**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

WASHINGTON, D.C. 20460

![](media/image1.wmf){width="0.85in" height="0.925in"}

> OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 8-JUNE-2007

**[MEMORANDUM]{.underline}**

SUBJECT: Pyrasulfotole: Human-Health Risk Assessment for Proposed Uses
on Small Cereal Grains. PC Code: 000692. PP#: 6F7059. DP#: 328640.
Decision #: 366490.

Regulatory Action: Section 3, Registration Action

Risk Assessment Type: Single Chemical Aggregate

FROM: Jennifer R. Tyler, Chemist

> Robert Mitkus, Ph.D., Toxicologist

Kelly Lowe, Environmental Scientist

Registration Action Branch 1 (RAB1)

Health Effects Division (HED; 7509P)

THROUGH: PV Shah, Ph.D., Acting Branch Chief

RAB1/HED (7509P)

TO: Tracy White/Dan Kenny, RM Team 23

Registration Division (RD) (7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides. The RD
of OPP has requested that HED evaluate hazard and exposure data and
conduct dietary, occupational, residential and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from proposed tolerances for the new active ingredient (ai)
pyrasulfotole on small cereal grains. A summary of the findings and an
assessment of human-health risk resulting from the proposed tolerances
for pyrasulfotole are provided in this document. The risk assessment,
residue chemistry data review, and dietary exposure assessment were
provided by Jennifer Tyler (RAB1), the hazard characterization and
endpoint selection by Robert Mitkus (RAB1), and occupational exposure
assessment by Kelly Lowe (RAB1), and the drinking water exposure
assessment by Marietta Echeverria of the Environmental Fate and Effects
Division (EFED).

Table of Contents

[1.0 Executive Summary 4](#__RefHeading___Toc170186426)

[2.0 Ingredient Profile 11](#__RefHeading___Toc170186427)

[2.1 Summary of Proposed Uses 12](#__RefHeading___Toc170186428)

[2.2 Structure and Nomenclature 13](#__RefHeading___Toc170186432)

[2.3 Physical and Chemical Properties 14](#__RefHeading___Toc170186433)

[3.0 Hazard Characterization/Assessment
14](#__RefHeading___Toc170186434)

[3.1 Hazard and Dose-Response Characterization
14](#__RefHeading___Toc170186435)

[3.1.1 Database Summary 14](#__RefHeading___Toc170186436)

[3.2 Absorption, Distribution, Metabolism, Excretion (ADME)
16](#absorption-distribution-metabolism-excretion-adme)

[3.3 FQPA Considerations 17](#__RefHeading___Toc170186438)

[3.4 Hazard Identification and Toxicity Endpoint Selection
18](#__RefHeading___Toc170186439)

[3.4.1 Acute Reference Dose (aRfD) 18](#__RefHeading___Toc170186440)

[3.4.2 Chronic Reference Dose (cRfD) 18](#__RefHeading___Toc170186441)

[3.4.3 Incidental Oral Exposure (Short- and Intermediate-Term)
18](#__RefHeading___Toc170186442)

[3.4.4 Dermal Absorption 18](#__RefHeading___Toc170186443)

[3.4.5 Dermal Exposure (Short- and Intermediate-Term)
19](#__RefHeading___Toc170186444)

[3.4.6 Dermal Exposure (Long-Term) 19](#__RefHeading___Toc170186446)

[3.4.7 Inhalation Exposure (All Durations)
19](#__RefHeading___Toc170186447)

[3.4.9 Level of Concern for Margin of Exposure
20](#__RefHeading___Toc170186448)

[3.4.10 Recommendation for Aggregate Exposure Risk Assessments
20](#__RefHeading___Toc170186449)

[3.4.11 Classification of Carcinogenic Potential
20](#__RefHeading___Toc170186450)

[3.4.12 Summary of Toxicological Doses and Endpoints for Pyrasulfotole
for Use in Human-Health Risk Assessments
21](#__RefHeading___Toc170186451)

[3.5 Endocrine Disruption 23](#__RefHeading___Toc170186452)

[4.0 Public Health and Pesticide Epidemiology Data
23](#__RefHeading___Toc170186453)

[5.0 Dietary Exposure/Risk Characterization
24](#__RefHeading___Toc170186454)

[5.1 Pesticide Metabolism and Environmental Degradation
24](#__RefHeading___Toc170186455)

[5.1.1 Metabolism in Primary Crops 24](#__RefHeading___Toc170186456)

[5.1.2 Metabolism in Rotational Crops 25](#__RefHeading___Toc170186457)

[5.1.3 Metabolism in Livestock 26](#__RefHeading___Toc170186458)

[5.1.4 Analytical Methodology 26](#__RefHeading___Toc170186459)

[5.1.5 Environmental Degradation 27](#__RefHeading___Toc170186460)

[5.1.6 Comparative Metabolic Profile 28](#__RefHeading___Toc170186461)

[5.1.7 Toxicity Profile of Major Metabolites and Degradates
28](#__RefHeading___Toc170186462)

[5.1.8 Pesticide Metabolites and Degradates of Concern
29](#__RefHeading___Toc170186463)

[5.1.9 Drinking Water Residue Profile 31](#__RefHeading___Toc170186464)

[5.1.10 Food Residue Profile 32](#__RefHeading___Toc170186465)

[5.1.11 International Residue Limits 35](#__RefHeading___Toc170186466)

[5.2 Dietary Exposure and Risk 35](#__RefHeading___Toc170186467)

[5.2.1 Acute Dietary Exposure/Risk 36](#__RefHeading___Toc170186468)

[5.2.2 Chronic Dietary Exposure/Risk 36](#__RefHeading___Toc170186469)

[6.0 Residential (Non-Occupational) Exposure/Risk Characterization
37](#__RefHeading___Toc170186470)

[6.1 Other (Spray Drift, etc.) 37](#__RefHeading___Toc170186471)

[7.0 Aggregate Risk Assessments and Risk Characterization
37](#__RefHeading___Toc170186472)

[7.1 Acute Aggregate Risk 37](#__RefHeading___Toc170186473)

[7.2 Chronic Aggregate Risk 38](#__RefHeading___Toc170186474)

[8.0 Cumulative Risk Characterization/Assessment
38](#__RefHeading___Toc170186475)

[9.0 Occupational Exposure/Risk Pathway
39](#__RefHeading___Toc170186476)

[9.1 Short-Term Handler Risk 39](#__RefHeading___Toc170186477)

[9.2 Short-Term Post-application Risk 40](#__RefHeading___Toc170186478)

[10.0 Data Needs and Label Recommendations
42](#__RefHeading___Toc170186479)

[10.1 Toxicology 42](#__RefHeading___Toc170186480)

[10.2 Residue Chemistry 42](#__RefHeading___Toc170186481)

[Appendix A. Toxicology Assessment 43](#__RefHeading___Toc170186482)

[A.2. Toxicity Profiles 44](#__RefHeading___Toc170186483)

[A.3. Executive Summaries 51](#__RefHeading___Toc170186484)

[Appendix B. Metabolism Assessment 72](#__RefHeading___Toc170186485)

[]{.mark}

[]{.mark}

[]{#__RefHeading___Toc170186426 .anchor}**1.0 Executive Summary**

Bayer CropSciences has submitted a petition for the use of
pyrasulfotole, a new postemergence dicot herbicide, for use on small
cereal grains, including wheat, barley, oats, rye and triticale.
Pyrasulfotole is an effective inhibitor of the enzyme
4-hydroxyphenylpyruvate dioxygenase (HPPD) and consequently blocks the
pathway of prenylquinone biosynthesis in plants. The end-use products
are applied to the target weeds and act primarily through leaf uptake
and translocation to the target site. The first symptoms appear three to
five days after application. Bleaching and discoloration appear
initially and symptoms progress to tissue necrosis and plant death
within two weeks.

There are currently no food/feed uses or tolerances for pyrasulfotole in
the United States (U.S.). In addition, there are currently no registered
or proposed residential uses for pyrasulfotole. Pyrasulfotole is being
evaluated as part of a trilateral joint review with Canada and
Australia.

Pyrasulfotole will be formulated as AE 0317309 SE06 Herbicide, a
suspo-emulsion (SE) containing 50 grams (g)/liter (L) of pyrasulfotole
and the safener mefenpyr-diethyl; and AE 0317309 + Bromo Herbicide, an
emulsifiable concentrate (EC) comprised of 37.5 g/L of pyrasulfotole,
bromoxynil (present as the mixed heptanoate and octanoate esters), and
the safener mefenpyr-diethyl on cereal grains. The SE and EC
formulations are being proposed for one ground or foliar application per
season to the above crops at rates of 0.045 lb pyrasulfotole/A and 0.037
lb pyrasulfotole/A, respectively. *HED notes that this document pertains
to the ai pyrasulfotole only.*

[]{.mark}

*Hazard Assessment*: The toxicology database for pyrasulfotole is
considered complete and adequate for purposes of risk assessment.
Pyrasulfotole has a low to moderate order of acute toxicity (Appendix
A.2) 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). The eye is
the primary target organ of pyrasulfotole. Decreased locomotor activity
was observed on the day of treatment in the acute neurotoxicity study in
the rat.

Ocular toxicity was observed in male and female rats exposed to
pyrasulfotole for 90 days (subchronic oral exposure) 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.

Chronic oral exposure of rats to pyrasulfotole resulted in extensive eye
toxicity at almost all doses tested. These included corneal opacity,
neovascularization of the cornea, inflammation of the cornea,
regenerative corneal hyperplasia, corneal atrophy, and/or retinal
atrophy. Ocular toxicity is believed to be an indirect result of
tyrosinemia caused by inhibition of hepatic HPPD. In mice, ocular
toxicity was not observed at any dose, thereby reflecting accepted
differences in effects among rodent species for HPPD inhibitors.
Long-term exposure of mice to pyrasulfotole did cause toxicity of the
urinary system, including the kidney, urinary bladder, and ureters at
the highest dose tested, as well as gallstone formation at all doses
tested. Dogs treated with pyrasulfotole for one year exhibited toxicity
of the urinary system (kidneys and bladder) at mid and high doses, as
well as cataracts at a very low incidence at the highest dose tested.

In the combined chronic/carcinogenicity study in rats, an increase in
the incidence of corneal squamous cell tumors was observed in males only
at the highest dose tested. HED's Carcinogenicity Assessment Review
Committee (CARC) considered these rare tumors, which were observed
following adequate dosing, to be treatment-related. In the
carcinogenicity study in mice, an increase in the incidence of
transitional cell carcinomas and papillomas of the urinary bladder were
observed in males and females at the highest dose tested. However, these
tumors were observed at doses that were considered excessive due to
increased mortality caused by urinary bladder stones. Pyrasulfotole was
negative for mutations and chromosomal aberrations across four *in
vitro*/*in vivo* genotoxicity studies and was considered by the CARC not
to pose a mutagenic concern.

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. Both
effects were observed in the presence of maternal toxicity (decreased
body weight gain, enlarged placenta, clinical signs) at the same dose.
In the developmental neurotoxicity (DNT) study in rats, ocular toxicity
as well as several adverse developmental effects (delayed preputial
separation, morphometric changes, delays in learning/memory) were
observed at the mid dose. Ocular toxicity was also observed at this dose
in maternal animals; an identical no-observed-adverse-effect-level
(NOAEL) was established in both dams and offspring. 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 quantitative 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 rats following short-term dermal and chronic oral exposure of rats,
although they were attributed to aging in the latter case. 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.

Following oral administration of 10 mg/kg phenyl or pyrazole
ring-labeled pyrasulfotole, \~60% of radiolabeled compound was excreted
in the urine after 6 hours, while \~73% of the administered dose was
recovered in the urine by the time of sacrifice (52 hours). Therefore,
approximately 60% of the compound was absorbed within 6 hours of
exposure. Less than 2% of the administered dose remained in the residual
carcass and tissues at sacrifice, and the highest residues were found in
the liver and kidney. Approximately 30% of labeled compound was excreted
in the feces 52 hours after dosing, approximately 25% of which was
parent. Pyrasulfotole was metabolized via hydroxylation and
N-demethylation.

[]{.mark}

*Dose Response Assessment and Food Quality Protection Act (FQPA)
Decision*: The pyrasulfotole risk assessment team recommends that the
10X FQPA safety factor (SF) for the protection of infants and children
be reduced to 1X since there is a complete toxicity database for
pyrasulfotole and exposure data are complete or are estimated based on
data that reasonably account for potential exposures. The recommendation
is based on the following: 1) Clear NOAELs were established for all
exposure scenarios and these are considered protective of the offspring
susceptibility observed in the rabbit developmental toxicity study. 2)
There are no residual uncertainties concerning pre- and postnatal
toxicity. 3) There are no residual uncertainties with respect to
exposure data. 4) The dietary food exposure assessment utilizes
tolerance-level residues and 100% crop treated (CT) information for all
proposed commodities. By using this screening-level assessment, the
acute and chronic exposures/risks will not be underestimated. 5) The
dietary drinking water assessment (Tier 1 estimates) utilizes values
generated by model and associated modeling parameters which are designed
to provide conservative, health protective, high-end estimates of water
concentrations. 6) There are no registered or proposed uses of
pyrasulfotole which would result in residential exposure.

Risk assessments were conducted for the following specific exposure
scenarios listed below. The acute and chronic reference doses (aRfD and
cRfD) were calculated by dividing the NOAEL by 100 (10X for interspecies
extrapolation and 10X for intraspecies variation). Since the FQPA SF has
been reduced to 1X, the acute and chronic population adjusted doses
(aPAD and cPAD) are equal to the aRfD and cRfD, respectively. The dermal
absorption factor was estimated to be 2.5%; however, a dermal
penetration study is required to confirm the estimate. A 100 % oral
equivalent inhalation absorption factor is assumed. The level of concern
(LOC) for occupational dermal and inhalation exposures are for margins
of exposure (MOEs) \<100.

[]{.mark}

  ----------------------- ------------------------ ------------------------- ----------------------------------
  [Exposure               [Point of                [RfD, PAD, LOC for Risk   [Study/Effect]{.underline}
  Scenario]{.underline}   Departure]{.underline}   Assessment]{.underline}   

  Acute dietary           NOAEL = 3.8 mg/kg/day    aRfD and aPAD = 0.038     Developmental neurotoxicity study
                                                   mg/kg/day                 in rats/Delayed preputial
                                                                             separation (males), decreased
                                                                             cerebrum length (PND 21 females),
                                                                             and decreased cerebellum height
                                                                             (PND 21 males)

  Chronic dietary         NOAEL = 1.0 mg/kg/day    cRfD and cPAD = 0.01      Combined chronic
                                                   mg/kg/day                 toxicity/carcinogenicity study in
                                                                             rats/Corneal opacity,
                                                                             neovascularization of the cornea,
                                                                             inflammation of the cornea,
                                                                             regenerative corneal hyperplasia,
                                                                             corneal atrophy, and/or retinal
                                                                             atrophy (both sexes), and
                                                                             hepatocellular hypertrophy along
                                                                             with increased serum cholesterol
                                                                             (males)

  Short-term dermal       NOAEL = 10 mg/kg/day     LOC for MOE \< 100        28-day dermal toxicity in
                                                   (occupational)            rats/Focal degeneration of
                                                                             pancreas (both sexes) and
                                                                             alteration of thyroid colloid
                                                                             (males)

  Short-term inhalation   NOAEL = 1.0 mg/kg/day    LOC for MOE \< 100        Combined chronic
                                                   (occupational)            toxicity/carcinogenicity study in
                                                                             rats/Corneal opacity,
                                                                             neovascularization of the cornea,
                                                                             inflammation of the cornea,
                                                                             regenerative corneal hyperplasia,
                                                                             corneal atrophy, and/or retinal
                                                                             atrophy (both sexes), and
                                                                             hepatocellular hypertrophy along
                                                                             with increased serum cholesterol
                                                                             (males)
  ----------------------- ------------------------ ------------------------- ----------------------------------

[]{.mark}

*Residue Chemistry and Drinking Water Assessments:* The residue
chemistry and drinking water databases are adequate to assess potential
human exposure to pyrasulfotole. Several residue chemistry deficiencies
have been determined as listed in Section 10.0 of this risk assessment.

For the purposes of this risk assessment only, the residues of concern
in cereal grains (primary crops) and livestock for tolerance and risk
assessment purposes are pyrasulfotole and its metabolite
pyrasulfotole-desmethyl. For rotational crops, the residue of concern is
parent *per se* for tolerance and risk assessment purposes. For drinking
water, the residue of concern for risk assessment purposes is
pyrasulfotole *per se*.

Adequate crop field trial data have been submitted for wheat, barley and
oats. For all commodities, the data reflect the maximum rates and
minimum PHIs requested and have sufficient geographic representation to
support tolerances for the proposed uses (See Appendix C). All crop
field trial studies are supported by adequate storage stability data.
Adequate processing data have been submitted for wheat, and indicate
that tolerances should be established for oat, bran. Based on the
available livestock feeding and poultry metabolism studies, and in order
to harmonize with Canada's Pesticide Management Regulatory Agency (PMRA)
policy, tolerances on livestock commodities should be established (see
Appendix C). Provided that two ion transitions are monitored during mass
spectrometry (MS)/MS analysis for each analyte, there is an adequate
analytical method to enforce the recommended tolerances for cereal
grains. For livestock commodities, the company should submit an
analytical method to measure both residues of pyrasulfotole and
pyrasulfotole-desmethyl. It should be noted that the Analytical
Chemistry Branch of the Biological & Economics Analysis Division
(ACB/BEAD) believes that the proposed analytical enforcement method will
work for pyrasulfotole-desmethyl (e-mail from C. Stafford to J. Tyler;
3/3/007). Therefore, HED is recommending for a conditional registration
until an updated method is submitted.

The existing confined and field rotational crop data are adequate to
support the proposed rotational crop restrictions.

The available environmental fate data indicate that pyrasulfotole is
likely to be persistent and mobile to moderately mobile in the
environment. EFED provided Tier 1 estimated drinking water
concentrations (EDWCs) for surface and ground water which were generated
using the FQPA Index Reservoir Screening Tool (FIRST) and Screening
Concentration in Ground Water (SCIGROW) models, respectively.

[]{.mark}

*Dietary (Food and Drinking Water) Exposure Estimates:* Acute and
chronic dietary exposure analyses were conducted using the Dietary
Exposure Evaluation Model-Food Commodity Intake Database (DEEM-FCID;
ver. 2.03) program which incorporates consumption data from the United
States Department of Agriculture's (USDA's) Continuing Surveys of Food
Intakes by Individuals (CSFII), 1994-1996/1998. For acute and chronic
dietary risk estimates, HED's level of concern is for estimates that
exceed 100% aPAD or cPAD, respectively.

Unrefined, acute and chronic dietary exposure assessments were performed
for the general U.S. population and various other population subgroups
(including infants and children) using tolerance-level residues and
assuming 100% CT for all proposed uses. Drinking water was incorporated
directly in the dietary assessment using the acute or chronic
concentrations for surface water generated by the FIRST model. The acute
dietary exposure estimates (95^th^ percentile) are not of concern to HED
(\<100% of the aPAD) for the general U.S. population (2% of the aPAD)
and all other population subgroups. The most highly-exposed population
subgroup is children 1-2 years old at 4% of the aPAD. The chronic
dietary exposure estimates are not of concern to HED (\<100% of the
cPAD) for the general U.S. population (2% of the cPAD) and all
population subgroups. The most highly exposed population subgroup is
children 1-2 years old at 7% of the cPAD.

*Aggregate Exposure Scenarios and Risk Conclusions*: For the proposed
uses, human health aggregate risk assessments have been conducted for
the following exposure scenarios: acute aggregate exposure (food +
drinking water), and chronic aggregate exposure (food + drinking water).
Short- and intermediate-term aggregate risk assessments were not
performed because there are no registered or proposed residential uses
for pyrasulfotole. A cancer aggregate risk assessment was not performed
because pyrasulfotole is classified as "Suggestive Evidence of
Carcinogenic Potential" by the HED CARC. All potential exposure pathways
were assessed in the aggregate risk assessment. **All aggregate exposure
and risk estimates are not of concern to HED for the scenarios listed
above.**

[]{.mark}

*Occupational Exposure Estimates*: Based on the proposed use patterns (1
application per season), short-term (1-30 days) dermal and inhalation
exposures are expected for commercial and private applicators. The most
highly exposed occupational workers are expected to be mixer/loaders
using open-pour loading of liquids for aerial applications, and
applicators using aerial equipment. No chemical-specific data are
available with which to assess potential exposure to pesticide handlers;
therefore, estimates of exposure are based on data available in the
Pesticide Handler Exposure Database Version 1.1 (PHED Surrogate Exposure
Guide, 8/98). Exposure/risks for short-term dermal and inhalation
handler mixer/loader exposures were presented at baseline (workers
wearing a single layer of work clothing consisting of a long-sleeved
shirt, long pants, shoes plus socks and no protective gloves). . HED has
no data to assess exposures to pilots using open cockpits.  The only
data available is for exposure to pilots in enclosed cockpits. 
Therefore, risks to pilots are assessed using the engineering control
(enclosed cockpits) and baseline attire (long-sleeve shirt, long pants,
shoes, and socks). All occupational handler MOEs are \>100 with baseline
attire; and, therefore, are not of concern to HED (*i.e.*, MOE \>100).

Short-term (1-30 days) dermal exposures are expected for
post-application agricultural activities. Post-application inhalation
exposure is expected to be negligible due to the low vapor pressure of
pyrasulfotole. The labels for pyrasulfotole recommend that the products
be applied between the 1 leaf and up to flag leaf emergence. There are
no chemical-specific data with which to estimate post-application
exposure of agricultural workers to dislodgeable residues of
pyrasulfotole. Therefore, post-application worker exposure was estimated
using the HED Science Advisory Council for Exposure Policy (ExpoSAC;
Policy 003.1, Rev. 7 Aug. 2000, Regarding Agricultural Transfer
Coefficients (TCs); Amended ExpoSAC Meeting notes - 13 Sept 01), which
lists scouting and irrigating as the activities with the highest
(*i.e.*, most conservative) TCs related to the proposed uses. All MOEs
are \>100; therefore, post-application dermal exposure to agricultural
workers is not of concern to HED (*i.e.*, MOE \>100).

[]{.mark}

Based on the acute Toxicity Category classification for pyrasulfotole,
the interim worker protection standard (WPS) restricted-entry interval
(REI) of 12 hours is adequate to protect agricultural workers from
post-application exposures. The two proposed end-use product labels list
an REI of 12 hours.

[]{.mark}

*Environmental Justice Considerations***:** 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/eo12898.pdf>).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures.
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures 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 the USDA under 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, OPP is able to assess dietary exposure to smaller,
specialized subgroups and exposure assessments are performed when
conditions or circumstances warrant. Whenever appropriate, non-dietary
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 OPP 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 subgroups.

*Review of Human Research*: This risk assessment relies in part on data
from PHED studies in which adult human subjects were intentionally
exposed to a pesticide or other chemical. These studies have been
determined to require a review of their ethical conduct, and have
received that review.

[]{.mark}

*Recommendations for Tolerances*: Provided revised Sections B and F are
submitted and analytical reference standards for pyrasulfotole,
pyrasulfotole-desmethyl and labeled internal standards are submitted to
the EPA National Pesticide Standards Repository, the residue chemistry,
toxicological, and occupational databases support the establishment of a
*conditional registration* and the following permanent tolerances for
residues of pyrasulfotole and its metabolite pyrasulfotole-desmethyl
(see Appendix C for a detailed listing of the HED-recommended
tolerances):

[]{.mark}

  ----------------------- ----------- ----------------------- ------------
  Wheat, grain            0.02 ppm    Cattle, meat            0.06 ppm
                                      byproducts, except      
                                      liver                   

  Wheat, straw            0.20 ppm    Cattle, liver           0.35 ppm

  Wheat, forage           0.20 ppm    Goat, fat               0.02 ppm

  Wheat, hay              0.80 ppm    Goat, meat byproducts,  0.06 ppm
                                      except liver            

  Aspirated grain         0.40 ppm    Goat, liver             0.35 ppm
  fractions                                                   

  Oat, grain              0.08 ppm    Sheep, meat             0.02 ppm

  Oat, straw              0.20 ppm    Sheep, fat              0.02 ppm

  Oat, forage             0.10 ppm    Sheep, meat byproducts, 0.06 ppm
                                      except liver            

  Oat, hay                0.50 ppm    Sheep, liver            0.35 ppm

  Barley, grain           0.02 ppm    Horse, meat byproducts, 0.05 ppm
                                      except liver            

  Barley, straw           0.20 ppm    Horse, liver            0.30 ppm

  Barley, hay             0.30 ppm    Hog, meat               0.02 ppm

  Rye, grain              0.02 ppm    Hog, fat                0.02 ppm

  Rye, straw              0.20 ppm    Hog, meat byproducts    0.02 ppm

  Rye, forage             0.20 ppm    Poultry, meat           0.02 ppm

  Milk                    0.01 ppm    Poultry, fat            0.02 ppm

  Cattle, meat            0.02 ppm    Poultry, meat           0.02 ppm
                                      byproducts              

  Cattle, fat             0.02 ppm    Eggs                    0.02 ppm

  Goat, meat              0.02 ppm                            
  ----------------------- ----------- ----------------------- ------------

[]{.mark}

The registration should be made unconditional upon submission of the
following:

-   Submission of a new ruminant analytical enforcement method to
    determine residues of pyrasulfotole and pyrasulfotole-desmethyl as
    well as adequate radiovalidation and independent laboratory
    validation (ILV) data. Upon submission, the method will be forwarded
    to ACB/BEAD for a petition method validation (PMV) trial. Successful
    completion of the PMV trial will be necessary before Method
    AI-004-A05-01 can be considered adequate for tolerance-enforcement
    purposes.

-   For Method AI-001-P04-01, the ACB recommends that the petitioner
    provide information for a second MS/MS ion transition to provide a
    confirmation of analyte identities. If two ion transitions are not
    available, HED recommends that the petitioner provide an alternate
    chromatographic column and/or mobile-phase combination to add an
    additional degree of specificity and further reduce the possibility
    of false positive residues.

-   In vivo dermal penetration study.

    []{#__RefHeading___Toc170186427 .anchor}**2.0 Ingredient Profile**

Pyrasulfotole is a postemergence dicot herbicide for use on small cereal
grains, including wheat, barley, oats, rye and triticale. Pyrasulfotole
is an effective inhibitor of the enzyme HPPD and consequently blocks the
pathway of prenylquinone biosynthesis in plants. The end-use products
are applied to the target weeds and act primarily through leaf uptake
and translocation to the target site. The first symptoms appear three to
five days after application. Bleaching and discoloration appear
initially and symptoms progress to tissue necrosis and plant death
within two weeks.

As pyrasulfotole is a new ai, there are no tolerances currently
established for pyrasulfotole under 40 CFR. Pyrasulfotole is being
evaluated as part of a trilateral joint review with Canada and
Australia.

Pyrasulfotole will be formulated as AE 0317309 SE06 Herbicide, a SE
formulation containing 50 g/L of pyrasulfotole and the safener
mefenpyr-diethyl; and AE 0317309 EC23 Herbicide, an EC formulation
comprised of 37.5 g/L of pyrasulfotole, bromoxynil (present as the mixed
heptanoate and octanoate esters), and the safener mefenpyr-diethyl on
cereal grains. The following rotational crop restrictions are listed on
both the SE and EC labels: 7 days for wheat (spring, durum, winter) and
spring barley; 4 months for soybeans; 9 months for alfalfa, canaryseed,
canola, corn, flax, field peas, lentils, and tame oats; and 12 months
for mustards. Rotational crop restriction for all other crops not listed
on label were not included. Table 2.1 is a summary of the proposed use
patterns.

[]{#__RefHeading___Toc170186428 .anchor}**2.1 Summary of Proposed Uses**

> []{.mark}

+--------+-------+------------+----+-----+------+----+-------+-------+
| *      |       |            |    |     |      |    |       |       |
| *Table |       |            |    |     |      |    |       |       |
| 2.1.   |       |            |    |     |      |    |       |       |
| S      |       |            |    |     |      |    |       |       |
| ummary |       |            |    |     |      |    |       |       |
| of     |       |            |    |     |      |    |       |       |
| Pr     |       |            |    |     |      |    |       |       |
| oposed |       |            |    |     |      |    |       |       |
| Use    |       |            |    |     |      |    |       |       |
| Patte  |       |            |    |     |      |    |       |       |
| rns.** |       |            |    |     |      |    |       |       |
+========+=======+============+====+=====+======+====+=======+=======+
| **C    | ## Pr | ## Applic  | ** | *   |      | ** | **PHI | *     |
| rops** | oduct | ation Timi | \# | *Ap |      | RT | ^1^** | *Rest |
|        |       | ng; Type;  | Ap | pli |      | I^ |       | ricti |
|        | ##    | and Equip. | p. | cat |      | 1^ | **(da | ons** |
|        |  (EPA |            | ** | ion |      | (d | ys)** |       |
|        |  Reg. |            |    | Rat |      | ay |       |       |
|        |  No.) |            |    | e** |      | s) |       |       |
|        |       |            |    |     |      | ** |       |       |
|        |       |            |    | **  |      |    |       |       |
|        |       |            |    | (lb |      |    |       |       |
|        |       |            |    | a   |      |    |       |       |
|        |       |            |    | i/A |      |    |       |       |
|        |       |            |    | )** |      |    |       |       |
+--------+-------+------------+----+-----+------+----+-------+-------+
|        |       |            |    | **  | *    |    |       |       |
|        |       |            |    | Per | *Per |    |       |       |
|        |       |            |    | app | seas |    |       |       |
|        |       |            |    | .** | on** |    |       |       |
+--------+-------+------------+----+-----+------+----+-------+-------+
| Wheat, | AE    | Crop       | 1  | 0.  | 0    | NA | B     | Apply |
| b      | 03    | a          |    | 045 | .045 |    | arley | g     |
| arley, | 17309 | pplication |    |     |      |    | and   | round |
| oats   | 02    | -- apply   |    |     |      |    | oats  | app.  |
| and    | SE06  | between 1  |    |     |      |    | grain | in    |
| trit   | (No   | leaf and   |    |     |      |    | or    | 10-15 |
| icale. | EPA   | up to flag |    |     |      |    | s     | g     |
|        | Reg.  | leaf       |    |     |      |    | traw- | al/A, |
|        | No.)  | emergence. |    |     |      |    | 45;   | and   |
|        |       |            |    |     |      |    |       | a     |
|        |       | Ground and |    |     |      |    | Wheat | erial |
|        |       | aerial     |    |     |      |    | and   | app.  |
|        |       | equipment. |    |     |      |    | trit  | in    |
|        |       |            |    |     |      |    | icale | mi    |
|        |       |            |    |     |      |    | grain | nimum |
|        |       |            |    |     |      |    | or    | of 5  |
|        |       |            |    |     |      |    | straw | g     |
|        |       |            |    |     |      |    | --    | al/A. |
|        |       |            |    |     |      |    | 50;   |       |
|        |       |            |    |     |      |    | gr    |       |
|        |       |            |    |     |      |    | azing |       |
|        |       |            |    |     |      |    | or    |       |
|        |       |            |    |     |      |    | for   |       |
|        |       |            |    |     |      |    | aging |       |
|        |       |            |    |     |      |    | -- 25 |       |
|        |       |            |    |     |      |    | days. |       |
+--------+-------+------------+----+-----+------+----+-------+-------+
| Wheat, | H     | Crop       | 1  | 0.0 | 0.   | NA | Grain | G     |
| b      | uskie | a          |    | 037 | 0037 |    | and   | round |
| arley, | Herb  | pplication |    |     |      |    | straw | app.- |
| oats,  | icide | -- apply   |    |     |      |    | -- 60 | Apply |
| rye    | (No   | between 1  |    |     |      |    | days; | in    |
| and    | EPA   | leaf and   |    |     |      |    | gr    | mi    |
| trit   | Reg.  | up to flag |    |     |      |    | azing | nimum |
| icale. | No.)  | leaf       |    |     |      |    | or    | of 5  |
|        |       | emergence. |    |     |      |    | for   | g     |
|        |       |            |    |     |      |    | aging | al/A; |
|        |       | Fallow     |    |     |      |    | -- 25 | A     |
|        |       | a          |    |     |      |    | days. | erial |
|        |       | pplication |    |     |      |    |       | app.  |
|        |       | -- apply   |    |     |      |    |       | --    |
|        |       | in fallow  |    |     |      |    |       | Apply |
|        |       | period     |    |     |      |    |       | in    |
|        |       | prior to   |    |     |      |    |       | mi    |
|        |       | planting   |    |     |      |    |       | nimum |
|        |       | or the     |    |     |      |    |       | of 5  |
|        |       | emergence  |    |     |      |    |       | g     |
|        |       | of crops   |    |     |      |    |       | al/A. |
|        |       | listed on  |    |     |      |    |       |       |
|        |       | label.     |    |     |      |    |       | In    |
|        |       |            |    |     |      |    |       | struc |
|        |       | Ground,    |    |     |      |    |       | tions |
|        |       | sprinkler  |    |     |      |    |       | on    |
|        |       | irrigation |    |     |      |    |       | addit |
|        |       | (wheat and |    |     |      |    |       | ives, |
|        |       | barley     |    |     |      |    |       | such  |
|        |       | only), and |    |     |      |    |       | as    |
|        |       | aerial     |    |     |      |    |       | non-  |
|        |       | equipment. |    |     |      |    |       | ionic |
|        |       |            |    |     |      |    |       | s     |
|        |       |            |    |     |      |    |       | urfac |
|        |       |            |    |     |      |    |       | tants |
|        |       |            |    |     |      |    |       | are   |
|        |       |            |    |     |      |    |       | inc   |
|        |       |            |    |     |      |    |       | luded |
|        |       |            |    |     |      |    |       | on    |
|        |       |            |    |     |      |    |       | l     |
|        |       |            |    |     |      |    |       | abel. |
+--------+-------+------------+----+-----+------+----+-------+-------+

^1^ RTI = retreatment interval; PHI = preharvest interval; NA = not
applicable.

[HED Conclusions]{.underline}: The use directions provided by the
petitioner are adequate to allow evaluation of the residue data relative
to the proposed uses on small cereal grains, with the exception of the
rotational crop restrictions. **Section B of the petition should be
revised to include instructions on rotation to all other crops not
currently listed.**

[]{#__RefHeading___Toc170186432 .anchor}**2.2 Structure and
Nomenclature**

The test compound and metabolite nomenclature are presented below in
Table 2.2.

+-------------------+--------------------------------------------------+
| **Table 2.2. Test |                                                  |
| Compound and      |                                                  |
| Metabolite        |                                                  |
| Nomenclature.**   |                                                  |
+-------------------+--------------------------------------------------+
| Chemical          | ![                                               |
| Structure         | ](media/image2.wmf){width="1.4444444444444444in" |
|                   | height="0.9520833333333333in"}                   |
+-------------------+--------------------------------------------------+
| Empirical Formula | C~14~H~13~F~3~N~2~O~4~S                          |
+-------------------+--------------------------------------------------+
| Common name       | Pyrasulfotole                                    |
+-------------------+--------------------------------------------------+
| Company           | AE 0317309                                       |
| Experimental name |                                                  |
+-------------------+--------------------------------------------------+
| IUPAC name        | 5-hydroxy-1,3-dimethylpyrazol-4-yl               |
|                   | 2-mesyl-4-(trifluoromethyl)phenyl ketone         |
+-------------------+--------------------------------------------------+
| CAS name          | (5-                                              |
|                   | hydroxy-1,3-dimethyl-1*H*-pyrazol-4-yl)\[2-(meth |
|                   | ylsulfonyl)-4-(trifluoromethyl)phenyl\]methanone |
+-------------------+--------------------------------------------------+
| CAS \#            | 365400-11-9                                      |
+-------------------+--------------------------------------------------+
| End-use           | AE 0317309 SE06 Herbicide and AE 0317309 EC23    |
| product/(EP)      | Herbicide                                        |
+-------------------+--------------------------------------------------+
| Compound          | Chemical Structure                               |
|                   |                                                  |
|                   | ![                                               |
|                   | ](media/image3.wmf){width="1.1659722222222222in" |
|                   | height="0.8888888888888888in"}                   |
+-------------------+--------------------------------------------------+
| Common name       | Pyrasulfotole-desmethyl                          |
+-------------------+--------------------------------------------------+
| Company           | AE 1073910                                       |
| Experimental name |                                                  |
+-------------------+--------------------------------------------------+
| CAS name          | (5-hydroxy-1*H*-pyrazol-4-y                      |
|                   | l)\[2-mesyl-4-(trifluoromethyl)phenyl\]methanone |
+-------------------+--------------------------------------------------+
| Compound          | Chemical Structure                               |
|                   |                                                  |
|                   | ![](media/image4.wmf)                            |
+-------------------+--------------------------------------------------+
| Common name       | Pyrasulfotole-benzoic acid                       |
+-------------------+--------------------------------------------------+
| Company           | AE B197555                                       |
| Experimental name |                                                  |
+-------------------+--------------------------------------------------+
| CAS name          | 2-(Methylsulfonyl)-4-(trifluoromethyl)benzoic    |
|                   | acid                                             |
+-------------------+--------------------------------------------------+

[]{#__RefHeading___Toc170186433 .anchor}**2.3 Physical and Chemical
Properties**

The physicochemical properties of pyrasulfotole are presented below in
Table 2.3.

+---------------------+-----------------+---------------------+-------+
| **Table 2.3.        |                 |                     |       |
| Physicochemical     |                 |                     |       |
| Properties of the   |                 |                     |       |
| Technical Grade     |                 |                     |       |
| Test Compound.**    |                 |                     |       |
+=====================+=================+=====================+=======+
| **Parameter**       | **Value**       |                     | **R   |
|                     |                 |                     | efere |
|                     |                 |                     | nce** |
+---------------------+-----------------+---------------------+-------+
| Melting point       | Pure: 201°C     |                     | MRID  |
|                     |                 |                     | 468   |
|                     | No boiling      |                     | 01701 |
|                     | point,          |                     |       |
|                     | decomposition   |                     |       |
|                     | starts at 245°C |                     |       |
+---------------------+-----------------+---------------------+-------+
| pH at 22.9°C        | 3.03            |                     |       |
+---------------------+-----------------+---------------------+-------+
| Density             | 1.53            |                     |       |
+---------------------+-----------------+---------------------+-------+
| Water solubility    | 2.3             | pH 3.0 (distilled   |       |
| (g/L at 20°C)       |                 | water)              |       |
|                     | 4.2             |                     |       |
|                     |                 | pH 3.9 (buffer pH   |       |
|                     | 69.1            | 4.0)                |       |
|                     |                 |                     |       |
|                     | 49.0            | pH 5.4 (buffer pH   |       |
|                     |                 | 7.0)\*              |       |
|                     |                 |                     |       |
|                     |                 | pH 5.2 (buffer pH   |       |
|                     |                 | 9.0)\*              |       |
|                     |                 |                     |       |
|                     |                 | \* exceeded buffer  |       |
|                     |                 | capacity            |       |
+---------------------+-----------------+---------------------+-------+
| Solvent solubility  | Ethanol         | 21.6                |       |
| (g/L at 20°C)       |                 |                     |       |
|                     | n-Hexane        | 0.038               |       |
|                     |                 |                     |       |
|                     | Tolune          | 6.86                |       |
|                     |                 |                     |       |
|                     | Dichloromethane | 120-150             |       |
|                     |                 |                     |       |
|                     | Acetone         | 89.2                |       |
|                     |                 |                     |       |
|                     | Ethyl acetate   | 37.2                |       |
|                     |                 |                     |       |
|                     | Dimethyl        | ≥ 600               |       |
|                     | sulfoxide       |                     |       |
+---------------------+-----------------+---------------------+-------+
| Vapor pressure at   | 2.7 X 10^-7^ Pa |                     |       |
| 20°C                |                 |                     |       |
+---------------------+-----------------+---------------------+-------+
| Dissociation        | 4.2             |                     |       |
| constant (pK~a~)    |                 |                     |       |
+---------------------+-----------------+---------------------+-------+
| *n*-octanol-water   | 0.276           | pH 4.0              |       |
| partition           |                 |                     |       |
| coefficient         | -1.362          | pH 7.0              |       |
| Log(K~OW~) at 23°C  |                 |                     |       |
|                     | -1.580          | pH 9.0              |       |
+---------------------+-----------------+---------------------+-------+
| UV/visible          | λ~max~= 264,    |                     |       |
| absorption spectrum | 241, 216 nm in  |                     |       |
|                     | water, 0.1M     |                     |       |
|                     | HCl, 0.1M NaOH  |                     |       |
|                     | respectively.   |                     |       |
+---------------------+-----------------+---------------------+-------+

[]{#__RefHeading___Toc170186434 .anchor}**3.0 Hazard
Characterization/Assessment**

[]{#__RefHeading___Toc170186435 .anchor}**3.1 Hazard and Dose-Response
Characterization**

[]{#__RefHeading___Toc170186436 .anchor}**3.1.1 Database Summary**

**3.1.1.1 Studies Available and Considered**

Data from the following studies were used to evaluate the hazard
potential of pyrasulfotole:

-   Acute: One acute neurotoxicity study (rat) and standard acute
    toxicity battery

-   Subchronic: Two oral (rat), two oral (dog), and two oral (mouse)
    toxicity studies; and one dermal toxicity study (rat)

-   Developmental: Two prenatal developmental toxicity studies (rat,
    rabbit) and one developmental neurotoxicity study (rat)

-   Reproduction: One 2-generation reproductive toxicity study (rat)

-   Chronic: One combined oral toxicity/carcinogenicity study in rat,
    one carcinogenicity study in mouse, and one oral (1-year) toxicity
    study in dog

-   Genotoxicity: Four *in vivo/in vitro* genotoxicity screens
    (including mutagenicity)

-   Metabolism: one metabolism study (rat; Tier 1)

-   Special: Four mechanistic studies

**3.1.1.2 Mammalian Mechanism of Action for Ocular Toxicity**

Pyrasulfotole is an inhibitor of the hepatic enzyme HPPD. HPPD is an
important enzyme in the catabolism of the amino acid tyrosine. In
mammals, inhibition of HPPD leads to an increase in blood tyrosine
concentrations (tyrosinemia) that is often followed by ocular toxicity.

**3.1.1.3 Sufficiency of Studies/Data**

The toxicity database is complete for pyrasulfotole and is adequate for
risk assessment evaluations and determination of FQPA. All studies
evaluated were deemed acceptable and met guideline criteria.

**3.1.2 Mammalian Toxicology**

Pyrasulfotole has a low to moderate order of **acute toxicity**
(Appendix A.2) 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).
Decreased locomotor activity was observed on the day of treatment in the
acute neurotoxicity study in the rat.

[]{.mark}

Ocular toxicity was observed in male and female rats exposed to
pyrasulfotole for 90 days (**subchronic**) 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.

**Chronic oral exposure** of rats to pyrasulfotole resulted in extensive
eye toxicity at almost all doses tested. These included corneal opacity,
neovascularization of the cornea, inflammation of the cornea,
regenerative corneal hyperplasia, corneal atrophy, and/or retinal
atrophy. Ocular toxicity is believed to be an indirect result of
tyrosinemia caused by inhibition of hepatic HPPD, as mentioned above. In
mice, ocular toxicity was not observed at any dose, thereby reflecting
accepted differences in effects among rodent species for HPPD
inhibitors. Long-term exposure of mice to pyrasulfotole did cause
toxicity of the urinary system, including the kidney, urinary bladder,
and ureters at the highest dose tested, as well as gallstone formation
at all doses tested. Dogs treated with pyrasulfotole for one year
exhibited toxicity of the urinary system (kidneys and bladder) at mid
and high doses, as well as cataracts at a very low incidence at the
highest dose tested.

In the combined **chronic/carcinogenicity** study in rats, an increase
in the incidence of corneal squamous cell tumors was observed in males
only at the highest dose tested. HED's CARC considered these rare
tumors, which were observed following adequate dosing, to be
treatment-related. In the carcinogenicity study in mice, an increase in
the incidence of transitional cell carcinomas and papillomas of the
urinary bladder were observed in males and females at the highest dose
tested. However, these tumors were observed at doses that were
considered excessive due to increased mortality caused by urinary
bladder stones. Pyrasulfotole was negative for mutations and chromosomal
aberrations across four *in vitro*/*in vivo* **genotoxicity** studies
and was considered by the CARC not to pose a mutagenic concern.

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. Both
effects were observed in the presence of maternal toxicity (decreased
body weight gain, enlarged placenta, clinical signs) at the same dose.
In the DNT study in rats, ocular toxicity as well as several adverse
developmental effects (delayed preputial separation, morphometric
changes, delays in learning/memory) were observed at the mid dose.
Ocular toxicity was also observed at this dose in maternal animals; an
identical NOAEL was established in both dams and offspring. 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.

## 3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

One single/low-dose disposition study by the oral and intravenous routes
in rats was performed with pyrasulfotole. Following oral administration
of 10 mg/kg phenyl or pyrazole ring-labeled pyrasulfotole, \~60% of
radiolabeled compound was excreted in the urine after 6 hours, while
\~73% of the administered dose was recovered in the urine by the time of
sacrifice (52 hours). Therefore, approximately 60% of the compound was
absorbed within 6 hours of exposure. Less than 2% of the administered
dose remained in the residual carcass and tissues at sacrifice, and the
highest residues were found in the liver and kidney.
Hydroxymethyl-parent, desmethyl-parent, and benzoic acid metabolite were
observed as metabolites in urine and feces at levels of 2%, \<9%, and
\<2% of the administered dose. Further biotransformation (including
Phase II metabolism) is unknown. Approximately 30% of labeled compound
was excreted in the feces 52 hours after dosing, approximately 25% of
which was parent. Following intravenous injection, approximately 5% of
parent compound was excreted in feces. This implies that 5% of
systemically absorbed parent compound is excreted in the bile. No
metabolism or absorption studies are available via the dermal or
inhalation routes.

[]{#__RefHeading___Toc170186438 .anchor}**3.3 FQPA Considerations**

Executive summaries of developmental toxicity, developmental
neurotoxicity, and reproductive toxicity studies are located in Appendix
A.2. Increased quantitative susceptibility of offspring was observed in
the rabbit developmental toxicity study, since offspring toxicity
(skeletal anomalies/variations) was observed at a lower dose than
maternal toxicity (decreased body weight gain, food consumption). No
evidence of quantitative susceptibility following *in utero* and/or
postnatal exposure was observed in the prenatal developmental toxicity
study in rats, the developmental neurotoxicity (DNT) study in rats, or
in the 2-generation rat reproductive toxicity study. Offspring toxicity
\[skeletal variations; decreased body weight (males)\] was observed at
the same dose as maternal toxicity (clinical signs, decreased body
weight, enlarged placenta) in the prenatal developmental toxicity study
in rats. Offspring toxicity (e.g., ocular toxicity, effects on
learning/memory, effects on brain morphometry) was also observed at the
same dose as maternal toxicity (ocular opacity) in the DNT study. Last,
offspring toxicity (ocular toxicity) was observed at the same as or
higher doses than parental toxicity (thyroid effects) in the
2-generation rat reproductive toxicity study.

The pyrasulfotole risk assessment team recommends that the 10X FQPA SF
for increased susceptibility be reduced to 1X for all exposure
scenarios. This recommendation is based on the following considerations:

-   The toxicology database is complete.

-   There are no residual uncertainties concerning pre- and postnatal
    toxicity. Clear NOAELs were established for all exposure scenarios
    and these are considered protective of the offspring susceptibility
    observed in the rabbit developmental toxicity study. The concern for
    increased susceptibility seen in rabbit developmental toxicity study
    is low because a) there is well established developmental NOAEL in
    the rabbit developmental toxicity study in rabbits protecting
    fetuses from skeletal anomalies/variations, b) the increased
    susceptibility was not seen in rat developmental toxicity study,
    developmental neurotoxicity study in rats and two generation
    reproduction study in rats, c) the NOAEL of the study chosen for the
    chronic RfD is 10x lower than the rabbit developmental toxicity
    study NOAEL (10 mg/kg/day).

```{=html}
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```
-   There are no residual uncertainties with respect to exposure data.

-   The dietary food exposure assessment utilizes proposed
    tolerance-level residues and 100% CT information for all proposed
    commodities. By using this screening-level assessment, the acute and
    chronic exposures/risks will not be underestimated.

-   The dietary drinking water assessment (Tier 1 estimates) utilizes
    values generated by model and associated modeling parameters which
    are designed to provide conservative, health protective, high-end
    estimates of water concentrations.

-   There are no registered or proposed uses of pyrasulfotole which
    would result in residential exposure.

    []{#__RefHeading___Toc170186439 .anchor}**3.4 Hazard Identification
    and Toxicity Endpoint Selection**

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for dietary and occupational human health
risk assessments is provided in Tables 3.4.12a and 3.4.12b. The
conventional interspecies extrapolation (10X) and intraspecies variation
(10X) uncertainty factors were applied for all exposure scenarios. The
FQPA SF for increased susceptibility was reduced to 1X for all exposures
scenarios.

[]{#__RefHeading___Toc170186440 .anchor}**3.4.1 Acute Reference Dose
(aRfD)**

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.

[]{#__RefHeading___Toc170186441 .anchor}**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.

[]{#__RefHeading___Toc170186442 .anchor}**3.4.3 Incidental Oral Exposure
(Short- and Intermediate-Term)**

**There are no residential uses proposed for pyrasulfotole at this
time.** If residential uses are proposed in the future, the effects of
concern that are relevant to the selection of the short‑ and
intermediate-term incidental oral doses are corneal opacity and/or
corneal neovascularization that were observed in F1- and F2-generation
offspring at 26.3/32.6 mg/kg bw/day (M/F) (LOAEL) in the 2-generation
reproduction toxicity study in the rat (NOAEL = 2.5 mg/kg/day). The
study length is appropriate for the durations of exposure, namely, 1-30
days (short-term) and 1-6 months (intermediate-term), and the observed
adverse effects are among the primary toxic effects observed in the
database.

[]{#__RefHeading___Toc170186443 .anchor}**3.4.4 Dermal Absorption**

A dermal absorption study is not available in the database. Based on the
submitted toxicology data, an estimate of dermal absorption was made.
The LOAEL from the 28-day dermal toxicity study (100 mg/kg/day) was
compared to the parental LOAEL from the oral 2-generation reproductive
toxicity study (2.5 mg/kg/day). Alteration of thyroid colloid was
observed in both studies in rats. The dermal absorption factor was
estimated to be 2.5%. Because exposure in the 2-generation reproduction
study is much longer than in the dermal study, the study durations are
not equivalent, and an in vivo dermal penetration study is required to
confirm the estimated dermal absorption factor.

[]{#__RefHeading___Toc170186444 .anchor}**3.4.5 Dermal Exposure (Short-
and Intermediate-Term)**

**There are no residential uses proposed for pyrasulfotole at this
time.** The effects of concern that are relevant to the selection of the
short‑ and intermediate‑term dermal doses for occupational risk
assessment are focal degeneration of the pancreas and alteration of
thyroid colloid that were observed at 100 mg/kg bw/day (M/F) (LOAEL) in
the dermal toxicity study in the rat (NOAEL = 10 mg/kg/day). This study
is considered protective of exposure to pregnant female workers
(worst-case scenario), since the dermal NOAEL (10 mg/kg/day) is much
less than the dermal equivalent dose (152 mg/kg/day) calculated for the
DNT study (NOAEL = 3.8 mg/kg/day; used to calculate aRfD) using the
estimated dermal absorption factor (2.5%). An MOE of \>100 is adequate.

[]{#__RefHeading___Toc170186446 .anchor}**3.4.6 Dermal Exposure
(Long-Term)**

**There are no residential uses proposed for pyrasulfotole at this
time.** A long-term dermal exposure endpoint was chosen based on the
LOAEL from the chronic oral toxicity/carcinogenicity study in the rat. A
long-term dermal toxicity study was not available. Ocular toxicity
(corneal opacity, neovascularization of the cornea, inflammation of the
cornea, regenerative corneal hyperplasia, corneal atrophy, and/or
retinal atrophy), and mild hepatotoxicity (hepatocellular hypertrophy
along with increased serum cholesterol) were observed at the LOAEL of
10/14 mg/kg/day (M/F) (NOAEL = 1 mg/kg/day). The NOAELs are the lowest
in the database following long-term oral animal exposure, and the study
duration is ideal for the duration of exposure. The 2-generation
reproduction study is a co-critical study for this exposure scenario.
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. An MOE of \>100 is considered
protective.

[]{#__RefHeading___Toc170186447 .anchor}**3.4.7 Inhalation Exposure (All
Durations)**

**There are no residential uses proposed for pyrasulfotole at this
time.** The effects of concern that are relevant to the selection of the
short-, intermediate-, and long-term

inhalation doses for occupational risk assessment are ocular toxicity
(corneal opacity, neovascularization of the cornea, inflammation of the
cornea, regenerative corneal hyperplasia, corneal atrophy, and/or
retinal atrophy), and mild hepatotoxicity (hepatocellular hypertrophy
along with increased serum cholesterol) that were observed at 10/14
mg/kg bw/day (M/F) (LOAEL) in the combined chronic
toxicity/carcinogenicity study in the rat (NOAEL = 1 mg/kg/day). 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 studies are considered appropriate,
because the effects were observed in adult animals, and provide the
lowest point of departure in the database. An MOE \>100 is considered
adequate. One hundred percent oral equivalent inhalation absorption is
assumed in the absence of inhalation absorption data.

[]{#__RefHeading___Toc170186448 .anchor}**3.4.9 Level of Concern for
Margin of Exposure**

  --------------- ----------------- ----------------------- -------------------
  **Table 3.4.9.                                            
  Summary of                                                
  Levels of                                                 
  Concern for                                               
  Occupational                                              
  (Worker)                                                  
  Exposure Risk                                             
  Assessment.**                                             

  **Route**       **Short-Term      **Intermediate-Term     **Long-Term (\>6
                  (1-30 Days)**     (1-6 Months)**          Months)**

  Dermal          \<100             \<100                   \<100

  Inhalation      \<100             \<100                   \<100
  --------------- ----------------- ----------------------- -------------------

[]{#__RefHeading___Toc170186449 .anchor}**3.4.10 Recommendation for
Aggregate Exposure Risk Assessments**

For oral exposure, dietary and drinking water exposures were combined.
For occupational exposure dermal and inhalation exposure were combined
since the effects of concern are the same and identified from the same
study.

[]{#__RefHeading___Toc170186450 .anchor}**3.4.11 Classification of
Carcinogenic Potential**

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.

[]{#__RefHeading___Toc170186451 .anchor}**3.4.12 Summary of
Toxicological Doses and Endpoints for Pyrasulfotole for Use in
Human-Health Risk Assessments**

+---------+--------+-------------+-----------------+-----------------+
| **Table |        |             |                 |                 |
| 3.4.12a |        |             |                 |                 |
| Summary |        |             |                 |                 |
| of      |        |             |                 |                 |
| Toxico  |        |             |                 |                 |
| logical |        |             |                 |                 |
| Doses   |        |             |                 |                 |
| and     |        |             |                 |                 |
| En      |        |             |                 |                 |
| dpoints |        |             |                 |                 |
| for     |        |             |                 |                 |
| Pyrasu  |        |             |                 |                 |
| lfotole |        |             |                 |                 |
| for Use |        |             |                 |                 |
| in      |        |             |                 |                 |
| Dietary |        |             |                 |                 |
| and     |        |             |                 |                 |
| No      |        |             |                 |                 |
| n-Occup |        |             |                 |                 |
| ational |        |             |                 |                 |
| Human   |        |             |                 |                 |
| Health  |        |             |                 |                 |
| Risk    |        |             |                 |                 |
| Asses   |        |             |                 |                 |
| sments. |        |             |                 |                 |
| There   |        |             |                 |                 |
| are no  |        |             |                 |                 |
| resi    |        |             |                 |                 |
| dential |        |             |                 |                 |
| uses    |        |             |                 |                 |
| p       |        |             |                 |                 |
| roposed |        |             |                 |                 |
| for     |        |             |                 |                 |
| pyrasu  |        |             |                 |                 |
| lfotole |        |             |                 |                 |
| at this |        |             |                 |                 |
| time.** |        |             |                 |                 |
+=========+========+=============+=================+=================+
| **E     | *      | **Uncer     | **RfD, PAD, LOC | **Study and     |
| xposure | *Point | tainty/FQPA | for Risk        | Relevant        |
| Sce     | of     | Safety      | Assessment**    | Toxicological   |
| nario** | Depar  | Factors**   |                 | Effects**       |
|         | ture** |             |                 |                 |
+---------+--------+-------------+-----------------+-----------------+
| Acute   | NOAEL  | UF~A~ = 10X | aRfD = aPAD =   | **Developmental |
| Dietary | = 3.8  |             | 0.038 mg/kg/day | neurotoxicity   |
| (All    |        | UF~H~ = 10X |                 | (rat;           |
| popul   | mg/    |             |                 | dietary)**      |
| ations) | kg/day | UF~FQPA~ =  |                 | Offspring LOAEL |
|         |        | 1X          |                 | = 37 mg/kg/day  |
|         |        |             |                 | based on        |
|         |        |             |                 | delayed         |
|         |        |             |                 | preputial       |
|         |        |             |                 | separation      |
|         |        |             |                 | (males),        |
|         |        |             |                 | decreased       |
|         |        |             |                 | cerebrum length |
|         |        |             |                 | (PND 21         |
|         |        |             |                 | females), and   |
|         |        |             |                 | decreased       |
|         |        |             |                 | cerebellum      |
|         |        |             |                 | height (PND 21  |
|         |        |             |                 | males).         |
+---------+--------+-------------+-----------------+-----------------+
| Chronic | NOAEL  | UF~A~ = 10X | cRfD = cPAD =   | **Combined      |
| Dietary | = 1.0  |             | 0.01mg/kg/day   | chronic         |
| (All    |        | UF~H~ = 10X |                 | toxicity/       |
| popul   | mg/    |             |                 | carcinogenicity |
| ations) | kg/day | UF~FQPA~ =  |                 | (rat;           |
|         |        | 1X          |                 | dietary)**      |
|         |        |             |                 | LOAEL = 10/14   |
|         |        |             |                 | mg/kg/day (M/F) |
|         |        |             |                 | based on        |
|         |        |             |                 | corneal         |
|         |        |             |                 | opacity,        |
|         |        |             |                 | neo             |
|         |        |             |                 | vascularization |
|         |        |             |                 | of the cornea,  |
|         |        |             |                 | inflammation of |
|         |        |             |                 | the cornea,     |
|         |        |             |                 | regenerative    |
|         |        |             |                 | corneal         |
|         |        |             |                 | hyperplasia,    |
|         |        |             |                 | corneal         |
|         |        |             |                 | atrophy, and/or |
|         |        |             |                 | retinal atrophy |
|         |        |             |                 | (both sexes),   |
|         |        |             |                 | and             |
|         |        |             |                 | hepatocellular  |
|         |        |             |                 | hypertrophy     |
|         |        |             |                 | along with      |
|         |        |             |                 | increased serum |
|         |        |             |                 | cholesterol     |
|         |        |             |                 | (males).^1^     |
+---------+--------+-------------+-----------------+-----------------+
| Inc     | NOAEL  | UF~A~ = 10X | No residential  | **Reproduction  |
| idental | = 2.5  |             | uses proposed.  | and fertility   |
| Oral    |        | UF~H~ = 10X |                 | effects**       |
|         | mg/    |             |                 | **(rat;         |
| Short-  | kg/day | UF~FQPA~ =  |                 | dietary)**      |
| and     |        | 1X          |                 | Offspring LOAEL |
| Int     |        |             |                 | = 26.3/32.6     |
| ermedia |        |             |                 | mg/kg bw/day    |
| te-Term |        |             |                 | \[M/F\] based   |
| (1-30   |        |             |                 | on corneal      |
| days    |        |             |                 | opacity and/or  |
| and 1-6 |        |             |                 | corneal         |
| months) |        |             |                 | neo             |
|         |        |             |                 | vascularization |
|         |        |             |                 | (F1 and F2      |
|         |        |             |                 | generations).   |
+---------+--------+-------------+-----------------+-----------------+
| Dermal  | NOAEL  | UF~A~ = 10X | No residential  | **28-day dermal |
|         | = 10   |             | uses proposed.  | toxicity**      |
| Short-  |        | UF~H~ = 10X |                 | **(rat)** LOAEL |
| and     | mg/    |             |                 | = 100 mg/kg     |
| Interm  | kg/day | UF~FQPA~ =  |                 | bw/day \[M/F\]  |
| ediate- |        | 1X          |                 | based on focal  |
| Term    |        |             |                 | degeneration of |
| (1-30   |        |             |                 | pancreas (both  |
| days    |        |             |                 | sexes) and      |
| and 1-6 |        |             |                 | alteration of   |
| months) |        |             |                 | thyroid colloid |
|         |        |             |                 | (males)         |
+---------+--------+-------------+-----------------+-----------------+
| Dermal  | NOAEL  | UF~A~ = 10X | No residential  | **Combined      |
|         | = 1.0  |             | uses proposed.  | chronic         |
| Lo      |        | UF~H~ = 10X |                 | toxicity/       |
| ng-Term | mg/    |             |                 | carcinogenicity |
| (\>6    | kg/day | UF~FQPA~ =  |                 | (rat;           |
| months) |        | 1X          |                 | dietary)**      |
|         | Est    |             |                 | LOAEL = 10/14   |
|         | imated |             |                 | mg/kg/day (M/F) |
|         | dermal |             |                 | based on        |
|         | abso   |             |                 | corneal         |
|         | rption |             |                 | opacity,        |
|         | factor |             |                 | neo             |
|         | = 2.5% |             |                 | vascularization |
|         |        |             |                 | of the cornea,  |
|         |        |             |                 | inflammation of |
|         |        |             |                 | the cornea,     |
|         |        |             |                 | regenerative    |
|         |        |             |                 | corneal         |
|         |        |             |                 | hyperplasia,    |
|         |        |             |                 | corneal         |
|         |        |             |                 | atrophy, and/or |
|         |        |             |                 | retinal atrophy |
|         |        |             |                 | (both sexes),   |
|         |        |             |                 | and             |
|         |        |             |                 | hepatocellular  |
|         |        |             |                 | hypertrophy     |
|         |        |             |                 | along with      |
|         |        |             |                 | increased serum |
|         |        |             |                 | cholesterol     |
|         |        |             |                 | (males).        |
+---------+--------+-------------+-----------------+-----------------+
| Inh     | NOAEL  | UF~A~ = 10X | No residential  | **Combined      |
| alation | = 1.0  |             | uses proposed.  | chronic         |
|         |        | UF~H~ = 10X |                 | toxicity/       |
| (All    | mg/    |             |                 | carcinogenicity |
| dur     | kg/day | UF~FQPA~ =  |                 | (rat;           |
| ations) |        | 1X          |                 | dietary)**      |
|         | 100%   |             |                 | LOAEL = 10/14   |
|         | inha   |             |                 | mg/kg/day (M/F) |
|         | lation |             |                 | based on        |
|         | a      |             |                 | corneal         |
|         | ssumed |             |                 | opacity,        |
|         |        |             |                 | neo             |
|         |        |             |                 | vascularization |
|         |        |             |                 | of the cornea,  |
|         |        |             |                 | inflammation of |
|         |        |             |                 | the cornea,     |
|         |        |             |                 | regenerative    |
|         |        |             |                 | corneal         |
|         |        |             |                 | hyperplasia,    |
|         |        |             |                 | corneal         |
|         |        |             |                 | atrophy, and/or |
|         |        |             |                 | retinal atrophy |
|         |        |             |                 | (both sexes),   |
|         |        |             |                 | and             |
|         |        |             |                 | hepatocellular  |
|         |        |             |                 | hypertrophy     |
|         |        |             |                 | along with      |
|         |        |             |                 | increased serum |
|         |        |             |                 | cholesterol     |
|         |        |             |                 | (males).        |
+---------+--------+-------------+-----------------+-----------------+
| Cancer  | Cla    |             |                 |                 |
| (oral,  | ssific |             |                 |                 |
| dermal, | ation: |             |                 |                 |
| inha    | "Sugg  |             |                 |                 |
| lation) | estive |             |                 |                 |
|         | Ev     |             |                 |                 |
|         | idence |             |                 |                 |
|         | of     |             |                 |                 |
|         | Carcin |             |                 |                 |
|         | ogenic |             |                 |                 |
|         | Pote   |             |                 |                 |
|         | ntial" |             |                 |                 |
|         | based  |             |                 |                 |
|         | on     |             |                 |                 |
|         | inc    |             |                 |                 |
|         | reased |             |                 |                 |
|         | inci   |             |                 |                 |
|         | dences |             |                 |                 |
|         | of     |             |                 |                 |
|         | c      |             |                 |                 |
|         | orneal |             |                 |                 |
|         | tumors |             |                 |                 |
|         | in     |             |                 |                 |
|         | male   |             |                 |                 |
|         | rats   |             |                 |                 |
|         | (oral  |             |                 |                 |
|         | car    |             |                 |                 |
|         | cinoge |             |                 |                 |
|         | nicity |             |                 |                 |
|         | study) |             |                 |                 |
|         | and    |             |                 |                 |
|         | u      |             |                 |                 |
|         | rinary |             |                 |                 |
|         | b      |             |                 |                 |
|         | ladder |             |                 |                 |
|         | tumors |             |                 |                 |
|         | in     |             |                 |                 |
|         | male   |             |                 |                 |
|         | and    |             |                 |                 |
|         | female |             |                 |                 |
|         | mice   |             |                 |                 |
|         | (oral  |             |                 |                 |
|         | car    |             |                 |                 |
|         | cinoge |             |                 |                 |
|         | nicity |             |                 |                 |
|         | s      |             |                 |                 |
|         | tudy). |             |                 |                 |
+---------+--------+-------------+-----------------+-----------------+

Abbreviations: UF = uncertainty factor, UF~A~ = extrapolation from
animal to human (interspecies), UF~H~ = potential variation in
sensitivity among members of the human population (intraspecies),
UF~FQPA~ = FQPA Safety Factor, NOAEL = no observed adverse effect level,
LOAEL = lowest observed adverse effect level, RfD = reference dose (a =
acute, c = chronic), PAD = population adjusted dose, MOE = margin of
exposure, LOC = level of concern.

^1^ The cRfD was harmonized across American (USEPA), Canadian (PMRA),
and Australian (APVMA) regulatory agencies based on ocular toxicity
observed in the combined chronic toxicity/carcinogenicity study in rats.

+---------+--------+-------------+-----------------+-----------------+
| **Table |        |             |                 |                 |
| 3.4.12b |        |             |                 |                 |
| Summary |        |             |                 |                 |
| of      |        |             |                 |                 |
| Toxico  |        |             |                 |                 |
| logical |        |             |                 |                 |
| Doses   |        |             |                 |                 |
| and     |        |             |                 |                 |
| En      |        |             |                 |                 |
| dpoints |        |             |                 |                 |
| for     |        |             |                 |                 |
| Pyrasu  |        |             |                 |                 |
| lfotole |        |             |                 |                 |
| for Use |        |             |                 |                 |
| in      |        |             |                 |                 |
| Occup   |        |             |                 |                 |
| ational |        |             |                 |                 |
| Human   |        |             |                 |                 |
| Health  |        |             |                 |                 |
| Risk    |        |             |                 |                 |
| Assess  |        |             |                 |                 |
| ments** |        |             |                 |                 |
+=========+========+=============+=================+=================+
| **E     | *      | **Uncer     | **RfD, PAD,     | **Study and     |
| xposure | *Point | tainty/FQPA | Level of        | Toxicological   |
| Sce     | of     | Safety      | Concern for     | Effects**       |
| nario** | Depar  | Factors**   | Risk            |                 |
|         | ture** |             | Assessment**    |                 |
+---------+--------+-------------+-----------------+-----------------+
| Dermal  | NOAEL  | UF~A~ = 10X | Occupational    | **28-day dermal |
|         | = 10   |             | LOC for MOE \<  | toxicity**      |
| Short-  |        | UF~H~ = 10X | 100             | **(rat)** LOAEL |
| and     | mg/    |             |                 | = 100 mg/kg     |
| Interm  | kg/day |             |                 | bw/day \[M/F\]  |
| ediate- |        |             |                 | based on focal  |
| Term    |        |             |                 | degeneration of |
| (1-30   |        |             |                 | pancreas (both  |
| days    |        |             |                 | sexes) and      |
| and 1-6 |        |             |                 | alteration of   |
| months) |        |             |                 | thyroid colloid |
|         |        |             |                 | (males)         |
+---------+--------+-------------+-----------------+-----------------+
| Dermal  | NOAEL  | UF~A~ = 10X | Occupational    | **Combined      |
|         | = 1.0  |             | LOC for MOE \<  | chronic         |
| Lo      |        | UF~H~ = 10X | 100             | toxicity/       |
| ng-Term | mg/    |             |                 | carcinogenicity |
| (\>6    | kg/day |             |                 | (rat;           |
| months) |        |             |                 | dietary)**      |
|         | Est    |             |                 | LOAEL = 10/14   |
|         | imated |             |                 | mg/kg/day (M/F) |
|         | dermal |             |                 | based on        |
|         | abso   |             |                 | corneal         |
|         | rption |             |                 | opacity,        |
|         | factor |             |                 | neo             |
|         | = 2.5% |             |                 | vascularization |
|         |        |             |                 | of the cornea,  |
|         |        |             |                 | inflammation of |
|         |        |             |                 | the cornea,     |
|         |        |             |                 | regenerative    |
|         |        |             |                 | corneal         |
|         |        |             |                 | hyperplasia,    |
|         |        |             |                 | corneal         |
|         |        |             |                 | atrophy, and/or |
|         |        |             |                 | retinal atrophy |
|         |        |             |                 | (both sexes),   |
|         |        |             |                 | and             |
|         |        |             |                 | hepatocellular  |
|         |        |             |                 | hypertrophy     |
|         |        |             |                 | along with      |
|         |        |             |                 | increased serum |
|         |        |             |                 | cholesterol     |
|         |        |             |                 | (males).        |
+---------+--------+-------------+-----------------+-----------------+
| Inh     | NOAEL  | UF~A~ = 10X | Occupational    | **Combined      |
| alation | = 1.0  |             | LOC for MOE \<  | chronic         |
|         |        | UF~H~ = 10X | 100             | toxicity/       |
| (All    | mg/    |             |                 | carcinogenicity |
| dur     | kg/day |             |                 | (rat;           |
| ations) |        |             |                 | dietary)**      |
|         | 100%   |             |                 | LOAEL = 10/14   |
|         | inha   |             |                 | mg/kg/day (M/F) |
|         | lation |             |                 | based on        |
|         | a      |             |                 | corneal         |
|         | ssumed |             |                 | opacity,        |
|         |        |             |                 | neo             |
|         |        |             |                 | vascularization |
|         |        |             |                 | of the cornea,  |
|         |        |             |                 | inflammation of |
|         |        |             |                 | the cornea,     |
|         |        |             |                 | regenerative    |
|         |        |             |                 | corneal         |
|         |        |             |                 | hyperplasia,    |
|         |        |             |                 | corneal         |
|         |        |             |                 | atrophy, and/or |
|         |        |             |                 | retinal atrophy |
|         |        |             |                 | (both sexes),   |
|         |        |             |                 | and             |
|         |        |             |                 | hepatocellular  |
|         |        |             |                 | hypertrophy     |
|         |        |             |                 | along with      |
|         |        |             |                 | increased serum |
|         |        |             |                 | cholesterol     |
|         |        |             |                 | (males).        |
+---------+--------+-------------+-----------------+-----------------+
| Cancer  | Cla    |             |                 |                 |
| (oral,  | ssific |             |                 |                 |
| dermal, | ation: |             |                 |                 |
| inha    | "Sugg  |             |                 |                 |
| lation) | estive |             |                 |                 |
|         | Ev     |             |                 |                 |
|         | idence |             |                 |                 |
|         | of     |             |                 |                 |
|         | Carcin |             |                 |                 |
|         | ogenic |             |                 |                 |
|         | Pote   |             |                 |                 |
|         | ntial" |             |                 |                 |
|         | based  |             |                 |                 |
|         | on     |             |                 |                 |
|         | inc    |             |                 |                 |
|         | reased |             |                 |                 |
|         | inci   |             |                 |                 |
|         | dences |             |                 |                 |
|         | of     |             |                 |                 |
|         | c      |             |                 |                 |
|         | orneal |             |                 |                 |
|         | tumors |             |                 |                 |
|         | in     |             |                 |                 |
|         | male   |             |                 |                 |
|         | rats   |             |                 |                 |
|         | (oral  |             |                 |                 |
|         | car    |             |                 |                 |
|         | cinoge |             |                 |                 |
|         | nicity |             |                 |                 |
|         | study) |             |                 |                 |
|         | and    |             |                 |                 |
|         | u      |             |                 |                 |
|         | rinary |             |                 |                 |
|         | b      |             |                 |                 |
|         | ladder |             |                 |                 |
|         | tumors |             |                 |                 |
|         | in     |             |                 |                 |
|         | male   |             |                 |                 |
|         | and    |             |                 |                 |
|         | female |             |                 |                 |
|         | mice   |             |                 |                 |
|         | (oral  |             |                 |                 |
|         | car    |             |                 |                 |
|         | cinoge |             |                 |                 |
|         | nicity |             |                 |                 |
|         | s      |             |                 |                 |
|         | tudy). |             |                 |                 |
+---------+--------+-------------+-----------------+-----------------+

Abbreviations: UF = uncertainty factor, UF~A~ = extrapolation from
animal to human (interspecies), UF~H~ = potential variation in
sensitivity among members of the human population (intraspecies),
UF~FQPA~ = FQPA Safety Factor, NOAEL = no observed adverse effect level,
LOAEL = lowest observed adverse effect level, RfD = reference dose (a =
acute, c = chronic), PAD = population adjusted dose, MOE = margin of
exposure, LOC = level of concern.

[]{#__RefHeading___Toc170186452 .anchor}**3.5 Endocrine Disruption**

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) "may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate."
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system. EPA also
adopted EDSTAC's recommendation that the Program include evaluations of
potential effects in wildlife. For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations. As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

When additional appropriate screening and/or testing protocols being
considered under the Agency's EDSP have been developed, pyrasulfotole
may be subjected to further screening and/or testing to better
characterize effects related to endocrine disruption.

[]{#__RefHeading___Toc170186453 .anchor}**4.0 Public Health and
Pesticide Epidemiology Data**

No public health/epidemiology data were used in developing this risk
assessment. Since pyrasulfotole is a new a.i, data are not available.

[]{#__RefHeading___Toc170186454 .anchor}**5.0 Dietary Exposure/Risk
Characterization**

The residue chemistry data submitted in support of the proposed uses
were summarized in the HED-memorandum dated 06/08/07 (J. Tyler; DP#
333412). The drinking water assessment was provided by EFED in a memo
dated 1/18/07 (M. Echeverria; DP# 330817). The acute and chronic dietary
exposure assessments were completed in a HED-memorandum dated 06/08/07
(J. Tyler, DP# 333435).

[]{#__RefHeading___Toc170186455 .anchor}**5.1 Pesticide Metabolism and
Environmental Degradation**

[]{#__RefHeading___Toc170186456 .anchor}**5.1.1 Metabolism in Primary
Crops**

The available wheat metabolism studies (a phenyl-labeled study, a
pyrazole-labeled study, and a phenyl-labeled study comparing the nature
of the residue in spring wheat with and without the safener) are
adequate, and indicate that the metabolism of pyrasulfotole in spring
wheat involves the demethylation and subsequent glucosylation of the
parent compound, yielding pyrasulfotole-desmethyl-*O*- glucoside. There
was also cleavage of the complete pyrazole moiety resulting in the
pyrasulfotole-benzoic acid metabolite as detected by the phenyl-label
study and a polar fraction (p1) formed from the pyrazole-label study.
Fraction p1 was characterized as being natural or incorporated into the
matrix.

Following spray applications of either phenyl- and pyrazole-labeled
pyrasulfotole at a nominal rate of 0.089 lb ai/A (\~2x maximum proposed
application rate), total radioactive residues (TRR) levels were
0.44-0.47 ppm in forage, 0.06-0.18 ppm in hay, 0.38-0.55 ppm in straw,
and 0.03-0.30 ppm in grain. In the phenyl-labeled study, the predominant
residue was pyrasulfotole-benzoic acid in all wheat matrices with levels
increasing as the plant matured (24.1-89.5% of the TRR; 0.11-0.35 ppm).
Pyrasulfotole-desmethyl-*O*-glucoside was also a major component in
wheat forage and hay, and a minor component in straw. In the
pyrazole-labeled study, pyrasulfotole-desmethyl-*O*-glucoside was the
only metabolite identified in forage, hay, straw (21.7-43.0% of the TRR;
0.015-0.20 ppm), and grain (0.7% of the TRR; \<0.001 ppm). A polar
fraction, p1, was a major part of the residue in hay (20.9% of the TRR;
0.01 ppm), straw (10.9% of the TRR; 0.04 ppm), and grain (11.2% of the
TRR; 0.003 ppm). Several unknown metabolite fractions of varying
polarity were detected in wheat matrices, none of them exceeding 7.7% of
the TRR (0.04 ppm).

Following a spray application of either phenyl-labeled pyrasulfotole at
a nominal rate of 0.089 lb ai/A (2x maximum proposed application rate)
or phenyl-labeled pyrasulfotole with the safener mefenpyr-diethyl, the
TRR levels were 2.40-2.44 ppm in forage, 3.12-3.14 ppm in hay, 2.44-2.90
ppm in straw, and 0.16-0.24 ppm in grain, indicating that the overall
distribution of the radioactive residues was quantitatively similar to
wheat with and without safener. The predominant residue in wheat forage,
hay and straw was comprised of the metabolites pyrasulfotole-benzoic
acid (16.3-37.2% of the TRR; 0.39-1.06 ppm) and
pyrasulfotole-desmethyl-*O*-glucoside (19.6-43.5% of the TRR; 0.49-1.16
ppm). Minor components were pyrasulfotole (4.4-7.3% of the TRR;
0.13-0.18 ppm), and pyrasulfotole-sulfinyl-lactate (3.8-9.6% of the TRR;
0.09-0.28 ppm). In grain, pyrasulfotole-benzoic acid was the only
residue identified (97.6-97.7% of the TRR; 0.15-0.23 ppm).

[]{#__RefHeading___Toc170186457 .anchor}**5.1.2 Metabolism in Rotational
Crops**

The submitted confined rotational crop study is adequate, and indicates
that the metabolic breakdown of pyrasulfotole involves the cleavage of
the complete pyrazole moiety yielding the benzoic acid metabolite. In
rotational crops, the predominant residue is the pyrasulfotole-benzoic
acid metabolite.

Wheat (small grain), Swiss chard (leafy vegetable), and turnips (root
crop) were planted approximately 120 days and 300 days (wheat only)
following an application of either phenyl- or pyrazole-labeled
pyrasulfotole to soil in large troughs at a rate of 0.073 lb ai/A (2.2x
the maximum proposed application rate). Total residues amounting to 27.0
to 91.3% of the TRR were identified in rotational crop matrices
following application of phenyl-labeled pyrasulfotole. Total identified
residues were 3 to 9% of the TRR (\<0.001-0.002 ppm) following
application of pyrazole-labeled pyrasulfotole. A number of components
were characterized as acetonitrile (ACN)/H~2~O soluble. Nonextractable
residues following extraction procedures accounted for 3.1 to 29% of the
TRR (0.001-0.008 ppm) in phenyl-label samples, and 40 to 47% of the TRR
(0.006-0.008 ppm) in pyrazole-label samples.

The predominant residue was identified as pyrasulfotole-benzoic acid in
all wheat matrices (27.0-91.3% of the TRR; 0.004-0.078 ppm) at 120-days
after treatment (DAT) and 301-DAT when dosed with phenyl-labeled
pyrasulfotole. Pyrasulfotole-benzoic acid was not identified in the
120-DAT wheat straw and hay following application of pyrazole-labeled
pyrasulfotole. Pyrasulfotole was identified in 120-DAT wheat grain and
301-DAT wheat hay samples (0.9-2.0% of the TRR; 0.001 ppm) for the
phenyl-labeled study. Pyrasulfotole was the only identified component in
the 120-DAT wheat hay and straw samples (3-9% of the TRR; \<0.001-0.002
ppm) for the pyrazole-labeled study. Multiple components were
characterized as ACN/H2O soluble or remaining solid phase extraction
fractions in wheat matrices for the phenyl-labeled study (3.9-47.2% of
the TRR; 0.001-0.025 ppm) and the pyrazole-labeled (37-50% of the TRR;
0.003-0.013 ppm).

[]{#__RefHeading___Toc170186458 .anchor}**5.1.3 Metabolism in
Livestock**

The nature of the pyrasulfotole residues in livestock is understood
based on the acceptable phenyl- and pyrazole-labeled lactating goat and
laying hen metabolism studies. The goat study indicates that the
metabolism of pyrasulfotole in lactating goats involved either
*N*-demethylation of pyrasulfotole to produce pyrasulfotole-desmethyl,
or oxidation of pyrasulfotole to produce pyrasulfotole-hydroxymethyl.
The hen study indicates that the metabolism pyrasulfotole in laying hens
involved the *N*-demethylation of pyrasulfotole to yield the
pyrasulfotole-desmethyl metabolite.

[]{.mark}

In the lactating goat studies, following three consecutive days of
dosing with \[^14^C\]pyrasulfotole at levels equivalent to 51.2 \[phenyl
label; 130x the maximum theoretical dietary burden (MTDB) to dairy
cattle\] or 28.1 ppm (pyrazole label; 72x the MTDB to dairy cattle) in
the diet, TRR levels were highest in liver (1.447-1.723 ppm) and were
considerably lower in kidney (0.269-0.533 ppm), fat (0.008-0.010), and
muscle (0.007-0.010 ppm.) Residues in milk increased slightly over time
to 0.017-0.044 ppm by Day 3 (p.m.). In the phenyl-labeled study, the
majority of the residue was comprised of pyrasulfotole in muscle (80.2%
of the TRR; 0.008 ppm), kidney (99.6% of the TRR; 0.532 ppm), liver
(95.5% of the TRR; 1.411 ppm) and milk (82.7% of the TRR; 0.014 ppm).
Lesser amounts were identified as pyrasulfotole-desmethyl metabolite in
milk (11.7% of the TRR, 0.002 ppm), and hydroxymethyl pyrasulfotole in
muscle (8.3% of the TRR; 0.001 ppm) and milk (4.4% of the TRR; 0.002
ppm). In the pyrazole-labeled study, pyrasulfotole was identified as the
major residue in the liver (93.3% of the TRR, 1.603ppm) and kidney
(92.4% of the TRR, 0.249 ppm). Additionally, two minor metabolites were
identified/characterized from the extractable liver residue as
pyrasulfotole-desmethyl (1.4% of the TRR, 0.025 ppm), and an
unidentified polar metabolite (1.7% of the TRR, 0.030 ppm). In milk, the
predominant residue was pyrasulfotole (38.8% of the TRR, 0.017 ppm) with
lesser amounts of three unknown polar compounds, none of which exceeded
0.006 ppm. In both radiolabeled studies, the majority of the
radioactivity (\>67%) was recovered in urine and feces (phenyl \>67%,
and pyrazole \>92%), with less than 1.15% (phenyl) and 0.1% (pyrazole)
in milk, and 1.12% (phenyl) and 0.925% (pyrazole) in tissues.

In the laying hen studies, following 14 consecutive days of dosing at
levels equal to 8.6 (phenyl label; 150x the MTDB to poultry) or 10.5 ppm
(pyrazole label; 180x the MTDB to poultry) pyrasulfotole equivalents in
the diet, TRR levels were highest in liver (1.285-1.560 ppm) and were
considerably lower in fat (0.015-0.066), muscle (0.020-0.038 ppm.), and
eggs (\<0.001-0.004 ppm). The predominant residue in muscle (95.5% of
the TRR; 0.036 ppm), fat (97.1% of the TRR; 0.064 ppm) and liver (93.3%
of the TRR; 1.456 ppm) was pyrasulfotole. Pyrasulfotole-desmethyl was a
minor metabolite in muscle (2.2% o the TRR; 0.001 ppm), fat (1.8% of the
TRR; 0.001 ppm) and liver (6.5% of the TRR; 0.101 ppm). In both
radiolabeled studies, the majority of the radioactivity (phenyl \>97%,
and pyrazole \>85%) was recovered in urine and feces, with less than
0.4% (phenyl) and 0.2% (pyrazole) in tissues and eggs.

[]{#__RefHeading___Toc170186459 .anchor}**5.1.4 Analytical Methodology**

An adequate high-performance liquid chromatography (HPLC)/MS/MS method
(Method AI-001-P04-1) is available for collecting data on residues of
pyrasulfotole and its metabolite pyrasulfotole-desmethyl in/on plant
commodities. The limit of quantitation (LOQ) is 0.010 ppm for each
analyte. Method AI-001-P04-1, which is also the proposed enforcement
method for plant commodities, has been adequately radiovalidated and
undergone a successful ILV trial. The proposed method was forwarded to
the ACB/BEAD for a Memo, J. Tyler, 1/30/07; DP# 335558). ACB reviewed
the proposed enforcement method data without an ACB validation (Memo, C.
Stafford, 6/7/07; D335559). Provided the method is revised as specified
in the ACB review, Method AI-001-P04-01 is a suitable enforcement method
for determination of pyrasulfotole and pyrasulfotole-desmethyl in crop
matrices. In particular, the ACB determined that the plant method does
not meet general requirement as a confirmatory method since only one
MS/MS ion transition is documented. The ACB recommends that the
petitioner provide information for a second MS/MS ion transition to
provide a confirmation of analyte identities. If two ion transitions are
not available, HED recommends that the petitioner provide an alternate
chromatographic column and/or mobile-phase combination to add an
additional degree of specificity and further reduce the possibility of
false positive residues.

The HPLC-MS/MS method (Method AI-004-A05-01) is adequate for collecting
data on pyrasulfotole in livestock tissues, including milk, matrices.
However, based on the results of the livestock metabolism studies, the
residues of concern in livestock are pyrasulfotole and
pyrasulfotole-desmethyl for tolerance and risk assessment purposes.
Therefore, the petitioner should submit a ruminant analytical
enforcement method to determine residues of pyrasulfotole and
pyrasulfotole-desmethyl as well as adequate radiovalidation and ILV
data. Upon submission, the method will be forwarded to ACB/BEAD for a
PMV trial. It should be noted that ACB believes that the proposed
analytical enforcement method will work for pyrasulfotole-desmethyl
(e-mail from C. Stafford to J. Tyler; 3/3/007). Therefore, HED
recommends for a conditional registration until an updated method is
submitted.

Pyrasulfotole and the metabolite pyrasulfotole-desmethyl were subjected
to analysis by selected Protocols of the Food and Drug Administration
(FDA) Pesticide Analytical Manual, Volume I (PAM I), third edition. The
results indicate that pyrasulfotole is partially recovered through
Protocol B, and completely recovered through Protocol C module DG-17.
Pyrasulfotole-desmethyl was not recovered through any of the Protocols.
The report has been forwarded to FDA for inclusion in PAM I (Memo, J.
Tyler, 01/30/07; D335562).

[]{#__RefHeading___Toc170186460 .anchor}**5.1.5 Environmental
Degradation**

Pyrasulfotole is expected to be persistent and mobile to moderately
mobile in the environment. Major routes of dissipation include microbial
degradation in soils, formation of non-extractable residues in soils and
sediments, and dilution.

Under aerobic conditions pyrasulfotole degraded in 3 soils (loamy sand,
silt loam, sandy loam) according to an apparent bi-phasic pattern with
observed DT~50~s ranging from 4-65 days and observed DT~90~s ranging
from \>120-\>358 days. A 2-compartment, 4-parameter exponential model,
also known as Double First Order Parallel (DFOP), was used to fit the
data and resulted in modeled DT~50~s ranging from 6-63 days and DT~90~s
ranging from 208-1424 days. Degradation products included
pyrasulfotole-benzoic acid, CO~2~ and non-extractable residues.
Non-extractable residues were identified at maximums of 35-62% of
applied radioactivity in the 3 soils. The non-extractable residues are
uncharacterized and it is uncertain whether they consist of degradates
of risk concern. Under sterile conditions, however, the formation of
non-extractable residues (as well as the formation of CO~2~ and the
benzoic acid degradate) were negligible. In terrestrial field
dissipation studies, pyrasulfotole dissipated from the whole soil
profile with modeled (DFOP) DT~90~s ranging from 44-531 days and the
amount of parent pyrasulfotole carry over to the following growing
season ranged from 4.7 to 37%.

In aquatic systems, pyrasulfotole is stable to hydrolysis and
photolysis. In aerobic aquatic metabolism studies, pyrasulfotole
partitioned to the sediment and formed non-extractable residues but
there was no evidence of degradation. Pyrasulfotole is considered stable
to microbial degradation in aquatic systems. Under anaerobic conditions
pyrasulfotole is also stable.

Batch equilibrium studies resulted in organic carbon sorption
coefficients (K~­oc~­) ranging from 20-345 ml/g~oc­~ with a median value of
68 ml/g~oc~. In terrestrial field dissipation studies pyrasulfotole
showed variable downward migration in the soil profile under bare soil
conditions. In some studies pyrasulfotole was confined to 0-15 cm
whereas in others it was detected at quantifiable levels as deep as
75-90 cm. Since pyrasulfotole has a K~d~ less than 5 in most soils and
is persistent (hydrolysis half-life greater than 25 weeks, photolysis
half-life greater than 1 week, aerobic soil metabolism half-life greater
than 2-3 weeks), not volatile (Henry's Law constant less than 10^-2^
atm\*m^-3^/mol), and shows movement to 45 cm during some field
dissipation studies, there is indication for potential groundwater
contamination (Cohen 1984). Depending on soil, site and meteorological
conditions pyrasulfotole may be transported off-site to drinking water
sources via runoff, leaching and spray drift.

[]{#__RefHeading___Toc170186461 .anchor}**5.1.6 Comparative Metabolic
Profile**

Pyrasulfotole is readily absorbed through the rat gastrointestinal tract
and is primarily excreted in the urine (73-75% via oral dose, and 87-91%
via intravenous dose) and feces (31-32% via oral dose, and 8-10% TRR via
intravenous dose) by 48-52 hours. The tissue burden is low, with \<2% of
the dose remaining in the carcass and tissues at sacrifice. Following
both oral and intravenous administration, most of the dose was excreted
unchanged as pyrasulfotole. Hydroxymethyl pyrasulfotole,
pyrasulfotole-desmethyl, and pyrasulfotole-benzoic acid were observed as
minor metabolites in the urine and feces.

The metabolism of pyrasulfotole in primary plants and livestock appears
to be similar to its metabolism in rats. The primary metabolic pathway
in animals (rats, goats and hens) involves the N-demethylation of
pyrasulfotole to produce pyrasulfotole-desmethyl. In plants (primary
crops), formation of pyrasulfotole-desmethyl via N-demethylation was
also a major metabolic pathway, followed by either glucosylation to
produce a pyrasulfotole-desmethyl-O-glucose conjugate or conjugation
with gluthathione to produce pyrasulfotole-sulfonyl-lactate. Another
metabolic pathway in rats, primary crops and rotational crops involved
the cleavage of the pyrazole moiety resulting in pyrasulfotole-benzoic
acid. Pyrasulfotole-benzoic acid was a major metabolite in rotational
crops, which was consistent with it also being the major metabolite in
soil degradation studies. Another minor metabolic pathway in goats and
rats involved the hydroxylation of the pyrazole methyl group.

[]{#__RefHeading___Toc170186462 .anchor}**5.1.7 Toxicity Profile of
Major Metabolites and Degradates**

Little information is available on the toxicity of
pyrasulfotole-desmethyl. However, based on the structural similarity of
the parent and the pyrasulfotole-desmethyl metabolite, and in the
absence of toxicological evidence to the contrary,
pyrasulfotole-desmethyl is assumed to be of comparable toxicity to the
parent.

Pyrasulfotole-benzoic acid is not of toxicological concern. This
decision was based on the results of several toxicology studies
submitted for the benzoic acid metabolite. In an acute oral toxicity
study in rats on pyrasulfotole-benzoic acid, no mortalities were
observed. The oral LD~50~ for male and female rats was \>5000 mg/kg
(Category IV). In separate 28-day and 90-day dietary toxicity studies in
rats, no toxicity was observed for the benzoic acid metabolite up to and
including the highest doses tested (1118/1269 and 769/952 mg/kg/day in
males/females, respectively). Pyrasulfotole-benzoic acid metabolite was
negative for mutagenicity and clastogenicity in four separate
genotoxicity studies. No evidence of teratogenicity was observed in a
developmental toxicity study in the rat. In the same study, decreased
body weight gain and food consumption and clinical signs of toxicity
(salivation, piloerection, red nasal discharge around the time of
treatment) were observed in dams at doses ≥ 250 mg/kg/day. The clinical
signs of toxicity were considered due to daily boluses by gavage since
they were not seen at much higher dietary doses. In addition, the
pregnancy status of the animals may have contributed to the observed
results.

[]{#__RefHeading___Toc170186463 .anchor}**5.1.8 Pesticide Metabolites
and Degradates of Concern**

  -----------------------------------------------------------------------------------
  **Table 5.1.8.                                         
  Summary of                                             
  Metabolites and                                        
  Degradates to                                          
  be included in                                         
  Risk Assessment                                        
  and Tolerance                                          
  Expression.**                                          
  --------------- ------------ ------------------------- ----------------------------
  **Matrix**                   **Residues included in    **Residues included in
                               Risk Assessment**         Tolerance Expression**

  Plants          Primary Crop Parent and                Parent and
                               Pyrasulfotole-desmethyl   Pyrasulfotole-desmethyl

                  Rotational   Parent only               Parent only
                  Crop                                   

  Livestock       Ruminant     Parent and                Parent and
                               Pyrasulfotole-desmethyl   Pyrasulfotole-desmethyl

                  Poultry      Parent and                Parent and
                               Pyrasulfotole-desmethyl   Pyrasulfotole-desmethyl

  Drinking Water               Parent only               Not Applicable
  -----------------------------------------------------------------------------------

**Plants (Primary Crops):** For wheat, the pyrasulfotole risk assessment
team determined that the residues of concern in cereal grains for both
tolerance and risk assessment purposes are parent and the
pyrasulfotole-desmethyl metabolite. This decision was based on the
following:

-   Pyrasulfotole-desmethyl-*O*-glucoside, the conjugated form of
    pyrasulfotole-desmethyl, was seen in the available wheat metabolism
    studies.

    -   Wheat (without safener) study: In the phenyl-labeled study,
        pyrasulfotole-desmethyl-*O*-glucoside was a major component in
        wheat forage (34.2% TRR; 0.152 ppm) and hay (10.4% TRR; 0.02
        ppm); and a minor component in straw (5.1% TRR; 0.03 ppm). In
        the pyrazole-label study, pyrasulfotole-desmethyl-*O*-glucoside
        was the only metabolite identified in forage (43.4% TRR; 0.202
        ppm), hay (25.4 TRR; 0.015 ppm), straw (21.7% TRR, 0.08 ppm),
        and grain (0.7% TRR, \<0.001 ppm).

    -   Wheat (with and without safener) study: In the phenyl-labeled
        study with safener, pyrasulfotole-desmethyl-*O*-glucoside was a
        major component in wheat forage (43.5% TRR; 1.04 ppm), hay
        (36.7% TRR; 1.16 ppm), and straw (27.9% TRR, 0.81 ppm). In the
        phenyl-label study without safener,
        pyrasulfotole-desmethyl-*O*-glucoside was the major metabolite
        identified in forage (30.2% TRR; 0.74 ppm), hay (25.7 TRR; 0.80
        ppm), and straw (19.6% TRR, 0.55 ppm).

-   Based on the structure similarity of the parent and the
    pyrasulfotole-desmethyl metabolite, and in the absence of
    toxicological evidence to the contrary, pyrasulfotole-desmethyl
    metabolite is assumed to be of comparable toxicity to the parent.

-   Pyrasulfotole-desmethyl was seen in quantifiable levels in wheat
    (forage, hay, and straw), barley (hay and straw), and oat (forage,
    grain, hay and straw) in the submitted crop field trial studies. In
    addition, in the majority of the commodities,
    pyrasulfotole-desmethyl was present at levels equal to or greater
    than the parent pyrasulfotole.

-   The proposed enforcement and data collection method, Method
    AI-001-P04-01 is a HPLC-MS/MS method for residues of pyrasulfotole
    and pyrasulfotole-desmethyl in crop matrices.

Although pyrasulfotole-benzoic acid was a major metabolite in the wheat
metabolism and wheat, barley and oat crop field trial studies, based on
available toxicology studies on pyrasulfotole-benzoic acid, the risk
assessment team determined that it is not of toxicological concern (see
rationale below). Therefore, it was not included in the residue
definition for tolerance or risk assessment purposes for cereal grains.

**Plants (Rotational Crops):** The pyrasulfotole risk assessment team
determined that the residue of concern in rotational crops for both
tolerance and risk assessment purposes is parent only. This decision was
based on the results of the available confined rotational crop study,
which indicate that the metabolic breakdown of pyrasulfotole in
rotational crops involves the cleavage of the complete pyrazole moiety
yielding the benzoic acid metabolite. Although pyrasulfotole-benzoic
acid was the predominant residue in all wheat matrices at 120-and
301-day PBI, based on available toxicology studies on
pyrasulfotole-benzoic acid, the risk assessment team determined that it
is not of toxicological concern (see rationale below).

**Livestock:** The pyrasulfotole risk assessment team determined that
the residues of concern in livestock for both tolerance and risk
assessment purposes are parent and the pyrasulfotole-desmethyl
metabolite. This decision was based on the following:

-   In available crop field trials, pyrasulfotole-desmethyl was one of
    the major residues in livestock feed items; therefore, secondary
    residues to livestock are likely to be pyrasulfotole-desmethyl
    instead of parent.

Although pyrasulfotole-benzoic acid was a major metabolite in the wheat,
barley and oat crop field trial studies, based on available toxicology
studies on pyrasulfotole-benzoic acid, the risk assessment team
determined that it is not of toxicological concern (see rationale
below). Therefore, it was not included in the residue definition for
tolerance or risk assessment purposes for livestock commodities.

**Drinking Water:** The pyrasulfotole risk assessment team determined
that the residue of concern in drinking water for risk assessment
purposes is parent only. Although pyrasulfotole-benzoic acid was
identified as the only environmental degradate in the soil metabolism
and terrestrial field dissipation studies, based on available toxicology
studies on pyrasulfotole-benzoic acid, the risk assessment team
determined that it is not of toxicological concern (see rationale
below); and, thus should not be included in the drinking water
assessment for pyrasulfotole.

**[Rationale for not including benzoic acid metabolite of pyrasulfotole
as metabolite of concern]{.underline}:** Although pyrasulfotole benzoic
acid was a major metabolite in wheat and rotational crops and a minor
metabolite in rats and drinking water, the pyrasulfotole risk assessment
team determined that it is not of toxicological concern. This decision
was based on the results of several toxicology studies submitted for the
benzoic acid metabolite. The following were observed in the submitted
toxicology studies:

-   No mortalities were observed in the acute oral toxicity study in the
    rat. The oral LD~50~ for male and female rats was \>5000 mg/kg
    (Category IV).

-   In separate 28-day and 90-day dietary toxicity studies in rats, no
    toxicity was observed for the benzoic acid metabolite up to and
    including the highest doses tested (1118/1269 and 769/952 mg/kg/day
    in males/females, respectively), whereas toxicity was observed with
    the parent compound in similar short-term studies in rats and dogs
    at much lower doses (see Appendix A.2 for summary).

-   The benzoic acid metabolite was negative for mutagenicity and
    clastogenicity in four separate genotoxicity studies.

-   No evidence of teratogenicity was observed in a developmental
    toxicity study in the rat. In the same study, decreased body weight
    gain and food consumption and clinical signs of toxicity
    (salivation, piloerection, red nasal discharge around the time of
    treatment) were observed in dams at doses ≥ 250 mg/kg/day. The
    clinical signs of toxicity were considered due to daily boluses by
    gavage since they were not seen at much higher dietary doses. In
    addition, the pregnancy status of the animals may have contributed
    to the observed results.

Based on the lack of mortality in the acute oral toxicity study (LD~50~
\>5000 mg/kg), lack of toxicity in two short-term toxicity studies, lack
of developmental toxicity, questionable toxicity in pregnant dams, and
the lack of genotoxicity in four acceptable assays, the risk assessment
team recommended that the benzoic acid metabolite of pyrasulfotole not
be included in the residue definition for tolerance or risk assessment
purposes for any commodity.

[]{#__RefHeading___Toc170186464 .anchor}**5.1.9 Drinking Water Residue
Profile**

EFED provided Tier 1 EDWCs for surface and ground water which were
generated using FIRST and SCIGROW, respectively. Based on the results of
these simulations, EFED recommends 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 is **1.4 µg/L** and is also based on the use of
pyrasulfotole on cereal grains at the previously stated rate. Table
5.1.9 lists the summary of estimated surface and groundwater EDWCs for
pyrasulfotole.

+--------------------------+---------------------+---------------------+
| **Table 5.1.9. Summary   |                     |                     |
| of Estimated Surface     |                     |                     |
| Water and Groundwater    |                     |                     |
| EDWCs for                |                     |                     |
| Pyrasulfotole.**         |                     |                     |
+==========================+=====================+=====================+
|                          | **Pyrasulfotole**   |                     |
+--------------------------+---------------------+---------------------+
|                          | **Surface Water     | **Groundwater       |
|                          | Concentration       | Concentration       |
|                          | (ppb)^a^**          | (ppb)^b^**          |
+--------------------------+---------------------+---------------------+
| Acute                    | 4.0                 | 1.4                 |
+--------------------------+---------------------+---------------------+
| Chronic (non-cancer)     | 2.8                 | 1.4                 |
+--------------------------+---------------------+---------------------+
| Chronic (cancer)         | \-                  | \-                  |
+--------------------------+---------------------+---------------------+
| ^a^ From the Tier I      |                     |                     |
| FIRST model. Input       |                     |                     |
| parameters are based on  |                     |                     |
| aerial spray             |                     |                     |
| applications to small    |                     |                     |
| grains at a rate of      |                     |                     |
| 0.045 lb ai/A/year.      |                     |                     |
|                          |                     |                     |
| ^b^ From the SCI-GROW    |                     |                     |
| model assuming a maximum |                     |                     |
| seasonal use rate of     |                     |                     |
| 0.045 lb ai/A, a K~oc~   |                     |                     |
| of 20 ml/g~OC~, and      |                     |                     |
| half-life of 226 days.   |                     |                     |
+--------------------------+---------------------+---------------------+

[]{#__RefHeading___Toc170186465 .anchor}**5.1.10 Food Residue Profile**

[]{.mark}

The available crop field trial data on wheat, barley and oats on both
the SE06 and EC23 end-use products are classified as scientifically
acceptable for determination of the magnitude of residues for
pyrasulfotole and the metabolites pyrasulfotole-benzoic acid and
pyrasulfotole-desmethyl when treated with the end use products AE 017309
02 SE06 or AE 017309 03 + Bromo. Although pyrasulfotole-benzoic acid was
a primary residue in most commodities, it was determined by the
pyrasulfotole risk assessment team to be not of toxicological concern;
and, therefore, should not be included in the tolerance expression for
small cereal grains.

[]{.mark}

In general, in wheat and barley, residues of pyrasulfotole and
pyrasulfotole-desmethyl appeared to be slightly higher following
application of the SE06 formulation. In oats, the amount of each analyte
detected was essentially the same between formulations. In wheat, barley
and oats, the highest residue levels were observed in/on the hay samples
and the lowest levels observed in/on the grain samples. Available
residue decline data on wheat, barley and oats indicate that residues of
pyrasulfotole and pyrasulfotole-desmethyl decreased with time in forage
and wheat hay, but decreased only slightly or remained unchanged in
straw and grain with increasing preharvest intervals. There are adequate
storage stability data to validate the storage conditions and intervals
of samples collected from the field trials.

For purposes of determining appropriate tolerance levels for the
proposed uses, individual pyrasulfotole and pyrasulfotole-desmethyl
residues were summed to yield a total residue value. In many cases,
individual apparent residues were either \<LOQ (\<0.01 ppm) but \> limit
of detection (\>LOD; \>0.005 ppm), or \<LOD (0.005 ppm). In cases where
the individual value (pyrasulfotole and/or pyrasulfotole-desmethyl) was
\<LOQ (\<0.01 ppm) but \>LOD (\>0.005 ppm), the actual value was used.
In cases where an individual value (pyrasulfotole or
pyrasulfotole-desmethyl) was \<LOD (\<0.005 ppm), the LOD (0.005 ppm)
was used. The pyrasulfotole and pyrasulfotole-desmethyl were then
summed, and in cases where either parent or desmethyl was \<LOD, the
data were considered to be censored.

Therefore, based on the percentage of censored data, appropriate
tolerances were either determined using either rounding up from the
highest-average field trial (HAFT) values from the respective crop field
trial studies, or the methodology formulated by the North America Free
Trade Agreement (NAFTA) Maximum Residue Level (MRL)/Tolerance
Harmonization Workgroup for calculating statistically based pesticide
tolerances for plant commodities based on field trial residue data. For
wheat hay, wheat straw, barley hay, barley straw, oat forage, oat grain,
and oat hay, the appropriate tolerance levels were calculated using the
NAFTA MRL/Tolerance Harmonization Workgroup methodology. For wheat
forage, wheat grain, and barley grain the appropriate tolerance levels
were calculated by rounding up from the HAFT values from the respective
crop field trial data.

The available crop field trial data indicate that the appropriate
tolerances for residues of pyrasulfotole and pyrasulfotole-desmethyl are
0.20 ppm in/on wheat, forage; 0.80 ppm in/on wheat, hay; 0.02 ppm in/on
wheat, grain; 0.20 ppm in/on wheat, straw; 0.30 ppm in/on barley, hay;
0.02 ppm in/on barley, grain; 0.20 ppm in/on barley, straw, 0.10 ppm
in/on oat, forage; 0.50 ppm in/on oat, hay; 0.08 ppm in/on oat, grain;
and 0.20 ppm in/on oat, straw. In addition, the wheat, barley and oat
crop field trial data are adequate to support the proposed uses on rye
and triticale. The available data indicate that the appropriate
tolerances for residues of pyrasulfotole and pyrasulfotole-desmethyl are
0.02 ppm in/on rye, grain; 0.20 ppm, in/on rye, straw; and 0.20 ppm
in/on rye, forage. HED notes that the proposed tolerance for triticale,
grain is not needed as it is covered under the wheat, grain tolerance.

[]{.mark}

The results of the processing study indicate that residues of
pyrasulfotole and pyrasulfotole-desmethyl do not appear to concentrate
in wheat flour (0.26x), middling (0.38x), shorts (0.56x) and germ
(0.70x). Total residues of pyrasulfotole and pyrasulfotole-desmethyl do
appear to concentrate in aspirated wheat grain fractions (33x), and
wheat bran (1.6x). Based on these processing factors and a HAFT residue
of 0.011 ppm from the wheat field trials, a separate tolerance is not
needed for wheat, bran, but a tolerance should be established for
aspirated grain fractions at 0.40 ppm. In addition, based on the results
of the processed food/feed data on wheat, HED concludes that residues of
pyrasulfotole and pyrasulfotole-desmethyl are not expected to
concentrate in pearled barley, barley flour, oat flour, groats/rolled
oats, and rye flour. Therefore, tolerances on these processed
commodities are not needed. Because the results of the processing study
indicate that residues concentrated in wheat bran, residues can be
expected to concentrate in barley bran, oat bran and rye bran as well.
Based on the 1.6x processing factor for wheat bran, and a HAFT residue
of 0.010 ppm from the barley field trials, the maximum expected residues
in barley bran would be 0.016 ppm, which is below the recommended 0.02
ppm tolerance for barley, grain. Therefore, a separate tolerance is not
needed for barley, bran. Based on the 1.6x processing factor for wheat
bran, and a HAFT residue of 0.109 ppm from the oat field trials, the
maximum expected residues in oat bran would be 0.17 ppm, which is above
the recommended 0.08 ppm tolerance for oat, grain. Therefore, a separate
tolerance should be established for oat, bran at 0.20 ppm. However,
according to current HED guidelines, HED does not currently set
tolerances for residues on oat, bran. The residue level was incorporated
into the dietary exposure assessment. Based on the 1.6x processing
factor for wheat bran, and a HAFT residue of 0.011 ppm from the wheat
field trials, the maximum expected residues in rye bran would be 0.018
ppm, which is below the recommended 0.02 ppm tolerance for rye, grain.
Therefore, a separate tolerance is not needed for rye, bran.

[]{.mark}

Using the data from the adequate cattle feeding study and a calculated
MTDB of 0.39 ppm for pyrasulfotole and pyrasulfotole-desmethyl residues
in dairy cattle diets, estimated pyrasulfotole and
pyrasulfotole-desmethyl residues in ruminants at a 1X dose level are
0.16 ppm in liver, 0.029 ppm in kidney; and \<LOQ in milk, meat and fat.
Based on the quantifiable residues and in order to harmonize with PMRA,
tolerances should be established for residues of pyrasulfotole and
pyrasulfotole-desmethyl on liver of cattle, goat, horse, and sheep at
0.35 ppm; and meat byproducts, except liver, of cattle, goat, horse, and
sheep at 0.06 ppm. Although, there is no reasonable expectation of
finding quantifiable residues of pyrasulfotole and
pyrasulfotole-desmethyl in milk; milk, fat; and fat and muscle of
cattle, goat, horse and sheep, PMRA policy requires the establishment of
tolerances at the LOQ level for commodities in which there is no
expectation of finite residues. Therefore, in order to harmonize with
PMRA, the following tolerances for residues of pyrasulfotole and
pyrasulfotole-desmethyl should be established: 0.01 ppm in milk; and
0.02 ppm in fat and meat of cattle, goat, horse and sheep.

[]{.mark}

Using data from the adequate cattle feeding study and a calculated MTDB
of 0.014 ppm pyrasulfotole and pyrasulfotole-desmethyl in hogs, the
estimated pyrasulfotole and pyrasulfotole-desmethyl residues in hogs
were 0.0000046 ppm in muscle, 0.0011 ppm in kidney, and 0.0059 ppm in
liver. There is no reasonable expectation of finding quantifiable
residues of pyrasulfotole and pyrasulfotole-desmethyl in hog tissues.
However, in order to harmonize with PMRA, the following tolerances for
residues of pyrasulfotole and pyrasulfotole-desmethyl should be
established: 0.02 ppm in fat, meat, and meat byproducts of hogs.

[]{.mark}

For purposes of this petition, using the data from the poultry
metabolism studies and a calculated MTDB of 0.058 ppm for poultry, the
maximum estimated pyrasulfotole and pyrasulfotole-desmethyl residues in
poultry were 0.00025 ppm in muscle, 0.00043 ppm in fat, and 0.010 ppm in
liver. As the total extractable residues in eggs were \<0.01 ppm; the
samples were not analyzed further for identification purposes. Based on
the results of the poultry metabolism study, there is no reasonable
expectation of finding quantifiable residues of pyrasulfotole and
pyrasulfotole-desmethyl in eggs and poultry tissues. However, in order
to harmonize with PMRA, the following tolerances for residues of
pyrasulfotole and pyrasulfotole-desmethyl should be established: 0.02
ppm in fat, meat, and meat byproducts of poultry.

[]{.mark}

The results of the submitted confined and limited field rotational crop
studies together are adequate to determine appropriate plantback
intervals (PBIs) for rotational crops. In the confined rotational crop
study, following application of either phenyl- or pyrazole-labeled
pyrasulfotole, the TRR in the 122-DAT Swiss chard, turnip tops, and
turnip roots were \<0.01 (\<LOQ). In the limited field rotational crop
study, maximum residue levels of pyrasulfotole and
pyrasulfotole-desmethyl were \<LOD in all corn and soybean RACs at PBIs
of 114-123 days. Maximum residues levels for pyrasulfotole-benzoic acid
were 0.0018 ppm in corn forage, 0.0027 ppm in soybean forage, 0.0126 ppm
in soybean hay and \<LOD in corn grain, corn stover and soybean seed.
However, it was determined that residues of pyrasulfotole-benzoic acid
are not of concern for both tolerance and risk assessment purposes.
Therefore, the submitted confined and limited field trial data support
the proposed PBIs.

The residue chemistry database supports the establishment of the
permanent tolerances for the combined residues of pyrasulfotole and
pyrasulfotole-desmethyl in/on the RACs listed in Appendix C.

[]{.mark}

[]{#__RefHeading___Toc170186466 .anchor}**5.1.11 International Residue
Limits**

There are no established Mexican, Canadian or Codex MRLs for the
proposed uses. As mentioned previously, pyrasulfotole is being evaluated
as part of a trilateral joint review with Canada and Australia. All
HED-recommended tolerances are the same as those being established in
Canada and Australia. Therefore, harmonization is not an issue at this
time.

[]{.mark}

[]{#__RefHeading___Toc170186467 .anchor}**5.2 Dietary Exposure and
Risk**

Pyrasulfotole acute and chronic dietary exposure assessments were
conducted using DEEM-FCID, Version 1.30), which incorporates
consumption data from USDA's CSFII, 1994-1996 and 1998. The 1994-96, 98
data are based on the reported consumption of more than 20,000
individuals over two non-consecutive survey days. Foods "as consumed"
(e.g., apple pie) are linked to EPA-defined food commodities (e.g.
apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour -
cooked; fresh or N/S, baked) using publicly available recipe translation
files developed jointly by USDA/ARS and EPA. Consumption data are
averaged for the entire U.S. population and within population subgroups
for chronic exposure assessment, but are retained as individual
consumption events for acute exposure assessment.

For chronic exposure and risk assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form. The resulting residue
consumption estimate for each food/food-form is summed with the residue
consumption estimates for all other food/food-forms on the commodity
residue list to arrive at the total average estimated exposure. Exposure
is expressed in mg/kg body weight/day and as a percent of the cPAD. This
procedure is performed for each population subgroup.

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis. The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or "matched" in multiple random
pairings with residue values and then summed in a probabilistic
assessment. The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (*i.e.*, those who reported eating
relevant commodities/food forms) and a per-capita (*i.e.*, those who
reported eating the relevant commodities as well as those who did not)
basis. In accordance with HED policy, per capita exposure and risk are
reported for all tiers of analysis. However, for Tiers 1 and 2,
significant differences in user vs. per capita exposure and risk are
identified and noted in the risk assessment.

HED's level of concern is when the exposure is greater than 100% of the
PAD. That is, estimated exposures above this level are of concern, while
estimated exposures at or below this level are not of concern. The
DEEM-FCID™ analysis estimates the dietary exposure of the U.S.
population and 26 population subgroups. The results reported in Table
5.2 are for the U.S. Population, all infants (\<1 year old), children
1-2, children 3-5, children 6-12, youth 13-19, females 13-49, males
20-49, and adults 50+ years.

[]{#__RefHeading___Toc170186468 .anchor}**5.2.1 Acute Dietary
Exposure/Risk**

An unrefined, acute dietary exposure assessment was performed for the
general U.S. population and all other population subgroups (including
infants and children) using tolerance-level residues and assuming 100%
CT for all proposed uses. Drinking water was incorporated directly in
the dietary assessment using the acute concentration for surface water
generated by the FIRST model. The results of this assessment indicate
that the acute dietary exposure estimates (95^th^ percentile) are not of
concern to HED (\<100% of the aPAD) for the general U.S. population (2%
of the aPAD) and all other populations subgroups. The most highly
exposed population subgroup is children 1-2 years old at 4% of the aPAD.

[]{#__RefHeading___Toc170186469 .anchor}**5.2.2 Chronic Dietary
Exposure/Risk**

[]{.mark}

An unrefined, chronic dietary exposure assessment was performed for the
general U.S. population and various population subgroups using
tolerance-level residues and assuming 100% CT for all proposed uses.
Drinking water was incorporated directly into the dietary assessment
using the chronic concentration for surface water generated by the FIRST
model. The results of the assessment conclude that the chronic dietary
exposure estimates are below HED's level of concern (\<100% of the cPAD)
for the general U.S. population (2% of the cPAD) and all population
subgroups. The most highly exposed population subgroup is children 1-2
years old at 7% of the cPAD.

+-----------------+-------------+--------+--------------+------------+
| **Table 5.2.    |             |        |              |            |
| Summary of      |             |        |              |            |
| Dietary         |             |        |              |            |
| Exposure and    |             |        |              |            |
| Risk for        |             |        |              |            |
| P               |             |        |              |            |
| yrasulfotole.** |             |        |              |            |
+=================+=============+========+==============+============+
| **Population**  | **Acute     |        | **Chronic    |            |
|                 | D           |        | Dietary^2^** |            |
| **Subgroup**    | ietary^1^** |        |              |            |
+-----------------+-------------+--------+--------------+------------+
|                 | **Dietary   | **%    | **Dietary    | **% cPAD** |
|                 | Exposure**  | aPAD** | Exposure**   |            |
|                 |             |        |              |            |
|                 | **(m        |        | **(          |            |
|                 | g/kg/day)** |        | mg/kg/day)** |            |
+-----------------+-------------+--------+--------------+------------+
| U.S. Population | 0.000633    | 2      | 0.000224     | 2          |
| (total)         |             |        |              |            |
+-----------------+-------------+--------+--------------+------------+
| All Infants (\< | 0.001259    | 3      | 0.000410     | 4          |
| 1 year old)     |             |        |              |            |
+-----------------+-------------+--------+--------------+------------+
| **Children 1-2  | *           | **4**  | **0.000698** | **7**      |
| years old**     | *0.001393** |        |              |            |
+-----------------+-------------+--------+--------------+------------+
| Children 3-5    | 0.001053    | 3      | 0.000541     | 5          |
| years old       |             |        |              |            |
+-----------------+-------------+--------+--------------+------------+
| Children 6-12   | 0.000691    | 2      | 0.000339     | 3          |
| years old       |             |        |              |            |
+-----------------+-------------+--------+--------------+------------+
| Youth 13-19     | 0.000431    | 1      | 0.000190     | 2          |
| years old       |             |        |              |            |
+-----------------+-------------+--------+--------------+------------+
| Adults 20-49    | 0.000378    | 1      | 0.000168     | 2          |
| years old       |             |        |              |            |
+-----------------+-------------+--------+--------------+------------+
| Adults 50+      | 0.000331    | 1      | 0.000160     | 2          |
| years old       |             |        |              |            |
+-----------------+-------------+--------+--------------+------------+
| Females 13-49   | 0.000368    | 1      | 0.000161     | 2          |
| years old       |             |        |              |            |
+-----------------+-------------+--------+--------------+------------+
| ^1^ Acute       |             |        |              |            |
| dietary         |             |        |              |            |
| endpoint of     |             |        |              |            |
| 0.038 mg/kg/day |             |        |              |            |
| applies to the  |             |        |              |            |
| general U.S.    |             |        |              |            |
| population and  |             |        |              |            |
| all population  |             |        |              |            |
| subgroups.      |             |        |              |            |
|                 |             |        |              |            |
| ^2^ Chronic     |             |        |              |            |
| dietary         |             |        |              |            |
| endpoint of     |             |        |              |            |
| 0.01 mg/kg/day  |             |        |              |            |
| applies to the  |             |        |              |            |
| general U.S.    |             |        |              |            |
| population and  |             |        |              |            |
| all population  |             |        |              |            |
| subgroups.      |             |        |              |            |
+-----------------+-------------+--------+--------------+------------+

[]{#__RefHeading___Toc170186470 .anchor}**6.0 Residential
(Non-Occupational) Exposure/Risk Characterization**

As there are currently no registered or proposed residential uses for
pyrasulfotole, a residential exposure assessment was not conducted.

[]{#__RefHeading___Toc170186471 .anchor}**6.1 Other (Spray Drift,
etc.)**

Spray drift is always a potential source of exposure to residents nearby
to spraying operations. This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for
pyrasulfotole. The Agency has been working with the Spray Drift Task
Force, EPA Regional Offices and State Lead Agencies for pesticide
regulation and other parties to develop the best spray drift management
practices. On a chemical by chemical basis, the Agency is now requiring
interim mitigation measures for aerial applications that must be placed
on product labels/labeling. The Agency has completed its evaluation of
the new database submitted by the Spray Drift Task Force, a membership
of U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT^®^ computer model to its
risk assessments for pesticides applied by air, orchard airblast and
ground hydraulic methods. After the policy is in place, the Agency may
impose further refinements in spray drift management practices to reduce
off-target drift with specific products with significant risks
associated with drift.

[]{#__RefHeading___Toc170186472 .anchor}**7.0 Aggregate Risk Assessments
and Risk Characterization**

[]{.mark}

In accordance with the FQPA, HED must consider and aggregate pesticide
exposures and risks from three major sources: food, drinking water, and
residential exposures. In an aggregate assessment, exposures from
relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated. When aggregating exposures and risks from various
sources, HED considers both the route and duration of exposure.

For pyrasulfotole, aggregate exposure risk assessments were performed
for the following scenarios: acute aggregate exposure (food and drinking
water), and chronic aggregate exposure (food and drinking water). Short-
and intermediate-term assessments, which are used to evaluate aggregate
dietary and residential exposures, were not performed because there are
no registered or proposed residential non-food uses. Because
pyrasulfotole is classified as "Suggestive Evidence of Carcinogenicity"
and HED CARC recommended that a separate quantification of cancer risk
is not required. Therefore, cancer aggregate risk assessments were not
performed.

[]{#__RefHeading___Toc170186473 .anchor}**7.1 Acute Aggregate Risk**

The acute aggregate risk assessment takes into account exposure
estimates from dietary consumption of pyrasulfotole (food and drinking
water). The acute dietary exposure estimates, are not of concern to HED
(\<100% aPAD) at the 95^th^ exposure percentile for the general U.S.
population and all other population subgroups (see Table 5.2). The
dietary exposure assessment was a screening-level assessment, utilizing
tolerance-level residues and 100% CT information for all proposed
agricultural uses and a Tier 1 acute surface water EDWCs generated by
FIRST. Therefore, the acute aggregate risk associated with the proposed
uses of pyrasulfotole is not of concern to HED for the general U.S.
population or any population subgroups.

[]{#__RefHeading___Toc170186474 .anchor}**7.2 Chronic Aggregate Risk**

The chronic aggregate risk assessment takes into account average
exposure estimates from dietary consumption of pyrasulfotole (food and
drinking water). The chronic dietary exposure estimates are not of
concern to HED (\<100% cPAD) for the general U.S. population and all
population subgroups (see Table 5.2). The dietary exposure assessment
was a screening-level assessment, utilizing tolerance-level residues and
100% CT information for all proposed agricultural uses and a Tier 1
chronic surface water EDWCs generated by FIRST. Therefore, the chronic
aggregate risk associated with the proposed uses of pyrasulfotole is not
of concern to HED for the general U.S. population or any population
subgroups.

[]{.mark}

[]{#__RefHeading___Toc170186475 .anchor}**8.0 Cumulative Risk
Characterization/Assessment**

[]{.mark}

Pyrasulfotole, mesotrione, isoxaflutole and topramezone belongs to a
class of herbicides that inhibit the liver enzyme
4-hydroxyphenylpyruvate dioxygenase (HPPD), which is involved in the
catabolism (metabolic breakdown) of tyrosine (an amino acid derived from
proteins in the diet). Inhibition of HPPD can result in elevated
tyrosine levels in the blood, a condition called tyrosinemia.
HPPD-inhibiting herbicides have been found to cause a number of
toxicities in laboratory animal studies including ocular, developmental,
liver and kidney effects. Of these toxicities, it is the ocular effect
(corneal opacity) that is highly correlated with the elevated blood
tyrosine levels. In fact, rats dosed with tyrosine alone show ocular
opacities similar to those seen with HPPD inhibitors. Although the other
toxicities may be associated with chemically-induced tyrosinemia, other
mechanisms may also be involved.

There are marked differences among species in the ocular toxicity
associated with inhibition of HPPD. Ocular effects following treatment
with HPPD inhibitor herbicides are seen in the rat but not in the mouse.
Monkeys also seem to be recalcitrant to the ocular toxicity induced by
HPPD inhibition. The explanation of this species-specific response in
ocular opacity is related to the species differences in the clearance of
tyrosine. A metabolic pathway exists to remove tyrosine from the blood
that involves a liver enzyme called tyrosine aminotransferase (TAT). In
contrast to rats where ocular toxicity is observed following exposure to
HPPD-inhibiting herbicides, mice and humans are unlikely to achieve the
levels of plasma tyrosine necessary to produce ocular opacities because
the activity of TAT in these species is much greater compared to rats.
Thus, humans and mice have a highly effective metabolic process for
handling excess tyrosine.

HPPD inhibitors (e.g., Nitisinone) are used as an effective therapeutic
agent to treat patients suffering from rare genetic diseases of tyrosine
catabolism. Treatment starts in childhood but is often sustained
throughout patient's lifetime. The human experience indicates that a
therapeutic dose (1 mg/kg/day dose) of Nitisinone has an excellent
safety record in infants, children and adults and that serious adverse
health outcomes have not been observed in a population followed for
approximately a decade. Rarely, ocular effects are seen in patients with
high plasma tyrosine levels; however these effects are transient and can
be readily reversed upon adherence to a restricted protein diet. This
indicates that an HPPD inhibitor in it of itself cannot easily overwhelm
the tyrosine-clearance mechanism in humans.

Therefore, exposure to environmental residues of HPPD-inhibiting
herbicides are unlikely to result in the high blood levels of tyrosine
and ocular toxicity in humans due to an efficient metabolic process to
handle excess tyrosine. In the future, assessments of HPPD-inhibiting
herbicides willl consider more appropriate models and cross species
extrapolation methods.

Therefore, EPA has not conducted cumulative risk assessment with other
HPPD inhibitors (HED Doc. D 341612; dated 7/02/07).

[]{.mark}

[]{#__RefHeading___Toc170186476 .anchor}**9.0 Occupational Exposure/Risk
Pathway**

An occupational exposure assessment was provided in a HED memorandum
dated 05/01/07 (K. Lowe; DP# 333434). Based on the proposed use
patterns, occupational handler and post-application exposure to
pyrasulfotole is expected. The labels for pyrasulfotole recommend that
the products be applied between the 1 leaf and up to flag leaf emergence
and only one application is allowed per season, therefore, most
exposures will be short-term (i.e., 1-30 days) in duration; and, only
short-term dermal and inhalation exposures were assessed.

[]{#__RefHeading___Toc170186477 .anchor}**9.1 Short-Term Handler Risk**

The proposed use patterns indicate that the most highly-exposed
occupational pesticide handlers are likely to be mixer/loaders using
open-pour loading of liquids for aerial applications, and applicators
using aerial equipment. As no chemical-specific data were available with
which to assess potential exposure of pyrasulfotole to pesticide
handlers, the estimates of exposure to pesticide handlers are based upon
surrogate study data available in the PHED Surrogate Exposure Guide
(August 1998). For pesticide handlers, it is HED standard practice to
present estimates of dermal exposure for "baseline" that is, for workers
wearing a single layer of work clothing consisting of a long-sleeved
shirt, long pants, shoes plus socks and no protective gloves, as well as
for "baseline" and the use of protective gloves or other PPE as might be
necessary. The proposed product labels involved in this assessment
direct applicators and other handlers to wear a long-sleeved shirt and
long pants, socks, shoes, chemical-resistant gloves and protective
eyewear.

Table 9.1 presents the exposure/risks for short and intermediate-term
dermal and inhalation exposures at baseline. HED has no data to assess
exposures to pilots using open cockpits.  The only data available is for
exposure to pilots in enclosed cockpits.  Therefore, risks to pilots are
assessed using the engineering control (enclosed cockpits) and baseline
attire (long-sleeve shirt, long pants, shoes, and socks). A MOE of 100
is adequate to protect occupational pesticide handlers. All MOEs are
\>100 with baseline attire; and, therefore, are not of concern to HED.

+---------+---------+---------+---------+---------+---------+---------+
| **Table |         |         |         |         |         |         |
| 9.1.    |         |         |         |         |         |         |
| Sho     |         |         |         |         |         |         |
| rt-Term |         |         |         |         |         |         |
| Occup   |         |         |         |         |         |         |
| ational |         |         |         |         |         |         |
| E       |         |         |         |         |         |         |
| xposure |         |         |         |         |         |         |
| and     |         |         |         |         |         |         |
| Risk    |         |         |         |         |         |         |
| Es      |         |         |         |         |         |         |
| timates |         |         |         |         |         |         |
| for use |         |         |         |         |         |         |
| of      |         |         |         |         |         |         |
| Pyrasu  |         |         |         |         |         |         |
| lfotole |         |         |         |         |         |         |
| on      |         |         |         |         |         |         |
| Small   |         |         |         |         |         |         |
| Cereal  |         |         |         |         |         |         |
| Grain   |         |         |         |         |         |         |
| s.^1^** |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **E     | **M     | **      | **      | **D     | **Inhal | **C     |
| xposure | itigati | Daily** | Daily** | ermal** | ation** | ombined |
| Sce     | on^2^** |         |         |         |         | M       |
| nario** |         | **D     | **Inhal | **M     | **M     | OE^5^** |
|         |         | ermal** | ation** | OE^4^** | OE^4^** |         |
|         |         |         |         |         |         |         |
|         |         | **Dose  | **Dose  |         |         |         |
|         |         | (m      | (m      |         |         |         |
|         |         | g/kg/da | g/kg/da |         |         |         |
|         |         | y)^3^** | y)^3^** |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **      |         |         |         |         |         |         |
| Mixer/L |         |         |         |         |         |         |
| oader** |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Aerial  | B       | 0.056   | 0.00093 | 180     | 1,100   | 150     |
| Appli   | aseline |         |         |         |         |         |
| cations |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
|         |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Appli |         |         |         |         |         |         |
| cator** |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Aerial  | Engi    | 0       | 0       | 100,000 | 19,000  | 16,000  |
| Eq      | neering | .000096 | .000052 |         |         |         |
| uipment | control |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+

1\. Short-term handler assessment was conducted assuming 1) the maximum
proposed application rate for cereal grains (0.045 lb ai/A); and 2) 1200
and 200 acres treated per day for mixer/loaders and applicators,
respectively (based on Exposure SAC SOP #9 "Standard Values for Daily
Acres Treated in Agriculture," industry sources, and HED estimates).

2\. Baseline Dermal: Long-sleeve shirt, long pants, and no gloves.
Baseline Inhalation: no respirator. Engineering control: enclosed
cockpit and baseline attire (long-sleeve shirt, long pants, shoes, and
socks).

3\. Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre) x
Area Treated (acres/day) x %Absorption (2.5% dermal and 100% inhalation)
/ Body weight (70 kg).

4\. MOE = NOAEL/Dose; where the short-term dermal NOAEL = 10 mg/kg/day
and the short-term inhalation NOAEL = 1.0 mg/kg/day

5\. Combined MOE = NOAEL / (dermal + inhalation daily dose)

[]{#__RefHeading___Toc170186478 .anchor}**9.2 Short-Term
Post-application Risk**

Typically, there is the possibility for agricultural workers to
experience post-application exposures to dislodgeable pesticide
residues. There are no chemical-specific data with which to estimate
post-application exposure of agricultural workers to dislodgeable
residues of pyrasulfotole. Therefore, theoretical estimates of exposure,
based on surrogate studies, have been conducted. The ExpoSAC (SOP 003.1,
Rev. 7 Aug. 2000, Regarding Agricultural Transfer Coefficients; Amended
ExpoSAC Meeting notes - 13 Sept 01) lists a number of possible
post-application agricultural activities relative the proposed uses that
might result in pesticide exposure to agricultural workers. TCs
expressed as cm²/hr are identified for each of the post-application,
agricultural activities. The TCs are derived from data in surrogate
exposure studies conducted during the various activities listed.

The activities with the highest (*i.e.*, most conservative) TCs related
to the proposed uses on small cereal grains were scouting and
irritating. For risk assessment purposes, the TCs are 100 cm²/hr and
1,500 cm²/hr for scouting and irritating fields with plants of low and
medium height, respectively. In addition to the above TCs, exposures
during post-application activities were estimated using the following
assumptions:

-   Application Rate = 0.045 lb ai/A

-   Exposure Duration = 8 hours per day

-   Body Weight = 70 kg

-   Dermal Absorption = 2.5%

-   Fraction of ai retained on foliage is assumed to be 20% (0.2) on day
    zero (= % dislodgeable foliar residue, DFR, after initial
    treatment). This fraction is assumed to further dissipate at the
    rate of 10% (0.1) per day on following days. These are default
    values established by ExpoSAC.

Daily dermal doses were calculated on each post-application day after
application using the following equations:

Dermal Dose (mg/kg/day) = \[DFR~(t)~ (µg/cm^2^) x TC (cm^2^/hr) x ET
(hr/day) \* CF1 \* Abs (%)\] / BW (kg)

Where:

DFR(t) = Dislodgeable foliar residues at time "t" (0.1 µg/cm^2^ on day
0);

TC = Transfer Coefficient (cm^2^/hour);

ET = Exposure time meant to represent a typical workday (8 hours);

CF1 = Conversion factor (0.001 mg/ug);

> Abs = Dermal absorption (2.5%); and
>
> BW = Body weight (70 kg).

and

DFR~(t)~ (µg/cm^2^) = \[AR (lb ai/A) \* (CF2/CF3)\] \* TR

Where:

DFR(t) = Dislodgeable foliar residues at time "t" (0.1 µg/cm^2^ on day
0);

AR = Application rate (lb ai/A);

CF2 = Conversion factor (4.54E+08 ug/lb)

CF1 = Conversion factor (4.05E+07 cm^2^/A); and

> TR = Transferable residue that can be dislodgeable foliar residue at
> time (t) (20% on day 0).

Table 9.2 presents a summary of occupational short-term post-application
risks associated with the proposed uses of pyrasulfotole. These
estimates are considered to be screening-level estimates (*i.e.*,
conservative and protective). HED's level of concern for dermal exposure
is for MOEs \<100. In this case, MOEs are greater than 100; therefore,
post-application dermal exposure is not of concern to HED for
agricultural workers. Post-application inhalation exposure is expected
to be negligible.

+------------+---------+----------------+---------+------------------+
| **Table    |         |                |         |                  |
| 9.2.       |         |                |         |                  |
| Summary of |         |                |         |                  |
| Short-term |         |                |         |                  |
| Oc         |         |                |         |                  |
| cupational |         |                |         |                  |
| Post-a     |         |                |         |                  |
| pplication |         |                |         |                  |
| Risks for  |         |                |         |                  |
| Pyr        |         |                |         |                  |
| asulfotole |         |                |         |                  |
| on Small   |         |                |         |                  |
| Cereal     |         |                |         |                  |
| Grains.**  |         |                |         |                  |
+------------+---------+----------------+---------+------------------+
| **Ac       | **TC    | **Maximum      | **MOE   | **REI (days)**   |
| tivities** | (       | Application    | at Day  |                  |
|            | cm^2^/h | Rate**         | 0**     | **(Target MOE=   |
|            | r)^1^** |                |         | 100)**           |
|            |         | **(lb          |         |                  |
|            |         | ai/acre)**     |         |                  |
+------------+---------+----------------+---------+------------------+
| Scouting,  | 100     | 0.045          | 350,000 | 12 hours         |
| irrigation |         |                |         |                  |
+------------+---------+----------------+---------+------------------+
|            | 1500    |                | 23,000  | 12 hours         |
+------------+---------+----------------+---------+------------------+

1\. TC = transfer coefficient.

Pyrasulfotole is classified in Acute Toxicity Category III for acute
oral toxicity, acute dermal toxicity, and primary eye irritation. It
classified in Category IV for acute inhalation toxicity and primary skin
irritation. It is not a dermal sensitizer. Therefore, the interim WPS
REI of 12 hours is adequate to protect agricultural workers from
post-application exposures. The two proposed end-use product labels list
a REI of 12 hours.

[]{#__RefHeading___Toc170186479 .anchor}**10.0 Data Needs and Label
Recommendations**

[]{#__RefHeading___Toc170186480 .anchor}**10.1 Toxicology**

-   In vivo dermal penetration study.

    []{#__RefHeading___Toc170186481 .anchor}**10.2 Residue Chemistry**

```{=html}
<!-- -->
```
-   Revised Section B to include instructions on rotation to all other
    crops not currently listed.

-   Revised Section F to include the correct chemical name for
    pyrasulfotole-desmethyl
    \[(5-hydroxy-1*H*-pyrazol-4-yl)\[2-mesyl-4-(trifluoromethyl)phenyl\]methanone\],
    and the HED-recommended tolerances and the correct commodity
    definitions for small grain RACs and processed commodities. In
    addition, the proposed tolerance for triticale, grain deleted as it
    is covered under the wheat, grain tolerance.

-   Submission of a new ruminant analytical enforcement method to
    determine residues of pyrasulfotole and pyrasulfotole-desmethyl as
    well as adequate radiovalidation and ILV data.

-   Submission of an analytical reference standard for pyrasulfotole,
    pyrasulfotole-desmethyl and labeled internal standards to the EPA
    National Pesticide Standards Repository.

-   For Method AI-001-P04-01, a separate confirmatory method will not be
    required provided that two ion transitions are monitored during
    MS/MS analysis for each analyte. The petitioner can either revise
    the method to include the information about the available second ion
    transition, or submit a method addendum to include the second ion
    transition.

**10.3 Occupational Exposure**

-   None.

[]{.mark}

[]{#__RefHeading___Toc170186482 .anchor}**Appendix A. Toxicology
Assessment**

**A.1. Toxicology Data Requirements**

The data requirements (40 CFR 158.340; 2005) for the proposed food uses
of pyrasulfotole technical are presented below. Use of the guideline
numbers does not imply that the guideline protocols (1998) were used.

+-----------------------------------------+-------------+-------------+
| **Test**                                | **          |             |
|                                         | Technical** |             |
+=========================================+=============+=============+
|                                         | *           | **          |
|                                         | *Required** | Satisfied** |
+-----------------------------------------+-------------+-------------+
| 870.1100 Acute Oral Toxicity            | yes         | yes         |
|                                         |             |             |
| 870.1200 Acute Dermal Toxicity          | yes         | yes         |
|                                         |             |             |
| 870.1300 Acute Inhalation Toxicity      | yes         | yes         |
|                                         |             |             |
| 870.2400 Primary Eye Irritation         | yes         | yes         |
|                                         |             |             |
| 870.2500 Primary Dermal Irritation      | yes         | yes         |
|                                         |             |             |
| 870.2600 Dermal Sensitization           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3100 Oral Subchronic (rodent)       | yes         | yes         |
|                                         |             |             |
| 870.3150 Oral Subchronic (nonrodent)    | yes         | yes         |
|                                         |             |             |
| 870.3200 21-Day Dermal                  | yes         | yes         |
|                                         |             |             |
| 870.3250 90-Day Dermal                  | no          | \-          |
|                                         |             |             |
| 870.3465 90-Day Inhalation              | no          | \-          |
+-----------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity        | yes         | yes         |
| (rodent)                                |             |             |
|                                         | yes         | yes         |
| 870.3700b Developmental Toxicity        |             |             |
| (nonrodent)                             | yes         | yes         |
|                                         |             |             |
| 870.3800 Reproduction                   |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4100a Chronic Toxicity (rodent)     | yes         | yes         |
|                                         |             |             |
| 870.4100b Chronic Toxicity (nonrodent)  | yes         | yes         |
|                                         |             |             |
| 870.4200a Oncogenicity (rat)            | yes         | yes         |
|                                         |             |             |
| 870.4200b Oncogenicity (mouse)          | yes         | yes         |
|                                         |             |             |
| 870.4300 Chronic/Oncogenicity           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity---Gene Mutation - | yes         | yes         |
| bacterial                               |             |             |
|                                         | yes         | yes         |
| 870.5300 Mutagenicity---Gene Mutation - |             |             |
| mammalian                               | yes         | yes         |
|                                         |             |             |
| 870.5375 Mutagenicity---Structural      | yes         | yes         |
| Chromosomal Aberrations                 |             |             |
|                                         |             |             |
| 870.5395 Mutagenicity---Other Genotoxic |             |             |
| Effects                                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100a Acute Delayed Neurotox. (hen) | no          | \-          |
|                                         |             |             |
| 870.6100b 90-Day Neurotoxicity (hen)    | no          | \-          |
|                                         |             |             |
| 870.6200a Acute Neurotox. Screening     | yes         | yes         |
| Battery (rat)                           |             |             |
|                                         | yes         | yes         |
| 870.6200b 90-Day Neuro. Screening       |             |             |
| Battery (rat)                           | yes         | yes         |
|                                         |             |             |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 General Metabolism             | yes         | yes         |
|                                         |             |             |
| 870.7600 Dermal Penetration             | yes         | no          |
+-----------------------------------------+-------------+-------------+
| Special Studies for Ocular              | yes         | yes         |
| Effects.                                |             |             |
| ....................................... |             |             |
+-----------------------------------------+-------------+-------------+

[]{#__RefHeading___Toc170186483 .anchor}**A.2. Toxicity Profiles**

+---------+---------------------+-------+---------------+------------+
| **ACUTE |                     |       |               |            |
| T       |                     |       |               |            |
| OXICITY |                     |       |               |            |
| PROFILE |                     |       |               |            |
| FOR     |                     |       |               |            |
| P       |                     |       |               |            |
| YRASULF |                     |       |               |            |
| OTOLE** |                     |       |               |            |
+---------+---------------------+-------+---------------+------------+
| **Gu    | **Study Type**      | *     | **Results**   | **Toxicity |
| ideline |                     | *MRID |               | Category** |
| No.**   |                     | No.** |               |            |
+---------+---------------------+-------+---------------+------------+
| 8       | Acute oral toxicity | 468   | LD~50~ \>     | III        |
| 70.1100 | (rat)               | 01836 | 2000 mg/kg    |            |
|         |                     |       | (F)           |            |
|         | **Acc               |       |               |            |
|         | eptable/Guideline** |       |               |            |
+---------+---------------------+-------+---------------+------------+
| 8       | Acute dermal        | 468   | LD~50~ \>     | III        |
| 70.1200 | toxicity (rat)      | 01837 | 2000 mg/kg    |            |
|         |                     |       | (M,F)         |            |
|         | **Acc               |       |               |            |
|         | eptable/Guideline** |       |               |            |
+---------+---------------------+-------+---------------+------------+
| 8       | Acute inhalation    | 468   | LC~50~ \>     | IV         |
| 70.1300 | toxicity (rat)      | 01838 | 5.03 mg/L     |            |
|         |                     |       | (M,F)         |            |
|         | **Acc               |       |               |            |
|         | eptable/Guideline** |       |               |            |
+---------+---------------------+-------+---------------+------------+
| 8       | Primary dermal      | 468   | Not a dermal  | IV         |
| 70.2500 | irritation (rabbit) | 01840 | irritant      |            |
|         |                     |       |               |            |
|         | **Acc               |       |               |            |
|         | eptable/Guideline** |       |               |            |
+---------+---------------------+-------+---------------+------------+
| 8       | Primary eye         | 468   | Moderate eye  | III        |
| 70.2400 | irritation (rabbit) | 01839 | irritant      |            |
|         |                     |       |               |            |
|         | **Acc               |       |               |            |
|         | eptable/Guideline** |       |               |            |
+---------+---------------------+-------+---------------+------------+
| 8       | Skin sensitization  | 468   | Not a dermal  | N/A        |
| 70.2600 | (guinea pig)        | 01841 | sensitizer    |            |
|         |                     |       |               |            |
|         | **Acc               |       |               |            |
|         | eptable/Guideline** |       |               |            |
+---------+---------------------+-------+---------------+------------+

+----------------+--------------------+---------------+---------------+
| **SUBCHRONIC   |                    |               |               |
| AND CHRONIC    |                    |               |               |
| TOXICITY AND   |                    |               |               |
| GENOTOXICITY   |                    |               |               |
| PROFILE FOR    |                    |               |               |
| P              |                    |               |               |
| YRASULFOTOLE** |                    |               |               |
+----------------+--------------------+---------------+---------------+
| **Guideline    | **Study Type**     | **Results**   | **MRID No.    |
| No.**          |                    |               | (year)/       |
|                |                    |               | C             |
|                |                    |               | lassification |
|                |                    |               | /Doses**      |
+----------------+--------------------+---------------+---------------+
| N/A            | 28-day oral        | LOAEL =       | 46801843      |
|                | toxicity (mouse;   | 961/1082      | (2002)        |
|                | dietary)           | mg/kg/day     | Acceptable/   |
|                |                    | \[M/F\],      | Non-guideline |
|                |                    | based on      |               |
|                |                    | gritty        | 0, 200, 1000, |
|                |                    | content in    | or 5000 ppm   |
|                |                    | the urinary   | (equal to     |
|                |                    | bladder and   | 0/0,          |
|                |                    | h             | 35.8/45.0,    |
|                |                    | istopathology | 192/233, or   |
|                |                    | (urothelial   | 961/1082      |
|                |                    | hyperplasia,  | mg/kg bw/day  |
|                |                    | diffuse       | \[M/F\])      |
|                |                    | submucosal    |               |
|                |                    | granulation   |               |
|                |                    | tissue,       |               |
|                |                    | diffuse       |               |
|                |                    | suburothelial |               |
|                |                    | mixed-cell    |               |
|                |                    | infiltrate)   |               |
|                |                    | in the        |               |
|                |                    | urinary       |               |
|                |                    | bladder       |               |
|                |                    | (males) and   |               |
|                |                    | subcapsular   |               |
|                |                    | hyperplasia   |               |
|                |                    | of the        |               |
|                |                    | adrenal gland |               |
|                |                    | (females)     |               |
|                |                    |               |               |
|                |                    | NOAEL =       |               |
|                |                    | 192/233       |               |
|                |                    | mg/kg/day     |               |
|                |                    | \[M/F\].      |               |
+----------------+--------------------+---------------+---------------+
| 870.3100       | 90-day oral        | LOAEL not     | 46801844      |
|                | toxicity (mouse;   | observed      | (2003)        |
|                | dietary)           |               |               |
|                |                    | NOAEL =       | Accepta       |
|                |                    | 500/617       | ble/guideline |
|                |                    | mg/kg/day     |               |
|                |                    | (M/F).        | 0, 100, 1500, |
|                |                    |               | or 3000 ppm   |
|                |                    |               | (equal to     |
|                |                    |               | 0/0,          |
|                |                    |               | 16.5/19.7,    |
|                |                    |               | 124/152,      |
|                |                    |               | 259/326, or   |
|                |                    |               | 500/617 mg/kg |
|                |                    |               | bw/day        |
|                |                    |               | \[M/F\])      |
+----------------+--------------------+---------------+---------------+
| 870.3200       | 28-day dermal      | LOAEL = 100   | 46801904      |
|                | toxicity (rat)     | mg/kg/day     | (2005)        |
|                |                    | based on      |               |
|                |                    | focal         | Accepta       |
|                |                    | degeneration  | ble/Guideline |
|                |                    | of the        |               |
|                |                    | pancreas      | 0, 10, 100,   |
|                |                    | (both sexes)  | or 1000 mg/kg |
|                |                    | and           | bw/day        |
|                |                    | alteration of |               |
|                |                    | thyroid       |               |
|                |                    | colloid       |               |
|                |                    | (males)       |               |
|                |                    |               |               |
|                |                    | NOAEL = 10    |               |
|                |                    | mg/kg/day.    |               |
+----------------+--------------------+---------------+---------------+
| 870.6200       | Subchronic         | LOAEL = 42    | 46801916      |
|                | neurotoxicity      | mg/kg bw/day  | (2005)        |
|                | (rat; dietary)     | in females    |               |
|                |                    | based on      | Accepta       |
|                |                    | increased     | ble/Guideline |
|                |                    | incidences of |               |
|                |                    | corneal       | 0, 500, 2500, |
|                |                    | opacity and   | or 5000 ppm   |
|                |                    | corneal       | (equivalent   |
|                |                    | neovas        | to 0/0,       |
|                |                    | cularization; | 32/42,        |
|                |                    | not observed  | 166/206, or   |
|                |                    | in males.     | 345/416 mg/kg |
|                |                    | NOAEL was not | bw/day        |
|                |                    | observed in   | \[M/F\])      |
|                |                    | females; 345  |               |
|                |                    | mg/kg bw/day  |               |
|                |                    | in males.     |               |
+----------------+--------------------+---------------+---------------+
| 870.6300       | Developmental      | Maternal      | 46801917      |
|                | neurotoxicity      | LOAEL = 37    | (2006)        |
|                | (rat; dietary)     | mg/kg/day,    |               |
|                |                    | based on      | Acceptable/   |
|                |                    | ocular        | Non-guideline |
|                |                    | opacities     |               |
|                |                    | during        | 0, 3.8, 37,   |
|                |                    | lactation     | or 354 mg/kg  |
|                |                    |               | bw/day        |
|                |                    | Maternal      | (gestation    |
|                |                    | NOAEL = 3.8   | and           |
|                |                    | mg/kg/day.    | lactation)    |
|                |                    |               |               |
|                |                    | Offspring     |               |
|                |                    | LOAEL = 37    |               |
|                |                    | mg/kg/day     |               |
|                |                    | based on      |               |
|                |                    | ocular        |               |
|                |                    | opacity       |               |
|                |                    | (p            |               |
|                |                    | ost-weaning), |               |
|                |                    | decreased     |               |
|                |                    | body weight,  |               |
|                |                    | delayed       |               |
|                |                    | preputial     |               |
|                |                    | separation    |               |
|                |                    | (males),      |               |
|                |                    | increase in   |               |
|                |                    | number of     |               |
|                |                    | trials to     |               |
|                |                    | criterion and |               |
|                |                    | decreases in  |               |
|                |                    | trial         |               |
|                |                    | latencies     |               |
|                |                    | (passive      |               |
|                |                    | avoidance;    |               |
|                |                    | PND 22        |               |
|                |                    | males),       |               |
|                |                    | retinal       |               |
|                |                    | degeneration  |               |
|                |                    | at            |               |
|                |                    | o             |               |
|                |                    | phthalmoscopy |               |
|                |                    | (females),    |               |
|                |                    | decreased     |               |
|                |                    | brain weight  |               |
|                |                    | (PND 21       |               |
|                |                    | females),     |               |
|                |                    | decreased     |               |
|                |                    | cerebrum      |               |
|                |                    | length (PND   |               |
|                |                    | 21 females),  |               |
|                |                    | and decreased |               |
|                |                    | cerebellum    |               |
|                |                    | height (PND   |               |
|                |                    | 21 males)     |               |
|                |                    |               |               |
|                |                    | Offspring     |               |
|                |                    | NOAEL = 3.8   |               |
|                |                    | mg/kg/day.    |               |
+----------------+--------------------+---------------+---------------+
| 870.6200       | Acute              | LOAEL = 200   | 46801915      |
|                | neurotoxicity      | mg/kg bw (F)  | (2005)        |
|                | (rat; gavage)      | and 2000      |               |
|                |                    | mg/kg bw (M)  | Accepta       |
|                |                    | based on      | ble/Guideline |
|                |                    | decreased     |               |
|                |                    | locomotor     | 0, 200, 500,  |
|                |                    | activity on   | or 2000 mg/kg |
|                |                    | day 0         | bw            |
|                |                    |               |               |
|                |                    | NOAEL not     |               |
|                |                    | observed in   |               |
|                |                    | females; 500  |               |
|                |                    | mg/kg bw in   |               |
|                |                    | males.        |               |
+----------------+--------------------+---------------+---------------+
| 870.4300       | Combined chronic   | LOAEL = 10/14 | 46801910      |
|                | toxici             | mg/kg (M/F)   | (2006)        |
|                | ty/carcinogenicity | based on      |               |
|                | (rat; dietary)     | corneal       | Accepta       |
|                |                    | opacity,      | ble/Guideline |
|                |                    | neova         |               |
|                |                    | scularization | 0, 25, 250,   |
|                |                    | of the        | 1000, or 2500 |
|                |                    | cornea,       | ppm           |
|                |                    | inflammation  | (equivalent   |
|                |                    | of the        | to 0/0,       |
|                |                    | cornea,       | 1.0/1.4,      |
|                |                    | regenerative  | 10/14, 41/57, |
|                |                    | corneal       | or 104/140    |
|                |                    | hyperplasia,  | mg/kg bw/day  |
|                |                    | corneal       | \[M/F\])      |
|                |                    | atrophy,      |               |
|                |                    | and/or        |               |
|                |                    | retinal       |               |
|                |                    | atrophy (both |               |
|                |                    | sexes),       |               |
|                |                    | h             |               |
|                |                    | epatocellular |               |
|                |                    | hypertrophy   |               |
|                |                    | along with    |               |
|                |                    | increased     |               |
|                |                    | serum         |               |
|                |                    | cholesterol   |               |
|                |                    | (males) and   |               |
|                |                    | an increased  |               |
|                |                    | incidence of  |               |
|                |                    | chronic       |               |
|                |                    | progressive   |               |
|                |                    | nephropathy   |               |
|                |                    | (males)       |               |
|                |                    |               |               |
|                |                    | NOAEL =       |               |
|                |                    | 1.0/1.4 mg/kg |               |
|                |                    | (M/F).        |               |
+----------------+--------------------+---------------+---------------+
| N/A            | 28-day oral        | LOAEL =       | 46801845      |
|                | toxicity (dog;     | 171/174 mg/kg | (2002)        |
|                | dietary)           | bw/day (F/M)  |               |
|                |                    | based on      | Acceptable/   |
|                |                    | increases in  | Non-guideline |
|                |                    | serum         |               |
|                |                    | triglycerides | 0, 5000,      |
|                |                    | and elevated  | 13000 or      |
|                |                    | liver weights | 26000 ppm     |
|                |                    | (M&F), and    | (equivalent   |
|                |                    | increased     | to 0/0,       |
|                |                    | midzonal      | 174/171,      |
|                |                    | multifocal    | 469/440 or    |
|                |                    | vacuolation   | 860/782 mg/kg |
|                |                    | of liver (M)  | bw/day        |
|                |                    |               | \[M/F\])      |
|                |                    | NOAEL not     |               |
|                |                    | observed.     |               |
+----------------+--------------------+---------------+---------------+
| 870.3150       | 29/90-day oral     | N/A           | 46801901      |
|                | toxicity (dog;     |               | (2004)        |
|                | dietary)           |               |               |
|                |                    |               | Unaccepta     |
|                |                    |               | ble/Guideline |
|                |                    |               |               |
|                |                    |               | 0, 1500, 9000 |
|                |                    |               | or 18000 ppm; |
|                |                    |               | study         |
|                |                    |               | terminated on |
|                |                    |               | day 29        |
+----------------+--------------------+---------------+---------------+
| 870.3150       | 90-day oral        | LOAEL not     | 46801902      |
|                | toxicity (dog;     | established   | (2005)        |
|                | dietary)           |               |               |
|                |                    | NOAEL = 40/33 | Accepta       |
|                |                    | mg/kg bw/day  | ble/Guideline |
|                |                    | (M/F).        |               |
|                |                    |               | 0, 100, 500,  |
|                |                    |               | or 1000 ppm   |
|                |                    |               | (equivalent   |
|                |                    |               | to 0/0, 3/3,  |
|                |                    |               | 17/17, or     |
|                |                    |               | 40/33 mg/kg   |
|                |                    |               | bw/day        |
|                |                    |               | \[M/F\])      |
+----------------+--------------------+---------------+---------------+
| 870.3100       | 90-day oral        | LOAEL = 77    | 46801842      |
|                | toxicity (rat;     | mg/kg bw/day  | (2003)        |
|                | dietary)           | (F) and 454   |               |
|                |                    | mg/kg bw/day  | Accepta       |
|                |                    | (M), based on | ble/Guideline |
|                |                    | increased     |               |
|                |                    | incidences of | 0, 2, 30,     |
|                |                    | corneal       | 1000, 7000,   |
|                |                    | opacity       | or 12000 ppm  |
|                |                    | (M&F),        | (equivalent   |
|                |                    | mortality,    | to 0/0,       |
|                |                    | and           | 0.13/0.15,    |
|                |                    | h             | 1.96/2.32,    |
|                |                    | istopathology | 66/77,        |
|                |                    | in the        | 454/537, or   |
|                |                    | kidney,       | 830/956 mg/kg |
|                |                    | urinary       | bw/day        |
|                |                    | bladder,      | \[M/F\])      |
|                |                    | thyroid, and  |               |
|                |                    | ureters (M)   |               |
|                |                    |               |               |
|                |                    | NOAEL = 2.32  |               |
|                |                    | mg/kg bw/day  |               |
|                |                    | (F) and 66    |               |
|                |                    | mg/kg bw/day  |               |
|                |                    | (M).          |               |
+----------------+--------------------+---------------+---------------+
| 870.3700       | Prenatal           | Maternal      | 46801905      |
|                | developmental      | LOAEL = 100   | (2006)        |
|                | toxicity (rat;     | mg/kg/day     |               |
|                | gavage)            | based on      | Accepta       |
|                |                    | increased     | ble/Guideline |
|                |                    | incidence of  |               |
|                |                    | salivation,   | 0, 10, 100,   |
|                |                    | decreased     | or 300 mg/kg  |
|                |                    | corrected     | bw/day        |
|                |                    | body weight   |               |
|                |                    | gain,         |               |
|                |                    | decreased     |               |
|                |                    | body weight   |               |
|                |                    | during GD 6-8 |               |
|                |                    | and enlarged  |               |
|                |                    | placenta.     |               |
|                |                    | Maternal      |               |
|                |                    | NOAEL = 10    |               |
|                |                    | mg/kg/day.    |               |
|                |                    |               |               |
|                |                    | Developmental |               |
|                |                    | LOAEL = 100   |               |
|                |                    | mg/kg/day     |               |
|                |                    | based on      |               |
|                |                    | increased     |               |
|                |                    | fetal and/or  |               |
|                |                    | litter        |               |
|                |                    | skeletal      |               |
|                |                    | variations;   |               |
|                |                    | and decreased |               |
|                |                    | body weight   |               |
|                |                    | (males);      |               |
|                |                    |               |               |
|                |                    | Developmental |               |
|                |                    | NOAEL = 10    |               |
|                |                    | mg/kg/day.    |               |
+----------------+--------------------+---------------+---------------+
| 870.3700       | Prenatal           | Maternal      | 46801906      |
|                | developmental      | LOAEL = 250   | (2006)        |
|                | toxicity (rabbit;  | mg/kg bw/day  |               |
|                | gavage)            | based on      | Accepta       |
|                |                    | decreased     | ble/Guideline |
|                |                    | body weight   |               |
|                |                    | gain during   | 0, 10, 75, or |
|                |                    | GD 8-10 and   | 250 mg/kg     |
|                |                    | decreased     | bw/day        |
|                |                    | food          |               |
|                |                    | consumption   |               |
|                |                    |               |               |
|                |                    | Maternal      |               |
|                |                    | NOAEL = 75    |               |
|                |                    | mg/kg bw/day. |               |
|                |                    |               |               |
|                |                    | Developmental |               |
|                |                    | LOAEL = 75    |               |
|                |                    | mg/kg bw/day  |               |
|                |                    | based on      |               |
|                |                    | increased     |               |
|                |                    | incidences of |               |
|                |                    | fetal/litter  |               |
|                |                    | skeletal      |               |
|                |                    | variations    |               |
|                |                    | Developmental |               |
|                |                    | NOAEL = 10    |               |
|                |                    | mg/kg/day.    |               |
+----------------+--------------------+---------------+---------------+
| 870.3800       | Reproduction and   | Parental      | 46801907      |
|                | fertility effects  | LOAEL =       | (2005)        |
|                | (rat; dietary)     | 2.5/3.1 mg/kg |               |
|                |                    | bw/day (M/F), | Accepta       |
|                |                    | based on      | ble/Guideline |
|                |                    | colloid       |               |
|                |                    | alteration    | 0, 30, 300 or |
|                |                    | and/or        | 3000 ppm      |
|                |                    | pigment       | (equivalent   |
|                |                    | deposition in | to premating  |
|                |                    | the thyroid   | doses of 0/0, |
|                |                    |               | 2.5/3.1,      |
|                |                    | Parental      | 26.3/32.6, or |
|                |                    | NOAEL not     | 272.4/345.7   |
|                |                    | observed.     | mg/kg bw/day  |
|                |                    |               | \[F~0~ M/F\]; |
|                |                    | Offspring     | and 0/0,      |
|                |                    | LOAEL =       | 3.68/4.2,     |
|                |                    | 26.3/32.6     | 34.1/38.9 or  |
|                |                    | mg/kg bw/day  | 353.6/393.4   |
|                |                    | \[M/F\] based | mg/kg bw/day  |
|                |                    | on corneal    | \[F~1~ M/F\]) |
|                |                    | opacity       |               |
|                |                    | and/or        |               |
|                |                    | corneal       |               |
|                |                    | neova         |               |
|                |                    | scularization |               |
|                |                    | (F1 and F2    |               |
|                |                    | generations)  |               |
|                |                    |               |               |
|                |                    | Offspring     |               |
|                |                    | NOAEL =       |               |
|                |                    | 2.5/3.1 mg/kg |               |
|                |                    | bw/day        |               |
|                |                    | \[M/F\].      |               |
|                |                    |               |               |
|                |                    | Reproductive  |               |
|                |                    | LOAEL =       |               |
|                |                    | 26.3/32.6     |               |
|                |                    | mg/kg bw/day  |               |
|                |                    | (M/F), based  |               |
|                |                    | on delayed    |               |
|                |                    | bal           |               |
|                |                    | ano-preputial |               |
|                |                    | separation in |               |
|                |                    | F~1~ pups.    |               |
|                |                    |               |               |
|                |                    | Reproductive  |               |
|                |                    | NOAEL =       |               |
|                |                    | 2.5/3.1 mg/kg |               |
|                |                    | bw/day (M/F). |               |
+----------------+--------------------+---------------+---------------+
| 870.4100       | Chronic toxicity   | LOAEL = 34    | 46801908      |
|                | (dog; dietary)     | (M) & 93 (F)  | (2006)        |
|                |                    | mg/kg/day,    |               |
|                |                    | based on      | Accepta       |
|                |                    | increased     | ble/Guideline |
|                |                    | incidence and |               |
|                |                    | severity of   | 0, 250, 1000, |
|                |                    | kidney        | or 3000 ppm   |
|                |                    | tubular       | (equivalent   |
|                |                    | dilatation    | to 0/0, 7/9,  |
|                |                    | (M) and       | 34/33, or     |
|                |                    | cataracts     | 101/93 mg/kg  |
|                |                    | (F).          | bw/day        |
|                |                    |               | \[M/F\])      |
|                |                    | NOAEL = 7 (M) |               |
|                |                    | & 33 (F)      |               |
|                |                    | mg/kg/day.    |               |
+----------------+--------------------+---------------+---------------+
| 870.4200       | Carcinogenicity    | LOAEL =       | 46801909      |
|                | (mouse; dietary)   | 13.6/16.7     | (2006)        |
|                |                    | mg/kg bw/day  |               |
|                |                    | (M/F) based   | Accepta       |
|                |                    | on increased  | ble/Guideline |
|                |                    | incidences of |               |
|                |                    | gallstones    | 0/0,          |
|                |                    |               | 13.6/16.7,    |
|                |                    | NOAEL not     | 137/168 and   |
|                |                    | observed.     | 560/713 mg/kg |
|                |                    |               | bw/day (M/F)  |
+----------------+--------------------+---------------+---------------+
| 870.5100       | Gene mutation      | Negative      | 46801911      |
|                | (bacterial; *in    |               | (2004)        |
|                | vitro*)            |               |               |
|                |                    |               | Accepta       |
|                |                    |               | ble/Guideline |
|                |                    |               |               |
|                |                    |               | 0, 16, 50,    |
|                |                    |               | 158, 500,     |
|                |                    |               | 1581 or 5000  |
|                |                    |               | μg/plate (+/- |
|                |                    |               | S9)           |
+----------------+--------------------+---------------+---------------+
| 870.5300       | Gene mutation      | Negative      | 46801912      |
|                | (mammalian; *in    |               | (2004)        |
|                | vitro*)            |               |               |
|                |                    |               | Accepta       |
|                |                    |               | ble/Guideline |
|                |                    |               |               |
|                |                    |               | 0, 30, 60,    |
|                |                    |               | 120, 240,     |
|                |                    |               | 480, or 960   |
|                |                    |               | μg/mL (+/-    |
|                |                    |               | S9)           |
+----------------+--------------------+---------------+---------------+
| 870.5375       | Chromosome         | Negative      | 46801913      |
|                | aberration         | (chromosome   | (2004)        |
|                | (mammalian; *in    | isodeletions  |               |
|                | vitro*)            | observed at   | Accepta       |
|                |                    | cytotoxic     | ble/Guideline |
|                |                    | concentration |               |
|                |                    | only).        | 0, 200, 400,  |
|                |                    |               | 500, 600,     |
|                |                    |               | 800, 1000,    |
|                |                    |               | 1500, 2000,   |
|                |                    |               | or 2500 μg/mL |
|                |                    |               | (+/- S9)      |
+----------------+--------------------+---------------+---------------+
| 870.5395       | Erythrocyte        | Negative      | 46801914      |
|                | micronucleus       |               | (2003)        |
|                | (mouse; *in vivo*) |               |               |
|                |                    |               | Accepta       |
|                |                    |               | ble/Guideline |
|                |                    |               |               |
|                |                    |               | 0/0, 125/250, |
|                |                    |               | 250/500 or    |
|                |                    |               | 500/1000      |
|                |                    |               | mg/kg bw      |
|                |                    |               | (M/F)         |
+----------------+--------------------+---------------+---------------+
| 870.7485       | Metabolism and     | Following     | 46801918      |
|                | Pharmacokinetics   | oral          | (2005)        |
|                |                    | ad            |               |
|                |                    | ministration, | Accepta       |
|                |                    | \~60% of      | ble/Guideline |
|                |                    | radioactivity |               |
|                |                    | absorbed and  | 0 or 10 mg/kg |
|                |                    | excreted in   | bw (single    |
|                |                    | urine in 6    | low dose;     |
|                |                    | hrs; \~70% of | dietary and   |
|                |                    | radioactivity | iv); high     |
|                |                    | excreted in   | dose and      |
|                |                    | urine and 30% | repeated      |
|                |                    | in feces by   | dosing not    |
|                |                    | 52 hrs;       | tested        |
|                |                    | hydroxymethyl |               |
|                |                    | AE 0317309    |               |
|                |                    | (2%),         |               |
|                |                    | desmethyl AE  |               |
|                |                    | 0317309       |               |
|                |                    | (\<9%), and   |               |
|                |                    | AE B197555    |               |
|                |                    | (benzoic      |               |
|                |                    | acid; \<2%)   |               |
|                |                    | observed as   |               |
|                |                    | metabolites   |               |
|                |                    | in urine &    |               |
|                |                    | feces;        |               |
|                |                    | further       |               |
|                |                    | metabolism    |               |
|                |                    | unknown; \<2% |               |
|                |                    | of            |               |
|                |                    | administered  |               |
|                |                    | dose remained |               |
|                |                    | in residual   |               |
|                |                    | carcass and   |               |
|                |                    | tissues after |               |
|                |                    | 52 hrs,       |               |
|                |                    | highest       |               |
|                |                    | residues in   |               |
|                |                    | liver and     |               |
|                |                    | kidney.       |               |
+----------------+--------------------+---------------+---------------+
| N/A            | 14-day ocular      |               | 46801922      |
|                | toxicity study in  |               | (1995)        |
|                | rat and mouse      |               |               |
|                | (mechanistic)      |               | Acceptable/   |
|                |                    |               | Non-guideline |
+----------------+--------------------+---------------+---------------+
| N/A            | Effect of          |               | 46801921      |
|                | tyrosinemia on     |               | (2006)        |
|                | pregnancy and      |               |               |
|                | embryo-fetal       |               | Acceptable/   |
|                | development in rat |               | Non-guideline |
|                | (mechanisitic)     |               |               |
+----------------+--------------------+---------------+---------------+
| N/A            | *In vitro*         |               | 46801920      |
|                | inhibition of HPPD |               | (2006)        |
|                | (mechanisitic)     |               |               |
|                |                    |               | Acceptable/   |
|                |                    |               | Non-guideline |
+----------------+--------------------+---------------+---------------+
| N/A            | 14-day comparative |               | 46801903      |
|                | toxicity feeding   |               | (2006)        |
|                | study in dog       |               |               |
|                |                    |               | Acceptable/   |
|                |                    |               | Non-guideline |
+----------------+--------------------+---------------+---------------+

+---------+------------------------+----------------+-----------------+
| **T     |                        |                |                 |
| OXICITY |                        |                |                 |
| PROFILE |                        |                |                 |
| FOR     |                        |                |                 |
| BENZOIC |                        |                |                 |
| ACID    |                        |                |                 |
| MET     |                        |                |                 |
| ABOLITE |                        |                |                 |
| AE      |                        |                |                 |
| B197555 |                        |                |                 |
| (RPA    |                        |                |                 |
| 20      |                        |                |                 |
| 3328)** |                        |                |                 |
+---------+------------------------+----------------+-----------------+
| **Gu    | **Study Type**         | **Results**    | **MRID No.      |
| ideline |                        |                | (year)/         |
| No.**   |                        |                | Classification  |
|         |                        |                | /Doses**        |
+---------+------------------------+----------------+-----------------+
| 8       | Acute oral toxicity    | LD~50~ \> 5000 | 43904812 (1995) |
| 70.1100 | (rat)                  | mg/kg bw (M,F; |                 |
|         |                        | toxicity       | Accep           |
|         |                        | category IV)   | table/Guideline |
|         |                        |                |                 |
|         |                        |                | 5000 mg/kg bw   |
+---------+------------------------+----------------+-----------------+
| N/A     | 28-day oral toxicity   | LOAEL not      | 43904813 (1995) |
|         | (rat; dietary)         | observed       |                 |
|         |                        |                | Acceptabl       |
|         |                        | NOAEL =        | e/Non-guideline |
|         |                        | 1118/1269      |                 |
|         |                        | mg/kg/day      | 0, 150, 500,    |
|         |                        | (M/F)          | 5000, or 15000  |
|         |                        |                | ppm (equal to   |
|         |                        |                | 0/0, 11.1/12.7, |
|         |                        |                | 37.6/42.7,      |
|         |                        |                | 377/421, or     |
|         |                        |                | 1118/1269 mg/kg |
|         |                        |                | bw/day \[M/F\]) |
+---------+------------------------+----------------+-----------------+
| 8       | 90-day oral toxicity   | LOAEL not      | 45655903 (1998) |
| 70.3100 | (rat; dietary)         | observed       |                 |
|         |                        |                | Accep           |
|         |                        | NOAEL =        | table/Guideline |
|         |                        | 769/952        |                 |
|         |                        | mg/kg/day      | 0, 1200, 4800,  |
|         |                        | (M/F**)**      | or 12000 ppm    |
|         |                        |                | (equivalent to  |
|         |                        |                | 0, 73.2/93.1,   |
|         |                        |                | 306/371, or     |
|         |                        |                | 769/952 mg/kg   |
|         |                        |                | bw/day \[M/F\]) |
+---------+------------------------+----------------+-----------------+
| 8       | Prenatal developmental | Maternal LOAEL | 45655906 (1999) |
| 70.3700 | toxicity (rat; gavage) | = 250 mg/kg    |                 |
|         |                        | bw/day, based  | Accep           |
|         |                        | on clinical    | table/Guideline |
|         |                        | signs          |                 |
|         |                        | (salivation,   | 0, 75, 250, or  |
|         |                        | piloerection,  | 750 mg/kg       |
|         |                        | red nasal      | bw/day          |
|         |                        | discharge      |                 |
|         |                        | around time of |                 |
|         |                        | treatment),    |                 |
|         |                        | decreased body |                 |
|         |                        | weight gain,   |                 |
|         |                        | and decreased  |                 |
|         |                        | food           |                 |
|         |                        | consumption    |                 |
|         |                        |                |                 |
|         |                        | Maternal NOAEL |                 |
|         |                        | = 75 mg/kg     |                 |
|         |                        | bw/day         |                 |
|         |                        |                |                 |
|         |                        | Developmental  |                 |
|         |                        | LOAEL not      |                 |
|         |                        | observed       |                 |
|         |                        | Developmental  |                 |
|         |                        | NOAEL = 750    |                 |
|         |                        | mg/kg bw/day   |                 |
+---------+------------------------+----------------+-----------------+
| 8       | 0, 100, 250, 500,      | Negative       | 43904814        |
| 70.5100 | 1000, 2500, or 5000    |                |                 |
|         | μg/plate (+/- S9)      |                |                 |
| Gene    |                        |                |                 |
| m       | **                     |                |                 |
| utation | Acceptable/Guideline** |                |                 |
| (bac    |                        |                |                 |
| terial; |                        |                |                 |
| *in     |                        |                |                 |
| vitro*) |                        |                |                 |
+---------+------------------------+----------------+-----------------+
| 8       | 0, 924, 931, 1320,     | Negative       | 44545301        |
| 70.5375 | 1330, 1890, 1900,      |                |                 |
|         | 2700, or 2710 μg/mL    |                |                 |
| Chr     | (+/- S9)               |                |                 |
| omosome |                        |                |                 |
| abe     | **                     |                |                 |
| rration | Acceptable/Guideline** |                |                 |
| (mam    |                        |                |                 |
| malian; |                        |                |                 |
| *in     |                        |                |                 |
| vitro*) |                        |                |                 |
+---------+------------------------+----------------+-----------------+
| 8       | 500, 1000, or 2000     | Negative       | 44545302        |
| 70.5395 | mg/kg bw               |                |                 |
|         |                        |                |                 |
| Eryt    | **                     |                |                 |
| hrocyte | Acceptable/Guideline** |                |                 |
| micro   |                        |                |                 |
| nucleus |                        |                |                 |
| (mouse; |                        |                |                 |
| *in     |                        |                |                 |
| vivo*)  |                        |                |                 |
+---------+------------------------+----------------+-----------------+
| 8       | 84.5-2700 μg/mL (-S9)  | Negative       | 44545301        |
| 70.5300 |                        |                |                 |
|         | 338-2700 μg/mL (+S9)   |                |                 |
| Gene    |                        |                |                 |
| m       | **                     |                |                 |
| utation | Acceptable/Guideline** |                |                 |
| (mam    |                        |                |                 |
| malian; |                        |                |                 |
| *in     |                        |                |                 |
| vitro*) |                        |                |                 |
+---------+------------------------+----------------+-----------------+

[]{#__RefHeading___Toc170186484 .anchor}**A.3. Executive Summaries**

**A.3.1 Subchronic Toxicity**

**870.3100 90-Day Oral Toxicity -- Rat**

In a 90-day oral toxicity study (MRID 46801842), AE 0317309 (97.4% w/w
ai, batch H2235) was administered in the diet to groups of 10 Rj:WI(IOPS
HAN) Wistar rats rats/sex/dose at dose levels of 0, 2, 30, 1000, 7000
and 12000 ppm (equivalent to 0.0, 0.13, 1.96, 66, 454, and 830 mg/kg
bw/day for males and 0.0, 0.15, 2.32, 77, 537 and 956 mg/kg bw/day in
females) for a period of 90 days.

No abnormalities were detected during the neurotoxicity assessment and
there were no treatment related effects on hematological parameters.

At 12000 ppm, six male and one female were either sacrificed for humane
reasons or were found dead during the treatment period. The group was
terminated at week 11 due to excessive toxicity. At 7000 ppm, two males
were found dead or were sacrificed for humane reasons during the
treatment period. Treatment related clinical signs were observed in a
large number of rats at 7000 and 12000 ppm and consisted of intensely
yellow colored urine associated on a few occasions with soiled
anogenital area, soiled fur, piloerection, general pallor and wasted
appearance. Other clinical signs noted included: few or no feces, cold
to touch, reduced motor activity, labored respiration, hunched posture,
increased salivation and soiling around the mouth. White areas on eyes
were noted in two males at 7000 ppm and in one male and four females at
12000 ppm. At 1000 ppm, yellow coloured urine was noted in all males on
a few days and one female presented a white area on the eyes.

At 12000 ppm, a reduction in mean body weight gain of 70% was recorded
in males during the first week of exposure. At this dose level, the
depressions in body weight gain ranged from 11.5 to 56% over days 22 to
70. In females at 7000 ppm and 12000 ppm, the depressions in mean body
weight gain were 12.5 and 15.6%, respectively, relative to controls at
the end of the 90 day period. At 12000 ppm food consumption in males was
lower than control values throughout the study. In females at 12000, the
mean food consumption was lower than control value on the first week of
treatment only (reduction of 28%) without reaching statistical
significance. At 7000 ppm, a reduction of food consumption was noted
during the first week in males (28%) and females (15%), the difference
with controls reaching statistical significance in males only. Very
slight reductions thereafter were also observed in both sexes but were
not statistically significant.

Neovascularization of the cornea and characteristic "snowflake" corneal
opacities were noted at 7000 and 12000 ppm in males, and at 1000, 7000,
and 12000 ppm in females.

In males, bilirubin, AST and ALT, urea, and creatinine were increased
(but not statistically significantly) at 7000 ppm. Cholesterol was
statistically significantly (p≤0.01) increased in males at 1000 ppm
(45%) and 7000 ppm (51%). Triglycerides were statistically significantly
(p≤0.01) increased in males at 1000 ppm (112%) and 7000 ppm (68%).
Ketone levels were increased from 1000 ppm in both males and females.
This is likely due to detection of the diketone structure of the test
substance itself, as the vast majority of the parent molecule is
excreted in the urine unchanged. There was an increased incidence of
occult blood, erythrocytes, leukocytes, and epithelial cells in the
urine in both males and females at 7000 ppm and in females at 12000 ppm
(males in the 12000 ppm group did not survive until the end of the study
and urine was therefore not collected).

At 1000 ppm and 7000 ppm, the relative liver to body weight in males was
statistically significantly increased by 22 and 26% respectively. At
1000 ppm and 7000 ppm, relative kidney to body weight in males was
increased 3.5 and 38.6%, respectively, the latter increase being
statistically significant. For females relative liver weight was
increased 8.7, 13 and 8.7% at 1000, 7000 and 12000 ppm and relative
kidney weight was increased 8, 25.4 and 30%, respectively.

At 7000 ppm and 12000 ppm, abnormal shape of the kidneys, mottled
kidneys, dilation of and gritty content in the renal pelvis, gritty
content, distension of the urinary bladder, and gritty content of the
ureters, and enlarged livers were observed in males and females. Livers
were enlarged in 3/10 males at 1000 ppm. Prominent lobulation was noted
in 1/7 male at 7000 ppm and in 2/10 males at 1000 ppm. The thyroid gland
was enlarged in one male at 1000 ppm.

The 12000 ppm group was terminated early at 11 weeks and tissues from
animals in this group were not microscopically examined. Histological
changes associated with the presence of calculi (urolithiasis) were
found in the kidneys/urinary bladder/ureters in 4/8 males and 6/10
females at 7000ppm. Associated histological changes included:

pelvic dilatation (unilateral or bilateral), urinary epithelial
hyperplasia (pelvis, urinary bladder and ureters), interstitial fibrosis
of the urinary tract, cystitis and Ureteritis. Slight to moderate
diffuse centrilobular hepatocellular hypertrophy was observed in

6/7 males at 7000 ppm, in 9/10 males at 1000 ppm and in 1/10 female at
7000 ppm. In females, a periportal vacuolation was found in 8/10 animals
at 7000 ppm and 3/10 animals at 1000 ppm.

**The LOAEL is 1000 ppm (77 mg/kg bw/day) in females based on
neovascularization of the cornea and "snowflake" corneal opacity; and
7000 ppm (454 mg/kg bw/day) in males based on mortality,
neovascularization of the cornea and "snowflake" corneal opacity, and
histopathology in the kidney, urinary bladder, thyroid, and ureters. The
NOAEL is 30 ppm (2.32 mg/kg bw/day) in females and 1000 ppm (66 mg/kg
bw/day) in males.**

This 90-day oral toxicity study in the rat is **acceptable (guideline)**
and satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3100; OECD 408) in the rat.

**870.3100 90-Day Oral Toxicity -- Mouse**

In a 90-day oral toxicity study (MRID 46801844), pyrasulfotole (95.7%
w/w ai, batch Op. 1-4) was administered to 10 C57BL/6 J@ Ico
mice/sex/dose in the diet at dose levels of 0, 100, 1500, or 3000 ppm
(equal to 0/0, 16.5/19.7, 124/152, 259/326, or 500/617 mg/kg bw/day for
males/females).

There were no compound-related effects on mortality, clinical signs,
ophthalmology, body weight, food consumption, clinical chemistry, organ
weights, or gross and histologic pathology. Urinary pH was slightly
increased at 3000 ppm in females (6.3, p\<0.05 vs. 6.0 in controls). Due
to the small number or volume of samples obtained, urinary pH was not
measured in 3000 ppm males. Examination of the individual animal data
revealed that urinary pH for the other male dose groups was similar to
controls (\~6.0).

**The LOAEL was not observed. The NOAEL is 3000 ppm (500/617 mg/kg/day
\[M/F\]).**

This 90-day oral toxicity study in the mouse is **Acceptable
(guideline)** and satisfies the guideline requirement for a 90-day oral
toxicity study (OPPTS 870.3100; OECD 408) in rodents.

**870.3150 90-Day Oral Toxicity -- Dog**

In a 90-day oral toxicity study (MRID 46801902), AE 0317309 (95.7% w/w
ai, batch Op:1-4) was administered in the diet to groups of 4 Beagle
dogs/sex/dose at dose levels of 0, 100, 500, or 1000 ppm (equivalent to
0/0, 3/3, 17/17 and 40/33 mg/kg bw/day in male/female dogs,
respectively) for a period of 90 days.

There were no compound-related effects on mortality, clinical signs,
body weight, food and water consumption, hematology, clinical chemistry,
urinalysis, gross pathology and microscopic pathology.

**The LOAEL was not established. The NOAEL is 40 mg/kg bw/day for males
and 33 mg/kg bw/day for females.**

This 90-day oral toxicity study in the dog is **acceptable/guideline**
and satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3150 OECD 409) in dogs.

**870.3200 21/28-Day Dermal Toxicity -- Rat**

In a 28-day dermal toxicity study (MRID 46801904), AE 0317309 (96.3% w/w
ai, batch Op:1-4) was applied to the shaved skin of 10 Wistar HsdCpb:WU
rats/sex/dose at dose levels of 0, 10, 100, or 1000 mg/kg bw/day, 6
hours/day for 5 days/week during a 28-day period.

There were no compound-related effects on mortality, clinical signs
(including ophthalmology), body weight, food and water consumption,
hematology, or gross pathology. Statistically significant increases in
cholesterol (27%), triglycerides (46%), and protein (4%) were observed
in males, and total bilirubin (17%) in females at 1000 mg/kg bw/day.
Since the observed changes were minor and within the limits of the
submitted historical control data, they were not considered
toxicologically significant. Absolute liver weights were statistically
significantly increased in males (13.9%) and females (11.3%) at 1000
mg/kg bw/day. Hepatocellular hypertrophy and hypertrophy of the pars
distalis of the pituitary gland were observed in males at 1000 mg/kg
bw/day. Focal degeneration of the pancreas was observed in 2/10 males
and 1/10 females at 100 mg/kg bw/day and in 8/10 males and 8/10 females
at 1000 mg/kg bw/day. An increased incidence of thyroid follicular cell
hypertrophy was seen in high-dose males. Alteration of thyroid colloid
was seen with increasing incidence and severity at ≥10 mg/kg bw/day in
males. However, since the alteration was predominantly minimal at 10
mg/kg, it was not considered toxicologically relevant at this dose.

The LOAEL is 100 mg/kg/day, based on focal degeneration of the pancreas
(both sexes) and alteration of thyroid colloid (males). The NOAEL was 10
mg/kg/day.

This 28-day dermal toxicity study in the rat is **Acceptable
(guideline)** and satisfies the guideline requirement for a 28-day
dermal toxicity study (OPPTS 870.3200; OECD 410) in mammals.

**A.3.2 Prenatal Developmental Toxicity**

**870.3700a Prenatal Developmental Toxicity Study -- Rat**

In a developmental toxicity study (MRID 46801905), AE 0317309 (95.7%
w/w; Batch# OP. 1-4) in 0.5% methylcellulose 400 was administered via
gavage at a dose volume of 10 mL/kg to 25 Sprague Dawley rats/dose group
at dose levels of 0, 10, 100, or 300 mg/kg/day from gestation days (GD)
6-20. On GD 21, all dams were euthanized, and the uterus was removed via
cesarean section and its contents examined. Fetuses were examined for
external, visceral, and skeletal malformations, anomalies, and
variations.

All dams survived until scheduled termination, and there were no
treatment-related macroscopic findings at termination, except for yellow
sediment in the kidney and gritty material in the bladder of one 300
mg/kg/day dose female..

At 300 mg/kg/day, maternal body weight decreased slightly throughout the
study, but was not statistically significant. Body weight change was
statistically significantly decreased 53 and 84%, at 100 and 300 mg/kg
bw/day, respectively during the gestation days 6-8, compared to
controls. Thereafter, body weight change was similar across all groups.
Maternal corrected body weight change was statistically significantly
reduced 8.4% compared to controls at 300 mg/kg /day.

There was a treatment-related, biologically and/or statistically
significant decrease in food consumption at 300 mg/kg /day between
gestation days 6 and 16, compared to controls. The effect was more
pronounced between GD 6-8 where there was a 15% reduction in food
consumption and 7% reduction during GD 8-10.

**The maternal LOAEL is 100 mg/kg/day based on increased incidence of
salivation, decreased corrected body weight gain, decreased corrected
body weight gain during GD 6-8 and dose-related enlarged placenta. The
maternal NOAEL is 10 mg/kg/day.**

There were no abortions, premature deliveries, or complete litter
resorptions. Furthermore, there were no effects of treatment on numbers
of litters, live fetuses, dead fetuses, resorptions (early or late), or
on sex ratio or post-implantation loss. There were no treatment-related
visceral malformations.

Mean fetal body weights (combined sexes) were significantly (P ≤ 0.01)
decreased by 5.5% at 300 mg/kg/day; male fetal body weights were
decreased 2 -- 5.5% at \> 100 mg/kg/day. In males the body weights were
significantly decreased (P≤0.05 or 0.01) at ≥ 100 mg/kg/day. Fetal body
weights at and above 100 mg/kg/day is considered treatment-related.
Additionally at 300 mg/kg/day, a total of 4 fetuses from two different
litters presented the malformation of hindpaw polydactyly. Three of the
fetuses with hindpaw polydactyly, all from the same litter showed an
anomaly of kyphosis, forelimb hyperflexion, misshapen digits on the
forepaws, and malpositioning of the digits on both the forepaws and the
hindpaws. Two of the four fetuses with the external observation of
hindpaw polydactyly had malformations including short tibia and femur,
supernumerary cartilaginous phalanges, fused cartilage for several
metatarsals and phalanges, and unossified 5^th^ metatarsal (presumably
the other two fetuses with externally observed hindpaw polydactyly were
not included among those subjected to skeletal observation). There was a
slight increase at the mid and high dose in the occurrence of 27
pre-sacral vertebrae. Treatment-related variants observed in this study
were primarily linked to ossification. Some of these occurred at an
increased fetal and/or litter incidence in the low dose group. These
were 7^th^ cervical centrum: unossified/normal cartilage; forepaws:
3^rd^ and/or 4^th^ proximal phalanges: unossified/normal cartilage;
1^st^ metatarsal: unossified/normal cartilage; and less than 9
sacrocaudal vertebrae ossified/9 first sacrocaudal vertebrae: normal
cartilage. Since the skeletal changes at the low dose were limited to
low incidences of variations and since skeletal variations were also
observed in the rabbit developmental toxicity study at 75 mg/kg/day
(NOAEL = 10 mg/kg/day), they were not considered toxicologically
significant.

**The developmental LOAEL is 100 mg/kg/day based on increased fetal
and/or litter skeletal variations and decreased body weight (males). The
developmental NOAEL is 10 mg/kg/day.**

This study is classified **acceptable/guideline** and satisfies the
guideline requirement for a developmental toxicity study (OPPTS
870.3700; OECD 414) in rats.

**870.3700b Prenatal Developmental Toxicity Study - Rabbit**

In a developmental toxicity study (MRID 46801906), AE 0317309Technical
(95.7% ai; Batch \# Op. 1-4) in 0.5% aqueous methylcellulose was
administered daily via oral gavage to 24 time-mated New Zealand White
rabbits/group at a dose volume of 4 mL/kg at dose levels of 0, 10, 75,
or 250 mg/kg bw/day from gestation day (GD) 6 through 28 inclusive. All
surviving rabbits were killed on GD 29; their fetuses were removed by
cesarean section and examined. Liver weight and the number of ribs were
noted for each animal. The gravid uterine weight, number of corpora
lutea, number of implantations, resorptions (early and late), and live
and dead fetuses, and the individual weight of live fetuses, was
recorded for each animal. Live fetuses were sacrificed and examined
externally. The heads of approximately half the fetuses were fixed for
later examination. All fetuses were dissected for visceral findings,
fixed, and stained for skeletal examination.

No effects of treatment were observed on mortality, number of corpora
lutea, implantation sites, early or late resorptions, number of live or
dead fetuses, or percent pre- or post-implantation losses per dam and
fetal sex ratio, fetal external, and visceral malformations at any dose
level.

At 250 mg/kg bw/day maternal body weight gain decreased (↓230% or 0g
gain vs 30g in control) significantly between GD 8-10 and food
consumption decreased significantly throughout the study. At necropsy
2/25 does had prominent liver lobulations, however, no histopathology
information was available.

**The maternal LOAEL is 250 mg/kg bw/day based on decreased body weight
gain during GD 8-10 and decreased food consumption during the study. The
maternal NOAEL was 75 mg/kg bw/day.**

At 250 mg/kg bw/day, fetal body weight was statistically significantly
decreased both for combined sexes and for the sexes taken separately.
Mean combined fetal body weights decreased 4.7 -- 14.9% at ≥ 10 mg/kg
bw/day and was dose--related. However, a follow-up historical control
analysis revealed that concurrent controls were at the upper end of the
historical control range and that body weights at the low and mid doses
were within the historical control range. A number of skeletal anomalies
and variants were recorded at ≥75 mg/kg bw/day; however; their
incidences at 10 mg/kg/day did not exceed rates in historical control
data.

**The developmental LOAEL was 75 mg/kg bw/day based on an increased
incidence of fetal/litter skeletal anomalies/variations. The
developmental NOAEL was 10 mg/kg bw/day.**

This study is classified **acceptable/guideline (OPPTS 870.3700b)** and
satisfy the guideline requirements for a developmental study in the
rabbit.

**A.3.3 Reproductive Toxicity**

**870.3800 Reproduction and Fertility Effects - Rat**

In a 2-generation reproduction study (MRID 46801907) AE0317309 (95.7%
ai, batch# Op. 1-4) was administered to 25 Wistar rats/sex/dose in the
diet at dose levels of 0, 30, 300 or 3000 ppm (equivalent to 0, 2.5,
26.3, and 272.4 mg/kg bw/day for F~0~ males and 0, 3.1, 32.6 and 345.7
mg/kg bw/day for F~0~ females, and 0, 3.68, 34.1 and 353.6 mg/kg bw/day
in F~1~ males and 0, 4.2, 38.9 and 393.4 mg/kg bw/day in F~1~ females
during the premating period).

There was a dose-related increase in the incidence of either diffuse
and/or reticulate corneal opacities, and of corneal neovascularization
in both F~0~ and F~1~ males and females at 300 ppm and 3000 ppm.

There were significant increases in absolute liver (12.9%) and kidney
(12.2%) weights in F~1~ males in the 3000 ppm group. Absolute thyroid
weight was significantly increased in F~1~ males in the 300 ppm (28.6%)
and 3000 ppm (35.7%) groups. Significant increases in absolute adrenal
weights were observed in F1 females at 3000 ppm. There were significant
increases in relative liver weight (6.0 and 10.3%, respectively),
relative kidney weight (6.2% and 16.4%, respectively), and relative
thyroid weight (both 37.9%) in F~1~ males at 300 ppm and 3000 ppm.

Treatment related effects were observed in the eyes and thyroid of both
males and females of the F~0~ and F~1~ generations, and in pituitary,
kidneys, and liver of F~0~ and F~1~ males. Findings in the eyes, at 300
ppm and 3000 ppm in both males and females of the F~0~ and F~1~
generations, included keratitis and vascularization, correlating with
in-life observations.

Thyroid findings included colloid alteration at all doses in male F~0~
and F~1~ rats, and females of the F~0~ generation and from 300 ppm in
F~1~ females, pigment deposition at all doses in F~0~ and F~1~ males and
from 300 ppm in F~0~ and F~1~ females, and increased follicular cell
hypertrophy in F~0~ males at 3000 ppm and F~1~ males from 3000 ppm and
F~0~ females at 3000 ppm. It is noted that follicular cell hypertrophy
was not observed and that colloid alteration/pigment deposition was
minimal at 30 ppm. Eosinophilic inclusions were increased in the
anterior pituitary of males at 300 ppm and 3000 ppm in both the F~0~ and
F~1~ generations. Findings in the liver included hepatocellular
hypertrophy, cellular alteration, and slight increases in periportal fat
accumulation in F~0~ and F~1~ males at 300 ppm and 3000 ppm. The kidneys
of males in the F~0~ and F~1~ generation had increased incidence and/or
severity of basophilic tubules and tubular dilation, in a dose related
manner from 300 ppm.

Number of pups born dead appeared to have been elevated at all doses in
the F~1~ generation and at 30 ppm and 3000 ppm in F~2~ generation.
However, the data did not show a clear dose-response association or any
statistical significance and the live birth index was unaffected in
either generation. Treatment related clinical signs in pups included
cold to the touch, which was increased in F~1~ pups at 3000 ppm only (12
pups), compared to control (5 pups). There was an increased incidence of
autolysis and no milk in the stomach in the F~2~ pups at 3000 ppm (4-5
pups) compared to controls (1 pup). The incidence of dilated and/or
enlarged kidneys was increased at 3000 ppm in F~1~ and F~2~ pups. The
mean viability index was non-significantly reduced in a dose-related
manner in F~2~ pups at all doses as shown: 92.45±23.326, 83.79±32.046,
78.89±35.016, and 71.60±38.201 at 0, 30, 300 and 3000 ppm, respectively.
A benchmark dose analysis for this endpoint by R. Mitkus yielded a
BDM=227.6 ppm and a BMDL=68.13 ppm. This supported the conclusion not to
consider the decrease in viability index at the low dose as
treatment-related. In addition, only the index at 3000 ppm of test
substance was lower than the historical data presented by the study
authors. Examination of pups at the time of weaning on postnatal day 28
showed an increased incidence of corneal opacity and/or corneal
neovascularization at 300 ppm and 3000 ppm in both F~1~ and F~2~ pups,
showing a dose-related increase. Both litter (mean body weight for males
and females taken together) and pup (mean body weight for males or
females, taken separately) body weights were statistically significantly
decreased in the F~1~ (mean liter weight decr. 7.9%) and F~2~ (mean
liter weight decr. 11.1%) pups at 3000 ppm at weaning on day 28. In F~2~
females at 3000 ppm, body weight was also statistically significantly
decreased at lactation day 21. Statistically significant delays of
balano-preputial separation at 300 ppm and 3000 ppm, and a statistically
significant delay of vaginal opening at 3000 ppm, were observed in F~1~
pups. These parameters were not assessed in F~2~ pups.

**The parental systemic LOAEL is 30 ppm (2.5 mg/kg bw/day in males, 3.1
mg/kg bw/day in females), based on minimal colloid alteration and/or
pigment deposition in the thyroid. The parental systemic NOAEL was not
observed.**

**The offspring LOAEL is 300 ppm (26.3 mg/kg bw/day in males, 32.6 mg/kg
bw/day in females), based on corneal opacity and/or corneal
neovascularization (F1 and F2 generations). The offspring NOAEL is 30ppm
(2.5 mg/kg bw/day in males, 3.1 mg/kg bw/day in females).**

**The reproductive LOAEL is 300 ppm (26.3 mg/kg bw/day in males, 32.6
mg/kg bw/day in females), based on delays in balano-preputial separation
in F~1~ pups. The reproductive NOAEL is 30ppm (2.5 mg/kg bw/day in
males, 3.1 mg/kg bw/day in females).**

This study is **acceptable/guideline** and satisfies the guideline
requirement for a 2-generation reproduction study (OPPTS 870.3800; OECD
416) in the rat*.*

**A.3.4 Chronic Toxicity**

**870.4100b Chronic Toxicity - Dog**

In a chronic toxicity study (MRID 46801908), AE 0317309 (95.7% w/w,
Batch #: OP. 1-4) was administered to 4 beagle dogs/sex/dose in the diet
for 52 weeks at doses of 0, 250, 1000, or 3000 ppm (equivalent to 0/0,
7/9, 34/33, and 101/93 mg/kg/day in males/females).

No treatment-related adverse effects were observed on mortality, body
weights, body weight gains, food consumption, ophthalmoscopic
examination, urinalysis, or clinical chemistry at any dose. LDH levels
were decreased in the mid and high dose females at 12months. However,
the pretest values were also low in these groups, suggesting that this
was not treatment-related. There was no evidence of treatment-related
increased blood levels in the urine.

At 3000 ppm, APTT was significantly depressed in males (16%) and females
(14-16%) at ≥ 1000 ppm. The prothrombin time was not significantly
effected. Since the APTT was decreased rather than increased, the
clinical and toxicological significance is unknown.

A dose-related, non-statistically significant, increase in the absolute
and relative liver, kidney and thyroid weights increased in males and
females. Specifically at the 3000 ppm dose, absolute and relative liver
weights in males and females (34-49%), absolute and relative kidney
weights in males (26-38%), and absolute and relative thyroid weights in
females (18-30%) increased. Microscopically, increased incidence of
hepatocytomegaly was observed in 2/4 males and 3/4 females at the high
dose, compared to 0/4 in controls. Hepatocytomegaly was observed as 1
(minimal) on a scale of 1 to 5. Kidney tubular dilatation was observed
in 1/4, 1/4, 3/4, and 4/4 in the control, 250, 1000 and 3000 ppm males,
respectively with a severity grade of 2 in the mid- and high dose groups
and grade severity of 1 each in control and low dose groups.
Additionally, cataracts were observed one each in 3000 ppm males and
females; grade severity of 2. One high-dose male showed inflammation,
hemorrhage and debris in bladder. Increased thyroid weights were not
associated with any treatment-related micropathology observed.

**The LOAEL is 1000 ppm (equivalent to 34 mg/kg/day) in males, based
upon the increased incidence and severity of kidney tubular
dilatation.** **The NOAEL was 250 ppm (equivalent to 7 mg/kg/day) in
males. The LOAEL is 3000 ppm (equivalent to 93 mg/kg bw/day) in females,
based on cataracts. The NOAEL is 1000 ppm (equivalent to 33 mg/kg/day)
in females.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirement (OPPTS 870.4100b, OECD 452) for a chronic oral
toxicity study in dogs.

**A.3.5 Carcinogenicity**

**870.4300 Combined chronic toxicity/Carcinogenicity Study - rat**

In a combined chronic toxicity/carcinogenicity study (MRID 46801910), AE
0317309 (95.7% ai, batch Op. 1-4) was administered in the diet to 75
six-week-old Wistar Rj:WI (IOPS HAN) rats/sex/group at dose levels of 0,
25, 250, 1000, or 2500 ppm (equivalent to 0/0, 1.0/1.4, 10/14, 41/57, or
104/140 mg/kg bw/day in males/females) for 24 months. Animals were
sacrificed at 6 (10/dose group), 12 (10/dose group), and 24 months
(55/dose group).

There were no treatment-related effects on food consumption and
hematology. Mortality was 73% (P\<0.05) in high-dose males at 24 months;
however, survival was \>25% after 24 months in control and all treated
groups and therefore was considered acceptable for evaluating the
carcinogenic potential of pyrasulfotole. Increased incidences of white
area on the eye and soiled fur in one or more areas were observed
clinically in males and females at all time points at ≥250 ppm. Body
weight in males was decreased (≥10%) throughout the study at ≥1000 ppm.
A consistent treatment-related effect on body weight or body weight gain
was not observed in treated females. During ophthalmoscopic examination,
corneal opacity, neovascularization of the cornea, edema of the cornea,
and "snow flake" corneal opacities were observed in males at ≥250 ppm
after 6, 12, and 24 months of treatment. At 24 months, increased
incidences of corneal opacity and neovascularization of the cornea were
observed in males and females at ≥250 ppm. Plasma cholesterol was
increased in males and females at 250 ppm at 7 months (**≥**20%) and in
males at 12 months (**≥**52%). Plasma cholesterol was also increased in
males at ≥1000 ppm at 18 and 24 months (**≥**33%) and at 2500 ppm in
females at 24 months (63%). Increases in cholesterol at ≥250 ppm were
considered toxicologically significant in light of the increased
incidence of hepatocellular hypertrophy and/or vacuolation and increased
liver weight throughout the study. Triglyceride levels were also
increased (NSS) by 124% and 135% in males and females, respectively, at
2500 ppm. Increased levels of ketones were observed in the urine of
males and females at ≥1000 ppm at all collection periods and in males at
250 ppm at months 19 and 24 only. Urinary pH was decreased at ≥250 ppm
in males at all time points and in females at 3 months only. Urinary
protein was increased in males in all treatment groups from 6 months
onwards. Decreases in urinary pH and increased urinary protein in males
were considered toxicologically significant in conjunction with
treatment-related increases in chronic progressive nephropathy and
collecting duct hyperplasia. The increased level of ketones may have
been due to unmetabolized test substance.

Absolute and relative liver and kidney weights were elevated in males at
≥250 ppm from 6 months onwards (liver: 20%; kidney: \>15%). There were
no significant effects on organ weights in females. At macroscopic
examination, the incidence of eye opacities was increased in males and
females at ≥250 ppm. Enlarged liver was observed in males at 6 months in
all treated groups and at 12 months at ≥250 ppm. At 24 months, there was
an increased incidence among males of pale kidneys and irregular surface
of the kidney at ≥1000 ppm. Non-neoplastic histopathology included
peripheral retinal atrophy, corneal inflammation, corneal hyperplasia,
and/or corneal neovascularization at ≥250 ppm in both sexes and an
increased incidence of chronic progressive nephropathy in males at ≥250
ppm. Histopathology observed in several other organs at higher doses is
summarized in the Australian review (attached). The only
treatment-related neoplastic finding was that of rare squamous cell
tumors of the cornea (one papilloma, one carcinoma) observed in two
separate males at 2500 ppm.

**The LOAEL was 250 ppm (10/14 mg/kg \[M/F\]) based on corneal opacity,
neovascularization of the cornea, inflammation of the cornea,
regenerative corneal hyperplasia, corneal atrophy, and/or retinal
atrophy (both sexes), and hepatocellular hypertrophy along with
increased serum cholesterol (males). The NOAEL was 25 ppm (1.0/1.4 mg/kg
\[M/F\]).**

At the doses tested, there was a treatment-related increase in the
incidence of corneal squamous cell tumors when compared to controls.
Dosing was considered adequate, but not excessive, based on decreased
body weight/body weight gain and non-neoplastic lesions of the eyes,
liver, pancreas, thyroid and kidney at the high dose.

This chronic toxicity/carcinogenicity study in the rat is classified as
**Acceptable (guideline)** and satisfies the guideline requirement for a
chronic toxicity/carcinogenicity study (OPPTS 870.4300; OECD 453) in
rat. Although motor activity, grip strength, and reactivity to sensory
stimuli were not assessed in the chronic phase of the study as required
by the guideline, they were assessed in other, short-term studies.

**870.4200b Carcinogenicity (feeding) - Mouse**

In a carcinogenicity study (MRID 46801909), AE 0317309 (95.7% w/w ai)
(95.7% w/w ai; Batch No. OP. 1-4) was administered in the diet to
C57BL/6J mice (50/dose) at doses of 0, 100, 1000, or 4000 ppm for males.
Groups of 50 females/group received 0, 100, 1000, or 6000 ppm for the
first 10 weeks, then reduced the high-dose to 4000 ppm from week 11
onwards. The high-dose in females was considered excessive because of
increased mortality. The concentrations resulted in doses of 0/0,
13.6/16.7, 137/168 and 560/713 mg/kg/day in males and females for up to
78 weeks. Additionally, 10 mice/sex/dose were treated similarly for up
to 52 weeks and then scheduled for interim sacrifice.

There was no effect of treatment on food consumption. Liver and urinary
system was identified as target system. Treatment-related effects were
observed on mortality, clinical signs, body weight body weight gains,
hematology, liver and kidney weights, urolithiasis, and gall stones in
males and females. At 4000 ppm, survival rate at 18 months was 50 and
40%, respectively in males and females. The survival rate is above the
guideline recommended level and is acceptable. Survival rates at 100 and
1000 ppm were comparable to controls.

At 4000 ppm clinical signs suggested of compound administration include
hardness in the urinary bladder area, soiled fur, reduced motor
activity, labored or rapid respiration and red urine. The study authors
presumed red urine color was due to compound excretion, however, no
urine analysis was performed to confirm.

At 4000 ppm mean body weight significantly in both males and females.
Body weight was unaffected 1000 ppm in males, however, body weight gain
was significantly decreased; the incidence was dose-related. At this
dose, in females, body weight gains were significantly decreased during
two time periods (days 92-176 and 344-450).

Red blood cells, Hb, Hct, and MCHC were decreased in females at 4000 ppm
at 18 months (showing indications of dose-response relationships). MCV
was slightly increased in females at 4000 ppm at 18 months. In males at
4000 ppm, similar hematological effects were generally observed at 18
months. The perturbations seen at 4000 ppm were considered to be
treatment-related. Hematological changes at 100 ppm were comparable to
controls.

The majority of statistically significant organ weight changes were
restricted to 4000 ppm mice sacrificed at 18 months. Absolute and
relative kidney weights increased in males and males at 4000 ppm dose
group at the terminal sacrifice. Absolute brain weight was reduced at
4000 ppm at 18 months in males, although it was actually significantly
increased as a percentage of body weight. Relative liver weights were
increased in both males and females at 18 months, reaching statistical
significance in all treated males, with no clear dose-response
associated effects on absolute liver weights. Absolute and relative
spleen weights were increased in males and relative spleen weights in
females at 18 months in 4000 ppm group.

In all treatment groups (males and females) at 12 months, incidences (n=
7 - 10) of the following lesions were increased in the kidneys: (i)
large kidneys (2-7 treated vs 0 control); (ii) small kidneys (1-4
treated vs 0 controls); stones (1-4 vs 0 control); pelvic dilation (3-6
vs 0 control); pale (1-3 vs 0 control) cysts (1-2 vs 0 control) gritty
content in the bladder (6-8 vs 0 control) and distended bladder (4-8 vs
0 control). At 18 months, the majority of those which died unscheduled
at 4000 ppm were found to have died due to acute or chronic renal
failure, due to urinary tract blockage or chronic kidney and/or urinary
bladder inflammation, respectively. Stones were found in the kidney
and/or urinary bladder of these animals; other findings at necropsy of
unscheduled deaths were enlarged or small kidneys, renal pelvic
dilation, pale kidneys, renal cyst(s), distention of the urinary
bladder, and gallbladder stones or concretions. Similar findings were
observed in animals sacrificed at 18 months. The incidence of above
findings at 4000 ppm were higher than the incidence at 12 months of
sacrifice.

Increased incidence of gallstones was a relatively common observation in
all treated groups at scheduled sacrifice, although there was no
dose-response relationship.

Microscopic examination was not conducted at 12 months. At 18 months,
histopathologic findings included a dose-related increase in the
incidence of minor to moderate centrilobular hepatocellular hypertrophy
in males and females at 1000 and 4000 ppm; which was statistically
significant in the males at 1000 and 4000 ppm and the females at 4000
ppm. This was considered to be treatment-related. Most of the other
treatment-related findings were observed in the urinary system (kidney,
urinary bladder, and ureters) at the high dose in males and females and
were associated with stones and concretions observed in the urinary
system at the same dose.

**The LOAEL is 100 ppm (equivalent to 13.6/16.7 mg/kg/day \[M/F\]),
based on an increased incidence of gallstones. The NOAEL was not
established.**

Treatment-related neoplastic findings included urinary bladder
transitional cell carcinomas (including urethral transitional cell
carcinoma) and papillomas and carcinomas combined in males and urinary
bladder transitional cell papillomas, carcinomas, and papillomas and
carcinomas combined in females at 4000 ppm.

Dosing was considered excessive in both sexes because of significantly
increased mortality in males (53% vs 16% in controls) and females (62%
vs 30% in controls), much of which occurred in the first year of the
study. The increased mortality was due to the presence of urinary
bladder stones. However, the dose was considered appropriate for risk
assessment purposes because it also caused tumors in the target organ
responsible for increased mortality. In addition, dose selection for the
long term study was reasonable based on the results of the 90-day study
where no effects were seen at 3000 ppm.

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.4200b; OECD 451) for a carcinogenicity
study in mice.

**A.3.6 Mutagenicity**

Please refer to toxicological profile table above.

**A.3.7 Neurotoxicity**

**870.6200 Acute Neurotoxicity Screening Battery**

In an acute neurotoxicity study (MRID 46801915), groups of 12 unfasted,
9-week-old Wistar rats/sex/dose were given a single oral dose by gavage
of AE 0317309 (95.7% ai, batch Op. 1-4) in aqueous 0.5%
methylcellulose/0.4% Tween 80 at doses of 0, 200, 500, or 2000 mg/kg bw
and observed for 14 days. Cage-side observations were performed at least
once daily (once daily on holidays and weekends) for mortality or
clinical signs of moribundity. Detailed physical examinations for
clinical signs of toxicity were carried out and recorded daily. Animals
were weighed weekly as a component of the FOB (functional observational
battery) and at sacrifice. Neurobehavioral assessment (FOB and motor
activity testing) was performed in all animals (fasted) one week prior
to dosing, approximately 30 minutes after dosing on day 0, and on days 7
and 14 after dosing. The 30-min evaluation time was selected based on a
preliminary disposition study wherein blood concentrations peaked at
approximately 30 minutes post dosing. The FOB included standard
parameters including home cage and open field observations, reflex
testing, and determination of fore-limb and hind-limb grip strength, and
landing foot splay. Motor and locomotor activity were measured over a
60-minute period for each animal. At study termination, all animals were
euthanized and 6 rats/sex/dose were perfused *in situ* for
neuropathological examination. Of the perfused animals, all were
subjected to histopathological evaluation of brain and peripheral
nervous system tissues.

There were no treatment-related effects on mortality, body weight, brain
weight, gross pathology, or microscopic neuropathology. The FOB revealed
no toxicologically significant effects. During clinical observations, an
increased incidence of urine staining was observed in all treated male
and female groups on the day of treatment, as well as across several
days post-treatment (Appendix 1). Similar staining was reported in
high-dose animals only during the FOB. A dose-dependent increase in red
nasal stain was observed at ≥500 mg/kg in males and at ≥200 mg/kg in
females. The incidence of oral stain or red stained forepaws was also
increased in males or females at ≥200 mg/kg. All stainings were
considered to be due to excretion of test compound and therefore not
toxicologically significant. Mean locomotor activity was significantly
decreased (P\<0.01) in all treated females on the day of dosing. When
compared to both control and pre-test levels, the decrease was
dose-dependent. Although not statistically significant, dose-dependent
decreasing trends were observed in motor activity (days 0 and 7) and
locomotor activity (day 7) in females. The decreases in overall
locomotor activity were corroborated by statistically significant
decreases in locomotor activity in treated females at several
subsessions across days of testing. A 34% (NSS) decrease in mean overall
locomotor activity was observed in males at 2000 mg/kg on day 0. The
decrease was corroborated by decreased interval locomotor activity in
males at 2000 mg/kg on day 0, which reached statistical significance
during interval 3.

**The LOAEL was 200 mg/kg bw in females and 2000 mg/kg bw in males based
on decreased locomotor activity on day 0. The NOAEL was not observed in
females and was 500 mg/kg bw in males.**

This neurotoxicity study is classified as **acceptable (guideline)** and
satisfies the guideline requirement for an acute neurotoxicity study in
rats (870.6200; OECD 424).

**870.6200 Subchronic Neurotoxicity Screening Battery**

In a subchronic neurotoxicity study (MRID 46801916), AE 0317309 (95.7%
ai, batch Op. 1-4) was administered to 12 eight-week-old Wistar
rats/sex/group at dose levels of 0, 500, 2500, or 5000 ppm (equivalent
to 0/0, 32/42, 166/206, or 345/416 mg/kg bw/day in males/females) for 90
days. Clinical signs were assessed twice daily on weekdays and once
daily on weekends and holidays. Body weight and food consumption were
measured on a weekly basis. Neurobehavioral assessment (functional
observational battery and motor activity testing) was performed in all
animals/sex/group once in the week prior to the start of the feeding
period, and once each during weeks 2, 4, 8, and 13. The FOB included
standard parameters including home cage and open field observations,
reflex testing, and determination of fore-limb and hind-limb grip
strength, and landing foot splay. Motor and locomotor activity were
measured over a 60-minute period for each animal. Ophthalmoscopic
examinations were conducted in all animals prior to the start of the
study and during week 12. At study termination, all animals were
euthanized and 6 rats/sex/dose were perfused *in situ* for
neuropathological examination. Of the perfused animals, all were
subjected to histopathological evaluation of brain and peripheral
nervous system tissues.

There were no treatment-related effects on mortality, body weight, brain
weight, gross pathology, or microscopic neuropathology. The FOB and
loco/motor activity assessments revealed no toxicologically significant
effects. During clinical observations, an increased incidence of urine
staining was observed in all treated male and female groups (Appendix
1), however without a relationship to dosing in males. Because the urine
was not analyzed, the cause of the staining is unclear, but is
hypothesized to be related to unmetabolized parent compound and
therefore not toxicologically significant. Similar staining was reported
in high-dose animals only during the FOB. Food consumption was slightly
increased (≤12%) at 5000 ppm at several intervals, but was not
considered toxicologically significant in the absence of adverse effects
on any other parameter, including body weight. Increased incidences of
corneal opacity (2, 3, and 1 vs. 0 in controls) and corneal
neovascularization (1, 2, and 1 vs. 0 in controls) were observed in all
treated females. Incidences of retinal degeneration were
dose-dependently increased in females (1, 2, and 3 vs. 1 in controls),
but not males. The increased incidence of corneal neovascularisation was
considered toxicologically significant at the low dose, since the
incidence was 0 in control females at ophthalmoscopy in the 90-day
toxicity study in rat and 0 in control females at ophthalmoscopy at 6
and 12 months in the chronic toxicity study in rats.

**The LOAEL was 500 ppm (42 mg/kg bw/day) in females based on increased
incidences of corneal opacity and corneal neovascularization in females
and not observed in males. The NOAEL was not observed in females and was
5000 ppm (345 mg/kg bw/day) in males.**

The study is classified as **Acceptable (guideline)** and satisfies the
guideline requirement for a subchronic neurotoxicity study in rats
(870.6200b).

**870.6300 Developmental Neurotoxicity Study**

In a developmental neurotoxicity study (MRID 46801917), AE 0317309
(95.7% w/w ai, batch Op. 1-4) was administered from gestation day 6
through postnatal day 21 to 30 female Wistar rats per dose in the diet
at nominal concentrations of 0, 45, 450, or 4500 ppm during gestation
and 0/0/0, 24/20/16, 237/196/161, or 2368/1957/1607 ppm during weeks
1/2/3 of lactation. These concentrations provided an average daily
intake of 0, 3.8, 37, or 354 mg/kg bw/day over gestation and lactation.
Offspring were not dosed directly in this study. Dams were observed for
clinical signs at least once daily. FOB (functional observational
battery) tests were conducted on GDs 13 and 20 and LDs 11 and 21. Body
weight and food consumption were measured on GDs 6, 13, and 20 and on
LDs 0, 7, 14, and 21. On LD 4 litters were culled to eight pups, with
four male and four female pups wherever possible. Dams were sacrificed
on LD 21 following weaning of their litters, and a gross necropsy
examination was conducted. Offspring were allocated for FOB and
assessment of motor activity, auditory startle reflex habituation,
learning and memory (passive avoidance and watermaze testing), and
neuropathology (including brain weights). Offspring were monitored daily
throughout lactation for clinical signs or morbidity and were weighed
individually on LDs 0, 4, 11, 17, and 21 and weekly thereafter. The age
of sexual maturation (vaginal opening in females and preputial
separation in males) was also recorded.

There were no treatment-related effects on mortality, clinical signs
during gestation, or body weight in dams. During lactation, ocular
opacities were observed in up to 5/21 dams from LD 9 at 37 mk/kg/day and
in up to 14/20 females from LD 10 at 354 mg/kg/day. During the FOB,
ocular opacities were observed on LD 11 in 3/10 dams at 37 mk/kg/day and
in 7/10 dams at 354 mg/kg/day; and on LD 21 in 2/10 and 7/10 dams at 37
and 354 mg/kg/day, respectively. Food consumption was reduced in dams
during weeks 1-2 of lactation at 37 (12-19%) and 354 (9-20%) mg/kg/day,
however without a corresponding effect on body weight. The fertility
index was decreased (NSS) at 37 mg/kg/day (3%) and 354 mg/kg/day
(13.3%); however, this observation was not considered treatment-related,
since dosing began on GD 6. All other reproductive parameters were
unaffected by treatment.

**The maternal LOAEL is 37 mg/kg/day, based on ocular opacities during
lactation. The maternal NOAEL is 3.8 mg/kg/day.**

There were no treatment-related effects on litter size,
viability/mortality, or other litter parameters in offspring. Clinical
signs and body weight were unaffected during lactation. During
post-weaning, ocular opacities were observed in 6/58 males at 354
mg/kg/day on or after PND 29, as well as in 2/63 females at 37 mg/kg/day
and 1/60 females at 354 mg/kg/day on or after PND 30. Body weight was
decreased in males and females by 6-9% and 4-8% each at 37 mg/kg/day and
by 8-13% and 8-11% each at 354 mg/kg/day. Preputial separation was
delayed at 37 mg/kg/day (46.0 days) and 354 mg/kg/day (46.7 days, P\<
0.01), compared to controls (44.1 days). Vaginal patency was unaffected
by treatment. During the FOB, ocular opacity was observed in 1/15
females at both 37 mg/kg/day and 354 mg/kg/day. These changes were first
noted on postnatal days 45 and 35, respectively, and persisted in both
cases through postnatal day 60.

No treatment-related effects were observed on motor activity or auditory
startle response. For PND 22 animals tested for passive avoidance, an
increase (P\<0.05) in the number of trials to criterion, as well as
dose-dependent decreases in trials 1 and 2 latencies, were observed at
≥37 mg/kg/day during the learning session. During the retention session,
an increase (P\<0.05) in the number of trials to criterion and reduced
latency at trial 1 were observed at 354 mg/kg/day. There were no
treatment-related effects on acquisition and retention in either adult
males or females during the water maze testing. An increase in the mean
time required to complete trial 1 was observed in the retention phase in
males at 37 mg/kg/day; however, the result was not considered
treatment-related in the absence of dose response and treatment-related
effects on the number of trials to reach criterion.

During ophthalmoscopic examinations, retinal degeneration was observed
in 4/10 males at 354 mg/kg/day. Retinal degeneration was also observed
in 0/13, 1/13, 3/11, and 4/10 females at 0, 3.8, 37, and 354 (P\<0.05)
mg/kg/day, respectively. The increase in one female animal at the low
dose was not considered treatment-related based on the low incidence and
lack of statistical significance in the current study and since retinal
degeneration was not observed at a similar dose in F1 or F2 offspring in
the 2-generation reproduction study. Absolute fixed brain weight on PND
21 was statistically significantly decreased for males (8%) at 354
mg/kg/day and for females at 37 mg/kg/day (6%) and 354 mg/kg/day (11%).
Absolute fixed brain weight on PND 75 was also decreased for females at
354 mg/kg/day (5%). At necropsy, an increased incidence of opacity was
observed in the eyes of 3/10 PND 75 males at 354 mg/kg/day. During
macroscopic morphometry at PND 21, cerebellum length was decreased
(P\<0.05) in perfused males (6%) and females (7%) at 354 mg/kg/day.
Cerebrum length was also decreased (P\<0.05) in females at 37 (4%) and
354 (5%) mg/kg/day. At PND 75, cerebellum length was decreased in males
(5%, P\<0.05) and females (4%, NSS) at 354 mg/kg/day. During microscopic
morphometry on PND 21, cerebellum height was decreased (P\<0.05) in
males at 37 mg/kg/day (7%) and 354 mg/kg/day (8%) and in females at 354
mg/kg/day (10%). The hippocampal gyrus was decreased (P\<0.05) by 11%
and 9% in males and females, respectively, at 354 mg/kg/day on PND 21.
On PND 75, cerebellum height was changed at the mid and high doses in
males (↑14% and ↓6%, respectively) and females (↑13% and ↓6%); however,
in the absence of a consistent change across dose, the findings were not
considered toxicologically significant.

**The offspring LOAEL is 37 mg/kg/day, based on ocular opacity
(post-weaning), decreased body weight, delayed preputial separation
(males), increase in the number of trials to criterion and decreases in
trial latencies (passive avoidance; PND 22 males), retinal degeneration
at ophthalmoscopy (females), decreased brain weight (PND 21 females),
decreased cerebrum length (PND 21 females), and decreased cerebellum
height (PND 21 males). The offspring NOAEL was 3.8 mg/kg/day.**

This study is classified **Acceptable/Non-guideline** and may be used
for regulatory purposes. It does not, however, satisfy the guideline
requirement for a developmental neurotoxicity study in rats \[OPPTS
870.6300, §83-6; OECD 426 (draft)\] due to the pending review of the
positive control data.

**A.3.8 Metabolism**

**870.7485 Metabolism - Rat**

In a metabolism study (MRID 46801918), AE 0317309 (97.6-100% ai, Vial #s
C-938, C-939, C-938B, C-1024A, K-1196, K-1267), male Wistar Hanover rats
(five rats for each radiolabel) were given single oral doses of
\[phenyl-UL-^14^C\] AE 0317309 {methanone,
(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)\[2-(methylsulfonyl)-4-(trifluoro-methyl)
phenyl\] \[phenyl-UL-^14^C\]} or \[pyrazole-3-^14^C\] AE 0317309
{methanone,
(5‑hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)\[2-(methylsulfonyl)-4-(trifluoromethyl)phenyl\]
\[pyrazole-3-^14^C\]} at dose rates of 10.0 and 9.88 mg/kg bw,
respectively. In two separate experiments, male Wistar Hanover rats with
surgically implanted jugular cannula were dosed intravenously with
\[phenyl-UL-^14^C\] AE 0317309 (four rats) or \[pyrazole-3-^14^C\] AE
0317309 (five rats) at dose rates of 9.81 and 9.60 mg/kg bw,
respectively.

The \[phenyl-UL-^14^C\] AE 0317309 was readily absorbed following oral
dosing, with approximately 62% of the administered radioactivity dose
being recovered in the urine within 6 h post dose. A total of
approximately 73% of the administered radioactivity dose was recovered
in the urine by the time of sacrifice (52 h).

The \[pyrazole-3-^14^C\] AE 0317309 was readily absorbed following a
single oral dose, with approximately 57% of the administered
radioactivity dose being recovered in the urine within 6 h post dose. A
total of approximately 75% of the dose was recovered in the urine by the
time of sacrifice (48 h).

In the case of intravenous administration, approximately 90% of the
radioactivity was excreted in the urine and approximately 10% in the
feces by 48 h. Most (over 80%) of the intravenous dose was excreted in
the urine within 6 h.

In all experiments, \<2% of the administered dose remained in the
residual carcass and tissues at sacrifice. In all experiments, the
highest residues were found in the liver and kidney. There was no
apparent difference between the phenyl-UL-^14^C label and the
pyrazole-3-^14^C label in the distribution of equivalents in the tissues
following intravenous dosing. However, concentrations in the tissues
were consistently higher in the case of the pyrazole-3-^14^C label than
in the case of the phenyl-UL-^14^C label following oral dosing. The
distribution of radioactivity in tissues did not differ greatly between
oral and intravenous dosing, with the exception that the concentration
in the residual carcass is somewhat higher in the latter case. Following
both oral and intravenous administration, most of the dose was excreted
unchanged as AE 0317309. Hydroxymethyl AE 0317309, desmethyl AE 0317309,
and AE B197555 were observed as minor metabolites in the urine and
feces. Following oral dosing, approximately 70% of the radioactivity was
excreted in the urine and 30% in the feces by 48 or 52 h.

This metabolism study in the rat is classified **Acceptable/guideline**
and satisfies the Tier 1 guideline requirement for a metabolism study
\[OPPTS 870.7485, OECD 417\] in rats.

**A.3.9 Special/Mechanistic Studies**

In an *in vivo* study (**MRID 46801922**), 5 Crl:CD(SD)BR rats, 5 Brown
Norway rats (BN/Crl BR), and 5 Crl:CD-1(ICR)BR mice/sex (6 weeks old)
were administered 0%, 2%, or 5% L-tyrosine (batch# 68160-123) in the
diet for 14 days (equivalent to 0/0, 2240/1900, or 5600/4750 mg/kg
bw/day for SD rats; 0/0, 2443/2182, or 6107/5455 mg/kg bw/day for Brown
Norway rats; and 0/0, 4000/4800, or 10000/12000 mg/kg bw/day for mice,
respectively \[M/F\]). The study was designed to determine the relative
sensitivities of SD rats, Brown Norway rats, and CD-1 mice to the
development of corneal lesions after consuming diet supplemented with
tyrosine. Clinical signs and mortality were monitored daily. Body
weights and food consumption were measured weekly. Ophthalmoscopic
examinations were reported for study days 2, 3, 7, 8, and 14. Blood was
collected on study day 15 prior to necropsy for determination of plasma
tyrosine concentration. Animals were sacrificed by exsanguination under
deep anesthesia and subjected to a gross necropsy. Histological sections
of the eyes of selected animals were prepared. Plasma samples from all
male rats, control and high-dose female SD rats, and control and
high-dose male mice were analyzed for tyrosine concentrations.

There were no treatment-related effects on mortality, body weight, or
food consumption or at necropsy. Treatment-related clinical signs in SD
rats at 5% tyrosine included dark urine in all males in the second week
of the study and in 3 females on day 14 only. Corneal opacity was
observed in 1/5 male SD rats at 5% tyrosine. This same animal appeared
thin and showed slight ptosis and moderate piloerection from Days 10 and
13, respectively. At ophthalmoscopic examination, all male SD rats at 5%
tyrosine showed "snow flake" corneal opacities by day 7 with progression
of the opacity over time. By day 14, two male SD rats also showed signs
of edema and vascularization of the cornea. In 3/5 SD males, congestion
of the iris was also evident. One male Brown Norway rat at 5% tyrosine
had a slight "snow flake" corneal opacity visible on day 14 only. Male
SD and Brown Norway rats showed a dose-related increase in mean plasma
tyrosine concentrations. One high-dose male Brown Norway rat, which was
observed on day 14 to have a corneal opacity, was found to have plasma
tyrosine concentrations markedly higher than those observed in the other
four male Brown Norway rats. Male CD-1 mice showed no increase in plasma
tyrosine concentrations at 5% dietary tyrosine. No changes in plasma
tyrosine concentrations were observed in females; however, plasma
tyrosine concentrations were only determined for control and high-dose
SD females rats. In 2/2 male SD rats at 5% tyrosine, treatment-related
microscopic findings included inflammatory reactions in the cornea,
edematous or swollen nuclear changes in the corneal epithelial cells,
and corneal vacuolation. In 1/2 Brown Norway rats treated with 5%
tyrosine, microscopic findings included inflammation of the anterior
chamber and cornea. A focal area of moderate vacuolation of the corneal
epithelial cells was observed in 1/2 male Brown Norway rats treated at
2%. This was not observed in 2/2 control Brown Norway males or in this
animal at ophthalmoscopic examination.

The study is classified as **Acceptable/Non-guideline** and is
acceptable for determining the relative sensitivities of SD rats, Brown
Norway rats, and CD-1 mice to the development of corneal lesions after
consuming diet supplemented with tyrosine.

In an *in vivo* study (**MRID 46801921**), 23 pregnant female SD
rats/dose group were administered vehicle alone (demineralized water) by
gavage from GD 6-20 or 10 µg/kg bw/day NTBC, 1433 mg/kg bw/day
L-tyrosine, or NTBC (10 µg/kg bw/day) + L-tyrosine (1424 mg/kg bw/day)
by gavage from GD 6-21. The study was designed to test the hypothesis
that maternal tyrosinemia has no effect on fetal skeletal development.
Morbidity, mortality, and clinical signs were monitored daily throughout
gestation. Body weights and food consumption were measured on gestation
days 6, 8, 10, 12, 14, 16, 18, and 21. Maternal plasma tyrosine
concentrations were measured at sacrifice (GD 21). At necropsy, the
reproductive tract and livers were weighed and the number of corpora
lutea, implantations, resorptions, and live and dead fetuses, and the
sex and individual body weights of the live fetuses were recorded.
Following external examination of all fetuses, a limited number of
skeletal endpoints were evaluated from approximately half the fetuses in
each litter.

There were no treatment-related effects on maternal mortality, clinical
signs, body weight, corrected body weight, food consumption, litter
parameters, or fetal external findings. Four of the 23 dams in the group
receiving tyrosine + NTBC showed minimal corneal opacity. Mean plasma
tyrosine concentrations at GD 21 were 5-, 8-, and 63-fold those of
controls in the L-tyrosine, NTBC, or L-tyrosine + NTBC groups,
respectively. Mean fetal body weight was reduced by 7% (P\<0.05) in male
and female fetuses whose dams were administered tyrosine + NTBC and was
slightly but statistically non-significantly reduced by 2-3% in fetuses
whose dams were administered NTBC alone. Increases (relative to
concurrent controls) in the incidences of the following skeletal
findings were observed in animals receiving tyrosine + NTBC: 7^th^
cervical centrum: unossified / normal cartilage; 6^th^ sternebra:
incomplete ossification / normal cartilage; 5th sternebra: unossified /
normal cartilage; Extra ossification point(s) (unilateral / bilateral)
on 14^th^ thoracic vertebra; Forepaws: 3^rd^ and/or 4^th^ proximal
phalanges: unossified / normal cartilage; 5^th^ metacarpal: incomplete
ossification / normal cartilage; 1^st^ metatarsal: unossified: normal
cartilage; and Less than 9 sacrocaudal vertebrae ossified / 9 first
sacrocaudal vertebrae: normal cartilage. Increases in the incidences of
the following skeletal findings were also observed in animals receiving
tyrosine alone and NTBC alone: 7^th^ cervical centrum: unossified /
normal cartilage; and Extra ossification point(s) (unilateral /
bilateral) on 14^th^ thoracic vertebra. Because historical control data
were not submitted and statistical analysis was not performed, the
increased incidences in each of these groups were considered
treatment-related.

The study is classified as **Acceptable/Non-guideline** and is
acceptable for demonstrating an association between increased maternal
blood tyrosine concentrations, fetal skeletal anomalies, and decreased
fetal body weight.

In an *in vitro* study (**MRID 46801920**), mouse, rat, rabbit, dog, and
human Liverbeads^TM^ (immobilized hepatocytes) were incubated with
buffer, buffer + NTBC (30 µM), buffer + tyrosine (550 µM), or buffer +
tyrosine (550 µM) + NTBC (30 µM) for 0, 2, or 4 h at 37°C. The study was
designed to test the hypothesis that species differences exist in the
production of HPLA, a downstream product of tyrosine catabolism, by
hepatocytes incubated with NTBC, a known inhibitor of the liver enzyme
4-hydroxyphenylpyruvate dioxygenase (4-HPPD). One experiment consisted
of incubation of Liverbeads^TM^ for one species on one 12-well plate.
Experiments were performed in duplicate at each time point. Following
incubation, Liverbeads™ preparations were dissolved, hepatocytes were
sonicated, and the suspension was transferred to vials for storage at
-80°C. Concentrations of L-tyrosine and of *p*-hydroxyphenyl lactic acid
(HPLA) were then determined by HPLC analysis.

Baseline HPLA concentrations (µg/mg protein) were below the limit of
quantitation (LOQ) at each time point for all species except mouse. HPLA
concentrations were increased in mice and human hepatocytes at 2 and 4 h
following incubation with NTBC. HPLA concentrations returned to baseline
levels when hepatocytes were exposed to basal medium supplemented with
tyrosine. When Liverbeads^TM^ were incubated with tyrosine and NTBC,
HPLA concentrations were increased at 2 h in rat, mouse, and human and
at 4 h in all species except dog. Mean tyrosine concentrations in mouse
hepatocytes incubated with L-tyrosine alone were slightly lower than
concentrations in hepatocytes measured in the other species tested
(Appendix 1). Mean tyrosine concentrations in mouse hepatocytes
incubated with L-tyrosine + NTBC were increased over those in mouse
hepatocytes incubated with L-tyrosine alone (Appendix 1). The results
suggest that under basal conditions more HPLA is formed in mouse
hepatocytes than in hepatocytes of the other tested species and that
inhibition of HPPD by NTBC leads to increased concentrations of HPLA in
mouse hepatocytes and detectable concentrations of HPLA in human
hepatocytes. The results also suggest that HPLA is formed in hepatocytes
of all tested species, except dog, under conditions of increased
tyrosine concentration and inhibition of HPPD by NTBC.

The study is classified as **Acceptable/Non-guideline** and is
acceptable for assessing the species differences in the production of
the tyrosine metabolite HPLA following incubation of hepatocytes with
NTBC.

In a comparative feeding study (**MRID 46801903**), 5 male Beagle
dogs/group were administered 18000 ppm AE 0317309 (batch Op. 1-4) mixed
with either dry feed (300g Purina Certified Canine Diet Etts 5006-3) or
wet feed (300g Purina Certified Canine Diet 5007 meal + 450 mL tap
water) for 1.5 hrs/day for 16 days. Untreated control groups were not
included in the study. The study was designed to determine if
administration of treated feed with water affects the blood and urinary
concentrations of AE 0317309 relative to the blood and urinary
concentrations of AE0317309 following administration of treated dry
feed. Test substance intake was 318 mg/kg bw/day on days 1-7 and 479
mg/kg bw/day on days 8-16 in the dry feed group and 272 mg/kg bw/day on
days 1-7 and 388 mg/kg bw/day on days 8-16 in the wet feed group.
Animals were examined for clinical signs of toxicity twice daily. Body
weights were measured on study days 0, 7, and 16, and food consumption
was measured on a daily basis. Blood urea nitrogen and creatinine, as
well as standard urinalysis parameters, were measured pre-test, and on
study days 6 and 14. Urine was also collected at 2, 4, 6, 8, 12, and 24
h after the last feeding on day 15 for measurement of urinary AE 0317309
concentration. Blood was collected at 2, 4, and 6 h after the last
feeding on day 15 for measurement of plasma AE 0317309 concentration. On
study day 16, the animals were sacrificed and subjected to a gross
necropsy of the urinary tract with kidney weight measurement.

No mortalities were observed during the study, and there was no
difference in food consumption or kidney weight between the wet-feed or
the dry-feed group. Treatment-related clinical signs were limited to red
urine in 2/5 dogs of the dry-feed group on or after day 7. A tan
substance was noted in the feces of all wet-feed dogs. Mean body weight,
relative to day 0, was decreased by 4% (day 7) and 5% (day 16) in the
dry-feed group and by 6% (day 7) and 9% (day 16) in the wet-feed group.
On days 6 and 14, blood urea nitrogen (BUN) levels were increased 67-87%
over pre-test values (15 mg/dl) in the dry-feed group and were more than
double pre-test values (11 mg/dl) in the wet-feed group. Blood was
observed in the urine in both dietary groups, albeit to a greater extent
in the dry-feed group. Urinary calculi were observed in 2/5 dogs in the
dry-feed group, and the urinary bladders of these animals showed
moderate thickening. These findings were not observed in any of the dogs
in the wet-feed group. Plasma concentrations of test substance in the
dry-feed group were increased by 52% and 64% over those in the wet-feed
group at 2 and 4 hrs. post feeding, but were similar by 6 hrs. post
feeding. Urine concentrations of test substance in the dry-feed group
were more than double those in the wet-feed group at 12 hrs. post
feeding, but were similar by 24 hrs. post dosing. The results of the
study are inconclusive, since test substance intake was 20% higher in
dogs receiving dry feed than in those receiving wet feed.

The study is classified as **Acceptable/Non-guideline** and is
acceptable for assessing the general differences in toxicological effect
between dry feed and wet feed treated with AE 0317309 in dogs.

**Benzoic acid metabolite**

3100. **90-Day Oral Toxicity - Rat (2)**

In a **28-day oral toxicity** study (MRID 43904813), RPA 203328 (99.7%
w/w ai, batch DA 938) was administered to 10 Sprague Dawley
rats/sex/dose in the diet at dose levels of 0, 150, 500, 5000, or 15000
ppm (equal to 0/0, 11.1/12.7, 37.6/42.7, 377/421, and 1118/1269 mg/kg
bw/day in males/females).

There were no compound-related effects on mortality, clinical signs,
body weight, food consumption, hematology, clinical chemistry,
ophthalmology, organ weights, or gross and histological pathology. Mean
urinary pH was reduced in males at 15000 ppm (6.5, P\<0.01 vs. 7.28 in
controls). In the absence of corroborating evidence of toxicity in any
other parameter, the finding was not considered toxicologically
significant.

**The LOAEL was not observed. The NOAEL is 15000 ppm (1118/1269
mg/kg/day \[M/F\]).**

This 28-day oral toxicity study in the rat is **Acceptable
(non-guideline)** as a range-finding study and does not satisfy the
guideline requirement for a 90-day oral toxicity study (OPPTS 870.3100;
OECD 408) in rodents.

In a **90-day oral toxicity** study (MRID 45655903), RPA 203328 (99%
a.i, batch \# NMI874) was administered to 10 Sprague Dawley
rats/sex/dose in the diet at dose levels of 0, 1200, 4800, or 12000 ppm
(equivalent to 0, 73.2/93.1, 306/371, or 769/952 mg/kg bw/day in
males/females, respectively).

There were no compound-related effects on mortality, clinical signs
(including reflexes), ophthalmology, body weight, food consumption,
hematology, clinical chemistry, urinalysis, organ weights, or gross and
histologic pathology. Urinary pH was slightly reduced (P\<0.01) at the
mid and high doses (5.45 vs. 6.11 in controls); however, the findings
were not considered toxicologically significant in the absence of
corroborating evidence of toxicity in any other measure. **The LOAEL was
not observed. The NOAEL is 12000 ppm (769/952 mg/kg/day in
males/females).**

This 90-day oral toxicity study in the rat is **Acceptable (guideline)**
and satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3100; OECD 408) in rodents.

**870.3700 Prenatal Developmental Toxicity Study - Rat**

In a developmental toxicity study (MRID 45655906), RPA 203328 (99% a.i,
batch \# NMI874) was administered to 25 Sprague Dawley rats/dose by
gavage in 0.5% aqueous methylcellulose at dose levels of 0, 75, 250, or
750 mg/kg bw/day from days 6 through 20 of gestation.

There were no treatment-related effects on survival or cesarean
parameters. An increased incidence of salivation was observed at 250
(6/25) and 750 mg/kg/day (18/25). This finding was associated with red
nasal discharge shortly after treatment in 3 animals at 750 mg/kg. Both
salivation and nasal discharge were resolved within approximately one
hour after treatment. Piloerection was also observed around the time of
treatment in 2/25 and 3/25 dams at 250 and 750 mg/kg/day, respectively.
Piloerection was associated with reduced motor activity in 1 animal at
750 mg/kg. Decreases (P\<0.01) in body weight gain were observed from GD
8-10 at 750 mg/kg (65%) and from GD 10-14 at ≥250 mg/kg (26%). Mean
cumulative body weight gain corrected for gravid uterine weight was
reduced by 31% and 37% (P\<0.01) at 250 and 750 mg/kg, respectively.
Food consumption was decreased throughout the treatment period by ≤15%
(P\<0.01) at ≥250 mg/kg.

**The maternal LOAEL is 250 mg/kg bw/day, based on clinical signs
(salivation, piloerection, red nasal discharge around time of
treatment), decreased body weight gain, and decreased food consumption.
The maternal NOAEL is 75 mg/kg bw/day.**

No treatment-related effects were observed on cesarean parameters or
external, visceral, or skeletal observations.

**The developmental LOAEL was not observed. The developmental NOAEL is
750 mg/kg bw/day.**

The developmental toxicity study in the rat is classified **Acceptable
(guideline)** and satisfies the guideline requirement for a
developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat.

[]{#__RefHeading___Toc170186485 .anchor}**Appendix B. Metabolism
Assessment**

+------+----+------+------------------+------------------+------------+
| **T  |    |      |                  |                  |            |
| able |    |      |                  |                  |            |
| B.2. |    |      |                  |                  |            |
| Tab  |    |      |                  |                  |            |
| ular |    |      |                  |                  |            |
| Sum  |    |      |                  |                  |            |
| mary |    |      |                  |                  |            |
| of   |    |      |                  |                  |            |
| Met  |    |      |                  |                  |            |
| abol |    |      |                  |                  |            |
| ites |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| D    |    |      |                  |                  |            |
| egra |    |      |                  |                  |            |
| date |    |      |                  |                  |            |
| s**. |    |      |                  |                  |            |
+======+====+======+==================+==================+============+
| **   | *  |      | **Percent TRR    |                  | **S        |
| Chem | *C |      | (PPM) ^1^**      |                  | tructure** |
| ical | om |      |                  |                  |            |
| Na   | mo |      |                  |                  |            |
| me** | di |      |                  |                  |            |
|      | ty |      |                  |                  |            |
|      | ** |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    |      | **Matrices -     | **Matrices -     |            |
|      |    |      | Major Residue    | Minor Residue    |            |
|      |    |      | \>10%TRR)**      | (\<10%TRR)**     |            |
+------+----+------+------------------+------------------+------------+
| P    | W  | Fo   | *Phenyl label    | *Phenyl label    | ![](media  |
| yras | he | rage | (wos) 28.7%      | (ws) 7.3% (0.18  | /image5.wm |
| ulfo | at |      | (0.71 ppm)*      | ppm)*            | f){width=" |
| tole |    |      |                  |                  | 1.41736111 |
| (AE  |    |      |                  |                  | 1111111in" |
| 0317 |    |      |                  |                  | height="0. |
| 309) |    |      |                  |                  | 9472222222 |
|      |    |      |                  |                  | 222222in"} |
+------+----+------+------------------+------------------+------------+
|      |    | Hay  | *Phenyl label    | *Phenyl label    |            |
|      |    |      | (wos) 12.1%      | (ws) 4.4% (0.14  |            |
|      |    |      | (0.37 ppm)*      | ppm)*            |            |
+------+----+------+------------------+------------------+------------+
|      |    | S    |                  | *Phenyl label    |            |
|      |    | traw |                  | (ws) 4.6% (0.13  |            |
|      |    |      |                  | ppm)*            |            |
|      |    |      |                  |                  |            |
|      |    |      |                  | *Phenyl label    |            |
|      |    |      |                  | (wos) 7.5% (0.21 |            |
|      |    |      |                  | ppm)*            |            |
+------+----+------+------------------+------------------+------------+
|      | La | Mu   | Phenyl label     |                  |            |
|      | yi | scle | 95.3% (0.036     |                  |            |
|      | ng |      | ppm)             |                  |            |
|      | H  |      |                  |                  |            |
|      | en |      | Pyrazole label   |                  |            |
|      |    |      | 92.9% (0.018     |                  |            |
|      |    |      | ppm)             |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | Fat  | Phenyl label     |                  |            |
|      |    |      | 97.1% (0.064     |                  |            |
|      |    |      | ppm)             |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | Pyrazole label   |                  |            |
|      |    |      | 97.7% (0.014     |                  |            |
|      |    |      | ppm)             |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | L    | Phenyl label     |                  |            |
|      |    | iver | 93.3% (1.456     |                  |            |
|      |    |      | ppm)             |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | Pyrazole label   |                  |            |
|      |    |      | 94.6% (1.215     |                  |            |
|      |    |      | ppm)             |                  |            |
+------+----+------+------------------+------------------+------------+
|      | L  | Mu   | Phenyl label     |                  |            |
|      | ac | scle | 80.2% (0.008     |                  |            |
|      | ta |      | ppm)             |                  |            |
|      | ti |      |                  |                  |            |
|      | ng |      |                  |                  |            |
|      | Go |      |                  |                  |            |
|      | at |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | Ki   | Phenyl label     |                  |            |
|      |    | dney | 99.6% (0.532     |                  |            |
|      |    |      | ppm)             |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | Pyrazole label   |                  |            |
|      |    |      | 92.4% (0.249     |                  |            |
|      |    |      | ppm)             |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | L    | Phenyl label     |                  |            |
|      |    | iver | 95.5% (1.411     |                  |            |
|      |    |      | ppm)             |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | Pyrazole label   |                  |            |
|      |    |      | 93.3% (1.603     |                  |            |
|      |    |      | ppm)             |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | Milk | Phenyl label     |                  |            |
|      |    |      | 82.7% (0.014     |                  |            |
|      |    |      | ppm)             |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | Pyrazole label   |                  |            |
|      |    |      | 38.8% (0.017     |                  |            |
|      |    |      | ppm)             |                  |            |
+------+----+------+------------------+------------------+------------+
|      | Ro | 120  |                  | Phenyl label     |            |
|      | ta | -DAT |                  | 0.9% (\<0.001    |            |
|      | ti | g    |                  | ppm)             |            |
|      | on | rain |                  |                  |            |
|      | al |      |                  |                  |            |
|      | C  |      |                  |                  |            |
|      | ro |      |                  |                  |            |
|      | ps |      |                  |                  |            |
|      | (  |      |                  |                  |            |
|      | Wh |      |                  |                  |            |
|      | ea |      |                  |                  |            |
|      | t) |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | 301  |                  | Phenyl label 2%  |            |
|      |    | -DAT |                  | (0.001 ppm)      |            |
|      |    | hay  |                  |                  |            |
+------+----+------+------------------+------------------+------------+

+------+----+------+------------------+------------------+------------+
| **T  |    |      |                  |                  |            |
| able |    |      |                  |                  |            |
| B.2. |    |      |                  |                  |            |
| Tab  |    |      |                  |                  |            |
| ular |    |      |                  |                  |            |
| Sum  |    |      |                  |                  |            |
| mary |    |      |                  |                  |            |
| of   |    |      |                  |                  |            |
| Met  |    |      |                  |                  |            |
| abol |    |      |                  |                  |            |
| ites |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| D    |    |      |                  |                  |            |
| egra |    |      |                  |                  |            |
| date |    |      |                  |                  |            |
| s**. |    |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+
| **   | *  |      | **Percent TRR    |                  | **S        |
| Chem | *C |      | (PPM) ^1^**      |                  | tructure** |
| ical | om |      |                  |                  |            |
| Na   | mo |      |                  |                  |            |
| me** | di |      |                  |                  |            |
|      | ty |      |                  |                  |            |
|      | ** |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    |      | **Matrices -     | **Matrices -     |            |
|      |    |      | Major Residue    | Minor Residue    |            |
|      |    |      | \>10%TRR)**      | (\<10%TRR)**     |            |
+------+----+------+------------------+------------------+------------+
| P    | W  | Fo   | Phenyl label     |                  | ![](media/ |
| yras | he | rage | 26.0% (0.119     |                  | image6.wmf |
| ulfo | at |      | ppm)             |                  | ){width="1 |
| tole |    |      |                  |                  | .041666666 |
| ben  |    |      | *Phenyl label    |                  | 6666667in" |
| zoic |    |      | (ws) 16.3% (0.39 |                  | height="0. |
| acid |    |      | ppm)*            |                  | 8513888888 |
|      |    |      |                  |                  | 888889in"} |
| (AE  |    |      | *Phenyl label    |                  |            |
| B197 |    |      | (wos) 20.1%      |                  |            |
| 555) |    |      | (0.49 ppm)*      |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | Hay  | Phenyl label     |                  |            |
|      |    |      | 60.8% (0.11 ppm) |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | *Phenyl label    |                  |            |
|      |    |      | (ws) 24.9% (0.78 |                  |            |
|      |    |      | ppm)*            |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | *Phenyl label    |                  |            |
|      |    |      | (wos) 33.6%      |                  |            |
|      |    |      | (1.06 ppm)*      |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | S    | Phenyl label     |                  |            |
|      |    | traw | 66.0% (0.36 ppm) |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | *Phenyl label    |                  |            |
|      |    |      | (ws) 30.5% (0.88 |                  |            |
|      |    |      | ppm)*            |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | *Phenyl label    |                  |            |
|      |    |      | (wos) 37.2%      |                  |            |
|      |    |      | (1.04 ppm)*      |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | G    | Phenyl label     |                  |            |
|      |    | rain | 89.5% (0.27 ppm) |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | *Phenyl label    |                  |            |
|      |    |      | (ws) 97.6% (0.15 |                  |            |
|      |    |      | ppm)*            |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | *Phenyl label    |                  |            |
|      |    |      | (wos) 97.7%      |                  |            |
|      |    |      | (0.23 ppm)*      |                  |            |
+------+----+------+------------------+------------------+------------+
|      | Ro | 120  | Phenyl label     |                  |            |
|      | ta | -DAT | 90.2% (0.024     |                  |            |
|      | ti | fo   | ppm)             |                  |            |
|      | on | rage |                  |                  |            |
|      | al |      |                  |                  |            |
|      | C  |      |                  |                  |            |
|      | ro |      |                  |                  |            |
|      | ps |      |                  |                  |            |
|      | (  |      |                  |                  |            |
|      | Wh |      |                  |                  |            |
|      | ea |      |                  |                  |            |
|      | t) |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | 120  | Phenyl label     | Pyrazole label   |            |
|      |    | -DAT | 80.2% (0.049     | 3% (\<0.001 ppm) |            |
|      |    | hay  | ppm)             |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | 120  | Phenyl label     | Pyrazole label   |            |
|      |    | -DAT | 49.7% (0.012     | 9% (0.002 ppm)   |            |
|      |    | s    | ppm)             |                  |            |
|      |    | traw |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | 120  | Phenyl label     |                  |            |
|      |    | -DAT | 89.4% (0.028     |                  |            |
|      |    | g    | ppm)             |                  |            |
|      |    | rain |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | 301  | Phenyl label     |                  |            |
|      |    | -DAT | 91.3% (0.078     |                  |            |
|      |    | fo   | ppm)             |                  |            |
|      |    | rage |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | 301  | Phenyl label     |                  |            |
|      |    | -DAT | 58.3% (0.021     |                  |            |
|      |    | hay  | ppm)             |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | 301  | Phenyl label     |                  |            |
|      |    | -DAT | 27.0% (0.004     |                  |            |
|      |    | s    | ppm)             |                  |            |
|      |    | traw |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | 301  | Phenyl label     |                  |            |
|      |    | -DAT | 77.0% (0.008     |                  |            |
|      |    | g    | ppm)             |                  |            |
|      |    | rain |                  |                  |            |
+------+----+------+------------------+------------------+------------+

+------+----+------+------------------+------------------+------------+
| **T  |    |      |                  |                  |            |
| able |    |      |                  |                  |            |
| B.2. |    |      |                  |                  |            |
| Tab  |    |      |                  |                  |            |
| ular |    |      |                  |                  |            |
| Sum  |    |      |                  |                  |            |
| mary |    |      |                  |                  |            |
| of   |    |      |                  |                  |            |
| Met  |    |      |                  |                  |            |
| abol |    |      |                  |                  |            |
| ites |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| D    |    |      |                  |                  |            |
| egra |    |      |                  |                  |            |
| date |    |      |                  |                  |            |
| s**. |    |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+
| **   | *  |      | **Percent TRR    |                  | **S        |
| Chem | *C |      | (PPM) ^1^**      |                  | tructure** |
| ical | om |      |                  |                  |            |
| Na   | mo |      |                  |                  |            |
| me** | di |      |                  |                  |            |
|      | ty |      |                  |                  |            |
|      | ** |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    |      | **Matrices -     | **Matrices -     |            |
|      |    |      | Major Residue    | Minor Residue    |            |
|      |    |      | \>10%TRR)**      | (\<10%TRR)**     |            |
+------+----+------+------------------+------------------+------------+
| Pyr  | W  | Fo   | Phenyl label     |                  | ![](media/ |
| asul | he | rage | 34.2% (0.152     |                  | image7.wmf |
| foto | at |      | ppm)             |                  | ){width="1 |
| le-d |    |      |                  |                  | .415972222 |
| esme |    |      | Pyrazole label   |                  | 2222222in" |
| thyl |    |      | 43.4% (0.202     |                  | height="0  |
| -*O* |    |      | ppm)             |                  | .93125in"} |
| g    |    |      |                  |                  |            |
| luco |    |      | *Phenyl label    |                  |            |
| side |    |      | (ws) 43.5% (1.04 |                  |            |
|      |    |      | ppm)*            |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | *Phenyl label    |                  |            |
|      |    |      | (wos) 30.2%      |                  |            |
|      |    |      | (0.74 ppm)*      |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | Hay  | Phenyl label     |                  |            |
|      |    |      | 10.4% (0.02 ppm) |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | Pyrazole label   |                  |            |
|      |    |      | 25.4% (0.015     |                  |            |
|      |    |      | ppm)             |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | *Phenyl label    |                  |            |
|      |    |      | (ws) 36.7% (1.16 |                  |            |
|      |    |      | ppm)*            |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | *Phenyl label    |                  |            |
|      |    |      | (wos) 25.7%      |                  |            |
|      |    |      | (0.80 ppm)*      |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | S    | Pyrazole label   | Phenyl label     |            |
|      |    | traw | 21.7% (0.08 ppm) | 5.1% (0.03 ppm)  |            |
|      |    |      |                  |                  |            |
|      |    |      | *Phenyl label    |                  |            |
|      |    |      | (ws) 27.9% (0.81 |                  |            |
|      |    |      | ppm)*            |                  |            |
|      |    |      |                  |                  |            |
|      |    |      | *Phenyl label    |                  |            |
|      |    |      | (wos) 19.6%      |                  |            |
|      |    |      | (0.55 ppm)*      |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | G    |                  | Pyrazole label   |            |
|      |    | rain |                  | 0.7% (\<0.001    |            |
|      |    |      |                  | ppm)             |            |
+------+----+------+------------------+------------------+------------+
| Pyr  | La | Mu   |                  | Phenyl label     | ![](media  |
| asul | yi | scle |                  | 2.2% (0.001 ppm) | /image3.wm |
| foto | ng |      |                  |                  | f){width=" |
| le-d | H  |      |                  | Pyrazole label   | 1.41736111 |
| esme | en |      |                  | 2.2% (\<0.001    | 1111111in" |
| thyl |    |      |                  | ppm)             | height="   |
|      |    |      |                  |                  | 1.0875in"} |
| (AE  |    |      |                  |                  |            |
| 1073 |    |      |                  |                  |            |
| 910) |    |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | Fat  |                  | Phenyl label     |            |
|      |    |      |                  | 1.8% (0.001 ppm) |            |
+------+----+------+------------------+------------------+------------+
|      |    | L    |                  | Phenyl label     |            |
|      |    | iver |                  | 6.5% (0.101 ppm) |            |
|      |    |      |                  |                  |            |
|      |    |      |                  | Pyrazole label   |            |
|      |    |      |                  | 4.8% (0.062 ppm) |            |
+------+----+------+------------------+------------------+------------+
|      |    | L    | Pyrazole label   |                  |            |
|      |    | iver | 1.4% (0.025 ppm) |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    | Milk | Phenyl label     |                  |            |
|      |    |      | 11.7% (0.002     |                  |            |
|      |    |      | ppm)             |                  |            |
+------+----+------+------------------+------------------+------------+
| Pyr  | L  | Mu   | Phenyl label     |                  | ![](media/ |
| asul | ac | scle | 8.3% (0.001 ppm) |                  | image8.wmf |
| foto | ta |      |                  |                  | ){width="1 |
| le-h | ti |      |                  |                  | .541666666 |
| ydro | ng |      |                  |                  | 6666667in" |
| xyme | Go |      |                  |                  | height="0. |
| thyl | at |      |                  |                  | 9881944444 |
|      |    |      |                  |                  | 444445in"} |
+------+----+------+------------------+------------------+------------+
|      |    | Milk | Phenyl label     |                  |            |
|      |    |      | 4.4% (0.001 ppm) |                  |            |
+------+----+------+------------------+------------------+------------+

+------+----+------+------------------+------------------+------------+
| **T  |    |      |                  |                  |            |
| able |    |      |                  |                  |            |
| B.2. |    |      |                  |                  |            |
| Tab  |    |      |                  |                  |            |
| ular |    |      |                  |                  |            |
| Sum  |    |      |                  |                  |            |
| mary |    |      |                  |                  |            |
| of   |    |      |                  |                  |            |
| Met  |    |      |                  |                  |            |
| abol |    |      |                  |                  |            |
| ites |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| D    |    |      |                  |                  |            |
| egra |    |      |                  |                  |            |
| date |    |      |                  |                  |            |
| s**. |    |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+
| **   | *  |      | **Percent TRR    |                  | **S        |
| Chem | *C |      | (PPM) ^1^**      |                  | tructure** |
| ical | om |      |                  |                  |            |
| Na   | mo |      |                  |                  |            |
| me** | di |      |                  |                  |            |
|      | ty |      |                  |                  |            |
|      | ** |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+
|      |    |      | **Matrices -     | **Matrices -     |            |
|      |    |      | Major Residue    | Minor Residue    |            |
|      |    |      | \>10%TRR)**      | (\<10%TRR)**     |            |
+------+----+------+------------------+------------------+------------+
| Py   | W  | Fo   |                  | *Phenyl label    | ![](media/ |
| rasu | he | rage |                  | (ws) 7.8% (0.19  | image9.wmf |
| lfot | at |      |                  | ppm)*            | ){width="1 |
| ole- |    |      |                  |                  | .296527777 |
| sulf |    |      |                  |                  | 7777777in" |
| inyl |    |      |                  |                  | height="1. |
| -lac |    |      |                  |                  | 3965277777 |
| tate |    |      |                  |                  | 777778in"} |
+------+----+------+------------------+------------------+------------+
|      |    | Hay  |                  | *Phenyl label    |            |
|      |    |      |                  | (ws) 8.9% (0.28  |            |
|      |    |      |                  | ppm)*            |            |
+------+----+------+------------------+------------------+------------+
|      |    | S    |                  | *Phenyl label    |            |
|      |    | traw |                  | (ws) 9.6% (0.28  |            |
|      |    |      |                  | ppm)*            |            |
+------+----+------+------------------+------------------+------------+
|      |    | G    |                  |                  |            |
|      |    | rain |                  |                  |            |
+------+----+------+------------------+------------------+------------+
| Wh   |    |      |                  |                  |            |
| eat: |    |      |                  |                  |            |
| MRID |    |      |                  |                  |            |
| No.  |    |      |                  |                  |            |
| 4680 |    |      |                  |                  |            |
| 1748 |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 4    |    |      |                  |                  |            |
| 6801 |    |      |                  |                  |            |
| 748; |    |      |                  |                  |            |
| 0    |    |      |                  |                  |            |
| .089 |    |      |                  |                  |            |
| lb   |    |      |                  |                  |            |
| ai/A |    |      |                  |                  |            |
| (100 |    |      |                  |                  |            |
| g    |    |      |                  |                  |            |
| ai/  |    |      |                  |                  |            |
| ha); |    |      |                  |                  |            |
| 2x   |    |      |                  |                  |            |
| the  |    |      |                  |                  |            |
| max  |    |      |                  |                  |            |
| imum |    |      |                  |                  |            |
| prop |    |      |                  |                  |            |
| osed |    |      |                  |                  |            |
| seas |    |      |                  |                  |            |
| onal |    |      |                  |                  |            |
| rate |    |      |                  |                  |            |
| for  |    |      |                  |                  |            |
| ce   |    |      |                  |                  |            |
| real |    |      |                  |                  |            |
| gra  |    |      |                  |                  |            |
| ins; |    |      |                  |                  |            |
| PHIs |    |      |                  |                  |            |
| = 0  |    |      |                  |                  |            |
| d    |    |      |                  |                  |            |
| ays, |    |      |                  |                  |            |
| 2    |    |      |                  |                  |            |
| 7-28 |    |      |                  |                  |            |
| days |    |      |                  |                  |            |
| (    |    |      |                  |                  |            |
| fora |    |      |                  |                  |            |
| ge), |    |      |                  |                  |            |
| 4    |    |      |                  |                  |            |
| 9-50 |    |      |                  |                  |            |
| days |    |      |                  |                  |            |
| (h   |    |      |                  |                  |            |
| ay), |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 8    |    |      |                  |                  |            |
| 9-90 |    |      |                  |                  |            |
| days |    |      |                  |                  |            |
| (h   |    |      |                  |                  |            |
| arve |    |      |                  |                  |            |
| st). |    |      |                  |                  |            |
|      |    |      |                  |                  |            |
| *Wh  |    |      |                  |                  |            |
| eat: |    |      |                  |                  |            |
| MRID |    |      |                  |                  |            |
| No.  |    |      |                  |                  |            |
| 4    |    |      |                  |                  |            |
| 6801 |    |      |                  |                  |            |
| 801; |    |      |                  |                  |            |
| 0    |    |      |                  |                  |            |
| .087 |    |      |                  |                  |            |
| lb   |    |      |                  |                  |            |
| ai/A |    |      |                  |                  |            |
| \[98 |    |      |                  |                  |            |
| g    |    |      |                  |                  |            |
| ai   |    |      |                  |                  |            |
| /ha; |    |      |                  |                  |            |
| p    |    |      |                  |                  |            |
| heny |    |      |                  |                  |            |
| l-la |    |      |                  |                  |            |
| bel; |    |      |                  |                  |            |
| with |    |      |                  |                  |            |
| saf  |    |      |                  |                  |            |
| ener |    |      |                  |                  |            |
| (w   |    |      |                  |                  |            |
| s)\] |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 0    |    |      |                  |                  |            |
| .086 |    |      |                  |                  |            |
| lb   |    |      |                  |                  |            |
| ai/A |    |      |                  |                  |            |
| \[96 |    |      |                  |                  |            |
| g    |    |      |                  |                  |            |
| ai   |    |      |                  |                  |            |
| /ha; |    |      |                  |                  |            |
| p    |    |      |                  |                  |            |
| heny |    |      |                  |                  |            |
| l-la |    |      |                  |                  |            |
| bel; |    |      |                  |                  |            |
| wit  |    |      |                  |                  |            |
| hout |    |      |                  |                  |            |
| saf  |    |      |                  |                  |            |
| ener |    |      |                  |                  |            |
| (wos |    |      |                  |                  |            |
| )\]; |    |      |                  |                  |            |
| 2x   |    |      |                  |                  |            |
| max  |    |      |                  |                  |            |
| imum |    |      |                  |                  |            |
| prop |    |      |                  |                  |            |
| osed |    |      |                  |                  |            |
| seas |    |      |                  |                  |            |
| onal |    |      |                  |                  |            |
| rate |    |      |                  |                  |            |
| for  |    |      |                  |                  |            |
| ce   |    |      |                  |                  |            |
| real |    |      |                  |                  |            |
| gra  |    |      |                  |                  |            |
| ins; |    |      |                  |                  |            |
| PHI  |    |      |                  |                  |            |
| = 21 |    |      |                  |                  |            |
| days |    |      |                  |                  |            |
| (    |    |      |                  |                  |            |
| fora |    |      |                  |                  |            |
| ge), |    |      |                  |                  |            |
| 44   |    |      |                  |                  |            |
| days |    |      |                  |                  |            |
| (h   |    |      |                  |                  |            |
| ay), |    |      |                  |                  |            |
| 79   |    |      |                  |                  |            |
| days |    |      |                  |                  |            |
| (ha  |    |      |                  |                  |            |
| rves |    |      |                  |                  |            |
| t).* |    |      |                  |                  |            |
|      |    |      |                  |                  |            |
| Ro   |    |      |                  |                  |            |
| tati |    |      |                  |                  |            |
| onal |    |      |                  |                  |            |
| cr   |    |      |                  |                  |            |
| ops: |    |      |                  |                  |            |
| MRID |    |      |                  |                  |            |
| 4    |    |      |                  |                  |            |
| 6801 |    |      |                  |                  |            |
| 833; |    |      |                  |                  |            |
| 0    |    |      |                  |                  |            |
| .073 |    |      |                  |                  |            |
| lb   |    |      |                  |                  |            |
| ai/A |    |      |                  |                  |            |
| \[82 |    |      |                  |                  |            |
| g    |    |      |                  |                  |            |
| ai   |    |      |                  |                  |            |
| /ha; |    |      |                  |                  |            |
| phen |    |      |                  |                  |            |
| yl-l |    |      |                  |                  |            |
| abel |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| p    |    |      |                  |                  |            |
| yraz |    |      |                  |                  |            |
| ole- |    |      |                  |                  |            |
| labe |    |      |                  |                  |            |
| l\]; |    |      |                  |                  |            |
| 2.2x |    |      |                  |                  |            |
| (phe |    |      |                  |                  |            |
| nyl) |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 1.6x |    |      |                  |                  |            |
| (p   |    |      |                  |                  |            |
| yraz |    |      |                  |                  |            |
| ole) |    |      |                  |                  |            |
| max  |    |      |                  |                  |            |
| imum |    |      |                  |                  |            |
| prop |    |      |                  |                  |            |
| osed |    |      |                  |                  |            |
| seas |    |      |                  |                  |            |
| onal |    |      |                  |                  |            |
| rate |    |      |                  |                  |            |
| for  |    |      |                  |                  |            |
| ce   |    |      |                  |                  |            |
| real |    |      |                  |                  |            |
| gra  |    |      |                  |                  |            |
| ins; |    |      |                  |                  |            |
| PBI  |    |      |                  |                  |            |
| =    |    |      |                  |                  |            |
| 120  |    |      |                  |                  |            |
| days |    |      |                  |                  |            |
| (wh  |    |      |                  |                  |            |
| eat, |    |      |                  |                  |            |
| s    |    |      |                  |                  |            |
| wiss |    |      |                  |                  |            |
| ch   |    |      |                  |                  |            |
| ard, |    |      |                  |                  |            |
| turn |    |      |                  |                  |            |
| ips) |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 301  |    |      |                  |                  |            |
| days |    |      |                  |                  |            |
| (whe |    |      |                  |                  |            |
| at). |    |      |                  |                  |            |
|      |    |      |                  |                  |            |
| La   |    |      |                  |                  |            |
| ying |    |      |                  |                  |            |
| Hen: |    |      |                  |                  |            |
| MRID |    |      |                  |                  |            |
| Nos. |    |      |                  |                  |            |
| 4680 |    |      |                  |                  |            |
| 1802 |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 4    |    |      |                  |                  |            |
| 6801 |    |      |                  |                  |            |
| 803; |    |      |                  |                  |            |
| 8.6  |    |      |                  |                  |            |
| ppm  |    |      |                  |                  |            |
| (p   |    |      |                  |                  |            |
| heny |    |      |                  |                  |            |
| l-la |    |      |                  |                  |            |
| bel) |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 10.5 |    |      |                  |                  |            |
| ppm  |    |      |                  |                  |            |
| (    |    |      |                  |                  |            |
| pyra |    |      |                  |                  |            |
| zole |    |      |                  |                  |            |
| -lab |    |      |                  |                  |            |
| el); |    |      |                  |                  |            |
| 150x |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 180x |    |      |                  |                  |            |
| the  |    |      |                  |                  |            |
| MTDB |    |      |                  |                  |            |
| for  |    |      |                  |                  |            |
| poul |    |      |                  |                  |            |
| try, |    |      |                  |                  |            |
| r    |    |      |                  |                  |            |
| espe |    |      |                  |                  |            |
| ctiv |    |      |                  |                  |            |
| ely; |    |      |                  |                  |            |
| 14   |    |      |                  |                  |            |
| days |    |      |                  |                  |            |
| of   |    |      |                  |                  |            |
| dos  |    |      |                  |                  |            |
| ing; |    |      |                  |                  |            |
| \~30 |    |      |                  |                  |            |
| mi   |    |      |                  |                  |            |
| nute |    |      |                  |                  |            |
| PSI. |    |      |                  |                  |            |
|      |    |      |                  |                  |            |
| L    |    |      |                  |                  |            |
| acta |    |      |                  |                  |            |
| ting |    |      |                  |                  |            |
| G    |    |      |                  |                  |            |
| oat: |    |      |                  |                  |            |
| MRID |    |      |                  |                  |            |
| Nos. |    |      |                  |                  |            |
| 4680 |    |      |                  |                  |            |
| 1804 |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 4    |    |      |                  |                  |            |
| 6801 |    |      |                  |                  |            |
| 805; |    |      |                  |                  |            |
| 52.1 |    |      |                  |                  |            |
| ppm  |    |      |                  |                  |            |
| (p   |    |      |                  |                  |            |
| heny |    |      |                  |                  |            |
| l-la |    |      |                  |                  |            |
| bel) |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 28.1 |    |      |                  |                  |            |
| ppm  |    |      |                  |                  |            |
| (    |    |      |                  |                  |            |
| pyra |    |      |                  |                  |            |
| zole |    |      |                  |                  |            |
| -lab |    |      |                  |                  |            |
| el); |    |      |                  |                  |            |
| 130x |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 72x  |    |      |                  |                  |            |
| the  |    |      |                  |                  |            |
| MTDB |    |      |                  |                  |            |
| for  |    |      |                  |                  |            |
| beef |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| d    |    |      |                  |                  |            |
| airy |    |      |                  |                  |            |
| cat  |    |      |                  |                  |            |
| tle, |    |      |                  |                  |            |
| r    |    |      |                  |                  |            |
| espe |    |      |                  |                  |            |
| ctiv |    |      |                  |                  |            |
| ely; |    |      |                  |                  |            |
| 3    |    |      |                  |                  |            |
| days |    |      |                  |                  |            |
| of   |    |      |                  |                  |            |
| dos  |    |      |                  |                  |            |
| ing; |    |      |                  |                  |            |
| 24   |    |      |                  |                  |            |
| hour |    |      |                  |                  |            |
| PSI. |    |      |                  |                  |            |
|      |    |      |                  |                  |            |
| Rat  |    |      |                  |                  |            |
| Met  |    |      |                  |                  |            |
| abol |    |      |                  |                  |            |
| ism: |    |      |                  |                  |            |
| MRID |    |      |                  |                  |            |
| No.  |    |      |                  |                  |            |
| 4    |    |      |                  |                  |            |
| 6801 |    |      |                  |                  |            |
| 918; |    |      |                  |                  |            |
| si   |    |      |                  |                  |            |
| ngle |    |      |                  |                  |            |
| oral |    |      |                  |                  |            |
| dos  |    |      |                  |                  |            |
| es - |    |      |                  |                  |            |
| 10.0 |    |      |                  |                  |            |
| m    |    |      |                  |                  |            |
| g/kg |    |      |                  |                  |            |
| (p   |    |      |                  |                  |            |
| heny |    |      |                  |                  |            |
| l-la |    |      |                  |                  |            |
| bel) |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 9.88 |    |      |                  |                  |            |
| m    |    |      |                  |                  |            |
| g/kg |    |      |                  |                  |            |
| (    |    |      |                  |                  |            |
| pyra |    |      |                  |                  |            |
| zole |    |      |                  |                  |            |
| -lab |    |      |                  |                  |            |
| el); |    |      |                  |                  |            |
| int  |    |      |                  |                  |            |
| rave |    |      |                  |                  |            |
| nous |    |      |                  |                  |            |
| d    |    |      |                  |                  |            |
| oses |    |      |                  |                  |            |
| --   |    |      |                  |                  |            |
| 9.81 |    |      |                  |                  |            |
| m    |    |      |                  |                  |            |
| g/kg |    |      |                  |                  |            |
| (p   |    |      |                  |                  |            |
| heny |    |      |                  |                  |            |
| l-la |    |      |                  |                  |            |
| bel) |    |      |                  |                  |            |
| and  |    |      |                  |                  |            |
| 9.60 |    |      |                  |                  |            |
| m    |    |      |                  |                  |            |
| g/kg |    |      |                  |                  |            |
| (    |    |      |                  |                  |            |
| pyra |    |      |                  |                  |            |
| zole |    |      |                  |                  |            |
| -lab |    |      |                  |                  |            |
| el); |    |      |                  |                  |            |
| Wi   |    |      |                  |                  |            |
| star |    |      |                  |                  |            |
| Han  |    |      |                  |                  |            |
| over |    |      |                  |                  |            |
| rats |    |      |                  |                  |            |
+------+----+------+------------------+------------------+------------+

<table>
<colgroup>
<col style="width: 16%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="11"><strong>Table B.3. Environmental Fate Summary for
Pyrasulfotole.</strong></th>
</tr>
<tr class="odd">
<th rowspan="2"><strong>Degradate Name and Structure</strong></th>
<th colspan="8"><strong>Report % Applied Dose, PPB, T<sub>1/2</sub>,
Other Pertinent Information</strong></th>
<th rowspan="2"><p><strong>Monitoring Data</strong></p>
<p><strong>Available?</strong></p></th>
<th rowspan="2"><p><strong>Cleaned Up</strong></p>
<p><strong>By Drinking</strong></p>
<p><strong>Water Treatment?</strong></p></th>
</tr>
<tr class="header">
<th><strong>Aerobic Soil Metabolism</strong></th>
<th><strong>Aerobic Aquatic Metabolism</strong></th>
<th><strong>Field Dissipation</strong></th>
<th><strong>Hydrolysis</strong></th>
<th><p><strong>Soil</strong></p>
<p><strong>Photolysis</strong></p></th>
<th><strong>Aqueous Photolysis</strong></th>
<th><strong>Anaerobic Aquatic Metabolism</strong></th>
<th><strong>Anaerobic Soil Metabolism</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td rowspan="4"><p>Pyrasulfotole (AE 0317309; K-1196; K1267); Parent</p>
<p><img src="media/image5.wmf"
style="width:1.41736in;height:0.94722in" /></p></td>
<td>DT<sub>50</sub> = 5.8 d</td>
<td>Stable</td>
<td>DT<sub>50</sub> = 8.9 d</td>
<td>Stable</td>
<td>Stable</td>
<td>Stable</td>
<td>Stable</td>
<td>Stable</td>
<td rowspan="10">No national-scale monitoring data available.</td>
<td rowspan="10">No information available on drinking water treatment
effects on pyrasulfotole.</td>
</tr>
<tr class="even">
<td>DT<sub>50</sub>= 63 d</td>
<td></td>
<td>DT<sub>50</sub> = 5.7 d</td>
<td></td>
<td></td>
<td></td>
<td>Stable</td>
<td></td>
</tr>
<tr class="odd">
<td>DT<sub>50</sub> = 23 d</td>
<td></td>
<td>DT<sub>50</sub> = 5.7 d</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td>DT<sub>50</sub> = 9.2 – 18 d</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td rowspan="4"><p>Pryasulfotole-benzioc acid (RPA 203328)</p>
<p><img src="media/image6.wmf"
style="width:1.04167in;height:0.85139in" /></p></td>
<td>12</td>
<td>--</td>
<td>6.1 ppb</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>9.9</td>
</tr>
<tr class="even">
<td>3.8</td>
<td></td>
<td>14 ppb</td>
<td></td>
<td></td>
<td></td>
<td>--</td>
<td></td>
</tr>
<tr class="odd">
<td>9.3</td>
<td></td>
<td>3.9 ppb</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td>27-37 ppb</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Study MRID No(s).</td>
<td><p>46801709</p>
<p>46801710</p>
<p>46801711</p></td>
<td>46801713</td>
<td><p>46801716</p>
<p>46801717</p>
<p>46801718</p>
<p>46801719</p></td>
<td>46801705</td>
<td>46801707</td>
<td>46801706</td>
<td><p>46801714</p>
<p>46801715</p></td>
<td>46801712</td>
</tr>
<tr class="even">
<td>Study Characterization <sup>3</sup></td>
<td>Acceptable</td>
<td>Acceptable</td>
<td>Acceptable</td>
<td>Acceptable</td>
<td>Acceptable</td>
<td>Acceptable</td>
<td>Acceptable</td>
<td>Acceptable</td>
</tr>
</tbody>
</table>

1\. % of theoretically applied based on target application rate.

**Appendix C. Tolerance Summary Table for Pyrasulfotole**

+-----------------+---------+----------+------------------------------+
| **Table 14.     |         |          |                              |
| Tolerance       |         |          |                              |
| Summary for     |         |          |                              |
| P               |         |          |                              |
| yrasulfotole.** |         |          |                              |
+=================+=========+==========+==============================+
| **Commodity**   | **P     | **Rec    | **Comments**                 |
|                 | roposed | ommended |                              |
|                 | To      | T        | **(*correct commodity        |
|                 | lerance | olerance | definition*)**               |
|                 | (ppm)** | (ppm)**  |                              |
+-----------------+---------+----------+------------------------------+
| Wheat, grain    | 0.07    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Wheat, straw    | 0.25    | 0.20     |                              |
+-----------------+---------+----------+------------------------------+
| Wheat, forage   | 0.25    | 0.20     |                              |
+-----------------+---------+----------+------------------------------+
| Wheat, hay      | 0.8     | 0.80     |                              |
+-----------------+---------+----------+------------------------------+
| Wheat,          | 1.4     | 0.40     | *Aspirated grain fractions*  |
| aspirated grain |         |          |                              |
| fractions       |         |          |                              |
+-----------------+---------+----------+------------------------------+
| Oat, grain      | 0.07    | 0.08     |                              |
+-----------------+---------+----------+------------------------------+
| Oat, straw      | 0.25    | 0.20     |                              |
+-----------------+---------+----------+------------------------------+
| Oat, forage     | 0.25    | 0.10     |                              |
+-----------------+---------+----------+------------------------------+
| Oat, hay        | 0.8     | 0.50     |                              |
+-----------------+---------+----------+------------------------------+
| Barley, grain   | 0.07    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Barley, straw   | 0.25    | 0.20     |                              |
+-----------------+---------+----------+------------------------------+
| Barley, hay     | 0.8     | 0.30     |                              |
+-----------------+---------+----------+------------------------------+
| Triticale,      | 0.07    | \-       | Tolerance not required.      |
| grain           |         |          | Triticale is covered under   |
|                 |         |          | wheat, grain tolerance.      |
+-----------------+---------+----------+------------------------------+
| Rye, grain      | 0.07    | 0.02     | Tolerance translated from    |
|                 |         |          | wheat, grain.                |
+-----------------+---------+----------+------------------------------+
| Rye, straw      | 0.25    | 0.20     | Tolerance translated from    |
|                 |         |          | barley, straw; wheat, straw; |
|                 |         |          | and oat, straw.              |
+-----------------+---------+----------+------------------------------+
| Rye, forage     | 0.25    | 0.20     | Tolerance translated from    |
|                 |         |          | wheat, forage.               |
+-----------------+---------+----------+------------------------------+
| Milk            | 0.005   | 0.01     |                              |
+-----------------+---------+----------+------------------------------+
| Cattle, meat    | 0.01    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Cattle, fat     | 0.01    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Cattle, meat    | 0.3     | 0.06     | *Cattle, meat byproducts,    |
| byproducts      |         |          | except liver*                |
+-----------------+---------+----------+------------------------------+
| Cattle, liver   | \-      | 0.35     |                              |
+-----------------+---------+----------+------------------------------+
| Goat, meat      | 0.01    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Goat, fat       | 0.01    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Goat, meat      | 0.3     | 0.06     | *Goat, meat byproducts,      |
| byproducts      |         |          | except liver*                |
+-----------------+---------+----------+------------------------------+
| Goat, liver     | \-      | 0.35     |                              |
+-----------------+---------+----------+------------------------------+
| Hog, meat       | 0.01    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Hog, fat        | 0.01    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Hog, meat       | 0.3     | 0.02     |                              |
| byproducts      |         |          |                              |
+-----------------+---------+----------+------------------------------+
| Sheep, meat     | 0.01    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Sheep, fat      | 0.01    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Sheep, meat     | 0.3     | 0.06     | *Sheep, meat byproducts,     |
| byproducts      |         |          | except liver*                |
+-----------------+---------+----------+------------------------------+
| Sheep, liver    | \-      | 0.35     |                              |
+-----------------+---------+----------+------------------------------+
| Horse, meat     | 0.01    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Horse, fat      | 0.01    | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Horse, meat     | 0.3     | 0.06     | *Horse, meat byproducts,     |
| byproducts      |         |          | except liver*                |
+-----------------+---------+----------+------------------------------+
| Horse, liver    | \-      | 0.35     |                              |
+-----------------+---------+----------+------------------------------+
| Poultry, meat   | \-      | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Poultry, fat    | \-      | 0.02     |                              |
+-----------------+---------+----------+------------------------------+
| Poultry, meat   | \-      | 0.02     |                              |
| byproducts      |         |          |                              |
+-----------------+---------+----------+------------------------------+
| Eggs            | \-      | 0.02     |                              |
+-----------------+---------+----------+------------------------------+