UNITED STATES ENV IRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460



### MEMORAND UM

Date: May 8, 2013 OFFICE OF CH EMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: TriOoxysulfuron-sodium. Human H ea lth Assessme nt Scoping Document in Support of Registration R eview.



### PC C odes: 119009 

### Decision No.: 474095 

### Petition No.: NA 

### Risk Assessment Type: NA 

### TXRNo .: NA



### MRIDNo.: NA 

### DP Ba r code: D408404 

### Registration No.: NA 

### Regulatory Action: Registrat i on Revi ew 

### Case No.: 7028 

### CAS N o

. : 145099-21-4 (free sulfonylurea)

, 199119-58-9 (sodium salt)

, 290332-10

- 4 (sodium salt monohydrate) 40 

### CFR: 180 .5 91



### FROM: Elizabeth Ho lman

, Ph ysica l Sc i e nti s t

### ~**~** Linn e a Hansen
, P h.D

., Toxico l ogist**J** 

### dVV" Risk Assessment Branch II

Matth ew Ll oyd, C !H

# ~**~** Ri s k Assessment Branch VII Heal t h Effects Division (7509P) Office of Pesticide Pro gra m s



### THRO UGH: Christina Swartz, Branch Chief Risk Assessment Branch II

Jess Rowland

, Acti n g Assoc i ate Director

### ka.C2o~ Dana Vogel, Assoc iat e Direc t or 

### "'/'i f"\ · .. _s:::z.____.-- Health Effects Di v i sion (7 509P) \ '\ \**~** Office of Pesticide Programs



### TO: Kelly Ballard

, Chem ical Review Manager P es ticide Re-Evaluation Di vision (75 08P ) 

### Office of Pesticide Pr ograms

Page 1 of23Attached is the Health Effects Division 's (HED) human health risk assessment seeping document for trifloxysul fu ron-sodium to support registration review.

Executive Summary

The Heal th Effects Division trifloxysulfuron-sodiurn Risk Assessment Team has evaluated t he databas e and the most recent human health ri sk assessments for the sulfonylurea herbicide trifloxysulfuron-sodiurn. HED performed this eval ua t ion in order to determine the scope of work

nece ssary to support the established tolerances and existing registrations. The primary sources of information for this evaluation were recent human health risk assessments written for this chemical.

Trifloxy su lfuron- so dium

, a broad-spectrum

, low -application ra te su lfony lurea herbicide, is currently registered for use on numerous agricultural food/feed crops, including almonds, citrus,
cotton (picker variety only), sugarcane and tomatoes. Non-agricul tu ra l uses include sports fields and residential turf grass. Like other herbicide s in th i s class, trifloxysulfuron-sodium acts by inhibiting the plant enzyme acetolactate synthase, re su l t ing in reduced produc t ion of branchedchain amino acids. The primary registered end-use product (EP) is a 75% wettable granule (WG) formulation. Application is via ground and handheld application equi p ment only (groundboom, back pack sprayer and airblast); aerial applications are prohibited. There are no international registrations of trifloxysulfuron-sodium under Codex, or in Canada and Mexico.

The toxicological database for trifloxy su lfuron- sodi um i s complete fo r the purpose of registration review. Although the subchronic inhalation study is listed as being required per the pesticide registration data requirements published in Title 40 Part 158 of the Code of Federa l Regulations (CFR), th e Hazard and Science Policy Council (HASPOC) has determined, based on the availa ble data and the weight of the evidence, that the subchronic inhalation study is not required (TXR# 0056564). HED previously determined that a dermal penetration study i s not required (Memo, D352260, M. Doherty eta!., 11/12/2008). HED continues to s upport this conclusion, and will not req u ire submission of the · s tudy during registration review.

As a class, s u flony lureas exhibit relatively low toxicity, and the database for triflo xysu l furon

sodium is typical of the toxici ty seen with the class overall. Primarily, effects were seen in the kidn eys, the urinary bladder, the liver, heart development

, body weight gain, motor activity, and lung tissue at relativ e ly high dose levels. Trifloxysulfuron-sodium is classified as "not likely to be carcinogenic to humans" and there is no ev id ence of mutagenicity in geno to x icit y st

udies. The required 1 

### OX Food Quality Protection Act (FQP A) safety factor was reduced to IX in the most current risk assessment based on hazard and exposure considerations. During registration review, i t is unlikely that the endpoints, doses, and safety factors used in the most
recent human health risk assessments would be reconsidered, unless new data are received.

The most recent risk assessment (2008; D352260) for trifloxysulfuron-sodium addresses potentia l risks associated with dietary, residential post-application (dermal and oral) and occupational (derma l and inhalation) exposures. In the absence of a route-specific inhalation

Page 2 of23Page 3 of 23

toxicity study, the inhalation risk assessment was based on the point of departure (POD) and the endpoint from an oral toxicity study.

Acute and chroni c dietary exposure w as assessed for all populations. The acute dietary endpoints selected were decreased motor activity in the rat acute neurotoxicity study for the general population

, and heart malformations in the rabbit developmental study for females age 13

- 49 . The chronic dietary endpoint selected was kidney pathology in the rat two

- year chronic toxicity/carcinogenicity study , considered relevant for all populations . Incidental oral exposure was assessed using the rat two

- generation reproductive tox icity study, based on decreased pup weights.

T he dietary exposure database is adequate to support the registration review of trifloxysulfuron

sodium . However, if the dietary endpoints change or new drinking water estimates become available , an updated dietary risk assessment could be needed . Currently, there are no dietary risk estimates of concern for the existing uses of trifloxysulfuron

- sodium

.

Current use s of tr ifloxysulfuron

- sodium on turf are likely limited to commercial or profes sional applicators only, although trifloxysulfuron

- sodium is not a restricted use product

. N on

occupational or residential handlers ’ exposure has not been assessed in the past, but will be evaluated during registration review since “commercial applicators only” language is not enforceable

. Post

- application residential and occupational inhalation exposure was not previously assessed due to the low volatility of trifloxysulfuron

- sodium. All e xposure s are expected to be of short

- or intermediate

- term durati on.

The residential exposure database is adequate to support registration review for trifloxysulfuron

sodium

. Although a turf transferable residue study is required under the updated Part 158 data requirements (2007) for all occupational (e.g., sod far ms, golf courses, parks, and recreational areas) or residential turf uses, HED has determined that this study is not needed for trifloxysulfuron

- sodium. This decision is consistent with current HED policy, given that the risk estimates calculated for the residential post

- application scenarios are well above the l evel of

concern

. An updated residential exposure assessment may be needed during registration review as a result of the revisions to HED’s Residential Exposure Standard Operating Procedures (SOPs). Furthermore, because of the potential for residential bystander exposure t o trifloxysulfuron

- sodium from airblast applications, volatilization, and/or transport from treated

areas (drift) , HED will evaluate the need for a bystander assessment during registration review.

For trifloxysulfuron

- sodium , residential exposures are aggregated with dietary exposures. In the most recent human health risk assessment, there were no aggregate risk estimates of concern ( Memo, D 352260

, M. Doherty et al ., 11/12/2008 ). During registration review, an updated
aggre gate risk assessment may be needed to incorporate residential handler exposure estimates or any potential changes in exposure from drinking water

. The occupational exposure database is adequate to support registration review for trifloxysulfuron

- sodium

. There are no occupational handler and post

- application risk estimates of concern. Although no chemical

- specific dislodgeable foliar residue (DFR) data are available, these data are not required for the current uses based on weight of evidence considerat ions. ThisPage 4 of 23

conclusion may change if new uses and/or higher application rates are proposed. HED will consider the need for an updated occupational exposure assessment during registration review

, but at this time it is not considered likely

.

Introduction

HED evaluated the most recent human health risk assessments for trifloxysulfuron

- sodium in association with the updates to their toxicity, exposure, and usage databases to determine if sufficient data are available and if further updates are needed to support registration review. Recent human health risk assessments include the 200 8 assessm ent for the use of trifloxysulfuron

- sodium on sports fields and residential turfgrass (Memo, D352260, M. Doherty et al ., 11/12/2008 ). In addition, HED considered the latest Agency science policies and risk assessment methodologies. The structure of trifl oxysulfuron

- sodium , as well as its chemical name and other identifiers can be found in the chemical identity table attached to this document (Attachment 1)

. Trifloxysulfuron

- sodium is registered for use on sugarcane, tomato, almonds, citrus, and cotton. The associated t olerances for residues of trifloxysulfuron in the corresponding raw agricultural commodities are listed in 40 CFR 180.591, with values ranging from 0.01 to 1.0 ppm (see Attachment 2 )

. Non

- agricultural uses include sports fields and residen tial turf grass. Current labels for tr ifloxysulfuron

- sodium use on turf contain language stating that the products are to be used by commercial or professional applicators only, although trifloxysulfuron

- sodium is not a restricted use product

. HED notes that this label language is not considered enforceable, and therefore assumes a residential homeowner could purchase and use the product. The end use products and sites are summarized in Attachment 3.

Hazard Identification/ Toxicology

The toxicological database for trifloxysulfuron

- sodium is largely complete , missing only a subchronic inhala tion study and a dermal penetration study . Although the subchronic inhalation study is listed as being required per the pesticide registration data requirements published in Title 40 Part 158 of the Code of Federal Regulations (CFR) , the Hazard and Science Policy Council (HASPOC) has determined, based on the available data and the weight of the evidence

, that the subchronic inhalation study is not re quired ( TXR# 0056564 ). The HASPOC conclusion was based on considerations such as the low acute inhalation toxicity ; the low vapor pressure of trifloxysulfuron

- sodium ; the low risks estimated for occupational workers exposed via the inhalation route with t he use of an oral point of departure ( POD ) ; and the overall conclusion that any potential endpoint such as portal of entry effects from a subchronic inhalation toxicity study would not be more protective than the available POD from an oral study.

A devel opmental neurotoxicity study (DNT) is listed as being conditionally required under Title 40 Part 158 of the CFR. However, HED previously determined that a DNT study is not required based on the overall toxicity database and weight of evidence, including t he lack of neurotoxicity observed in the subchronic neurotoxicity study in rats, as well as subchronic or chronic studies in rats, mice, and dogs ( Memo, D 352260

, M. Doherty et al ., 11/12/2008 ). HED continues to support this conclusion, and will not requir e submission of the study during registration review

.Page 5 of 23

A dermal penetration study is also listed as being conditionally required under Title 40 Part 158 of the CFR. In the submitted 21/28

- day dermal toxicity study , the only treatment

- related effect

was decreased body weight gain in females at the limit dose of 1000 mg/kg/day

. No effects were observed in males and no dermal irritation was noted in males or females. In the most recent risk assessment ( Memo, D 352260

, M. Doherty et al ., 11/12/2008), endpo ints and doses for dermal risk assessment were chosen from oral studies. In the case of the short

- term endpoint, developmental effects in the rabbit were selected (fetal heart abnormalities) and in the case of the intermediate

- term endpoint, lung effects, decreased body weight gains and urinary bladder inflammation were selected from a chronic dog study. In both cases, the doses (no observed adverse effects levels, or NOAELs), selected were lower than the dose observed in the dermal study; the dermal stud y did not evaluate developmental effects and would not have been considered protective of potentially pregnant females. In the case of the intermediate

- term assessment, the use of the oral POD was considered to be protective.

Since oral doses and endpoin ts w ere selected for both short and intermediate

- term dermal risk
assessment , a dermal absorption factor of 30% was applied in this most recent risk assessment. This dermal absorption factor was derived from dermal absorption data available from other sul fonylurea herbicides . During registration review, HED may assess whether this dermal absorption factor needs to be updated based on currently available information on sulfonylureas. Regardless, even if the estimated dermal absorption factor were to chang e, the dermal penetration study is not required at this time and HED does not anticipate risks of concern associated with dermal exposure.

An immunotoxicity study was recently submitted and has been review ed by HED (MRID 48857701). This review indicat es that the study is acceptable and that the results show no evidence of immunotoxicity for trifloxysulfuron

- sodium. These results are consistent with the existing toxicological database for trifloxysulfuron

- sodium which does not indicate that the chemica l targets the immune system . Given the above information, HED concludes that this new immunotoxicity study has no impact on the overall assessment and revisions to the toxicological endpoints will not be required during registration review. The doses and endpoints selected (along with traditional uncertainty factors) are considered protective of potential immunotoxicity.

As a class, suflonylureas exhibit relatively low toxicity, and the database for trifloxysulfuron

sodium is typical of the toxicity seen with the class overall. Primarily, effects were seen in the kidneys, the urinary bladder, the liver, heart development, body weight gain, motor activity, and lung tissue at relatively high dose levels. Other effects observed in the toxicological database included testicular atrophy and organ weight changes (e.g. thymus, spleen); however, these changes were observed at dos es higher than those used as endpoints for risk assessment.

There was no evidence of carcinogenicity seen in mice and rats. Mutagenicity studies were also all negative. An acceptable rat metabolism study is also available.

The LD 50 acute (lethality) studies generally reflected a low level of toxicity: The acute oral study in rats, the acute inhalation in rats, and the primary skin irritation in rabbits were category IV; thePage 6 of 23

acute dermal in rats and the primary eye irritation in rabbits wer e category III. Trifloxysulfuron

sodium is not a dermal sensitizer in the dermal sensitization study with guinea pigs.

There was no evidence of i ncreased pre

- and/or postnatal quantitative and qualitative susceptibility in the rat. Developmental effects observed in th e prenatal developmental rat study (decreased weight gain and increased skeletal variations) and offspring effects observed in the rat reproduction study ( decreased pup weight/weight gain, decreased spleen and thymus weight and increased vag inal patency) were observed at the same doses that caused maternal effects

. There was evidence of increased quantitative susceptibility in the prenatal developmental study in rabbits . The maternal NOAEL was 100 mg/kg/day based on mortality and vaginal/an al bleeding observed at the lowest observed adverse effects level (LOAEL) of 250 mg/kg/day, but at 100 mg/kg/day, fetal heart abnormalities were observed. However, concern for this effect is low because there was a clear NOAEL (50 mg/kg/day) and only a si ngle fetus was affected at the LOAEL. In addition, the endpoint and dose from the study were selected for relevant exposed populations, and therefore the risk assessment is protective of the observed susceptibility.

In the most recent risk assessment, t he required 10X FQPA safety factor was reduced to 1X based on: 1) the completeness of the toxicology database; 2) the lack of increased pre

- and postnatal susceptibility of rats to in utero and/or postnatal exposure in the developmental and reproductive to xicity studies; and 3) the conservative nature of the dietary, occupational, and residential exposure assessments. Although there was evidence of increase quantitative susceptibility in the developmental toxicity study in rabbits, the degree of concern i s low because there was a clear NOAEL for th e effect ; o nly one fetus had the effect at the LOAEL; the effect was characterized as an abnormality (rather than a malformation); and the effect is being used a s

a toxicological endpoint in appropriate risk asse ssments.

These conclusions are not expected to change during registration review. The toxicological endpoints and doses used in the most recent human health risk assessment are summarized in Attachment 4 . The toxicity profile of trifloxysulfuron

- sodium is summarized in Attachment 5

. Conclusions for Hazard Identification/Toxicology

The toxicity database is considered complete for the purpose of registration review, allowing for assessment of potential carcinogenic, mutagenic, d evelopmental, and reproductive effects . In the most recent risk assessment, the FQPA safety factor was reduced to 1X based on a number of factors including the completeness of the database, the lack of susceptibility in developmental and reproduction stud ies in rats, the low level of concern for the quantitative susceptibility observed in the developmental study in rabbits , and the conservative assumptions used in the exposure assessments

. During registration review, HED will consider the appropriateness of the existing endpoints based on current policies and risk assessment methodologies. However, no significant rework is anticipated to the endpoints, doses, and safety factors used for risk
assessment.

. Dietary ExposurePage 7 of 23

Tolerances for trifloxysulfur on

- sodium are listed in 40 CFR 180.591 and range from 0.01 to 1.0
ppm

. The residue chemistry database for trifloxysulfuron

- sodium is complete for the purpose of supporting the currently registered uses. HED has previously determined that the residue of

c oncern in plants and livestock commodities for both tolerance enforcement and risk assessment purposes is parent trifloxysulfuron. In drinking water, the residues of concern for risk assessment purposes are parent trifloxysulfuron, as well as metabolites CGA

- 053052, CGA

382997, and CGA

- 368732.

Dietary exposure estimates in the previous risk assessment assume 100% percent crop treated and direct ly incorporat ed estimated residues in drinking water. Residue estimates for drinking water are from models designed to produce high

- end results. All dietary risk estimates were less than 1% of the acute and chronic population

- adjusted dose and were, therefore, well below HED’s level of concern.

Since the l ast dietary assessment, HED updated its dietary model to incorporate more recent consumption data from the National Health and Nutrition Examination Survey (NHANES). EFED recommended that modeled estimates of residues in drinking water be used in the most recent dietary risk assessment. During registration review, HED will evaluate whether updated drinking water estimates are available and whether these revised estimates make it necessary to complete a new dietary assessment. Depending on the magnitude o f any updates, a new dietary assessment may be required to appropriately estimate risks associated with drinking water
exposure.

Conclusions for Dietary Exposure

The dietary exposure database is adequate to support the existing registrations and tolerances. No new residue chemistry data are required. A new dietary assessment may be needed if one or more of the following occur: new data are identified which impact dietary exposure estimates, including those from drinking water; new toxicological points of departure are identified, including revisions to the FQPA SF; OPP dietary exposure policies and procedures are revised. HED recently updated its dietary model t o incorporate more recent consumption data from the National Health and Nutrition Examination Survey (NHANES). This new version of the model will be used during registration review if a new dietary assessment is needed.

Residential Exposure and Risk

Residential Handlers

Based on the current use pattern, there is potential for residential handler exposure. While trifloxysulfuron

- sodium is likely mainly applied to turf and industrial turf (e.g., golf courses and other non

- residential turf areas such as industrial parks, sod farms, seed farms, and professionally managed sports fields ), it is not restricted from purchase or use by residential handlers. Therefore, during registration review HED will conduct a residential handler assessment using the most r ecent exposure methodology and toxicological endpoints.

Residential Post

- A pplicationPage 8 of 23

Based on the current use pattern, there is only potential for post

- application dermal exposure for recreational golfers and individuals contacting treated turf in commercially treated areas. T rifloxysulfuron

- sodium is restricted from use on residential turf/lawns.

In accordance with the updated Part 158 data requirements (2007), a turf

- transferrable residue (TTR) study is required for all occupational (e.g., sod farms) or residential turf uses ; TTR data are not available for trifloxysulfuron

- sodium. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment

, HED analyzed all of the available TTR data and selected new liquid and granular default values for the fraction of the application rate available for transfer after a turf application (F AR ). This default is 0.2 % for granular formulations

. Of the available TTR studies submi tted to the Agency, the maximum F AR value seen using a granular product was 0.69% or 3.5 times higher than the default residue transfer value. Therefore, HED has decided that a calculated MOE of approximately 10 times higher than the LOC (e.g., an MOE >1, 000 if the LOC = 100) using the default residue transfer values would provide an adequate margin of safety for any potentially higher residues seen in a chemical

- specific TTR study ( HED Memo, 12/12 /12, “ Guidance for Requiring/Waiving Turf Transferrable Res idue (TTR) and Dislodgeable Foliar Residue (DFR) Studies ” ). For the current uses of trifloxysulfuron

- sodium , a TTR study will not be required for Registration Review since estimated dermal MOEs for all residential post

- application scenarios are greater th an 1000. If the use pattern and/or toxicological points of departure change in the future, this requirement may be revisited.

Spray Drift

Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) might

occur as a result of applications of trifloxysulfuron

- sodium. The Agency is in the process of evaluating these types of exposures and might, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate these post

- application exposures into the Agency’s risk assessments. The need for spray drift and volatilization risk assessment for trifloxysulfuron

- sodium will be examined during registration review

Conclusions for Residential Exposure :

A new risk assessment may be needed to address the short

- term handler and post

- application dermal exposure potential for recreational golfers and individuals (adults and children) contacting commercially treated turf

. TTR data are not required for trifloxysulfuron based on a screen of 2012 Residential SOP revisions and the estimated risks from contacting treated turf

. Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and non

- occupational

s ources

. In the 200 8 human health risk asse ssment ( Memo, D 352260

, M. Doherty et al

., 11/12/2008 ), aggregate risks were estimated for the acute (food and drinking water), short

- term (non

- occupational, food and drinking water), and chronic (food and drinking water) exposure duration s . The aggregate risks for each of the exposure durations were below HED’s level ofPage 9 of 23

concern. However
, the 200 8 assessment did not account for recent policy and scientific changes in the disciplinary assessments.

Conclusions for Aggregate Risk Assessment :

For trifloxysulfuron

- sodium , residential exposures are aggregated with dietary exposures. The 200 8 aggregate risk assessment did not identify risks of concern. However, during registration review HED may need to revisit the aggregate risks to include the latest policies for dietary
assessment and methodological changes for calculating non

- occupational exposure potential. During registration review, an updated aggregate risk assessment may be needed to incorporate residential handler exposure estimat es or any potential changes in exposure from drinking water

. Even if new assessments are needed, risks of concern are not anticipated.

Occupational E xpos ure

Trif l oxysulfuron

- sodium is currently registered for use on several agricultural crops as well as on golf course and other professionally managed turf areas. There is potential for short

- and intermediate

- term occupational exposure to t rif l oxysulfuron

- sodium during handling (mixing, loading, and applying) and post

- application activities.

Occupational Handlers A revised occupational handler risk assessment may be needed for trif l oxysulfuron

- sodium. Updated occupational handler exposure assessment may be required under registration review based upon revisions to the Agency’s scenario

- specifi c surrogate handler exposure data. HED assessed occupational handler exposure in a 2003 risk assessment for the following agricultural crops: cotton, citrus, almonds, and transplanted tomatoes ( D284104, M. Doherty, 09/24/ 03)

. Additionally, in 2008 HED conducted an occupational assessment for commercial handlers of trifloxysulfuron for application to turf.

Based on the 2003 risk assessment, the resulting risk estimates for occupational handlers treating agricultural crops were not of concern ( margi ns of exposure, or MOEs

, ranged from 22,000 to 540,000 , whereas MOEs >100 are not of concern ). Occupational exposure and risk assessments for uses on golf course, sod farms athletic fields, industrial and commercial lawns and similar nonresidential areas resulted in risk estimates that were not of concern (MOEs ranged from 75,000 to 3,800,000 a ssuming the baseline level of personal protective equipment, or PPE).

Occupational Post

- A pplication

A revised occupational post

- application risk assessment may be needed for trif l oxysulfuron

sodium. There is a possibility for agricultural workers to have post

- application dermal exposure to trifloxysulfuron

- sodium following its uses. In the absence of chemical

- specific data, the 2003 and 2008 assessments were based on the registered use pattern for agricultural crops ( cotton, sugarcane, citrus, almonds, and tomatoes ) and commercial turf and on the use of default DFR and TTR assumptions

.Page 10 of 23

I n accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has residential or occupational uses that could result in post

application dermal exposure. There are currently no site

- or chemical

- spe cific DFR data for trifloxysulfuron

- sodium. HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a foliar application (F AR ). This default value is 25%. Of the analy zed DFR studies, the maximum F AR value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, a calculated MOE of approximately 4 times higher than the LOC (i.e., an MOE >400 if the LOC = 100) using the default dislodged resi due value would provide an adequate margin of safety for any potentially higher residues seen in a chemical

- specific DFR study ( HED Memo, 12/12 /12,

“ Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studi es ” ). A DFR study (875.2100) for trifloxysulfuron

- sodium will not be required for Registration Review

, since estimated post

- application MOEs for occupational

wo rkers exposed to treated foliage from registered crops are all greater than 400 (MOEs range fro m 2,000 to 290,000)

. The requirement for a DFR study may need to be reconsidered if application rates, use patterns, or points of departure change.

MOEs for the post

- application agricultural scenarios included in the 2003 assessment ranged from 2,000 [ harvesting/thinning citrus] to 290,000 [irrigating cotton]. The 2008 assessment evaluated occupational post

- application exposure for turf maintenance; MOEs for those scenarios ranged from 5,400 to 180,000.

Based on the Agency's current practices, a quant itative occupational post

- application inhalation exposure assessment has not been performed for trif l oxysulfuron

- sodium. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

application activ ities 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 pesti cides 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 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, subsequen tly, 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 trif l oxysulfuron

- sodium.

Conclusions for Occupational Exposure :
There is sufficient information available to assess occupational handler and post

- application
exposures , and the relevant exposure scenarios have been assessed in the 2003 and 2008 exposure assessments. However, not all of the occupational exposure scenarios were assessed based on current ORE policies. During registration review HED will consider the need for a n up

- to

- date handler and post

- application occupational assessment to account for the se policyPage 11 of 23

changes ; if a new assessment is needed, potential changes to the endpoints and safety factors will be included

. Public Health and Pesticide Epidemiology Data

D408657, S. Recore, February 5, 2013

For this evalu ation, both OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases were

cons ulted for pesticide incident data on the active ingredient trifloxysulfuron

- sodium (PC Code : 119009 ). Main IDS incidents involving only one pesticide are considered to provide more certain information about the potential effects of exposure from the pesti cide. When an incident involves more than one pesticide, it is difficult to determine which effects are attributed to the pesticide being considered. The less severe human incidents (minor, unknown, or no effects outcomes) are reported by registrants as counts called aggregate summaries and are recorded in a separate module called Aggregate IDS.

For the M ain IDS, from January 1, 200 7 to December 11, 2012, there were no incidents reported in the database involving trifloxysulfuron

- sodium

.

In A ggregate IDS , from January 1, 200 7 to December 11, 2012, there were 3 reported incidents involving trifloxysulfuron

- sodium

. These incidents were classified as minor severity.

The NIOSH SENSOR database covers 11 states from 1998

- 2009, although reporting varies from state to state. Cases of pesticide

- related illnesses are ascertained from a variety of sources, including: reports from local Poison Control Cente rs, state Department of Labor workers’ compensation claims when reported by physicians, reports from Stat e Departments of Agriculture, and physician reports to s tate Departments of Health . A query of SENSOR

Pesticides 1998

- 2009 found no reported cases for trifloxysulfuron

- sodium.

Trifloxysulfuron

- sodium is not included in the Agricultural Health Survey ( AHS ) , and therefore does not provide information for this report.

Based on the low frequency and low severity of incident cases reported for trifloxysulf uron

sodium , there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the registration review risk assessment.

Tolerance Assessment and International Harmonization

The qualitative nature of the residue for the existing uses has been adequately delineated based
upon adequate metabolism s tudies in lemon, sugarcane, cotton , goats, and hens (memo, M. Doherty

, 08/25/03 , D2 84480 ). The residue definition for risk assessment and tolerance enforcement is the parent compound for both plant and livestock commodities.Page 12 of 23

Livestock feeding studies have not been submitted to date. Based on the feedi ng rate and resulting residues in the livestock metabolism studies, quantifiable residues of trifloxysulfuron are not expected to occur in meat, milk, poultry, and egg matrices. Due to this 40 CFR 180.6(a)(3) situation, HED previously concluded that lives tock feeding studies are not required and no livestock commodity tolerances have been established. Such studies may be required if new uses of trifloxysulfuron

- sodium are sought for crops that are significant livestock feedstuffs. Such revisions would oc cur during new use risk assessments and would likely not need to be considered during registration review.

During registration review, the tolerance expression should be revised to address both coverage and measurement: The tolerance expression for trifloxysulfuron

- sodium should be revised as follows:

“ Tolerances are established for residues of trifloxysulfuron

- sodium , including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specifi ed below is to be determined by measuring only trifloxysulfuron

- sodium .”

Currently, there are no established maximum residue limits (MRLs) for trifloxysulfuron

- sodium in Canada, Mexico, or Codex. Therefore, i nternational harmonization of regulatory leve ls will not be an issue for registration review.

The international residue limit status sheet can be found in Attachment 2

.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. 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 sub groups 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 b y the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, eth nic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary
exposures and risks based on home use of pesticide products for adult applicators and postapplication activities for toddlers, youths, and adults entering or playing on treated areas are evaluated. Further considerations are currently in development as OPP has committe d 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.Page 13 of 23

Endocrine Disruptor Screening Program

A s required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicit y, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As p art of trifloxysulfuron

- sodium ’s most recent registration decision, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p),
t rifloxysulfuron

- sodium is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effec t 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 potenti al to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- r elated effects caused by the substance, and establish a dose

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 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. Trifloxysulfuron

- sodium is not among the group of 58 pesticide active ingredients on the initial list to be screened un der the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call

- ins, requiring the submission of EDSP screening assays for trifloxysulfuron

- sodium

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

.

Cumulative Risk Assessments

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

- sodium and any other substances

, and trifloxysulfuron

- sodi um does not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has not assumed that trifloxysulfuron

- sodium has a common mechanism of toxicity with other substances. For information regardin g EPA’s efforts to determine whichPage 14 of 23

chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations a nd procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

Human Studies

The previous risk assessments rely 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 PHED, the Outdoor Residential Exposure Task Force (ORETF), and the Agricultural Reentry Task Force (A RTF), have been determined to require a review of their ethical conduct, and have received that review.

Data Requirements

None.

R eferences

The Reference s below identify the human health risk assessment and occupational/residential exposure assessment documents that HED has produced for Trifloxysulfuron

- sodium

. Memoranda Relevant to Registration Review of Rimsulfuron Author Barcode

(DP#) Date Title

S. Recore D408657 02/05/13 Trifloxysulfuron

- Sodium : Review of Human Incidents M. Doherty D284104 09/24/03 Human Health Risk Assessment for the Section 3 Registration of Trifloxysulfuron

- sodium on Almond, Citrus, Cotton, Sugarcane, Tomato, and Turf. PP# 1F06280. M. Doherty D352260 11/12/08 Trifloxysulfuron

- Sodium : Human Health Risk Assessment for the Requested Use on Sports Fields and Residential Turfgrass. S. Wang D353060 08/22/08 Trifloxysulfuron

- Sodium : Occupational and Residential Exposure/Risk Assessment of Trifloxysulfuron

- Sodium for Section 3 Registration of a New Use on Turf S. Wang D284482 09/20/03 Occupational and Residential Exposure/Risk Assessment for a New Active Ingredient, Trifloxysulfuron , on Cotton, Sugarcane, Citrus, Almonds, Tomatoes, and Turfgrass. S. Wang. 9/20/03. DP Barcode D284482.

Attachment s Attachment 1. Chemical Identity Table Attachment 2 . International Residue Limit Status Attachment 3. Trifloxysulfuron

- sodium Summary of Use Products and SitesPage 15 of 23

Attachment 4

. Trifloxysulfuron

- sodium Endpoint Selection Tables Attachment 5

. Trifloxysulfuron

- sodium Toxicity Profile TablesPage 16 of 23

Attachment 1

. Chemical Identity Table

Chemical Identity

Common Name Trifloxysulfuron

- sodium

CAS Name N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (2,2,2

- trifluoroethoxy)

- 2

- pyridinesulfonamide sodium salt IUPAC Name N

- [(4,6

- dimethoxy

- 2

- pyrimidinyl)carbamoyl]

- 3

- (2,2,2

- trifluoroethoxy)

- pyridin

- 2

- sulfonamide sodium salt PC Code 119009

Chemical Abstracts Number s 199119

- 58

- 9 (sodium salt); 290332

- 10

- 4 (sodium salt monohydrate); 145099

- 21

- 4 (free sulfonylurea) Registration Review Case No. 7028

Chemical Class Sulfonylurea herbicide Vapor Pressure <1 x 10 - 7 Pa at 25 C
Chemical StructurePage 17 of 23

Attachment 2. International Residue Limit (IRL) Status

International Residue Limits Trifloxysulfuron

- sodium (PC Code 119009 ) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex 40 CFR 180.591 trifloxysulfuron, N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (2,2,2

- trifluoroethoxy)

- 2

- pyridinesulfonamide None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex Almond, hulls 0.02

Almond 0.01 Fruit, citrus, Group 10 0.03
Cotton, undelinted seed 0.05 Cotton, gin byproducts 1.0 Sugarcane 0.01

Tomatoes 0.01

Completed: M. Negussie; 12/18/2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.Page 18 of 23

Attachment 3. Trifloxysulfuron

- sodium Use Products and Sites Summary

Attachment 3 . Use Patterns of Sec. 3/24C End

- use Product Formulations of Trifloxysulfuron

- Sodium

. Registered products & Formul. Types % AI Use Sites and Applicable ORE Reviews Application equipment Comments

100

- 1133 94 Technical Product N/A N/A

100

- 1132 WDG Formulation 75 Citrus, cotton (soil treatments) Almonds, tomatoes, sugarcane, cotton (foliar treatments)

Occupational and Residential Exposure/Risk Assessment for a New Active Ingredient, Trifloxysulfuron , on Cotton, Sugarcane, Citrus, Almonds, Tomatoes, and Turfgrass. S. Wang. 9/20/03. DP Barcode D284482. G round equipment, handheld equipment, backpack do not apply

within: * 14 days of harvest (citrus) * 3 days of harvest (almonds)

100

- 1134 WDG Formulation 75 Ornamentals Turf (golf course, industrial use, and residential)

Trifloxysulfuron

- Sodium : Occupational and Residential Exposure/Risk Assessment of Trifloxysulfuron

- Sodium for Section 3 Registration of a New Use on Turf Ground equipment, Handwand, backpack, handgun No

chemigation

100

- 1163 Granular 0.7 Cotton (soil treatment)

Occupational and Residential Exposure/Risk Assessment for a New Active Ingredient, Trifloxysulfuron , on Cotton, Sugarcane, Citrus, Almonds, Tomatoes, and Turfgrass. S. Wang. 9/20/03. DP Barcode D284482. Ground equipment No aerial or

chemigation

MS110004 WDG Formulation 75 Transplanted tomatoes

Occupational and Residential Exposure/Risk Assessment for a New Active Ingredient, Trifloxysulfuron , on Cotton, Sugarcane, Citrus, Almonds, Tomatoes, and Turfgrass. S. Wang. 9/20/03. DP Barcode D284482. G round equipment, handheld equipment, backpack Registered

in MSPage 19 of 23

Attachment 4

. Trifloxysulfuron

- sodium Endpoint Selection Table s 1

Toxicological Doses and Endpoints for Trifloxysulfuron

- sodium for Use in Dietary and Non

- Occupational Human Health Risk Assessments. Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD, Level

of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (General population) NOAEL = 600

mg/kg/day UF A = 10x

UF H =10x FQPA SF=1x Total UF=100x Acute RfD =6

mg/kg/day

aPAD = 6 mg/kg/day Acute Neurotoxicity Studies in Rats.

LOAEL = 2000 mg/kg based on decreased motor activity on Day 1 and histopathological lesions in nervous system tissues of males and females. Acute Dietary (Females 13

- 49 years of age) Developmental

NOAEL = 50 mg/kg/day UF A = 10x

UF H =10x FQPA SF=1x Total UF=100x Acute RfD =0.5

mg/kg/day

aPAD = 0.5mg/kg/day Developmental Toxicity Study in

Rabbits. Developmental LOAEL=100 mg/kg/day based on increased incidence of abnormally shaped hearts in fetuses. Chronic Dietary (All Populations) NOAEL=23.7

mg/kg/day UF A = 10x

UF H =10x FQPA SF=1x Total UF=100x Chronic RfD

=0.237mg/kg/day

cPAD

= 0.237mg/kg/day Combined Chronic/Carcinogenicity

Rat LOAEL = 99.3 mg/kg/day based on increased tubular atrophy in the kidneys of females.

Incidental oral

- Short

Term (1

- 30 days) Offspring

NOAEL = 79 mg/kg/day UF A = 10x

UF H =10x FQPA SF=1x Total UF=100x Residential LOC

for MOE = 100 2

- Generation Reproduction Study in

Rats . Offspring LOAEL = 631/676 (M/F) mg/kg/day based on decreased pup body weights on Day 21. Incidental oral

Intermediate

Term (1

- 6 months) NOAEL =

45 mg/kg/day UF A = 10x

UF H =10x FQPA SF=1x Total UF=100x Residential LOC

for MOE = 100 1

- Year Chronic Feeding Study in

Dogs. LOAEL = 123/121 (M/F) mg/kg/day based on decreased body weight gain and histopathology in lungs in males and chronic urinary bladder inflammation in females. Dermal

Short

- Term (1

- 30 day s) Oral study

NOAEL= 50 mg/kg/day UF A =10x

UF H =10x

DAF=30 % Occupational

LOC for MOE = 100 Developmental Toxicity Study in

Rabbits. LOAEL = 100 mg/kg/day based on increased incidence of abnormally shaped hearts in fetuses. Dermal

Intermediate

Term (1

- 6 months) Oral study

NOAEL= 45 mg/kg/day UF A =10x

UF H =10x

DAF=30 % Occupational

LOC for MOE = 100 1

- Year Chronic Feeding Study in

Dogs. LOAEL = 123/121 (M/F) mg/kg/day based on decreased body weight gain and histopathology in lungs in males and chronic urinary bladder inflammation in females. Cancer (oral, dermal, inhalation) Classification: “Not Likely to be Carcinogenic to Humans”

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. N/A = not applicable.Page 20 of 23

Summary of Toxicological Doses and Endpoints for Trifloxysulfuron 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

Short

- Term (1

- 30 days) Oral study NOAEL=

50 mg/kg/day UF A =10x

UF H =10x

DAF=30 % Occupational

LOC for MOE = 100 Developmental Toxicity Study in

Rabbits. LOAEL = 100 mg/kg/day based on increased incidence of abnormally shaped hearts in fetuses. Dermal

Intermediate

Term (1

- 6 months) Oral study NOAEL=

45 mg/kg/day UF A =10x

UF H =10x

DAF=30 % Occupational

LOC for MOE = 100 1

- Year Chronic Feeding Study in Dogs.

LOAEL = 123/121 (M/F) mg/kg/day based on decreased body weight gain and histopathology in lungs in males and chronic u rinary bladder inflammation in females. Inhalation Short

- Term (1

- 30 days) Oral study NOAEL=

50 mg/kg/day UF A =10x

UF H =10x

IAF=100% Occupational

LOC for MOE = 100 Developmental Toxicity Study in

Rabbits. LOAEL = 100 mg/kg/day based on increased incidence of abnormally shaped hearts in fetuses. Inhalation Intermediate

Term (1

- 6 months) Oral study NOAEL=

45 mg/kg/day UF A =10x

UF H =10x

IAF=100% Occupational

LOC for MOE = 100 1

- Year Chronic Feeding Study in Dogs

.

LOAEL = 123/121 (M/F) mg/kg/day based on decreased body weight gain and histopathology in lungs in males and chronic urinary bladder inflammation in females. Cancer (oral, dermal, inhalation) Classification: “Not Likely to be Carcinogenic to Hum ans”

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. IAF=inhalation absorption factor.

1 This endpoint selection table was taken directly from the last human health risk assessment ( Memo, D352260, M. Doherty et al ., 11/12/2008 ).Page 21 of 23

Attachment 5

- Trifloxysulfuron

- sodium

– Toxicity Profiles

Table A4

- 1. Acute Toxicity Profile

- Trifloxysulfuron

- sodium Test Material GDLN Study Type MRID Results Tox Category Technical 870.1100 Acute Oral

- rat 45371922 LD 50 > 5000 mg/kg IV Technical 870.1100 Acute Oral

- mouse 45371923 LD 50 > 5000 mg/kg IV Technical 870.1200 Acute Dermal

- rat 45371925 LD 50 > 2000 mg/kg III Technical 870.1300 Acute Inhalation 45371927 LC 50 (M & F): > 5.03 mg/L IV Technical 870.2400 Primary Eye Irritation 45371929 Moderate irritation to the eye III Technical 870.2500 Primary Dermal Irritation 45371931 Mild irritation to the skin IV

Technical 870.2600 Dermal Sensitization (Buehler) 45371933 Negative N/A

Technical 870.2600 Dermal Sensitization (Maximization) 45371934 Negative N/A

Table A4

- 2. Toxicity Profile of Trifloxysulfuron

- sodium Technical Grade Active Ingredient. Guideline No. Study Type Results

870.3100 90

- Day oral toxicity

rodents (rats) NOAEL : 507/549 mg/kg/day (M/F) LOAEL : 1052/1128 mg/kg/day (M/F): M = decreased body weight, decreased body weight gain, equivocal increased testicular atrophy at end of recovery phase; F = decreased body weight, decreased body weigh t gain, equivocal slightly increased histopathology in liver (single cell necrosis, focal necrosis, inflammation, hepatocellular hypertrophy). 870.3100 90

- Day oral toxicity

rodents (mice) NOAEL : 1023/1507 mg/kg/day (M/F) LOAEL : >1023/>1507 mg/kg/day (M/F): M = not attained; F = not attained 870.3150 90

- Day oral toxicity in

nonrodents (dogs) NOAEL :19.8/19.6 mg/kg/day (M/F) LOAEL : 164.2/167.3 mg/kg/day (M/F): M = decreased body weight gain (20%), slight hematological effects, clinical chemistry changes suggesting hepatotoxicity, decreased thymus weight, thymic atrophy, increased glycogen in liver, hemorrhage in mesenteric lymph nodes; F = decreased body weight gain (44%), anemia with extramedullary hematopoiesis in liver/spleen and myeloid hyperplasia i n bone marrow, clinical chemistry changes suggesting hepatotoxicity, decrease thymus weight, thymic atrophy and hyaline tubular change in kidney. 870.3200 21/28

- Day dermal

toxicity (rats) NOAEL : 1000/100 mg/kg/day (M/F) LOAEL : >1000/1000 mg/kg/day(M/F): M = not attained; F = decreased body weight gain. No dermal irritation M/F. 870.3700 Prenatal developmental

in rodents (rats) Maternal NOAEL : 300 mg/kg/day Maternal LOAEL : 1000 mg/kg/day based on decreased food consumption during treatment, decreased body weight gain during post

treatment. Developmental NOAEL : 300 mg/kg/day Developmental LOAEL : 1000 mg/kg/day based on slight decrease in fetal weight, increased skeletal anomalies, increased poor/absent skeletal ossification. 870.3700 Prenatal developmental

in nonrodents (rabbit) Maternal NOAEL : 100 mg/kg/day Maternal LOAEL : 250 mg/kg/day based on increased mortality, increased vaginal/anal bleeding. Developmental NOAEL : 50 mg/kg/dayPage 22 of 23

Table A4

- 2. Toxicity Profile of Trifloxysulfuron

- sodium Technical Grade Active Ingredient. Guideline No. Study Type Results

Developmental LOAEL : 100 mg/kg/day based on abnormally shaped heart (one fe tus at 100 mg/kg/day and 3 fetuses from 2 litters at 250 mg/kg/day). 870.3800 Reproduction and

fertility effects (rat) Parental systemic NOAEL :78.8/83.5 mg/kg/day (M/F) Parental systemic LOAEL :631/676 mg/kg/day (M/F) based on decreased body weight and gain as well as decreased food consumption. Offspring systemic NOAEL :78.8/83.5 mg/kg/day (M/F) Offspring systemic LOAEL : 631/676 mg/kg/day (M/F):decreased pup weight and weight gain, decreased spleen weight, thymus weight and increased vaginal patency. Rep roductive NOAEL :968/1030 mg/kg/day (M/F) Reproductive LOAEL :>968/1030 (M/F) 870.4100a Chronic toxicity rodents

(rat) See 870.4300

870.4100 Chronic toxicity dogs NOAEL : 51.1/45.3 mg/kg/day (M/F) LOAEL : 123/121 mg/kg/day (M/F): M = gray

- white foci in lungs

, fibrous thickening of lung pleura, equivocal decreased body weight gain; F = equivocal increased incidence and severity of chronic urinary bladder inflammation. 870.4200 Carcinogenicity rats See 870.4300 870.4200 Carcinogenicity mice NOAEL :854/112 mg/kg/day (M/F) LOAEL :>854/818 mg/kg/day (M/F): M = not determined; F = decreased body weight, body weight gain and food consumption. Negative for carcinogenicity in M and F. 870.4300 Chronic

feeding/Carcinogenicity
rats NOAEL : 82.6/23.7 mg/kg/day (M/F) LOAEL : 429/99.3 mg/kg/day (M/F): M = decreased body weight and gains, decreased food consumption and increased Leydig cell hyperplasia in testes; F = increased tubular atrophy in kidneys. At 500 mg/kg/day decreased body weight, body weight gain, food cons umption and increased tubular atrophy in kidneys. Negative for carcinogenicity in M and F. 870.5100 Gene Mutation bacterial

reverse mutation assay (S. typhimurium/E. coli) Negative without and with S

- 9 activation.

870.5300 In vitro mammalian cell

forward gene mutation assay (CHO cells/HGPRT locus) Negative without and with S

- 9 activation.

870.5375 In vitro mammalian

cytogenetics assay in CHO cells Negative without and with S

- 9 activation.

870.5395 Cytogenetics

-

mammalian erythrocyte micronucleus test in the

mouse Negative at single oral doses up to 5000 mg/kg.

870.5500 In vitro unscheduled

DNA synthesis (primary rat hepatocytes) Negative response up to 250 μg/mL. Cytotoxicity at 15.63 μg/mL.

870.6200 Acute neurotoxicity

screening battery (rat) NOAEL :<2000 mg/kg/day (M/F) LOAEL : 2000 mg/kg/day (M/F): M&F = decreased motor activity on day 1, histopathological lesions in nervous system tissues. 870.6200 Acute neurotoxicity NOAEL : 2000/600 mg/kg/day (M/F)Page 23 of 23

Table A4

- 2. Toxicity Profile of Trifloxysulfuron

- sodium Technical Grade Active Ingredient. Guideline No. Study Type Results

screening battery (rat) LOAEL : > 2000/2000 mg/kg/day (M/F): M = not attained; F = decreased motor activity on day 1 870.6200 Subchronic

neurotoxicity screening battery (rat) NOAEL :112/553 mg/kg/day (M/F) LOAEL :472/1128 mg/kg/day (M/F): M = decreased body weight, body weight gai n and food consumption.; F = decreased body weight. 870.6300 Developmental

neurotoxicity (rat) No study performed.

870.7485 Metabolism and

pharmacokinetics (rat) Rapidly absorbed and excreted. Most (>87%) of the administered dose (AD) was excreted within 24 hours. After 7 days, very little ( 0.3% of AD) remained in the tissues. Urine was the primary route of excretion in males (50

- 61% of AD) and in females (70

- 80% of AD). Unchanged parent in males (11

- 20% of AD) and in females (37

- 47% of AD) was excreted almost entirely in the urine and only trace amounts were found in the feces. With the exception of the parent, the metabolite profile was similar between the urine and feces. The 2 primary metabolites in both urine and feces were Metabolite J ( desmethyl parent, up to 26% of AD) and Metabolite K (5'hydroxy

- pyrimidine of parent, up to 19% of AD). Other metabolites were Metabolites X, N, F, A and D, each up to 8.2% of the AD in males and up to 4.7% of the AD in females. Several minor metabolites were also identified as Metabolite Q, Metabolite P, guanidine, CGA

- 382997 and CGA

- 368732 (each 4.4% of the AD). 870.7485 Biliary Metabolism (rat) In bile duct cannulated rats, absorption was 84

- 88% of the Administered Dose (AD) at 48 hours. Nearly all o f the AD was excreted within 48 hours. Excretion in urine ranged from 58

- 76%, in bile from 5

- 27%, and in feces was about 6% of the AD. There was no evidence for an enterohepatic circulation. Biotransformation was similar to that in the conventional rat metabolism study. The metabolite profiles in urine, bile fluid and feces were all similar. 870.7600 Dermal Penetration (rat) No study performed. 870.7800 Immunotoxicity The systemic NOAEL is 4000 ppm (1066.6 mg/kg/day); the LOAEL was not established (t ested above the limit dose). No clinical signs of toxicity were observed and all mice survived to scheduled sacrifice. No
treatment

- related effects were found on body, liver, spleen, or thymus weights. Food intake was not affected by treatment.