Pyrasulfotole Human

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

 

MEMORANDUM

Date: 16-MAR-2011

SUBJECT: Pyrasulfotole: REVISED

3 Uses on Grain Sorghum and Grass Grown for Seed.

PC Code: 000692

Decision No.: 425581

Petition No.: 9F7680

Risk Assessment Type: Single Chemical/Aggregate

TXR No.: NA

MRID No.: NA

FROM: Allison Nowotarski, Biologist

Jennifer R. Tyler, Chemist

Anwar Y. Dunbar, Ph.D., Pharmacologist

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED

THROUGH: George F. Kramer, Ph.D., Branch Senior Chemist

Dana Vogel, Branch Chief 

RAB1/HED (7509P)

TO: Bethany Benbow/

Registration Division (7505P)

This Risk Assessment has been revised from the October 20, 2010 draft to modify language in 

the hazard characterization. Specifically,

were separated and better distuingshed

to better reflect the current endpoints.

strengthen the rationale for using a non

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 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from all registered 

and proposed uses of pyrasulfotole (

(methylsulfonyl)-4-(trifluoromethyl)phenyl]methanone

assessment of human risk resulting from the registered and proposed uses for pyrasulfotole are 

Human-Health Risk Assessment 

Page 1 of 39

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

REVISED Human-Health Risk Assessment for Proposed Section 

Sorghum and Grass Grown for Seed.

DP Barcode: D374607 

Registration No.: 264-1023

Regulatory Action: Section 3

Single Chemical/Aggregate Case No.: 7272

CAS No.: 365400-11-9

40 CFR: §180.631

Allison Nowotarski, Biologist

Jennifer R. Tyler, Chemist

Dunbar, Ph.D., Pharmacologist

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED; 7509P)

Kramer, Ph.D., Branch Senior Chemist

Dana Vogel, Branch Chief 

RAB1/HED (7509P)

Bethany Benbow/Joanne Miller, RM 23

Registration Division (7505P)

This Risk Assessment has been revised from the October 20, 2010 draft to modify language in 

. Specifically, the nuerotoxic and ocular toxic effects of Pyrasulfotole

were separated and better distuingshed. Characterization in the FQPA section was also revised 

better reflect the current endpoints. Finally, language was added to the cancer assessment to 

strengthen the rationale for using a non-linear approach for cancer risk. 

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 all registered 

tole (5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)[2

(trifluoromethyl)phenyl]methanone). A summary of the findings and an 

assessment of human risk resulting from the registered and proposed uses for pyrasulfotole are 

 DP#: 374607 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

Health Risk Assessment for Proposed Section 

1023

Section 3

This Risk Assessment has been revised from the October 20, 2010 draft to modify language in 

nuerotoxic and ocular toxic effects of Pyrasulfotole

. Characterization in the FQPA section was also revised 

added to the cancer assessment to 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

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 all registered 

yl)[2-

). A summary of the findings and an 

assessment of human risk resulting from the registered and proposed uses for pyrasulfotole are 
Pyrasulfotole Human-Health Risk Assessment DP#: 374607 

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provided in this document. The risk assessment and occupational/residential exposure 

assessment were provided by Allison Nowotarski (RAB1), the dietary risk assessment and 

residue chemistry data review by Jennifer Tyler (RAB1), the hazard characterization was 

provided by Anwar Dunbar (RAB1), and the drinking water assessment by Chuck Peck of the 

Environmental Fate and Effects Division (EFED).

Table of Contents

1.0 EXECUTIVE SUMMARY................................................................................................ 3

2.0 INGREDIENT PROFILE ................................................................................................. 8

2.1 Proposed Use Pattern ................................................................................................... 8

3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS ............................. 10

3.1 Hazard Profile ............................................................................................................. 10

3.2 Hazard Identification and Toxicity Endpoint Selection.......................................... 12

3.2.1 Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in .

Human-Health Risk Assessments...................................................................................... 13

3.3 FQPA Considerations................................................................................................. 14

3.4 Endocrine Disruption ................................................................................................. 15

4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION............................................ 16

4.1 Food Residue Profile................................................................................................... 16

4.2 Drinking Water Residue Profile................................................................................ 20

5.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK 

CHARACTERIZATION................................................................................................. 23

5.1 Spray Drift................................................................................................................... 23

5.2 Bystander Post-application Inhalation Exposure .................................................... 23

6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION......... 24

7.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT.............................. 24

8.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY.................................................... 25

8.1 Occupational Pesticide Handler Exposure and Risk............................................... 25

9.0 DATA NEEDS AND LABEL RECOMMENDATIONS .............................................. 29

9.1 Toxicology.................................................................................................................... 30

9.2 Residue Chemistry...................................................................................................... 30

9.3 Occupational and Residential Exposure................................................................... 30

Appendix A: TOXICOLOGY ASSESSMENT....................................................................... 31

A.1 Acute Toxicity Profile ................................................................................................. 31

A.2 Toxicity Profiles .......................................................................................................... 31
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1.0 EXECUTIVE SUMMARY

Bayer CropScience has submitted a Section 3 request to register the product HuskieTM Herbicide, 

containing pyrasulfotole as one of the active ingredients (ai), on grain sorghum and grass grown 

for seed. Pyrasulfotole is currently registered for use on small grains such as 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 enduse product is applied to the target weeds and acts 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.

The end-use product, HuskieTM Herbicide, is a 0.31 lbs per gallon emulsifiable-concentrate (EC) 

formulation. Up to two applications are proposed for a maximum seasonal rate of 0.039 lb ai per 

acre (ai/A).

Hazard Assessment: The toxicology database for pyrasulfotole is considered complete and 

adequate for purposes of risk assessment. Pyrasulfotole has a low to moderate 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 
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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. The CARC determined that quantification of human cancer risk using a 

linear low-dose (Q1*) extrapolation approach is not required.

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.

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 
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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 models 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% oralequivalent inhalation absorption factor is assumed. The level of concern (LOC) for occupational 

dermal and inhalation exposures are for margins of exposure (MOEs) <100.

Dietary Risk Estimates (Food + Water): Acute and chronic aggregate dietary (food and 

drinking water) exposure and risk assessments were conducted using the Dietary Exposure 

Evaluation Model-Food Commodity Intake Database (DEEM-FCID; ver. 2.03) which use food 

consumption data from the U.S. Department of Agriculture’s (USDA’s) Continuing Surveys of 

Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. No cancer dietary exposure

assessment was performed because the cRfD is protective of potential cancer effects. The 

analyses were performed to support Section 3 requests for use of pyrasulfotole on grain sorghum 

and grass grown for seed.

 

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% crop treated (CT) for all registered and proposed uses. Drinking water was 

incorporated directly into the dietary assessment using the acute concentration for surface water 

generated by the FQPA Index Reservoir Screening Tool (FIRST) model. The results of this 

assessment indicate that the acute dietary exposure estimates (95th percentile) are below HED’s 

LOC [<100% of the aPAD] for the general U.S. population (3% of the aPAD) and all other 

populations subgroups. The most highly exposed population subgroup is children 1-2 years old 

at 9% of the aPAD.

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 registered and 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 concludes that the chronic dietary exposure estimates are 

below HED’s LOC [<100% of the cPAD] for the general U.S. population (4% of the cPAD) and 

all population subgroups. The most highly exposed population subgroup is children 1-2 years 

old at 16% of the cPAD.

Aggregate-Risk Estimates: For the proposed uses, human-health aggregate risk assessments 
Pyrasulfotole Human-Health Risk Assessment DP#: 374607 

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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 uses which result in significant residential exposure. Pyrasulfotole is classified as 

“Suggestive Evidence of Carcinogenicity;” however, the HED CARC recommended that a 

separate quantification of cancer risk is not required. All aggregate exposure and risk 

estimates are not of concern to HED for the scenarios listed above.

Occupational Exposure and Risk Assessment: Based on application rate and label information, 

dermal and inhalation exposure is expected to occur for short- and intermediate-term durations. 

Chronic exposure is not expected for the proposed uses.

No chemical-specific handler exposure data were submitted in support of this Section 3 

registration. It is the policy of the HED to use data from the Pesticide Handlers Exposure 

Database (PHED) Version 1.1 as presented in PHED Surrogate Exposure Guide (8/98) to assess 

handler exposures for regulatory actions when chemical-specific monitoring data are not 

available. All inhalation risks for occupational handlers are above the target MOE of 100 with 

baseline protection (i.e., no respirator), and, therefore, do not exceed the LOC. All dermal risks 

for occupational handlers are above the target MOE of 100 with baseline protection or the 

addition of gloves (recommended by the label); therefore, the proposed uses are not of concern to 

HED. 

HED expects that post-application dermal exposure will occur since pyrasulfotole is applied 

postemergence as a foliar spray. Since no post-application data were submitted in support of this 

registration action, exposures during post-application activities were estimated using dermal 

transfer coefficients from HED’s Science Advisory Council for Exposure (ExpoSAC) Policy

Number 3.1 “Agricultural Transfer Coefficients” (August 2000). HED has determined that

short- and intermediate-term risk estimates are not of concern (i.e., MOEs ≥100) on the day of 

treatment (i.e., Day 0) for all post-application exposure activities. Based on the Agency's current 

practices, a quantitative occupational post-application inhalation exposure assessment was not 

performed for pyrasulfotole at this time. 

Pyrasulfotole is classified as acute Toxicity Category III for acute oral and acute dermal toxicity

and primary eye irritation. It is classified as Toxicity Category IV for acute inhalation toxicity

and primary skin irritation. Therefore, the Worker Protection Standard (WPS) interim restrictedentry interval (REI) of 12 hours is adequate to protect agricultural workers from exposures to 

pyrasulfotole. The proposed label has a 12-hour REI which is in compliance with the WPS.

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.hss.energy.gov/nuclearsafety/env/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 
Pyrasulfotole Human-Health Risk Assessment DP#: 374607 

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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 studies in which 

adult human subjects were intentionally exposed to a pesticide to determine their dermal and 

inhalation exposure. Many such studies, involving exposure to many different pesticides, 

comprise generic pesticide exposure databases such as the PHED and the Agricultural Reentry

Task Force (ARTF) Database. EPA has reviewed all the studies in these multi-pesticide generic 

exposure databases, and on the basis of available evidence has found them to have been neither 

fundamentally unethical nor significantly deficient relative to standards of ethical research 

conduct prevailing when they were conducted. There is no regulatory barrier to continued 

reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of 

Human Subjects of Research (40 CFR Part 26) have been satisfied.

Recommendations for Tolerances: Provided 1) Section B is revised to include a prohibition on 

the use of adjuvants on grain sorghum and grass grown for seed and instructions pertaining to

application equipment and spray volume for grass grown for seed; 2) Section F is revised to the 

HED-recommended tolerances, as well as correct commodity definitions and tolerance 

expressions; and 3) analytical reference standards for pyrasulfotole-desmethyl and labeled 

internal standards are submitted to the EPA National Pesticide Standards Repository, the 

toxicological, residue chemistry , and occupational/residential exposure databases support the 

establishment of a conditional registration and permanent tolerances as listed below. The 

registration should be conditional upon submission of an acceptable immunotoxicity study.

Tolerances are established for residues of the herbicide pyrasulfotole, including its metabolites 

and degradates, in or on the commodities in the table below. Compliance with the tolerance 

levels specified below is to be determined by measuring only the sum of pyrasulfotole ((5-

hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)[2-(methylsulfonyl)-4-

(trifluoromethyl)phenyl]methanone) and its desmethyl metabolite (5-hydroxy-3-methyl-1Hpyrazol-4-yl)[2-(methylsulfonyl)-4-(trifluoromethyl)phenyl]methanone), calculated as the 

stoichiometric equivalent of pyrasulfotole, in or on the following commodities:

Sorghum, grain, grain 0.70 ppm Hog, fat* 0.02 ppm

Sorghum, grain, forage 1.5 ppm Hog, liver 0.30 ppm

Sorghum, grain, stover 0.80 ppm Hog, meat byproducts, except liver 0.05 ppm

Grass, forage 25 ppm Sheep, meat* 0.02 ppm

Grass, hay 3.5 ppm Sheep, fat 0.03 ppm

Milk 0.03 ppm Sheep, liver 3.0 ppm

Cattle, meat* 0.02 ppm Sheep, meat byproducts, except liver 0.70 ppm

Cattle, fat 0.03 ppm Horse, meat* 0.02 ppm

Cattle, liver 3.0 ppm Horse, fat 0.03 ppm

Cattle, meat byproducts, except liver 0.70 ppm Horse, liver 3.0 ppm
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Goat, meat* 0.02 ppm Horse, meat byproducts, except liver 0.70 ppm

Goat, fat 0.03 ppm Poultry, meat* 0.02 ppm

Goat, liver 3.0 ppm Poultry, fat* 0.02 ppm

Goat, meat byproducts, except liver 1.0 ppm Poultry, meat byproducts 0.20 ppm

Hog, meat* 0.02 ppm Eggs* 0.02 ppm

* The recommended tolerances for these commodities are at the same level as the current tolerances under 40 CFR 180.631.

Data Needs/Deficiencies

Toxicology

 Immunotoxicity study.

Residue Chemistry

 Revised Section F. 

 Revised Section B.

 Analytical reference standards for pyrasulfotole-desmethyl and labeled internal standards 

must be submitted to the EPA National Pesticide Standards Repository. 

Occupational and Residential Exposure

 None.

2.0 INGREDIENT PROFILE

2.1 Proposed Use Pattern

Bayer submitted proposed labels for HuskieTM Herbicide (0.31 lbs/gal; EPA Reg. No. 264-1023) 

for use on grain sorghum and grass grown for seed. The proposed use patterns are detailed in 

Table 2.1.1.

Table 2.1.1. Summary of Proposed Directions for Use of Pyrasulfotole.

Commodity Trade Name 

Application 

Timing, Type, 

Equipment

Max 

Application 

Rate1

(lb ai/A)

Maximum 

Number 

Applications

Per Season

Maximum 

Seasonal 

Application 

Rate

(lb ai/A)

PHI2

(days)

Grain Sorghum Huskie 

Herbicide

(Reg. 264-

1022)

Groundboom, 

aerial, & 

chemigation

0.039

2

0.079

Forage – 7 days; 

grains or stover –

60 days

Grass grown for 

seed 0.037 0.074 Forage – 7 days; 

hay – 30 days

1. Maximum application rate on label. 

2. PHI = pre-harvest interval. 

HED Conclusions: The use directions provided by the petitioner are adequate to allow 

evaluation of the residue data relative to the proposed uses on grain sorghum and grass grown for 

seed, with the exception of instructions for the use of adjuvants and the proposed application 

type/equipment or spray volume for grass grown for seed. The submitted magnitude of residue 

studies were performed without the use of adjuvants. Therefore, the label should be amended 

to prohibit the use of adjuvants on grain sorghum and grass grown for seed. In addition, the 
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available magnitude of residue data support broadcast foliar spray applications, and a spray

volume of 10-24 gal/A. The proposed label should be revised to specify instructions of 

application equipment and spray volume for grass grown for seed.

2.2 Identification of Active Ingredient

Table 2.2.1. Test Compound and Metabolite Nomenclature.

Compound Chemical Structure

Common name Pyrasulfotole

Company Experimental name AE 0317309

IUPAC name 5-hydroxy-1,3-dimethylpyrazol-4-yl 2-mesyl-4-(trifluoromethyl)phenyl ketone

CAS name (5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)[2-(methylsulfonyl)-4-

(trifluoromethyl)phenyl]methanone

CAS # 365400-11-9

End-use products (EPs) AE 0317309 SE06 Herbicide and AE 0317309 +Bromo Herbicide

Compound Chemical Structure

Common name Pyrasulfotole-desmethyl

Company Experimental name AE 1073910

CAS name (5-hydroxy-1H-pyrazol-4-yl)[2-mesyl-4-(trifluoromethyl)phenyl]methanone

Table 2.2.2. Physicochemical Properties of the Technical Grade Test Compound.

Parameter Value Reference

Melting point Pure: 201°C

No boiling point, decomposition starts at 245°C

MRID 

46801701

pH at 22.9°C 3.03

Density 1.53

Water solubility (g/L at 20C) 2.3

4.2 

69.1 

49.0

pH 3.0 (distilled water)

pH 3.9 (buffer pH 4.0)

pH 5.4 (buffer pH 7.0)*

pH 5.2 (buffer pH 9.0)*

* exceeded buffer capacity

Solvent solubility (g/L at 20C) Ethanol 

n-Hexane

Tolune

Dichloromethane

Acetone

Ethyl acetate

Dimethyl sulfoxide

21.6

0.038

6.86

120-150

89.2

37.2

≥ 600

Vapor pressure at 20C 2.7 X 10-7

Pa

Dissociation constant (pKa) 4.2

n-octanol-water partition coefficient 

Log(KOW) at 23°C

0.276

-1.362

-1.580 

pH 4.0

pH 7.0

pH 9.0

S O

F3C

O O

N

N

HO

H

N

N

F3C

S O

O

HO

O
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Table 2.2.2. Physicochemical Properties of the Technical Grade Test Compound.

Parameter Value Reference

UV/visible absorption spectrum max= 264, 241, 216 nm in water, 0.1M HCl, 0.1M NaOH respectively.

3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS

3.1 Hazard Profile

Pyrasulfotole has a low to moderate order of acute toxicity via the oral, dermal, and inhalation 

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

has been shown to be a moderate eye irritant (Category III). Decreased locomotor activity was 

observed on the day of treatment at the limit dose in males only in the acute neurotoxicity study

in the rat.

Pyrasulfotole is an inhibitor of the hepatic enzyme 4-hydroxyphenylpyruvate dioxygenase 

(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 

(hypertyrosinemia) that is often followed by ocular toxicity. 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 the result of hypertyrosinemia caused by inhibition of hepatic HPPD, as 

mentioned above. In mice, ocular toxicity was not observed at any dose, which reflects accepted 

differences in effects among rodent species (mouse less sensitive) for HPPD inhibitors. 

However, 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 treatmentrelated. 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. The CARC 
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determined that quantification of human cancer risk using a linear low-dose (Q1*) extrapolation 

approach is not required and that the cRfD is protective of potential cancer effects.

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 in the 

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 the effects were attributed to aging in the latter case. Because

colloid alteration and pigment deposition were of minimal severity in the 2-generation 

reproductive toxicity study, they were not considered to be a 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.

Signs of neurotoxicity were observed in the acute, subchronic and developmental neurotoxicity

studies. These effects included decreased motor activity in females on day 0, decreased brain 

weight, decreased cerebrum length decreased cerebellum height, and learning deficits, and the 

changes in brain morphometry.

The Cancer classification for pyrasulfotole was determined to be “Suggestive Evidence of 

Carcinogenic Potential” based on increased incidences of corneal tumors in male rats (oral 

carcinogenicity study) and urinary bladder tumors in male and female mice (oral carcinogenicity

study).

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), 

there is “Suggestive Evidence of Carcinogenic Potential” for pyrasulfotole. This classification 

is based on the presence of ocular tumors in male rats and urinary bladder tumors in male and 

female mice.

The evidence from animal data is suggestive of carcinogenicity which raises a concern for 

carcinogenic effects but is judged not sufficient for quantification cancer risk in humans. Also, 

according to the Guidelines, when there is suggestive evidence, the Agency does not attempt a 

dose-response assessment as the nature of the data generally would not support one. 
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In the case of pyrasulfotole, cancer risk from dietary exposure is less of a concern based on the 

following weight of evidence considerations:

 The low incidences (2/55) of ocular tumors seen only at the high dose and was associated 

with widespread corneal inflammation, hyperplasia, metaplasia, neurovascularization 

and atrophy;

 It is biologically plausible for corneal tumors to result from a nongenotoxic mode of 

action that was secondary to corneal inflammation and regenerative hyperplasia caused 

by tyrosine;

 The urinary bladder tumors in mice were seen only at the high dose (one-half of the Limit 

Dose) which was determined to be an excessive dose due to occurrence of death, bladder 

stones, and bladder hyperplasia;

 Data from available toxicity studies showed dose and temporal concordance among 

putative key events for the biological plausibility for a nongenotoxicx proliferative 

mechanism for the bladder tumors. This was evidenced by the concurrent presence of 

secondary inflammation and hyperplastic lesions in the urinary bladder induced by the 

urinary stones;

 In both species tumors were observed only at the highest dose tested (i.e., lack of doseresponse);

 Pyrasulfotole and its benzoic metabolite, AE B197555, do not pose a mutagenic concern; 

and

 The NOAEL of 1.0 mg/kg/day used for deriving the chronic RfD is approximately100-

500-fold lower than the doses that induced ocular (104 mg/kg/day) tumors in rats and 

urinary bladder (560 mg/kg/day) tumors in mice. 

Thus, for all these reasons, the Agency has determined that a non-linear approach is 

adequate for assessing cancer risk and that the chronic PAD (0.01 mg/kg/day) will 

adequately account for all chronic effects, including carcinogenicity, likely to result from 

exposure to the pyrasulfotole. 

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, desmethylparent, 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. 

3.2 Hazard Identification and Toxicity Endpoint Selection
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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 3.2.1a and 

3.2.1b. 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.

Based on the available toxicity database and the Agency's current practices, the inhalation risk 

for pyrasulfatole was assessed using an oral toxicity study. The Agency sought expert advice 

and input on issues related to this route to route extrapolation approach (i.e. the use of oral 

toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency

received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, re-examine and develop new 

policies and procedures for conducting inhalation risk assessments, including route to route 

extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may

revisit the need for an inhalation toxicity study for pyrasulfotole and/or a re-examination of the 

inhalation toxicity risk assessment.

3.2.1 Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in 

Human-Health Risk Assessments

Table 3.2.1a. Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in Dietary and NonOccupational Human Health Risk Assessments. There are no residential uses proposed for pyrasulfotole at 

this time. 

Exposure 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC for Risk 

Assessment

Study and Relevant 

Toxicological Effects

Acute Dietary 

(All 

populations)

NOAEL = 

3.8

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X 

aRfD = aPAD = 0.038 

mg/kg/day

Developmental 

neurotoxicity (rat; dietary)

Offspring LOAEL = 37 

mg/kg/day based on delayed 

preputial separation (males), 

decreased cerebrum length 

(PND 21 females), and 

decreased cerebellum height 

(PND 21 males).

Chronic 

Dietary (All 

populations)

NOAEL = 

1.0

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X

cRfD = cPAD = 

0.01mg/kg/day

Combined chronic 

toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

10/14 mg/kg/day (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).1

Cancer (oral, 

dermal, 

inhalation)

Classification: “Suggestive Evidence of Carcinogenic Potential” based on increased incidences of 

corneal tumors in male rats (oral carcinogenicity study) and urinary bladder tumors in male and 

female mice (oral carcinogenicity study).
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Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential 

variation in sensitivity among members of the human population (intraspecies), UFFQPA = 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 3.2.1b. Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in Occupational 

Human Health Risk Assessments.

Exposure 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC for Risk 

Assessment

Study and Toxicological 

Effects

Dermal

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL = 

10

mg/kg/day

UFA = 10X

UFH = 10X

Occupational LOC for 

MOE <100

28-day dermal toxicity

(rat) LOAEL = 100 mg/kg 

bw/day [M/F] based on 

focal degeneration of 

pancreas (both sexes) and 

alteration of thyroid colloid 

(males)

Dermal

Long-Term

(>6 months)

NOAEL = 

1.0

mg/kg/day

Estimated 

dermal 

absorption 

factor = 

2.5%

UFA = 10X

UFH = 10X

Occupational LOC for 

MOE <100

Combined chronic 

toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

10/14 mg/kg/day (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).

Inhalation

(All 

durations)

NOAEL = 

1.0

mg/kg/day

100% 

inhalation 

assumed

UFA = 10X

UFH = 10X

Occupational LOC for 

MOE <100

Combined chronic 

toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

10/14 mg/kg/day (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).

Cancer (oral, 

dermal, 

inhalation)

Classification: “Suggestive Evidence of Carcinogenic Potential” based on increased incidences of 

corneal tumors in male rats (oral carcinogenicity study) and urinary bladder tumors in male and 

female mice (oral carcinogenicity study).

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential 

variation in sensitivity among members of the human population (intraspecies), UFFQPA = FQPA Safety Factor, 

NOAEL = no-observed-adverse-effect level, LOAEL = lowest-observed-adverse-effect level, MOE = margin of 

exposure, LOC = level of concern.

3.3 FQPA Considerations
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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 adequate for FQPA assessment.

 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 the rat developmental toxicity study, the 

developmental neurotoxicity study in rats, or the two generation reproduction study in 

rats, and c) the NOAEL of the study chosen for the chronic RfD (1 mg/kg/day) is 10X 

lower than the NOAEL observed in the rabbit developmental toxicity study.

 Although there were signs of neurotoxicity observed in the acute, subchronic and 

developmental neurotoxicity studies, the level of concern is low. The critical study

chosen for the acute reference dose (the developmental neurotoxicity study) has a well 

defined NOAEL and is 54-fold lower than the effects seen in the acute neurotoxicity

study. The critical study chosen for the chronic endpoint also hasa well defined NOAEL 

that is 42- and 37-fold lower than the effects observed in the subchronic and 

developmental neurotoxicity studies. 

 The toxicology database for pyrasulfotole does not show any evidence of treatmentrelated effects on the immune system. The overall weight of evidence suggests that this 

chemical does not directly target the immune system. An immunotoxicity study is 

required as a part of new data requirements in the 40 CFR Part 158 for conventional 

pesticide registration; however, the Agency does not believe that conducting a functional 

immunotoxicity study will result in a lower point of departure (POD) than that currently 

used for overall risk assessment, and therefore, a database uncertainty factor (UFDB) is 

not needed to account for lack of this study.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.

3.4 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 
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will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Pyrasulfotole is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

3.5 Recommendation for Aggregate Exposure Risk Assessments

For oral exposure, the dietary and drinking water exposures can be combined. Because they are 

based on the same oral studies with the same effects, the chronic dietary exposure can be 

combined with inhalation exposures of all durations. Dermal and Inhalation exposures cannot be 

combined due to different effects. 

4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION

The residue chemistry data submitted in support of the proposed uses are summarized in the 

pending HED memorandum by J. Tyler (D375391). The drinking water assessment was 

provided by C. Peck of EFED (D374622). The acute and chronic dietary exposure assessment is 

summarized in the pending HED memorandum by J. Tyler (D375390).

4.1 Food Residue Profile

Nature of the Residue – Plants: The nature of the pyrasulfotole residues in sorghum and grass 

is understood based on previously submitted and reviewed metabolism studies on wheat (Memo, 

J. Tyler, 6/8/07; D333412). The metabolism of pyrasulfotole in spring wheat involves the 

demethylation and subsequent glucosylation of the parent compound, yielding pyrasulfotoledesmethyl-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. Based on the results of the wheat metabolism studies, 

parent and pyrasulfotole-desmethyl are the residues of concern for tolerances and risk assessment 

purposes (Memo, J. Tyler et al., 06/08/07; D328640). Any future uses on other crops, such as 

leafy vegetables, or legumes, may require the submission of additional metabolism data.

Nature of the Residue – Livestock: The nature of the pyrasulfotole residues in livestock is 

understood based on previously submitted and reviewed lactating goat and laying hen 
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metabolism studies (Memo, J. Tyler, 6/8/07; D333412). The goat study indicates that the 

metabolism of pyrasulfotole in lactating goats involved either N-demethylation of pyrasulfotole 

to form pyrasulfotole-desmethyl, or oxidation of pyrasulfotole to form pyrasulfotolehydroxymethyl. The hen study indicates that the metabolism of pyrasulfotole in laying hens 

involved the N-demethylation of pyrasulfotole to yield the pyrasulfotole-desmethyl metabolite. 

The residues of concern in livestock for tolerance and risk assessment purposes are parent and 

the desmethyl metabolite (Memo, J. Tyler, 06/08/07; D328640).

Residue Analytical Method - Plants: An adequate high-performance liquid chromatography

(HPLC)/mass spectrometry (MS)/MS method (Method AI-001-P04-02) is available for 

collecting data on residues of pyrasulfotole and its metabolite pyrasulfotole-desmethyl in/on 

cereal grain and grass commodities. The limit of quantitation (LOQ) is 0.010 ppm for each 

analyte. A similar method, Method AI-001-P04-01, which is also the proposed enforcement 

method for the currently registered/proposed plant commodities, has been adequately 

radiovalidated and undergone a successful independent laboratory validation (ILV) trial. Method 

AI-001-P04-01 was forwarded to the Analytical Chemistry Branch of the Biological & 

Economics Analysis Division (ACB/BEAD) for a petition method validation (PMV, Memo, J. 

Tyler, 1/30/07; DP# 335558). ACB reviewed the proposed enforcement method data without an 

ACB validation, but recommended the petitioner provide information for a second MS/MS ion 

transition to provide a confirmation of analyte identities (Memo, C. Stafford, 6/7/07; D335559). 

In response, the company submitted Bayer Method AI-001-P04-02, which includes the requested 

information for a second MS/MS ion transition. HED reviewed this method, and determined it

suitable for determination of pyrasulfotole and pyrasulfotole-desmethyl in crop matrices (Memo, 

G. Kramer, 12/18/09; D367796).

Residue Analytical Method – Livestock: An HPLC-MS/MS method (Method AI-004-A05-01) 

for collecting data on pyrasulfotole in livestock tissues, including milk, matrices was previously 

submitted and reviewed by HED (Memo, J. Tyler, 06/08/07; D333412). 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 (Memo, J. Tyler et al., 

6/8/07; D328640). Therefore, HED requested the petitioner submit a ruminant analytical 

enforcement method to determine residues of pyrasulfotole and pyrasulfotole-desmethyl as well 

as adequate radiovalidation and ILV data. In response, the company submitted a new HPLCMS/MS (Method AI-006-A08-01) for collecting pyrasulfotole and pyrasulfotole-desmethyl in 

livestock tissues and milk, as well as ILV data. HED reviewed these submissions; and, based on 

validation data provided by the petitioner and the successful ILV, determined that Method AI006-A08-01 is suitable as an enforcement method for livestock commodities as defined in 

standard operating procedure (SOP) No. ACB-019 (9/15/08) (Memo, G. Kramer, 12/18/09; 

D367796). HED also determined that radiovalidation data are not necessary as the extraction 

procedures are identical to the previous version of the method (for which adequate extraction 

efficiency data were provided).

Multiresidue Methods (MRM): 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, 1/30/07; D335562). 
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Storage Stability: No storage stability data were submitted in conjunction with the proposed 

uses. The available storage stability data are acceptable and indicate that residues of 

pyrasulfotole and pyrasulfotole-benzoic acid are stable in soybean seed and wheat matrices for 

up to 11 months, and residues of pyrasulfotole-desmethyl decline in wheat forage and hay (ca. 

0.12 % per day) in frozen storage. The storage stability data support the sample storage intervals 

and conditions in the submitted crop field trials. Corrections to residues of pyrasulfotole due to 

in-storage dissipation are not necessary, but residues of pyrasulfotole-desmethyl in sorghum 

forage and stover, and grass forage and hay will require corrections for in-storage dissipation.

Meat, Milk, Poultry and Eggs: The results of the cattle feeding study are adequate for purposes 

of this action. HED assumed the transfer of pyrasulfotole-desmethyl from plant to livestock to 

be equivalent to that of the parent pyrasulfotole based on the similar structure. For any new uses 

which significantly increase the maximum reasonable dietary burden (MRDB) of the metabolite, 

the petitioner may be required to submit a feeding study with pyrasulfotole-desmethyl.

Based on the MRDB for dairy cattle (45 ppm), the actual dose levels in the feeding study are 

equivalent to 0.067x, 0.2x, and 0.67x the MRDB for dairy cattle. Based on the residues at the 

0.67x feeding level, the current tolerances of 0.02 ppm for meat of cattle, goat, horse and sheep 

are adequate to support the proposed uses. However, tolerances should be established for 

residues of pyrasulfotole and pyrasulfotole-desmethyl in/on milk at 0.03 ppm; fat of cattle, goat, 

horse and sheep at 0.03 ppm; liver of cattle, goat, horse, and sheep at 3.0 ppm; and meat 

byproducts, except liver, of cattle, goat, horse, and sheep at 0.70 ppm. A revised Section F 

should be submitted to include the above tolerances, as well as correct commodity 

definitions and tolerance expression for livestock commodities.

Based upon a MRDB of 0.56 ppm for hogs, there is no reasonable expectation of finding 

quantifiable residues of pyrasulfotole and pyrasulfotole-desmethyl in hog muscle and fat; thus, 

the current tolerances of 0.02 ppm are adequate. There is reasonable expectation of residues of 

pyrasulfotole and pyrasulfotole-desmethyl in hog liver and kidney. Therefore, the following 

tolerances for residues of pyrasulfotole and pyrasulfotole-desmethyl are necessary: hog, meat 

byproducts, except liver at 0.05 ppm; and hog, liver at 0.30 ppm. A revised Section F should 

be submitted to include the above tolerances, as well as correct commodity definitions and 

tolerance expression for livestock commodities.

The results of the poultry feeding study are inadequate to determine the need for poultry

tolerances as only residues of pyrasulfotole-benzoic acid were measured in the study. However, 

the results of the poultry metabolism studies can be used to determine the need for a new poultry

feeding study and/or poultry tolerances. Based on the MRDB of 0.52 ppm for poultry, the 

phenyl-labeled (8.6 ppm) and pyrazole-labeled (10.5 ppm) poultry metabolism studies were 

conducted at 16x and 20x the MRDB for poultry, respectively. 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 muscle and fat; thus, the current 

tolerances of 0.02 ppm for residues of pyrasulfotole and pyrasulfotole-desmethyl in fat, meat, 

and meat byproducts of poultry are adequate. There is reasonable expectation of residues of 

pyrasulfotole and pyrasulfotole-desmethyl in poultry meat byproducts. Therefore, a tolerance of 

0.20 ppm for residues of pyrasulfotole and pyrasulfotole desmethyl in poultry byproducts is 

necessary. A revised Section F should be submitted to include the above tolerances and 

correct tolerance expression for livestock commodities.
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Crop Field Trials: The available grain sorghum and grass residue data are classified as 

scientifically acceptable for determination of the magnitude of residue for and the metabolite 

pyrasulfotole-desmethyl when treated with the end use products HuskieTM Herbicide. As the 

number and geographical representation of the grain sorghum and grass trials are appropriate, the

residue data are adequate to support the proposed uses.

The grain sorghum crop field trial data support a maximum seasonal application rate of 0.078 lb 

ai/acre A (~1x the maximum proposed application rate) on sorghum forage, grain, and stover 

[preharvest interval (PHI) of 5-7 days for forage, 60 days for grain and stover]. With these use 

patterns, total residues of pyrasulfotole and pyrasulfotole-desmethyl are not expected to exceed 

0.902 ppm (forage, 7-day PHI), 0.325 ppm (grain), and 0.420 ppm (stover). Using the North 

American Free Trade Agreement (NAFTA) Maximum Residue Limit (MRL)/Tolerance 

Harmonization Workgroup methodology for forage, grain, and stover; the available grain 

sorghum crop field trial data indicate that the appropriate tolerances for residues of pyrasulfotole 

and pyrasulfotole-desmethyl in/on grain sorghum commodities are 1.5 ppm for sorghum, grain, 

forage; 0.70 ppm for sorghum, grain, grain; and 0.80 ppm for sorghum, grain, stover. Section F 

of the petition should be revised to include the aforementioned HED-recommended 

tolerances and the correct commodity definitions for grain sorghum RACs.

The grass crop field trial data support a maximum seasonal application rate of 0.076-0.091 lb 

ai/A (~1x the maximum proposed application rate) on grass forage and hay (PHI of 7 days for 

forage, and 30 days hay). With these use patterns, total pyrasulfotole and pyrasulfotoledesmethyl residue levels are not expected to exceed 6.52 ppm (forage, 7-day PHI) and 2.31 ppm 

(hay). Using the NAFTA MRL/Tolerance Harmonization Workgroup methodology for forage

(7-day PHI) and hay, the available grass crop field trial data indicate that the appropriate 

tolerances for residues of pyrasulfotole and pyrasulfotole-desmethyl in/on grass commodities are 

25 ppm for grass, forage; and 3.5 ppm for grass, hay. Section F of the petition should be 

revised to include the aforementioned HED-recommended tolerances.

Confined Accumulation in Rotational Crops: No rotational crop data were submitted in 

conjunction with the proposed uses. Adequate confined and field rotational crop data have been 

submitted by the petitioner and reviewed by HED in conjunction with PP#6F7509 (Memo, J. 

Tyler, 6/8/07; D366490). 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 addition, HED approved a requested to revise the Crop Rotation Guidelines on the 

currently approved HuskieTM Herbicide (EPA Reg. No. 264-1023). The submitted confined and 

limited field trial data support the proposed PBIs.

Proposed and Recommended Tolerances: The residue chemistry database supports the 

establishment of the permanent tolerances for the combined residues of pyrasulfotole and 

pyrasulfotole-desmethyl in/on the RACs and livestock commodities listed in Table 4.1.1. 

Section F should be revised to include these recommended tolerances as well as the correct 

tolerance expression for livestock commodities.

Table 4.1.1. Tolerance Summary for Pyrasulfotole.

Commodity Current 

Tolerance (ppm)

Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

(correct commodity definition)

Sorghum, grain -

0.8 0.70 Sorghum, grain, grain
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Table 4.1.1. Tolerance Summary for Pyrasulfotole.

Commodity Current 

Tolerance (ppm)

Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

(correct commodity definition)

Sorghum, forage -

1.2 1.5 Sorghum, grain, forage

Sorghum, stover - 0.35 0.80 Sorghum, grain, stover

Grass, forage - 10 25

Grass, hay - 2.5 3.5

Milk* 0.01 0.01 0.03

Cattle, meat 0.02 0.04 see current tolerance

Cattle, fat* 0.02 0.04 0.03

Cattle, meat byproducts* 0.06 2 0.70 Cattle, meat byproducts, except liver

Cattle, liver* 0.35 8 3.0

Goat, meat 0.02 0.04 see current tolerance

Goat, fat* 0.02 0.04 0.03

Goat, meat byproducts* 0.06 2 0.70 Goat, meat byproducts, except liver

Goat, liver* 0.35 8 3.0

Hog, meat 0.02 0.04 see current tolerance

Hog, fat 0.02 0.04 see current tolerance

Hog, meat byproducts* 0.06 2 0.05 Hog, meat byproducts, except liver

Hog, liver* - 8 0.30

Sheep, meat 0.02 0.04 see current tolerance

Sheep, fat* 0.02 0.04 0.03

Sheep, meat byproducts* 0.06 2 0.70 Sheep, meat byproducts, except liver

Sheep, liver* 0.35 8 3.0

Horse, meat 0.02 0.04 see current tolerance

Horse, fat* 0.02 0.04 0.03

Horse, meat byproducts* 0.06 2 0.70 Horse, meat byproducts, except liver

Horse, liver* 0.35 8 3.0

Poultry, meat 0.02 - see current tolerance

Poultry, fat* 0.02 - 0.03

Poultry, meat byproducts* 0.02 - 0.20

Eggs 0.02 - see current tolerance

* Livestock commodities with tolerances that are not harmonized with PMRA.

There are no established Mexican or Codex MRLs for the proposed uses. There are Canadian 

MRLs established for livestock commodities. However, due to the recommended tolerances on 

the proposed uses, there was an increase in MRDB for livestock commodities. This resulted in 

the need for an increase in tolerances for several livestock commodities (see commodities with 

asterisk in Table 4.1.1). Therefore, harmonization is not possible at this time.

4.2 Drinking Water Residue Profile

EFED provided ground and surface water estimated drinking water concentrations (EDWCs) for 

pyrasulfotole (C. Peck, 04-AUG-2010; D374622). Tier 1 surface water and groundwater 

modeling were conducted for the labeled grain sorghum use of two applications per year, at a 

rate of 0.039 lbs ai/A/application and a retreatment interval of 11 days, as specified by the label

(yielded the highest EDWCs for all registered/proposed uses). The recommended EDWCs for 

the human health risk assessment are in Table 4.2.1. There was one environmental degradate, 
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pyrasulfotole-benzoic acid (AE 197555), identified in the soil metabolism and terrestrial field 

dissipation studies; however, it is not of toxicological concern (J. Tyler, 7-JUN-2007, D328640) 

and is not considered. 

Total residue EDWCs for the proposed/registered uses of pyrasulfotole likely exceed actual 

values that occur in drinking water reservoirs and ground water due to the screening design of 

the models.

Table 4.2.1. Tier 1 EDWCs for Pyrasulfotole for Ground Spray Applications to Grain Sorghum.

Source Model Use rate (lbs ai/A) Acute (ppb) Chronic (ppb)

Surface water FIRST 0.039 6.9 4.8

Ground water SCI-GROW 0.039 2.4 2.4

4.3 Dietary Exposure and Risk

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments 

were conducted using the DEEM-FCID (ver. 2.03) which use food consumption data from the 

USDA’s CSFII from 1994-1996 and 1998. No cancer dietary exposure assessment was 

performed because the cRfD is protective of potential cancer effects. The analyses were 

performed to support Section 3 requests for use of pyrasulfotole on grain sorghum and grass 

grown for seed.

 

Pyrasulfotole acute and chronic dietary exposure assessments were conducted using the DEEMFCIDTM, Version 2.03 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. For chronic exposure assessment, consumption data 

are averaged for the entire U.S. population and within population subgroups, but for acute 

exposure assessment are retained as individual consumption events. Based on analysis of the 

1994-96, 98 CSFII consumption data, which took into account dietary patterns and survey

respondents, HED concluded that it is most appropriate to report risk for the following 

population subgroups: the general U.S. population, all infants (<1 year old), children 1-2, 

children 3-5, children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+ years old.

For chronic dietary exposure assessment, an estimate of the residue level in each food or foodform (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 to produce a residue intake estimate. 

The resulting residue intake estimate for each food/food form is summed with the residue intake 

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., only those who reported eating 
Pyrasulfotole Human-Health Risk Assessment DP#: 374607 

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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, any significant 

differences in user vs. per capita exposure and risk are specifically identified and noted in the 

risk assessment.

As stated above, for acute and chronic assessments, HED is concerned when dietary risk exceeds 

100% of the PAD. The DEEM-FCIDTM analyses estimate the dietary exposure of the U.S. 

population and various population subgroups. The results reported in Table 4.3.1 are for the 

general U.S. Population, all infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 

13-19, females 13-49, adults 20-49, and adults 50+ years.

4.3.1 Acute Dietary Exposure/Risk

An acute dietary exposure assessment (using tolerance level residues and 100% CT information 

for all registered and proposed uses) was conducted for the general U.S. population and various 

population subgroups (including infants and children). Drinking water was incorporated directly 

in the dietary assessments using the acute concentration for surface water generated by the 

FIRST model. The results of the acute assessment indicate that the acute dietary exposure 

estimates (95th percentile) are below HED’s level of concern (<100% of the aPAD) for the 

general U.S. population (3% of the aPAD) and all populations subgroups. The most highly 

exposed population subgroup is children 1-2 years old at 9% of the aPAD.

These analyses are considered to be conservative dietary exposure assessments. Residues were 

assumed to be equivalent to the tolerance levels. Tolerance-level residues should always exceed 

the residue levels found on food commodities at the time of consumption. When field trials are 

performed, the maximum allowable application rate is used and crops are harvested at the 

minimum preharvest interval (PHI). Samples are stored frozen until analysis to ensure minimal 

degradation of residues. In actual practice, however, growers will not usually use the maximum 

application rates for economic reasons. In addition, most crops are not harvested and 

immediately stored frozen. Also, 100% CT was assumed for all foods. For these reasons, HED 

is confident that this analysis does not underestimate risk to the general U.S. population or any

population subgroup. Further refinement to the analyses could be made through the use of 

monitoring data, %CT data, and additional empirical processing factors. Since risk estimates are 

not of concern to HED, a more highly refined analysis is not needed at this time.

4.3.2 Chronic Dietary Exposure/Risk

The chronic dietary exposure assessment (using tolerance level residues and 100% CT 

information for all registered and proposed uses) was conducted for the general U.S. population 

and various population subgroups. 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 chronic assessment indicate that the chronic dietary exposure estimates are 

below HED’s LOC (<100% of the cPAD) for the general U.S. population (4% of the cPAD) and 

all population subgroups. The most highly exposed population subgroup is children 1-2 years 

old at 16% of the cPAD.

Table 4.3.1. Summary of Dietary Exposure and Risk for Pyrasulfotole.
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Population

Subgroup

Acute Dietary1 Chronic Dietary2

Dietary Exposure

(mg/kg/day) % aPAD Dietary Exposure(mg/kg/day) % cPAD

U.S. Population (total) 0.001315 3 0.000433 4

All Infants (< 1 year old) 0.002549 7 0.000829 8

Children 1-2 years old 0.003428 9 0.001567 16

Children 3-5 years old 0.002288 6 0.001150 12

Children 6-12 years old 0.001480 4 0.000699 7

Youth 13-19 years old 0.000878 2 0.000352 4

Adults 20-49 years old 0.000695 2 0.000298 3

Adults 50+ years old 0.000616 2 0.000300 3

Females 13-49 years old 0.000698 2 0.000295 3

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.

5.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK 

CHARACTERIZATION

There are no residential uses proposed or currently registered for pyrasulfotole. Therefore, 

residential handler and post-application exposure/risk were not assessed. 

5.1 Spray Drift 

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 (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). 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.

5.2 Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative residential bystander post-application

inhalation exposure assessment was not performed for pyrasulfotole at this time. However, 

volatilization of pesticides may be a potential source of post-application inhalation exposure to 

individuals nearby to pesticide applications. The Agency sought expert advice and input on 

issues related to volatilization of pesticides from its FIFRA SAP in December 2009. The 
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Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures, 

to identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for pyrasulfotole.

6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

Chronic and acute aggregate exposure risk assessments were performed by incorporating the 

drinking water directly into the dietary-exposure assessment for the chronic and acute exposure 

scenarios. 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. Pyrasulfotole is classified as “Suggestive Evidence of 

Carcinogenicity;” however, the HED CARC recommended that a separate quantification of 

cancer risk is not required. Therefore, cancer aggregate risk assessments were not performed.

6.1 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 95th exposure percentile for the general U.S. 

population and all other population subgroups (see Table 4.3.1). 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.

6.2 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 4.3.1). 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.

7.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT

Pyrasulfotole, mesotrione, isoxaflutole and topramezone belong to a class of herbicides that 

inhibit the liver enzyme 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 
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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 will 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).

8.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY

An occupational exposure assessment for pyrasulfotole was provided in a HED memorandum 

dated 3-SEP-2010 (A. Nowotarski; D375392). See Table 2.1.1 for a summary of the proposed 

use patterns. There is the potential for occupational handler and post-application exposure from 

the proposed uses of pyrasulfotole. 

8.1 Occupational Pesticide Handler Exposure and Risk

Potential occupational handler exposure scenarios include: 1) mixer/loader using open pouring 

of liquids in support of aerial, groundboom, and chemigation operations; 2) aerial applicators; 3) 

applicators using open-cab ground boom equipment; and 4) flaggers. 

Handler exposure is expected to be short- and intermediate-term based on information provided 

on the proposed labels (e.g., 2 applications/season). The average adult body weight of 70 kg was 

used for estimating inhalation dose. Long-term exposures are not expected; therefore, a longterm assessment was not conducted. The proposed labels require mixers, loaders and other 
Pyrasulfotole Human-Health Risk Assessment DP#: 374607 

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handlers to wear long-sleeved shirt and long pants, chemical-resistant gloves, and shoes plus 

socks. The labels also require applicators to wear long-sleeved shirt and long pants, and shoes 

plus socks. 

No chemical specific data are available with which to assess potential exposure to pesticide 

handlers. The estimates of exposure to pesticide handlers are based upon surrogate study data 

available in PHED. The average adult body weight of 70 kg was used for estimating dermal and 

inhalation doses because toxicological effects were not sex-specific. 

Daily dermal and inhalation handler exposures are estimated for each applicable handler task 

with the application rate, the area treated in a day, and the applicable dermal or inhalation unit 

exposure using the following formula: 

Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x Application Rate (lbs ai/area) x Daily Area 

Treated (area/day)

Where:

Daily Exposure = Amount (mg ai/day) that is available for dermal or inhalation absorption;

Unit Exposure = Unit exposure value (mg ai/lb ai) derived from August 1998 PHED data;

Application Rate = Normalized application rate based on a logical unit treatment, such as acres; and

Daily Area Treated = Normalized application area based on a logical unit treatment such as acres 

(A/day).

The daily dermal or inhalation dose is calculated by normalizing the daily exposure by body

weight and adjusting, if necessary, with an appropriate absorption factor using the following 

formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x (Absorption Factor (%/100)) / Body Weight (kg)

Where:

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario (mg 

ai/kg body weight/day);

Daily Exposure = Amount (mg ai/day) inhaled that is available for absorption;

Absorption Factor = A measure of the amount of chemical that crosses a biological boundary such 

as the skin or lungs (% of the total available absorbed); and

Body Weight = Body weight determined to represent the population of interest in a risk 

assessment (kg).

Non-cancer dermal and inhalation risks for each applicable handler scenario are calculated using 

a MOE, which is a ratio of the NOAEL to the daily dose. All MOE values were calculated using 

the formula below:

MOE= NOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

Table 4 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). 
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A MOE  100 is adequate to protect occupational pesticide handlers. Since all the estimated 

MOEs are > 100 with baseline protection or the addition of gloves (recommended by the label), 

the proposed uses are not of concern for HED.

The minimum level of personal-protective equipment (PPE) for handlers is based on acute 

toxicity for the end-use product. The RD is responsible for ensuring that PPE listed on the label 

is in compliance with the WPS for agricultural pesticides. HED recommends that handlers 

follow all label requirements.

Table 8.1.1. Pyrasulfotole Occupational Non-cancer Dermal and Inhalation Exposures and Risks from Application to 

Grain Sorghum and Grass Grown for Seed.

Application Rate 

(lb ai/acre)a

Area Treated 

Daily (acres)b

Unit Exposures --

Dermal and Inhalation 

(mg/lb ai)

Doses (mg/kg/day)f MOEsg

Mixer/Loader for Aerial Applications

0.039 1200

Dermal

Baselinec: 2.9

PPE-G

h

: 0.023

Dermal

Baseline: 1.9

PPE-G: 0.015

Dermal

Baseline: 5.2

PPE-G: 650

Inhalation

Baselined: 0.0012

Inhalation

Baseline: 0.0008

Inhalation

Baseline: 1,200

Mixer/Loader for Chemigation Applications

0.039 350

Dermal

Baselinec: 2.9

PPE-G: 0.023

Dermal

Baselinec: 0.57

PPE-G: 0.0045

Dermal

Baselinec: 18

PPE-G: 2,200

Inhalation

Baselined: 0.0012

Inhalation

Baselined: 0.00023

Inhalation

Baselined: 4,300

Mixer/Loader for Groundboom Applications

0.039 200

Dermal

Baselinec: 2.9

PPE-G: 0.023

Dermal

Baselinec: 0.32

PPE-G: 0.0026

Dermal

Baselinec: 31

PPE-G: 3,900

Inhalation

Baselined: 0.0012

Inhalation

Baselined: 0.00013

Inhalation

Baselined: 7,500

Applicator for Aerial Equipment

0.039 1200

Dermal

Engineering controle: 0.005

Dermal

Engineering control: 0.0033

Dermal

Engineering control:

3,000

Inhalation

Engineering control: 

0.000068

Inhalation

Engineering control: 0.000045

Inhalation

Engineering control:

22,000

Applicator for Groundboom Equipment

0.039 200

Dermal

Baselinec: 0.014

Dermal

Baselinec: 0.0016

Dermal

Baselinec: 6,400

Inhalation

Baselined: 0.00074

Inhalation

Baselined: 0.000082

Inhalation

Baselined: 12,000

Flagger

0.039 350

Dermal

Baselinec: 0.011

Dermal

Baselinec: 0.0021

Dermal

Baselinec: 4,700

Inhalation

Baselined: 0.00035

Inhalation

Baselined: 0.000068

Inhalation

Baselined: 15,000

a Application rates are the maximum application rates determined from proposed labels for pyrasulfotole.

b Amount handled per day values are HED estimates of acres treated per day based on ExpoSAC SOP #9 “Standard Values for Daily 

Acres Treated in Agriculture,” industry sources, and HED estimates.

c Baseline Dermal: Long-sleeve shirt, long pants, and no gloves.

d Baseline Inhalation: no respirator.

e Engineering control: enclosed cockpit and baseline attire (long-sleeve shirt, long pants, shoes, and socks).

f Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre) x Area Treated (acres/day) x %Absorption (100% dermal and 

100% inhalation) / Body weight (70 kg). 
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g MOE = NOAEL/Dose; where the short-term dermal NOAEL = 10 mg/kg/day and the short-term inhalation NOAEL = 1.0 mg/kg/day

h PPE-G = long-sleeve shirt, long pants, and gloves. 

8.2 Occupational Post-Application Worker Exposure and Risk

Dermal: HED expects that post-application dermal exposure will occur since pyrasulfotole is 

applied postemergence as a foliar spray. Since no post-application data were submitted in 

support of this registration action, exposures during post-application activities were estimated 

using dermal transfer coefficients from HED’s ExpoSAC Policy Number 3.1 “Agricultural 

Transfer Coefficients” (August 2000). Table 8.2.1 summarizes the scenarios assessed. In 

addition, the following assumptions were used in the calculations:

• Exposure Duration = 8 hours per day

• Body Weight = 70 kg

• Dermal Absorption = NA

• Fraction of a.i. retained on foliage = assumed to be 20% on day zero

(= % dislodgeable foliar residue, DFR, after 

initial treatment). This fraction is assumed 

to further dissipate at the rate of 10% per 

day on following days. These are default 

values established by ExpoSAC. 

Table 8.2.1. Anticipated Post-application Activities and Dermal Transfer Coefficients.

Proposed 

Crops

Policy Crop 

Group Category

Application Rate

(lb ai/acre)

Transfer Coefficients 

(cm2/hr)

Activities

Sorghum Field/row crop, 

tall

0.037 1000 Irrigation, scouting

100 Weeding (hand)

Grass grown 

for seeda

Field/row crop, 

medium

0.039 1500 Irrigation, scouting

a. Representative crop group was used as the proposed crop is not included in Policy 3.1.

Equations/Calculations:

Daily dermal exposures were calculated on each post-application day after application using the 

following equations:

DFRt = AR x F x (1-D)tx CF1 x CF2

Where:

DFRt = dislodgeable foliage residue on day "t" (μg/cm2)

AR = application rate (lb ai/acre)

F = fraction of ai retained on foliage (unitless)

D = fraction of residue that dissipates daily (unitless)

and

Daily Dermal Doset = [DFRt (μg/cm2) x 0.001 mg/μg x TC (cm2/hr) x DA x ET (hrs)] / BW (kg)
Pyrasulfotole Human-Health Risk Assessment DP#: 374607 

Page 29 of 39

Where:

DFRt = dislodgeable foliage residue on day "t" (ug/cm2);

TC = transfer coefficient (cm2/hr);

 ET = exposure time (8 hr/day); and

BW = body weight (70 kg).

Once daily exposures are calculated, the calculation of daily absorbed dose and the resulting 

MOEs use the same algorithms that are described above for the handler exposures. These 

calculations are completed for each day or appropriate block of time after application.

HED has determined that short- and intermediate-term risk estimates are not of concern (i.e., 

MOEs ≥ 100) on the day of treatment (i.e., Day 0) for all post-application exposure activities. 

Table 8.2.2 presents a summary of occupational post-application risks associated with use of 

pyrasulfotole. 

Table 8.2.2. Post-application Risk Estimates for Pyrasulfotole.

Crop Application Rate

(lb ai/A)

Transfer 

Coefficient

(cm2/hr)

DFR1 

(ug/cm2)

Days 

After 

Treatment

Daily Dose2

(mg/kg/

day)

MOE3

Field/row

crop, medium

0.037 1500 0.08 0

(12 hours)

0.014 700

Field/row

crop, tall

0.039 1000 0.09 0.010 1,000

100 0.001 10,000

The information in the table is based on proprietary and non-proprietary data.

1: DFR (μg/cm2) = Application Rate (lb ai/A) x (1- Daily Dissipation Rate)tx CF (4.54E+8 μg/lb) x CF (2.47E-8 A/cm2) x 20% 

DFR after initial treatment.

2: Daily Dose = [DFR (ug/cm2) x TC (cm2/hr) x 0.001 mg/μg x Dermal Absorption (100%) x 8 hrs/day] ÷ Body Weight (70 kg).

3: MOE = NOAEL (Short- and Intermediate-term NOAEL = 10.0 mg/kg/day)/Daily Dose (LOC=100).

Inhalation: Based on the Agency's current practices, a quantitative occupational postapplication inhalation exposure assessment was not performed for pyrasulfotole at this time. 

However, there are multiple potential sources of post-application inhalation exposure to 

individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and resuspension of dusts and/or particulates that 

contain pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from its FIFRA SAP in December 2009. The Agency received the SAP’s final 

report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). 

The Agency is in the process of evaluating the SAP report as well as available post-application

inhalation exposure data generated by the Agricultural Reentry Task Force and may, as 

appropriate, develop policies and procedures, to identify the need for and, subsequently, the way

to incorporate occupational post-application inhalation exposure into the Agency's risk 

assessments. If new policies or procedures are put into place, the Agency may revisit the need 

for a quantitative occupational post-application inhalation exposure assessment for pyrasulfotole.

Restricted Re-entry Level: Pyrasulfotole is classified as acute Toxicity Category III for acute 

dermal toxicity and primary eye irritation. It is classified as Toxicity Category IV for primary

skin irritation. Therefore, the interim WPS REI of 12 hours is adequate to protect agricultural 

workers from post-application exposures to pyrasulfotole.

9.0 DATA NEEDS AND LABEL RECOMMENDATIONS
Pyrasulfotole Human-Health Risk Assessment DP#: 374607 

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9.1 Toxicology

 Immunotoxicity study.

9.2 Residue Chemistry

 Revised Section F. 

 Revised Section B.

 Analytical reference standards for pyrasulfotole-desmethyl and labeled internal standards 

must be submitted to the EPA National Pesticide Standards Repository. 

9.3 Occupational and Residential Exposure

 None.

cc: A. Nowotarski, J. Tyler, A. Dunbar

RDI: RAB1 Branch (13-OCT-2010); G. Kramer (13-OCT-2010); D. Vogel (13-OCT-2010)

A. Nowotarski: S-10941: Potomac Yard 1 (PY1): (703) 347-0138: 7509P: RAB1
Pyrasulfotole Human-Health Risk Assessment DP#: 374607 

Page 31 of 39

Appendix A: TOXICOLOGY ASSESSMENT

A.1 Acute Toxicity Profile

Table A.1. ACUTE TOXICITY PROFILE FOR PYRASULFOTOLE.

Guideline No. Study Type MRID No. Results Toxicity Category

870.1100 Acute oral toxicity (rat)

Acceptable/Guideline

46801836 LD50 > 2000 mg/kg (F) III

870.1200 Acute dermal toxicity (rat)

Acceptable/Guideline

46801837 LD50 > 2000 mg/kg 

(M,F)

III

870.1300 Acute inhalation toxicity (rat)

Acceptable/Guideline

46801838 LC50 > 5.03 mg/L (M,F) IV

870.2500 Primary dermal irritation (rabbit)

Acceptable/Guideline

46801840 Not a dermal irritant IV

870.2400 Primary eye irritation (rabbit)

Acceptable/Guideline

46801839 Moderate eye irritant III

870.2600 Skin sensitization (guinea pig)

Acceptable/Guideline

46801841 Not a dermal sensitizer N/A

A.2 Toxicity Profiles

Table A.2a. SUBCHRONIC AND CHRONIC TOXICITY AND GENOTOXICITY PROFILE FOR 

PYRASULFOTOLE.

Guideline No. Study Type Results MRID No. (year)/ 

Classification /Doses

N/A 28-day oral toxicity (mouse; 

dietary)

LOAEL = 961/1082 

mg/kg/day [M/F], based 

on gritty content in the 

urinary bladder and 

histopathology 

(urothelial hyperplasia, 

diffuse 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].

46801843 (2002) 

Acceptable/Nonguideline

0, 200, 1000, or 5000 

ppm (equal to 0/0, 

35.8/45.0, 192/233, or 

961/1082 mg/kg 

bw/day [M/F])

870.3100 90-day oral toxicity (mouse; 

dietary)

LOAEL not observed 

NOAEL = 500/617 

mg/kg/day (M/F).

46801844 (2003)

Acceptable/guideline

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])

870.3100 90-day oral toxicity (rat; dietary) LOAEL = 77 mg/kg 

bw/day (F) and 454 

46801842 (2003)

Acceptable/Guideline
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mg/kg bw/day (M), 

based on increased 

incidences of corneal 

opacity (M&F), 

mortality, and 

histopathology in the 

kidney, urinary bladder, 

thyroid, and ureters (M)

NOAEL = 2.32 mg/kg 

bw/day (F) and 66 

mg/kg bw/day (M).

0, 2, 30, 1000, 7000, or 

12000 ppm (equivalent 

to 0/0, 0.13/0.15, 

1.96/2.32, 66/77, 

454/537, or 830/956 

mg/kg bw/day [M/F])

870.3200 28-day dermal toxicity (rat) LOAEL = 100 

mg/kg/day based on 

focal degeneration of 

the pancreas (both 

sexes) and alteration of 

thyroid colloid (males)

NOAEL = 10 

mg/kg/day.

46801904 (2005)

Acceptable/Guideline

0, 10, 100, or 1000 

mg/kg bw/day

870.4300 Combined chronic 

toxicity/carcinogenicity (rat; 

dietary)

LOAEL = 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), hepatocellular 

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).

46801910 (2006)

Acceptable/Guideline

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 [M/F])

N/A 28-day oral toxicity (dog; 

dietary)

LOAEL = 171/174

mg/kg bw/day (F/M) 

based on increases in 

serum triglycerides and

elevated liver weights

(M&F), and increased 

midzonal multifocal 

vacuolation of liver 

(M).

NOAEL not observed.

46801845 (2002)

Acceptable/Nonguideline

0, 5000, 13000 or 

26000 ppm (equivalent 

to 0/0, 174/171, 

469/440 or 860/782 

mg/kg bw/day [M/F])

870.3150 29/90-day oral toxicity (dog; 

dietary)

N/A 46801901 (2004)

Unacceptable/Guideline

0, 1500, 9000 or 18000 

ppm; study terminated 

on day 29

870.3150 90-day oral toxicity (dog; 

dietary)

LOAEL not established 

NOAEL = 40/33 mg/kg 

bw/day (M/F).

46801902 (2005)

Acceptable/Guideline

0, 100, 500, or 1000 

ppm (equivalent to 0/0, 

3/3, 17/17, or 40/33 

mg/kg bw/day [M/F])
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870.3700 Prenatal developmental toxicity 

(rat; gavage)

Maternal LOAEL = 100 

mg/kg/day based on 

increased incidence of 

salivation, decreased 

corrected 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.

46801905 (2006)

Acceptable/Guideline

0, 10, 100, or 300 

mg/kg bw/day

870.3700 Prenatal developmental toxicity 

(rabbit; gavage)

Maternal LOAEL = 250 

mg/kg bw/day based on 

decreased body weight 

gain during GD 8-10 

and decreased 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.

46801906 (2006)

Acceptable/Guideline

0, 10, 75, or 250 mg/kg 

bw/day

870.3800 Reproduction and fertility effects 

(rat; dietary)

Parental LOAEL = 

2.5/3.1 mg/kg bw/day 

(M/F), based on colloid 

alteration and/or 

pigment deposition in 

the thyroid 

Parental NOAEL not 

observed.

Offspring LOAEL = 

26.3/32.6 mg/kg 

bw/day [M/F] based on 

corneal opacity and/or 

corneal 

neovascularization (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 

46801907 (2005)

Acceptable/Guideline

0, 30, 300 or 3000 ppm 

(equivalent to 

premating doses of 0/0, 

2.5/3.1, 26.3/32.6, or 

272.4/345.7 mg/kg 

bw/day [F0 M/F]; and 

0/0, 3.68/4.2, 34.1/38.9 

or 353.6/393.4 mg/kg 

bw/day [F1 M/F])
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delayed balanopreputial separation in 

F1 pups.

Reproductive NOAEL 

= 2.5/3.1 mg/kg bw/day 

(M/F).

870.4100 Chronic toxicity (dog; dietary) LOAEL = 34 (M) & 93 

(F) mg/kg/day, based 

on increased incidence 

and severity of kidney 

tubular dilatation (M) 

and cataracts (F). 

NOAEL = 7 (M) & 33 

(F) mg/kg/day.

46801908 (2006)

Acceptable/Guideline

0, 250, 1000, or 3000 

ppm (equivalent to 0/0, 

7/9, 34/33, or 101/93 

mg/kg bw/day [M/F])

870.4200 Carcinogenicity (mouse; dietary) LOAEL = 13.6/16.7 

mg/kg bw/day (M/F) 

based on increased 

incidences of 

gallstones.

NOAEL not observed.

46801909 (2006)

Acceptable/Guideline

0/0, 13.6/16.7, 137/168 

and 560/713 mg/kg 

bw/day (M/F)

870.5100 Gene mutation (bacterial; in 

vitro)

Negative 46801911 (2004)

Acceptable/Guideline

0, 16, 50, 158, 500, 

1581 or 5000 g/plate 

(+/- S9)

870.5300 Gene mutation (mammalian; in 

vitro)

Negative 46801912 (2004)

Acceptable/Guideline

0, 30, 60, 120, 240, 

480, or 960 μg/mL (+/-

S9)

870.5375 Chromosome aberration 

(mammalian; in vitro)

Negative (chromosome 

isodeletions observed at 

cytotoxic concentration 

only).

46801913 (2004)

Acceptable/Guideline

0, 200, 400, 500, 600, 

800, 1000, 1500, 2000, 

or 2500 μg/mL (+/- S9)

870.5395 Erythrocyte micronucleus 

(mouse; in vivo)

Negative 46801914 (2003)

Acceptable/Guideline

0/0, 125/250, 250/500 

or 500/1000 mg/kg bw

(M/F)

870.6200 Acute neurotoxicity (rat; gavage) LOAEL = 200 mg/kg 

bw (F) and 2000 mg/kg 

bw (M) based on 

decreased locomotor 

activity on day 0.

NOAEL not observed

in females; 500 mg/kg 

bw in males.

46801915 (2005)

Acceptable/Guideline

0, 200, 500, or 2000 

mg/kg bw

870.6200 Subchronic neurotoxicity (rat; 

dietary)

LOAEL = 42 mg/kg 

bw/day in females 

based on increased 

incidences of corneal 

opacity and corneal 

neovascularization; not 

observed in males. 

NOAEL was not 

observed in females; 

345 mg/kg bw/day in 

males.

46801916 (2005)

Acceptable/Guideline

0, 500, 2500, or 5000 

ppm (equivalent to 0/0, 

32/42, 166/206, or 

345/416 mg/kg bw/day 

[M/F])
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870.6300 Developmental neurotoxicity 

(rat; dietary)

Maternal LOAEL = 37 

mg/kg/day, based on 

ocular opacities during 

lactation.

Maternal NOAEL = 3.8

mg/kg/day.

Offspring LOAEL = 37 

mg/kg/day based on 

ocular opacity (postweaning), 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 

ophthalmoscopy

(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.

46801917 (2006)

Acceptable/Nonguideline

0, 3.8, 37, or 354 mg/kg 

bw/day (gestation and 

lactation)

N/A 14-day ocular toxicity study in rat and mouse (mechanistic). 46801922 (1995)

Acceptable/Nonguideline

N/A Effect of tyrosinemia on pregnancy and embryo-fetal 

development in rat (mechanisitic). 46801921 (2006)

Acceptable/Nonguideline

N/A In vitro inhibition of HPPD (mechanisitic). 46801920 (2006)

Acceptable/Nonguideline

N/A 14-day comparative toxicity feeding study in dog. 46801903 (2006)

Acceptable/Nonguideline

Table A.2b. TOXICITY PROFILE FOR BENZOIC ACID METABOLITE AE B197555 (RPA 203328).

Guideline 

No. 

Study Type Results MRID No. (year)/ 

Classification /Doses

870.1100 Acute oral toxicity (rat) LD50 >5000 mg/kg bw (M,

F; toxicity category IV).

43904812 (1995)

Acceptable/Guideline

5000 mg/kg bw

N/A 28-day oral toxicity (rat; dietary) LOAEL not observed.

NOAEL = 1118/1269 

mg/kg/day (M/F).

43904813 (1995)

Acceptable/Non-guideline

0, 150, 500, 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])

870.3100 90-day oral toxicity (rat; dietary) LOAEL not observed. 45655903 (1998)
Pyrasulfotole Human-Health Risk Assessment DP#: 374607 

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NOAEL = 769/952 

mg/kg/day (M/F).

Acceptable/Guideline

0, 1200, 4800, or 12000 

ppm (equivalent to 0, 

73.2/93.1, 306/371, or 

769/952 mg/kg bw/day 

[M/F])

870.3700 Prenatal developmental toxicity (rat; 

gavage)

Maternal LOAEL = 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. 

Maternal NOAEL = 75 

mg/kg bw/day.

Developmental LOAEL 

not observed.

Developmental NOAEL = 

750 mg/kg bw/day.

45655906 (1999)

Acceptable/Guideline

0, 75, 250, or 750 mg/kg 

bw/day

870.5100

Gene 

mutation 

(bacterial; in 

vitro)

0, 100, 250, 500, 1000, 2500, or 5000 

g/plate (+/- S9)

Acceptable/Guideline

Negative 43904814

870.5300

Gene 

mutation 

(mammalian; 

in vitro)

84.5-2700 μg/mL (-S9)

338-2700 μg/mL (+S9)

Acceptable/Guideline

Negative 44545301

870.5375

Chromosome 

aberration 

(mammalian; 

in vitro)

0, 924, 931, 1320, 1330, 1890, 1900, 

2700, or 2710 μg/mL (+/- S9)

Acceptable/Guideline

Negative 44545301

870.5395

Erythrocyte 

micronucleus 

(mouse; in 

vivo)

500, 1000, or 2000 mg/kg bw

Acceptable/Guideline

Negative 44545302
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A.3 Summary of Toxicological Doses and Endpoints.

Table A.3a. Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in Dietary and NonOccupational Human-Health Risk Assessments. There are no residential uses proposed for pyrasulfotole at 

this time. 

Exposure 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC for Risk 

Assessment

Study and Relevant 

Toxicological Effects

Acute Dietary 

(All 

populations)

NOAEL = 

3.8

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X 

aRfD = aPAD = 0.038 

mg/kg/day

Developmental 

neurotoxicity (rat; dietary)

Offspring LOAEL = 37 

mg/kg/day based on delayed 

preputial separation (males), 

decreased cerebrum length 

(PND 21 females), and 

decreased cerebellum height 

(PND 21 males).

Chronic 

Dietary (All 

populations)

NOAEL = 

1.0

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X

cRfD = cPAD = 

0.01mg/kg/day

Combined chronic 

toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

10/14 mg/kg/day (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).1

Incidental 

Oral

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL = 

2.5

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X 

No residential uses 

proposed.

Reproduction and fertility 

effects (rat; dietary)

Offspring LOAEL = 

26.3/32.6 mg/kg bw/day 

[M/F] based on corneal 

opacity and/or corneal 

neovascularization (F1 and 

F2 generations).

Dermal

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL = 

10

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X 

No residential uses 

proposed.

28-day dermal toxicity

(rat) LOAEL = 100 mg/kg 

bw/day [M/F] based on 

focal degeneration of 

pancreas (both sexes) and 

alteration of thyroid colloid 

(males)

Dermal

Long-Term

(>6 months)

NOAEL = 

1.0

mg/kg/day

Estimated 

dermal 

absorption 

factor = 

2.5%

UFA = 10X

UFH = 10X

UFFQPA = 1X

No residential uses 

proposed.

Combined chronic 

toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

10/14 mg/kg/day (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 
Pyrasulfotole Human-Health Risk Assessment DP#: 374607 

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Table A.3a. Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in Dietary and NonOccupational Human-Health Risk Assessments. There are no residential uses proposed for pyrasulfotole at 

this time. 

Exposure 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC for Risk 

Assessment

Study and Relevant 

Toxicological Effects

cholesterol (males).

Inhalation

(All 

durations)

NOAEL = 

1.0

mg/kg/day

100% 

inhalation 

assumed

UFA = 10X

UFH = 10X

UFFQPA = 1X

No residential uses 

proposed.

Combined chronic 

toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

10/14 mg/kg/day (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).

Cancer (oral, 

dermal, 

inhalation)

Classification: “Suggestive Evidence of Carcinogenic Potential” based on increased incidences of 

corneal tumors in male rats (oral carcinogenicity study) and urinary bladder tumors in male and 

female mice (oral carcinogenicity study).

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential 

variation in sensitivity among members of the human population (intraspecies), UFFQPA = 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 A.3b. Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in Occupational 

Human-Health Risk Assessments.

Exposure 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC for Risk 

Assessment

Study and Toxicological 

Effects

Dermal

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL = 

10

mg/kg/day

UFA = 10X

UFH = 10X

Occupational LOC for 

MOE <100

28-day dermal toxicity

(rat) LOAEL = 100 mg/kg 

bw/day [M/F] based on 

focal degeneration of 

pancreas (both sexes) and 

alteration of thyroid colloid 

(males)

Dermal

Long-Term

(>6 months)

NOAEL = 

1.0

mg/kg/day

Estimated 

dermal 

absorption 

factor = 

2.5%

UFA = 10X

UFH = 10X

Occupational LOC for 

MOE <100

Combined chronic 

toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

10/14 mg/kg/day (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).

Inhalation

(All 

NOAEL = 

1.0

UFA = 10X

UFH = 10X

Occupational LOC for 

MOE <100

Combined chronic 

toxicity/carcinogenicity 
Pyrasulfotole Human-Health Risk Assessment DP#: 374607 

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Table A.3b. Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in Occupational 

Human-Health Risk Assessments.

Exposure 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC for Risk 

Assessment

Study and Toxicological 

Effects

durations) mg/kg/day

100% 

inhalation 

assumed

(rat; dietary) LOAEL = 

10/14 mg/kg/day (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).

Cancer (oral, 

dermal, 

inhalation)

Classification: “Suggestive Evidence of Carcinogenic Potential” based on increased incidences of 

corneal tumors in male rats (oral carcinogenicity study) and urinary bladder tumors in male and 

female mice (oral carcinogenicity study).

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential 

variation in sensitivity among members of the human population (intraspecies), NOAEL = no-observed-adverseeffect level, LOAEL = lowest-observed-adverse-effect level, MOE = margin of exposure, LOC = level of concern.