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5.4.3 Acute Dietary Risk Assessment................................................................................ 21

5.4.4 Chronic Dietary Risk Assessment ............................................................................ 22

5.4.5 Cancer Dietary Risk Assessment.............................................................................. 23

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

6.1 Spray Drift .................................................................................................................... 23

7.0 Aggregate Exposure/Risk Characterization...................................................................... 23

7.1 Acute Aggregate Risk ................................................................................................... 23

7.2 Short- and Intermediate-Term Aggregate Risk............................................................. 23

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

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

8.0 Cumulative Exposure/Risk Characterization.................................................................... 24

9.0 Occupational Exposure/Risk Characterization ................................................................. 24

9.1 Short- and Intermediate-Term Handler and Post-Application Risk ............................. 24

10.0 References......................................................................................................................... 28

Appendix A. Toxicology Profile and Executive Summaries....................................................... 29

A.1 Toxicology Data Requirements .................................................................................... 29

A.2 Toxicity Profiles............................................................................................................ 30

A.3 Hazard Identification and Endpoint Selection .............................................................. 33

A.4 Executive Summaries.................................................................................................... 35

Appendix B. Human Research Reference ................................................................................... 37

Appendix C. Physicochemical Properties.................................................................................... 38
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1.0 Executive Summary

The Interregional Research Project Number 4 (IR-4) has submitted a tolerance petition (1E7885)

proposing the establishment of tolerances for residues of the herbicide, thifensulfuron methyl 

(with CAS name methyl-3-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]

sulfonyl]-2-thiophenecarboxylate), in or on chicory roots and tops (leaves). 

HED has reviewed the available toxicological and residue chemistry studies for thifensulfuron 

methyl, and is recommending that the requested use be registered, and that permanent tolerances

be established. 

The toxicological database adequately characterizes thifensulfuron methyl as having low acute 

oral, dermal and inhalation toxicity. The toxicological studies conducted with thifensulfruon

methyl did not indicate specific target organ toxicity. 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). There were no gross or histopathological 

changes reported in any of the studies. There was no indication of neurotoxicity, and the ai is a 

member of the sulfonylurea class of compounds, which are not known to be neurotoxic. 

The potential for increased susceptibility of infants and children from exposure to thifensulfuron 

methyl was evaluated. There was evidence of quantitative susceptibility in the rat developmental 

toxicity study, based on observed fetal effects at a dose which did not cause maternal toxicity. 

These effects included decreased mean fetal body weights, and an increased incidence of small 

renal papillae. HED had a low degree of concern for the observed susceptibility, based on the 

completeness of the toxicity database, the lack of evidence of susceptibility in the rabbit 

developmental and rat reproductive toxicity studies, and the lack of neurotoxicity in the database. 

In addition, endpoints and doses for risk assessment were chosen to be protective of the fetal 

effects. Based on these considerations, HED reduced the required 10X Food Quality Protection 

Act (FQPA) Safety Factor to 1X. 

Potential immunotoxicity was observed (only in mid-dose males) as a decrease in spleen weight 

in the subchronic rat study. However, in the submitted immunotoxicity study in female rats, 

dosing with thifensulfuron methyl did not affect any immunotoxicity parameters up to the 

highest dose tested (HDT). In the absence of dermal and inhalation toxicity, and dermal 

absorption studies, HED has relied on oral studies to assess hazard and risk from dermal and 

inhalation exposure. 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. 

Adequate metabolism, storage stability, analytical methods, and field trial data are available to 

support the proposed use. The chicory field trial study with thifensulfuron methyl resulted in 

residues below 0.010 ppm, the lowest limit of method validation (LLMV), in all samples of the 

raw agricultural commodities (RACs). 
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HED has used conservative assumptions to assess the risk from exposure to thifensulfuron 

methyl from dietary sources. These include the use of recommended tolerance-level residues, 

modeled drinking water estimates, and the assumption that all registered and requested 

commodities were treated, or 100% crop treated (CT). Both acute and chronic dietary risk 

estimates are below HED’s level of concern (LOC) for all population subgroups. 

There are currently no existing or proposed residential uses of thifensulfuron methyl. Therefore, 

acute and chronic aggregate risks are equivalent to acute and chronic dietary risks, respectively, 

which are not of concern. 

Occupational exposures to thifensulfuron methyl from the proposed new use on chicory, 

assuming single layer clothing with no gloves (baseline), result in margins of exposure (MOEs) 

that are all above 100. Therefore (because HED has concern for MOEs <100), HED concludes 

that risks are not of concern for occupational exposure in all handler and post-application 

scenarios. 

Review of human research: This risk assessment relies in part on data from studies in which 

adult human subjects were intentionally exposed to a pesticide or other chemical. These studies 

(listed in Appendix B) have been determined to require a review of their ethical conduct, have 

received that review, and have been determined to be ethically conducted. 

2.0 HED Recommendations

HED recommends that the requested use of thifensulfuron methyl on chicory be registered, and 

that permanent tolerances in both chicory roots and tops, as detailed in Section 2.2.3, be 

established. 

2.1 Data Deficiencies

None. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Methods

Two methods using high performance liquid chromatography (HPLC) with 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. For Method AMR646-86, straw samples are extracted with ethyl acetate, and the extract is partitioned with sodium 

bicarbonate. The aqueous phase is acidified, and partitioned with dichloromethane. The 

dichloromethane phase is evaporated to dryness, and then reconstituted for analysis via HPLC 

with photo-conductivity detection. For Method AMR-761-87, wheat grain is extracted with 

ethyl acetate, barley grain is extracted with 0.1 M sodium bicarbonate, and straw is extracted 
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with ethyl acetate/HCl (at pH 3). Extracts are then analyzed via HPLC with photo-conductivity 

detection. 

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. For this method, samples are extracted with an acetonitrile

(ACN)/ammonium carbonate buffer solution, and the concentrated residues are reconstituted in 

methanol for analysis. If required, a hexane wash step, or cleanup step using a strong anion 

exchange solid phase extraction (SPE) column, may be incorporated. Analysis is performed via 

column-switching LC. Extracts in methanol are applied to a size exclusion chromatography 

column, and the eluate is diverted onto a reversed phase XDB-C8 column for MS analysis. The 

validated limit of quantitation (LOQ) was 0.02 ppm. This method may also be used for 

enforcing tolerances in corn grain, sorghum grain, and soybean seeds. 

Additionally, an LC/MS/MS (tandem MS detection) method, DuPont Method 13412 (Revision 

#1), is available to enforce tolerances for residues of various sulfonylurea herbicides in oily 

commodities, including chicory roots and tops (leaves). Samples are extracted with ACN/20 

mM potassium phosphate, at pH 7 (3:1, v/v). This mixture is allowed to soak for 15 minutes 

prior to blending for 1 minute using a high-speed homogenizer. The mixture is vacuum-filtered, 

brought to volume with ACN, and partitioned using liquid/liquid extraction with hexane. After 

discarding the hexane layer, the extracts are concentrated using dry nitrogen on a TurboVap 

evaporator. The extracts are then diluted with reagent water, and cleaned up using a polystyrenedivinylbenzene SPE cartridge eluted with 25 mM ammonium hydroxide in methanol. The 

cleaned extract is evaporated to near dryness, reconstituted in ACN/50 mM ammonium acetate to 

a concentration of approximately 10%, and analyzed via LC/MS/MS. The LOQ, determined as 

the lowest limit of method validation (LLMV), is 0.010 ppm for thifensulfuron methyl in chicory 

roots and leaves. 

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. 

2.2.2 International Harmonization

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. However, no Canadian or Mexican MRLs for thifensulfuron methyl 

have been proposed nor established in chicory roots or tops. The residue definitions in Canada, 

Mexico and the US are harmonized. 

2.2.3 Recommended Tolerances

A summary of the proposed and recommended tolerances is presented in Table 2.2.3, below. 

The submitted data support tolerances for residues of thifensulfuron methyl, including its 
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metabolites and degradates, in or on chicory roots and chicory tops, at the levels listed below. 

Compliance with the tolerance levels specified below is to be determined by measuring 

thifensulfuron methyl only. 

TABLE 2.2.3 Tolerance Summary for Thifensulfuron Methyl. 

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Chicory, roots 0.01 0.01 Chicory, roots

Chicory, tops 0.01 0.01 Chicory, tops

2.2.4 Revisions to Petitioned-For Tolerances

No revisions to the tolerances or residue definition, as proposed by IR-4, were necessary. 

2.3 Label Recommendations

A revised Section B should be submitted that is in accordance with the supplemental label 

regarding the mandatory use of adjuvants. The required tank mix adjuvants are a non-ionic 

surfactant (NIS) at a minimum concentration of 0.25% (v/v), along with either a urea ammonium 

nitrogen (UAN) or ammonium sulfate (AS) fertilizer at the rate of 2 quarts per acre (qt/A). 

Additionally, the supplemental label should be revised to comport with Section B, which 

stipulates applications via ground equipment only, in spray volumes of 19-30 gallons per acre 

(GPA). 

3.0 Introduction

3.1 Chemical Identity

The chemical structure and nomenclature of thifensulfuron methyl are presented in Table 3.1 

(below). 

TABLE 3.1 Thifensulfuron Methyl Nomenclature. 

Chemical structure

Common name Thifensulfuron methyl

Molecular formula C12H13N5O6S2

Molecular weight 387.38

N

N

N

CH3

O

CH3

N

H

N

H

O

S

CO2CH3

S

O

O
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TABLE 3.1 Thifensulfuron Methyl Nomenclature. 

Company experimental name DPX-M6316

IUPAC name Methyl 3-(4-methoxy-6-methyl-1,3,5-triazin-2-ylcarbamoylsulfamoyl) thiophene2-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) Basis herbicide (EPA Registration #352-571), a water dispersible granule (WG) 

formulation containing 25% thifensulfuron methyl by weight. 

Chemical class Sulfonylurea herbicide (Group 2)

Known impurities of concern None.

3.2 Physical/Chemical Characteristics

Thifensulfuron methyl has a low vapor pressure (1.3 x 10-10 mm Hg), is not significantly volatile, 

and would therefore result in low inhalation exposures. The Environmental Fate and Effects 

Division (EFED) concluded that thifensulfuron methyl is a somewhat persistent chemical that 

partitions readily into water. Acid hydrolysis, photo-degradation in water, and aerobic soil 

metabolism are the primary routes of degradation. Rapid leaching is likely because of the low 

sorption coefficients. In soils, hydrolysis under acidic conditions, and via metabolism, will 

likely be the dominant routes of degradation. A detailed description of the physicochemical 

properties of the technical grade of thifensulfuron methyl is provided in Table C (see Appendix 

C). 

3.3 Pesticide Use Pattern

The end-use product (EP) proposed for use on chicory is DuPont Basis Herbicide (EPA 

Registration #352-571), a water dispersible granule (WG) formulation containing 25% 

thifensulfuron methyl (by weight) as an active ingredient (ai). This EP is a multiple active 

ingredient (MAI) formulation which also contains 50% rimsulfuron. Rimsulfuron is discussed in 

a separate document; only thifensulfuron methyl is addressed herein. The proposed use 

directions for application to chicory are summarized in Table 3.3 (below). The proposed use 

directions are consistent with the information provided in a revised Section B (14 December 

2011). 

According to the supplemental label, Basis Herbicide is to be applied as either: 

1. One post-emergence broadcast spray on Chrysolite (sulfonylureatolerant) variety of chicory (in the 2- to 8-true leaf stage) at an 

application rate of 0.005 pound ai per acre (lb ai/A), or 

2. two broadcast spray applications at 0.0025 lb ai/A per application, with 

the first at the 2-true leaf stage, and the second at or after the 6-true 

leaf stage. 
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A pre-harvest interval (PHI) of 90 days is stipulated. The proposed maximum single/seasonal 

use rate is 0.005 lb ai/A (0.3 ounce EP/A), and the minimum single use rate is 0.0025 lb ai/A 

(0.15 oz EP/A). Applications are to be made using ground equipment (applications via aerial 

equipment or chemigation are prohibited by Section B; chemigation is prohibited in the 

supplemental label). The inclusion of specific adjuvants in the spray mixture is mandated by the 

supplemental label directions (adjuvants are allowed, but not required, in Section B). The 

adjuvants to be added to spray mixtures consist of an NIS, along with a UAN or AS fertilizer. 

Additionally, Section B stipulates that applications should be made in spray volumes of 19-30 

GPA. The supplemental label does not mention spray volumes. 

TABLE 3.3 Summary of Proposed Use Pattern for Thifensulfuron Methyl Application to Chicory. 

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*

1 post-emergence application 

(in the 2- to 8-true leaf stage) 

with high numbers of weeds; 

broadcast; ground. 

Basis Herbicide

25% ai

[352-571]

0.005 1 0.005 90 Applications via 

aerial equipment or 

chemigation are 

prohibited. An NIS 

(0.25%, v/v), along 

with a UAN or AS 

fertilizer (2 qt/A), 

must be added to the 

spray mixture. 

2 post-emergence 

applications (first at 2-true 

leaf stage, second at or after 

the 6-true leaf stage) with 

low numbers of continually 

emerging weeds; broadcast;

ground. 

0.0025 2

* The approved label specifies plant-back intervals (PBIs) of 0 days (for corn and potatoes) to 18 months (for crops 

not listed on the approved product label). 

The proposed label directions for Basis Herbicide are adequate to allow evaluation of the chicory 

residue data. A revised Section B should be submitted to comport with the supplemental label 

regarding the mandatory use of adjuvants. HED concludes that the supplemental label should 

also be revised to specify that applications are to be made via ground equipment only, and to 

specify application spray volumes (19-30 GPA), as stated in Section B. 

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support IR-4’s requested new use of 

thifensulfuron methyl on chicory. Humans may be exposed to thifensulfuron methyl through 

consumption of food and drinking water, since thifensulfuron methyl may be applied directly to 

growing crops, and application may result in it reaching surface and ground water sources of 

drinking water. There are no residential uses of thifensulfuron methyl, so there is not likely to be 

exposure in residential or non-occupational settings. In an occupational setting, mixer/loaders 

may be exposed via the dermal and inhalation routes while handling the pesticide prior to 

application, and applicators may be exposed via the same routes during application. 
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Additionally, there is a potential for post-application dermal exposure of workers re-entering 

treated fields. 

Risk assessments have previously been prepared for the existing uses of thifensulfuron methyl. 

This risk assessment considers all of the aforementioned exposure pathways based on the 

proposed new use of thifensulfuron methyl, but also considers the existing uses for the dietary 

exposure assessment. 

3.5 Consideration of Environmental Justice

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.eh.doe.gov/oepa/guidance/justice/eo12898.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 Intake 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. Additionally, OPP is able to assess dietary exposure to smaller, 

specialized subgroups, and exposure assessments are performed when conditions or 

circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of 

pesticide products, and associated risks for adult applicators and for toddlers, youths and adults 

entering or playing on treated areas post-application are evaluated. Further considerations are 

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

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

as lifestyle and traditional dietary patterns among specific subgroups. 

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database is complete, and is sufficient for the purpose of conducting a human 

health risk assessment. The studies submitted to support a human health risk assessment 

included oral subchronic studies in rats, mice and dogs; a chronic/carcinogenicity studies in the 

rat, and a carcinogenicity study in mice; developmental and reproductive toxicity studies; an 

immunotoxicity study; the complete battery of mutagenicity studies; and a rat metabolism study. 

Recently submitted neurotoxicity studies are under review. 
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The HED Hazard Science Policy Council (HASPOC) concluded that the route-specific dermal 

and inhalation toxicity studies are not needed, and waived the requirement for these studies. 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

In the rat metabolism study, animals 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, at up to approximately 70% of the total dose male/female

(M/F) 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 percentages as were reported in urine. Three 

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

There were no major sex differences regarding any aspects of metabolism. 

4.2.1 Dermal Absorption

Dermal absorption data were not required for thifensulfuron methyl, and were not submitted. 

The 21/28-day dermal toxicity study in the rat was waived. 

4.3 Toxicological Effects

Following dosing with thifensulfuron methyl, most findings related to decreases in body weights, 

body weight gains, or organ weights (a reflection of lower body 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 gains in females after week 22. 

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 no observed adverse effect level (NOAEL) was 159 mg/kg/day, based on decreased 

mean fetal body weights, and an increased incidence of small renal papillae at the lowest

observed adverse effect level (LOAEL) of 725 mg/kg/day. This is considered to be an increase 

in quantitative susceptibility, since fetal effects were observed at a dose which did not cause 

maternal toxicity. Although HED does not consider decreased fetal body weights to be the result

of a single dose, in the absence of information pertaining to incidence of increased small renal 

papillae, HED took the conservative and health protective approach of assuming these could be 

the result of a single dose. The rabbit developmental toxicity study showed a decrease in 

maternal body weight 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 toxicity 
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study, there were no parental, reproductive or offspring effects observed at doses up to 175 or 

180 mg/kg/day in males, and 244 or 212 mg/kg/day in females. 

Neurotoxicity was not observed in any of the submitted studies, including the recently submitted 

neurotoxicity studies which are currently under review. Based on the lack of neurotoxicity in the 

submitted studies, a developmental neurotoxicity study (DNT) is not required. A decrease in 

spleen weight was noted only in mid-dose males in the subchronic rat study, and was considered 

a potential sign of immunotoxicty. However, in the recently submitted immunotoxicity study in 

female rats, dosing with thifensulfuron methyl did not affect any immunotoxicity parameters up 

to the HDT of 529 mg/kg/day. In the absence of dermal toxicity and dermal absorption studies, 

HED cannot characterize the potential for thifensulfuron methyl toxicity via the dermal route. 

Thifensulfuron methyl is classified as “not likely to be carcinogenic to humans,” based on an 

acceptable chronic/carcinogenicity study in rats, and a carcinogenicity study in mice at doses that 

are considered to be adequate, and not excessive, for the determination of carcinogenic potential. 

The available in vivo and in vitro mutagenicity studies did not show thifensulfuron methyl to be 

mutagenic or clastogenic. 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

There was an increase in quantitative susceptibility observed in the rat developmental toxicity 

study. However, there was no evidence of potential susceptibility or neurotoxicity in any of the 

other submitted studies. HED has recommended that the 10X FQPA safety factor be reduced to 

1X for the following reasons: 

1. The toxicity database is complete, and is adequate to characterize 

potential toxicity associated with dietary exposure (the only 

potential exposure route for infants and children). 

2. HED’s degree of concern for the increased quantitative susceptibility is 

low because it was only observed in the rat developmental toxicity 

study, and was observed at doses considerably higher than the 

doses chosen for risk assessment; therefore HED’s risk assessment 

is protective of the potential susceptibility. 

3. No neurotoxic signs were observed in any of the toxicity studies 

submitted to the Agency, including the required neurotoxicity 

screening battery, and a DNT study is not required. 

4. The exposure assessment is conservative, and does not underestimate 

exposure and risk associated with the existing and proposed uses of 

thifensulfuron. 
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4.4.1 Completeness of the Toxicology Database

The toxicity database is for thifensulfuron is complete. Required studies have either been 

received or have been waived (dermal and inhalation route-specific toxicity studies). In the 

submitted studies, clear NOAELs and LOAELs have been identified for the effects of concern.

4.4.2 Evidence of Neurotoxicity

There were no signs of neurotoxicity in any of the submitted toxicity studies, including the 

recently submitted neurotoxicity screening battery. In addition, thifensulfuron methyl is a 

member of the sulfonylurea class of herbicides, which are not known to be neurotoxic. Based on 

the lack of evidence that this chemical causes neurotoxic effects, HED has concluded that a DNT 

study is not needed. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was evidence of an increase in quantitative susceptibility in the rat developmental study, in 

which fetal effects were observed at a dose which did not cause maternal effects. The fetal 

effects observed at the NOAEL for the dams consisted of decreased mean fetal body weights,

and an increased incidence of small renal papillae. No increase in qualitative or quantitative 

susceptibility was observed in the developmental rabbit or 2-generation rat reproduction studies. 

Although there was evidence of increased quantitative susceptibility, HED has a low degree of 

concern for the observed susceptibility, because the doses and endpoints for risk assessment have 

been selected to be protective of the observed susceptibility. 

4.4.4 Residual Uncertainty in the Exposure Database

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 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 versus 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 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, show 

no indication of fetal or offspring effects. The Agency is confident that the risk to developing 

fetuses exposed to thifensulfuron methyl will not be underestimated, because the doses selected 
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for risk assessment are conservative, and protective of the effects of concern; there is no 

indication of increased susceptibility in the rabbit developmental study, nor in the 2-generation 

reproduction study in rats; and because the studies considered for FQPA analysis were all 

acceptable. 

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

An acute dietary endpoint (with NOAEL of 159 mg/kg/day) was chosen for females ages 13-49 

years of age, based on the fetal effect observed in the rat developmental toxicity study. The 

effect was an increased incidence of small renal papillae which was observed at a dose that was 

not maternally toxic. This is considered to be a very conservative health-protective approach 

because the effect is not likely to have occurred after a single dose. However, HED chose the 

endpoint to be protective of the developing fetus. Although decreased mean fetal body weight 

was also observed at the LOAEL, the effect is not considered to be the result of a single dose, 

and therefore was not included in the endpoint for risk assessment. In the absence of single-dose 

effects applicable to the general population, including infants and children, an acute dietary 

endpoint for these populations was not selected. 

For chronic dietary risk assessment, the decreased body weight and body weight gains observed 

in the 78-week dietary mouse carcinogenicity study served as the endpoint for risk assessment, 

with the NOAEL of 4.3 mg/kg/day used as the point of departure (POD). This dose was the 

lowest of the long-term studies conducted with thifensulfuron methyl (2-year rat, 1-year dog, and 

2-generation rat reproduction), and was therefore considered to be protective. Thifensulfuron 

methyl was considered “not likely to be a human carcinogen,” based on the lack of evidence of 

carcinogenicity in rats and mice; therefore, cancer risk is not of concern for this chemical. 

HED selected an oral study for short- (1-30 days) and intermediate-term (1-6 months) dermal 

risk assessments, since no dermal toxicity study was submitted. The endpoint and dose were 

selected from the 90-day study in rats, with the NOAEL of 7 mg/kg/day based on decreased 

body weight and body weight gains in males and females, as well as decreased spleen weights in 

males observed at the LOAEL of 177 mg/kg/day. The study was considered to be the most 

relevant for occupational dermal risk assessment, based on the duration, and because it had the 

lowest NOAEL of any of the other studies of similar durations. In the absence of dermal 

absorption data, HED conservatively assumed 100% dermal absorption for thifensulfuron 

methyl. The same 90-day study was selected for inhalation exposure and risk assessment since a 

route-specific study was not available. Furthermore, HED assumed equivalent toxicity via the 

oral and inhalation routes. 
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4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For occupational risk assessment, the dermal (short- and intermediate-term durations) and 

inhalation (short- and intermediate-term durations) routes of exposure utilize the same study for 

the POD and endpoint. Therefore, dermal and inhalation exposure should be combined to 

determine a total MOE. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

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 was classified as “not likely to be a human carcinogen.”

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

TABLE 4.5.4.1 Summary of Thifensulfuron Methyl Toxicological Doses and Endpoints for Use in Dietary 

Exposure and Risk Assessment. 

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 

an 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). 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. LOC = Level Of Concern. 

TABLE 4.5.4.2 Summary of Thifensulfuron Methyl Toxicological Doses and Endpoints for Use in 

Occupational Exposure and Risk Assessment.

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

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.
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TABLE 4.5.4.2 Summary of Thifensulfuron Methyl Toxicological Doses and Endpoints for Use in 

Occupational Exposure and Risk Assessment.

Exposure/

Scenario

Point of Departure Uncertainty/

FQPA Safety

Factors

LOC for 

Risk 

Assessment

Study and Toxicological Effects

Inhalation short-

(1-30 days) and 

intermediateterm (1-6 

months)

NOAEL = 7 

mg/kg/day (inhalation

toxicity equivalent to 

oral toxicity)

UFA = 10X

UFH = 10X

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). NOAEL = No Observed Adverse 

Effect Level. LOAEL = Lowest Observed Adverse Effect Level. MOE = Margin Of Exposure. LOC = Level Of 

Concern. 

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants is adequately understood, based on acceptable studies with 

wheat, corn and soybeans. The results 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 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 chicory. 

The nature of the residue in ruminants 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. 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 residue of 

concern in ruminant commodities is thifensulfuron methyl for the purposes of tolerance 

expression and risk assessment. 
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5.1.2 Summary of Environmental Degradation

EFED has provided a drinking water assessment (DWA) for the use of thifensulfuron methyl on 

chicory (D391089; W.J. Shaughnessy; 12 January 2012). 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 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. 

5.1.3 Comparison of Metabolic Pathways 

In the rat metabolism study, most of the radioactivity (triazine-2-[

14C]) was recovered in the 

urine and feces, with almost no tissue and carcass accumulation of radioactivity. Of the 

radioactivity eliminated in the urine and feces, most was parent compound, with 5 minor 

metabolites. Of the urinary metabolites, the parent compound accounted for the majority of the 

excreted radioactivity (55% and 72% in males and females, respectively). Minor metabolites 

included thifensulfuron (2% and 3%, M/F), O-demethyl thifensulfuron methyl (0.5% and 0.4%,

M/F), triazine amine (0.5% in both males and females), and lesser amounts of 2-ester-3-

sulfonamide and thiophene sulfonamide. The fecal metabolite profile was similar to that of the 

urine. Unchanged parent was the predominant excretory product (18% and 12%, M/F). Five 

metabolites were identified. These metabolites include thifensulfuron (1% and 2%, M/F), Odemethyl thifensulfuron methyl (0.3% and 0.7%, M/F), triazine amine (0.3% and 0.2%, M/F), 

and lesser amounts of 2-ester-3-sulfonamide, thiophene sulfonamide, and 2-acid-3-sulfonamide. 

Three metabolites remained unidentified. 

In general, parent and metabolite residues in plants were similar to those in rats, and the 

metabolites were present at low levels. The metabolic pathway in goats appears to be similar to 

that observed in plants, and the residues were low to non-detectable in goat tissues and milk. 

5.1.4 Residues of Concern Summary

The primary routes of dissipation for thifensulfuron methyl are acid hydrolysis, photodegradation in water, and aerobic soil metabolism. Thifensulfuron methyl is very mobile, and 

thus is able to move laterally and downward to surface water and groundwater sources of 

drinking water, respectively. 

Because thifensulfuron methyl degradates/metabolites were detected only at low levels in water, 

and in the plant and ruminant metabolism studies, HED has determined that the residue of 

concern in plants, ruminants, and drinking water is the parent compound only. 
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TABLE 5.1.4 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 NA 2

Livestock Ruminant Thifensulfuron methyl Thifensulfuron methyl

Poultry ND NA

Drinking Water Thifensulfuron methyl NA

1. ND = Not Determined. 

2. NA = Not Applicable. 

5.2 Food Residue Profile

There are adequate data for risk assessment and tolerance assessment. In the plant metabolism 

studies, thifensulfuron methyl residues were found to decline rather rapidly. The nature of the 

residue in livestock is adequately understood, based on the available goat metabolism study; 

however, tolerances for residues in livestock commodities are not needed (per 40CFR 

§180.6[a][3]). This determination 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. Because no detectable residues of thifensulfuron methyl were 

found in poultry feed items, a poultry metabolism study is not required. Confined rotational crop 

studies indicated that neither thifensulfuron methyl nor its metabolites accumulated to any 

significant amounts in rotated crops. 

The residue data for chicory roots and tops (leaves) are adequate to fulfill data requirements for 

the proposed use. The data reflect the proposed use pattern (maximum single/seasonal use rate 

of 0.005 lb ai/A, a PHI of 90 days, and use of both an NIS and a UAN or AS fertilizer in the 

spray mixture). HED concludes that the proposed tolerances of 0.01 ppm in chicory roots and 

tops are appropriate (D391756; W.T. Drew; 1 June 2012). 

Residues of thifensulfuron methyl were <0.010 ppm (below the LOQ) in all samples of chicory 

roots and leaves following foliar application at the proposed maximum use rate, and at an 

exaggerated (5X) rate. The residue data for chicory are summarized in Table 5.2 (below). 
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TABLE 5.2 Summary of Residue Data from Chicory Field Trials with Thifensulfuron Methyl. 

Chicory 

Matrix

Total Use 

Rate (lb ai/A)

PHI 

(Days)

Residue Levels (ppm)1

n Min. Max. LAFT2 HAFT3 Median Mean Std. Dev.

1X Rate

Roots 0.00482-

0.00509

109-134 4 <0.010 <0.010 0.010 0.010 0.010 0.010 0

Leaves 0.00482-

0.00509

109-134 4 <0.010 <0.010 0.010 0.010 0.010 0.010 0

5X Rate

Roots 0.0246 134 1 <0.010 <0.010 0.010 0.010 0.010 0.010 NA4

Leaves 0.0246 134 1 <0.010 <0.010 0.010 0.010 0.010 0.010 NA

1. Except for sample min and max, values reflect per trial averages. n = number of field trials. For calculation of 

median, mean and standard deviation, the LLMV (0.010 ppm) was used for any results reported as 

<LLMV. 

2. LAFT = Lowest Average Field Trial. 

3. HAFT = Highest Average Field Trial. 

4. NA = Not Applicable (standard deviation is not calculated for n < 3). 

5.3 Water Residue Profile

The thifensulfuron methyl drinking water residues used in risk assessment were provided 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 using the FQPA Index Reservoir 

Screening Tool (FIRST) model (D391089; W.J. Shaughnessy; 12 January 2012). The highest 

EDWC for chronic scenarios was also in surface water, at 0.0015 ppm. This concentration was 

also obtained 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 DWAs. 

The acute and chronic EDWCs used in the respective dietary analyses are shown in Tables 5.3.1 

and 5.3.2 (below), respectively, along with other scenarios assessed by EFED. 

TABLE 5.3.1 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
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TABLE 5.3.1 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)

Surface water [FIRST] Safflower [0.0188 lbs ai/A] Acute 1.656

Chronic 0.336

Barley, fallow [0.056 lbs ai/A] Acute 4.429

Chronic 0.900

* D391089; W.J. Shaughnessy; 12 January 2012. 

TABLE 5.3.2 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. 

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 days and 36 days. The field dissipation half-lives 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 ground water. 

The rate of degradation due to chemical processes varies widely. The rate of degradation in pH 

5, 7 and 9 aqueous buffered solutions were 5.5, 184, and 145 days, respectively. This indicates 

acid hydrolysis readily occurs. The major degradate was the thiophene portion of the molecule, 

2-ester-3-sulfonamide, which increased until the end of the study. However, the pH did not 

affect the rate of degradation in aqueous photolysis studies, based on dark-control adjusted halflives of 4.9-5.3 days at pH values of 5, 7 and 9. The half-lives due to soil photolysis were 41-54 

days, with the major degradates being the intact thiophene (2-ester-3-sulfonamide) and triazine 

(triazine amine) rings of the molecule. 

Microbial degradation also appears to degrade parent thifensulfuron methyl. The major 

metabolites were parent compound with hydroxyl and formyl group ring substitutions, the 

thiophene portion of the molecule (cyclized and non-cyclized), and aminotriazine (the triazine 

portion of the molecule). The linear half-lives of the parent compound in aerobic soil were 27 

and 36 days. In anaerobic aquatic conditions, the half-lives ranged from 19 to 29 days, forming 

2-ester-3-sulfonamide. Triazine amine was also formed and increased until the end of the study 

(365 days). In the field, the degradates O-demethyl DPX-M6316 and 2-ester-3-sulfonamide 

were present in all four test sites, and remained in the top 5 inches of soil primarily. In stainless 
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steel cylinders of silt loam soil, triazine amine (from applied chlorsulfuron) reached 23.5-24.9% 

of applied chlorsulfuron by 4-8 weeks after treatment, and mostly occurred in the top 10 cm. 

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

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

were conducted for thifensulfuron methyl (D399156; W.T. Drew; 1 June 2012) using the Dietary

Exposure Evaluation Model software with the Food Commodity Intake Database (DEEMFCIDTM), Version 2.03. This model uses food consumption data from the USDA’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. 

The LLMV was 0.010 ppm in chicory roots and tops (leaves). Thifensulfuron methyl residues 

were <LLMV in all samples from both the 1X and 5X field trials. There are no animal feedstuffs

associated with the proposed use on chicory. 

The thifensulfuron methyl drinking water residues used in risk assessment were provided 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.” 

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 

assessments. The highest EDWC for acute scenarios was in surface water, at 0.0044 ppm. The 

highest EDWC for chronic scenarios was also in surface water, at 0.0015 ppm. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

Both the acute and chronic dietary assessments assume 100%CT. 

5.4.3 Acute Dietary Risk Assessment

Based on 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 (see 

Table 5.4.3, below). This was the only population subgroup for which an acute dietary endpoint 

was identified. 
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TABLE 5.4.3 Summary of Acute Dietary Exposure and Risk Estimates for Thifensulfuron Methyl. 

Population Subgroup

[Years of Age]

DEEM Acute Dietary Analysis (95th Percentile)

aPAD (mg/kg/day) Exposure Estimate 

(mg/kg/day)

% aPAD

General US Population NA* NA NA

All Infants [< 1]

Children [1-2]

Children [3-5]

Children [6-12]

Youths [13-19]

Adults [20-49]

Adults [50+]

Females [13-49] 1.59 0.000544 <1

* NA = Not Applicable. 

Generally, the Agency is concerned when risk estimates exceed 100% of the PAD. Therefore, 

the acute dietary risk estimate is not of concern. 

5.4.4 Chronic Dietary Risk Assessment

Based on highly conservative assumptions, the results of the chronic analysis are summarized in 

Table 5.4.4 (below) for the general US population, all infants (<1 year old), children 1-2, 

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

Chronic dietary risk estimates are less than or equal to 1.4% of the chronic population-adjusted 

dose (cPAD) for all population subgroups. The most highly exposed population subgroup is 

children 3 to 5 years of age. 

TABLE 5.4.4 Summary of Chronic Dietary Exposure and Risk Estimates for Thifensulfuron Methyl. 

Population Subgroup*

[Years of Age]

DEEM Chronic Dietary Analysis

cPAD (mg/kg/day) Exposure Estimate 

(mg/kg/day)

% cPAD

General US Population 0.043 0.000284 <1

All Infants [<1] 0.000487 1.1

Children [1-2] 0.000602 1.4

Children [3-5] 0.000621 1.4

Children [6-12] 0.000447 1.0

Youth [13-19] 0.000310 <1

Adults [20-49] 0.000239 <1

Adults [50+] 0.000175 <1

Females [13-49] 0.000226 <1

* Values for the population subgroup with the highest risk are in bold type. 
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Generally, the Agency is concerned when risk estimates exceed 100% of the PAD. Therefore, 

all chronic dietary risk estimates are below HED’s LOC. 

5.4.5 Cancer Dietary Risk Assessment

Thifensulfuron methyl is classified as “not likely to be carcinogenic to humans.” Therefore, 

cancer risk is not of concern. 

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 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for thifensulfuron 

methyl. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices,

State Lead Agencies for pesticide regulation, and other parties to develop the best spray drift 

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

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of US pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast, or 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 of specific products with significant risks 

associated with drift. 

7.0 Aggregate Exposure/Risk Characterization

7.1 Acute Aggregate Risk

Acute aggregate risk estimates are equivalent to the acute dietary risk estimates discussed in 

Section 5.4, and are not of concern. 

7.2 Short- and Intermediate-Term Aggregate Risk

Because there are no existing or proposed residential uses for thifensulfuron methyl, short- and 

intermediate-term aggregate risks are not relevant to this petition. 
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7.3 Chronic /Long-Term Aggregate Risk

Chronic aggregate risk estimates are equivalent to the chronic dietary risk estimates discussed in 

Section 5.4, and are not of concern. 

7.4 Cancer Aggregate Risk

Thifensulfuron methyl is classified as “not likely to be carcinogenic to humans.” Therefore, 

cancer risk is not a concern for this chemical. 

8.0 Cumulative Exposure/Risk Characterization

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, and 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 Characterization

9.1 Short- and Intermediate-Term Handler and Post-Application Risk

An occupational exposure and risk assessment has been conducted for IR-4’s proposed new use 

of the herbicide thifensulfuron methyl on chicory (D391758; M. Collantes; 16 March 2012). The 

requested EP is BASIS Herbicide (EPA Registration #352-571), formulated as a WG containing 

25% of the ai. It is to be applied at a rate of 0.005 lb ai/A (0.3 oz EP/A) by ground equipment 

only. Occupational exposure is expected to occur for short- and intermediate-term durations, 

based on the proposed use pattern. 

Thifensulfuron methyl is currently registered for use on cereal grains (barley, field corn, oat, rice, 

sorghum, triticale and wheat), canola, cotton, flax, soybeans and safflower. In support of these 

registrations, HED previously assessed (D317652; S. Wang; 20 October 2006, and D369037; 

S.Wang; 10 January 2010) the herbicide products Harmony GT, Harmony Extra XP, and 

Harmony SG (Registration #352-633). These three products are formulated as either a WG or 

soluble granule (SG) and are applied by ground equipment, similar to BASIS. Application rates 

(0.0188 and 0.0281 lb ai/A) of the previously registered products are greater than the proposed 

application rate for BASIS (0.005 lb ai/A) on chicory. Furthermore, these higher application 

rates were assessed for large acreage crops using ground equipment (200 A), as opposed to the 
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standard row crop acreage (80 A) applicable to chicory. The LOC for occupational exposure is 

an MOE of 100; any MOEs greater than the LOC are not of concern. The occupational exposure 

and risk estimates for the previous assessments were MOEs ranging from 1,300 to 8,900 for 

occupational handler exposure, and from 970 to 15,000 for post-application exposure. As all 

scenarios resulted in MOEs significantly greater than 100, there were no risks of concern. 

HED performed an assessment for the use of thifensulfuron methyl on chicory using the 

proposed label application rate, revised unit exposures for mixer/loaders and applicators, new 

assumptions for adult body weight, typical acreage treated for row crops, and revised transfer 

coefficients for root and leafy vegetables. The estimated exposures resulted in MOEs ranging 

from 5,900 to 18,000 for handlers wearing baseline (long-sleeved shirt, long pants, socks, and 

shoes) personal protective equipment (PPE), and from 3,300 to 390,000 for post-application

exposures. The proposed new use on chicory does not result in risks of concern. The PPE 

specified on the master label require that applicators and other handlers must wear baseline 

clothing (long-sleeved shirt, long pants, socks, and shoes) plus chemical resistant gloves. 

Since the proposed use of thifensulfuron methyl on chicory results in the same exposure 

scenarios as the currently registered uses on cereal grains, canola, cotton, flax, soybeans and 

safflower, but at a lower application rate (0.005 versus 0.0281 lb ai/A) and lower acreage treated, 

and using conservative baseline unit exposure values, the resulting occupational exposures will 

result in higher MOEs than those previously assessed. Since there were no risks of concern 

identified for the registered uses, there are likewise no risks of concern for the use on chicory. 

Therefore, a new comprehensive assessment for occupational handler exposure is not required. 

HED concludes that the previous registrations for use of thifensulfuron methyl on cereal grains, 

canola, cotton, flax, soybeans and safflower are protective of the exposure expected from the 

proposed use on chicory. Summaries of the estimated occupational exposures provided in 

Tables 9.1.1 and 9.1.2 (below) support this conclusion.

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for thifensulfuron methyl, primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), and the low proposed use rate (0.005 lb ai/A). 

However, there are multiple potential sources of inhalation exposure to individuals performing 

post-application activities in previously treated fields. These potential sources include 

volatilization of pesticides and re-suspension of dusts and/or particulates that contain pesticides. 

The Agency sought expert advice and input on issues related to volatilization of pesticides from 

its Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) 

in December 2009, and received the SAP’s final report on 2 March 2010 

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

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 
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post-application inhalation exposure assessment for thifensulfuron methyl. 

Since post-application risks were not a concern on day 0 (12 hours following application), the 

restricted entry interval (REI) is based on the acute toxicity of thifensulfuron methyl technical 

material. Thifensulfuron methyl is classified as Toxicity Category III for dermal exposure and 

for eye irritation, and Toxicity Category IV for inhalation exposure and for dermal irritation. 

Under the Worker Protection Standard for Agricultural Pesticides, active ingredients classified as 

acute toxicity categories III or IV are assigned a 12-hour REI. However, the registered master 

label for BASIS herbicide specifies an REI of 4 hours, pursuant to Pesticide Registration (PR) 

Notice 95-3 (Reduction of Worker protection Standard (WPS) Interim Restricted Entry Intervals 

(REIs) for Certain Low Risk Pesticides). The change from a 12-hour REI to a 4-hour REI was 

made by notification in 1995, and therefore the 4-hour REI shown on the label is appropriate. 
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TABLE 9.1.1 Non-Cancer Handler Risk Estimates for Use of Thifensulfuron Methyl on Chicory. 

Exposure 

Scenario

Mitigation 

Level1

Dermal 

Unit 

Exposure2

(mg/lb ai)

Inhalation 

Unit 

Exposure3 

(mg/lb ai)

Use Rate

(lb ai/A)

Amount 

Treated4

(A/day)

Daily

Dermal

Dose5

(mg/kg/day)

Dermal 

MOE6

Daily

Inhalation

Dose7

(mg/kg/day)

Inhalation 

MOE8

Combined

Daily Dose9

(mg/kg/day)

Total

MOE10

Mixer/Loader

BASIS

Ground 

application

Baseline 0.227 0.00896 0.005 80 0.001135 6,200 0.0000448 160,000 0.00118 5,900

Applicator

BASIS

Sprays with 

Groundboom

Baseline 0.0786 0.00034 0.005 80 0.000393 18,000 0.0000017 4,100,000 0.00039 18,000

1. Baseline PPE consists of long-sleeve shirt, long pants, shoes, and socks (with no gloves or respirator). 

2. Baseline Dermal Unit Exposure represents long pants, long-sleeved shirt, no gloves, open mixing/loading, and open cab tractors, as appropriate. 

3. Baseline Inhalation Unit Exposure represents no respiratory protection, open mixing/loading, and open cab tractors, as appropriate. 

4. Daily acres treated values are from EPA estimates of acreage that could be treated in a single day for each exposure scenario of concern (ExpoSAC Policy 9; 5

July 2000). 

5. Daily dermal dose (mg/kg/day) = [unit dermal exposure (mg/lb ai) * dermal absorption (1.0) * use rate (lb ai/acre) * daily acres treated] ÷ [body weight 

(80kg)]. 

6. Dermal MOE = NOAEL (7 mg/kg/day) ÷ dermal dose (mg/kg/day). 

7. Daily inhalation dose (mg/kg/d) = [unit exposure (mg/lb ai) * inhalation absorption (1.0) * use rate (lb ai/acre) * daily acres treated] ÷ [body weight (80kg)]. 

8. Inhalation MOE = NOAEL (7 mg/kg/day) ÷ inhalation dose (mg/kg/day). 

9. Combined daily dose = daily dermal dose + daily inhalation dose.

10. Total MOE = NOAEL (7 mg/kg/day) ÷ combined daily dose. UF = 100.
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TABLE 9.1.2 Post-Application Exposure and Risk for Use of Thifensulfuron Methyl on Chicory. 

Crop Use

Rate

(lb ai/A)

Work 

Activity

Transfer 

Coefficients1

(cm2/hr)

PostApplication 

Day2

DFR3

(μg/cm2)

Daily Dose4

(mg/kg/day)

MOE5

Chicory (vegetable 

root and leafy 

vegetable

0.005 Scouting 210 0 0.0112 0.0000235 390,000

Irrigation 1900 0 0.002128 3,300

1. Transfer coefficients from ExpoSAC Policy Memo #003, Agricultural Transfer Coefficients, 3 June 2011. 

2. Day after treatment represents approximately 12 hours following application, when sprays have dried. 

3. DFR = [use rate (lb ai/acre) * fraction of ai that remains on the foliage when sprays have dried * 4.54E8 μg/lb *

24.7E-9 acre/cm2]. 

4. Daily dose = [DFR (μg/cm2) * TC (cm2/hr) * conversion factor (1 mg/1,000 μg) * exposure time (8 hrs/day) *

dermal absorption (100%)] ÷ [body weight (80 kg)]. 

5. MOE = NOAEL (7 mg/kg/day) ÷ daily dose (mg/kg/day). 

10.0 References

Thifensulfuron Methyl: Summary of Hazard and Science Policy Council (HASPOC) Meeting of 

February 23, 2012: Recommendations on the need for 28-day inhalation and 28-day dermal 

toxicity studies.; TXR #0054114; D. Smegal; 7 March 2012. 

Letter from Raymond C. Leonard (Associate Coordinator, IR-4 HQ) to Barbara Madden

(RD/RIMUERB); 7 June 2011. 

Ingredient: Thifensulfuron Methyl Title: 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-methyl on Chicory; D391089; 

W.J. Shaughnessy; 12 January 2012. 

Tier I Drinking Water Assessment for Tribenuron Methyl and Thifensulfuron New Uses; 

D332797; J. Breithaupt; 26 October 2006. 

Thifensulfuron Methyl. Acute and Chronic Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessments for the Section 3 Registration Action Associated with Food Use 

of the Herbicide on Chicory.; D399156; W.T. Drew; 1 June 2012. 

Thifensulfuron Methyl. Petition to Establish Permanent Tolerances (Associated with Section 3 

Registration) for Residues Resulting from Food Use of the Herbicide on Chicory. Summary of 

Analytical Chemistry and Residue Data.; D391756; W.T. Drew; 1 June 2012. 

Thifensulfuron methyl: Occupational and Residential Exposure/Risk Assessment for the New Use 

on Chicory.; D391758; M. Collantes; 16 March 2012. 
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APPENDIX A: Toxicology Profile and Executive Summaries

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

yes

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 yes

* The requirements for the dermal and inhalation toxicity studies were waived by HASPOC. 
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A.2 Toxicity Profiles

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 IV

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.
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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/

Carcinogenicity 

(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.
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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)

48817901 (2012)

Review Pending

Proposed NOAEL = 2000 mg/kg/day (limit dose). 

870.6200b Subchronic 

Neurotoxicity 

Study – Rat (diet)

48817902 (2012)

Review Pending

Proposed NOAEL = 421 mg/kg/day (the HDT). 

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

Guideline

Number

Study Title MRID Number Results

870.7800 Immunotoxicity 

Study – Rat (diet)

48686101 (2011)

Acceptable/guideline

Females only

ppm = 0, 250, 750, 

2500, 7000

mg/kg/day = 0, 19, 55, 

192, 529

Systemic Effects

NOAEL = 529 mg/kg/day

LOAEL = not attained (no clinical signs of toxicity)

Immunotoxicity Effects

NOAEL = 529 mg/kg/day

LOAEL = not attained (no immunotoxic effects)

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females Age 13-49

Study Selected: Developmental Oral Toxicity – Rat

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 small 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 small 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)

A.3.2 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. 
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A.3.3 Chronic Reference Dose (cRfD) `

Study Selected: Combined Chronic/Carcinogenicity – Mouse

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. 

Chronic RfD = 4.3 mg/kg/day (NOAEL) = 0.043 mg/kg/day

 100 (UF)

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

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

A.3.5 Dermal Exposure (Short-, Intermediate- and Long-Term) 

Dermal Absorption Factor: 100%. There was no dermal penetration study submitted. 

Therefore, the default absorption factor is 100%. 

A.3.6 Occupational Dermal Exposure (Short- and Intermediate-Term)

Study Selected: 90-day Oral Toxicity Study – Rat

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. 
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A.3.7 Occupational Inhalation Exposure (Short- and Intermediate-Term)

Study Selected: 90-day Oral Toxicity Study – Rat

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). 

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. 

A.4 Executive Summaries

A.4.1 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID #48686101), thifensulfuron methyl (DPX-M6316) (99.3% 

ai, Lot #AUG06MA076) was administered to female Crl:CD(SD) rats (10/dose) via diet at dose 

levels of 0, 250, 750, 2500 or 7000 ppm (0, 19, 55, 192, or 529 mg/kg/day, respectively) for 28 

days. The positive control animals (10/dose) were injected intraperitoneally with 

cyclophosphamide (25 mg/kg/day; 10 mL/kg) for 5 days (Days 23-28). On Day 23, all test 

animals received an intravenous injection of sheep red blood cells (SRBCs) (4 x 108 cells/mL; 

0.5 mL/animal). On Day 28, all animals were sacrificed by isoflurane anesthesia and 

exsanguination. Blood was obtained from the abdominal vena cava and serum samples were 

analyzed for anti-SRBC IgM concentrations with an Enzyme-Linked Immunosorbent Assay 

(ELISA). The necropsy included the examinations of all major organs and tissues. Thymus, 

spleen and brain weights were recorded. 

There were no significant treatment-related effects seen in clinical signs, body weights, body 

weight gains, food consumption, or organ (thymus, spleen, and brain) weights. The selections of 

dose levels and test species/sex were approved by the HED Dose Adequacy review Team 

(DART, TXR# 0055831). 

The systemic toxicity NOAEL is 7000 ppm (529 mg/kg/day), the highest dose tested. 
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For immunotoxicity, the anti-SRBC IgM concentrations in female rats treated with 

thifensulfuron methyl were not affected by the treatment. Inter-individual variability was noted 

in all the treatment groups, as well as in the control group. Evaluation of individual animal data 

in this study did not show any trend or distribution that would demonstrate significant 

suppression of anti-SRBC IgM response. The positive control group showed significantly lower 

(-45%) anti-SRBC IgM concentration compared to the control, and validated the sensitivity of 

the assay. 

The Natural Killer (NK) cells activity assay was not performed in this study. The toxicology 

database for thifensulfuron methyl does not show any evidence of treatment-related effects on 

the immune system. The overall weight of evidence suggests that this chemical does not directly 

target the immune system. Under HED guidance, NK cells activity assay is not required at this 

time.

Under conditions of this study, the immunotoxicity NOAEL for anti-SRBC IgM antibody 

response is 7000 ppm (529 mg/kg/day); the LOAEL was not established. 

This immunotoxicity study is classified acceptable/guideline and satisfies the guideline 

requirement for an immunotoxicity study (OCSPP 870.7800).
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APPENDIX B: Human Research Reference

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 data, which include studies from 

the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler 

Exposure Task Force (AHETF) database, and the Agricultural Re-entry Task Force (ARTF) 

database are subject to ethics review pursuant to 40CFR §26, have received that review, and are 

compliant with applicable ethics requirements. For certain studies that review may have 

included review by the Human Studies Review Board. Descriptions of data sources, as well as 

guidance on their use, can be found at: http://www.epa.gov/pesticides/science/handler-exposuredata.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html. 
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APPENDIX C: Physicochemical Properties

TABLE 3.2 Physicochemical Properties of Thifensulfuron Methyl. 

Parameter Value Reference

Melting point/range (oC) 171.1 ± 1.2 MRID #47138301 (D342084; 

pH 4.0 D. Dotson; 17 April 2008)

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 10-8Pa (1.3 x 10-10 mm Hg)

Dissociation constant (pKa) 4.0

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