United States
Environmental Protection
Agency
Prevention, Pesticides
And Toxic Substances
(7505C)
EPA-730-F-00-001
January, 2001
Description of
the Chemical
Pesticide Fact Sheet
Chlorfenapyr
Reason for Issuance: New Chemical Registration
Date Issued: January, 2001
Chemical Name: 4-bromo-2-(4-chlorophenyl)-l-(ethoxymethyl)-5-
(trifluoromethyl)-lH-pyrrole-3-carbonitrile
Chemical Class: Pyrroles (new)
Common Name: Chlorfenapyr, AC 303,630
Trade Name: Pylon Miticide-Insecticide
EPA Chemical Code (OPP Chemical Code): 129093
Chemical Abstracts Service (CAS) Number: 122453-73-0
Year of Initial Registration: January, 2001
Pesticide Type: Insecticide, Miticide
Manufacturer: BASF Corporation
P.O. Box 400
Princeton, NJ 08543-0400
Use Patterns Application Sites:
and Formulations
Types of Formulation:
Target Pest:
Use Patterns:
Ornamental Crops in Commercial Greenhouses, non-
food use
For manufacturing use; and as a foliar spray to
ornamental crops in greenhouses
For greenhouse ornamentals: mites, caterpillar pests,
thrips, and fungus gnats
Foliar spray on ornamental crops grown in
greenhouses
Science Findings Summary Statement:
Chlorfenapyr is a member of a new class of chemicals — the pyrroles. The
compound is a pro-insecticide, i.e. the biological activity depends on its activation to
another chemical. Oxidative removal of the N-ethoxymethyl group of Chlorfenapyr
by mixed function oxidases forms the compound CL 303268. CL 303268
uncouples oxidative phosphorylation at the mitochondria, resulting in disruption of
production of ATP, cellular death, and ultimately organism mortality.
Chlorfenapyr has not been previously registered in the United States. However, it
has been used on cotton (under the trade name Pirate) under Sec. 18 of the Federal
Insecticide Fungicide and Rodenticide Act (FIFRA).
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The use on ornamental crops grown in greenhouses is a non-food use so there will
be no dietary exposure. Since there are no residential uses of chlorfenapyr, no
chronic residential exposure is anticipated.
EPA has completed a review of the lexicological data submitted for this chemical.
There are no data gaps for this use pattern.
EPA has determined, for occupational exposure to chlorfenapyr, that an MOE
below 100 would be of concern to the Agency. For the commercial greenhouse use
on ornamentals, the MOEs for occupational exposure ranged from 100 for long-
term post-application activities to 2200 for short-intermediate dermal exposure for
mixer/loader/applicators. The long-term MOE for mixer/loader/applicators was
calculated to be 580. Thus no MOE exceeded levels of concern. Further, the
MOE of 100, calculated for a post-application irrigation scenario, is likely to
overestimate exposure for the following reasons: the estimates of potential exposure
do not take into account resistance management practices specified on the label
(such as no more than 2-3 consecutive applications); and these estimates assumed
an 8 hour work day, which is likely an overestimate for irrigation activities.
The Agency has previously considered and decided not to register outdoor use on
cotton because of persistence and concern about bird reproductive effects.
However, unlike outdoor uses, the greenhouse use is not expected to result in
outdoor residues, drift or runoff. Thus, the Agency expects no wildlife exposure and
or other significant environmental exposure or risk.
Chemical Technical Grade.
Characteristics physical: powdered solid
Color: light tan or light yellow
Odor: characteristic of halides and ketones
Melting Point: melting point 100-101 • C
pH: 7.16; 1% aqueous slurry at 24 • C
Density: 0.543 g/ml tapped bulk density
Empirical Formula: C^HnBrClFgNjO, mw 407.6
Vapor Pressure: <1.0 x 10-7 mm hg at 25 • C
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Solubility: Solvent Solubility at 25* C
deionized water 0.12 mg/ml
water, pH 4 0.13 mg/1
water, pH 7 0.14 mg/1
water, pH 10 0.12 mg/1
hexane 0.89 g/100 ml
methanol 7.09 g/100 ml
acetonitrile 68.4 g/100 ml
toluene 75.4 g/100 ml
acetone 114 g/100 ml
dichloromethane 141 g/100 ml
Dissociation Constant since there are no ionizable groups in the chlorfenapyr
structure, no dissociation will occur
Octanol/Water Partition
Coefficient Kow = 67,670 (log Kow = 4.83) at 25 • C
Pylon Miticide-Insecticide (21.4% chlorfenapyr)
Physical State liquid
pH: 7.1
Oxidation/reduction
incompatibility oxidizer
Explodability not explosive
Corrosion characteristics non-corrosive
Density/relative density
bulk density 1.11 g/cc
Human Health 1. TOXICOLOGY CHARACTERISTICS
Assessment Acute Toxicity:
1. Technical. The technical is categorized as Tox Category n based on the
results of an acute oral test with the rat. The signal word is danger. Note that both a
rat and a mouse study are available for the acute oral studies with the technical. EPA
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has determined that when both are available, the rat studies are routinely used to
compare relative toxicity across different labels for a given chemical.
Guideline
No.
81-1
81-1
81-2
81-3
81-4
81-5
81-6
Study type
Acute Oral(LD50)
Acute Oral(LD50)
Acute Dermal (LD50)
Acute Inhalation (LC50)
Primary Eye Irritation
Primary Skin Irritation
Dermal Sensitization
lesults
lat: 441 mg/kg, males
1152 mg/kg, females
626 mg/kg, combined
Mouse: 45 mg/kg, males
78 mg/kg, females
55 mg/kg, combined
Rabbit: > 2000 mg/kg
rat: 0.83 mg/1, males
> 2.7 mg/1, females
1.9 mg/1, combined
rabbit: Corneal opacity, iritis,
and conjunctivitis present at 48
lours. At 72 hours iritis was
resolved. All rabbits were
normal by Day-7.
rabbit: non-irritating
Tox
Category
II
I
m
m
m
IV
guinea pig: non-sensitizer
2. Formulated Product (Pylon Miticide-Insecticide). The formulated
product is Tox Category HI based on the oral, dermal, and inhalation study results.
The signal word is Caution.
Guideline
No.
81-1
81-2
Study type
Acute Oral
Toxicity in Rats
Acute Dermal
Toxicity in
Rabbits
Results
Acceptable. LD50 = 560 mg/kg,
males, 567 mg/kg, females
Acceptable. LD50 > 2000 mg/kg,
males and females
m
m
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Guideline
No.
81-3
81-4
81-5
81-6
Study type
Acute
Inhalation
Toxicity in Rats
Primary Eye
Irritation in
Rabbits
Primary Dermal
Irritation in
Rabbits
Dermal
Sensitization in
Guinea Pig
Results
Waived. Data requirements satisfied
by AC 303,630 3SC Formulation
(32% a.L).
Acceptable. Slight-to-moderate
redness of conjunctivae, and slight
ocular discharge were present at 1
hour. All signs of irritation had
resolved by 24 hours. It was
considered practically non-irritating.
Acceptable. Slight erythema was
observed at 1 hour and persisted in
1 rabbit at 24 hours. All signs of
irritation had resolved by 48 hours.
Waived. Data requirements satisfied
by Chlorfenapyr tech. and AC
303,630 3SC Formulation (32%
Tox
Category
m
IV
IV
Not a
sensitizer
Subchronic Toxicity
i. Subchronic Oral Toxicity in Rats. Rats were fed chlorfenapyr in feed at
doses of 0, 150, 300, 600, 900 or 1200 ppm (0, 11.7, 24.1, 48.4, 72.5 or 97.5
mg/kg/day, respectively) for 90 days. The NOAEL (the no observed adverse effects
level) is 300 ppm (24.1 mg/kg/day). The lowest observed adverse effect level
(LOAEL) is 600 ppm (48.4 mg/kg/day) based on the following effects: males had a
decreased body weight gain and increased relative liver weights, while females
exhibited decreased hemoglobin (HGB) and increased absolute/relative liver weights.
More severe effects occurred at higher doses.
ii. Subchronic Oral Toxicity in Mice. Mice were administered
chlorfenapyr at dietary dose levels of 0, 40, 80, 160, or 320 ppm (average 0, 7.1,
14.8, 27.6, or 62.6 mg/kg/day, respectively, for males; 0, 9.2, 19.3, 40.0, or 78.0
mg/kg/day, respectively, for females) for 91 days. The NOAEL is 7.1 mg/kg/day
(40 ppm). The LOAEL is 14.8 mg/kg/day (80 ppm) for male mice and 40.0
mg/kg/day (160 ppm) for female mice, based on hepatic cell hypertrophy in • 20%
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of the test animals at this treatment level. More severe effects occurred at higher
doses.
iii. Subchronic Oral Toxicity in Dogs. Chlorfenapyr was administered to
dogs for 13 weeks at doses of 0, 60, 120 or 247 ppm (0, 2.16, 4.23 or 6.1
mg/kg/day, respectively). The LOAEL is 6.1 mg/kg/day (247 ppm), based on
reduced body weight gain and feed efficiency and emaciation. The NOAEL is 4.23
mg/kg/day (120 ppm).
iv. Twenty-eight Day Dermal Toxicity Study in Rabbits Chlorfenapyr
was applied to the shaved skin of rabbits at dose levels of 0, 100, 400, or 1000
mg/kg for 6 hours/day 5 days/week for 4 weeks. The NOAEL is 100 mg/kg. The
LOAEL is 400 mg/kg for both sexes, based on changes in liver chemistry and
morphology (structure and form). More severe effects were observed at higher
doses.
Chronic Toxicity/Carcinogenicity
i. Chronic Oral Toxicity Dogs. Chlorfenapyr was administered to dogs in
the diet at dose levels of 0, 60, 120, or 240 ppm (0, 2.1, 4.0, or 8.7 mg/kg/day,
respectively, for males; 0, 2.3, 4.5, or 10.1 mg/kg/day, respectively, for females) for
52 weeks. The LOAEL is 8.7 mg/kg/day (240 ppm), based on decreased body
weights and body weight gains. The NOAEL is 4.0 mg/kg/day (120 ppm). No
treatment-related effects were observed on the survival, clinical signs,
ophthalmology, hematology, clinical chemistry or urinalysis parameters, organ
weights or gross and microscopic pathology at any dose level.
ii. Chronic Toxicity/Carcinogenicity Study in Rats. Chlorfenapyr
technical was administered to rats in the diet at dose levels of 0, 60, 300, or
600 ppm (0, 2.9, 15.0, or 30.8 mg/kg/day, respectively in males; 0, 3.6, 18.6, or
37.0 mg/kg/day, respectively in females) for 104 weeks. The NOAEL is 2.9 and 3.6
mg/kg/day for males and females, respectively (60 ppm). The LOAEL for systemic
toxicity is 15.0 and 18.6 mg/kg/day for males and females, respectively (300 ppm)
based on liver toxicity. More severe effects were observed at higher doses.
iii. Chronic Toxicity/Carcinogenicity Study in Mice. Chlorfenapyr was
administered to mice in the diet at dose levels of 0, 20, 120, or 240 ppm (0, 2.8,
16.6, or 34.5 mg/kg/day, respectively, in males; 0, 3.7, 21.9, or 44.5 mg/kg/day,
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respectively, in females) for 80 weeks. The NOAEL is 2.8 and 3.7 mg/kg/day for
males and females, respectively (20 ppm). The LOAEL for systemic toxicity is 16.6
and 21.9 mg/kg/day in males and females, respectively (120 ppm) based on
decreased body weight gains, brain toxicity and scabbing of the skin (males). More
severe effects occurred at higher doses.
Developmental Toxicity
i. Developmental Toxicity in Rats. Chlorfenapyr was administered to
pregnant rats by oral gavage at dose levels of 0, 25, 75 or 225 mg/kg/day from days
6 through 16 of gestation. The NOAEL for maternal systemic toxicity is 25
mg/kg/day. The LOAEL for maternal systemic toxicity is 75 mg/kg/day, based on
reduced body weight gain, reduced relative feed intake and reduced water
consumption. Developmental toxicity was not observed either in the form of maternal
cesarean section observations or fetal external, visceral or skeletal malformations and
variations. Therefore, the LOAEL for developmental (pup) toxicity is greater than
225 mg/kg/day and the NOAEL is greater than or equal to 225 mg/kg/day (highest
dose tested).
ii. Developmental Toxicity Study in Rabbits Pregnant rabbits received
0, 5, 15 or 30 mg/kg/day chlorfenapyr by oral gavage from gestation days 7 to 19.
The LOAEL for maternal systemic toxicity is 15 mg/kg/day, based upon reduced
body weight gain during treatment. The NOAEL for maternal systemic toxicity is 5
mg/kg/day. There was no evidence of developmental toxicity at any dose. The
NOAEL for developmental (pup) toxicity is greater than 30 mg/kg/day (highest dose
tested).
Reproductive Toxicity
Two generation rat reproduction study. Chlorfenapyr was administered
continuously in the diet to rats at concentrations of 0, 60, 300, or 600 ppm (0, 5, 22,
or 44 mg/kg/day, for two successive generations (1 litter/generation). The LOAEL
for parental toxicity was 22 mg/kg/day (300 ppm), based on pre-mating effects on
parental weight gain. The parental NOAEL was 5 mg/kg/day (60 ppm). The
LOAEL for reproductive toxicity was 22 mg/kg/day (300 ppm), based on
decreased lactational weight gains. The reproductive NOAEL was 5 mg/kg/day (60
ppm).
Mutagenicity
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The available mutagenicity studies clearly indicate that chlorfenapyr is neither
mutagenic in bacterial or mammalian cells nor clastogenic in cultured mammalian cells
in vitro or in male and female mice in vivo. There was also no evidence of
genotoxicity in primary rat hepatocytes. The studies are summarized in the following
table.
Study
Results
Gene Mutation-
Ames
Negative for reverse mutation in S. typhimurium and E.
coli exposed up to cytotoxicity (50 jig/plate, +/- S9)
Chinese hamster
ovary (CHO) cell
HGPRT gene
mutation
Independently performed tests were negative up to a
cytotoxic and precipitating concentration (500 |ig/mL) in
the presence of S9 activation or the solubility limit (250
|ig/mL) without S9 activation.
In vivo
micronucleus assay
The test was negative in mice administered single oral
gavage doses of 7.5-30 mg/kg (males) or 5-20 mg/kg
(females). Clinical toxicity (deaths in males and diarrhea
in females) was seen at the highest dose tested. There
was, however, no evidence of cytotoxicity for the target
organ.
In vitro CHO cell
chromosome
aberration assay
The test was negative up to 100 |ig/mL -S9 or 25 |ig/mL
+S9; higher doses with or without S9 activation were
cytotoxic.
In vitro Chinese
hamster lung
(CHL) fibroblasts
chromosome
aberration assay
The test was negative up to a precipitating level without
S9 activation (225 |ig/mL) or a concentration range of
3.5-14.1 |ig/mL +S9. Higher S9-activated doses (• 28
|ig/mL) were cytotoxic.
Repair in vitro
(UDS)
Negative for inducing unscheduled DNA synthesis in
primary rat hepatocyte cultures exposed up to severely
toxic concentrations (• 30 |ig/mL).
Metabolism
Radioactive chlorfenapyr was administered to rats by oral gavage at dose levels of
20 mg/kg/day as a single dose or following a 14-day pre-treatment with non-
radioactive chlorfenapyr, or at 200 mg/kg as a single dose. Based on the metabolites
identified, the major deposition route of orally administered chlorfenapyr is fecal
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excretion of unaltered parent compound. The two rings of the molecule are not
cleaved. Metabolites are excreted primarily in urine; accumulation in tissues is
minimal.
Neurotoxicity
i. Acute Neurotoxicity Study in Rats. Chlorfenapyr was administered
once, via gastric intubation to rats at dose levels of 0, 45, 90, or 180 mg/kg. All
rats were observed for 2 weeks following dosing. The rats were evaluated for
reactions in functional observational battery and motor activity measurements. In
addition, five rats per group were examined for neuropathologic lesions. No dose-
related effects on body weights, food consumption, neurobehavioral observations, or
gross or histological post mortem examinations were noted. The LOAEL is 90
mg/kg, based on lethargy of the rats on the day of treatment. The NOAEL is 45
mg/kg.
ii. One-Year Dietary Neurotoxicity Study in Rats Chlorfenapyr was
administered in the diet at 0, 60, 300, or 600 ppm (52-week average 0, 2.6, 13.6,
or 28.2 mg/kg/day respectively, for males; 0, 3.4, 18.0, or 37.4 mg/kg/day
respectively, for females) to rats for 52 weeks, followed by a 16-week recovery
period. The LOAEL is 13.6 mg/kg/day (300 ppm) based on the presence of
myelinopathic alterations in the 300 ppm group male rats, decreased average body
weights, body weight gains, feed efficiency, absolute feed consumption (females) and
water consumption (males). The NOAEL is 2.6 mg/kg/day (60 ppm).
Dermal Absorption
A dermal absorption study was not available. Therefore, a dermal absorption value
of 5% has been calculated using the maternal NOAEL of 5 mg/kg/day from the oral
developmental toxicity study in rabbits and the systemic NOAEL of 100 mg/kg/day
from the 28-day dermal toxicity study in rabbits.
2. OCCUPATIONAL EXPOSURE AND RISK ASSESSMENT
a. Toxicological Endpoints for Chlorfenapyr
Summary of Toxicological Endpoints for Chlorfenapyr
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Exposure
Duration
Exposure
Route
Endpoint and lexicological Effect
Short-Term
(1-7 days)
Occupational
Dermal
NOAEL: 100 mg/kg/day
(increased cholesterol, relative liver
weights and cytoplasmic vacuolation of the
liver in male and females in a 28-day
dermal toxicity study in rabbits).
Intermediate-
Term (one
week to
several
months)
Occupational
Dermal
NOAEL: 100 mg/kg/day
(increased cholesterol, relative liver
weights and cytoplasmic vacuolation of the
liver in male and females in a 28-day
dermal toxicity study in rabbits).
Chronic-Term
(greater than
several
months)
Occupational
Dermal
NOAEL: 2.6 mg/kg/day
(decreased body weight gains, brain
lesions (vacuolation), and/or scabbing of
the skin in a 1 year neurotoxicity study in
rats and a chronic/carcinogenicity study in
mice). Use a dermal absorption factor of
5% since the NOAEL is from an oral
study.
Short-Term
Occupational
Inhalation
NOAEL: 4.2 mg/kg/day
(reduced body weight gain and feed
efficiency and emaciation in a subchronic
oral study in dogs). Use the inhalation
absorption factor of 100% since the
NOAEL is from an oral study.
Intermediate
Term
Occupational
Inhalation
NOAEL: 4.2 mg/kg/day
(reduced body weight gain and feed
efficiency and emaciation in a sub-chronic
oral study in dogs).Use the inhalation
absorption factor of 100% since the
NOAEL is from an oral study
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Exposure
Duration
Exposure
Route
Endpoint and lexicological Effect
Long-Term
Occupational
Inhalation
NOAEL: 2.6 mg/kg/day
(decreased body weight gains, brain
lesions (vacuolation) and /or scabbing of
the skin in a one year neurotoxicity study
in rats and a chronic/carcinogenicity study
in mice). Use the inhalation absorption
factor of 100% since the NOAEL is from
an oral study.
Cancer
Dermal/
Inhalation
Classified as "cannot be determined,
suggestive." There was increased tumor
incidence in rats only at the highest dose
tested; however, this evidence was judged
to be not persuasive but could not be
dismissed. A Qj* has not been
established. Given the weak evidence of
carcinogenicity and the large difference
between the chronic LOAEL and the
cancer LOAEL, HED determined that a
quantitative cancer risk assessment was
not necessary for chlorfenapyr.
b. Occupational Exposure and Risk. The margin of exposure (MOE) is a
measure of how closely the anticipated exposure comes to the NOAEL and is
calculated as a ratio of the NOAEL to the exposure (NOAEL/exposure = MOE).
For this use, the Agency is not concerned unless the MOE is below 100.
1. Mixer/loader/applicator risk. The following table summarizes the
exposure and risk estimates for mixer/loaders and applicators from the proposed
greenhouse uses for chlorfenapyr. The mixer/loader/applicator using a high pressure
handwand is expected to represent the scenario with the highest potential exposure.
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Occupational Risk Estimates
Exposure Scenario
Mixer/
Loader/Applicator
Short-/Intermediate-
term MOEs
2200-dermal
1900-inhalation
Long-term
MOE
580
2. Post Application risk. The following table presents post application
risks.
Post-application Risk Estimates
Exposure Scenario
Irrigation of
ornamental plants
AR=0.641bai/A
Exposure duration
Short/intermediate-term
Long-term
MOE
150
100
As shown in the tables above, for the foliar spray of chlorfenapyr on ornamental
crops in commercial greenhouses, all occupational MOEs are above levels of
concern.
Greenhouse use has limited opportunity for outdoor residues, drift, runoff, and
FatG and wildlife exposure. Therefore, use on ornamental crops grown in enclosed commercial
Frnlnniral FffprtQ greenhouses is not expected to cause any significant environmental exposure or risk.
Characteristics
Data Gaps There are no data gaps for this use.
Reg U I atO ry Under the authority of Section 3 (c)(5), the Agency has determined that the database
Concl USJOn suPPorts granting an unconditional registration for Chlorfenapyr Technical, and for
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Pylon Miticide-Insecticide (21.4% chlorfenapyr), for use on ornamentals grown in
commercial greenhouses.
Note that this conclusion contrasts with the Agency's previous determination that the
use of chlorfenapyr on cotton would pose unreasonable adverse effects due to
persistence and potential adverse effects on the reproduction of birds. The Agency
finds there is no such concern with the use of this pesticide in an enclosed
greenhouse environment.
For More Information CONTACT PERSON:
Ann Sibold,
Acting Product Manager, PM-10
Insecticide Branch , Registration Division (7505C)
Office of Pesticide Programs
U.S. EPA, Ariel Rios Building
1200 Pennsylvania Avenue NW
Washington, DC 20460
Office Location, E-mail Address, and Telephone Number:
Rm. 201, Crystal Mall #2
1921 Jefferson Davis Highway
Arlington, VA 22202
sibold.ann@epa.gov
(703)305-6502
Electronic copies of the this fact sheet are available on the Internet. See
Printed copies of this fact sheet can be
obtained from EPA's National Center for Environmental Publications and
Information (EPA/NCEPI), PO Box 42419, Cincinnati, OH 45242-2419,
telephone 1-800-490-9198; fax 513-489-8695. For more information about EPA's
pesticide registration program, please contact the Registration Division (7505C),
OPP, US EPA, Washington, DC 20460, telephone 703-305-5446. For
information about the health effects of pesticides, or for assistance in recognizing and
managing pesticide poisoning symptoms, please contact the National Pesticides
Telecommunications Network (NPTN). Call toll-free 1-800-858-7378, from 6:30
a.m. to 4:30 p.m. Pacific Time, or 9:30 a.m. to 7:30 p.m. Easter n Standard Time,
seven days a week.
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Information about the environmental aspects of the proposed chlorfenapyr use on
cotton is available at the following internet address:
http://www.epa.gov/opprd001/chlorfenapyr/toc.htm
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Paper copies of these electronic materials are available at the following location:
Public Docket, Environmental Protection Agency, Rm. 119, Crystal Mall 2 (CM
#2), 1921 Jefferson Davis Hwy. Arlington, VA 22202.
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