United States Office of Prevention, Pesticides EPA-737-F-96-005
Environmental Protection and Toxic Substances May, 1996
Agency Washington DC 20460
Office of Pesticide Programs
New
Pesticide
Fact Sheet
1. Description of the Chemical;
Generic Name: 5-amino-l-[2,6-dichloro-4-
(trifluoromethyl)phenyl]-4-[(1R,S)-
(trifluoromethyl)sulfinyl]-lH-pyrazole-3-carbonitrile
Common Name: fipronil
Trade Name: Fipronil Technical; Chipco Choice Insecticide
EPA Shaughnessy Code (OPP Chemical Code): 129121
Chemical Abstracts Service (CAS) Number: 120068-37-3
Year of Initial Registration: MAY 1996
Pesticide Type: Insecticide
Chemical Family: Phenylpyrazoles
Producer: Rhone Poulenc Ag Company
2. Use Patterns and Formulations;
Application Sites: Golf Course Turf and Commercial Turf
Type and Method of Application: Application is made using
slit-placement equipment which puts the product into the
ground at the soil/thatch interface.
Type of Formulation: 0.1% flowable granular
Target Pest: Mole Cricket
Site: Golf Course and Commercial Turf
3. Science Findings;
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Summary Statement: The end-use product, Chipco Choice
Insecticide, has a low order of toxicity with respect to
acute oral, dermal, inhalation, eye/skin irritation routes
of exposure. It is not a sensitizer. The product is
assigned to Toxicity Category III (Caution) based on the
acute dermal route of exposure and eye irritation study.
The technical product has a high order of toxicity to
mammals with respect to acute oral, dermal, and inhalation
routes of exposure and eye/skin irritation. It is not a
sensitizer. The technical product is assigned to Toxicity
Category II (Warning) based on the acute oral, dermal, and
inhalation routes of exposure.
Fipronil has been classified as a Group C (Possible
Human) Carcinogen based on an increase in thyroid follicular
cell tumors in both sexes of the rat. The increase is
statistically significant by both pair-wise and trend
analyses. The RfD methodology was selected for
quantification because the thyroid tumors appeared to be
related to a disruption in the thyroid-pituitary status and
there was no apparent concern for mutagenicity or available
information from structurally related analogs.
An acceptable chronic rat feeding study identified the
following effects: seizures, including seizures resulting
in death, decreased body weight gain, decreased food
consumption and food conversion efficiency, decreased
hematology measures, alterations in clinical chemistry
(cholesterol, calcium, and protein), alterations in thyroid
hormones, alterations in urine chemistry, changes on gross
necropsy, increase in liver and thyroid weights, and
progressive senile nephropathy (kidney effects). The NOEL
for systemic toxicity was 0.5 ppm. The LOEL of 1.5 ppm was
based on an increase in incidence of clinical signs and
alterations in clinical chemistry and thyroid parameters.
Based on this study, the RfD Committee recommended that the
RfD be established using the NOEL and an uncertainty factor
of 100 to account for the interspecies extrapolation and
intraspecies variability. The RfD was set at 0.0002
mg/kg/day.
In addition to the toxicity endpoints identified above,
the toxic endpoint selection (TES) committee has identified
the following endpoints and dose levels of concern. The
acute dietary endpoint of concern is acute neurotoxicity.
The NOEL is 0.5 mg/kg, and the LOEL is 5.0 mg/kg based on
decreased hind leg splay observed at this level at seven
hours post treatment. The TES committee also identified
short and intermediate term occupational and residential
exposure end points based on a 21-day dermal toxicity study.
The NOEL was 5.0 mg/kg/day. The LOEL of 10.0 mg/kg/day was
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based on decreased body weight gain and food consumption in
rabbits.
An acceptable reproductive toxicity study in rats
showed that fipronil is associated with reproductive
effects. The NOEL for parental (systemic) toxicity was 3
ppm (0.25 mg/kg/day for males and 0.27 mg/kg/day for
females). The LOEL for parental (systemic) toxicity was 30
ppm (2.54 mg/kg/day for males and 2.74 mg/kg/day for
females) based on effects on the thyroid, liver, and
pituitary gland. The NOEL for reproductive toxicity was 30
ppm (2.54 and 2.74 mg/kg/day for males and females
respectively). The LOEL for reproductive toxicity was 300
ppm (26.03 mg/kg/day for males and 28.40 mg/kg/day for
females based on clinical signs of toxicity, decreased
litter size, decreased body weights, decrease in the
percentage of animals mating, reduction in fertility index,
reduced post-implantation survival and offspring postnatal
survivability, and delay in physical development.
Developmental toxicity studies in rats and rabbits
showed that fipronil was not associated with significant
developmental toxicity. Several mutagenicity tests were
negative. They include two Salmonella typhimurium/mammalian
microsome reverse gene mutation assays with and without S-9
activation, an in vitro cytogenics assay using human
lymphocytes, two Chinese hamster forward gene mutation
assays, and a mouse micronucleus test.
Available environmental fate lab data indicate that,
below the soil surface, fipronil dissipates by soil binding
followed by slower biotic mediated processes. However, on
the soil surface the major route of degradation may be slow
photolysis and/or soil binding followed by slower biotic
mediated processes. In addition, lab data indicate that
fipronil has low mobility in soils and degrades slowly under
alkaline hydrolytic conditions. Fipronil is stable to
hydrolysis at mildly acid to normal pH.
The field data support the lab data. Half lives for
fipronil of 1.1 to 1.5 months were reported for bare soil
and 0.4 to 0.5 for turfed soil. In bare soil, residues were
found only in the top 6 inches of soil. The potential for
ground water contamination is considered low.
The ecological effects data show that fipronil is
highly toxic to upland game birds on an acute oral basis,
very highly toxic on a subacute dietary basis, and is
practically non-toxic to waterfowl on both an acute and
subacute basis. The chronic (avian reproduction) studies
show no effects at the highest levels tested in mallards
(NOEC) = 1000 ppm) or quail (NOEC = 10 ppm). The metabolite
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MB 46136 is more toxic than the parent to avian species
tested (very highly toxic to upland game birds and
moderately toxic to waterfowl on an acute oral basis).
Fipronil is very highly toxic to bluegill sunfish and highly
toxic to rainbow trout on an acute basis. The results of a
fish early life-stage toxicity study in rainbow trout show
that fipronil affects larval growth with a NOEC of 0.0066
ppm and an LOEC of 0.015 ppm. The metabolite MB 46136 is
more toxic than the parent to freshwater fish (6.3 times
more toxic to rainbow trout and 3.3 times more toxic to
bluegill sunfish). Based on an acute daphnia study using
fipronil and three supplemental studies using its
metabolites, fipronil is characterized as highly toxic to
aquatic invertebrates. An invertebrate life cycle daphnia
study showed that fipronil affects length in daphnids at
concentrations greater than 9.8 ppb. A life cycle study in
mysids shows fipronil affects reproduction, survival and
growth of mysids at concentrations less than 5 pptr. Acute
studies of estuarine animals using oysters, mysids, and
sheepshead minnows shows that fipronil is highly acutely
toxic to oysters and sheepshead minnows, and very highly
toxic to mysids. Metabolites MB 46136 and MB 45950 are more
toxic than the parent to freshwater invertebrates (MB 46136
is 6.6 times more toxic and MB 45950 is 1.9 times more toxic
to freshwater invertebrates).
Chemical Characteristics; Technical Grade fipronil
Physical: Powder
Color: White
Odor: Moldy
Melting Point: 195.5 to 203 deg. C
Density: 1.6262 g/ml at 20 deg. C
Molecular Formula: C12H4C1,F6N4OS
Vapor Pressure: 2.8 x 10 mm Hg at 25 deg. C
Octanol/Water Partition Coefficient: log P0/w = 4.01
pH: 5.9 to 6.1 at 23 deg. C (1% w/v water)
Solubility: Solvent Solubility, g/1
water pH 5 0.0024
water pH 9 0.0022
acetone 545.9
2-propanol 36.2
dichloromethane 22.3
ethyl acetate 264.9
hexane 0.028
methanol 137.5
toluene 3 .0
octanol 12.2
Stability: degraded slightly by sunlight; stable at normal
temperatures for one year; not stable in presence of metal ions.
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Toxicology Characteristics; Technical Grade Fipronil
Acute oral (Rat): LD50 97 mg/kg; Tox Category II
Acute dermal (Rabbit): LD50 354 mg/kg; Tox Category II
Acute dermal (Rat): LD50 > 2000 mg/kg; Tox Category III
Acute inhalation (Rat): LC50 0.39mg/L; Tox Category II
Primary eye irritation (Rabbit): Mild transient eye irritation
clearing by 24 hours; Tox Category III
Primary dermal irritation (Rabbit): Slight dermal irritation; Tox
Category IV
Dermal sensitization (Guinea Pig): Not a sensitizer
Acute Neurotoxicity (Rat): NOEL = 0.5 mg/kg for males and
females. LOEL 5.0 mg/kg for males and females based on decreased
hind leg splay at the 7 hour post treatment evaluation in males
and females.
Subchronic Toxicity (Dog): NOEL = 2.0 mg/kg/day for males and
0.5 mg/kg/day for females. LOEL = 10.0 mg/kg/day for males
(based on clinical signs of toxicity and 2.0 mg/kg/day for
females (based on clinical signs of toxicity and decreased body
weight gain).
Subchronic Toxicity (Rat): NOEL = 5 ppm for males (0.33
mg/kg/day) and females (0.37 mg/kg/day. LOEL 30 ppm for males
(1.93 mg/kg/day) and females (2.28 mg/kg/day) based on
alterations in serum protein values and increased weight of the
liver and thyroid.
Subchronic Neurotoxicity (Rat): NOEL = 5.0 ppm (0.301 mg/kg/day
for males and 0.351 mg/kg/day for females). LOEL = 150 ppm (8.89
mg/kg/day for males and 10.8 mg/kg/day for females) based on
increased incidence of no urination and increased incidence of
exaggerated tail pinch response in males, increased incidence of
exaggerated startle responses in males and females, and increased
forelimb grip strength at week 13 in females.
21-Day Dermal Toxicity (Rabbit): Systemic NOEL =5.0 mg/kg/day;
Dermal irritation NOEL >= 10.0 mg/kg/day. Systemic LOEL = 10
mg/kg/day based on decreased body weight gain and food
consumption; Dermal irritation LOEL > 10 mg/kg/day.
Chronic Toxicity (Dog): NOEL 0.2 mg/kg/day. LOEL 2.0 mg/kg/day
based on clinical signs of neurotoxicity and abnormal
neurological examinations.
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Chronic Toxicity (Dog): NOEL = 0.3 mg/kg/day in females and 1.0
mg/kg/day in males. LEL is 1.0 mg/kg/day in females and 2.0
mg/kg/day in males based on clinical signs of neurotoxicity.
Carcinogenicity (Mouse): NOEL = 0.5 ppm (0.055 mg/kg/day for
males and 0.063 mg/kg/day for females). LOEL = 10 ppm (1.181
mg/kg/day for males and 1.230 mg/kg/day for females) based on
decreased body weight gain, decreased food conversion efficiency
(males), increased liver weights and increased incidence of
hepatic histopathological changes. The study demonstrated that
technical fipronil is not carcinogenic when administered at doses
of 30 ppm or greater to CD-I mice.
Combined Chronic Toxicity/Carcinogenicity (Rat): NOEL = 0.5 ppm
for males (0.019 mg/kg/day) and females (0.025 mg/kg/day). LOEL
1.5 ppm for males (0.059 mg/kg/day) and females (0.078 mg/kg/day)
based on an increased incidence of clinical signs and alterations
in clinical chemistry and thyroid parameters. The study
demonstrated that fipronil is carcinogenic to rats at doses of
300 ppm in males (12.68 mg/kg/day) and females (16.75 mg/kg/day).
Developmental Toxicity (Rat): Maternal toxicity NOEL = 4
mg/kg/day. Maternal toxicity LOEL =20 mg/kg/day based on
reduced body weight gain, increased water consumption, reduced
food consumption and reduced food efficiency. Developmental
toxicity NOEL is 20 mg/kg/day or higher. Developmental toxicity
LOEL is greater than 20/mg/kg/day.
Developmental Toxicity (Rabbit): Maternal toxicity NOEL < 0.1
mg/kg/day. Maternal toxicity LOEL is equal to or less than 0.1
mg/kg/day based on reduced body weight gain, reduced food
consumption and efficiency. Developmental toxicity NOEL is equal
to or greater than 1.0 mg/kg/day. Developmental toxicity LOEL is
greater than 1.0 mg/kg/day.
Multigeneration Reproduction Study (Rat): NOEL for parental
(systemic) toxicity was 3 ppm (0.25 mg/kg/day for males and 0.27
mg/kg/day for females). LOEL for parental (systemic) toxicity
was 30 ppm (2.54 mg/kg/day for males and 2.74 mg/kg/day for
females) based on systemic signs including increase in the
absolute and relative weights of the thyroid glands and liver in
males and females of the F0 and F1 generations; decrease in the
absolute weight of the pituitary gland in females in the F1
parental animals; and increase incidence of follicular epithelial
hypertrophy of the thyroid glands in females of the F1
generation. The NOEL for reproductive toxicity was 30 ppm (2.54
and 2.74 mg/kg/day for males and females respectively). The LOEL
for reproductive toxicity was 300 ppm (26.03 mg/kg/day for males
and 28.40 mg/kg/day for females based on clinical signs of
toxicity in the F1 and F2 offspring; decreased litter size in the
F1 and F2 litters; decreased body weights in the F1 and F2
litters; decrease in the percentage of F1 parental animals
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mating; reduction in fertility index in F^ parental animals;
reduced post-implantation survival and offspring postnatal
survivability in the F2 litters; and delay in physical
development in the F^ and F2 litters.
Mutagenicity. Several mutagenicity tests were negative. These
include an Ames (salmonella) test in the presence and absence of
S9 activation; an in vitro gene mutation (Chinese hamster V79
cells)/HGPRT assay both with and without S9 activation; a
cytogenic assay (Human lymphocytes) test of clastogenic effects
with and without S9 activation; and a mouse micronucleus assay.
Metabolism (Rat): 14C fipronil was administered orally in
aqueous methylcellulose to male and female rats at doses of 4 and
150 mg/kg (single dose) and 4 mg/kg for 14 days (repeated dose).
The rate and extent of absorption appeared similar among all
dose groups, but may have been decreased at the high dose.
Distribution data showed significant amounts of residual
radioactivity in the carcass, G.I. tract, liver, adrenals, and
abdominal fat at 168 hours post dose for all rats in all dose
groups. Repeated low oral dosing or a single high oral dose
resulted in an overall decrease in the amount of residual
radioactivity found but an increase in the amount in abdominal
fat, carcass, and adrenals. Feces appeared to be the major route
of excretion where 45-75% of an administered dose was excreted.
Excretion in urine was 5-25%. Increases in the percentages
excreted in urine and feces were observed with repeated low oral
dosing or a single high dose, while the percentage found in all
tissues combined decreased. There were no significant sex-
related differences in excretion. Major metabolites in urine
included ring opened products of the metabolite MB 45897, two
oxidation products, MB 46136 and RPA 200766, and the parent
chemical fipronil. In feces, the parent was detected as a
significant fraction of the sample radioactivity a well as the
oxidation products MB 46136 and MB 45950. Whole blood half
life ranged from 149.4 to 200.2 hours at 4 mg/kg. At 150 mg/kg,
whole blood half-life was noticeably decreased to 54.4 hours in
male rats and 51.2 hours in female rats.
Toxicology Characteristics; End-use product (Chipco Choice
Insecticide)
Acute oral (Rat): Estimated LD50> 5000mg/kg; Tox Category IV
Acute dermal (Rabbit): Estimated LD50> 2000mg/kg; Tox Category
III
Acute inhalation (Rat): Estimated LC50> 5.06mg/L; Tox Category
IV
Primary eye irritation (Rabbit): Irritation clearing by 3rd day;
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Tox Category III
Primary Dermal Irritation (Rabbit): Slight irritation, clearing
by 72 hours; Tox Category IV
Dermal Sensitization (Guinea Pig): Not a sensitizer
ENVIRONMENTAL FATE CHARACTERISTICS; Technical Grade Fipronil
HYDROLYSIS DATA. Fipronil is stable to hydrolysis at mildly acid
to neutral pH, but degrades with a half-life of 28 days in more
basic solutions (pH 9). The major degradation product from
alkaline hydrolysis is the amide (RPA 200766).
PHOTODEGRADATION IN WATER. Fipronil has a half-life of 3.63
hours when exposed to a xenon light source in the laboratory.
The major degradates were MB 46513 and RPA 104615 at 43% and 8%
of applied radioactivity. No volatile compounds were found.
PHOTODEGRADATION ON SOIL. Fipronil degrades slowly on loamy soil
when exposed to light. The half-life is 34 days. Three major
degradates were identified as RPA 200766, at a concentration of
10.86% of applied radioactivity. Two other degradates were
identified as MB 46513, and RPA 104615 and measured at 8.65% and
8.87% of interest regions. There was no evidence of volatility
of fipronil or its metabolites.
AEROBIC SOIL METABOLISM. Under aerobic conditions, soil
organisms slowly break down fipronil. The half life in sandy
loam soil is 122 (TLC data) - 128 (HPLC data) days. Several
metabolites were identified. Two of these (RPA 200766 and MB
46136) account for 27%-38% and 14-24% of the total applied
radioactivity, respectively.
ANAEROBIC AQUATIC METABOLISM. Fipronil degrades slowly in water
and sediment under anaerobic conditions. The half life is 116
(HPLC data) - 130 (TLC data) days. Two major metabolites were
found, MB 45950 and RPA 200766, at maximum concentrations of
about 47% and 18% of applied radioactivity, respectively. MB
45950 was found in the soil extracts and RPA 200766 was found in
both soil and water. The Anaerobic soil metabolism data
requirement was also met by the anaerobic aquatic metabolism
data.
LEACHING/ADSORPTION/DESORPTION. The column leaching and
adsorption/desorption studies show that fipronil has low mobility
in soil. It tends to bind to soil and it is expected not to
leach to groundwater.
TERRESTRIAL FIELD DISSIPATION. The terrestrial field dissipation
study showed that fipronil dissipates with a half life of 1.1 to
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1.5 months for bare soil and 0.4 to 0.5 months for turfed soil.
Fipronil residues tend to stay in the upper 6 inches of soil, and
thus exhibit low potential to leach to groundwater. Of the major
degradates identified in lab studies, only two (MB 46136 and RPA
200766) were found in field studies at amounts greater than the
limit of detection.
FISH ACCUMULATION. The fish accumulation study showed that
fipronil appears to bioaccumulate in fish when exposed to treated
water at a concentration of about 900 nanograms for 35 days. The
data indicate that the residues are almost completely eliminated
after 14 days depuration. Bioconcentration factors were 321,
164, and 575 for whole fish, edible tissue and non-edible tissue,
respectively. The major metabolites found were MB 46136, MB
45897, and MB 45950.
ECOLOGICAL EFFECTS CHARACTERISTICS; Technical Grade Fipronil
BIRDS. Fipronil is highly toxic to upland game birds on an acute
oral basis, very highly toxic on a subacute dietary basis, and is
practically non-toxic to waterfowl on both an acute and subacute
basis. The chronic (avian reproduction) studies show no effects
at the highest levels tested in mallards (NOEC) = 1000 ppm) or
bobwhite quail (NOEC = 10 ppm). The metabolite MB 46136 is more
toxic than the parent to avian species tested (very highly toxic
to upland game birds and moderately toxic to waterfowl on an
acute oral basis).
MAMMALS. Fipronil is moderately toxic to small mammals on an
acute oral basis. The LD50 is 97 mg/kg in rats.
FRESHWATER FISH. 96 hour acute toxicity studies show fipronil is
very highly toxic to bluegill sunfish (LC 50 = 0.083 ppm) and
highly toxic to rainbow trout (LC50 = 0.246 ppm). The results of
a fish early life-stage toxicity study in rainbow trout show that
fipronil affects larval growth with an NOEC of 0.0066 ppm and an
LOEC of 0.015 ppm. The metabolite MB 46136 is more toxic than
the parent to freshwater fish (6.3 times more toxic to rainbow
trout and 3.3 times more toxic to bluegill sunfish).
FRESHWATER INVERTEBRATES. A daphnia study using fipronil (EC50 =
190 ppb) shows fipronil is highly toxic to aquatic invertebrates.
An invertebrate life-cycle toxicity study using daphnia
(freshwater) showed that fipronil affects the length of daphnids
at concentrations greater than 9.8 ppb (NOEC). The LOEC = 20 ppb
and the maximum allowable toxicant concentration (MATC) = 14 ppb.
Metabolites MB 46136 and MB 45950 are more toxic than the parent
to freshwater invertebrates (MB 46136 is 6.6 times more toxic and
MB 45950 is 1.9 times more toxic to freshwater invertebrates).
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ESTUARINE AND MARINE ANIMALS. Three acute studies using oysters,
mysids, and sheepshead minnows shows that fipronil is highly
acutely toxic to oysters (EC50 = 0.77 ppm) and sheepshead minnows
(EC50 = 0.13 ppm), and very highly toxic to mysids (EC50 = 140
pptr). An invertebrate life-cycle toxicity study using mysid
shrimp (estuarine) showed that fipronil affects survival,
reproduction and growth in mysids at concentrations less than 5.0
pptr (LOEC = 5 pptr; NOEC < 5.0 pptr) and the MATC < 5 pptr.
AQUATIC PLANTS. The data for aquatic plants is summarized below:
Freshwater diatom EC50 > 0.12 ppm
Duckweed EC50 > 0.10 ppm
Freshwater green algae EC50 = 0.14 ppm
Marine Diatom EC50 > 0.14 ppm
Freshwater blue-green algae > 0.17 ppm.
4. SUMMARY OF DATA GAPS: There are no data gaps for this use.
5. CONTACT PERSON:
Ann Sibold
Reviewer, PM-10
Insecticide-Rodenticide Branch
Registration Division (7505C)
Office of Pesticide Programs
U.S. EPA
401 M St. SW
Washington, DC 20460
Office Location and Telephone Number:
Rm. 214, Crystal Mall # 2
1921 Jefferson Davis Highway
Arlington, VA 22202
(703) 305-6502
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