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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM

DATE: 03/01/11

SUBJECT: Pyraflufen-ethyl: Human Health Risk Assessment for a Section 3 Registration of 

New Food Uses on Tree Nuts (Crop Group 14), Pistachios, Pome Fruit (Crop 

Group 11-10), and Stone Fruits (Crop Group 12), Hops, Grapes, Olives and 

Pomegranates. 

PC Code: 030090 DP Barcode: 377359

Decision No. 432056 Registration Nos.: 71711-7, 71711-25

Petition No.: 0F7718 Regulatory Action: Section 3 

Registration

Risk Assessment Type: Single Chemical/Aggregate Case No.: N/A

TXR No.: N/A CAS No.: 129630-19-9

MRID No.: N/A 40 CFR: 180.585

FROM: Kristin Rury, Risk Assessor

Leung Cheng, Senior Chemist 

Myron Ottley, Toxicologist

Risk Assessment Branch III

Health Effects Division (7509P)

THROUGH: Paula Deschamp, Branch Chief

Risk Assessment Branch III 

Health Effects Division (7509P)

TO: James Stone, RM# 23

Registration Division (7505P)

The Registration Division (RD) of the Office of Pesticide Programs (OPP) requested that the 

Health Effects Division (HED) evaluate hazard and exposure data and conduct dietary, 

occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to 

human health that will result from all registered and proposed uses of pyraflufen-ethyl

Nichino America, Inc. (Nichino) has submitted revisions to their ET® Herbicide product labels 

proposing the use of the 0.208 lb ai/gal EC (emulsifiable concentrate) and 0.177 lb ai/gal SC 

(suspension concentrate) formulations of pyraflufen-ethyl on Tree Nuts (Crop Group 14), Pome 

Fruit (Crop Group 11-10), and Stone Fruits (Crop Group 12), Hops, Grapes, Olives and 

Pomegranates.The proposed uses allow application of pyraflufen-ethyl via groundboom 

application to the proposed crops. 
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This document addresses human-health risk resulting from the proposed expansion of the 

registered agricultural food uses and the currently registered food uses. The pyraflufen-ethyl 

hazard characterization/endpoint selection, and drinking water exposure assessment have not 

changed since the previous risk assessment (D339360, M. Ottley, 04/17/2008) and can be 

applied directly to this action. The risk assessment and occupational and residential risk 

assessments were provided by Kristin Rury, the hazard characterization by Myron Ottley, the 

residue chemistry data review and dietary assessment by Leung Cheng. The drinking water 

assessment was conducted by Michael Barrett of the Environmental Fate and Effects Division

(EFED). 
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Table of Contents

1.0 EXECUTIVE SUMMARY ................................................................................................ 5

2.0 HED RECOMMENDATIONS........................................................................................... 9

2.1 Data Deficiencies/Conditions of Registration ...................................................... 11

3.0 INGREDIENT PROFILE................................................................................................. 13

3.1 Summary of Proposed Uses.................................................................................. 13

3.2 Structure and Nomenclature ................................................................................. 14

3.3 Physical and Chemical Properties......................................................................... 15

4.0 HAZARD CHARACTERIZATION ................................................................................ 15

4.1 Hazard Profile ....................................................................................................... 15

4.2 FQPA Considerations ........................................................................................... 16

4.3 Dose-Response Assessment.................................................................................. 17

4.4 Residual Uncertainty in the Exposure Database................................................... 18

4.5 Endocrine Disruption............................................................................................ 18

5.0 DIETARY EXPOSURE/RISK CHARACTERIZATION................................................ 19

5.1 Pesticide Metabolism and Environmental Degradation........................................ 19

5.1.1 Summary of Plant and Animal Metabolism Studies................................. 19

5.1.2 Metabolism in Rotational Crops............................................................... 19

5.1.3 Analytical Methodology ........................................................................... 20

5.1.4 Environmental Degradation...................................................................... 20

5.1.5 Toxicity Profile of Major Metabolites and Degradates ............................ 21

5.1.6 Pesticide Metabolites and Degradates of Concern.................................... 21

5.1.7 Drinking Water Residue Profile................................................................ 22

5.1.8 Food Residue Profile................................................................................. 23

5.1.9 International Residue Limits..................................................................... 25

5.2 Dietary Exposure and Risk ................................................................................... 25

5.2.1 Acute Dietary Exposure/Risk ................................................................... 25

5.2.2 Chronic Dietary Exposure/Risk ................................................................ 25

5.3 Cancer Dietary Risk.............................................................................................. 26

5.4 Anticipated Residue and Percent Crop Treated (%CT) Information.................... 27

6.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK 

CHARACTERIZATION .................................................................................................. 27

6.1 Residential Handler Exposure and Risk ............................................................... 28

6.2 Non-Occupational (Post-Application) Exposure from Treated Lawns ................ 28

7.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION.............. 30

7.1 Acute Aggregate Risk ........................................................................................... 30

7.2 Short- and Intermediate-Term Aggregate Risk..................................................... 30

7.3 Chronic Aggregate Risk........................................................................................ 31

7.4 Aggregate Cancer Risk ......................................................................................... 31

8.0 CUMULATIVE RISK...................................................................................................... 32

9.0 OCCUPATIONAL EXPOSURE AND RISK.................................................................. 32

9.1 Occupational Handler ........................................................................................... 32

9.2 Occupational Post-Application ............................................................................. 36

9.3 Restricted Entry Interval (REI)............................................................................. 36

Appendix A. Toxicology Profile................................................................................................... 37

A.1. Toxicity Profile of Pyraflufen-Ethyl..................................................................... 37

A.2. Toxicology Data Requirements ............................................................................ 38

Appendix B. Residue Chemistry................................................................................... 39
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B.1. US and International Tolerances and MRLs......................................................... 39

REFERENCES: ............................................................................................................................ 40
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1.0 EXECUTIVE SUMMARY

Use Profile

Pyraflufen-ethyl, ethyl 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-

4-fluorophenoxy]acetate, is an herbicide belonging to the phenyl pyrazole class of chemicals. 

Pyraflufen-ethyl is formulated as 2.0% and 2.5% soluble concentrate (SC) solutions. 

Pyraflufen-ethyl is an herbicide proposed for application to post-harvest, dormant, pre-bloom, 

and in-season tree nuts, pistachios, pome fruits, hops, grapes, olives, stone fruits, and 

pomegranates for control of broadleaf weeds. Pyraflufen-ethyl may be applied at a single 

application rate of 0.0013 to 0.0053 lb ai per acre via ground application. Pyraflufen-ethyl may 

not be applied via chemigation or aircraft to the proposed use sites. Up to 3 applications may be 

made per year to post-harvest, dormant, or pre-bloom use sites, and up to 2 applications may be 

made per year to in season crops. The maximum seasonal application rate is 0.01 lb ai per acre

(0.007 for ET 2% Herbicide/Defoliant and 0.01 for ET Herbicide/defoliant (2.5%). 

Hazard Assessment

The toxicology database for pyraflufen-ethyl is of high quality and complete except for acute and 

subchronic neurotoxicity and immunotoxicity studies which are now required under 40 CFR 

§158.500 as part of the toxicology data requirements for registration of a pesticide (food and 

non-food uses). Additionally, because the proposed use pattern will result in repeated inhalation 

exposure, a 28-day inhalation toxicity study is required.

Although acute and subchronic neurotoxicity and immunotoxicity studies are needed to complete 

the database, there are no concerns for immunotoxicity or neurotoxicity based on the results of 

the existing studies. Further, in the absence of a route specific inhalation toxicity study, a point 

of departure (PoD) for inhalation exposure risk assessment has been extrapolated from an oral 

study.

The metabolic pathway in plants and animals involves ester hydrolysis and N-demethylation. 

Compounds of toxicological significance in rats, plants, and livestock included parent and 

metabolites E1 and E9. Other environmental transformation products (E-1, E-2, and E-3), 

predicted to be present in water, are also considered of toxicological significance. Table 3.2 

shows the chemical structures of pyraflufen-ethyl and its metabolites.

Pyraflufen-ethyl exhibits relatively low toxicity following single oral, dermal, and inhalation 

exposure. It is moderately irritating to the eye, but is not a skin irritant or a dermal sensitizer.

Following repeated short-term and chronic oral doses, the liver, kidney, and possibly the 

hematopoietic system are the target organs for pyraflufen-ethyl in the rat and/or mouse. No 

adverse toxic effects were noted in the dog following oral exposure or in the rat following 

dermal exposure. There was no evidence of increased susceptibility following pre-natal 

exposure to rats and rabbits and pre-and post-natal exposures to rats. Although not mutagenic 

or carcinogenic in the rat or in female mice, pyraflufen-ethyl is classified as a likely human 

carcinogen based on increased incidence of hepatocellular tumors (adenomas, carcinomas 

and/or hepatoblastomas) in male mice.

 

An acute dietary risk assessment was not conducted as there was no indication of an adverse 

effect attributable to a single dose. Short-term inhalation and incidental oral risk assessments 

utilized the most sensitive dose and endpoint in the database, a maternal no observable adverse 
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effect level (NOAEL) of 20 mg/kg/day based on decreased body weight and food consumption

observed in the rabbit developmental toxicity study. The chronic dietary risk assessment utilized 

the most sensitive chronic dose and endpoint in the database, a NOAEL of 20 mg/kg/day based 

on liver toxicity observed in the 18-month mouse carcinogenicity study. Although neurotoxicity 

and immunotoxicity studies are needed to complete the database, there are no concerns for 

neurotoxicity or immunotoxicity based on the results of the existing studies and no need for a 

database uncertainty factor. The Food Quality Protection Act (FQPA) factor was reduced to 1X 

because pyraflufen-ethyl showed no evidence of increased susceptibility of the young. The 

standard 100-fold safety factor for combined human variability and interspecies differences has 

been applied to the PoD selected for all non-cancer risk assessment scenarios. A linear low-dose 

extrapolation (Q1* of 3.32 x 10-2(mg/kg/day)-1) is used for quantification of human cancer risk

from oral, dermal and inhalation routes. In the absence of dermal absorption data, dermal 

absorption is assumed to be 100% and inhalation absorption is assumed to be equivalent to oral 

(100%).

Dietary Risk

For both tolerance enforcement and dietary risk assessment, the residues of concern in/on plants 

(primary and rotational crops) are the parent and the metabolite E-1, and the residues of concern 

in/on treated livestock commodities are the parent, metabolite E-1, and metabolite E-9. The 

residues of concern in drinking water are the parent, metabolites E-1, E-2, and E-3 .All chemical 

names and metabolic structures can be found in Table 3.2.

There was no indication of an adverse effect attributable to a single dose; therefore, no acute 

dietary risk assessment was performed. 

Chronic dietary exposure analyses using the Dietary Exposure Evaluation Model (DEEMFCID, Version 2.03) indicate that chronic dietary exposure to the combined residues of 

pyraflufen-ethyl and metabolite E-1 from food and drinking water are well below HED’s level of 

concern (LOC). Using a partially refined analysis, the estimated chronic dietary exposure is 

<1% of the chronic population adjusted dose (cPAD) for the general U.S. population and all 

population subgroups, including children 1-2 years old, the most highly exposed population 

subgroup. The cancer risk for the general U.S. population is estimated to be 2.7x10-6 which is in 

the 10-6 range and also below HED’s level of concern. 

Drinking Water

The drinking water residues used in the dietary risk assessment were provided by EFED. 

Due to its low persistence, pyraflufen-ethyl should not be available for runoff or leaching. 

However, three metabolites (E-1, E-2, and E-3) were identified as major transformation products 

and are included in the drinking water assessment. There are no data available on the toxicity of 

the metabolites; however, since the metabolites are structurally similar to the parent pyraflufenethyl, they are assumed to be of equal or lesser toxicity (Metabolism Assessment Review 

Committee [MARC] Decision memo, 07/19/02 and personal communication with A. Protzel and 

J. Doherty, 9/19/02). Based on the highest application rate, the acute surface water estimated 

drinking water concentration (EDWC) using the FIRST (FQPA Index Reservoir Screening Tool) 

model (surface water) is 1247 parts per trillion (ppt) of total residues of pyraflufen-ethyl and its 

major degradates and the annual average surface water value is 281 ppt. The groundwater 

screening concentration from SCIGROW (Screening Concentrations in Ground Water) is 1.8 

ppt. These values generally represent upper-bound conservative estimates of the total residue 
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concentrations that might be found in surface water and ground water due to the use of 

pyraflufen-ethyl.

Residential Risk

No new residential uses and no occupational uses at residential sites are being requested in this 

petition; therefore, a new residential risk assessment was not conducted. Residential exposure 

and risk due to residential handler application of pyraflufen-ethyl to residential turfgrass as well 

as post-application exposure/risk to adults and children were previously assessed and are 

incorporated in this assessment. Non-cancer risk assessments were conducted for short-term 

residential exposure scenarios. The inhalation margins of exposure (MOEs) for adult handlers 

(low pressure handwand and hose-end sprayer) were >35,000,000; no hazard from the dermal 

route was identified. The combined MOEs for post-application children’s incidential ingestion 

of residues of pyraflufen-ethyl on treated turf (hand-to-mouth exposure, object-to-mouth 

exposure, and soil ingestion) were 270,000; these non-cancer risks provide a substantial margin 

of safety for HED’s level of concern (MOE=100). Cancer risks for adult handlers (dermal + 

inhalation) were estimated to be in the 10-8range and for adult post-application activities 

(residential turf and adult golfer) in the 10-7range; these risks are not of concern to HED. 

Aggregate Risk

Short-term aggregate risk is based on residential handler exposure, children’s incidental oral 

exposure (from residential post-application treatment) and dietary exposure (food and drinking 

water). Risks for the highest exposed population (children, 1-2 years old) were below HED’s 

LOC, with an MOE of 66,000. An intermediate-term aggregate risk assessment was not 

conducted for adults because the exposure duration is expected to be short-term only. In 

addition, an intermediate-term aggregate risk assessment was not conducted for children (postapplication exposure) because standard assumptions (input values) for intermediate-term 

exposure are less conservative than those for short-term exposure. 

For chronic aggregate risk assessment, exposures from food and drinking water were considered. 

Therefore, exposures from residential uses are not expected to occur over the chronic duration

Aggregate food + water risk is <1% of the cPAD for the general population, and all subgroups. 

For the aggregate cancer risk assessment, exposure from residential uses is based on the lifetime 

average daily dose (LADD), and assumes an exposure period of 5 days per year and 50 years of 

exposure over a 70-year lifetime. Average food and water-source dietary exposure values were 

used. Cancer risk for the US population includes infants and children; therefore, in accordance 

with HED policy, children’s cancer risk was not reported separately. Aggregate (food, water and 

residential) cancer risk is in the 10-6 range and not of concern to HED. 

Occupational Risk

Occupational handlers may be exposed during mixing, loading, and application of pyraflufenethyl using groundboom equipment for broadcast treatment of the proposed use sites. Noncancer risks only considered inhalation exposures because no adverse effects were seen in the 

dermal toxicity study at the limit dose. The non-cancer inhalation MOEs for occupational 

exposure to pyraflufen-ethyl ranged from 2,400,000 to 3,800,000 at baseline. 

Cancer risks for adult handlers were assessed. Handler cancer risk estimates were based on 

dermal and inhalation exposures. All handler exposure scenarios with personal protective 

equipment (PPE) use (as required by the label) resulted in cancer risks below HED’s LOC. The 
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private grower mixer/loader cancer risks were 9.3x10-6at baseline and 7.8x10-8 with a single 

layer and gloves. The private grower applicator cancer risks were 4.7x10-8at baseline and with a 

single layer and gloves. Commercial mixer/loader cancer risks were to 2.8x10-5at baseline and 

1.4x10-7 with a single layer and gloves. Commercial applicator cancer risk was 1.4x10-7at 

baseline and with a single layer and gloves.

Occupational agricultural post-application cancer risks were not evaluated based on the proposed 

pyraflufen-ethyl use pattern. Pyraflufen-ethyl is applied to crop foliage as a burndown treatment 

only. In all other cases, the target sites of pyraflufen-ethyl are broadleaf weeds and grasses. 

Therefore, a post-application risk assessment is not needed. 

Pyraflufen-ethyl is classified as acute toxicity category III for acute dermal and primary eye 

irritation. It is classified as category IV for primary skin irritation and it is not a dermal 

sensitizer. Therefore, the interim Worker Protection Standard (WPS) restricted entry interval of 

12 hours (as stated on the label) is adequate to protect agricultural workers from post-application 

exposures to pyraflufen-ethyl.

The minimum level of PPE for handlers is based on acute toxicity for the end-use product. RD is 

responsible for ensuring that PPE listed on the label is in compliance with the WPS.

Regulatory Recommendations

The proposed agricultural uses have been assessed and no risks of concern were identified. HED 

has no objection to the registration of this new use pattern provided that the registration be made 

conditional pending submission of the newly required Part 158 toxicology data and well as 

additional residue chemistry data (see Section 2.0 for details). 

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," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population 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 under the Continuing Survey of Food Intake by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures 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.
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Review of Human Research

This risk assessment relies in part on data from Pesticide Handlers Exposure Database (PHED) 

studies in which adult human subjects were intentionally exposed to a pesticide or other 

chemical. These studies have been determined to require a review of their ethical conduct and 

have received that review.

2.0 HED RECOMMENDATIONS

HED has examined the toxicology and residue chemistry database for pyraflufen-ethyl. There 

are no residue chemistry issues that would preclude granting a conditional registration for use of 

pyraflufen-ethyl on the requested crops except for hops. The deficiencies below must be 

resolved before granting an unconditional registration. For hops, detailed field trial information 

such as the location of the trials, formulation type, application rate, application method, if an 

adjuvant was used, and the soil characteristics (if pyraflufen-ethyl is directed to the soil) must be 

provided. Therefore, registration for the requested use on hops cannot be granted at this 

time.

The proposed uses and the submitted data support the following tolerances for residues of 

pyraflufen-ethyl in/on the following raw agricultural commodities. In accordance with HED’s 

Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09), the tolerance expression for 

pyraflufen-ethyl should be revised to state:

“Tolerances are established for residues of pyraflufen-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 pyraflufen-ethyl, ethyl 2-[2-chloro-5-[4-

chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]acetate, and its acid 

metabolite, 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-

fluorophenoxy]acetic acid, in or on the commodity.”

Almond, hulls.......................................................................0.02 ppm

Nut, tree, group 14 ...............................................................0.01 ppm

Pistachio...............................................................................0.01 ppm

Fruit, pome, group 11...........................................................0.01 ppm

Fruit, stone, group 12...........................................................0.01 ppm

Pomegranate.........................................................................0.01 ppm

Olive.....................................................................................0.01 ppm

Grape....................................................................................0.01 ppm

The proposed uses and the submitted data support the following tolerances for residues of 

pyraflufen-ethyl in the following livestock commodities:

“Tolerances are established for residues of pyraflufen-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 pyraflufen-ethyl, ethyl 2-[2-chloro-5-[4-

chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]acetate, and its acid 

metabolites, 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-

fluorophenoxy]acetic acid and 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1H-pyrazol-3-yl]-4-

fluorophenoxy]acetic acid, in or on the commodity.”
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Cattle, fat..............................................................................0.03 ppm

Cattle, meat ..........................................................................0.03 ppm

Cattle, meat byproducts .......................................................0.03 ppm

Goat, fat................................................................................0.03 ppm

Goat, meat............................................................................0.03 ppm

Goat, meat byproducts.........................................................0.03 ppm

Horse, fat..............................................................................0.03 ppm

Horse, meat ..........................................................................0.03 ppm

Horse, meat byproducts .......................................................0.03 ppm

Milk......................................................................................0.03 ppm

Sheep, fat..............................................................................0.03 ppm

Sheep, meat..........................................................................0.03 ppm

Sheep, meat byproducts.......................................................0.03 ppm

Table 2 shows the proposed and recommended tolerances by commodity. 

Table 2. Tolerance Summary for Pyraflufen-ethyl.

Commodity Established 

Tolerance (ppm)

Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct 

Commodity Definition

Grapes -- 0.01 0.01 Grape

Adequate residue data are 

available.

Hop cones, dried -- 0.01 None Hop, dried cones

Registration cannot be granted 

at this time since additional 

information is needed 

regarding the proposed use and 

field trial data.

Fruit, Pome group 11 -- 0.01 0.01 Fruit, pome, group 11

Fruit, Stone group 12 -- 0.01 0.01 Fruit, stone, group 12

Adequate residue data are 

available by translation.

Nuts, tree group 14 -- 0.01 0.01 Nut, tree, group 14

Adequate residue data are 

available.

Almond, hulls -- 0.02 0.02 Adequate residue data are 

available.

Pistachio -- 0.01 0.01 Adequate residue data are 

available by translation.

Pomegranates -- 0.01 0.01 Pomegranate

Adequate residue data are 

available by translation.

Olives -- 0.01 0.01 Adequate residue data are 

available by translation.
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Table 2. Tolerance Summary for Pyraflufen-ethyl.

Commodity Established 

Tolerance (ppm)

Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct 

Commodity Definition

Cattle, fat None None 0.03

Cattle, meat None None 0.03

Cattle, meat byproducts 0.02 -- 0.03

Goat, fat None None 0.03

Goat, meat None None 0.03

Goat, meat byproducts 0.02 -- 0.03

Horse, fat None None 0.03

Horse, meat None None 0.03

Horse, meat byproducts 0.02 -- 0.03

Milk 0.02 -- 0.03

Sheep, fat None None 0.03

Sheep, meat None None 0.03

Sheep, meat byproducts 0.02 -- 0.03

2.1 Data Deficiencies/Conditions of Registration

RESIDUE CHEMISTRY

The following must be provided prior to a tolerance being established or registration 

allowed on hops:

860.1200 Directions for Use

• Detailed field trial information for the hop study (MRID#47872705) was not provided;

therefore, it is uncertain if the crop field trials are representative of the proposed label. 

• The label does not provide a pre-harvest interval (PHI); therefore, it could be assumed 

that hops can be collected immediately after application. Hop samples were collected at 

a PHI of 29 to 38 days. The crop field trials should reflect the proposed use directions; 

therefore, the label should be revised to reflect a 30-day PHI, or new crop field trials 

should be conducted using a PHI of 0 days. 

860.1500 Crop Field Trials

• Detailed field trial information for the hop study (MRID#47872705) was not provided. 

The petitioner needs to submit detailed field trial information for MRID#47872705, 

including the location of the trials, formulation type, application rate, application method, 

if an adjuvant was used, meteorological data, and the soil characteristics.

The following data are required as a condition of registration on pome fruit (crop group 

11), stone fruit (crop group 12), pomegranates, olives, grapes, tree nuts (crop group 14), 
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and pistachios:

RESIDUE CHEMISTRY

860.1300 Nature of the Residue - Plants

• The petitioner should submit information on sample storage conditions and durations for 

samples analyzed in the orange plant metabolism study.

860.1340 Residue Analytical Methods 

• Method validation data for the method development of Metabolite E-9 (PTRL West 

Study 1837W) should be submitted for confirming its limit of quantification (LOQ).

860.1360 Multiresidue Methods

• Data are required reflecting recovery of pyraflufen-ethyl and Metabolite E-1 through the 

FDA Protocols C and D with and without the use of Florisil cleanup. These data remain 

outstanding.

• Since Metabolite E-9 should also be included in the tolerance definition for livestock 

commodities, data will be required reflecting recovery of Metabolite E-9 through the 

FDA multiresidue methods.

860.1380 Storage Stability

• No storage stability data were submitted for Metabolite E-9. A storage stability study for 

Metabolite E-9 in milk and liver under frozen conditions for 3 months is required.

860.1480 Meat, Milk, Poultry, and Eggs

• A cattle feeding study to be conducted at the 10X dose of 18 ppm is required.

860.1650 Submittal of Analytical Reference Standards

• Analytical standards for Metabolites E-1 and E-9 must be submitted to the National 

Pesticide Standards Repository.

TOXICOLOGY

870.3465 28 Day Inhalation - Rat

 Since the proposed use pattern will result in repeated inhalation exposure, a 28-day 

inhalation toxicity study is being required. 

870.6200 Acute and Subchronic Neurotoxicity Studies

 Acute and subchronic neurotoxicity studies are now required under the revised 40 CFR 

§158.340 guidelines.
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870.7800 Immunotoxicity Study

● An immunotoxicity study in rats and/or mice is now required under the revised 40 CFR 

§158.340 guidelines.

EPA expects to receive reports from the conduct of these four studies for detailed review by late 

2011.

3.0 INGREDIENT PROFILE

Pyraflufen-ethyl is a herbicide that is currently registered for use as a harvest aid in cotton and 

potatoes; for a single preplant or preemergence burndown use in field corn, cotton, deciduous 

fruit and nut trees and vines, soybeans, and wheat; for postemergence use in cotton, corn (except 

sweet corn), and soybeans, for weed control in non-crop land and uncultivated agricultural areas 

(nonfood producing); and as a nonselective herbicide for control of broadleaf weeds in non-crop 

areas, including recreational and residential areas, established ornamental turf lawns, parks, 

cemeteries, athletic fields, golf courses, sod farms, and similar turf areas. 

3.1 Summary of Proposed Uses

Pyraflufen-ethyl is a herbicidal active ingredient (ai). The proposed formulated end-use products 

are labeled under the trade names ET® Herbicide/Defoliant which contains 2.5% (0.208 lb 

ai/gallon) pyraflufen ethyl, and ET® 2% SC Herbicide/Defoliant which contains 2% (0.17 lb 

ai/gallon) pyraflufen-ethyl. Pyraflufen-ethyl is proposed for use on post-harvest, dormant, prebloom, and in-season tree nuts, pome fruits, hops, grapes, olives, stone fruits, and pomegranates 

for control of broadleaf weeds. Pyraflufen-ethyl may be applied at a single application rate of 

0.0013 to 0.0053 lb ai per acre via ground application. Pyraflufen-ethyl may not be applied via 

chemigation or aerially to the proposed use sites. Up to 3 applications may be made per year to 

post-harvest, dormant, or pre-bloom use sites, and up to 2 applications may be made per year to 

in season crops. The maximum seasonal application rate is 0.01 lb ai per acre (0.007 for ET 2% 

Herbicide/Defoliant and 0.01 for ET Herbicide/defoliant (2.5%). 

The proposed use profile is summarized in Table 3.1. 

Table 3.1. Use Profile for Pyraflufen-Ethyl

Crop Application Type Methods of 

Application

Single 

Application 

Rate (lb ai/A)

Maximum 

Number of 

Applications 

(fl oz)

Maximum 

Seasonal 

Application 

Rate (lb ai/A)

Retreatment 

Interval 

(RTI)

ET 2% Herbicide/Defoliant (EPA Reg. No. 71711-25) (0.17 lb ai/gal)

Grapes, Olive Trees, 

Pomegranates, 

Pome Fruit (Apple, 

Crabapple, Loquat, 

Mayhaw, Pear, Pear 

(oriental), Quince), 

Stone Fruits

(Apricot, Cherry, 

Nectarine, Peach, 

Plum, Plumcot, 

Prune), Tree Nuts , 

Hops

Post-Harvest, 

Dormant, Prebloom

Groundboom 0.0013 - 0.0053

3 

(5.5)

0.009 30 days

In Season 2 

(5.5)
Page 14 of 40

Table 3.1. Use Profile for Pyraflufen-Ethyl

Crop Application Type Methods of 

Application

Single 

Application 

Rate (lb ai/A)

Maximum 

Number of 

Applications 

(fl oz)

Maximum 

Seasonal 

Application 

Rate (lb ai/A)

Retreatment 

Interval 

(RTI)

ET Herbicide/Defoliant EPA Reg. No. 71711-7 (0.208 lb ai/gal)

Grapes, Olive Trees, 

Pomegranates, 

Pome Fruit (Apple, 

Crabapple, Loquat, 

Mayhaw, Pear, Pear 

(oriental), Quince), 

Stone Fruits

(Apricot, Cherry, 

Nectarine, Peach, 

Plum, Plumcot, 

Prune), Tree Nuts 

Hops

Post-Harvest, 

Dormant, Prebloom

Groundboom 0.0013 - 0.0053

3 

(6.8)

0.009 30 days

In Season 2 

(6.8)

3.2 Structure and Nomenclature

Table 3.2. Pyraflufen-Ethyl Nomenclature

Chemical structure

Common name Pyraflufen-Ethyl

PC Code 030090

Company experimental name ET-751

IUPAC name Ethyl [2-chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-

fluorophenoxy]acetate

CAS name Ethyl 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-

fluorophenoxy]acetate

CAS registry number 129630-19-9

End-use product (EP) 0.208 lb/gal EC (2.5%EC; ET® Herbicide/Defoliant; EPA Reg. No. 71711-7;

Label Date 02/20/2007)

0.17 lb/gal FlC (2.0%FlC; ET® 2%SC Herbicide/Defoliant; EPA Reg. No. 71711-25;

Label Date 09/06/2007)

Chemical structure 

Common name Pyraflufen

PC Code 030091

N N

Cl

F

Cl

CH

3

OCHF

2

OCH

2

COOH

N N

Cl

F

Cl

CH

3

OCH

2

COOC

2

H

5

OCHF

2
Page 15 of 40

Table 3.2. Pyraflufen-Ethyl Nomenclature

Company experimental name Metabolite E-1; Pyraflufen-ethyl plant and livestock metabolite of concern

IUPAC name [2-chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxy]acetic acid

CAS name 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-

fluorophenoxy]acetic acid

CAS registry number 129630-17-7

Chemical structure 

Company experimental name Metabolite E-9; Pyraflufen-ethyl livestock metabolite of concern

Chemical structure 

Company experimental name GC/MSD Residue Method Analyte E-15; methyl ester of Metabolite E-1

3.3 Physical and Chemical Properties

For a detailed description, refer to Section 2.3, Physical and Chemical Properties of the previous 

risk assessment document (D339360, M. Ottley, 04/17/2008). 

4.0 HAZARD CHARACTERIZATION

4.1 Hazard Profile

Studies Available 

The toxicology database for pyraflufen-ethyl is of high quality and complete except for acute and 

subchronic neurotoxicity and immunotoxicity studies which are now included under 40 CFR Part 

§158.500 as part of the toxicology data requirements for registration of a pesticide (food and 

non-food uses). Additionally, because the proposed use pattern will result in repeated inhalation 

exposure, a 28-day inhalation toxicity study is required.

Although and acute and subchronic neurotoxicity and immunotoxicity studies are needed to 

complete the database, there are no concerns for immunotoxicity or neurotoxicity based on the 

results of the existing studies. Further, in the absence of a route specific inhalation toxicity 

study, a PoD for inhalation exposure risk assessment has been extrapolated from an oral study.

Absorption, Distribution, Metabolism, and Excretion

Radiolabeled kinetic studies in the rat show that pyraflufen-ethyl is rapidly absorbed in a doseN N

Cl

F

Cl

CH

3

OCHF

2

OCH

2

COOCH3

N N

Cl

F

Cl

H

OCHF

2

OCH

2

COOH
Page 16 of 40

dependent manner with 56% of the low dose present in urine and bile within 2 days. At 6 hours 

post-dose, the highest residues were found in the GI tract, liver and excretory organs. There was 

no evidence of accumulation. Excretion of residues was essentially complete 24 hours after 

dosing with <1% of the absorbed dose eliminated unchanged.

The metabolic pathway in plants and animals involves ester hydrolysis and N-demethylation. 

Compounds of toxicological significance in rats, plants, and livestock included parent and 

metabolites E1 and E9. Other environmental transformation products (E-1, E-2, and E-3), 

predicted to be present in water, are also considered of toxicological significance.

Acute, Short-, and Long-Term Toxicity

Pyraflufen-ethyl exhibits relatively low toxicity following single oral, dermal, and inhalation 

exposure. It is moderately irritating to the eye, but is not a skin irritant or a dermal sensitizer. 

Following repeated short-term and chronic oral doses, the liver, kidney, and possibly the 

hematopoietic system are the target organs for pyraflufen-ethyl in the rat and/or mouse. No 

adverse toxic effects were noted in the dog following oral exposure or in the rat following 

dermal exposure. There was no evidence of increased susceptibility following pre-natal 

exposure to rats and rabbits and pre-and post-natal exposures to rats. Although not mutagenic 

or carcinogenic in the rat, pyraflufen-ethyl is classified as a likely human carcinogen based 

increased incidence of hepatocellular tumors (adenomas, carcinomas and/or hepatoblastomas) 

in male and female mice.

 

Points of Departure and Uncertainty Factors Used for Risk Assessment 

An acute dietary risk assessment was not conducted as there was no indication of an adverse 

effect attributable to a single dose. Short-term inhalation and incidental oral risk assessments 

utilized the most sensitive dose and endpoint in the database, a maternal NOAEL of 20 

mg/kg/day based on decreased body weight and food consumption observed in the rabbit 

developmental toxicity study. The chronic dietary risk assessment utilized the most sensitive 

chronic dose and endpoint in the database, a NOAEL of 20 mg/kg/day based on liver toxicity 

observed in the 18-month mouse carcinogenicity study. Although neurotoxicity and 

immunotoxicity studies are needed to complete the database, there are no concerns for 

neurotoxicity or immunotoxicity based on the results of the existing studies and no need for a 

database uncertainty factor. The FQPA factor was reduced to 1X because pyraflufen-ethyl 

showed no evidence of increased susceptibility of the young. The standard 100-fold safety factor 

for combined human variability and interspecies differences has been applied to the points of 

departure selected for all non-cancer risk assessment scenarios. A linear low-dose extrapolation 

(Q1* of 3.32 x 10-2(mg/kg/day)-1) is used for quantification of human cancer risk from oral, 

dermal and inhalation routes. In the absence of dermal absorption data, dermal absorption is 

assumed to be 100% and inhalation absorption is assumed to be equivalent to oral (100%).

4.2 FQPA Considerations

HED recommends that the default 10X FQPA safety factor be reduced to1X for the following 

reasons: 

1. The database is complete with the exception of acute and subchronic neurotoxicity, 

immunotoxicity, and inhalation toxicity studies.

2. There is no evidence of increased susceptibility of rat or rabbit fetuses following in 

utero exposure in the developmental studies with pyraflufen-ethyl. There is no evidence 
Page 17 of 40

of increased susceptibility of young rats in the reproduction study with pyraflufen-ethyl 

and there are no residual uncertainties for pre- and/or postnatal exposure.

3. There are no concerns for neurotoxicity and no need for a developmental neurotoxicity 

study (DNT).

4. There are no residual uncertainties identified in the exposure databases. The dietary 

food exposure assessment, although somewhat refined, is conservative assuming 100% 

crop treated information. Dietary drinking water exposure is based on conservative 

modeling estimates. HED Residential SOPs were used to assess post-application 

exposure to children as well as incidental oral exposure of children (age 3 to <6). These 

assessments will not underestimate the exposure and risks posed by pyraflufen-ethyl.

4.3 Dose-Response Assessment

HED has evaluated the toxicology database of pyraflufen-ethyl, established reference doses 

(RfD) and selected the toxicological endpoints for dietary as well as occupational and 

residential exposure risk assessments. A summary of the endpoints identified for risk 

assessment is presented below in Table 4.3.1.

Table 4.3. Summary of Toxicological Doses and Endpoints for Pyraflufen-Ethyl for Use in Dietary, Residential 

(Non-Occupational) and Occupational Human Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(all populations)None None None An endpoint attributable to a single dose was 

not identified from the available data.

Chronic 

Dietary (all 

populations)

NOAEL = 

20

UFA=10X

UFH=10X

FQPA SF = 1X

Chronic

RfD = 0.20 

mg/kg/day

cPAD = 0.2 

mg/kg/day

Mouse Carcinogenicity

LOAEL = 98 mg/kg/day based on liver 

toxicity

Incidental 

Oral ShortTerm

(1-30 days)

Maternal 

NOAEL = 

20 

mg/kg/day 

UFA=10X

UFH=10X

FQPA SF = 1X

MOE = 100 

(residential)

Developmental Toxicity-Rabbit

LOAEL = 60 mg/kg/day based on decreases 

in body weight and food consumption, GI 

observations, and abortions

Incidental

Oral 

IntermediateTerm

(1-6 months)

Maternal 

NOAEL = 

20 

mg/kg/day

UFA=10X

UFH=10X

FQPA SF = 1X

MOE = 100 

(residential)

Mouse Carcinogenicity

LOAEL = 98 mg/kg/day based on liver 

toxicity at interim sacrifice

Dermal (All 

Durations) None None None

In a 28-dermal toxicity study in rats, no 

dermal or systemic toxicity was seen at the 

Limit Dose (1000 mg/kg/day).

Inhalation 

(All 

Durations)

Maternal 

NOAEL = 

20 

mg/kg/day 

UFA=10X

UFH=10X

FQPA SF = 1X

MOE = 100 

(occupational)

MOE = 100 

(residential)

Developmental Toxicity-Rabbit

LOAEL = 60 mg/kg/day based on decreases 

in body weight and food consumption, GI 

observations, and abortions

Cancer (oral, 

dermal, 

inhalation)

Classification: “Likely to be Carcinogenic to Humans” by the oral route.

Q1* = 3.32 x 10-2(mg/kg/day)-1
Page 18 of 40

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 = 

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

of concern. N/A = not applicable.

HED identified endpoints for chronic dietary exposure assessment (chronic reference dose), 

short- and intermediate-term incidental oral exposure assessment and short- and intermediateterm inhalation exposure assessment. Endpoints for short- and intermediate-term dermal 

exposure assessment were not identified, because in a 28-day dermal toxicity study in rats, no 

effects were seen at the limit dose (1000 mg/kg/day). Long-term or chronic exposure through 

dermal or inhalation routes is not expected based on the use pattern (intermittent use).

To quantify cancer risk, the Q1* is multiplied by the estimated lifetime average daily doses 

from occupational or residential exposure. In the absence of dermal absorption data, 100% 

dermal absorption was assumed, in spite of the fact that the octanol/water partition coefficient 

(Kow) is low, which indicates that dermal absorption is expected to be low. Therefore, nondietary cancer risk estimates in this document are considered very conservative. Lifetime 

average daily dermal and inhalation exposures were summed, because cancer risk is based on 

total exposure over a lifetime.

4.4 Residual Uncertainty in the Exposure Database

Although the registrant has been requested to conduct a cattle feeding study at the 10X dose of 

18 ppm to meet a guideline requirement, the existing feeding study results at the 5X dose are 

sufficient to establish meat and milk tolerances and do not underestimate the exposure to cattle 

commodities. Although partially refined with average field trials, the dietary exposure estimates 

assumed 100% crop treated. This conservative approach will not underestimate dietary 

exposure to pyraflufen-ethyl in the proposed agricultural commodities. HED Residential SOPs 

were used to assess post-application exposure to children as well as incidental oral exposure of 

children (toddlers). These assessments will not underestimate the exposure and risks posed by

pyraflufen-ethyl.

4.5 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (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.
Page 19 of 40

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. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Pyraflufen-ethyl is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA Sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

5.0 DIETARY EXPOSURE/RISK CHARACTERIZATION

HED has concluded that the residues of concern in plants include the parent and Metabolite E-1

for purposes of tolerance enforcement and risk assessment. The residues of concern in livestock 

commodities are parent, Metabolite E-1, and Metabolite E-9 2-[2-chloro-5-[4-chloro-5-

difluoromethoxy)-1H-pyrazol-3-yl]-4-fluorophenoxy]acetic acid]. 

5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Summary of Plant and Animal Metabolism Studies

The qualitative nature of the residue in plants is adequately understood based on a submitted 

mandarin orange study and previously submitted cotton, potato, and wheat metabolism studies. 

HED has concluded that the residues of concern in primary and rotational crops for the tolerance 

expression and risk assessment are the parent and Metabolite E-1. The qualitative nature of the 

residue in livestock is adequately understood based on adequate ruminant and poultry 

metabolism studies. HED has concluded that the residues of concern in livestock commodities 

for the tolerance expression and risk assessment are parent, Metabolite E-1, and Metabolite E-9. 

5.1.2 Metabolism in Rotational Crops

A confined rotational crop study on radish, lettuce, and barley was previously submitted 

reflecting a soil application of [14C-pyrazole]pyraflufen-ethyl at 0.0127 lb ai/A (0.9x the 

maximum seasonal rate on cotton). Detectable residues (0.001-0.003 ppm) were observed in 30-

day mature radish roots and tops, and barley chaff and straw, 120-day immature radish roots, and 

150-day barley forage. No pyraflufen-ethyl was identified on analysis of 30-day radish tops and 

barley straw; however, metabolites E-1, E-2, and E-3 were tentatively identified in radish tops at 

<3% TRR each. No residues were identified in barley straw. Pyraflufen-ethyl breaks down in 

the soil to its metabolites E-1, E-2, and E-3, and uptake of pyraflufen-ethyl and its soil 

metabolites by rotational crops only occurs at very low levels. 

Although the HED originally concluded that the confined rotational crop study was insufficient 

due to 14C-labeling in only the pyrazole ring, the Agency (ChemSAC minutes, 12/3/03) 
Page 20 of 40

concluded that an additional confined rotational crop study with pyraflufen-ethyl radiolabeled in 

the phenyl ring would not be required, as the metabolic pathways in soil, plants, and animals 

were similar and there was no evidence of cleavage of the bond between the phenyl and pyrazole 

rings. The available confined study supports the 30-day plantback interval specified on the label 

for all crops without primary uses of pyraflufen-ethyl. 

There are no rotational crop data requirements associated with the use on tree nuts (crop group 

14), pistachios, pome fruits (crop group 11), stone fruits (crop group 12), pomegranates, olives, 

and grapes; therefore, this guideline is not applicable to these crops. However, other crops may 

be planted following hops.

5.1.3 Analytical Methodology

Plant Commodities 

An adequate gas chromatography-mass spectrometry (GC/MS) method is available for tolerance 

enforcement, and similar GC/MS methods used for data collection in the apple, grape, tree nut, 

and hop field trials were adequately validated in conjunction with the analysis of field trial 

samples.

Livestock Commodities 

An adequate GC/MS method is available for collecting data on residues of parent and Metabolite 

E-1 (determined as E-15) in livestock commodities. The method has a validated LOQ of 0.01 

ppm for each analyte in milk and tissues, for a combined LOQ of 0.03 ppm. Method validation 

data for the method development of metabolite E-9 (PTRL West Study 1837W) should be 

submitted. 

The method has undergone a successful independent laboratory validation (ILV) for parent and 

metabolite E-1 and has been radiovalidated. There is an analytical method available for 

enforcement (D352195, C. Stafford, 02/03/2011).

Multiresidue Methods

No adequate multiresidue methods testing data have been submitted for pyraflufen-ethyl. 

Nichino previously submitted a method description and supporting data for an EEC (European) 

multiresidue enforcement method. This submission was not adequate to fulfill EPA’s 

multiresidue method requirement.

Data are required reflecting recovery of pyraflufen-ethyl and its metabolite E-1 through the FDA 

multiresidue methods according to Protocols C and D in the Pesticide Analytical Manual, 

Volume I, Appendix II. Evaluations should be performed with and without Florisil cleanup. 

Since Metabolite E-9 should also be included in the tolerance definition for livestock 

commodities, data will be required reflecting recovery of Metabolite E-9 through FDA 

multiresidue methods.

5.1.4 Environmental Degradation

Due to its low persistence and mobility pyraflufen-ethyl should not be available for runoff or 

leaching. However, three metabolites were identified as major transformation products (E-1, 

E-2 and E-3). HED concluded that the parent, E-1, E-2, and E-3 should all be included in the 

drinking water assessment. See appendix for metabolite structures. The metabolite E-1 is 
Page 21 of 40

moderately persistent, making it available for runoff during rain events occurring shortly after 

application. E-3, the most persistent of the three terminal degradates, generally appears at 

lower concentrations, later in time, and binds more strongly to soils. E-3 should also be 

available for runoff in rain events accompanied with erosion.

5.1.5 Toxicity Profile of Major Metabolites and Degradates

Pyraflufen-ethyl degrades into similar metabolites in plants, livestock, water and soil. HED 

considered the metabolites and concluded that none of them is likely to be more toxic than 

pyraflufen-ethyl itself. While there are no data specific to the toxicity of the metabolites, E-1, 

E-2 and E-3 are structurally similar to the parent pyraflufen-ethyl and as such are assumed to be 

of equal or lesser toxicity (MARC Decision memo, 07/19/02 and personal communication with 

A. Protzel and J. Doherty, 9/19/02). See the Appendix B for metabolite structures. The 

metabolites were included in the risk assessment (E-1 in the food-source dietary assessment and 

E-1, E-2 and E-3 in the drinking water assessment).

The conclusion that pyraflufen-ethyl metabolites are not expected to be more toxic than the 

parent compound was confirmed by HED’s Derek Analysis program which conducted structure 

activity analyses on the chemicals in question.

5.1.6 Pesticide Metabolites and Degradates of Concern

The nature of the residue in plants, rotational crops and livestock is adequately understood. HED 

has concluded that the residues of concern in plants and rotational crops include the parent and 

metabolite E-1 for purposes of tolerance enforcement and risk assessment. Although not 

relevant to the proposed non-food uses, the HED has concluded that the residues of concern in 

livestock commodities for the risk assessment are parent and metabolites E-1 and E-9, and that 

all three compounds should be measured in livestock feeding studies. HED also previously 

concluded in connection with food petitions that time-limited tolerances could be established for 

parent and metabolite E-1 pending results of the requested cattle feeding study. 

Environmental fate data indicate that metabolites E-1 and E-2 are the major metabolites (>10% 

total radioactive residues [TRR]) in photolysis, aerobic soil metabolism, anaerobic aquatic 

metabolism and aerobic aquatic metabolism studies for parent. E-3 is the major metabolite 

(>10% TRR) in aerobic soil metabolism resulting from E-2. Although U1 (2-fluoro-5-hydroxy5-(N-methylcarbamoyl)-4-oxo-2-pentenoic acid) was observed at 21% TRR under photolysis in 

soil, soil photolysis is not a major route of environmental degradation, and with the fact that the 

application rate is so low (<0.02 lbs ai/A), HED concluded that U1 is not a residue of concern in 

drinking water (MARC Decision memo, 07/19/02). Although PD-1 (parent compound with the 

chlorine on the phenyl ring replaced by hydroxyl) is a major degradate in aqueous photolysis, it 

is relatively unstable in water based on its short half-life (32.2% at 36 hours to 18.7% at 48 

hours). Therefore, HED concluded that the residues for risk assessment in drinking water 

include parent, E-1, E-2, and E-3 (MARC Decision memo, 07/19/02).

Table 5.1.6. Summary of Metabolites and Degradates To Be Included in the Risk Assessment and 

Tolerance Expression

Matrix Residues Included in Risk 

Assessment

Residues Included in 

Tolerance Expression
Page 22 of 40

Table 5.1.6. Summary of Metabolites and Degradates To Be Included in the Risk Assessment and 

Tolerance Expression

Matrix Residues Included in Risk 

Assessment

Residues Included in 

Tolerance Expression

Plants

Primary Crop parent, E-1 parent, E-1

Rotational Crop parent, E-1 parent, E-1

Livestock

Ruminant parent, E-1, E-9 parent, E-1, E-9*

Poultry parent, E-1, E-9 parent, E-1, E-9*

Drinking Water parent, E-1, E-2, E-3 Not Applicable

* Metabolite E-9 has been included in permanent tolerance for livestock commodities, based on the results of the 

cattle feeding study requested in connection with food uses.

5.1.7 Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by EFED in the 

following memorandum: “Tier I Estimated Environmental Concentrations of Pyraflufen for the 

Use in the Human Health Risk Assessment” (D337845, M. Barrett, 2/29/2008). 

Due to its low persistence, pyraflufen-ethyl should not be available for runoff or leaching. 

However, three metabolites were identified as major transformation products and are included in 

the drinking water assessment. The metabolite E-1 is moderately persistent, making it available 

for runoff during rain events occurring shortly after application. E-3, the most persistent of three 

terminal degradates, generally appears at lower concentrations, later in time, and binds more 

strongly to soils. E-3 should also be available for runoff in rain events accompanied with 

erosion. There are no data available on the toxicity of the metabolites. E-1, E-2 and E-3 are 

structurally similar to the parent pyraflufen-ethyl and as such are assumed to be of equal or lesser 

toxicity (MARC Decision memo, 07/19/02 and personal communication with A. Protzel and J. 

Doherty, 9/19/02).

Monitoring data for drinking water estimates are not available. Models were used to calculate 

drinking water estimates. Upper-bound Tier 1 EDWCs were calculated for pyraflufen-ethyl and 

its major residues E-1, E-2, and E-3, calculated using the FIRST model (surface water) and 

SCIGROW model (ground water). Based on the highest application rate, the acute surface water 

EDWC value is 1247 ppt of total residues of pyraflufen-ethyl and its major degradates and the 

annual average surface water value is 281 ppt. The ground water screening concentration from 

SCIGROW is 1.8 ppt. These values generally represent upper-bound conservative estimates of 

the total residue concentrations that might be found in surface water and ground water due to the 

use of pyraflufen-ethyl.

Table 5.1.7. Summary of Estimated Surface Water and Ground Water Concentrations for PyraflufenEthyl and Metabolites

Pyraflufen-Ethyl

Surface Water Conc., ppt 1 Ground Water Conc., ppt2

Acute (maximum single-day exposure) 1247 1.8

Chronic (non-cancer, one in 10-year 

average) 281 1.8
Page 23 of 40

1 From the Tier I FIRST (FQPA Index Reservoir Screening Tool) model. Input parameters are based on wheat, 

soybean, corn, pastures, sod farms, Christmas trees, nurseries, ornamental plantings, non-crop weed control; and 

for preplant burndown on root and tuber vegetables, cole crops, legumes, fruiting vegetables, cucurbits and small 

grains

2 From the SCI-GROW model assuming a maximum seasonal use rate of 0.00325 lb ai/A for pasture and range, 

and 0.00122 lb ai/A for post-emergence use on corn, soybean and wheat, a Koc of approx. 2000.

EFED provided HED with Tier 2 EDWCs for crops associated with this action as well as 

updated EDWCs for existing crop uses (e:mail dated 3/10/11 from Michael Barrett to Paula 

Deschamp). Tier 2 analysis for total residues of pyraflufen ethyl and it's metabolites/degradates 

E1, E2, and E3 shows that potatoes remain the highest exposure site with a maximum EDWC of 

268 ppt for the long-term mean.

5.1.8 Food Residue Profile

Crop Field Trials

The submitted field trial data for pome fruit, grapes and tree nuts are adequate. There is 

sufficient geographic representation of residue data, and the field trials were conducted 

according to the proposed use pattern for flowable concentrate (FlC) and/or emulsifiable 

concentrate (EC) formulations of pyraflufen-ethyl. Residues for apples, pears, grapes, almond 

nutmeat and pecan nutmeat were all below the combined LOQ for both the parent and 

metabolite; therefore, the recommended tolerances are 0.01 ppm in pome fruit (crop group 11), 

grapes, and tree nuts (crop group 12). The recommended tolerance for almond hulls was 

calculated using the maximum residue limit (MRL)/maximum likelihood estimation (MLE) 

tolerance spreadsheets. The calculated tolerance for almond hulls is 0.02 ppm. The submitted 

field trial data for hops is not adequate because the report did not provide enough field trial 

information, including the location of the trials, the application rate, application method, if an 

adjuvant was used, meteorological data, and the soil characteristics. Residue data were not 

submitted for stone fruit (crop group 12), pistachios, olives, or pomegranates. However, 

ChemSAC concluded that bridging the submitted data for pome fruit, tree nuts, and grapes to 

stone fruit (crop group 12), olives, and pomegranates was acceptable since the following criteria 

are met: 1) the pesticide is directed at the ground when applied, resulting in <LOQ residues in 

the edible RACs; 2) the application rate is low; and 3) uptake is low as demonstrated by results 

of rotational crop studies; and recommended tolerances of 0.01 ppm for stone fruit (crop group 

12), olives, and pomegranates(minutes, 1/13/2010). Currently, HED recommends the tolerance 

for the tree nut crop group be extended to pistachio.

Table 5.1.8.1. Summary of Tree Nut Residue Data from Crop Field Trials with Pyraflufen-Ethyl (SC).

Commodity Total Applic. 

Rate

lb ai/A

(kg ai/ha)

PHI 

(days)

Residue Levels1

(ppm in parent equivalents)

n Min. Max. HAFT2 Median

(STMdR)

Mean

(STMR)

Std. Dev.

Pyraflufen-Ethyl

Pecan 

Nutmeat

0.0088-0.0090 

(0.0099-(0.010)

0-1 10 <0.005 <0.005 <0.005 <0.005 <0.005 --

Almond 

Nutmeat

0.0086-0.0089

(0.0096-0.010)

0 10 <0.005 <0.005 <0.005 <0.005 <0.005 --

Almond Hulls 0.0086-0.0089

(0.0096-0.010)

0 10 <0.005 0.0074 0.0062 0.0051 0.005 0.0008

E-1
Page 24 of 40

Table 5.1.8.1. Summary of Tree Nut Residue Data from Crop Field Trials with Pyraflufen-Ethyl (SC).

Commodity Total Applic. 

Rate

lb ai/A

(kg ai/ha)

PHI 

(days)

Residue Levels1

(ppm in parent equivalents)

n Min. Max. HAFT2 Median

(STMdR)

Mean

(STMR)

Std. Dev.

Pecan 

Nutmeat

0.0088-0.0090 

(0.0099-(0.010)

0-1 10 <0.005 <0.005 <0.005 <0.005 <0.005 --

Almond 

Nutmeat

0.0086-0.0089

(0.0096-0.010)

0 10 <0.005 <0.005 <0.005 <0.005 <0.005 --

Almond Hulls 0.0086-0.0089

(0.0096-0.010)

0 10 <0.005 <0.005 <0.005 <0.005 <0.005 --

Pyraflufen-Ethyl + E-1

Pecan 

Nutmeat

0.0088-0.0090 

(0.0099-(0.010)

0-1 10 <0.01 <0.01 <0.01 <0.01 <0.01 --

Almond 

Nutmeat

0.0086-0.0089

(0.0096-0.010)

0 10 <0.01 <0.01 <0.01 <0.01 <0.01 --

Almond Hulls 0.0086-0.0089

(0.0096-0.010)

0 10 <0.01 0.0124 0.0112 0.010 0.011 0.0008

1 The LOQ (0.005 ppm for each analyte) was used for all values reported as ND and <LOQ to determine the minimum, 

maximum, and HAFT and for the calculation of the median, mean and standard deviation.

2 HAFT = Highest Average Field Trial.

Processing Studies 

The submitted apple and grape processing studies are adequate. The combined residues of 

pyraflufen-ethyl and Metabolite E-1 following a 5X application were <LOQ in/on apples and its 

processed fractions (juice and wet pomace) and grapes and its processed fractions (juice and 

raisins). These data indicate that quantifiable pyraflufen-ethyl residues are unlikely to occur in 

apple or grape processed commodities following applications at the maximum proposed use rate. 

Therefore, tolerances for the processed commodities of apple and grape are not required for the 

purpose of this petition request.

Storage Stability

The available storage stability data on apples, grapes, and almond hulls adequately support the 

storage conditions and intervals for the apple, pear, grape, and almond hull samples from the 

current field trials. No storage stability data are available for hops; however, the stability of 

pyraflufen-ethyl and Metabolite E-1 has been demonstrated in a variety of other crops, including 

wheat, and can be translated to hops. Additionally, no storage stability data are available for 

pecan and almond nutmeat, but data can be translated from soybean and cotton seeds (oily 

seeds). No storage stability data are required for the processed fractions from each of the 

processing studies, as all processed commodities were stored frozen for <1 month prior to 

analysis. 

The submitted storage stability data for pyraflufen-ethyl and Metabolite E-1 in milk and cattle 

tissues are adequate and support the stability of the combined residues in milk and all tissues for 

the intervals incurred during the feeding study. 

No storage stability data were submitted for Metabolite E-9. A storage stability study for 

Metabolite E-9 in milk and liver under frozen conditions for 3 months is required. 

Meat, Milk, Poultry and Eggs
Page 25 of 40

The additional cattle feeding study data adequately depict the levels of parent, Metabolite E-1 

and Metabolite E-9 in cattle milk and tissues following 29 days of dosing with pyraflufen-ethyl 

at levels equivalent to 1.0, 3.1 and 9.8 ppm in the diet. 

Because quantifiable residues of Metabolite E-1 and Metabolite E-9 were found in all kidney 

samples from the 9.8 ppm dose group (5.4X the maximum reasonably balanced dietary (MRBD)

burden; ranging from 0.019-0.045 ppm for Metabolite E-1 and ranging from 0.012-0.030 ppm 

for Metabolite E-9) and in one kidney sample (Metabolite E-1 at 0.012 ppm) from the 3.1 ppm 

dose group (1.7X MRBD burden), tolerances are required for the combined residues of 

pyraflufen-ethyl, Metabolite E-1, and Metabolite E-9 in meat byproducts from cattle, goats, 

horses and sheep. Likewise, because detectable residues of Metabolite E-1 (maximum of 0.01 

ppm) and Metabolite E-9 (maximum of 0.012 ppm) were found in some milk samples from the 

9.8 ppm dose group (5.4X MRBD burden) and pyraflufen-ethyl was found in one milk sample 

(0.0107 ppm) from the 1.0 ppm dose group (0.56X MRBD burden), tolerances are required for 

the combined residues of pyraflufen-ethyl, Metabolite E-1, and Metabolite E-9 in milk. These 

tolerances should be set at the combined LOQ (0.03 ppm) for the analytical method. 

Furthermore, tolerances are also required for residues in meat and fat of cattle, goats, horses or 

sheep since there are no residue data reflecting nonquantifiable residues of pyraflufen-ethyl, E-1 

and E-9 in meat and fat at the 18 ppm (10X dietary burden) feeding level to support a no 

reasonable expectation of finite residues situation. 

With regards to poultry and hog commodities, tolerances for residues in these commodities are 

not required for this petition. Based on the data from the poultry and goat metabolism studies 

and the current cattle feeding study, and considering the low levels of dietary exposure for 

poultry and hogs (0.01 ppm), there is no reasonable expectation of finite residues occurring in 

poultry or hog commodities.

5.1.9 International Residue Limits

There are no MRLs in Codex or Canada. There are currently no established Codex or Canadian 

maximum residue limits (MRLs) or tolerances for pyraflufen-ethyl on the proposed use sites (see 

Appendix B, Table B1).

5.2 Dietary Exposure and Risk

5.2.1 Acute Dietary Exposure/Risk

An acute dietary risk assessment was not performed as no adverse effect attributable to a single 

exposure (dose) was observed in oral toxicity studies; therefore, pyraflufen-ethyl has no acute 

toxicological endpoint.

5.2.2 Chronic Dietary Exposure/Risk

Reference: Pyraflufen-ethyl. Chronic and Cancer Aggregate Dietary (Food and Drinking Water) Exposure and Risk 

Assessments for the Section 3 Registration Action for Uses on Pome Fruit (crop group 11), Stone Fruit (crop group 

12), Pomegranates, Olives, Grapes, Tree Nuts (crop group 14) and Pistachios. DP#378643, L. Cheng, 2/8/2011.

A chronic aggregate (food and drinking water) dietary exposure and risk assessment was 

conducted using the DEEM-FCID, which uses food consumption data from the USDA’s 

Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. The 
Page 26 of 40

analyses were performed to support Section 3 requests for the use of pyraflufen-ethyl on pome 

fruit, stone fruit, pomegranates, olives, grapes, tree nuts, and pistachios. 

The chronic dietary (food and drinking water) analysis was conducted for pyraflufen-ethyl, 

assuming tolerance level residues in the established and proposed commodities except corn,

cottonseed, potato, soybean, wheat, pome fruit, stone fruit, pomegranate, olive, grape, tree nuts 

and pistachio for which 1⁄2 of the combined LOQs for the parent and the metabolite were used 

since all field trial data were <LOQ. All processed commodities derived from the treated corn 

grain, soybean seeds, wheat grain, apple and grape had nondetectable residues; therefore, no 

processing factors were applied to those commodities. A default processing factor of 6.5X was 

used for dry potato and a default processing factor of 1.5X was used for corn syrup. An 

experimental processing factor of 0.6X was used for cotton seed oil. One hundred percent crop 

treated (%CT) was assumed for all crop commodities. The anticipated residue value in milk was 

calculated to be 0.001 ppm. This analysis incorporates all current and proposed tolerances for the 

combined residues of pyraflufen-ethyl and Metabolite E-1 in plants and residues of pyraflufenethyl, Metabolite E-1 and Metabolite E-9 in animals.

Chronic (non-cancer) dietary exposure from drinking water was determined based on a Tier I 

model (surface water) estimate provided by EFED. The estimate for drinking water was 

incorporated directly into the dietary assessment using the EDWC value of 281 parts per trillion 

(ppt) for the combined residues of pyraflufen-ethyl and its metabolic products, E-1, E-2, and E-3. 

The non-cancer chronic dietary (food and drinking water) exposure to pyraflufen-ethyl is below 

HED’s level of concern [i.e., <100% Chronic Population Adjusted Doses (cPAD)] for the 

general U.S. population and all population subgroups. The chronic dietary exposure estimates 

are <1% of cPAD for the general U.S. population and all population subgroups, including 

children 1-2 years old, the most highly exposed population subgroup. 

5.3 Cancer Dietary Risk

The cancer dietary exposure assessment was conducted using DEEM software, which 

incorporates consumption data from USDA’s Continuing Surveys of Food Intake by Individuals 

(CSFII), 1994-1996, 1998. Estimated cancer risk is determined for the general U.S. population 

only. 

HED is generally concerned when the cancer risk is no longer considered negligible, typically 

when the risk exceeds 10-6. The aggregate (food and water) cancer risk estimates associated with 

exposure to pyraflufen-ethyl for the general U.S. population is 2.7x10-6. Although some inputs 

into this assessment are refined, other inputs are very conservative, as high-end tolerance levels

were used for some commodities, as well as the assumption of 100% crop treated. This result is 

conservative since the mean 0.281 ppt value EDWC determined for a non-cancer model (1 in 10 

year annual mean ) was used in the absence of an exposure estimate for cancer risk (1 in 30 year 

annual mean EDWC).

Table 5.3. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Pyraflufen-Ethyl

Population Subgroup cPAD Chronic Dietary Cancer
Page 27 of 40

(mg/kg/day) Dietary 

Exposure

(mg/kg/day)

% 

cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

Q* = 3.32 x 10-2

General U.S. Population 0.2 0.000081 <1 0.000081 2.7 x 10-6

All Infants (< 1 year old) 0.2 0.000119 <1

NA2 NA

Children 1-2 years old 0.2 0.000228 <1

Children 3-5 years old 0.2 0.000191 <1

Children 6-12 years old 0.2 0.000122 <1

Youth 13-19 years old 0.2 0.000080 <1

Adults 20-49 years old 0.2 0.000064 <1

Adults 50+ years old 0.2 0.000052 <1

Females 13-49 years old 0.2 0.000059 <1

1The population subgroup with the highest estimated chronic dietary (food + drinking water) 

exposure and risk is indicated by bold text.

2NA = not applicable

5.4 Anticipated Residue and Percent Crop Treated (%CT) Information

The chronic dietary exposure analysis is partially refined in that one-half the combined LOQs of 

the parent and metabolite are used as the residue values rather than the tolerances (for corn, 

wheat, soybeans, cottonseed, potatoes, pome fruit, stone fruit, pomegranates, olives, grapes, tree 

nuts and pistachios). However, the assessment assumed that 100% of crops are treated with 

pyraflufen-ethyl. In addition, drinking water exposure estimates were based on screening level 

estimates using Tier 1 estimates generated by the FIRST (surface water) and SCI-GROW 

(ground water) models. Dietary estimates could be further refined through the use of percent 

crop treated data, as well as Tier II estimated drinking water concentrations.

6.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK 

CHARACTERIZATION

Reference: Pyraflufen-ethyl: Occupational and Residential Exposure Assessment for proposed non-food uses of 

pyraflufen-ethyl on cool season grasses (bluegrass, fescue, and ryegrass) and warm season grasses (Bahia grass, 

common Bermuda grass, centipede grass, St. Augustine grass, and zoysia grass), DP#361213, K.Rury, 01/14/2010. 

Pyraflufen-ethyl is registered for use on turf at residential and recreational use sites, and

therefore, may result in residential handler exposure from mixing/loading and applying 

pyraflufen-ethyl, as well as post-application exposure to adults and children involved in 

recreational activities. Exposure to adults and children from the use of pyraflufen-ethyl at 

recreational use sites are assumed to be the same as those assessed for residential use sites, and 

therefore, a separate recreational exposure assessment was not included. Residential turf 

exposure assessment results in what are considered upper bound risk estimates. Therefore, it is 

not expected that the upper bound residential exposure scenario would occur on the same day as 

an upper bound recreational exposure scenario. Therefore, exposures from the residential and 

recreational scenarios are not aggregated. Rather, the residential risk estimate should serve as 

an upper bound for both residential and recreational exposure.
Page 28 of 40

6.1 Residential Handler Exposure and Risk

Residential handlers may be exposed from mixing, loading and applying liquid pyraflufen-ethyl 

for spot treatment and/or broadcast control of weeds on ornamental lawns. Mixing/loading and 

spot application of a liquid formulation with a low pressure hand sprayer for spot treatment of 

grasses, and mixing/loading and application via broadcast with a hose end sprayer was assessed. 

Exposure duration is expected to be short-term only and only inhalation risks are assessed 

because no dermal hazard was identified. Although a point of departure from an oral study was 

used to assess residential handler inhalation risks for pyraflufen-ethyl, HED does not believe 

this assessment is under-protective of adult handlers. MOEs calculated for residential handlers 

were all >35,000,000, thus providing an ample margin of safety to account for any uncertainties 

in route-to-route extrapolation. Cancer risk was determined by multiplying a Q1* = 3.32 x 10-2

mg/kg/day-1by the handler's combined dermal and inhalation exposures; dermal and inhalation 

exposures were assumed to be 100%. Calculation inputs and results of this assessment are 

presented in Table 6.1. Short-term inhalation MOEs range from 35,000,000 to 430,000,000. 

These risks are not of concern to HED. Cancer risks range from 2.8x10-8 to 4.7x10-8 and are not 

of concern to HED.

Table 6.1. Short-Term Exposure and Risk Estimates (MOE) and Cancer Risks for Homeowner Lawn/Garden Application 

with Pyraflufen-Ethyl 

Exposure Scenario Crop or 

Target

App 

Rate 

(lb 

ai/A)1

Acres 

Treated 

Daily2

Dermal 

Unit 

Exposure 

(ug/lb ai)

Inhalation 

Unit 

Exposure 

(ug/lb ai)3

Dose 

Baseline 

Dermal

Dose 

Baseline 

Inhalation4

MOE5 

Baseline 

Inhalation

Total LADD6

(mg/kg/day)

Cancer 

Risk7

Mixer/Loader/Applicator

Mixing/Loading and 

Spot application of 

Liquid Formulation 

with Low Pressure 

Hand Sprayer

Cool

Season 

Grasses, 

Warm

Season 

Grasses

0.004 0.023 100 30 0.00015 0.000000046 430,000,000 6.0E-07 2.0E-08

Mixing/Loading and 

Broadcast Application 

of liquid formulation 

with (Hose-End 

Sprayer)

Cool

Season 

Grasses, 

Warm

Season 

Grasses

0.004 0.5 11 17 0.00037 0.00000057 35,000,000 1.4E-06 4.7E-08

1 Application rate is based on maximum values found in proposed label: ET (2.5%)(EPA Reg. No. 71711-7) and ET (2%)(EPA Reg. No. 71711-25).

2 Area treated is based on the area that can be reasonably treated in a single day based on the application method (standard EPA/OPP/HED values – Policy 12).

3 Inhalation unit exposure values represent no respirator. 

4 Daily Dose (mg/kg/day) = (Unit Exposure x Application rate x Area treated) / 60 kg.

5 Short-Term MOE = NOAEL (20 mg/kg/day) / Daily Dose. The LOC is 100.

6 LADD= (Dermal Dose+Inhalation Dose) x average days of exposure (2 days /365 days)*(50 years/70 years)

7 Cancer Risk Estimates = LADD * Q1*, where Q1*=3.32E-2 (mg/kg/day)

6.2 Non-Occupational (Post-Application) Exposure from Treated Lawns

Toxicity endpoints were chosen by HED for short- and intermediate-term inhalation and oral 

exposures. Post-application inhalation exposure is considered to be negligible. However, nondietary, incidental ingestion of residues from treated turfgrass and contaminated soil are possible 

for children (hand-to-mouth, object-to-mouth and soil ingestion). While the NOAEL (20 

mg/kg/day) is the same for both short- and intermediate-term oral toxicity, the standard 

assumptions (input values) for intermediate-term exposure are less conservative than those for 

short-term (e.g., short-term hand-to-mouth events = 20/hr; intermediate-term= 9.5/hr). 

Therefore, only short-term exposure/risk is assessed as a worst-case for all children's post-
Page 29 of 40

application scenarios. Intermediate-term risk is expected to be lower than that for short-term. 

Post-application exposure assessments are summarized in Tables 6.2.1, 6.2.2, 6.2.3, 6.2.4, and 

6.2.5. All MOEs for each scenario are above 100, and therefore, are not of concern. 

Post-application dermal exposure is only estimated for adults for use in estimating adult cancer 

risk. Intermediate-term standard assumptions (input values for transfer coefficients), are used 

instead of the more conservative short-term assumptions for cancer assessments, because the 

effect is determined for a life-time of exposure (50 years).

The residential exposure estimates for adult dermal and three children's incidental oral scenarios 

are assessed for the day of application (day “0") because it is assumed that residential contact 

with the lawn can occur immediately after application. Chronic exposure is not expected (i.e., 

these activities are not expected to occur continuously for more than 6 months). 

 

Adult cancer risk from dermal contact with treated lawn (summarized in Table 6.2.5) is 

estimated as 7.6x10-7and is not of concern to HED. Adult golfer cancer risk from dermal 

contact with treated turf (also summarized in Table 6.2.5) is estimated as 1.4x10-7and is not of 

concern to HED.

Table 6.2.1. Oral Hand-to-Mouth Exposure and Risk for Children From Treated Lawns

Application 

Rate (AR) 

(lb ai/A)

Fraction 

of ai 

Available 

(F)

Turf 

Transferable 

Residue 

(TTR)1

(ug/cm2)

Exposure 

Time 

(hrs/day)

Extraction 

by Saliva 

(EX)

Hand 

Surface 

Area (SA) 

(cm2/event)

Frequency 

(FQ) 

(events/hr)

Body 

Weight 

(kg)

Daily Dose2 

(mg/kg/day)

Short 

Term 

MOE3

0.004 0.05 0.0022 2 0.5 20 20 15 5.98E-05 330,000

1 Turf Transferable Residue = TTR = AR*F*CF2(4.54E08 ug/lb)*CF3(2.47E-8 acre/cm2).

2 Potential Dose Rate (PDR) on Day '0' (mg/kg/day)=TTR*SA*EX*FQ*ET*CFI1 (0.001mg/ug). 

3 MOE = NOAEL/Daily Dose where the NOAEL = 20 mg/kg/day.

Table 6.2.2. Exposure and Risk for Children from Object-to-Mouth (Turfgrass) from Treated Lawns

Application 

Rate (AR) lb 

ai/A

Fraction of ai 

available (F)

Grass Residue 

(GR) (ug/cm2)1

Mouthing Rate 

(IgR) (cm2/day)

Body Weight 

(kg)

Daily Dose2

(mg/kg/day)

Short Term 

MOE3

0.004 0.2 0.0090 25 15 1.50E-05 1,300,000

1 GR = AR*F*CF2 (4.54E8 ug/lb)*CF3 (2.47E-8 acre/cm2).

2 Potential Dose Rate on Day ‘0’ (mg/kg/day) = GR*IgR*CF1 (.001 mg/ug).

3 MOE = NOAEL/Daily Dose where the NOAEL = 20 mg/kg/day.

Table 6.2.3. Exposure and Risk for Children from Ingestion of Soil from Treated Lawns

Application 

Rate (AR)

(lb ai/A)

Fraction of ai 

Available (F)

Soil Residue 

(SR) (ug/g)1

Ingestion Rate 

(IgR) (g/day)

Body Weight 

(kg)

Daily Dose2

(mg/kg/day)

Short Term 

MOE3

0.004 1 0.030 100 15 2.00E-07 100,000,000

1 SR =AR*F*CF2(4.54E8 ug/lb)*CF3(2.47E-8 acre/cm2)*CF4(0.67 cm3/g soil).

2 PDR for incidental ingestion of soil = SR*IgR*CF1 (1E-6 g/ug) and 

3 MOE = NOAEL/Daily Dose where the NOAEL = 20 mg/kg/day.

Table 6.2.4. Combined Short Term MOE1

Scenario Dose Combined MOE

Oral Hand-to-Mouth 5.98E-05

Object to Mouth 1.50E-05 270,000

Ingestion of Soil 2.00E-07

1 Total MOE=[1/(Oral Hand-to-Mouth Dose+Object-to-mouth Dose+Ingestion of Soil Dose)]*NOAEL 

(20 mg/kg/day)
Page 30 of 40

Table 6.2.5. Adult Residential Post Application Exposure and Cancer Risk from Dermal Contact with Treated Lawns

Scenario

Application 

Rate (lb 

ai/A)

Fraction of 

ai Available

Turf 

Transferrable 

Residue 

(ug/cm)

Exposure 

Time 

(hrs/day)

Transfer 

Coefficient 

(cm2/hr)

Body 

Weight (kg)

Daily Dose1

(mg/kg/d)

Dermal

LADD2

Cancer 

Risk3

Residential

Contact 

with 

Treated 

Turf

0.005 0.05 0.0028 2 7300 70 0.00058 2.29E-05 7.60E-07

Adult 

Golfer 0.005 0.05 0.0028 4 500 70 0/0000801 3.13E-06 1.04E-07

1 Daily Dose = unit exposure*Application Rate*Area treated)/body weight

2 LADD= (Dermal Cancer Dose)*average days of exposure (1)/year x 50 years of expected exposure/(365 days/year x 70 year lifetime)

3 Cancer Risk = LADDxQ1*; where Q1*=3.32E-2 (mg/kg/day)

7.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. For pyraflufen-ethyl, potential exposures from food, drinking water, and 

residential scenarios were aggregated.

7.1 Acute Aggregate Risk

No adverse effect attributable to a single exposure (dose) was observed in oral toxicity studies, 

including the developmental toxicity studies in rats and rabbits. Therefore, an acute reference 

dose was not established and an acute aggregate risk assessment was not conducted.

7.2 Short- and Intermediate-Term Aggregate Risk

The short-term aggregate risk assessment estimates risks likely to result from 1- to 30-day 

exposure to pyraflufen-ethyl residues from food, drinking water, and residential pesticide uses. 

High-end estimates of residential exposure are used in the short-term assessment, while average 

values are used for food and drinking water exposure (i.e., chronic exposures).

The same endpoints were identified for short-term incidental oral and inhalation risk assessment. 

No hazard via the dermal route was identified, therefore this route of exposure is not included in 

the aggregate assessment.

Short-term aggregate risk is based on residential handler exposure, children’s incidental oral 

exposure (from residential post-application treatment) and dietary exposure (food and drinking 

water). The anticipated exposure level for children, 1-2 years old (the highest exposed 

population) is below HED’s LOC, with an MOE of 66,000. 

An intermediate-term aggregate risk assessment was not conducted for adults because exposure 

duration is expected to be short-term only. In addition, an intermediate-term aggregate risk 

assessment was not conducted for children (post-application exposure) because standard 
Page 31 of 40

assumptions (input values) for intermediate-term exposure are less conservative than those for 

short-term exposure. 

Estimated aggregate (food + water + residential) exposure to adults and children from 

pyraflufen-ethyl residues is below HED’s LOC.

Table 7.2. Short- and Intermediate-Term Aggregate Risk Calculations.

Population

Short- or Intermediate-Term Scenario

NOAEL

Mg/kg/day LOC1

Max 

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure

mg/kg/day

Residential 

Exposure3

mg/kg/day

Aggregate MOE

(food and

residential)4

Adult Male 20 100 0.2 0.000081 0.00000057 250,000

Adult Female 20 100 0.2 0.000081 0.00000057 250,000

Children, 1-2 

years old 20 100 0.2 0.000228 0.000075 66,000

1

Interspecies variability = 10x, Intraspecies variability = 10x, FQPA Factor = 1x

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Dermal Exposure is not a 

concern since no effects were observed at the Limit Dose in a 28-day dermal study.

4 Aggregate MOE = [NOAEL/(Avg Food & Water Exposure + Residential Exposure)]

7.3 Chronic Aggregate Risk

Chronic exposure from the residential pathway is not anticipated based on the current/proposed 

use pattern. The chronic aggregate risk (food and drinking water) is below HED’s LOC (i.e., 

<100% cPAD for the general U.S. population and all population subgroups). Using the DEEMFCID software, dietary exposure is estimated at 0.000081 mg/kg/day for the general U.S. 

population (<1% of the cPAD) and 0.000228 mg/kg/day (<1% of the cPAD) for children one -

two years old, the population subgroup with the highest estimated chronic dietary exposure to 

pyraflufen-ethyl. See Section 5.2 for details.

7.4 Aggregate Cancer Risk

The aggregate cancer risk assessment for the general U.S. population takes into account 

exposure estimates from dietary consumption of pyraflufen-ethyl from food, residential and 

drinking water sources. Exposures from residential uses are based on the lifetime average daily 

dose and assume an exposure period of 5 days per year and 50 years of exposure in a lifetime 

(70 years). Average food+water source dietary exposure was used. Estimated cancer risk for 

the general U.S. population includes infants and children; therefore, in accordance with HED 

Policy, a children’s cancer risk estimate was not reported separately.

HED is concerned when the cancer risk is no longer considered negligible, typically when the 

risk exceeds 10-6. The aggregate cancer risk estimate for pyraflufen-ethyl is 2.8 x 10-6. 

Therefore, aggregate cancer risk estimate from pyraflufen-ethyl residues in food and drinking 

water is not of concern to HED for the general U.S. population.
Page 32 of 40

Table 7.4. Aggregate Cancer Calculations.

Population Q* Negligible

Risk Level

Chronic Food & Water

Exposure mg/kg/day

Residential

Exposure

(LADD)

mg/kg/day

Aggregate

Cancer Risk

(food, water and

residential)1

U.S. Pop 0.0332 10-6 0.000081 2.29x10-5 2.8 x 10-6

1 Aggregate MOE Cancer = Q* x [Chronic Food & Water Exposure + Residential Exposure (Lifetime Average Daily 

Dose).

8.0 CUMULATIVE RISK

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 for 

pyraflufen-ethyl and any other substances, and pyraflufen-ethyl does not appear to produce a 

toxic metabolite produced by other substances. For the purposes of this tolerance action, 

therefore, EPA assumed that pyraflufen-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 OPP 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 AND RISK

Reference: Pyraflufen-Ethyl: Occupational and Residential Exposure Assessment for proposed uses of pyraflufenethyl on the tree nut, pome fruit, and stone fruit crop groups, hops, grapes, olives and pomegranates, DP#378642, 

K.Rury, 12/14/2010. 

Pyraflufen-ethyl may be applied to post-harvest, dormant, pre-bloom, and in-season tree nuts, 

pome fruits, hops, grapes, olives, stone fruits, and pomegranates for control of broadleaf weeds. 

Pyraflufen-ethyl may be applied at a rate of 0.0013 to 0.0053 lb pyraflufen-ethyl per acre via 

ground application. Pyraflufen-ethyl may not be applied via chemigation or aerially to the 

proposed use sites. Up to 3 applications may be made per year to post-harvest, dormant, or prebloom use sites, and up to 2 applications may be made per year to in season crops. The 

maximum seasonal application rate is 0.009 lb pyraflufen-ethyl per acre. 

9.1 Occupational Handler

There is a potential for exposure to pyraflufen-ethyl during mixing, loading and application 

activities. An exposure/risk assessment using applicable endpoints selected by HED was 

performed. Handler’s exposure and risk were estimated for the following scenarios: 

 Mixing and loading liquid formulation 

 Applying with a groundboom 

Table 9.1.1 provides a summary of exposures and non-cancer risks to occupational pesticide 

handlers.
Page 33 of 40

Table 9.1.1. Exposure and Risk Estimates (MOE) for Occupational Application of Pyraflufen-Ethyl 

Exposure Scenario App Rate 

(lb ai/A)1

Acres Treated 

Daily2

Inhalation 

Unit Exposure 

(mg/lb ai)

Inhalation 

Dose Baseline3

Inhalation 

MOE 

Baseline4

Mixer/Loader

Mixing and Loading a 

Liquid Formulation 

(Groundboom)

0.0053 80 0.0012 0.0000085 2,400,000

Applicator

Applying with Groundboom 

- Open Cab (PHED) 0.0053 80 0.00074 0.0000052 3,800,000

1. Application rate is based on maximum values found in proposed label: ET (2% ai, EPA Reg. No 71711-25) and ET (2.5% ai, EPA Reg. 

No. 71711-7).

2. Area treated is based on the area that can be reasonably treated in a single day based on the application method (standard EPA/OPP/HED 

values)

3. Daily Dose (mg/kg/day) = (Unit Exposure x Application rate x Area treated) / 60 kg.

4. Short- and Intermediate-Term MOE = NOAEL (20 mg/kg/day) / Daily Dose. The LOC is 100.

A MOE of 100 is adequate to protect occupational pesticide handlers from short-term and 

intermediate-term exposures to pyraflufen-ethyl. The proposed use patterns do not exceed 

HED’s LOC for non-cancer risks. Intermediate-term exposures are not expected. However, the 

intermediate-term inhalation NOAEL is also 20 mg ai/kg bw/day. Therefore, the estimates of 

short-term risk are adequate to describe the risks from intermediate-term exposures should they 

occur.

Tables 9.1.2 and 9.1.3 show the estimated cancer risk for workers in baseline clothing, engaged 

in open mixing/loading liquids to support groundboom application is 2.8x10-5for commercial 

applicators (assumed to apply pyraflufen-ethyl 30 days per year) and 9.3x10-6for private 

applicators (assumed to apply pyraflufen-ethyl 10 days per year). The estimated cancer risks for 

mixer/loaders in baseline clothing plus gloves is 2.3x10-7for commercial workers and 7.8x10-3

for private workers. The estimated cancer risks is 1.4x10-7for commercial applicators in 

baseline clothing plus gloves and is 4.7x10-8for private applicators in baseline clothing plus 

gloves.
Page 34 of 40

Table 9.1.2. Cancer Risk Estimates for Commercial Application of Pyraflufen-Ethyl 

Exposure 

Scenario

App 

Rate (lb 

ai/A)1

Acres 

Treated 

Daily2

Dermal 

Unit 

Exposure 

(mg/lb 

ai)

PPE-G

Dermal 

Unit 

Exposure 

(mg/lb 

ai)

Inhalation 

Unit 

Exposure 

(mg/lb 

ai)3

Dose 

Baseline 

Dermal4

PPE 

Dermal 

Dose4

Dose 

Baseline 

Inhalation4

Commercial 

LADD5

(mg/kg/day)

Commercial 

LADD 

PPE6

(mg/kg/day)

Commercial 

Baseline 

Cancer 

Risk7

Commercial 

PPE Cancer 

Risk8

Mixer/Loader

Mixing and 

Loading a 

Liquid 

Formulation 

(Groundboom)

0.0053 80 2.9 0.023 0.0012 0.0205 0.000163 0.0000085 8.43E-04 7.0279E-06 2.8E-05 2.3E-07

Applicator

Applying with 

Groundboom -

Open Cab 

(PHED)

0.0053 80 0.014 0.014 0.00074 0.000099 0.000099 0.0000052 4.3E-06 4.3E-06 1.4E-07 1.4E-07

1 Application rate is based on maximum values found in proposed label: ET (2%) (EPA Reg. NO 71711-25) and ET (2.5%) (EPA Reg. No. 71711-7) . 

2 Area treated is based on the area that can be reasonably treated in a single day based on the application method (standard EPA/OPP/HED values).

3 Inhalation unit exposure values represent no respirator. 

4 Daily Dose (mg/kg/day) = (Unit Exposure x Application rate x Area treated) / 60 kg.

5 LADD= (Dermal Dose+Inhalation Dose) x average days of exposure (30/365) x (35 years/70 years).

6 LADD =(Dermal PPE Dose+Inahaltion Dose) x average days of exposure (30/365) x (35 years/70 years).

7 Cancer Risk Estimates = LADD x Q1*, where Q1*=3.32E-2 (mg/kg/day).

8 Cancer Risk PPE Estimates = LADD PPE x Q1*, where Q1*=3.32-2(mg/kg/day).

Table 9.1.3. Cancer Risk Estimates for Private Application of Pyraflufen-Ethyl 

Exposure 

Scenario

App 

Rate (lb 

ai/A)1

Acres 

Treated 

Daily2

Dermal 

Unit 

Exposure 

(mg/lb 

ai)

PPE-G 

Dermal 

Unit 

Exposure 

(mg/lb 

ai)

Inhalation 

Unit 

Exposure 

(mg/lb ai)3

Dose 

Baseline 

Dermal4

PPE 

Dermal 

Dose4

Dose 

Baseline 

Inhalation4

Private LADD5

(mg/kg/day)

Private LADD 

PPE6

(mg/kg/day)

Private 

Baseline 

Cancer 

Risk7

Private 

PPE 

Cancer 

Risk8

Mixer/Loader

Mixing and 

Loading a 

Liquid 

Formulation 

(Groundboom)

0.0053 80 2.9 0.023 0.0012 0.0205 0.000163 0.0000085 0.0002808 2.34E-06 9.3E-06 7.8E-08

Applicator

Applying with 

Groundboom -

Open Cab 

(PHED)

0.0053 80 0.014 0.014 0.00074 0.000099 0.000099 0.0000052 1.427E-06 1.43E-06 4.7E-08 4.7E-08

1 Application rate is based on maximum values found in proposed label: ET (2%) (EPA Reg. NO 71711-25) and ET (2.5%) (EPA Reg. No. 71711-7) .

2 Area treated is based on the area that can be reasonably treated in a single day based on the application method (standard EPA/OPP/HED values).
Page 35 of 40

3 Inhalation unit exposure values represent no respirator. 

4 Daily Dose (mg/kg/day) = (Unit Exposure x Application rate x Area treated) / 60 kg.

5 LADD= (Dermal Dose+Inhalation Dose) x average days of exposure (10/365) x (35 years/70 years).

6 LADD =(Dermal PPE Dose+Inahaltion Dose) x average days of exposure (10/365) x (35 years/70 years).

7 Cancer Risk Estimates = LADD x Q1*, where Q1*=3.32E-2 (mg/kg/day).

8 Cancer Risk PPE Estimates = LADD PPE x Q1*, where Q1*=3.32-2(mg/kg/day).
Page 36 of 40

9.2 Occupational Post-Application

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide. Such exposures may 

occur when workers enter previously treated areas to perform job functions, including activities 

related to crop production, such as scouting for pests or harvesting. Post-application exposure 

levels vary over time and depend on the type of activity, the nature of the crop or target that was 

treated, the type of pesticide application, or the pesticide’s degradation properties. In addition, 

the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential 

for post-application exposure. 

HED believes that the potential for dermal post-application worker exposure is low, provided the 

24 hour restricted entry interval (REI) stated on the proposed label is observed. As there is no

dermal endpoint, dermal non-cancer post-application risks were not assessed. Occupational 

post-application cancer risks were also not evaluated based on the proposed pyraflufen-ethyl use 

pattern. Pyraflufen-ethyl is applied to crop foliage as a burndown treatment only, minimizing 

potential for worker post-application exposure. In all other cases, the proposed target sites of 

pyraflufen-ethyl are broadleaf weeds and grasses. Therefore, a post-application risk assessment 

was not performed. 

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment was not performed for pyraflufen-ethyl at this time. However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication 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 Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. 

The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for pyraflufen-ethyl.

9.3 Restricted Entry Interval (REI)

Pyraflufen-ethyl is classified as Acute Toxicity Category III for acute dermal toxicity and for 

primary eye irritation. It is classified as Toxicity Category IV for acute inhalation toxicity and 

primary skin irritation. It is not a dermal sensitizer. Therefore the interim worker protection 

standard (WPS) restricted entry interval (REI) of 12 hours is adequate to protect agricultural 

workers from post-application exposures to pyraflufen-ethyl as might result from the proposed 

new use pattern. 
Page 37 of 40

Appendix A. Toxicology Profile 

A.1. Toxicity Profile of Pyraflufen-Ethyl

Table A.1.1. Acute Toxicity of Pyraflufen-ethyl.

Guideline

No. Study Type MRID # Results Toxicity Category

870.1100

81-1

Acute Oral 45327615 LD50 > 5000 mg/kg IV

870.1200

81-2

Acute Dermal 45327613 LD50 > 2000 mg/kg III

870.1300

81-3

Acute Inhalation 45282821 LC50 > 5.03 mg/L IV

870.2400

81-4

Primary Eye Irritation 45327614 moderate irritation III

870.2500

81-5 

Primary Skin Irritation 45282823 no irritation IV

870.2600

81-6

Dermal Sensitization 45282824 non-sensitizing N/A

Table A.1.2. Non-acute Toxicity Profile for Pyraflufen-Ethyl.

Guideline Number and Study Type Results

870.3100

13-Week Feeding in Rats; 1994; 

Dose Levels: 0, 200, 1000, 5000 or 15,000 ppm 

(representing 0, 17.8, 85.6,455.5 and 1489.4 mg/kg/day (M); 

0, 19.4, 95.4, 499.0 and 1502.9 mg/kg/day (F); 10 

rats/sex/group

NOAEL = 5000 ppm (456-499 mg/kg/day).

LOAEL = 15,000 ppm (1489-1503 mg/kg/day) based on clinical 

signs, death, effects on erythrocytes, changes in clinical chemicals for 

liver function and splenomegaly

870.3150

13-Week Feeding Study in Dogs-capsule; 1996;

Dose Levels: 0, 40, 200 or 1000 mg/kg/day

4 dogs/sex/group

NOAEL = 1000 mg/kg/day.

LOAEL not established. No effects observed.

870.3200

28-Day Dermal Toxicity in Rats; (2000);

Dose Levels: 0, 100, 300 or 1000 mg/kg/day; 10 

rats/sex/group;

Application: 6-7 hr/day, 7 days/week for 29 days

NOAEL = 1000 mg/kg/day.

LOAEL not established. No effects observed.

870.3700a

Developmental Toxicity Study in Rats; 1995;

Dose Levels: 0, 100, 300 or 1000 mg/kg/day; 22 

females/sex/group 

Maternal NOAEL > 1000 mg/kg/day.

Maternal LOAEL not determined; no effects observed.

Developmental NOAEL > 1000 mg/kg/day.

Developmental LOAEL not determined; no effects observed.
Page 38 of 40

870.3700b

Developmental Toxicity in Rabbits; 1996;

Dose Levels: 0, 20, 60 or 150 mg/kg/day; 15 females/group

Maternal NOAEL = 20 mg/kg/day. 

Maternal LOAEL= 60 mg/kg/day based on mortality.

Developmental = 60 mg/kg/day.

Developmental LOAEL = 150 mg/kg/day based on increased 

incidence of abortion.

870.3800

2-Generation Reproduction Study in Rats; 1996; 

Dose Levels: 0, 100, 1000 or 10, 000 ppm (representing 0, 

6.84, 70.8 and 721 mg/kg/day (F0[M]); 0, 7.78, 80.1 and 813 

mg/kg/day (F0[F]); 0, 8.10, 82.3 and 844 mg/kg/day 

(F1[M]); 0, 9.06, 91.2 and 901 mg/kg/day (F1[F])

24 rats/sex/group

Parental NOAEL = 1000 ppm (70.8-82.3 mg/kg/day [M]; 80.1-91.2 

[F].

Parental LOAEL = 10,000 ppm (721-844 and 813-901 mg/kg/day) 

based on decreased bwt and bwt gains of F0 and F1(M) and F1(F), 

gross and microscopic liver lesions of (M) and (F)-both generations.

Reproductive NOAEL > 10,000 ppm (721-844 and 813-901 

mg/kg/day).

Reproductive LOAEL not determined. No effects observed.

Offspring NOAEL = 1000 ppm (70.8-82.3 mg/kg/day [M]; 80.1-91.2 

[F].

Offspring LOAEL = 10, 000 ppm (721-844 and 813-901 mg/kg/day) 

based on decreased bwt and bwt gains of the F1 and F2 pups.

870.4100a/870.4200

2-year Feeding Study/Carcinogenicity in Rats; 1996;

Dose Levels: 0, 80, 400, 2000 or 10,000 ppm (representing 

0, 3.4, 17.2, 86.7 and 468.1 mg/kg/day (M); 0, 4.4, 21.8, 

11.5 and 578.5 mg/kg/day (F)

70 rats/sex/group

NOAEL = 2000 ppm (86.7 mg/kg/day (M); 111.5 mg/kg/day (F).

LOAEL = 10,000 ppm (468.1 mg/kg/day(M); 578.5 mg/kg/day (F) 

based on decreased bodyweight (bwt) and bodyweight gain in males 

and microcytic anemia, liver lesions and kidney toxicity (both sexes); 

possible increase pheochromocytomas in females

870.4100a/870.4300

78-Week Carcinogenicity Study in Mice; 1996;

Dose Levels: 0, 200, 1000 or 5000 ppm (representing 0, 

20.99, 109.7 and 546.8 mg/kg/day (M); 0, 19.58, 98.3, and 

523.7 mg/kg/day (F)

60 mice/sex/group

NOAEL = 200 ppm (20.99 mg/kg/day (M); 19.58 mg/kg/day (F).

LOAEL = 1000 ppm (109.7 mg/kg/day (M); 98.3 mg/kg/day (F) 

based on liver toxicity, hepatocellular tumors at 5,000 ppm; possibly 

hemangioma/ hemangioasarcomass.

870.4100b

52-Week Feeding in Dogs-capsule; 1996;

Dose Levels: 0, 40, 200 or 1000 mg/kg/day

4 dogs/sex/group

NOAEL > 1000 mg/kg/day. LOAEL not determined; no effects 

observed.

A.2. Toxicology Data Requirements

875.1300 Inhalation Exposure

● Since the proposed use pattern will result in repeated inhalation exposure, a 28-day

inhalation toxicity study is being required. Pyraflufen-ethyl may qualify for a waiver 

from the requirement of the 28-day inhalation toxicity study (see SOP 2002.01- HED 

Standard Operating Procedure: Guidance: Waiver Criteria for Multiple-Exposure 

Inhalation Toxicity Studies, 08/15/02).
Page 39 of 40

870.6200 Acute and Subchronic Neurotoxicity Studies

● Acute and subchronic neurotoxicity studies are now required under the revised 40 CFR 

§158.340 guidelines.

870.7800 Immunotoxicity Study

● An immunotoxicity study in rats and/or mice is now required under the revised 40 CFR 

§158.340 guidelines.

Appendix B. Residue Chemistry

B.1. US and International Tolerances and MRLs

Table B1. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.585:

Plant: Pyraflufen-ethyl, ethyl 2-chloro-5-(4-

chloro-5-difluoromethoxy-1-methyl-1Hpyrazol-3-yl)-4-fluorophenoxyacetate, and its 

acid metabolite, E-1, 2-chloro-5-(4-chloro-5-

difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-

fluorophenoxyacetic acid, expressed in terms of

the parent 

Livestock: Pyraflufen-ethyl and its 

metabolites E-1 and E-9 (2-chloro-5-(4-chloro5-difluoromethoxy-1H-pyrazol-3-yl)-4-

fluorophenoxyacetic acid), expressed in terms 

of the parent

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Grape 0.01

Fruit, pome, group 11 0.01

Fruit, stone, group 12 0.01

Nut, tree, group 14 0.01

Almond, hulls 0.02

Pistachio 0.01

Pomegranate 0.01

Olive 0.01

Milk 0.03

Cattle, meat byproducts 0.03

Goat, meat byproducts 0.03

Horse, meat byproducts 0.03

Sheep, meat byproducts 0.03

Completed: M. Negussie; 11/02/2010
Page 40 of 40

REFERENCES:

Pyraflufen-ethyl: Occupational and Residential Exposure Assessment for proposed non-food 

uses of pyraflufen-ethyl on cool season grasses (bluegrass, fescue, and ryegrass) and warm 

season grasses (Bahia grass, common Bermuda grass, centipede grass, St. Augustine grass, and 

zoysia grass), DP#361213, K. Rury, 01/14/2010. 

Pyraflufen-Ethyl: Occupational and Residential Exposure Assessment for proposed uses of 

pyraflufen-ethyl on the tree nut, pome fruit, and stone fruit crop groups, hops, grapes, olives and 

pomegranates, DP#378642, K. Rury, 12/14/2010. 

Tier I Estimated Environmental Concentrations of Pyraflufen for the Use in the Human Health 

Risk Assessment; DP#337845, M. Barrett, 2/29/2008. 

Pyraflufen-ethyl: Human Health Risk Assessment for Pyraflufen-ethyl: Proposed New Use on 

Pasture and Rangeland Grasses (PP#7F7190) and Amendment to Allow Early Season 

Postemergence Broadcast Uses to Corn (excluding sweet corn), Soybeans, and Wheat and 

Proposed Increased Tolerances on Soybean Forage and Hay (PP#1F6248); DP#339360, M. 

Ottley, 04/17/2008.

Pyraflufen-ethyl. Chronic and Cancer Aggregate Dietary (Food and Drinking Water) Exposure 

and Risk Assessments for the Section 3 Registration Action for Uses on Pome Fruit (crop group 

11), Stone Fruit (crop group 12), Pomegranates, Olives, Grapes, Tree Nuts (crop group 14) and 

Pistachios; DP#378643, L. Cheng, 02/08/2011. 

Pyraflufen-ethyl: Proposed New Use on Pome Fruit (crop group 11), Stone Fruit (crop group 12), 

Pomegranates, Olives, Hops, Grapes, Tree Nuts (crop group 14), and Pistachios. Summary of 

Analytical Chemistry and Residue Data; DP#377361, 377365, L. Cheng, 02/07/2011. 

Pyraflufen-ethyl: Human Health Risk Assessment for a Section 3 Registration of New Non-Food 

Uses on Established Ornamental Turf Lawns (Residential, Industrial, and Institutional), Parks, 

Cemeteries, Athletic Fields, Golf Courses (Fairways, Aprons, Tees and Roughs), Sod farms, and 

Similar Turf Areas; DP#361213, 361214, M. Negussie, 02/24/2010.