UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

Date: April 13, 2011

MEMORANDUM

SUBJECT: Triflusulfuron-methyl: Revised Human Health Risk Assessment for Use in 

Garden Beet.

PC Code: 129002 DP Barcode: D388621

Decision No.: 425459 Registration No.: 352-569

Petition No.: 9E7669 Regulatory Action: Section 3 Registration

Assessment Type: Single Chemical Aggregate Case No.: NA

TXR No.: NA CAS No.: 126535-15-7

MRID No.: 47943201 40 CFR: §180.492

FROM: Elizabeth Holman, Chemist/Risk Assessor

Margarita Collantes, Biologist

Linnea Hansen, Toxicologist

Risk Assessment Branch 2

Health Effects Division (7509P)

THROUGH: Richard A. Loranger, Ph.D., Senior Scientist

Christina Swartz, Branch Chief

Risk Assessment Branch 2

Health Effects Division (7509P)

TO: Laura Nollen, Risk Manager Reviewer

Barbara Madden, Review Manager #5

John Hebert, Acting Chief

Risk Integration, Minor Use, and Emergency Response Branch

Registration Division (7505P)

The Registration Division (RD) requested that the Health Effects Division (HED) conduct a risk 

assessment for the active ingredient triflusulfuron-methyl to estimate the risk to human health 

that will result from the proposed use to control broadleaf weeds in garden beet. The risk 

assessment completed 2/17/11 (E. Holman, D373493) was revised to provide additional 

characterization of the doses and severity at which hemolytic anemia was observed in studies 

conducted in the rat (E. Holman, 4/7/11, D388460). This revised risk assessment has been 

further revised to address issues related to plant-back intervals (PBI) for rotational crops and 

restricted entry intervals (REI). 
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Table of Contents

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

2.0 Ingredient Profile.............................................................................................................. 7

2.1 Summary of Proposed Uses.................................................................................... 7

3.0 Hazard Characterization/Assessment............................................................................. 9

3.1 Hazard and Dose-Response Characterization......................................................... 9

3.1.1 Database Summary ................................................................................... 10

3.1.1.1 Studies available and considered (animal, human, general 

literature)................................................................................................... 10

3.1.1.2 Mode of action, metabolism, toxicokinetic data ........................ 10

3.1.1.3 Sufficiency of studies/data ......................................................... 10

3.1.2 Toxicological Effects................................................................................ 11

3.1.3 Dose-response ........................................................................................... 12

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)................................. 12

3.3 FQPA Considerations ........................................................................................... 13

3.3.1 Adequacy of the Toxicity Database.......................................................... 13

3.3.2 Evidence of Neurotoxicity ........................................................................ 13

3.3.3 Developmental Toxicity Studies............................................................... 14

3.3.4 Reproductive Toxicity Study .................................................................... 14

3.3.5 Additional Information from Literature Sources...................................... 14

3.3.6 Pre-and/or Postnatal Toxicity ................................................................... 14

3.3.6.1 Determination of Susceptibility ................................................. 14

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Preand/or Postnatal Susceptibility.................................................................. 15

3.3.7 Recommendation for a Developmental Neurotoxicity Study................... 15

3.4 Safety Factor for Infants and Children.................................................................. 15

3.5 Hazard Identification and Toxicity Endpoint Selection........................................ 16

3.5 Hazard Identification and Toxicity Endpoint Selection........................................ 16

3.5.1 Acute Reference Dose (aRfD) - Females age 13-49 and the General 

Population ............................................................................................................. 16

3.5.2 Chronic Reference Dose (cRfD)............................................................... 16

3.5.5 Dermal Absorption.................................................................................... 17

3.5.8 Residential and Occupational Dermal Exposure, Long-Term (>30 days) 17

3.5.9 Residential and Occupational Inhalation Exposure, Short-Term (1 to 30 

days) 18

3.5.11 Residential and Occupational Inhalation Exposure (Long-Term) .......... 18

3.5.12 Level of Concern for Margin of Exposure .............................................. 18

3.5.2 Summary of Toxicological Doses and Endpoints for Use in Human Risk 

Assessments.......................................................................................................... 19

3.5.12 Recommendation for Aggregate Exposure Risk Assessments ............... 20

3.5.13 Classification of Carcinogenic Potential................................................. 20

3.6 Endocrine disruption............................................................................................. 21

4.0 Public Health and Pesticide Epidemiology Data.......................................................... 21
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5.0 Dietary Exposure/Risk Characterization ..................................................................... 22

5.1 Pesticide Metabolism and Environmental Degradation........................................ 24

5.1.9 Drinking Water Residue Profile................................................................ 26

5.2 Dietary Exposure and Risk ................................................................................... 27

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 28

7.0 Combined Risk Assessments and Risk Characterization............................................ 29

8.0 Cumulative Risk Characterization/Assessment........................................................... 29

9.0 Occupational Exposure/Risk Pathway.......................................................................... 29

10.0 Data Needs and Label Recommendations.................................................................... 31

10.1 Toxicology ............................................................................................................ 31

10.2 Residue Chemistry................................................................................................ 31

10.3 Occupational and Residential Exposure ............................................................... 32

References:................................................................................................................................... 32

Appendix A: Toxicology Assessment ........................................................................... 33

A.1 Toxicology Data Requirements ................................................................................ 33

A.2 Acute Toxicity Profile for Isoxaben.......................................................................... 34

A.3 Executive Summaries................................................................................................ 38

A.4 Rationale for Toxicology Data Requirements...................................................... 50
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1.0 Executive Summary

Triflusulfuron-methyl is a sulfonylurea herbicide that inhibits the biosynthesis of branched-chain 

amino acids in plants (via inhibition of the plant enzyme acetolactate synthase). Marketed as 

UpBeet®, a dry flowable (DF) formulation containing 50% active ingredient (ai), triflusulfuronmethyl is currently approved for use on sugar beet commodities and chicory using broadcast 

(ground- or aerial-based) or band application methods at seasonal rates of up to 0.078 pounds ai 

per acre (lb ai/A). UpBeet® is not to be applied via any type of irrigation system. The existing 

label for UpBeet® lists a pre-harvest interval (PHI) of 60 days for both sugar beet and chicory. 

The registrant, E. I. du Pont de Nemours and Company, has submitted a supplemental label for a 

proposed use on garden beets. HED has sufficient information to complete a human health risk 

assessment.

The maximum proposed single application rate on this supplemental label is 0.0156 lb ai/A for 

agricultural use on garden beets for control of broadleaf weeds, with a maximum seasonal 

application rate of 0.047 lb ai/A. Consistent with the existing uses, the requested new use on 

garden beet involves aerial or groundboom application methods. The proposed PHI on garden 

beet is 30 days, a value that is well supported by the garden beet field trial data submitted for this 

new use petition. The proposed supplemental label needs to be revised to reflect the 30 day PHI 

and specify that use of aerial application methods is allowed. 

The toxicology database is considered adequate for conducting a risk assessment in accordance 

with the Food Quality Protection Act (FQPA). The toxicology database is largely complete, 

missing only an immunotoxicity study. A subchronic inhalation study is not available but not 

required at this time due to low use rates, low vapor pressure and high MOEs associated with 

handler exposure; the need for this study may be reassessed once the Agency finalizes guidance 

on pesticide volatilization and postapplication exposure. Toxicological effects observed in 

mammals were decreased body weight and body weight gain, alterations in hematology

(decreases in red blood cell parameters, particularly in males), and increased interstitial cell 

hyperplasia in testes. No toxicological effects were attributable to a single, oral (i.e., acute) 

exposure. In dermal exposure studies, no effects were observed at the highest dose tested. For 

assessment of inhalation exposures, route-to-route extrapolation from oral exposures has been 

used, assuming 100% absorption for inhalation exposures. Triflusulfuron-methyl has been 

classified as a Category C “possible human carcinogen” and the chronic risk assessment based 

on the chronic Population Adjusted Dose (cPAD) is sufficiently protective of human health. 

HED recommends that the 10x FQPA safety factor for infants and children be reduced to 1x for 

triflusulfuron-methyl because there is no evidence of increased susceptibility in rat or rabbit 

fetuses from the developmental toxicity studies, and no evidence of susceptibility in the rat

reproductive toxicity study. There were no neuropathological or neurobehavioral effects 

observed in the database, which included acute and subchronic neurotoxicity studies, except for 

an increased incidence of degeneration of the sciatic nerve in female rats in the chronic 

toxicity/carcinogenicity study at study termination. However, HED considers this finding of low 

concern because it is commonly observed at high incidence in older rats and was not increased at 

the interim (1 year) sacrifice or in shorter-term studies. A developmental neurotoxicity (DNT) 
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study is therefore not required. There was no evidence of direct immunotoxicity observed in the

submitted studies. Although mild hemolytic anemia was observed in rats and dogs, the observed 

hemolytic effects were generally sporadic and marginal except at higher doses, with more 

pronounced changes observed at doses ≥100-fold above the selected point of departure (POD) in 

the rat, and ≥15-fold above the selected POD in the dog. The selected endpoints are protective 

of hematological effects and an additional 10x database uncertainty factor was therefore not 

retained to account for lack of the immunotoxicity study.

The residue chemistry database is complete and there are no residue chemistry issues that would 

preclude granting the requested new use and establishing permanent tolerances for residues in

garden beet roots and tops. For the purposes of this petition on garden beet, the previously

reviewed sugar beet metabolism study is sufficient to support the requested use of triflusulfuronmethyl on garden beets. The proposed tolerance expression in/on garden beets should include 

only the parent compound, triflusulfuron-methyl. HED is recommending for the establishment 

of permanent tolerances for the requested crops. Suitable analytical methods are available to 

enforce tolerances for residues of triflusulfuron-methyl. 

HED has assessed dietary and occupational exposures. Risks from these exposures, including

aggregate exposures, are below the level of concern. The existing registered label (for sugar beet 

and chicory uses) and the proposed supplemental label for garden beet include a 4-hr Restricted 

Entry Interval (REI). HED has no objections to these REI. 

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, which comprise the 

Pesticide Handlers Exposure Database (PHED), have been determined to require a review of 

their ethical conduct, have received that review, and have been determined to be ethically 

conducted.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered for 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, 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 USDA under the 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 
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based on home use of pesticide products, 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.

Proposed Tolerances

At this time, tolerances are not required for residues in livestock commodities. For plant 

commodities, existing tolerances are in place for the previously assessed sugar beets and chicory. 

New tolerances in/on garden beets are being requested in the petition under review (Petition 

9E7669). The registrant has proposed that tolerances for the residues of the herbicide 

triflusulfuron-methyl, or methyl 2-[[[[[4-(dimethylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin2-yl]amino]carbonyl]amino]sulfonyl]-3-methylbenzoate, be established on garden beet roots at 

0.01 ppm (parent only) and sugar beet tops at 0.02 ppm (parent only). For the purposes of this 

tolerance petition, the compound to be regulated is parent only. 

Note to RD: According to HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 27 

May 2009), the tolerance expression for triflusulfuron-methyl cited in 40CFR §180.492[a] 

should be revised to state: 

Tolerances are established for residues of triflusulfuron-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 triflusulfuron-methyl (methyl 2-[[[[[4-

(dimethylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-

yl]amino]carbonyl]amino]sulfonyl]-3-methylbenzoate) in or on the

commodity. 

A summary of the petitioned-for tolerances and HED’s recommendations is provided in Table 1, 

below. The requested new use on garden beet is being assessed as part of a work share 

agreement with Canada’s PMRA. The recommended tolerance for garden beet roots is identical 

to that of PMRA’s. However, the recommended tolerance of 0.02 ppm for garden beet tops is 

not harmonized with PMRA’s value of 0.01 ppm. The rationale for this recommendation is 

discussed further in Section 5.1.11. 

Table 1.1 Tolerance Summary for Triflusulfuron-methyl

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments (correct commodity definition)

Beet, garden, roots 0.01 0.01 --

Beet, garden, tops 0.02 0.02 --
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Provided the issues associated with the UpBeet label detailed in Sections 10.2 and 10.3 are 

addressed, HED can recommend for establishment of the tolerances in Table 1.1. HED 

recommends that the registration of the use on garden beets be conditional on future submission 

of the immunotoxicity study (see Section 10.1).

2.0 Ingredient Profile

2.1 Summary of Proposed Uses

Summary of Existing Uses on Garden Beet and Chicory

For sugar beet, UpBeet® may be broadcast applied via ground or air equipment at up to 0.032 lb 

ai/A/application. Multiple applications can be made at 5-10 day re-treatment intervals (RTIs) 

with the total application not to exceed 0.078 lb ai/A/season. For chicory, two applications may

be made, at 0.024 lb ai/A and at 5- to 10-day RTIs, for a maximum seasonal application rate of 

0.048 lb ai/A. This formulation may also be band-applied at rates equivalent to the broadcast 

rates (actual band rates are dependent upon crop row spacing). UpBeet® is not to be applied via 

any type of irrigation system. The existing label for UpBeet® lists a PHI of 60 days for both 

sugar beet and chicory, representing a potential mid-season use. Plant-back intervals (PBIs) are 

0 days for sugar beets, 14 days for all other crops except corn, and 21 days for corn. A plantback interval has not been proposed for chicory or garden beet. HED is satisfied with the 14-day

interval that these crops receive from being in the “other crop” category as listed on the current 

label.

Proposed Use on Garden Beet

Table 2.1 provides a summary of the proposed uses for DuPontTM UpBeet® Herbicide (DF, 

water-dispersible granule, WDG, containing 50% triflusulfuron-methyl by weight). The 

maximum single application rate is 0.0156 lb ai/A for agricultural use on garden beets for control 

of broadleaf weeds. Triflusulfuron-methyl (as UpBeet®) may be applied aerially or with 

groundboom equipment. 
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TABLE 2.1 Summary of Proposed Directions for Use of Triflusulfuron-Methyl on Garden Beets.

Trade 

Name

Application 

Timing

Application 

Rate 

(lb ai/A)

Max. 

No. 

Applic. 

per 

Season

RTI1

(days)

Max. 

Seasonal 

Applic. 

Rate

(lb ai/A)

PHI

(days)

Use Directions and other 

Limitations

(i.e. grazing, type of 

application/equipment, 

plant-back interval, other)

Garden Beets

UpBeet® 

Herbicide

Apply as a postemergent spray 

when garden 

beets are at the 

following 

stages: 2-4 leaf 

stage; 4-6 leaf 

stage; and 6-8 

leaf stage.

0.0156 

+ 

NIS or COC

(at 0.25% v/v)

3 See 

application 

timing

0.047 30 - Apply UpBeet® Herbicide 

with NIS or COC.2

- Apply UpBeet® Herbicide 

via groundboom or aerial 

application equipment. 

- Do not apply UpBeet® 

Herbicide through any type

of irrigation equipment.

1 RTI = retreatment interval

2 NIS = non-ionic surfactant; COC = crop oil concentrate

2.2 Structure and Nomenclature

TABLE 2.2 Test Compound Nomenclature.

Compound Chemical Structure

Common name Triflusulfuron-methyl

Company experimental name DPX 66037

IUPAC name methyl 2-[4-dimethylamino-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-

ylcarbamoylsulfamoyl]-m-toluic acid

CAS name methyl 2-[[[[[4-(dimethylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]amino] 

carbonyl]amino]sulfonyl]-3-methylbenzoate

CAS # 126535-15-7

End-use product/(EP) UpBeet Herbicide*

*The EP used in the submitted garden beet field trials under review was Safari 50DF, an EP that is equivalent to that of 

UpBeet®. 

SO2NHCONH

N

N

N

N(CH3)2

CH3 OCH2CF3

CO2CH3
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2.3 Physical and Chemical Properties

TABLE 2.3 Physicochemical Properties of the Triflusulfuron-Methyl.

Parameter Value Reference

Melting point/range 155-158oC Petition Administrative 

pH Not indicated Materials

Density (g/mL) 1.45 absolute

0.56 (Bulk)

Water solubility ( 25°C) pH ppm

3 1.0

5 2.7

7 110

9 11 000

Low solubility at pH3 and pH 5; soluble at 

pH 7; very soluble at pH 9. Solubility 

increases with increasing pH.

Solvent solubility (mg/L) solvent mg/L

hexane <0.0016

octanol 0.026

toluene 2.0

methanol 7.0

ethyl acetate 27

acetonitrile 80

acetone 120

chloroform 160

methylene chloride 580

Vapor pressure at 25°C <1 x 10-7 mm Hg

A relatively non-volatile compound; low 

potential for losses due to volatilization.

Dissociation constant (pKa) 4.4

This compound will dissociate and exist in its 

anionic form at most environmentally 

relevant pHs.

Octanol/water partition coefficient (KOW) pH Kow at 25°C

5 220

7 9.2

9 0.86

Low potential for bioaccumulation in biota.

UV/visible absorption spectrum λmax = 395 nm

absorption at λ>400 nm is not anticipated

Potential to absorb sunlight in the UV/visible 

range of 290-400 nm.

3.0 Hazard Characterization/Assessment

This hazard characterization updates the previous assessment for triflusulfuron-methyl, prepared 

February 12, 2002 for the Section 3 Registration on sugar beets (D260076).

3.1 Hazard and Dose-Response Characterization
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3.1.1 Database Summary

3.1.1.1 Studies available and considered (animal, human, general literature)

Studies considered for this assessment included acute lethality (oral, dermal and inhalation 

routes); primary eye and dermal irritation, dermal sensitization, subchronic oral toxicity (rat, 

mouse and dog), rabbit 21-day dermal toxicity, dog chronic toxicity, rat chronic toxicity and 

combined chronic toxicity/carcinogenicity, mouse carcinogenicity, developmental toxicity (rat 

and rabbit), rat two-generation reproductive toxicity, genotoxicity, rat metabolism and acute and 

subchronic neurotoxicity studies in the rat. An in vitro mode of action study on hepatic 

aromatase activity and testosterone/estradiol levels in Leydig (interstitial) cells was also 

submitted. Summaries of these studies are provided in Appendix A.3.

3.1.1.2 Mode of action, metabolism, toxicokinetic data

Triflusulfuron-methyl is a post-emergence sulfonylurea herbicide used to control broadleaf 

weeds. In plants, it inhibits growth by preventing branched-chain amino acid formation in plants 

(via inhibition of acetolactate synthase), but does not affect germination. A mode of action for 

mammalian toxicity has not been fully characterized. Data were submitted to determine whether 

the Leydig cell tumors observed in male rats were due to treatment-related hormonal activity. In 

an in vitro study in isolated rat Leydig cells, triflusulfuron-methyl induced hepatic aromatase 

activity and testosterone/estradiol levels, but the data were insufficient to demonstrate 

conclusively a hormonal mode of action. 

In metabolism studies conducted in the rat, triflusulfuron was well-absorbed and extensively

metabolized; however, at high doses, the extent of absorption was somewhat lower and the 

parent compound was the major radiolabeled component. The majority of the administered 

radioactivity was excreted in the urine at low doses, but at high doses, the major route of 

excretion was the feces. The major urinary metabolite was N-desmethyl triflusulfuron-methyl. 

3.1.1.3 Sufficiency of studies/data

The available toxicity data are considered adequate for conducting this risk assessment for 

triflusulfuron-methyl. However, in accordance with the recently revised 40 CFR Part 158 data 

requirements for conventional pesticides, an immunotoxicity study is required. The rationale for 

the immunotoxicity data requirement is provided in Appendix A.4. A 90-day inhalation toxicity

study in the rat is not available but is not required to support registration at this time. In the 

absence of inhalation data, an inhalation point of departure was selected for this assessment 

using route-to-route extrapolation of oral data and assuming 100% inhalation absorption. 

Although inhalation exposure may occur (handling and postapplication exposures), use of an oral 

study to assess inhalation toxicity is not expected to be under protective for either scenario. 

Triflusulfuron-methyl has low vapor pressure, shows low acute inhalation toxicity (category IV) 

and is used at a relatively low application rate. The MOEs calculated for occupational handlers 
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were at or above 56,000. Therefore, even if an inhalation study were to provide a lower point of 

departure than route-to-route extrapolation from the oral study, it is not expected to have a 

significant impact on estimated risk. A developmental neurotoxicity study is not required, based 

on lack of evidence of frank neurotoxicity in the available studies (see 3.1.2, below). 

3.1.2 Toxicological Effects

The primary target organs identified for triflusulfuron-methyl are the liver, testes and red blood 

cells. Hematological and histopathological changes consistent with mild hemolytic anemia were 

observed in the rat and the dog. Increased incidence of testicular interstitial hyperplasia was 

observed following subchronic or chronic-term dietary administration to the rat; the incidence of 

testicular interstitial adenomas was also increased with chronic exposure. In the dog, testicular 

atrophy and reduced size were observed following subchronic or chronic exposure. Liver effects 

were observed in the dog (increased weight, altered serum enzyme profile and histopathology) 

and mouse (increased weight and histopathology), but not in the rat. There was no indication of 

frank neurotoxicity in the available studies. Although a statistically significant increase in sciatic 

nerve myelin/axon degeneration in high dose female rats was observed in the rat combined 

chronic toxicity/carcinogenicity study, the incidence was high in all dose groups, no increases 

were seen in the interim sacrifice groups or in shorter-term studies and the lesion is commonly

observed in older rats. Therefore, HED did not consider this finding to be evidence of frank 

neurotoxicity. The only potential evidence of immunotoxicity observed for triflusulfuron-methyl 

was hemolytic anemia, an effect that is associated with exposure to some sulfonylurea 

compounds as an immune-mediated cytotoxicity. However, there are currently no data 

demonstrating that hemolytic anemia from triflusulfuron-methyl is immune-mediated. No 

effects of treatment were reported in a 21-day repeated application dermal toxicity study in the 

rabbit. Dermal absorption studies were not submitted.

Triflusulfuron-methyl is of low acute toxicity when administered orally (Toxicity Category IV), 

dermally (Category III), or via inhalation (Category IV). It is not a dermal sensitizer or irritant 

(Category IV) and causes only minor transient irritation to the eye (Category III).

There was no quantitative or qualitative evidence of increased pre- and/or postnatal susceptibility

in rat or rabbit developmental toxicity studies or in the rat reproductive studies. No 

developmental effects were seen in the rat developmental study, whereas maternal toxicity 

(decreased body weight gain, food consumption and feed efficiency) was observed at the highest 

two doses. Abortions were observed in the rabbit developmental toxicity study at a dose that 

also caused significant maternal toxicity, including mortality, clinical signs, sharply reduced food 

consumption and decreased weight gain. In the rat reproductive toxicity study, decreased 

parental body weight/weight gain and F1 pup weight during lactation were observed at the mid 

and high doses. No reproductive effects were observed.

Triflusulfuron-methyl was classified as a “Group C” (possible human) carcinogen under the 

1986 Agency Guidelines for Carcinogen Assessment. The classification was based on an 

increased incidence of testicular interstitial cell adenomas in male rats at two doses and evidence 
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of clastogenicity in some in vitro genotoxicity studies. A special mechanistic study that 

evaluated hormonal changes in male rats provided insufficient information to establish a 

nonlinear mode of action for the formation of these tumors. Although the incidence of 

hepatocellular adenomas was increased in mice, it was within historical control range and not 

considered as part of the weight-of-evidence for determination of cancer classification. Cancer 

risk was not quantified using a cancer potency factor because the tumors were benign and seen 

only in one species; the use of the reference dose (RfD) in risk assessment was therefore 

considered to be protective of potential carcinogenicity.

3.1.3 Dose-response

Several effects showed a dose-response in one or more species with subchronic or chronic 

exposures. Body weight decreases in the dog studies were only seen at the highest doses tested, 

but the rat studies showed a dose-response, usually at the highest two dose levels. Mild 

decreases in erythrocyte parameters in the clinical hematology evaluations were observed in the 

dog. In the subchronic dog study, significant hematological effects were only observed at the 

high dose of 8000 ppm but mild effects (decreases of 10% or less below controls) were seen at 

3500 ppm in the chronic study. Mild hematological effects in the rat were observed at 750 and 

1500 ppm in the chronic study and at higher doses following subchronic exposure (2000 ppm 

and above). More pronounced hematological regenerative changes in the rat were seen at 10,000 

and 15,000 ppm following subchronic exposure.

Testicular interstitial cell microscopic pathology was observed in the rat and the dog following 

subchronic and chronic exposure. In the rat, testicular effects were observed only at the high 

dose of 15,000 ppm following subchronic exposure, but were seen at 750 and 1500 ppm in the 

chronic study. Interstitial cell tumors observed in the chronic toxicity/carcinogenicity study in 

the rat were significantly increased at the two highest doses tested, although the incidence at 

these dose levels was the same. Liver and testicular effects in the dog were observed at the 

highest two doses (4000 and 8000 ppm) following subchronic exposure, but were observed only 

at the highest dose in the chronic study (3500 ppm). Liver effects in the mouse carcinogenicity 

showed a dose-response at the highest two doses tested (2500 and 7000 ppm). An increased 

incidence of sciatic nerve myelin/axon degeneration was only observed in female rats in the 

chronic toxicity/carcinogenicity study at the highest dose (1500 ppm).

Abortions and maternal toxicity were observed in the rabbit developmental toxicity study at the 

LOAEL of 270 mg/kg/day, with a NOAEL of 90 mg/kg/day. Abortions and maternal toxicity

both showed a dose-response, with increased incidence and severity of maternal effects 

(including clinical signs and mortality) at the highest dose of 800 mg/kg/day. In the reproductive 

toxicity study, parental and pup (lactation period) body weights were decreased at the highest 

two dose levels.

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

The metabolism of triflusulfuron-methyl following oral dosing was evaluated in the rat at a 
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single low dose of 25 mg/kg, a single high dose of 250 mg/kg, and after repeated low doses of 25 

mg/kg/day for 14 days. The rate of absorption was unaffected by dose or dosing regimen, but 

the extent of absorption was decreased at 250 mg/kg. Urine was the major route of excretion (61 

to 77% of the administered dose, or AD) at 25 mg/kg, but feces were the primary route of 

excretion at 250 mg/kg (43-63% of dose). Excretion of radiolabel via expired air was negligible. 

By 120 hr post-dosing, significant amounts of radioactivity remained in the liver. Comparison of 

triflusulfuron-methyl triazine-label with the ester carbonyl-label indicated greater levels of the 

triazine-label radioactivity in tissues.

Several metabolites of triflusulfuron-methyl were identified. At 25 mg/kg, the major urinary

metabolite was N-desmethyl triflusulfuron-methyl (25-44% of AD), with females excreting 

higher levels than males of this metabolite. The N-hydroxymethyl metabolite was also found in 

urine (10-16% of the dose). Triazine metabolites (triazine amine, N-desmethyl triazine amine 

and N,N-bis-desmethyl triazine amine) were identified in liver as well as urine; in feces none of 

these metabolites represented more than 2% of AD. In rats dosed with the ester carbonyl-labeled 

triflusulfuron-methyl, methyl saccharin was a major metabolite in the urine and liver.

3.3 FQPA Considerations

3.3.1 Adequacy of the Toxicity Database

The database is considered adequate for purposes of assessment of susceptibility of infants and 

children to the effects of triflusulfuron-methyl. Acceptable developmental toxicity studies in two 

species (rat, rabbit) and a multigeneration reproductive toxicity study (rat) are available. There

was no frank evidence of neurotoxicity in the available studies (see 3.3.2, below). Other than 

hemolytic anemia as previously discussed (see 3.1.2, above), there was no evidence of direct 

immunotoxicity observed in the available studies. However, this effect is of low concern 

because effects were generally sporadic and marginal (except at high doses) and a large margin 

of safety was provided by the PODs selected for risk assessment. In the rat, more pronounced 

hematological alterations and regenerative changes were observed at doses ≥100-fold higher 

than the selected PODs (≥15-fold higher in the dog). Therefore, although an immunotoxicity

study has not been submitted, it is not considered likely to identify a more sensitive endpoint 

(and lower points of departure) than those already selected, and an additional 10X safety factor 

to account for data gaps is not required. An oral study was selected for inhalation exposure 

assessment using route-to-route extrapolation, with an assumption of 100% inhalation absorption

and is considered adequate for that purpose at this time (see Section 3.1.1.3).

3.3.2 Evidence of Neurotoxicity

Triflusulfuron-methyl did not show evidence of frank neurotoxicity in the available studies, 

which included rat acute and subchronic neurotoxicity studies. In the rat chronic 

toxicity/carcinogenicity study, the incidence of myelin/axon degeneration in females at study 

termination was increased at the high dose only. HED considers this finding to be of low 

concern because increases were only observed in females at the terminal sacrifice and not in 
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animals examined at one year (or in shorter-term studies, including the acute and subchronic 

neurotoxicity studies). Furthermore, it is typically observed at a high incidence in aged rats.

Although an increase was seen in high dose females, it was also observed at a high incidence in 

all dose groups.

3.3.3 Developmental Toxicity Studies

Acceptable developmental toxicity studies in the rat and rabbit are available. No developmental 

toxicity was observed in rats dosed by gavage at 0, 30, 120, 350 or 1000 mg/kg/day. Maternal 

toxicity was observed at the LOAEL of 350 mg/kg/day, based on decreased body weight gain 

and food efficiency; the maternal NOAEL was 120 mg/kg/day. In rabbits dosed by gavage at 0, 

90, 270 or 800 mg/kg/day, developmental effects (decreased pup weight and abortions) were 

observed at the LOAEL of 270 mg/kg/day, a dose that also caused significant maternal toxicity

including mortality, decreased body weight gain and clinical signs. The frequency and severity 

of maternal toxicity was increased at 800 mg/kg/day, along with an increased number of 

abortions. The maternal and developmental NOAELs were 90 mg/kg/day. 

3.3.4 Reproductive Toxicity Study

An acceptable two-generation reproductive toxicity study in the rat is available. Male and 

female rats were administered triflusulfuron-methyl continuously in the diet at 0, 10, 100, 750 or 

1500 ppm (0, 0.588, 5.81, 44.0 or 89.5 mg/kg/day in males and 0, 0.764, 7.75, 58.0 or 115 

mg/kg/day in females). Decreased body weight/weight gain, food efficiency and food 

consumption were observed at the parental LOAEL of 44/58 mg/kg/day in males/females, 

respectively. Decreased F1 pup body weights at lactation day 14 were observed at the offspring 

LOAEL of 44/58 mg/kg/day. The NOAELs for parental and offspring toxicity were 5.81/7.75 

mg/kg/day in males/females. Reproductive toxicity was not observed at any dose tested.

3.3.5 Additional Information from Literature Sources

A screening-level literature search was conducted for information on the toxicity of 

triflusulfuron. No relevant studies providing additional information were identified. However, 

immune-mediated hemolytic anemia in patients receiving sulfonylurea drugs as therapeutic 

agents for treatment of diabetes has been described in the literature.1

3.3.6 Pre-and/or Postnatal Toxicity

3.3.6.1 Determination of Susceptibility

There was no evidence of increased quantitative or qualitative pre- and/or postnatal susceptibility

 

1

Kopicky, J. A. and Packman, C. H. (1986), The mechanisms of sulfonylurea-induced immune hemolysis: Case report and 

review of the literature. American Journal of Hematology, 23: 283–288. 
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in developmental toxicity studies in two species or the rat multigeneration reproductive toxicity

study. Abortions in the rabbit developmental toxicity study occurred at a dose that caused

significant maternal toxicity, including mortality, a sharp reduction in food consumption and 

decreased body weight gain. All abortions occurred either post-dosing or during the later part of 

the dosing period.

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre- and/or Postnatal 

Susceptibility

There is low concern and no residual uncertainty for postnatal susceptibility for the reasons 

discussed above (Section 3.3.6.1).

3.3.7 Recommendation for a Developmental Neurotoxicity Study

A developmental neurotoxicity study is not recommended for triflusulfuron-methyl. No 

developmental abnormalities were observed in the developmental toxicity studies at doses up to 

the limit dose, and increased pre- and/or postnatal susceptibility was not observed. Other than 

the sciatic nerve degeneration in aged rats (described above; see 3.3.2), no evidence of 

neurotoxicity was observed in any studies in the available toxicology database, including acute 

and subchronic rat neurotoxicity studies. 

3.4 FQPA Safety Factor for Infants and Children

HED recommends that the 10x FQPA safety factor for infants and children be reduced to 1x for 

triflusulfuron-methyl, for the following reasons:

 The toxicology database is largely complete, missing only an immunotoxicity

study. There was no evidence of direct immunotoxicity in the available studies. 

Although sulfonylurea compounds may cause anemia, a potential immunemediated cytotoxic effect, the endpoints selected for this risk assessment are 

protective of hematological changes. The observed hemolytic effects are 

considered to be of low concern because they were generally sporadic and 

marginal except at higher doses: the more pronounced hematological and 

regenerative changes were observed at doses exceeding a 10X margin of safety

(in the rat, ≥100-fold above and in the dog, ≥15-fold above the selected PODs). 

An additional 10x database factor was therefore not included for lack of the 

immunotoxicity study. An oral study of appropriate duration has been selected 

for assessment of risk from inhalation exposure and is considered adequately 

protective (see Section 3.1.1.3); additionally, there are no residential uses of 

triflusulfuron-methyl that would result in postapplication exposure to infants or 

young children.

 Based on the lack of frank neurotoxicity observed in the available data, which 

include rat acute and subchronic neurotoxicity studies, a developmental 
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neurotoxicity study is not needed.

 There is no evidence of increased quantitative or qualitative pre- and/or postnatal 

susceptibility observed in developmental toxicity studies in the rat and rabbit or in 

a two-generation reproduction study in the rat.

 The exposure assessment for food and drinking water will not underestimate 

potential exposure to triflusulfuron-methyl, and a conservative approach was used 

for aggregate risk assessment. 

3.5 Hazard Identification and Toxicity Endpoint Selection

3.5.1 Acute Reference Dose (aRfD) – All Populations (Including Infants and Children and 

Females age 13-49)

An acute reference dose was not selected because an appropriate endpoint resulting from 

a single exposure was not identified. Abortions observed in the rabbit developmental 

toxicity study were not considered a potential single-dose effect. They were not observed 

until post-dosing (Gestation Days 21-26) at the maternal/developmental toxicity LOAEL 

of 270 mg/kg/day (and during late dosing at the high dose of 800 mg/kg/day), and 

appeared to be secondary to significant maternal toxicity. Two does died (GD 24 and 27) 

at this dose. The animals that died and/or aborted showed evidence of significant 

gastrointestinal toxicity, based on sharp reductions in food consumption after GD 13, 

clinical signs (no stool or small stool) and necropsy findings (gastric ulceration, gas 

distension of intestines). 

3.5.2 Chronic Reference Dose (cRfD)

Study Selected: Chronic Toxicity/Carcinogenicity in the Rat (Dietary)

MRID No: 42991413

Dose and Endpoint for Risk Assessment: NOAEL = 2.44 mg/kg/day, based on 

decreased body weight and weight gain in males and females, hematological changes 

(primarily in males) and testicular interstitial hyperplasia in males observed at the 

LOAEL of 30.6 mg/kg/day.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Chronic RfD = 

100 ( )

2.44 / /

UF

mg kg day = 0.0244 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors: The study is of the 

appropriate duration and exposure route (i.e., long-term oral exposure) and represents the 

most conservative available endpoint and dose available in the database for assessment of 
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chronic dietary exposure. The FQPA safety factor was reduced from 10x to 1x, based on 

the lack of evidence of increased offspring susceptibility, and availability of clearly 

defined NOAELs for developmental and offspring toxicity. An additional database 

uncertainty factor for lack of an immunotoxicity study was not applied. Although 

sulfonamide compounds may cause anemia via an immune-mediated cytotoxic 

mechanism, there is currently no data demonstrating that the hematological effects of 

triflusulfluron-methyl are immune-mediated. The hematological effects are of low 

concern because they were generally sporadic and marginal (except at high doses) and a 

large margin of safety was provided by the selected POD. In the rat, more pronounced 

hematological alterations and regenerative changes were observed at doses ≥100-fold 

greater (and in the dog, ≥15-fold greater) than the selected POD. There was no other 

evidence of immune effects in the available studies. 

3.5.3 Incidental Oral Exposure, All Durations

An endpoint for incidental oral exposure was not selected because there are no residential 

uses for triflusulfuron-methyl. 

3.5.4 Dermal Absorption

There is no dermal absorption study available. A dermal absorption factor was not 

estimated because a dermal study was selected to evaluate short- and intermediate-term 

dermal exposure. In addition, based on that study, no dermal short- or immediate-term 

toxicity is expected (see 3.5.5 below).

3.5.5 Occupational Dermal Exposure, Short-Term (1 to 30 days) and Intermediate-Term 

(1 to 6 months)

Study Selected: 21-Day Dermal Toxicity in the Rabbit

MRID No: 42991409

Dose and Endpoint for Risk Assessment: An appropriate dose/endpoint was not 

selected due to lack of effects in the dermal study.

Comments about Study/Endpoint/Uncertainty Factors: No toxicity was observed up 

to the limit dose of 1000 mg/kg/day in the rabbit 21-day dermal toxicity study. The 

endpoints of concern identified in the subchronic oral studies (decreased body weight 

gain and hematological changes) were not observed in rabbits following exposure via the

dermal route. 

3.5.6 Occupational Dermal Exposure, Long-Term (>6 months)

A long-term occupational risk assessment is not required because long-term dermal 

exposure is not anticipated from the proposed or existing uses.

3.5.7 Occupational Inhalation Exposure, Short-Term (1 to 30 days) and Intermediate-
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Term (1 to 6 months)

Study Selected: 90-Day Subchronic Toxicity in the Rat (Dietary)

MRID No: 42991408

Dose and Endpoint for Risk Assessment: 6.56 mg/kg/day, based on decreased body 

weight gain in males and hematological effects in females at 133 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: Since an inhalation toxicity

study was not available, an oral toxicity study was used to select a dose and endpoint. 

The study selected showed decreases in body weight gain after the first week of dosing 

(and continuing to Week 13) and is therefore of an appropriate duration. The dose 

selected is also protective of potential hematologic effects, which were observed at later 

times but were not evaluated at one month of treatment. A second rat 90-day oral 

toxicity study (MRID 42991406) had a similar NOAEL (6.20 and 7.54 mg/kg/day in 

males and females, respectively) based on decreased body weight gain in both sexes by

Week 1 (and other effects by Week 13). The 90-day oral study in the dog (MRID 

42991440) showed body weight decreases in females by Week 4 at a similar LOAEL 

(146.9 mg/kg/day), but had a lower NOAEL (3.7 mg/kg/day) that was due to dose 

spacing. The selected endpoint is protective for offspring toxicity (decreased F1 pup 

weight during lactation) based on the offspring NOAEL of 5.81 and 7.52 mg/kg/day in 

males and females, respectively, in the rat two-generation reproduction toxicity study

(MRIDs 42496843; 42991412). The NOAEL for abortions observed in the rabbit 

developmental toxicity study was 90 mg/kg/day, which is much higher than other 

NOAELs being considered for short- and intermediate-term inhalation doses. In the 

absence of inhalation data, inhalation absorption of 100% was assumed for route-to-route 

extrapolation from oral to inhalation exposure. An additional uncertainty factor for lack 

of inhalation toxicity data is not needed; based on low acute inhalation toxicity, low 

vapor pressure and lack of persistence of triflusulfuron-methyl in the environment, 

exposure via volatilization is expected to be low. A database uncertainty factor for lack 

of an immunotoxicity study is also not needed (see Comments in Section 3.5.2).

3.5.8 Occupational Inhalation Exposure, Long-Term (> 6 months)

A long-term occupational risk assessment is not required because long-term inhalation 

exposure is not anticipated from the proposed or existing uses.

3.5.9 Level of Concern for Margin of Exposure (MOE)

Table 3.5.1 Summary of Levels of Concern for Risk Assessment.

Route

Short-Term

(1 - 30 Days)

Intermediate-Term

(1 - 6 Months)

Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal N/A N/A N/A
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Inhalation 100 100 N/A

3.5.10 Summary of Toxicological Doses and Endpoints for Use in Human Risk 

Assessments

Table 3.5.2a. Summary of Toxicological Doses and Endpoints for Triflusulfuron-Methyl for 

Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, 

Level of 

Concern for

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary, 

General 

Population 

(including 

Infants and 

Children and 

Females age 13 

to 49)

Not required. An appropriate endpoint for this risk assessment was not identified.

Chronic Dietary 

(All 

Populations)

NOAEL= 

2.44 

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 1x 

Chronic RfD = 

0.0244

mg/kg/day

cPAD = 0.0244

mg/kg/day

Chronic oral toxicity/carcinogenicity in 

the rat 

LOAEL = 30.6 mg/kg/day, based on

decreased body weight/weight gain, 

hematological changes (primarily males) 

and increased interstitial cell hyperplasia 

(males).

Cancer (oral, 

dermal, 

inhalation)

Classification: Group C (1986 Cancer Guidelines), based on increased incidence of testicular 

interstitial cell adenomas in rats. The RfD is considered adequately protective of these effects 

and a quantitative assessment of cancer risk using a cancer potency factor is not required.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

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

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 3.5.2b Summary of Toxicological Doses and Endpoints for Triflusulfuron-Methyl for 

Use in Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects
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Table 3.5.2b Summary of Toxicological Doses and Endpoints for Triflusulfuron-Methyl for 

Use in Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal ShortTerm (1 to 30 

days) and 

IntermediateTerm (1 to 6 

months)

Not required. No toxicity was observed in the rabbit 21-day dermal toxicity study up to the limit 

dose of 1000 mg/kg/day.

Dermal LongTerm (> 6 

months)

Not required. Long-term dermal exposure is not anticipated from current and proposed uses.

Inhalation 

Short-Term (1 

to 30 days) and 

IntermediateTerm (1 to 6 

months)

NOAEL = 

6.56

mg/kg/day

(inhalation 

absorption 

rate = 

100%)

UFA=10x

UFH=10x Occupational LOC 

for MOE = 100

90-day oral toxicity in the rat

LOAEL = 133 mg/kg/day (males)/153 

mg/kg/day (females), based on decreased 

body weight gain (observed after the first 

week of dosing) and body weight, and in 

females, extramedullary hematopoiesis.

Inhalation 

Long-Term (> 

6 months)

Not required. Long-term inhalation exposure is not anticipated from current and proposed uses.

Cancer (oral, 

dermal, 

inhalation)

Classification: Group C (1986 Cancer Guidelines), based on increased incidence of testicular 

interstitial cell adenomas in rats. The RfD is considered adequately protective of these effects 

and a quantitative assessment of cancer risk using a cancer potency factor is not required.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

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

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

3.5.12 Recommendation for Aggregate Exposure Risk Assessments

For chronic dietary assessments, exposure from food and drinking water should be combined. 

There are no residential uses at this time. Therefore, it is not necessary to address the suitability

of combining exposures from different routes (e.g., oral and inhalation). 

3.5.13 Classification of Carcinogenic Potential

In 1996, triflusulfuron-methyl was reviewed by the HED Cancer Peer Review Committee (TXR 

# 0011939). Triflusulfuron-methyl was classified under the 1986 Agency Guidelines for 

Assessment of Carcinogenicity as a “Group C,” possible human carcinogen, based on a 

statistically significant increase in the incidence of testicular interstitial cell adenomas in male 

rats in the rat two-year dietary study. Although there was suggestive evidence of a hormonal 
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basis for induction of these tumors, the data were considered insufficient to demonstrate 

conclusively a hormonal mode of action. Genotoxicity data were mixed, with in vitro 

chromosomal aberration studies showing positive results but other studies, including a mouse 

micronucleus assay, being negative. For risk assessment purposes, the use of the chronic 

RfD/PAD is considered to be protective of potential carcinogenicity since the tumors were 

benign. The increased incidence of tumors was observed at doses that were ≥12.5-fold greater 

than the study NOAEL. No interstitial cell tumors were observed in the one-year interim 

sacrifice animals. As a chemical class, the sulfonylurea compounds in general do not induce 

tumors, but treatment-related tumor increases have been reported for prosulfuron, primisulfuronmethyl (both Group D, not classifiable as to human carcinogenicity) and tribenuron-methyl 

(Group C, possible human carcinogen based on increased mammary gland tumors in female 

rats).

3.6 Endocrine disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including all 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 designated 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 early 2010, EPA issued test orders/data call-ins for the first group of 

67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of 

chemicals was selected based on the potential for human exposure through pathways such as 

food and water, residential activity, and certain post-application agricultural scenarios. This list 

should not be construed as a list of known or likely endocrine disruptors. Triflusulfuron-methyl 

is not among the group of 58 pesticide active ingredients on the initial list to be screened under 

the EDSP. Under FFDCA sec. 408(p), the Agency must screen all pesticide chemicals. 

Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all pesticide active 

ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

4.0 Public Health and Pesticide Epidemiology Data and Incident Reports
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There are no public health, pesticide epidemiology or incident data to report at this time.

5.0 Dietary Exposure/Risk Characterization

(Triflusulfuron-methyl. Petition for the Establishment of Permanent Tolerances and Registration

for Use on Garden Beets (PP 9E7669). Summary of Analytical Chemistry and Residue Data; D376350; E. Holman;

February 2011)

5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Metabolism in Primary Crops

For the purposes of this petition (9E7669) on garden beet, the previously reviewed sugar beet 

metabolism study is sufficient to support the new requested uses of triflusulfuron-methyl on 

garden beets. The proposed tolerance expression should include only the parent compound, 

triflusulfuron-methyl, as determined by HED [Per memo of J. Stokes (February 1996), meeting 

of 16 January 1996].

5.1.2 Metabolism in Livestock

HED previously reviewed the submitted goat metabolism study and cited deficiencies to be 

addressed if additional Section 3 registrations were pursued by the petitioner. However, HED 

has determined that measurable triflusulfuron-methyl residues above the limit of detection 

(LOD; 0.005 ppm) will not be detectable in milk, meat, fat, muscle, or meat byproducts from the 

existing use on sugar beets and the new proposed use on garden beet. Therefore, the deficiencies 

cited in the HED memorandum of 7 June 1993 (J. Herndon) do not need to be addressed for the 

purpose of this new food use on garden beet. However, if future uses on large-acreage crops 

such as wheat, corn, or soybean are proposed, and consequently involve relevant livestock 

feedstuffs, then an adequate ruminant metabolism study should be provided.

5.1.3 Metabolism in Rotational Crops

Additional rotational crop studies or rotational crop tolerances are not needed at this time. Such 

studies may be needed if uses are proposed on major crops (e.g., wheat, cotton, corn, soybeans) due 

to the observed uptake of triazine-derived soil residues into wheat straw in the confined study. [See

memo of J. Stokes (31 January 1996) for HED meeting of 16 January 1996].

5.1.4 Environmental Degradation

Triflusulfuron-methyl is not a very persistent sulfonylurea herbicide. The principal pathway of 

dissipation in the environment is through aerobic and anaerobic metabolism and to a lesser 

degree hydrolysis. Direct photolysis on soil and in water is not a very important pathway, but 

indirect photolysis may play a minor role in its degradation on soils. Biotically, triflusulfuron-
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methyl degradation follows a bi-phasic pattern with an approximate soil half-life of 6 days 

initially, followed by a secondary half-life of approximately 170 days in aerobically incubated 

soil. Under anaerobic soil conditions, triflusulfuron-methyl degraded with a half-life of 20 days. 

Triflusulfuron-methyl is mobile in all soils tested; Kd’s are less than 1.3. However, the parent 

was not detected below 14 inches in the two field dissipation studies and decreased in 

concentration over the period of the study indicating biotic degradation. Sorption was not well 

correlated to organic matter, but was better correlated to the soil pH.
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5.1.5 Comparative Metabolic Profile

Triflusulfuron-methyl degrades through cleavage of the sulfonylurea bridge to form degradates 

containing either the triazine or phenyl ring. The principle degradates seen in the laboratory

studies are methyl saccharin and various triazine amines. Methyl saccharin is more mobile than 

the parent with Kd’s all less than 1.0 (KOC’s <25). In several of the soils, binding was so low that 

analysis could not be performed to determine the extent of binding. The half-life of methyl 

saccharin is 50-days under aerobic conditions and further degrades via mineralization. The other 

major degradates, triazine-amines, are less mobile than the parent. Among the triazine-amines, 

mobility increases with a higher degree of demethylation. The bis-NDM-triazine amine is the 

most mobile with Kd’s up to 3.72 (KOC’s <220) and the least mobile, triazine-amine, had Kd’s up 

to 10 (KOC’s <2175). For NDM-triazine-amine, Kd’s were up to 4.88 (KOC’s <300). The halflife of triazine amine is approximately 40 days and further degrades by demethylation. Both 

degradates were detected up to the 36-inch segment in one or both of the field dissipation 

studies. Concentrations of methyl saccharin and triazine amine were very similar during the 

studies and dissipated with very similar patterns. 

In a rat metabolism study, the liver, (as well as the ovaries and skin at the high dose), had a 

significant proportion of residual radioactivity at 120 hours post-dose at all dose levels. Urine 

was the major route of excretion at the low dose, with feces being the major route at the high 

dose. The major urinary metabolite (N-desmethyl triflusulfuron-methyl) composed between 25-

44% of the dose at the low dose. Female rats showed higher urinary levels than males of this 

metabolite. The N-hydroxymethyl metabolite was also found in urine, but did not vary

significantly with dose. The triazine metabolites of triflusulfuron-methyl (Triazine amine, Ndesmethyl triazine amine, N,N-bis-desmethyl triazine amine) were found in urine and liver. The 

parent chemical was found as a major component only in feces and liver from high dose 

treatments. 

In plants, triflusulfuron-methyl undergoes cleavage of the sulfonylurea bridge to form triazine 

urea and ester sulfonamide. This cleavage occurs readily in soil and on the leaf surface, leaving 

no measurable residues of parent in sugar beets (whole plant) after 7 days post treatment. Thus, 

there are no metabolites observed in plant metabolism studies that were not observed in the rat 

metabolism studies. Due to low total radioactivity in mature sugar beets and no quantifiable 

residues of the parent or three triazine metabolites observed in field trials with exaggerated use 

rates (2-8X), HED previously determined that the parent compound, triflusulfuron-methyl, is the 

only residue of concern for risk assessment (See memo of J. Stokes (31 January 1996) for HED 

meeting of 16 January 1996).

5.1.6 Pesticide Metabolism and Degradates of Concern 

Based on the available metabolism studies, HED concluded that for these uses, the nature of the 

residue has been adequately delineated for tolerance enforcement and risk assessment (Table 

5.1.6). 
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Table 5.1.6: Residue Definition for Triflusulfuron-methyl

Matrix Risk Assessment Compliance Monitoring

Plants Primary Crop Triflusulfuron-methyl Triflusulfuron-methyl

Rotational Crop Not applicable at this time (no rotational 

crops associated with this use)

Not applicable at this time 

Livestock Ruminant Not applicable at this time (no livestock 

commodities associated with this use)

Not applicable this time (under 40 

CFR 180.6 (a)(3))

Poultry Not applicable at this time (no poultry 

feed items associated with this use)

Not applicable at this time (under 40 

CFR 180.6 (a)(3))

Drinking Water Triflusulfuron-methyl Not Applicable

5.1.8 Analytical Methodology

The review of Method 4480 was originally completed by PMRA, but has been reviewed by HED 

and is consistent with OCSPP policy. An adapted version of Method 4480 was utilized in the 

garden beet field trials submitted for this new use petition. 

The independent laboratory validation (ILV) of Method 4480 successfully demonstrated the 

reliability of the HPLC/MS/MS method for the analysis of residues of triflusulfuron-methyl in 

sugar beet foliage and sugar beet roots on the first attempt. Method 4480 also included a 

scientifically acceptable rationale to waive the requirement of a radiovalidation study for this 

method, based on the similarities in extraction steps between this method and those employed in 

a corresponding sweet potato metabolism study (received and reviewed by PMRA). Therefore, 

method 4480 is considered acceptable as a data-gathering and enforcement method for the 

determination of triflusulfuron-methyl in plant matrices (including garden beets). 

The enforcement method on record for triflusulfuron-methyl is method AMR 1930-91 (MRID 

42496873). Method AMR 2021-91 (MRID 42496872) is very similar to AMR 1930-91 and was 

used in the previously submitted sugar beet and chicory field trials. Method 4480 is also similar to 

both these methods, with the primary difference being the addition of a tandem mass spectrometric 

detection protocol in Method 4480. In addition, the ILV of Method 4480 successfully demonstrated 

the reliability of the method on the first attempt. The registrant should clarify whether they want to 

replace the existing enforcement method with Method 4480 when applying for future new uses, as 

this newer method appears to be an acceptable enforcement method. 

5.1.9 Food Residue Profile

Crop Field Trials and Processing Studies: The crop field trials for chicory and sugar beets 

were previously classified acceptable and satisfied the guideline requirement for crop field trials 

(M. Doherty, et al., D260076, 12 February 2002). 

The newly submitted crop field trials are adequate to support the requested new use of 

triflusulfuron-methyl on garden beet. The review of these field trials was originally conducted 

by PMRA under a work share agreement, but their conclusions have been reviewed by HED and 

are consistent with OCSPP policy. The freezer storage stability of triflusulfuron-methyl residues 

in/on garden beets was demonstrated concurrently, with samples spiked at 0.10 ppm stored 

frozen for 436 days. Analysis of these samples showed no significant degradation of residues 
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occurred throughout this time interval. The maximum frozen storage time for garden beet 

samples was 381 days, a duration that is shorter than the demonstrated residue stability period. 

Therefore, there are no concerns with the stability of residues over time in this study.

The data indicate that residues of triflusulfuron-methyl in/on garden beet roots and tops were all 

≤ 0.01 ppm when treated at total rates of 0.047-0.049 lb ai/A (using a NIS/COC or not) and 

harvested at PHIs of 22-56 days. It should be noted that the petition under review requests a 

30-day PHI for garden beet, whereas a 60-day PHI is currently approved for sugar beets. The 

requested 30-day PHI for garden beet is supported by the submitted field trial data.

Based on the available data, the field trial and residue decline data demonstrate that 

triflusulfuron-methyl is rapidly degraded after application to sugar beet plants. Even at 

exaggerated rates (8X), no triflusulfuron-methyl was found in the sugar beet roots (RAC) or 

processed commodities; therefore concentration of residues in processed commodities is unlikely

at the currently approved use rates on sugar beets. Additional residue decline data were not 

submitted for the garden beet proposed use currently under review. There are no known 

processed commodities for garden beets in which residues are expected to concentrate; thus, 

processed food and feed should not be an issue for this new food use petition. 

Meat, Milk, Poultry and Eggs: Using information in the goat metabolism studies, residues 

of triflusulfuron-methyl (as defined by the livestock residue definition) are expected to be below 

the LOQ of a reasonable livestock analytical method. Hence a 40 CFR 180.6(a)(3) situation (no 

expectation of finite residues) exists. Neither feeding studies nor tolerances in livestock 

commodities are required at this time. Feeding studies and analytical methods may be required 

to support future uses of triflusulfuron-methyl that involve significant livestock feed items. 

Rotational Crops: Additional rotational crop studies or rotational crop tolerances are not 

needed at this time. Such studies may be needed if uses are proposed on major crops (e.g., wheat, 

cotton, corn, soybeans) due to the observed uptake of triazine-derived soil residues into wheat straw 

in the confined study. [See memo of J. Stokes (31 January 1996) for HED meeting of 16 January

1996].

5.1.10 Drinking Water Residue Profile

(Estimated Drinking Waters Concentrations (EDWCs) of Triflusulfuron-methyl for the Use in the Human Health

Risk Assessment: New Use (IR-4) of the Chemical on Garden Beets; J. Meléndez, D373494; July 22, 2010)

The registrant is proposing the use of the chemical on garden beets. Based on an inspection of 

the new use of triflusulfuron-methyl, it was found that sugar beet still represents the scenario 

with the highest exposure with respect to potential residues in drinking water. The previously

modeled use on sugar beets covers the proposed new use on garden beets. Therefore, the 

drinking water assessment results do not change from the previous ones (DP Barcode D260078). 

Triflusulfuron-methyl may be found in surface water used as a source of drinking water at peak 

concentrations up to 0.42 μg/L and on a long-term basis (mean) at 0.005 μg/L from use on sugar

beets in Minnesota. Ground water concentrations, independent of the use area, may be found at 

up to 0.5 μg/L for both peak and mean concentrations. Triflusulfuron-methyl will not persist in 

the environment (accumulate between repeated yearly applications) due to its short initial halflife (bi-phasic) and hydrolytic half-life at environmental pH’s. The low adsorption coefficients 
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may facilitate triflusulfuron’s leaching to ground water under favorable conditions (shallow 

depth to groundwater, coarse soils, or soils with significant preferential flow). Due to 

triflusulfuron-methyl’s structure and physical properties, it is not likely to be significantly

affected by common treatment methods employed at most community water systems. 

Triflusulfuron-methyl is currently registered for use on sugar beets. The drinking water 

concentrations used to estimate exposure via drinking water are included in Table 5.1.10. 

Table 5.1.10 Estimated Drinking Water Concentrations (EDWCs) for human health risk 

assessment for aerial application of triflusulfuron-methyl on sugar beets

Chemical

Acute Surface Water 

PRZM/EXAMS (ppb)

Chronic Surface Water 

PRZM/EXAMS (ppb)

Acute and Chronic Ground Water 

SCI-GROW (ppb)

Triflusulfuronmethyl 0.42 0.005 0.50

5.1.11 International Residue Limits

The requested new use on garden beet is being assessed as part of a work share agreement with 

Canada’s PMRA. Therefore, implemented tolerances stemming from this new use will be 

harmonized with the PMRA review. The recommended tolerance for garden beet roots of 0.01 

ppm is identical to that of PMRA’s, with all garden beet roots having concentrations less than the 

LOQ of 0.01 ppm in observed field trials. However, the recommended tolerance of 0.02 ppm for 

garden beet tops is not harmonized with PMRA’s value of 0.01 ppm. Based on the submitted 

garden beet field trial data, garden beet tops had concentrations equal to 0.01 ppm at a single 

field trial in Texas (Trial 08043.05-TX*19). Given the level of uncertainty for quantification 

around the LOQ of 0.01 ppm and the limited number of field trials, HED does not consider

setting the garden beet top tolerance at 0.01 ppm to be appropriate. Therefore, HED is 

concurring with the registrant-proposed tolerance of 0.02 ppm for garden beet tops. 

5.2 Dietary Exposure and Risk

(Triflusulfuron-methyl: Chronic Aggregate Dietary Exposure (Food and Drinking Water) and Risk Assessment for

the Section 3 Registration on Garden Beet; E. Holman; D376268; February 2011)

A chronic aggregate dietary risk assessment (food and drinking water) was conducted using the 

Dietary Exposure Evaluation Model (DEEM-FCIDTM, Version 2.03), which uses food 

consumption data from the U.S. Department of Agriculture (USDA’s) Continuing Surveys of 

Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. The analysis was performed to 

support a Section 3 registration for use of triflusulfuron-methyl [methyl 2-[[[[[4-

(dimethylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]amino]carbonyl]amino]sulfonyl]-3-

methylbenzoate] on garden beets. Triflusulfuron-methyl is currently registered for use on sugar 

beets and chicory. This chronic analysis is based on tolerance-level residues and 100% crop 

treated assumptions. For chronic assessments, HED is concerned when dietary risk exceeds 

100% of the PAD. The chronic dietary exposure analysis results are reported in Table 5.2 and 

show all population exposures are well below HED’s level of concern.
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No appropriate endpoint attributable to a single dose was identified. As no acute dietary

endpoint was identified, an acute exposure analysis was not performed.

The chronic dietary risk estimates are less than 1% of the cPAD for the U.S. population and all 

population subgroups, including those of infants and children.

Table 5.2 Summary of Dietary Exposure and Risk for Triflusulfuron-Methyl.

Population Subgroup*

Acute Dietary Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day) % aPAD

Dietary 

Exposure

(mg/kg/day) % cPAD

Dietary 

Exposure

(mg/kg/day) Risk

General U.S. Population N/A

No acute 

dietary 

endpoint 

was 

identified

N/A 0.000025 <1%

N/A N/A All Infants (< 1 year old) 0.000050 <1%

Children 1-2 years old 0.000052 <1%

Children 3-5 years old 0.000056 <1%

Children 6-12 years old 0.000041 <1%

Youth 13-19 years old 0.000023 <1%

Adults 20-49 years old 0.000020 <1%

Adults 50+ years old 0.000019 <1%

Females 13-49 years old 0.000021

<1%

5.2.1 Cancer Dietary Risk

Triflusulfuron-methyl is a Group C (1986 Cancer Guidelines - possible human carcinogen) 

chemical, based on increased incidence of testicular cell adenomas in rats. The chronic RfD is 

considered adequately protective of these effects and indicates no concern for cancer risk. 

Therefore, a quantitative assessment of cancer risk using a cancer potency factor is not required. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no current or pending residential uses associated with triflusulfuron; therefore, a 

residential exposure assessment was not performed nor required.

6.2 Spray Drift

Spray drift is a potential source of exposure for 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 triflusulfuron-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 
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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 appropriately 

apply 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, 

and risks associated with pesticide application. 

7.0 Aggregate Risk Assessments and Risk Characterization

There is no acute dietary exposure endpoint; therefore, an acute aggregate risk assessment was 

conducted and there is no concern with acute risks 

Additionally, because there are no residential uses and only dietary (food + water) pathways of 

exposure are being considered, short- and intermediate-term aggregate risk assessments are not 

required. Other than dietary exposure, there are no other sources of aggregate exposure that 

constitute a long-term exposure scenario; therefore, long-term aggregate exposure and risk 

estimates are equivalent to the chronic dietary exposure (food+water) and risk estimates 

summarized in Table 5.2 and are below HED’s level of concern.

8.0 Cumulative Risk Characterization/Assessment

FQPA (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base 

its assessment of the risk posed by the chemical on, among other things, available information 

concerning the cumulative effects to human health that may result from dietary, residential, or 

other non-occupational exposure to other substances that have a common mechanism of toxicity. 

The reason for consideration of other substances is due to the possibility that low-level exposures 

to multiple chemical substances that cause a common toxic effect by a common mechanism 

could lead to the same adverse health effect as would a higher level of exposure to any of the 

other substances individually. A person exposed to a pesticide at a level that is considered safe 

may, in fact, experience harm if that person is also exposed to other substances that cause a 

common toxic effect by a mechanism common with that of the subject pesticide, even if the 

individual exposure levels to the other substances are also considered safe.

EPA does not have, at this time, available data to determine whether triflusulfuron-methyl has a 

common mechanism of toxicity with other substances or how to include this pesticide in a 

cumulative risk assessment. For the purposes of this tolerance action, EPA has not assumed that 

triflusulfuron-methyl has a common mechanism of toxicity with other substances. At such time 

as the Agency has a scientific basis for evaluating cumulative risk, the petitioner must submit, 

upon EPA’s request and according to a schedule determined by the Agency, such information as 

the Agency directs to be submitted in order to evaluate cumulative risk issues for 

triflusulfuron-methyl. At that time, the Agency will determine whether any tolerances for 

triflusulfuron-methyl need to be modified or revoked.

9.0 Occupational Exposure/Risk Pathway

(Triflusulfuron-methyl: Occupational and Residential Exposure Assessment for Use on Garden Beets; 
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M. Collantes: January 2011; D376267)

The registrant, E.I. du Pont de Nemours and Company, has requested a Section 3 registration for 

the use of the herbicide triflusulfuron methyl on garden beets. The proposed product, UpBeet®,

is a herbicide recommended for selective postemergence control of broadleaf and grass weeds. It 

is a dry flowable formulation currently registered to control weeds in sugar beets. The 

supplemental label proposed an application rate of 0.0156 lbs. of active ingredient (a.i.) per acre 

to be applied by ground and/or aerial equipment. A previous occupational exposure assessment 

was performed for the use of triflusulfuron methyl on sugar beets at a higher application rate of 

0.032 lbs a.i. per acre using ground and aerial applications (S. Wang, D260076, 2/12/02). 

Occupational exposure and risk resulting in MOEs greater than or equal to 100 will not be of 

concern to HED. No systemic toxicity was seen at the limit dose (1000 mg/kg/day) of a 28-day

dermal study in the rabbit. Therefore, neither a quantitative dermal handler nor postapplication 

exposure assessment was performed. The inhalation handler exposure assessment resulted in 

MOEs greater than 100, which are not of concern. 

Since the new proposed use of triflusulfuron methyl on garden beets will result in the same 

agricultural practice and exposure scenarios as with sugar beets, only at a lower application rate 

(0.0156 vs. 0.032 lb a.i./acre), the previous occupational exposure assessment for sugar beets 

will be protective of exposures resulting from use of triflusulfuron on garden beets. Therefore, a 

new quantitative assessment for occupational handler exposure is not required.

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

assessment was not performed for triflusulfuron-methyl at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category IV), low vapor pressure (less than 1.0 x 10-7 mm 

Hg), and the low proposed use rate (0.0156 lb ai/A). However, there are multiple potential 

sources of post-application inhalation exposure to individuals performing post-application 

activities in previously treated fields. These potential sources include volatilization of pesticides 

and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and 

received the SAP’s final report on March 2, 2010 

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

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

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

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

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

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for triflusulfuron-methyl.

Restricted Entry Interval

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

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

material. Triflusulfuron-methyl is classified as Toxicity Category III by the dermal route, 

Toxicity Category IV for eye irritation potential, and Toxicity Category IV for skin irritation 

potential. Under the Worker Protection Standard for Agricultural Pesticides, active ingredients 

classified as acute toxicity categories III or IV for these routes are usually assigned a 12-hour 
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REI. However, triflusulfuron-methyl meets the criteria in PR Notice 95-3 for low risk pesticides 

that are permitted to have a 4-hour REI. Therefore, HED has no objections to the 4-hour REIs 

on the existing registered label (for sugar beet and chicory uses) and the proposed supplemental 

label for garden beet.

10.0 Data Needs and Label Recommendations

10.1 Toxicology

An immunotoxicity study (OCSPP 870.7800) is required for triflusulfuron-methyl under the 

revised 40 CFR Part 158 Guidelines for toxicology data requirements. HED recommends that 

future submission of this study be a condition of registration for the use on garden beets.

Based on the available toxicity database and the Agency's current practices, the inhalation risk 

for triflusulfuron-methyl was assessed using route-to-route extrapolation from an oral toxicity

study. The Agency sought expert advice and input on issues related to this route-to-route 

extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from 

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

December 2009. The Agency received the SAP’s final report on March 2, 2010 

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

process of evaluating the SAP report and may, as appropriate, re-examine and develop new 

policies and procedures for conducting inhalation risk assessments, including route-to-route 

extrapolation of toxicity data. At this time a subchronic inhalation study is not required for 

triflusulfuron-methyl (see Section 3.1.1.3). If any new policies or procedures are developed, the 

Agency may revisit the need for an inhalation toxicity study for triflusulfuron-methyl and/or a reexamination of the inhalation toxicity risk assessment.

10.2 Residue Chemistry

The residue chemistry data are complete with the exception of: 

1. The following label amendments are needed: a) The requested 30-day PHI for garden beet 

needs to be added to the supplemental label. b) The use of the aerial application method needs to 

be clarified in the supplemental label. The submitted supplemental label for garden beet does not 

include the petition-requested 30-day PHI, nor does it delineate the use of the aerial application 

method. Aerial application method instructions are included in the existing label for sugar 

beets.

2. Analytical Method – An adapted version of DuPont Method 4480 (MRID 48207101) was used 

in the submitted garden beet field trials under review in this petition. The enforcement method 

on record for triflusulfuron-methyl is method AMR 1930-91 (MRID 42496873), an HPLC-UV 

method. Method AMR 2021-91 (MRID 42496872) is very similar to AMR 1930-91, with the 

addition of an automatic switching column protocol, and was used in the previously submitted sugar 

beet and chicory field trials. Method 4480 is also similar to both these methods, with the primary

difference being the addition of a tandem mass spectrometric detection protocol in Method 4480. In 
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addition, the independent laboratory validation (ILV) of Method 4480 successfully demonstrated 

the reliability of the method on the first attempt. The registrant should clarify whether they want 

to replace the existing enforcement method with Method 4480 when applying for future new uses, 

as this newer method does appear to be an acceptable enforcement method. 

Should the registrant decide to request Method 4480 be used for enforcement purposes, they will 

need to ensure that the standards are made available to the USEPA’s Analytical Chemistry Branch 

(ACB) in the event that they differ from those used in method AMR 1930-91. 

10.3 Occupational and Residential Exposure

1. The petition under review (9E7669, pg. 17) for the new use on garden beets lists both ground 

and aerial application methods. The existing label for sugar beets covers both of these 

application methods. The proposed supplemental label for garden beets covers only the ground 

application method. The sponsor has confirmed that aerial application is requested for this new 

use. Therefore, the aerial application method needs to be added to the supplemental label. 

11.0 References

1. Triflusulfuron-methyl: Occupational and Residential Exposure Assessment for Use on 

Garden Beets; M. Collantes: D376267; January 2011.

2. Triflusulfuron-methyl: Chronic Aggregate Dietary Exposure (Food and Drinking Water) 

and Risk Assessment for the Section 3 Registration on Garden Beet; E. Holman; 

D376268; February 2011.

3. Estimated Drinking Waters Concentrations (EDWCs) of Triflusulfuron-methyl for the 

Use in the Human Health Risk Assessment: New Use (IR-4) of the Chemical on Garden 

Beets; J. Meléndez; D373494; July 2010.

4. Triflusulfuron-methyl. Petition for the Establishment of Permanent Tolerances and 

Registration for Use on Garden Beets (PP 9E7669). Summary of Analytical Chemistry

and Residue Data; E. Holman; D376350; February 2011.

5. Triflusulfuron-methyl: Human Health Risk Assessment for Use in Garden Beet. 

E.Holman; D373493; February 2011. 
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Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for are shown below in the following table. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used.

Test Triflusulfuron-methyl, Technical

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 (nonrodent).........................................

870.3200 21-Day Dermal ..............................................................

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

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

yes

yes

yes

no

no

yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

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

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

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...

870.5550 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

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 Develop. Neurotoxicity .................................................

no

no

yes

yes

no

--

--

yes

yes

--

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

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

yes

no

yes

no

870.7800 Immunotoxicity series......................................................... yes no

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

no

no

no

--

--

--
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A.2.1 Acute Toxicity Profile for Triflusulfuron-methyl (technical)

A.2.1 Acute Toxicity Profile – Triflusulfuron technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral - rat 42496819 LD50 > 5000 

mg/kg (both 

sexes)

IV

870.1200 Acute dermal - rabbit 42496826 LD50 > 2000 

mg/kg (both 

sexes)

III

870.1200 Acute dermal - rat 42496825 LD50 > 2000 

mg/kg (both 

sexes)

III

870.1300 Acute inhalation - rat 42496828 LC50 > 5.1 mg/L 

(both sexes)

IV

870.2400 Primary eye irritation - rabbit 42496830 Slight irritation of 

cornea and 

conjunctive 

clearing within 72 

hrs.

III

870.2500 Primary dermal irritation - rabbit 42496834 Slight irritation 

clearing within 48 

hrs.

IV

870.2600 Skin sensitization - guinea pig 42496837 Not a sensitizer 

(Buehler method)

N/A

870.6200a Acute neurotoxicity - rat 43398601 NOAEL≥2000 

mg/kg (HDT)

N/A
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Triflusulfuron-Methyl

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

MRID 42991408 (1992)

Acceptable/guideline

0, 100, 2000, 10,000 or 

15,000 ppm

(0, 6.56, 133, 658 or 1036 

mg/kg/day in males;

0, 7.71, 153, 783 or 1124 

mg/kg/day in females)

NOAEL = 6.56/7.71 mg/kg/day in m/f 

LOAEL = 133/153 mg/kg/day in m/f, based on 

decreased body weight gain and food efficiency 

in males; increased incidence of extramedullary 

hematopoiesis in females. Mild regenerative 

anemia was observed at 10,000 ppm. 

870.3100 90-Day oral 

toxicity (rat)

MRID 42991406 and -07 

(1990)

Acceptable/guideline

0, 100, 2000, 10,000 or 

15,000 ppm 

(males 0, 6.20, 127, 646 

or 965 mg/kg/day;

Females 0, 7.54, 150, 774 

or 1070 mg/kg/day)

NOAEL = 6.2/7.54 mg/kg/day in m/f

LOAEL = 127/150 mg/kg/day in m/f, based on 

decreased body weight and weight gain and 

food efficiency, mild regenerative anemia in 

males and hemosiderin in the renal proximal 

tubular epithelium of females. At 15,000 ppm, 

testicular tubular atrophy in males and renal 

tubular cell atrophy in females were observed.

870.3150 90-Day oral 

toxicity (dog)

MRID 42991440 (1991)

Acceptable/guideline

0, 100, 4000 or 8000 ppm 

in the diet

(males 0, 3.9, 146.9 or 

267.6 mg/kg/day;

females 0, 3.7, 159.9 or 

250.7 mg/kg/day) 

NOAEL = 3.9/3.7mg/kg/day in m/f

LOAEL = 146.9/159.9 mg/kg/day in m/f, based 

on increased SGOT, SGPT and alkaline 

phosphatase, increased liver weight, decreased 

testes weight, and microscopic changes in the 

testes and liver. Decreased body weights and 

effects on hematologic parameters were seen at 

8000 ppm only.

870.3200 21-Day dermal 

toxicity (New 

Zealand white 

rabbit)

MRID 42991409 (1993)

Acceptable/guideline

0, 50, 350 or 1000 

mg/kg/day applied for 6 

hr/day, 21 days

NOAEL = 1000 mg/kg/day (HDT). 

LOAEL was not observed (>1000 mg/kg/day). 

870.3700a Prenatal 

developmental in 

Crl:CD(BR) rat

MRID 42496841 (1991)

Acceptable/guideline

0, 30, 120, 350 or 1000 

mg/kg/day by gavage

Maternal NOAEL = 120 mg/kg/day

Maternal LOAEL = 350 mg/kg bw/day, based 

on reduced body weight gain and lower food 

efficiency.

Developmental NOAEL = 1000 mg/kg /day

Developmental LOAEL was not observed 

>1000 mg/kg/day).

870.3700b Prenatal 

developmental in 

New Zealand white 

rabbit

MRID 42496842 (1991)

Acceptable/guideline

0, 15, 90, 270 or 800 

mg/kg/day by gavage

Maternal NOAEL = 90 mg/kg/day

Maternal LOAEL = 270 mg/kg/day, based on 

maternal death and abortions, clinical signs and 

decreased weight gain. 

Developmental NOAEL = 90 mg/kg/day

Developmental LOAEL = 270 mg/kg/day, 

based on increased abortions and decreased 

mean fetal body weight. 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Triflusulfuron-Methyl

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3800 Reproduction and 

fertility effects

(rat) 

MRID 42496843; 

42991412 (1993)

Acceptable/guideline

0, 10, 100, 750 or 1500 

ppm in the diet (males 0, 

0.588, 5.81, 44.0 or 89.5 

mg/kg/day; 

females 0, 0.764, 7.75, 

58.0 or 115 mg/kg/day)

Parental NOAEL = 5.81/7.75 mg/kg/day in m/f

Parental LOAEL = 44/58 mg/kg/day in m/f, 

based on decreased body weight/body weight

gain.

Offspring NOAEL = 5.81/7.75 mg/kg/day in 

m/f

Offspring LOAEL = 44/58 mg/kg/day in m/f, 

based on decreased F1 pup body weight during 

lactation.

Reproductive NOAEL = 89.5/115 mg/kg/day in 

m/f

Reproductive LOAEL = not determined 

(>89.5/115 mg/kg/day in m/f)

870.4100a Chronic toxicity

(rat) –

See 870.4300, MRID 42991413

870.4100b Chronic toxicity 

(dog)

MRID 42991410 (1993)

Acceptable/guideline

0, 35, 875 or 3500 ppm in 

the diet

(males 0, 1.0, 26.9 or 

111.6 mg/kg/day;

females 0, 1.2, 27.7 or 

95.5 mg/kg/day)

NOAEL = 26.9/27.7 mg/kg/day in m/f

LOAEL = 111.6/95.5 mg/kg/day in m/f, based 

on increased alkaline phosphatase (males), liver 

weight and incidence of minimal centrilobular 

hepatocellular hypertrophy. Marginal 

reductions in RBC parameters were also 

observed.

870.4200a Carcinogenicity

(rat) See 870.4300, below

870.4200b Carcinogenicity

(CD-1mouse)

MRID 42991411 (1993)

Acceptable/guideline

0, 150, 2500 or 7000 ppm

in the diet 

(males 0, 1.37, 20.9, 349 

or 1024 mg/kg/day ;

females 0, 1.86, 27.7, 488 

or 1360 mg/kg/day)

NOAEL = 20.9/27.7 mg/kg/day in m/f

LOAEL = 349/488 mg/kg/day in m/f, based on

increased liver weights and hepatocellular 

microscopic findings (necrosis and intracellular 

pigment accumulation in Kupffer 

cells/macrophages in males; intrahepatocellular 

erythrocytes in males and females). At 7000 

ppm, body weight gain was decreased only 

during the first 90 days for males and from 

days 0-364 and 0-546 for females.

No evidence of carcinogenicity. A statistically 

significant increase in hepatocellular adenomas 

observed in males at 2500 and 7500 ppm was 

within historical control range.

870.4300 Combined 

carcinogenicity/chr

onic toxicity (rat)

MRID 42991413 (1993)

Acceptable/guideline

0, 10, 100, 750 or 1500 

ppm in the diet 

(males 0, 0.406, 2.44, 30.6 

NOAEL = 2.44/3.28 mg/kg/day in m/f

LOAEL = 30.6/41.5 mg/kg/day in m/f, based 

on decreased body weight and weight gain,

decreases in hematology parameters (primarily 

in males) and increased incidence of testicular 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Triflusulfuron-Methyl

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

or 64.5 mg/kg/day; 

females 0, 0.546, 3.28, 

41.5 or 87.7 mg/kg/day)

interstitial cell hyperplasia. 

Evidence of carcinogenicity was observed as an 

increased incidence of testicular interstitial cell 

adenomas at 750 and 1500 ppm.

870.5100 Bacterial Gene 

Reverse Mutation 

S. typhimurium

Ames Assay, 

strains TA 98, 100, 

1535, 1537, 1538

MRID 42496846 (1992) 

Acceptable/guideline

62.5, 125, 250, 500 or 

1000 μg/plate (with and

without S9 activation)

Negative. There was no evidence of induced 

reverse mutations with or without metabolic 

activation in 5 strains of Salmonella.

870.5100 Bacterial Gene 

Reverse Mutation

S. typhimurium

TA98, 100, 1535, 

1537 and 1538

42496849 (1991)

Acceptable/guideline

50, 100, 250, 500, 1000 or 

3000 μg/plate (with and 

without S9 activation)

Negative. There was no evidence of induced 

reverse mutation with or without metabolic 

activation in 5 strains of Salmonella.

870.5300 In Vitro

Mammalian Cell 

Forward Gene 

Mutation

Chinese Hamster 

Ovary (CHO) cells

42496850 (1991) 

Acceptable/guideline

Tested up to 2000 μg/mL

(with and without S9 

activation)

Negative. There was no evidence of induced 

forward mutations with or without activation.

870.5375 In Vitro

Mammalian 

Chromosome 

Aberration 

Human 

lymphocytes cells

42496852 (1991)

Acceptable/guideline

100 to 2000 μg/mL (with 

and without S9 activation)

Positive for induction of a treatment-related 

increase in the frequency of chromosomal 

aberrations at concentrations ≥1700 μg/mL in the 

presence of metabolic activation; inconclusive in 

the absence of metabolic activation.

870.5375 In Vitro

Mammalian 

Chromosome 

Aberration 

Human 

lymphocytes cells

42496845 (1992)

Acceptable/guideline

100 to 2000 μg/mL (with 

and without S9 activation)

Positive for induction of a treatment-related 

increase in the frequency of chromosomal 

aberrations at 2000 μg/mL in the presence of 

metabolic activation; inconclusive in the absence 

of metabolic activation. Follow-up assay to 

MRID 42496852.

870.5395 In vivo Mammalian 

Micronucleus 

Assay 

Mouse (male and 

female)

42496853 (1991)

Acceptable/guideline

Tested up to 5000 mg/kg

Negative. There was no significant increase in 

the frequency of micronucleated polychromatic 

erythrocytes in bone marrow of mice up to the 

limit dose at 24, 48 or 72 hr postdosing.

870.6200b Subchronic 

neurotoxicity (rat)

43398602 (1994)

Acceptable/guideline

0, 100, 750, 1500 or 3000 

ppm in the diet

(males 0, 6.1, 46.1, 92.7 

or 186.2 mg/kg/day;

females 0, 7.1, 51.6, 104.1 

or 205.2 mg/kg/day)

NOAEL = 92.7 mg/kg/day (males) and 

 7.1 mg/kg/day (females)

LOAEL = 186.2 mg/kg/day (males) and 

 51.6 mg/kg/day (females), based on 

decreased body weight/body weight gain.

No evidence of neurotoxicity.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Triflusulfuron-Methyl

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

pharmacokinetics

(rat)

42991416 (1992)

Acceptable/guideline

14C-triazine labeled 

triflusulfuron-methyl was 

administered as :

Low dose 25 mg/kg single 

oral dose; repeated low

dose 25 mg/kg/day for 14 

days; high dose 250 

mg/kg, single oral dose. 

Ester 14C-carbonyl labeled 

triflusulfuron-methyl was 

also administered at 250 

mg/kg, single oral dose.

Evaluated for absorption, 

distribution, metabolism 

and excretion

Rate of absorption was unaffected by dose or 

dosing regimen but the extent of absorption 

was decreased at 250 mg/kg. Urine was the 

major route of excretion at 25 mg/kg but the 

primary route of excretion at 250 mg/kg was 

the feces. Excretion of radioactivity via 

expired air was negligible. By 120 hr postdosing, significant amounts of radioactivity 

remained in the liver. At 25 mg/kg the major 

urinary metabolite was N-desmethyl 

triflusulfuron-methyl (25-44% of AD), with 

females excreting higher levels than males of 

this metabolite. The N-hydroxymethyl 

metabolite was also found in urine (10-16% of 

AD). Triazine metabolites (triazine amine, Ndesmethyl triazine amine and N,N-bisdesmethyl triazine amine) were identified in 

liver as well as urine; in feces none of these 

metabolites represented more than 2% of AD. 

In rats dosed with the ester carbonyl-labeled 

triflusulfuron-methyl, methyl saccharin was a 

major metabolite in the urine and liver. 

Nonguideli

ne

Evaluation of 

Mode of Action of 

Leydig Tumor Cell 

Induction

42991414 (1993)

Acceptable/nonguideline 

(as supplemental 

information)

(1)0, 1000, 1500 or 2000 

mg/kg/day for 15 days to 

male rats; examined for ;

(2)In vitro studiesinduction of male rat 

hepatic microsomal 

aromatase activity;

(3)in vitro evaluation of 

testosterone, progesterone 

and estradiol in rat Leydig 

cells ±hCG stimulation

(1) male rats showed decreased body weight, 

decreased absolute/relative accessory sex gland 

weights, decreased estradiol levels. No effects 

on beta-oxidation or aromatase activity, or 

cytochrome p-450 content;

(2) hepatic microsomal activity showed dosedependent treatment-related decreases;

(3)in vitro incubation with triflusulfuronmethyl ±hCG caused decreased synthesis of 

estradiol and –hCG increased synthesis of 

testosterone .

A.3 Executive Summaries

A.3.1 Subchronic Toxicity

870.3100a 90-Day Oral Toxicity - Rat

(1) In a subchronic oral rat toxicity study (MRID 42991406), 10 Crl:CD®BR rats/sex/group were 

administered DPX-66037 in the diet for 90 days at dosages of 0, 100, 2000, 10,000 or 15,000 

ppm (equivalent to average daily intakes of 0, 6.2, 127, 646 or 965 mg/kg/day, males and 0, 7.54, 

150, 774 or 1070 mg/kg/day, females, respectively). 
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Overall mean body weight and mean body weight gain were significantly decreased in males and 

females at ≥2000 ppm. The range of decreases in body weight in the 2000 to 15,000 ppm group 

males was 9% to 40%; the range in females was 16% to 35%. The decreases in body weight 

gain were more pronounced and ranged from 16% to 72% in males and from 41% to 82% in 

females. Overall mean food consumption was significantly decreased in males in the 10,000 and 

15,000 ppm groups and in females in the 2000, 10,000 and 15,000 ppm groups. In general, the 

magnitude of the decreases in food consumption was less than the decreases in body weight and 

weight gain. Significant decreases in overall mean food efficiency were seen in the three highest 

dosage groups of both sexes. Evidence of a mild regenerative anemia was seen in males and 

females in the 10,000 and 15,000 ppm groups and in males in the 2000 ppm group in the form of 

significantly decreased RBC counts, HGB and HCT, and increased reticulocyte counts. Changes 

in clinical chemistry parameters (decreased glucose, phosphate, total protein and globulin) in 

males and females in the two highest dosage groups were thought to be caused by decreased food 

intake. The only finding on gross necropsy was an increase in the number of males in the 15,000 

ppm group with small testes. The absolute weight of most of the organs evaluated decreased, 

most likely due to decreased body weights. The relative weights of several organs were also 

increased in these groups; the toxicological significance of these findings is unknown. The only 

histopathology lesions which appeared to be treatment-related were bilateral 

atrophy/degeneration of the seminiferous tubules of the testes and oligospermia of the 

epididymides in the 15,000 ppm group males, and hemosiderin deposition in the proximal 

tubular epithelium of the kidneys in males and females in the 10,000 and 15,000 ppm groups, 

and females in the 2000 ppm group. Females in the 15,000 ppm group also had an increased 

incidence of atrophy of the tubular epithelium. The testicular effects were possibly secondary to 

poor nutrition. The LOAEL is 2000 ppm (127 mg/kg/day in males and 150 mg/kg/day in 

females), based on decreased mean body weight and mean body weight gain, decreased 

mean food consumption (females), mean food efficiency, altered hematology parameters 

(males) and hemosiderin deposition in the kidneys (females). The NOAEL is 100 ppm (6.2 

mg/kg/day in males and 7.54 mg/kg/day in females).

This study is classified as acceptable/guideline and satisfies the guideline requirement for a 

subchronic toxicity study in the rat (OCSPP 870.3100).

(2) In a subchronic oral toxicity study (MRID 42991408), 10 Crl:CD®BR rats/sex/group were 

administered DPX-66037-59 (triflusulfuron-methyl technical, 98.7% a.i., lot no. DPX-66037-59) 

at dietary concentrations of 0, 100, 2000, 10,000 or 15,000 ppm (equivalent to average daily 

intakes of 0, 6.56, 133, 658 or 1036 mg/kg/day in males and 0, 7.71, 153, 783 or 1124 mg/kg/day

in females, respectively).

Mean body weights were significantly decreased throughout the study in male and female rats 

treated at concentrations of 10,000 and 15,000 ppm. The decreases at Day 91 in the males at 

10,000 and 15,000 ppm were 12% and 19%, respectively. Mean body weights of females at Day

91 were decreased by 14% and 17% for those in the 10,000 and 15,000 ppm groups. Overall 

mean body weight gains of male rats were decreased 11%, 18% and 28% for the 2000, 10,000 

and 15,000 ppm groups, respectively. Weight gains of females in the 10,000 and 15,000 ppm 

groups were decreased by 26% and 33%, respectively. The overall mean food consumption of 
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males in the 15,000 ppm group was decreased by 10% in comparison to the controls. Decreases 

in the 10,000 and 15,000 ppm group females were 13% and 17%, respectively. Decreases in 

food efficiency were observed in males treated at 2000, 10,000 and 15,000 ppm and in females 

treated at 10,000 and 15,000 ppm. Significant alterations in hematology parameters (decreases 

in RBC, HGB and HCT and increases in reticulocyte counts) seen in the 10,000 and 15,000 ppm 

group males and females at the 45- and 90-day evaluations indicated that the chemical produced 

a regenerative anemia. Terminal mean body weights were significantly decreased for males and 

females in the 10,000 and 15,000 ppm groups. The absolute weights of all organs from the 

treated animals were comparable to the control group. The mean relative weights of the majority

of the organs were increased in the 10,000 and 15,000 ppm group males and females. The 

increase in the relative weight of the liver was considered to be compound-related. There were 

increased incidences of microscopic changes in the kidney (pigment accumulation) and spleen 

(extramedullary hematopoiesis) which were considered secondary to compound-related 

hemolysis. Pigment accumulation in the proximal tubules of the kidney was present in males 

and females in the 10,000 and 15,000 ppm groups. Increased incidences of extramedullary

hematopoiesis were present in males treated at 10,000 ppm and above, and in females at 2000 

ppm and above. This study was done to compare the toxicity of the chemical produced by the 

cyanate method (DPX-66037-59) to that produced by the carbamate method (DPX-66037-8). A 

prior subchronic rat study (MRID 42991406) was conducted with DPX-66037-8 at the same 

dosage levels. Actual mg/kg/day intake in the studies was very similar. The results of the two 

studies demonstrate that DPX-66037-8 affected some of the quantitative measures (body weight, 

body weight gain, food consumption and food efficiency) more severely than DPX-66037-59. 

The LOAEL is 2000 ppm (133 mg/kg/day) in males, based on decreased body weight gain 

and food efficiency and 153 mg/kg/day in females, based on increased incidence of 

histopathological changes. The NOAEL is 100 ppm (6.56 mg/kg/day in males and 7.71 

mg/kg/day in females).

This study is classified as acceptable/guideline and satisfies the guideline requirements (OCSPP 

870.3100) for a subchronic oral toxicity study in the rat.

870.3150 90-Day Oral Toxicity – Dog

In a subchronic oral toxicity study (MRID 42496840), DPX-66037-24 (triflusulfuron-methyl 

technical, 95.6% a.i., lot no. 02) was administered to male and female dogs at nominal dose 

levels of 0, 100, 4000 or 8000 ppm (equivalent to average daily intakes of 0, 3.9, 146.9 or 267.6 

mg/kg/day in males and 0, 3.7, 159.9 or 250.7 mg/kg/day in females).

Toxic effects from administration of technical DPX-66037-24 to male and female dogs were 

observed at the 4000 ppm dose level and above. At 4000 ppm, increased plasma SGOT and 

SGPT, increased liver and decreased testes weights were observed. These findings were 

supported by microscopic effects in the liver (brown pigment in sinusoidal macrophages and in 

females, bile stasis) and testes/epididymes (tubular atrophy, aspermia/oligospermia, cellular 

debris). At 8000 ppm, decreased mean body weight and body weight gain, decreased 

erythrocytes, hemoglobin and hematocrit, increased SGOT, SGPT and alkaline phosphatase, 

increased absolute and relative weight of the liver and testes, and microscopic abnormalities of 

the testes and liver were observed. Bone marrow of the sternum and femur showed 
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hypercellularity in both sexes. The LOAEL is 4000 ppm (146.9 mg/kg/day in males and 159.9 

mg/kg/day in females), based on hematological and liver enzyme changes, increased liver 

and decreased testes weights, and microscopic changes in the liver and testes. The NOAEL 

is 100 ppm (3.9 mg/kg/day in males and 3.7 mg/kg/day in females).

This study is classified acceptable/guideline and meets the guideline requirements for a 

subchronic oral toxicity study in the dog (OCSPP 870.3150).

870.3200 21-Day Dermal Toxicity – Rabbit

In a 21-day dermal toxicity study (MRID 42991409), 5 New Zealand White rabbits/sex/group 

were treated topically with dosages of 0, 50, 300 or 1000 mg/kg/day of DPX-66037 

(triflusulfuron-methyl technical, 95.6% a.i., batch no. DPX-66037-24) for 21 days, 6 hrs/day. 

There were no differences between the control and treated groups in any of the parameters 

measured. Signs of dermal irritation and the finding of inflammation and acanthosis on 

histopathology were reported in both the control and treated groups and were attributed to the 

mechanical trauma of frequent washing and clipping. The systemic toxicity NOAEL is ≥1000 

mg/kg/day (HDT). A LOAEL for systemic toxicity was not determined (>1000 mg/kg/day). 

The dermal toxicity NOAEL is ≥1000 mg/kg/day. A LOAEL for local dermal toxicity was 

not determined (>1000 mg/kg/day).

This study is classified as acceptable/guideline and satisfies the guideline requirement for a 21-

day dermal toxicity study in the rabbit.

A.3.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study - Rat

In an oral developmental toxicity study, DPX-66037-24 (triflusulfuron-methyl technical,95.6% 

a.i., lot no. 18649-02) was administered by gavage in 0.5% aqueous methylcellulose vehicle (10 

mL/kg) to 25 Crl:CD®BR albino rats at dose levels of 0, 30, 120, 350 or 1000 mg/kg/day from 

gestation day (GD) 7 through 16, inclusive.

Maternal toxicity: At 350 mg/kg/day, decreased body weight gain (about 20% less than controls 

during dosing) and a slight reduction in food efficiency (2.6%) were observed. At 1000 

mg/kg/day, effects were more pronounced and decreased weight gain and food consumption 

were statistically significant. The maternal toxicity LOAEL is 350 mg/kg/day, based on 

decreased body weight gain, food consumption and food efficiency. The NOAEL is 120 

mg/kg/day.

Developmental toxicity: No developmental effects were observed in this study. The 

developmental toxicity NOAEL is ≥1000 mg/kg/day. A LOAEL was not observed (>1000 

mg/kg/day).

This study is classified as acceptable/guideline and satisfies the guideline requirement for a
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developmental toxicity study in the rat (OCSPP 870.3700a).

870.3700b Prenatal Developmental Toxicity Study - Rabbit

In an oral developmental toxicity study, DPX-66037-24 (triflusulfuron-methyl technical, 95.6% 

a.i., lot no. 18649-02) was administered by gavage in 0.5% aqueous methylcellulose vehicle (8 

mL/kg) to 20 HRA(NZW)SPF rabbits at dose levels of 0, 15, 90, 270 or 800 mg/kg/day from 

gestation day (GD) 7 through 19, inclusive.

Maternal toxicity: At 270 mg/kg/day, clinical signs of toxicity included absent/reduced stool and 

stained fur, postdosing maternal death (10%), increased abortions (40%), mean body weight loss 

(-82.9 g vs. gain of 165 g in controls) and lower food efficiency (4.1% vs. 8.5%, controls). 

Abortions and mortality did not occur until post-dosing. At 800 mg/kg/day, effects were more 

severe, with mortality reaching 45% and abortions 60% (both findings first observed on GD 15). 

Postmortem findings indicated gastrointestinal effects, including ulcerations of the gastric 

mucosa, lack of formed feces in the large intestine, and gaseous distension in various parts of the 

digestive tract; these findings were observed in all of the animals that died during the study. The 

maternal toxicity LOAEL is 270 mg/kg/day, based on mortality, clinical signs of toxicity, 

abortions and body weight loss. The NOAEL is 90 mg/kg/day.

Developmental toxicity: At 270 mg/kg/day, decreased mean fetal weight (-11% less than 

controls) and increased abortions were observed. At 800 mg/kg/day, the incidence of abortions 

was increased. Abortions were considered secondary to significant maternal toxicity. The 

developmental toxicity LOAEL is 270 mg/kg/day, based on decreased mean fetal body 

weight and abortions (secondary to maternal toxicity). The LOAEL is 90 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the guideline requirement for a

developmental toxicity study in the rabbit (OCSPP 870.3700b).

A.3.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

In a two-generation reproduction study (MRID 42991412), 30 CD rats/sex/dose received DPX66037-24 continuously in the diet at concentrations of 0, 10, 100, 750 or 1500 ppm (equivalent 

to average daily intakes of 0, 0.588, 5.81, 44.0 or 89.5 mg/kg/day in males and 0, 0.764, 7.75, 

58.0 or 115 mg/kg/day in females, respectively). The protocol was for a standard reproduction 

study with litters culled to 4 animals per sex per dose on postpartum Day 4.

Parental toxicity: At 750 and 1500 ppm, mean body weight and body weight gain were 

significantly decreased in males during the premating period of both the F0 and F1 generations. 

Body weights for the 750 ppm and 1500 ppm F0 males were 94% and 90% of the controls, 

respectively, at the end of the premating period. Mean body weight gains for these groups 

during this time period were 87% and 81% of controls, respectively. Mean body weight during 

the premating period was significantly decreased for the F1 generation females at 750 and 1500 

ppm (93% and 90% of controls, respectively). Mean body weight gain during the premating 
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period was decreased for the 750 and 1500 ppm groups of the F0 generation and the 1500 ppm 

group of the F1 generation (86% and 82%, respectively, for the F0 generation and 89% for the 

F1 generation). Mean daily food consumption for the F0 males in the 1500 ppm group was 

significantly reduced during the premating period (94% of controls). Overall mean food 

efficiency during this period was significantly reduced for the F0 males in the 750 and 1500 ppm 

groups (91% and 83% of controls, respectively). Food consumption in the F1 males during the 

premating period was comparable to the controls. However, food efficiency was significantly

lower in the 1500 ppm group (94% of controls). Decreases in food efficiency were seen in the 

750 and 1500 ppm group females of the F0 generation during this period (90% and 86% of 

controls, respectively). Food consumption in the F1 female rats in the 750 and 1500 ppm groups 

was significantly decreased during the premating period (95% and 93% of controls, 

respectively). There was a slight reduction in food efficiency that was not statistically

significant. The LOAEL for parental/systemic toxicity is 750 ppm (44 mg/kg/day in males 

and 58 mg/kg/day in females), based on decreased body weight and body weight gain and 

food efficiency. The NOAEL is 100 ppm (5.81 mg/kg/day in males and 7.75 mg/kg/day in 

females).

Offspring toxicity: At 750 and 1500 ppm (44.0 mg/kg/day in males and 58.0 mg/kg/day in 

females), the mean body weights of male F1 pups were significantly decreased on Day 14 postpartum (90.5-92.6% of controls); body weights at Day 21 were slightly lower but did not achieve 

statistical significance. At 1500 ppm, the mean combined male and female pup body weights 

were significantly decreased (90%-93% of controls). The LOAEL for offspring toxicity is 750 

ppm (44 mg/kg/day in males and 58 mg/kg/day in females), based on decreased mean F1 

pup body weight in males during lactation. The NOAEL is 100 ppm (5.81 mg/kg/day in 

males and 7.75 mg/kg/day in females).

Reproductive toxicity: No reproductive toxicity was observed in this study, which tested up to 

doses causing maternal and offspring toxicity. The NOAEL for reproductive toxicity is 1500 

ppm (89.5 mg/kg/day in males and 115 mg/kg/day in females). A LOAEL was not 

determined (>1500 ppm).

A.3.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

See 870.4300

870.4100b Chronic Toxicity – Dog

In a chronic oral toxicity study (MRID 42991410), DPX-66037-24 (technical, 95.6% a.i., Lot 

No. 02) was administered daily in the diet to 5 beagle dogs/sex/dose at concentrations of 0, 35, 

875 or 3500 ppm (equivalent to average daily intakes of 0, 1.0, 26.9 or 111.6 mg/kg/day in males 

and 0, 1.2, 27.7 or 95.5 mg/kg/day in females, respectively).

At 3500 ppm, one male and one female were sacrificed in moribund condition during the first 

five months of the study. On necropsy, the female was diagnosed with a pulmonary bacterial 
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infection; the male was found to have acute hemorrhage in the pleural cavity and gastrointestinal 

tract compounded with thymic necrosis. These deaths were not considered treatment-related. 

Mean body weight gain of the 3500 ppm group males was significantly lower than controls at 

Weeks 7, 11, 12 and 13 only (approximately 50% of the control value). There was no treatmentrelated effect on food consumption or food efficiency. Mean total erythrocyte counts and 

hematocrit values for the 3500 ppm group males and females were slightly lower than controls 

throughout the study; however, the differences were statistically significant only at the 3 month 

evaluation. Mean alkaline phosphatase (AP) values were increased relative to controls at all 

evaluation times; differences were significant at Months 6, 9 and 12. A significant increased at 

3500 ppm in females at Month 3 resulted from an exceptionally high value (259 IU/L) in the 

female that was euthanized. On necropsy, there was a treatment-related increase in mean 

absolute, relative liver:body and relative liver:brain weights in males and in relative weight in 

females. Minimal centrilobular hepatocellular hypertrophy was observed in 3/4 males and 2/4 

females. The LOAEL was 3500 ppm (111.6 mg/kg/day in males and 95.5 mg/kg/day in 

females), based on increased alkaline phosphatase (males, liver weight and incidence of 

minimal centrilobular hepatocellular hypertrophy. The NOAEL was 875 ppm (26.9 

mg/kg/day, males and 27.7 mg/kg/day, females).

This study is classified as acceptable/guideline and satisfies the guideline requirement for a 

chronic toxicity study in the dog.

A.3.5 Carcinogenicity

870.4200b Carcinogenicity (feeding) – Mouse

In an oral carcinogenicity study (MRID 42991411), 80 CD-1 mice/sex/dose were administered 

DPX-66037-24 in the diet at concentrations of 10, 50, 2500 or 7000 ppm (equivalent to average 

daily intakes of 0, 1.37, 20.9, 349 or 1024 mg/kg/day in males and 0, 1.86, 27.7, 488 or 1360 

mg/kg/day in females). An additional ten groups of 30 mice/sex (5 groups for each sex) were 

designated for a cell proliferation, cytochrome P-450 and beta-oxidation substudy.

Mean body weight gain for the first 90 days was statistically significantly decreased (13%) in the 

7000 ppm group males. There was a statistically significant increase of body weight gain in the 

150 ppm group males and the 2500 ppm group females during this time period. Males in the 10 

ppm group had a significant body weight gain increase over the course of the study. The 7000 

ppm group females had significant body weight decreases during the periods 0-364 days and 0-

546 days. The 7000 ppm group males had slightly decreased food efficiency (15.4%) over the 

first 91 days of the study as compared to the control group. There were increases in the hepatic 

cytochrome P-450 levels in the 7000 ppm group males and females at two weeks and three 

months; this finding was statistically significant at both time points in females and at three 

months for the males. There was a treatment-related increase in the absolute and relative liver 

weights of males and females in the 2500 and 7000 ppm groups. There was an increase in the 

incidence of hepatic microscopic alterations in both male and female mice in the 2500 and 7000 

ppm groups. There was a statistically significant increase in hepatocellular adenomas in male 

mice in the 2500 and 7000 ppm groups (16% and 19% incidence in the 2500 and 7000 ppm 

groups, respectively, vs. 12% in the controls) using the Cochran-Armitage trend test. The 
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incidence of the combined adenomas and carcinomas was statistically increased in the 7000 ppm 

group males (20% in the treated group vs. 15% in the controls) and 2500 ppm group females (6% 

in the treated group vs. 0% in the controls). However, these findings were within the historical 

range of these tumors, alone and combined. Dosing was considered adequate based on and 

testing up to the limit dose of 1000 mg/kg/day. The LOAEL is 2500 ppm (349 mg/kg/day) 

based on increases in liver weights and increased incidence of microscopic changes in the 

liver. The 150 ppm dose was adjusted to the lowest concentration level for the chemical in 

stability studies (70%). The NOAEL is 105 ppm (14.6 mg/kg/day). 

This study is classified acceptable/guideline and satisfies the guideline requirement for a 

carcinogenicity study in the mouse (OCSPP 870.4200b).

870.4300 Carcinogenicity Study - rat

In a combined chronic toxicity/carcinogenicity study (MRID 42991413), 62 male and 62 female 

CD rats per group were treated with triflusulfuron-methyl in the diet for 96 weeks at dosages of 

0, 10, 100, 750, or 1500 ppm (0, 0.406, 4.06, 30.6 or 64.5 mg/kg/day in males and 0, 0.546, 5.47, 

41.5, or 87.7 mg/kg/day in females respectively). The study was terminated early so that there 

were enough animals for the terminal necropsy. Survival in the treated animals was comparable 

to that of the controls. Mean body weights in the 750 and 1500 ppm group males and females 

were statistically significantly decreased in comparison to the control group at a majority of the 

time points evaluated. Body weight gains for the first three months were statistically

significantly decreased in the 1500 and 750 ppm group males (≈21% and 11%, respectively) and 

females (21% and 8%, respectively); the decreases persisted at the 1 year evaluations. There 

were no statistical differences in mean food consumption and mean food efficiency. Statistically

significant decreases in hematology parameters (RBC, HGB and HCT) were occasionally seen in 

the 750 and 1500 ppm group males at the 3-, 6- and 12-month sampling periods. The only organ 

weight change for which there were also microscopic changes was an increase in the relative 

weight of the testes in the 1500 ppm group males at the interim and terminal sacrifices. There 

was a statistically significant increase in the incidence of Leydig (interstitial) cell hyperplasia in 

the testes of males in the 750 and 1500 ppm groups at the terminal sacrifice only. There was a 

statistically significant increase in myelin/axon degeneration of the sciatic nerve in females at 

1500 ppm (control to high dose, 52, 61, 67, 69 and 86%, respectively), but the lesion is 

commonly observed in older rats and was not increased in the interim sacrifice animals (males 

showed an incidence of 93, 84, 85, 80 and 92%, control to high dose, respectively). The 

LOAEL for chronic toxicity is 750 ppm (30.6 mg/kg/day) for males and females based on 

decreased body weight and body weight gain, alterations in the hematology parameters 

(males predominantly) and an increased incidence of interstitial cell hyperplasia in males. 

The 100 ppm dose was adjusted to the lowest concentration level of the chemical at this 

dosage (60%); therefore, the NOAEL is 60 ppm (2.44 mg/kg/day). 

A statistically significantly and treatment-related increase in the incidence of interstitial cell 

adenomas was observed at 750 and 1500 ppm. From control to high dose, incidence was 0, 4.3, 

2.1, 14.0 and 13.7%, respectively. 

This study is classified acceptable/guideline and satisfies the guideline requirement for a 
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combined chronic toxicity/carcinogenicity study in the rat (OCSPP 870.4300).

A.3.6

870.6200a Acute Neurotoxicity Screening Study – Rat

In an acute oral neurotoxicity screening study (MRID 43398601), DPX-66037-24 (triflusulfuronmethyl technical, 95.6% a.i., Lot No. H-18649-02) was administered to 10 Crl:CD®BR 

VAF/Plus® rats in single gavage doses of 0, 500, 1000 or 2000 mg/kg in 0.5% aqueous (w/v 

methylcellulose vehicle (10 mL/kg). Neurobehavioral screening, consisting of functional 

observational battery (FOB) and motor activity (MA) evaluations, was performed before 

treatment on Days 1 (2 hrs post-dosing), 2-8 and 15. Six animals/sex/dose were anesthetized and 

perfusion-fixed in situ for neuropathological evaluation; the remaining animals were examined 

grossly.

Mean body weights, body weight gains and absolute and relative food consumption of treated 

animals were comparable to controls. All animals survived to terminal sacrifice without the 

appearance of any treatment-related clinical signs. Neurobehavioral evaluations did not reveal 

any treatment-related changes in the FOB or in motor activity. Neuropathological evaluations of 

high dose animals were comparable to controls. The NOAEL is ≥2000 mg/kg/day (highest 

dose tested. A LOAEL was not determined (>2000 mg/kg).

This study is classified as acceptable/guideline and satisfies the guideline requirements for an 

acute neurotoxicity screening study in the rat (OCSPP 870.6200a).

870.6200b Subchronic Neurotoxicity Screening Study - Rat

In a subchronic oral neurotoxicity screening study, 11 Crl:CD®BR VAF/Plus® rats were 

administered DPX-66037-24 (triflusulfuron-methyl technical, 95.6% a.i., Lot No. H-18649-02) 

in the diet at concentrations of 0, 100, 750, 1500 or 3000 ppm (equivalent to average daily 

intakes of 6.1, 46.1, 92.7 or 186.2 mg/kg/day in males and 0, 7.1, 51.6, 104.1 or 205.2 mg/kg/day

in females). Neurobehavioral screening (functional observational battery or FOB, and motor 

activity or MA) was performed prior to treatment and during weeks 4, 8 and 13. Six 

animals/sex/dose were anesthetized and perfusion fixed in situ for neuropathological evaluation.

With the exception of one control female which was sacrificed in moribund condition on Days 

52, all other animals survived to terminal sacrifice without the appearance of any treatmentrelated clinical signs. At 3000 ppm, biological (>10%) and/or statistically (p≤0.01) significant 

decreases in the mean body weights were observed in males at weeks 8 and 13 and in females at 

weeks 4, 8 and 13; biologically significant decreases were observed at 750 and 1500 ppm 

females at week 13. Mean body weight gains were lower in 3000 ppm males between days 1-8, 

43-50, 64-71 and 1-92, and in females at ≥750 ppm for days 1-8 and 1-92. Results of the FOB 

and MA evaluations did not reveal any neurobehavioral effects in any of the treated animals; 

neuropathological evaluations of high-dose animals were comparable to controls. The LOAEL 

is 3000 ppm in males (186.2 mg/kg/day) and 750 ppm (51.6 mg/kg/day) in females, based on 

decreased body weight/weight gains. The NOAEL is 1500 ppm in males (92.7 mg/kg/day) 
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and 100 ppm in females (7.1 mg/kg/day).

This study is classified acceptable/guideline and satisfies the guideline requirements for a 

subchronic neurotoxicity screening battery in the rat (OCSPP 870.6200b).

A.3.7 Mutagenicity

Gene Mutation

870.5100 Bacterial Gene Reverse 

Mutation in S. typhimurium TA 98, 

100, 1535,1537, 1538

MRID 42496846

Acceptable/guideline

0, 62.5, 125, 250 or 1000 μg/plate with and without S9 activation.

Negative up to precipitating concentrations.

870.5100 Bacterial Gene Reverse 

Mutation, S. typhimurium TA98, 100, 

1535, 1537 and 1538

MRID 42496848

Acceptable/guideline

0, 50, 100, 250, 500, 1000 or 3000 μg/plate with and without S9 

activation.

Negative up to precipitating concentrations.

870.5300 in Vitro Forward Mutation, 

Chinese hamster ovary (CHO) cells

MRID 42496850

Acceptable/guideline

0 to 2000 μg/mL with and without activation.

Negative up to cytotoxic concentrations.

Cytogenetics

870.5375 In Vitro Chromosomal 

Aberration in human lymphocyte cells

MRID 42496852

Acceptable/guideline

0 to 2000 μg/mL with and without activation.

Positive for induction of a treatment-related increase in the frequency of 

chromosomal aberrations at concentrations ≥1700 μg/mL in the presence 

of S9 activation; inconclusive in the absence of metabolic activation.

870.5375 In Vitro Chromosomal 

Aberration in human lymphocyte cells

MRID 42496845

Acceptable/guideline

0 to 2000 μg/mL with and without activation.

Positive for induction of a treatment-related increase in the frequency of 

chromosomal aberrations up to 2000 μg/mL in the presence of S9 

activation; inconclusive in the absence of metabolic activation. Followup assay to MRID 42496852.

870.5395 In Vivo Micronucleus Assay

in Male Mice

MRID 42496853

Acceptable/guideline 

0 to 5000 mg/kg

Negative for induction of an increase in frequency of micronucleated 

polychromatic erythrocytes at 24, 48 hrs or 72 h.

A.3.8 Metabolism

870.7485 Metabolism – Rat

In a rat metabolism study (MRID 42991416), [triazine-(U14C)] DPX-66037 (triflusulfuronmethyl technical, radiochemical purity 95-97%, Lot No. 2622-175) was administered orally in 

PEG 200 vehicle to 5-6 Sprague-Dawley rats/sex/dose at the following dose levels: a single low 

oral dose of 25 mg/kg, a repeated low oral dose of 25 mg/kg/day for 14 consecutive days, or a 
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single high dose of 250 mg/kg. An additional group of 10 rats/sex received a single oral dose of 

[ester carbonyl14C]-DPX-66037 at 250 mg/kg. Urine and feces were collected at 0-6 hr, 6-24 hr 

and at 24 hr post-dose. Metabolite analysis was performed in urine and feces of all dose groups, 

and in liver of high dose females. Pilot experiments showed less than 0.01% of the dose 

excreted through expired air, which was not measured in the main study.

The rate of absorption (as suggested by the time of peak urinary excretion) was not affected by 

dosing regimen or dose of test chemical. The extent of absorption was decreased at the high 

dose as suggested by the increase in percentage of radioactivity excreted in feces and by the 

increased percentage of parent chemical observed in feces at the high dose. The majority of 

residual radioactivity at 120 hours post-dose was found in the liver in all dose groups, and was 

observed to be composed of parent DPX-66037 (41.5-62.3% of the sample radioactivity), and the 

metabolites N-desmethyl DPX-66037 (18.7% - 24.8% of the sample radioactivity), triazine 

amine (8.4%-15.9% of the sample radioactivity), N,N-bis-desmethyl triazine amine (0.7%-2.3% 

of the sample radioactivity), and methyl saccharin (18.4% of the sample radioactivity). The skin 

and ovaries were also found with measurable amounts of residual radioactivity at the high dose 

of 250 mg/kg. Whole blood:plasma ratios were approximately 1 for the single and repeated low 

dose groups, but at the high dose, the ratio increased to approximately 2 for the triazine labeled 

material. For the ester carbonyl labeled material, the ratio at the high dose was less than 1. 

Urine was the major route of excretion at the low dose, with between 61%-77% excreted via this 

route at 25 mg/kg. Repeated oral dosing had no effect on the percentage of radioactivity

excreted through urine. At the 250 mg/kg dose, fecal excretion increased to between 43%-64% 

of the administered dose. The percentage excreted through urine was higher in female rats than 

male rats in all dosing regimens. The major urinary metabolite of DPX-66037 in urine was Ndesmethyl DPX-66037, found to compose 25%-44% of the administered dose at the low dose 

level (single and repeated). At the high dose, the percentage of this metabolite was decreased in 

urine (14%-28%). Female rats showed higher urinary levels than males of this metabolite. The 

N-hydroxymethyl metabolite of DPX-66037 was also found in urine, but did not vary

significantly with dose (10%-16% of the dose). Female rats also showed higher percentages of 

this metabolite in urine vs. males. The triazine metabolites of DPX-66037 (triazine amine or T9, 

N-desmethyl triazine amine or T5, N,N-bis-desmethyl triazine amine or T3) were found in urine 

and liver. In urine, only T3 was in significant percentage (3.6%-6.8%); T5 and T9 were less than 

1.0% of the administered dose. In feces, none of these metabolites represented more than 2.0% 

of the administered dose. Parent compound was found as a major component only in high dose 

feces and liver. Methyl saccharin was found as a major metabolite in urine and liver of rats 

dosed with the ester carbonyl labeled test material. Based on the identified metabolites, a

scheme for metabolism of DPX-66037 was proposed.

This study is classified acceptable/guideline and satisfies the guideline requirement for a 

general metabolism study in the rodent (OCSPP 870.7485).

A.3.9 Additional Studies

Nonguideline mechanistic study

In a 2-week in vivo study, CD male rats were administered DPX-66037-24 at dosages of either 0, 
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1,000, 1,500 or 2,000 mg/kg/day for fifteen days. An additional untreated control group was 

pair-fed to the 2,000 mg/kg/day group. Ten animals in the unpaired control group and the 2,000 

mg/kg/day group were administered 100 IU of human chorionic gonadotropin one hour prior to 

sacrifice on test day 16. Various clinical parameters and serum hormonal levels were measured, 

along with determinations of beta-oxidation activity, cytochrome P-450 content and aromatase 

activity on liver homogenates at necropsy. The body weight, body weight gain, food 

consumption and food efficiency results demonstrated that decreases in these parameters for the 

treated groups were due to reduced intake. Final body weights for the treated groups and the 

pair-fed control were decreased in comparison to the unpaired control. Only decreases in the 

absolute and relative weights of the accessory sex glands, decrease in absolute weight of the liver 

and increase in relative weight of the liver in the 2,000 mg/kg/day group was significantly 

different from the pair-fed control. The only hormone level which was statistically significantly 

different from either the pair-fed or unpaired control group was the serum estradiol level. There 

were significant decreases in the serum estradiol levels in the 1,000, 1,500 and 2,000 mg/kg/day

groups (31.9, 13.6 and 13.4% of the unpaired control level). No differences were found with the 

interstitial estradiol levels. In the 2,000 mg/kg/day group rats treated with hCG, serum 

testosterone levels were significantly elevated and serum estradiol levels were significantly 

decreased. There were no treatment-related effects on beta-oxidation activity, cytochrome P-450 

content or aromatase activity.

In an in vitro experiment, the hepatic microsomal fraction from ammonium perfluorooctanoateinduced male rats was studied to determine if DPX-66037-24 had an effect on aromatase 

activity. There was a dose-dependent statistically significant decrease in aromatase activity in the 

microsomes treated with 0.01, 0.02, 0.05, 0.1, 0.2 or 0.5 uM DPX-66037-24.

Hormonal analyses were also conducted on the male rats treated with DPX-66037-24 in the 

combined chronic toxicity/carcinogenicity study. The following statistically significant trends in 

hormonal levels were observed in the study: increasing serum testosterone levels, decreasing 

serum estradiol levels and increasing serum FSH levels. LH levels were not affected.

In another study, isolated Leydig cells from 11-week old rats were incubated for two hours with 

increasing concentrations of DPX-66037-24. Some of the cultures were then treated with hCG 

for three hours prior to analysis for testosterone, estradiol and progesterone. There was no 

treatment-related effect on hCG-induced testosterone biosynthesis. However, Leydig cells 

incubated with 1,000 uM DPX-66037-24 and no hCG stimulation produced testosterone at levels 

198.8% of control. Cells incubated with 100 and 1,000 uM DPX-66037-24 had significant 

decreases in estradiol, both with and without hCG stimulation. There was no treatment-related 

effect on progesterone production.

The studies demonstrated that DPX-66037-24 produces a dose-dependent decrease in aromatase 

activity in vitro. However, the effects of the chemical on the enzyme in vivo are not conclusive 

since no inhibition of activity at extremely high dose levels after a two-week exposure period 

was observed. Further, the hypothesis that this effect is mediated by a chronic depression in 

estradiol altering the negative feedback mechanism for LH upon the Leydig cells of the testes 

has been suggested but not clearly demonstrated. A trend but not pair-wise statistical significance 

has been shown for either the 750 or 1500 ppm serum levels of testosterone or estradiol after one 
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year of exposure. In addition, no elevation in serum levels of LH was noted at either dose level.

This study is classified acceptable/nonguideline. It was not submitted to satisfy/does not satisfy

guideline requirements for triflusulfuron-methyl, but provides supplemental information 

evaluating effects on cytochrome p450 enzyme activities and hormonal levels in male rats

A.4 Rationale for Toxicology Data Requirements

Table A.4.1 Guideline Number: 870.7800

Study Title: Immunotoxicity

Rationale for Requiring the Data

The immunotoxicity study is a new data requirement under 40 CFR Part 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 a repeated chemical exposure to produce adverse effects (i.e., 

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 not 

specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s 

potential immunotoxicity. While data from hematology, lymphoid organ weights, and histopathology in 

routine chronic or subchronic toxicity studies may offer useful information on potential immunotoxic 

effects, these endpoints alone are insufficient to predict immunotoxicity. 

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to characterize potential hazard to 

the human population on the immune system from pesticide exposure. Since epidemiologic data on the 

effects of chemical exposures on immune parameters are limited and are inadequate to characterize a 

pesticide’s potential immunotoxicity in humans, animal studies are used as the most sensitive endpoint for 

risk assessment. 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 these data, a 10X database uncertainty factor may be applied for conducting a 

risk assessment from the available studies.