                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460      

                                                 	OFFICE OF CHEMICAL SAFETY AND
                                                                                               POLLUTION PREVENTION
	



MEMORANDUM

Date:		16-MAR-2011

SUBJECT:	Pyrasulfotole:  REVISED Human-Health Risk Assessment for Proposed Section 3 Uses on Grain Sorghum and Grass Grown for Seed.

PC Code:  000692
DP Barcode:  D374607  
Decision No.:  425581
Registration No.:  264-1023
Petition No.:  9F7680
Regulatory Action:  Section 3
Risk Assessment Type:  Single Chemical/Aggregate
Case No.:  7272
TXR No.:  NA
CAS No.:  365400-11-9
MRID No.:  NA 
40 CFR:  §180.631

FROM:	Allison Nowotarski, Biologist
      Jennifer R. Tyler, Chemist 
      Anwar Y. Dunbar, Ph.D., Pharmacologist
      Risk Assessment Branch 1 (RAB1)
            Health Effects Division (HED; 7509P)

THROUGH:	George F. Kramer, Ph.D., Branch Senior Chemist
	Dana Vogel, Branch Chief 
            RAB1/HED (7509P)

TO:		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 the hazard characterization.  Specifically, the nuerotoxic and ocular toxic effects of Pyrasulfotole were separated and better distuingshed.  Characterization in the FQPA section was also revised to 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 and proposed uses of pyrasulfotole (5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)[2-(methylsulfonyl)-4-(trifluoromethyl)phenyl]methanone).  A summary of the findings and an assessment of human risk resulting from the registered and proposed uses for pyrasulfotole are 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

    
1.0	EXECUTIVE SUMMARY

Bayer CropScience has submitted a Section 3 request to register the product Huskie[(TM)] 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 end-use 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, Huskie[(TM)] 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 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 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% oral-equivalent inhalation absorption factor is assumed.  The level of concern (LOC) for occupational dermal and inhalation exposures are for margins of exposure (MOEs) <100.

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 (95[th] 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 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 restricted-entry 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 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-1H-pyrazol-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
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 Huskie[(TM)] 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 Rate[1]
(lb ai/A)
Maximum Number Applications
Per Season
Maximum Seasonal Application Rate
(lb ai/A)
PHI[2]
(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 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 20C)
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 20C)
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 20C
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

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 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 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.  

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  dose-response);
   * 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, desmethyl-parent, and benzoic acid metabolite were observed as metabolites in urine and feces at levels of 2%, <9%, and <2% of the administered dose.  Further biotransformation (including Phase II metabolism) is unknown.  Approximately 30% of labeled compound was excreted in the feces 52 hours after dosing, approximately 25% of which was parent.  Following intravenous injection, approximately 5% of parent compound was excreted in feces.  This implies that 5% of systemically absorbed parent compound is excreted in the bile.  No metabolism or absorption studies are available via the dermal or inhalation routes.  

3.2	Hazard Identification and Toxicity Endpoint Selection

A summary of the toxicological endpoints and doses chosen for the relevant exposure scenarios for dietary and occupational human health risk assessments is provided in Tables 3.2.1a 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 Non-Occupational 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).
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 Intermediate- Term (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

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 treatment-related 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 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 pyrasulfotole-desmethyl-O- glucoside.  There was also cleavage of the complete pyrazole moiety resulting in the pyrasulfotole-benzoic acid metabolite as detected by the phenyl-label study and a polar fraction (p1) formed from the pyrazole-label study.  Fraction p1 was characterized as being natural or incorporated into the matrix.  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 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 pyrasulfotole-hydroxymethyl.  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 HPLC-MS/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 AI-006-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). 

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.

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 Huskie[(TM)] 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 pyrasulfotole-desmethyl 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 Huskie[(TM)] 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
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, 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 DEEM-FCID(TM), 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 food-form (e.g., orange or orange juice) on the food commodity residue list is multiplied by the average daily consumption estimate for that food/food form 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 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-FCID(TM) 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 (95[th] 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.
                                   Population
                                    Subgroup
                                Acute Dietary[1]
                               Chronic Dietary[2]
                                        
                                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[(R)] 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 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 95[th] 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 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 long-term assessment was not conducted.  The proposed labels require mixers, loaders and other 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). 
   
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]
                                    MOEs[g]
                                       
                     Mixer/Loader for Aerial Applications
                                     0.039
                                     1200
                                    Dermal
                               Baseline[c]: 2.9 
                                PPE-G[h]: 0.023
                                    Dermal
                                Baseline:  1.9
                                 PPE-G: 0.015
                                    Dermal
                                 Baseline: 5.2
                                  PPE-G: 650
                                       
                                       
                                  Inhalation
                              Baseline[d]: 0.0012
                                  Inhalation
                               Baseline: 0.0008
                                  Inhalation
                                Baseline: 1,200
                   Mixer/Loader for Chemigation Applications
                                     0.039
                                      350
                                    Dermal
                               Baseline[c]: 2.9
                                 PPE-G: 0.023
                                    Dermal
                               Baseline[c]: 0.57
                                 PPE-G: 0.0045
                                    Dermal
                                Baseline[c]: 18
                                 PPE-G: 2,200
                                       
                                       
                                  Inhalation
                              Baseline[d]: 0.0012
                                  Inhalation
                             Baseline[d]: 0.00023
                                  Inhalation
                              Baseline[d]: 4,300
                   Mixer/Loader for Groundboom Applications
                                     0.039
                                      200
                                    Dermal
                               Baseline[c]: 2.9
                                 PPE-G: 0.023
                                    Dermal
                               Baseline[c]: 0.32
                                 PPE-G: 0.0026
                                    Dermal
                                Baseline[c]: 31
                                 PPE-G: 3,900

                                       
                                  Inhalation
                              Baseline[d]: 0.0012
                                  Inhalation
                             Baseline[d]: 0.00013
                                  Inhalation
                              Baseline[d]: 7,500
                        Applicator for Aerial Equipment
                                     0.039
                                     1200
                                    Dermal
                         Engineering control[e]: 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
                              Baseline[c]: 0.014
                                    Dermal
                              Baseline[c]: 0.0016
                                    Dermal
                              Baseline[c]: 6,400
                                       
                                       
                                  Inhalation
                             Baseline[d]: 0.00074
                                  Inhalation
                             Baseline[d]: 0.000082
                                  Inhalation
                              Baseline[d]: 12,000
                                    Flagger
                                     0.039
                                      350
                                    Dermal
                              Baseline[c]: 0.011
                                    Dermal
                              Baseline[c]: 0.0021
                                    Dermal
                              Baseline[c]: 4,700
                                       
                                       
                                  Inhalation
                             Baseline[d]: 0.00035
                                  Inhalation
                             Baseline[d]: 0.000068
                                  Inhalation
                              Baseline[d]: 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).  
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 (cm[2]/hr)
                                   Activities
                                    Sorghum
                              Field/row crop, tall
                                     0.037
                                      1000
                              Irrigation, scouting
                                        
                                        
                                        
                                      100
                                 Weeding (hand)
                            Grass grown for seed[a]
                             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)t x CF1 x CF2
 
 Where:	
 
 DFRt	=	dislodgeable foliage residue on day "t" (ug/cm[2])
 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 (ug/cm[2]) x 0.001 mg/ug x TC (cm[2]/hr) x DA x ET (hrs)]  /  BW (kg)
		
Where:
		DFRt 	=	dislodgeable foliage residue on day "t" (ug/cm[2]);
		TC	=	transfer coefficient (cm[2]/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
                                  (cm[2]/hr)
                                DFR1 (ug/cm[2])
                             Days After Treatment
                                 Daily Dose[2]
                                    (mg/kg/
                                     day)
                                    MOE[3]
                            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 (ug/cm[2]) = Application Rate (lb ai/A) x (1- Daily Dissipation Rate)[t] x CF (4.54E+8 ug/lb) x CF (2.47E-8 A/cm[2]) x 20% DFR after initial treatment.
2:  Daily Dose = [DFR (ug/cm[2]) x TC (cm[2]/hr) x 0.001 mg/ug 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 post-application 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

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
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/Non-guideline
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 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).
46801842 (2003)
Acceptable/Guideline
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/Non-guideline
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])
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 delayed balano-preputial separation in F1 pups.
Reproductive NOAEL = 2.5/3.1 mg/kg bw/day (M/F).
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])

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])

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 (post-weaning), decreased body weight, delayed preputial separation (males), increase in number of trials to criterion and decreases in trial latencies (passive avoidance; PND 22 males), retinal degeneration at 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/Non-guideline
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/Non-guideline
N/A
Effect of tyrosinemia on pregnancy and embryo-fetal development in rat (mechanisitic).




46801921 (2006)
Acceptable/Non-guideline
N/A
In vitro inhibition of HPPD (mechanisitic).

46801920 (2006)
Acceptable/Non-guideline
N/A
14-day comparative toxicity feeding study in dog.


46801903 (2006)
Acceptable/Non-guideline

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. 
NOAEL = 769/952 mg/kg/day (M/F).
45655903 (1998)
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
A.3	Summary of Toxicological Doses and Endpoints.

Table A.3a.  Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in Dietary and Non-Occupational 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 Intermediate-Term (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 Intermediate- Term (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 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 Intermediate- Term (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), NOAEL = no-observed-adverse-effect level, LOAEL = lowest-observed-adverse-effect level, MOE = margin of exposure, LOC = level of concern.

