Document ID: EPA-HQ-OPP-2010-0266-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-05-05T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Kathryn Montague 703-305-1243

Bayer CropScience LLC

PP# 9F7680

The EPA has received a pesticide petition (9F7680) from Bayer
CropScience LLC, 2 T. W. Alexander Drive, Research Triangle Park, NC
27709 proposing, pursuant to section 408(d) of the Federal Food, Drug,
and Cosmetic Act (FFDCA), 21 U.S.C.346a(d), to amend 40 CFR part 180. by
establishing tolerances for residues of the herbicide, pyrasulfotole
including its metabolites and degradates. Compliance with the tolerance
levels specified is to be determined by measuring residues of
pyrasulfotole (AE
0317309)5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-[2-(methylsulfonyl)-4-(t
rifluoromethyl)-phenyl methanone and its metabolite
(5-Hydroxy-3-methyl-1H-pyrazol-4-yl)-[2-(methylsulfonyl)-4-(trifluoromet
hyl)phenyl] methanone, calculated as the stoichiometric equivalent of
pyrasulfotole] in or on the raw agricultural commodities [sorghum,
grain] at [0.8] parts per million (ppm); [sorghum, forage] at [1.2] ppm;
[sorghum, stover] at [0.35] ppm; [grass, hay] at [2.5] ppm; and [grass,
forage] at [10] ppm. In addition, increased tolerances are proposed for
residues of the herbicide pyrasulfotole including its metabolites and
degradate. Compliance with the tolerance levels specified is to be
determined by measuring residues of pyrasulfotole (AE0317309)
(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)[2-(methylsulfonyl)-4-(trifluoro
methyl)phenyl]-methanone and its metabolite
(5-Hydroxy-3-methyl-1H-pyrazol-4-yl-2-(methylsulfonyl)
-4-(trifluoromethyl)phenyl] methanone, calculated as the stoichiometric
equivalent of pyrasulfotole in or on [cattle, goat, hog, sheep and horse
meat] at [0.04] ppm;[cattle, goat, hog, sheep and horse fat] at [0.04]
ppm; [cattle, goat, hog, sheep and horse, meat byproducts except liver]
at [2] ppm and [cattle, goat, hog, sheep and horse, liver] at [8] ppm.
EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data supports granting of the petition.
Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The nature of pyrasulfotole residues in plants and
livestock

is adequately understood. The residues of concern are combined residues
of pyrasulfotole and its

metabolite
(5-Hydroxy-3-methyl-1H-pyrazol-4-yl)[2-(methylsulfonyl)-4-(trifluorometh
yl)

phenyl] methanone, calculated as pyrasulfotole, calculated as the
stoichiometric equivalent of

pyrasulfotole.

2. Analytical method. The analytical method is an LC/MS/MS method which

quantifies pyrasulfotole and its metabolite
(5-Hydroxy-3-methyl-1H-pyrazol-4-yl)[2-(methylsulfonyl)-
4-(trifluoromethyl)phenyl]methanone with an LOQ of 0.01 mg/kg.
Pyrasulfotole and its metabolite are solvent extracted, hydrolyzed to
released conjugated residues and purified by C18 solid phase extraction.
Residues are quantified by LC/MS/MS using isotopically labeled internal
standards. Validation of the methodology for the determination of
pyrasulfotole and its metabolite demonstrated that it could accurately
determine residues at the LOQ of 0.01 ppm in all appropriate matrices.
Pyrasulfotole and its metabolite are stable for at least 11 months for
the above matrices.

3. Magnitude of residues. The appropriate number of residue trials was
conducted in sorghum and grasses in the appropriate locations in the
United States to support the

requested tolerances on the sorghum and grass commodities. Specifically,
twelve field trials were

conducted to measure the magnitude of total pyrasulfotole residues in/on
sorghum forage, grain,

and stover or grass hay and forage following two foliar spray
applications of HUSKIE herbicide

to sorghum or grass. Residues of pyrasulfotole and its metabolite
(5-Hydroxy-3-methyl-1Hpyrazol-4-yl)-[2-(methylsulfonyl)-
4-(trifluoromethyl)-phenyl]methanone were quantified in the harvested
matrices (sorghum grain, forage and stover as well as grass hay and
grass forage)

following a postemergence application of Huskie Herbicide. The addition
of sorghum and grass matrices to the cattle diets resulted in a change
to the maximum theoretical dietary burden (MTDB) for cattle and
therefore, a revision of the cattle commodity tolerances as given above.

B. Toxicological Profile

1. Acute toxicity. Pyrasulfotole has a low order of acute toxicity via
the oral, dermal,

and inhalation routes (Category III or IV). Pyrasulfotole is not a
dermal sensitizer or irritant

(Category IV) and has been shown to be a moderate eye irritant (Category
III).

2. Genotoxicty. Pyrasulfotole is not genotoxic based on genotoxicity
studies using in

vivo and in vitro tests, including mammalian cell gene mutation tests,
chromosomal aberration

tests, unscheduled DNA synthesis tests, bacterial DNA repair tests and
other mutagenicity

studies.

3. Reproductive and developmental toxicity. In the prenatal
developmental toxicity study

in rats, an increased incidence of skeletal variations was observed in
fetal offspring at the mid

dose, as was decreased fetal body weight in male offspring. However,
both effects were

observed in the presence of maternal toxicity at the same dose. In the
DNT study in rats, an

identical NOAEL was established in both dams and offspring based on
ocular toxicity as well as

several developmental effects observed at the mid dose. In the prenatal
developmental toxicity

study in rabbits, an increased incidence of skeletal variations was
observed in fetal offspring at

the mid dose. However, maternal toxicity (decreased body weight gain and
food consumption)

was observed only at the next highest dose tested. Therefore, increased
susceptibility of

offspring was observed in the rabbit developmental toxicity study but
not in the developmental

toxicity study in rats or DNT study in rats. In the 2-generation
reproductive toxicity study in rats, ocular toxicity (keratitis, corneal
opacity and/or corneal neovascularization), was observed at the mid and
high doses in the adults and offspring of two generations. Thyroid
(colloid alteration, pigment deposition) and kidney (tubular dilation)
toxicity were observed in adult animals of each generation. Colloid
alteration and pigment deposition were also observed in adult rats
following short-term dermal and chronic oral exposure of rats, although
they were attributed to aging in the latter case. Colloid alteration and
pigment deposition were of minimal severity in the 2-generation
reproductive toxicity study and therefore not of concern. At the highest
dose tested, decreased viability and decreased body weight were observed
in offspring of both generations. At the mid and/or high doses, delays
in balanopreputial separation (males) and vaginal patency (females) were
observed in first generation offspring.

4. Subchronic toxicity. Ocular toxicity was observed in male and female
rats exposed to

pyrasulfotole for 90 days either in the diet or by gavage. Mortality and
multi-organ

histopathology in the kidney, urinary bladder, thyroid, and ureters were
also observed in the

dietary study. In mice, toxicity of the urinary bladder was observed in
males, while toxicity of

the adrenal glands was observed in females treated in the diet for 28
days. Neither effect was

reproduced in the 90-day toxicity study in mice; however, urinary
bladder toxicity was observed

in the 29-day toxicity study in the dog, the 90-day toxicity study in
the rat, and the mouse

carcinogenicity study. Rats treated with pyrasulfotole for 28 days by
the dermal route

demonstrated toxicity of the thyroid and pancreas.

In a dermal toxicity study in rats, the local dermal NOAEL was >1,000
mg/kg/day. The

systemic NOAEL was 10 mg/kg/day based on histopathological changes in
the pancreas at 100

mg/kg/day.

5. Neurotoxicity. Acute, subchronic and developmental neurotoxicity of
pyrasulfotole

was assessed in the rat. No neurotoxic effects were observed in the
acute and subchronic

neurotoxicity studies or the developmental neurotoxicity study. Thus,
based on the mode of

action of pyrasulfotole and the available data from multiple studies,
the chemical is not

considered neurotoxic.

6. Chronic toxicity. Pyrasulfotole has been classified by the HED CARC
as having

“Suggestive Evidence of Carcinogenic Potential,” based on increased
incidences of corneal

tumors in male rats at the highest dose tested (2500 ppm) in the chronic
toxicity/carcinogenicity

study in rat and urinary bladder transitional cell tumors in male and
female mice at the highest

dose tested (4000 ppm) in the mouse carcinogenicity study.
Quantification of carcinogenic

potential is not required. The chronic RfD of 0.01 mg/kg/day, based on
the rat chronic

toxicity/carcinogenicity study (NOAEL = 25 ppm [1 mg/kg/day] and LOAEL
of 250 ppm [10

mg/kg/day]) would be protective of both non-cancer and potential cancer
precursor effects.

7. Animal metabolism. The excretion of pyrasulfotole was rapid.
Following oral

administration, greater than 96% of the administered dose was excreted
within 24 hours. In all

experiments, the majority of the radioactivity was excreted in the
urine. Fecal excretion

represented 8 to 10% of the administered dose during the intravenous
experiments. No volatile

residues were detected, and no mineralization was observed. Residue
levels in all tissues were

highest in liver and kidney. Once absorbed, pyrasulfotole was not
greatly metabolized, as 87 to 95% of the administered dose was excreted
unchanged as pyrasulfotole. Hydroxymethyl pyrasulfotole, desmethyl
pyrasulfotole, and pyrasulfotole benzoic acid were observed as minor
metabolites in the urine and feces. Greater than 96% of the administered
dose in each experiment was identified. The major metabolic pathway
occurred via N-demethylation of pyrasulfotole.

8. Metabolite toxicology. Plant and animal metabolism studies showed two
primary

metabolites of pyrasulfotole in food and feed commodities - the
desmethyl pyrasulfotole

(5-hydroxy-3-methyl-1H-pyrazol-4-yl)[2-(methylsulfonyl)-
4-(trifluoromethyl)phenyl]

methanone and a benzoic acid metabolite
(2-(methylsulfonyl)-4-(trifluoromethyl)benzoic acid).

Based on the structure of the compound and its presence as a rat
metabolite the desmethyl

pyrasulfotole is considered to have toxicity similar to parent
pyrasulfotole. EPA has determined

that the benzoic acid metabolite is not of toxicological relevance for
human risk assessment

based on a series of toxicology studies conducted with the compound. The
studies have shown

that it is not an inhibitor of HPPDase, is not genotoxic, and not orally
toxic. A 28-day repeated

dose rat feeding study with the benzoic acid metabolite resulted in a
NOAEL of 15,000 ppm

(1118 mg/kg b.w.) in males and 15,000 ppm (1269 mg/kg b.w.) in females,
making it

significantly less toxic than the parent compound. Similarly, dietary
administration of the

benzoic acid metabolite for 90 days at 0, 1200, 4800, and 12000 ppm had
no effects on clinical

signs, food consumption, body weight or body weight gain,
ophthalmological findings,

hematology or clinical chemistry, organ weights, or histopathological
findings. The NOAEL

was 12,000 ppm (769 mg/kg bw/day for males and 952 mg/kg bw/day for
females), the highest

dose tested. In a developmental toxicity study, AE B197555 was
administered to pregnant

female rats at doses of 0, 75, 250, and 750 mg/kg bw/day. Maternal body
weight and food

consumption were decreased at the top two doses, but there was no effect
at any dose on fetal

body weight or external, visceral, or skeletal findings. The maternal
NOAEL was 75 mg/kg

bw/day, while the fetal NOAEL was 750 mg/kg bw/day. As a result of these
studies, AE

B197555 is considered not of toxicological concern for risk assessment
and was not included in

the risk assessment.

9. Endocrine disruption. The toxicology database for pyrasulfotole is
current and

complete. Studies in this database include evaluation of the potential
effects on reproduction and

development and an evaluation of the pathology of the endocrine organs
following short or

long-term exposure. There is no indication of endocrine disruption in
any study following

administration of pyrasulfotole.

C. Aggregate Exposure

Assessments were conducted to evaluate potential risks due to chronic
and acute dietary

exposure of the U.S. population and selected population subgroups to
residues of pyrasulfotole

and its metabolite
(5-Hydroxy-3-methyl-1H-pyrazol-4-yl)[2-(methylsulfonyl)-

4-(trifluoromethyl)phenyl] methanone. These assessments included current
and proposed uses of

pyrasulfotole (registered cereal grains, as well as proposed uses on
sorghum and grass grown for

seed).Exponent Inc.'s Dietary Exposure Evaluation Model (DEEM-FCID,
Version 2.14), which is licensed to Bayer, was used to estimate the
chronic and acute dietary exposure. This software

uses the food consumption data from the 1994-1998 USDA Continuing
Surveys of Food Intake

by Individuals (CSFII 1994-1998). The aRfD for the general U.S.
population, including infants and children, was established based on
adverse effects observed in the developmental neurotoxicity study in the
rat. Relevant toxicological effects that could be the result of a single
dose to the fetus during gestation were delayed preputial separation
(males), decreased cerebrum length (PND 21 females), and decreased
cerebellum height (PND 21 males). These adverse effects were observed in
offspring at the lowest-observable-adverse-effect-level (LOAEL) of 37
mg/kg/day (NOAEL = 3.8 mg/kg/day). The aRfD/aPAD is 0.038 mg/kg. This
study and endpoint are the most appropriate for the population of
concern following a single oral exposure.

3.4.2 Chronic Reference Dose (cRfD)

The cRfD was established based on ocular toxicity observed in the
combined chronic

toxicity/carcinogenicity study in the rat. Adverse effects included
corneal opacity,

neovascularization of the cornea, inflammation of the cornea,
regenerative corneal hyperplasia,

corneal atrophy, and/or retinal atrophy in both sexes, and
hepatocellular hypertrophy along with

increased serum cholesterol in males at the LOAEL of 10/14 mg/kg/day
(M/F) (NOAEL = 1.0

mg/kg/day). This study provided the critical effect across three chronic
toxicity studies in the

rat, mouse, and dog. The 2-generation reproduction study is a
co-critical study. Altered colloid

and/or pigment deposition were observed in the thyroid of parental
animals at the LOAEL of

2.5/3.1 mg/kg bw/day (M/F). Application of a 3X uncertainty factor for
extrapolation of a

LOAEL to a NOAEL, based on minimal severity of the effect at the LOAEL,
would lead to a

point of departure of 1 mg/kg/day. The cRfD/cPAD is 0.01 mg/kg/day.

Results from the acute and chronic dietary exposure analyses described
below demonstrate a

reasonable certainty of no harm to the overall U.S. population or any
population subgroup will

result from the proposed use of pyrasulfotole on cereal grains.]

i. Food. Tier 1 acute and chronic risk assessments were conducted using
the results of

field trials conducted at maximum label application rates and the
shortest pre-harvest intervals.

No adjustments were made to account for dissipation of residues during
storage, transportation

from the field to the consumer, washing or peeling. Therefore, the
actual dietary exposure will

be less than that presented here.

The acute dietary exposure assessment estimated the percent of the aRfD
for the U.S. Population

and numerous population subgroups. This analysis showed that the
population subgroup with

highest acute exposure was Children 1-2 with exposure equal to 12.6% of
the aRfD for food and

water. Exposure to U.S. Population was 3.7% of the aRfD for food and
water. Therefore, the

acute dietary exposure estimates are below EPA's level of concern for
the overall U.S.

population as well as the various subpopulations.

The chronic dietary exposure estimated the percent of the chronic
reference dose (cRfD) for the

overall US population and various subpopulations. In this analysis, the
population subgroup

with the highest exposure was Children 1-2 with exposure equal to 13.7%
of the cRfD while the

U.S. population had exposure equal to 4.6% of the cRfD. Therefore, the
chronic exposure

estimates are below EPA's level of concern for the overall U.S.
population as well as all

subpopulations.

ii. Drinking water. EPA’s Tier 1 EDWCs for surface and ground water
were generated

using FIRST and SCIGROW, respectively. Based on the results of these
simulations, EPA

recommended an acute surface water EDWC of 4.0 μg/L and a chronic EDWC
of 2.8 μg/L for

use in the human-health risk assessment. These recommendations are based
on the use of

pyrasulfotole on cereal grains (wheat, barley, oats, and triticale) at
an annual application rate of

0.045 lb ai/A/year. The recommended EDWC for groundwater was 1.4 μg/L
and is also based

on the use of pyrasulfotole on cereal grains at the previously stated
rate. Potential water residues

are included in the dietary exposure calculated above.

2. Non-dietary exposure. There are no current residential uses for
pyrasulfotole.

D. Cumulative Effects

Pyrasulfotole is an herbicide that acts by inhibiting the breakdown of
the amino acid

tyrosine in plants and animals at the 4-hydroxyphenypyruvic acid
dioxygenase (HPPDase)

enzyme; the second enzyme in the tyrosine catabolism pathway. Although
there are other

herbicides that are HPPDase inhibitors, it has not been established that
pyrasulfotole will have

cumulative effects with other HPPDase inhibitors.

E. Safety Determination

1. U.S. population. [Using the conservative exposure assumptions
described above and

based on the completeness of the toxicity data, it can be concluded that
aggregate exposure to

residues of pyrasulfotole presents a reasonable certainty of no harm.
The acute assessment

indicated that exposure from residues in crops utilized approximately
3.4% of the acute RfD for

the U. S. Population when food and water are included. Exposure from
residues in crops and water utilizes 4.6% of the cRfD for the U.S.
Population. EPA generally has no concerns for exposures below 100% of
the cRfD. An aggregate assessment for the proposed uses for
pyrasulfotole demonstrates that there is a reasonable certainty that no
harm will result to the US Population from these uses of imidacloprid.

2. Infants and children. Developmental studies have been conducted in
the rat and the

rabbit and a developmental neurotoxicity study conducted in the rat. In
addition, a twogeneration

reproduction study was conducted in the rat. Based on the available
data, there is no

concern for pre- and/or postnatal toxicity resulting from exposure to
pyrasulfotole. There is no

evidence of increased susceptibility following pre-/post-natal exposure
to rats in the

developmental neurotoxicity study or the 2-generation reproduction
study. Evidence of

quantitative susceptibility was noted in the rabbit developmental
toxicity study based on skeletal

variants in fetuses (75 mg/kg bw/day), in the absence of overt clinical
toxicity in the dams.

However, based on the data available regarding sensitivity of the rabbit
to tyrosinemia, and since

the skeletal variants were similar to those noted in rats and rabbits
with other HPPDase

inhibitors, these effects are considered secondary to elevated tyrosine
in the dams and are not

relevant for human health risk assessment.

FFDCA section 408 provides that EPA shall apply an additional tenfold
margin of safety for

infants and children in the case of threshold effects to account for pre
and post natal toxicity

and the completeness of the data base unless EPA determines that a
different margin of

safety will be safe for infants and children. The toxicological database
for pyrasulfotole is

complete for FQPA purposes and there are no residual uncertainties for
pre-/post-natal

toxicity for pyrasulfotole. Based on the available toxicity data the
Special FQPA Safety

ˆ

”

Based on the exposure assessments described above and on the
completeness and reliability of the toxicity data, it can be concluded
that the dietary exposure from the proposed uses for pyrasulfotole
consumes 12.6% of the aRfD and 13.7% of the cRfD for Children 1-2 (the
most sensitive population subgroup). Thus, it can be concluded that
there is a reasonable certainty that no harm will result from aggregate
exposure to pyrasulfotole residues.

F. International Tolerances

No CODEX Maximum Residue Levels (MRLs) have been established for
residues

of pyrasulfotole on cereal grains, sorghum or grass grown for see