United States
Environmental Protection Agency
Office of Prevention, Pesticides and Toxic Substances
(7505P)
P/EPA
Pesticide
Fact Sheet
Name of Chemical:
Reason for Issuance:
Date Issued:
Metofluthrin
New Chemical
Nonfood Use
September 2006
Description of Chemical
IUPAC name:
CAS name:
Common Name:
Empirical Formula:
EPA Chemical Code:
Chemical Abstracts
Service (CAS) Number:
Chemical Class:
Registration Status:
Pesticide Type:
2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (EZ)-
(lRS,3RS;lRS,3SR)-2,2-dimethyl-3-prop-l-
enylcyclopropanecarboxylate
[2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl
2,2-dimethyl-3-(l-propenyl)cyclopropanecarboxylate
Metofluthrin
109709
240494-70-6
Pyrethroid ester
New Chemical, nonfood use
Insecticide repellent not applied to human skin
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U.S.Technical Registrant: Sumitomo Chemical Company, LTD.
1330 Dillon Hghts. Ave.
Baltimore, MD 21228
Use Pattern and Formulations
Currently there are two end use products being proposed for metofluthrin.
DeckMate ™ Mosquito Repellent Strip is an impregnated paper strip (-3,528 cm2)
containing 1.82 percent metofluthrin as the active ingredient. The product also contains
Bitrex ™ to discourage oral exposure to children or animals. The product is for use on
patios, campsites, decks, cabanas, and other outdoor areas. One strip is applied per 10 ft
x 10 ft outdoor area. Indoors the application rate is two strips per 50 m3. There are
approximately 200 mg of metofluthrin initially in the strip. The strips can provide up to
one week of protection Metofluthrin evaporates readily and therefore requires no
external heat.
Norm 1- is a personal outdoor insect repellent product consisting of a holder containing a
replaceable cartridge insert coated with up to 50 mg of metofluthrin. The product is
activated by turning on a battery powered fan to release the metofluthrin into the air
surrounding the individual. The device can be worn by adults or children for up to 12
hours although a specific time is not presented on the proposed label. A time of 12 hours
was used in the exposure study and was used by the Agency. There are no label
restrictions on who can use the products or the use frequency.
There are no proposed agricultural or occupational uses for metofluthrin.
Science Findings
Available product chemistry data supporting the use of flufenoxuron are summarized
below in Tables 1 and 2.
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TABLE 1 Nomenclature and Physiochemical Properties of Metofluthrin
Chemical Structure
Empirical Formula
Common name
Company
experimental name
IUPAC name
CAS name
CAS Registry
Number
End-use product/EP
Chemical Class
"^
"i.
if"
n*.-*_
J
.K.
7 \—/
V F^Q^
F CM,
\J-C-b
Ci8H2oF4O3
Metofluthrin
S-1264
2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl(£'Z)-(1^5',3^5';1^5',3SR)-2,2-
dimethy 1-3 -prop- 1 -eny Icy clopropanecarboxy late
[2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl2,2-dimethyl-3-(l-
propenyl)cyclopropanecarboxylate
240494-70-6
SumiOne®, Eminence®
Pyrethroid ester
TABLE 2 Physiochemical Properties of Technical Grade Metofluthrin
Molecular Weight
Melting point/range
pH
Density
Water solubility (20°C)
Solvent solubility (20°C to 25°C)
(g/L)
Vapor pressure (25°C)
Dissociation constant, pKa
Octanol/water partition coefficient,
logPow (25°C)
UV/visible absorption spectrum
360.34
NA
5.24 at 25°C (1% aqueous solution)
1.21at20°C
0.67 mg/L (20°C) for (S-1264RTE)
0.50 mg/L (20°C) for (S-1264RTZ)
Acetone 303.4, methanol 312.2, ethyl acetate 307.6, toluene 326.9,
n-hexanes 328.7, dichloromethane 318.9, n-octanol 325.1, isopropyl
alcohol 3 13. 2
1.47xlO"5 Ton-
Could not be measured
5.03 (S-RTE)
4.97 (S-RTZ)
In 100% methanol: peak maximum = 273
= 1670 M^cm"1, band width 23 nm
nm, extinction coefficient
TOXICOLOGY SUMMARY
The Registrant submitted the studies listed in Tables 3 and 4, which include a number of
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toxicity studies. These include the usual acute studies for metofluthrin technical. The
Registrant has also submitted oral, dermal and inhalation studies as well as chronic,
carcinogenicity and developmental studies as shown in Table 4.
TABLE 3 Acute Toxicity Profile - Test Substance
Guideline No./
Study Type
870. 11 00 Acute
oral toxicity
870. 1200 Acute
dermal toxicity
870. 1300 Acute
inhalation
toxicity
870.2400 Acute
eye irritation
870.2500 Acute
dermal irritation
870.2600 Skin
sensitization
MRID
No.
46406719
46406721
46406723
46406724
46406724
46406726
Results
LD50 > 2000
mg/kg
LD50 >= 2000
mg/kg
LC50> 1.08 and
< 1.96 mg/L
Not an eye
irritant
Mildly irritating
to the skin (PDI
= 0.8)
Not a dermal
sensitizer
Toxicity Category
III
III
III
IV
IV
-
Table 4 Subchronic, Chronic, and Other Toxicity Profile
Guideline No./ Study
Type
MRID No. (year)/ Classification
/Doses
Results
870.3100
90-Day oral toxicity
rats
(Wistar rats)
46454109 (2003)
Acceptable/Guideline
0, 100, 300, 1000, or 2500 ppm
M: 0,6.8, 20.6, 70.4, or 183.6
mg/kg/day
F: 0,7.5,21.6, 73.0, or 185.6
mg/kg/day
NOAEL = 20.6/21.6 mg/kg/day
LOAEL = 70.4/73.0 mg/kg/day, based on increased
absolute and relative liver weights in both sexes;
increased serum total cholesterol and phospholipids
levels in males, and increased incidences of
enlarged livers, hepatocellular hypertrophy, and
basophilia in males; and decreased body weight
gain in females.
870.3100
Subchronic (6-month)
oral toxicity rats
(Sprague-Dawley rats)
46406733 (2002)
Acceptable/Guideline
0, 100, 300, 1000, or 3000 ppm
M: 0,5.3,16.0,54.1,164.6
mg/kg/day
F: 0,6.4,19.0,65.4,191.4
mg/kg/day
NOAEL = 16.0/19.0 mg/kg/day
LOAEL = 54.1/65.4 mg/kg/day, based on increased
relative liver weights, serum phospholipids, and
total cholesterol levels in males; increased
incidences of dark, enlarged livers and
hepatocellular hypertrophy in both sexes; and an
increased incidence of slight focal hepatic necrosis
in females.
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Table 4 Subchronic, Chronic, and Other Toxicity Profile
Guideline No./ Study
Type
MRID No. (year)/ Classification
/Doses
Results
870.3100
90-Day oral toxicity in
mice
(CD-I mice)
46454108 (2004)
Acceptable/Guideline
0, 100, 1500, 2500, or 3500 ppm
M: 0,13.7,20.9, 35.7, or 48.7
mg/kg/day
F: 0,17.2, 25.2, 43.9, or 58.7
mg/kg/day
NOAEL = 35.7/43.9 mg/kg/day
LOAEL = 48.7/58.7 mg/kg/day, based on findings
indicative of hepatotoxicity including increased
absolute and relative liver weights in both sexes;
increased serum total cholesterol, phospholipids,
and triglycerides in females; and minimal
degeneration/necrosis of the liver and minimal to
moderate hepatocellular hypertrophy in both sexes,
and increased Kupffer cells in males.
870.3150
90-Day oral toxicity in
dogs (Beagles)
46406734 (2002)
Acceptable/Guideline
0,10, 30, or 100 mg/kg/day
NOAEL = 30 mg/kg/day
LOAEL = 100 mg/kg/day, based on tremor and
vomiting observed in both sexes
870.3250
90-Day dermal
toxicity in rats
(Sprague-Dawley)
46556101 (2004)
Acceptable/Guideline
0, 30, 100, 300, or 1000
mg/kg/day
Systemic NOAEL = 300 mg/kg/day
Systemic LOAEL = 1000 mg/kg/day, based on
mortality and clinical signs (tremor and salivation)
Dermal NOAEL = not determined
Dermal LOAEL = 30 mg/kg/day, based on
hyperactivity and vocalization in the females during
the daily exposure period
870.3465
Subchronic inhalation
study in rats
(Sprague-Dawley)
46406736 (2002)
Acceptable/Guideline
0,10, 50, 100, or 200 mg/m3
0,0.01,0.051,0.099, or 0.196
mg/L)
M: 4 hrs/day, 28 days
F: 4 hrs/day, 29 days
NOAEL = 0.099 mg/L
LOAEL = 0.196 mg/L, based on mortality and
clinical signs including tremors, hypersensitivity,
ataxic gait, tiptoe gait, lateral position, clonic
convulsion, and hypothermia in both sexes.
Clinical signs began on days 1-4 and occurred
consistently in the males and transiently in females
thereafter.
870.3700a
Prenatal
developmental in rats
(Sprague-Dawley)
46454111(2002)
Acceptable/Guideline
0, 5, 15, or 30 mg/kg/day from
GD6-GD19
Maternal NOAEL = 15 mg/kg/day
Maternal LOAEL = 30 based on increased
incidence of tremor
Developmental NOAEL = 30 mg/kg/day
Developmental LOAEL = not observed
Prenatal
developmental in rats
(Sprague-Dawley)
46454112(2002)
Acceptable/Non-Guideline
M: 0,10, or 20 mg/kg/day
beginning 2 weeks prior to mating
through necropsy (57 days)
F: 0, 10, 20, or 40 mg/kg/day
beginning 2 weeks prior to mating
through GD7
Parental NOAEL = 20 mg/kg/day (both sexes)
Parental LOAEL = 40 mg/kg/day, based on
mortality and incidences of tremors and salivation
in females.
Reproduction NOAEL = 20/40 mg/kg/day M/F
Developmental NOAEL = 40 mg/kg/day in females
Developmental LOAEL = not observed
Prenatal
developmental in rats
(Sprague-Dawley
46454113(2002)
Acceptable/Non-guideline
0, 5, 15, or 30 mg/kg/day from
GD6 through LD20
Maternal NOAEL = 15 mg/kg/day
Maternal LOAEL = 30 mg/kg/day, based on
mortality and increased incidences of tremors and
salivation.
Reproductive NOAEL = 30 mg/kg/day
Reproductive LOAEL = not observed
Developmental NOAEL = 30 mg/kg/day
Developmental LOAEL = not observed
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Table 4 Subchronic, Chronic, and Other Toxicity Profile
Guideline No./ Study
Type
MRID No. (year)/ Classification
/Doses
Results
870.3700b
Prenatal
developmental in
rabbits
(New Zealand White)
46454114(2002)
Acceptable/Guideline
0, 25, 125, or 250 mg/kg/day
from GD6 - GD27
Maternal NOAEL = 25 mg/kg/day
Maternal LOAEL = 125 mg/kg/day, based on
mortality
Developmental NOAEL = 250 mg/kg/day
Developmental LOAEL = not observed
870.4100a
Chronic toxicity
rodents
(Wistar rats)
46611301(2005)
Acceptable/Guideline
0,20,200, 900, or 1800 ppm
M:0, 0.8, 8.2, 38.1, or 77.8
mg/kg/day
F:0, 1.0,10.1,47.4, or 96.1
mg/kg/day
NOAEL = 8.2/10.1 mg/kg/day
LOAEL - 38.1/47.4 mg/kg/day, based on decreased
body weights and body weight gains in both sexes;
increased incidence of hepatic clear cell foci in both
sexes; increased fatty liver change, and kidney
lesions (including interstitial fibrosis, lipofuscin,
mononuclear foci, and glomerulosclerosis) in
males; increased centrilobular hepatocellular
hypertrophy in females
870.4100b
Chronic toxicity dogs
(Beagle)
46454110(2004)
Acceptable/Guideline
0, 10, 30, or 100 mg/kg/day
NOAEL = 10 mg/kg/day
LOAEL = 30 mg/kg/day, based on increased
incidence of tremor in males.
870.4300
Carcinogenicity mice
(CD-I mice)
46611302(2005)
Acceptable/Guideline
0, 100, 1000, or 1750/2500 ppm
M: 0, 12,116, or 209 mg/kg/day
F: 0, 15, 155, or 277 mg/kg/day
NOAEL = 116/155 mg/kg/day
LOAEL = 209/277 mg/kg/day, based on decreased
body weight gain in both sexes.
Gene Mutation
870.5100 Bacterial
Reverse Gene
Mutation Assay
46406742 (2002)
Acceptable/Guideline
0, 156, 313, 625, 1250, 2500, or
5000 |ig/plate +/- S9 in S.
typhimurium TA98, TA100,
TA1535 and TA1537 andE. Coli
WP2 uvrA
There was no evidence of induced mutant colonies
over background levels.
Gene Mutation
870.5100/wv//ro
Bacterial Gene
Mutation Assay
46454115(2004)
Acceptable/Guideline
Trial 1 (-S9): 4.88, 9.77,19.5,
39.1, 78.1, or 156 |ig/plate strains
TA100,TA1535
Trial2(+S9): 19.5,39.1,78.1,
156, 313, or 625 |ig/plate strains
TA100, TA1535, andTA1537
Trial 3 (+/-S9): 156,313,625,
1250, 2500, or 5000 |ig/plate
strains TA98 and WP2uvrA
There was no evidence of induced mutant colonies
over background levels.
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Table 4 Subchronic, Chronic, and Other Toxicity Profile
Guideline No./ Study
Type
MRID No. (year)/ Classification
/Doses
Results
Cytogenetics
870.5375 In vitro
Mammalian
Cytogenics
(Chromosomal
Aberration Assay in
Chinese Hamster Lung
Fibroblasts)
46406744 (2002)
Acceptable/Guideline
Trial 1 (-S9): 50, 70, 90, 110, or
130 ug/mL
Trial 1 (+S9): 50, 100, 150, 200,
or 250 ug/mL
Trial 2 (-S9) 20, 50, 80, or 110
ug/mL Trial 2 (+S9): 100, 150,
200, or 250 ug/mL
There was no evidence of chromosome aberration
induced over background in the presence or absence
of S9-activation.
Other Effects
870.5395 In vivo
Mammalian
Cytogenetics -
Erythrocyte
Micronucleus Assay in
Mice
46406745 (2002)
Acceptable/Guideline
0, 12.5, 25, or50mg/kg
There was no significant increase in the frequency
of micronucleated poly chromatic erythrocytes in
bone marrow compared to controls.
870.6200a
Acute neurotoxicity
screening battery
(Sprague-Dawley)
46406728 (2004)
Acceptable/Guideline
0, 20, 50, or lOOmg/kg
NOAEL = 50 mg/kg
LOAEL = 100 mg/kg, based on mortality, adverse
clinical signs, FOB (unusual behavior, limb
twitches/tremors, and abnormal respiration) effects,
and increased motor activity in both sexes.
870.6200b
Subchronic
neurotoxicity
screening battery
(Sprague-Dawley)
46406729 (2004)
Acceptable/Guideline
0,300, 1000, or 3000 ppm
M: 0,18.3, 59.8, or 178.8
mg/kg/day
F: 0,20.9,68.8,206.0
mg/kg/day
Systemic NOAEL = 59.8/68.8 mg/kg/day
Systemic LOAEL = 178.8/206.0 mg/kg/day, based
on mortality (females only); clinical signs
(soft/liquid feces and scant feces in the males and
tremors and twitches in the females); decreased
body weight, body weight gain, and absolute and
relative food consumption in both sexes.
Neurotoxicity NOAEL = 59.8/68.8 mg/kg/day
Neurotoxicity LOAEL = 178.8/206.0 mg/kg/day,
based on the clinical signs of tremors and twitches
in the females
870.7485
Metabolism and
pharmacokinetics
46406746, 46406747, 46406748,
46414002, and 46414003 (2004)
Acceptable/Guideline
1 or 20 mg/kg for single dose
studies
1 mg/kg for 21 day studies
Overall recoveries were 95-97% for both dose
groups. Absorption was rapid (detectable plasma
residues within 30 minutes, Tmax 3.3-8.0 hours) and
thorough (>80% absorption). Absorption was not
dose limited. At 168 hours post dosing, urinary and
fecal excretion accounted for 29-71% and 25-66%
of the total administered dose, respectively.
Radioactivity increased above plasma levels in both
liver and kidney, but dissipated 12 hours post-dose.
46 metabolites were identified, including all major
metabolites.
Non-Guideline
An evaluation of the
human relevance of
the metofluthrin-
induced liver tumors
in rats based on mode
of action
46756304 (2006)
Acceptable/Nonguideline
Summary of proposed MOA and weight of the
evidence. The MOA for metofluthrin-induced liver
tumors is postulated to involve liver cytochrome
P450 enzyme induction leading to stimulation of
increased cellular proliferation.
MOA not accepted by CARC due to insufficient
data.
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Table 4 Subchronic, Chronic, and Other Toxicity Profile
Guideline No./ Study
Type
MRID No. (year)/ Classification
/Doses
Results
Non-Guideline
Study for the mode of
action of S-1264 for
liver tumor promotion
in rats
(Wistar rats)
46581501 (2005)
Acceptable/Nonguideline
0, 900, 1800, or 3600 ppm in the
diet for 7 days
Concurrent recovery group fed
basal diet for 7 days following
treatment period
Liver morphology and enzyme induction were
affected in at 900 ppm and above, as evidenced by
increased liver weights, hepatocellular hypertrophy,
replicative DNA synthesis in the hepatocytes,
induction of CYP 2B and 3A mRNA, and increased
expression of CYP 2B. All of these findings were
reversible on cessation of treatment.
Non-Guideline
The 2nd study of mode
of action of S-1264 for
liver tumor promotion
in rats
46756301 (2006)
Acceptable/Nonguideline
0, 200, 900, 1800, or 3600 ppm in
diet for 7 days
Metofluthrin inhibited gap junction interactions (as
evidenced by decreased dye transfer) and induced
oxidative stress (measured by lipid oxidation and
GSH levels).
Non-guideline
Study for mode of
action of S-1264 for
liver tumor promotion
in rats (in vitro effects
of S-1264 on
cytochrome P450
activity and mRNA
levels)
46756302 (2006)
Acceptable/Nonguideline
Rat, mouse, and human
hepatocytes were exposed 50 |_iM
metofluthrin for 3 days, and
comparative metabolic profiles
were examined.
Metofluthrin induced CYP 2B mRNA and 7-
pentoxyresorufin O-depentylase activity in rat and
human hepatocytes, but not in mouse hepatocytes,
but the induction level was less than that of
phenobarbital induction in human hepatocytes.
Non-Guideline
Gene expression
profiling analysis of
early phase treatment
in the liver from S-
1264 treated rats
46756303 (2006)
Acceptable/Nonguideline
Wistar rats were exposed to 1800
ppm metofluthrin for 1 week.
DNA microarray was used to
evaluate gene expression.
The majority of genes upregulated by metofluthrin
were GSTs, CYPs, and UDPGTs. In general, this
resembled the upregulation of Phenobarbital, only
to a lesser degree.
HAZARD CHARACTERIZATION/ASSESSMENT
Potential areas of environmental justice concerns, to the extent possible, were considered
in this human health risk assessment, in accordance with U.S. Executive Order 12898,
"Federal Actions to Address Environmental Justice in Minority Populations and Low-
Income Populations." http://www.eh.doe.gov/oepa/guidance/justice/eol2898.pdf
Human Testing: This risk assessment does not rely on any data from studies in which
human subjects were intentionally exposed to a pesticide or other chemical.
Hazard and Dose-Response Characterization
The toxicology database for metofluthrin is complete for the proposed use pattern.
Although metofluthrin is a neurotoxicant, a developmental neurotoxicity (DNT) study is
not necessary at this time. However, if new uses are proposed, the need for a DNT study
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will need to be re-evaluated. The risk assessment team is confidant that risk to pregnant
women and children will not be underestimated due to: 1) regulatory endpoints are based
on neurotoxicity, 2) no neuropathy or changes in morphometrics were observed in the
acute and subchronic neurotoxicity studies, and 3) for pyrethroids where DNT studies
are available for endpoint consideration, the regulatory endpoints are generally based on
neurotoxicity to dogs because dogs are more sensitive to pyrethroids than rats (it is
unlikely that a DNT in rats would produce a lower neurotoxicity NOAEL than the
NOAEL from the chronic dog study).
Summary and Discussion of Dose Related Effects
Metofluthrin, like other pyrethroids, is neurotoxic in rats, rabbits, and dogs; both sexes
were equally sensitive to metofluthrin. Clinical signs include tremor (all species),
vomiting (dog only), and increased salivation (rats and dogs). Clinical signs appeared
within 206 hours post-dosing and generally disappeared by the dosing period the
following day. All routes of exposure (oral, dermal, and inhalation) elicited neurotoxic
effects in rats. Rats appeared to be most sensitive via the inhalation route, based on
clinical signs including ataxic gait, tremors, tip-toe gait, lateral position, clonic
convulsion, hypothermia, and mortality in both sexes. In the acute neurotoxicity battery,
neurotoxic effects were seen in rats following a single dose of 100 mg/kg/day including
mortality, tremors/twitches, abnormal respiration, and increased motor activity (acute
NOAEL = 50 mg/kg/day). Dermal exposure to 10 mg/kg/day in rats produced increased
vocalization during the daily application period, which subsided after the removal of the
chemical. There were no systemic effects resulting from dermal exposure. In
subchronic exposures in rats (based on the subchronic and developmental studies,
NOAELs ranged 15-20 mg/kg/day) the LOAELs range from 30-54.1 mg/kg/day, based
on liver effects and neurotoxicity. Neurotoxicity was not noted in the chronic studies.
The dose-response curve for neurotoxicity is steep with mortality occurring frequently at
the LOAEL; death was preceded by tremor, convulsion, salivation, and prostration.
Metofluthrin also targeted the liver in rats and mice, producing increased absolute and
relative liver weights, hepatocellular hypertrophy, and increase incidence of enlarged,
discolored livers. Hepatocellular toxicity was present at or above 48.7 mg/kg/day in mice
and 54.1 mg/kg/day in rats in the subchronic studies. In the chronic rat study, exposure
to metofluthrin was connected to increased incidence of hepatocellular adenomas,
carcinomas, and combined tumor types at doses greater than or equal to 38.1 mg/kg/day.
The registrant submitted a proposed mitogenic mode of action (MOA) for hepatocellular
tumor induction. While these studies did suggest a mitogenic MOA was plausible, the
studies did not provide enough information for the Agency to accept their proposed
MOA. Metofluthrin is not mutagenic or cytotoxic; it does not induce peroxisomal
proliferation. The Agency classified this chemical as "likely to be carcinogenic to
humans" and generated a Ql* of 1.62x10-2, based on the increased liver tumors in
female rats.
In utero and/or post-natal exposure to metofluthrin did not produce any evidence of
increased qualitative or quantitative susceptibility in fetuses or pups. Four acceptable
developmental studies in rats and rabbits were submitted for metofluthrin. Maternal
toxicity was seen at or above 30 mg/kg/day in rats (tremor, salivation, and mortality) and
125 mg/kg/day in rabbits (mortality, preceded by tremor/convulsion). These doses did
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not produce any developmental effects on the fetuses or pups. A developmental toxicity
study is not being requested at this time for the following reasons: 1) neurotoxicity is well
defined within the toxicology database, 2) regulatory endpoints are based on the
neurotoxicity, and 3) there were no pathology findings or changes in morphometrics
noted in either the acute or subchronic neurtoxicity studies. The FQPA safety factor has
been reduced to Ix.
Considerations for Infants and Children
The toxicity database for this chemical is complete for the purposes of this risk
assessment. Acceptable neurotoxicity and developmental studies have been submitted
for review. Though not required for a non-food use registration, a 2-generation rat
reproduction study is being conducted. The Agency has received preliminary results in a
6(a)(2) document, but the final study report has not been submitted at this time.
Neurotoxicity
Evidence of neurotoxicity exists throughout the entire toxicology database via the oral
route of exposure in three species (rats, rabbits, and dogs) and via dermal and inhalation
routes of exposure in rats.
In the acute neurotoxicity study in rats, a single dose of 100 mg/kg produced tremors,
twitches, abnormal respiration, increased motor activity, and mortality. The animals
found dead or in extremis 24 hours post-dosing (7 out of 20 animals) exhibited signs of
clonic convulsions, hyperpnea, prostration, lost righting reflex, soft or liquid feces, tonic
extensor convulsions, salivation, chromorhinorrhea, and chromodachyorrhea. In the
subchronic neurotoxicity study, the LOAEL (59.8/68.8 M/F, respectively) was based on
mortality in the females; clinical signs including tremors and twitches (in females);
decreased body weight and body weight gain, and absolute and relative food
consumption in both sexes. Neither study indicated neuropathy.
In a subchronic oral study in rats, all animals exhibited signs of tremor 2-6 hours post-
dosing during Week 1 of treatment at doses above 164.6 mg/kg/day; 0-2 animals/sex
exhibited transient tremors throughout Weeks 2-3. No clinical signs were observed after
Week 3. At 100 mg/kg/day in the subchronic dog study, 5/6 males showed signs of
tremor (1-7 incidences/animal) beginning on Day 23 and 5/6 females showed signs of
tremor (1-5 incidences/animal) beginning on Day 10. Mild repetitive jerks or tremors of
the head, limb or body were seen in 1 animal/sex at Weeks 12-13 (male) and Weeks 11
and 13 (female); these effects were evidenced during cage-side and table top
observations. Three developmental rat studies were performed for metofluthrin; all three
maternal LOAELs were based on tremor and salivation and two maternal LOAELs
included mortality.
In the subchronic dermal study in rats, two females were found dead on Day 2 in the
1000 mg/kg/day dose group. One female, before being found dead, displayed tremors
prior to dosing and salivation 3-5 hours post-dosing. Hyperactivity and vocalization were
transiently observed in the >= 30 mg/kg/day females and >= 100 mg/kg/day males during
the daily application period on Days 1-4. There were no treatment-related clinical signs
outside of the daily dosing period.
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In the 28-day inhalation toxicity study in rats, 7/10 males and 3/10 females in the 0.196
mg/L dose group died. At this concentration, tremors of the tail and body were observed
during the treatment period; tremor, hypersensitivity, ataxic gait, tiptoe gait, lateral
position, clonic convulsion, and hypothermia were observed. Onset occurred on Days 1-
4, and clinical signs were transiently seen until Day 26 in males and less frequently in the
females until Day 24.
No evidence of neurotoxicity was recorded in either the rat or the mouse
chronic/carcinogenicity studies. Increased incidence of tremor was observed in males at
30 mg/kg/day in the chronic dog study. Tremor was observed in the head, limbs, or body
of all males beginning on Day 96 (1-5 incidences/dog except one male with 46
incidences) and in only one female and only on Day 289. Tremors were observed 2-6
hours post-dosing and disappeared by the time of observation the next morning.
Developmental Toxicity
Acceptable guideline developmental toxicity studies in rats and rabbits have been
submitted for review, along with two acceptable non-guideline developmental studies in
rats. In the three rat studies (MRID 46454111, 46454112, 46454113) maternal toxicity
was observed in the form of neurotoxicity (tremors and salivation) and death. Neurotoxic
effects were observed 2-3 hours post dosing and disappeared by the following day. The
maternal NOAELs ranged from 15-20 mg/kg/day, and the maternal LOAELs ranged
from 30-40 mg/kg/day. No developmental effects were seen in the rat studies up to 40
mg/kg/day. In one non-guideline study (MRID 46454112) males and females were dosed
during the premating and mating periods all the way through gestation day (GD)7 for
females. No reproductive effects were noted in either the males or females up to 20/40
mg/kg/day (males/females, respectively, highest dose tested). In the other non-guideline
study (MRID 46454113), the female rats were dosed from GD6 (implantation) through
lactation day (LD)20. Reproductive effects were not observed in the P or Fl generations.
There were no offspring effects noted with regard to FOB results, sensory reflexes,
clinical signs, developmental landmarks, body weights, or gross pathology up to the
highest dose tested of 30 mg/kg/day.
In the rabbit developmental study, one female in the 125 mg/kg/day group exhibited
sneezing and convulsions before death on GD23. One female in the 250 mg/kg/day dose
group was found dead on GD14. These deaths were considered treatment related because
another female was found dead with convulsions preceding death in the range finding
study at 200 mg/kg/day. There were no other mortalities or clinical signs; the LOAEL
was determined to be 125 mg/kg/day. The maternal NOAEL is 25 mg/kg/day. There
were no treatment-related effects on developing fetuses; the developmental LOAEL was
not observed. The developmental NOAEL was determined to be 250 mg/kg/day, the
highest dose tested.
Reproductive Toxicity
A reproductive study in rats has not been submitted to the EPA at this time. However,
the Agency has received a 6(a)(2) document indicating that a 2-generation reproduction
study in rats is being performed. Preliminary findings include neurotoxic effects
(tremors, convulsions, and salivation) in the Fl and F2 generations. When the final study
report is submitted, a full review of the data will be conducted.
-------
Pre-and/or Postnatal Toxicity
There were no effects on fetal growth or development up to 40 mg/kg/day in rats or 250
mg/kg/day in rabbits; doses at which maternal toxicity was present. There were no
treatment related effects on the numbers of litters, fetuses (live or dead), resorptions, sex
ratio, or post-implantation loss. There were no effects on fetal body weights or skeletal
ossification; and no external, visceral, or skeletal malformations or variations were
observed.
Developmental Neurotoxicity
A DNT study is not being requested at this time; however, because this chemical is part
of the pyrethroid class, the need for a DNT study will be re-evaluated for all future
proposed uses
Summary of Toxicological Doses and Endpoints for Metofluthrin for Use in Human
Risk Assessments
Table 3.4.2 Summary of Toxicological Doses and Endpoints for Metofluthrin for Use in Non-
Occupational Human Health Risk Assessments
Exposure/
Scenario
Incidental Oral
Short-Term (1-
30 days)
Dermal Short-
Term (1-30
days)
Inhalation
Short-Term
(ALL
DURATIONS)
Cancer (oral,
dermal,
inhalation)
Point of
Departure
NOAEL =
15
mg/kg/day
NOAEL=
300
mg/kg/day
NOAEL =
16
mg/kg/day
Likely to
be a human
carcinogen
Uncertainty
Factors
UFA= lOx
UFH=10x
UFA= lOx
UFH= lOx
UFA= lOx
UFH=10x
Qi* =
1.62X10'2
(mg/kg/day)"
i
Dermal
absorption
factor =
17%
Level of
Concern for
Risk
Assessment
Residential
LOCforMOE
= 100
Residential
LOCforMOE
= 100
Residential
LOCforMOE
= 100
Study and Toxicological Effects
Developmental Rat Study
LOAEL = 30 mg/kg/day based on
increased incidence of tremor in
maternal animals
90-Day Dermal Rat Study
LOAEL = 1000 mg/kg/day based on
mortality and clinical signs
28-Day Inhalation Study in Rats
LOAEL = 32 mg/kg/day based on
mortality and clinical signs including
tremors, ataxia, hypersensitivity, ataxic
gait, tiptoe gait, lateral position, clonic
convulsion, and hypothermia in both
sexes
Based on female rat liver combined
adenoma and carcinoma tumor rates
NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF =
uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in
sensitivity among members of the human population (intraspecies). UFDB = to account for the absence of
key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose
(a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOG = level of concern. N/A
= not applicable.
-------
Public Health and Pesticide Epidemiology Data
Metofluthrin is a new active ingredient; therefore, no epidemiological data is available at
this time.
Dietary Exposure/Risk Characterization
There are no proposed agricultural uses for metofluthrin at this time; therefore dietary
exposure is not expected.
Residential (Non-Occupational) Exposure/Risk Pathway
The aggregate exposure assessment is based solely on residential use patterns. Due to the
seasonal nature of insect repellents, only short-term exposure scenarios were considered.
The incidental oral endpoint for children was based on maternal neurotoxicity in the rat
developmental study (NOAEL =15 mg/kg/day). This endpoint was selected because of
the appropriate time period in which the maternal neurotoxic effects were seen. The
short-term dermal endpoint for adults and children (15 mg/kg/day) was selected from the
same developmental rat study based on neurtoxic effects because no systemic toxicity
was present in the 90-day dermal study. A dermal penetration study in rats was
submitted for metofluthrin, which suggests a 17% dermal absorption rate. This 17%
dermal absorption rate was applied to all dermal exposure scenarios. The 28-day
inhalation study in rats provided a sensitive inhalation endpoint (0.099 mg/L) based on
mortality and neurotoxic effects (including tremors, hypersensitivity, ataxic gait, tip-toe
gait, clonic convulsion, and hypothermia. The default absorption value of 100% was
applied to the inhalation exposure assessment. All levels of concern are set at 100, based
on a 1 Ox interspecies extrapolation safety factor and lOx intraspecies variability safety
factor. The FQPA safety factor was reduced to Ix.
As a part of every pesticide risk assessment, the Agency considers a large variety of
consumer subgroups according to well-established procedures. The Agency estimates
risks to population subgroups from pesticide exposure that are based on patterns of that
subgroup's food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting. Extensive data on food consumption
patterns are compiled by USD A under the Continuing Survey of Food Intake by
Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses
of a pesticide. These data are analyzed and categorized by subgroups based on age,
season of the year, ethnic group, and region of the country. Additionally, the Agency is
able to assess dietary exposure to smaller, specialized subgroups and exposure
assessments are performed when conditions or circumstances warrant. Whenever
appropriate, nondietary exposures based on home use of pesticide products and
associated risks for adult applicators and for toddlers, youths, and adults entering or
playing on treated areas post-application are evaluated. Further considerations are
currently in development as the Agency has committed resources and expertise to the
development of specialized software and models that consider exposure to bystanders and
farm workers as well as lifestyle and traditional dietary patterns among specific
populations.
Estimated Cancer Risk
The Ql* for metofluthrin was based on female hepatocellular adenomas, carcinomas, and
-------
combined adenomas/carcinomas in rats. The Ql* is 1.62 x 10-2 (mg/kg/day) -1. This
cancer assessment is conservative in assuming that the product will be used 12 times per
year for 50 years out of a 70 year lifespan.
A high-end worst case inhalation cancer assessment was performed for the metofluthrin
products (DeckMate and NORM-1). The saturation concentration of 0.28 mg/ m3 was
used, with a 12 hour / day exposure time (half a day). An adult breathes 20 m3 of air per
day. The use frequency was 12 applications per year from the use survey conducted by
the Residential Exposure Joint Venture (REJV). The users are expected to use the
products over a 50 year period in their 70 year lifetime. This results in a Lifetime
Average Daily Dose (LADD) of 0.000939 mg/kg/day. The LADD is multiplied by the
Ql*, which results in an estimated cancer risk of 1.5 x 10-5.
Aggregate Exposure Assessment
Metofluthrin is proposed for residential use only at this time. No food uses exist.
Residues in water are unlikely. An aggregate exposure assessment is not needed at this
time.
Cumulative Risk Characterization/Assessment
Metofluthrin is a member of the pyrethroid class of pesticides. Although all pyrethroids
alter nerve function by modifying the normal biochemistry and physiology of nerve
membrane sodium channels, EPA is not currently following a cumulative risk approach
based on a common mechanism of toxicity for the pyrethroids. Although all pyrethroids
interact with sodium channels, there are multiple types of sodium channels and it is
currently unknown whether the pyrethroids have similar effects on all channels. Nor do
we have a clear understanding of effects on key downstream neuronal function e.g., nerve
excitability, nor do we understand how these key events interact to produce their
compound specific patterns of neurotoxicity. There is ongoing research by the EPA's
Office of Research and Development and pyrethroid registrants to evaluate the
differential biochemical and physiological actions of pyrethroids in mammals. This
research is expected to be completed by 2007. When available, the Agency will consider
this research and make a determination of common mechanism as a basis for assessing
cumulative risk. For information regarding EPA's procedures for cumulating effects
from substances found to have a common mechanism on EPA's website at
http://www.epa.gov/pesticides/cumulative/.
Occupational Exposure/Risk Pathway
Only residential uses are proposed for metofluthrin at this time; dietary and occupational
risk assessments are not necessary at this time.
ENVIRONMENTAL FATE AND EFFECTS SUMMARY
Metofluthrin, like other synthetic pyrethroids, is practically non-toxic to mammals and
birds, but it is highly to very highly toxic to aquatic animals and insects. Its repellency
power is related to its insecticidal character. The published literature supports its
character both as a repellent and as an insecticide. No Level of Concern was exceeded,
but the insecticidal properties of metofluthrin imply that it will pose a risk to non-target
-------
insects and to species federally listed as endangered or threatened by the United States
government.
Since there is no geographic restriction on metofluthrin's use, it will be used in every
place where there are mosquitoes. The proposed use is not expected to stress aquatic or
terrestrial vertebrates or aquatic invertebrates even though it is toxic to them, because it is
not expected to have a high aquatic concentration.
Environmental Effects
The registrant has submitted adequate effects and fate data needed to complete a Tier 1
Risk Assessment. A summary of all submitted studies are shown in Table 5 and 6 below.
Metofluthrin's effect on aquatic organisms is estimated from acute, subacute and chronic
laboratory studies submitted to the Agency. The registrant has submitted acute and
chronic studies on aquatic vertebrates and invertebrates. Freshwater fish, e.g., bluegill
sunfish (Lepomis macrochirus), rainbow trout (Oncorhynchus mykiss) and fathead
minnow (Pimephales promelas) are used as surrogates for all freshwater fish species.
Freshwater fish are used as surrogates for aquatic-phase amphibians. No acute bluegill
sunfish (§72-la) was submitted. A common carp study was ruled "supplemental,"
because it is not a standard species. The Agency shall require confirmatory data to
satisfy the acute bluegill sunfish data requirement.
The effect of metofluthrin on all bird species is estimated from acute, subacute and
chronic studies on two species, bobwhite quail (Colinus virginianus) and mallard duck
(Anas platyrhynchos). These species also act as surrogates for reptiles and terrestrial-
phase amphibians. Effects on mammals are estimated from acute and chronic rat studies
submitted to and reviewed by the Agency.
No studies have been submitted that address toxicity to insects. The registrants have
requested a waiver for a study on beneficial insects (bees), but this has not been granted.
There are no published field surveys or monitoring data. Published information
(Kawada, et al.) found that metofluthrin kills insects (mosquitoes) in a cage. All
experimental mosquitoes directly under a paper strip were killed within 24-hours. This
was not quantified nor was a measure of toxicity (LD50, etc.) calculated. The Agency
shall require confirmatory data to satisfy this data requirement.
TABLE 5 Measures of Envrionmental Effects of metofluthrin
Guidelines
71-l(a)
71-2(a)
71-2(b)
OPPTS 870. 1100
Data Requirements
Acute Avian Oral Quail or
Duck
Avian Dietary /Quail
Avian Dietary /Duck
Rat Acute Oral LD50
Measures Of Effect
LD50 >2250 mg/kg-bw.
LC50 >5760 mg/kg-bw
LC50 >5760 mg/kg-bw.
LD50 >2,000 mg/kg
-------
Non-guideline
72-1
72-l(c)
72-2(a)
Rat reproductive
development study
Fish Toxicity- Common carp
Fish Toxicity Rainbow Trout
Invertebrate Toxicity,
Daphnid
NOAEL = 20 mg/kg bw/day
during the 57 days of dosing
LC50 = 2.61
IAo=1.2
48-hr LC50 = 4.7 ppb
dose based on maternal mortality
Table 5. Environmental Fate properties of metofluthrin.
PARAMETER
Solubility
in water (20 °C)
Vapor Pressure (20 °C)
Henry's Law Constant
(20 °C)
Hydrolysis Half-life
(25 °C)
Aqueous Photolysis
Half-life (pH 4)
Aerobic Soil
Metabolism Half-life
Soil Partition
Coefficient (Kd)
Organic Carbon
Partition
Coefficient (Koc)
VALUE(S)
0.50 mg/L (Z-isomer)
0.67 mg/L (E-isomer)
1.47xlO-5mmHg
1.5xlO"5atmm3/mol(Z-
isomer)
1.1 x 10"5 atm mVmol (E-
isomer)
PH4&7: Stable
pH9: 33 days
6 days
MS sandy loam'. DT50 = 3-8
days
CA sandy loam: DT50 = 1-3
days
57.5,75.8,85.3, 163
mL/g
3704,4489,5414,7187
mL/goc
SOURCE
MRID 46406754
MRID 46402005
Estimated from vapor pressure & solubility1
MRID 46406750
MRID 46406754
(Based on 12-hour light/12-hour dark cycle
with Xe lamp)
MRID 46406751
MRID 46406753
(calculated, based on submitted data)
MRID 46406753
(Calculated, based on calculated Kd)
Estimated as Hg = vapor pressure (atm) + solubility (mol/L)
-------
Contact Person at USEPA
Mailing address:
Mark Suarez
Product Manager (10)
Environmental Protection Agency
Office of Pesticide Programs
Registration Division (7505P)
Insecticide Branch
1200 Pennsylvania Avenue NW
Washington, D.C. 20460
Office location and telephone number:
Room S-7246, One Potomac Yard
2777 S. Crystal Drive
Arlington, VA 22202
703-305-0120
DISCLAIMER: The information in this Pesticide Fact Sheet is for information only
and is not to be used to satisfy data requirements for pesticide registration. The
information is believed to be accurate as of the date on the document.
-------
APPENDIX I
GLOSSARY OF TERMS AND ABBREVIATIONS
ADNT Acute delayed neurotoxicity
a.i. Active Ingredient
aPAD Acute Population Adjusted Dose
ARI Aggregate Risk Index
BCF Bioconcentration Factor
CAS Chemical Abstracts Service
ChE Cholinesterase
ChEI Cholinesterase inhibition
cPAD Chronic Population Adjusted Dose
%CT Percent crop treated
DAT Days after treatment
DEEM-FCID Dietary Exposure Evaluation Model - Food Consumption Intake Database
DNA Deoxyribonucleic acid
DNT Developmental neurotoxicity
DIT Developmental immunotoxicity
DWLOC Drinking Water Level of Comparison.
EC Emulsifiable Concentrate Formulation
EEC Estimated Environmental Concentration. The estimated pesticide
concentration in an environment, such as a terrestrial ecosystem.
EPA U.S. Environmental Protection Agency
FQPA Food Quality Protection Act
GLC Gas Liquid Chromatography
GLN Guideline Number
Median Lethal Concentration. A statistically derived concentration of a
substance that can be expected to cause death in 50% of test animals. It is
usually expressed as the weight of substance per weight or volume of
water, air or feed, e.g., mg/1, mg/kg or ppm.
Median Lethal Dose. A statistically derived single dose that can be
expected to cause death in 50% of the test animals when administered by
the route indicated (oral, dermal, inhalation). It is expressed as a weight of
substance per unit weight of animal, e.g., mg/kg.
LOAEL Lowest Observed Adverse Effect Level
LOAEC Lowest Observed Adverse Effect Concentration
LOG Level of Concern
LOD Limit of Detection
LOQ Limit of Quantitation
mg/kg/day Milligram Per Kilogram Per Day
mg/L Milligrams Per Liter
MOE Margin of Exposure
-------
MRID Master Record Identification (number), EPA's system of recording and
tracking studies submitted
MTD Maximum tolerated dose
NA Not Applicable
NOEC No Observable Effect Concentration
NOEL No Observed Effect Level
NOAEL No Observed Adverse Effect Level
NOAEC No Observed Adverse Effect Concentration
NPDES National Pollutant Discharge Elimination System
OP Organophosphate
OPP EPA Office of Pesticide Programs
OPPTS EPA Office of Prevention, Pesticides and Toxic Substances
PAD Population Adjusted Dose
PAG Pesticide Assessment Guideline
PAM Pesticide Analytical Method
PHED Pesticide Handler's Exposure Data
PHI Preharvest Interval
ppb Parts Per Billion
PPE Personal Protective Equipment
ppm Parts Per Million
PRZM/EXAMS
Tier II Surface Water Computer Model
RAC Raw Agriculture Commodity
RBC Red Blood Cell
RED Reregi strati on Eligibility Decision
REI Restricted Entry Interval
RfD Reference Dose
SCI-GROW Tier I Ground Water Computer Model
SF Safety Factor
TGAI Technical Grade Active Ingredient
UF Uncertainty Factor
jig micrograms
|ig/L Micrograms Per Liter
|iL/g Microliter per gram
USDA United States Department of Agriculture
WPS Worker Protection Standard
-------
APPENDIX II
Citations Considered to be Part of the Data Base Supporting the Registration of
Metofluthrin.
MRID
46406701
Citation
| Todd, R. (2004) Product Identity and Disclosure of
Ingredients of S-1264 Technical Grade. Project Number:
QAP/0034. Unpublished study prepared by Insect Control
and Research Inc. 5 p.
Receipt Date
12-Nov-2004
46406702
Suzuki, M. (2004) Description of Beginning Materials and
Manufacturing Process for S-1264: Description of
Formation of Impurities. Project Number: QAP/0033.
Unpublished study prepared by Sumitomo Chemical
Company, Ltd. 18 p.
12-Nov-2004
46406703
Inoue, H. (2002) Preliminary Analysis of S-1264 Technical
Grade: Final Report. Project Number: 3771, QAP/0016.
Unpublished study prepared by Sumitomo Chemical
Company, Ltd. 38 p.
12-Nov-2004
46406704
Todd, R. (2004) Certification of Ingredient Limits of S-
1264 Technical Grade. Project Number: QAP/0035.
Unpublished study prepared by Insect Control and Research
Inc. 9 p.
12-Nov-2004
46406705
Inoue, H. (2002) Enforcement Analytical Methods of S-
1264 Technical Grade: Final Report. Project Number: 3679,
QAA/0009. Unpublished study prepared by Sumitomo
Chemical Company, Ltd. 106 p.
12-Nov-2004
46406706
Sweetapple, G.; Lentz, N. (2003) Determination of
Physical-Chemical Properties of S-1264. Project Number:
QAP/0020, 015682/1. Unpublished study prepared by
Ricerca Biosciences, LLC. 44 p.
12-Nov-2004
46406707
Sweetapple, G.; Lentz, N. (2004) Determination of
UV/Visible Absorption and Boiling Point of S-1264.
Project Number: 015681/1, 015681. Unpublished study
prepared by Ricerca Biosciences, LLC. 36 p.
12-Nov-2004
46406708
Walsh, K.; Lentz, N. (2003) Determination of Water
Solubility - S-1264. Project Number: 015634/1, QAP/0019,
015634. Unpublished study prepared by Ricerca
Biosciences, LLC. 112 p.
12-Nov-2004
46406710
Beckwith, R.; Lentz, N. (2003) Determination of
Dissociation Constant (pKa) - S-1264. Project Number:
12-Nov-2004
-------
MRID
Citation
015635/1, QAP/0021, 015635/0. Unpublished study
prepared by Ricerca Biosciences, LLC. 34 p.
46406711
46406712
Walsh, K.; Lentz, N. (2003) Determination of n-
Octanol/Water Partition Coefficient - S-1264. Project
Number: 015633/1, QAP/0023, 015633/0/1. Unpublished
study prepared by Ricerca Biosciences, LLC. 86 p.
Inoue, H. (2004) Stability of S-1264 Technical Grade to
Normal and Elevated Temperatures, Metals and Metal Ions:
Final Report. Project Number: 0007, QAP/0024.
Unpublished study prepared by Sumitomo Chemical Co.
Ltd., Envr. Health. 15 p.
T
Receipt Date
12-Nov-2004
12-Nov-2004
46406715
j Inoue, H. (2004) Storage Stability of S-1264 Technical
j Grade: Final Report. Project Number: 0001, QAP/0025.
j Unpublished study prepared by Sumitomo Chemical Co.
I Ltd., Envr. Health. 54 p.
12-Nov-2004
46406716
r~
Inoue, H. (2004) Corrosion Characteristics of S-1264
Technical Grade: Final Report. Project Number: 0002,
QAP/0026. Unpublished study prepared by Sumitomo
Chemical Co., Ltd. lip.
12-Nov-2004
46406717
Todd, R. (2004) Waiver Rationale for Dielectric
Breakdown Voltage Study on SumiOne (Metofluthrin).
Project Number: 110804/DIEL. Unpublished study
prepared by Insect Control and Research, Inc. 4 p.
12-Nov-2004
46406718
Lentz, N. (2004) Determination of Freezing Point, Solvent
Solubility, Absorption Spectra and Autoflammability of S-
1264. Project Number: QAP/0030, 016369/1, 016369/0.
Unpublished study prepared by Ricerca Biosciences, LLC.
72 p.
12-Nov-2004
46406719
r~
Kunimatsu, T. (2002) Acute Oral Toxicity STudy of S-1264
in Rats: Final Report. Project Number: QAT/0004, 3670.
Unpublished study prepared by Sumitomo Chemical Co.
Ltd., Envr. Health. 30 p.
12-Nov-2004
46406721
Kunimatsu, T. (2002) Acute Dermal Toxicity Study of S-
1264 in Rats: Final Report. Project Number: QAT/0005,
3671. Unpublished study prepared by Sumitomo Chemical
Co. Ltd., Envr. Health. 23 p.
46406723
Deguchi, Y. (2002) Acute Inhalation Toxicity Study of S-
1264 in Rats: Final Report. Project Number: 3666,
QAT/0028, P01096. Unpublished study prepared by
12-Nov-2004
12-Nov-2004
-------
MRID
Citation
Sumitomo Chemical Co. Ltd., Envr. Health and Sumika
Chemical Analysis Service, Ltd. 61 p.
46406724
46406726
46406728
Nakamura, Y. (2001) Skin and Eye Irritation Tests of S-
1264 in Rabbits: Final Report. Project Number: 3634,
QAT/0014. Unpublished study prepared by Sumitomo
Chemical Co. Ltd., Envr. Health. 19 p.
Nakamura, Y. (2002) Skin Sensitization Test of S-1264 in
Guinea Pigs (Maximization Test): Final Report. Project
Number: 3684, QAT/0017. Unpublished study prepared by
Sumitomo Chemical Co. Ltd., Envr. Health. 27 p.
York, R. (2004) Oral (Gavage) Acute Neurotoxicity Study
of S-1264 in Rats: Final Report. Project Number: 1119/032,
QAT/0059, PACA/DE04. Unpublished study prepared by
Argus Research Laboratories, Inc and Pathology
Associates, Inc. 451 p.
Receipt Date
12-Nov-2004
12-Nov-2004
12-Nov-2004
46406729
York, R. (2004) Oral (Diet) Subchronic Neurotoxicity
Study of S-1264 in Rats: Final Report. Project Number:
1119/033, QAT/0060, PACA/DE05. Unpublished study
prepared by Argus Research Laboratories, Inc and Charles
River Laboratories and Pathology Associates, Inc. 510 p.
12-Nov-2004
r~
46406731
j Kunimatsu, T. (2002) One-Month Oral Toxicity Study of S-
j 1264 in Rats: Final Report. Project Number: 3641,
| Q AT/0029, P01063. Unpublished study prepared by
! Sumitomo Chemical Co. Ltd., Envr. Health. 432 p.
12-Nov-2004
46406733
Kunimatsu, T. (2002) Six-Month Oral Toxicity Study of S-
1264 in Rats: Final Report. Project Number: QAT/0030,
3663, P01063. Unpublished study prepared by Sumitomo
Chemical Co. Ltd., Envr. Health. 452 p.
12-Nov-2004
46406734
Uchida, H. (2002) 90-Day Oral Toxicity Study with S-1264
in Beagle Dogs Followed by 42-Day Recovery Study: Final
Report. Project Number: QAT/0018, 20142. Unpublished
study prepared by Panapharm Laboratories Co., Ltd. 230 p.
12-Nov-2004
r~
46406735
Furukawa, H. (2004) A 90-Day Repeated Dose Dermal
Toxicity Study of S-1264 in Rats: Final Report. Project
Number: P030373, QAT/0064. Unpublished study prepared
by Panapharm Laboratories Co., Ltd. 393 p.
1 Deguchi, Y. (2002) Four-Week Repeated Inhalation
46406736 | Toxicity Study of S-1264 in Rats: Final Report. Project
1 Number: 3704, Q AT/0031, P02027. Unpublished study
12-Nov-2004
12-Nov-2004
-------
MRID
Citation
prepared by Sumitomo Chemical Co. Ltd., Envr. Health.
413 p.
Kitamoto, S. (2002) Reverse Mutation Test of S-1264 in
4640674? I Bacterial Systems: Final Report. Project Number: 3673,
' QAT/0026. Unpublished study prepared by Sumitomo
Chemical Co. Ltd., Envr. Health. 18 p.
46406744
Odawara, K. (2002) In Vitro Chromosomal Aberration Test
on S-1264 in Chinese Hamster Lung Cells (CHL/IU): Final
Report. Project Number: 3633, QAT/0022. Unpublished
study prepared by Sumitomo Chemical Co. Ltd., Envr.
Health. 27 p.
Receipt Date
12-Nov-2004
12-Nov-2004
T
46406745
j Odawara, K. (2002) Micronucleus Test on S-1264 in Mice:
j Final Report. Project Number: 3685, QAT/0032.
j Unpublished study prepared by Sumitomo Chemical Co.
| Ltd., Envr. Health. 20 p.
12-Nov-2004
46406746
46406747
Sugimoto, K. (2002) The Disposition and Metabolism of
[Carbonyl-(Carbon-14)]S-1264RTZ in Rats. Project
Number: PK0141, QAM0001, PPLK/PK0141. Unpublished
study prepared by Sumitomo Chemical Co. Ltd., Envr.
Health. 1043 p.
12-Nov-2004
Sugimoto, K. (2002) The Disposition and Metabolism of
Metoxymethylbenzyl-(alpha)-(Carbon 14)S-1264TRZ in
Rats. Project Number: QAM/0003, PK0142, X0081.
Unpublished study prepared by Panapharm Laboratories
Co., Ltd. 871 p.
! 12-Nov-2004
46406748
Sugimoto, K. (2004) The Disposition and Metabolism of
[carbonyl-(Carbon 14)]S-1264RTE in Rats. Project
Number: QAM/0002, PK0143, RIA01028. Unpublished
study prepared by Panapharm Laboratories Co., Ltd. 777 p.
12-Nov-2004
46406749
Tomigahara, Y. (2004) Percutaneous Absorption of S-1264
in Rats. Project Number: X0088, QAM/0022. Unpublished
study prepared by Sumitomo Chemical Co. Ltd., Envr.
Health. 8 p.
12-Nov-2004
46406750
Ponte, M. (2004) Hydrolysis of [Carbon-14]S-1264 at pH 4, j
7 and 9. Project Number: 1192W, 1192W/001. Unpublished j 12-Nov-2004
study prepared by PTRL West, Inc. 187 p. !
46406751
Kodaka, R.; Sugano, T.; Yoshimura, J.; et. al. (2003)
Aerobic Soil Metabolism Study of [Carbon-14]S-1264.
Project Number: SOI2002B, EF/2003/003, QAM/0014.
12-Nov-2004
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MRID
Citation
Unpublished study prepared by Sumitomo Chemical Co. 67
P-
Curry, K.; Brookman, D. (2004) Metofluthrin Aerobic Soil
| 46406752 t Metabolism: Supplemental Information. Unpublished study
prepared by Technology Sciences Group, Inc. 29 p.
Receipt Date
12-Nov-2004
46406753
Ponte, M. (2004) Soil Adsorption/Desorption of [Carbon-
14]S-1264 by the Batch Equilibrium Method. Project
Number: 1191W, 1191W/1, QAM/0018. Unpublished study
prepared by PTRL West, Inc. 291 p.
12-Nov-2004
j Ponte, M. (2004) Aqueous Photolysis of (Carbon 14)S-
i 1^4 in pH 4 Buffer by Artificial Light. Project Number:
! QAM/0019, 1238W. Unpublished study prepared by PTRL
I West, Inc. 251 p.
12-Nov-2004
46406755
Curry, K.; Brookman, D. (2004) Request for a Waiver of
the Requirement for Data on Metofluthrin Terrestrial Field
Dissipation. Unpublished study prepared by Technology
Sciences Group, Inc. 19 p.
12-Nov-2004
46406756
Todd, R. (2004) Waiver Rationale for Honey Bee Acute
Contact Toxicity Study on SumiOne (Metoflurin). Project
Number: 110804/BEE. Unpublished study prepared by
Insect Control And Research Inc. 5 p.
12-Nov-2004
46406757
Gallagher, S.; Grimes, J.; Beavers, J. (2003) An Acute Oral
Toxicity Study with the Northern Bobwhite. Project
Number: QAW/0005, 166/172. Unpublished study prepared
by Wildlife International, Ltd. 50 p.
12-Nov-2004
i™"
46406758
Gallagher, S.; Grimes, J.; Martin, K.; et. al. (2003) A
Dietary LC 50 Study With the Northern Bobwhite. Project
Number: QAW/0003, 166/170. Unpublished study prepared
by Wildlife International, Ltd. 63 p.
12-Nov-2004
46406759
Gallagher, S.; Grimes, J.; Martin, K.; et. al.; (2003) S-1264:
A Dietary LC50 Study With the Mallard. Project Number:
QAW/0004, 166/171. Unpublished study prepared by
Wildlife International, Ltd. 64 p.
12-Nov-2004
46406760
46406761
Takimoto, Y. (2002) [Methoxymethylbenzyl-alpha-(Carbon
14)]S-1264: Acute Toxicity Test with Common Carp
(Cyprinus carpio) Under Flow-Through Conditions. Project 12-Nov-2004
Number: QAW/0002, 1043/010/174. Unpublished study
prepared by Springborn Laboratories (Europe) Ag. 89 p.
j
Lima, W. (2004) S-1264 - Acute Toxicity to Rainbow Trout j 12-Nov-2004
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MRID
Citation
(Oncorhynchus mykiss) Under Flow-Through Conditions.
Project Number: 13048/6398, QAW/0007. Unpublished
study prepared by Springborn Smithers Laboratories. 51 p.
46406762
46406764
r~
Putt, A. (2004) S-1264 - Acute Toxicity to Water Fleas
(Daphnia magna) Under Flow-Through Conditions. Project
Number: 13048/6397, QAW/0006. Unpublished study
prepared by Springborn Smithers Laboratories. 53 p.
Receipt Date
Todd, R.; Burin, G.; Brookman, D.; et. al. (2004) Reduced
Risk Document for Metofluthrin-Based Mosquito Repellent
Devices. 75 p.
12-Nov-2004
12-Nov-2004
46414001
Sweetapple, G.; Lentz, N. (2003) Determination of
UV/Visible Absorption and Boiling Point of S-1264.
Project Number: QAP/0022, 015681/1, 015681/0.
Unpublished study prepared by Ricerca Biosciences, LLC.
36 p.
30-Nov-2004
46414002
46414003
Sugimoto, K. (2004) The Disposition and Metabolism of j
[Carbonyl-(Carbon 14)] S-1264RTZ (IR-trans-Z) After j
Repeated Administration to Rats. Project Number: | 30-Nov-2004
P020096, QAM/0004. Unpublished study prepared by j
Panapharm Laboratories Co., Ltd. 113 p. j
Sugimoto, K. (2004) The Disposition and Metabolism of j
[methoxymethylbenzyl-(alpha)-(Carbon 14)] S-1264RTZ |
(IR-trans-Z) After Repeated Administration to Rats. Project j 30-Nov-2004
Number: QAM/0005, P020095. Unpublished study |
prepared by Panapharm Laboratories Co., Ltd. 118 p. J
46454101
DiFrancesco, D.; Lentz, N. (2004) Determination of Vapor
Pressure - S-1264. Project Number: 015632/1, QAP/0028.
Unpublished study prepared by Ricerca Biosciences, LLC.
82 p.
26-Jan-2005
46454102
Nishiyama, M.; Katagi, T.; Takimoto, Y. (2004) Stability in
Air of MFFO. Project Number: STA2004B, EF/2004/033, j
QAP/0031. Unpublished study prepared by Sumitomo )
Chemical Co. 8 p. !
26-Jan-2005
46454103
Nishyama, M.; Katagi, Takimoto, Y. (2004) Stability in Air
of S-1264. Project Number: STA2004A, EF/2004/032,
QAP/0032. Unpublished study prepared by Sumitomo
Chemical Co. 9 p.
26-Jan-2005
46454104
Ose, K. (2004) Acute Oral Toxicity Study of MFFO in
Rats. Project Number: 3910. Unpublished study prepared
26-Jan-2005
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MRID
Citation
by Sumitomo Chemical Co. Ltd., Envr. Health. 30 p.
46454105
Ose, K. (2004) Acute Dermal Toxicity Study of MFFO in
Rats. Project Number: 3911, QAT/0069. Unpublished study
prepared by Sumitomo Chemical Co. Ltd., Envr. Health. 28
P-
Receipt Date
26-Jan-2005
46454106
Nakamura, Y. (2004) Primary Skin Irritation Test of MFFO
in Rabbits. Project Number: 3909, QAT/0071. Unpublished
study prepared by Sumitomo Chemical Co. Ltd., Envr.
Health. 16 p.
26-Jan-2005
46454107
Nakamura, Y. (2004) Skin Sensitization Test of MFFO in
Guinea Pigs (Buehler Method). Project Number: 3908.
Unpublished study prepared by Sumitomo Chemical Co.
Ltd., Envr. Health. 25 p.
26-Jan-2005
46454108
Sommer, E.; Knuppe, C.; Gretener, P.; et. al. (2004) S-
1264: 13-Week Repeated Dose Oral Toxicity (Feeding)
Study in the CD-I Mouse: Final Report. Project Number:
841949, 41620/WEK, QAT/0072. Unpublished study
prepared by RCC Umweltchemie Ag. 592 p.
26-Jan-2005
46454109
Sommer, E.; Knuppe, C.; Gretener, P.; et. al. (2003) S-
1264: 13-Week Repeated Dose Oral Toxicity (Feeding)
Study in the Wistar Rat: Final Report. Project Number:
Q AT/0051, 841950. Unpublished study prepared by RCC
Ltd. 658 p.
26-Jan-2005
46454110
Uchida, H. (2004) 12-Month Repeated Dose Oral Toxicity
Study of S-1264 in Dogs: Final Report. Project Number:
P020637, Q AT/0061. Unpublished study prepared by
Panapharm Laboratories Co., Ltd. 353 p.
26-Jan-2005
46454111
Kara, H.; Suyami, S.; Ushimaru, T. et. al. (2002) Study for
Effects on Embryo-Fetal Developmental of S-1264
Administered Orally to Rats. Project Number: QAT/0003,
ST01085. Unpublished study prepared by Ina Research Inc.
106 p.
26-Jan-2005
46454112
Kara, H.; Suyami, S.; Ushimaru, T.; et. al. (2002) Study of
Fertility and Early Embryonic Development to Implantation
of S-1264 Administered Orally to Rats. Project Number:
Q AT/0011, ST01083. Unpublished study prepared by Ina
Research Inc. 173 p.
26-Jan-2005
46454113
Kara, H.; Suyama, S.; Ushimaru, T.; et. al. (2002) Study for
Effects on Pre - and Postnatal Development, Including
26-Jan-2005
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MRID
Citation
Material Function, of S-1264 Administered Orally to Rats.
Project Number: ST01084, QAT/0020. Unpublished study
prepared by Ina Research Inc. 274 p.
46454114
Horie, N. (2002) Study for Effects on Embryo-fetal
Develpment of S-1264 Administered Orally to Rabbits:
Final Report. Project Number: QAT/0019, 3644.
Unpublished study prepared by Sumitomo Chemical Co.
Ltd., Envr. Health. 241 p.
Receipt Date
26-Jan-2005
46454115
Kitamoto, S. (2004) Reverse Mutation Test of MFFO in
Bacterial Systems: (S. typhimurium, E. coli). Project
Number: 3907, QAT/0070. Unpublished study prepared by
Sumitomo Chemical Co. Ltd., Envr. Health. 23 p.
26-Jan-2005
j Todd, R. (2004) Summary of Physical/Chemical Properties:
464
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MRID Citation
Receipt Date
46611302
Umweltchemie Ag. 3741 p. Relates to L0000976.
Schmid, H.; Flade, D.; Gretener, P.; et. al. (2005) S-1264:
78-Week Oncogen!city (Feeding) Study in the CD-I
Mouse. Project Number: 847663, QAT/0079, 42667/WEK.
Unpublished study prepared by RCC Umweltchemie Ag.
2636 p.
| Todd, R. (2005) Appendix G: Testing Facility Positive
j Control Data for: Subchronic Neurotoxicity of S-1264 in
46620601 | Rats: Final Report. Project Number: 1119/033, QAT/0060,
j 012/058. Unpublished study prepared by Sumitomo
j Chemical Co., Ltd. 165 p.
02-Aug-2005
10-Aug-2005
46636501
Todd, R. (2005) Ina Research Laboratory Historical Control {
Data of Embyro-Fetal Development to Rats. Unpublished j 06-Sep-2005
study prepared by Sumitomo Chemical Co., Ltd. 3 p. {
46636502
Todd, R. (2005) Environmental Health Science Laboratory
of Sumitomo Chemical Co., Ltd. Historical Control Data of
Embryo-Fetal Development to Rabbits. Unpublished study
prepared by Sumitomo Chemical Co., Ltd. 3 p.
! 06-Sep-2005
46756301
Deguchi, Y. (2006) The 2nd Study for Mode of Action of
S-1264 for Liver Tumor Promotion in Rats. Project j
Number: S1255. Unpublished study prepared by Sumitomo j 09-Feb-2006
Chemical Co. Ltd., Envr. Health. 147 p. Relates to j
L0000976. |
46756302
Nagahori, H. (2006) Study for Mode of Action of S-1264
for Liver Tumor Promotion in Rats (In vitro Effect of S-
1264 on Cytochrome P450 Activity and mRNA Level).
Project Number: X0145. Unpublished study prepared by
Sumitomo Chemical Co. Ltd., Envr. Health. 13 p. Relates
to L0000976.
09-Feb-2006
r~
I Yamada, T. (2006) Gene Expression Profiling Analysis of
j Early Phase of Treatment in the Liver From S-1264-Treated j
46756303 | Rats. Project Number: S1274. Unpublished study prepared j 09-Feb-2006
! by Sumitomo Chemical Co. Ltd., Envr. Health. 19 p. j
! Relates to L0000976. I
46756304
Yamad, T. (2006) An Evaluation of the Human Relevance j
of the Metofluthrin-Induced Liver Tumors in Rats Based on j
Mode of Action. Unpublished study prepared by Sumitomo 1 09-Feb-2006
Chemical Co. Ltd., Envr. Health. 17 p. Relates to |
L0000976.
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MRID
Citation
Receipt Date
Schmid, H. (2005) Combined Chronic Toxicity/
Oncogenicity (Feeding) Study in the Rat: S-1264. Project
Number: 846244. Unpublished study prepared by RCC
Umweltchemie Ag. 3741 p.
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