Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 3 of 38 5.4.3 Acute Dietar y Risk Assessment

................................ ................................ ................ 21

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ............ 22

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ .............. 23

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ ... 23

6.1 Spray Drift

................................ ................................ ................................ .................... 23

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ...... 23

7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 23

7.2 Short

- and Intermediate

- Term Aggregate Risk

................................ ............................. 23

7. 3 Chronic /Long

- Term Aggregate Risk

................................ ................................ ............ 24

7. 4 Cancer Aggregate Risk

................................ ................................ ................................ . 24

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ .... 24

9.0 Occupational Exposure/Risk Characterization

................................ ................................ . 24

9.1 S hort

- and Intermediate

- Term Handler and Post

- Application Risk

............................. 24

10.0 References

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

................................ ....................... 29

A.1 Toxicology Data Requirements

................................ ................................ .................... 29

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 30

A.3 Hazard Identification and Endpoint Selection

................................ .............................. 33

A.4 Executive Summaries

................................ ................................ ................................ .... 35 Appendix B. Human Research Re ference

................................ ................................ ................... 37 Appendix C. Physic oc hemical Properties

................................ ................................ .................... 38Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 4 of 38 1.0 Executive Summary

The Interregional Research Project Number 4 (IR

- 4) has submitted a tolerance petition ( 1E7885 ) proposing the establishment of tolerance s for residues of the herbicide

, thifensulfuron methyl (with CAS name meth yl

- 3

- [[[[(4

- methoxy

- 6

- methyl

- 1, 3,5

- triazin

- 2

- yl )amino] carbonyl] amino] sulfonyl]

- 2

- thiophenecarboxylate)

, in or on chicory roots and tops (leaves)

.

HED has reviewed the available toxicological and residue chemistry studies for thifensulfuron methyl, and is recommending that the requested use be regis tered, and that permanent tolerance s be established.

The toxicological database adequately characterizes t hifensulfuron methyl as having low acute oral, dermal and inhalation toxicity. The toxicological studies conducted with thifensulfruon methyl did not indicate specific target organ toxicity. Most findings in the submitted studies related to decreases in body weights, body weight gains, or organ weights (a reflection of the lower body weights compared with control weights). There were n o gross or histopathological changes reported in any of the studies. There wa s no indication of neurotoxicity , and the ai is a member of the sulfonylurea class of compounds, which are not known to be neurotoxic.

The potential for increased susceptibili ty of infants and children from exposure to thifensulfuron methyl was evaluated. There was evidence of quantitative susceptibility in the rat developmental toxicity study, based on observed fetal effects at a dose which did not cause maternal toxicity.

T hese effects included decreased mean fetal body weights, and an increased incidence of small renal papillae. HED had a low degree of concern for the observed susceptibility

, based on the completeness of the toxicity database, the lack of evidence of susce ptibility in the rabbit developmental and rat reproductive toxicity studies, and the lack of neurotoxicity in the database

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

effects. Based on these considerati ons, HED reduced the required 10X Food Quality Protection Act (FQPA) Safety Factor to 1X.

Potential i mmunotoxicity was observed ( only in mid

- dose males ) as a decrease in spleen weight in the subchronic rat study. However, in the submitted immunotoxicit y study in female rats, dosing with thifensulfuron methyl did not affect any immunotoxicity parameters up to the highest dose tested (HDT)

. In the absence of dermal and inhalation toxicity

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

. Thifensulfuron methyl was classified as “ not likely to be a human carcinogen, ” based on the lack of evidence of carcinogenicity in both the rat and the mouse.

Adequate metabolism, storage stability, analytical methods, and field trial data are available to support the proposed use. The chicory field trial study with t hifensulfuron methyl resulted in residues below 0.010 ppm, the lowest limit of method validatio n (LLMV), in all samples of the raw agricultural commodities ( RACs )

.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 5 of 38 HED has used conservative assumptions to assess the risk from exposure to thifensulfuron methyl from dietary sources. These include the use of recommended tolerance

- level residues,

mo deled drinking water estimates, and the assumption that all registered and requested

commodities we re treated, or 100% crop treated (CT). B oth acute and chronic dietary r isk estimates are below HED’s level of concern (LOC) for all population subgroups

.

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

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

, which are not of concern

.

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

, assuming single layer clothing with no gloves ( baseline )

, result in margins of exposure (MOEs) that are all above 100. Therefore (because HED has concern for MOEs <100), HED concludes

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

- application

scenarios.

Review of human research : This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or ot her chemical. These studies (listed in Appendix B ) have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethically conducted.

2.0 HED Recommendations

HED recommends that the requested use of t hifensulfuron methyl on chicory be registered , and that permanent tolerance s in both chicory roots and tops , as detailed in Section 2 .2 .3 , be

established.

2.1 Data Deficiencies

None.

2.2 Tolerance Considerat ions

2.2.1 Enforcement Analytical Method s

Two methods using high performance liquid chromatography (HPLC) with photo

- conductivity detection methods (Methods AMR

- 646

- 86 and AMR

- 761

- 87) are available for enforcing tolerances for residues of thifensulfuron methyl in cereal grains and straw. For Method AMR

646

- 86, straw samples are extracted with ethyl acetate, and th e extract is partitioned with sodium bicarbonate. The aqueous phase is acidified, and partitioned with dichloromethane. The dichloromethane phase is evaporated to dryness, and then reconstituted for analysis via HPLC with photo

- conductivity detection. F or Method AMR

- 761

- 87, wheat grain is extracted with ethyl acetate, barley grain is extracted with 0.1 M sodium bicarbonate, and straw is extractedThifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 6 of 38 with ethyl acetate/HCl (at pH 3). Extracts are then analyzed via HPLC with photo

- conductivity

detection.

A liquid chromatography with mass spectrometric detection (LC/MS) method (DuPont Method 1381) is also available for enforcing tolerances for residues of thifensulfuron methyl in canola, cotton and flax commodities. For this method, samples are extracted w ith an acetonitrile (ACN)/ammonium carbonate buffer solution, and the concentrated residues are reconstituted in methanol for analysis. If required, a hexane wash step, or cleanup step using a strong anion exchange solid phase extraction (SPE) column, may be incorporated. Analysis is performed via

column

- switching LC. Extracts in methanol are applied to a size exclusion chromatography column, and the eluate is diverted onto a reversed phase XDB

- C 8 column for MS analysis. The

validated limit of quantitat ion ( LOQ ) was 0.02 ppm. This method may also be used for enforcing tolerances in corn grain, sorghum grain, and soybean seeds.

A dditionally, an LC/MS /MS ( tandem MS detection ) method

, DuPont Method 13412 ( Revision

# 1 ), is available t o enforc e tolerances for residues of various sulfonylurea herbicide s in oily commodities, including chicory roots and tops (leaves)

. S amples a re extracted with ACN/20

mM potassium phosphate, at pH 7 (3:1, v/v). This mixture i s allowed to soak for 15 minutes prior to blending for 1 minute using a high

- speed homogenizer. The mixture i s vacuum

- filtered, brought to volume with ACN, and partitioned using liquid/liquid extraction with hexane. After discarding the hexane layer, the extracts a re concentrated using dry nitrogen on a TurboVap evaporator. The extracts a re then diluted with reagent water, and cleaned up using a polystyrene

divinylbenzene SPE cartridge eluted with 25 mM ammonium hydroxide in methanol. The

cleaned extrac t i s evaporated to near dryness, reconstituted in ACN/50 mM ammonium acetate to a concentration of approximately 10%, and analyzed via LC/MS/MS. The LOQ, determined as the lowest limit of method validation (LLMV), is 0.010 ppm for thifensulfuron methyl in chicory

roots and leaves.

The FDA multiresidue methods are not suitable for tolerance enforcement, as thifensulfuron methyl is not recovered through any of the FDA Multiresidue Method Testing protocols.

2.2.2 International Harmonization

There are n o established or proposed Codex Maximum Residue Limits (MRLs) for residues of thifensulfuron methyl. Canada and Mexico have established MRLs for thifensulfuron methyl in several plant commodities. However, no Canadian or Mexican MRLs for thifensulfuron m ethyl have been proposed n or established in chicory roots or tops. The residue definition s in Canada,

Mexico and the US are harmonized.

2.2.3 Recommended Tolerances

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

T he submitted data support tolerance s for residues of thifensulfuron methyl, including itsThifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 7 of 38 metabolites and degradates, in or on chicory roots and chicory tops , at the level s listed below. Compliance with the tolerance level s specified below is t o be determined by measuring thifensulfuron methyl only.

TABLE 2.2.3 Tolerance Summary for Thifensulfuron Methyl. Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition
Chicory, roots 0.01 0.01 Chicory, roots Chicory, tops 0.01 0.01 Chicory, tops

2.2.4 Revisions to Petitioned

- For Tolerances

No revisions to the tolerances or residue definition , as proposed by IR

- 4

, were necessary.

2.3 Label Recommendations

A revised Section B should be submitted that is in accordance with the supplemental label regarding the mandatory use of adjuvants

. The required tank mix adjuvants are a n on

- ionic surfactant ( NIS ) at a minimum concentration of 0.25% (v/v), a lo n g with eith er a urea ammonium nitrogen (UAN) or ammonium sulfate (AS) fertilizer at the rate of 2 quarts per acre (qt/A)

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

, which stipulates applications via ground equipment only, in spray volumes of 19

- 30 gallons per acre ( GPA).

3.0 Introduction

3.1 Chemical Identity

The chemical structure and nomenclature of thifensulfuron methyl are presented in Table 3. 1 (below).

TABLE 3. 1 Thifensulfuron Methyl Nomenclature.

Chemical structure

Common name Thifensulfuron methyl

Molecular formula C 12 H 13 N 5 O 6 S 2 Molecular weight 387.38Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 8 of 38 TABLE 3. 1 Thifensulfuron Methyl Nomenclature.

Company experimental name DPX

- M6316

IUPAC name Methyl 3

- (4

- methoxy

- 6

- methyl

- 1,3,5

- triazin

- 2

- ylcarbamoylsulfamoyl) thiophene

2

- carboxylate

CAS name Methyl 3

- [[[[(4

- methoxy

- 6

- methyl

- 1,3,5

- triazin

- 2

- yl)amino]carbonyl]amino] sulfonyl]

- 2

- thiophenecarboxylate CAS registry number 79277

- 27

- 3

End

- use product (EP) Basis herbicide (EPA Registration #352

- 571), a water dispersible granule (WG)

formulation cont aining 25% thifensulfuron methyl by weight.

Chemical c lass Sulfonylurea herbicide (Group 2)

Known i mpurities of c oncern None.

3.2 Physical/Chemical Characteristics

T hifensulfuron methyl has a low vapor pressure (1.3 x 10 - 10 mm Hg), is not significantly volatile, and would therefore result in low inhalation exposures

. The Environmental Fate and Effects Division ( EFED) concluded that thifensulfuron methyl is a somewhat persistent chemical that partitions readily in to water. A cid hydrolysis, photo

- degradation in water

, and aerobic soil

metabolism are the primary routes of degradation . R apid leaching is likely because of the low sorption coefficients. In soils, hydrolysis under acidic conditions

, and via metabolism

, will likely be the dominant routes of degradation

. A detailed description of the physicochemical properties of the technical grade of thifensulfuron methyl is provided in Table C (see Appendix

C )

.

3.3 Pesticide Use Pattern

The end

- use product (EP) proposed for use on chicory is DuPont Basis Herbicide (EPA Registration #352

- 571), a water dispersible granule (WG) formulation containing 25% thifensulfuron methyl (by weight) as an active ingredient (ai) . This EP is a multiple active ingredient (MAI) f

ormulation which also contains 50% rimsulfuron. Rimsulfuron is discussed in a separate document; only thifensulfuron methyl is addressed herein. The proposed use

directions for application to chicory are summarized in Table 3. 3 (below). The proposed use directions are consistent with the information provided in a revised Section B (14 December 2011).

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

1. One post

- emergence broadcast spray on C hrysolite (sulfonylurea

tolerant) variety of chicory (in the 2

- to 8

- true leaf stage) at an application rate of 0.005 pound ai per acre (lb ai/A), or 2. two broadcast spray applications at 0.0025 lb ai/A per application, with

the first at the 2

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

- true leaf stage.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 9 of 38 A pre

- harvest interval (PHI) of 90 days is stipulated. The proposed maximum single/seasonal use rate is 0.005 lb ai/A (0.3 ounce EP/A), and the minimum single use rate is 0.0025 lb ai/A (0.15 oz EP /A). Applications are to be made using ground equipment (applications via aerial equipment or chemigation are prohibited by Section B; chemigation is prohibited in the supplemental label). The inclusion of specific adjuvants in the spray mixture is man dated by the supplemental label directions (adjuvants are allowed, but not required, in Section B). The adjuvants to be added to spray mixtures consist of an NIS, along with a UAN or AS fertilizer. Additionally, Section B stipulates that applications sho uld be made in spray volumes of 19

- 30 GPA. The supplemental label does not mention spray volumes.

TABLE 3 .3 Summary of Proposed Use Pattern for Thifensulfuron Methyl Application to Chicory. Application Timing; Type; and Equipmen t EP [EPA Registration #] Use

Rate (lb ai/A) Max. # of

Uses per

Season Max.

Seasonal

Use Rate (lb ai/A) PHI

(Days) Use Directions and

Limitation s*

1 post

- emergence application (in the 2

- to 8

- true leaf stage) with high numbers of weeds; broadcast; ground. Basis Herbicide

25% ai [352

- 571] 0.005 1 0.005 90 Applications via aerial equipment or chemigation are prohibited. An NIS (0.25%, v/v), along

with a UAN or AS fertilizer (2 qt/A),

must be added to the spray mixture. 2 post

- emergence applications (first at 2

- true leaf stage, second at or after

the 6

- true leaf stage) with low numbers of continually emerging weeds; broadcast; ground. 0.0025 2

* The approved label specifies plant

- back intervals ( PBIs ) of 0 days (for corn and potatoes) to 18 months (for crops not listed on the approved product label).

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

residue data. A revised Section B should be submitte d to comport with the supplemental label regarding the mandatory use of adjuvants. HED concludes that the supplemental label should also be revised to specify that applications are to be made via ground equipment only, and to specify application spray vol umes (19

- 30 GPA), as stated in Section B.

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support IR

- 4’s request ed new use of thifensulfuron methyl on chicory . Humans may be exposed to thifensulfuron methyl through consumption of food and drinking water, since thifensulfuron methyl may be applied directly to growing crops

, and application may result in it reaching surface and ground water sources of drinking water. There are no residential uses of thifensulf uron methyl , so there is not likely to be exposure in residential or non

- occupational settings. In an occupational setting, mixer/loaders may be exposed via the dermal and inhalation routes while handling the pesticide prior to application, and applicator s may be exposed via the same routes during application.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 10 of 38 Additionally, t here is a potential for post

- application dermal exposure o f workers re

- entering

treated fields.

Risk assessments have previously been prepared for the existing uses of thifensulfur on methyl

. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new use of thifensulfuron methyl , but also considers the existing uses for the dietary

exposure assessment.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with US Executive Order 12898, Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations

, ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf )

.

As a part of every pesticide risk assessment, the Office of Pesticide Programs ( OPP ) considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and acti vities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII)

, and are used in pesticide risk asses sments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups

, based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, speciali zed subgroups

, and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products

, and associated risks for adult appli cators and for toddlers, youths and ad ults 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 bys tanders and farm workers

, as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

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

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

included oral subchronic studies in rats, mice and dogs; a chronic/carcinogenicity studies in the rat, and a carcino genicity study in mice; developmental and reproductive toxicity studies; an immunotoxicity study; the complete battery of mutagenicity studies; and a rat metabolism study. Recently submitted neurotoxicity studies are under review.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 11 of 38 The HED Hazard Science Policy Council ( HASPOC) concluded that the route

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

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

In the rat metabolism study, animals receiving an oral dose excreted most of the radioactivity (triazine

- 2

- [ 14 C]) in the urine and feces within 72 hours, with almost no tissue or carcass accumulation. Of the radioactivity eliminated, most was parent

, with five minor metabolite s. In the urine, parent thifensulfuron methyl , at up to approximately 70% of the total dose male/female ( M/F ) accounted for the majority of the excreted radioactivity. Minor metabolites included thifensulfuron methyl acid (2.3/2.5% M/F), O

- demethyl thife nsulfuron methyl (0.5/0.4% M/F), triazine amine (0.5% M/F), and lesser amounts of 2

- ester

- 3

- sulfonamide and thiophene sulfonamide. The fecal metabolite profile was similar to that for urine. Unchanged thifensulfuron methyl is the predominant fecal produc t (17.8/12.3% M/F), with the metabolites being present in approximately the same percentage s as w ere reported in urine. Three

metabolites remain unidentified. None of the metabolites exceeded 5% of the administered dose. There were no major sex differen ces regarding any aspects of metabolism.

4.2.1 Dermal Absorption

Dermal absorption data were not required for thifensulfuron methyl

, and were not submitted.

The 21/28

- day dermal toxicity study in the rat was waived

.

4.3 Toxicological Effects

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

, or organ weights (a reflection of lower body weights). In the one

- year dog study, there were increased absolute liver weights in males

, and relative thyroid/parathyroid weights in females

, with decreased body weight and body weight gain s in females after week 22. There were no gross or histopathological changes reported in any of the studies.

In the rat developmental study, there were no maternal effects at the HDT of 725 mg/kg/day.

The fetal no observed adverse effect level ( NOAEL ) was 159 mg/kg/day, based on decreased mean fetal body weights

, and an increased incidence of small renal papillae at the lowest

observed adverse effect level (LOAEL) of 725 mg/kg/day . This is considered to be an increase in quantitative susceptibility , since fetal effects were observed at a dose which did not cause maternal toxicity

. Although HED does not consider decreased fetal body weights to be the result of a single dose , in the absence of information pertaining to incidence of increased small renal papillae, HED took the conservative and health protective approach of assuming these could be the result of a single dose . The rabbit developmental toxicity study showed a decrease in maternal body weight at the HDT of 511 mg/kg/day

, with the NOAEL being 158 mg/kg/day. There were no developmental effects at the HDT. In the 2

- generation rat reproduction toxicityThifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 12 of 38 study, there were no parental, reproductive or offspring effects observed at doses up to 175 or 180 mg/kg/day in males

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

Neurotoxicity was not observed in any of the submitted studies , including the recently submitted neurotoxicity studies which are currently under review

. Based on the lack of neurotoxicity in the submitted studies, a developmental neurotoxicity study (DNT) is not required. A decrease in spleen weight was noted only in mid

- dose males in the subchronic rat study

, and was considered a potential sign of immunotoxicty. However, in the recently submitted immunotoxicity study in female rats, dosing with thifensulfuron methyl did not affect any immunotoxicity parameters up to the HDT of 529 mg/kg/day. In the absence of dermal toxicity and dermal abs orption studies, HED cannot characterize the potential for thifensulfuron methyl toxicity via the dermal route.

Thifens ulfuron methyl is classified as “not likely to be carcinogenic to humans,” based on an acceptable chronic/carcinogenicity study in rat s
, and a carcinogenicity study in mice at doses that are considered to be adequate, and not excessive, for the determination of carcinogenic potential.

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

mutage nic or clastogenic.

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

There was an increase in quantitative susceptibility observed in the rat developmental toxicity study . However, there was no evidence of potential susceptibility or ne urotoxicity in any of the

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

1 X for the following reasons:

1. The toxicity database is complete, and is adequate to characterize potential toxicity associated with dietary exposure (the only potential exposure route for infants and children)

. 2. HED’s degree of concern for the increased quantitative susceptibility is low because it was only observed in the rat developmental toxicity study, and was observed at doses considerably higher than the doses chosen for risk assessment; therefore HED’s risk assessment is protective of the potential susceptibility

. 3. No neurotoxic signs were observed in any of the toxicity studies submitted to the Agency, including the requ ired neurotoxicity screening battery, and a DNT study is not required.

4. The exposure assessment is conservative, and does not underestimate exposure and risk associated with the existing and proposed uses of

thifensulfuron.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 13 of 38 4.4.1 Completeness of the Toxicology Database

The toxicity database is for thifensulfuron is complete. Required studies have either been received or have been waived (dermal and inhalation route

- specific toxicity studies). In the submitted studies, clear NOAELs and LOAELs have been identified for the effects of concern.

4.4.2 Evidence of Neurotoxicity

There were no signs of neurotoxicity in any of the submitted toxicity studies , including the recently submitted neurotoxicity screening battery . In addition, thifensulfuron meth yl is a member of the sulfonylurea class of herbicides

, which are not known to be neurotoxic. Based on the lack of evidence that this chemical causes neurotoxic effects, HED has concluded that a DNT study is not needed.

4.4.3 Evidence of Sensitivity/Su sceptibility in the Developing or Young Animal

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

, in

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

effects observe d at the NOAEL for the dams consisted of decreased mean fetal body weights

, and an increased incidence of small renal papillae. No increase in qualitative or quantitative susceptibility was observed in the developmental rabbit or 2

- generation rat reproduc tion studies. Although there was evidence of increased quantitative susceptibility, HED has a low degree of concern for the observed susceptibility

, because the doses and endpoints for risk assessment have been selected to be protective of the observed su sceptibility.

4.4.4 Residual Uncertainty in the Exposure Database

The degree of concern for residual uncertainties is low. Acceptable developmental studies in rats and rabbits, and a 2

- generation reproduction study are available for the determination of fetal susceptibility. There is evidence of increased susceptibility of rat fetuses to in utero exposure to thifensulfuron methyl, based on decreased mean fetal body weights, and increased incidence of small renal papillae at the LOAEL of 725 mg/kg/day. Decreased body weights are generally considered to result from multiple exposures to a chemical. The dose selected for multiple dose exposure scenarios is 2 orders of magnitude below the developmental rat LOAEL (725 mg/kg/day v ersu s 7 mg/kg/day). The i ncreased incidence of small renal papillae could result from a single in utero exposure; however, this incidence rate was not much greater than that in the control group, and the dose spacing between the NOAEL and LOAEL is wide (the LOAEL is 4.5X the NOAEL). Evidence from the 2

- generation study in rats provides further support that the developmental NOAEL from the developmental rat study is a true NOAEL, because no reproductive or developmental effects were seen at the highest dose tested of 180 mg/kg/day. The developmental study in the rabbit, and the 2

- generation reproduction stu dy in the rat, show

no indication of fetal or offspring effects. The Agency is confident that the risk to developing fetuses exposed to thifensulfuron methyl will not be underestimated, because the doses selectedThifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 14 of 38 for risk assessment are conservative, and prot ective of the effect s of concern; t here is no indication of increased susceptibility in the rabbit developmental study, n or in the 2

- genera tion reproduction study in rats; and because the studies considered for FQPA analysis were a ll acceptable.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

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

- 49 years of age, based on the fetal effect observed in the rat developmental toxici ty study. The

effect was an increased incidence of small renal papillae which w as observed at a dose that was not maternally toxic. This is considered to be a very conservative health

- protective approach

because the effect is not likely to have occurred after a single dose. However, HED chose the endpoint to be protective of the developing fetus. Although decreased mean fetal body weight was also observed at the LOAEL, the effect is not considered to be the result of a single dose,

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

- dose effects applicable to the general population, including infants and children, an acute dietary endpoint for these populations was not selected.

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

in the 78

- week dietary mouse carcinogenicity study served as the endpoint for risk assessment, with the NOAEL of 4.3 mg/kg/day used as the point of departure (POD). This dose was the

lowe st of the long

- term studies conducted with thifensulfuron methyl (2

- year rat, 1

- year dog

, and

2

- generation rat reproduction)

, and was therefore considered to be protective. Thifensulfuron methyl was considered “not likely to be a human carcinogen,” based o n the lack of evidence of carcinogenicity in rats and mice ; therefore

, cancer risk is not of concern for this chemical.

HED selected an oral study for short

- (1

- 30 days) and intermediate

- term (1

- 6 months) dermal risk assessments, since no dermal toxicit y study was submitted. The endpoint and dose were

selected from the 90

- day study in rats

, with the NOAEL of 7 mg/kg/day based on decreased body weight and body weight gains in males and females

, as well as decreased spleen weights in

males observed at the LOAEL of 177 mg/kg/day. The study was considered to be the most relevant for occupational dermal risk assessment

, based on the duration, and because it had the lowest NOAEL of any of the other studies of similar durations. In the absence of dermal

absor ption data, HED conservatively assumed 100% dermal absorption for thifensulfuron methyl. The same 90

- day study was selected for inhalation exposure and risk assessment since a

route

- specific study was not available. Further more , HED assumed equivalent to xicity via the

oral and inhalation routes.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 15 of 38 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For occupational risk assessment, the dermal (short

- and intermediate

- term durations) and inhalation (short

- and intermediate

- term durations) routes of exposure utilize the same study for

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

determine a total MOE.

4.5.3 Cancer Classification and Risk Assessment Recommendation

There was no evidence of increased incidences of tumors in either the 2

- year rat or the 78

- week

mouse studies. In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March 2005), thifensu lfuron methyl was classified as “not likely to be a human carcinogen.”

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

Assessment

TABLE 4 .5. 4 .1 Summary of Thifensulfuron Methyl Toxicological Doses and Endpoints for Use in Dietary

Exposure and Risk Assessment. Exposure/

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors LOC for Risk

Assessment Study and Toxicological Effects

Acute dietary (females 13

- 49 only) NOAEL =

159 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1 aRfD = 1.59

mg/kg/day

aPAD = 1.59 mg/kg/day Developmental oral toxicity in rats.

LOAEL = 725 mg/kg/day, based on

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

4.3 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1 cRfD = 0.043

mg/kg/day

cPAD = 0.043 mg/kg/day Carcinogenicity oral toxicity in mice.

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

and mice.
Point of Departure (POD) = a data point or estimated point derived from observed dose

- response data, which is used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human

exposures. UF = Uncertainty Factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intra

- species). FQPA SF = FQPA Safety Factor.

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

TABLE 4 .5. 4 .2 Summary of Thifensulfuron Methyl Toxicological Doses and Endpoints for Use in

Occupational Exposure and Risk Assessment. Exposure/

Scenario Point of Departure Uncertainty / FQPA Safety

Factors LOC for

Risk

Assessment Study and Toxicological Effects

Dermal short

- (1

- 30 days) and

intermediate

term (1

- 6 months) NOAEL = 7

mg/kg/day (dermal absorption rate = default of 100%) UF A = 10X

UF H = 10X MOE = 100 90

- Day Oral Toxicity in Rats. LOAEL = 177 mg/kg/day based on decreased body weight and body weight gain in males and females and decreased spleen weights in males.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 16 of 38 TABLE 4 .5. 4 .2 Summary of Thifensulfuron Methyl Toxicological Doses and Endpoints for Use in

Occupational Exposure and Risk Assessment. Exposure/

Scenario Point of Departure Uncertainty / FQPA Safety

Factors LOC for

Risk

Assessment Study and Toxicological Effects

Inhalation short

- (1

- 30 days) and

intermediate

term (1

- 6 months) NOAEL = 7

mg/kg/day ( inhalation toxicity equivalent to oral toxicity ) UF A = 10X

UF H = 10X MOE = 100 90

- Day Oral Toxicity in Rats. LOAEL = 177 mg/kg/day based on decreased body weight and body weight gain in males and females and decreased spleen weights in males.
Point of Departure (POD) = a data point or estimated point derived from observed dose

- response data, which is used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human

exposures. UF = Uncertainty Factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intra

- species). NOAEL = No Observed Adverse

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

Concern.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants is adequately understood, based on acceptable studies with wheat, corn and soybeans. The results of these metabolism studies were recently summarized in a residue chemistry summary document ( D342084 ; D. Dotson; 17 April 2008 ) . The metabolism of thifensulfuron methyl in tested crops proceeds by hydrolysis of the methyl ester and sulfonyl urea moieties, with some demethylation of the triazine methoxy group. HED has determined that

the residue of concern in plant commodit ies is thifensulfuron methyl for the purposes of tolerance expression and risk assessment. The available plant metabolism studies are adequate to support the requested use on chicory

.

The nature of the residue in ruminants is adequately understood, bas ed on the available goat metabolism study. HED has previously concluded in D342084 that the goat metabolism study is adequate in supporting the registered uses of thifensulfuron methyl. This conclusion is based on

the low level of transfer of thifensulfu ron methyl residues to goat matrices, and the lack of detectable residues in livestock feed items, even at exaggerated application rates. HED also concluded that, because no detectable residues of thifensulfuron methyl were found in poultry feed items, a poultry metabolism study is not required. HED has determined that the residue of

concern in ruminant commodities is thifensulfuron methyl for the p urposes of tolerance expression and risk assessment.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 17 of 38 5.1.2 Summary of Environmental Degradation

EFED has provided a drinking water assessment (DWA) for the use of thifensulfuron methyl on chicory ( D 391089 ; W.J. Shaughnessy ; 12 January 2012 ). The primary routes of dissipation for thifensulfuron methyl are acid hydrolysis, photodegradation in water, and aerobic soil metabolism, with half

- lives of 5 to 36 days. The aerobic soil metabolism half

- lives were 27 and 36 days. The field dissipation half

- lives range from 3 to 21 days, and are consistent with the laboratory half

- lives. Longer half

- lives in the field may be associated with cooler temperatures used in the studies. Thifensulfuron methyl is also very mobile, and thus may move laterally to surface water, or downward to groundwater.

5.1.3 Comparison of Metabolic Pathways

In the rat metabolism study, most of the radioactivity (triazine

- 2

- [ 14 C ] ) was recovered in the

urine and feces

, with almost no tissue and carcass accumulation of radioactivity. Of the radioactivity eliminated in the urine and feces, most was parent compound

, with 5 minor metabolites. Of the urinary metabolites, the parent compound accounted for the majority of the excreted radioactivity (55% and 72% in males and females, respectively). Minor metabolites

include d thifensulfuron (2% and 3 %

, M/F ), O

- demethyl thifensu lfuron methyl (0.5% and 0.4%

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

- ester

- 3

- sulfonamide and thiophene sulfonamide. The fecal metabolite profile wa s similar to that of the urine. Unchanged parent wa s the predominant excretory product (18% and 12%

, M/F ). Five

metabolites were identified. These metabolites include thifensulfuron (1% and 2 %

, M/F ), O

demethyl thifensulfuron methyl (0.3% and 0.7%

, M/F ), triazine amine (0.3% and 0.2%

, M/F ),

and lesser amounts of 2

- ester

- 3

- sulfonamide, thiophene su lfonamide, and 2

- acid

- 3

- sulfonamide.

Three metabolites remained unidentified.

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

metabolite s were present at low levels. The metabolic pathway in goats appears to be similar to that observed in plants , and the residues were low to non

- detectable in goat tissues and milk

.

5.1.4 Residues of Concern Summary

The primary routes of dissipation for thifensulfuron methyl are acid hydrolysis, photo

degradation in water, and aerobic soil metabolism

. Thifensulfuron methyl is very mobile, and

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

.

Because thifensulfuron methyl degradates / metabolites were detected only at low levels in water, and in the plant and ruminant metabolism studies , HED has determined that the residue of

concern in plant s, ruminant s
, and drinking water is the parent compound only.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 18 of 38 TABLE 5.1 .4 Summary of Metabolites and Degradates to be Included in Risk Assessments and the

Tolerance Expression.

Matrix Residues Included in Risk

Assessments Residues Included in the Tolerance Expression

Plants Primary crop Thifensulfuron methyl Thifensulfuron methyl

Rotational crop ND 1 NA 2

Livestock Ruminant Thifensulfuron methyl Thifensulfuron methyl

Poultry ND N A Drinking Water Thifensulfuron methyl NA

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

5.2 Food Residue Profile

T here a re adequate data for risk assessment and tolerance assessment

. In the plant metabolism studies, thifensulfuron methyl residues were found to decline rather rapidly. The nature of the residue in livestock is adequately understood, based on the available goat metaboli sm study; however, tolerances for residues in livestock commodities are not needed ( per 40CFR §180.6[a][3])

. This determination is based on the low level of transfer of thifensulfuron methyl residues to goat matrices, and the lack of detectable residues i n livestock feed items, even at exaggerated application rates. B ecause no detectable residues of thifensulfuron methyl were found in poultry feed items, a poultry metabolism study is not required. C onfined rotational crop

studies indicated that neither t hifensulfuron methyl nor its metabolites accumulated to any significant amounts in rotated crops.

The residue data for chicory roots and tops ( leaves ) are adequate to fulfill data requirements for the proposed use. The data reflect the proposed use pat tern (maximum single/seasonal use rate of 0.005 lb ai/A, a PHI of 90 days, and use of both an NIS and a UAN or AS fertilizer in the spray mixture). HED concludes that the proposed tolerances of 0.01 ppm in chicory roots and tops are appropriate ( D 391756; W.T. Drew; 1 June 2012 ).

Residues of thifensulfuron methyl were <0.010 ppm (below the LOQ) in all samples of chicory roots and leaves following foliar application at the proposed maximum use rate, and at an exaggerated (5X) rate . The residue data for chicory are summarized in Table 5.2 (below).Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 19 of 38 TABLE 5 .2 Summary of Residue Data from Chicory Field Trials with Thifensulfuron Methyl. Chicory

Matrix Total Use

Rate (lb ai/A) PHI

(Days) Residue Levels (ppm) 1

n Min. Max. LAFT 2 HAFT 3 Median Mean Std. Dev.

1X Rate

Roots 0.00482

-

0.00509 109

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

Leaves 0.00482

-

0.00509 109

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

5X Rate

Roots 0.0246 134 1 <0.010 <0.010 0.010 0.010 0.010 0.010 NA 4

Leaves 0.0246 134 1 <0.010 <0.010 0.010 0.010 0.010 0.010 NA
1. Except for sample min and max, values reflect per trial averages. n = number of field trials. For calculation of median, mean and standard deviation, the LLMV (0.010 ppm) was used for any results reported as

<LLMV. 2. LAFT = Lowest Average Field Tri al. 3. HAFT = Highest Average Field Trial. 4. NA = Not Applicable (standard deviation is not calculated for n < 3).

5.3 Water Residue Profile

The t hifensulfuron methyl drinking water residues used in risk assessment were provided by
EFED, and incorporated directly into the dietary exposure and risk assessments. Water residues were incorporated in the dietary assessments via entry into the food categories “water, direct, all sources” and “water, indirect, all sources.”

The highest estim ated drinking water concentration (EDWC) for acute scenarios was in surface water, at 0.0044 ppm. This concentration was derived using the FQPA Index Reservoir Screening Tool ( FIRST) model ( D 391089 ; W.J. Shaughnessy ; 12 January 2012). The highest

EDWC fo r chronic scenarios was also in surface water, at 0.0015 ppm. This concentration was also obtained utilizing the FIRST model ( D332797; J. Breithaupt; 26 October 2006 ).

I n order t o be more conservative, the highest of the acute, and the highest of the c hronic EDWCs (among all the various acute and chronic scenarios modeled) were taken from EFED’s DWAs. The acute and chronic EDWCs used in the respective dietary analyses are shown in Tables 5.3. 1

and 5.3. 2 (below), respectively, along with other scenarios assessed by EFED.

TABLE 5. 3 .1 Maximum EDWCs for Drinking Water Risk Assessment, Based upon Ground Application

of Thifensulfuron Methyl.* Drinking Water Source [Model Used] Use [Rate Modeled] Scenario Maximum EDWC (ppb)
Groundwater [SCIGROW] Safflower [0.0188 lbs ai/A] Acute and Chronic 0.0326 Barley, fallow [0.056 lbs ai/A] Acute and Chronic 0.0972Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 20 of 38 TABLE 5. 3 .1 Maximum EDWCs for Drinking Water Risk Assessment, Based upon Ground Application

of Thifensulfuron Methyl.* Drinking Water Source [Model Used] Use [Rate Modeled] Scenario Maximum EDWC (ppb)
Surface water [FIRST] Safflower [0.0188 lbs ai/A] Acute 1.656

Chronic 0.336 Barley, fallow [0.056 lbs ai/A] Acute 4.429

Chronic 0.900

* D 391089 ; W.J. Shaughnessy ; 12 January 2012

.

TABLE 5. 3 .2 Maximum EDWCs for Drinking Water Risk Assessment, Based upon Aerial Application

of Thifensulfuron Methyl.* Drinking Water Source [Model Used] Use [Rate Modeled] Scenario Maximum EDWC (ppb)
Surface water [FIRST] Soybean [ 0.032 lbs ai/A] Acute 3.9

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

The various models used by EFED in conducting DWAs, and their descriptions, are available at

the EPA website via the web link, http://www.epa.gov/oppefed1/models/water/

. No surface or groundwater monitoring data were available for t hifensulfuron methyl

.

The primary routes of dissipation for thifensulfuron methyl are acid hy drolysis, photo

degradation in water

, and aerobic soil metabolism, with half

- lives of 5 to 36 days. The aerobic

soil metabolism half

- lives were 27 days and 36 days. The field dissipation half

- lives range from 3 to 21 days, and are consistent with the laboratory half

- lives. Longer half

- live s in the field may be associated with cooler temperatures used in the studies. Thifensulfuron methyl is also very mobile, and thus may move laterally to surface water or downward to ground water.

The rate of degradation due to chemical processes varies widely. The rate of degradation in pH 5, 7 and 9 aqueous buffered solutions were 5.5, 184, and 145 days, respectively. This indicates acid hydrolysis readily occurs. The major degradate was the thiophene portion of the molecule,

2

- ester

- 3

- sulfonamide, which increased until the end of the study. However, the pH did not affect the rate of degradation in aqueous photolysis studies, based on dark

- control adjusted half

lives of 4.9

- 5.3 days at pH values of 5, 7 and 9. The half

- lives due to soil photolysis were 41

- 54 days, with the major degradates being the intact thiophene (2

- ester

- 3

- sulfonamide) and triazine (triazine amine) rings of the molecule.

Microbial degradation also appears to degrade parent thifensulfuron methyl. The major metabolites were pa rent compound with hydroxyl and formyl group ring substitutions, the thiophene portion of the molecule (cyclized and non

- cyclized), and aminotriazine (the triazine portion of the molecule). The linear half

- lives of the parent compound in aerobic soil were 27 and 36 days. In anaerobic aquatic conditions, the half

- lives ranged from 19 to 29 days, forming

2

- ester

- 3

- sulfonamide. Triazine amine was also formed and increased until the end of the study (365 days). In the field, the degradates O

- demethyl DPX

- M6 316 and 2

- ester

- 3

- sulfonamide were present in all four test sites, and remained in the top 5 inches of soil primarily. In stainlessThifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 21 of 38 steel cylinders of silt loam soil, triazine amine (from applied chlorsulfuron) reached 23.5

- 24.9% of applied chlorsulfuron by 4

- 8 weeks after treatment, and mostly occurred in the top 10 cm.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

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

were conducted for t hifensulfuron methyl ( D 399156; W.T. Drew; 1 June 2012 ) using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

FCIDTM), Version 2.03. This model uses fo od consumption data from the US D A ’s Continuing Surveys of Food Intakes by Individuals (CSFII), collected from 1994 to 1996, and 1998

.

Both the acute and chronic assessments are highly conservative, and assume 100%CT, along

with tolerance

- level residues for all agricultural commodities. T he default processing factor from DEEM 7.81 was used for corn syrup in the analyses.

The LLMV was 0.0 10 ppm in chicory roots and tops (leaves) . T hifensulfuron methyl residues were <LLMV in all samples from both the 1X and 5X field trials. There are no animal feedstuff s associated with the proposed use on chicory

.

The t hifensulfuron methyl drinking water residues used in risk assessment were provided by EFED, and incorporated directly into the dietary exposure and risk assessments. Water residues

we re incorporated in the dietary assessments via entry into the food categories “water, direct, all sources” and “water, indirect, all sources.”

In order to be more conservative, the highest of the acute, and the highest of the chronic EDWCs (among all th e various acute and chronic scenarios modeled) were taken from EFED’s

assessment s. The highest EDWC for acute scenarios was in surface water, at 0.0044 ppm. The highest EDWC for chronic scenarios was also in surface water, at 0.0015 ppm.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Both the acute and chronic d ietary assessments assume 100%CT

.

5.4.3 Acute Dietary Risk Assessment

Based on highly conservative assumptions, the acute dietary risk estimate, at the 95 th percentile of exposure, is less than 1% of the acute population

- adjuste d dose (aPAD) for females 13

- 49 (see

Table 5.4 .3 , below) . This was the only population subgroup for which an acute dietary endpoint

was identified.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 22 of 38 TABLE 5.4. 3 Summary of Acute Dietary Exposure and Risk Estimates for Thifensulfuron Methyl

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

General US Population NA* NA NA

All Infants [< 1]

Children [1

- 2]

Children [3

- 5]

Children [6

- 12]

Youths [13

- 19]

Adults [20

- 49]

Adults [50+]

Females [13

- 49] 1.59 0.000544 <1

* NA = Not Applicable.

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

the acute dietary risk estimate i s not of concern

.

5.4.4 Chronic Dietary Risk Assessment

Based on highly conservative assumptions, the results of the chronic ana lys is are summarized in

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

- 2,

children 3

- 5, children 6

- 12, youth 13

- 19, females 13

- 49, adults 20

- 49, and adults 50+ years. Chronic dietary risk estimates are less than o r equal to 1.4% of the chronic population

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

c hildren 3 to 5 years of age.

TABLE 5 .4.4 Summary of Chronic Dietary Exposure and Risk Estimates for Thifensulfuron Methyl

. Population Subgroup* [Years of Age] DEEM Chronic Dietary Analysis cPAD (mg/kg/day) Exposure Estimate (mg/kg/day) % cPAD

General US Population 0.043 0.000284 <1

All Infants [<1] 0.000487 1.1

Children [1

- 2] 0.000602 1.4

Children [3

- 5] 0.000621 1.4

Children [6

- 12] 0.000447 1.0

Youth [13

- 19] 0.000310 <1

Adults [20

- 49] 0.000239 <1

Adults [50+] 0.000175 <1

Females [13

- 49] 0.000226 <1

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

.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 23 of 38 Generally, the Agency is concerned when risk estimates exceed 100% of the PAD. Therefore, all chronic dietary risk estimates are below HED’s LOC.

5.4.5 Cancer Dietary Risk Assessment

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

cancer risk is not of concern.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed residential uses for t hifensulfuron methyl associated with the subject petition, nor are there any c urrently registered residential uses.

6. 1 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application but, to a lesser extent, could also be a

poten tial source of exposure from the ground application method employed for t hifensulfuron methyl . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices

, State Lead Agencies for pesticide regulation

, and other parties to develop th e best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm ). On a chemical by chemical bas is, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of US pes ticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast , or ground hydraulic methods. After the policy is in place, the Ag ency may impose further refinements in spray drift management practices to reduce off

- target drift of specific products with significant risks

associated with drift.

7.0 Aggregate Exposure/Risk Characterization

7.1 Acute Aggregate Risk

Acute aggregate risk estimates are equivalent to the acute dietary risk estimates discussed in Section 5.4, and are not of concern

.

7.2 Short

- and Intermediate

- Term Ag gregate Risk

Because t here are no existing or proposed residential uses for t hifensulfuron methyl , short

- and

intermediate

- term aggregate risks are not relevant to th i s petition

.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 24 of 38 7.3 Chronic / Long

- Term Aggregate Risk

Chronic aggregate risk estimates are equivalent to the chronic dietary risk estimates discussed in Section 5.4, and are not of concern

.

7.4 Cancer Aggregate Risk

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

cancer risk is not a concern for this chemical.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative r isk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to t hifensulfuron methyl and any other substances

, and t hifensulfuron methyl does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that t hifensulfuron methyl has a common mechanism of toxicity with other substances. For information reg arding EPA’s efforts to determine which chemicals have a common mechanism of toxicity

, and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism

determinations

, and procedures for cumulating effects from substances found to have a common

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- and Intermediate

- Term Handler and Post

- Application Risk

An occupational exposure and risk assessment has been conducted for IR

- 4 ’s proposed new use of the herbicide thifensulfuron methyl on chicory ( D391758; M. Collantes; 16 March 2012) . The requested EP is BASIS Herbicide (EPA Registration #352

- 571 ), formulated as a WG containing 25% of the ai. It is to be applied at a rate of 0 .005 lb ai/A (0.3 o z EP /A) by ground equipment only. Occupational exposure is expected to occur for short

- and intermediate

- term durations, based on the proposed use pattern.

Thifensulfuron methyl is currently registered for use on cereal grains (barle y, field corn, oat, rice, sorghum, triticale and wheat), canola, cotton, flax, soybeans and safflower. In support of these registrations, HED previously assessed (D317652; S. Wang; 20 October 20 06

, and D369037; S.Wang; 10 January 2010 ) the herbicide produ cts Harmony GT, Harmony Extra XP, and Harmony SG ( Registration # 352

- 633) . These three products are formulated as either a WG or soluble granule (SG) and are applied by ground equipment, similar to BASIS. Application rates (0.0188 and 0.0281 lb ai/A) o f t he previously registered products are greater than the proposed application rate for BASIS (0.005 lb ai/A) on chicory. Furthermore, these higher application rates were assessed for large acreage crops using ground equipment (200 A )

, as opposed to theThifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 25 of 38 stan dard row crop acreage (80 A ) applicable to chicory. The LOC for occupational exposure is

a n MOE of 100 ; any MOEs greater than the LOC are not of concern . The occupational exposure and risk estimates for the previous assessments were MOEs ranging from 1,3 00 to 8,900 for occupational handler exposure , and from 970 to 15,000 for post

- application exposure. As all scenarios resulted in MOEs significantly greater than 100

, there were no risks of concern.

HED performed an assessment for the use of thifensulfuron methyl on chicory using the proposed label application rate, revised unit exposures for mixer/loaders and applicators, new assumptions for adult body weight, typical acreage treated for row crops

, and revised transfer

coefficients for root a nd leafy vegetables. The estimated exposures resulted in MOEs ranging from 5,900 to 18,000 for handlers wearing baseline ( long

- sleeved shirt, long pants, socks

, and

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

- application

exposure s . The proposed new use on chicory does not result in risks of concern. The PPE specified on the master label require that applicators and other handlers must wear baseline clothing (long

- sleeved shirt, long pants, socks , and shoes) plus chemica l resistant gloves.

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

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

safflower , but a t a lower application rate (0.005 v ersu s 0.0281 lb a i/ A ) and lower acreage treated, and using conservative baseline unit exposure values, the resulting occupational exposure s will result in higher MOEs than those previously assessed. Since there were no risks of concern

identified for th e registered uses, there are likewise no risks of concern for the use on chicory. Therefore, a new comprehensive assessment for occupational handler exposure is not required. HED concludes that the previous registrations for use of thifensulfuron methyl on cereal grains, canola, cotton, flax, soybeans and safflower are protective of the exposure expected from the proposed use on chicory. Summaries of the estimated occupational exposures provided in

Tables 9.1.1 and 9.1.2 (below) support this conclusio n.

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for thifensulfuron methyl

, primarily because of the low acute inhalation toxicity (Toxicity Category IV), and the low proposed use rate (0.005 lb ai/A). However, there are multiple potential sources of inhalation exposure to individuals performing

post

- application activities in pre viously treated fields. These potential sources include volatilization of pesticides and re

- suspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from

i ts Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 2 March 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the

pro cess 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 t o 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 occupationalThifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 26 of 38 post

- application inhalation exposure asse ssment for thifensulfuron methyl

.

Since post

- application risks were not a concern on day 0 (12 hours following application), the restricted entry interval (REI) is based on the acute toxicity of thifensulfuron methyl technical

material. Thifensulfuron methyl is classified as Toxicity Category III for dermal exposure and for eye irritation, and Toxicity Category IV for inhalation exposure and for dermal irritation. Under the Worker Protection Standard for Agricultural Pesticides, active ingredients clas sified as acute toxicity categories III or IV are assigned a 12

- hour REI. However, the registered master

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

Notice 95

- 3 ( Reduction of Worker protection Standard (W PS) Interim Restricted Entry Intervals (REIs) for Certain Low Risk Pesticides ) . The change from a 12

- hour REI to a 4

- hour REI was made by notification in 1995, and therefore the 4

- hour REI shown on the label is appropriate.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 27 of 38 TABLE 9.1.1 Non

- Cancer Handler Risk Estimates for Use of Thifensulfuron M ethyl on Chicory.

Exposure

Scenario Mitigation

Level 1 Dermal

Unit Exposure 2
(mg/lb ai) Inhalation

Unit Exposure 3
(mg/lb ai) Use Rate

(lb ai/A) Amount

Treated 4
(A/day) Daily

Dermal

Dose 5
(mg/kg/day) Dermal

MOE 6 Daily

Inhalation

Dose 7
(mg/kg/day) Inhalation

MOE 8 Combined

Daily Dose 9
(mg/kg/day) Total

MOE 10

Mixer/ Loader

BASIS

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

Applicator

BASIS Sprays with

Ground

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

1. Baseline PPE consists of long

- sleeve shirt, long pants, shoes, and socks (with no gloves or respirator )

. 2. Baseline Dermal Unit Exposure represents long pants, long

- sleeved shirt, no gloves, open mixing/loading, and open cab tractors, as appropriate.

3. Baseline Inhalation Unit Exposure represents no respiratory protection

, open mixing/loading, and open cab tractors, as appr opriate.

4. Daily acres treated values are from EPA estimates of acreage that could be treated in a single day for each exposure scenario of concern (ExpoSAC Policy 9; 5 July 2000 )

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

. 6. Dermal MOE = NOAEL (7 mg/kg/day) ÷ d ermal d ose (mg/kg/day)

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

. 8. Inhal ation MOE = NOAEL (7 mg/kg/day) ÷ inhalation d ose (mg/kg/day)

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

10. Total MOE = NOAEL (7 mg/kg/d ay ) ÷ combined daily dose. UF = 100.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 28 of 38 TABLE 9.1.2 Post

- A pplication Exposure and Risk for Use of Thifensulfuron M ethyl on Chicory.

Crop Use

Rate (lb ai/A) Work

Activity Transfer

Coefficients 1

(cm 2 /hr) Post

A pplication Day 2 DFR 3

(μg/cm 2 ) Daily Dose 4

(mg/kg/day) MOE 5

Chicory (vegetable root and leafy vegetable 0.005 S couting 210 0 0.0112 0.0000235 390,000

I rrigation 1900 0 0.002128 3,300

1. Transfer coefficient s from ExpoSAC Policy Memo #003

, Agricultural Transfer Coefficients

, 3 June 2011.

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

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

24.7E

- 9 acre/cm 2 ]

. 4. Daily dose = [ DFR (μg/cm 2 ) * TC (cm 2 /hr) * conversion factor (1 mg/1,000 μg) * exposure time (8 hrs/day) * dermal absorption (100%) ] ÷ [ body weight (80 kg) ]

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

10.0 References

Thifensulfuron Methyl: Summary of Hazard and Science Policy Council (HASPOC) Meeting of February 23, 2012 : Recommendations on the need for 28

- day inhalation and 28

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

Letter from Raymond C. Leonard (Associate Coordinator, IR

- 4 HQ) to Barbara Madden (RD/RIMUERB) ; 7 June 2011

.

Ingredient: Thifensulfuron Methyl Title: Label Amendments and Petition for Tolerances on Wheat Forage and Hay, Oat Forage an d Hay, and Barley Hay. Summary of Analytical Chemistry and Residue Data. ; D342084 ; D. Dotson; 17 April 2008.

Tier I Drinking Water Assessment for New Use of Thifensulfuron

- methyl on Chicory ; D 391089 ; W.J. Shaughnessy ; 12 January 2012

.

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

Thifensulfuron Methyl. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 R egistration Action Associated with Food Use of the Herbicide on Chicory

. ; D 399156; W.T. Drew; 1 June 2012

.

Thifensulfuron Methyl. Petition to Establish Permanent Tolerances (Associated with Section 3 Registration) for Residues Resulting from Food Use of the Herbicide on Chicory. Summary of Analytical Chemistry and Residue Data. ; D 391756; W.T. Drew; 1 June 2012

.

Thifensulfuron methyl: Occupa tional and Residential Exposure/Risk Assessment for the New Use on Chicory. ; D391758; M. Collantes; 16 March 2012.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 29 of 38 APPENDIX A: Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

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

TABLE A.1 Toxicology Data Requirements for Thifensulfuron Methyl

.

Test Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

................................ ................................ .... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (Rodent)

................................ ........................... 870.3150 Oral Subchronic (Non

- Rodent)

................................ ................... 870.3200 21/28

- Day Dermal

................................ ................................ ....... 870.3250 90

- Day Dermal

................................ ................................ ............ 870.3465 90

- Day Inhalation

................................ ................................ ....... yes

yes

yes

no

yes yes

yes no*

no

no *

870.3700a Developmental Toxicity (Rodent)

................................ ............... 870.3700b Developmental Toxicity (Non

- Rodent)

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

................................ ................................ ............... yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (Rodent)

................................ ........................... 870.4100b Chronic Toxicity (Non

- Rodent)

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

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

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

................................ ................................ . yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

– Gene Mutation (Bacterial)

................................ .. 870.5300 Mutagenicity

– Gene Mutation (Mammalian)

............................. 870.5375 Mutagenicity

– Structural Chromosomal Aberrations

................. 870.5395 Mutagenicity

– Mammaliam Erythrocyte Micronucleus

............. 870.5550 Mutagenicity

– Unscheduled DNA Synthesis

............................. 870.5915 Mutagenicity

– In Viv o Sister Chromatid Exchange

................... yes

yes

yes

no

no

no yes

yes

yes

yes

yes

no

870.6100a Acute Delayed Neurotoxicity (Hen)

................................ ............ 870.6100b 90

- Day Neurotoxicity (Hen)

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

.............................. 870.6200b 90

- Day Neurotoxicity Screening Battery (Rat)

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

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

no

yes

yes

no no

no

no

no

no

870.7485 General Metabolism

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

................................ ................................ ...... yes

no yes

no

870.7800 Immunotoxicity yes yes * The requirements for the dermal and inhalation toxicity studies were waived by HASPOC.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 30 of 38 A.2 Toxicity Profiles

TABLE A.2.1 Acute Toxicity Profile for Technical Thifensulfuron Methyl.

Guideline

Number Study Type MRID

Number Results Tox Category

870.1100 Acute Oral

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

870.1100 Acute Oral

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

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

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

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

870.2400 Primary Eye Irritation 00143658 Moderate irritation. III

870.2500 Primary Skin Irritation 40921502 Slight irritation. IV

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

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

Guideline

Number Study Title MRID Number Results

870.3100 90

- Day Oral

Toxicity

- Rat (diet) 00143660 (1984)

Acceptable/guideline ppm = 0, 100, 2500, &

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

870.3100 90

- Day Oral

Toxicity

- Mouse (diet) 00161276 (1984)

Acceptable/guideline ppm=0, 500, 2500 &

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

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

LOAEL = could not be determined.

870.3150 13

- Week Oral

Toxicity

- Dog (diet) 00145160 (1984)

Acceptable/guideline ppm = 0, 75, 1500 &

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

- dose males.

870.3200 21/28

- Day

Dermal Toxicity

– Rat No study has been submitted.

870.3700a Developmental

Toxicity

- Rat (gavage) 00143661 (1984)

Acceptable/guideline mg/kg/day = 0, 26, 159, & 725 (analytically

determined doses) Maternal NOAEL = 725 mg/kg/day.

LOAEL = could not be determined. Developmental NOAEL = 159 mg/kg/day. LOAEL = 725 mg/kg/day, based on decreased mean fetal body weights, and increased incidence of small renal papillae.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 31 of 38 TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Thifensulfuron Methyl.

Guideline

Number Study Title MRID Number Results

870.3700b Developmental

Toxicity

- Rabbit (gavage) 00161277 (1984)

Acceptable/guideline mg/kg/day = 0, 22, 158 & 511 (analytically determined doses) Maternal NOAEL = 158 mg/kg/day. LOAEL = 511 mg/kg/day, based on decreased mean body weights. Developmental NOAEL = 511 mg/kg/day.

LO AEL = could not be determined.

870.3800 Reproduction (2

-

Generation)

– Rat (diet) 00161278 (1985)

Acceptable/guideline ppm = 0, 25, 500 &

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

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

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

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

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

LOAEL = cou ld not be determined.

870.4100 Chronic (1 year)

–

Dog (diet) 00161273 (1986)

Acceptable/guideline ppm = 0, 50, 750 &

7500 mg/kg/day (M&F) = 0, 1.25, 18.75 & 187.5 NOAEL = 18.75 (males & females) mg/kg/day. LOAEL = 187.5 (males & females) mg/kg/day,

based on increased liver weights in males, and increased relative thyroid/parathyroid weights in females, with decreased body weight and body weight gain in females after week 22.

870.4200 Carcinogenicity

(18

- Month)

– Mouse (diet) 00161275 (1985)

40340321 (1987 ) (individual pathology sheets) Acceptable/guideline ppm = 0, 25, 750 &

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

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

No evidence of carcinogenicity.

870.4300 Chronic/

Carcinogenicity (2

- Year)

– Rat (diet) 00161274 (1986)

Acceptable/guideline 40340324 (1987) Supplement 40340323 (1987) Supplement ppm = 0, 25, 500 &

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

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

No evidence of carcinogenicity.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 32 of 38 TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Thifensulfuron Methyl.

Guideline

Number Study Title MRID Number Results

870.5100

870.5265 Gene Mutation in

S. typhimurium

and E. coli 00143662 (1984)

Acceptable/guideline No mutagenic response ± S9 activation in TA 1535, 97, 98 & 100. Cytotoxicity seen at HDT.

870.5300 Gene Mutation in

CHO Mammalian

Cells at HGPRT

Locus 00145161 (1987)

403403 25 (1987) Acceptable/guideline No mutations at HDT (7mM), which was above limit of solubility.

870.5375 CHO Cell

Cytogenetics 44710403 (1996)

Acceptable/guideline No evidence of chromosomal aberrations when tested up to cytotoxic or solubility limit

concentrations.

870.5395 In vivo Rat Bone

Marrow

Micronucleus 00145560 (1984)

Acceptable/guideline Negative for clastogenic response at 5000 mg/kg.

870.5550 Unscheduled

DNA Synthesis in Primary

Mammalian Cells 00143663 (1985)

Acceptable/guideline No significant increase in UDS.

870.6200a Acute

Neurotoxicity Screening Battery

– Rat (gavage) 48817901 (2012)

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

870.6200b Subchronic

Neurotoxicity Study

– Rat (diet) 48817902 (2012)

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

870.6300 Developmental

Neurotoxicity Study

– Rat (diet) No study has been submitted.

870.7485 Metabolism Study

– Rat (gavage) 00161281 (1986)

Acceptable/guideline low dose = 20 mg/kg high dose = 2000 mg/kg Most of the radioactivity was recovered in the urine and feces (parent with 5 metabolites) with parent accounting for 55 and 72% for males and females, respectively. Minor metabolites included DPX

M6316 acid (2.3

- 2.4%), O

- demethyl DPX

- M6316 (0.4

- 0.5 %), triazine amine (0.5%) and lesser

amounts of 2

- ester

- e

- sulfonamide and thiophene sulfonamide. Fecal metabolite profile was similar to that in urine. Unchanged DPX

- M6316 acid is the primary excretory product (18 or 12% in males and females, respectivel y). Three metabolites

remained unidentified.

870.7600 Dermal

Absorption

– Rats No study has been submitted.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 33 of 38 TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Thifensulfuron Methyl.

Guideline

Number Study Title MRID Number Results

870.7800 Immunotoxicity

Study

– Rat (diet) 48686101 (2011)

Acceptable/guideline Females only ppm = 0, 250, 750, 2500, 7000 mg/kg/day = 0, 19, 55, 192, 529 Systemic Effects NOAEL = 529 mg/kg/day LOAEL = not attained (no clinical signs of toxicity) Immunotoxicity Effects NOAEL = 529 mg/kg/day LOAEL = not attained (no immunotoxic effects)

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

- Females Age 13

- 49

Study Selected : Developmental Oral Toxicity

– Rat

MRID Number : 00143661 Dose and Endpoint for Establishing aRfD : Maternal NOAEL = 725 mg/kg/day (HDT), with a LOAEL not established. Developmental NOAEL = 159 mg/kg/day, with a LOAEL of 725 mg/kg/day based on increased incidence of small renal papillae. Uncertainty Factors : A UF of 100 was applied to account for interspecies extrapolation (10X), and intra

- species variation (10X). Comments on Study/Endpoints/Uncertainty Factors : The rat developmental study was chosen because the increased incidence of small renal papillae may be the result of a single

exposure. This endpoint is appropriate for females age 13

- 49 because it is based on a developmental effect, and is of appropriate route and duration. However, it is not likely that increased small renal papilla is a single

- dose effect, and the degree to which this effect is adverse is equivocal. Therefore, the Agency considers this to be a conservative endpoint for risk assessment. The remaining studies were considered, but the available endpoints (decreased body weight and/or body weight gain, as well as increas ed liver or organ weights) were not selected, because they either occurred at higher doses, or were the result of multiple exposures.

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

100 (UF)

A.3.2 Acute Reference Dose (aRfD)

- General Population

The risk assessment team determined that there were no single

- dose effects appropriate for acute exposure assessment for the general population. Effects in mature rats, rabbits, mice and dogs (mainly decreases in body weight and body weight ga in) were not considered to be the result of a single exposure to thifensulfuron methyl. Therefore, an acute dietary exposure assessment for the general population is not necessary.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 34 of 38 A.3.3 Chronic Reference Dose (cRfD) `

Study Selected : Combined Chron ic/Carcinogenicity

– Mouse

MRID Numbers : 00161275, 40340321 Dose and Endpoint for Establishing cRfD : NOAEL = 4.3 mg/kg/day in females, with a LOAEL of 128 mg/kg/day, based on a decrease in terminal body weights at the mid

- and high

dose animals.

Unc ertainty Factors : A UF of 100 was applied to account for interspecies extrapolation (10X), and intra

- species variation (10X). Comments on Study/Endpoint/Uncertainty Factors : The chronic dietary endpoint is based on decreased body weights in females on ly. This endpoint was selected because it is of appropriate duration (lifetime study), and was administered via the oral route. This endpoint occurred at a lower dose than chronic effects from the remaining studies, and is, therefore, protective.

Chr onic RfD = 4.3 mg/kg/day (NOAEL) = 0.043 mg/kg/day 100 (UF)

A.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

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

A.3.5 Dermal Exposure (Short

- , Intermediate

- and Long

- Term)

Dermal Absorption Factor: 100%

. There was no dermal penetration study submitted. Therefore, the default absorption factor is 100%.

A.3.6 Occupational Dermal Exposure (Short

- and Intermediate

- Term)

Study Selected : 90

- day Oral Toxicity Study

– Rat

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

- species extrapolation (10X), and intraspecies variation (10X). Comments on Study/Endpoint : This endpoint is based on an oral study. No dermal

studies are available. Therefore, an oral study was selected to estimate risk using a route

- to

route extrapolation. The study and endpoint were selected because they are of an appropriate length for short

- and intermediate

- term exposure, and occur at a lower dose l evel than effects in the remaining subchronic studies. The default rate of 100% dermal absorption is assumed for

risk assessment.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 35 of 38 A.3.7 Occupational Inhalation Exposure (Short

- and Intermediate

- Term)

Study Selected : 90

- day Oral Toxicity Study

– Rat

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

- species variation (10X). Comments About the Study/Endpoint : This endpoint is based on an oral study. No inhalation studies are available. Therefore, an oral study was selected to estima te risk using a

route

- to

- route extrapolation. The study and endpoint were selected because they are of an appropriate length for short

- and intermediate

- term exposure, and occur at a lower dose level than effects in the remaining subchronic studies. Abso rption via inhalation is assumed to be equivalent to absorption via the oral route, so 100% inhalation absorption is assumed for risk

assessment.

A.4 Executive Summaries

A.4.1 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID # 48686101 ), t hifensulfuron methyl (DPX

- M6316) (99.3% ai, L ot # AUG06MA076) was administered to female Crl:CD(SD) rats (10/dose) via diet at dose levels of 0, 250, 750, 2500 or 7000 ppm (0, 19, 55, 192, or 529 mg/kg/day, respectively) for 28 days. The positi ve control animals (10/dose) were injected intraperitoneally with cyclophosphamide (25 mg/kg/day; 10 mL/kg) for 5 days (Days 23

- 28). On Day 23, all test animals received an intravenous injection of sheep red blood cells (SRBCs) (4 x 10 8 cells/mL;

0.5 mL/a nimal). On Day 28, all animals were sacrificed by isoflurane anesthesia and exsanguination. Blood w as obtained from the abdominal vena cava and serum samples were analyzed for anti

- SRBC IgM concentrations with an Enzyme

- Linked Immunosorbent Assay (ELISA). The necropsy included the examinations of all major organs and tissues. Thymus, spleen and brain weights were recorded.

There were no significant treatment

- related effects seen i n clinical signs, body weights , body weight gains, food consumption, or organ (thymus, spleen, and brain) weights. The selections of dose levels and test species/sex were approved by the HED Dose Adequacy review Team (DART, TXR# 0055831).

The systemic toxicity NOAEL is 7000 ppm (529 mg/kg/day), the highest dose tested.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 36 of 38 For immunotoxicity, the anti

- SRBC IgM concentrations in female rats treated with thifensulfuron methyl were not affected by the treatment. Inter

- individual variability was noted in all the treatment groups

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

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

- SRBC IgM response. The positive control group showed significantly lower (

- 45%) ant i

- SRBC IgM concentration compared to the control

, and validated the sensitivity of the assay.

The Natural Killer (NK) cells activity assay was not performed in this study. The toxicology database for thifensulfuron methyl does not show any evidence of treatment

- related effects on the immune system. The overall weight of evidence suggests that this chemical does not directly target the immune system. Under HED guidance, NK cells activity assay is not required at this

time.

Under conditions of this study, the immunotoxicity NOAEL for anti

- SRBC IgM antibody response is 7000 ppm (529 mg/kg/day); the LOAEL was not established

.

This immunotoxicity study is classified accept able/guideline and satisfies the guideline requirement for an immunotoxicity study ( OCSPP 870.7800 )

.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 37 of 38 APPENDIX B : H uman R esearch R eference

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Re

- entry Task Force (ARTF) database are subject to ethics review pursuant to 40CFR §26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at: http:// www.epa.gov/pesticides/science/handler

- exposure

data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.Thifensulfuron Methyl Human Health Risk Assessment DP Barcode D391088

Page 38 of 38 APPENDIX C: Physic oc hem i cal Properties

TABLE 3. 2 Physicochemical Properties of Thifensulfuron Methyl.

Parameter Value Reference

Melting point/range (oC) 171.1 ± 1.2 MRID #47138301 (D342084; D. Dotson; 17 April 2008) pH 4.0 Density (g/cm 3 ) 1.58 ± 0.004 Water solubility (g/L at 25oC) pH 5 0.223 pH 7 2.24 pH 9 8.83 Solvent solubility (g/L at 25oC) Acetone

- 11.9

Acetonitrile

- 7.3

Dichloromethane

- 27.5

Ethanol

- 0.9 Ethyl acetate

- 2.6

Hexane

- <0.1

Methanol

- 2.6 Xylene

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

a ) 4.0 Octanol/water partition coefficient (Log [K OW ]) pH 5 1.06 pH 7 0.0222 pH 9 0.0078 UV/visible absorption (max, λ) pH <2 224, 250 nm pH 7 233 nm pH >10 234 nm