UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON

, D.C

. 20460



### MEMORANDUM

Date: November 4, 2013 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Flucarbazone-Sodium. Human Health Assessment Scoping Document in Support of Registration Review.



### PC Code: 114009 

### DP Barcode : D411 036 

### Decision No.: t/11.55'2. 

### Registration No.: N/A 

### Petition No.: N/A 

### Regulatory Action: Registration Review Scoping Document 

### Risk Assessment Type: N/A 

### Case No.: 7251 

### TXR No.: N/A 

### CAS Nos.: 181274-17-9, 145026-88

- 6 

### MRID No .: N/A 40 

### CFR: §180.562 

## I

## ~**II ~""\**  

# rcr---;;-t4 { t) FROM: Charles W. Smith III
, Branch**Chief (.___---::~**  •. ,. Monique M. Perron, S.D., Toxicologis t

## ~**-I"~** Julie L. Van Alstine, MPH, Environmental Health Scientist 

### far Risk Assessment Branch 1 (RAB 1) Health Effects Division (HED, 7509P)



### THROUGH: George F. Kramer, Ph.D., Senior Chemist RAB 1 /HED (7 509P)



### TO: Jolene Trujillo, Chemical Re v iew Manager Risk Management and Implementation Branch V Pes ticide Re-Evaluation Di v ision (PRD) (7508P)

Attached is HED's human heal th risk assessment scoping document for flucarbazone-sodium to support Registration Review.___ _ _____**Fluca rb~** **~~~ ~~l~** **l_!l Regi** **stra tion** **~~ ew**  Human**He~ ~~~** **~~m _!_l.!_~** **copi~ ~}?** **?~ ur~** **n!** ___________ _ Execu tive Summary

Flucarbazone-sodium [4,5

- dihydro-3-methoxy-4-methyl-5-oxo-N-[[2(trifluoromethoxy)phenyl]

su lfonyl]-lH-1 ,2,4 -t riazole-1-carboxamide, sodium salt) is a selective herbicide registered in the U.S

. for pre- and post-emergent control ofbroadleaf weeds in wheat, tree nurseries, res idential
tu rf

, golf courses, and sod farms. There are currently six flucarbazone

- sodium containing enduse products sold under the following names: E verest 70% Water Dispersible Granular Herbicide (66330-49), E verest 70% Water Dispersible Granular Herbicide in W. S. Packets (66330-50), ARY

- 0454-105 SC Herbicide (66330-39 1), Pre-Pare SC Herbicide (66330-396), Raze Herbicide (66330-405), and DuPont Finesse Grass & BroadleafHerbicide (352-718). In addition, there are several Special Local Need (SLN) l abels, which allow applications to grasses grown fo r seed.

Flu carbazone

- sodium was first registered for use on wheat i n 2000 (J. Rowell

, 

### et al.; D257851; 8/31 / 2000). The most recent human health risk assessment was performed in 2009 for registration for use i n tree nurseries, on residential turf, on golf courses , and on sod f arms (M

. Clock-Rust, 

### et al. ; D357818 ; 7 / 28 / 2009)

. There are currently no pending PRIA actions for f1 ucarbazone-sodi um.

HED has evaluated the status of the h uman health assessments f or flucarbazone-sodium to determine whether sufficient data are available and whether any updates are needed to support Registration Review

. HED has considered all availab le da ta and human health risk assessments for flucarbazone-sodi um with respect to i ts tox icity

, exposure, and usage databases, and th e most updated Agency science policy and risk assessment methodologies to determine the scope of work necessary to support Registration Review.

The toxicity database for flucarbazone-sod i um is complete with respec t to the 2007 revised 40 CFR Toxicology Data Requirements. No additional toxicological stud i es are currently required

. F lucarbazone -sod i um was categorized as having low acute toxicity via the or a l

, dermal, and inhalation routes ( T oxicity Category IV). It is a slight eye irritant (Tox icity Category III), nonirri tat ing to the sk in and no t a dermal sensitizer. The existing tox ici ty database for flucarbazonesodium indicates tha t the dog is the most sensitive species with subchronic and chronic effects

seen in the thyroid (inc r eased thyrox ine -b indin g capacity and decreased thyroxine l evels) and liver (induction of microsomal liver enzymes, increased liver weights, and histopathological findin gs)

. In a 90-day rat inhalation toxici ty s tudy

, eosinophilic g lobu les (nasal cavity) and
squamous cell metaplasia (larynx) were observed in both sexes

. In a 28-day rabbit dermal toxicity study, no tr eatmen t rela ted effects were seen up to th e limit dose. There was no evidence of incr eased quantitative or qualitative suscept i bility to offspring in the database for flucarbazone-sodium. T he Hazard Iden t ification and Assessment Review Committee (HIARC) classified flucarbazone-sodium as not likely to be carcinogenic to human s by all routes of
exposure based upon lack of evidence of carcinogenicity in rats and mice. F urt her

, genotox ici ty assays indicate that there is no evidence of genotoxicity for fl ucarbazone-sodium

. During Registration Review, HED will reeva l uate the points of departure (PODs) and uncerta i nty facto rs (UFs) for the dietary, residential, and occupational exposure assessments

.
Adequate metabolism (crops, livestock

, and ro tational crops) and magnitude of the residue data

are available to support t he currently regis ter ed uses of fluca rba zone

- sodium. A formal review of a submitted magnitude of the residue in fie ld rotational crops study on wheat

, mustard greens, and turn i p (MRID 46083802) will be conducted during Re gistration Rev i ew. Based on the results of this re view, re-evaluation of the flucarbazone-sodi um rotational crop plant-back Page 2 of26Flucarbazone

- sodium Registration Review Human H ealth Assessment Scoping Document

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Page 3 of 26 

### interval s (PBIs) may be required. Although adequate methods are available for enforcement of the currently established tolera nces , petition method validations (PMVs) of the plant and livestock analytical enforcement methods using Standard Operating Procedures (SOP) ACB

- 019 ( 9/15/ 2008) need to be completed.

The dietary exposure database is adequate to support existing registrations; however, a revised dietary assessment that utilizes the most recent version of the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID)

, incorporates any updated estimated drinking water concentrations and, incorporates any revised toxicological PODs may be required during Registration Review

.

The residential and occupational exposure database s for flucarbazone

- sodium are adequate for Registration Review. R esidential exposure/risk assessments may need to be reassessed during Registration Review to address updates to HED’s exposure policies, including updates to the SOPs for Residential Pesticide Exposure Assessment (Residential SOPs) and assumptions for body weights

. Occupational exposure/risk assessments may need to be reassessed during Registration Review to address updates to HED’s exposure policies, including updates to default exposure data and assumptions for body weights

. Residential and occupati onal exposure/risk assessments may also need to be reassessed if changes to the toxicity endpoints or uncertainty factors are made during Registration Review.

HED did not identify any data deficiencies for flucarbazone

- sodium

. EPA anticipates conducting the following risk assessment updates during Registration Review: Toxicology:

o Reevaluat ion of the toxicity endpoint/dose selection, along with the Food Quality Protection Act (FQPA) Safety Factor (SF) may be required. Residue Chemistry:

o A formal review of the magnitude of the residue in field rotational crops study on wheat, mustard greens, and turnip (MRID 46083802) will be required. Based on the results of this review, reevaluation of the flucarbazone

- sodium rotational crop PBIs may be required.

o PMVs of the plant and livestock analytical enforcement methods using SOP ACB

- 019 ( 9/15/ 2008) n eed to be completed. Dietary Exposure:

o Revised dietary risk assessment may be necessary to reflect the potential revised EDWCs, dietary exposure models, and/or toxic ological PODs. Occupational/Residential Exposure:

o Revised residential exposure/risk assessments may be necessary to reflect updates to HED’s exposure policies, including updates to the Residential SOPs and assumptions for body weights

. Residential exposure/risk assessments may also need to be reassessed if changes to the toxicity endpoints or uncertainty factors are made during Registration Review.

o Revised occupational exposure/risk assessments may be necessary to reflect updates to HED’ s exposure policies, including updates to default exposure data and assumptions for body weights

. O ccupational exposure/risk assessments may also need to be reassessed if changes to the toxicity endpoints or uncertainty factors are made during Registratio n Review.Flucarbazone

- sodium Registration Review Human H ealth Assessment Scoping Document

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Page 4 of 26 

### 1.0 Introduction

Flucarbazone

- sodium [ 4,5

- dihydro

- 3

- methoxy

- 4

- methyl

- 5

- oxo

- N

- [[2(trifluoromethoxy)phenyl] sulfonyl]

- 1 H

- 1,2,4

- triazole

- 1

- carboxamide, sodium salt ] is a selective herbicide registered in the U.S. for pre

- and post

- emergen t con t rol of broadleaf weeds in wheat, t ree n urseries, residential turf, go lf courses, and sod farms. There are currently six flucarbazone

- sodium containing end

use products sold under the following names: Everest 70% Water Dispersible Granular Herbicide (66330

- 4 9), Everest 70% Water Dispersible Granular Herbicide in W. S. Packets (66330

- 50), ARY

- 0454

- 105 SC Herbicide (66330

- 391), Pre

- Pare SC Herbicide (66330

- 396), Raze Herbicide (66330

- 405), and DuPont Finesse Grass & Broadleaf Herbicide (352

- 718). In addition, there are several SLN labels, which allow applications to grasses grown for seed

. Flucarbazone

- sodium products are formulated as water

- dispersible granulars, water

- dispersible granulars in water

- soluble bags, and soluble concentrates. This memo only evaluate s the status of the human health assessments for flucarbazone

- sodium

.

Flucarbazone

- sodium was first registered for use on wheat in 2000 (J. Rowell

, et al. ; D257851; 8/31/2000). The most recent human health risk assessment was performed in 2009 fo r registration for use in t ree n urseries, on residential turf, on go lf courses, and on sod farm s (M. Clock

- Rust
, et al. ; D357818; 7/28/2009)

. There are currently no pending PRIA action s for flucarbazone

- sodium

.

2.0 Hazard Identification/Toxicology

Rad iolabeled flucarbazone was readily absorbed in rats when administered as single or repeated oral doses with maximum plasma concentrations achieved within 30 minutes of dosing. Based on the amount of radioactivity collected by urinary excretion, the fracti on absorbed was relatively low (estimated at 15

- 30%). Less than 1% of the administered dose remained in the carcass and tissues at sacrifice with the highest tissue residues in the liver. Excretion primarily occurred within 24 hours of dosing via the uri ne and feces. The major component in urine and feces was unchanged parent

.

Flucarbazone

- sodium was categorized as having low acute toxicity via the oral, dermal, and inhalation routes (Toxicity Category IV). It is a slight eye irritant (Toxicity Category III), non

irritating to the skin and not a dermal sensitizer. The endpoints and PODs from the most recent hum an health risk assessment for flucarbazone (M. Clock

- Rust
, et al. ; D357818; 7/28/2009) can be found in Attachment C

. The existing toxicity database for flucarbazone indicates that the dog is the most sensitive species with subchronic and chronic effects seen in the thyroid (increased thyroxine

- binding capacity and decreased thyroxine levels) and liver (induction of microsomal liver enzymes, increased liver weights

, and histopathological findings)

. Other findings indicative of a
treatment

- related effect in dogs included histopathological findings in the stomach, body

- weight gain decrements and decreased food consumption.

No treatment

- related adverse effects were seen in subchronic oral toxicity studies in mice. In rats, immunological changes were obse rved in both sexes in subchronic dietary studies and in males at the one

- year interim sacrifice in the combined chronic/carcinogenicity study, but not at study termination. Subsequent studies investigating the immuno toxic potential of flucarbazone

sodium up to and including the limit dose found the immunotoxic potential to be negative at allFlucarbazone

- sodium Registration Review Human H ealth Assessment Scoping Document

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Page 5 of 26 

### dose levels tested. Therefore, the immunological findings in the rat studies are considered to represent slight or moderate non

- specific toxicity rather than immunotoxicity.

In a 90

- day rat inhalation toxicity study, eosinophilic globules (nasal cavity) and squamous cell metaplasia (larynx) were observed in both sexes. In a 28

- day rabbit dermal toxicity study, no treatment related effects were seen up to the limit dose.

There was no evidence of increased quantitative or qualitative susceptibility to offspring in the database for flucarbazone. In the rat developmental toxicity study, no effects we re seen up to the limit dose . In rabbits, developme ntal effects (decreased fetal body weight and increased incidence of delayed ossification) occurred at 500 mg/kg/day while maternal effects (decreased food consumption and increased clinical signs) were observed at 300 mg/kg/day. In the rat reproductive t oxicity study, offspring effects ( reduced pup weights, decreased liver weights, marbl ed liver

, and air filled stomach) occurred in the presence of parental toxicity. Liver weights were decreased in parental males. Decreased uterine weights and increased incidence of severe cecal enlargement were observed in parental females.

In the acute neurotoxicity study in rats, both sexes had transient decreases in motor activity and locomotor activity and an increase in the incidence of low levels of activity in the open field at
t he limit dose

. In the subchronic neurotoxicity study, body weight, body

- weight gain and food consumption were reduced in males at the highest dose tested (1482 mg/kg/day) while no treatment related effects were observed in females. The re were no treatment

- related histopathological findings in the central or peripheral nervous system in the acute or subchronic neurotoxicity studies.

In the combined chronic/carcinogenicity study in rats, adverse effects were observed at 1000 mg/kg/day (t hickened mucosa of the glandular stomach in both sexes; decreased body weight, increased food consumption

, and vacuolation of squamous epithelium in the forestomach in females ; inflammatory infiltrates and immunological effects in males). In the mouse

car cinogenicity study, reduced body weights in both sexes and increased food consumption in males were seen at the highest dose tested ( 2066 and 3212 mg/kg/day in males and females, respectively ). The HIARC (2000) classified flucarbazone

- sodium as not likely to be carcinogenic to humans by all routes of exposure based upon lack of evidence of carcinogenicity in rats and mice. Further, genotoxicity assays indicate that there is no evidence of genotoxicity for flucarbazone

- sodium

.

Conclusions: The toxicity database for flucarbazone

- sodium is complete with respect to the 2007 revised 40 CFR Toxicology Data Requirements

. No additional toxicological studies are currently required. As part of registration review, the endpoints, doses

, and safety factors used in the most recent risk assessment will be re

- evaluated according to current HED policy.

3.0 Residue Chemistry

Flucarbazone

- sodium is registered for use on conifers (plantations and nurseries), grasses grown for seed, ornamental lawns and turf, and wheat. Tolerances are established in 40 CFR §180.562 for residues in/on the following commodities: wheat forage, grain, hay, and straw ; milk ; and the meat, meat byproducts (except liver), and liver of cattle, goat s , hog s , horse s , and sheep

. The nature of the residue in wheat is adequately understood based on the results of two wheat metabolism studies (phenyl

- labeled and triazolinone

- labeled). The metabolism of flucarbazone

-Flucarbazone

- sodium Registration Review Human H ealth Assessment Scoping Document

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Page 6 of 26 

### sodium in wheat was rapid; little or no parent compound wa s found in any of the raw agricultural commodities ( RACs ). The nature of the residues in livestock is understood based on the results of two ruminant metabolism studies (phenyl

- labeled and triazolinone

- labeled) and two poultry metabolism studies (phenyl

- l ab eled and triazolinone

- labeled).

The HED Metabolism Assessment Review Committee (MARC) has determined that the residues of concern in wheat for risk assessment purposes are flucarbazone

- sodium, N

- desmethyl flucarbazone

- sodium, and flucarbazone

- sodium sul fonamide and its conjugates and that the residues of concern for the wheat tolerance expression are flucarbazone

- sodium and N

- desmethyl flucarbazone

- sodium. For rotational crops, the MARC determined that the residues of concern for risk assessment purposes are flucarbazone

- sodium, flucarbazone

- sodium sulfonic acid, flucarbazone

- sodium sulfonamide and its conjugates. For livestock, the r esidues of concern for tolerance enforcement and risk assessment are flucarbazone

- sodium and flucarbazone

- sodium sulfonamide and its conjugates. For drinking water, the residues of concern for risk assessment purposes are flucarbazone

- sodium and flucarbaz one

- sodium sulfonamide (J. Rowell ; D267418; 8/14/ 2000 and J. Tyler ; D271382 ; 3/12/ 2001 ).

In the August 2000 HED risk assessment for the proposed use of flucarbazone

- sodium on wheat, HED requested additional field accumulation data on flucarbazone

- sodium s ulfonamide and its conjugates. These data were requested because the MARC determined that adequate data were not available to rule out flucarbazone

- sodium sulfonamide and its conjugates as residues of concern in ro tational crops (Memo, J. Tyler; D271382 ; 3/12/ 2001 ). Therefore, a 9

- month PBI was placed on the flucarbazone

- sodium labels. A magnitude of the residue in field rotational crops study on wheat, mustard greens, and turnip (MRID 46083802) was subsequently submitted in 2003. A preliminary review o f th e s e data indicates that flucarbazone

- sodium, N

- desmethyl flucarbazone

- sodium, and flucarbazone

- sodium sulfonamide and its conjugates are all less than the LOQ of the analytical method at a PBI of 4 months. During Registration Review, HED will formally review the above study and reevaluate the flucarbazone

- sodium rotational crop PBI s

.
C onfined rotational crop studies (phenyl

- labeled and triazolinone

- labeled) were submitted for wheat , kale, and turnips

, and were reviewed by HED . S torage stability data for turnip tops (≥228 days) and kale (≥258 days) from the phenyl

- UL

14 

### C rotational crop study were not submitted (Memo, J. Tyler; D273561; 3/21/2001). Although these data were previously required, HED has determined that these data are no longer needed b ased on a preliminary review of the submitted rotational field trial studies ( MRID 46083802 ) , which indicated that residues were <LOQ at a PBI of 4 months.

A nalytical enforcement method s for plant and livestock commodities are available for enforcing tolerances . Both of these methods were forwarded to the Analytical Chemistry Branch (ACB)/ Biological and Economics Analysis Division ( J. Rowell ; D260775 ; 11/17/1999 and J. Rowell ; D260776 ; 11/17/ 1999 ) for PMV. HED has not received the results of the PMV . The PMVs of the plant and livestock analytical enforcement methods using SOP ACB

- 019 ( 9/15/ 2008 ) will need to be completed during Registration Review

.

Conclusions : The qualitative nature of flucarbazone

- sodium residues is adequately understood

. The residue chemistry database is sufficient to support the current registrations for flucarbazone

sodium. D uring Registration Review

, HED will formally review the magnitude of the residue in field rotational crops study on wheat, mustard greens, and t urnip

, and reevaluate the flucarbazone

- sodium rotational crop PBI s

. In addition , review of the plant and livestockFlucarbazone

- sodium Registration Review Human H ealth Assessment Scoping Document

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Page 7 of 26 

### analytical enforcement methods using SOP ACB

- 019 ( 9/15/2008 ) will need to be completed during Registration Review.

4.0 Dietary Exposure

Th e most recent acute and chronic dietary exposure and risk assessments for flucarbazone

sodium were performed in conjunction with the 2009 risk assessment for use of flucarbazone

sodium on turf, tree nurseries, Christmas tree farms, golf courses, and other non

- food use sites (J. Van Alstine ; D366918 ; 7/28/2009 and M. Clock

- Rust et al. ; D357818 ; 7/28/2009 ). Tolerances were not recommended for the uses proposed in 2009; however

, an updated dietary assessment was required since the dietary exposure model had been updated since the previous assessment in 2000 (J. Rowell ; D267413 ; 8/17/2000 ).

The most recent (2009) acute and chronic dietary exposure and risk assessments were perf ormed using the DEEM

- FCID model ( ver. 2.03)

, which uses food consumption data from the United States Department of Agriculture Continuing Surveys of Food Intakes by Individuals (1994

- 1996 and 1998). A cancer analysis was not conducted because f lucarbazone

- sodium was classified as “n ot likely to be carcinogenic to humans.”

The acute and chronic assessments utilized anticipated residues (ARs) for wheat, tolerance

- level residues for all remaining commodities, and DEEM (ver. 7.81) default processing factors. Both the acute and chronic assessments assumed 100% crop treated (CT) for all commodities. The Environmental Fate and Effects Division (EFED) provided estimated drinking water residues for the assessment

. The degradates of flucarbazone

- sodium are resist ant to aerobic metabolism in soil; therefore, a value for the concentration of total flucarbazone

- sodium residues in the soil pore water of the top 1

- foot of soil immediately postapplication was estimated. This estimate resulted in the highest concentrati on of total flucarbazone

- sodium residues in water (50 ppb) and was incorporated in the DEEM

- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources” for the acute and chronic assessments.

The acute and chronic dietar y exposure and risk estimates were below HED’s level of concern. The acute dietary analysis was only conducted for females 13

- 49 years old as no acute dietary endpoint was selected for the general population . At the 95 th 

### percentile, the acute dietary risk estimate for females 13

- 49 years old accounted for <1% of the acute population

- adjusted dose (aPAD). The chronic dietary risk estimates are <1% of the chronic population

- adjusted dose (cPAD) for the general U.S. population, and 1% of the cPAD for infants <1 year, the mostly highly exposed population subgroup.

Conclusions: The most recent acute and chronic dietary risk estimates were below HED’s level of concern for the general U.S. population and all population subgroups examined. As part of Registration Review, a new dietary exposure and risk assessment may be required

, utiliz ing the most recent version of DEEM

- FCID. A new dietary exposure and risk assessment should also incorporate any updated estimated drinking water concentrations and any revised toxicological PODs

.

5.0 Residential Exposure

Residential handler and postapplication exposures are expected based on the registered turf uses of flucarbazone

- sodium . Attachment 4 provides a summary of the residential use pattern. The application rates range from 0. 0088

– 0.027 lb ai/A

.Flucarbazone

- sodium Registration Review Human H ealth Assessment Scoping Document

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Page 8 of 26 

### Residential Handlers There is the potential for dermal and inhalation exposure to residential handlers from the currently registered use pattern of flucarbazone

- sodium . In all past risk assessments, no chemical

- specific data were available with which to assess potential exposure to pesticide handlers; therefore, residential handler assessments were based primarily on surrogate unit exposures from the Pesticide Handlers Exposure Database (PHED) and the O utdoor Residential Exposure Task Force ( ORETF ) . Previous risk calculations were based on the maximum application rates and assum ed maximum area treated per day or gallons handled. Residential h andlers were assumed to be wearing shorts and a short

- sleeve shirt.

The most recent human health risk assessment in 2009 included a residential handler assessment for homeowner application of flucarbazone

- sodium to turf ( M. Clock

- Rust
, et al. ; D357818; 7/28/2009)

. None of the application scenarios resulted in risk s of concern as the margins of exposure (MOEs) ranged from 26,000 to 130,000)

.

Residential Postapplication There is the potential for p ost application dermal exposure to adults and children as well as incidental oral exposure to children following applicat ions of flucarbazone

- sodium to residential turf

. There is also the potential for postapplication dermal exposure to adults and children following applications of flucarbazone

- sodium to golf courses.

The 2009 human health risk assessment included residential postapplication assessments for both the residential turf and golf course scenarios. None of the adult postapplication dermal scenarios resulted in risks of concern (MOEs for golfing = 320,000 and MOEs for residential turf = 22,000)

. None of the children postapplication dermal scenarios (MOEs for residential turf = 13,000) or children postapplication incidental oral scenarios (MOEs for hand

- to

- mouth = 84,000; object

- to

- mouth = 330,000; and soil ingestion 26,000,000) r esulted in risks of concern.

In accordance with the updated Part 158 data requirements (2007), a t urf t ransferrable r esidue (TTR) stud y is required when a pesticide has occupational (e.g., sod farms, golf courses) or residential turf uses that could resul t in postapplication dermal exposure. HED analyzed all available TTR data and selected new liquid and granular default value s for the fraction of the

a pplication rate available for transfer after a turf application (F AR 

### ). These values are based on an analysis of 59 TTR studies that used the Modified California Roller Method (36 studies using liquids, 11 studies using wettable powders/ water

- dispersible granules, and 12 studies using granulars). Th ese default value s are 1% for formulations applie d as liquids and 0.2% for granular formulations. Of the analyzed liquid TT R studies, the maximum F AR 

### value seen was 6.1 % or 6.1 times higher than the default residue transfer value. Therefore, HED has decided that a calculated MOE of approximately 10 tim es higher than the level of concern (e.g., an MOE

> 1,0 00 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 TT R study. This policy is desc ribed in Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies (J. Housenger ; 12/12/12). A TT R study is not required at this time for flucarbazone

- sodium since estimated residential postapplication M OEs are greater than 1,0 00.

Spray Drift and Volatilization Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of flucarbazone

- sodium

. The Agency is in the process ofFlucarbazone

- sodium Registration Review Human H ealth Assessment Scoping Document

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Page 9 of 26 

### evaluat ing these types of exposures and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate these postapplication exposures into the Agency's risk assessments. The need for spray drift and volat ilization risk assessment for flucarbazone

- sodium will be examined during R egistration R eview

.

Conclusions : All of th e most recent residential risk estimates (handler and postapplication ) were below HED’s level of concern. The residential exposure database for flucarbazone

- sodium is adequate for Registration Review. Residential exposure/risk assessments for flucarbazone

sodium may need to be reassessed during Registration Review to address updates to HED’s exposure policies, including upda tes to the Residential SOPs and assumptions for body weights

. Residential exposure/risk assessments may also need to be reassessed if changes to the toxicity endpoints or uncertainty factors are made during Registration Review. In addition, t he need for spray drift and volatilization risk assessment s for flucarbazone

- sodium will be examined during R egistration R eview

.

6.0 Aggregate Risk Assessment

The most recent aggregate risk assessment was performed in conjunction with the 2009 human health risk assessment conducted by HED ( M. Clock

- Rust
, et al. ; D357818; 7/28/2009)

. In that
assessment HED determined that acute, short

- term , and chronic aggregate risk assessments were appropriate. The acute and chronic aggregate risk estimate s were equivale nt to the acute and chronic dietary risk assessments. The acute and chronic dietary risk estimates for the general population and all population subgroups did not result in risks of concern (see Section 4.0)

.

For the short

- term aggregate assessment, HED combined the residential adult and children turf
exposures with background chronic dietary exposures. HED concluded that the combined residues of flucarbazone

- sodium from food, drinking water, and residential ex posures do n ot result in short

- term aggregate risks of concern (MOEs ranged from 1,700 to 7,700)

.

Conclusions : All of t he most recent aggregate risk estimates were below HED’s level of

concern. The aggregate risk assessments for flucarbazone

- sodium may need to be reassessed during Registration Review if dietary or residential exposure estimates are updated , or if changes to the toxicity endpoints or uncertainty factors are made during Registration Review.

7 .0 Occupational Exposure

Occupational handler and postapp lication exposures are expected b ased on the registered uses of flucarbazone

- sodium

. Attachment 5 provides a summary of the occupational use pattern. The current registrations allow several SLN registrations. The application rates range from 0.013

– 0.027 ai/A, and applications can be made either pre

- or post

- emergence.
Occupational Handlers There is the potential for dermal and inhalation exposure to occupational handlers from the currently registered use s of flucarbazone

- sodium . In all past risk a ssessments, no chemical

specific data were available with which to assess potential exposure to pesticide handlers; therefore, occupational handler assessments were based primarily on su rrogate unit exposures from PHED and ORETF

. Previous risk calculation s were based on the maximum application rates and assum ed maximum area treated per day or gallons handled. Occupational h andler exposure and risk were calculated at baseline (long pants, a long

- sleeved shirt, no chemical

-Flucarbazone

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Page 10 of 26 

### resistant gloves, and no respirato r) and with personal protective equipment (PPE) when necessary (e.g., chemical

- resistant gloves, respirators, and engineering controls).

The occupational handler assessment for the wheat uses of flucarbazone

- sodium was included in the 2000 human health risk assessment ( J. Rowell

, et al. ; D257851; 8/31/2000) . In addition, the most recent human health risk assessment in 2009 included an occupational handler assessment for application of flucarbazone

- sodium to tree nurseries, residential turf, golf courses, and sod farms ( M. Clock

- Rust
, et al. ; D357818; 7/28/2009). None of the application scenarios for the registered uses resulted in risks of concern (MOEs ranged from 3

, 7 00 to 130,000)

. Occupational Postapplication There is the potential for postapplication dermal exposure to workers following applications of flucarbazone

- sodium from the currently registered use s of flucarbazone

- sodium

. The occupational postapplication assessment for the wheat uses of flucarbazone

- sodium was included in the 2000 human health risk assessment ( J. Rowell

, et al. ; D257851; 8/31/2000) while the most recent human health risk assessment in 2009 included an occupational postapplication assessment for application of flucarbazone

- sodium to tree nur series, turf, golf courses, and sod farms ( M. Clock

- Rust
, et al. ; D357818; 7/28/2009). None of the application scenarios for the registered uses resulted in risks of concern (MOEs ranged from 2,400 to 160,000)

. All c urrent flucarbazone

- sodium labels have a 12

- hour restricted entry interval (REI)

. In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has occupational uses that could result in postapplication dermal exposure. 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 analyzed DFR studies, the maxi mum F AR 

### value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore , HED has decided that a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE > 400 if the LOC = 100) using the default disl odged residue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical

- specific DFR study . This policy is described in Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies ( Memo, J. Housenger, 12/12 /12). A DFR study is not required at this time for flucarbazone

- sodium since estimated occupational postapplication MOEs are greater than 400.

Conclusions: The most recent occupational risk estimates (hand ler and postapplication ) were below HED’s level of concern. The occupational exposure database is adequate to support the Registration Review process for flucarbazone

- sodium

. Occupational exposure/risk assessments for flucarbazone

- sodium may need to be r eassessed during Registration Review to address updates to HED’s exposure policies, including updates to default exposure data used for handler scenarios

, postapplication transfer coefficients, transferable residue assumptions, and assumptions for body wei ghts . Occupational exposure/risk assessments may also need to be reassessed if changes to the toxicity endpoints or uncertainty factors are made during Registration Review.Flucarbazone

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Page 11 of 26 

### 8.0 Public Health and Pesticide Epidemiology Data

An updated review of flucarbazone

- sodium incident reports was recently prepared by HED ( Recore and Evans, D 414420 , 08/ 29 /2013 )

. For this evaluation, both the 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 was consulted for pesticide incident data on the active ingredient flucarbazone

- sodium

. Flucarbazone

- sodium is not included in the Agricul tural Health Study ( AHS ) and therefore no information from AHS was included in this report

.

No flucarbazone

- sodium incidents were found in the IDS or SENSOR databases. Therefore, there does not appear to be a concern for flucarbazone

- sodium at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, a dditional analysis will be included in the preliminary risk assessment.

9 .0 Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR §180.562) and maximum residue limits (MRLs) are summarized in Attachment D . Codex and Mexico do not have residue definitions or established MRLs for flucarbazone

- sodium; however, Mexico does adopt U.S. tolerances for export purposes. The U.S. and Canadian residue definitions are not harmonized. HED is recommending revising th e tolerance expression for flucarbazone

- sodium. The revised expression will not be harmonized with Canada as the Canadian residue definition is for flucarbazone

- sodium only and the U.S. tolerance expression includes additional residues of concern for plan t and livestock commodities

. Many of the U.S. to lerance levels for flucarbazone

- sodium are harmonized with the Canadian MRLs; however, there are also tolerances and MRLs that are not harmonized. In particular, the Canadian MRLs are lower for milk and t he liver of cattle, goats, hogs, horse, and sheep. There are Canadian MRLs for eggs and the meat and meat byproducts of poultry; however, there are no corresponding U.S. tolerances since HED determined that there is no reasonable expectation of finite res idues in poultry (40 CFR § 180.6(a)(3)). Tolerance harmonization may be reexamined during Registration Review.

The current tolerance expressions for plant and livestock commodities as listed in the 40 CFR § 180.562 have not been updated to reflect curren t HED policies. The revised tolerance expression for flucarbazone

- sodium [40 CFR §180.562(a)(1)] for plant commodities should be updated as follows:

“Tolerances are established for residues of flucarbazone

- sodium, including its metabolites and degradat es, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of flucarbazone

- sodium, 4,5

- dihydro

- 3

- methoxy

- 4

- methyl

- 5

- oxo

- N

- [[2

- (trifluoromethoxy)phenyl]sulfonyl]

- 1 H

- 1, 2,4

- triazole

- 1

- carboxamide, sodium salt and its metabolite N

- desmethyl flucarbazone

- sodium (4,5

- dihydro

- 3

- methoxy

- 5

- oxo

- N

- [[2(trifluoromethoxy)phenyl]sulfonyl]

- 1 H

- 1,2,4

- triazole

- 1

- carboxamide), calculated as the stoichiometric equivalent of flucarbazone

- so dium , in or on the commodity .”Flucarbazone

- sodium Registration Review Human H ealth Assessment Scoping Document

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Page 12 of 26 

### The revised tolerance expression for flucarbazone

- sodium [40 CFR §180.562(a)(2)] for livestock commodities should be updated as follows:

“ Tolerances are established for residues of flucarbazone

- sodium [ 5

- dihydro

- 3

- methoxy

4

- methyl

- 5

- oxo

- N

- [[2

- (trifluoromethoxy)phenyl]sulfonyl]

- 1 H

- 1,2,4

- triazole

- 1

- carboxamide, sodium salt ] , including its metabolites and degradates, in or on the commodities in the table below

. Compliance with the tolerance levels specified below is to be de termined by measuring only those flucarbazone

- sodium residues convertible to 2

- (trifluoromethoxy)benzene sulfonamide, expressed as the stoichiometric equivalent of flucarbazone

- sodium , in or on the commodity.”

10 .0 Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the
most recent flucarbazone

- sodium 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.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human health ri sk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate
po tential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.

11.0 Cumulative

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a

c ommon mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as
to flucarbazone

- sodium and any other substances. For the purposes of this assessment , therefore, EPA has not assumed that flucarbazone

- sodium has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesti cide Programs 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/cumula tive/

.

12.0 Endocrine Disruption

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA) , EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemi cals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 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 maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard a ssessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision , EPA reviewed these data and selected the most sensitive e ndpoints for relevant risk assessment scenarios from theFlucarbazone

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Page 13 of 26 

### existing hazard database. However, as required by FFDCA section 408(p), flucarbazone

- 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 effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, a ndrogen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if an y, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

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

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 ingr edients. Flucarbazone

sodium is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of Registration R eview, EPA will issue future EDSP orders/data call

- ins, requiring the submissi on of EDSP screening assays for flucarbazone

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/

.

1 3 .0 Human Studies

Past flucarbazone

- sodium risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their derm al and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED, the ORETF Database , and the Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevaili ng at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.

1 4 .0 Ri sk Assessment Updates and Data Deficiencies

HED did not identify any data deficiencies for flucarbazone

- sodium

. EPA anticipates conducting the following risk assessment updates during Registration Review: Toxicology:

o Reevaluation of the toxicity endpoint/dose selection, along with the FQPA SF may be required. Residue Chemistry:

o A formal review of the magnitude of the residue in field rotational crops study on wheat, mustard greens, and turnip (MRID 46083802) will be required. Based onFlucarbazone

- sodium Registration Review Human H ealth Assessment Scoping Document

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Page 14 of 26 

### the results of this review, reevaluation of the flucarbazone

- sodium rotational crop PBIs may be required.

o PMVs of the plant and livestock analytical enforcement methods using SOP ACB

- 019 ( 9/15/ 2008) need to be completed. Dietary Exposur e:

o Revised dietary risk assessment may be necessary to reflect the potential revised EDWCs, dietary exposure models, and/or toxicological PODs. Occupational/Residential Exposure:

o Revised residential exposure/risk assessments may be necessary to reflect u pdates to HED’s exposure policies, including updates to the Residential SOPs and assumptions for body weights

. Residential exposure/risk assessments may also need to be reassessed if changes to the toxicity endpoints or uncertainty factors are made during Registration Review.

o Revised occupational exposure/risk assessments may be necessary to reflect updates to HED’s exposure policies, including updates to default exposure data and assumptions for body weights

. O ccupational exposure/risk assessments may al so need to be reassessed if changes to the toxicity endpoints or uncertainty factors are made during Registration Review.

1 5 .0 References

Table 1 : Flucarbazone

- Sodium Memoranda Relevant to Registration Review. Author Barcode Date Title

J. Rowell D260775 11/17/ 19 99 PP# 9F06011. New Chemical

- Flucarbazone

- Sodium in/on Wheat. Request for Petition Method Validation. MRID#s 448448

- 41 and 448448

- 25. Barcode D260775. Chemical # 114009. Case 292030. Submission S565287.

J. Rowell D260776 11/17/ 19 99 PP# 9F06011. New Chemical

- Flucarbazone

- Sodium in/on Cattle Tissue and Milk. Request for Petition Method Validation. MRID#s 448448

- 28 and 448448

- 19. Barcode D260776. Chemical # 114009. Case 292030. Submission S565287.

J. Rowell, et al

. D267417 7/20/ 2000 Flucarbazone

- Sodium. Issues to be Presented to the Health Effects Division (HED) Metabolism Assessment Review Committee (MARC) Meeting on 7/27/00. Barcode D267417. Chemical 114009. Case 292030. Submission S565287.

J. Rowell D267418 8/14/ 2000 Flucarbazone

- Sodium. Results of the Health Effects Division (HED) Metabolism Assessment Review Committee (MARC) Meeting of 7/27/00. Barcode D267418. Chemical 114009. Case 292030. Submission S565287.

J. Rowell D267413 8/17/ 2000 Flucarbazone

- Sodium

- Acute and Chronic Dietary Exposure Analyses. PP#: 9F06011. Chemical: 114009. DP Barcode: D267413. Case: 292030. Submission: S565287.

J. Rowell, et al. D267412 8/23/ 2000 PP# 9F06011. Flucarbazone

- Sodium in/on Wheat and Livestock Commodities. Review of Analytical Methodology and Residue Data. MRID#s 448488

- 19 thru

- 21, 448488

- 23 thru

- 28, and 448488

- 34 thru

- 41. Chemical# 114009

. DP Barcode D267412. Case# 292030. Submission# S565287.

J. Rowell

, et al. D257851 8/31/ 2000 PP# 9F06011. Flucarbazone

- Sodium in/on Wheat and Livestock Commodities. Health Effects Division (HED) Risk Assessment. PC Code: 114009. DP Barcode: D257851. Case: 292030. Submission: S565287. J. Rowell D267415 12/1/ 2000 Letter to FDA.

J. Tyler, et al. D272091 1/23/ 2001 ID# 003125

- 00533. Flucarbazone

- Sodium. Issues to be Presented to the Health Effects Division (HED) Metabolism Assessment Review Committee (MARC) Meeting on 1/30/01. Barcode D272091. Chemical 114009. Case 065974. Submission S589907.Flucarbazone

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Page 15 of 26 J. Tyler D271382 3/12/ 2001 Flucarbazone

- Sodium. Results of the Health Effects Division (HED) Metabolism Assessment Review Committee (MARC) Meeting of 1/31/01. Barcode D271382. Chemical 114009. Case 065974. Submission S589907.

J. Tyler D273561 3/21/ 2001 ID#: 003125

- 00533. Flucarbazone

- Sodium in/on Wheat and Livestock Commodities. Review of Amendment Submitted in Response to HED’s Memo Dated 8/23/00. MRID#s None. Chemical 114009. DP Barcode D273561. Case 065974. Submission S589907.

J. Van Alstine D366918 7/28/ 2009 Flucarbazone

- Sodium: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action of an Outdoor Non

- Food Use.

M. Clock

- Rust
, et al. D357818 7/28/ 2009 Flucarbazone

- Sodium. Human health Risk Assessment for Application to Turf, Tree Nurseries, and Christmas Tree Farms, Golf Courses and Other Non

- food Use Sites.
Recore and Evans D414420 08/29/2013 Flucarbazone

- sodium: Tier I Review of Human IncidentsFlucarbazone

- sodium Registration Review Human H ealth Assessment Scoping Document

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Page 16 of 26 

### Attachments:

Attachment A : Flucarbazone

- sodium Chemical Identity Table Attachment B : Flucarbazone

- sodium Acute, Subchronic, and Chronic Toxicity Profile Attachment C : Flucarbazone

- sodium Endpoint Selection Tables Attachment D: Summary of Residential Registered Flucarbazone

- sodium Uses Attachment E: Summary of Occupational Registered Flucarbazone

- sodium Uses Attachment F : Flucarbazone

- sodium International Residue Limit Status SheetFlucarbazone

- sodium Registration Review Human H ealth Assessment Scoping Document

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Page 17 of 26 

### Attachment A : Flucarbazone

- sodium Chemical Identity.

Table A1.1. Flucarbazone

- sodium Nomenclature.
Chemical Structure

Common name Flucarbazone

- sodium Company name Not applicable
Chemical class Triazolone herbicide

IUPAC name sodium 4,5

- dihydro

- 3

- methoxy

- 4

- methyl

- 5

- oxo

- N

- {[2

- (trifluoromethoxy)phenyl]sulfonyl}

- 1 H

- 1,2,4

- triazole

- 1

- carboximidate

CAS name 4,5

- Dihydro

- 3

- methoxy

- 4

- methyl

- 5

- oxo

- N

- ((2

- (trifluoromethoxy)phenyl)sulfonyl)

- 1H

- 1,2,4

- triazole

- 1

- carboxamide sodium salt
CAS # 181274

- 17

- 9

Table A1.2. Physicochemical Properties of the Technical Grade Test Compound: Flucarbazone

- sodium

. Parameter Value Reference Molecular weight 418.29g/mol

Refer to M. Clock

- Rust et al. , D357818, 7/28/2009 Melting point/range 200°C (under decomposition) pH 7.97 (1% solution in water at 22.7 °C) Density 1.59 g/mL at 20 C Vapor pressure <1x10 - 9 mmHg at 20 C
Solubility in Water 44g/L in neutral, acidic, and alkaline conditions at 20 C
Dissociation Constant 1.9 for free acidFlucarbazone

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Page 18 of 26 

### Attachment B: Flucarbazone

- sodium Acute, Subchronic, and Chronic Toxicity Profile

B .1. Toxicology Data Requirements The s tudy requirements (40 CFR 158.340) for flucarbazone

- sodium are presented below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical Required Satisfied 870.1100 Acute Oral Toxicity

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

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

................................ .............. 870.2400 Acute Eye Irritation

................................ ....................... 870.2500 Acute Dermal Irritation

................................ ................. 870.2600 Skin Sensitization

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

yes yes yes yes yes 870.3 100 90

- Day Oral Toxicity (r odent )

................................ ....... 870.3150 90

- Day Oral Toxicity (n onrodent )

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

- Day Dermal Toxicity

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

- Day Dermal Toxicity

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

- Day Inhalation Toxicity

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

no yes yes

yes yes

-- yes 870.3700a Prenatal Developmental Toxicity (rodent)

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

............... 870.3800 Reproduction and Fertility Effects

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

yes yes 870.4100a Chronic Toxicity (rodent)

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

................................ ........ 870.4200a Carcinogenicity (rat)

................................ ...................... 870.4200b Carcinogenicity (mouse)

................................ ................ 870.4300 Combined Chronic Toxicity/Carcinogenicity

................ yes yes yes yes yes yes 1

yes yes 1
yes yes 870.5100 Mutagenicity

— Bacterial Reverse Mutation Test

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

— Mammalian Cell Gene Mutation Test

.. 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5xxx Mutagenicity

— Other Genotoxic Effects

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

yes yes yes 870.6200a Acute Neurotoxicity Screening Battery (rat)

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

- Day Neurotoxicity Screening Battery (rat)

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

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

no yes

yes

-- 870.7485 Metabolism and Pharmacokinetics

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

................................ ........................ 870.7800 Immunotoxicity

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

no yes yes

-- yes 1 The combined chronic toxicity/carcinogenicity study satisfies the requirement of the study.Flucarbazone

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Page 19 of 26 

### B .2. Acute Toxicity Profile

– Flucarbazone

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

870.1100 Acute oral (rat) 44848716 LD 50 > 5000 mg/kg (M) LD 50 > 5000 mg/kg (F) IV

870.1200 Acute dermal (rat) 44848717 LD 50 > 5000 mg/kg (M & F) IV

870.1300 Acute inhalation (rat) 44848718 LC 50 > 5.13 mg/L IV

870.2400 Acute eye irritation (rabbit) 44848719 Slight irritation, cleared by 72 hours III

870.2500 Acute dermal irritation (rabbit) 44848719 No erythema after 24 hours IV

870.2600 Skin sensitization (guinea pig) 44848720 Not a sensitizer NAFlucarbazone

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Page 20 of 26 

### B.3. Subchronic, Chronic, and Other Toxicity Profile

– Flucarbazone

- sodium

Guideline No. Study Type MRID No. (year)/ Classification/Doses Results

870.3100 90

- Day Oral

Toxicity in Rodents (rat) 44848732 (1996)

Acceptable/nonguideline 0, 100, 250, 2500, or 10,000 ppm M: 0, 10.3, 27, 266, or 1134 mg/kg/day F:0, 10.8, 25, 251, or 1150 mg/kg/day NOAEL = 27 mg/kg/day in males and 25 mg/kg/day in females. LOAEL = 266 mg/kg/day in males and 251 mg/kg/d ay in females based on immunological changes in both sexes.

870.3100 90

- Day Oral

Toxicity in Rodents (rat) 44848727, 44848728

(1998) Acceptable/guideline 0, 250, 1000, 4000 or 20,000 ppm M: 0, 17.6, 73.5, 287, or 1,669 mg/kg/day F: 0, 21.4, 102, 358, or 2314 mg/kg/day NOAEL = 73.5 mg/kg/day in males and 102 mg/kg/day in females

. LOAEL = 287 mg/kg/day in males and 358 mg/kg/day in females based on immunological findings in both sexes

.

870.3100 90

- Day Oral

Toxicity in Rodents (mouse) 44848733 (1998)

Acceptable/nonguideline 0, 100, 1000, or 10,000
ppm M: 0, 45.2, 472, or 4,554 mg/kg/day F: 0, 61.2, 603, or 6,429 mg/kg/day NOAEL = >4,554 mg/kg/day in males and 6,429 mg/kg/day in females. LOAEL >4,554 mg/kg/day in males and 6,429 mg/kg/day in females. There were no signs of toxicity attributable to treatment at any dose level.

870.3100 90

- Day Oral

Toxicity in Rodents (mouse) 44848725, 44848726

(1998) Acceptable/guideline 0, 260, 780, 2340, or 7,000 ppm M: 0, 77, 209, 696, or 2,083 mg/kg/day F: 0, 115, 337, 1038, or 3,051 mg/kg/day NOAEL = > 2,083 mg/kg/day in males and 3,051 mg/kg/day in females. LOAEL > 2,083 mg/kg/day in males and 3,051 mg/kg/day in females. There were no signs of toxicity attributable to treatment at any dose level.

870.3150 90

- Day Oral

Toxicity in Non

Rodent (dog) 44848735, 44848736

(1996) Acceptable/nonguideline 0, 1000, 5000, or 50,000
ppm M: 0, 33.1, 164, or 1,614 mg/kg/day F: 0, 36.1, 171, or 1,319 mg/kg/day NOAEL = 164 mg/kg/day in males and 171 mg/kg/day in females. L OAEL = 1,614 mg/kg/day in males and 1,319 mg/kg/day in females based on decreased body weight gain, decreased food consumption, decreased T4 levels and increased thyroxine

binding capacity, induction of microsomal enzymes, increased liver weight and liver histopathology in both sexes.

870.3150 90

- Day Oral

Toxicity in Non

Rodent (dog) 44848737, 44848733

(1998) Acceptable/guideline 0, 1000, 5000, or 50,000
ppm M: 0, 33.8, 162, or 1,674 mg/kg/day F: 0, 35.2, 170, or 1,750 mg/kg/day NOAEL = 33.8 mg/kg/day in males and 35.2 mg/kg/day in females with the occurrence of slight, adaptive induction of hepatic microsomal enzymes. LOAEL = 162 mg/kg/day in males and 170 mg/kg/day in females based on decreased T4 levels, increased thyroxine

- binding capacity , induction of microsomal enzymes, gross pathology and histopathology in the stomach, and histopathology in the liver in both sexes.

870.3200 21/28

- Day Dermal

Toxicity (rat) 44848734 (1996)

Acceptable/guideline M & F: 0, or 1,000 mg/kg/day NOAEL 1,000 mg/kg/day for both sexes. LOAEL >1,000 mg/kg/day

. There were no signs of toxicity attributable to treatment at any dose level.Flucarbazone

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Page 21 of 26 Guideline No. Study Type MRID No. (year)/ Classification/Doses Results

870.3465 90

- Day Inhalation

Toxicity (rat) 46168501 (2003)

Acceptable/non

- guideline

0, 5.0, 30.0, 180, or 500 mg/m 3 (0, 0.005, 0.03, 0.18, or 0.5 mg/L) for 28 days LOAEL = 0.18 mg/L based on eosinophilic globules (nasal cavity) and squamous cell metaplasia (larynx) in males and females

. NOAEL = 0.03 mg/L

.

870.3700a Prenatal

Developmental in Rodent (rat) 44848748, 44848749,

44848750, 44848751, 44848752 (1998) Acceptable/guideline F: 0, 100, 300, or 1,000 mg/kg/day Maternal NOAEL = > 1,000 mg/kg/day LOAEL > 1,000 mg /kg/day

. Developmental NOAEL = > 1,000 mg/kg/day LOAEL > 1,000 mg/kg/day

.

870.3700b Prenatal

Developmental in Non

- Rodent (rabbit) 44848753, 44848801,

44848802 (1997) Acceptable/guideline F: 0, 100, 300, 500, or 1,000 mg/kg/day Maternal NOAEL = 100 mg/kg/day

. LOAEL = 300 mg /kg/day based on decreased food consumption and increased clinical signs

. Developmental NOAEL = 300 mg/kg/day

. LOAEL = 500 mg/kg/day based on decreased fetal weight and increased incidence of delayed fetal ossification

.

870.3800 Reproduction and

Fertility Effects (rat) 44848745, 44848746,

44848747 (1998) Acceptable/guideline 0, 50, 4000, 20,000/12,000 ppm (dose reduced in week 6) F 0 M: 3.5, 287 or 800 mg/kg/day, F 0 F: 4.2, 340, or 991 mg/kg/day F 1 M: 4.2, 346 or 1,059 mg/kg/day F 1 F: 5.5, 453, or 1,249 mg/kg/day Parental/Systemic NOAEL = 287 mg/kg/day for males and 340 mg/kg/ day for females with a slight, increased incidence of moderate cecal enlargement occurring as an adaptive response to treatment. LOAEL = 800 mg/kg/day for males based decreased liver weight and 991 mg/kg/day for females based on decreased uterine weight an d increased incidence of severe cecal enlargement. Reproductive / Offspring NOAEL = 287 mg/kg/day for males and 340 mg/kg/day for females

. LOAEL = 800 mg/kg/day for males and 991 mg/kg/day for females based on reduced pup weights, decreased liver weight in m ale pups, marbled liver, air filled stomach

. 870.4100a Chronic Toxicity

(rodent) See 870.4300 See 870.4300

870.4100b Chronic Toxicity

(dog) 44848729, 44848730,

44848731 (1998) Acceptable/guideline 0, 200, 1000, or 5,000
ppm M: 0, 6.7, 35.9, or 183 mg/kg/day F: 0, 7.43, 37.1, or 187 mg/kg/day NOAEL = 35.9 mg/kg/day in males and 37.1 mg/kg/day in females. LOAEL = 183 mg/kg/day in males and 187 mg/kg/day in females based upon body weight gain depression and increased N

- demethylase levels in both sexes, decreased T4 levels and marginally increased liver weight in females.

870.4200a Carcinogenicity (rat) See 870.4300 See 870.4300

870.4200b Carcinogenicity

(mouse) 44848740, 44848741,

44848742 (1998) Acceptable/guideline 0, 50, 1000, or 7,000 ppm M: 0, 12.2, 275, or 2,066 mg/kg/day F: 0, 22.6, 459, or 3,212 mg/kg/day NOAEL = 275 mg/kg/day in males and 459 mg/kg/day in females

. LOAEL = 2,066 mg/kg/day in males and 3,212 mg/kg/day in females based on decreased body weight in both sexes and increased food consumption in males. No evidence of carcinogenicity.Flucarbazone

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Page 22 of 26 Guideline No. Study Type MRID No. (year)/ Classification/Doses Results

870.4300 Combined Chronic

Toxicity/ Carcinogenicity (rat) 44848739, 44848743,

44848744 (1998) Acceptable/guideline M/F: 0, 2.5, 7.5, 125, or 1,000 mg/kg/day NOAEL = 125 mg/kg/day in males and females

. LOAEL = 1,000 mg/kg/day in males and females based on decreased body weight and increased food consumption in females, thickened mucosa of the glandular stomach in both sexes, inflammatory infiltrates (males), v acuolation of the squamous epithelium in the fore

- stomach (females) and immunological effects in males. No evidence of carcinogenicity.

870.5100 Bacterial reverse

mutation 44848803 (1993)

Acceptable/guideline There was no evidence of induced mutant colonies over background.

870.5100 Bacterial reverse

mutation 44848705 (1999)

Acceptable/guideline

MKH 10868, an animal, plant, and soil metabolite There was no evidence of induced mutant colonies over background.

870.5300 In vitro mammalian

cell gene mutation 44848804 (1996)

Acceptable/guideline No increase in mutant frequency above that of negative controls up to the limit dose.

870.5375 In vitro mammalian

chromosome aberration (RL) 44848805 (1996)

Acceptable/guideline No increases in aberrant metaphases were observed up to the limit dose.

870.5395 Mammalian

micronucleus (mouse) 44848806 (1996)

Acceptable/guideline There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow at 2000 mg/kg.

870.5550 Other genotoxicity 44848807 (1996) Acceptable/guideline There was no evidence of unscheduled DNA synthesis up to cytotoxic levels.

870.6200a Acute Neurotoxicity

Screening Battery (rat) 44848809 (1998)

Acceptable/guideline M & F: 0, 125, 500 or 2000 mg/kg/day NOAEL = 500 mg/kg/day for males and females

. LOAEL = 2000 mg/kg/day based on increased incidence of perianal staining in males, decreased motor activity and locomotor activity in both sexes and increase in the inciden ce of animals exhibiting low levels of activity in open field in both sexes.

870.6200b Subchronic

Neurotoxicity Screening Battery (rat) 44848808 (1998)

Acceptable/guideline 0, 250, 2000, or 20,000
ppm M: 0, 18.5, 147, or 1,482 mg/kg/day F: 0, 21.9, 174, or 1,736 mg/kg/day NOAEL = 147 mg/kg/day in males and 1,736 mg/kg/day in females

. LOAEL = 1,482 mg/kg/day based on decreased body weight, decreased body weight gain, and decreased food consumption in males. LOAEL >1,736 mg/kg/day in females.

870.7485 Metabolism and

Pharmacokinetics 44848830 (1998)

Acceptable/guideline M & F: 17.5 mg/kg of phenyl

- C 14 ; M: 398.5 mg/kg of phenyl

- C 14 ; M: Repeat 14 days of unlabeled followed by 17.6 mg/kg of phenyl

- C 14

. Also, bile fistula, plasma concentration and expired air studies were conducted. There were no sex

- related differences in the absorption, distribution, metabolism

, or excretion. Based on urinary excretion, absorption was 15

- 30% and maximum plasma concentrations were achieved within 30 minutes. At sacrific e, tissues and carcass contained less than 1% of radioactivity. The highest residue in the tissues was in the liver. Greater than 90% of the administered dose was eliminated within 24 hours. The major component in urine and feces was unchanged parent wh ich represented 90

- 95% of the administered dose.

870.7485 Metabolism and

Pharmacokinetics 44848831 (1998)

Acceptable/nonguideline together with 44848830 M: 17.7 mg/kg of triazolinone

- 3

- C 14 Major component in urine and feces was unchanged parent which represented 94% of the administered dose. Less than 1% of the administered dose was recovered in the carcass, tissues, expired air, or cage wash. Highest residue was in the liver.Flucarbazone

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Page 23 of 26 Guideline No. Study Type MRID No. (year)/ Classification/Doses Results

870.7485 Metabolism and

Pharmacokinetics 44848833 (1998)

Acceptable/guideline M: 5.13 mg/kg of phenyl

UL

- C 14 MKH 6562 sulfonamide lactate ( plant metabolite of MKH 6562) Metabolized via two pathways. One pathway involved the oxidative decarboxylation of sulfonamide lactate to form sulfonamide acetate. The oth er pathway involved the hydrolysis of sulfonamide lactate and sulfonamide acetate to give sulfonamide.

870.7485 Metabolism and

Pharmacokinetics 44848832 (1998)

Acceptable/guideline M: 5 mg/kg of phenyl

- C 14 MKH 6562 sulfonamide alanine (a plant metabolite of MKH 6562) Approximately 70% absorption and elimination with 98% recovery in urine and feces. Several metabolites in addition to parent (17%). Less than 1% of the administered dose was recovered in the carcass, tissues, expired air, or cage wash. Highest residue was in the liver.

870.7800 Immunotoxicity 44848703 (1999) 0, 15, 150, or 1,000 mg/kg/day NOAEL = >1,000 mg/kg/day

. LOAEL >1,000 mg/kg/day

.

870.7800 Immunotoxicity 44848707 (1999) 0, 15, 150, or 1,000 mg/kg/day NOAEL = >1,000 mg/kg/day

. LOAEL >1,000 mg/kg/day

.

870.7800 Immunotoxicity 44848704 (1999) 0, 15, 150, or 1,000 mg/kg/day NOAEL = >1,000 mg/kg/day

. LOAEL >1,000 mg/kg/day

.

870.7800 Immunotoxicity 44848709 (1999) 0, 15, 150, or 1,000 mg/kg/day NOAEL = >1,000 mg/kg/day

. LOAEL >1,000 mg/kg/day

.

870.7800 Immunotoxicity 44848810, 44848811, 44848812 (1998) 0, 1000, 5000, or 20,000
ppm M: 0, 107, 510, or 2,205 mg/kg/day F: 0, 115, 612, or 2,556 mg/kg/day NOAEL = 2,205 mg/kg/day in males and 2,556 mg/kg/day in females

. LOAEL >2,205 mg/kg/day in males and 2,556 mg/kg/day in females

.Flucarbazone

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Page 24 of 26 

### Attachment C . Summary of Toxicological Doses and Endpoints for Flucarbazone

- sodium for Use in Human health Risk Assessment (taken from 2009 risk assessment)

.

Exposure/ Scenario POD Uncertainty/ FQPA Safety Factors RfD, PAD,

LOC for Risk Assessment Study and Toxicological Effects

Acute Dietary (females 13

- 49 years of age) NOAEL =

300 mg/kg/day UF A = 10X

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

3.0 mg/kg/day Developmental Toxicity Study (Rabbit)

Developmental LOAEL = 500 mg/kg/day based on decreased fetal body weight and delayed ossification

.

Chronic Dietary (all populations) NOAEL =

35.9 mg/kg/day UF A = 10X

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

0.36 mg/kg/day Chronic Toxicity S tudy (Dog)

LOAEL = 183 mg/kg/day based on decreased body weight gain, decreased thyroxine, increased N

- demethylase, and increased liver weight

.

Incidental oral

Short

- and Intermediate

- term (1

- 30 days and 1

- 6 months) NOAEL =

33.8 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X LOC for MOE

= 100 (Residential) 90

- Day Oral Study (Dog)

LOAEL = 162 mg/kg/day based on decreased thyroxine, increased thyroxine

- binding capacity, induction of microsomal liver enzymes, gross pathology and histopathology in the stomach, and histopathology in the liver

.

Dermal

Short

- and Intermediate

- term (1

- 30 days and 1

- 6 months) NOAEL =

33.8 mg/kg/day

(Dermal absorption = 25%) UF A = 10X

UF H = 10X FQPA SF = 1X Residential and

Occupational LOC for MOE = 100 90

- Day Oral Study (Dog)

LOAEL = 162 mg/kg/day based on decreased thyroxine, increased thyroxine

- binding capacity, induction of microsomal liver enzymes, gross pathology and histopathology in the stomach, and histopathology in the liver

.

Dermal Long

- Term (>6 months) NOAEL =

35.9 mg/kg/day

(Dermal absorption = 25%) UF A = 10X

UF H = 10X FQPA SF = 1X Residential and

Occupational LOC for MOE = 100 Chronic Toxicity Study (Dog)

LOAEL = 183 mg/kg/day based on decreased body weight gain, decreased thyroxine, increased N

- demethylase, and increased liver weight

.

Inhalation

Short

- , Intermediate

- , and Long

- Term (1

- 30 days, 1

- 6 months, >6 months) NOAEL =

0.03 mg/L (8.1 mg/kg/day 1 ) UF A = 10X

UF H = 10X FQPA SF = 1X Residential and

Occupational LOC for MOE = 100 Subchronic Inhalation Toxicity Study (Rat)

LOAEL = 0.18 mg/L (48.8 mg/kg/day) based on eosinophilic globules (nasal cavity) and squamous cell metaplasia (larynx) in males and females

.

Cancer (oral, dermal, inhalation) Not likely to be carcinogenic to humans (2000).

Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- obs erved adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. FQPA SF = FQPA Safety Factor. PAD = population

- adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.

1 Calculated as follows: 0.03 mg/L * 45.2 L/hr/kg * 6 hr/day = 8.1 mg/kg/day.Flucarbazone

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Page 25 of 26 

### Attachment D: Summary of Residential Registered Flucarbazone

- sodium Uses

Formulation Use Site Application Equipment Application Timing Max App Rate (lb ai/A) Comments

WDG Residential turf sites

(including homes, schools, playgrounds, parks, recreational areas and sports fields, common areas) Handheld

equipment Postemergence application to

actively

- growing b roadleaf and grass weeds that are in the seedling growth stage. 0.027 lb ai/A Do not apply this product using aerial application equipment or through any type of irrigation system.



### Attachment E: Summary of Occupational Registered Flucarbazone

- sodium Uses

Formulation Use Site Application Equipment Application Timing Max App Rate (lb ai/A) REI Comments

WDG Residential turf sites

(including homes, schools, playgrounds, parks, recreational areas and sports fields, common areas) Handheld

equipment Postemergence application to

actively growing broadleaf and grass weeds that are in the seedling growth stage. 0.027 lb ai/A N/A

Do not apply this product using aerial application equipment or through any type of irrigation system. Golf courses Groundboom,

handheld equipment Postemergence application to

actively growing broadleaf and grass weeds that are in the seedling growth stage. 0.027 lb ai/A N/A

Sod farms Groundboom,

handheld equipment Postemergence application to

actively growing broadleaf and grass weeds that are in the seedling growth stage. 0.027 lb ai/A 12 hrs

Tree nurseries Groundboom,

handheld equipment Postemergence application to

actively growing broadleaf and grass weeds that are in the seedling growth stage. 0.027 lb ai/A 12 hrs

Wheat, spring

Groundboom Apply prior to jointing, when the majority of plants have from one leaf to a maximum of 4 leaves on the main stem plus two tillers. 0.027 lb ai/A 12 hrs

Wheat, winter Apply in the fall or spring when the majority of plants have one leaf to full tillering, but prior to jointing. 0.027 lb ai/A 12 hrs

WDG in Water Soluble Packets Wheat, spring

Groundboom Apply prior to jointing, when the majority of plants have from one leaf to a maximum of 4 leaves on the main stem plus two tillers. 0.027 lb ai/A 12 hrs Do not apply this product using aerial application equipment or through any type of irrigation system. Wheat, winter Apply in the fall or spring when the majority of plants have one leaf to full tillering, but prior to jointing. 0.027 lb ai/A 12 hrs

Liquid Wheat, spring

Wheat, winter Groundboom,

Aerial Apply after wheat emergence

up to 4 leaf 2 tillered stage of growth or prior to wheat jointing. 0.027 lb ai/A 12 hrs Do not apply this product through any type of irrigation system. Liquid Grasses grown for

Seed Groundboom,

Aerial Postemergence. 0.027 lb ai/A 12 hrs SLNs in WA, OR, MN, and IDFlucarbazone

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Page 26 of 26 

### Attachment F : Flucarbazone

- Sodium Internationa l Residue Limit Status

Flucarbazone

- sodium (114009; 05

- 28

- 2013) Summary of US and International Tolerances and Maximum Residue Limits. Residue Definition : US Canada Mexico 1 Codex 40 CFR §180.562: Combined residues of the herbicide flucarbazone

- sodium, 4,5

- dihydro

- 3

- methoxy

- 4

- methyl

- 5

- oxo

- N

- [[2(trifluoromethoxy)phenyl] sulfonyl]

- 1H

1,2,4

- triazole 1

- carboxamide, sodium salt) and its N

- desmethyl metabolite; and its metabolites converted to 2

- (trifluor omethoxy)benzene sulfonamide and calculated as flucarbazone

- sodium 4,5

- dihydro

- 3

- methoxy

- 4

- methyl

- 5

- oxo

- N

- [[2

- (trifluoromethoxy)phenyl]su lfonyl]

- 1 H

- 1,2,4

- triazole

1

- carboxamide, sodium salt None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex Cattle, liver 1.50 0.05 Cattle, meat 0.01 0.01 Cattle, meat byproducts, except liver 0.01 0.01 Goat, liver 1.50 0.05 Goat, meat 0.01 0.01 Goat, meat byproducts, except liver 0.01 0.01 Hog, liver 1.50 0.05 Hog, meat 0.01 0.01 Hog, meat byproducts, except liver 0.01 0.01 Horse, liver 1.50 0.05 Horse, meat 0.01 0.01 Horse, meat byproducts, except liver 0.01 0.01 Milk 0.005 0.0025 Sheep, liver 1.50 0.05 Sheep, meat 0.01 0.01 Sheep, meat byproducts, except liver 0.01 0.01

Wheat, forage 0.30 Wheat, grain 0.01 0.01 Wheat, hay 0.10 Wheat, straw 0.05 MRLs with No US Tolerances Eggs 0.01 Meat byproducts of poultry 0.01 Meat of poultry 0.01 Completed: M. Negussie; 05/30/2013
1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.