UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

Date: 26-NOV-2014 

SUBJECT: Flufenpyr-Ethyl. Human Health Assessment Scoping Document and 

Preliminary Human Health Risk Assessment in Support of Registration Review. 

PC Code: I 08853 

Decision No.: 492594 

Petition No.: N/A 

DP Barcode: 0421190 

Registration No.: N/ A 

Regulatory Action: Registration Review Risk 

Assessment 

Risk Assessment Type: Single Case No.: 7262 

Chemical/ Aggregate 

TXR No.: NA CAS No.: 188489-07-8 

MRID No.: NA 7 40 CFR: § 180.595 

FROM: Jennifer R. Tyler, Chemist / ff/1./M ; ),_OZ. ~ 

THRU: 

TO: 

MoniqueM. Perron, Sc.D., ljox ico ;~ 1"~ ~ ~ £-"' _. 

Lata V enkateshwara, Envir nrnental Scientist z..~.n.... V c......, 

Risk Assessment Branch 1 (RAB 1) 

Health Effects Division (HED; 7509P) 

Charles W. Smith III, Branch Chief 

George F. Kramer, Ph.D., Senior ~em~~~~-:':~~~;:;~~oRABl/HED (7509P) 

Steven Snyderman 

Pesticide Re-evaluation Division (PRD; 7508P) 

As part of Registration Review, PRD of the Office ofPesticide Programs (OPP) has requested 

that HED evaluate the hazard and exposure data and conduct occupational and residential 

exposure assessments, as needed, to estimate the risk to human health that will result from the 

currently registered uses of pesticides. This memorandum serves as HED's scoping document 

AND preliminary human health risk assessment of the dietary, occupational and residential 

exposure, and aggregate risk from the registered uses of flufenpyr-ethyl. The most recent 

quantitative human health risk assessment was performed in 2003, and was for the use of 

flufenpyr-ethyl on field corn, soybeans, and sugarcane (Memo, J. Tyler eta!., 31 -JUL-2003; 

D270403). The following risk assessment updates have been made: 

• Chronic dietary exposure assessment to include estimated drinking water concentrations 

(EDWCs) and updated consumption data from the United States Department of 

Agriculture (USDA) National Health and Nutrition Examination Survey/What We Eat in 

America (NHANES/WWEIA; 2003-2008); 

• Quantitative spray-drift exposure/risk assessment; 

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Flufenpyr-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) along with policy changes for body weight assumptions. 

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 Lata V enkateshwara (RAB 1 ), the hazard characterization 

was provided by Monique Perron (RAB 1 ), and the drinking water assessment was provided by 

James Wolf of the Environmental Fate and Effects Division (EFED). 

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Flufenpyr-ethyl Human Health Risk Assessment D421190

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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. .................................................................................26
Flufenpyr-ethyl Human Health Risk Assessment D421190

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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 currently registered for use on field 

corn, soybeans, and sugarcane. There are currently no registered special local needs (SLN) or 

Section 18 Emergency Exemptions, and no pending PRIA actions for flufenpyr-ethyl. The most 

recent quantitative human health risk assessment was performed in 2003 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 evaluated the status of the human health risk assessments for flufenpyr-ethyl to 

determine whether sufficient data are available and whether any 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 document 

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 for flufenpyrethyl 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 Council (HASPOC) concluded,

based on a weight-of-evidence approach, that these studies are not required at this time (Memo, 

U. Habiba, 07-OCT-2014; TXR#0057056). Therefore, the toxicology database is complete to 

support existing registrations and Registration 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 updated 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 the general U.S. population and all population subgroups 

(<1% of the cPAD).

Residential (Non-Occupational) Exposure and Risk Assessment: There are no proposed or 

current registrations for products containing flufenpyr-ethyl that allow residential use. 

Therefore, residential handler and conventional residential post-application exposure 

assessments were not conducted to support Registration Review. A quantitative spray drift 
Flufenpyr-ethyl Human Health Risk Assessment D421190

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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 aggregate 

exposure. In accordance with FQPA, HED must consider and aggregate pesticide exposures and 

risks from three major sources: food, drinking water, 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 population 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-ethyl is classified as “not likely to be carcinogenic to humans.” A chronic 

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 represent 

chronic aggregate exposure. Therefore, the chronic aggregate (food + drinking water) flufenpyrethyl 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 margins 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 practices, a 

quantitative non-cancer occupational post-application inhalation exposure assessment 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 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.”

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 review may 

have included review by the Human Studies Review Board. Descriptions of data sources, as well as 

guidance on their use, can be found at 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-ethyl Human Health Risk Assessment D421190

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2.0 Recommendations

HED has examined the toxicology and residue chemistry databases for flufenpyr-ethyl. There are no 

residue chemistry, residential, occupational/residential, or toxicology data deficiencies that would 

preclude the continuation of permanent tolerances for residues of flufenpyr-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, adequate 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 

agricultural 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 compound 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 Codex 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 been established in 40 CFR §180.595 for residues of flufenpyr-ethyl 

in/on field corn, soybeans, and sugarcane. The residue chemistry database supports the currently 

established tolerances as listed in 40 CFR §180.595. Table 2.2.3.1 is a summary of the 

established tolerances for residues of flufenpyr-ethyl. HED is not recommended any changes to 

the established tolerances. However, the tolerance expressions for flufenpyr-ethyl have been 

reviewed and should be updated as follows:

40 CFR §180.595(a)(1): Tolerances are established for residues of the herbicide 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 

flufenpyr-ethyl (ethyl 2-[2-chloro-4-fluoro-5-[5-methyl-6-oxo-4-(trifluoromethyl)-1(6H)-

pyridazinyl]phenoxy]acetate) in or on the following commodities:
Flufenpyr-ethyl Human Health Risk Assessment D421190

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40 CFR §180.595(a)(2): Tolerances are established for residues of the herbicide 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 the 

sum of flufenpyr-ethyl (ethyl 2-[2-chloro-4-fluoro-5-[5-methyl-6-oxo-4-(trifluoromethyl)-1(6H)-

pyridazinyl]phenoxy]acetate) 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 conjugated, 

calculated as the stoichiometric equivalent of flufenpyr-ethyl, 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-

(6H)-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-methyl6- oxo-4-(trifluoromethyl)-1-(6H)-pyridazinyl]-phenoxy]-acetic acid, free and conjugated

Corn, field, forage 0.05

Corn, field, stover 0.05

2.3 Label Recommendations

No revision to the registered labels are required to support Registration Review.

3.0 Ingredient Profile

3.1 Chemical Identity and Physical/Chemical Properties

The chemical structure and nomenclature of flufenpyr-ethyl and its metabolites, and a detailed 

description of the physicochemical 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 summary of the 

registered uses are included in Attachment 3. 

3.3 Anticipated Exposure Pathways

Based on the registered application scenarios, dietary exposure is an anticipated exposure 

pathway as residues of flufenpyr-ethyl may be found in/on crops, and drinking water. Although 

there are no registered residential uses of flufenpyr-ethyl, there is a potential for spray drift that 

may result in exposures 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 flufenpyr-ethyl.
Flufenpyr-ethyl Human Health Risk Assessment D421190

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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 according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve 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 exposures 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 

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.

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 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 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 primarily 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 primary target in mice. In subchronic mouse studies, increased 

liver weights and hepatic centrilobular vacuolation 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 

(1000 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, increased mortality, and necropsy findings in the stomach at doses ≥200 

mg/kg/day with no developmental effects observed. No maternal toxicity or developmental 
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effects were seen in the rat developmental study. No parental or offspring effects were seen in 

reproduction toxicity studies.

Flufenpyr-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 classified 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 immunotoxicity 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, the toxicology database is complete to 

support existing registrations and Registration Review (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 NonOccupational Human Health Risk Assessments.1

Exposure/ Scenario POD UFs/

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

UFA = 10X

UFH = 10X

FQPA SF = 1X

cRfd =

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

UFA = 10X

UFH = 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 adverse-effect level. 

LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = populationadjusted dose (a = acute, c = chronic). RfD = reference dose (a = acute, c = chronic). MOE = margin of exposure. LOC = level of concern. 
Flufenpyr-ethyl Human Health Risk Assessment D421190

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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 UFs

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 ShortTerm 

(1-30 days) and 

Intermediate-term 

(1-6 months)

NOAEL = 

40 mg/kg/day

Inhalation 

assumed 

equivalent to 

oral

UFA = 10X

UFH = 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 adverseeffect level. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). 

UFH = 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 required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal 

Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential 

adverse outcomes from exposure to 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 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 Registration Review for flufenpyr-ethyl, 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), 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 (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, 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 substance, and 

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list 
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of chemicals identified for EDSP screening was published on June 14, 20131and 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 established 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 established for residues of flufenpyr-ethyl and metabolite S-3153 acid4-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 rotational crops.

The nature of the residue in sugarcane, corn, and soybean is adequately understood based on 

available metabolism studies. The HED Metabolism Assessment Review Committee (MARC) 

concluded that parent only is the residue of toxicological concern 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 and 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 rotational crop data are available 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 applied at the maximum use 

rate. The submitted 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) are supported by available confined rotational crop data. Therefore, 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-ethyl Human Health Risk Assessment D421190

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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. The HED MARC concluded that 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 risk 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 assuming 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 highest postbreakthrough 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-ethyl 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).

Residue1 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-OCH3 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 only found in the 

top soil layer of one out of three field studies at the analytical method detection limit level. Therefore 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 directly 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 

pesticide in food, drinking water, and through residential uses. In support of Registration 

Review, an updated chronic dietary (food and drinking water) 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 modeled drinking water estimates. The 

groundwater EDWC of 0.017 ppm was 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-ethyl Human Health Risk Assessment D421190

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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) Exposure 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 offtarget 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 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 analogous 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 utilized. 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 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.

Exposures 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 assessment was based on the algorithms and input values specified in the 

recently revised (2012) Standard Operating Procedures For Residential Risk Assessment

(SOPs). 

 
Flufenpyr-ethyl Human Health Risk Assessment D421190

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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 incorporated 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 Deposition 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 90th 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 downwind direction for entire 

application/drift event).5

There are no short- or intermediate-term dermal PODs. Only incidental oral risk estimates were

evaluated. The total applicable LOC is 100, so MOEs <100 would be of concern. Children (1 to 

<2 years old) 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).

 

3http://www.agdrift.com/ 

4 Note that for many cases the scenarios outlined in the screening approach represent actual 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 screening 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 as 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-ethyl Human Health Risk Assessment D421190

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Table 6.1.1.1. Children (1 to <2 years old) Incidental Oral Risk Estimates (MOEs) Related to 

Spray Drift Exposure for Flufenpyr-ethyl.

Crop/Rate 

Group Spray Type/Nozzle Configuration

Application 

Rate

(lb ai/A)

Estimated 

TTRt (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 Agency 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, 20106. The Agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis7. During Registration Review, the Agency 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; D270403). 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 were 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 estimates did not exceed HED's 

LOC.

Updated chronic dietary (food and drinking water) exposure and risk assessments were

conducted to include the updated EDWCs and 2003-2008 NHANES/WWEIA consumption data 

(discussed in Section 5.3). Since there are no residential uses, the chronic dietary (food and 

water) exposure estimates represent chronic aggregate exposure. Therefore, the 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-2014-0219
Flufenpyr-ethyl Human Health Risk Assessment D421190

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8.0 Cumulative Exposure/Risk Characterization

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 registered 

agricultural uses of flufenpyr-ethyl. Table A.3.1 in Attachment 3 provides 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/applicators). In addition, there is a potential for post-application worker 

exposure from entering into areas previously 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 

exposure 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 personalprotective 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-ethyl Human Health Risk Assessment D421190

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Table 9.1.1. Summary of Occupational Handler Inhalation Risks for Flufenpyr-ethyl.

Activity Application 

Equipment Crop/Target

Inhalation 

Unit Exposure 

(μg/lb ai)1

App 

Rate2 Acres3 Dose4 ST and IT Inhalation MOE5

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 Policy #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 

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 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 Tool and a subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the Agency will utilize 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 inhalation 

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 pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 
Flufenpyr-ethyl Human Health Risk Assessment D421190

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. There were no incidents involving flufenpyrethyl 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 incident 

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 flufenpyrethyl 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-AUG2003FLUFENYPYR-ETHYL – Health Effects Division (HED) 

Metabolism Assessment Review Committee (MARC) Decision 

Document. Meeting Date: 18-JUN-2003.

S. Recore, E. Evans D422322 20-AUG2014Flufenpyr-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 07-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-ethyl Human Health Risk Assessment D421190

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Attachment 1: Chemical Identity Tables.

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(6H)-

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-dihydropyridazin1-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 (pKa) Very insoluble in water, DC could not by measured

Octanol/water partition coefficient Log(KOW) 2.99
Flufenpyr-ethyl Human Health Risk Assessment D421190

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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

no1

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

yes2

yes

yes2

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........................................

no1

no1

no

--

--

--

870.7485 Metabolism and Pharmacokinetics................................

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

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

yes

no

no1

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 LD50 > 5,000 mg/kg (Limit Test) IV

870.1200 Acute Dermal 45118906 LD50 > 5,000 mg/kg (Limit Test) IV

870.1300 Acute Inhalation 45152805 LC50 > 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/A
Flufenpyr-ethyl Human Health Risk Assessment D421190

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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

F0 (M/F): 0/0, 14/16, 135/162, 

1463/1672 mg/kg/day

F1 (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-ethyl Human Health Risk Assessment D421190

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 females, 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 considering urinary and fecal elimination (including 

the biliary contribution). 
Flufenpyr-ethyl Human Health Risk Assessment D421190

Page 23 of 26

Attachment 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) PHI1 

(days)

RTI2

(days)

REI3

(hours) PBI4

Per 

App.

Per 

Year

Field Corn

S-3153 WDG 

Herbicide 

(WDG)

Ground 

or Air 2

0.027

0.054

NS5

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 = plantback interval.

5. NS = not specified.
Flufenpyr-ethyl Human Health Risk Assessment D421190

Page 24 of 26

Attachment 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.r08

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, field, 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 1.000 

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 ppb
Flufenpyr-ethyl Human Health Risk Assessment D421190

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, Chronic) = .4 mg/kg bw/day

===============================================================================

 Total exposure by population subgroup

-------------------------------------------------------------------------------

 Total Exposure

 -----------------------------------

 Population mg/kg Percent of 

 Subgroup body wt/day Rfd 

-------------------------------------- ------------- ----------------

Total US Population 0.000378 0.1%

Hispanic 0.000367 0.1%

Non-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-ethyl Human Health Risk Assessment D421190

Page 26 of 26

Attachment 5: Flufenpyr-ethyl IRLS Sheet.

Table A.5.1. Summary of US and International Tolerances and Maximum Residue Limits.

Residue Definition:

US Canada Mexico1 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 Mexico1 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 conjugated

Canada Mexico1 Codex

None

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

US Canada Mexico1 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.