.10 ppm
Section 408(b)(2)(A) of the amended FFDCA allows EPA to establish a
tolerance if it determines that the tolerance is ``safe, '' i.e.,
``there is a reasonable certainty that no harm will result from
aggregate exposure to the pesticide chemical residue, including all
anticipated dietary exposure, and all other exposures for which there
is reliable information.''
All of the studies required for the proposed use pattern have been
completed according to EPA requirements. American Cyanamid believes
that the available information indicates there is a reasonable
certainty that no harm will result from various types of exposure.
The following is a summary of the information on chlorfenapyr
submitted to the EPA which supports the establishment, under section
408(b)(2)(D) of the amended FFDCA, of the proposed tolerances in or on
cottonseed and in food items derived from ruminants exposed to
processed cottonseed commodities.
A. Residue Chemistry
1. Plant metabolism. American Cyanamid believes that the nature of
the residues of chlorfenapyr in plants is adequately understood and
that the residue of concern in cotton consists of the parent molecule.
Expressed on a whole seed basis, the parent compound accounted for 59-
68% of the total radioactive residue (TRR).
2. Analytical method. Section 408(b)(3) of the amended FFDCA
requires EPA to determine that there is a practical method for
detecting and measuring levels of the pesticide chemical residue in or
on food and that the tolerance be set at a level at or above the limit
of detection of the designated method. The gas chromatographic (GC)
analytical method, M2216.01, which is proposed as the enforcement
method for the residues of chlorfenapyr in cottonseed, has been
validated at the EPA laboratories in Beltsville, MD and has a limit of
detection (LOD) of 0.05 ppm and a limit of quantitation (LOQ) of 0.5
ppm.
3. Magnitude of residue. Extensive cotton field trials were
conducted over multiple growing seasons in all major cotton growing
regions of the U.S. Residues of chlorfenapyr were 0.32 ppm
and 0.31 ppm in/on cottonseed samples harvested 21 and 28
days, respectively following the last of 5 foliar broadcast
applications for a total of approximately 2x the proposed current
maximum seasonal application rate of 1.05 lbs active ingredient/acre/
season (ai/acre/season). These field trial data are adequate to support
the proposed tolerance of 0.5 ppm in/on cottonseed harvested 21 days
following the last application. Processing studies have also
demonstrated that there is no concentration of chlorfenapyr residues
apparent in crude or refined oils or in the meal and hull and no
tolerances are needed for these commodities.
B. Toxicological Profile
American Cyanamid has conducted a full battery of acute and chronic
toxicology studies to characterize any potential toxic effects of
chlorfenapyr. The data base is complete, valid, and reliable and all
meet EPA requirements. The following are important conclusions from
these studies:
1. Acute toxicity. Based on the EPA's toxicity category criteria,
the acute toxicity category for chlorfenapyr technical and the 3SC
formulation is Category II or moderately toxic (signal word WARNING)
and the acute toxicity category for the 2SC formulation is Category III
or slightly toxic (signal word CAUTION). Males appear to be more
sensitive to the effects of chlorfenapyr than females. The acute
toxicity profile indicates that absorption by the oral route appears to
be greater than by the dermal route. The following are the results from
the acute toxicity tests conducted on the technical material:
Rat oral LD50................... 441/1152 milligram/ Tox. Category II
kilogram of body
weight (mg/kg
b.w.)(M/F).
Rabbit dermal LD50.............. >2000 mg/kg b.w.(M/ Tox. Category III
F).
Acute inhaltion LC50............ 0.83/>2.7 mg/L (M/ Tox. Category III
F).
Eye irritation.................. Moderately Tox. Category III
irritating.
Dermal irritation............... Non-irritating.... Tox. Category IV
Dermal sensitization............ Non-sensitizer.... Non-sensitizer
Acute neurotoxicity............. NOEL 45 mg/kg b.w. Not an acute
neurotoxicant
2. Genotoxicity. Chlorfenapyr technical (94.5% active ingredient
(ai)) was examined in a battery of in vitro and in vivo tests to assess
its genotoxicity and its potential for carcinogenicity.
[[Page 5401]]
These tests are summarized below:
Microbial/Microsome Mutagenicity Assay.... Non-mutagenic
Mammalian Cell CHO/HGPRT Mutagenicity Non-mutagenic
Assay.
In Vivo Micronucleus Assay................ Non-genotoxic
In Vitro Chromosome Aberration Assay in Non-clastogenic
CHO.
In Vitro Chromosome Aberration Assay in Non-clastogenic
CHLC.
Unscheduled DNA Synthesis (UDS) Assay..... Non-genotoxic
3. Reproductive and developmental toxicity. Chlorfenapyr is neither
a reproductive or developmental toxicant and is not a teratogenic agent
in the Sprague-Dawley rat or the New Zealand white rabbit. This is
demonstrated by the results of the following studies:
Rat oral teratology.................. NOEL for maternal toxicity 25 mg/
kg b.w./day
NOEL for fetal/developmental
toxicity 225 mg/kgb.w./day
Rabbit oral teratology............... NOEL for maternal toxicity 5 mg/
kg b.w./day
NOEL for fetal/developmental
toxicity 30 mg/kg b.w./day
Rat two-generation reproduction...... NOEL for parental toxicity/growth
and offspring development 60 ppm
(5mg/kg b.w./day)
NOEL for reproductive performance
600 ppm (44 mg/kg b.w./day)
4. Subchronic toxicity. The following are the results of the
subchronic toxicity tests that have been conducted with chlorfenapyr:
28-Day rabbit dermal................. NOEL 100 mg/kg b.w./day
28-Day rat feeding................... NOEL <600 ppm (<71.6 mg/kg b.w./
day)
28-Day mouse feeding................. NOEL <160 ppm (<32 mg/kg b.w./
day)
13-Week rat dietary.................. No observed adverse effects level
(NOAEL) 150 ppm (11.7 mg/kg b.w./
day)
13-Week mouse dietary................ NOEL 40 ppm (8.2 mg/kg b.w./day)
13-Week dog dietary.................. NOAEL 120 ppm (4.2 mg/kg b.w./
day)
5. Chronic toxicity. Chlorfenapyr is not oncogenic in either
Sprague-Dawley rats or CD-1 mice and is not likely to be carcinogenic
in humans. The following are the results of the chronic toxicity tests
that have been conducted with chlorfenapyr:
1-Year neurotoxicity in rats......... NOEL 60 ppm (2.6/3.4 mg/kg b.w./
day M/F)
1-Year dog dietary................... NOEL 120 ppm (4.0/4.5 mg/kg b.w./
day M/F)
24-Month rat dietary................. NOEL for chronic effects 60 ppm
(2.9/3.6 mg/kg b.w./day M/F)
NOEL for oncogenic effects 600
ppm (31/37 mg/kg b.w./day M/F)
18-Month mouse dietary............... NOEL for chronic effects 20 ppm
(2.8/3.7 mg/kg b.w./day M/F)
NOEL for oncogenic effects 240
ppm (34.5/44.5 mg/kg b.w./day M/
F)
6. Endocrine effects. Collective organ weights and
histopathological findings from the two-generation rat reproduction
study, as well as from the subchronic and chronic toxicity studies in
two or more animal species, demonstrate no apparent estrogenic effects
or effects on the endocrine system. There is no information available
which suggests that chlorfenapyr would be associated with endocrine
effects.
7. Animal metabolism. A metabolism study was conducted in Sprague-
Dawley rats at approximately 20 and 200 mg/kg b.w. using radiolabeled
chlorfenapyr. Approximately 65% of the administered dose was eliminated
during the first 24 hours (62% in feces and 3% in urine) and by 48
hours following dosing, approximately 85% of the dose had been excreted
(80% in feces and 5% in urine). The absorbed chlorfenapyr-related
residues were distributed throughout the body and detected in tissues
and organs of all treatment groups. The principal route of elimination
was via feces, mainly as unchanged parent plus minor N-dealkylated,
debrominated, and hydroxylated oxidation products.
The metabolic pathway of chlorfenapyr in the laying hen and the
lactating goat was also similar to that in laboratory rats.
8. Metabolite toxicology. The parent molecule is the only moiety of
toxicological significance which needs
[[Page 5402]]
regulation in plant and animal commodities.
C. Aggregate Exposure
1. Dietary exposure--i. Food. The potential dietary exposure has
been calculated from the tolerance of chlorfenapyr in/on cottonseed at
0.5 ppm. This exposure assessment is based on very conservative
assumptions, namely 100% of all cotton is treated with chlorfenapyr and
that the residues of chlorfenapyr in cottonseed are at the tolerance
level. As there are no other established U.S. permanent tolerances for
chlorfenapyr, the only dietary exposure to residues of chlorfenapyr in
or on food will be limited to residues in cottonseed meal and food and
feed items derived from cottonseed. As cottonseed meal is a dairy and
beef cattle feed item, a cold feeding study with dairy cattle was
conducted. Since this study demonstrated that measurable residues of
chlorfenapyr may occur in milk, meat, and meat by products, appropriate
residue tolerances for these items are proposed. The contribution of
all these tolerances to the daily consumption uses less than 1% (actual
0.62%) of the reference dose (RfD) for the overall U.S. population and
less than 2% (actual 1.8%) and less than 1% (actual 0.81%) of the RfDs
for children aged 1-6 and for non-nursing infants, respectively.
ii. Drinking water. There is no available information about
chlorfenapyr exposures via levels in drinking water. There is no
concern for exposure to residues of chlorfenapyr in drinking water
because of its extremely low-water solubility (120 parts per billion
(ppb) at 25 deg. C). Chlorfenapyr is also immobile in soil and does not
leach because it is strongly absorbed in all common soil types. In
addition, the label explicitly prohibits applications near aquatic
areas. American Cyanamid believes that there is a reasonable certainty
that no harm will result from dietary exposure to chlorfenapyr, because
dietary exposure to residues on food will use only a small fraction of
the RfD (including exposure of sensitive subpopulations), and exposure
through drinking water is expected to be insignificant.
2. Non-dietary exposure. There is no available information
quantifying non-dietary exposure to chlorfenapyr. However, based on the
physico-chemical characteristics of the compound, the proposed use
pattern and available information concerning its environmental fate,
non-dietary exposure is expected to be negligible. The vapor pressure
of chlorfenapyr is less than 1 x 10-7millimeters (mm) of mercury
(Hg); therefore, the potential for non-occupational exposure by
inhalation is insignificant. Moreover, the current proposed
registration is for outdoor, terrestrial uses which severely limit the
potential for non-occupational exposure.
D. Cumulative Effects
The pyrrole insecticides represent a new class of chemistry with a
unique mechanism of action. The parent molecule, AC303,630 is a pro-
insecticide which is converted to the active form, CL303,268, via rapid
metabolism by mixed function oxidases (MFOs). The active form uncouples
oxidative phosphorylation in the insect mitochondria by disrupting the
proton gradient across the mitochondrial membrane. The production of
adenosine triphosphate (ATP) is inhibited resulting in the cessation of
all cellular functions. Because of this unique mechanism of action,
American Cyanamid believes that it is highly unlikely that toxic
effects produced by chlorfenapyr would be cumulative with those of any
other pesticide chemical.
In mammals, there is a lower titer of MFOs, and chlorfenapyr is
metabolized by different pathways (including dehalogenation, oxidation,
and ring hydroxylation) to other polar metabolites without any
significant accumulation of the potent uncoupler, CL303,268. In the
rat, approximately 85% of the administered dose is excreted in the
feces within 48 hours, thereby reducing the levels of AC303,630 and
CL303,268 that are capable of reaching the mitochondria. This
differential metabolism of AC303,630 to CL303,268 in insects, versus to
other polar metabolites in mammals, is responsible for the selective
insect toxicity of the pyrroles.
E. Safety Determination
1. U. S. population. The RfD of 0.03 mg/kg b.w./day for the
residues of chlorfenapyr in cotton is calculated by applying a 100-fold
safety factor to the overall no observed effect level (NOEL) of 3 mg/kg
b.w./day. This NOEL is based on the results of the chronic feeding
studies in the rat and mouse and the two-generation reproduction study
in the rat (see Unit I.E.2. of this document). Therefore, the combined
exposure for the proposed chlorfenapyr tolerances in cottonseed, milk,
and meat (0.0001866 mg/kg b.w./day) will utilize approximately 0.62% of
the RfD for the general U.S. population.
2. Infants and children. The theoretical maximum residue
contribution (TMRC) in milk consumed by a non-nursing infant (<1 year
of age) is 0.0002435 mg/kg b.w./day. This will use less than 1% (actual
0.81%) of the RfD for non-nursing infants. The TMRC in milk consumed by
a child (1-6 years of age) is 0.0003886 mg/kg b.w./day. The combined
TMRC for the proposed chlorfenapyr tolerances in meat and milk consumed
by a child 1-6 years of age is 0.0005415 mg/kg b.w./day, which is less
than 2% (actual 1.8%) of the RfD. Therefore, American Cyanamid believes
that the results of the toxicology and metabolism studies support both
the safety of chlorfenapyr to humans based on the intended use as an
insecticide-miticide on cotton and the granting of the requested
tolerances in cottonseed, milk, milk fat solids, meat, and meat by-
products.
Based on the conservative assumptions used in proposing the above
tolerances and the absence of other non-dietary routes of exposure to
chlorfenapyr, and since the calculated exposures are well below 100% of
the RfD, American Cyanamid believes that there is a reasonable
certainty that no harm will result from aggregate exposure to residues
of chlorfenapyr, including all anticipated dietary exposure and all
other non-occupational exposures. American Cyanamid believes that the
use of a 100-fold safety factor ensures an acceptable margin of safety
for both the overall U. S. population as well as infants and children.
American Cyanamid concludes that the toxicology data base
(reproduction/developmental and teratology studies) is complete, valid,
and reliable, and therefore no additional safety factor is needed.
The 100-fold margin of safety is adequate to assure a reasonable
certainty of no harm to infants and children from the proposed use. As
stated earlier, the NOEL is based on the effects observed in the rat
and mouse chronic oncogenicity studies, (reduced body weight gains,
increased globulin and cholesterol values, and increased liver weights
in the rat and reduced body weight gains and vacuolation of white
matter of the mouse brain), the 1-year neurotoxicity study in the rat,
(reduced body weight gains and vacuolar myelinopathy of the brain and
spinal cord that is completely reversible following termination of
treatment and is not associated with any damage to neuronal cell bodies
or axons; vacuolation of the white matter is a consequence of edema
(water) formation between the myelin layers which result from the
unrestricted movement of ions across the cell membranes) and the two-
generation rat reproduction study, (reduced body weight gains for
parental animals and reduced pup body weights for the F1 and
F2 litters; however no
[[Page 5403]]
behavioral changes were observed in either F1 or F2
offsprings in the two-generation reproduction study). Moreover, as the
NOELs for fetal/developmental toxicity are significantly higher than
those for maternal toxicity, the results indicate that chlorfenapyr is
neither a developmental toxicant nor a teratogenic agent in either the
Sprague-Dawley rat or New Zealand white rabbit. Thus, there is no
reliable information to indicate that there would be a variability in
the sensitivities of infants and children and adults to the effects of
exposure to chlorfenapyr.
Therefore, a chronic dietary exposure analysis for the residues of
chlorfenapyr in cotton, meat, and milk, using the ``worst case''
proposed tolerance-level residues, demonstrates that these levels are
well below the RfD of 0.03 mg/kg b.w./day and thus the proposed use of
chlorfenapyr is toxicologically supported.
F. International Tolerances
Section 408(b)(4) of the amended FFDCA requires EPA to determine
whether a maximum residue level has been established for the pesticide
chemical by the Codex Alimentarius Commission.
There is neither a Codex proposal, nor Canadian or Mexican
tolerances/limits for residues of chlorfenapyr in/on cottonseed.
Therefore, a compatibility issue is not relevant to the proposed
tolerance.
II. Public Record
EPA invites interested persons to submit comments on this notice of
filing. Comments must bear a notification indicating the docket control
number [PF-697]. All written comments filed in response to this
petition will be available, in the Public Response and Program
Resources Branch, at the address given above from 8:30 a.m. to 4 p.m.,
Monday through Friday, except legal holidays.
A record has been established for this notice under docket control
numbers [PF-697] (including comments and data submitted electronically
as described below). A public version of this record, including
printed, paper versions of electronic comments, which does not include
any information claimed as CBI, is available for inspection from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
public record is located in Room 1132 of the Public Response and
Program Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, Crystal Mall #2,
1921 Jefferson Davis Highway, Arlington, VA.
Electronic comments can be sent directly to EPA at:
[email protected]
Electronic comments must be submitted as ASCII file avoiding the
use of special characters and any form of encryption. The official
record for this notice, as well as the public version, as described
above will be kept in paper form. Accordingly, EPA will transfer all
comments received electronically into printed, paper form as they are
received and will place the paper copies in the official record which
will also include all comments submitted directly in writing.
The official record is the paper record maintained at the address
in ``ADDRESSES'' at the beginning of this notice.
List of Subjects
Environmental protection, Agricultural commodities, Pesticides and
pests, Reporting and recordkeeping.
Dated: January 24, 1997.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
[FR Doc. 97-2466 Filed 2-4-97; 8:45 am]
BILLING CODE 6560-50-F