### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 3 of 51 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

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 4 of 51 1.0 Executive Summary

Introduction Pyraflufen

- ethyl is an herbicide that is registered for use as a defoliant, a single preplant or post

emergence burndown, and as a post

- emergence use. The proposed uses of pyraflufen

- ethyl are for the control of broadleaf w eeds 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 time

limited 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

- 1 H

- 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 f ormulations 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 bro adcast application to hops at and m ay 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 ret reatment 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 py raflufen

- 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. A dverse effects were not noted in the dog following oral exposure n or 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
stu dies, n or following pre

- and post

- natal exposure to rats in the mult i

- generation reproduction

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 5 of 51 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 (Q 1 

### * of 3.32 x 10 - 2 

### (mg/kg/day) - 1 

### ) based on combined hepatocellul ar 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 inhalatio n (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 r obust 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 a dverse 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 asses sments. 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 resi dual 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 . H owever, additional residue chemistry data are needed to grant reg istration of pyraflufen

- ethyl on hops. The assessments are based on reliable data and will not underestimate exposure or risk. The proposed use of p yraflufen

- 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 Exp osure 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 prop osed 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

- ethy l 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. populati on and all population subgroups, including children 1

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

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 6 of 51 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) est imate 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 ×1 0 - 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 exposure s and risks from use on turf w ere reassessed using the updated 2012 HED Residential Standard Operating Procedures 1 

### (SOPs). A dermal endpoint was not sele cted 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 m argins of e xposure ( MOEs ) ranged from 1,300,000 to 70,000,000. All residential handler cancer risk estimates ranged from 2.0 ×1 0 - 8 

### to 2.1 ×1 0 - 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 ×1 0 - 8 

### to 7.3 ×1 0 - 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 effec t 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 toxici ty 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 short

term exposure to pyraflufen

- ethyl via dietary (which is considered background exposu re) 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

, 6 00 and is not of concern to HED. Chronic exposure from the residential pathway is not anticipated based on the current pyraflufen

ethyl use pattern. The refore, the chronic aggregate risk is equivalent to the chronic dietary (food and drinking water) risk, w hich 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. T he aggregate cancer risk estimate for pyraflufen

- ethyl is 2.6 ×1 0 - 6



### .

Occupational Exposure

1 http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 7 of 51 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 prote ctive eyewear. Handlers of ET Herbicide/Defoliant (EPA Reg

. N o. 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 L imit D ose (1,000 mg/kg/day). The results of the occupational handler exposure and risk assessment indicate inhalation short

- and intermediate

term MOEs are >100 with baseline attire (no respirator)

, and therefore, are not of con cern 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 ×1 0 - 7 

### to 1.9 ×1 0 - 5 

### with baseline attire, and from 3.3 ×1 0 - 7 

### to 3.3 ×1 0 - 6 

### with PPE required by the labels. The combined (dermal and inhalation) cancer exposure risk estimates for private pesticide handlers ranged from 1.5 ×1 0 - 7 

### to 6.5 ×1 0 - 6 

### with baseline PPE, and from 1.1 ×1 0 - 7 

### to 1.1 ×1 0 - 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 pyraflufen

ethyl 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, o ccupational post

- application cancer risks were assessed for scouting in peanut fields and hand

- setting irrigation for peanuts. Non

cancer post

- application risks were not assessed because adverse eff ects 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 - 6 

### and the occupational cancer risk estimat e 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 p lace, 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

- exposure

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

- app

- exposure

- data.html

.

Environmental Justice Considerations Potential a reas of environmental justice concerns, to the extent possible, were considered in this

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 8 of 51 human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Po pulations," ( 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

- eth yl 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 tole rance 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 R epository

.
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 a t 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

- 1 H

- pyrazol

- 3

- yl]

- 4

- fluorophenoxy]acetate.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 9 of 51 In support of requested use on hops , t he 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 ar e 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 peanut s

. 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/g al 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 Con siderations

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 dete rmine Metabolite E

- 1 as its methyl ester ( Metabolite E

- 15), and monitor s two ion transitions each for pyraflufen

- ethyl and the E

- 15 analyte. The methods also contain appendices that provide parameters for other detection sc hemes such as GC/electron captur e detection (ECD), GC/nitrogen phosphorus detection (NPD), and GC/MS/MS. The methods have been determined to be acceptable for tolerance enforcement (D P# 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 (I LV ) 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 Metabo lite E

- 1 in crops. Minor modification s 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.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 10 of 51 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 followi ng 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 re

assessed 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/ 1 5/12) 0.03 Goat, meat byproducts 0.02 (expires 10/ 1 5/12) 0.03 Horse, meat byproducts 0.02 (expires 10/ 1 5/12) 0.03 Sheep, meat byproducts 0.02 (expires 10/15/12) 0.03 Milk 0.02 (expires 10/15/12) 0.03 Additional Re quired 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

- 1 H

- 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 peanu t due to several data deficiencies noted above

.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 11 of 51 Time

- limited tolerances we re established for combined residues of pyraflufen

- ethyl and M etabolite E

- 1 in milk and the meat byproducts of cattle, goat, horse, and sheep at 0.02 ppm ( e xpiration/revocation da te 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 t he 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 u nconditional 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 pyraflufen

ethyl on any commodity (see Appendix D ).

3.0 In troduction

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 post

emergence 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 orn amental 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

- emergenc e 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 (E PA Reg. No. 71711

- 25) on hops

. B oth 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

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 12 of 51 Table 3.1. Pyraflufen

- Ethyl and Its Metabolite s Nomenclature

. Chemical structure

Common name Pyraflufen

- E thyl
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

- 1 H

- 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

- c hloro

- 5

- (4

- chloro

- 5

- difluoromethoxy

- 1

- methylpyrazol

- 3

- yl)

- 4

- fluorophenoxy ] acetic acid
CAS name 2

- [2

- c hloro

- 5

- [4

- chloro

- 5

- (difluoromethoxy)

- 1

- methyl

- 1 H

- pyrazol

- 3

- yl]

- 4

- fluorophenoxy] acetic acid CAS registry number 129630

- 17

- 7
Chemical structure

C ompany experimental name Metabolite E

- 9; Pyraflufen

- ethyl livestock metabolite of concern N N Cl

F Cl

H O C H F 2 O C H 2 C O O H N N Cl

F Cl

C H 3 O C H F 2 O C H 2 C O O H N N Cl

F Cl

C H 3 O C H 2 C O O C 2 H 5

O C H F 2

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 13 of 51 Table 3.1. Pyraflufen

- Ethyl and Its Metabolite s 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 K ow 

### ) 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 p roduct, 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 hydroly sis, 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
p yraflufen

- ethyl is considered low (4.3 ×1 0 - 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 Herbicid e/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 ground

directed 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 4 0 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 0.006 5 lb ai/A. Occupational handle rs must wear long

sleeved shirts, long pants, chemical resistant gloves, and protective eyewear. Handlers of ET Herbicide/Defoliant (EPA Reg

. N o. 71711

- 7) must also wear chemical resistant headgear for overhead exposures. The 12 hour REI listed on the la bels is appropriate. N N Cl

F Cl

C H 3 O C H F 2 O C H 2 C O O CH 3

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 14 of 51 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 S C

(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 E C

(EPA Reg. No. 71711

- 7 ) 0.0033 lb ai/A

(broadcast & ground directed) Up to 4 4.0 fl oz /A or 0.006 4 lb ai/A ( all uses ) 7 RTI = 30 days

S C (EPA Reg. No. 71711

- 25) 0.0033 lb ai/A

(broadcast & ground directed) Up to 4 4.8 fl oz/A or 0.00 64 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 use s 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 di rectly 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 f ollowing 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. Execu tive 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 pat terns 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 Healt h 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

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 15 of 51 year, ethni c 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

- Respo nse Assessment

This assessment includes an update d 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 re peated short

- term and chronic oral doses , t he 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. A dverse 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

- nat al 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 hepatocellu lar adenomas, carcinomas, and/or hepatoblastomas in male and female mice. A linear low

- dose extrapolation approach is used to estimate human cancer risk (Q 1 

### * of 3.32 x 10 - 2 

### (mg/kg/day) - 1 

### ) based on combined hepatocellular adenomas, carcinomas and/or hepato blastomas 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. Addition ally, 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)

.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 16 of 51 Developmental effects for b oth 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 the se 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 M etabolites E1 and E9. Other environmental transformation products (E

- 1, E

- 2, and E

- 3), predicted to be present in water, are also considere d of toxicological significance, with toxicity profiles similar to pyraflufen

- ethyl and degrees of toxicity less than o r 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 dose

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

- dose, the highest residues were found in the gastrointestin al ( 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 F actor for Infants and Children (FQPA S afety 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 follo wing considerations:

4.2.1 Completeness o f 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 h as been extr apolated from an oral study.

4.2.2 Evidence of N eurotoxicity

The acute and subchronic neurotoxicity studies showed no evidence of neurotoxicity a fter acute exposure up to 2000 mg/kg and subchronic exposure up to 625 mg/kg/day (females) , and no
neuroto xic 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 o f Sensitivity/Su sceptibility in the Developing o r 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 s tudy and there are no residual uncertainties for pre

- and/or postnatal exposure.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 17 of 51 4.2.4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertainties identif ied in the exposure databases. The die tary food exposure assessments were performed assuming 100% of the crop s were treat ed with pyraflufen

ethyl , tolerance

- level residues for the proposed commodities, a nd residue inputs of 1⁄2 LOQ as refined e stimate s of the currently registered residues in fo od

. EPA made conservati ve (protectiv e) assumptions in the gro und and surface water modeling used to assess exposure to pyraf lufen

- eth yl in drinking water. EPA used similar ly conservative assumptions to assess post

application exposure of adults and child ren 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 treat ed 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 ex pected to underestimate risk. Although some of the residue values used in the dietary exposure assessment were refined, th ese assessments will not underestimate the exposure and risks posed by p yraflufen

- ethyl.

4. 3 Toxicity Endpoint and Point of D eparture Selections

The toxicological doses and e ndpoints 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). T he 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 i nhalation absorption is assumed to be equivalent to oral exposure for non

- cancer and cancer risk
assessment s

. Assuming 100% dermal absorption for cancer risk assessment is an conservative estimate based on low acute dermal toxicity (the acute LD 50 

### > 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 assessmen t, 69 kg was used to estimate exposure

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 18 of 51 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 endpoi nts and PODs for risk assessment are presented in Tables 4.3.1 and 4.3.2.

Table 4. 3

. 1. Summary of Toxicol ogical 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 UF A = 10 x

UF H = 10 x FQPA SF= 1 x 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 Short

Term (1

- 30 days) NOAEL =

20 mg/kg/day UF A = 10 x

UF H = 10 x FQPA SF = 1 x 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 D ermal T oxicity

– Rats N o dermal or systemic toxicity was seen at the Limit Dose (1000 mg/kg/day)

Inhalation Short

- (1

- 30 days) and Intermediate

and Long

Term (1

- 6 months) NOAEL =

20 mg/kg/day UF A = 10 x

UF H = 10 x FQPA SF= 1 x 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

.

Q 1 * = 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). 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.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 19 of 51 Table 4. 3 .2

. Summary of Toxicological Doses and Endpoints for Pyraflufen

- ethyl fo r 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 D ermal T oxicity

– Rats N o dermal or systemic toxicity was seen at the Limit Dose (1000 mg/kg/day)

Inhalation Short

- (1

- 30 days) and Intermediate

and Long

Term (1

- 6 months) NOAEL =

20 mg/kg/day UF A = 10 x

UF H = 10 x FQPA SF= 1 x 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

.

Q 1 * = 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. 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 summa rized in Table 5.1. HED has concluded that the residues of concern in plants includ e 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 a re 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 a erobic aquatic metabolism studies for parent. Metabolite E

- 3 is the major metabolite (>10% TRR) in aerobic soil metabolism resulting from Metabolite E

- 2.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 20 of 51 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 o n 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 t he seven day PHI. In the residue decline trial s , 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 re sidues 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 stabilit y 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 rec ommends 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

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 21 of 51 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 samp les 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 requ ired 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 con ducted 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 tol erance 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 Tria ls with Pyraflufen

- ethyl. Commodity Analyte Total Rate (lb ai/A) PHI (days) Residue Levels 1 (ppm in parent equivalents)

n Sample Min. Sample Max. LAFT 2 HAFT 2 Median Mean Std. Dev.

HOPS: P roposed use = 0.0090 lb ai/A total application rate (p ost

- harvest d ormant and/or i n - s eason application ), 30

- day PHI Hops, cones Pyraflufen

ethyl 0.0142 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 Unite d 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 requir ements. 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. T he submitted data for the EC formulation are not sufficient for translat ation to the SC formulation. Because a 7

- day PHI is proposed, additional bridging data

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 22 of 51 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 form ulation 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 res idues 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 tri als is provided in Table 5.2.2.

T able 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. LAFT 2 HAFT 2 Median Mean Std. Dev.

PEANUT: P roposed use = 0.0064 lb ai/A total application rate (p replant burndown, p ostplant

preemergence, and /or p ostemergence application) , 7

- day PHI
Peanut Nutmeat Pyraflufen

ethyl 0.0064

- 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 Pyraflufen

ethyl 0.0064

- 0.0066 7 8 <0.005 0.01 4 <0.005 <0.008 0.005 0.00 6 0.00 2

Metabolite E

- 1 3 <0.005 0.03 9 <0.005 0.030 0.016 0.016 0.008

Combined <0.01 0.05 2 <0.01 <0.035 0.023 0.022 0.00 9

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 a n 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) . Th ese data indicate that quantifiable pyraflufen

- ethyl residues are unlikely to occur in peanut processed commodities following applications at an exaggerated use rate ; t herefore, 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) PHI 1 Residues (ppm) 2 [Average] Processing Factor 3

Pyraflufen

- ethyl Metabolite

E

- 1 Combined

Residues Pyraflufen

ethyl Metabolite

E

- 1 Combined

Residues

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 23 of 51 Table 5.2.3. Residue Data from Peanut Processing Study with Pyraflufen

- ethyl.
RAC Processed Commodity Total

Rate (lb ai/A) PHI 1 Residues (ppm) 2 [Average] Processing Factor 3

Pyraflufen

- ethyl Metabolite

E

- 1 Combined

Residues Pyraflufen

ethyl Metabolite

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] NC 4 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 nutme at 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, D 377361 and D 377365 02/07/2011 )

. The calculated dietary burdens were 0. 1 2 ppm for beef cattle (versu s 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 diet ary 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.

H ED has recently revised its approach to calculating dietary burdens, replac ing 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 cont ributions 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 b e 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 com modities 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

Page 24 of 51 No additional data are needed to support the proposed new uses of pyraflufen

- ethyl EC formulation on peanut . Bas ed 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

nee ded 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 py raflufen

- 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 c ones ≤

- 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 soybe an 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 A n acceptable confined rotational crop study on radish, lettuce, and barley was previously submitted reflecting a soil application of [ 14 

### C

- 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 o f 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, a nd E

- 3, and uptake

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 25 of 51 of pyraflufen

- ethyl and its soil metabolites by rotational crops only occurs at very low levels. Therefore, t he residues of concern in rotational crops are parent and Metabolite E

- 1 and t he available confined rotational crop study suppor ts 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, D4 02766, 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 pyraflu fen

- 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 num bers 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 a verage 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 pyrafluf en

- 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., ppb c

Acute 0.640
0.0018 Chronic (non

- cancer) 0.295 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.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 26 of 51 The chronic dietary exp osure 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 follow ing 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

- sp ecific 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, an d 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, mil k , 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 dri nking 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 “likel y 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 dieta ry 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 assum ed 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 a ttributable to a single dose was not identified from the available data.

5.4.4 Chronic & Cancer Dietary Risk Assessment s
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) exposur e estimate for the general U.S. population to pyraflufen

- ethyl is 2 ×1 0 - 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 assess ment, rather than the established tolerances

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 27 of 51 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 Pyraflufen

ethyl.

Population Subgroup Chronic Dietary Cancer
Dietary Exposure (mg/kg/day) % cPAD 1 Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.000053 <1.0% 0.00005 2 2 ×1 0 - 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, flow ers, 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

Page 28 of 51 exposure only) were reassess ed to reflect updates to the 2012 HED Residential SOPs 2 

### (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 endpoin t 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 believ e 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 ris k assessment that a handler could treat turf up to 2 times per year, because the labels require less than two application s per year or specify that only one treatment is usually necessary to be effective or that a repeat application would be needed only af ter 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 uncert ainty 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 li sts the residential handler non

- cancer inhalation risk estim ates 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 Rate 1 Area Treated

or Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 5 MOE 6

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

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 29 of 51 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 Rate 1 Area Treated

or Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 5 MOE 6

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 ×1 0 - 8 

### to 2.1 ×1 0 - 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 Estimate 4 Liquids

Turf M/L/A with a

Manually Pressurized Handwand 3.0 ×1 0 - 6 8.7 ×1 0 - 9 3.0 ×1 0 - 6 1.0 ×1 0 - 7

Turf M/L/A with a Hose

end Sprayer 1.4 ×1 0 - 6 2.73 

### × 10 - 9 1.4 ×1 0 - 6 4.7 ×1 0 - 8

Turf M/L/A with a

Backpack Sprayer 6.3 ×1 0 - 6 6.8 ×1 0 - 9 6.3 ×1 0 - 6 2.1 ×1 0 - 7

Turf M/L/A Ready

- to

- Use

Hose

- end Sprayer 6.1 ×1 0 - 7 3.3 ×1 0 - 9 6.1 ×1 0 - 7 2.0 ×1 0 - 8

Dry Flowable

Turf M/L/A with a

Manually Pressurized Handwand 2.9 ×1 0 - 6 4.6 ×1 0 - 8 2.9 ×1 0 - 6 9.7 ×1 0 - 8

Turf M/L/A with a Hose

end Sprayer 1.1 ×1 0 - 6 1.7 ×1 0 - 9 1.1 ×1 0 - 6 3.5 ×1 0 - 8

Turf M/L/A with a

Backpack Sprayer 2.9 ×1 0 - 6 4.6 ×1 0 - 8 2.9 ×1 0 - 6 9.7 ×1 0 - 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 year s) / (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 * Q 1 * , where Q 1 * = 3.32 ×1 0
- 2 (mg/kg/day)
- 1

.



### 6.2 Post

- Application Exposure

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 30 of 51 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 adult s contacting treated turf and retail plants

. The exposure assessment for treated pla nts 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 exposur e in outdoor settings is considered negligible. Tables 6.2.1 and 6.2.2 list the updated assessments of residential post

application 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 ×1 0 - 8 

### to 7.3 ×1 0 - 7



### .

Table 6.2.1. Residential Post

- A pplication Non

- cancer Exposure and Risk Estimates for Pyraflufen

ethyl. Lifestage Post

- application Exposure Scenario Dose 1 MOEs 2

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/cm 2 ) x (fraction hand surface area mouthed/event (0.127/event) x typical surface area of one hand (150 cm 2 )) 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 ho ur (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 cm 2 ). Object

- to

- Mouth = ((Object Residue (μg/cm 2 ) x CF1 ( 1.0E

- 3 mg/μg) x Object Surface Area Mouthed/Event (10 cm 2 /event)) x (Exposure Time (1.5 hrs/day) x #Replenishment I ntervals/hr (4)) x (1

- ((1

- Extraction by Saliva (0.48))^(#Object

- to

- Mouth Events/hr (8.8 events/hr)/#Replenishment intervals/hr))))/Body Weigh t (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 NOA EL = 20 mg/kg/day.

Table 6.2.2. Residential Post

- A pplication Cancer Exposure and Risk Estimates for Pyraflufen

- ethyl.

Lifestage Post

- application Exposure Scenario Dermal LADD 1 (mg/kg/day) Cancer Risk Estimate 2

Adult Turf

- sprays High Contact Lawn Activities 2.2 ×1 0 - 5 7.3 ×1 0 - 7
Mowing Turf 4.5 ×1 0 - 7 1.5 ×1 0 - 8 Golfing 1.7 ×1 0 - 6 5.7 ×1 0 - 8

Gardens/Trees Dermal Contact to Trees and Retail Plants 3.4 ×1 0 - 6 1.2 ×1 0 - 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 * Q 1 * , where Q 1 * = 3.32 ×1 0
- 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 post

application 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 ×1 0 - 7



### .

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 31 of 51 Table 6.3. Cancer Residential Combined (Multiple Exposure Scenarios) Exposure and R isk Estimates for

Pyraflufen

- ethyl

.
Combined Exposure Scenario Lifestage Exposure Scenario LADD (mg/kg/day) Combined Total

LADD 1 (mg/kg/day) Combined Total

Cancer Risk Estimate 2

Outdoor Scenario (Turf) Adult Post

- application: Turf 2.2 ×1 0 - 5
2.5 ×1 0 - 5 8.4 ×1 0 - 7 Post

- application:

– Trees and Retail

Plants 3.4 ×1 0 - 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 * Q 1 * , where Q 1 * = Q 1 * = 3.32 ×1 0
- 2 (mg/kg/day)
- 1

.


### 6.4 Residential Risk Estimates for Use in Aggregate Assessment

Table s 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 inclusio n 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 mo st conservative residential exposure scenario) is recommended for inclusion in the cancer aggregate assessment.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 32 of 51 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 MOE 4 Post

- application Exposure

(mg/kg/day) 5 Residential Total Exposure (mg/kg/day) Residential

Total MOE 6 Scenario Inhalation Dermal Inhalation Oral

Short

- Term Non

- Cancer

Adult Handler: Treating

Turf 0.000015 0.000015 1,300,000 N/A 7 0.000015 1,300,000

Child N/A 7 N/A 7 N/A 7 Hand

- to

Mouth: 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 F or adults, r esidential 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, in halation 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 MOE 4 Post

- application Exp osure (mg/kg/day) 5 Residential Total Exposure (mg/kg/day) Residential

Total MOE 6 Scenario Inhalation Scenario Dermal LADD (mg/kg/day) Combined

LADD (mg/kg/day) Cancer (Adults Only)

Adult N/A 7 High Contact Lawn Activities 2.2 ×1 0 - 5

2.5 ×1 0 - 5 2.5 ×1 0 - 5 8.4 ×1 0 - 7
Adult N/A 7 Dermal Contact with Trees/Retail Plants 3.4 ×1 0 - 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 F or adults, r esidential total exposure combines the highest dermal and inhalation cancer exposures (Table 6.2.2 ), where applicable.
4 Total Cancer Ris k Estimate = Total Residential Handler LADD * Q 1 * , where Q 1 * = 3.32 ×1 0
- 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

- applic ation total exposure * Q 1 * , where Q 1 * = 3.32 ×1 0
- 2 (mg/kg/day)
- 1

. 7 NA = Not Applicable.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 33 of 51 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, v olatilization 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, Fun gicide, 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/2009/1 20109meeting.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 exposur e 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 be en 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 pro duct 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 comput er 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 spe cific 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 inh alation 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 post

application 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

Page 34 of 51 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 co nsider 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 ha zard (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 co nducted.

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 exp osure via oral (background) as well as dermal and inhalation (primary) routes. The most conservative scenario was chosen for each population (e.g., hand

- to

mouth 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

, 6 00 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 ca ncer assessment, further refinement to the percent of pyraflufen

- ethyl absorbed via the skin could be incorporated into future assessments.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 35 of 51 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 wi th 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 pyraflufen

ethyl 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 yea rs old, the population subgroup with the highest estimated chronic dietary exposure to p yraflufen

- 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 residentia l 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 can cer 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. T he aggregate cancer risk estimate for pyraflufen

- ethyl is 2. 6 ×1 0 - 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 conserv ative 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 LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Tota l

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult 20 100 1 0.000053 0. 0000 15 0. 000 068 2 90 ,000 Child 20 100 1 0. 00 20 0.000073 0. 0021 9

, 6 00

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 36 of 51 Table 7. 5

. Aggregate Cancer R isk Estimates

.

Population Cancer Slope

Factor (Q 1 

### *) Food and Water

Exposure (mg/kg/day) 1 

### Residential

Exposure (LADD

- mg/kg/day 2 

### Aggregate

Cancer Risk (food, water, residential) US Population 0.0332 0. 0000 52 2

. 5 ×1 0 - 5 2.6 ×1 0 - 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 = (Q 1 *, 0.0332)* (Foo d & 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 pyr aflufen

- 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 o f 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 Pesti cide 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, D37 8642, 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

- eth yl 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 post

application activities. B ased on the registered and proposed use s , short

- and intermediate

- term occupational handler exposures are expected . Pyraflufen

- ethyl is registered and propos ed 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, s ince 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

Page 37 of 51 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

. N o. 71711

- 7) must also wear chemical resistant headgear for overhe ad 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 sp ecies 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 grea ter 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 w as 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 concer n 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 commercia l pesticide handlers ranged from 4.4 ×1 0 - 7 

### to 1.9 ×1 0 - 5 

### with baseline attire, and from 3.3 ×1 0 - 7 

### to 3.3 ×1 0 - 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 resp ectively). The cancer (dermal and inhalation) exposure risk estimates for private pesticide handlers ranged from 1.5 ×1 0 - 7 

### to 6.5 ×1 0 - 6 

### with baseline PPE, and from 1.1 ×1 0 - 7 

### to 1.1 ×1 0 - 6 

### with the PPE required on the pyraflufen

- ethyl labels (Table 9.2 and 9.3 respectively).

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 38 of 51 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 Rate 2 Area Treated

or Amount Handled Daily 3 Inhalation

Baseline or EC for Aerial Application Dose (mg/kg/day) 4 MOE 5

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 label s (Reg. No s . # 71711

- 7 and 71711

- 25 ).
3 Exposure Science Advisory Council Policy #9.1.
4 Inhalati on Dose = Inhalation Unit Exposure ( μ g/lb ai) x Conversion Factor (0.001 mg/ μ g) 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 ( long

sleeves, no gloves or respirator ).

Crop or Target Exposure Scenario Total LADD c Cancer

Private Handler Commercial Handler Private Handler Commercial Handler
LADD 3 (mg/kg/day) LADD (mg/kg/day) 3 Mitigation Level Risk

Estimate 4 Mitigation

Level Risk

Estimate 4
Mixing/Loading

Peanuts Mixing/L oading for Aerial Application 0.000 19 0.000 58 Baseline 6 .5 ×1 0 - 6 Baseline 1.9 ×1 0 - 5

Hops Mixing/Loading for Groundboom 0.000072 0.00021 Baseline 2.4 ×1 0 - 6 Baseline 7.1 ×1 0 - 6

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 39 of 51 Table 9 .2

. Occupational Handler Cancer Exposure and Risk Estimates for Pyraflufen

- ethyl

. All estimates are at baseline mitigation ( long

sleeves, no gloves or respirator ).

Crop or Target Exposure Scenario Total LADD c Cancer

Private Handler Commercial Handler Private Handler Commercial Handler
LADD 3 (mg/kg/day) LADD (mg/kg/day) 3 Mitigation Level Risk

Estimate 4 Mitigation

Level Risk

Estimate 4

Peanuts Application 0.0000 44 0.000 0 1 3 Baseline 1. 5 ×1 0 - 7 Baseline 4.4 ×1 0 - 6

Applying

Peanuts Applying Aerially 0.00000 45 0.0001 3 Engineering Control 1. 5 ×1 0 - 7 Engineering Control 4.4 ×1 0 - 7

Hops Groundboom Application 0.0000 26 0.0000 77 Baseline 8.5 ×1 0 - 7 Baseline 2.5 ×1 0 - 6

Peanuts 0.00001 6 0.0000 48 Baseline 5.3 ×1 0 - 7 Baseline 1 .6 ×1 0 - 6 Flagging

Peanuts Flagging for Aerial Application 0.00001 0 0.00003 0 Baseline 3. 3 ×1 0 - 7 Baseline 1.0 ×1 0 - 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 pe r lifetime of exposure (35 years) / (365 days/year x Lifetime expectancy ).
4 Cancer risk estimates = LADD * Q 1 * , where Q 1 * = 3.32 ×1 0
- 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 LADD c Cancer

Private Handler Commercial Handler Private Handler Commercial Handler
LADD 3 (mg/kg/day) LADD (mg/kg/day) 3 Mitigation Level Risk

Estimate 4 Mitigation

Level Risk

Estimate 4
Mixing/Loading

Peanuts Mixing/Loading for Aerial Application 0.00003 3 0.0001 0 Single Layer, Gloves 1. 1 ×1 0 - 6 Single Layer, Gloves 3. 3 ×1 0 - 6

Hops Mixing/Loading for Groundboom Application 0.00001 2 0.0000 37 Single Layer, Gloves 4. 1 ×1 0 - 7 Single Layer, Gloves 1. 2 ×1 0 - 6

Peanuts 0.00000 76 0.00002 3 Single Layer, Gloves 2. 5 ×1 0 - 7 Single Layer, Gloves 7.6 ×1 0 - 7

Applying

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 40 of 51 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 LADD c Cancer

Private Handler Commercial Handler Private Handler Commercial Handler
LADD 3 (mg/kg/day) LADD (mg/kg/day) 3 Mitigation Level Risk

Estimate 4 Mitigation

Level Risk

Estimate 4

Peanuts Applying Aerially 0.00000 45 0.00000 45 Engineering Control 1. 5 ×1 0 - 7 Engineering Control 4.5 ×1 0 - 7

Hops Groundboom Application 0.00000 53 0.00001 6 Single Layer, Gloves 1.8 ×1 0 - 7 Single Layer, Gloves 5.3 ×1 0 - 7

Peanuts Groundboom Application 0.000003 3 0.0000 099 Single Layer, Gloves 1. 1 ×1 0 - 7 Single Layer, Gloves 3. 3 ×1 0 - 7

Flagging

Peanuts Flagging for Aerial Application 0.00001 1 0.00003 3 Single Layer, Gloves 3.6 ×1 0 - 7 Single Layer, Gloves 1. 1 ×1 0 - 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 (3 5 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 dos e + 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 * Q 1 * , where Q 1 * = 3.32 ×1 0
- 2 (mg/kg/day)
- 1

.

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 41 of 51 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. Pyraflu fen

- 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 post

application 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 pyraflufen

ethyl 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, o ccupational post

- application cancer risks were assessed for scouting in peanut fields and hand

- setting irrigation for peanuts. Non

cancer post

- application ris ks 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 - 6 

### and 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 se ason 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

Estimate 2

Peanut Hand

- set Irrigation 0 6.5x10 - 5 2.2x10 - 6

Peanut Scouting 0 7.2x10 - 6 2.4x10 - 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 * Q 1 * , where Q 1 * = 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
prev iously 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 it s 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

Page 42 of 51 ( 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 ide ntify 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 occupat ional 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 oc cupational 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 Regi stration of New Food Uses on Tree Nuts (Crop Grou p 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 wi th 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; Mu lti

- 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 A ppendix 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

-- waived 4 870.3700a 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 yes 1

y es 2

yes 1

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

no 3

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 th e 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 (T XR# 00564072 )

### Pyraflufen

- ethyl Human Health Risk Assessment DP No. 396779

Page 44 of 51 A.2 Toxicity Profile s Table A.2.1. Acute Toxicity of Pyraflufen

- ethyl

Guideline No. Study Type MRID # Results Toxicity Category

81

- 1 Acute Oral 45327615 LD 50 > 5000 mg/kg IV

81

- 2 Acute Dermal 45327613 LD 50 > 2000 mg/kg III

81

- 3 Acute Inhalation 45282821 LC 50 > 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 (F 0 [M]); 0, 7.78, 80.1 and 813 mg/kg/day (F 0 [F]); 0, 8.10, 82.3 and 844 mg/kg/day (F 1 [M]); 0, 9.06, 91.2 and 901 mg/kg/day (F 1 [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 F 0 and F 1 (M) and F 1 (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 determi ned. 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 b ody weight and body weight gains of the F 1 and F 2 pups. 870.4 300 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 M ous e 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

Page 46 of 51 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 abs ence 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 μ g/ml

- S9; 350
μ g/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 dose

related increase in the number of mutant colonies was seen in the presence of S9

- mix.

870.5375 In Vitro Mammalian Chromosome Aberra tion 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

Page 47 of 51 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 s trains 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

Page 48 of 51 Guideline Number and Study Type MRID (Year)

Dose Levels Results

870.7485 Metabolism and Pharmaco

kinetics Rat 45282932, 45282933, 45282934,

45282935 (1996)

5.0, 500 mg/kg single oral dose 5 mg/kg/day 14

- day repeated oral dose

Acceptable /g uideline ET

- 751(pyraflufen

- ethyl) was readily absorbed and excreted within 96 hours following a single or repeated oral dose of 5 mg/kg (plasma t 1/2 of 3

- 3.5 hrs). However, at a dose of 500 mg/kg, a bsorption was saturated as indicated by C max values which did not reflect the 100

- fold dose differential (2.7

- 2.8 μ g eq/g for the low

- dose group and 100

- 107 μ g eq

- hr/g for the high

- dose group). Following single or multiple oral low doses (5 mg/kg) of ET

- 7 51, 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. Excr etion 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 excret ion 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 μ g eq

- hr/g for the high

- dose group). Radioactivity concen trations indicated tissue concentrations at or near detection limits (generally <0.01 μ g eq/g and never exceeding 0.02 μ g eq/g) at 96 hrs postdose for any tissues. Therefore, neither ET

751 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 xenobiotic s.
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 E

1 and E

- 9 both of which are quantitatively prominent components detected in the urine and feces from all treatme nt 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 /g uideline 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 - 9 at 20 oC 1.6 x 10 - 8 at 25 oC DP# 299196, 4/7/04, H. Johnson

Dissociation constant, pK a Not applicable Octanol/water partition coefficient, Log(K OW ) 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 P yraflufen

- 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 5 1 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 Mexico 2 

### Codex 3 

### 40 CFR 180.585: Plant: Pyraflufen

- ethyl, ethyl 2

- chloro

5

- (4

- chloro

- 5

- difluoromethoxy

- 1

- methyl

- 1 H

- pyrazol

- 3

- yl)

- 4

- fluorophenoxyacetate, and its acid metabolite, E

- 1, 2

- [2

- chloro

- 5

- (4

- chloro

- 5

- (difluoromethoxy)

- 1

- methyl

1 H

- pyrazol

- 3

- yl)

- 4

- fluorophenoxy]acetic acid, expressed in terms of the parent. None None



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 

### Codex 3


### 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 porti on of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.