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9.2 Short-Term/Cancer Post-Application Risk ............................................................... 41

9.2.1 Dermal Post-Application Risk................................................................................. 41

9.2.2 Inhalation Post-Application Risk............................................................................ 41

10.0 References......................................................................................................................... 42

Appendix A. Toxicology Profile and Executive Summaries .................................................. 43

A.1 Toxicology Data Requirements................................................................................... 43

A.2 Toxicity Profiles............................................................................................................ 44

Appendix B. Physicochemical Properties of Pyraflufen-ethyl............................................... 48

Appendix C. Review of Human Research................................................................................ 50

Appendix D. International Residue Limits Status Sheet........................................................ 51
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1.0 Executive Summary

Introduction

Pyraflufen-ethyl is an herbicide that is registered for use as a defoliant, a single preplant or postemergence burndown, and as a post-emergence use. The proposed uses of pyraflufen-ethyl are 

for the control of broadleaf weeds and for sucker management in hops, and for the preplant and 

post-emergence control of broadleaf weeds in peanuts. Nichino America, Inc. (Nichino) has 

submitted two draft supplemental amended labels adding the use of pyraflufen-ethyl on peanuts 

and hops to the ET®2% SC Herbicide/Defoliant suspension concentrate (SC) label (EPA Reg. 

No. 71711-7) and adding peanuts to the ET® Herbicide/Defoliant emulsifiable concentrate (EC) 

label (EPA Reg. No. 71711-25). Due to outstanding data deficiencies, HED recommends the 

pyraflufen-ethyl registration request be denied for use on hops, and granted for use on peanuts 

for the EC formulation only (EPA Reg. No. 71711-7). Additional data are required to support 

the registration of the SC formulation (EPA Reg. No. 71711-25) on peanuts. In addition, HED 

has also reviewed radiovalidation data, and animal feeding and storage stability studies that were 

recently submitted. Because of these submitted data, HED recommends that the current timelimited tolerances of 0.03 ppm in milk and meat byproducts of cattle, goat, horse, and sheep 

become permanent. HED also recommends that permanent tolerances be established on the fat 

and meat of cattle, goat, horse and sheep at 0.03 ppm.

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. 

Both the ET®2%SC Herbicide Defoliant SC and ET® Herbicide Defoliant EC formulations have 

been proposed as a preplant burndown, after planting but before crop emergence, and 

postemergence broadcast application on peanuts, and the ET®2%SC formulation has been 

proposed as a post-harvest and in-season use on hops. Pyraflufen-ethyl is proposed for broadcast 

application to hops at and may not be applied by air or chemigation. For sucker management, 

the application should be focused in the row and onto the lower 18 inches of the hop plant. The 

pre-harvest interval (PHI) for hops is 30 days, and the retreatment interval (RTI) is 40 days. 

Pyraflufen-ethyl may also be applied via broadcast application to preplant and post-emergent 

peanuts. Pyraflufen-ethyl may not be applied through chemigation to peanuts. 

Hazard Assessment 

The risk assessment for pyraflufen-ethyl is based on a well-characterized and complete 

toxicology database. The data gaps for acute and subchronic neurotoxicity and immunotoxicity 

studies noted in the previous risk assessment have been satisfied, and the requirement for a 

subchronic inhalation toxicity study has been waived (D. Smegal, TXR#00564072, 03/02/2012). 

In repeat-dose oral studies, the liver, kidney, and hematopoietic system are the target organs for 

pyraflufen-ethyl in the rat and the mouse. Adverse effects were not noted in the dog following 

oral exposure nor in the rat following dermal exposure. There is no evidence of neurotoxicity 

following acute and subchronic dosing. In the submitted immunotoxicity study, an 

immunosuppressant response was observed only at dose levels approaching the Limit Dose

(946.2 mg/kg/day males and 1114.0 mg/kg/day females). There was no evidence of increased 

susceptibility following pre-natal exposure to rats and rabbits in the developmental toxicity 

studies, nor following pre- and post-natal exposure to rats in the multi-generation reproduction 
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study. Although not mutagenic or carcinogenic in the rat, pyraflufen-ethyl is classified as

“Likely to be Carcinogenic to Humans” and produced a compound-related increase in incidence 

of hepatocellular adenomas, carcinomas, and/or hepatoblastomas in male and female mice. A

linear low-dose extrapolation approach is used to estimate human cancer risk (Q1* of 3.32 x 10-2

(mg/kg/day)-1) based on combined hepatocellular adenomas, carcinomas and/or hepatoblastomas

seen in male mice. Pyraflufen-ethyl exhibits relatively low acute toxicity for oral (Toxicity 

Category IV), dermal (Toxicity Category III), and inhalation exposure (Toxicity Category IV). It 

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

available data, toxicity endpoints, and points of departure (PODs) have been selected for chronic 

dietary, incidental oral (short- and intermediate term), and inhalation (all time periods) exposure 

scenarios. While a transient decrease in body weight gain was observed in females at 2000 

mg/kg in the acute neurotoxicity study, this single-dose effect occurred only at the Limit Dose, 

and is not considered a sufficiently robust adverse effect for acute exposure risk assessment. In 

the absence of dermal absorption data, dermal absorption for cancer exposure estimates is 

assumed to be 100%, which is a conservative estimate of dermal absorption, including that there 

were no adverse effects seen in the 28-day dermal toxicity study. Therefore, assuming 100% 

dermal absorption will not underestimate risks via the dermal route. Inhalation absorption is 

assumed to be equivalent to oral exposure for non-cancer and cancer risk assessments. The Food 

Quality Protection Act (FQPA) Safety Factor has been reduced to 1X because the toxicity 

database is complete, there is no concern for susceptibility in infants and young children, there 

are no neurotoxicity concerns, and there are no residual uncertainties regarding exposure. 

Dietary Exposure

The residue chemistry data and environmental fate data are adequate to assess human dietary 

exposure to treated hops and peanuts. However, additional residue chemistry data are needed to 

grant registration of pyraflufen-ethyl on hops. The assessments are based on reliable data and 

will not underestimate exposure or risk. The proposed use of pyraflufen-ethyl on hops was 

incorporated into the previous drinking water assessment (M. Barrett, D377360, 03/23/2011) and 

the proposed use on peanuts was not expected to change the estimated drinking water 

concentrations (EDWCs) (M. Barrett, D402766, 09/21/2012). The EDWCs were incorporated 

directly into the dietary exposure assessments. There were no adverse effects attributable to a 

single dose; therefore, an acute dietary exposure assessment was not performed. A partially 

refined chronic dietary assessment using 1⁄2 limit of quantitation (LOQ) residues was conducted 

using the Dietary Exposure Evaluation Model (DEEM-FCID) using food consumption data from 

the U.S. Department of Agriculture’s (USDA) National Health and Nutrition Examination 

Survey, What We Eat in America (NHANES/WWEIA). The dietary analysis incorporates all 

current and proposed tolerances for combined residues of pyraflufen-ethyl and Metabolite E-1 in 

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

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

HED’s level of concern (LOC) [i.e., <100% of the chronic population adjusted dose (cPAD)] for 

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

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

including children 1-2 years old, the most highly exposed population subgroup. 
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Pyraflufen-ethyl is classified as “likely to be carcinogenic to humans” by the oral route; 

therefore, a cancer dietary risk assessment is required. All exposure inputs for the cancer 

assessment were the same as for the chronic dietary exposure assessment, except the EDWC. 

Chronic cancer dietary exposure from drinking water was determined based on a Tier 2 drinking 

water (surface water) estimate provided by EFED. The EDWC estimate (30-year average) value 

of 0.268 ppb for the combined residues of pyraflufen-ethyl and its metabolic products, E-1, E-2, 

and E-3 were incorporated directly into the dietary assessment to estimate carcinogenic risk from 

drinking water containing pyraflufen-ethyl. The cancer dietary (food and drinking water) risk 

estimate for pyraflufen-ethyl is 2×10

-6

. 

Residential Exposure

New residential uses were not requested in this petition. However, pyraflufen-ethyl is currently 

registered for use on several residential/non-agricultural use sites. Residential exposures and 

risks from use on turf were reassessed using the updated 2012 HED Residential Standard 

Operating Procedures1(SOPs). A dermal endpoint was not selected for pyraflufen-ethyl because 

adverse effects were not seen in the 28-day dermal toxicity study up to the Limit Dose (1,000 

mg/kg/day). All residential handler non-cancer inhalation risk estimates were not of concern and 

the margins of exposure (MOEs) ranged from 1,300,000 to 70,000,000. All residential handler 

cancer risk estimates ranged from 2.0×10

-8 to 2.1×10-7

. All residential post-application 

incidental oral estimated MOEs ranged from 270,000 to 120,000,000, and were not of concern to 

HED. All residential post-application adult cancer risk estimates ranged from 1.5×10

-8

to 

7.3×10

-7

. 

Aggregate Exposure

While a transient decrease in body weight gain was observed in females at 2000 mg/kg in the 

acute neurotoxicity study, this single-dose effect occurred only at the Limit Dose, and is not 

considered a sufficiently robust adverse effect for acute exposure risk assessment. No other 

adverse effects attributable to a single dose were observed in oral toxicity studies, including 

developmental toxicity studies in rats and rabbits. Therefore, an acute reference dose was not 

established and an acute aggregate risk assessment was not conducted. There is potential shortterm exposure to pyraflufen-ethyl via dietary (which is considered background exposure) and 

residential (which is considered primary) exposure pathways. The adult non-cancer aggregate 

MOE is 290,000 and is not of concern to HED. The aggregate MOE for children 1-2 years old, 

including incidental oral exposures from treated turf, is 9,600 and is not of concern to HED. 

Chronic exposure from the residential pathway is not anticipated based on the current pyraflufenethyl use pattern. Therefore, the chronic aggregate risk is equivalent to the chronic dietary (food 

and drinking water) risk, which is not of concern to HED for the general U.S. population and all 

population subgroups. The aggregate cancer risk assessment for the general U.S. population 

considers exposure estimates from dietary consumption of pyraflufen-ethyl in food and drinking

water, and exposure through residential uses of pyraflufen-ethyl. Estimated cancer risk for the 

general U.S. population includes infants and children; therefore, a children’s cancer risk estimate 

was not reported separately. The aggregate cancer risk estimate for pyraflufen-ethyl is 2.6×10

-6

. 

Occupational Exposure

 

1

http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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Based on the proposed use pattern of pyraflufen-ethyl on hops and peanuts, there is potential for 

short- and intermediate-term occupational exposure during mixing, loading, and other handling 

tasks; and during post-application activities. The proposed labels require occupational handlers 

to wear the following personal protective equipment (PPE): long-sleeved shirts, long pants, 

chemical resistant gloves, and protective eyewear. Handlers of ET Herbicide/Defoliant (EPA 

Reg. No. 71711-7) must also wear chemical resistant headgear for overhead exposures. A

dermal endpoint was not selected for pyraflufen-ethyl because adverse effects were not seen in 

the 28-day dermal toxicity study up to the Limit Dose (1,000 mg/kg/day). The results of the 

occupational handler exposure and risk assessment indicate inhalation short- and intermediateterm MOEs are >100 with baseline attire (no respirator), and therefore, are not of concern to 

HED; the inhalation MOEs ranged from 5,400,000 to 24,000,000. The combined (dermal and 

inhalation) cancer risk estimates for commercial pesticide handlers ranged from 4.4×10

-7

to 

1.9×10

-5 with baseline attire, and from 3.3×10-7

to 3.3×10

-6 with PPE required by the labels. The 

combined (dermal and inhalation) cancer exposure risk estimates for private pesticide handlers 

ranged from 1.5×10

-7 to 6.5×10-6 with baseline PPE, and from 1.1×10-7

to 1.1×10

-6 with the PPE 

required on the pyraflufen-ethyl labels. Based on the pyraflufen-ethyl use pattern, minimal 

exposure is expected to occur following application to hops and peanuts. Although pyraflufenethyl is used as a pre-emergent and defoliant herbicide, it may be applied as a broadcast aerial

and ground spray to post-emergent peanuts. Therefore, occupational post-application cancer 

risks were assessed for scouting in peanut fields and hand-setting irrigation for peanuts. Noncancer post-application risks were not assessed because adverse effects were not seen in the 28-

day dermal toxicity study up to the Limit Dose (1,000 mg/kg/day). The occupational cancer risk 

estimates for setting irrigation by hand to peanuts on the day of application was 2.2×10-6and the 

occupational cancer risk estimate for scouting peanuts on the day of application was 2.4×10-7. 

These estimates are considered a conservative, screening level assessment because the 

assessment assumed 100% dermal absorption, 30 days per year of scouting and hand-set 

irrigation, and full foliage of the peanut plant. Based on the Agency's current practices, a 

quantitative non-cancer occupational post-application inhalation exposure assessment was not 

performed for pyraflufen-ethyl at this time. 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. The 12 hour restricted entry interval (REI) listed on the labels is 

appropriate. 

Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler 

Exposure Task Force (AHETF) database, the Residential SOPs (lawns and turf), and MRID 

45773201 are subject to ethics review pursuant to 40 CFR 26, have received that review, and are 

compliant with applicable ethics requirements. For certain studies that review may have 

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

guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html. 

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent possible, were considered in this 
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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. 

2.0 HED Recommendations

Nichino submitted two draft supplemental amended labels adding the use of pyraflufen-ethyl on 

peanuts to both the SC label (EPA Reg. No. 71711-7) and the EC label (EPA Reg. No. 71711-

25), and the use of hops only on the SC label (EPA Reg. No. 71711-25). Due to the outstanding 

data deficiencies listed below, HED recommends that the pyraflufen-ethyl registration request be 

granted for use on peanuts for the EC formulation only (EPA Reg. No. 71711-7) and denied for 

the SC formulation (EPA Reg. No. 71711-25); additional data are required to support the 

registration of the SC formulation (EPA Reg. No. 71711-25) on peanuts. In addition, HED 

recommends the pyraflufen-ethyl registration request be denied for use on hops because 

additional crop field trials are required. 

860.1200 Directions for Use

Until the requested crop field trial data for peanut have been submitted, use on peanut 

may not be added to the SC formulation ET®2%SC Herbicide/Defoliant label (EPA Reg. 

No. 71711-25).

Note to RM: In 40 CFR 180.585, the entries in the “expiration/revocation date” column of the 

pyraflufen-ethyl tolerance for residues listing should be consistent (i.e., none. vs. none). 

2.1 Data Deficiencies

860.1650 Submittal of Analytical Reference Standards

Analytical standards for Metabolites E-9 and E-15 must be submitted to the National 

Pesticide Standards Repository.

860.1550 Proposed Tolerances

The petitioner should submit a revised Section F reflecting the tolerances and commodity 

definitions presented in Table 2.2.3 and requesting permanent tolerances on the fat and 

meat of cattle, goat, horse and sheep at 0.03 ppm.

Note to RM: The name for the parent in 40 CFR 180.585 should be the following:

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

fluorophenoxy]acetate.
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In support of requested use on hops, the following additional data are required:

860.1500 Crop Field Trials

Two additional crop field trials should be conducted on hops reflecting application of the 

0.17 lb ai/gal SC formulation (EPA Reg. No. 71711-25) of pyraflufen-ethyl according to 

the maximum proposed use pattern. The trials should be conducted in the U.S. in Zone 

11, which accounts for 94% of U.S. hops production.

In support of requested use on peanuts, the following additional data are required:

860.1500 Crop Field Trials

Both EC and SC formulations are proposed for use on peanuts; the number of field trials 

is adequate to support the EC formulation, but because a 7-day PHI has been proposed, 

additional bridging data with the EC formulation are required to support use of the SC 

formulation on peanuts. Three additional trials should be conducted in Zone 2 on peanut 

reflecting two postemergence applications of the 0.208 lb ai/gal EC formulation (EPA 

Reg. No. 71711-7), separated by a 30-day RTI, and including three side-by-side trials 

with the 0.17 lb ai/gal SC formulation (EPA Reg. No. 71711-25). Residues should be 

determined on both peanuts and peanut hay. If residues are higher following application 

of the SC formulation, then a complete data set for the SC formulation may be required.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Tolerance enforcement methods are available for determining residues of pyraflufen-ethyl and 

Metabolite E-1 in/on plant commodities. The gas chromatography-mass spectrometry (GC/MS)

analytical methods determine Metabolite E-1 as its methyl ester (Metabolite E-15), and monitors

two ion transitions each for pyraflufen-ethyl and the E-15 analyte. The methods also contain 

appendices that provide parameters for other detection schemes such as GC/electron capture 

detection (ECD), GC/nitrogen phosphorus detection (NPD), and GC/MS/MS. The methods have 

been determined to be acceptable for tolerance enforcement (DP#281319) with minor comments, 

and are suitable for enforcing tolerances on a variety of crop matrices. The LOQ for the 

enforcement method is 0.02 ppm. 

In conjunction with the current petition, Nichino has submitted the results of an independent 

laboratory validation (ILV) of RCC Method A25986 (for apple, pear, and grape) and Agrisearch 

Method AS12354NN (a modified version of RCC Method A25986 for oilseed rape), both high 

performance liquid chromatography methods with tandem mass spectrometry detection (liquid 

chromatography/MS/MS; LC/MS/MS) for the determination of residues of pyraflufen-ethyl and 

Metabolite E-1 in crops. Minor modifications were made to the methods by the independent 

laboratory to produce one method for the analysis of pyraflufen-ethyl and Metabolite E-1 in 

apple, pear, grapes, and rape oilseed. The extraction procedures of the method(s) are similar to 

those of the established enforcement methods.
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2.2.2 Recommended Tolerances

HED has examined the residue chemistry database for pyraflufen-ethyl and evaluated the 

adequacy of submissions associated with the current action. For the proposed use on hops, HED 

has concluded that the available data are not adequate to support any U.S. registration of 

pyraflufen-ethyl. For the proposed use on peanuts, HED has concluded that the available data 

are only adequate to support the U.S. registration of the EC formulation (EPA Reg. No. 71711-

7). The submitted data support tolerances for combined residues of pyraflufen-ethyl and 

Metabolite E-1 (plants); and pyraflufen-ethyl, Metabolite E-1, and Metabolite E-9 (livestock) 

in/on the following raw agricultural commodities: 

Table 2.2.3. Tolerance Summary for Pyraflufen-ethyl.1

Commodity Established/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Proposed Tolerances

Hop, dried cone 0.01 The proposed tolerance will be reassessed when the requested field 

trial data have been received. Hop, 

dried cones

Peanut 0.01 0.01

Peanut, hay 0.07 0.07

Peanut, meal 0.01 Not required Residues in peanut meal and oil will 

be covered by the recommended 

tolerance on peanut. 

Peanut, refined oil 0.01 Not required

Established Tolerances

Cattle, meat byproducts 0.02 (expires 10/15/12) 0.03

Goat, meat byproducts 0.02 (expires 10/15/12) 0.03

Horse, meat byproducts 0.02 (expires 10/15/12) 0.03

Sheep, meat byproducts 0.02 (expires 10/15/12) 0.03

Milk 0.02 (expires 10/15/12) 0.03

Additional Required Tolerances

Goat, fat 0.03

Horse, Fat 0.03

Cattle, fat 0.03

Sheep, fat 0.03

Goat, meat 0.03

Horse, meat 0.03

Cattle, meat 0.03

Sheep, meat 0.03

1 Note to RM: The name for the parent in 40 CFR 180.585 should be the following:

ethyl 2-[2-chloro-5-(4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]acetate.

2.2.3 Revisions to Petitioned-For Tolerances

There are no revisions to the petitioned tolerances for hops and peanuts; however HED does not 

recommend granting a tolerance on hops and for the SC formulation on peanut due to several 

data deficiencies noted above. 
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Time-limited tolerances were established for combined residues of pyraflufen-ethyl and 

Metabolite E-1 in milk and the meat byproducts of cattle, goat, horse, and sheep at 0.02 ppm 

(expiration/revocation date of 10/15/12); HED recommended the time-limited tolerances for the 

combined residues of pyraflufen-ethyl, Metabolite E-1, and Metabolite E-9 be established at the 

combined LOQ of 0.03 ppm for the analytical method. Based on the recently submitted animal

feeding study, storage stability, and radiovalidation data, HED recommends that the time-limited 

tolerances of 0.02 ppm be established as unconditional and permanent at 0.03 ppm in milk and 

the meat byproducts of cattle, goat, horse, and sheep, and that unconditional and permanent 

tolerances be established at 0.03 ppm on the fat and meat of cattle, goat, horse and sheep. 

2.2.4 International Harmonization

There are no maximum residue limits (MRLs) in Codex or Canada or tolerances for pyraflufenethyl on any commodity (see Appendix D). 

3.0 Introduction

Pyraflufen-ethyl is an herbicide that is registered for use as a defoliant for cotton and potatoes; 

for a single preplant or post-emergence burndown use on field corn, cotton, pome fruits, stone 

fruits, grapes, tree nuts, olives, pistachios, pomegranates, soybeans, and wheat; for postemergence use on cotton, corn (except sweet corn), and soybeans; for weed control in non-crop 

land and uncultivated agricultural areas (non-food 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. The proposed uses of pyraflufen-ethyl are for the control of broadleaf weeds 

and for sucker management in hops, and for the preplant and post-emergence control of 

broadleaf weeds in peanuts. Nichino has petitioned for use of both the ET®2%SC 

Herbicide/Defoliant (EPA Reg. No. 71711-7) and the ET® Herbicide/Defoliant (EPA Reg. No. 

71711-25) on peanuts, and use of only the ET®2%SC Herbicide/Defoliant (EPA Reg. No. 

71711-25) on hops. Both the ET 2% SC Herbicide/Defoliant (EPA Reg. No. 71711-25) and ET 

Herbicide/Defoliant (EPA Reg. No. 71711-7) are liquid formulations which contain 0.17 and 

0.208 lbs pyraflufen-ethyl per gallon, respectively. Exposure to pyraflufen-ethyl use on hops 

was evaluated previously (K. Rury, 377359, 03/01/2011); however, the use on hops was denied

because detailed information on the residue chemistry field trials was not included in the 

submission. Nichino has re-petitioned the Agency to allow pyraflufen-ethyl use on hops as part 

of the current petition. Since exposure inputs and standard body weights have changed since the 

previous hops assessment, HED has reevaluated dietary and occupational exposure from 

pyraflufen-ethyl use on hops.

3.1 Chemical Identity
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Table 3.1. Pyraflufen-Ethyl and Its Metabolites 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

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

N N

Cl

F

Cl

H

OCHF

2

OCH

2

COOH

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
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Table 3.1. Pyraflufen-Ethyl and Its Metabolites Nomenclature.

Chemical structure 

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

3.2 Physical/Chemical Characteristics

Pyraflufen-ethyl has a log octanol/water partition coefficient (log Kow) of 3.49 and is considered 

relatively insoluble in water. Additionally, pyraflufen-ethyl has a molecular weight of 413.2 

g/mol; therefore, the potential to cross biological barriers is somewhat limited. However, 

pyraflufen-ethyl’s major transformation product, E-1 is more soluble by many orders of 

magnitude. Based on laboratory and field studies, pyraflufen-ethyl was found to be short-lived 

under most environmental conditions (half-lives generally <2 days). The major transformation 

pathways are hydrolysis, photolysis and metabolism, forming transformation products E-1, E-2 

and E-3. The E-1 and E-2 transformation products are moderately persistent but E-3, which is 

the terminal degradate, is highly persistent in the environment. The vapor pressure of 

pyraflufen-ethyl is considered low (4.3×10

-9 mm Hg at 20 oC), limiting the potential for 

inhalation exposure from volatilization. The physiochemical properties of pyraflufen-ethyl are 

summarized in Appendix B. 

3.3 Pesticide Use Pattern

Nichino has submitted two draft supplemental amended labels adding use of pyraflufen-ethyl on 

peanuts to both the ET®2%SC Herbicide/Defoliant (EPA Reg. No. 71711-7) and the ET®

Herbicide/Defoliant (EPA Reg. No. 71711-25), and use of hops on the ET®2%SC 

Herbicide/Defoliant label (EPA Reg. No. 71711-25). Table 3.3 provides a summary of the 

proposed use sites of pyraflufen-ethyl. Pyraflufen-ethyl is proposed for broadcast or grounddirected application to hops at a maximum single application rate of 0.0053 lb ai/A and may not 

be applied by air or chemigation. For sucker management, the application should be focused in 

the row and onto the lower 18 inches of the hop plant. The pre-harvest interval (PHI) for hops is 

30 days, and the retreatment interval (RTI) is 40 days. The maximum seasonal application rate is 

0.009 lb ai/A. Pyraflufen-ethyl may also be applied via broadcast or ground-directed application 

to preplant and post-emergent peanuts at a maximum single application rate of 0.0033 lb ai/A, or 

as a ground-directed spray of 0.00033 lb ai/gallon. Pyraflufen-ethyl may not be applied through 

chemigation to peanuts. For peanuts, the RTI is 30 days and the PHI is 7 days. The maximum 

seasonal application rate for peanuts is 0.0065 lb ai/A. Occupational handlers must wear longsleeved shirts, long pants, chemical resistant gloves, and protective eyewear. Handlers of ET 

Herbicide/Defoliant (EPA Reg. No. 71711-7) must also wear chemical resistant headgear for 

overhead exposures. The 12 hour REI listed on the labels is appropriate. 

N N

Cl

F

Cl

CH

3

OCHF

2

OCH

2

COOCH3
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Table 3.3. Summary of Directions for Use of Pyraflufen-ethyl.

Applic. 

Timing, Type, 

and Equip.

Formulation 

[EPA Reg. No.]

Max Single 

Applic. Rate 

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate

PHI 

(days)

Use Directions 

and Limitations

Hops

Groundboom

SC

(EPA Reg. No. 

71711-25)

0.0053 lb ai/A 

(broadcast & 

ground directed) 

Up to 6 6.8 fl oz/A 

0.009 lb ai/A 30 RTI = 40 days

Peanuts

Aerial, 

Groundboom

EC

(EPA Reg. No. 

71711-7)

0.0033 lb ai/A

(broadcast & 

ground directed)

Up to 4 

4.0 fl oz/A or 

0.0064 lb 

ai/A 

(all uses)

7 RTI = 30 days

SC

(EPA Reg. No.

71711-25)

0.0033 lb ai/A

(broadcast & 

ground directed)

Up to 4

4.8 fl oz/A or 

0.0064 lb 

ai/A

7 RTI = 30 days

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new uses of pyraflufen-ethyl on hops and peanuts. Humans may be exposed to 

pyraflufen-ethyl in food and drinking water, since pyraflufen-ethyl may be applied directly to 

growing crops and application may result in pyraflufen-ethyl reaching surface and ground water 

drinking water sources. There are residential uses of pyraflufen-ethyl so there is exposure to 

residential handlers and those entering treated areas following application. In occupational 

settings, applicators may be exposed while handling pyraflufen-ethyl. There is a potential for 

post-application exposure for workers re-entering treated fields. 

Risk assessments have been completed for existing uses of pyraflufen-ethyl. This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 

uses of pyraflufen-ethyl, but also considers existing uses of pyraflufen-ethyl, particularly in the 

dietary exposure assessment. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://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 U.S. Department of 

Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age, season of the 
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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.

4.0 Hazard Characterization and Dose-Response Assessment

This assessment includes an updated hazard characterization of pyraflufen-ethyl; the last 

comprehensive risk assessment was conducted in 2011 (K. Rury, D377359, 03/01/2011). At that 

time, the toxicity database was judged complete with the exception of the neurotoxicity battery 

(§870.6200a, §870.6200b), an immunotoxicity study (§870.7800), and a 28-day inhalation study 

(§870.3465). These studies all have been either received or waived, and are discussed in the 

sections below. 

4.1 Summary of Toxicological Effects

Pyraflufen-ethyl exhibits relatively low acute toxicity from oral, dermal, and inhalation exposure. 

Pyraflufen-ethyl has low acute toxicity via the oral (Toxicity Category IV), dermal (Toxicity 

Category III), and inhalation (Toxicity Category IV) routes of exposure. It produces moderate 

eye irritation (Toxicity Category III), and is not a dermal irritant or a dermal sensitizer. 

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

system are the target organs for pyraflufen-ethyl in the rat and/or mouse. The rabbit appears to 

be the most sensitive species to the toxic effects. Adverse toxic effects were not 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 in the developmental 

toxicity studies, or following pre- and post-natal exposure to rats in the multi-generation 

reproduction study. Although not mutagenic or carcinogenic in the rat, pyraflufen-ethyl is 

classified as “Likely to be Carcinogenic to Humans” and produced a compound-related increase 

in incidence of hepatocellular adenomas, carcinomas, and/or hepatoblastomas in male and 

female mice. A linear low-dose extrapolation approach is used to estimate human cancer risk 

(Q1* of 3.32 x 10-2(mg/kg/day)-1) based on combined hepatocellular adenomas, carcinomas 

and/or hepatoblastomas seen in male mice (J. Kidwell, TXR#0050930, 10/08/2002). 

Since the last risk assessment, the neurotoxicity battery was reviewed and determined to be 

negative for both acute and subchronic neurotoxicity (TXR#0056461). While a transient 

decrease in body weight gain was observed in females at 2000 mg/kg in the acute neurotoxicity 

study, this single-dose effect occurred only at the Limit Dose, and is not considered a 

sufficiently robust adverse effect for risk assessment purposes. Additionally, the

immunotoxicity study (TXR#0056271) showed a decreased immune response (decreases of 

anti-SRBC AFC response in male rats) only at a dose level of 946 mg/kg/day, which is 

approaching the limit dose (1,000 mg/kg/day). 
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Developmental effects for both rats and rabbits occurred at either the same dose levels or were 

above the NOAELs and LOAELs for maternal toxicity. The NOAEL for offspring effects in the 

2-generation rat reproduction study was identical to that of the parental animals. Based on these 

data, there was no increased quantitative susceptibility. 

The metabolic pathway of pyraflufen-ethyl 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, 

with toxicity profiles similar to pyraflufen-ethyl and degrees of toxicity less than or equal to the 

parent compound. See Table 3.1 for the structures of pyraflufen-ethyl and its metabolites.

Radiolabeled kinetic studies in the rat show that pyraflufen-ethyl is rapidly absorbed in a dosedependent 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 gastrointestinal (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.

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

HED has determined that reliable data show that it would be safe for infants and children to 

reduce the FQPA safety factor to 1X for acute, short-term, intermediate-term, and chronic risk 

assessment. This determination is based on the following considerations: 

4.2.1 Completeness of the Toxicology Database

The toxicity database for pyraflufen-ethyl is complete and considered adequate for risk 

assessment. The required inhalation toxicity study for pyraflufen-ethyl has been waived based 

on pyraflufen-ethyl’s use pattern, physical chemical properties, and low acute inhalation toxicity 

(D. Smegal, TXR#0054072, 03/02/2012). In the absence of a route specific inhalation toxicity 

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

4.2.2 Evidence of Neurotoxicity

The acute and subchronic neurotoxicity studies showed no evidence of neurotoxicity after acute 

exposure up to 2000 mg/kg and subchronic exposure up to 625 mg/kg/day (females), and no 

neurotoxic effect was seen in other toxicity studies. Therefore, there are no concerns for 

neurotoxicity and no need for a developmental neurotoxicity study. 

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

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 of increased 

susceptibility of young rats in the pyraflufen-ethyl reproduction study and there are no residual 

uncertainties for pre- and/or postnatal exposure.
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4.2.4 Residual Uncertainty in the Exposure Database

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

exposure assessments were performed assuming 100% of the crops were treated with pyraflufenethyl, tolerance-level residues for the proposed commodities, and residue inputs of 1⁄2 LOQ as 

refined estimates of the currently registered residues in food. EPA made conservative 

(protective) assumptions in the ground and surface water modeling used to assess exposure to 

pyraflufen-ethyl in drinking water. EPA used similarly conservative assumptions to assess postapplication exposure of adults and children as well as incidental oral exposure of children. In 

addition, the residential exposure assessment is based on the updated 2012 Residential SOPs 

employing surrogate study data, including conservative exposure assumptions based on Day 0 

dermal/oral contact to turf and surfaces treated at the maximum application rate. These data are 

reliable and are not expected to underestimate risks to adults or children. The Residential SOPs 

are based upon reasonable “worst-case” assumptions are not expected to underestimate risk. 

Although some of the residue values used in the dietary exposure assessment were refined, these 

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

4.3 Toxicity Endpoint and Point of Departure Selections

The toxicological doses and endpoints supporting this petition remain unchanged and have been 

summarized in the previous human health risk assessment (K. Rury, D377359, 03/01/2011). 

Since the last risk assessment, the neurotoxicity battery was submitted, reviewed, and 

determined to be negative for both acute and subchronic neurotoxicity (TXR#0056461). While 

a transient decrease in body weight gain was observed in females at 2000 mg/kg in the acute 

neurotoxicity study, this single-dose effect occurred only at the Limit Dose, and is not 

considered a sufficiently robust adverse effect for risk assessment purposes; and is not suitable 

for establishing an acute reference dose (aRfD). 

Additionally, the submitted and reviewed immunotoxicity study (TXR#0056271) showed a 

decreased immune response (decreases of anti-SRBC AFC response in male rats) only at a dose 

level of 946 mg/kg/day, which is approaching the limit dose (1,000 mg/kg/day). The 

immunosuppressant effect seen in the immunotoxicity study occurred only near the Limit Dose, 

and does not impact on the toxicity endpoints and PODs or risk assessment, because the current 

endpoints are already protective of this effect. 

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

has been applied to the PODs selected for all non-cancer risk assessment scenarios. The FQPA 

safety factor was reduced to 1X as discussed in Section 4.2. In the absence of dermal absorption 

data, dermal absorption for cancer exposure estimates is assumed to be 100% and inhalation 

absorption is assumed to be equivalent to oral exposure for non-cancer and cancer risk 

assessments. Assuming 100% dermal absorption for cancer risk assessment is an 

conservative estimate based on low acute dermal toxicity (the acute LD50 > 2000 mg/kg) and low 

subchronic dermal toxicity study (no adverse effects up to the Limit Dose of 1000 mg/kg/day), 

which both suggest that pyraflufen-ethyl is not well absorbed dermally. For residential and

occupational non-cancer inhalation exposure assessment, 69 kg was used to estimate exposure 
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risks to adult handlers because the endpoint is based on developmental effects. For residential 

and occupational cancer (dermal + inhalation) risk assessment, 80 kg was used to estimate 

exposure. The toxicity endpoints and PODs for risk assessment are presented in Tables 4.3.1 and 

4.3.2.

Table 4.3.1. Summary of Toxicological Doses and Endpoints for Pyraflufen-ethyl for Use in Dietary 

and Non-Occupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for 

Risk Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

None

An endpoint attributable to a single dose 

was not identified for pyraflufen-ethyl from 

the available data.

Chronic 

Dietary (All 

Populations)

NOAEL = 

20

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF= 1x

Chronic RfD = 

0.20

mg/kg/day

cPAD = 0.2

mg/kg/day

Mouse Carcinogenicity Study 

LOAEL = 98 mg/kg/day based on liver 

toxicity

Incidental 

Oral ShortTerm (1-30 

days)

NOAEL = 

20

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 

1x

Residential LOC 

for MOE = 100

Developmental Toxicity-Rabbit

Maternal LOAEL = 60 mg/kg/day based on 

decreases in body weight and food 

consumption, GI observations, and 

abortions

Dermal 

Short- (1-30 

days), 

Intermediate 

(1-6 months), 

and Long-

(>6 months) 

Term

None 28-Day Dermal Toxicity – Rats

No dermal or systemic toxicity was seen at 

the Limit Dose (1000 mg/kg/day)

Inhalation 

Short- (1-30 

days) and 

Intermediateand LongTerm (1-6 

months)

NOAEL =

20

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF= 1x

Residential LOC 

for MOE = 100

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

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.
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Table 4.3.2. Summary of Toxicological Doses and Endpoints for Pyraflufen-ethyl for Use in 

Occupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for 

Risk Assessment

Study and Toxicological Effects

Dermal 

Short- (1-30 

days), 

Intermediate 

(1-6 months),

and Long-

(>6 months) 

Term

None 28-Day Dermal Toxicity – Rats

No dermal or systemic toxicity was seen at 

the Limit Dose (1000 mg/kg/day)

Inhalation 

Short- (1-30 

days) and 

Intermediateand LongTerm (1-6 

months)

NOAEL =

20

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF= 1x

Residential LOC 

for MOE = 100

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

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). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable.

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

The residues of concern for dietary risk assessment and the tolerance expression are summarized 

in Table 5.1. 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. HED previously 

concluded that the residues of concern in livestock commodities are parent and Metabolites E-1 

and E-9, and that all three compounds should be measured in livestock feeding studies. Based on 

the Metabolite E-9 results of the livestock feeding study, HED concludes that the tolerance 

expression for livestock commodities should include parent and Metabolites E-1 and E-9. 

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. Metabolite E-3 is the major 

metabolite (>10% TRR) in aerobic soil metabolism resulting from Metabolite E-2. 
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Table 5.1. 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

5.2 Food Residue Profile

Adequate residue data are available to support dietary risk assessment as well as the proposed 

tolerances of pyraflufen-ethyl on peanuts. However, the submitted hop field trial data are not 

adequate to support the proposed tolerances of pyraflufen-ethyl on hops. Additional hop field 

trials conducted in the U.S. are required using the proposed SC formulation. 

Residues of pyraflufen-ethyl, Metabolite E-1 and combined residues in peanut nutmeat are below 

the LOQ (0.005 ppm) when peanuts are harvested at the seven day PHI. In the residue decline 

trials, residue decline could not be assessed for pyraflufen-ethyl or E-1 in peanut nutmeat or 

peanut hay because all residues were near or below the LOQ (0.005 ppm). Processing studies 

indicate that residues do not concentrate in the peanut fractions (peanut meat and peanut oil). 

Livestock feeding study data indicate low transfer of residues to meat and milk. No quantifiable 

residues were found in poultry and hog commodities.

Data indicate that the combined residues of pyraflufen-ethyl and Metabolite E-1 are relatively 

stable under frozen conditions and that there were some conversions of pyraflufen-ethyl to 

Metabolite E-1 during frozen storage, particularly in liver and kidney. The total combined 

recoveries of pyraflufen-ethyl and Metabolite E-1 were relatively stable in milk, liver, kidney, 

muscle, and fat. 

Currently Registered Uses & Additional Required Tolerances

Based on the recently submitted radiovalidation data, and animal feeding and storage stability

studies, HED recommends that the time-limited tolerances of 0.02 ppm in milk and meat 

byproducts of cattle, goat, horse, and sheep be established as unconditional and permanent at 

0.03 ppm. Additionally, and based on the recently submitted data, HED recommends that 

unconditional and permanent tolerances be established at 0.03 ppm in the meat and fat of cattle, 

goat, horse, and sheep. 

Proposed Uses 

Field trial data on hops and peanuts have been submitted to support the proposed tolerances. 

Hops
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Three field trials on hops were conducted in Germany during the 2005 growing season. The 

submitted hop data are not adequate to fulfill data requirements. Although the study was 

conducted at a rate slightly higher than the maximum proposed rate, and samples were harvested 

at the proposed PHI, the type of application was not identified, and the number and location of 

crop field trials are not in accordance with OCSPP 860.1500. 

HED concludes that additional hop field trials conducted in the U.S. are required to support the 

proposed use on hops. Because HED believes that the proposed use pattern is likely to result in 

low residues on hops, the German field trial data will be accepted as one trial. Therefore, two 

additional crop field trials should be conducted on hops reflecting application of the 0.17 lb 

ai/gal SC formulation of pyraflufen-ethyl according to the maximum proposed use pattern. The 

trials should be conducted in U.S. Zone 11, which accounts for 94% of U.S. hops production. 

The proposed tolerance of 0.01 ppm for hop, dried cones will be assessed when the requested 

field trial data have been received. A summary of the residue data from the hop field trials is 

provided in Table 5.2.1.

Table 5.2.1. Summary of Residue Data from Hop Field Trials with Pyraflufen-ethyl.

Commodity Analyte Total

Rate

(lb 

ai/A)

PHI 

(days)

Residue Levels1(ppm in parent equivalents)

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. 

Dev.

HOPS: Proposed use = 0.0090 lb ai/A total application rate (post-harvest dormant and/or in-season 

application), 30-day PHI

Hops, cones Pyraflufenethyl0.0142 29-38 1 <0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

Metabolite 

E-1

<0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

Combined <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. N/A = Not applicable.2 LAFT

= lowest average field trial; HAFT = highest average field trial.

Peanuts 

Nichino has submitted acceptable field trial data for pyraflufen-ethyl on peanuts using an EC 

formulation. Twelve field trials were conducted in the United States during the 2010 growing 

season. However, HED has concluded that the differences between the trials are insufficient to 

classify them as separate trials; therefore, each pair of trials constitutes a single trial with 

replicate samples for purposes of 860.1500 data requirements. The adjustment in trial numbers 

results in a total of eight field trials, with four trials conducted in NAFTA Zone 2. An acceptable 

method was used for residue quantitation, and the data are supported by adequate storage 

stability data; although, due to the designation of four trial pairs as single trials with replicate 

samples, the number of the field trials is not in accordance with the number requested under 

OCSPP 860.1500. However, since residues were consistently <LOQ for peanut nutmeat and low 

residues (<0.04 ppm) for peanut hay, it is unlikely that additional trials will reveal higher 

residues. Therefore, eight trials are adequate to support the EC formulation. In addition, the 

petitioner is currently proposing use of an SC formulation on peanuts but submitted only data 

using an EC formulation. The submitted data for the EC formulation are not sufficient for

translatation to the SC formulation. Because a 7-day PHI is proposed, additional bridging data 
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

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are required to support use of the 0.17 lb ai/gal SC formulation on peanut, consistent with the 

Organization of Economic Cooperation and Development (OECD) Crop Field Trial guidance. If 

residues are higher following application of the SC formulation, then a complete data set for the 

SC formulation may be required. Pending submission of the required additional bridging field 

trial, the data are sufficient for establishing the proposed tolerances associated with the requested 

registration of the 0.208 lb ai/gal EC formulation for combined residues of pyraflufen-ethyl and 

Metabolite E-1 in/on peanut at 0.01 ppm (LOQ) and peanut, hay at 0.07 ppm. Tolerance 

calculations could not be performed for peanut nutmeat because all values were <LOQ. A 

summary of the residue data from the peanut field trials is provided in Table 5.2.2. 

Table 5.2.2. Summary of Residue Data from Peanut Field Trials with Pyraflufen-ethyl.

Commodity Analyte Total

Rate

(lb 

ai/A)

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. 

Dev.

PEANUT: Proposed use = 0.0064 lb ai/A total application rate (preplant burndown, postplant 

preemergence, and/or postemergence application), 7-day PHI

Peanut 

Nutmeat

Pyraflufenethyl0.0064

-

0.0066

7 8 <0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

Metabolite 

E-1

3

<0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

Combined <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Peanut Hay Pyraflufenethyl0.0064

-

0.0066

7 8 <0.005 0.014 <0.005 <0.008 0.005 0.006 0.002

Metabolite 

E-1

3

<0.005 0.039 <0.005 0.030 0.016 0.016 0.008

Combined <0.01 0.052 <0.01 <0.035 0.023 0.022 0.009

1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. N/A = Not applicable.

2

 LAFT = lowest average field trial; HAFT = highest average field trial.

3

 Data reflect conversion of quantifiable residues of E-1 to parent equivalent by the study reviewer.

Nichino has submitted an adequate and acceptable processing study for pyraflufen-ethyl on 

peanut. The combined residues of pyraflufen-ethyl and Metabolite E-1 following a 5x maximum 

seasonal application rate were below the LOQ (<0.01 ppm) in/on all samples of peanut and 

peanut processed fractions (meal and refined oil). These data indicate that quantifiable 

pyraflufen-ethyl residues are unlikely to occur in peanut processed commodities following 

applications at an exaggerated use rate; therefore, tolerances for the processed commodities of 

peanut are not needed. A summary of the residue data from the peanut field trials is provided in 

Table 5.2.3. 

Table 5.2.3. Residue Data from Peanut Processing Study with Pyraflufen-ethyl.

RAC Processed 

Commodity

Total 

Rate

(lb ai/A)

PHI1 Residues (ppm)2[Average] Processing Factor3

Pyraflufen

-ethyl

Metabolite 

E-1

Combined 

Residues

PyraflufenethylMetabolite 

E-1

Combined 

Residues
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Table 5.2.3. Residue Data from Peanut Processing Study with Pyraflufen-ethyl.

RAC Processed 

Commodity

Total 

Rate

(lb ai/A)

PHI1 Residues (ppm)2[Average] Processing Factor3

Pyraflufen

-ethyl

Metabolite 

E-1

Combined 

Residues

PyraflufenethylMetabolite 

E-1

Combined 

Residues

Peanut Nutmeat

(RAC)

0.0325 7 (6) ND ND <0.01 -- -- --

Meal ND, ND 

[<0.005]

ND, ND 

[<0.005]

<0.01, 

<0.01 

[<0.01]

NC4 NC NC

Refined Oil ND, ND 

[<0.005]

ND, ND 

[<0.005]

<0.01, 

<0.01 

[<0.01]

NC NC NC

1 The number of days peanut samples were allowed to dry in the field prior to collection is reported in parenthesis.

2 The LOQ was 0.005 ppm for all analytes in all matrices. Per trial average residues were calculated by the study reviewer using 

the LOQ for all residues reported as <LOQ.

3

Processing Factor = [Measured residue for analyte in the processed fraction] / [Measured residue for analyte in the nutmeat 

RAC]. 

4 NC = Not calculated; residues were below the LOQ (<0.005 ppm for each analyte) in the RAC and processed fraction.

Livestock

The livestock feedstuffs associated with the proposed uses in this petition are peanut hay and 

peanut meal.

The livestock dietary burdens of pyraflufen-ethyl, based on a maximum reasonably balanced diet 

(MRBD), were calculated recently under PP#0F7718 (L. Cheng, D377361 and D377365

02/07/2011). The calculated dietary burdens were 0.12 ppm for beef cattle (versus 0.25 ppm), 

0.076 ppm for dairy cattle (versus 1.8 ppm), 0.01 ppm for swine, and 0.01 ppm for poultry. The 

dietary burden calculations reflected established tolerances for corn, cotton, grass, soybean, and 

wheat commodities. Based on the calculated dietary burdens and a revision of the original cattle 

feeding study to include residue data for Metabolite E-9, HED previously recommended for the 

establishment of tolerances for the combined residues of pyraflufen-ethyl, Metabolite E-1, and 

Metabolite E-9 in milk, and the fat, meat, and meat byproducts of cattle, goat, horse, and sheep at 

the combined LOQ of 0.03 ppm for the analytical method. 

HED has recently revised its approach to calculating dietary burdens, replacing tolerance values 

in the calculation with HAFT residues for most feedstuffs, median residues for blended feeds, 

and median residues multiplied by processing factors for most processed commodities. This has 

generally resulted in appreciably lower dietary burdens for all species. Using the revised 

approach, the expected dietary contribution of peanut hay would be 0.006 ppm to dairy cattle 

(based on the HAFT value of <0.035 ppm for combined residues of pyraflufen-ethyl and

Metabolite E-1 in peanut hay), and the expected dietary contributions of peanut meal would be 

0.001 ppm to dairy cattle, 0.003 ppm to poultry, and 0.002 ppm to swine (based on the median 

value of 0.01 ppm for combined residues of pyraflufen-ethyl and Metabolite E-1 in peanut 

nutmeat; a processing factor could not be calculated for peanut meal because residues were 

below the LOQ in the raw agricultural commodity (RAC) and processed fractions).

Time-limited tolerances have been established under 40 CFR § 180.585. HED concluded that 

tolerances for poultry and hog commodities were not required because there is no reasonable

expectation of finite residues in poultry or hog commodities (40 CFR §180.6(a)(3)).
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

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No additional data are needed to support the proposed new uses of pyraflufen-ethyl EC 

formulation on peanut. Based on the relatively minor expected dietary contributions from the 

feedstuffs associated with use on peanut, and the available ruminant feeding studies, no changes 

are needed to the recommended tolerances for ruminant commodities, and no tolerances are 

needed for poultry or hog commodities. The Agency may revisit the need for additional 

tolerances upon submission of additional required peanut field trial data for the SC formulation.

Storage Stability (In Plants)

The available storage stability data for pyraflufen-ethyl and Metabolite E-1 are adequate to 

support the storage durations and conditions of samples of hop and peanut from the residue field 

trials. Although data from several of the studies showed some conversion of parent to 

Metabolite E-1 during frozen storage, the levels of the combined residues remained relatively 

steady during storage. The storage durations and conditions for samples from the crop field trials 

and processing study submitted to support this petition are presented in Table 5.2.4.

Table 5.2.4. Sample Storage Conditions and Durations from Crop Field Trials and Processing Study.

Study 

type

Matrices Storage 

Temperature 

(°C)

Actual Storage 

Duration

(days)

Interval of Demonstrated Storage Stability

Hops Hop cones ≤-18 125-127 days

(4.1-4.2 months)

Adequate storage stability data are available 

indicating that the combined residues of 

pyraflufen-ethyl and metabolite E-1 are 

relatively stable under frozen conditions for the 

following intervals on plant commodities: 5.8 

months in soybean hay and seed; 6.1 months in 

cotton seed; and 43 months in wheat hay.

Peanut Peanut, 

nutmeat

-20 38-77 days

(1.3-2.5 months)

Peanut, hay 51-91 days

(1.7-3.0 months)

Peanut, meal 25 days

(0.8 months)

No data are required because samples were 

analyzed within 30 days of processing.

Peanut, 

refined oil

26 days

(0.9 months)

Storage Stability (In Livestock)

The storage stability data of 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 intervals 

incurred during the feeding study. No storage stability data have been presented for Metabolite 

E-9, but E-9 is anticipated to demonstrate stability similar to E-1, and no additional data will be

required.

Rotational Crops

An acceptable 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). Residues below the LOQ of 0.005 ppm and estimated as 

0.001-0.003 ppm were detected in 30-day mature radish roots and tops, 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 
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

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of pyraflufen-ethyl and its soil metabolites by rotational crops only occurs at very low levels. 

Therefore, the residues of concern in rotational crops are parent and Metabolite E-1 and the 

available confined rotational crop study supports the 30-day plant-back interval (PBI) specified 

on the labels for all crops without primary uses of pyraflufen-ethyl.

5.3 Water Residue Profile

EFED estimates drinking water concentrations of a chemical based on the highest rate of 

application of the chemical on all registered and proposed crops. The drinking water residues 

used in the dietary risk assessment were provided by EFED (M. Barrett, D402766, 09/21/2012). 

The proposed use on peanuts did not change the EDWCs provided in the last drinking water 

assessment (M. Barrett, D377360, 03/23/2011). The EDWCs were incorporated directly into this 

dietary exposure assessment. In the case of pyraflufen-ethyl, the drinking water inputs 

(estimated drinking water concentrations; EDWCs) were based on the potato use pattern with the 

highest seasonal application rate of 0.01789 lb ai/A. The assessment was completed with Tier 2 

modeling using the Pesticide Root Zone Model/Exposure Analysis Modeling System 

(PRZM/EXAMS). The model and its description are available at the EPA internet site: 

http://www.epa.gov/oppefed1/models/water. The drinking water numbers are slightly revised 

from those used in the previous risk assessment (K. Rury, D377359, 03/01/2011); EFED 

provided a 30-year average EDWC estimate, representative of lifetime exposure, for assessing 

cancer exposure risks and a slightly higher annual average EDWC (0.295 ppb) than previously 

recommended (0.281 ppb) for estimating chronic dietary exposure. Residues of the metabolite 

E-1 are expected to be the predominant component in the EDWCs, but the estimation procedure 

is inclusive of parent pyraflufen-ethyl. 

Table 5.3. Summary of Estimated Surface Water and Groundwater Concentrations for Pyraflufen-ethyl.

(M. Barrett, D377360, 03/23/2011).

Scenario Surface Water Conc., ppb a,b Groundwater Conc., ppbc

Acute 0.640

Chronic (non-cancer) 0.295 0.0018

Chronic (cancer) 0.268

a

From the Tier II PRZM-EXAMS - Index Reservoir model. Input parameters are based on the registered potato use pattern. 

b Bolded values are used in the dietary assessment.

c

From the SCI-GROW model.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Pyraflufen-ethyl does not require an acute dietary exposure assessment since a toxicological 

endpoint attributable to a single dose was not identified from the available data. The dietary 

exposure analysis incorporates all current and proposed tolerances for combined residues of 

pyraflufen-ethyl and Metabolite E-1 in plants and residues of pyraflufen-ethyl, Metabolite E-1, 

and Metabolite E-9 in animals. 
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The chronic dietary exposure assessment was partially refined. All available pyraflufen-ethyl 

field trials showed residues less than the LOQ. Therefore, the chronic dietary exposure 

assessment incorporated 1⁄2 of the combined LOQ for the parent and the metabolites for the 

following commodities: corn, cottonseed, potato, soybean, wheat, pome fruit, stone fruit, 

pomegranate, olive, grape, tree nuts, and pistachio. All other established and proposed 

commodities were analyzed using tolerance-level residues. Because the commodity-specific 

processing studies did not show pyraflufen-ethyl concentration after processing, the chronic 

dietary exposure assessment did not incorporate processing factors for the following 

commodities: treated corn grain, soybean seeds, wheat grain, apples, and grapes. However, 

default processing factors were used for dry potatoes (6.5X), peanut butter (1.89X), dried beef 

(1.92X), and corn syrup (1.5X). An empirical processing factor of 0.6X was used for cotton seed 

oil. The anticipated residue in meat, milk, fat, and meat byproducts was calculated to be 0.001 

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

Tier 2 (surface water) drinking water estimate provided by EFED. The chronic (annual average) 

estimate for drinking water was incorporated directly into the dietary assessment using the 

EDWC value of 0.295 parts per billion (ppb) for the combined residues of pyraflufen-ethyl and 

its metabolic products, E-1, E-2, and E-3. 

Pyraflufen-ethyl is classified as “likely to be carcinogenic to humans” by the oral route; 

therefore, a cancer dietary risk assessment is also required. All exposure inputs were the same as 

the chronic dietary exposure assessment for the cancer assessment, except the EDWC. Chronic 

cancer dietary exposure from drinking water was determined based on a Tier 2 (surface water) 

drinking water estimate provided by EFED. The EDWC estimate (30-year average) value of 

0.268 ppb for the combined residues of pyraflufen-ethyl and its metabolic products, E-1, E-2, 

and E-3 were incorporated directly into the dietary assessment to estimate carcinogenic risk from 

drinking water containing pyraflufen-ethyl. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

One hundred percent crop treated (% CT) was assumed for all registered and proposed crop 

commodities in both the chronic and cancer dietary exposure assessments. 

5.4.3 Acute Dietary Risk Assessment

Pyraflufen-ethyl does not require an acute dietary exposure assessment since a toxicological 

endpoint attributable to a single dose was not identified from the available data. 

5.4.4 Chronic & Cancer Dietary Risk Assessments

A chronic dietary assessment was conducted for the general U.S. population and all population 

subgroups. The chronic dietary exposure estimates utilize <1% of the 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 chronic dietary (food and water) exposure estimate for 

the general U.S. population to pyraflufen-ethyl is 2×10

-6

. The chronic and cancer dietary 

exposure analysis is partially refined in that 1⁄2 the combined LOQs of the parent and metabolites 

are used for the residue values in the dietary assessment, rather than the established tolerances 
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

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for corn, wheat, soybeans, cottonseed, potatoes, pome fruit, stone fruit, pomegranates, olives, 

grapes, tree nuts, and pistachios. The drinking water assessment was based on partially refined, 

Tier 2 estimates generated by PRZM-EXAMS. However, the assessment assumed that 100% of 

the crops are treated with pyraflufen-ethyl, and the assessment incorporated some default 

processing factors (6.5X for dried potatoes, 1.89X for peanut butter, 1.5X for corn syrup, and 

1.92 for dried beef), both conservative assumptions. Dietary estimates could be further refined 

through the use of %CT data or monitoring data. 

5.4.5 Summary Table

Table 5.4.5. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Pyraflufenethyl.

Population Subgroup

Chronic Dietary Cancer

Dietary 

Exposure

(mg/kg/day)

% cPAD1

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.000053 <1.0% 0.000052 2×10

-6

All Infants (< 1 year old) 0.00012 <1.0%

N/A N/A

Children 1-2 years old 0.00020 <1.0%

Children 3-5 years old 0.00014 <1.0%

Children 6-12 years old 0.000085 <1.0%

Youth 13-19 years old 0.000048 <1.0%

Adults 20-49 years old 0.000040 <1.0%

Adults 50+ years old 0.000035 <1.0%

Females 13-49 years old 0.000039 <1.0%

1 Highest exposure is in bold.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Although the proposed uses of pyraflufen-ethyl do not involve applications by homeowners in or 

commercial applicators in residential settings, pyraflufen-ethyl is currently registered for use by 

residential and commercial applicators on several residential/non-agricultural use sites; i.e., 

established ornamental turf lawns (residential, industrial, and institutional), parks, cemeteries, 

athletic fields, golf courses, sod farms, nurseries and ornamental plantings, and christmas trees. 

The existing residential use pattern for liquid formulations of pyraflufen-ethyl has been 

previously assessed by HED and did not result in risks of concern; however, dry flowable 

formulations of pyraflufen-ethyl have been registered since the last residential exposure 

assessment. Because the labels specify nursery grown ornamentals, and to avoid drift of 

pyraflufen-ethyl on susceptible plants such as vegetables, flowers, ornamental trees, shrubs, and 

other desirable plants, a residential handler assessment has only been conducted for use on turf. 

Residential exposure and risks from use on turf and trees and retail plants (post-application 
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

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exposure only) were reassessed to reflect updates to the 2012 HED Residential SOPs2(K. Rury, 

D397423, 09/04/2012). 

6.1 Residential Handler Exposure

Residential exposure and risks from use on turf were reassessed to reflect updates to the 2012 

HED Residential SOPs. It is assumed that most residential uses will result in short-term (1-30 

day) exposures. Residential handlers are assumed to be wearing short-sleeved shirts, short pants, 

shoes, and socks during pyraflufen-ethyl application. Because there was no dermal endpoint 

chosen for pyraflufen-ethyl, non-cancer risk from exposure to pyraflufen-ethyl was assessed for 

the inhalation route only. Although PODs from an oral study were used to assess residential 

handler inhalation risks to pyraflufen-ethyl, HED does not believe this assessment is under 

protective of adult handlers because of pyraflufen-ethyl’s physical chemical properties and low 

acute inhalation toxicity. Cancer risks (dermal + inhalation) were assessed for residential 

handlers. It was assumed for cancer risk assessment that a handler could treat turf up to 2 times 

per year, because the labels require less than two applications per year or specify that only one 

treatment is usually necessary to be effective or that a repeat application would be needed only 

after 30 days. 

HED’s LOC for the MOE is defined by the uncertainty factors that are applied to the assessment. 

HED applies a 10X factor to account for variability among species and a 10X factor to account 

for variability within species. The total uncertainty factor that has been applied to the non-cancer 

assessment of pyraflufen-ethyl is 100X for residential exposure. Residential exposure and risk 

resulting in MOEs greater than or equal to 100 will not be of concern to HED (LOC = 100). 

Table 6.1.1 lists the residential handler non-cancer inhalation risk estimates for application to 

turf. Residential handler inhalation MOEs were not of concern to HED, and ranged from 

1,300,000 to 70,000,000. 

Table 6.1.1. Residential Handler Non-cancer Exposure and Risk Estimates for Pyraflufen-Ethyl.

Exposure Scenario Level of Concern

Inhalation 

Unit 

Exposure

(mg/lb ai)

Maximum 

Application 

Rate1

Area Treated 

or Amount 

Handled 

Daily2

Inhalation

Dose

(mg/kg/day)5 MOE6

Liquids

M/L/A with a Manually 

Pressurized Handwand to Turf 100 0.018 0.00022 lb ai/gal 5 gal 0.00000029 70,000,000

M/L/A with a Hose-end Sprayer to 

Turf 100 0.022 0.0048 lb ai/A 0.5 acres 0.00000077 26,000,000

M/L/A with a Backpack Sprayer to 

Turf 100 0.14 0.00027 lb ai/gal 5 gal 0.0000022 9,000,000

M/L/A a Ready-to-Use Hose-end 

Sprayer to Turf 100 0.034 0.0044 lb ai/A 0.5 acres 0.0000011 18,000,000

Dry Flowables

M/L/A Manually Pressurized 

Handwand to Turf 100 1.1 0.00019 lb ai/gal 5 gal 0.000015 1,300,000

 

2

http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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Table 6.1.1. Residential Handler Non-cancer Exposure and Risk Estimates for Pyraflufen-Ethyl.

Exposure Scenario Level of Concern

Inhalation 

Unit 

Exposure

(mg/lb ai)

Maximum 

Application 

Rate1

Area Treated 

or Amount 

Handled 

Daily2

Inhalation

Dose

(mg/kg/day)5 MOE6

M/L/A Hose-end Sprayer to Turf 100 0.022 0.0036 lb 

ai/A 0.5 acres 0.00000057 35,000,000

M/L/A Backpack Sprayer to Turf 100 1.1 0.00019 lb 

ai/A 5 gal 0.000015 1,300,000

1 Based on registered Pyraflufen-ethyl labels.

2 Exposure Science Advisory Council Policy #9.1.

3

Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated 

or Amount Handled (A or gallons/day) / BW (69 kg).

4

Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day) where NOAEL = 20 mg/kg/day.

Table 6.1.2 presents the residential handler (dermal and inhalation) cancer risk estimates for 

application to turf. All residential handler cancer risk estimates ranged from 2.0×10

-8 to 

2.1×10

-7

. 

Table 6.1.2. Residential Handler Cancer Exposure and Risk Estimates for Pyraflufen-ethyl.

Crop or Target Exposure Scenario Handler Dermal 

LADD (mg/kg/day)1

Handler Inhalation 

LADD (mg/kg/day)2

Total LADD

(mg/kg/day)3

Residential Handler 

Cancer Risk 

Estimate4

Liquids

Turf

M/L/A with a 

Manually 

Pressurized 

Handwand

3.0×10

-6

8.7×10

-9

3.0×10

-6

1.0×10

-7

Turf M/L/A with a Hoseend Sprayer 1.4×10

-6

2.73×10-9 1.4×10

-6

4.7×10

-8

Turf M/L/A with a 

Backpack Sprayer 6.3×10

-6

6.8×10

-9

6.3×10

-6

2.1×10

-7

Turf M/L/A Ready-to-Use 

Hose-end Sprayer 6.1×10

-7

3.3×10

-9

6.1×10

-7

2.0×10

-8

Dry Flowable

Turf

M/L/A with a 

Manually 

Pressurized 

Handwand

2.9×10

-6

4.6×10

-8

2.9×10

-6

9.7×10

-8

Turf M/L/A with a Hoseend Sprayer 1.1×10

-6

1.7×10

-9

1.1×10

-6

3.5×10

-8

Turf M/L/A with a 

Backpack Sprayer 2.9×10

-6

4.6×10

-8

2.9×10

-6

9.7×10

-8

1 Dermal LADD = Dermal dose x Days per year of exposure (2 days) x Years per lifetime of exposure (50 years) / (365 days/year x Lifetime 

expectancy (78 years)). Dermal Dose = [Unit Exposure (μg ai/lb ai)*(0.001 mg/μg)*Application Rate (lb ai/A or gal) * Area treated per day * 

100% Absorption] / Body Weight (80 kg).

2

Inhalation LADD = Inhalation Dose x Days per year of exposure (2 days) x Years per lifetime of exposure (50 years)/ (365 days/year x Lifetime 

expectancy (78 years)). Inhalation Dose = [Unit Exposure (μg ai/lb ai)*(0.001 mg/μg)*Application Rate (lb ai/A or gal) * Area treated per day 

* 100% Absorption] / Body Weight (80 kg).

3 Total LADD = total absorbed dose [Dermal dose + Inhalation Dose] x Days per year of exposure x Years per lifetime of exposure / (365 

days/year x Lifetime expectancy).

4 Cancer risk estimates = Total LADD * Q1*

, where Q1

*

= 3.32×10

-2

(mg/kg/day)-1.

6.2 Post-Application Exposure
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When determining the potential for residential exposure, the Agency considers residues, leaf to 

skin/hand residue transfer, children’s hand-to-mouth transfer, and exposure time. No dermal 

endpoint was chosen for pyraflufen-ethyl; therefore, a dermal post-application risk assessment 

was not conducted. A combined (dermal + inhalation) post-application cancer risk assessment 

was conducted for adults contacting treated turf and retail plants. The exposure assessment for 

treated plants is considered extremely conservative in that the plants are assumed to be treated 

the same day that residential post-application contact occurs, with no residue transfer between 

treatment and purchase of the plants. Post-application inhalation exposure in outdoor settings is 

considered negligible. Tables 6.2.1 and 6.2.2 list the updated assessments of residential postapplication exposures and risk estimates. Residential incidental oral risk estimates ranged from 

270,000 to 120,000,000, and were not of concern to HED. All residential post-application adult 

cancer risk estimates ranged from 1.5×10

-8

to 7.3×10

-7

. 

Table 6.2.1. Residential Post-Application Non-cancer Exposure and Risk Estimates for Pyraflufenethyl.

Lifestage Post-application Exposure Scenario Dose1 MOEs2

Child Turf - sprays

Hand to Mouth 0.000073 270,000

Object to Mouth 0.0000022 9,000,000

Incidental Soil Ingestion 0.00000016 120,000,000

1 Hand-to-Mouth = [Hand residue loading (mg/cm2

) x (fraction hand surface area mouthed/event (0.127/event) x typical surface area of one 

hand (150 cm2)) x (exposure time (1.5 hr/day)*number of replenishment intervals/hr (4 intervals/hr) x (1-(1-saliva extraction factor 

(0.5)^(number of hand-to-mouth contact events per hour (13.9 events/hr); Hand Residue Loading = (fraction of ai on hands compared to total 

surface residue from dermal TC study (0.06) x dermal exposure (mg))/typical surface area of one hand (150 cm2). 

 Object-to-Mouth = ((Object Residue (μg/cm2) x CF1 (1.0E-3 mg/μg) x Object Surface Area Mouthed/Event (10 cm2/event)) x (Exposure 

Time (1.5 hrs/day) x #Replenishment Intervals/hr (4)) x (1-((1-Extraction by Saliva (0.48))^(#Object-to-Mouth Events/hr (8.8 

events/hr)/#Replenishment intervals/hr))))/Body Weight (11 kg).

Soil Ingestion = (Soil Residue (7.0746975 μg/g) x Ingestion Rate (50 mg/kg/day) x CF(0.000001))/Body Weight (11 kg).

2 MOE = NOAEL/Daily Dose (mg ai/kg/day); Oral NOAEL = 20 mg/kg/day. 

Table 6.2.2. Residential Post-Application Cancer Exposure and Risk Estimates for Pyraflufen-ethyl.

Lifestage Post-application Exposure Scenario Dermal LADD1

(mg/kg/day)

Cancer Risk Estimate2

Adult

Turf - sprays

High Contact Lawn 

Activities 2.2×10

-5

7.3×10

-7

Mowing Turf 4.5×10

-7

1.5×10

-8

Golfing 1.7×10

-6

5.7×10

-8

Gardens/Trees Dermal Contact to Trees 

and Retail Plants 3.4×10

-6

1.2×10

-7

1 Dermal LADD = Dermal dose * Days per year of exposure (2) x Years per lifetime of exposure (35)/ (365 days/year x Lifetime expectancy)

2 Cancer risk estimates = LADD * Q1*

, where Q1

*

= 3.32×10

-2

(mg/kg/day)-1

6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

Because exposure to treated gardens and turf could be expected within the same day adult postapplication cancer exposure to treated trees and retail plants and turf were combined (Table 6.3). 

The combined residential post-application cancer risk estimate was 8.4×10

-7

. 
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Table 6.3. Cancer Residential Combined (Multiple Exposure Scenarios) Exposure and Risk Estimates for 

Pyraflufen-ethyl.

Combined Exposure 

Scenario Lifestage Exposure Scenario LADD(mg/kg/day)

Combined Total 

LADD1

(mg/kg/day)

Combined Total 

Cancer Risk

Estimate2

Outdoor Scenario 

(Turf) Adult

Post-application: Turf 2.2×10

-5

2.5×10

-5

8.4×10

-7

Post-application: –Trees and Retail 

Plants 3.4×10

-6

1 Reasonably conservative, high end dermal AND inhalation post application exposures (Table 6.2.2) may also be combined. Handler exposures

should not routinely be combined with post-application exposures. 

2 Cancer risk estimates = Combined LADD * Q1*

, where Q1

*

= Q1

*

= 3.32×10

-2

(mg/kg/day)-1.

6.4 Residential Risk Estimates for Use in Aggregate Assessment

Tables 6.4.1 and 6.4.2 reflect the residential risk estimates that are recommended for use in the 

aggregate assessment for pyraflufen-ethyl. 

The inhalation exposure estimate from treating turf with a backpack sprayer or manually 

pressurized handwand is recommended for inclusion in the non-cancer aggregate 

assessment. 

Hand-to-mouth exposure of children 1 to <2 years old is recommended for inclusion in 

the aggregate assessment.

The combined post-application exposure estimate from treated turf and trees and retail 

plants (the most conservative residential exposure scenario) is recommended for 

inclusion in the cancer aggregate assessment. 
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Table 6.4.1. Recommendations for the Residential Exposures for the Pyraflufen-ethyl Non-Cancer Aggregate Assessment.1

Lifestage

Handler Exposure 

(mg/kg/day)2

Residential

Handler Total 

Exposure 

(mg/kg/day)3

Residential 

Handler 

Total 

MOE4

Post-application Exposure 

(mg/kg/day)5 Residential 

Total Exposure 

(mg/kg/day)

Residential 

Total MOE6

Scenario Inhalation Dermal Inhalation Oral

Short-Term Non-Cancer

Adult Handler: Treating 

Turf 0.000015 0.000015 1,300,000 N/A7

0.000015 1,300,000

Child N/A7N/A7 N/A7

Hand-toMouth: 

0.000073

0.000073 270,000

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

2 Handler exposure represents high-end handler exposure (i.e., the highest handler exposure of all scenarios assessed).

3

For adults, residential total exposure combines the highest inhalation exposures (Table 6.1.2), where applicable. For young children, total residential exposure combines high-end post application 

incidental oral, where applicable (Table 6.2.1)

4 Total MOE = 1 / (1/Inhalation MOE Turf) + (1/Inhalation MOE Gardens). Inhalation NOAEL = 20 mg/kg/day

5

Post-application exposure represents high-end dermal, inhalation and/or incidental oral exposure for the relevant exposure duration

6 Total MOE = (1/Inhalation MOE) + (1/Incidental oral MOE). Inhalation NOAEL = 20 mg/kg/day; Incidental oral NOAEL = 20 mg/kg/day.

7 N/A = Not applicable. 

Table 6.4.2. Recommendations for the Residential Exposures for the Pyraflufen-ethyl Cancer Aggregate Assessment (Adults only).

1

Lifestage

Handler Exposure 

(mg/kg/day)2 Residential

Handler Total 

Exposure 

(mg/kg/day)3

Residential 

Handler 

Total MOE4

Post-application Exposure (mg/kg/day)5 Residential 

Total 

Exposure 

(mg/kg/day)

Residential 

Total 

MOE6

Scenario Inhalation Scenario Dermal LADD 

(mg/kg/day)

Combined 

LADD 

(mg/kg/day)

Cancer (Adults Only)

Adult N/A7

High Contact Lawn 

Activities 2.2×10

-5

2.5×10

-5

2.5×10

-5

8.4×10

-7

Adult N/A7 Dermal Contact 

with Trees/Retail 

Plants

3.4×10

-6

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

2 Handler exposure represents high-end handler exposure (i.e., the highest handler exposure of all scenarios assessed).

3

For adults, residential total exposure combines the highest dermal and inhalation cancer exposures (Table 6.2.2), where applicable. 

4 Total Cancer Risk Estimate = Total Residential Handler LADD * Q1*

, where Q1

*

= 3.32×10

-2

(mg/kg/day)-1

5

Post-application exposure represents high-end dermal and inhalation exposure for the relevant exposure duration

6 Total Cancer Risk Estimate = Residential Post-application total exposure * Q1*

, where Q1

*

= 3.32×10

-2

(mg/kg/day)-1. 

7 NA = Not Applicable. 
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6.5 Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for pyraflufen-ethyl at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category IV), low vapor pressure (4.3×10-9 mm Hg at 20 oC), 

and the low proposed use rate (0.0053 lb ai/A). However, volatilization of pesticides may be a 

source of post-application inhalation exposure to individuals nearby pesticide applications. The 

Agency sought expert advice and input on issues related to volatilization of pesticides from its 

Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 2010

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are developed, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for pyraflufen-ethyl.

6.6 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for pyraflufen-ethyl. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risk 

estimates associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios. 

It is noted that the 0.0048 lb ai/acre application rate for turf was modeled to estimate postapplication residential exposure of children. As this rate is similar to, equal to, or higher than 

many of the agricultural application rates (except for the proposed use on hops), this scenario is 
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

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considered protective of any exposure of farm children via spray drift from agricultural 

pyraflufen-ethyl applications.

7.0 Aggregate Exposure/Risk Characterization

In accordance with 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. 

This assessment considers the changes in the new Residential SOPs implemented in January 

2012. HED confirms that there are no exposure risks of concern resulting from pyraflufen-ethyl 

on hops or peanuts, nor from utilizing the new Residential SOPs to estimate residential exposure 

and risk. 

7.1 Acute Aggregate Risk

No adverse effects attributable to a single dose were observed in oral toxicity studies, including 

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-Term Aggregate Risk

There is potential short-term exposure to pyraflufen-ethyl via dietary (which is considered 

background exposure) and residential (which is considered primary) exposure pathways. For 

adults, these pathways lead to exposure via oral (background) as well as dermal and inhalation 

(primary) routes. The most conservative scenario was chosen for each population (e.g., hand-tomouth exposure from treated turf for children 1-2 years old). For a description of the residential

exposure scenarios considered in the aggregate assessment, see Section 6.4. 

The adult (inhalation) non-cancer aggregate MOE is 290,000 and is not of concern to HED. The 

aggregate MOE for children 1-2 years old, including incidental oral exposures from treated turf, 

is 9,600 and is not of concern to HED. 

Further refinement using additional %CT estimates or more refined EDWCs could be 

incorporated into future assessments. Additionally, 100% dermal absorption was assumed in the 

residential exposure cancer assessment, further refinement to the percent of pyraflufen-ethyl 

absorbed via the skin could be incorporated into future assessments. 
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1 LOC includes standard inter- (10X) and intra- (10X) species uncertainty factors totaling 100. 

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

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Source of residential exposure 

values used in the aggregate assessment (Tables 6.4.1 and 6.4.2). Exposure estimate for adults includes handler 

exposures from treating turf with pyraflufen-ethyl (Table 6.4.1). Exposure estimate for Children 1-2 years includes 

post-application exposure to treated turf. 

4 Total Exposure = (Avg Food & Water Exposure + Residential Exposure)

5 Residential Exposure)], NOAEL = 20 mg/kg/day

7.3 Chronic Aggregate Risk

Chronic exposure from the residential pathway is not anticipated based on the current pyraflufenethyl 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). The dietary 

exposure is estimated at 0.000053 mg/kg/day for the general U.S. population (<1% of the cPAD) 

and 0.00020 mg/kg/day (<1% of the cPAD) for children 1-2 years old, the population subgroup 

with the highest estimated chronic dietary exposure to pyraflufen-ethyl. See Section 5.4.4 for 

details.

7.4 Cancer Aggregate Risk

The aggregate cancer risk assessment for the general U.S. population considers exposure 

estimates from dietary consumption of pyraflufen-ethyl in food and drinking water, and exposure 

through residential uses of pyraflufen-ethyl. Exposures from residential uses are based on the 

lifetime average daily dose and assume an exposure period of 2 days per year and 35 years of 

exposure over a 78 year lifetime. Average food and water exposure to pyraflufen-ethyl was used 

in the aggregate assessment. Estimated cancer risk for the general U.S. population includes 

infants and children; therefore, a children’s cancer risk estimate was not reported separately. 

For a description of the residential exposure scenarios considered in the aggregate assessment, 

see Section 6.4. The aggregate cancer risk estimate for pyraflufen-ethyl is 2.6×10

-6

. Therefore, 

the 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. This is a conservative estimate of 

pyraflufen-ethyl exposure based on the inputs to the dietary and residential exposure 

assessments. Further refinement using additional %CT estimates or more refined EDWCs could 

be incorporated into future assessments. Additionally, 100% dermal absorption was assumed in 

the residential exposure cancer assessment, further refinement to the percent of pyraflufen-ethyl 

absorbed via the skin could be incorporated into future assessments. 

Table 7.2.1, Short-Term and/or Intermediate Term Aggregate Risk Calculations.

Population

Short- or Intermediate-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult 20 100 1 0.000053 0.000015 0.000068 290,000

Child 20 100 1 0.0020 0.000073 0.0021 9,600
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Table 7.5. Aggregate Cancer Risk Estimates.

Population Cancer Slope 

Factor (Q1*)

Food and Water 

Exposure 

(mg/kg/day)1

Residential 

Exposure (LADD 

-mg/kg/day2

Aggregate 

Cancer Risk 

(food, water, 

residential)

US Population 0.0332 0.000052 2.5×10

-5

2.6×10

-6

1

Food and water exposure may different than the chronic exposure value, since EFED calculates the water exposure 

differently.

2 Residential exposure values used in aggregate assessment are shown in Table 6.4.2.

3 Aggregate Cancer Risk = (Q1*, 0.0332)* (Food & Water Exposure + LADD).

8.0 Cumulative Exposure/Risk Characterization

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

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to 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 has not assumed that pyraflufen-ethyl has a common mechanism of toxicity with 

other substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

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

9.0 Occupational Exposure/Risk Characterization

The proposed uses of pyraflufen-ethyl are for the control of broadleaf weeds and for sucker 

management in hops, and for the preplant and postemergence control of broadleaf weeds in 

peanuts. Occupational exposure to hops was evaluated previously (K. Rury, D378642, 

12/14/2010); however, the previous petition for pyraflufen-ethyl use on hops was not granted 

because detailed information on the residue chemistry field trials was not included in the 

petition. Nichino has re-petitioned the Agency for pyraflufen-ethyl use on hops as part of the 

current petition. Since exposure inputs and standard body weights have changed since the 

previous hops assessment, HED has reevaluated occupational exposure from pyraflufen-ethyl 

use on hops. 

9.1 Short-/Intermediate-Term/Cancer Handler Risk

Pyraflufen-ethyl is proposed for use as a broadcast application and ground-directed spray to hops 

and peanuts. Application methods, maximum application rates, and use sites are summarized in 

Table 3.3. Based on the proposed use pattern, there is a potential for short-term occupational 

exposure to pyraflufen-ethyl during handling (mixing, loading, and applying) and postapplication activities. Based on the registered and proposed uses, short- and intermediate-term

occupational handler exposures are expected. Pyraflufen-ethyl is registered and proposed for use 

on a number of crops for multiple applications, although the retreatment intervals range from 30 

days to 40 days for most uses. Additionally, since the same endpoint and point of departure were 

selected for short- and intermediate-term durations, short-term exposure and risk estimates are 
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

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considered to be protective of intermediate-term exposure and risk. The proposed labels require 

occupational handlers to wear the following personal protective equipment (PPE): long-sleeved 

shirts, long pants, chemical resistant gloves, and protective eyewear. Handlers of ET 

Herbicide/Defoliant (EPA Reg. No. 71711-7) must also wear chemical resistant headgear for 

overhead exposures. The 12 hour restricted entry interval (REI) listed on the labels is 

appropriate. 

HED’s LOC for the MOE is defined by the uncertainty factors that are applied to the assessment. 

HED applies a 10X factor to account for variability among species and a 10X factor to account 

for variability within species. The total uncertainty factor that has been applied to the non-cancer 

assessment of pyraflufen-ethyl is 100X for occupational exposure. Occupational exposure and 

risk resulting in MOEs greater than or equal to 100 will not be of concern to HED. 

Summaries of the short-term non-cancer risks and cancer risks for occupational handlers 

applying pyraflufen-ethyl to peanuts and hops are summarized in Tables 9.1, 9.2, and 9.3. No 

dermal hazard was identified for pyraflufen-ethyl; therefore, only a quantitative non-cancer 

inhalation exposure assessment was performed. The results of the short-term inhalation 

occupational handler exposure and risk assessment indicate that the MOEs are not of concern to 

HED with baseline attire (no respirator); the inhalation MOEs for all handler scenarios for 

pyraflufen-ethyl application to hops and peanuts ranged from 5,400,000 to 24,000,000. The 

cancer (dermal and inhalation) exposure risk estimates for commercial pesticide handlers ranged 

from 4.4×10

-7

to 1.9×10

-5 with baseline attire, and from 3.3×10-7

to 3.3×10

-6 with the personal 

protective equipment (PPE; long-sleeved shirt, long pants, chemical resistant gloves) required by 

the labels (Table 9.2 and 9.3 respectively). The cancer (dermal and inhalation) exposure risk 

estimates for private pesticide handlers ranged from 1.5×10

-7 to 6.5×10-6 with baseline PPE, and 

from 1.1×10

-7

to 1.1×10

-6 with the PPE required on the pyraflufen-ethyl labels (Table 9.2 and 9.3 

respectively). 
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Table 9.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Pyraflufen-ethyl. All estimates are at baseline 

 mitigation (no respirator). 

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure (μg/lb ai)1 Maximum

Application Rate2

Area Treated 

or Amount 

Handled 

Daily3

Inhalation

Baseline or EC for 

Aerial Application

Dose 

(mg/kg/day)4 MOE5

Mixer/Loader

M/L for Aerial Application Peanuts 0.219 0.0033 lb ai/A 350 acres 0.0000037 5,400,000

M/L for Groundboom 

Application

Peanuts 0.219 0.0033 lb ai/A 80 acres 0.00000084 24,000,000

Hops 0.219 0.0053 lb ai/A 80 acres 0.00000014 15,000,000

Applicator

Aerial Application Peanuts 0.068 0.0033 lb ai/A 350 0.0000012 18,000,000

Groundboom Application

Peanuts 0.34 0.0033 lb ai/A 80 0.0000013 15,000,000

Hops 0.34 0.0053 lb ai/A 80 0.0000021 9,600,000

Flagger

Flagging for Aerial Application Peanuts 0.35 0.0033 lb ai/A 350 0.0000059 3,400,000

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); includes data from PHED/ORETF/AHETF and MRID 45773201 (level of mitigation: Baseline, 

PPE, Eng. Controls).

2 Based on registered or proposed labels (Reg. Nos. #71711-7 and 71711-25).

3 Exposure Science Advisory Council Policy #9.1.

4

Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled Daily (A or gal/day) /BW (kg).

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

Table 9.2. Occupational Handler Cancer Exposure and Risk Estimates for Pyraflufen-ethyl. All estimates are at baseline mitigation (longsleeves, no gloves or respirator). 

Crop or Target Exposure 

Scenario

Total LADDc Cancer

Private Handler Commercial Handler Private Handler Commercial Handler

LADD3

(mg/kg/day) LADD (mg/kg/day)3 Mitigation 

Level

Risk 

Estimate4

Mitigation 

Level

Risk 

Estimate4

Mixing/Loading

Peanuts

Mixing/Loading 

for Aerial 

Application 

0.00019 0.00058 Baseline 6.5×10

-6 Baseline 1.9×10-5

Hops Mixing/Loading 

for Groundboom 0.000072 0.00021 Baseline 2.4×10

-6 Baseline 7.1×10-6
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Table 9.2. Occupational Handler Cancer Exposure and Risk Estimates for Pyraflufen-ethyl. All estimates are at baseline mitigation (longsleeves, no gloves or respirator). 

Crop or Target Exposure 

Scenario

Total LADDc Cancer

Private Handler Commercial Handler Private Handler Commercial Handler

LADD3

(mg/kg/day) LADD (mg/kg/day)3 Mitigation 

Level

Risk 

Estimate4

Mitigation 

Level

Risk 

Estimate4

Peanuts

Application

0.000044 0.000013 Baseline 1.5×10

-7 Baseline 4.4×10-6

Applying

Peanuts Applying 

Aerially 0.0000045 0.00013

Engineering 

Control 1.5×10

-7 Engineering 

Control 4.4×10

-7

Hops Groundboom 

Application

0.000026 0.000077 Baseline 8.5×10

-7 Baseline 2.5×10-6

Peanuts 0.000016 0.000048 Baseline 5.3×10

-7 Baseline 1.6×10-6

Flagging

Peanuts

Flagging for 

Aerial 

Application

0.000010 0.000030 Baseline 3.3×10

-7 Baseline 1.0×10-6

1 Dermal LADD = Dermal dose * Days per year of exposure x Years per lifetime of exposure (35 years) / (365 days/year x Lifetime expectancy ).

2

Inhalation LADD = Inhalation Dose * Days per year of exposure x Years per lifetime of exposure (35 years) / (365 days/year x Lifetime expectancy ).

3 Total LADD = total absorbed dose [Dermal dose + Inhalation Dose] * Days per year of exposure x Years per lifetime of exposure (35 years) / (365 days/year x Lifetime expectancy ).

4 Cancer risk estimates = LADD * Q1*

, where Q1

*

= 3.32×10

-2

(mg/kg/day)-1.

Table 9.3. Occupational Handler Cancer Exposure and Risk Estimates for Pyraflufen-ethyl. All estimates are at label-specified mitigation 

(long-sleeves, gloves). 

Crop or Target Exposure 

Scenario

Total LADDc Cancer

Private Handler Commercial Handler Private Handler Commercial Handler

LADD3

(mg/kg/day) LADD (mg/kg/day)3 Mitigation 

Level

Risk 

Estimate4

Mitigation 

Level

Risk 

Estimate4

Mixing/Loading

Peanuts

Mixing/Loading 

for Aerial 

Application 

0.000033 0.00010

Single Layer, 

Gloves 1.1×10

-6 Single Layer, 

Gloves 3.3×10

-6

Hops Mixing/Loading 

for Groundboom 

Application

0.000012 0.000037 Single Layer, 

Gloves 4.1×10

-7 Single Layer, 

Gloves 1.2×10

-6

Peanuts 0.0000076 0.000023

Single Layer, 

Gloves 2.5×10

-7 Single Layer, 

Gloves 7.6×10

-7

Applying
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Table 9.3. Occupational Handler Cancer Exposure and Risk Estimates for Pyraflufen-ethyl. All estimates are at label-specified mitigation 

(long-sleeves, gloves). 

Crop or Target Exposure 

Scenario

Total LADDc Cancer

Private Handler Commercial Handler Private Handler Commercial Handler

LADD3

(mg/kg/day) LADD (mg/kg/day)3 Mitigation 

Level

Risk 

Estimate4

Mitigation 

Level

Risk 

Estimate4

Peanuts Applying 

Aerially 0.0000045 0.0000045 Engineering Control 1.5×10

-7 Engineering 

Control 4.5×10

-7

Hops Groundboom 

Application 0.0000053 0.000016

Single Layer, 

Gloves 1.8×10

-7 Single Layer, 

Gloves 5.3×10

-7

Peanuts Groundboom 

Application 0.0000033 0.0000099 Single Layer, Gloves 1.1×10

-7 Single Layer, 

Gloves 3.3×10

-7

Flagging

Peanuts

Flagging for 

Aerial 

Application

0.000011 0.000033

Single Layer, 

Gloves 3.6×10

-7 Single Layer, 

Gloves 1.1×10

-6

1 Dermal LADD = Dermal dose * Days per year of exposure x Years per lifetime of exposure (35 years)/ (365 days/year x Lifetime expectancy ). Dermal Dose = [Unit Exposure (μg ai/lb ai)*(0.001 

mg/μg)*Application Rate (lb ai/A or gal) * Area treated per day * 100% Absorption] / Body Weight (80 kg)

2

Inhalation LADD = Inhalation Dose * Days per year of exposure x Years per lifetime of exposure (35 years)/ (365 days/year x Lifetime expectancy ). Inhalation Dose = [Unit Exposure (μg ai/lb 

ai)*(0.001 mg/μg)*Application Rate (lb ai/A or gal) * Area treated per day * 100% Absorption] / Body Weight (80 kg)

3 Total LADD = total absorbed dose [Dermal dose + Inhalation Dose] * Days per year of exposure x Years per lifetime of exposure (35 years) / (365 days/year x Lifetime expectancy ).

4 Cancer risk estimates = LADD * Q1*

, where Q1

*

= 3.32×10

-2

(mg/kg/day)-1.
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9.2 Short-Term/Cancer Post-Application Risk

9.2.1 Dermal Post-Application Risk

Based on the pyraflufen-ethyl use pattern, minimal exposure is expected to occur following 

application to hops and peanuts. Pyraflufen-ethyl is is used to manage suckers on hops; but this 

application is meant to target the lower 18 inches of the plant, minimizing the potential for postapplication exposure. Additionally, the use directions specify that users should not allow spray 

to drift onto desirable foliage or vines of the hop plants because pyraflufen-ethyl will damage the 

plant. Therefore, a post-application risk assessment on hops is not needed. Although pyraflufenethyl is used as a pre-emergent and defoliant herbicide, it may be applied as a broadcast aerial 

and ground spray to post-emergent peanuts. Therefore, occupational post-application cancer 

risks were assessed for scouting in peanut fields and hand-setting irrigation for peanuts. Noncancer post-application risks were not assessed because adverse effects were not seen in the 28-

day dermal toxicity study up to the Limit Dose (1,000 mg/kg/day). The occupational cancer risk 

estimates for setting irrigation by hand to peanuts on the day of application was 2.2×10-6and the 

occupational cancer risk estimate for scouting peanuts on the day of application was 2.4×10-7. 

These estimates are considered a conservative, screening level assessment because the 

assessment assumed 100% dermal absorption; the maximum application rate versus average 

application rates that are normally assumed for cancer assessment; 30 days of exposure per year 

from scouting and hand-set irrigation to peanuts; and contact with full foliage peanut plants, 

while pyraflufen-ethyl is mostly an early season herbicide. 

Table 6.2.2.3. Occupational Cancer Post-Application Exposures and Risk Estimates for [chemical].

Crop 

Grouping/Crop Activity Days After Treatment

Dermal LADD

(mg/kg/day)

1

Cancer Risk

Estimate2

Peanut Hand-set Irrigation 0 6.5x10-52.2x10-6

Peanut Scouting 0 7.2x10-62.4x10-7

1 Dermal LADD = Dermal dose * Day per year of exposure x Years per lifetime of exposure / (365 days/year x 

Lifetime expectancy).

2 Cancer risk estimates = LADD * Q1*

, where Q1

*

= 0.0332 (mg/kg/day)-1

9.2.2 Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for pyraflufen-ethyl at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category IV), low vapor pressure (4.3×10-9 mm Hg at 20 oC), 

and the low proposed use rate (0.0053 lb ai/A). However, there are multiple potential sources of 

post-application inhalation exposure to individuals performing post-application activities in 

previously treated fields. These potential sources include volatilization of pesticides and 

resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and 

received the SAP’s final report on March 2, 2010 
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

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(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 ARTF 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.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

10.0 References

M. Barrett, 03/23/2011, DP#377360. Drinking Water Assessment for the Registration of new 

uses of pyraflufen-ethyl on tree nuts, stone fruit, pome fruit, hops, grapes, olives, and

pomegranates. 

M. Barrett, 09/21/2012, DP#377360. Drinking water assessment for the registration of new uses 

of pyraflufen-ethyl on hops and peanuts. 

K. Rury, 03/01/2011, DP#377359. 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. 

K. Rury, 09/04/2012, DP#397423. Pyraflufen-ethyl. Occupational and Residential Exposure 

Assessment for a Proposed Use on Hops and Peanuts and a Reevaluation of Existing Residential 

Uses with the Updated Residential SOPs.

K. Rury, 09/09, 2012, DP#397422. Pyraflufen-ethyl: Chronic and Cancer Aggregate Dietary 

(Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration 

Action on Hops and Peanuts. 

A. Acierto, 09/12/2012, DP#396779. Petition for Establishment of Tolerances on Hops and 

Peanuts; Multi-Residue Method (MRM) and Independent Laboratory Validation (ILV); 

Unconditional Registrations for Use on Pastures, Rangeland and Post Emergence Application to 

Corn, Soybean and Wheat; and Amended Report for Residues in Bovine Tissues and Milk from 

a 28-day Feeding Study Data, Radiovalidation in Goat Liver and Milk and Storage Stability. 

Summary of Analytical Chemistry and Residue Data.

D. Smegal, 03/02/2012, DP#388000. Pyraflufen-ethyl: Summary of Hazard and Science 

Policy Council (HASPOC) Meeting of February 16, 2012: Recommendations on a waiver 

request for a 28-day inhalation study.
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

Page 43 of 51

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food uses of pyraflufen-ethyl are in Table 1. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents ..................................

870.3150 90-Day Oral Toxicity in Nonrodents.............................

870.3200 21/28-Day Dermal Toxicity...........................................

870.3250 90-Day Dermal Toxicity................................................

870.3465 90-Day Inhalation Toxicity ...........................................

yes

yes

yes

no

yes

yes

yes

yes

--

waived4

870.3700a Prenatal Developmental Toxicity (rodent).....................

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

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

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent) ..............................................

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

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

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

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

yes

no

yes

yes

yes

yes1

yes2

yes1

yes

yes

870.5100 Mutagenicity—Bacterial Reverse Mutation Test ..........

870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test ..

870.5375 Mutagenicity—Structural Chromosomal Aberrations..

870.5395 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

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

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

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

yes

yes

no

yes

yes

--

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

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

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

yes

no3

yes

yes

--

yes

1 The chronic (rodent) and carcinogencity (rat) data requirements are satisfied by the Combined Chronic Toxicity / 

Carcinogenicity study (870.4300).

2

 A chronic study in the dog is available, although it is no longer required.

3 A dermal penetration study is not required because a) a dermal endpoint was not identified (no effects in the 21-

day dermal study up to the Limit Dose) and b) there were no effects of concern observed in studies such as the 

developmental and reproduction oral studies that reveal adverse effects (such as effects on the offspring) that the 

21-day dermal study is not designed to detect or measure.

4 The requirement for a subchronic inhalation toxicity study has been waived (TXR#00564072)
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

Page 44 of 51

A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity of Pyraflufen-ethyl

Guideline

No.

Study Type MRID # Results Toxicity Category

81-1 Acute Oral 45327615 LD50 > 5000 mg/kg IV

81-2 Acute Dermal 45327613 LD50 > 2000 mg/kg III

81-3 Acute Inhalation 45282821 LC50 > 5.03 mg/L IV

81-4 Primary Eye Irritation 45327614 moderate irritation III

81-5 Primary Skin Irritation 45282823 no irritation IV

81-6 Dermal Sensitization 45282824 non-sensitizing N/A

Table A.2.2. Non-acute Toxicity Profile for Pyraflufen-Ethyl

Guideline 

Number and 

Study Type

MRID (Year)

Dose Levels Results

870.3100

13-Week 

Oral Feeding Rat 

45282903 (1994)

0, 200, 1000, 5000, 15000 ppm 0, 

M;0, 17.8, 85.6,456, 1489 mg/kg/day 

F: 0, 19.4, 95.4, 499, 1503 

mg/kg/day 

Acceptable/guideline

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 

Oral Capsule 

Dog 

45282905 (1996)

0, 40, 200 or 1000 mg/kg/day

Acceptable/guideline

NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day. No effects observed at Limit Dose.

870.3200

28-Day Dermal 

Rat

45283001 (2000)

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

Acceptable/guideline

NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day. No effects observed at Limit Dose.

870.3700a

Developmental 

Toxicity Rats

45282917 (1995)

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

Acceptable/guideline

Maternal NOAEL = 1000 mg/kg/day.

Maternal LOAEL > 1000 mg/kg/day. No effects observed at 

Limit Dose.

Developmental NOAEL = 1000 mg/kg/day.

Developmental LOAEL > 1000 mg/kg/day. No effects observed 

at Limit Dose.
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

Page 45 of 51

Guideline 

Number and 

Study Type

MRID (Year)

Dose Levels Results

870.3700b

Developmental 

Toxicity Rabbit

45282918 (1996)

0, 20, 60 or 150mg/kg/day

Acceptable/guideline

Maternal NOAEL = 20 mg/kg/day. 

Maternal LOAEL= 60 mg/kg/day based on mortality.

Developmental NOAEL = 60 mg/kg/day.

Developmental LOAEL = 150 mg/kg/day based on increased 

incidence of abortion.

870.3800

2-Generation 

Reproduction Rat

45282922 (1996)

0, 100, 1000 or 10, 000 ppm 

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])

Acceptable/guideline

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 body wt and body wt 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 body weight and body weight gains 

of the F1 and F2 pups.

870.4300

2-yr Chronic/

Carcino-genicity 

Rat

45282911 (1996)

0, 80, 400, 2000 or 10,000 ppm 

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)

Acceptable/guideline

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 body weight and body weight gain in males 

and microcytic anemia, liver lesions and kidney toxicity (both 

sexes); possible increase pheochromocytomas in females

870.4200b

78-Week 

Carcino-genicity 

Mouse

45282913 (1996)

0, 200, 1000 or 5000 ppm 

0, 20.99, 109.7 and 546.8 mg/kg/day 

(M)

0, 19.58, 98.3, and 523.7 mg/kg/day 

(F)

Acceptable/guideline

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/ hemangioasarcomas.

870.4100b

52-Week Oral 

Feeding Dogs

45282906 (1996)

0, 40, 200 or 1000 mg/kg/day

Acceptable/guideline

NOAEL = 1000 mg/kg/day. 

LOAEL > 1000 mg/kg/day; no effects observed.
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

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Guideline 

Number and 

Study Type

MRID (Year)

Dose Levels Results

870.5100

Bacterial Reverse 

Gene Mutation 

Assay

45282924 (1994), 

0, 156.3, 312.5, 625, 1250, 2500, 

5000 μg/plate in the presence and 

absence of mammalian metabolic 

activation (S9-mix) in two 

independent assays.

Acceptable/guideline

There was no evidence of induced mutant colonies over 

background.

870.5300

In Vitro

Mammalian Cell 

Gene Mutation 

Assay (mouse 

lymphoma)

45327623 (1994)

0, 10, 20, 30, 40 or 50 μg/mL for 4 

hours in the absence of mammalian 

metabolic activation (S9-mix). 

0, 150, 200, 250, 300 or 350 μg/mL 

for 4 hours with S9-mix. Two 

independent assays were conducted.

Acceptable/guideline

There was no evidence of induced mutant colonies over 

background up to cytotoxic concentrations (50 μg/ml -S9; 350

μg/ml +S9).

870.5300

In Vitro

Mammalian Cell 

Gene Mutation 

Assay (mouse 

lymphoma)

45282928 (1984),

Assay 1

0, 10, 20, 40, 60 or 80 μg/mL for 4 

hours in the absence of mammalian 

metabolic activation (S9-mix).

0, 20, 40, 80, 120 or 160 μg/mL for 4 

hours with S9-mix. 

Assay 2

0, 20, 40, 60, 80 or 100 μg/mL 

without S9-mix

0, 40, 80, 120, 160 or 200 μg/mL 

with S9-mix 

Acceptable/guideline

There was no increase in the number of mutant colonies over 

background in the absence of S9-mix but a non-reproducible doserelated increase in the number of mutant colonies was seen in the 

presence of S9-mix.

870.5375

In Vitro

Mammalian 

Chromosome 

Aberration

45282927 (1994)

0, 650, 1300 or 2600 μg/mL for 19 

or 43 hours without metabolic 

activation (S9-mix) or for three 

hours with S9-mix. 

A second assay was conducted at the 

same three concentrations but using 

a 19 hour sampling time only.

Acceptable/guideline

There was no evidence of chromosomal aberration induction over 

background.
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

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Guideline 

Number and 

Study Type

MRID (Year)

Dose Levels Results

870.5500

Bacterial DNA 

Damage and 

Repair

45282929 (1994)

0, 343.75, 687.5, 1375, 2750 or 5500 

μg/disk in the presence and absence 

of metabolic activation (S9-mix). 

Acceptable/guideline

There was no evidence of greater growth inhibition or cell killing 

in repair-defective strains compared to repair competent strains up 

to the limit of test material solubility.

870.5550

in vivo/in vitro

unscheduled 

DNA Synthesis 

(UDS) 

45282930 (1998)

600 and 2000 mg/kg 

Acceptable/guideline

The mean net nuclear grain count was below zero for both doses at 

both treatment times indicating no induction of UDS as tested in 

this study.

870.5395

mouse 

micronucleus 

assay

45282931(1994)

a single dose at 0, 1250, 2500 or 

5000 mg/kg with sacrifice at 24 

hours; 

a single dose of 5000 mg/kg with 

sacrifice at 48 and 72 hours; 

two doses of 2500 or 5000 mg/kg 

separated by 24 hours with sacrifice 

24 hours after the second dose

Acceptable/guideline

There was no statistically significant increase in the frequency of 

micronucleated polychromatic erythrocytes in bone marrow after 

any dose or treatment time.

870.6300a

Acute 

Neurotoxicity Rat

48802401 (2012)

0, 125, 500 or 2000, mg/kg

Acceptable/guideline

NOAEL = 500 mg/kg

LOAEL = 2000 mg/kg based on transiently decreased body weight 

gain in females (↓26%, ns). No neurotoxicity was observed.

870.6300b

Subchronic

Neurotoxicity Rat

48802402 (2012)

0, 1000, 2800, 8000 ppm

(M) 0, 61, 174, 502 mg/kg/day

(F) 0, 80, 222, 625 mg/kg/day

Acceptable/guideline

NOAEL = 61 mg/kg/day (M), 222 mg/kg/day (F)

LOAEL = 174 mg/kg/day (M), 625 mg/kg/day (F) based on 

transient decrease in body weight gain and changes in hematology 

parameters. No neurotoxicity was observed.
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

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Guideline 

Number and 

Study Type

MRID (Year)

Dose Levels Results

870.7485

Metabolism and 

Pharmacokinetics Rat

45282932, 45282933, 45282934, 

45282935 (1996)

5.0, 500 mg/kg single oral dose

5 mg/kg/day 14-day repeated oral 

dose

Acceptable/guideline

ET-751(pyraflufen-ethyl) was readily absorbed and excreted within 96 hours 

following a single or repeated oral dose of 5 mg/kg (plasma t1/2 of 3-3.5 hrs). 

However, at a dose of 500 mg/kg, absorption was saturated as indicated by Cmax

values which did not reflect the 100-fold dose differential (2.7-2.8 μg eq/g for the 

low-dose group and 100-107 μg eq-hr/g for the high-dose group). Following single 

or multiple oral low doses (5 mg/kg) of ET-751, urinary excretion accounted for 27-

33% of the administered radioactivity suggesting that a multiple exposure regimen 

did not affect the absorption/excretion processes. Urinary excretion was reduced to 

only 5-7% following a single 500 mg/kg dose. Excretion via the feces accounted for 

the remainder of the administered radioactivity in all treatment groups. Analysis of 

biliary excretion following a single 5 mg/kg dose showed that 36% of the 

administered dose appeared in the bile. Based upon the excretion data, total 

bioavailability of a low dose was approximately 56%. Biliary excretion data were 

not available for a high-dose group which prevented a definitive assessment of 

bioavailability. Excretory patterns did not exhibit gender-related variability. 

However, plasma and blood clearance was more rapid in females than in males as 

shown by plasma/blood radioactivity time-course and the greater AUC values for 

males (32.3 vs 18.4 g eq-hr/g for the low-dose group and 2738 vs 1401 μg eq-hr/g 

for the high-dose group). Radioactivity concentrations indicated tissue 

concentrations at or near detection limits (generally <0.01 μg eq/g and never 

exceeding 0.02 μg eq/g) at 96 hrs postdose for any tissues. Therefore, neither ET751 nor its metabolites appear to undergo significant sequestration. Tissue burden 

data following compound administration did not suggest a specific target beyond 

those tissues, namely liver and kidney, which are associated with absorption and 

elimination of orally administered xenobiotics.

Both urinary and fecal metabolites were quantified by HPLC and most were 

identified using HPLC and TLC in conjunction with known standards. The 

metabolites identified (primarily hydrolysis and subsequent demethylation products) 

were consistent with Phase I processes. The major metabolic pathway appears to be 

a sequential hydrolysis and demethylation of the parent compound to metabolites E1 and E-9 both of which are quantitatively prominent components detected in the 

urine and feces from all treatment groups. Extraction efficiencies appeared to be 

excellent and most components in all of the matrices examined (urine, feces, 

plasma, and bile) were adequately quantified and characterized. The available data, 

based upon studies using both the pyrazole-5 and the uniformly labeled phenyl ring, 

affirmed the metabolism pathway proposed by the investigators.

870.7800

Immuno-toxicity 

Rat

48577901 (2011)

0, 750, 3000 or 12,000 ppm 

0, 59.4, 236.2, 946.2 mg/kg/day (M)

0, 67.1, 277.5, 1114.0 mg/kg /day (F)

Acceptable/guideline

Systemic Toxicity 

NOAEL= 3000 ppm (236.2 mg/kg/day) (M); 

 = 12,000 ppm (1114.0 mg/kg /day) (F)

LOAEL = 12,000 ppm (946.2 mg/kg/day) (M) based on decreases 

in body weight, body weight gain, food consumption and feed 

efficiency; not established in (F).

Immunotoxicity 

NOAEL= 3000 ppm (236.2 mg/kg/day) (M); 

 = 12,000 ppm (1114.0 mg/kg /day) (F)

LOAEL = 12,000 ppm (946.2 mg/kg/day) (M) based on decreases 

of anti-SRBC AFC response; not established in (F).

Appendix B. Physicochemical Properties of Pyraflufen-ethyl.
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

Page 49 of 51

TABLE B. Physicochemical Properties of Technical Grade of Pyraflufen-ethyl.

Parameter Value Reference

Melting point/range 126.4-127.2 oC DP#299196, 4/7/04, H. Johnson

pH 4.27 at 25 oC

Relative Density 1.565 at 24 oC

Water solubility (mg/L at 20oC) 0.082 at pH 7

Solvent solubility (g/L at 20oC) acetone 167-182

dichloromethane 100-111

ethyl acetate 105-111

n-heptane 0.234

methanol 7.39

p-xylene 41.7-43.5

European Commission Review 

Report for the Active Substance 

Pyraflufen-ethyl (7/2/02)

Vapor pressure 4.3 x 10-9at 20 oC

1.6 x 10-8at 25 oC

DP#299196, 4/7/04, H. Johnson

Dissociation constant, pKa Not applicable

Octanol/water partition 

coefficient, Log(KOW)

3.49 at ambient temperature, pH 7

UV/visible absorption spectrum γmax = 203 nm: ε = 28700 L/mol/cm

γmax = 243 nm: ε = 12800 L/mol/cm

γmax = 291 nm: ε = 5900 L/mol/cm

No further maxima between 291 and 700 nm

European Commission Review 

Report for the Active Substance 

Pyraflufen-ethyl (7/2/02)
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

Page 50 of 51

Appendix C. Review of Human Research

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. 

Electronic Database. Task Force Members: Health Canada, U.S. EPA, and the National 

Agricultural Chemicals Associations, released February 1995. 

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit 

Exposure Surrogate Reference Table. U.S. EPA. Released June 21, 2011. 

Data from the Outdoor Residential Exposure Task Force (ORETF). 

HED Residential Standard Operating Procedures (2012). 

MRID 45773201. 
Pyraflufen-ethyl Human Health Risk Assessment DP No. 396779

Page 51 of 51

Appendix D. International Residue Limits Status Sheet

Pyraflufen-ethyl (PC Code 030090; 09/18/2012)

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-chloro5-(4-chloro-5-difluoromethoxy-1-

methyl-1H-pyrazol-3-yl)-4-

fluorophenoxyacetate, and its acid 

metabolite, E-1, 2-[2-chloro-5-(4-

chloro-5-(difluoromethoxy)-1-methyl1H-pyrazol-3-yl)-4-

fluorophenoxy]acetic acid, expressed in 

terms of the parent. 

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

Peanut 0.01

Peanut, hay 0.07

Cattle, meat by products 0.03

Goat, meat by products 0.03

Horse, meat by products 0.03

Sheep, meat by products 0.03

Milk 0.03

Cattle, meat 0.03

Goat, meat 0.03

Horse, meat 0.03

Sheep, meat 0.03

Cattle, fat 0.03

Goat, fat 0.03

Horse, fat 0.03

Sheep, fat 0.03

Completed: M. Negussie; 09/19/2012

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

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

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.