### UNITED STATES ENVIRONME NTAL PROTECTION AGENCY WASHINGTON , D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PRE V ENTIO N



### MEMORANDUM
Dat e : 26

- NOV-20 1 4


### SUBJECT: Fl ufenp y r- Et h y l. H uman Health Assessment Scoping Do cument and Preliminary Human H ea l th Risk Assessment in Suppo rt of R eg i st ration Re view.
PC Co d e: I 08853 Decision No.: 49 259 4 Pe t iti on No .: N/ A DP Barcode: 0421190 Registration No.: N/ A Regulatory Act ion: R eg i stration Review Ri sk Assessment 

### Risk Assess ment Type: Si n gle 

### Case No .: 7262 Chemical/ Aggregate 

### TXR No .: NA CAS No.: 188489-07

- 8 MRID No.: NA 

# 7 40 CFR : § 

### 1 80.595 

## FROM: Jennifer R. 

## Ty ler , Chemist / 

# ff/1./M ; 

# ),_OZ

.

# ~

THR U:

TO: MoniqueM. Perr on, Sc.D. ,

# ljox**ico ;~** **1" ~** **~ ~**  

# £-"' _. Lata V enkateshwara,

## Envir**nrnental** Scientist

## z..~.n.... V c......, R isk Asse ssme nt Bran ch 1 (RAB 1) Hea lt h E ffec ts Div i s i on (HED; 7509P)
Charle s W. Smith II I , Bran ch Chief George F. Kramer, Ph.D. , Senior**~em~ ~~~-:':~~~;:;~~o**  

### RABl/H ED (7509 P)
S te ven Snyderman Pesticide Re-evaluation Divi s ion (PRD; 7508P)
As part of Registra t ion Review , PRD of the Office ofPesticide Program s (OP P) has reque sted t h at HED evaluat e th e hazard and expo sure data and conduct occupational and residential exposur e assessmen t s, as needed, to estimate the ris k to h uman heal t h that will result from the currently registe r ed uses of pesticides. Thi s memorandum serves as HED's scop i ng d ocu ment AND preliminary hu man health risk asses sme nt of the dietar y, occupational and resi dent ial exposure , and aggregate risk from the registered uses of flufenpyr-ethyl. The most recent quantitati ve human health risk assessment was performed in 2003, and was for the use of flufenpyr -ethyl on field corn, soybeans, and sugarc ane (Memo, 

### J

. Tyler 

### eta!., 31 -JUL-200 3; D27040 3). The fo llowing risk assessment updates have been made :

• Chronic dietary exposure assessm ent to include estimated d rinkin g water concentrations (E DWC s) and updated consumption data from t he Uni t ed States Dep artment of Agricu l ture (USDA) Nationa l H ealth and N utriti on Exami nation Survey / What We E at in America (NHANES/WWEIA; 2003 -2008);
• Quantitative sp ra y-drift exposure / ri s k assess men t; Pag e 1 of26Flufenpyr-ethyl Human Health Risk Assessment D421190


### • Aggregate exposure assessment to include updated dietary (food and drinking water) exposure estimates; and
• Occupational exposure assessment to reflect updates to HED's Standard Operating Procedures (SOPs) a lon g w i th policy changes for body weight assumpt i ons.
A summary of the findings and an assessment of human risk resulting from the registered uses of flufenpyr-ethyl are provided in this document. The risk assessment, dietary risk assessment, and residue chemistry review were provided by Jennifer Tyler (RAB 1 ), the occupational/residential exposure assessment was provided by L ata V enkateshwara (RAB 1 ), the hazard characterization was provided by Moniq u e Perron (RAB 1 ), and the drinking water assessment was provided by James Wolf of the Environmental Fate and Effects Division (EFED).

Page 2 of26Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 3 of 26 

### Table of Contents
1.0 Executive Summary

................................ ................................ ................................ .............. 4 2.0 Recommendations

................................ ................................ ................................ ................. 6 3.0 Ingredient Profile

................................ ................................ ................................ .................. 7 4.0 Hazard Identification/Toxicology

................................ ................................ ......................... 8 5.0 Dietary Exposure and Risk Assessment

................................ ................................ ............. 11 6.0 Residential (Non

- Occupational) Exposure and Risk Assessment

................................ ...... 13 7.0 Aggregate Exposure and Risk Assessment

................................ ................................ ......... 15 8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ...... 16 9.0 Occupational Exposure

................................ ................................ ................................ ....... 16 10.0 Public Health and Pesticide Epidemiology Data

................................ ................................ 18 11.0 References

................................ ................................ ................................ ........................... 18 Attachment 1: Chemical Identity Tables.

................................ ................................ ..................... 19 Attachment 2: Flufenpyr

- ethyl Acute, Subchronic, and Chronic Toxicity Profile.

...................... 20 Attachment 3: Registered Flufenpyr

- ethyl End Use Products and Use Patterns.

......................... 23 Attachment 4: Chronic Dietary Exposure Files.

................................ ................................ ........... 24 Attachment 5: Flufenpyr

- ethyl IRLS Sheet.

................................ ................................ ................. 26Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 4 of 26 

### 1.0 Executive Summary Flufenpyr

- ethyl is a contact herbicide and is a member of the pyridazinone class of pesticides. It is formulated as a water

- dispersible granule ( WDG ), and is c urrently registered for use on field corn, soybeans, and sugarcane. There are current ly no registered special local needs ( SLN ) or Section 18 Emergency Exemptions, and no pe nding PRIA actions for flufenpyr

- ethyl . The most recent quantitative human health risk assessment was performed in 20 0 3 in conjunction with the request for the use of flufenpyr

- ethyl on field corn , soybeans , and sugarcane ( Memo, J. Tyler et al. , 31

- JUL

- 2003; D270403 ).
HED has ev aluated the status of the human health risk assessments for flufenpyr

- ethyl to determine whether sufficient data are available and whether an y updates are needed to support Registration Review. Since the last human health risk assessment for flufenpyr

- ethyl , no new data have been submitted , and no changes have been made to the selected endpoints, toxicological points of departure (PODs) , or recommended tolerances . This doc ument incorporates changes made to HED policies, revised exposure and risk estimates, and a quantitative spray
- drift exposure /risk assessment

. Hazard Assessment and Dose Response Assessment : The toxicology database fo r flufenpyr

ethyl is complete except for subchronic inhalation, neurotoxicity (acute and subchronic), and immunotoxicity studies that are required in accordance with the current 40 CFR Part 158 Toxicology Data Requirements. The Hazard and Science Policy C ouncil (HASPOC) concluded , based on a weight

- of

- evidence approach , that these studies are not required at this time ( Memo, U. Habiba, 0 7

- OCT

- 2014; TXR#0057056). Therefore , t he toxicology database is complete to support existing registr ations and Registrat ion Review

. The endpoints , PODs, and safety factors (SFs) from the most recent human health risk assessment for flufenpyr

- ethyl are considered protective of all effects seen in the database. For all exposure scenarios, a 100

- fold uncertainty factor (UF) (10X for interspecies extrapolation, 10X for intraspecies variation, and 1X for Food Quality Protection Act ( FQPA ) SF if applicable) was applied. Residue Chemistry and Dietary Risk Estimates (Food + Drinking Water ): The residue chemistry database is adequate to support current Registration Review data requirements. Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the residue, and processing data are available to support the registered uses. Adequate methods are available for enforcement of the currently established tolerances. The dietary exposure database is adequate to support current Registration Review requirements. The chronic dietary exposure assessment was upd ated to reflect revised EDWCs using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID, ver. 3.16) which incorporates consumption data from USDA NHANES/WWEIA ( 2003

- 2008) . The unrefined [ tolerance

- level residues, 100% crop treated ( CT ) , DEEM (ver. 7.81) default processing factors, and modeled drinking water estimates ] chronic dietary (food and drinking water) exposure estimates are below HED’s level of concern [LOC; <100% of the chronic population

- adjusted dose ( cPAD) ] for t he general U.S. population and all population subgroups (<1% of the cPAD).
Re sidential (Non

- Occupational) Exposure and Risk Assessment: There are no proposed or current registrations for products containing flufenpyr

- ethyl that allow residential use. Th erefore, residential handler and conventional residential post

- application ex posure assessments were not conducted to support Registration Review. A quantitative spray driftFlufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 5 of 26 

### assessment was conducted. Risk estimates from groundboom and aerial applications are not of concern from the field edge for all scenarios considered. Aggregate

- Risk Estimates: There is sufficient information available to assess ag gregate exposure. In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking wa ter, and residential exposures. An acute aggregate risk assessment was not performed because an endpoint of concern attributable to a single oral dose was not selected for any popula tion subgroup (including infants and children). Short

- and intermediate

- term aggregate risk assessments were not performed because there are no registered residential non

- food uses. A cancer aggregate risk assessment was not performed because flufenpyr

- e thyl is classified as “ not likely to be carcinogenic to humans .” A chron ic aggregate assessment was included in this risk assessment, and is made up only of dietary sources; therefore, the exposure estimates provided in the dietary exposure analyses repre sent chronic aggregate exposure. Therefore, the chronic aggregate (food + drinking water) flufenpyr

ethyl risk estimates are not of concern to HED. Occupational Exposure and Risk Assessment: The occupational exposure database is adequate to support the Registration Review process for flufenpyr

- ethyl. There is the potential for occupational exposure from the registered uses of flufenpyr

- ethyl. These uses have been assessed using the most up

- to

- date exposure policies and data available. Since no dermal hazard was identified for flufenpyr

- ethyl, a quantitative dermal assessment was not conducted for the occupational uses of flufenpyr

- ethyl. The occupational handler exposure and risk estimates indicate that the short

- and intermediate

- term inhalation mar gins of exposure (MOEs) are not of concern to HED (i.e., MOE > the LOC of 100). Occupational post

- application dermal exposure and risk estimates were not quantitatively assessed since a dermal hazard was not identified. Based on the Agency's current prac tices, a quantitative non

- cancer occupational post

- application inhalation exposure assessmen t was not performed for flufenpyr

- ethyl at this time. If new policies or procedures are put into place, then the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for flufenpyr

- ethyl

. Environmental Justice Considerations: Potential areas of environmental justice concerns, to the extent possible , were co nsidered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations.” 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 data, which include studies from the Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task Force ( AHETF) database, and the Agricultural Reentry Task Force (ARTF) database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics revi ew may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the following Agency websites: http://www.epa.gov/pesticides/science/handler

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

- app
- exposure
- data.html

.Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 6 of 26 

### 2.0 Recommendations
HED has exam ined the toxicology and residue chemistry databases for flufenp yr
- ethyl. There are no residue chemistry, residential, occupational /residential , or toxicology data deficiencies that would preclude the continuation of permanent tolerances for residues of fl ufenpyr

- ethyl and its metabolites as outlined in Table 2.2.3 .1.
2.1 Data Deficiencies/Data Needs There are no data deficiencies for flufenpyr

- ethyl.
2.2 Tolerance Considerations
2.2.1 Enforcement Analytical Method For purposes of Registration Review, a dequate methods are available for enforcing the current tolerances. The gas chromatography /nitrogen/phosphorus detector (GC/NPD) method (Valent Method RM

- 36/RM

- 36

- 1) is adequate for determining residues of flufenpyr

- ethyl in/on corn raw agricultu ral commodities ( RACs ) and processed commodities, soybean RACs and processed commodities, and sugarcane. The gas chromatography/mass

- selective detector (GC/MSD) method (Valent Method RM

- 36

- 3c) is adequate for determining free and conjugated residues of S

- 3153 acid

- 4

- OH in/on corn forage and stover and sugarcane. Food and Drug Administration (FDA) multiresidue method (MRM) testing data have been submitted for flufenpyr

- ethyl and its metabolite S

- 3153

- acid

- 4

- OH. Acceptable recoveries for the parent compoun d only were obtained with Protocols D and F. These data were forwarded to the FDA for inclusion in the Pesticide Analytical Method (PAM) Vol. I (Memo G. Kramer, 12/14/01; D279240).
2.2.2 International Harmonization There are no Canadian, Mexican, or C odex maximum residue limits (MRLs) established for residues of flufenpyr

- ethyl; therefore, harmonization is not an issue at this time. For a summary of U.S. tolerances , refer to Attachment 5

. 2.2.3 Tolerance Recommendations
Permanent tolerances have bee n established in 40 CFR §180.595 f or residues of flufenpyr

- ethyl in/on field corn, soybeans , and sugarcan e. The residue chemistry database supports the currently established tolerances as listed in 40 CFR §180.595. T able 2.2.3 .1 is a sum mary of the estab lished tolerances for residues of flufenpyr

- ethyl

. HED is not recommended any changes to the established tolerances. However, t he tolerance expression s for flufenpyr

- ethyl ha ve been reviewed and should be updated as follows: 40 CFR §180.595(a)(1): Tole rances are established for residues of the herb icide flufenpyr

- ethyl, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only flufenp yr
- ethyl ( ethyl 2

- [2

- chloro

- 4

- fluoro

- 5

- [5

- methyl

- 6

- oxo
- 4

- (trifluoromethyl)

- 1(6 H )

- pyridazinyl]phenoxy]acetate ) in or on the following commodities:Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 7 of 26 

### 40 CFR §180.595(a)( 2 ): Tolerances are established for residues of the herb icide flufenpyr

- ethyl, including i ts metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of flufenpyr

- ethyl ( ethyl 2

- [2

- chloro

- 4

- fluoro

- 5

- [5

- methyl

- 6

- oxo
- 4

- (trifluoromet hyl)

- 1(6 H )

- pyridazinyl]phenoxy]acetate ) and its metabolite S

- 3153 acid

- 4

- OH ([ 2

- chloro

- 4

- hydroxy

- 5

- [5

- methyl

- 6

- oxo
- 4

- (trifluoromethyl)

- 1

- (6 H )

- pyridazinyl]phenoxy]acetic acid ) , free and conjugated, calculated as the stoichiometric equivalent of flufenpyr

- e thy l , in or on the following commodities:
Table 2.2.3.1. Tolerance Summary for Flufenpyr
- ethyl (40 CFR §180.595). Commodity Established Tolerance (ppm) Comments 40 CFR §180.595(a)(1): flufenpyr

- ethyl; acetic acid, [2

- chloro

- 4

- fluoro

- 5

- [5

- methyl

- 6

- oxo
- 4

- (trifluoromethyl)

- 1

- (6 H )

- pyridazinyl]

- phenoxy]

- ethyl ester] Corn, field grain 0.01 Soybean, seed 0.01 Sugarcane, cane 0.01 40 CFR §180.595(a)(2): flufenpyr

- ethyl; acetic acid, [2

- chloro

- 4

- fluoro

- 5

- [5

- methyl

- 6

- oxo
- 4

- (trifluoromethyl)

- 1

- (6H)

- pyridazinyl]

- phenoxy]

- ethyl ester], and its metabolite, S

- 3153 acid

- 4

- OH; [2

- chloro

- 4

- hydroxy

- 5

- [5

- methyl

6

- oxo
- 4

- (trifluoromethyl)

- 1

- (6H)

- pyridazinyl]

- phenoxy]

- acetic acid, free and conjugat ed Corn, field, forage 0.05 Corn, field, stover 0.05


### 2.3 Label Recommendations No revision to the registered label s are required to support Registration Review.
3.0 Ingredient Profile
3.1 Chemical Identity and Physical/Chemical Proper ties
The chemical structure and nomenclature of flufenpyr

- ethyl and its metabolites , and a detailed description of the physicochem ical properties of flufenpyr

- ethyl are provided in Attachment 1

. 3.2 Use Pattern Flufenpyr

- ethyl is a contact herbicide and a member of the pyridazinone class of pesticides. It is formulated as a WDG, and is currently registered for use on field corn, soybeans, and sugarcane. Foliar applications can be made using either ground or air equipment. A s ummary of th e registered uses are included in Attachment 3

. 3.3 Anticipated Exposure Pathways Based on the regist ered application scenarios, dietary exposure is an anticipated exposure path way as residues of flufenpyr

- ethyl may be found in/on crops , and drinking water. Although t h ere are no registered r esidential uses of flufenpyr

- ethyl, there is a potential for spray drift that may result in exposure s in residential and non

- occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is also potential for post

- application exposure for workers re

- entering treated sites. This risk assessment considers all of the aforementioned exposure pathways based on the existing uses of flu fenpyr

- ethyl

.Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 8 of 26 

### 3.4 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 Address Environmental Justice in Minority Populations and Low

- Income Populations," (http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups acco rding to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involv e pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA ’s NHANES/WWEIA and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. 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 exposure s based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has c ommitted 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.
4 .0 Hazard Identification/Toxicology In a rat metabolism study, there were no differences attributable to gender or radiolabel position. Approximately 54

- 72% of the administered dose was absorbed based on urinary excretion and tissue/carcass burden data. Flufenpyr

- ethyl was rapidly eliminat ed in the urine (49

- 72%) and feces (30

- 44%) within 24 to 48 hours. Removal via the bile accounted for about 37% of the fecal radioactivity over a 72

- hour period and 16.4% of the total administered radioactivity. One week post

- dosing, tissue/carcass burde ns were 0.15% and 0.07% in males and females, respectively, and most tissues had less than 0.1 μg eq/g wet tissue. The liver, pituitary, and thyroid had higher concentrations ranging from 0.2

- 0.9 μg eq/g wet tissue. The parent compound was metabolized pr imarily via cleavage of the ester linkage to form the major metabolite, S

- 3153 acid, which comprised 91

- 96% of the administered dose when considering urinary and fecal elimination (including the biliary contribution). The liver was found to be the prima ry target in mice. In subchronic mouse studies, increased liver weights and hepatic centrilobular vacuolat ion were observed at relatively high doses (>900 mg/kg/day). In the mouse carcinogenicity study, liver toxicity (hepatocyte necrosis) in both sexes and mild anemia in males were seen at doses >400 mg/kg/day. In the subchronic and chronic dog studies, toxic effects (body weight decrements, decreased food consumption/efficiency, and increased incidence of vomiting) were only seen at the limit dose (100 0 mg/kg/day). No effects were seen in rats. There is no evidence of quantitative or qualitative susceptibility to offspring from exposure to flufenpyr

- ethyl. In rabbits, maternal toxicity was evidenced by clinical signs, decreased food consumption, incr eased mortality, and necropsy findings in the stomach at doses ≥200 mg/kg/day with no developmental effects observed. No maternal toxicity or developmentalFlufenpyr

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Page 9 of 26 

### effects were seen in the rat developmental study. No parental or offspring effects were seen in re production toxicity studies.
F lufenpyr

- ethyl is classified as having low acute toxicity (Toxicity Category IV) via the oral, dermal, and inhalation routes. It is not an eye or skin irritant. It is not a dermal sensitizer. Flufenpyr

- ethyl is classifie d as “not likely to be carcinogenic” based on lack of evidence of carcinogenicity in mice and rats, and is not mutagenic. The toxicology database for flufenpyr

- ethyl is complete except for subchronic inhalation, neurotoxicity (acute and subchronic), and i mmunotoxicity studies that are required in accordance with the current 40 CFR Part 158 Toxicology Data Requirements. The HASPOC concluded based on a weight

- of

- evidence approach that these studies are not required at this time ( Memo, U. Habiba, 7

- OCT

- 2014; TXR#0057056). Therefore, t he toxicology database is complete to supp ort existing registrations and Registration R eview ( Attachment 2 ). The endpoints , PODs , and SFs from the most recent human health risk assessment ( Tables 4. 0. 1 and 4

. 0. 2) for flufenpyr

- ethyl are considered protective of all effects seen in the database. For all exposure scenarios, a 100

- fold UF (10X for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF if applicable) was applied.

Table 4
. 0. 1. Summary of Toxicological Doses and Endpoints for Flufenpyr
- ethyl for Use in Dietary and Non
Occupational Human Health Risk Assessments. 1 Exposure/ Scenario POD UF s/ FQPA SF RfD, PAD, LOC for

Risk Assessment Study and Toxicological Effects Acute Dietary (All populations) A dose and endpoint of concern attributable to a single dose was not observed.

Chronic Dietary (All Populations) NOAEL = 40 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X c Rfd =

0.4 mg/kg/day
cPAD = 0.4 mg/kg/day Carcinogenicity Study (Mice) LOAEL = 401.8 mg/kg/day based on liver toxicity in both sexes and mild anemia in males

. Dermal Short

- Term (1

- 30 days) and Intermediate

- Term (1

- 6 months) No dermal assessment required. No adverse effects were seen up to the limit dose in the route

- specific dermal

toxicity study and there was no evidence of quantitative susceptibility.

Incidental Oral Short

- Term (1

- 30 days) and Intermediate

- Term (1

- 6 months) NOAEL = 100 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential LOC for MOE < 100 Developmental Toxicity Study (Rabbit)

LOAEL = 300 mg/kg/day based on clinical signs, decreased food consumption, and necropsy findings

. Cancer (oral, dermal, inhalation) Classification: “not likely to be carcinogenic to humans

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

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

- observed adv erse
- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population

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

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Page 10 of 26 Table 4
. 0. 2. Summary of Toxicological Doses and Endpoints for Flufenpyr
- ethyl for Use in Occupational Human Health Risk Assessments. 1 Exposure/ Scenario POD UF s LOC for Risk Assessment Study and Toxicological Effects Dermal Short

- Term (1

- 30 days) and Intermediate

- Term (1

- 6 months) No dermal assessment required. No adverse effects were seen up to the limit dose in the route

- specific dermal

toxicity study and there was no evidence of quantitative susceptibility.

Inhalation Short

Term (1

- 30 days) and Intermediate

- term (1

- 6 months) NOAEL =

40 mg/kg/day
Inhalation assumed equivalent to oral UF A = 10X

UF H = 10X Occupational LOC for MOE < 100 Carcinogenicity Study (Mice)

LOAEL = 401.8 mg/kg/day based on liver toxicity in both sexes and mild anemia in males

. Cancer (oral, dermal, inhalation) Classification: “not likely to be carcinogenic to humans

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

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

- observed adverse

effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. 

### 4 .1 Endocrine Disruptor Screening Program As requi red by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA) , EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic , and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including eff ects 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 R egistration Review for flufenpyr

- ethyl, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from th e existing hazard database. However, as required by FFDCA section 408(p), flufenpyr

- ethyl is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). EPA has developed the EDSP to determine whether certain substances (i ncluding pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

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

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

- response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pesti cide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second listFlufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 11 of 26 

### of chemicals identified for EDSP scree ning was published on June 14, 2013 1 

### and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.
For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website. 2


### 5.0 Dietary Exposure and Risk Assessment
5.1 Residue Chemistry
Permanent tolerances are estab lished for residues of flufenpyr

- ethyl in/on corn, field, grain (0.01 ppm ) ; soybean, seed (0.01 ppm); and sugarcane, cane (0.01 ppm) (40 CFR §180.595 (a)). Permanent tolerances are estab lished for residues of flufenpyr

- ethyl and metabolite S

- 3153 acid

4

- OH in/on corn, field, forage (0.05 ppm); and corn, field, stover ( 0. 05) (40 CFR §180.595 (b )). There are currently no Section 18 Emergency Exemptions, tolerances with regional registrations, or tolerances for indirect/inadvertent residues in rotat ional crops.
The nature of the residue in sugarcane, corn , and soybean is adequately understood based on available metabolism studies. T he HED Metabolism Assessment Review Committee (MARC) concluded that parent only is the residue of toxicological concer n and the only residue to be included in the risk assessment and tolerance expression for field corn grain, soybean seed, and sugarcane ( Memo , G. Kramer, et al. ; 06

- AUG

- 2003; D289691). MARC further concluded that for field corn forage and stover, parent a nd S

- 3153 acid

- 4

- OH are the residues of toxicological concern to be used in risk assessment and in the tolerance expression. The nature of the residue in livestock is understood based on submitted metabolism studies on ruminants (dairy cattle) and poultry (laying hens). The MARC concluded that parent plus S

- 3153 acid are the residues of concern for risk assessment and the tolerance expression (if necessary) ( Memo, G. Kramer, et al. ; 06

- AUG

- 2003; D289691 ). Adequate field trial , processing , and confined ro tational crop data are availabl e to support the use of flufenpyr

- ethyl on the registered crops. An adequate number of trials were conducted in the appropriate geographical regions using the appropriate formulation ap plied at the maximum use rate. The sub mitted soybean, corn , and sugarcane processing studies indicate that tolerances are not required for flufenpyr

- ethyl in sugarcane, corn , and soybean processed commodities . The rotational crop restrictions specified on the S

- 3153 WDG Herbicide label (see Table A.3.2 in Attachment 3) a re supported by available confi ned rotational crop data. T herefore, limited field rotational crop studies and tolerances for flufenpyr

- ethyl residues in rotational crops are not required to support the registered uses. Based on the calculated maximum theoretical dietary burden (MTDB) and the data from the available livestock metabolism studies , there is no reasonable expectation that quantifiable residues of flufenpyr

- ethyl will occur in livestock commodities [40 CFR 180.6(a)(3)]. Therefore, livestock feeding studies and tolerances for livestock commodities are not required at

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/Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 12 of 26 

### the present time. If the use of flufenpyr

- ethyl is expanded in the future to include other livestock feed items, then the need for feeding studies will be reevaluated.
5.2 Drinking Water
The residues of concern in drinking water are adequately understood based on available environmental fate studies. T he HED MARC concluded t hat the following degradates will likely have similar toxicity to the parent: S

- 3153

- acid, S

- 3153

- 1

- OH, S

- 3153

- 1

- OCH3, S

- 3153

- 1

- OCH3

- 5'

- CH2OH. Therefore, in addition to the parent, these degradates should be included in the drinking water r isk assessment (Memo , G. Kramer, et al. , 06

- AUG

- 2003; D289691). Updated groundwater EDWCs for flufenpyr

- ethyl and three degradates (S

- 3153

- acid, S

- 3153

- OH, and S

- 3153

- OCH3) were provided by EFED (Memo, J. Wolf, 30

- SEP

- 2014; D423057). The EDWCs were derived using the Pesticide Root Zone Model

- Ground Water (PRZM

- GW) model and a ssuming maximum application rates ( two applications at 0.027 lb ai/A) and are higher than the previously generated surface water estimates . The highest concentrations were estimated for the S

- 3153

- acid. The highest daily concentration was 11.8 μg/L and h ighest post

breakthrough average concentration was 10.4 μg/L, respectively. The parent compound does not exhibit a potential for leaching as the estimated parent flufenpyr

- ethyl concentrations were essentially zero
. The summary of EDWCs for flufenpyr

- eth yl is found on Table 5.2.1. Table 5.2.1. Summary of PRZM
- GW EDWCs for Groundwater for Flufenpyr
- ethyl and three degradates of concern (2 applications @ 0.027 lb ai/A per application). Residue 1 Post breakthrough Average (μg/L) Average Breakthrough Time (Days) Flufenpyr

- ethyl 0 4892 S

- 3153

- acid 10.4 2965 S

- 3153

- OH 0.40 4805 S

- 3153

- OCH 3 5.84 5615 Total Residues of Concern 17

- 1. It should be noted that, although the S

- 3153

- 1

- OCH3

- 5'

- CH2OH Insufficient data were submitted for S

- 3153

- 1

- OCH3

- 5'

- CH2OH to estimate its DWECs. Although a major degradate in the aerobic soil metabolism study (maximum 13.9% of applied), this degradate was on ly found in the top soil layer of one out of three field studies at the analytical method detection limit level. There fore EFED expects the risk of this degradate to the drinking water resources to be negligible compared to that of the parent and the other three degradates. 

### 5.3 Dietary (Food + Drinking Water ) Risk Assessment Drinking water estimates were not incorporated dir ectly in the 2003 dietary exposure assessment. HED calculated drinking water levels of comparison (DWLOCs), which is a theoretical upper limit on a pesticide’s concentration in drinking water in light of total aggregate exposure to a pesti cide in food, drinking water, and through residential uses. In support of Registration Review, a n updated chronic dietary (food and drinking wate r) exposure and risk assessment was conducted using DEEM

- FCID ( ver. 3.16) which incorporates consumption data from the USDA NHANES/WWEIA; 2003

- 2008 . The chronic analyses assumed tolerance

- level residues, 100% CT, DEEM (ver. 7.81) default processing factors, and mod eled drinking water estimates. The groundwater EDWC of 0.017 ppm w as incorporated directly into the chronic dietary analyses as “water, direct, all sources” and “water, indirect, all sources.” The chronic dietary (food and drinking water) exposure estimates are below HED’s LOC (<100% cPAD) for the general U.S. population and all population subgroups (<1% of the cPAD) (see Table 5.3.1)

. The residue file for the chronic assessment as well as the results of the chronic assessment are provided in Attachment 4

.Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 13 of 26 Table 5.3.1 . Summary of Chronic Dietary (Food and Drinking Water) Exposure and Risk for Flufenpyr
- ethyl. 1 Population Subgroup cPAD (mg/kg/day) Exposure (mg/kg/day) %cPAD General U.S. Population

0.4 0.000378 <1 All Infants (<1 year old) 0.000960 <1 Children 1

- 2 years old 0.000567 <1 Children 3

- 5 years old 0.000487 <1 Children 6

- 12 years old 0.000351 <1 Youth 13

- 19 years old 0.000285 <1 Adults 20

- 49 years old 0.000374 <1 Adults 50

- 99 years old 0.000364 <1 Females 13

- 49 years old 0.000372 <1 1 The population subgroup with the highest exposure is in bold. 

### 6 .0 Residential (Non
- Occupational ) Exposur e and Risk Assessment There are no proposed or registered products containing flufenpyr

- ethyl that would result in residential exposure. Therefore, a residential exposure assessment was not performed.
6.1 Spray Drift
Off

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

target and can lead to exposures to those it may directly con tact. 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 calculate d using drift modeling coupled with methods employed for residential risk assessments for turf products. The approach to be used 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 exposure scenario. Aside from the predicted residues available for transfer, the routes of exposure and assessment methodology is anal ogous to how exposures to turf products are considered in risk assessment. In order to evaluate the drift potential and associated risks, an approach based on drift modeling coupled with techniques used to evaluate residential uses of pesticides was uti lized. Essentially, a residential turf assessment based on exposure to deposited residues has been completed to address drift from the agricultural applications of flufenpyr

- ethyl

. In the spray drift scenario, the deposited residue value was determined b ased 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 were determined, the remainder of the spray drift a ssessment was based on the algorithms and input values specified in the recently revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

.Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 14 of 26 

### A screening approach was developed for situations where specific label guidance for application parameters is not available. 3 , 4 

### 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 i ncorporated into the model and represent each equipment type and use under varied conditions. The screening options specifically recommended in this methodology were selected because 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 are not typically applied to tree canopies) or specific label prohibitions (e. g., aerial applications are not allowed). Section 6.1 .1 provides the screening level drift related risk estimates. These drift estimates represent plausible options based on the available pesticide labels

. 6.1 .1 Combined Risk Estimates From Lawn Deposi tion Adjacent to Applications The spray drift risk estimates are based on an estimated deposited residue concentration as a result of the screening level agricultural application scenarios. Flufenpyr

- ethyl is used on corn, soybean , and sugarcane and can be applied via groundboom and 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.

 Aerial applications are based on the use of AgDrift ® 

### Tier 1 aerial option for a fine to medium spray type 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 down wind direction for entire application/drift event). 5


### There are no short

- or intermediate

- term dermal PODs. Only incidental oral risk estimates w ere evaluated. The total applicable LOC is 100 , so MOEs <100 would be of conc ern. Children (1 to <2 year s ol d) incidental oral risk estimates from exposure to flufenpyr

- ethyl related to spray drift result in no risks of concern at the field edge for either groundboom or for aerial applications (Table 6.1.1.1)

.

3 http://www.agdrift.com/ 4 Note that for many cases the scenarios outlined in the screening approach represent actu al use practice so risk assessors should be aware and characterize these appropriately. 5 AgDrift ® allows for consideration of even finer spray patterns characterized as very fine to fine. However, this spray pattern was not selected as the common screeni ng basis since it is used less commonly for most agriculture. If assessors identify this use pattern, then it should be used as the screening criteria and deposition values associated with it a s provided in Table 1 below. Justification for including this spray quality should be included in any assessment based on specific label directions for its use.Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 15 of 26 Table 6.1.1.1. Children (1 to <2 years old) Incidental Oral Risk Estimates (MOEs) Related to Spray Drift Exp osure for Flufen pyr - e thyl . Crop/Rate Group Spray Type/Nozzle Configuration Application Rate (lb ai/A) Estimated

TTR t (ug/cm2) At Edge

HtM MOE

Aerial Fine to Medium

0.054 0.0060021 470,000

Medium to Coarse 580,000 Coarse to Very Coarse 660,000 Very Fine to Fine 330,000

Groundboom High Boom Very fine to Fine 650,000

Low Boom Very fine to Fine 1,400,000 High Boom Fine to Medium/Coarse 2,500,000 Low Boom Fine to Medium/Coarse 3,700,000


### 6.2 Residential Bystander Post
- Application Inhalation Exposure Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The A gency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 6 

### . The A gency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 7 

### . During Registration Review, the A gency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for flufenpyr

- ethyl.
7 .0 Aggregate Exposure and Risk Assessment The most recent aggregate

- risk assessment was performed in conjunction with the 2003 HED human health risk assessment ( Memo, J. Tyler et al. , 31

- JUL

- 2003; D27040 3 ). A chronic aggregate (food only ) risk assessment was conducted. Since drinking water was not incorporated directly into the dietary exposure assessment, DWLOCs were calculated. An acute aggregate risk assessment was not performed because an endpoint of concern attributable to a single oral dose was not selected for any population subgroup (including infants and children). Short

- and intermediate

- term aggregate risk assessments w ere not performed because there are no registered residential non

- food uses. A cancer aggregate risk assessment was not performed because flufenpyr

- ethyl is not classified by HED as “ not likely to be carcinogenic to humans

. ” The chronic aggregate (food + drinking water) exposure and risk estim ates did not exceed HED's LOC

. U pdated chronic dietary (food and drinking water) exposure and risk ass essment s were conducted to include the updated EDWCs and 2003

- 2008 NHANES/WWEIA consumption data ( discussed in Se ction 5. 3). Since there are no residential uses, the chronic dietary (food and water) exposure estimates represent chronic aggregate exposure. T herefore, t he chronic aggregate risk estimates are not of concern to HED.

6 http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html 7 http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 16 of 26 

### 8.0 Cumulative Exposure/Risk Cha racterization Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to flufenpyr

- ethyl and any other substances and flufenpyr

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

- ethyl does not have a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.
9 .0 Occupational Exposure Occupational handler and post

- application exposures are expected based on the re gistered agricultural uses of flufenpyr

- ethyl. Table A.3.1 in Attachment 3 provide s a summary of the registered use pattern. Flufenpyr

- ethyl is registered as a WDG, the maximum application rate is 0.054 lb ai/A, and applications can be made using aerial and groundboom equipment. Based on these uses, there is a potential for exposure to flufenpyr

- ethyl in occupational settings from handling flufenpyr

- ethyl products during the application process (i.e., mixer/loaders, applicators, and mixer/loader/applicat ors). In addition, there is a potential for post

- application worker exposure from entering into areas p reviously treated with flufenpyr

- ethyl

. 9 .1 Occupational Handlers Occupational handlers are anticipated to have short

- and intermediate

- term dermal and inhalation exposures. However, since no short

- or intermediate

- term dermal PODs were selected, only inhalation exposures are assessed. In support of Registration Review , an updated occupational e xposure assessment for flufenpyr

- ethyl was conducted for mixers/loaders, applicators, and flaggers for aerial and groundboom applications of a WDG formulation

. The assessment was based on the maximum registered application rate of 0.054 lb ai/A, and maximum area treated per day or gallons handled. Handler's exposure and risk were calculated at baseline (long pants, a long

- sleeved shirt, no chemical

- resistant gloves, and no respirator) and with personal

protectiv e equipment (PPE) when necessary [ e.g., chemical

- resistant gloves, respirators, and engineering controls (EC)] . Inhalation risk estimates were not of concern (i.e., MOEs ≥ 100) with baseline protection ( see Table 9 .1.1 ).Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 17 of 26 Table 9 .1.1 . Summary of Occupat ional Handler Inhalation Risks for Flufenpyr
- ethyl. Activity Application Equipment Crop/Target Inhalation Unit Exposure (μg/lb ai) 1 App

Rate 2 Acres 3 Dose 4 ST and IT Inhalation MOE 5 Mixer/Loader Groundboom application of WDG formulation Field corn,

soybean, sugarcane 8.96 (baseline ) 0.054 200 0.00121 33,000 (baseline) Aerial application of WDG formulation 1,200 0.00726 5,500 (baseline) Applicator Applicator, Open Cab Groundboom Field corn, soybean, sugarcane 0.34 (baseline) 0.054 200 0.0000459 870,000 (baseline) Applicator, Aerial 0.0049 (EC) 1,200 0.0000040 10,000,000 (EC) Flagger
Aerial Field corn,

soybean, sugarcane 0.35 (baseline) 0.054 350 0.000083 480,000 (baseline)

1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline, PPE (gloves), Eng. Controls. 2. Based on 59639

- 109 and 59639

- 110 labels. 3. Exposure Science Advisory Council Pol icy #9.1. 4. Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A/day) x IAF (100 %) ÷ BW (80 kg). 5. Inhalation MOE = Inhalation NOAEL (40 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). 

### 9 .2 Occupational Post
- Application
Dermal : Typically, it is possible for agricultural workers to have post

- application exposure to pesticide residues during the course of typical agricultural activities. However the Agency did not identify a dermal toxicological endpoint; therefore, a quantitative assessment for dermal post

- application exposure was not conducted.
Inhalation : There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sourc es 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 FIFRA SAP in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). In terms of volatilization, the Agency has evaluated the SAP report and has developed a Volatilization Screening Too l and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration Review, the Agency will util ize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for specific chemicals. In addition, the Agency is continuing to evaluate the available post

- application inhalatio n exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. Although a quantitative occupational post

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

- application exposure. Therefore, it is expected that these handlerFlufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 18 of 26 

### inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.
10 .0 Public Health and Pesticide Epidemiology Data The Agency has reviewed the available incident data for flufenpyr

- ethyl (Memo , E. Evans and S. Recore, 20

- AUG

- 2014 ; D422322 ) and concluded that there does not appear to be a concern at this time that would warrant further investigation . T here were no incidents involving flufenpyr

ethyl reported to either OPP Incident Data System (IDS) or Sentinel Event Notification System for Occupational Risk (SENSOR)

- Pesticides. The Agency will continue to monitor the i ncident information and if a concern is triggered, additional analysis will be included in the risk assessment.
11 .0 References
HED Memoranda Relevant to Registration Review. Author Barcode Date Title G. Kramer D279240 14

- DEC

- 2001 Correspondence to Mark Wirtz, FDA, Pesticides and Industrial Chemicals Branch, HFS

- 337 Division of Contaminants Chemistry regarding the multiresidue method for Flufenpyr

- ethyl* and flufenpyr

ethyl acid

- 4

- OH

. S. Mathur D286251 29

- OCT

- 2002 Product Chemistry Review of S

- 3153 WDG Herbicide J. Tyler et al. D270403 31

- JUL

- 2003 PP#: 0F06164. Flufenpyr

- Ethyl in/on Field Corn, Soybeans and Sugarcane . Health Effects Division (HED) Risk Assessment. G. Kramer, et al. D289691 06

- AUG

2003 FLUFENYPYR

- ETHYL

– Health Effects Division (HED)

Metabolism Assessment Review Committee (MARC) Decision Document. Meeting Date: 18

- JUN

- 2003. S. Recore, E. Evans D422322 20

- AUG

2014 Flufenpyr

- ethyl: Tier I Review of Human Incidents
J. Wolf D423057 30

- SEP

- 2014 Tier 1 Groundwater Assessment for Flufenpyr ethyl and three degradates using PRZM

- GW. U. Habiba TXR#0057056 0 7

- OCT

- 2014 Flufenpyr
- ethyl: Summary of Hazard and Science Policy Council (HASPOC) Meeting of September 11, 2014: Recommendation on the Requirements for Subchronic Inhalation, Neurotoxicity (Acute and Subchronic), and Immunotoxicity Studies.Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 19 of 26 

### Attachment 1: Chemical Identity Table s.

Table A.1.1. Nomenclature for Flufenpyr
- ethyl and its Metabolites. Chemical structure

Common name Flufenpyr

- ethyl IUPAC name ethyl 2

- chloro

- 5

- [1,6

- dihydro

- 5

- methyl

- 6

- oxo
- 4

- (trifluoromethyl)pyridazin

- 1

- yl]

- 4

- fluorophenoxyacetate CAS name ethyl 2

- [2

- chloro

- 4

- fluoro

- 5

- [5

- methyl

- 6

- oxo
- 4

- (trifluoromethyl)

- 1(6 H )

- pyridazinyl]phenoxy]acetate CAS registry number 188490

- 07

- 5 End

- use product (EP) S

- 3152 WDG Herbicide Chemical structure of S

- 3153

- acid

- 4

- OH metabolite

Chemical name [2

- chloro

- 4

- hydroxy

- 5

- (5

- methyl

- 6

- oxo
- 4

- trifluoromethyl

- 1,6

- dihydropyridazin

1

- yl)phenoxy]

- acetic acid
Table A.1.2. Physicochemical Properties of Flufenpyr
- ethyl (Technical Grade Active Ingredient (TGAI)). Parameter Value References Melting range 100

- 101  C

Memo, S. Mathur, 29

- OCT

- 2002; D270192 And Memo, J. Wolf, 30

- SEP

- 2014; D423057 pH 5.7 at 20  C Density 0.1558 g/ml (9.7 lbs/cu.ft) Water solubility 4.1 ppm Solvent solubility (g/L at 20  C) Acetone 364.00 Acetonitrile 343.00 Hexane 1.24 Methanol 36.10 1

- octanol 6.38 Vapor pressure 3.76 x 10

- 7 Pa at 20  C; 1.01 x 10

- 6 Pa at 25  C Dissociation constant (pK a ) Very insoluble in water, DC could not by measured Octanol/water partition coefficient Log(K OW ) 2.99Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 20 of 26 

### Attachment 2: Flufenpyr
- ethyl Acute, Subchronic, and Chronic Toxicity Profile. Study requirements (40 CFR 158.340) for flufenpyr

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

Table A.2.1. Toxicology Study Requirements. Study Technical Required Satisfied 870.1100 Acute Oral Toxicity

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

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

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

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

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

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

yes yes yes yes yes 870.3100 90

- Day Oral Toxicity (rodent)

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

- Day Oral Toxicity (nonrodent)

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

- Day Dermal Toxicity

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

- Day Dermal Toxicity

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

- Day Inhalation Toxicity

................................ ........... yes yes yes no no 1 yes

yes yes

--

-- 870.3700a Prenatal Developmental Toxicity (rodent)

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

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

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

yes yes 870.4100a Chronic Toxicity (rodent)

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

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

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

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

................ yes yes yes yes yes y es 2

yes yes 2 yes yes 870.5100 Mutagenicity

— Bacterial Reverse Mutation Test

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

— Mammalian Cell Gene Mutation Test

.. 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5xxx Mutagenicity

— Other Genotoxic Effects

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

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

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

- Day Neurotoxicity Screening Battery (rat)

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

................................ ........ no 1
no 1
no --

--

-- 870.7485 Metabolism and Pharmacokinetics

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

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

................................ ............................. yes no no 1 yes

--

-- 1 HED HASPOC concluded that the subchronic inhalation, neurotoxicity (acute and subchronic), and immunotoxicity studies are not required at this time (U. Habiba; 7

- OCT

- 2014; TXR#0057056). 2 The combined chronic toxicity/carcinogenicity study satisfies the requirement of the study.
Table A.2 .2
. Acute Toxicity Profile

– Flufenpyr
- ethyl . Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute Oral 45118902 LD 50 > 5,000 mg/kg (Limit Test) IV 870.1200 Acute Dermal 45118906 LD 50 > 5,000 mg/kg (Limit Test) IV 870.1300 Acute Inhalation 45152805 LC 50 > 5.0 mg/L (Limit Test) IV 870.2400 Primary Eye Irritation 45118909 Minimally irritating, resolved within 24 hrs IV 870.2500 Primary Skin Irritation 45118909 Non irritating IV 870.2600 Dermal Sensitization 45118912 Non

- sensitizer N/AFlufenpyr

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Page 21 of 26 Table A.2 .3 . Subchronic, Chronic, and Other Toxicity Profile

– Flufenpyr
- ethyl.
Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.3100 90

- Day Oral Toxicity

in Rodents (rat) 45118914 (1997) Acceptable/guideline M: 0, 39, 134, 414, 1434 mg/kg/day F: 0, 47, 154, 467, 1591 mg/kg/day NOAEL >1434/1591 mg/kg/day (M/F)

. LOAEL not established

.

870.3100 90

- Day Oral Toxicity

in Rodents (rat) 45118915 (1998) Acceptable/guideline M: 0, 55, 595, 1195 mg/kg/day F: 0, 65, 682, 1378 mg/kg/day NOAEL >1195/1378 mg/kg/day (M/F)

. LOAEL not established

.

870.3100 28

- Day Oral Toxicity

in Rodents (mouse) 45118916 (1998) Acceptable/non

- guideline M: 0, 44.9, 145.0, 447.5, 1009 mg/kg/day F: 0, 57.1, 210.5, 629.1, 1212.5 mg/kg/day NOAEL = 448/629 mg/kg/day (M/F)

. LOAEL = 1009/1213 mg/kg/day (M/F) based on increased incidence of hepatic centrilobular vacuolation.

870.3100 90

- Day Oral Toxicity

in Rodents (mouse) 45118916 (1998) Acceptable/guideline M: 0, 37.2, 128.4, 394.8 and 907.6 mg/kg/day F: 0, 45, 155.7, 449.7, and 1088 mg/kg/day NOAEL = 395 mg/kg/day

. LOAEL = 908 mg/kg/day based on increased absolute and relative liver weights and increased incidence of hepatic centrilobular vacuolation in males.

870.3150 90

- Day Oral Toxicity

in Non

- Rodent (dog) 45118918 (1999) Acceptable/guideline 0, 100, 300, 1000 mg/kg/day NOAEL = 300 mg/kg/day

. LOAEL = 1000 mg/kg/day based on decreased body weight gains, food consumption, and food efficiency and increased incidence of vomiting. 870.3200 21

- Day Dermal

Toxicity (rat) 45118919 (1999) Acceptable/guideline 0, 100, 300, 1000 mg/kg/day NOAEL > 1000 mg/kg/day

. LOAEL not established

. 870.3700a Prenatal

Developmental in Rodent (rat) 445118925 (1999) 0, 100, 300, 1000 mg/kg/day Maternal NOAEL > 1000 mg/kg/day

. Maternal LOAEL not established. Developmental NOAEL > 1000 mg/kg/day. Developmental LOAEL not established. 870.3700b Prenatal

Developmental in Non

- Rodent (rabbit) 45118922 (2000) 0, 100, 300, 1000 mg/kg/day Maternal NOAEL = 100 mg/kg/day. Maternal LOAEL = 300 mg/kg/day based on increased mortality, clinical signs, decreased food consumption, and necropsy findings. Developmental NOAEL > 1000 mg/kg/day. Developmental LOAEL not established. 870.3700b Prenatal

Developmental in Non

- Rodent (rabbit) 45118923 (2000) 0, 100, 200, 300, 1000 mg/kg/day Maternal NOAEL = 100 mg/kg/day. Maternal LOAEL = 200 mg/kg/day based on increased mortality. Developmental NOAEL > 1000 mg/kg/day. Developmental LOAEL not established. 870.3800 Reproduction and

Fertility Effects (rat)
Two

- generation 45119001; 45119002 (2000) Acceptable/guideline F 0 (M/F): 0/0, 14/16, 135/162, 1463/1672 mg/kg/day F 1 (M/F): 0/0, 17/19, 170/186, 1766/1914 mg/kg/day Parental NOAEL = 1463

- 1914 mg/kg/day. Parental LOAEL not established. Offspring NOAEL = 1463

- 1914 mg/kg/day. Offspring LOAEL not established. Reproductive NOAEL= 1463

- 1914 mg/kg/day. Reproductive LOAEL not established. 870.3800 Reproduction and

Fertility Effects (rat)
One

- generation 45796601 (2000) Acceptable/guideline M: 0, 1.1, 3.2, 6.4 mg/kg/day
F: 0, 1.3, 3.6, 7.5 mg/kg/day Parental NOAEL = 6.4

- 7.5 mg/kg/day. Parental LOAEL not established. Offspring NOAEL = 6.4

- 7.5 mg/kg/day. Offspring LOAEL not established. Reproductive NOAEL = 6.4

- 7.5 mg/kg/day. Reproductive LOAEL not established.Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 22 of 26 Table A.2 .3 . Subchronic, Chronic, and Other Toxicity Profile

– Flufenpyr
- ethyl.
Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.3800 Reproduction and

Fertility Effects (rat)
One

- generation 45800701 (2002) Acceptable/guideline M: 0, 139.4 mg/kg/day
F: 0, 151.7 mg/kg/day Parental NOAEL = 139.4

- 151.7 mg/kg/day. Parental LOAEL not established. Offspring NOAEL = 139.4

- 151.7 mg/kg/day. Offspring LOAEL not established. Reproductive NOAEL= 139.4

- 151.7 mg/kg/day. Reproductive LOAEL not established. 870.4100a Chronic Toxicity

(rodent) See 870.4300 See 870.4300 870.4100b Chronic Toxicity

(dog) 43492834 (1194) Acceptable/guideline 0, 50, 200, 1000 mg/kg/day NOAEL = 200 mg/kg/day

. LOAEL = 1000 mg/kg/day based on body

- weight decrements in females. 870.4200a Carcinogenicity (rat) See 870.4300 See 870.4300 870.4200b Carcinogenicity

(mouse) 45118920 (1999) Acceptable/guideline M: 0, 39.9, 401.8, 814.7 mg/kg/day F: 0, 43.7, 447.9, 882.8 mg/kg/day NOAEL = 39.9/43.7 mg/kg/day (M/F). LOAEL = 401.8/447.9 mg/kg/day (M/F) based on liver toxicity in both sexes and mild anemia in males. No evidence of carcinogenicity.
870.4300 Combined Chronic

Toxicity/ Carcinogenicity (rat) 45152807 (2000) Acceptable/guideline M: 0, 3.6, 36.5, 375, 777.8 mg/kg/day F: 0, 4.7, 46.4, 486.4, 1024.7 mg/kg/day NOAEL = 777.8/1024.7 mg/kg/day (M/F)

. LOAEL not established. No evidence of carcinogenicity.

870.5100 Bacterial gene

mutation assay 45119003 (1998) Acceptable/guideline No evidence of mutagenicity at any dose levels tested.
870.5300 In vitro mammalian

cell gene mutation 45119005 (1998) Acceptable/guideline No evidence of induced mutant colonies.
870.5395 Mammalian

micronucleus (mouse) 45119006 (1998) Acceptable/guideline No significant increase in frequency of micronucleated polychromatic erythrocytes in bone marrow

. 870.7485 Metabolism and

Pharmacokinetics (rat) 45119007; 45119008; 45119009 (1999) Acceptable/guideline No differences attributable to gender or radiolabel position. Approximately 54

- 72% of the administered dose was absorbed based on urinary excretion and tissue/carcass burden data. Flufenpyr

- ethyl was rapidly eliminated in the urine (49

- 72%) and feces (30

- 44%) within 24 to 48 hours. Removal via the bile accounted for about 37% of the fecal radioactivity over a 72

- hour period and 16.4% of the total administered radioactivity. One week post

- dosing, tissue/carcass burdens were 0.15% and 0.07% in males and f emales, respectively, and most tissues had less than 0.1 μg eq/g wet tissue. The parent compound was metabolized primarily via cleavage of the ester linkage to form the major metabolite, S

- 3153 acid, which comprised 91

- 96% of the administered dose when co nsidering urinary and fecal elimination (including the biliary contribution).Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 23 of 26 

### A ttachment 3 : Registered Flufenpyr
- ethyl End Use Products and Use Patterns . Table A.3.1 . Registered Flufenpyr
- ethyl End Use Products. EPA Reg. No. Formulation Type Product Label Name Company 59639

- 109 WDG Flufenpyr

- ethyl Technical Valent 59639

- 110 WDG S

- 3153 WDG Herbicide Valent Table A.3.2. Summary of Registered Uses for Flufenpyr
- ethyl.
Crop/Use Site Product

(Formulation) App.

Method #

App./ Year Max. App.

Rate (lb/ai/A) PHI 1

(days) RTI 2 (days) REI 3 (hours) PBI 4 Per App. Per Year Field Corn
S

- 3153 WDG

Herbicide (WDG) Ground

or Air 2 0.027

0.054 NS 5

14 12 28 days for soybeans, corn, cotton, grain sorghum, oats, wheat, barley, rice and rye in cases of crop failure; 3 months for all other crops. Sugarcane 0.027 90 Soybeans 0.054 45

1. PHI = preharvest interval. 2. RTI = retreatment interval

. 3. REI = restricted entry interval. 4. PBI = plan t

back interval. 5 . NS = not specified.Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 24 of 26 

### At tachment 4 : Chronic Dietary Exposure Files
. The following dietary exposure files were reviewed by two peer reviewers of the DESAC per DESAC SOP 2012.1.

Filename: C: \ Users \ jtyler \ Documents \ JenWork \ $Flufen_ethyl \ 2014 Reg Review \ 108853.r0 8 Chemical: Flufenpyr

- ethyl RfD(Chronic): .4 mg/kg bw/day NOEL(Chronic): 40 mg/kg bw/day RfD(Acute): 0 mg/kg bw/day NOEL(Acute): 0 mg/kg bw/day Date created /last modified: 10

- 08

- 2014/13:32:53 Program ver. 3.16, 03

- 08

- d

----------------------------------------------------------------------------------- EPA Crop Def Res Adj.Factors Comment Code Grp Commodity Name (ppm) #1 #2

---------- -- -- ------------------------------- ---------- ------ ------ ------- 1500122000 15 Corn, field, bran 0.010000 1.000 1.000 1500120000 15 Corn, field, flour 0.010000 1.000 1.000 1500120001 15 Corn, field, flour

- babyfood 0.010000 1.000 1.000 1500121000 15 Corn, field, meal 0.010000 1.000 1.000 1500121001 15 Corn, field, meal

- babyfood 0.010000 1.000 1.000 1500125000 15 Corn, fie ld, oil 0.010000 1.000 1.000 1500125001 15 Corn, field, oil

- babyfood 0.010000 1.000 1.000 1500123000 15 Corn, field, starch 0.010000 1.000 1.000 1500123001 15 Corn, field, starch

- babyfood 0.010000 1.000 1.000 1500124000 15 Corn, field, syrup 0.010000 1.000 1.000 1500124001 15 Corn, field, syrup

- babyfood 0.010000 1.000 1.000 0603348000 6C Soybean, flour 0.010000 1.000 1.000 0603348001 6C Soybean, flour

- babyfood 0.010000 1.000 1.000 0600350000 6 Soybean, oil 0.010000 1.000 1.000 0600350001 6 Soybean, oil

- babyfood 0.010000 1.000 1.000 0600347000 6 Soybean , seed 0.010000 1.000 1.000 0600349000 6 Soybean, soy milk 0.010000 1.000 1.000 0600349001 6 Soybean, soy milk

- babyfood or in 0.010000 1.000 1.000 0601349500 6AB Soybean, vegetable 0.010000 1.000 1.000 9500363000 O Sugarcane, molasses 0.010000 1.000 1.000 9500363001 O Sugarcane, molasses

- babyfood 0.010000 1.000 1.000 9500362000 O Sugarcane, sugar 0.010000 1.000 1.00 0 9500362001 O Sugarcane, sugar

- babyfood 0.010000 1.000 1.000 8601000000 86A Water, direct, all sources 0.017000 1.000 1.000 ground water EDWC 16.64 ppb 8602000000 86B Water, indirect, all sources 0.017000 1.000 1. 000 ground water EDWC 16.64 ppbFlufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 25 of 26 US EPA Ver. 3.16, 03

- 08

- d DEEM

- FCID Chronic analysis for FLUFENPYR

- ETHYL NHANES 2003

- 2008 2

- day Residue file name: C: \ Users \ jtyler \ Documents \ JenWork \ $Flufen_ethyl \ 2014 Reg Review \ 108853.r08 Adjustment factor #2 used. Analysis Date 10

- 08

- 2014/13:36:57 Residue file dated: 10

- 08

- 2014/13:34:23 Reference dose (RfD, Ch ronic) = .4 mg/kg bw/day

=============================================================================== Total exposure by population subgroup

------------------------------------------------------------------------------- Total Exposure

----------------------------------- Population mg/kg Percent of Subgroup body w t/day Rfd

-------------------------------------- ------------- ---------------- Total US Population 0.000378 0.1% Hispanic 0.000367 0.1% N on - Hisp

- White 0.000387 0.1% Non

- Hisp

- Black 0.000318 0.1% Non

- Hisp

- Other 0.000433 0.1% Nursing Infants 0.000338 0.1% Non

- Nursing Infants 0.001238 0.3% Female 13+ PREG 0.000356 0.1% Children 1

- 6 0.000510 0.1% Children 7

- 12 0.000334 0.1% Male 13

- 19 0.000272 0.1% Female 13

- 19/NP 0.000297 0.1% Male 20+ 0.000349 0.1% Female 20+/NP 0.000389 0.1% Seniors 55+ 0.000357 0.1% All Infants 0.000960 0.2% Female 13

- 50 0.000373 0.1% Children 1

- 2 0.000567 0.1% Children 3

- 5 0.000487 0.1% Children 6

- 12 0.000351 0.1% Youth 13

- 19 0.000285 0.1% Adults 20

- 49 0.000374 0.1% Adults 50

- 99 0.000364 0.1% Female 13

- 49 0.000372 0.1%

-------------------------------------------------------------------------------Flufenpyr

- e thyl Human Health Risk Assessment D 421190

Page 26 of 26 

### Attachment 5: Flufenpyr
- ethyl IRLS Sheet.

Table A.5.1 . Summary of US and Intern ational Tolerances and Maximum Residue Limits. Residue Definition : US Canada Mexico 1 Codex US [40 CFR §180.595(a)(1)] flufenpyr

- ethyl; acetic acid, [2

- chloro

- 4

- fluoro

- 5

- [5

- methyl

- 6

- oxo
- 4

- (trifluoromethyl)

- 1

- (6H)

- pyridazinyl]

- phenoxy]

- ethyl ester] None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex Corn, field, grain 0.01 Soybean, seed 0.01 Sugarcane, cane 0.01

US [40 CFR §180.595(2)] flufenpyr

- ethyl; acetic acid, [2

- chloro

- 4

- fluoro

- 5

- [5

- methyl

- 6

- oxo
- 4

- (trifluoromethyl)

- 1

- (6H)

- pyridazinyl]

- phenoxy]

- ethyl ester], and its metabolite, S

- 3153 acid

- 4

- OH; [2

- chloro

- 4

- hydroxy

- 5

- [5

- methyl

- 6

- oxo
- 4

- (trifluoromethyl)

- 1

- (6H)

- pyridazinyl]

- phenoxy]

- acetic acid, free and conjugat ed Canada Mexico 1 Codex

None Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex Corn, field, forage 0.05 Corn, field, stover 0.05 Completed: M. Negussie; 10/07/14
1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.