Py

rasulfotole Human

UNITED STA

TES ENVIRONMENTA L PROTECTION AGENCY

MEMORANDUM Date: 16
- MAR
- 201 1 SUBJECT: Pyrasulfotole: REVISED

3 Uses on Grain Sorghum and Grass Grown for Seed. PC Code: 0 00692 Decision No.: 425581 Petition No.: 9F7680 Risk Assessment Type: Single Chemical/Aggregate T XR No.: NA MRID No.: NA FROM: Allison Nowotarski, Biologist

Jennifer R. Tyler, Chemist Anwar Y. Dunbar, Ph.D., Pharmacologist Risk Assessment Branch 1 (RAB1) Health Effects Division (HED THROUGH: George F. Kramer, Ph.D., Branch Senior Chemist

Dana Vogel, Branch Chief RAB1/HED (7509P) TO: Bethan y Benbow/

Registration Division (7505P) This Risk Assessment has been revised from the October 20, 2010 draft to modify language in the hazard characterization . Specificall y, were separated and better distuingshed to better reflect the current endpoints. strengthen the rationale for using a non The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The RD of OPP exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from all registered and proposed uses of p yr asulfo tole ( (methylsulfonyl)
- 4
- (trifluoromethyl)phenyl]methanone assessment of human risk resulting from the registered and proposed uses for pyrasulfotole are Human
- Health Risk Assessment

Page 1 of 39 UNITED STA

TES ENVIRONMENTA L PROTECTION AGENCY WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

REVISED Human
- Health Risk Assessment for Proposed Section Sorghum and Grass Grown for Seed. DP Barcode: D374607 Registration No. : 264
- 1023 Regulatory Action: Section 3 Single Chemical/Aggregate Case No.: 7272 CAS No.: 365400
- 11
- 9 40 CFR: §180.631 Allison Nowotarski, Biologist Jennifer R. Tyler, Chemist

Dunbar, Ph.D., Pharmacologist Risk Assessment Branch 1 (RAB1) Health Effects Division (HED ; 7509P)

Kramer, Ph.D., Branch Senior Chemist Dana Vogel, Branch Chief RAB1/HED (7509P) Bethan y Benbow/ Joanne Miller, RM 23 Registration Division (7505P) This Risk Assessment has been revised from the October 20, 2010 draft to modify language in . Specificall y, the nuerotoxic and ocular toxic effects of P yr asulfotole were separated and better distuingshed . Characterization in the FQPA section was also revised better reflect the current endpoints. Finally , language was added to the cancer assessment to strengthen the rationale for using a non
- linear approach for cancer risk. The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from all registered tole ( 5
- hydrox y - 1,3
- dimethyl
- 1 H
- py razol
- 4
- yl )[2 (trifluoromethyl)phenyl]methanone ). A summary of the findings and an assessment of human risk resulting from the registered and proposed uses for pyrasulfotole are DP#: 374607 UNITED STA

TES ENVIRONMENTA L PROTECTION AGENCY
OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

Health Risk Assessment for Proposed Section

1023 Section 3

This Risk Assessment has been revised from the October 20, 2010 draft to modify language in nuerotoxic and ocular toxic effects of P yr asulfotole . Characterization in the FQPA section was also revised

added to the cancer assessment to The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from all registered yl )[2
- ). A summary

of the findings and an assessment of human risk resulting from the registered and proposed uses for pyrasulfotole arePy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 2 of 39 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 b y Anwar D unbar (RAB1), and the drinking water assessm ent 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 Propos ed Use Pattern ................................ ................................ ................................ ... 8 3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS ............................. 10 3.1 Hazard Profile ................................ ................................ ................................ ............. 10 3.2 Hazard Ide ntification 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 FQ PA 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) EXPOSU RE/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 ................................ ................................ ................................ .......... 31Py

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 3 of 39 1.0 EXECUTIVE SUMMARY Ba ye r CropScien ce has submitted a Section 3 request to register the product Huskie TM Herbicide, containing p yr asulfotole as one of the active ingredients (ai), on grain sorghum and grass grown for seed. P yr asulfotole is currentl y registered for use on small grains such as wheat, barley , oats, rye, and triticale. Py rasulfotole is an ef

fective inhibitor of the enzyme 4
- hydroxy phen ylpy ruvate dioxygenase (HPPD) and consequently blocks the pathway of prenylquinone biosy

nthesis 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 sy mptoms appear three to five day s after application. Bleaching and discoloration appear initiall y and s ymptoms 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 adequ ate for purposes of risk assessment. Py rasulfotole has a low to moderate acute toxicity (Appendix A.2) via the oral, dermal, and inhalation routes (Category I II or IV). Py

rasulfotole is not a dermal sensitizer or irritant (Category IV) and has been shown to be a moderate eye irritant (Category III). The ey e is the primary target organ of py

rasulfotole. D ecreased 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 py rasulfotole for 90 day s (subchronic oral exposure) either in the diet or b y gavage. Mortality and multi
- organ histopathology

in the kidney , urinary

bladder, thy

roid, and ureters were also o bserved 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 day s. 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 carcinogenici ty

study . Rats treated with py rasulfotole for 28 day s by the dermal route demonstrated toxicity

of the thy

roid and pancreas. Chronic oral exposure of rats to py rasulfotole resulted in extensive ey e toxicity at almost all doses tested. These included cor neal opacit y, neovascularization of the cornea, inflammation of the cornea, regenerative corneal h yp erplasia, corneal atroph y, and/or retinal atrophy. Ocular toxicity is believed to be an indirect result of ty rosinemia caused b y inhibition of hepatic HPPD
. In mice, ocular toxicity

was not observed at any

dose, thereb y reflecting accepted differences in effects among rodent species for HPPD inhibit ors . L ong - term exposure of mice to py rasulfotole did cause toxicity

of the urinary

s ys tem, including the kidne y, urinary bladder, and ureters at the highest dose tested , as well as gallstone formation at all doses tested. Dogs treated with py rasulfotole for one year exhibited toxicity of the urinary

s ys tem (kidney s and bladder) at mid and high doses, as well as c ataracts 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 onl y at the highest dose tested. HED’sPy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 4 of 39 Carcinogenicit y Assessment Review Committee (CARC) considered these rare tumors, which were observed following adequate dosing, to be treatment
- related. In the carcinogenicit y stud y 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 b y urinary bladder stones. Py

rasulfotole 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 (Q 1 *) extrapolation ap proach 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 preput ial separation, morphometric changes, delay s 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 offs pring. 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 onl y 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 reproduc tive toxicity study in rats, ocular toxicity

(keratitis, corneal opacit y and/or corneal neovascularization), was observed at the mid and high doses in the adults and offspring of two generations. Thy roid (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, delay s in balanopreputial separation (males) and vaginal patency

(females) were observ ed in first
- generation offspring. Following oral administration of 10 mg/kg phen yl or py razole ring
- labeled py

rasulfotole , ~60% of radio labeled compound was excreted in the urine after 6 h ours, while ~73% of the administered dose was recovered in the urine b y 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 h ours after dosing, approximately 25% of which was parent. Py rasulfotole was metabolized vi a hydrox yl ation and N
- demeth yl ation. Dose Response Assessment and Food Quality Protection Act (FQPA) Decision : The py rasulfotole risk assessment team recommends that the 10X FQPA S afety F actor (SF) for the protection of infants and children be reduced to 1X since there is a complete toxicity database for py rasulfotole and exposure data are complete or are estimated based on data that reasonabl y account for potential exposures. The recommendation is based on the following: 1) ClearPy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 5 of 39 NOAELs were establishe d 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 expos ure 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 b y model s 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 p yrasulfotole which would result in residential exposure. Risk assessments were conducted for the following specific exposure scenarios listed be low. The acute and chronic referen ce doses (aRfD and cRfD) were cal culated b y 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, respectivel y. 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 Di etary 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 Survey s 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 anal ys es were performed to support Section 3 requests for use of p yr asulfotole 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 prop osed uses. Drinking water was incorporated directl y into the dietary assessment using the acute concentration for surface water generated b y the FQPA Index Reservoir Screening Tool (FIRST) model. The results of this assessment indicate that the acute die tary 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 highl y exposed population subgrou p 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 incorporate d 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 gene ral U.S. population (4 % of the cPAD) and all population subgroups. The most highl y exposed population subgroup is children 1
- 2 years old at 16 % of the cPAD. Aggregate-

Risk Estimates: F or the proposed uses, human
- health aggregate risk assessmentsPy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 6 of 39 have be en conducted for the following exposure scenarios: acute aggregate exposure (food + drinking water), and chronic aggregate exposure (f ood + drinking water). Short
- and intermediate
- term aggregate risk assessments were not performed because there are no r egistered or proposed uses which result in significant residential exposure
. Py rasulfotole is classified as “Suggestive Evidence of Carcinogenicity; ” however, the HED CARC recommended that a separate quantification of cancer risk is not required. All agg regate exposure a nd 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 mo nitoring data are not available. All inhalation risks for occupational handle rs are above the target MOE of 1 00 with baseline protection (i.e., no respirator) , and , therefore, do not exceed the LOC
. All dermal risks for occupational handle rs are above the target MOE of 1 00 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 py rasulfotole 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 ≥1 00) on the day of treatment (i.e., Day

0) for all post - application exposure activities. Bas ed on the Agency 's current practices, a quantitative occupational post - application inhalation exposure assessment was not performed for py

rasulfotole at this time. Py rasulfotole is classified as acute Toxicity Category I II for acute oral and acute derma l toxicity and primary

eye irritation . It is classified as T oxicity C ategory 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 pr otect agricultural workers from exposures to py rasulfotole
. The proposed label ha s 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 Lo w - Income Populations,” ( http://www.hss.energy .gov/nuclearsafet y/ env/guidance/justice/eo12898.pdf ). As a part of every

pesticide risk assessment, OPP considers a large variet y 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 compiledPy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 7 of 39 by the USDA under CSFII and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, 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 cond itions 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 by standers and farm workers as well as lifest yle and traditional di etary 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 s uch 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 exposur e databases, and on the basis of available evidence has found them to have been neither fundamentall y unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted. There is no regulatory barri er 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 co mmodity definitions and tolerance expressions; and 3) anal ytical reference standards for p yrasulfotole
- 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 i mmunotoxicity study
. Tolerances are established for residues of the herbicide py rasulfotole, 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 b y measuring onl y the sum of pyrasu lfotole ((5
- hydrox y - 1,3
- dimethyl
- 1 H
- py razol
- 4
- yl )[2
- (methylsulfonyl)
- 4
- (trifluorometh yl )phen yl ]methanone) and its desmethyl metabolite (5
- hydroxy
- 3
- methyl
- 1 H
py razol
- 4
- yl )[2
- (methylsulfonyl)
- 4
- (trifluoromethyl)phenyl]methanone), calculated as the stoichiom etric equivalent of py rasulfotole, 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 ppmPy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 8 of 39 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.  Analy tical reference standards for p yr asulfotole
- 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 Ba ye r 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 ty pe/equipment or spray

volume for grass grown for seed. The submitted magnitude of residue studies were performed without the use of adjuv ants. Therefore, the label should be amended to prohibit the use of adjuvants on grain sorghum and grass grown for seed. In addition, thePy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 9 of 39 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 Py rasulfotole 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
- 1 H
- 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 Py rasulfotole
- desmethyl Company Experimental name AE 1073910 CAS name (5
- hydroxy
- 1 H
- py razol
- 4
- yl)[2
- mesyl
- 4
- (trifluoromethyl)phenyl]methanone Table 2.2.2. Physicochemical Properties of the Technical Grade Test Compound
. Parameter Value Reference Melting point Pure: 201°C No boiling point, decomposition starts at 245°C

MRID 46801701 pH at 22.9°C 3.03 Density 1.53 Water solubility (g/L at 20  C) 2.3 4.2 69.1 49.0 pH 3.0 (distilled water) pH 3.9 (buffer pH 4.0) pH 5.4 (buffer pH 7.0)* pH 5.2 (buffer pH 9.0)* * exceeded buffer capacity Solvent solubility (g/L at 20  C) Ethanol n - Hexane Tolune Dichloromethane Acetone Ethyl acetate Dimethyl sulfoxide 21.6 0.038 6.86 120
- 150 89.2 37.2 ≥ 600 Vapor pressure at 20  C 2.7 X 10 - 7 Pa Dissociation constant (pKa) 4.2 n - octanol
- water partition coefficient Log(KOW) at 23°C 0.276

- 1.362

- 1.580 pH 4.0 pH 7.0 pH 9.0 O S

F 3 C O O

N N

H O H N N

F 3 C O

S O

H O OPy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 10 of 39 Table 2.2.2. Physicochemical Properties of the Technical Grade Test Compound
. Parameter Value Reference UV/visible absorption spectrum  ma x = 264, 241, 216 nm in water, 0.1M HCl, 0.1M NaOH respectively. 3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS 3.1 Hazard Profile Py rasulfotole has a low to moderate order of acute toxicity via the oral, dermal, and inhalation routes (Category

I II or IV). Py

rasulfotole is not a dermal sensitizer or irritant (Category IV) and has been shown to be a moderate ey e irritant (Category I II). D ecreased locomotor activity was observed on the day

of treatment at the limit dose in males only in the acute neurotoxicity study in the rat. Py rasulfotole is an inhibitor of the hepatic enzy me 4
- hydroxy

phen ylpy ruvate dioxygenase (HPPD)
. HPPD is an important enzy me in the catabolism of the amino acid ty rosine. In mammals, inhibition of HPPD leads to an increase in blood ty rosine concentrations (hy pert yrosinemia) that is often followed b y ocular toxicity
. Ocular toxicity was obse rved in male and female rats exposed to py rasulfotole for 90 day s ( subchronic ) either in the diet or b y gavage. Mortality

and multi
- organ histopathology in the kidney , urinary bladder, thy

roid, 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 day s. Neither effect was reproduced in the 90
- day toxicity study in mice; however, urinary bladder toxicity

wa s observed in the 29
- day toxicity study in the dog, the 90
- day

toxicity study in the rat, and the mouse carcinogenicit y study. Rats treated with pyrasulfotole for 28 days by the dermal route demonstrated toxicity of the thy

roid and pancreas. Chronic oral exposure of rats to p yrasulfotole resulted in extensive eye toxicity at almost all doses tested. These included corneal opacit y, neovascularization of the cornea, inflammation of the cornea, regenerative corneal h yp erplasia, corneal atroph y, and/or retin al atrophy . Ocular toxicity is believed to be the result of hy perty rosinemia caused b y inhibition of hepatic HPPD, as mentioned above. In mice, ocular toxicity was not observed at any

dose, which reflect s accepted differences in effect s among rodent spec ies (mouse less sensitive) for HPPD inhibit ors . However, l ong - term exposure of mice to p yr asulfotole did cause toxicity of the urinary

s ys tem, including the kidney , urinary bladder, and ureters at the highest dose tested , as well as gallstone formation at all doses tested. Dogs treated with py rasulfotole for one year exhibited toxicity of the urinary

s ys tem (kidney s 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/carcino genicity study in rats, an increase in the incidence of corneal squamous cell tumors was observed in males onl y at the highest d ose 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 c onsidered excessive due to increased mortality caused b y urinary

bladder stones. Py

ra sulfotole 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 CARCPy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 11 of 39 determined that quantification of human cancer risk using a linear low
- dose (Q 1 *) 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 pla centa, clinical signs) at the same dose. In the DNT study in rats, ocular toxicity as well as several adverse developmental effects (delay ed preputial separation, morphometric changes, delay s in learning/memory) were observed at the mid dose. Ocular toxi city was also observed at this dose in maternal animals; an identical NOAELwas 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 onl y at the next highest dose tested. Therefore, increased susceptibility of offspring was observed in the rabbit developmental toxicity study but n ot 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. Thy roid (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 c olloid alteration and pigment deposition were of minimal severity in the 2
- generation reproductive toxicity

stu dy , they

were not considered to be a concern. At the highest dose tested, decreased viabilit y and decreased body weight were observed in offspring of both generations. At the mid and/or high doses, delay s 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 we ight, decreased cerebrum length decreased cerebellum height, and learning deficits, and the changes in brain morphometry
. The Cancer c lassification for p yrasulfotole 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 p yr asulfotole. This classification is based on the presence of ocular tumors in male rats and urinary bladder tumors in male and female m ice. 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 generall y would not support one.Py

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 12 of 39 In the case of p yr asulfotole, cancer risk from dietary exposure is less of a concern based on the following weight of evidence considerat ions:

 The low incidences (2/55) of ocular tumors seen only at the high dose and was associated with widespread corneal inflammation, hy perplasia, metaplasia, neurovascularization and atroph y;  It is biologicall y plausible for corneal tumors to result from a nongenotoxic mode of action that was secondary to corneal inflammation and regenerative hyperplasia caused by t yrosine;  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 excessiv e dose due to occurrence of death, bladder stones, and bladder h yp erplasia;  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 b y the concurrent presence of secondary inflammation and hy

perplastic lesion s in the urinary bladder induced by

the urinary stones ;  In both species tumors were observed onl y at the highest dose tested (i.e., lack of dose
response);  Py rasulfotole 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 approximately 100
- 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 adequatel y account for all chronic effects, including carcinogenicity , likel y t o result from exposure to the py

rasulfotole
. One single/low
- dose disposition study by the oral and intravenous routes in rats was performed with py rasulfotole. Following oral administration of 10 mg/kg phen ylor p yrazole ring
- labeled py rasulfotole , ~60% of radio labeled compound was excreted in the urine after 6 h ours, while ~73% of the administered dose was recovered in the urine b y the time of sacrifice (52 hours). Ther efore, 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 . Hydrox ym eth yl
- parent, desmeth yl
parent , an d benzoic acid metabolite were ob served 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 inject ion, approximately

5% of parent compound was excreted in feces. This implies that 5% of sy stemicall y absorbed parent compound is excreted in the bile. No metabolism or absorption studies are available via the dermal or inhalation routes. 3.2 Hazard Id entification and Toxicity Endpoint SelectionPy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 13 of 39 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 conventiona l interspecies extrapolation (10X ) and intraspecies variation (10X ) uncertaint y factors were applied for all exposure scenarios. T he FQPA SF for increased susceptibility

was reduced to 1X for all exposures scenarios. Based on the available toxicity datab ase and the Agency 's current practices, the inhalation risk for p yrasulfatole 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 toxici ty 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/m eetings/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 t oxicity

data. If any

new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for py rasulfotole and/or a re
- examination of the inhalation toxicity

risk assessment. 3.2.1 Summary of Toxicological Dos es 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 Hum an 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 Ac ute Dietary (All populations) NOAEL =

3.8 mg/kg/day UF A = 10X

UF H = 10X UF FQPA = 1X aRfD = aPAD = 0.038

mg/kg/day Developm ental 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 UF A = 10X

UF H = 10X UF FQPA = 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).Py

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 14 of 39 Abbreviations: UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF FQPA = FQPA Safety Factor , NOAEL = no
- observed
- adverse
- effect level, LOAEL = lowest
- observed
- adverse
- effect level, RfD = reference dose (a = acute, c = chronic), PAD = population
- adjusted dose, MOE = margin of exposure, LOC = level of concern. 1 The cRfD was harmonized across American (USEPA), Canadian (PMRA), and Australian (APVMA ) regulatory agencies based on ocular toxicity observed in the c om bined chronic toxicity/carcinogenicity study in rats. Table 3.2.1b . Summ ary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in Occupational Hum an Health Risk Assessments . E xposure Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, LO C for Risk

Assessment Study and Toxicological Effects Dermal Short
- and Intermediate
Term (1
- 30 days and 1
- 6 mo nths) NOAEL =

10 mg/kg/day UF A = 10X

UF H = 10X Occupational LOC for

MOE <100 28 - day derm al 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 fa ctor = 2.5% UF A = 10X

UF H = 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 UF A = 10X

UF H = 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, UF A = extrapolation from animal to human (interspecies), UF H = potential variation i n sensitivity among members of the human population (intraspecies), UF FQPA = FQPA Safety Factor , NOAEL = no
- observed
- adverse
- effect level, LOAEL = lowest
- observed
- adverse
- effect level, MOE = margin of exposure, LOC = level of concern. 3.3 FQ PA ConsiderationsPy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 15 of 39 T he py rasulfotole risk assessment team recommends that the 10X FQPA SF for increased susceptibility

be reduced to 1X f

or all exposure scenarios . This recommendation is based on the following considerations :

 The toxicology

database is adequate for FQPA assessment.  T here 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 deve lopmental 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 sk eletal 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. T he 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 stud y chosen for the chronic endpoint also ha s a well defined NOAEL that is 42
- and 3 7
- fold lower than the effects observed in the subchronic and developmental neurotoxicity studies.  The toxicology

database for py

rasulfotole does not show any evidence of treatment
related effects on the immune sy stem. The overall weight of evid ence suggests that this chemical does not directly target the immune s ys tem . 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 currentl y used for overall risk assessment, and therefore, a database uncertainty factor (UF DB ) is not needed to account for lack of this study
. T here 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 propo sed 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 b y 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 p yra sulfotole 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 employ s a two - tiered approach to making the st atutorily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or th yroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 s creening and are found to have the potential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPAPy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 16 of 39 will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is d esigned to identify an y 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 pathway s such as food and water, residential activity , and certain p ost - application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors. Py rasulfotole 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. Accordingl y, 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 proce dures, 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 exp osure, the dietary and drinking w ater 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 b y 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 py rasulfotole 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 py rasulfotole in spring wheat involves the demethylation an d subsequent glucos yl ation of the parent compound, yielding py rasulfotole
desmethyl
- O
- glucoside. There was also cleavage of the complete p yr azole moiety resulting in the py rasulfotole
- benzoic acid metabolite as detected by the phenyl
- label study

and a po lar fraction (p1) formed from the py razole
- 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 p yr asulfotole
- desmethyl are the residues of concern f or tolerances and risk assessment purposes (Memo, J. Tyler et al. , 06/08/07; D328640). An y 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 py rasulfotole residues in lives tock is understood based on previously submitted and reviewed lactating goat and laying henPy

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 17 of 39 metabolism studies (Memo, J. Tyler, 6/8/07; D333412). The goat study indicates that the metabolism of py

rasulfotole i n lactating goats involved either N
- demeth yl ation of py

rasulfotole to form py

rasulfotole
- desmethyl, or oxidation of py rasulfotole to form py

rasulfotole
hydrox ym ethyl. The hen study indicates that the metabolism of py rasulfotole in laying hens involved the N

- demeth yl ation of py

rasulfotole to yield the py rasulfotole
- 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 Analyt

ical Method - Plants: An adequate high
- performance liquid chromatography (HPL C)/mass spectrometry (MS)/MS method (Method AI
- 001
- P04
- 02) is available for collecting data on residues of p yrasulfotole and its metabolite pyrasulfotole
- desmeth ylin/on cereal grain and grass commodities. The limit of quantitation (L OQ) is 0.010 ppm for each anal yt e. A similar method, Method AI
- 001
- P04
- 01, which is also the proposed enforcement method for the currentl y registered/proposed plant commodities, has been adequatel y radiovalidated and undergone a successful independent laboratory validation (ILV) trial. Method AI
- 001
- P04
- 01 was forwarded to the Analy tical Chemistry

Branch of the Biological & Economics Anal ys is 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 anal yt e identities (Memo , C. Stafford, 6/7/07; D335559). In response, the compan y 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 py rasulf otole and p yrasulfotole
- desmeth ylin 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 p yr asulfotole in livestock t issues, including milk, matrice s was previousl y 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 p yr asulfotole and py rasulfotole
- desmethyl for tolerance and ris k assessment purposes (Memo, J. Tyler et al. , 6/8/07; D328640). Therefore, HED requested the petitioner submit a ruminant anal yt ical enforcement method to determine residues of p yr asulfotole and py rasulfotole
- desmeth ylas well as adequate radiovalidation and ILV data. In response, the compan y submitted a new HPLC
MS/MS (Method AI
- 006
- A08
- 01) for collecting py rasulfotole and py

rasulfotole
- desmeth yl 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 de termined 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): Py rasulfotole and the metabolite py rasulfotole
- desmeth ylwere subjected to anal ys is by

selected Protocols of the Food and Drug Administration (FDA) Pesticide Analy tical Manual, Volume I(PAM I), third edition. The results indicate that py rasulfotole is partially recovered through Protocol B, and completely recovered through Protocol C module DG
- 17. Py

rasulfotole
- 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).Py

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 18 of 39 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 py rasulfotole and py

rasulfotole
- benzoic acid are stable in so yb ean seed and wheat matrices for up to 11 months, and residues of p yrasulfotole
- 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 py rasulfotole
- 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 p yr asulfotole
- desmeth ylfrom plant to livestock to be equivalent to that of the parent p yr asulfotole 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 py rasulfotole
- desmeth yl
. 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 res idues 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 p yr asulfotole and py rasulfotole
- 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 sh eep at 3.0 ppm; and meat by products, 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 comm odities. Based upon a MRDB of 0.56 ppm for hogs, there is no reasonable expectation of finding quantifiable residues of py rasulfotole and py

rasulfotole
- desmeth ylin hog muscle and fat; thus, the current tolerances of 0.02 ppm are adequate. There is reaso nable expectation of residues of py rasulfotole and py

rasulfotole
- desmeth ylin hog liver and kidney . Therefore, the following tolerances for residues of py rasulfotole and py

rasulfotole
- desmeth ylare necessary : hog, meat by products, except liver at 0.05 pp m; 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 t o determine the need for poultry tolerances as only

residues of py

rasulfotole
- 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 stud y and/or poultry tolerances. Based on the MRDB of 0.52 ppm for poultry , the phenyl
- labeled (8.6 ppm) and py razole
- labeled (10.5 ppm) poultry metabolism studies were conducted at 16x and 20x the MRDB for poultry , respectivel y. Based on the results of the poultry metabolis m study, there is no reasonable expectation of finding quantifiable residues of py rasulfotole and py

rasulfotole
- desmeth ylin eggs and po ultry muscle and fat; thus, the current tolerances of 0.02 ppm for residues of p yr asulfotole and py rasulfotole
- desmethyl in fat, meat, and meat b yproducts of poultry are adequate . There is reasonable expectation of residues of py rasulfotole and py

rasulfotole
- desmeth ylin poultry meat by products. Therefore, a tolerance of 0.20 ppm for residues of py rasulfotole and py

rasulf otole desmeth ylin poultry by products is necessary . A revised Section F should be submitted to include the above tolerances and correct tolerance expression for livestock commodities.Py

rasulfotole Human
- Health Risk Assessment DP#: 374607

Page 19 of 39 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 py rasulfotole
- desmeth ylwhen 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 day s for forage, 60 day s for grain and stover ]. With these use patterns, total residues of py rasulfotole and py

rasulfotole
- desmeth ylare not expected to exceed 0.902 ppm (forage, 7
- day PH I), 0.325 ppm (grain), and 0.420 ppm (stover). Using the North American Free Trade Agreement (NAFTA) Maximum Residue L imit (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 py rasulfotole and py rasulfotole
- 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 . Sectio n 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 (PHIof 7 day s for forage, and 30 day s hay). With these use patterns, total py rasulfotole and py

rasulfotole
desmethyl residue levels are not expected to exceed 6.52 ppm (forage, 7
- day PH I) 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 py rasulfotole and py

rasulfotole
- des methyl 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 subm itted 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 currentl y approved Huskie TM Herbicide (EPA Reg. No. 264
- 1023). The submitted confined and limited field trial data support the proposed PBI s . Proposed and Recommended Tolerances: The residue chemistry database supports the establishment of the permanent tolerances for the combined residues of p yrasulfotole and py rasulfotole
- desmeth ylin/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 c ommodities. 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, grainPy

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Page 20 of 39 Table 4.1.1 . Tolerance Summary for Pyrasulfotole.

Commodity Current Tolerance (ppm) Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments ( correct commodity definition ) Sorghum, forage
- 1.2 1.5 Sorghum, grain, forage Sorghum, stover
- 0.35 0.80 Sorghum, grain, stover Grass, forage
- 10 25 Grass, hay
- 2.5 3.5 Milk* 0.01 0.01 0.03 Cattle, meat 0.02 0.04 see current tolerance Cattle, fat* 0.02 0.04 0.03 Cattle, meat byproducts* 0.06 2 0.70 Cattle, meat byproducts, except liver Cattle, liver* 0.35 8 3.0 Goat, meat 0.02 0.04 see current tolerance Goat, fat* 0.02 0.04 0.03 Goat, meat byproducts* 0.06 2 0.70 Goat, meat byproducts, except liver Goat, liver* 0.35 8 3.0 Hog, meat 0.02 0.04 see current tolerance Hog, fat 0.02 0.04 see current tolerance Hog, meat byproducts* 0.06 2 0.05 Hog, meat byproducts, except liver Hog, liver*
- 8 0.30 Sheep, meat 0.02 0.04 see current tolerance Sheep, fat* 0.02 0.04 0.03 Sheep, meat byproducts* 0.06 2 0.70 Sheep, meat byproducts, except liver Sheep, liver* 0.35 8 3.0 Horse, meat 0.02 0.04 see current tolerance Horse, fat* 0.02 0.04 0.03 Horse, meat byproducts* 0.06 2 0.70 Horse, meat byproducts, except liver Horse, liver* 0.35 8 3.0 Poultry, meat 0.02
- see current tolerance Poultry, fat* 0.02
- 0.03 Poultry, meat byproducts* 0.02
- 0.20 Eggs 0.02
- see current tolerance * Livestock commodities with tolerances that are not harmonized with PMRA. There are no established Mexican or Codex MRLs for the proposed uses. There are Canadian MRL s 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 an d surface water estimated drinking water concentrations ( EDWCs ) for py rasulfotole ( 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 y ear, at a rate of 0.039 lbs ai/A/application and a retreatment interval of 11 day s, as specified b y 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 environm ental degradate,Py

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Page 21 of 39 py rasulfotole
- 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 f

or the proposed

/registered uses of p yrasulfotole 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. T ier 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 anal ys es were performed to support Section 3 requests for use of py rasulfotole on grain sorghum and grass grown for seed. Py rasulfotole acute and chronic dietary exposure assessments were conducted using the DEEM
FCIDTM, 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 day s. 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 publicl y available recipe translation files develope d 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 anal ys is 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 ye ar old), children 1
- 2, children 3
- 5, children 6
- 12, youth 13
- 19, adults 20
- 49, females 13
- 49, and adults 50+ y ears 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 dail y 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 fo r 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 exp osure 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 ., onl y those who reported eatingPy

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Page 22 of 39 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 anal ysis. However, for tiers 1 and 2, an y significant differences in user vs. per capita exposure and risk are specificall y identified and noted in the risk assessment. As stated above, for acute and chronic assessments, HED is concerned wh en dietary risk exceeds 100% of the PAD. The DEEM
- FCIDTM anal ys es 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 ye ar old), ch ildren 1
- 2, ch ildren 3
- 5, children 6
- 12, youth 13
- 19, females 13
- 49, adults 20
- 49, and a dults 50+ y ears . 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 directl y 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 subgroup s. The most highl y exposed population subgroup is children 1
- 2 years old at 9% of the aPAD. These analy ses are considered to be conservative dietary exposure assessments. Residues were assumed to be equivalent to the tolerance levels. Tolerance
- level residues should alway s 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). Sampl es are stored frozen until anal ys is 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 analy ses could be made through the u se of monitoring data, %CT data, and additional empirical processing factors. Since risk estimates are not of concern to HED, a more highl y refined analysis is not needed at this time. 4.3.2 Chronic Dietary Exposure/Risk The chronic dietary

exposure ass essment (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 usin g 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 highl y 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.Py

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Page 23 of 39 Population Subgroup Acute Dietary 1 Chronic Dietary 2 Dietary Exposure (m g/kg/day) % aPAD Dietary Exposure (m g/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) EXPOSU RE/RISK CHARACTERIZATION There are no residential uses proposed or currently registered for p yr asulfotole. Therefore, residential handler and post
- application exposure/risk were not assessed. 5 .1 Spray Drift Spray drift is al way s 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 py rasulfotole. 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 fo r 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 appropriatel y apply the data and the AgDRIFT ® computer model to its risk assessments for pesticides applied b y 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 b ys tander post - application inhalation exposure assessment was not performed for py rasulfotole at this time . However, volatilization of pesticides may be a potential source of post - application inhalation exposure to individuals nearb y to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from it s FIFRA SAP in December 2009. ThePy

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Page 24 of 39 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 polici es 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 py rasulfotole
. 6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION Chronic and acute a ggregate exposure risk assessment s w ere perform ed by incorporating the drinking water directly

into the di etary - exposure assessment for the chronic and acute exposure scenario s . 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 reside ntial non
- food uses
. Py rasulfotole is classified as “Suggestive Evidence of Carcinogenicit y; ” however, the HED CARC recommended that a separate quantification of cancer risk is not required. Therefore, cancer aggregate risk assessment s were not performed
. 6.1 Acute Aggregate Risk The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of py

rasulfot o le (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 pop ulation 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 a gricultural uses and a Tier 1 acute surface water EDWCs generated by FIRST. T he refore, the acute aggregate risk associated with the proposed uses of p yrasulfotole 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 py

rasulfotole (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 b y FIRST. Therefore, the chronic aggregate risk associated with the proposed uses of p yrasulfotole is not of concern to HED for the general U.S. population or any population subgroups. 7 .0 CUMULATIVE RISK CHARACTERIZAT ION/ASSESSMENT P yrasulfotole, mesotrione, isoxaflutole and topramezone belong to a class of herbicides that inhibit the liver enzy

me HPPD, which is involved in the catabolism (metabolic breakdown) of ty rosine (an amino acid derived from proteins in the di et). Inhibition of HPPD can result in elevated t yrosine 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 an d kidney effects. Of these toxicities, it is the ocular effect (corneal opacity) that is highl y correlated with the elevated blood tyrosine levels. Infact, rats dosed withPy

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Page 25 of 39 ty rosine alone show ocular opacities similar to those seen with HPPD inhibitors. Although the other toxicities may

be associated with chemically
- induced t yrosinemia, 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 b y HPPD inhibition. The explanation of this species
- specific response in ocular opacity is related to th e species differences in the clearance of tyrosine. A metabolic pathway exists to remove tyrosine from the blood that involves a liver enz ym e called ty rosine 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 ty rosine 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 highl y effective metabolic process for handling excess ty rosine. HPPD inhibitors (e.g., n itisinone) are used as an effective therapeutic agent to treat patients suffering from rare genetic diseases of t yrosine catabolism. Treatment starts in childhood but is o ften sustained throughout patient ’ s lifetime. The human experience indicates that a therapeutic dose (1 mg/kg/day

dose) of n itisinone has an excellent safety record in infants, children , and adults and that serious adverse health outcomes have not been ob served in a population followed for approximately

a decade. Rarel y, ocular effects are seen in patients with high plasma tyrosine levels; however , these effects are transient and can be readil y reversed upon adherence to a restricted protein diet. This i ndicates that an HPPD inhibitor in it of itself cannot easil y overwhelm the t yrosine
- clearance mechanism in humans. Therefore, exposure to environmental residues of HPPD
- inhibiting herbicides are unlikel y to result in the high blood levels of tyrosine and ocular toxicity in humans due to an efficient metabolic process to handle excess ty rosine. 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 E XPOSURE/RISK PATHWAY An occupational exposure assessment for py rasulfotole was pr ovided in a HED memorandum dated 3
- SEP
- 2010 ( A. Nowotarski ; D3 75392 ). 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 p roposed uses of p yr asulfotole. 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) flagg ers. 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. Lo ng - term exposure s are not expected ; therefore, a long
term assessment was not conducted. The proposed labels require mixers, loaders and otherPy

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Page 26 of 39 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 est imates 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 dose s 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) derive d 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 ass essment (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 pilo ts 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).Py

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Page 27 of 39 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 t oxicity 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 . App lication Rate (lb ai/acre) a Area Treated

Daily (acres) b Unit Exposures
--

Dermal and Inhalation (mg/lb ai) D oses (mg/kg/day) f MOEs g
Mixer/Loader for Aerial Applications
0.03 9 1200 Dermal Baseline c : 2.9 PPE
- Gh : 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

0.03 9 350 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 : 0.00 023 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 : 0.00 013 Inhalation Baseline d : 7,500 Applicator for Aerial Equipment
0.0 39 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 : 0.00 074 Inhalation Baseline d : 0.00 0082 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 : 0.0 00068 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 I

nhalation: 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 A pp R ate (lb ai/acre) x Ar ea Treated (acres/day) x %Absorptio n ( 100 % d ermal and 100% inhalation) / Body weight (70 kg)
.Py

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Page 28 of 39 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 py rasulfotol e 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
• Bod y Weight = 7 0 kg
• Dermal Absorpti on = 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 day s. These are default values established b y ExpoSAC. Table 8.2.1 . Anticipated Post - application Activities and Derm al Transfer Coefficients . Pr oposed Crops Policy Crop

Group Category Application Rate

(lb ai/acre) Transfer Coefficients (cm 2 /hr) Activities Sorghum Field/row crop, tall 0.0 37 1 000 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 equation s : DFR t = AR x F x (1
- D) t x CF1 x CF2 Where: DFR t = dislodgeable foliage residue on day "t" (μg/cm2 ) AR = application rate (lb ai/acre) F = fraction of ai retained on foliage (unitless) D = fraction of residue that dissipates daily (unitless) and Daily Dermal Dose t = [DFR t (μg/cm

2 ) x 0.001 mg/μg x TC (cm2 /hr) x DA x ET (hrs)] / BW (kg)Py

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Page 29 of 39 Where : DFR t = dislodgeable foliage residue on day "t" (ug/cm2 ); TC = transfer coefficient (cm 2 /hr); ET = exposure time (8 hr/day); and BW = body weight ( 7 0 kg). Once dail y 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 bl ock of time after application. HED has determined that short
- and intermediate
- term risk estimates are not of concern (i.e., MOEs ≥ 1 00) 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 py rasulfotole. Table 8.2.2 . Post - application Risk Estimates for Pyrasulfotole . Crop Application Rate

(lb ai/A) Transfer

Coefficient (cm 2 /hr) DFR 1

(ug/cm2 ) Day s

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 ,0 00 100 0.001 1 0 ,000 The information in the table is based on proprietary and non
- proprietary data. 1: DFR (μg/cm2 ) = Application Rate (lb ai/A) x (1
- Daily Dissipation Rate) t x CF (4.54E+8 μg/lb) x CF (2.47E
- 8 A/cm2 ) x 20% DFR after initial treatment. 2: Daily Dose = [DFR (ug/cm2 ) x TC (cm2 /hr) x 0.001 mg/μg x Dermal Absorption (100%) x 8 hrs/day] ÷ Body Weight (70 kg)
. 3: MOE = NOAEL (Short
- and Intermediate
- term NOAEL = 10.0 mg/kg/day)/Daily Dose (LOC=100)
. Inhalation: Based on the Agency 's current practices, a quantitative occupational post application inhalation exposure assessment was not performed for py rasulfotole 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 pestic ides 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 Mar ch 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 py rasulfotole
. Restricted Re- entry Level: Py rasulfotole 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 REIof 12 hours is adequate to protect agricultural workers from post
- application exposures to py rasulfotole. 9.0 DATA NEEDS AND LABEL RECOM MENDATIONSPy

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Page 30 of 39 9.1 Toxicology

 Immunotoxicity

study
. 9.2 Residue Chemistry  Revised Section F.  Revised Section B.  Analy tical reference standards for p yr asulfotole
- 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: RAB1Py

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Page 31 of 39 Appendix A: TOXICOLOGY ASSESSMENT A.1 Acute Toxicity Profile Table A.1 . ACUTE TOXICITY PROFILE FOR PYRASULFOTOLE . Guideline No. Study Type MRID No. Results Toxicity Category 870.1100 Ac ute oral toxicity ( rat)

Acceptable/Guideline 46801836 LD 50 > 2000 mg/kg (F) III 870.1200 Ac ute dermal toxicity ( rat)

Acceptable/Guideline 46801837 LD 50 > 2000 mg/kg (M,F) III 870.1300 Ac ute inhalation toxicity ( rat)

Acceptable/Guideline 46801838 LC 50 > 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 b w/day [M/F])

870.3100 90
- day oral toxicity (mouse; dietary) LOAEL not observed NOAEL = 500/617 mg/kg/day (M/F). 46801844 (2003) Acceptable/guideline 0, 100, 1500, or 3000 ppm (equal to 0/0, 16.5/19.7, 124/152, 259/326, or 500/617 mg/kg bw/day [M/F]) 870.3100 90
- day oral toxicity (rat; dietary) LOAEL = 77 mg/kg bw /day (F) and 454 46801842 (2003)

Acceptable/GuidelinePy

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Page 32 of 39 mg/kg bw/day (M),

based on increased incidences of corneal opacity (M&F), mo rtality, and histopathology in the kidney, urinary bladder, thyroid, and ureters (M) NOAEL = 2.32 mg/kg bw /day (F) and 66 mg/kg bw/day (M). 0, 2, 30, 1000, 7000, or 12000 ppm (equivalent to 0/0, 0.13/0.15, 1.96/2.32, 66/77, 454/537, or 830/956 mg/kg bw/day [M/F])

870.3200 28
- day dermal toxicity (rat) LOAEL = 100 mg/kg/day based on focal degeneration of the pancreas (both sexes) and alteration of thyroid colloid (males) NOAEL = 10 mg/kg/day. 46801904 (2005) Acceptable/Guideline 0, 10, 100, or 1000 mg/kg bw/day

870.4300 Com bined 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 = 17 1/174 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])Py

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Page 33 of 39 870.3700 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 N OAEL = 10 mg/kg/day. 46801905 (2006) Acceptable/Guideline 0, 10, 100, or 300 mg/kg bw/day

870.3700 Prenatal developmental toxicity (rabbit; gavage) Maternal LOAEL = 250 mg/kg bw/day based on decreased body weight gain during GD 8
- 10 and decreased food consumption
. Maternal NOAEL = 75 mg/kg bw/day. Developmental LOAEL = 75 mg/kg bw/day based on increased incidences of fetal/litter skeletal variations
. Developmental NOAEL = 10 mg/kg/day. 46801906 (2006) Acceptable/Guideline 0, 10, 75, or 250 mg/kg bw /day

870.3800 Reproduction and fertility effects (rat; dietary) Parental LOAEL = 2.5/3.1 mg/kg bw/day (M/F), based on colloid alteration and/or pigment deposition in the thyroid Parental NOAEL not observed. Offspring LOAEL = 26.3/32.6 mg/kg bw /day [M/F] based on corneal opacity and/or corneal neovascularization (F1 and F2 generations) Offspring NOAEL = 2.5/3.1 mg/kg bw/day [M/F]. Reproductive LOAEL = 26.3/32.6 mg/kg bw /day (M/F), based on 46801907 (2005)

Acceptable/Guideline 0, 30, 300 or 3000 ppm (equivalent to premating doses of 0/0, 2.5/3.1, 26.3/32.6, or 272.4/345.7 mg/kg bw /day [F 0 M/F]; and 0/0, 3.68/4.2, 34 .1/38.9 or 353.6/393.4 mg/kg bw /day [F 1 M/F])Py

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Page 34 of 39 delayed balano
prep utial separation in F 1 pups. Reproductive NOAEL = 2.5/3.1 mg/kg bw/day (M/F). 870.4100 Chronic toxicity (dog; dietary) LOAEL = 34 (M) & 93 (F) mg/kg/day, based on increased incidence and severity of kidney tubular dilatation (M) and cataracts (F). NOAEL = 7 (M) & 33 (F) mg/kg/day. 46801908 (2006) Acceptable/Guideline 0, 250, 1000, or 3000 ppm (equivalent to 0/0, 7/9, 34/33, or 101/93 mg/kg bw/day [M/F])
870.4200 Carcinogenicity (mouse; dietary) LOAEL = 13.6/16.7 mg/kg bw/day (M/F) based on increased incidences of gallstones
. NOAEL not observed. 46801909 (2006) Acceptable/Guideline 0/0, 13.6/16.7, 137/168 and 560/713 mg/kg bw /day (M/F) 870.5100 Gene mutation (bacterial; in vitro ) Negative 46801911 (2004) Acceptable/Guideline 0, 16, 50, 158, 500, 1581 or 5000  g/plate (+/
- S9) 870.5300 Gene mutation (mammalian; in vitro ) Negative 46801912 (2004) Acceptable/Guideline 0, 30, 60, 120, 240, 480, or 960 μg/mL (+/
- S9) 870.5375 Chromosome aberration (mammalian; in vitro ) Negative (chromosome isodeletions observed at cy totoxic 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, 12 5/250, 250/500 or 500/1000 mg/kg bw (M/F) 870.6200 Ac ute 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])Py

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Page 35 of 39 870.6300 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 ophthalmosc opy (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 (ge station 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 Ac ute oral toxicity (rat) LD 50 >5000 mg/kg bw (M, F; toxicity category IV)
. 43904812 (1995) Acceptable/Guideline 5000 mg/kg bw N/A 28
- day oral toxicity (rat; dietary) LOAEL not observed
. NOAEL = 1118/1269 mg/kg/day (M/F)
. 43904813 (1995) Acceptable/Non
- guideline 0, 150, 500, 5000, or 15000 ppm (equal to 0/0, 11.1/12.7, 37.6/42.7, 377/421, or 1118/1269 mg/kg bw/day [M/F]) 870.3100 90
- day oral toxicity (rat; dietary) LOAEL not observed
. 45655903 (1998)Py

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Page 36 of 39 NOAEL = 769/952 mg/kg/day ( M/F). Acceptable/Guideline 0, 1200, 4800, or 12000 ppm (equivalent to 0, 73.2/93.1, 306/371, or 769/952 mg/kg bw/day [M/F]) 870.3700 Prenatal developmental toxicity (rat;

gavage) Maternal LOAEL = 250 mg/kg bw/day, based on clinical signs (salivation, piloerection, red nasal discharge around time of treatment), decreased body weight gain, and decreased food consumption
. Maternal NOAEL = 75 mg/kg bw/day
. Developmental LOAEL not observed
. Developmental NOAEL = 750 mg/kg bw/day
. 45655906 (1999) Acceptable/Guideline 0, 75, 250, or 750 mg/kg bw /day

870.5100 Gene mutation (bacterial; in vitro ) 0, 100, 250, 500, 1000, 2500, or 5000

 g/plate (+/
- S9) Acceptable/Guideline Negative 43904814

870.5300 Gene mutation (mammalian; in vitro ) 84.5
- 2700 μ g/mL (
- S9)

338
- 2700 μ g/mL (+S9) Acceptable/Guideline Negative 44545301

870.5375 Chromosome aberration (mammalian; in vitro ) 0, 924, 931, 1320, 1330, 1890, 1900,

2700, or 2710 μ g/mL (+/
- S9) Acceptable/Guideline Negative 44545301

870.5395 Erythrocyte micronucleus (mouse; in vivo ) 500, 1000, or 2000 mg/kg bw

Acceptable/Guideline Negative 44545302Py

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Page 37 of 39 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 Hum an - 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 Ac ute Dietary (All populations) NOAEL =

3.8 mg/kg/day UF A = 10X

UF H = 10X UF FQPA = 1X aRfD = aPAD = 0.038

mg/kg/day Developm ental 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 UF A = 10X

UF H = 10X UF FQPA = 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 mo nths) NOAEL =

2.5 mg/kg/day UF A = 10X

UF H = 10X UF FQPA = 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 mo nths) NOAEL =

10 mg/kg/day UF A = 10X

UF H = 10X UF FQPA = 1X No residential uses

proposed. 28 - day derm al 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% UF A = 10X

UF H = 10X UF FQPA = 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 serumPy

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Page 38 of 39 Table A.3a . Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in Dietary and Non Occupational Hum an - Health Risk Assessments. There are no residential uses proposed for pyrasulfotole at this time. Exposure Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, LOC for Risk Assessment Study and Relevant Toxicological Effects cholesterol (males). Inhalatio n (All durations) NOAEL =

1.0 mg/kg/day 100% inhalation assumed UF A = 10X

UF H = 10X UF FQPA = 1X No residential uses

proposed. Combined chronic toxicity/carcinogenicity (rat; dietary) LOAEL = 10/14 mg/kg/day (M/F) based on corneal opacity, neovascularizati on 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, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF FQPA = FQPA Safety Factor , NOAEL = no
- observed
- adverse
- effect level, LOAEL = lowe st - 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) re gulatory agencies based on ocular toxicity observed in the c om bined chronic toxicity/carcinogenicity study in rats. Table A.3b . Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in Occupational Hum an - 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 mo nths) NOAEL =

10 mg/kg/day UF A = 10X

UF H = 10X Occupational LOC for

MOE <100 28 - day derm al 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% UF A = 10X

UF H = 10X Occupational LOC for

MOE <100 Combined chronic toxicity/carcinogenicity (rat; dietary) LOAEL = 10/14 mg/kg/day (M/F) based on corneal opacity, neovascularization of the cornea, inflammation of the cornea, regenerative corneal hyperplasia, corneal atrophy, and/or retinal atrophy (both sexes), and hepatocellular hypertrophy along with increased serum cholesterol (males). Inhalation (All NOAEL =

1.0 UF A = 10X

UF H = 10X Occupational LOC for

MOE <100 Combined chronic toxicity/carcinogenicityPy

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Page 39 of 39 Table A.3b . Summary of Toxicological Doses and Endpoints for Pyrasulfotole for Use in Occupational Hum an - Health Risk Assessments . Exposure Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, LOC for Risk

Assessment Study and Toxicological Effects durations) mg/kg/day

100% inhalation assumed (rat; dietary) LOAEL = 10/14 mg/kg/day (M/F) based on corneal opacity, neovascularization of the cornea, inflammation of the cornea, regenerative corneal hyperplasia, corneal atrophy, and/or retinal atrophy (both sexes), and hepatocellular hypertrophy along with increased serum cholesterol (males). Cancer (oral, dermal, inhalation) Classification: “Suggestive Evidence of Carcinogenic Potential” based on increased incidences of

corneal tumors in male rats (oral carcinogenicity study) and urinary bladder tumors in male and female mice (oral carcinogenicity study). Abbreviations: UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = 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.