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 (Associated 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 38 
Page 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 ....................................................................................... 20 
Page 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 Residue 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-Term 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............................................................................... 38 
1.0 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-thiophenecarboxylate) 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 characterizes 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 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, but only at 

the highest dose tested (HDT). There were no gross 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-observed-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. Risk 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 single 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 aggregate 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 Guideline 
870.3200, 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 for toddlers, youths and adults entering or playing 

on treated areas post-application are evaluated. Further considerations are currently in 

development, as OPP has committed resources and expertise to the development of specialized 

software and models that consider exposure to bystanders and farm workers, as well as lifestyle 

and traditional dietary patterns among specific subgroups. 

 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 review. 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 cereal 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 absorbed through the foliage of treated weeds, 

inhibiting growth, causing necrosis of the growing plant, and eventual plant death. 

 Tolerances for residues of thifensulfuron 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 interval (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 Thifensulfuron 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 spray 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 restrictions: 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 spray mixture at a rate of 2-4 pints per 100 gallons of spray 

 solution (concentration of 0.25-0.55% v/v). The surfactant 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 least 80% of a high quality, petroleum (mineral) or modified 

 vegetable seed oil with at least 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

CH3

O

CH3

N

H

N

H

O

S CO2CH3

S

O

O

Common name Thifensulfuron methyl 

Molecular formula C12H13N5O6S2

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-methoxy-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/cm3) 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 (pKa) 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 [KOW]) 

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 developmental 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-[14C]) 

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-acid-3-sulfonamide), with some demethylation of 

the triazine methoxy group. 

3.1.1.3 Sufficiency of Data

 Data are sufficient for FQPA evaluation, toxicity 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 (Category 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). There 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 available 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 availability of a clear NOAEL, and the absence of 

immunotoxic effects in the remainder of the database 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/parathyroid 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-[14C]) 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 developmental 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 neurotoxicity 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 maternal 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 neurotoxicity, 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 directly 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 neurotoxicity 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 (UFDB) 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 (decreased 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 a 

LOAEL 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 is 
based on decreased body weights in females only. This endpoint was selected because it is of 

appropriate duration (lifetime study), and was administered 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 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. 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 incidental 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 

UFA = 10X 

UFH = 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

UFA = 10X 

UFH = 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, based on the lack of evidence of carcinogenicity in rats 

and mice. 

Point of Departure (POD) = a data point or estimated point derived from observed dose-response data, which is used 

to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. UF = Uncertainty Factor. UFA = extrapolation from animal to human (interspecies). UFH = potential 

variation in sensitivity among members of the human population (intra-species). UFDB = 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 Toxicological 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%) 

UFA = 10X 

UFH = 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) 

UFA = 10X 

UFH = 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 point derived from observed dose-response data, which is used 

to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. UF = Uncertainty Factor. UFA = extrapolation from animal to human (interspecies). UFH = potential 

variation in sensitivity among members of the human population (intra-species). UFDB = 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 has developed the Endocrine Disruptor 

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

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

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

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

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

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

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

interact with E, A or T hormonal systems, will proceed to the next stage of the EDSP, where 

EPA will determine which, if any, of the Tier 2 tests are necessary, based on the available data. 

Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the 

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

 Between October 2009 and February 2010, EPA 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. Under FFDCA §408[p], the Agency must screen all 

pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders, and data 
call-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 Division (EFED) has provided a drinking water 

assessment (DWA) for the use of thifensulfuron methyl on safflower (D363089; A. Shelby and 

N. Thurman; 29 September 2009). The primary routes 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 

Plants Primary crop Thifensulfuron methyl Thifensulfuron methyl 

Rotational crop ND 1 ND 

Livestock Ruminant ND ND 

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 chromatography (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 residues 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 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 

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 thifensulfuron 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 oil, 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 safflower 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) 

Groundwater [SCIGROW] Safflower [0.0188 lbs ai/A] Acute and Chronic 0.0326 

Barley, fallow [0.056 lbs ai/A] Acute and Chronic 0.0972 
Page 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) 

Safflower [0.0188 lbs ai/A] Acute 1.656 

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) 

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

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 (food 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 

95th percentile of exposure, is less than 1% of the acute population-adjusted dose (aPAD) for 

females 13-49, the only population subgroup for which 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 Thifensulfuron Methyl. 

DEEM Acute Dietary Analysis (95th Population Subgroup Percentile) 

[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 Thifensulfuron Methyl. 

Population Subgroup* DEEM Chronic Dietary Analysis 

[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 applications on safflower (D369037; S.C. Wang; 10 

January 2010). 

 A NOAEL of 7 mg/kg/day was selected for dermal 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 because 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 be 
exposed 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 using 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-end 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 38 

TABLE 9.1 Non-Cancer Short- and Intermediate-Term Exposures and Risks to Handlers from the Use of Thifensulfuron 

Exposure 

Scenario 

Mitigation 

Level 1 

Dermal Unit 

Exposure 2

(mg/lb ai) 

Inhalation Unit 

Exposure 3

(μg/lb ai) 

Use Rate 

(lb ai/A) 

Acres 

Treated 4 

(A/day) 

Daily 

Dermal Dose 5

(mg/kg/day) 

Daily 

Inhalation Dose 6

(mg/kg/day) 

Com

Dail

(mg/

Mixer/Loader 

Ground 

application 

Baseline 0.066 0.77 0.0188 200 0.003545 0.000041 0.0

Aerial 

application 

Baseline 0.066 0.77 0.0188 1200 0.02127 0.000247 0.

Applicator 

Sprays using 

ground-boom 

Baseline 0.014 0.74 0.0188 200 0.00075 0.0000395 0.0

Sprays using 

fixed-wing 

aircraft 

Engineerin

g controls 

0.0050 0.068 0.0188 1200 0.001611 0.000021 0.0

Flagger 

Flagging for 

aerial 

application 

Baseline 0.011 0.35 0.0188 350 0.001034 0.0000325 0.0

1. Baseline consists of long-sleeve shirt, long pants, shoes, and socks, with no respirator. Engineering controls consists of an enclosed c2. Baseline DUE represents long pants, long-sleeve shirt, no gloves, open mixing/loading, and open cab tractors, as appropriate. Engine represents an enclosed cockpit. 3. Baseline IUE represents no respiratory protection, open mixing/loading, and open cab tractors, as appropriate. Engineering controls  enclosed cockpit. 4. Daily acres treated values are from EPA estimates of acreage that could be treated in a single day for each exposure scenario of conce

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 wei6. 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 a

 [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 da
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 Activities and Dermal Transfer Coefficients. 

Proposed 

Crop 

Policy Crop Group; 

Category 

Exposure 

Potential 

Transfer Coefficients 

(cm2/hour) 

Activities 

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

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

(cm2/hr) 

PostApplication 

Day 2 

DFR 3 

(μg/cm2) 

Daily Dose 4

(mg/kg/day) 

MOE 5 

Scouting, 

hand weeding 

Safflower 0.0188 100 0 0.042 0.0005 15,000 

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/cm2

]. 

4. Daily dose = [DFR (μg/cm2

) x TC (cm2/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 tolerance levels specified below is to be 

determined by measuring only thifensulfuron 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 Requirements for Thifensulfuron Methyl. 

Test Required Satisfied

870.1100 Acute Oral Toxicity..................................................................... 

870.1200 Acute Dermal Toxicity ................................................................ 

870.1300 Acute Inhalation Toxicity............................................................ 

870.2400 Primary Eye Irritation................................................................... 

870.2500 Primary Dermal Irritation ............................................................ 

870.2600 Dermal Sensitization .................................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (Rodent)............................................................ 

870.3150 Oral Subchronic (Non-Rodent) ................................................... 

870.3200 21/28-Day Dermal....................................................................... 

870.3250 90-Day Dermal............................................................................ 

870.3465 90 -Day Inhalation....................................................................... 

yes 

yes 

yes 

no 

no 

yes 

yes 

no 

no 

no 

870.3700a Developmental Toxicity (Rodent) ............................................... 

870.3700b Developmental Toxicity (Non-Rodent) ....................................... 

870.3800 Reproduction ............................................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (Rodent)........................................................... 

870.4100b Chronic Toxicity (Non-Rodent) .................................................. 

870.4200a Oncogenicity (Rat) ...................................................................... 

870.4200b Oncogenicity (Mouse)................................................................. 

870.4300 Chronic/Oncogenicity.................................................................. 

yes 

yes 

yes 

yes 

yes 

yes

yes 

yes

yes 

yes 

870.5100 Mutagenicity – Gene Mutation (Bacterial).................................. 

870.5300 Mutagenicity – Gene Mutation (Mammalian) ............................. 

870.5375 Mutagenicity – Structural Chromosomal Aberrations ................. 

870.5395 Mutagenicity – Mammaliam Erythrocyte Micronucleus ............. 

870.5550 Mutagenicity – Unscheduled DNA Synthesis ............................. 

870.5915 Mutagenicity – In Vivo Sister Chromatid Exchange.................... 

yes 

yes 

yes 

no 

no 

no 

yes

yes 

yes 

yes 

yes 

no 

870.6100a Acute Delayed Neurotoxicity (Hen) ............................................ 

870.6100b 90-Day Neurotoxicity (Hen)........................................................ 

870.6200a Acute Neurotoxicity Screening Battery (Rat).............................. 

870.6200b 90-Day Neurotoxicity Screening Battery (Rat) ........................... 

870.6300 Developmental Neurotoxicity...................................................... 

no 

no 

yes 

yes 

no 

no 

no 

no 

no 

no 

870.7485 General Metabolism .................................................................... 

870.7600 Dermal Penetration...................................................................... 

yes 

no 

yes 

no 

870.7800 Immunotoxicity yes no 
A.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 LD50 >5000 mg/kg (M+F) IV 

870.1100 Acute Oral - Rat 00146034 LD50 >5000 mg/kg (M+F) IV 

870.1200 Acute Dermal 00146035 LD50 >2000 mg/kg (M+F) III 

870.1200 Acute Dermal 40467606 LD50 >2000 mg/kg (M+F) III 

870.1300 Acute Inhalation 00143657 LC50 >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 Toxicity 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 Toxicity 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 F0 M/F = 

0/0, 1.8/2.4, 34/48 & 

175/244 

mg/kg/day F1b 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 Toxicity 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 having 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-route 

extrapolation (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 new 

data. 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 Battery (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 resulting 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 neurotoxicity 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), Severe 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 developmental, 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.