UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, DC 20460

OFFICE OF PREVENTION,

PESTICIDES AND TOXIC SUBSTANCES

MEMORANDUM

DATE: 29 January 2010

SUBJECT: Thifensulfuron Methyl. Human Health Risk Assessment for the Proposed Food/Feed Use of the Herbicide (Asso ciated with Regional Section 3 Registration) on Safflower.

PC Code: 128845 DP Barcode: D361902

Decision Number: 405073 Registration Number: 352-633

Petition Number: 9F7523 Regulatory Action: Amended Section 3 Risk Assessment Type: Single Chemical Aggregate Case Number: NA

TXR Number: NA CAS Number: 79277-27-3

MRID Number: 47641801 40CFR: §180.439

Chemical Class: Triazinylsulfonylurea Herbicide Trade Name: DuPontTM Harmony® SG

FROM: William T. Drew, Chemist, Risk Assessor Alan Levy, PhD, Toxicologist Shih-Chi Wang, PhD, Biologist, Occupational Exposure Assessor Risk Assessment Branch 2 (RAB2) Health Effects Division (HED), 7509P

THRU: Douglas Dotson, PhD, Chemist Margarita Collantes, Biologist Edward Scollon, PhD, Toxicologist Richard A. Loranger, PhD, Senior Scientist Christina Swartz, Branch Chief RAB2/HED, 7509P

TO: Barbara Madden, RM Team 5 Risk Integration, Minor Use and Emergency Response Branch (RIMUERB) Registration Division (RD), 7505P

Page 1 of 38Page 2 of 38 TABLE OF CONTENTS

1.0 Executive Summary .......................................................................................................... 4

2.0 Ingredient Profile .............................................................................................................. 5

2.1 Summary of Proposed Uses .................................................................................... 6

2.2 Structure and Nomenclature ................................................................................... 6

2.3 Physical and Chemical Properties........................................................................... 7

3.0 Hazard Characterization/Assessment ............................................................................. 8

3.1 Hazard and Dose-Response Characterization......................................................... 8 3.1.1 Database Summary ..................................................................................... 8 3.1.1.1 Studies Available and Considered (Animal, Human, General Literature) . 8 3.1.1.2 Mode of Action, Metabolism, Toxicokinetic Data ..................................... 9 3.1.1.3 Sufficiency of Data ..................................................................................... 9 3.1.2 Toxicological Effects.................................................................................. 9 3.1.3 Dose-Response.......................................................................................... 10

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)................................. 11

3.3 FQPA Considerations ........................................................................................... 11 3.3.1 Adequacy of the Toxicity Database.......................................................... 11 3.3.2 Evidence of Neurotoxicity ........................................................................ 11 3.3.3 Developmental Toxicity ........................................................................... 11 3.3.4 Reproductive Toxicity .............................................................................. 12

3.3.5 Additional Information from Literature Sources ...................................... 12 3.3.6 Pre- and/or Post-Natal Toxicity ................................................................ 12 3.3.6.1 Determination of Susceptibility ................................................................ 12 3.3.6.2 Degree of Concern Analysis and Residual Uncertainties......................... 12

3.4 FQPA Safety Factor for Infants and Children ...................................................... 13

3.5 Hazard Identification and Toxicity Endpoint Selection ....................................... 14 3.5.1 Acute Reference Dose (aRfD) - Females Age 13-49................................ 14 3.5.2 Acute Reference Dose (aRfD) - General Population................................ 14 3.5.3 Chronic Reference Dose (cRfD)............................................................... 14 3.5.4 Incidental Oral Exposure (Short- and Intermediate-Term)....................... 15 3.5.5 Dermal Absorption.................................................................................... 15 3.5.6 Occupational Dermal Exposure (Short- and Intermediate-Term) ............ 15 3.5.7 Occupational Inhalation Exposure (Short- and Intermediate-Term) ........ 15 3.5.8 Level of Concern (LOC) for Margins of Exposure (MOEs) .................... 16 3.5.9 Recommendation for Aggregate Exposure Risk Assessments ................. 16 3.5.10 Classification of Carcinogenic Potential................................................... 17 3.5.11 Summary of Toxicological Doses and Endpoints..................................... 17

3.6 Endocrine disruption............................................................................................. 18

4.0 Public Health and Pesticide Epidemiology Data .......................................................... 19

5.0 Dietary Exposure/Risk Characterization ..................................................................... 19

5.1 Pesticide Metabolism and Environmental Degradation........................................ 19

5.2 Analytical Methodology ....................................................................................... 20Page 3 of 38 5.3 Food Residue Profile ............................................................................................ 20 5.3.1 Anticipated Residues and Percent Crop Treated (%CT) Information ...... 21

5.3.2 International Re sidue Limits..................................................................... 21

5.4 Drinking Water Residue Profile ........................................................................... 21

5.5 Dietary Exposure and Risk ................................................................................... 22

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 23

6.1 Other (Spray Drift)................................................................................................ 24

7.0 Aggregate Risk Assessments and Risk Characterization ............................................ 24

7.1 Acute Aggregate Risk........................................................................................... 24

7.2 Short- and Intermediate -Term Aggregate Risk .................................................... 24

7.3 Long-Term Aggregate Risk .................................................................................. 24

7.4 Cancer Aggregate Risk ......................................................................................... 24

8.0 Cumulative Risk Characterization/Assessment ........................................................... 25

9.0 Occupational Exposure/Risk Pathway .......................................................................... 25

9.1 Short- and Intermediate-Term Handler Risk ........................................................ 25

9.2 Short- and Intermediate-T erm Post-Application Risk.......................................... 28

10.0 Data Needs and Label/Regulatory Recommendations ................................................ 28

10.1 Toxicology ............................................................................................................ 28

10.2 Residue Chemistry................................................................................................ 29

10.3 Occupational and Residential Exposure ............................................................... 29

References:

............................................................................................................................... ... 30 Appendix A: Toxicology Assessment ....................................................................................... 31

A.1 Toxicology Data Requirements ............................................................................ 31

A.2 Toxicity Profiles ................................................................................................... 32 Appendix B: Rationale for Toxicology Data Requirements .................................................. 35 Appendix C: Human Research Reference ............................................................................... 381.0 Executive Summary

Page 4 of 38 The Interregional Research Project Number 4 (IR-4) has submitted a tolerance petition, 9F7523, proposing the establishment of a tolerance for “combined” residues of the herbicide thifensulfuron methyl (with the CAS name of methyl-3-[[[[(4-methoxy-6- methyl-1, 3, 5-triazin2-yl)amino] carbonyl] amino] sulfonyl]-2-thiophen ecarboxylate) in or on safflower seeds, the raw agricultural commodity (RAC), as listed below.

Safflower, seed.....................................................................0.05 ppm

HED has reviewed the available toxicological and residue chemistry studies for thifensulfuron methyl, and is recommending that the requested use be conditionally registered, and that a permanent tolerance be established. The toxicological database adequately char acterizes thifensulfuron methyl as having low acute oral, dermal and inhalation toxicity. It is not a dermal sensitizer. Most findings in the submitted studies related to decreases in body wei ghts, body weight gains, or organ weights (a reflection of the lower body weights compared with control weights). In the one-year dog study, there were increased absolute liver weights in males, and relative thyroid/parathyroid weights in females, with decreased body weight and body weight gain in females after week 22, but only at the highest dose tested (HDT). There were no gr oss or histopathological changes reported in any of the studies. The potential for increased susceptibility of infants and children from exposure to thifensulfuron methyl was evaluated. HED concluded that the FQPA Safety Factor should be reduced to 1X, as there are no residual uncertainties for pre- and/or post-natal toxicity. There is no indication of neurotoxic activity. Immunotoxicity was observed as a decrease in spleen weight in the subchronic rat study. However, this effect was only noted in males, and only at the mid-level dose of 177 mg/kg. The lack of response at the high-level dose, the occurrence in a single sex, the availability of a clear no-obser ved-adverse-effects level (NOAEL), and the

absence of immunotoxic effects in the remainder of the database reduce HED’s concern for immunotoxicity. Thifensulfuron methyl was classified as not likely to be a human carcinogen, based on the lack of evidence of carcinogenicity in both the rat and the mouse. HED has used conservative assumptions to assess the risk from exposure to thifensulfuron methyl from dietary sources. Ri sk estimates are below HED’s level of concern (LOC) for all population subgroups at both acute and chronic exposure durations. Occupational exposures to thifensulfuron methyl, assuming si ngle layer clothing with no gloves, are also

below HED’s LOC for all scenarios. There are currently no residential uses of thifensulfuron methyl. Therefore, acute and long-term aggreg ate risks are equivalent to acute and chronic dietary risks, respectively. Safflower field trial and processing studies with thifensulfuron methyl resulted in residues below 0.050 ppm, the lowest limit of method validation (LLMV), in all samples of the RAC and processed commodities. The residue data are adequate to support the establishment of a tolerance at 0.05 ppm in safflower seeds. Provided that a revised Section F is submitted to delete the word “combined” in the tolerance expression, HED recommends that the requested use be conditionally granted, and that a permanent tolerance, as detailed in Section 10.2, be established. Submission of acceptable toxicity studies ( OPPTS Health Effects Test Guideline870.3200 , 21/28-Day Dermal Toxicity; 870.6200 , Acute and Subchronic Neurotoxicity; and

870.7800 , Immunotoxicity) should be made a condition of registration. Additionally, RD should ensure that the requirement for a 12-hour restricted entry interval (REI) appears on the label directions for the use of thifensulfuron methyl on safflower.

Page 5 of 38 Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with US Executive Order 12898, Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations ( http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf ). As a part of every pesticide risk assessment, the Office of Pesticide Programs (OPP) considers a large variety of consumer subgroups according to well-established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intakes by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and fo r toddlers, youths and adults entering or playing on treated areas post-application are evaluated. Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers, as well as lifestyle and traditional dietary patterns among specific subgroups. This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the Pesticide Handlers Exposure Database (PHED), have been determined to require a review of their ethical conduct, and have received that re view. The studies in PHED are considered appropriate (were ethically conducted) for use in risk assessments.

2.0 Ingredient Profile

Thifensulfuron methyl is a sulfonylurea herbicide (Group 2) registered to E.I. DuPont de

Nemours for the control of broadleaf weeds on cer eal grains, canola, cotton, flax and soybeans.The current registered use patterns on these crops include post-emergence, and pre-plant or atplanting burndown. Thifensulfuron methyl is abso rbed through the foliage of treated weeds, inhibiting growth, causing necrosis of the growing plant, and eventual plant death.

Tolerances for residues of thifensulf uron methyl are listed under 40CFR §180.439[a]. Permanent tolerances are established for thifensulfuron methyl in/on barley, canola, corn, cotton, flax, oat, rice, sorghum, soybean and wheat commodities, at levels ranging from 0.02 to 2.5 ppm. No tolerances are currently established for residues in animal commodities or rotational crops.2.1 Summary of Proposed Uses

Page 6 of 38 The end-use product (EP) proposed for use on safflower is DuPontTM Harmony® SG Herbicide (EPA Registration #352-633), a soluble granule (SG) formulation containing 50% (by weight) thifensulfuron methyl as the active ingredient (ai). Harmony® SG is proposed for one post-emergence broadcast foliar spray on safflower at a maximum application rate of 0.019 pound ai per acre (lb ai/A), with a pre-harvest in terval (PHI) of 81 days. Application may be made up to the time of flower bud initiation, using ground or aerial equipment, with adjuvants in the spray mixture. The proposed use is limited to safflower grown in the states of North Dakota, South Dakota, Nebraska, Montana (East of Route 87 or East of I-15), and Wyoming (East of I-25 or North of I-90). The proposed use directions for safflower are summarized in Table 2.1 (below), and were extracted from an undated supplemental label. The proposed use directions are consistent with the information provided in a revised Section B.

TABLE 2.1 Summary of Proposed Use of Th ifensulfuron Methyl on Safflower. Application Timing; Type; and Equipment EP [EPA Registration #] Use Rate (lb ai/A) Max. # of Uses per

Season Max.

Seasonal

Use Rate (lb ai/A) PHI (Days) Use Directions and

Limitations 2

Post-emergence (up until flower bud initiation); broadcast foliar; ground or aerial 1 Harmony® SG,
50% ai [352-633] 0.014-

0.019 1 0.019 81 Use limited to North Dakota, South Dakota, Nebraska, Montana (east of Route 87 or east of I-15), and Wyoming (east of I-25 or north of I-90). Spray adjuvants may be included with the spray treatment. 3

1. The supplemental label does not specify application sp ray volumes. The approved label specifies minimum spray volumes of 10-25 gallons per acre (GPA) via ground equipment, and 5 GPA via aerial equipment for most field crops. The field trials were conducted with 15-19 GPA via ground equipment. 2. The approved label specifies the following rotational crop re strictions: Wheat, barley, oat, triticale, soybeans, and field corn may be replanted anytime after the application of Harmony® SG. Any other crop may be planted 45 days after the application of Harmony® SG. 3. Non-ionic surfactants (NISs) may be mixed with the spra y mixture at a rate of 2-4 pints per 100 gallons of spray solution (concentration of 0.25-0.55% v/v). The surf actant product must contain at least 60% NIS, with a hydrophilic/lipophilic balance (HLB) greater than 12. Crop oil concentrate may be used under dry conditions or during cool weather. A petroleum-based oil concentrate may be used in place of an NIS at 1- 2% (v/v). Use an oil adjuvant that contains at l east 80% of a high quality, petroleum (mineral) or modified vegetable seed oil with at leas t 15% surfactant emulsifiers.

2.2 Structure and Nomenclature

The chemical structure and nomenclature of thifensulfuron methyl are presented in Table 2.2 (below).Page 7 of 38 TABLE 2.2 Thifensulfuron Methyl Nomenclature.

Chemical structure

N

N N CH 3

O CH 3 N H N H O

S CO 2 CH 3 S O

O

Common name Thifensulfuron methyl

Molecular formula C 12 H 13 N 5 O 6 S 2 Molecular weight 387.38
Company experimental

name DPX-M6316

IUPAC name Methyl 3-(4-methoxy-6-methyl-1,3,5-triazin-2-ylcarbamoylsulfamoyl) thiophene-2- carboxylate

CAS name Methyl 3-[[[[(4-met hoxy-6-methyl-1,3,5- triazin-2-yl)amino]carbonyl]amino] sulfonyl]-2-thiophenecarboxylate
CAS registry number 79277-27-3

End-use product (EP) Field trials: 75% ai DF, DuPontTM Harmony® GT XP, EPA Registration #352-446 Proposed use: 50% ai SG, DuPontTM Harmony® SG, EPA Registration #352-633

2.3 Physical and Chemical Properties

The physicochemical properties of the technical grade of thifensulfuron methyl are presented in Table 2.3 (below).

TABLE 2.3 Physicochemical Properties of Thifensulfuron Methyl.

Parameter Value Reference

Melting point/range (oC) 171.1 ± 1.2 pH 4.0 Density (g/cm 3 ) 1.58 ± 0.004 Water solubility (g/L at 25oC) pH 5 0.223 pH 7 2.24 pH 9 8.83 Solvent solubility (g/L at 25oC) Acetone - 11.9

Acetonitrile - 7.3

Dichloromethane - 27.5

Ethanol - 0.9 Ethyl acetate - 2.6

Hexane - <0.1

Methanol - 2.6 Xylene - 0.2 Vapor pressure (25oC) 1.7 x 10 -8 Pa (1.3 x 10 -10 mm Hg) Dissociation constant (pK

a ) 4.0 MRID #47138301 (D342084; D. Dotson; 17 April 2008)Page 8 of 38 TABLE 2.3 Physicochemical Properties of Thifensulfuron Methyl.

Parameter Value Reference

Octanol/water partition coefficient (Log [K OW ]) pH 5 1.06 pH 7 0.0222 pH 9 0.0078 UV/visible absorption (max, λ ) pH <2 224, 250 nm pH 7 233 nm pH >10 234 nm

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

The scientific quality of the submitted studies is relatively high, and the toxicity profile of thifensulfuron methyl can be characterized for potential carcinogenic, mutagenic, developmental, and reproductive effects. A de velopmental neurotoxicity (DNT) study was not included, but is not considered necessary at this time, as there was no indication in the submitted studies that there was an increase in fetal or offspring susceptibility, or neurotoxicity. However, the toxicological database for thifensulfuron methyl is not complete. Due to recent changes in 40CFR §158 pesticide study requirements, the following studies are considered to be data gaps:

1. Acute and subchronic neurotoxicity, 2. Immunotoxicity, and 3. Dermal toxicity.

3.1.1.1 Studies Available and Considered (Animal, Human, General Literature)

The following studies were submitted:

1. Subchronic in rats, mice and dogs, 2. Chronic/carcinogenicity in rats, 3. Carcinogenicity in mice, 4. Chronic in dogs, 5. Developmental in rats and rabbits, 6. Reproduction, 7. Mutagenicity battery (including Bacterial reverse assay, Mammalian cell mutation (CHO cells), In vitro chromosome aberration (CHO cells), and Micronucleus assay and unscheduled DNA synthesis in cultured mammalian cells), and

8. Metabolism in rats.Page 9 of 38 3.1.1.2 Mode of Action, Metabolism, Toxicokinetic Data

Thifensulfuron methyl inhibits acetolactate synthase (ALS), a key enzyme in the biosynthesis of the branched-chain amino acids isoleucine, leucine and valine. It is rapidly absorbed through the foliage and roots of treated weeds, and translocates extensively via the xylem and phloem. It accumulates in the meristematic areas, inhibiting growth, causing necrosis of the growing plant, and eventual plant death ( WSSA Herbicide Handbook, 7th Edition ). Thifensulfuron methyl is not very susceptible to metabolism in mammals. In the rat metabolism study, rats receiving an oral dose excreted most of the radioactivity (triazine-2-[ 14 C]) in the urine and feces within 72 hours, with almost no tissue or carcass accumulation. Of the radioactivity eliminated, most was parent with five minor metabolites. None of the metabolites

exceeded 5% of the administered dose. Routes of metabolism include hydrolytic cleavage of the amide bonds of the urea moiety, yielding the triazine amine and the 2-ester-3-sulfonamide, which undergoes cyclization to form thiophene sulfonamide. Other metabolic pathways proceed via hydrolysis of the methyl ester and then sulfonyl urea moieties (yielding the 2-aci d-3-sulfonamide), with some demethylation of the triazine methoxy group.

3.1.1.3 Sufficiency of Data

Data are sufficient for FQPA evaluation, t oxicity endpoint selection, and dose-response evaluation. Data gaps include the following studies:

1. Acute and subchronic neurotoxicity, 2. Immunotoxicity, and 3. 21/28-Day dermal toxicity.

A DNT study is not considered necessary at this time.

3.1.2 Toxicological Effects

Thifensulfuron methyl has low (Category IV) acute toxicity via the oral route. By inhalation and dermal routes of exposure in the rat, there was relatively low (Category III) acute toxicity. There was moderate eye irritation (Cat egory III), and slight dermal irritation (Category IV). It is not a dermal sensitizer. Most findings in the submitted studies related to decreases in body weights, body weight gains, or organ weights (a reflection of the lower body weights compared with control weights). In the one-year dog study, there were increased absolute liver weights in males, and relative thyroid/parathyroid weights in females, with decreased body weight and body weight gain in females after week 22 (only at the HDT). Th ere were no gross or histopathological changes reported in any of the studies. In the rat developmental study, there were no maternal effects at the HDT of 725 mg/kg/day. The fetal NOAEL was 159 mg/kg/day, based on decreased mean fetal body weights,and an increased incidence of small renal papillae. The rabbit developmental study showed a decrease in maternal body weights at the HDT of 511 mg/kg/day, with the NOAEL being 158 mg/kg/day. There were no developmental effects at the HDT. In the 2-generation rat reproduction study, at doses up to 175 or 180 mg/kg/day in males, and 244 or 212 mg/kg/day in females, there were no parental, reproductive or offspring effects. There was an increase in quantitative susceptibility in the rat developmental study, based on decreased mean fetal body weights, and an increase in the incidence of small renal papillae (only at the HDT). The NOAEL of 159 mg/kg/day was equal to, or higher than, the NOAELs from other toxicity studies which have been chosen for endpoints, and which are considered to be protective regarding the increased quantitative susceptibility. Therefore, no additional safety factor is needed.

Page 10 of 38 Thifensulfuron methyl is classified as “not likely to be carcinogenic to humans,” based on acceptable chronic/carcinogenicity studies in rats and mice at doses that are considered to be adequate, and not excessive for the determination of carcinogenic potential. The available mutagenicity studies in vivo and in vitro show that thifensulfuron methyl is neither mutagenic nor clastogenic. Neurotoxicity was not observed in the submitted guideline studies. However, there were no acute or subchronic neurotoxicity studies ava ilable for review. Immunotoxicity was observed as a decrease in spleen weight in the subchronic rat study. However, this effect was only noted in males, and only at the mid-level dose of 177 mg/kg. The lack of response at the high-level dose, the occurrence in a single sex, the availa bility of a clear NOAEL, and the absence of

immunotoxic effects in the remainder of the data base reduce HED’s concern for immunotoxicity. None of the reviewed studies examined the possibility of dermal toxicity. A 21/28-day dermal toxicity study was not received. Therefore, the two neurotoxicity studies, as well as the immunotoxicity and dermal toxicity studies, are considered to be data gaps, and are required. However, based on our lack of concern for potential immunotoxicity and neurotoxicity, an additional safety factor is not considered necessary.

3.1.3 Dose-Response

Thifensulfuron methyl does not appear to affect any specific organ systems. The most consistent effect among the animal studies is a decrease in body weight and body weight gain, compared to controls. Decreased body weight and/or body weight gain was observed in the subchronic rat (7/177 mg/kg/day; NOAEL/lowest- observed-adverse-effects level, LOAEL) and dog (37.5/188 mg/kg/day) studies, and the chronic mouse (4.3/128 mg/kg/day), dog (18.8/188 mg/kg/day) and rat (20/120 mg/kg/day) studies. The effect did not appear to occur at lower NOAELs in the chronic studies, compared to the subchronic study, in the rat or dog. Decreased body weight was, however, observed at 4.3 mg/ kg/day in the chronic mouse studies, a NOAEL lower than that observed in any of the rat or dog studies. Furthermore, there was an increase in absolute liver weight, and relative thyroid/para thyroid weights in the chronic dog studies. The increased liver weight is most likely a general response to long term toxicity.

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

In the rat metabolism study, rats receiving an oral dose excreted most of the radioactivity(triazine-2-[ 14 C]) in the urine and feces within 72 hours, with almost no tissue or carcass accumulation. Of the radioactivity eliminated, most was parent with five minor metabolites. In the urine, parent thifensulfuron methyl (55.4/72% of the total dose Male/Female) accounted for the majority of the excreted radioactivity. Minor metabolites included thifensulfuron methyl acid (2.3/2.5% M/F), O-demethyl thifensulfuron methyl (0.5/0.4% M/F), triazine amine (0.5% M/F), and lesser amounts of 2-ester-3-sulfonamide and thiophene sulfonamide. The fecal metabolite profile was similar to that for urine. Unchanged thifensulfuron methyl is the predominant fecal product (17.8/12.3% M/F), with the metabolites being present in approximately the same percentage as was reported in urine. Three metabolites remain

unidentified. None of the metabolites exceeded 5% of the administered dose.

Page 11 of 38 3.3 FQPA Considerations

3.3.1 Adequacy of the Toxicity Database

Developmental toxicity studies in rats and rabbits, and a 2-generation reproduction study in rats are available for evaluating in utero or post-natal susceptibility. These studies contain clear NOAELs that are protective of any developm ental or offspring effects. However, the following guideline-required studies for FQPA consideration have not been submitted, and are considered data gaps:

1. Acute and subchronic neurotoxicity studies in rats, and 2. An immunotoxicity study.

3.3.2 Evidence of Neurotoxicity

In the available studies, there were no findings indicating any effect on the nervous systems. However, the acute or subchronic ne urotoxicity studies were not submitted and are considered to be data gaps. There was no evidence that a DNT study is required at this time.

3.3.3 Developmental Toxicity

The following FQPA-related studies have been submitted:

1. Developmental rat, 2. Developmental rabbit, and 3. Two-generation rat reproduction.

In the rat developmental study, there were no maternal effects at the HDT of 725 mg/kg/day. However, there were decreased fetal body weights, and an increased incidence of small renal papillae. The NOAEL for this effect was 159 mg/kg/day. No maternal or developmental effects were observed in the rabbit developmental study at the HDT of 511 mg/kg/day.3.3.4

Page 12 of 38 Reproductive Toxicity

In the 2-generation rat reproduction study, no parental/systemic, reproductive or offspring effects were noted at the HDT of 175-244 mg/kg/day.

3.3.5 Additional Information from Literature Sources

No additional information was available from literature sources that would significantly impact this risk assessment.

3.3.6 Pre-and/or Post-Natal Toxicity

3.3.6.1 Determination of Susceptibility

There was evidence of increased quantitative susceptibility in the rat developmental toxicity study. At the HDT, decreased mean fetal weights, and an increase in incidence of small renal papillae were observed in the absence of mate rnal toxicity. There was no indication of preor post-natal susceptibility in the rabbit developmental or rat reproduction studies. As there were no neurotoxicity or immunotoxicity studies submitted, an evaluation of increased susceptibility cannot be made. However, there were no indications in the reviewed studies that these parameters were affected.

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties

The degree of concern for residual uncertainties is low. Acceptable developmental studies in rats and rabbits, and a 2-generation reproduction study are available for the determination of fetal susceptibility. There is some evidence of increased susceptibility of rat

fetuses to in utero exposure to thifensulfuron methyl, based on decreased mean fetal body weights, and increased incidence of small renal papillae at the LOAEL of 725 mg/kg/day. Decreased body weights are generally considered to result from multiple exposures to a chemical. The dose selected for multiple dose exposure scenarios is 2 orders of magnitude below the developmental rat LOAEL (725 mg/kg/day vs 7 mg/kg/day). The increased incidence of small renal papillae could result from a single in utero exposure; however, this incidence rate was not much greater than that in the control group, and the dose spacing between the NOAEL and LOAEL is wide (the LOAEL is 4.5X as great as the NOAEL). Evidence from the 2- generation study in rats provides further support that the developmental NOAEL from the developmental rat study is a true NOAEL, because no reproductive or developmental effects were seen at the highest dose tested of 180 mg/kg/day. The developmental study in the rabbit, and the 2-generation reproduction study in the rat, do not show offspring effects. The Agency is confident that the risk to developing fetuses exposed to thifensulfuron methyl will not be underestimated, based on the following:

1. The doses selected for risk assessment are conservative, and protective of the effect of concern,Page 13 of 38 2. There is no indication of increased susceptibility in the rabbit developmental study, or the 2-generation reproduction study in rats, and 3. All the studies considered for FQPA analysis were acceptable/guideline.

3.4 FQPA Safety Factor for Infants and Children

It is recommended that the 10X FQPA safety factor (for the protection of infants and children) be reduced to 1X because:

1. The concern for residual susceptibility is low, 2. The doses selected for risk assessment are conservative, and protective of the effect of concern, and 3. The dietary risk assessment was very conservative (100% crop treated, tolerance-level residues), and there are no residential uses of thifensulfuron methyl.

FQPA data gaps include the acute neurotoxic ity, subchronic neurotoxicity, and immunotoxicity studies. Neurotoxicity was not observed in any of the studies up to the highest doses tested, nor is there any expectation of neurotoxicity based on the mechanism of action. Furthermore, the toxicity database for thifensulfuron methyl does not indicate that the immune system is the primary target organ. Immunotoxicity was observed as a decrease in spleen weight in the subchronic rat study. However, this effect was only noted in males, and only at the mid-level dose of 177 mg/kg. The lack of response in the high-level dose, the occurrence in a single sex, the availability of a clear NOAEL, and the absence of immunotoxic effects in the remainder of the database reduces HED’s concern for immunotoxicity. The overall weight of evidence suggests that thifensulfuron methyl does not direc tly target the immune system, and this finding (decrease in spleen weight) may be due to secondary effects of a primary toxicity. The immunotoxicity study, and acute and subchronic neurot oxicity studies are required as part of the data requirements in 40CFR §158 for conventional pesticide registration. However, the Agency does not believe that conducting these studies will result in a lower Point of Departure (POD) than the currently selected endpoints for overall risk assessment, and therefore, a database uncertainty factor (UF DB ) is not needed to account for the lack of these studies.3.5

Page 14 of 38 Hazard Identification and Toxicity Endpoint Selection

3.5.1 Acute Reference Dose (aRfD) - Females Age 13-49

Study Selected : Developmental Oral Toxicity – Rat ( OPPTS Health Effects Test

Guideline 870.3700 )

MRID Number : 00143661 Dose and Endpoint for Establishing aRfD : Maternal NOAEL = 725 mg/kg/day (HDT), with a LOAEL not established. Developmental NOAEL = 159 mg/kg/day, with a LOAEL of 725 mg/kg/day based on increased incidence of small renal papillae. Uncertainty Factors : A UF of 100 was applied to account for interspecies extrapolation (10X), and intra-species variation (10X). Comments on Study/Endpoints/Uncertainty Factors : The rat developmental study was chosen because the increased incidence of renal papillae may be the result of a single exposure. This endpoint is appropriate for females age 13-49 because it is based on a developmental effect, and is of appropriate route and duration. However, it is not likely that increased renal papilla is a single-dose effect, and the degree to which this effect is adverse is equivocal. Therefore, the Agency considers this to be a conservative endpoint for risk assessment. The remaining studies were considered, but the available endpoints (d ecreased body weight and/or body weight gain, as well as increased liver or organ weights) were not selected, because they either occurred at higher doses, or were the result of multiple exposures.

Acute RfD = 159 mg/kg/day (NOAEL) = 1.59 mg/kg/day 100 (UF)

3.5.2 Acute Reference Dose (aRfD) - General Population

The risk assessment team determined that there were no single-dose effects appropriate for acute exposure assessment for the general population. Effects in mature rats, rabbits, mice and dogs (mainly decreases in body weight and body weight gain) were not considered to be the result of a single exposure to thifensulfuron methyl. Therefore, an acute dietary exposure assessment for the general population is not necessary.

3.5.3 Chronic Reference Dose (cRfD)

Study Selected : Combined Chronic/Carcinogenicity – Mouse ( OPPTS Health Effects

Test Guideline 870.4300 )

MRID Numbers : 00161275, 40340321 Dose and Endpoint for Establishing cRfD : NOAEL = 4.3 mg/kg/day in females, with aLOAEL of 128 mg/kg/day, based on a decrease in terminal body weights at the mid- and highdose animals. Uncertainty Factors : A UF of 100 was applied to account for interspecies extrapolation (10X), and intra-species variation (10X). Comments on Study/Endpoint/Uncertainty Factors : The chronic dietary endpoint isbased on decreased body weights in females only. This endpoint was selected because it is of appropriate duration (lifetime study), and was admi nistered via the oral route. This endpoint occurred at a lower dose than chronic effects from the remaining studies, and is, therefore, protective.

Page 15 of 38 Chronic RfD = 4.3 mg/kg/day (NOAEL) = 0.043 mg/kg/day 100 (UF)

3.5.4 Incidental Oral Exposure (Short- and Intermediate-Term)

No endpoint was selected for this exposure, as there is no residential use intended.

3.5.5 Dermal Absorption

Dermal Absorption Factor : 100% There was no dermal penetration study submitted. Therefore, the default absorption

factor is 100%.

3.5.6 Occupational Dermal Exposure (Short- and Intermediate-Term)

Study Selected : 90-day Oral Toxicity Study – Rat ( OPPTS Health Effects Test Guideline

870.3100 )

MRID Number : 00143660 Dose and Endpoint for Risk Assessment : NOAEL = 7/9 mg/kg/day, with a LOAEL of 177/216 mg/kg/day, based on decreased body weight, body weight gains, and spleen weight in males only (13%). Uncertainty Factors : A UF of 100 was applied to account for inter-species extrapolation (10X), and intraspecies variation (10X). Comments on Study/Endpoint : This endpoint is based on an oral study. No dermal studies are available. Therefore, an oral study was selected to estimate risk using a route-toroute extrapolation. The study and endpoint were selected because they are of an appropriate length for short- and intermediate-term exposure, and occur at a lower dose level than effects in the remaining subchronic studies. The default rate of 100% dermal absorption is assumed for

risk assessment.

3.5.7 Occupational Inhalation Exposure (Short- and Intermediate-Term)

Study Selected : 90-day Oral Toxicity Study – Rat ( OPPTS Health Effects Test Guideline

870.3100 )

MRID Number : 00143660 Dose and Endpoint for Risk Assessment : NOAEL = 7/9 mg/kg/day, with a LOAEL of 177/216 mg/kg/day, based on decreased body weight, body weight gains, and spleen weight in males only (13%). Uncertainty Factors : A UF of 100 was applied to account for interspecies extrapolation(10X), and intra-species variation (10X).

Page 16 of 38 Comments About the Study/Endpoint : This endpoint is based on an oral study. No inhalation studies are available. Therefore, an oral study was selected to estimate risk using a route-to-route extrapolation. The study and endpoi nt were selected because they are of an appropriate length for short- and intermediate-term exposure, and occur at a lower dose level than effects in the remaining subchronic studies. Absorption via inhalation is assumed to be equivalent to absorption via the oral route, so 100% inhalation absorption is assumed for risk

assessment.

3.5.8 Level of Concern (LOC) for Margins of Exposure (MOEs)

TABLE 3.5.8 Summary of LOCs for Risk Assessment.

Route Short-Term (1 to 30 Days) Intermediate-Term (1 to 6 Months) Long-Term (More Than 6 Months)

Occupational (Worker) Exposure

Dermal 100 100 NA*

Inhalation 100 100 NA

Residential Exposure

Dermal NA NA NA

Inhalation NA NA NA

Incidental Oral NA NA NA

* NA = Not Applicable.

3.5.9 Recommendation for Aggregate Exposure Risk Assessments

According to FQPA (1996), when there are potential residual exposures to a pesticide, an aggregate risk assessment must consider exposures from three major routes, namely, oral, dermal

and inhalation. An acute endpoint has been selected as appropriate for use in dietary and residential human health risk assessments for females 13-49 only. A chronic endpoint has been selected as appropriate for use in dietary and residential human health risk assessments for all populations, including infants and children. There is no incident al oral exposure scenario. In addition, there are no dermal or inhalation exposure scenarios for residential human health risk assessments. Therefore, acute and long-term aggregate risks are equivalent to acute and chronic dietary risks, respectively.From the hazard perspective, the dietary, dermal and inhalation PODs all include bodyweight effects. Therefore, when multiple routes of exposure do exist (such as dermal and inhalation for occupational scenarios), it is appropriate to combine the exposures and risks.Page 17 of 38 3.5.10 Classification of Carcinogenic Potential

There was no evidence of increased incidences of tumors in either the 2-year rat or the

78-week mouse studies. In accordance with the EPA’s Final Guidelines for Carcinogen Risk

Assessment (March 2005), thifensulfuron methyl is classified as, “not likely to be a human carcinogen.”

3.5.11 Summary of Toxicological Doses and Endpoints

TABLE 3.5.11.1 Summary of Thifensulfuron Methyl Toxicological Doses and Endpoints for Use in Dietary Exposure and Risk Assessments. Exposure/

Scenario Point of Departure Uncertainty/FQPA Safety Factors LOC for Risk

Assessment Study and Toxicological Effects

Acute dietary (females 13-49 only) NOAEL =

159 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1 aRfD = 1.59 mg/kg/day

aPAD = 1.59 mg/kg/day Developmental oral toxicity in rats. LOAEL = 725 mg/kg/day, based on decreased mean body weight, and

increased incidence of small renal papillae. Chronic dietary (all populations) NOAEL =

4.3 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1 cRfD = 0.043 mg/kg/day

cPAD = 0.043 mg/kg/day Carcinogenicity oral toxicity in mice. LOAEL = 128 mg/kg/day, based on decreased body weight and body weight gain. Cancer (oral) Not likely to be a human carcinogen, ba sed on the lack of evidence of carcinogenicity in rats

and mice. Point of Departure (POD) = a data point or estimated poi nt derived from observed dose-re sponse data, which is used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. UF = Uncertainty Factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intra-species). UF DB = database uncertainty factor to account for the absence of key data (such as the lack of a critical study). FQPA SF = FQPA Safety Factor.

NOAEL = No Observed Adverse Effect Level. LOAEL = Lowest Observed Adverse Effect Level. PAD = Population Adjusted Dose (a = acute, c = chronic). RfD = Reference Dose. MOE = Margin Of Exposure. LOC =

Level Of Concern.Page 18 of 38 TABLE 3.5.11.2 Summary of Thifensulfuron Methyl T oxicological Doses and Endpoints for Use in Occupational Exposure and Risk Assessments. Exposure/

Scenario Point of Departure Uncertainty/ FQPA Safety

Factors LOC for Risk

Assessment Study and Toxicological Effects

Dermal short- (1-30 days) and

intermediateterm (1-6 months) NOAEL = 7 mg/kg/day (dermal absorption rate = default of 100%) UF A = 10X

UF H = 10X FQPA SF = 1 MOE = 100 90-Day Oral Toxicity in Rats. LOAEL = 177 mg/kg/day based on decreased body weight and body weight gain in males and females and decreased spleen weights in

males.

Inhalation short- (1-30 days) and

intermediateterm (1-6 months) NOAEL = 7 mg/kg/day (inhalation absorption rate =

100% of oral absorption) UF A = 10X

UF H = 10X FQPA SF = 1 MOE = 100 90-Day Oral Toxicity in Rats. LOAEL = 177 mg/kg/day based on decreased body weight and body weight gain in males and females and decreased spleen weights in

males. Point of Departure (POD) = a data point or estimated poi nt derived from observed dose-re sponse data, which is used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. UF = Uncertainty Factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intra-species). UF DB = database uncertainty factor to account for the absence of key data (such as the lack of a critical study). FQPA SF = FQPA Safety Factor.

NOAEL = No Observed Adverse Effect Level. LOAEL = Lowest Observed Adverse Effect Level. PAD = Population Adjusted Dose (a = acute, c = chronic). RfD = Reference Dose. MOE = Margin Of Exposure. LOC =

Level Of Concern.

3.6 Endocrine Disruption

As required under FFDCA §408[p], EPA ha s developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen or thyroid (E, A or T) hormonal systems. Chemicals that go through Tier 1 screening, and are found to have the potential to interact with E, A or T hormonal systems, will proceed to the next stage of the EDSP, where EPA will determine which, if any, of the Tier 2 tests are necessary, based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A or T effect. Between October 2009 and February 2010, EPA is issuing test orders, and data call-ins, for the first group of 67 chemicals, which contains 58 pesticide active, and 9 inert, ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post-application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors. Thifensulfuron methyl is not among the group of 58 pesticide active ingredients on the

initial list to be screened under the EDSP. U nder FFDCA §408[p], the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders, and datacall-ins, for all pesticide active ingredients.

Page 19 of 38 For further information on the status of the EDSP, policies and procedures, list of 67 chemicals, test guidelines, and the Tier 1 screening battery, please visit our website, http://www.epa.gov/endo/

.

4.0 Public Health and Pesticide Epidemiology Data

Public health and pesticide epidemiology data were not used for this risk assessment.

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Metabolism and Environmental Degradation

The nature of the residue in plants is adequately understood, based on acceptable studies with wheat, corn and soybeans. The salient features of these metabolism studies were recently summarized in a residue chemistry summary document (D342084; D. Dotson; 17 April 2008). The metabolism of thifensulfuron methyl in tested crops proceeds by hydrolysis of the methyl ester and sulfonyl urea moieties, with some demethylation of the triazine methoxy group. HED has determined that the residue of concern (ROC) in plant commodities is thifensulfuron methyl for the purposes of tolerance expression, and risk assessment. The available plant metabolism studies are adequate to support the requested use on safflower. The nature of the residue in livestock is adequately understood, based on the available goat metabolism study. HED has previously concluded in D342084 that the goat metabolism study is adequate in supporting the registered uses of thifensulfuron methyl residues on cereal grains, and soybeans. This conclusion is based on the low level of transfer of thifensulfuron methyl residues to goat matrices, and the lack of detectable residues in livestock feed items, even at exaggerated application rates. HED also concluded that, because no detectable residues of thifensulfuron methyl were found in poultry feed items, a poultry metabolism study is not required. HED has determined that the ROC in livestock commodities is thifensulfuron methyl for the purposes of tolerance expression, and risk assessment. The current petition does not alter HED’s earlier conclusions regarding livestock metabolism.

The Environmental Fate and Effects Divi sion (EFED) has provided a drinking water assessment (DWA) for the use of thifensulfur on methyl on safflower (D363089; A. Shelby and N. Thurman; 29 September 2009). The primary r outes of dissipation for thifensulfuron methyl are acid hydrolysis, photodegradation in water, and aerobic soil metabolism, with half-lives of 5 to 36 days. The aerobic soil metabolism half-lives were 27 and 36 days. The field dissipation half-lives (based on lysimeters) range from 3 to 21 days, and are consistent with the laboratory half-lives. Longer half-lives in the field may be associated with cooler temperatures used in the studies. Thifensulfuron methyl is also very mobile, and thus may move laterally to surface water, or downward to groundwater.Page 20 of 38 TABLE 5.1 Summary of Metabolites and Degradates to be Included in Risk Assessments and the Tolerance Expression.

Matrix Residues Included in Risk

Assessments Residues Included in the Tolerance Expression Primary crop Thifensulfuron methyl Thifensulfuron methyl Plants Rotational crop ND 1 ND

Ruminant ND ND Livestock Poultry ND ND Drinking Water Thifensulfuron methyl NA 2

1. ND = Not Determined. 2. NA = Not Applicable.

5.2 Analytical Methodology

Two high performance liquid chromatogr aphy (HPLC) photo-conductivity detection methods (Methods AMR-646-86 and AMR-761-87) are available for enforcing tolerances for residues of thifensulfuron methyl in cereal grains and straw. A liquid chromatography with mass spectrometric detection (LC/MS) method (DuPont Method 1381) is also available for enforcing tolerances for residues of thifensulfuron methyl in canola, cotton and flax commodities; the validated limit of quantitation (LOQ) for this method is 0.020 ppm. The LC/MS method will be suitable for enforcing the proposed tolerance in safflower seed. The FDA multiresidue methods are not suitable for tolerance enforcement, as thifensulfuron methyl is not recovered through any of the FDA Multiresidue Method Testing protocols. Samples collected from the safflower field trial and processing studies were analyzed for re sidues of thifensulfuron methyl using an HPLC photo-conductivity method (DuPont Method AMR-973-87). The method was adequate for data collection based on acceptable method validation and concurrent method recoveries.

5.3 Food Residue Profile

A residue chemistry summary document has been prepared by RAB2 (D361945; W.T. Drew; 19 January 2010). The submitted residue data for safflower seeds are adequate to fulfill data requirements for the requested use in the st ates of North Dakota, South Dakota, Nebraska, Montana (East of Route 87 or East of I-15), and Wyoming (East of I-25 or North of I-90). The number and location of the safflower field trials support the requested regional use of Harmony® SG on safflower. The data reflect the proposed use pattern, which involves a maximum use rate of 0.019 lb ai/A, a PHI of 81 days, and use of a non- ionic surfactant (NIS) in the spray mixture. Following one broadcast foliar application of thif ensulfuron methyl to safflower at rates of 0.0176-0.0187 lb ai/A, residues in safflower seeds were <0.050 ppm for all 6 samples harvested at either 81 days after treatment (DAT) or 36 DAT. HED concludes that the proposed tolerance of 0.05 ppm is appropriate. The submitted safflower processing study showed that residues of thifensulfuron methyl were <0.050 ppm in safflower meal, and refined o il, processed from safflower seeds treated at 1X. DuPont has previously submitted a processing study depicting the magnitude of thifensulfuron methyl residue in cotton seeds. Residues of thifensulfuron methyl were nondetectable (<0.006 ppm) in cotton seeds harvested at normal maturity (133 days after treatment)following a single defoliant broadcast application of the 50% ai dry flowable (DF) formulation at 0.094 lb ai/A (roughly 4X the normal use rate), made one day after planting of cotton. The requirement for processing studies in canola and flax has previously been waived, based on the results of the cotton study. Therefore, a 5X sa fflower processing study is not required, because residues are not expected to be found in the processed commodities.

Page 21 of 38 5.3.1 Anticipated Residues and Percent Crop Treated (%CT) Information

This assessment is based on tolerance-level residues, and assumes 100%CT for all crops with registered or proposed uses on thifensulfuron methyl labels.

5.3.2 International Residue Limits

There are no established or proposed Codex Maximum Residue Limits (MRLs) for residues of thifensulfuron methyl. Canada and Mexico have established MRLs for thifensulfuron methyl in several plant commodities. The ROCs in Canada, Mexico and the US are harmonized. However, no Canadian or Mexican MRLs for thifensulfuron methyl have been proposed or established in safflower seed.

5.4 Drinking Water Residue Profile

The thifensulfuron methyl drinking water residues used in risk assessment were provided in DWAs by EFED, and incorporated directly into the dietary exposure and risk assessments. Water residues were incorporated in the dietary assessments via entry into the food categories “water, direct, all sources” and “water, indirect, all sources.” The highest estimated drinking water concentration (EDWC) for acute scenarios was in surface water, at 0.0044 ppm. This concentration was derived via utilization of the FQPA Index Reservoir Screening Tool (FIRST) model (D363089; A. Shelby and N. Thurman; 29 September 2009). The highest EDWC for chronic scenarios was also in surface water, at 0.0015 ppm. This concentration was also obtained by utilizing the FIRST model (D332797; J. Breithaupt; 26 October 2006). In order to be more conservative, the highest of the acute, and the highest of the chronic EDWCs (among all the various acute and chronic scenarios modeled) were taken from EFED’s two most recent DWAs. The acute and chronic EDWCs used in the respective dietary analyses are shown in Tables 1 and 2 (below), respectively, along with the other scenarios assessed by

EFED.

TABLE 5.4.1 Maximum EDWCs for Drinking Water Risk Assessment, Based upon Ground Application of Thifensulfuron Methyl.* Drinking Water Source [Model Used] Use [Rate Modeled] Scenario Maximum EDWC (ppb) Safflower [0.0188 lbs ai/A] Acute and Chronic 0.0326 Groundwater [SCIGROW] Barley, fallow [0.056 lbs ai/A] Acute and Chronic 0.0972Page 22 of 38 TABLE 5.4.1 Maximum EDWCs for Drinking Water Risk Assessment, Based upon Ground Application of Thifensulfuron Methyl.* Drinking Water Source [Model Used] Use [Rate Modeled] Scenario Maximum EDWC (ppb)

Acute 1.656 Safflower [0.0188 lbs ai/A]

Chronic 0.336

Acute 4.429 Surface water [FIRST]

Barley, fallow [0.056 lbs ai/A]

Chronic 0.900 * D363089; Andrew Shelby and Nelson Thurman; 29 September 2009.

TABLE 5.4.2 Maximum EDWCs for Drinking Water Risk Assessment, Based upon Aerial Application of Thifensulfuron Methyl.* Drinking Water Source [Model Used] Use [Rate Modeled] Scenario Maximum EDWC (ppb)

Acute 3.9 Surface water [FIRST] Soybean [0.032 lbs ai/A]

Chronic 1.5 * D332797; James Breithaupt; 26 October 2006.

The various models used by EFED in conducting DWAs, and their descriptions, are available at the EPA website via the web link, http://www.epa.gov/oppefed1/models/water/ . No surface or groundwater monitoring data were available for thifensulfuron methyl.

5.5 Dietary Exposure and Risk

Acute and chronic aggregate dietary (f ood and drinking water) exposure and risk assessments were conducted for thifensulfuron methyl (D369038; W.T. Drew; 19 January 2010) using the Dietary Exposure Evaluation Model software with the Food Commodity Intake

Database (DEEM-FCIDTM), Version 2.03. This model uses food consumption data from the US Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII), collected from 1994 to 1996, and 1998. Both the acute and chronic assessments are highly conservative, and assume 100%CT, along with tolerance-level residues for all agricultural commodities. The default processing factor from DEEM 7.81 was used for corn syrup in the analyses. Based on these highly conservative assumptions, the acute dietary risk estimate, at the

95 th percentile of exposure, is less than 1% of the acute population-adjusted dose (aPAD) for females 13-49, the only population subgroup for whic h an acute dietary endpoint was identified (see Table 5.5.1, below).Page 23 of 38 TABLE 5.5.1 Summary of Acute Dietary Exposure and Risk Estimates for Thif ensulfuron Methyl.

DEEM Acute Dietary Analysis (95 th Percentile) Population Subgroup [Years of Age] aPAD (mg/kg/day) Exposure Estimate (mg/kg/day) % aPAD

General US Population
All Infants [< 1]

Children [1-2]

Children [3-5]

Children [6-12]

Youths [13-19]

Adults [20-49]

Adults [50+] NA* NA NA

Females [13-49] 1.59 0.000544 <1

* NA = Not Applicable.

Chronic dietary risk estimates are less than or equal to 1% of the chronic populationadjusted dose (cPAD) for all population subgroups. Children 3 to 5 years of age are the most highly-exposed subgroup, utilizing 1% of the cPAD, while the general US population also utilizes 1% of the cPAD (see Table 5.5.2, below).

TABLE 5.5.2 Summary of Chronic Dietary Exposure and Risk Estimates for Thif ensulfuron Methyl. DEEM Chronic Dietary Analysis Population Subgroup* [Years of Age] cPAD (mg/kg/day) Exposure Estimate (mg/kg/day) % cPAD

General US Population 0.000284 1
All Infants [<1] 0.000487 1
Children [1-2] 0.000602 1

Children [3-5] 0.000621 1
Children [6-12] 0.000447 1
Youth [13-19] 0.000310 1
Adults [20-49] 0.000239 1
Adults [50+] 0.000175 <1
Females [13-49] 0.043

0.000226 1

* Values for the population subgroup with the highest risk are in bold type.

Generally, the Agency is concerned when risk estimates exceed 100% of the PAD. Therefore, all acute and chronic dietary risk estimates are below HED’s LOC.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed residential uses for thifensulfuron methyl associated with the subject petition, nor are there any currently registered residential uses.6.1 Other (Spray Drift, etc)

Page 24 of 38 Spray drift is always a potential source of exposure to residents living in close proximity to spraying operations. This situation is particularly the case with aerial application. However, to a lesser extent, spray drift resulting from the ground application of thifensulfuron methyl could also be a potential source of exposure. The Agency has been working with the Spray Drift Task Force (a membership of US pesticide registrants), EPA Regional Offices, State Lead Agencies for pesticide regulation, and other parties to develop the best spray drift management practices. 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, and is developing a policy on how to apply appropriately the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift risks associated with pesticide application.

7.0 Aggregate Risk Assessments and Risk Characterization

7.1 Acute Aggregate Risk

Acute aggregate risk estimates are equivalent to the acute dietary risk estimates discussed in Section 5.5 (above), and are below HED’s LOC.

7.2 Short- and Intermediate-Term Aggregate Risk

Because there are no proposed residential uses for thifensulfuron methyl associated with the subject petition, nor any currently registered residential uses, short- and intermediate-term aggregate risks are not of concern for this chemical.

7.3 Long-Term Aggregate Risk

Long-term aggregate risk estimates are equivalent to the chronic dietary risk estimates discussed in Section 5.5 (above), and are below HED’s LOC.

7.4 Cancer Aggregate Risk

Thifensulfuron methyl has been classified as “Not Likely to be Carcinogenic to Humans.” Therefore, cancer risk is not a concern for this chemical.8.0 Cumulative Risk Characterization/Assessment

Page 25 of 38 Unlike other pesticides for which EPA has followed a cumulative risk approach, based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to thifensulfuron methyl and any other substances. Also, thifensulfuron methyl does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that thifensulfuron methyl has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity, and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism determinations, and procedures for cumulating effects from substances found to have a common mechanism, on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

9.0 Occupational Exposure/Risk Pathway

9.1 Short- and Intermediate-Term Handler Risk

The registrant did not submit a product-specific exposure study with this petition to estimate the occupational risks to handlers. Therefore, surrogate data from the Agency's Pesticide Handler and Worker Exposure Database (PHED), and Scientific Advisory Committee on Exposure (ExpoSAC) Policy #9 were used. Default values were utilized for acres treated per day, and body weight, to calculate the occupational exposures of mixer/loaders, applicators and flaggers to thifensulfuron methyl during a pplications on safflower (D369037; S.C. Wang; 10 January 2010). A NOAEL of 7 mg/kg/day was selected for de rmal and inhalation exposures of shortand intermediate-term duration. The selection was based on decreased body weight and body weight gain in males and females, and decreased spleen weights in males. The dermal absorption factor was 100%. Daily dermal and inhalation doses were combined, and then compared to the NOAEL to determine the level of risk. The LOC is an MOE of ≤ 100. A cancer risk assessment for handlers is not applicable b ecause thifensulfuron methyl was classified as “Not Likely to be Carcinogenic to Humans.” Handler exposure: There are five handler scenarios that are applicable to the proposed

use on safflower:

1. Mixing/loading for ground-boom applications, 2. Mixing/loading for aerial applications, 3. Applying sprays using ground-boom equipment, 4. Applying sprays using fixed-wing aircraft, and 5. Flagging during aerial application.

No data regarding the number of exposure days per year were provided. However, due to the frequency of applications, HED assumes that handlers involved in applications would beexposed for less than 6 months per year. Thus, handler exposures are expected to be short- or

intermediate-term in duration.

Page 26 of 38 Although HED’s ExpoSAC Policy #9 does not include safflower in the high-acre crops, the ExpoSAC (5 November 2009) recommended that 200 acres treated per day should be assumed for applications using ground-boom equipment, and 1200 acres treated per day treated should be assumed for applications us ing fixed-wing aircraft on safflower. The handler exposure estimates in this assessment are based on a central tendency estimate of unit exposure, and an upper-percentile assumption for the application rate, and are assumed to be representative of high-end exposures. The uncertainties associated with this assessment stem from the use of surrogate exposure data (such as differences in use scenario and data confidence), and assumptions regarding that amount of chemical handled. The estimated exposures are believed to be reasonable high-e nd estimates, based on observations from field studies and professional judgment. The handler MOEs for Harmony® SG use, based on the maximum use rate of 0.0188 lb ai/A, range from 330 to 8,900 at the single-layer, no-gloves level. These MOEs do not exceed HED’s LOC, an MOE of ≤ 100 (see Table 9.1, below).Page 27 of 38TABLE 9.1 Non-Cancer Short- and Intermediate-Term Exposures and Risks to Handlers fromthe Use of Thifensulfuron Methyl on Safflower.ExposureScenarioMitigationLevel1Dermal UnitExposure2(mg/lb ai)Inhalation UnitExposure3(μg/lb ai)Use Rate(lb ai/A)AcresTreated4(A/day)DailyDermal Dose5(mg/kg/day)DailyInhalation Dose6(mg/kg/day)CombinedDaily Dose7(mg/kg/day)Short- andIntermediateTerm MOE8Mixer/LoaderGroundapplicationBaseline0.0660.770.01882000.0035450.0000410.0035862,000AerialapplicationBaseline0.0660.770.018812000.021270.0002470.02152330ApplicatorSprays usingground-boomBaseline0.0140.740.01882000.000750.00003950.0007898,900Sprays usingfixed-wingaircraftEngineering controls0.00500.0680.018812000.0016110.0000210.0016324,300FlaggerFlagging foraerialapplicationBaseline0.0110.350.01883500.0010340.00003250.0010676,6001. Baseline consists of long-sleeve shirt, long pants, shoes, and socks, with no respirator. Engineering controls consists ofan enclosed cockpit.2. Baseline DUE represents long pants, long-sleeve shirt, no gloves, open mixing/loading, and open cab tractors, as appropriate. Engineering controls DUErepresents an enclosed cockpit.3. Baseline IUE represents no respiratory protection, open mixing/loading, and open cab tractors,as appropriate. Engineeringcontrols IUE represents anenclosed cockpit.4. Daily acres treated values are from EPAestimates of acreage that could be treatedin a single day for each exposure scenario of concern (ExpoSAC Policy #9).5. Daily dermal dose (mg/kg/d) = [DUE (mg/lb ai) x dermal absorption (1.0) x use rate (lb ai/acre) x acres treated (A/day)] ÷ [body weight (70kg)].6. Daily inhalation dose (mg/kg/d) = [IUE (μg/lb ai) x conversion (1mg/1000 μg) x inhalation absorption (1.0) x use rate (lb ai/acre) x acres treated (A/day)] ÷[body weight (70kg)].7. Combined daily dose = daily dermal dose + daily inhalation dose.8. Short-term MOE = NOAEL (7 mg/kg/day) ÷ combined daily dose.Intermediate-term MOE = NOAEL (7 mg/kg/day) ÷ combined daily dose.9.2 Short- and Intermediate-Term Post-Application Risk

Page 28 of 38 Post-application exposure: Because Harmony® SG is used for selective post-emergence control of weeds in safflower fields, workers performing post-application activities can be exposed to thifensulfuron methyl. Anticipated post-application activities, and their respective dermal transfer coefficients (TCs) are summarized in Table 9.2.1, below. The information in the

table is based on ExpoSAC Policy #3.1 , and is based on proprietary and non-proprietary data.

TABLE 9.2.1 Anticipated Post-Application Activi ties and Dermal Transfer Coefficients.

Proposed

Crop Policy Crop Group; Category Exposure

Potential Transfer Coefficients (cm 2 /hour) Activities

Low 100 Scouting, hand weeding Safflower Field/row crop;

low/medium Medium 1500 Irrigation, scouting

The post-application MOEs range from 970 to 15,000, and thus do not exceed HED’s LOC, an MOE of ≤ 100. A summary of the post-application exposures and risks is presented in Table 9.2.2, below.

TABLE 9.2.2 Post-Application Exposure and Risk from the Use of Thifensulfuron Methyl on Safflower. Crop Use Rate (lb ai/A) Work Activity TCs 1
(cm 2 /hr) PostApplication Day 2 DFR 3
(μg/cm 2 ) Daily Dose 4
(mg/kg/day) MOE 5

Scouting, hand weeding 100 0 0.042 0.0005 15,000 Safflower 0.0188

Irrigation, scouting 1500 0 0.042 0.0072 970

1. Transfer coefficients from ExpoSAC Policy #3 , Agricultural Transfer Coefficients, 7 May 1998. 2. Day after treatment represents approximately 12 hours following application, when sprays have dried. 3. DFR = Dislodgable Foliar Residue = [use rate (lb ai/acre) x fraction of ai remaining on foliage when spray dries x 4.54E8 μg/lb x 24.7E-9 acre/cm 2 ]. 4. Daily dose = [DFR (μg/cm 2 ) x TC (cm 2 /hr) x conversion factor (1 mg/1000 μg) x exposure time (8 hrs/day) x dermal absorption (100%)] ÷ [body weight (70 kg)]. 5. MOE = NOAEL (7 mg/kg/day) ÷ daily dose (mg/kg/day).

The technical material is Category III for acute dermal toxicity, and acute eye irritation, and Category IV for acute dermal irritation. Per the Worker Protection Standard (WPS), a 12- hour REI is required. Therefore, RD should ensure that the requirement for a 12-hour REI appears on the label directions for the use of thifensulfuron methyl on safflower.

10.0 Data Needs and Label/Regulatory Recommendations

10.1 Toxicology

In order to satisfy recently revised pesticide registration data requirements (40CFR §158), the following toxicity studies are required (see Appendix B):Page 29 of 38 1. OPPTS Health Effects Test Guideline 870.3200 , 21/28-Day Dermal Toxicity,

2. OPPTS Health Effects Test Guideline 870.6200 , Acute and Subchronic Neurotoxicity, and

3. OPPTS Health Effects Test Guideline 870.7800 , Immunotoxicity.

10.2 Residue Chemistry

OPPTS Residue Chemistry Test Guideline 860.1550 , Proposed Tolerances: A revised Section F should be submitted to delete the word “combined” in the tolerance expression. Note to RD: According to HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 27 May 2009), the tolerance expression for thifensulfuron methyl cited in 40CFR §180.439[a] should be revised to state:

Tolerances are established for residues of thifensulfuron methyl, including its metabolites and degradates, in or on the commodities listed in the table below. Compliance with the tol erance levels specified below is to be determined by measuring only thif ensulfuron methyl (methyl 3-[[[[(4- methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino] sulfonyl]-2- thiophenecarboxylate).

HED is recommending that a tolerance for residues of thifensulfuron methyl be established, as summarized in Table 10.2, below.

TABLE 10.2 Tolerance Summary for Thifensulfuron Methyl. Commodity Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments; Correct Commodity Definition
Safflower, seed 0.05 0.05

10.3 Occupational and Residential Exposure

RD should ensure that the requirement for a 12-hour REI appears on the label directions for the use of thifensulfuron methyl on safflower.Page 30 of 38 References

PP #7F7219 Label Amendments and Petition for Tolerances on Wheat Forage and Hay, Oat Forage and Hay, and Barley Hay. Summary of Analytical Chemistry and Residue Data. ; D342084; D. Dotson; 17 April 2008.

Tier I Drinking Water Assessment for New Use of Thifensulfuron on Safflower ; D363089; A. Shelby and N. Thurman; 29 September 2009.

Tier I Drinking Water Assessment for Tribenuron Methyl and Thifensulfuron New Uses ; D332797; J. Breithaupt; 26 October 2006.

Thifensulfuron Methyl. Petition to Establish a Permanent Tolerance (Associated with Regional Section 3 Registration) for Residues Resulting from Food/Feed Use of the Herbicide on Safflower. Summary of Analytical Chemistry and Residue Data. ; D361945; W.T. Drew; 19 January 2010.

Thifensulfuron Methyl. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action Associated with Food/Feed Use of the Herbicide on Safflower. ; D369038; W.T. Drew; 19 January 2010.

Thifensulfuron-Methyl: Occupational and Residential Exposure/Risk Assessment for the New Uses on Safflower ; D369037; S.C. Wang; 10 January 2010.

Herbicide Handbook, 7th Edition ; Weed Science Society of America; 1994.Appendix A: Toxicology Assessment

Page 31 of 38 A.1 Toxicology Data Requirements

The requirements (40CFR §158.340) for food use of thifensulfuron methyl are shown in Table A.1 (below), and are based on revisions to 40CFR §158 (March 2009). Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

TABLE A.1 Toxicology Data Requiremen ts for Thifensulfuron Methyl.

Test Required Satisfied

870.1100 Acute Or al Toxi city.....................................................................

870.1200 Acute De rmal Toxi city ................................................................

870.1300 Acute Inha lation Toxi city............................................................ 870.2400 Primary Eye Irrita tion................................................................... 870.2500 Primary De rmal Irrita tion ............................................................

870.2600 Dermal Sensitiza tion .................................................................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subc hronic (Rode nt)............................................................

870.3150 Oral Subchr onic (Non-R odent) ...................................................

870.3200 21/28- Day Derm al.......................................................................

870.3250 90-Da y Derm al............................................................................ 870.3465 90 -Day Inhala tion....................................................................... yes

yes

yes

no

no yes

yes

no

no

no

870.3700a Developmental Toxicity (R odent) ............................................... 870.3700b Developmental Toxi city (Non-R odent) .......................................

870.3800 Re productio n ............................................................................... yes

yes

yes yes

yes

yes

870.4100a Chronic Toxi city (Rode nt)...........................................................

870.4100b Chronic Toxic ity (Non-R odent) .................................................. 870.4200a Oncogeni city (R at) ...................................................................... 870.4200b Oncogenic ity (Mous e).................................................................

870.4300 Chronic/ Oncogeni city.................................................................. yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity – Ge ne Mutation (B acteria l).................................. 870.5300 Mutagenicity – Ge ne Mutation (M ammalian) ............................. 870.5375 Mutagenicity – Struct ural Chromosoma l Aberra tions ................. 870.5395 Mutagenicity – Mamma liam Erythrocyte Micronucle us ............. 870.5550 Mutagenicity – Un scheduled DNA S ynthesi s ............................. 870.5915 Mutagenicity – In Vivo Sister Chroma tid Exch ange.................... yes

yes

yes

no

no

no yes

yes

yes

yes

yes

no

870.6100a Acute Delayed Ne urotoxicity (Hen) ............................................ 870.6100b 90-Day Neurot oxicity (H en)........................................................ 870.6200a Acute Neurotoxicity Screening Batte ry (Rat ).............................. 870.6200b 90-Day Neurotoxicity Sc reening Battery (Rat) ........................... 870.6300 Developmen tal Neurot oxicity

...................................................... no

no

yes

yes

no no

no

no

no

no

870.7485 Genera l Metabo lism ....................................................................

870.7600 Dermal Penetra tion...................................................................... yes

no yes

no

870.7800 Immunotoxicity yes noA.2 Toxicity Profiles

Page 32 of 38 TABLE A.2.1 Acute Toxicity Profile for Technical Thifensulfuron Methyl.

Guideline

Number Study Type MRID

Number Results Tox Category

870.1100 Acute Oral - Rat 00146033 LD 50 >5000 mg/kg (M+F) IV

870.1100 Acute Oral - Rat 00146034 LD 50 >5000 mg/kg (M+F) IV

870.1200 Acute Dermal 00146035 LD 50 >2000 mg/kg (M+F) III

870.1200 Acute Dermal 40467606 LD 50 >2000 mg/kg (M+F) III

870.1300 Acute Inhalation 00143657 LC 50 >7.9 mg/L/4 hours III

870.2400 Primary Eye Irritation 00143658 Moderate irritation. III

870.2500 Primary Skin Irritation 40921502 Slight irritation. IV

870.2600 Dermal Sensitization 00146037 Not a sensitizer. NA* * NA = Not Applicable.

TABLE A.2.2 Subchronic, Chronic and Other Toxici ty Profile for Thifensulfuron Methyl.

Guideline

Number Study Title MRID Number Results

870.3100 90-Day Oral Toxicity - Rat (diet) 00143660 (1984) Acceptable/guideline ppm = 0, 100, 2500, &

7500 mg/kg/day (M/F) = 0/0, 7/9, 177/216, 559/697 NOAEL = 7 (males), 9 (females) mg/kg/day. LOAEL = 177 (males), 216 (females) mg/kg/day, based on decreased body weight, body weight gain, and spleen weight in males only (13%).

870.3100 90-Day Oral Toxicity- Mouse (diet) 00161276 (1984) Acceptable/guideline ppm=0, 500, 2500 &

7500 mg/kg/day (M/F) = 0/0, 97/123, 523/690 &

1427/2287 NOAEL = 1427 (males), 2287 (females) mg/kg/day.

LOAEL = could not be determined.

870.3150 13-Week Oral Toxicity- Dog (diet) 00145160 (1984) Acceptable/guideline ppm = 0, 75, 1500 &

7500 mg/kg/day (M&F) = 0, 1.88, 37.5 & 187.5 NOAEL = 37.5 males & females mg/kg/day. LOAEL = 187.5 males & females mg/kg/day, based on decreased body weight and adrenal weight in high-dose males.

870.3200 21/28-Day Dermal Toxicity –

Rat No study has been submitted.

870.3700a Developmental Toxicity- Rat (gavage) 00143661 (1984) Acceptable/guideline mg/kg/day = 0, 26, 159, & 725 (analytically determined doses) Maternal NOAEL = 725 mg/kg/day.

LOAEL = could not be determined. Developmental NOAEL = 159 mg/kg/day. LOAEL = 725 mg/kg/day, based on decreased mean fetal body weights, and increased incidence of small renal papillae.Page 33 of 38 TABLE A.2.2 Subchronic, Chronic and Other Toxici ty Profile for Thifensulfuron Methyl.

Guideline

Number Study Title MRID Number Results

870.3700b Developmental Toxicity- Rabbit (gavage) 00161277 (1984) Acceptable/guideline mg/kg/day = 0, 22, 158 & 511 (analytically determined doses) Maternal NOAEL = 158 mg/kg/day. LOAEL = 511 mg/kg/day, based on decreased mean body weights. Developmental NOAEL = 511 mg/kg/day.

LOAEL = could not be determined.

870.3800 Reproduction (2- Generation) – Rat (diet) 00161278 (1985) Acceptable/guideline ppm = 0, 25, 500 &

2500 mg/kg/day F 0 M/F = 0/0, 1.8/2.4, 34/48 &

175/244 mg/kg/day F 1b M/F = 0/0, 1.7/2.1, 36/43 &

180/212 Parental/Systemic NOAEL = 175 (males), 244 (females) mg/kg/day.

LOAEL = could not be determined. Reproductive NOAEL = 180 (males), 212 (females) mg/kg/day.

LOAEL = could not be determined. Offspring NOAEL = 180 (males), 212 (females) mg/kg/day.

LOAEL = could not be determined.

870.4100 Chronic (1 year) – Dog (diet) 00161273 (1986) Acceptable/guideline ppm = 0, 50, 750 &

7500 mg/kg/day (M&F) = 0, 1.25, 18.75 & 187.5 NOAEL = 18.75 (males & females) mg/kg/day. LOAEL = 187.5 (males & females) mg/kg/day, based on increased liver weights in males, and increased relative thyroid/parathyroid weights in females, with decreased body weight and body weight gain in females after week 22.

870.4200 Carcinogenicity (18-Month) – Mouse (diet) 00161275 (1985) 40340321 (1987) (individual pathology sheets) Acceptable/guideline ppm = 0, 25, 750 &

7500 mg/kg/day (M/F) = 0/0, 3.2/4.3, 97/128 &

979/1312 NOAEL = 979 (males), 4.3 (females) mg/kg/day. LOAEL = could not be determined (males), 128 (females) mg/kg/day, based on a decrease in terminal body weights in the mid and high doses.

No evidence of carcinogenicity.

870.4300 Chronic/Carcinog enicity (2-Year) – Rat (diet) 00161274 (1986) Acceptable/guideline 40340324 (1987) Supplement 40340323 (1987) Supplement ppm = 0, 25, 500 &

2500 mg/kg/day (M/F) = 0/0, 0.96/1.3, 20/26 &

120/133 NOAEL = 20 (males), 26 (females) mg/kg/day. LOAEL = 120 (males), 133 (females) mg/kg/day, based on decreased body weight and body weight gain.

No evidence of carcinogenicity.Page 34 of 38 TABLE A.2.2 Subchronic, Chronic and Other Toxici ty Profile for Thifensulfuron Methyl.

Guideline

Number Study Title MRID Number Results

870.5100

870.5265 Gene Mutation in S. typhimurium

and E. coli 00143662 (1984) Acceptable/guideline No mutagenic response ± S9 activation in TA 1535, 97, 98 & 100. Cytotoxicity seen at HDT.

870.5300 Gene Mutation in

CHO Mammalian

Cells at HGPRT

Locus 00145161 (1987) 40340325 (1987) Acceptable/guideline No mutations at HDT (7mM), which was above limit of solubility.

870.5375 CHO Cell Cytogenetics 44710403 (1996) Acceptable/guideline No evidence of chromosomal aberrations when tested up to cytotoxic or solubility limit

concentrations.

870.5395 In vivo Rat Bone

Marrow
Micronucleus 00145560 (1984) Acceptable/guideline Negative for clastogenic response at 5000 mg/kg.

870.5550 Unscheduled DNA Synthesis in Primary

Mammalian Cells 00143663 (1985) Acceptable/guideline No significant increase in UDS.

870.6200a Acute Neurotoxicity Screening Battery – Rat (gavage) No study has been submitted.

870.6200b Subchronic Neurotoxicity Study – Rat (diet) No study has been submitted.

870.6300 Developmental Neurotoxicity Study – Rat (diet) No study has been submitted.

870.7485 Metabolism Study

– Rat (gavage) 00161281 (1986) Acceptable/guideline low dose = 20 mg/kg high dose = 2000 mg/kg Most of the radioactivity was recovered in the urine and feces (parent with 5 metabolites) with parent accounting for 55 and 72% for males and females,respectively. Minor metabolites included DPXM6316 acid (2.3-2.4%), O-demethyl DPX-M6316 (0.4-0.5%), triazine amine (0.5%) and lesser amounts of 2-ester-e-sulfonamide and thiophene sulfonamide. Fecal metabolite profile was similar to that in urine. Unchanged DPX-M6316 acid is the primary excretory product (18 or 12% in males and females, respectively). Three metabolites

remained unidentified.

870.7600 Dermal Absorption – Rats No study has been submitted.

870.7800 Immunotoxicity Study No study has been submitted.Appendix B: Rationale for Toxicology Data Requirements

Page 35 of 38 Guideline Number: 870.3200 Study Title: 21/28-Day Dermal Toxicity Rationale for Requiring the Data

The subchronic (21/28-day) dermal toxicity study is a data requirement under 40CFR §158, as a part of the data requirements for registration of a pesticide for food use. The dermal toxicity Test Guideline ( OPPTS.870.3200 ) is intended to evaluate the toxic effects associated with continuous or repeated exposures to a test substance for a period of 21- 28 days.

Practical Utility of the Data

How will the data be used? A route specific (such as dermal) study will provide critical scientific information needed to characterize potential hazard to the human population exposed to the pesticide by the dermal route. This study will provide a dose, and a toxicological endpoint of concern for quantification of risks for dermal exposures. This study would eliminate the uncertainties associated with the use of an oral study ha ving a default (100% oral equivalent) dermal absorption factor. In many cases, toxicity observed via the dermal route will be different than toxicity observed via oral exposure, due to absorption and distribution of the toxic agent after exposure, or differences in metabolism (systemic versus local). This means that the route-to-routeextrapolation (use of an oral dose/endpoint) in risk assessment could result in under- or overestimation of risks from the dermal route.

How could the data impact the Agency’s future decision-making? If the dermal toxicity study indicates that the test material poses either a greater or lesser risk than that calculated using an oral dose (as used in the interim decision), the risk assessment would be revised to reflect the magnitude of potential risk derived from the newdata. Also, the requested data would allow the Agency to determine if the risks had been overestimated or under-estimated. If the risks were under-estimated, additional risk mitigation measures could be required. If the risks were over-estimated, risk mitigation measures could

be reduced.Page 36 of 38 Guideline Number: 870.6200 Study Title: Neurotoxicity Batt ery (Acute and Subchronic Studies) Rationale for Requiring the Data

This is a new data requirement under 40CFR §158, as a part of the data requirements for registration of a pesticide (food and non-food uses). The Neurotoxicity Screening Battery Test Guideline ( OPPTS 870.6200 ) is designed to evaluate the potential adverse effects on the nervous system from exposure to pesticide chemicals. The Agency believes that the guideline studies are inadequate in their assessment of behavioral effects, and do not use optimal methods to evaluate the potential toxicity to the nervous tissue structure and function. To detect and characterize these potential effects more fully, a battery of more sensitive testing is required. The objective of this neurotoxicity battery testing is to evaluate the incidence and severity of the functional and/or behavioral effects, the level of motor activity, and the histopathology of the nervous system. The acute neurotoxicity study is required to detect possible effects re sulting from a single exposure. The subchronic neurotoxicity study is intended to detect possible effects resulting from repeated or long-term

exposures.

Practical Utility of the Data

How will the data be used? The acute and subchronic neurotoxicity studies provide critical scientific information needed to characterize potential hazards to the human population on the nervous system from pesticide exposure. These studies can provide data on a wide range of functional tests for evaluating neurotoxicity, including sensory effects, neuromuscular effects, learning and memory, and histopathology of the nervous system. For example, animal studies with organophosphorous chemicals have shown neurotoxi city to be the primary toxic endpoints (cholinesterase inhibition) of concern in rodents and non-rodents. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios, and are considered a primary data source for reliable reference dose calculation. The Agency has established an oral reference dose (RfD) for assessing dietary risks for a number of chemicals (such as organophoshates and carbamates) where neurotoxicity was the most sensitive endpoint

of concern.

How could the data impact the Agency's future decision-making? If the acute or subchronic neurotoxicity studies show that thifensulfuron methyl poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessment for thifensulfuron methyl may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have this data, a 10X database uncertainty factor may need to be applied when conducting a risk assessment using the currently available studies.Page 37 of 38 Guideline Number: 870.7800 Study Title : Immunotoxicity
Rationale for Requiring the Data

This is a new data requirement under 40CFR §158, as a part of the data requirements for registration of a pesticide (food and non-food uses). The Immunotoxicity Test Guideline ( OPPTS 870.7800 ) prescribes functional immunotoxicity testing, and is designed to evaluate the potential of repeated chemical exposure to produce adverse effects (such as suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Seve re Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide’s potential immunotoxicity. These data will be used in combination with data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies to characterize potential immunotoxic effects.

Practical Utility of the Data

How will the data be used? These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios, and are considered a primary data source for reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8- tetrachlorodibenzo-p-dioxin) among devel opmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from

the new data. If the Agency does not have this data, a 10X database uncertainty factor may need to be applied for conducting a risk assessment from the available studies.Page 38 of 38 Appendix C: Human Research Reference

The Pesticide Handlers Exposure Database, Version 1.1 (Electronic Database); The PHED Task Force, 1995; (Task Force members: Health Canada, US Environmental Protection Agency, and the National Agricultural Chemicals Association); released February 1995.