Flumet s ulam Human Health Risk Assessment DP No. D411276

UNITED STATES ENVIRONMEN T AL PRO T ECTION AGENCY

WASHINGTON

, D

. C

. 2 0460



### MEMORANDUM

Date: 19-S E P- 2013 OFFICE OF

CHEMICAL SAFETY AND
POLLUTION PREVENTION



### SUBJECT: Flumetsulam. Preliminary Human Health Risk Assessment for Registration

Revi e w



### PC Code: 129016



### Decision No.: 4 77891


### Petition No

. : NA



### Risk Assessment Type: Sin g l e Chemical / Aggregate 

### DP Barcode: D411276 

### Registration No.: NA 

### Regulatory Action: Regist r ation Review



### Case No.: 7 2 29



### TXR No.: NA 

### CAS No.: 98967-40-9



### MRID No.: NA 40 

### CFR: 180.468 //



### FROM: Mohsen Sahafeyan, Risk Assessor

# vf**/~ ~_,_____**  P. Yvonne Barnes

, Chemi s t 

# -/?**~ ~~**  Brid ge tt Bobowiec

, Biol o gi s t**· ~**  ' Yung Yang, Ph.D., Toxico lo gist 

### c, _;r 

## 7 G-. 

### ?</---;r

Risk Assessment Branch VI 

### t7 (/ v
Health E ffects Division ( 7509P)



### THROUGH: Fel ecia Fort, Branch Chief

# ~" /' 

## V

Risk Assessment Branch VI

## -jP.~"{'/CJ 

# -:jdt 1)

Health Effects Di v ision (7509P )



### TO: Katherine StCla i r
, Chemical Review Manager

Ri s k Management and Implementation Branch II

Pesticide Re-Evaluation Division (7508P)

Page 1 of 40Flumetsulam Human Health Risk Assessment DP No. D411276

Page 2 of 40 The Health Effects Division (HED) of the Of fice of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. As part of Registration Review,

t he Pesticide Re

- evaluation Division ( P RD) of OPP has requested that HED evaluate the hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the registered

uses of flumetsulam

.

HED has evaluated the toxicity and exp osure databases for the active ingredient, Flumetsulam

, and has conducted a human heal th risk assessment in support of Registration Review

. Based on this assessment, HED has determined that there are no potential risk estimates of concern for t he

currentl y registered uses of Flumetsulam.

A summary of the findings and an assessment of human health risk resulting from the currently registered uses of Flumetsulam are provided in this document. The HED team members contributing to this risk assessment includ e Mohsen Sahafeyan (risk assessment), Bridgett

Bobowiec (occupational risk assessment), P. Yvonne Barnes (chemistry and dietary exposure assessment) and Yung Yang (hazard assessment)

. James Wolf of the Environmental Fate and Effects Division (EFED) perfor med the drinking water assessment for Flumetsulam

.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 3 of 40 2.0 Introduction

................................ ................................ ................................ ............... 7

2.1 Tolerances

................................ ................................ ................................ ......................... 7

2.2 International Harmonization

................................ ................................ .............................. 7

2.3 Structure and Nomenclature

................................ ................................ .............................. 8

2.4 Physical/Chemical Characteristics

................................ ................................ ....................... 8

2.5 Summary of Existing Uses

................................ ................................ ................................ ... 8

2.6 Anticipated Exposure Pathways

................................ ................................ ....................... 11

2.7 Consideration of Environmental Justice

................................ ................................ ............ 11

3.0 Hazard Characterization and Dose

- Response Assessment

................................ ......... 12

3.1 Summary of Toxicological Effects

................................ ................................ ...................... 12

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

................................ .............. 13

3.2.1 Completeness of the Toxicology Database

................................ ................................ .......................... 13

3.2.2 Evidence of Neurotoxicity

................................ ................................ ................................ .................... 13

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

................................ .......... 13

3.2.4 Residual Uncertainty in the Exposure Database

................................ ................................ .................. 13

3.3 Toxicity Endpoint and Point of Departure Selections

................................ ......................... 13

3.4 Endocrine Disruption

................................ ................................ ................................ ....... 14

4.0 Dietary Exposure and Risk Assessment

................................ ................................ ...... 15

4.1 Degradate Residue Profile

................................ ................................ ................................ 15

4.1.1 Summary of Environmental Degradation

................................ ................................ ............................ 16

4.1.2 Residues of Concern Summary and Rationale

................................ ................................ ..................... 16

4.1.3 Enforcement Analytical Method

................................ ................................ ................................ .......... 17

4.2 Food Residue Profile

................................ ................................ ................................ ........ 17

4.3 Water Residue Profile

................................ ................................ ................................ ...... 18

4.4 Dietary Risk Assessment

................................ ................................ ................................ ... 19

4.4.1 Description of Residue Data Used in Dietary Assessment

................................ ................................ ... 19

4.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ................................ ............. 19

4.4.3 Acute Dietary Risk Assessment

................................ ................................ ................................ ............ 19

4.4.4 Chronic Dietary Risk Assessment

................................ ................................ ................................ ......... 19

4.4.5 Cancer Dietary Risk Assessment

................................ ................................ ................................ .......... 20

4.4.6 Dietary Risk Assessment Summary Table

................................ ................................ ............................ 20

5.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................... 20

5.1 Spray Drift

................................ ................................ ................................ ....................... 20

5.2 Inhalation Post

- application Exposure

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

6.0 Aggregate Exposure/Risk Characterization

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

7.0 Cumulative Exposure/Risk Characterization

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

8.0 Occupational Exposure/Risk Characterization

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

8.1 Occupational Handler Exposure and Risk

................................ ................................ .......... 23Flumetsulam Human Health Risk Assessment DP No. D411276

Page 4 of 40 8.1.1 Short

- /Intermediate

- Term Non

- Cancer Handler Exposure and Risk

................................ ................... 25

8.1.2 Cancer Handler Exposure and Risk

................................ ................................ ................................ ...... 28

8.2 Occupational Post

- Application Exposure and Risk

................................ ............................. 28

8.2.1 Post

- application Inhalation Exposure

................................ ................................ ................................ .. 28

8.2.2 Post

- application Dermal Exposure and Risk

................................ ................................ ........................ 28

8.2.2.1 Short

- /Intermediate

- Term Non

- Cancer Post

- application Exposure and Risk

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

8.2.2.2 Cancer Post

- application Exposure and Risk

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

References

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

Appendix A. Toxicology Assessment

................................ ................................ .................. 32

A.1 Toxicology Data Requirements

................................ ................................ ......................... 32

A.2 Toxicity Profile

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

Appendix B. Physical/Chemical Properties

................................ ................................ ........... 36

Appendix C. Review of Human Research

................................ ................................ .............. 37

Appendix D. Occupational Exposure/Risk Summary Tables

................................ .................. 38

Appendix E. Summary of US and International Tolerances and Maximum Residue Limits

..... 40Flumetsulam Human Health Risk Assessment DP No. D411276

Page 5 of 40 1.0 Executive Summary

As part of Registration Review, the Pesticide Re

- evaluation Division (PRD) of the Office of Pesticide Programs (OPP) has requested that the Health Effects Division (HED) evaluat e the hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the registered uses of Flumetsulam. This document provides a summary o f the findings and an assessment of human health risk resulting from the currently registered uses of flumetsulam.

Use Profile: Flumetsulam (N

- (2,6

- difluorophenyl)

- 5

- methyl

- (1,2,4)triazolo(1,5

- a)pyrimidine

- 2

- sulfonamide) is an herbicide in the triazolopyrimidine chemical class used to control broadleaf

weeds in field corn , dry bean and soybean , applied as a pre emergent and early post

- emergent
herbicide

. HED notes that although dry bean is a registered primary crop, all labels for dry be an are inactive at present ; any reference to use rate and use pattern s for dry bean in this document

are based on older inactive labels, field trial data, and p reviously reviewed occupational/residential exposure (ORE) assessment ( Dow, Mark I., 2004, D30 6178 )

. Flumetsulam can be applied by ground and by aerial application with restrictions. It is

formulated as a water dispersible granular ( WDG ), a water dispersible granular packa ged in water soluble packet ( WSP ) , and as an emulsifiable concentrate (EC)

. The highest maximum application rate is 0.07 lb ai/A for field corn, soybeans, and dry beans.

Hazard Assessment: The toxicology database for flumetsulam is complete. A subchronic inhalation study was not available; however, t he HED Hazard and Science Policy Council (HASPOC) determined that a subchronic inhalation toxicity study is not needed for flumetsulam at this time (TXR# 0056689).

The kidney appears to be the primary target organ of rats and dogs following exposure to high doses of flumetsulam in subchronic and chronic toxicity studies. Flumetsulam has low acute toxicity by oral, dermal, or inhalation route s of exposure. It is not a skin or eye irritant and is not

a skin sensitizer. The available toxicity database sh ows that flumetsulam is not a neurotoxic or immunotoxic chemical and it does not induce developmental or reproductive toxicity.

Flumetsulam is classified as “Group E”, ( evidence of non

- carcinogenicity f or humans) ;

m utagenicity studies conducted with flume tsulam were negative.

An acute reference dose has not been established for either the general population or for females

13

- 49 years of age since there were no appropriate studies that demonstrated evidence of toxicity attributable to a single dose for the se populations. For chronic dietary and other exposure scenarios, the chronic feeding study in the dog was selected because the study encompasses the appropriate exposure duration and provides a screening level hazard with a NOAEL of 100 mg/kg/day and LOAE L of 500 mg/kg/day based on renal inflammatory and atrophic changes secondary to renal calculi and hepatic effects consisting of inflammation, focal necrosis, and biliary stasis. For the dermal exposure scenario, n o systemic toxicity was found in the 21

- da y rabbit dermal study at the limit dose (1000 mg/kg/day). Quantification of dermal risk assessment is not required for this exposure due to a lack of dermal, systemic, neuro, or developmental toxicity concerns.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 6 of 40 The flumetsulam risk assessment team has recommended that the FQPA Safety Factor be

reduced to 1X based on and adequate and complete toxicity database and exposure data. There is no evidence of qualitative or quantitative susceptibility in utero or during post

- natal exposure in developmental and reproduction studies and there is no evidence of neurotoxicity in the

submitted studies. A developmental neurotoxicity study is not required since there was no evidence of neurotoxicity or neuropathy from the avail able studies.

Dietary Exposure (Food and Drinking Water): The residue chemistry data and environmental fate data are adequate to assess human exposure. E stimated drinking water concentrations (EDWCs) from surface water and groundwater sources were generated by the Environmental Fate and Effects Division (EFED) using computer modeling methods.

Acute: An acute dietary exposure assessment was not performed as n o appropriate endpoints

were identified from the available flumetsulam toxicity studies f or the acute dietary scenario

.

Chronic: Both food and water were incorporated in the dietary exposure analysis. Tolerance

level residues and 100% crop treated assumptions for all the crops were used in the chronic dietary exposure assessment. Flumets ulam residue in water was assumed to be 14.8 ppb according to EFED’s highest estimated chronic drinking water concentration. The estimated exposure for the general U.S. population and all population subgroups result ed in exposures less

than 1 percentage of the chronic population adjusted dose (cPAD).

Cancer: A cancer dietary exposure assessment was not performed as f lumetsulam is classified as Group E (Evidence of non

- carcinogenicity for humans).

Residential Exposure : There are currently no registered residential uses associated with

flumetsulam ; therefore, a residential/non

- occupational exposure assessment is not required.

Aggregate Risk: Aggregate risk assessments evaluate the combined risk from dietary exposure (f ood and water) and any non

- occupational (residential) uses. There are currently no registered

residential uses associated with flumetsulam ; therefore, a residential/non

- occupational exposur e assessment is not required. As a result, the flumetsulam aggreg ate risk assessment includes only dietary exposure (food and water). An acute dietary exposure assessment was not performed as no appropriate endpoints were identified from the available flumetsulam toxicity studies for the acute dietary scenario. The ch ronic dietary exposure estimates from food and drinking water do

not exceed HED’s level of concern (<1% of cPAD)

. A cancer dietary exposure assessment was not performed as Flumetsulam is classified as Group E (Evidence of non

- carcinogenicity for humans)

.

Occupational Exposure/Risk: The occupational database is complete. Occupational handler exposures to the existing uses of flumetsulam may occur via dermal and inhalation route. However, quantification of dermal risk is not required due to a lack of dermal, systemic, neuro, or developmental toxicity concerns. Therefore, only inhalation exposure was assessed for

handlers.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 7 of 40 The short

- and intermediate

- term inhalation risk estimates for all occupational handler scenarios

do not exceed HED’s level of conc ern , i.e., margin of exposures are greater than 100 (MOEs > 100) at baseline personal protective equipment (PPE)

. The flumetsulam product labels direct mixers, loaders, applicators and other handlers to wear long

- sleeved shirts, long pants, waterproof glo ves, and shoes plus socks. Some of the labels require the PPE to include goggles or face shields because some end use products contain a mixture of chemicals with different acute toxicity categories than flumetsulam. HED recommends that the Registration Division ( RD ) ensure the appropriate safety directions and a 12 hour restricted entry interval (REI) are included in the label based on the acute toxicity of flumetsulam and that products that include a formulated mixture of active ingredients should retai n the 48 hour REI.

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

- application inhalation exposure assessment was not performed for flumetsulam at this time primarily because of the low acute inhalation toxicity

, vapor pressure and the use ra tes. However, since handler inhalation exposure is likely to be higher than post

- application exposure and the estimates for handler inhalation exposure are below the level of concern (MOE >100), it is expected that these handler inhalation exposure estima tes would be protective of most occupational post

- application inhalation exposure scenarios. 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

flumetsulam.

Spray drift analysis was conducted for a hand to mouth ( HtM ) scenario for children ages 1<2 years of age using Tier 1 screening parameters. The aerial and ground applications of flumetsulam at the current maximum application rates resulte d in MOEs not of concern for field corn, soybeans, and dry beans.

There are no label recommendations from the occupational assessment. There are no data deficiencies or additional requirements for flumetsulam at this time.

Review of Human Research: This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (listed in Appendix C ) have been determined to require a r eview of their ethical conduct and a ll

of the studies utilized in this assessment have received the appropriate review.

Data Deficiency: The databases for toxicology, residue chemistry, occupational and residential requirements are complete. There are no outstanding data deficiencies.

2 .0 Introduction

2.1 Tolerances

Tolerances are established for the herbicide f lumetsulam under 40 CFR: § 180.468 for b ean, dry,

seed ; c orn, field, forage ; c orn, field, grain ; c orn, field, stover ; s oybean, seed , each at 0.05 ppm.

2.2 International HarmonizationFlumetsulam Human Health Risk Assessment DP No. D411276

Page 8 of 40 The Codex Alimentarius Commission has not established Maximum Residue Limits ( MRLs ) for

residues of flumetsulam. Canadian MRLs are established for field corn and dry soybean each at 0.05 ppm; Canada does not establish MRLs on feed stuffs. N o harmonization is needed. For a summary of US and International Tolerances and Maximum Residue Limits, see Appendix E.

2 .3 Structure and Nomenclature

Table 2.3

- Flumetsulam Nomenclature

Chemical structure

Common Name Flumetsulam Company Experimental Name DE

- 498 and TSN

- 100986 Empirical Formula C 12 H 9 F 2 N 5 O 2 S

IUPAC Name 2

- (2,6

- difluorophenylsulphamoyl)

- 5

- methyl(1,2,4)

- Triazolo(1,5

- a)pyrimidine

CAS Name N

- (2,6

- difluorophenyl)

- 5

- methyl

- (1,2,4)triazolo(1,5

- a)pyrimidine

- 2

- sulfonamide

CAS Registry Number 98967

- 40

- 9

2 .4 Physical/Chemical Characteristics

Listed in Appendix B are the physical and chemical properties as well as the relevant

environmental fate parameters. Flumetsulam low vapor pressure ( 1.0 x 10 - 1 5 mm Hg at 25.0 °C)

indicates that flumetsulam is non

- volatile. Flumetsulam is soluble in water and is stable under photolysis. Degradation studies indicate the aerobic soil half

- life ranges from approximately two weeks to four months with the majority degrading in less than two months (mean of 69.5 days).

2 .5 Summary of Existing Uses

Flumetsulam is a pre emergent and early post

- emergent herbicide used to control broadleaf

weeds in fiel d corn, soybeans, and dry beans; HED notes that although dry be an is a registered primary crop, all labels for dry bean are inactive at present; any reference to use rate and use pattern for dry bean in this document are based on older inactive labels, field trial data, and

p reviously reviewed ORE document (Dow, Mark I., 2004, D306178 )

. Flumetsulam is in the triazolopyrimidine chemical class and has a mode of action similar to the sulfonylurea herbicides that are acetolactate synthase inhibitors, which regulate plant growth. Flumetsulam is formulated as water dispersible granular WDG , wa ter dispersible granular packag ed in water soluble packets WSP, and as an emulsifiable concentrate EC . Flumetsulam can also be incorporated with liquid and dry bulk fertilizer. The water soluble packets must be combined with water to create slurry

first before attempting to mix with a carrier fertilizer. Some of the registered products contain a mixture of flumetsulam and additional active ingredients which are not evaluated in this registration review document.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 9 of 40 Flumetsulam can be applied by ground and by air with restrictions. Chemigation is prohibited. Field corn and soybeans have application rates ranging from 0.035 lb ai/A to 0.07 lb ai/A. Flumetsulam application rates on dry beans ra nge from 0.04 to 0.07 lb ai/A based on older

inactive labels, f

ield trial data, and p reviously reviewed ORE document (Dow, M., 2004, D306178). Rotational crop restrictions are direct ed on labels. Currently, t here are two registered

manufacturin g

- use products ; (EPA Reg. No. 62719

- 223) Flumetsulam Technical 98 % a.i. , and (EPA Reg. No. 62719

- 300) Hornet MUP 23.1 % a.i. flumetsulam. Application rates and

restrictions for a ll other labels are summa rized in the following Table 2.5

.

Table 2.5

- Summary Use Profile for Flumetsulam

Registration

Number and

Product

Name Application

Equipment. Formulati

on Applic. Rate (lb

a

. i

. /A) Max.

No. Applic.

Per

Season Max.

Seasonal Applic. Rate (lb

a

. i

. /A) PHI

(days) Use Directions and

Limitations RE

I

Field Corn

352

- 612

DuPont

Accent Gold

15.9 % a.i. Ground with

aerial application only in following

states, Colorado,
Iowa,
Kansas, Minnesota, Nebraska, Oklahoma,

South Dakota, and

Texas Water

dispersibl e granular packaged

in a

soluble packet 0.035

1 0.03 5 85 Do not apply to popcorn or sweet corn. Can apply

to corn up to 12 inches tall and when grass and

broadleaf weeds are

young or pre

- emergent. Adequate soil moisture is required for residual activity. Use at least 15 gallon water per acre for broadcast application and 5 gallons per acre for aerial application. Do not apply a cumulative rate

of more than 0.07 lbs of flumetsulam per year. 48

ho

urs 352

- 593

Accent Gold

19.1 % a.i Ground

Broadcast or

Branded

62719

- 278

NAF

- 280

13.9 % a.i. Ground

Do not apply aerially

0.07 0.07

85 Preplant, surface, incorporated,
preemergence, or post
emergence treatment. Adequate soil moisture is required for residual activity. Must make slurry to mix with fertilizer. Apply a minimum of 200 pound of dry impregnated

fertilizer Spray volume of 10 to 60 gallons per a cre Post

- emergent treatment should be applied with

water Do not apply aerially 62719

- 253

Hornet

23.1 % a.i. Ground

and aerially

with supplemental

labels New

York

Restrictions

62719

- 315

Hornet

WDG

18.5 % a.i Ground

New York

Restrictions 0.07 0.07

62719

- 279

NAF

- 281

12.1 % a.i. Ground

Do not apply aerially 0.05 0.05Flumetsulam Human Health Risk Assessment DP No. D411276

Page 10 of 40 Table 2.5

- Summary Use Profile for Flumetsulam

Registration

Number and

Product

Name Application

Equipment. Formulati

on Applic. Rate (lb

a

. i

. /A) Max.

No. Applic.

Per

Season Max.

Seasonal Applic. Rate (lb

a

. i

. /A) PHI

(days) Use Directions and

Limitations RE

I

unless by EPA approved supplemental labeling.

62719

- 570

Sure Start

1.3 % a.i Emulsifia

ble

concentrat

e 0.05 1 0.05 Contains 3 active ingredients. PPE includes gloves, eyewear, headgear, and apron. Post emergent corn can be sprayed up to 11

inches Apply a minimum of 200 pound of dry impregnated fertilizer Spray volume of 10 to 60 gallons per acre 12

ho

urs

Soybeans

62719

- 299

Frontrow

Flumetsulam

80 WDG

80% a.i. Ground and

aerial application

with supplemental labeling.

Aerial application prohibited

New York Water

dispersibl

e granulars

in w ater
soluble packet s 0.00 6 2 0.012 70 Front Row is a co

- pack product. Do not mix and apply separately water

– soluble packets . Use of product in Nassau and

Suffolk counties in New York are prohibited. Do not graze of feed soybean forage. 12

ho

urs

Field Corn and Soybeans

62719

- 224

Broad Strike formerly

XRM

- 6019

74 % a.i

Ground,

Aerially (no

aerial application

in New

York ) Water

dispersibl

e granulars 0 .0 7 1 0.07 85 days

for corn

and soybean

harvest 45 days

for corn forage

harvest Preplant, surface,

incorporated,

preemergence, or post
emergence treatment. Application may be made to field corn up to 12

inches tall and soybea ns in the first to fifth trifoliate leaf stage. Use at least 10 gallons of spray per acre for ground application. Apply a minimum of 200 pound of dry impregnated

fertilizer. Must make slurry to mix with

fertilizer. Do not make

post emergence applicatio ns near freezing temperatures 12

ho

urs 62719

- 277 Python

WDG

80 % a.i.

Dr y Beans 1Flumetsulam Human Health Risk Assessment DP No. D411276

Page 11 of 40 Table 2.5

- Summary Use Profile for Flumetsulam

Registration

Number and

Product

Name Application

Equipment. Formulati

on Applic. Rate (lb

a

. i

. /A) Max.

No. Applic.

Per

Season Max.

Seasonal Applic. Rate (lb

a

. i

. /A) PHI

(days) Use Directions and

Limitations RE

I

62719

- 239

Broadstrike ®

+ Dual

20 % a.i.

Ground only Emulsifia

ble

concentrat

e 0.063

1 0.07 lb

ai/acre 85 days Products may be applied

10

- 14 days prior to planting as a soil incorporated application

or as a surface application. It may be applied post

- plant but prior to crop or weed

emergence. 12

ho

urs 62719

- 222

Broadstrike ®

+ Treflan ®

25 % a.i. 0.07

62719

- 277

Broadstrike

WDG

80 % a.i. Water dispersibl e granule 0.067

1 Dry bean labels are inactive. Use and rates are based on older inactive labels, field trial data, and previously reviewed ORE document (Dow, Mark I., D306178 )

.

2 .6 Anticipated Exposure Pathways

Humans may be exposed to flumetsulam in their diet resulting from residues present in foods

treated with flumetsulam . Further, given the environmental fate parameters of flumetsulam and the registered agricultural uses, the potential exists for flumetsulam to reach water resource s resulting in potential residues in drinking water. There are currently no residential uses of

flumetsulam , so exposure in residential and non

- occupational settings is not likely. T here is a potential for occupational handler and post

- application exposures.

2 .7 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions

to Addr ess 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, OP P considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumpt ion, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categor ized by subgroups based on age and ethnic group

.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 12 of 40 Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddler s, youths, and adults entering or playing on treated areas

post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

3.0 Hazard Characterization and Dose

- Response Assessment

Previously, a comprehensive risk assessment for flumetsulam was conducted i n 2004 (E. Reaves, D306238, 11/22/2004) and a scoping document was issued in 2008 (S. Recore, D349638, 8/12/2008). Since then, new studies including acute and subchronic neurotoxicity and immunotoxicity studies were submitted. In addition, the Hazard and S cience Policy Council ( HASPOC ) determined that a subchronic inhalation toxicity study is not needed for flumetsulam at this time (TXR # 0056689). Please refer to Appendix A for the hazard profile table. This assessment includes summaries of prior assessment s

.

3 .1 Summary of Toxicological Effects

Flumetsulam has low acute toxicity by oral, dermal, or inhalation route s of exposure. It is not a skin or eye irritant and is not a skin sensitizer. The kidney appears to be the primary target organ

of rats and do gs following exposure to high doses of flumetsulam in subchronic to chronic toxicity studies. Following subchronic oral exposure, rats developed bilateral tubular nephritis at concentrations equal to the limit dose; however, no renal effects were found in mice at doses five times the limit dose. In chronic dog and rat studies, renal calculi, inflammation, and atrophic changes were found in the kidney of male animals. These effects were not observed in female rats or dogs, or in treated male and female mi ce. There were no evidences of neurotoxicity, immunotoxicity, developmental, or reproductive toxicity in the submitted studies for

flumetsulam.

Mutagenicity studies conducted with flumetsulam were negative. Flumetsulam did not alter the spontaneous tumor profile in these strains of rats and mice at the limit dose . Therefore, on th e basis of the two studies, the Health Effects Division RfD/Peer Re view Committee classified flumetsulam as a “Group E”, evidence of non

- carcinogenicity f or humans ( TXR # 011039

, 03/24/1993 ).

Available metabolism and pharmacokinetics studies in mice and rats indicate that flumetsulam is primarily eliminated within 48 hour s from all test animals following oral administration. The primary route was urinary excretion of unchanged flumetsulam. The rapid clearance of flumetsulam demonstrated little potential for bioaccumulation. Metabolic studies show that

appr oximately 52

- 6 3% of the adminis tered test material was absorbed by male and female rats. Plasma pharmacokinetic studies suggest that increased doses were associated with increased clearance, possibly due to saturation of plasma binding sites. In addition, there was a dose

-Flumetsulam Human Health Risk Assessment DP No. D411276

Page 13 of 40 dependent decrease in the rate of plasma absorption and elimination for both rats and mice. Two

very m inor metabolites were detected in the urine of mice (not identified). At the limit dose, mice showed a greater capacity for absorption and eliminat ion than rats.

3 .2 Safety Factor for Infants and Children (FQPA Safety Factor)

The flumetsulam risk assessment team has recommended that the FQPA Safety Factor be reduced to 1X based on adequate toxicity database and exposure data. There is no evidenc e of qualitative or quantitative susceptibility in utero or during post

- natal exposure in developmental and reproduction studies and there is no evidence of neurotoxicity in the submitted studies. A developmental neurotoxicity study is not required since t here was no evidence of neurotoxicity or neuropathy from the available studies.

3 .2.1 Completeness of the Toxicology Database

The database for flumetsulam is complete and adequate to characterize potential pre

- and/or
post

- natal risk for infants and chi ldren

.

3 .2.2 Evidence of Neurotoxicity

There are acute and subchronic neurotoxicity studies available. No evidence of neurotoxicity was observed in any of the submitted studies for flumetsulam. A developmental neurotoxicity study is not required.

3 .2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The available data do not provide evidence of any increased susceptibility or sensitivity in the offspring in either of the two developmental toxicity studies, nor in the two

- generation reproduction study.

3 .2.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to dietary exposure. C onservative, upper

- bound assumptions were used to determine exposure through dietary sources (food and drinking water )

, such that these exposures have not been underestimated. There are currently no residential uses and no outstanding exposure data requirements for flumetsulam.

3 .3 Toxicity Endpoint and Point of Departure Selections

Previously, HED has conducted a comprehensive risk assessment for flumetsulam ( E. Reeves and S. Ary, D306238, 11/22/ 20 04 ). There have been no changes to the prior dose

- response assessment and no changes to the prior recommendations for combining routes of exposure

and/o r cancer classification

.

An acute reference dose has not been established for either the general population or for females

13

- 49 years of age since there were no appropriate studies that demonstrated evidence of toxicity attributable to a single dose for these populations. For chronic dietary and other exposureFlumetsulam Human Health Risk Assessment DP No. D411276

Page 14 of 40 scenarios, the chronic feeding study in the dog was selected because the study encompasses the appropriate exposure duration and provides a screening level hazard with a NOAEL of 100 mg/kg/day and LOAEL of 500 mg/kg/day based on renal inflammatory and atrophic changes secondary to renal calculi and hepatic effects consisting of inflammation, focal necrosis, and biliary stasis. For dermal exposure scenario, n o systemic toxicity was found in the 21

- da y rabbit dermal study at the limit dose (1000 mg/kg/day). Quantification of dermal risk assessment is not required for this exposure due to lack of dermal, systemic, neuro, or developmental toxicity

concerns. The detailed endpoint selection is listed in the following Table 3 .3

.

Table 3.3

- Toxicological Doses and Endpoint for Use in Flumetsulam Dietary and Non

Occupational and 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 ( al l populations) An acute reference dose has not been established for either the general population or for females

13

- 49 years of age since there were no appropriate studies that demonstrated evidence of toxicity attributable to a single dose for these populations.

Chronic Dietary (all populations) NOAEL =

100 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X

Total UF = 100X Chronic RfD

= 1.0 mg/kg/day

cPAD = Chronic RfD FQPA SF

= 1.0 mg/kg/day Chronic feeding study in dogs LOAEL = 500 mg/kg/day based on renal inflammatory and atrophic changes secondary to renal calculi and hepatic effects (inflammation, focal necrosis, biliary stasis)

Incidental Oral (short and

intermediated

term) NOAEL =

100 mg/kg/day UF A = 10X

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

MOE=100 Same as chronic dietary endpoint.

Dermal Exposure (all durations) No hazard identified. No systemic toxicity was found in the 21

- day rabbit dermal study at the

limit dose (1000 mg/kg/day). Quantification of dermal risk assessment is not required for this exposure due to lack of dermal, systemic, neuro, or developmental toxicity concerns.

Inhalation Exposure

( a ll durations) Oral NOAEL= 100

mg/kg/day (inhalation absorption rate = 100%) UF A = 10X

UF H = 10X

Total UF =

100X Occupational LOC

for MOE = 100 Same as chronic dietary

endpoint.

Cancer (oral, dermal, inhalation) Flumetsulam is classified as Group E (Evidence of non

- carcinogenicity for humans).

Not mutagenic.

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic)

, RfD = reference dose, LOC = level of concern, NA = Not Applicable. UF A = extrapol ation from animal to human (inter species), UF H = potential variation in sensitivity among membe rs of the human population (intra species).

3. 4 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse

outco mes from exposure to chemicals. Collectively, these studies include acute, subchronic andFlumetsulam Human Health Risk Assessment DP No. D411276

Page 15 of 40 chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmen tal, 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 assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its mo st recent registration decision for flumetsulam

, 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),

flumetsulam is subje ct 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

m ay designate.” The EDSP employs a two

- tiered approach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 sc reening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal

systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the su bstance, and

establish a dose

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

Under FFDCA section 408(p), the Agency must s creen 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 ingre dients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 and includes

flumetsulam

. For further information on the sta tus of the EDSP, the policies and procedures, the

list s of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our

website. 2

In the interim, EPA is making no human health or environmental safety findings associated with the EDSP screening of flumetsulam . Before completing this Registration Review, the Agency will make an EDSP FFDCA section 408(p) determination.

4 .0 Dietary Exposure and Risk Assessment

4.1 Degradate Residue Profile

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

2 http://www.epa.gov/endo/Flumetsulam Human Health Risk Assessment DP No. D411276

Page 16 of 40 4.1.1 Summary of Environmental Degradation

F lumetsulam is classified as moderately persistent to persistent , and mobile to highly mobile in

the environment. T he environmental fate database for flumetsulam is largely complete.

Environmental f

ate studies s how that flumetsulam is moder at e ly persistent in soil (aerobic half

lives on the order of weeks to months), more persistent under anaerobic aquatic conditions (half

li f e of about 6 months) and aerobic aquatic conditions (half

- life > 1 year) , and stable to both hydrolysis and photolysis. However, the persistence and mobility of flumetsulam appear to be influenced by pH and organic carbon content

. Flumetsulam has a low vapor pressure and Henry’s Law constant, and its physical properties indicate a low potential for volatilization

.

While flumetsulam is more soluble in neutral waters than in acidic water, it is very resistant to abiotic reactions (stable to hydrolysis, as well as photolysis in water and on soil). The major route of dissipation for flumetsulam is believed to be metabolism in aerobic soils, where metabolism half lives range d from 1 3 days in sandy loam to 1 30 days in loam soil. Metabolites were less than 10% of applied radioactivity and were not identified. Metabolism in the aquatic environment is expected to be much slower, wi th a reported anaerobic aquatic half

- life of 183 days and an estimated aerobic aquatic half

- life greater than a year

. Under anaerobic aquatic conditions flumetsulam is reduced to flumetsulam hydrate. Oxidation will cause a transformation

back to flumetsul am.

Flumetsulam degrades to CO 2 with no significant accumulation of intermediate degradate s , except for reduced flumetsulam hydrate [N

- (2,6 difluorophenyl)

- 4,5,6,7

- tetrahydro

- 5

- hydroxy

- 5

- methyl

- (1,2,4)

- triazolo(1,5

- a)pyrimidine

- 2

- sulfonamide] , formed in the anaerobic aquatic study

. Flumetsulam hydrate accounted for 52% of the total applied radiation at day 360, and degraded

with a half life of about 1 80 d ays. However, this degradate was found to accumulate less (max of <8% of total applied radiation) and degrade more quickly (t 1⁄2 about 2 days) in a weakly anaerobic test system that became progressively more anaerobic with time . Flumetsulam degraded much slower in aerobic aquatic systems compared to anaerobic aquatic conditions. No degradation products were identified. Calculated pseudo

- first order half

- lives were 1762 and 1319 days for

the 14 C

- pyrimidine and 14 C

- analine labels, respectively.

Since flumetsulam does not rapidly metabolize when in contact with soils and does not bind strongly to soil surface s , there is a potential for run off from application sites to adjacent surface

waters. P ersistence in water indicates that flumetsulam may persist long enough to present some

concern to surface water and ground water resources. V olatilization is not expected to be a major route of dissipation from either water or soil for flumetsulam

.

EFED provided an updated drinking water assessment which estimated flumetsulam in surface and ground water based on the latest product label information, newly available environmental data, exposure models, and model scenarios.

4.1 .2 Residues of Concern Summary and Rationale

On April 21, 1993, the HED Metabolism Committee concluded that the residue of concern resulting from the uses of flumetsulam on plant commodities is flumetsulam only

. The basis forFlumetsulam Human Health Risk Assessment DP No. D411276

Page 17 of 40 this decision was on the low levels of total radioactive residues present in plant metabolism studies and the lack of toxicological concern for metabolites having the sulfonamide linkage intact (N. Dodd, HED Metabolism C ommittee Memorandum, 04/26/1993).

The HED Metabolism Committee has not determined the residue of concern in livestock; however, based on the previously submitted data, the nature of the residue in livestock (goats and hens) is adequately defined ; n o detectable residues of flumetsulam were found in feed items.

Table 4.1.2 Summary of Metabolites and Degradates to be included in th e Risk

Assessment and Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Flumetsulam Flumetsulam

Livestock Ruminant NA 1 NA 1

Drinking Water Flumetsulam Not Applicable

1 HED previously concluded that there is no reasonable expectation of finite residues in ruminant and poultry commodities ; i.e., 40 CFR §180.6(a)(3) situation.

4.1.3 Enforcement Analytical Method

The available analytical methodology (Gas Chromatography/Mass Spectrometry [GC/MS]) is considered adequate for tolerance enforcement of flumetsulam in/on plant commodities;

Dow Elanco’s Method ACR 91.6 (Method I) on soybean grain and DowElanco’s Method ACR 91.61S (Method II) on corn grain and corn fodder (D189444, N. Dodd, 03/29/1993) The method has been submitted for inclusion in the Pesticide Analytical Manual (PAM), Volume II

. The stated limit of quantitation (LOQ) of the method is 0.010 ppm; however, Analytical Bio

Chemistry Laboratories, Inc (ACB) validated the method LOQ at 0.05 ppm.

4.2 Food Residue Profile

Crop Field Trials Adequate crop field trial data are available for flumetsulam in/on field corn, soybean and dry

beans. All flumetsulam residues were below the LOQ at the maximum label rate for all the registered crops. The established tolerances are at 0.05 ppm (40 CFR §180.468).

Meat, Milk, Poultry, and Eggs

The re are no registered direct livestock treatment uses for f lumetsulam and no detectable

residues of flumetsulam in /on the feed items except in soybean . However, for soybean, the registrant had proposed a tolerance for the soybean (bean) only and put grazin g/feedi ng restrictions on the label; therefore, livestock analytical methods or feeding studies are not required ( see memorandum by Dodd, N

. , “Issues to be Presented at the 4/21/93 Meeting of the HED Metabolism Committee.”). R estriction on soybean feed items for li vestock consumption

should be on all labels

. Nature of residue studies for ruminant (goat) and poultry (hens) have

been submitted and reviewed. T he nature of the residue in animals is adequate for the current

uses. HED previous ly conclude d t hat the registered uses on corn, soybeans, and dry beans results in a 40 CFR §180.6(a)(3) situation for ruminant and poultry commodities; i.e., there is noFlumetsulam Human Health Risk Assessment DP No. D411276

Page 18 of 40 reasonable expectation of finite residues in ruminant and poultry commodities. Theref ore, additional data on the transfer of residues to meat, milk, and poultry are not required. However,

for any future uses which may result in detectable residues in feed items, additional animal metabolism data on ruminants and poultry may be required. Such data may, in turn, trigger the need for magnitude of the residue (feeding) studies in livestock.

Processed Food and Feed

Proce ssing studies for the currently registered flumetsulam uses are adequate. Flumetsulam processing studies are available for corn. Flumetsula m residues in the treated corn at exaggerated maximum application rate and in the processed fractions were non

- detects. A processing study is not required for soybeans as no detectable residues were found in soybeans from exaggerated appli cation rate (D188957, N. Dodd, 06/28/1993) and (PP# 1G4006, N. Dodd, 03/27/1993)

.

Storage Stability Storage stability studies using fortified samples of field corn and soybean for the currently registered flumetsulam uses are adequate. The results indicate that residues of flumetsulam are stable in corn grain, forage, and fodder stored for at least 555 d ays and in soybean for at up to thirty months (908 days) at

- 15 °C ( N. Dodd, PP# 3F4185, 0 6/28/1993 , and PP# 2F4036,

0 4/14/1993 ). For dry beans

, i n the absence of specific storage stability data, it was assumed that

residues on samples which were stored for 97 days will behave similarly in beans as in corn and soybeans S. Ary (D306242, 08/31/2004).

Rotational Crops

The current use labels for flumetsulam restricts crop rotation after treatment to four months or greater for all crops except soybean.

4

. 3 Water Residue Profile

Flumetsulam is soluble in water and is stable under photolysis. Degradation studies indicate the

soil half

- life ranges from approximately two weeks to four months with majority degrading in less than two months (mean of 69.5 days). The Environmental Fate and Effects Division (EFED) provided estimated drinking water concentrations (EDWCs) by using either a Tier I Screening Concentration In Ground Water ( SCI

- GROW ) and/or Pesticide Root Zone Model

– Ground Water ( PRZM

- GW ) models for gr ound water ; Tier II Pesticide Root Zone Model/Exposure Analysis Modeling System ( PRZM/EXAMS ) was used to obtain surface water

concentrations. The estimated 1

- in

- 10 year annual mean residue of flumetsulam for chronic

surface water u sing PRZM/EXAMS was 1.4 5 ppb, based on application on the K ansas corn scenario . The estimated flumetsulam residue using PRZM

- GW model for chronic ground water

EDWC was 14.8 ppb (J. Wolf, D411277, 8/16/2013).Flumetsulam Human Health Risk Assessment DP No. D411276

Page 19 of 40 Table 4.3

- Maximum Flumetsulam EDWCs for Corn scenario in Surface Water and

Groundwater

Drinking Water Source
(Model) 1

- in

- 10 y ear 30

- year Ave rage 30

- y ear

Simulation

Acute Chronic Cancer Acute Chronic

(μg/L /ppb )

Surface Water ( PRZM/EXAMS) 6.68 1.45 0.76

- - Groundwater (PRZM

- GW)

- - - 19.8 14.8

4

. 4 Dietary Risk Assessment

An aggregate dietary food and drinking water, exposure and risk assessment was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16 . This software uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). The analysis also incorporated the highest estimated flumetsulam residue in water provided by EFED

. In a chronic dietary risk assessment, risk is expressed as a percentage of a maximum acceptable dose (i.e., the

dose which HED has concluded will result in no unreasonable adverse health effects). The population

- adjust ed chronic dose or cPAD is equivalent to the reference dose (RfD) divided by the Food Quality Protection Act (FQPA) Safety Factor. D ietary risk assessments incorporates both exposure and toxicity data for a given pesticide.

4.4.1 Description of Residue Data Used in Dietary Assessment

T olerance

- l evel residues were used for all registered commodities in the unrefined chronic aggregate dietary analysis for flumetsulam . For drinking water, the highest estimated chronic drinking water concentration of 14.8 ppb from grou nd water sources was used

.

4.4.2 Percent Crop Treated Used in Dietary Assessment

It was assumed that 100% of the registered crop s were treated (100%CT) in the unrefined chronic aggregate dietary analysis for flumetsulam.

4.4.3 Acute Dietary Risk Assessment

Since n o appropriate endpoints were identified from the available flumetsulam toxicity studies

, an acute dietary exposure risk assessment is not required.

4.4.4 Chronic Dietary Risk Assessment

The chronic dietary exposure analysis results for the general U.S. population, all infants (less than 1 year old), children 1

- 2, children 3

- 5, children 6

- 12, youth 13

- 19, females 13

- 49, adultsFlumetsulam Human Health Risk Assessment DP No. D411276

Page 20 of 40 20

- 49, and adults 50

- 99 years. The resulting food exposure estimates are below HED’s level of

concern for the U.S. population and all population subgroups at less than 1% of cPAD.

4.4.5 Cancer Dietary Risk Assessment

Since flumetsulam is classified as Group E (Evidence of non

- carcinogenicity for humans), no cancer dietary risk exposure risk assessment is required.

4.4

. 6 Dietary Risk Assessment Summary Table

Table 4.4.6. Summary of Dietary (Food and Drinking) Exposure and Risk for Flumetsulam.

Population Subgroup Acute Dietary Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) %

aPAD Dietary Exposure

(mg/kg/day) %

cPAD Dietary

Exposure (mg/kg/day) Risk

General U.S. Population

N/A N/A 0.000435

< 1 N/A N/A All Infants (<1 year old) 0.001007

Children 1

- 2 years old 0.000735

Children 3

- 5 years old 0.000665

Children 6

- 12 years old 0.000481

Youth 13

- 19 years old 0.000372

Adults 20

- 49 years old 0.000420

Adults 50

- 99 years old 0.000376

Females 13

- 49 years old 0.000412

5.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are currently no registered residential uses associated with flumetsulam . Any future proposed residential uses could impact the human health aggregate risk assessment for

flumetsulam.

5

. 1 Spray Drift

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays t hat are released and do not deposit in the application area end up off

-Flumetsulam Human Health Risk Assessment DP No. D411276

Page 21 of 40 target and can lead to exposures to those it may directly contact. They can also deposit on surfaces where contact with residues can eventually lead to exposures ( e.g. , children playing on lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling coupled with methods employed for residential risk assessments for turf products.

The approach to be u sed for quantitatively incorporating spray drift into risk assessment include assessing exposures for children (1 to 2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an expos ure scenario. Aside from the predicted residues available for transfer, the routes of exposure and assessment methodology is analogous to how exposures to turf products are considered in risk assessment.

In order to evaluate the drift potential and ass ociated risks, an approach based on drift modeling coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, a residential turf assessment based on exposure to deposited residues has been completed to

address drift from the agricultural applications of flumetsulam. In the spray drift scenario, the deposited residue value was determined based on the amount of spray drift that may occur at varying distances from the edge of the treated field using the AgDrift ( v2.1.1) model. E xposures were considered for 50 feet wide lawns where the nearest side of the property was directly adjoining the treated field (at field edge) and at varied distances up to 300 feet downwind of a treated field. Once the deposited residue values w ere determined, the remainder of the spray drift assessment was based on the algorithms and input values specified in the recently revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

.

A screening approach was developed f or situations where specific label guidance for application parameters is not available. 3 AgDrift is appropriate for use only when applications are made by aircraft, airblast sprayers, and groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 1 option) were incorporated into the model and represent each equipment type and use under varied conditions. The screening options specifically recommended in this methodology were selected bec ause they are plausible and represent a reasonable upper bound level of drift for common application methods in agriculture. In all cases, each scenario is to be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides a re not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are not allowed).

The spray drift risk estimates are based on an estimated deposited residue concentration as a result of the screening level agricultur al application scenarios. Flumetsulam is used on soybeans field corn, and dry beans. The chemical can be applied via groundboom and for field corn and soybeans by aerial equipment. The recommended drift scenario screening level options are listed

below:

Groundboom applications are based on the AgDrift option for high boom height and
using very fine to fine spray type using the 90 th percentile results.

3 Note that for many cases the scenarios outlined in the screening approach represent actual use practice.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 22 of 40 Aerial applications are based on the use of AgDrift Tier 1 aerial option for a fine to
medium spray ty pe and a series of other parameters which will be described in more
detail below (e.g., wind vector assumed to be 10 mph in a downwind direction for entire
application/drift event).

There are no dermal endpoints selected for flumetsulam, therefore adult an d children (1<2 years old) dermal spray drift exposure was not assessed. However the HtM exposure for children 1<2 years old was assessed using the incidental oral endpoint from a chronic oral dog study with an oral NOAEL of 100 mg/kg/day. The total appl icable Level of Concern is 100 so MOEs < 100

would be of concern.

Results are presented in Table 1: Appendix D , “Residential Exposure to Flumetsulam from Agricultural Drift for Children Ages 1<2 years Hand to Mouth, HtM only.” The spray drift risk estimates indicate that there are no major risk concerns from aerial and ground boom applications to field corn, and soybeans from field edge. In addition there are also no major spray drift risk concerns for the ground application to flumetsulam to dry beans from field edge.
All MOE estimates were ≥ 100 and ranged from 370,000 to 4,000,000 at edge

. Risk estimates for the varying flumetsulam product formulations, (i.e. water dispersible granular and emulsifiable concentrate) were below the level of concern, MOEs <100. The risk can be even further reduced by ch anging nozzle types with c oarser sprays resulting in less drift.

5.2 Inhalation Post

- application Exposure

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

- application inhalation exposure assessment was not performed for flumetsulam at this time primarily because of the low acute inhalation toxicity (Toxicity Category III and IV), low vapor pressure 1.0 x 10 - 15 mm HG @ 25 ̊

C , and the low proposed use rate ( 0.05 lb ai/A and 0. 07 lb ai/A). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought exper t advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 4 . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or p rocedures are developed, the Agency may revisit the need for a quantitative post

application inhalation exposure assessment for flumetsulam.

A n inhalation exposure assessment was performed for flaggers exposed from aerial application

of flumetsulam . This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

application inhalation exposure scenarios. The estimated MOE for flaggers is 930,000 which i s well above the margin of concern of 100 ; i.e., not a risk concern

.

4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlFlumetsulam Human Health Risk Assessment DP No. D411276

Page 23 of 40 6.0 Aggregate Exposure/Risk Characterization

Aggregate risk assessments evaluate the combined risk from dietary exposure (food and water) and any non

- occupational (residential) uses. There are currently no registered residential uses

associated with flumet sulam ; therefore, a residential/non

- occupational exposure assessment is not required. As a result, the flumetsulam aggregate risk assessment includes only dietary exposure (food and water). An acute dietary exposure assessment was not performed as n o appropriate endpoints were identified from the available flumetsulam toxicity studies for the acute dietary scenario

. The c hronic d ietary exposure estimates from food and drinking water do

not exceed HED’s level of concern

. A cancer dietary exposure assessment was not performed as

f lumetsulam is classified as Group E (Evidence of non

- carcinogenicity for humans). Sectio ns 4 .4. 4 and 4 .4. 5 discuss the chronic and dietary (food and water) exposure assessments.

7.0 Cumulative Exposure/Risk Characterization

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

to flumetsulam and any other substances

. For the purposes of this assessment , therefore, EPA

has not assumed that flumetsulam has a common mechanism of toxicity with other substances.

For informatio n 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 Pesticide Programs concerning common mechanism

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

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

.

8.0 Occupational Exposure/Risk Characterization

Flumetsulam is currently registered on field corn, soybean and dry bean by ground and aerial applications (see Table 2.3)

. Based on the existing use pattern for flumet s u lam , there is potential

for both occupational handler and occupation al post

- application exposure to occur. There is a potential for agricultural handlers and post

- application workers to have dermal exposure to flumetsulam during the course of typical agricultural activities. However, quantification of

dermal risk assessme nt is not required for this exposure due to lack of dermal, systemic, neuro, or developmental toxicity concerns. Therefore, only inhalation exposure was assessed for

handlers.

8 .1 Occupational Handler Exposure and Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 24 of 40 Based on the currently registered use patterns and types of equipment and techniques that can potentially be used, occupational handler exposure is expected for flumetsulam . The quantitative exposure/risk assessment developed for occupational handlers i s based on the following

scenarios:

1) Mixing/loading water dispersible granular (WDG) for groundboom application,
2) Mixing/loading WDG for aerial application,
3) Mixing/loading water soluble packet (WSP) for groundboom application,
4) Mixing/loading WSP for aerial application,
5) Mixing/loading emulsifiable concentrate for ground application,
6) I mpregnating dry bulk fertilizer with EC, WDG, and WSP formulations.
7) Applying liquid spray with a groundboom,

8) Applying liquid spray with aerial application; and
9) Flagger scenario.

F ield corn
, soybeans , and dry beans are considered to be high acreage crops and it is unlikely that a farmer would apply the chemical with handheld equipment because of acreage size. Therefore, the handheld equipment scenario was not included i n this assessment.

For impregnation of dry bulk fertilizer, the product labels provide the amount of product to be applied to a ton of fertilizer based on the pounds of fertilizer used per acre and amount of product recommended per acre. Flumetsulam labe l s require a minimum of 200 pounds of dry fertilizer per acre multiplied by the label rate per acre with a conversion fact of 2000 lbs per ton. HED does not have data regarding the mixing/loading or the application of flumetsulam impregnated dry bulk fert ilizer. Additionally, HED does not have scenario specific exposure data for impregnated dry bulk fertilizer. However, a mixing and loading processing rate of dry bulk fertilizer has been calculated to be 960 tons of fertilizer processed per 8 hour day. This rate was supplied by a registrant concerning the chemical alachlor and is referenced in the RED document D330812. The processing rate and label specific information specifying a closed system for impregnating the fertilizer with flumetsulam was achie ved using this exposure surrogate data. HED assumed closed mixing/loading for commercial applications as the exposure scenario. On

farm application was then assessed using an open cab spreader as surrogate data with 320 acres/day for commercial equipment

.

It is the policy of HED to use the best available data to assess handler exposure. Sources of generic occupational handler data, used as surrogate data in the absence of chemical

- specific data, include the Pesticide Handlers Exposure Database Version 1 .1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data) and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting occupational handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Un it Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf), which, along withFlumetsulam Human Health Risk Assessment DP No. D411276

Page 25 of 40 additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

data.html

.

8 .1.1 Short

- /Intermediate

- Term Non

- Cancer Handler Exposure and Risk

HED classifies exposures from 1 to 30 days as s hort

- term and exposures 30 days to six months

as intermediate

- term. For flumetsulam based on the use pattern for application to field corn and soybeans, and dry beans short

- term exposure is expected however it is possible that large agribusiness or commer cial applicators could apply flumetsulam over a period of weeks. Therefore intermediate exposure could be expected as well. The same endpoints were selected

for short

- term and long term exposure. Long

- term exposures are not expected ; therefore, a long

t erm assessment was not conducted.

Short

- and intermediate

- term occupational handler exposure and risks were estimated using 1) unit exposures taken from the “Occupational Pesticide Handler Unit Exposure Surrogate

Reference Table” ; 2) the maximum flumetsulam label application rates ; and 3) amount
handled/area treated values take from ExpoSAC SOP No. 9.1, “Standard Values for Daily Acres Treated in Agriculture ”.

There is a potential for agricultural handlers and post

- application wor kers to have dermal exposure to flumetsulam during the course of typical agricultural activities. However , there is no hazard identified for dermal exposure. Therefore, only inhalation exposure was assessed for

handlers.

Table 8 .1.1 presents the estimat ed inhalation occupational handler risk estimate s for the curr ently registered uses of flumetsulam at baseline personal protective equipment (PPE)

. Baselines PPE

is defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoe s plus socks, no protective gloves, and no respirator . T he short

- and intermediate

- term risk estimates

for all occupational handler scenarios do not exceed HED’s level of concern (MOEs > 100 )

. The occupational handler inhalation risk estimates range from 11,000 to 19,000,000. HED notes that

current flumetsulam labels require PPE consisting of a long

- sleeved shirt, long pants, shoes plus socks, and pair of chemical

- resistant gloves for all appli cators and other handlers.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 26 of 40 Table 8.1.1

- Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flumetsulam Use on Field Corn and Soybeans at Baseline 1

Exposure Scenario Crop Inhalation Unit Exposure (μg/lb ai) 2 Maximum
Application Rate 3 Area Treated or

Amount Handled Daily 4 Inhalat ion

Mitigation Level Dose (mg/kg/day) 5 MOE 6

Mixer/Loader

Aerial
Water Dispersible Granular Field Corn and Soybeans 8.96
No Respirator

0.07 lb a.i./acre

0.7 lb ai/ton of

fertilizer 1200 acres 0.0094 11,000

Aerial

Water Soluble Packet 7

Field Corn and Soybeans 0.24

EC 0.0003 400,000

Ground

Water Soluble Pack 7
impregnating fertilizer 0.24

EC
Closed System 960 tons of fertilizer 0.00201 50,000 Ground
Water Dispersible Granular
impregnating fertilizer

Ground

Emulsifiable Concentrate impregnating fertilizer Field Corn 0.083

EC
Closed System 0.05 lb a.i./acre

0.5 lb a.i/ton of

fertilizer 0.0005 200,000

Ground

Emulsifiable Concentrate 0.219
No Respirator

200 acres 0.00003 3,600,000

Ground
Water Dispersible Granular Field Corn and Soybeans 8.96
No Respirator 0.07 lb a.i./acre 0.0016 64,000

Ground

Water Soluble Packet 0.24

EC 0.00004 2,400,000

Ground

Emulsifiable Concentrate impregnating fertilizer

Dry beans 10 0.083

EC
Closed System 0.07 lb a.i./acre

0.7 lb a.i./ton of

fertilizer 960 tons of fertilizer 0.0007 140,000

Ground

Emulsifiable Concentrate 0.219
No Respirator

200 acres 0.00004 2,600,000

Ground
Water Dispersible Granular 8.96
No Respirator 0.0016 64,000Flumetsulam Human Health Risk Assessment DP No. D411276

Page 27 of 40 Table 8.1.1

- Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flumetsulam Use on Field Corn and Soybeans at Baseline 1

Exposure Scenario Crop Inhalation Unit Exposure (μg/lb ai) 2 Maximum
Application Rate 3 Area Treated or

Amount Handled Daily 4 Inhalat ion

Mitigation Level Dose (mg/kg/day) 5 MOE 6

Applicator

Aerial 8

Water Dispersible Granular

within a Water Soluble

Packet Field Corn and

Soybeans 0.0049

EC
Closed Cockpit

0.07 lb a.i./acre 1200 .0000052 19,000,000

Ground
Water Dispersible Granular and Water Dispersible

Granular within a Water

Soluble Packet Field Corn,

Soybeans, and Dry Beans 0.34
No Respirator 200 0.00006 1,700,000

Ground

Emulsifiable Concentrate Field Corn s 0.05 lb a.i./acre 0.00004 2,400,000

Dry Beans 0.07 lb a.i./acre 0.00006 1,700,000

Impregnated Fertilizer 9

Tractor drawn spreader Field Corn, Soybeans, Dry

Beans 1.2

No Respirator 0.07 lb a.i./acre 360 acres 0.00034 300,000

Impregnated Fertilizer 9

Tractor drawn spreader Field Corn and Soybeans 0.05 lb a.i./acre 360 acres 0.00024 420,000

Flagger

Sprays
Water Dispersible Granular

within a Water Soluble

Packet Field Corn, and

Soybeans 0.35
No Respirator 0.07 lb a.i./acre 350 0.00011 930,000

1 Baseline PPE includes long sleeved pants, long sleeved shirt, shoes and sock and no respirator.

2 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table; Level of mitigation: No respirator , EC = Engineering Controls

3 Based on registered or proposed labels for flumetsulam. See Profile Table 4.1

4 Exposure Science Advisory Council Policy #9.1.

5 Inhalation Dose = Inhalat ion Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated or Amount Hand led Daily (A) ÷ BW (kg).

6 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

7 Water Soluble Packets, or WSPs are considered an engineering control. Unit exposures for chemicals packaged this way are lower than baseline which ass umes no respirator

8 Aerial application is assumed to be done with closed cockpit which is considered an engineered control not ba seline protection.

9 EPA reg number 62719

- 570 label notates for impregnating fertilizer use a minimum of 200 lb of dry bulk fertilizer per acre with maximum of 3 pints of product per acre.

10 Dry Bean use scenarios and application rates based on inactive registration numbers and 2004 memo D306178

.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 28 of 40 8 .1. 2 Cancer Handler Exposure and Risk

A cancer handler exposure and risk assessment was not performed as f lumetsulam is classified as Group E (Evidence of non

- carcinogenicity for humans).

8. 2 Occupat ional Post

- Application Exposure and Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treat ed with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- ap plication exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pestici de applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

8 .2.1 Post

- application Inhalation Exposure

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

- application inhalation exposure assessment was not performed for flumetsulam at this time primarily because of the low acute inhalation toxicity (Toxicity Category III and IV), low vapor pressure 1.0 x 10 - 15 mm HG @
25 ̊C , and the low proposed use rate s (0.07 and 0.5 lb ai/A). However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated fields. Th ese potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fun gicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 5

. The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data

ge nerated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

application inhalation exposure into the Agency's risk assessments . If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational

post

- application inhalation exposure assessment for flumetsulam

.

Although a quantitative post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure

t han post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure

scenarios.

8 .2.2 Post

- application Dermal Exposure and Risk

5 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlFlumetsulam Human Health Risk Assessment DP No. D411276

Page 29 of 40 8.2.2.1 Short

- /Intermediate

- Term Non

- Cancer Post

- application Exposure and Risk

A quantitative occupational post application dermal exposure assessment was not performed due to lack of dermal endpoint selection.

Restricted Entry Interval The REI specified on th e proposed label i s based on the acute toxicity of flumetsulam

. Flumetsulam is classified as Toxicity Category III or IV via the dermal route and skin irritation potential. It is not a skin sensitizer. Short

- and intermediate

- term post

- application risk estimates were not a concern on day 0 (12 hours following application) for all post

- application activities.

Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation a re assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to flumetsulam

. Products that include a

formulated mixture of active ingredient should retain the 48 hour REI.

8

. 2

. 2.2 Cancer Post

- application Exposure and Risk

A cancer post

- application exposure and risk assessment was not performed as f lumetsulam is classified as Group E (Evidence of non

- carcinogenicity for humans).Flumetsulam Human Health Risk Assessment DP No. D411276

Page 30 of 40 References

Ary, S. (2004)

. Flumetsulam. Summary of Analytical Chemistry and Residue Data for the Tolerance Reassessment Eligibility Decision (TRED) Document. PC Code: 129016, DP

Number: D306242

. August 31, 2004.

Barnes, P.Y. (2013). Flumetsulam Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for Registration Review. PC Code: 129016, DP Number:

D412998 , September 2013.

Bobowiec , B. (2013). Flumetsulam. Occupational and Residential Exposure Registrat ion

Review Assessment

. PC Code: 129016, DP Number: D415189 , September 2013.

Dod d, N (1993). Flumetsulam Metabolism in Soybeans and Field Corn, The HED Metabolism Committee Meeting Held on 04/21/1993

. April 26, 1993

Dodd, N

. , “Issues to be Presented at the 4/21/93 Meeting of the HED Metabolism

Committee.”

Dodd, N. (1993)

. PC Code: 129016 , DP Numbers: D188957 and D190750 . June 28, 1993

Dodd, N. (1993). Flumetsulam (DE

- 498) on Soybeans and Corn. PC Code: 129016, DP

Number: D189444). Evaluation of Method Trial Report dated 3/19/93.

Dodd, N (1993)

. Flumetsulam (DE

- 498) o n Soybeans and Corn. Amendments dated 9/25/92, 10/8/92, 11/30/92, and 12/7/92

. PC Code: 129016, DP Number s: D183274, D18440 5/D184530, D185716, and D185720.

Dow, Mark I. (2004)

. Flumetsulam

- Exposure/Risk Assessment for Flumetsulam Applied to Dried Bean. PC Code: 129016, DP Number: D306178. August 10,

2004.

Reaves, E. and Ary, S.(2004). [Flumetsulam:] Revised Phase 2 HED Chapte r of the Tolerance

Reassessm ent Eligi bility Decision Document (TRED). PC Code: 129016, DP Barcode: D306238. November 22, 2004

Recore, S., S.C. Dapson, . Barnes, P.Y (2008). Flumetsulam. Amended Human Health Assessment Scoping Document in Support of Registration Review ; PC Code: 129016 ; DP

Number: D 349638

. August 12, 2008

.

Recore, S. (2013). Flumetsulam : Review of Human Incidents for Preliminary Risk Assessment. PC Code: 129016, DP Number: D412985 . July 10, 2013.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 31 of 40 Van Alstine, J . (2013). Flumetsulam: Summary of Hazard and Science Policy Council (HASPOC) Meetings: Recommendations on the need for an inhalation study. Sept, 5, 2013

, TXR No. 0056689.

Wolf, J.K. (2013). Registration Review Drinking Water Assessment for Flumetsulam. PC

Code: 129016

, DP Number: D411277. August 16, 2013.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 32 of 40 Appendix A. Toxicology Assessment

A.1 Toxicology Data Requirements The requirements (40CFR §158.3 40) for food use of flumetsulam are in Table A.1.

TABLE A.1

- Toxicology Data Requirements for Flumetsulam

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (non

- rodent)

870.3200 21/28

- Day Dermal

870.3250 90

- Day Dermal

870.3465 90

- Day Inhalation yes

yes

yes

no

yes yes

yes

yes

no

yes a

870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (non

- rodent) 870.3800 Reproduction yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (non

- rodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation (bacterial) 870.5300 Mutagenicity

— Gene Mutation (mammalian) 870.5375 Mutagenicity

— Structural Chromosomal Aberrations 870.5395 Mutagenicity

— Other Genotoxic Effects yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90

- Day Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90

- Day Neurotoxicity Screening Battery (rat) 870.6300 Developmental Neurotoxicity no

no

yes

yes

no no

no

yes

yes

no

870.7485 General Metabolism

870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

no

yes yes

no

yes

a Inhalation study is waived by the HASPOC.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 33 of 40 A.2 Toxicity Profile

TABLE A.2.1

- Acute Toxicity Profile for Flumetsulam

Guideline

Number Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [Rat] 41263202 LD 50 >5000 mg/kg (M/F) IV

870.1200 Acute dermal [Rabbit] 41263203 LD 50 >2000 mg/kg (M/F) III

870.1300 Acute inhalation [Rat] 41556501 LC 50 >0.65 mg/L (M/F) IV

870.2400 Acute eye irritation [Rabbit] 41263204 Slight conjunctival reddening and

chemosis and iridal redness at 1 hour IV

870.2500 Acute dermal irritation [Rabbit] 41263205 Not an irritant IV

870.2600 Skin sensitization [Guinea pig] 41263206 Not a skin sensitizer NA

TABLE A.2.2

- Subchronic, Chronic, and other Toxicity Profile for Flumetsulam

Guideline Number/ Study Type MRIDs/Year/Doses

Classification Results

870.3100

90

- Day oral toxicity,

Rat 41263212 (1988) 0, 250, 1000, 2000/2500 mg/kg/day Acceptable/Guideline NOAEL (M/F) 250 mg/kg/day LOAEL (M/F) 1000 mg/kg/day based on severe bilateral

tubular

- interstitial nephritis.

870.3100

90

- Day oral toxicity,

Mice 41931704 (1987)

0, 100, 500, 1000, 5000 mg/kg/day Acceptable/Guideline NOAEL (M/F) 5000 mg/kg/day (98.6% a.i.) LOAEL (M/F) Not identified. Statistically increased full cecum weights and decreased kidney weights were found at 5000 mg/kg/day but were considered adaptive and/or toxicologically irrelevant.

870.3200

21

- Day Dermal,

Rabbit 41931706 (1990)

0, 100, 500, 1000 mg/kg/day

Acceptable/Guideline Systemic & dermal NOAEL (M/F) >1000 mg/kg/day. LOAEL (M/F) Not identified

Diffuse treatment

- related epidermal hyperplasia observed at application site.

870.3700a

Developmental Toxicity,

Rat (GD 6

- 15) 41263213, 41615301 (1990) 0, 100, 500, 1000, mg/kg/day Acceptable/Guideline Maternal NOAEL 500 mg/kg/day Maternal LOAEL 1000 mg/kg/day, based on statistically increased full cecum weights and decreased kidney weights, but considered adaptive and/or toxico logi cally

irrelevant. Developmental NOAEL >1000 mg/kg/day Developmental LOAEL Not identified. No developmental toxicity reported.

870.3700b

Developmental Toxicity,

Rabbit (GD 7

- 19) 41931709 (1989)

0, 100, 500, 700 mg/kg/day

Acceptable/Guideline Maternal NOAEL=100 mg/kg/day Maternal LOAEL= 500 mg/kg/day based on anorexia, moribundity, and decreased body weight gain (GD 10

- 13

at 500 and GD 7

- 10 at 700 mg/kg/day) Developmental NOAEL> 700 mg/kg/day Developmental LOAEL= Not identified

870.3800

Reproduction (2

- 41931710 (42474001) (1990) 0, 100, 500, 1000 Reproductive NOAEL >1000 mg/kg/day Reproductive LOAEL Not identified Offspring NOAEL > 1000 mg/kg/dayFlumetsulam Human Health Risk Assessment DP No. D411276

Page 34 of 40 TABLE A.2.2

- Subchronic, Chronic, and other Toxicity Profile for Flumetsulam

Guideline Number/ Study Type MRIDs/Year/Doses

Classification Results

Generation),

Rat mg/kg/day

Acceptable/Guideline Offspring LOAEL Not identified

Parental NOAEL >1000 mg/kg/day

Parental LOAEL Not identified

870.4100b

Chronic Feeding,

Dog 41952103 (1991)

0, 20, 100, 500 mg/kg/day

Acceptable/Guideline Systemic NOAEL (M) = 100 mg/kg/day Systemic NOAEL (F) >500 mg/kg/day Systemic LOAEL (M) = 500 mg/kg/day based on renal inflammatory and atrophic changes secondary to renal calculi and hepatic effects consisting of inflammation, focal necrosis, and biliary stasis LOAEL (F) Not identified

870.4200b

Carcinogenicity,

Mouse 41931708 (1991) 0, 100, 500, 1000 mg/kg/day Acceptable/Guideline Systemic NOAEL (M/F) > 1000 mg/kg/day LOAEL (M/F) Not identified Not evidence for carcinogenicity in M/F

870.4300

Chronic/Oncogenicity, 2

- Year

Rat 41931707 (1991)

0, 100, 500, 1000 mg/kg/day

Acceptable/Guideline NOAEL (M) = 500 mg/kg/day NOAEL (F) > 1000 mg/kg/day LOAEL (M) = 1000 mg/kg/day based on dilated renal pelvises containing renal calculi, atrophy of renal papillae, renal pelvic epithelial hyper plasia, and mineralization of pelvic epithelium LOAEL (F) Not identified

Not evidence for carcinogenicity in M/F

870.5100

Ames bacterial mutagenicity test 41263214 (1988)

Acceptable/Guideline Salmonella

- Negative in strains TA98, TA100, TA1535, TA1537, and TA1538 with and without metabolic

activation at concentrations of 0.01

- 1.0 mg/plate

870.5300

In vitro mammalian cell gene mutation test (Chinese hamster ovary cells) 41263217 (1988) Acceptable/Guideline The study was negative at concentrations from 500 to 3000 μg/mL with and without metabolic activation with

Arochlor 1254 induced rat liver S

- 9

870.5395

In Vivo Micronucleus Assay 41263216 (1988)

Acceptable/Guideline Negative for micronucleus induction in bone marrow cells

of male and female CD

- 1 mice at 24 hrs after oral gavage

administration of 500 to 5000 mg/kg.

870.5550

Unscheduled DNA Synthesis 41263215 (1988)

Acceptable/Guideline Negative at concentrations from 3.16 x 10 - 6 to 3.16 x 10 - 4

M

870.7485

General Metabolism,

Rat and Mouse 41931711 (1991) 41993801 (1988)

Acceptable/Guideline Absorbed test material (52

- 63%) excreted unchanged in urine. Unabsorbed test material eliminated unchanged in feces. Test material essentially eliminated within 48 hours by male and female rats. Plasma 14 C exhibited a dose

dependent increase in absorption and elimination. Increasing dose associated with increasing clearance possibly due to saturation of plasma binding sites. Male mice exhibited faster absorption and elimination at 1000Flumetsulam Human Health Risk Assessment DP No. D411276

Page 35 of 40 TABLE A.2.2

- Subchronic, Chronic, and other Toxicity Profile for Flumetsulam

Guideline Number/ Study Type MRIDs/Year/Doses

Classification Results

mg/kg than male ra ts. Urine primary elimination route in

both male and female rats and mice. Two minor

metabolites identified in urine in mice.

870.6200

Acute Neurotoxicity

Rat 48297902 (2009)

0,250,1000, 2000 mg/kg

Acceptable/Guideline Systemic/neurotoxicity NOAEL=2000 mg/kg

No evidence of neurotoxicity

870.6200

Subchronic Neurotoxicity

Rat 48798101 (2012)

0, 100, 300, 1000 mg/kg/day

Acceptable/Guideline Systemic/neurotoxicity NOAEL=1000 mg/kg/day

No evidence of neurotoxicity.

870.7800

Immunotoxicity

Rat 48694401 (2011)

0, 1000 mg/kg/day

Acceptable/Guideline Systemic/Immunotoxicity NOAEL=1000 mg/kg/day

No evidence of immunotoxicityFlumetsulam Human Health Risk Assessment DP No. D411276

Page 36 of 40 Appendix B. Physical/Chemical Properties

Table B.1

- Physicochemical Properties of the Technical Grade Test Compound

Flumetsulam.

Parameter Value Reference /Comment

Melting point 252.9 °C N. Dodd, PP# 1G4006,

03/27/1992 pH 3.44 at 24.4 °C for a 10% suspension in water Density 1.77 g/cm 3 at 21°C

Water solubility 49.1 ± 0.5 mg/L at 25 °C, pH 2.5 5.65 ± 0.01 g/L at 25 °C, pH 7.0

Solvent solubility (g/L) 17.0 g/L in acetone N. Dodd, PP# 2F4036,

04/14/1993 5.2 g/L in acetonitrile 0.0016 g/L in aromatic 100 9.0 g/L in cyclohexanone 261.0 g/L in dimethylformamide Less than 0.001 g/L in hexane 3.3 g/L in methanol Less than 0.001 g/L in o

- xylene 0.06 g/L in octanol 11.0 g/L in tetrahydrofuran

Vapor pressure 1.0 x 10 - 15 mm Hg at 25 °C N. Dodd, PP# 1G4006,

03/27/1992

Dissociation constant pK

a = 4.6 Octanol/water partition coefficient Log(K OW ) log P = 0.21

Henry’s Law Constant (25 o C) 6.14e
- 15 atm

- m 3 /mol @25 ° C Calculated

Aerobic Soil Metabolism Half

- life (ASM) ( T 1/2 ) 93 , 48, 47, 30, 23 , 44, 88, 36,19, 81,51,28, 44, 130, 13, 17, 20, 46, 60 , 59, 102 days [ range 13 to 130 days; mean = 51.0 days] T 1/2 indentified in the problem formulation 23 , 60, 93, 102 days; mean = 69,5 days ( MRID 41263230 ). Anaerobic Aquatic Soil Metabolism 183 days
Aerobic Aquatic Metabolism Half

- life (days)
1762 [ 14 C

- pyrimidine ring] days 1319 [ 14 C

- analine ring] days Studied reviewed but DER has not been completed by

EFED

.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 37 of 40 Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the Pesticide Handlers Exposure Database (PHED), the Outdoor Residential Expo sure Task Force (ORETF) Database, the Agricultural Handler Exposure Task Force (AHETF), and the Agricultural Reentry Task Force (ARTF) have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethically conducted.Flumetsulam Human Health Risk Assessment DP No. D411276

Page 38 of 40 Appendix D. Occupational Exposure/Risk Summary Tables

Table D

. 1

- Residential Exposure to Flumetsulam from Agricultural Drift for Children Ages 1<2 years Hand to Mouth, HtM only

Crop/Rate Group Spray Type/

Nozzle Configuration Application

Rate (lb ai/A) Estimated

or Adjusted

TTR t (ug/cm2) At Edge 10 Fee t 25 Feet 50 Feet 75 Feet 100 Feet 125 Feet 150 Feet 200 Feet 250 Feet 300 Feet

HtM

MOE HtM

MOE HtM

MOE HtM

MOE HtM

MOE HtM

MOE HtM

MOE HtM

MOE HtM

MOE HtM

MOE HtM

MOE

Soybeans, Field Corn, and Dry Beans 1

Aerial Fine to

Medium

0.07 0.0077805 370000 450000 560000 730000 960000 1200000 1500000 1700000 2300000 2800000 3400000

Medium to

Coarse 440000 600000 820000 1100000 1600000 2100000 2700000 3200000 4500000 5900000 7200000

Coarse to Very

Coarse 510000 760000 1100000 1800000 2500000 3400000 4300000 5200000 7200000 9400000 12000000

Very Fine to

Fine 250000 280000 310000 360000 420000 480000 540000 610000 740000 870000 990000

AT401, M, 10 mph, 37% SD 400000 510000 660000 890000 1200000 1600000 1900000 2200000 2900000 3600000 4500000

WASP, M, 10 mph, 37% SD 430000 550000 730000 1100000 1500000 1900000 2300000 2800000 3600000 4500000 5200000

AT401, C, 10 mph, 25% SD 470000 670000 950000 1400000 2000000 2600000 3200000 3900000 5500000 7200000 8500000

WASP, C, 10 mph, 25% SD 550000 780000 1100000 1800000 2500000 3400000 4100000 5200000 7200000 9400000 10000000

AT401, VC, 10 mph, 20% SD 540000 820000 1300000 2100000 3000000 4100000 5200000 6700000 9400000 12000000 16000000

WASP, VC, 10 mph, 20% SD 680000 1100000 1600000 2600000 3800000 4900000 6700000 7800000 12000000 13000000 16000000

Groundboom High Boom

Very fine to

Fine 500000 1000000 1700000 2700000 3800000 4700000 5500000 6700000 8500000 12000000 13000000

Low Boom Very fine to

Fine 1100000 2900000 4700000 7200000 9400000 12000000 13000000 16000000 19000000 23000000 31000000

High Boom

Fine to

Medium/Coarse 1900000 4900000 7200000 10000000 13000000 16000000 19000000 19000000 23000000 31000000 31000000

Low Boom

Fine to

Medium/Coarse 2800000 7800000 12000000 16000000 19000000 23000000 31000000 31000000 47000000 47000000 47000000

Field Corn

Groundboom High Boom

Very fine to

Fine 0.05 0.0055575 700000 1400000 2300000 3800000 5300000 6600000 7700000 9400000 12000000 16000000 19000000Flumetsulam Human Health Risk Assessment DP No. D411276

Page 39 of 40 Low Boom Very fine to

Fine 1500000 4100000 6600000 10000000 13000000 16000000 19000000 22000000 26000000 33000000 44000000

High Boom

Fine to

Medium/Coarse 2700000 6900000 10000000 15000000 19000000 22000000 26000000 26000000 33000000 44000000 44000000

Low Boom

Fine to

Medium/Coarse 4000000 11000000 16000000 22000000 26000000 33000000 44000000 44000000 66000000 66000000 66000000

1 No aerial application to dry beans. Only field corn and soybeansFlumetsulam Human Health Risk Assessment DP No. D411276

Page 40 of 40 Appendix E. Summary of US and International Tolerances and Maximum Residue Limits

Table E.1

- Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 Codex

40 CFR 180.468

Plant/Livestock: N

- (2,6

- difluorophenyl)

- 5

- methyl

- (1,2,4)triazolo(1,5

- a)pyrimidine

- 2

- sulfonamide) [1,2,4]triazolo[1,5

- a]pyrimidine

- 2

- sulfonmide,

N

- (2,6

- difluorophenyl)

- 5

- methyl

None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex Bean, dry, seed 0. 0 5 Corn, field, forage 0. 0 5 Corn, field, grain 0. 0 5 0.05 field corn
Corn, field, stover 0. 0 5 Soybean, seed 0. 0 5 0.05 dry soybeans

Completed: M. Negussie; 05/09/13

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.