Document ID: EPA-HQ-OPP-2010-0426-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-06-01T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C. 20460

                                                    OFFICE OF                  
                                                           CHEMICAL SAFETY AND 
                                                   POLLUTION PREVENTION        

MEMORANDUM

DATE:	03/01/11

SUBJECT:	Pyraflufen-ethyl: Human Health Risk Assessment for a Section 3 Registration of New Food Uses on Tree Nuts (Crop Group 14), Pistachios, Pome Fruit (Crop Group 11-10), and Stone Fruits (Crop Group 12), Hops, Grapes, Olives and Pomegranates. 

PC Code:  030090
DP Barcode: 377359 
Decision No.  432056
Registration Nos.:  71711-7, 71711-25
Petition No.:  0F7718
Regulatory Action:  Section 3 Registration
Risk Assessment Type: Single Chemical/Aggregate
Case No.:  N/A
TXR No.:  N/A
CAS No.:  129630-19-9
MRID No.:  N/A
40 CFR:  180.585
                  
FROM:	Kristin Rury, Risk Assessor
		Leung Cheng, Senior Chemist 
		Myron Ottley, Toxicologist
		Risk Assessment Branch III
		Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Branch Chief
		Risk Assessment Branch III 
		Health Effects Division (7509P)

      TO:	James Stone, RM# 23
      Registration Division (7505P)

The Registration Division (RD) of the Office of Pesticide Programs (OPP) requested that the Health Effects Division (HED) evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from all registered and proposed uses of pyraflufen-ethyl
Nichino America, Inc. (Nichino) has submitted revisions to their ET(R) Herbicide product labels proposing the use of the 0.208 lb ai/gal EC (emulsifiable concentrate) and 0.177 lb ai/gal SC (suspension concentrate) formulations of pyraflufen-ethyl on Tree Nuts (Crop Group 14), Pome Fruit (Crop Group 11-10), and Stone Fruits (Crop Group 12), Hops, Grapes, Olives and Pomegranates.The proposed uses allow application of pyraflufen-ethyl via groundboom application to the proposed crops.  

This document addresses human-health risk resulting from the proposed expansion of the registered agricultural food uses and the currently registered food uses. The pyraflufen-ethyl hazard characterization/endpoint selection, and drinking water exposure assessment have not changed since the previous risk assessment (D339360, M. Ottley, 04/17/2008) and can be applied directly to this action.  The risk assessment and occupational and residential risk assessments were provided by Kristin Rury, the hazard characterization by Myron Ottley, the residue chemistry data review and dietary assessment by Leung Cheng.  The drinking water assessment was conducted by Michael Barrett of the Environmental Fate and Effects Division (EFED).  

                               Table of Contents
            
1.0	EXECUTIVE SUMMARY	5
2.0	HED RECOMMENDATIONS	9
2.1	Data Deficiencies/Conditions of Registration	11
3.0	INGREDIENT PROFILE	13
3.1	Summary of Proposed Uses	13
3.2	Structure and Nomenclature	14
3.3	Physical and Chemical Properties	15
4.0	HAZARD CHARACTERIZATION	15
4.1 	Hazard Profile	15
4.2	FQPA Considerations	16
4.3 	Dose-Response Assessment	17
4.4	Residual Uncertainty in the Exposure Database	18
4.5	Endocrine Disruption	18
5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION	19
5.1 	Pesticide Metabolism and Environmental Degradation	19
5.1.1	Summary of Plant and Animal Metabolism Studies	19
5.1.2	Metabolism in Rotational Crops	19
5.1.3	Analytical Methodology	20
5.1.4	Environmental Degradation	20
5.1.5	Toxicity Profile of Major Metabolites and Degradates	21
5.1.6	Pesticide Metabolites and Degradates of Concern	21
5.1.7	Drinking Water Residue Profile	22
5.1.8	Food Residue Profile	23
5.1.9	International Residue Limits	25
5.2	Dietary Exposure and Risk	25
5.2.1 	Acute Dietary Exposure/Risk	25
5.2.2	Chronic Dietary Exposure/Risk	25
5.3	Cancer Dietary Risk	26
5.4	Anticipated Residue and Percent Crop Treated (%CT) Information	27
6.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION	27
6.1	Residential Handler Exposure and Risk	28
6.2	Non-Occupational (Post-Application) Exposure from Treated Lawns	28
7.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION	30
7.1 	Acute Aggregate Risk	30
7.2	Short- and Intermediate-Term Aggregate Risk	30
7.3	Chronic Aggregate Risk	31
7.4	Aggregate Cancer Risk	31
8.0	CUMULATIVE RISK	32
9.0	OCCUPATIONAL EXPOSURE AND RISK	32
9.1	Occupational Handler	32
9.2	Occupational Post-Application	36
9.3	Restricted Entry Interval (REI)	36
Appendix A. Toxicology Profile	37
A.1. 	Toxicity Profile of Pyraflufen-Ethyl	37
A.2.	Toxicology Data Requirements	38
Appendix B.	 Residue Chemistry	39
B.1.	US and International Tolerances and MRLs	39
REFERENCES:	40

1.0	EXECUTIVE SUMMARY

Use Profile
Pyraflufen-ethyl, ethyl 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]acetate, is an herbicide belonging to the phenyl pyrazole class of chemicals.  Pyraflufen-ethyl is formulated as 2.0% and 2.5% soluble concentrate (SC) solutions.  

Pyraflufen-ethyl is an herbicide proposed for application to post-harvest, dormant, pre-bloom, and in-season tree nuts, pistachios, pome fruits, hops, grapes, olives, stone fruits, and pomegranates for control of broadleaf weeds.  Pyraflufen-ethyl may be applied at a single application rate of 0.0013 to 0.0053 lb ai per acre via ground application.  Pyraflufen-ethyl may not be applied via chemigation or aircraft to the proposed use sites.  Up to 3 applications may be made per year to post-harvest, dormant, or pre-bloom use sites, and up to 2 applications may be made per year to in season crops.  The maximum seasonal application rate is 0.01 lb ai per acre (0.007 for ET 2% Herbicide/Defoliant and 0.01 for ET Herbicide/defoliant (2.5%).  

Hazard Assessment
The toxicology database for pyraflufen-ethyl is of high quality and complete except for acute and subchronic neurotoxicity and immunotoxicity studies which are now required under 40 CFR §158.500 as part of the toxicology data requirements for registration of a pesticide (food and non-food uses).  Additionally, because the proposed use pattern will result in repeated inhalation exposure, a 28-day inhalation toxicity study is required.

Although acute and subchronic neurotoxicity and immunotoxicity studies are needed to complete the database, there are no concerns for immunotoxicity or neurotoxicity based on the results of the existing studies.  Further, in the absence of a route specific inhalation toxicity study, a point of departure (PoD) for inhalation exposure risk assessment has been extrapolated from an oral study.

The metabolic pathway in plants and animals involves ester hydrolysis and N-demethylation. Compounds of toxicological significance in rats, plants, and livestock included parent and metabolites E1 and E9.  Other environmental transformation products (E-1, E-2, and E-3), predicted to be present in water, are also considered of toxicological significance.  Table 3.2 shows the chemical structures of pyraflufen-ethyl and its metabolites.

 Pyraflufen-ethyl exhibits relatively low toxicity following single oral, dermal, and inhalation exposure.  It is moderately irritating to the eye, but is not a skin irritant or a dermal sensitizer.  Following repeated short-term and chronic oral doses, the liver, kidney, and possibly the hematopoietic system are the target organs for pyraflufen-ethyl in the rat and/or mouse.  No adverse toxic effects were noted in the dog following oral exposure or in the rat following dermal exposure.  There was no evidence of increased susceptibility following pre-natal exposure to rats and rabbits and pre-and post-natal exposures to rats.  Although not mutagenic or carcinogenic in the rat or in female mice, pyraflufen-ethyl is classified as a likely human carcinogen based on increased incidence of hepatocellular tumors (adenomas, carcinomas and/or hepatoblastomas) in male mice.
   
An acute dietary risk assessment was not conducted as there was no indication of an adverse effect attributable to a single dose.  Short-term inhalation and incidental oral risk assessments utilized the most sensitive dose and endpoint in the database, a maternal no observable adverse effect level (NOAEL) of 20 mg/kg/day based on decreased body weight and food consumption observed in the rabbit developmental toxicity study.  The chronic dietary risk assessment utilized the most sensitive chronic dose and endpoint in the database, a NOAEL of 20 mg/kg/day based on liver toxicity observed in the 18-month mouse carcinogenicity study.  Although neurotoxicity and immunotoxicity studies are needed to complete the database, there are no concerns for neurotoxicity or immunotoxicity based on the results of the existing studies and no need for a database uncertainty factor.  The Food Quality Protection Act (FQPA) factor was reduced to 1X because pyraflufen-ethyl showed no evidence of increased susceptibility of the young.  The standard 100-fold safety factor for combined human variability and interspecies differences has been applied to the PoD selected for all non-cancer risk assessment scenarios.  A linear low-dose extrapolation (Q1* of 3.32 x 10[-2] (mg/kg/day)[-1]) is used for quantification of human cancer risk from oral, dermal and inhalation routes.  In the absence of dermal absorption data, dermal absorption is assumed to be 100% and inhalation absorption is assumed to be equivalent to oral (100%).

Dietary Risk
For both tolerance enforcement and dietary risk assessment, the residues of concern in/on plants (primary and rotational crops) are the parent and the metabolite E-1, and the residues of concern in/on treated livestock commodities are the parent, metabolite E-1, and metabolite E-9.  The residues of concern in drinking water are the parent, metabolites E-1, E-2, and E-3 .All chemical names and metabolic structures can be found in Table 3.2. 

There was no indication of an adverse effect attributable to a single dose; therefore, no acute dietary risk assessment was performed.  

Chronic dietary exposure analyses using the Dietary Exposure Evaluation Model (DEEM-FCID, Version 2.03) indicate that chronic dietary exposure to the combined residues of pyraflufen-ethyl and metabolite E-1 from food and drinking water are well below HED's level of concern (LOC).  Using a partially refined analysis, the estimated chronic dietary exposure is  <1% of the chronic population adjusted dose (cPAD) for the general U.S. population and all population subgroups, including children 1-2 years old, the most highly exposed population subgroup.  The cancer risk for the general U.S. population is estimated to be 2.7x10[-][6] which is in the 10-6 range and also below HED's level of concern. 

Drinking Water
The drinking water residues used in the dietary risk assessment were provided by EFED.  
 
Due to its low persistence, pyraflufen-ethyl should not be available for runoff or leaching.  However, three metabolites (E-1, E-2, and E-3) were identified as major transformation products and are included in the drinking water assessment.  There are no data available on the toxicity of the metabolites; however, since the metabolites are structurally similar to the parent pyraflufen-ethyl, they are assumed to be of equal or lesser toxicity (Metabolism Assessment Review Committee [MARC] Decision memo, 07/19/02 and personal communication with A. Protzel and J. Doherty, 9/19/02).  Based on the highest application rate, the acute surface water estimated drinking water concentration (EDWC) using the FIRST (FQPA Index Reservoir Screening Tool) model (surface water) is 1247 parts per trillion (ppt) of total residues of pyraflufen-ethyl and its major degradates and the annual average surface water value is 281 ppt.  The groundwater screening concentration from SCIGROW (Screening Concentrations in Ground Water) is 1.8 ppt.  These values generally represent upper-bound conservative estimates of the total residue concentrations that might be found in surface water and ground water due to the use of pyraflufen-ethyl.

Residential Risk
No new residential uses and no occupational uses at residential sites are being requested in this petition; therefore, a new residential risk assessment was not conducted.  Residential exposure and risk due to residential handler application of pyraflufen-ethyl to residential turfgrass as well as post-application exposure/risk to adults and children were previously assessed and are incorporated in this assessment.  Non-cancer risk assessments were conducted for short-term residential exposure scenarios.  The inhalation margins of exposure (MOEs) for adult handlers (low pressure handwand and hose-end sprayer) were >35,000,000; no hazard from the dermal route was identified.  The combined MOEs for post-application children's incidential ingestion of residues of pyraflufen-ethyl on treated turf (hand-to-mouth exposure, object-to-mouth exposure, and soil ingestion) were 270,000; these non-cancer risks provide a substantial margin of safety for HED's level of concern (MOE=100).  Cancer risks for adult handlers (dermal + inhalation) were estimated to be in the 10[-8] range and for adult post-application activities (residential turf and adult golfer) in the 10[-7] range; these risks are not of concern to HED. 

Aggregate Risk
Short-term aggregate risk is based on residential handler exposure, children's incidental oral exposure (from residential post-application treatment) and dietary exposure (food and drinking water).  Risks for the highest exposed population (children, 1-2 years old) were below HED's LOC, with an MOE of 66,000.   An intermediate-term aggregate risk assessment was not conducted for adults because the exposure duration is expected to be short-term only.  In addition, an intermediate-term aggregate risk assessment was not conducted for children (post-application exposure) because standard assumptions (input values) for intermediate-term exposure are less conservative than those for short-term exposure.  

For chronic aggregate risk assessment, exposures from food and drinking water were considered.  Therefore, exposures from residential uses are not expected to occur over the chronic duration Aggregate food + water risk is <1% of the cPAD for the general population, and all subgroups.  

For the aggregate cancer risk assessment, exposure from residential uses is based on the lifetime average daily dose (LADD), and assumes an exposure period of 5 days per year and 50 years of exposure over a 70-year lifetime.  Average food and water-source dietary exposure values were used.  Cancer risk for the US population includes infants and children; therefore, in accordance with HED policy, children's cancer risk was not reported separately.  Aggregate (food, water and residential) cancer risk is in the 10-6 range and not of concern to HED.  

Occupational Risk
Occupational handlers may be exposed during mixing, loading, and application of pyraflufen-ethyl using groundboom equipment for broadcast treatment of the proposed use sites.  Non-cancer risks only considered inhalation exposures because no adverse effects were seen in the dermal toxicity study at the limit dose.  The non-cancer inhalation MOEs for occupational exposure to pyraflufen-ethyl ranged from 2,400,000 to 3,800,000 at baseline.  

Cancer risks for adult handlers were assessed. Handler cancer risk estimates were based on dermal and inhalation exposures.  All handler exposure scenarios with personal protective equipment (PPE) use (as required by the label) resulted in cancer risks below HED's LOC.  The private grower mixer/loader cancer risks were 9.3x10[-6] at baseline and 7.8x10[-8] with a single layer and gloves.  The private grower applicator cancer risks were 4.7x10[-8] at baseline and with a single layer and gloves.  Commercial mixer/loader cancer risks were to 2.8x10[-5] at baseline and 1.4x10[-7] with a single layer and gloves.  Commercial applicator cancer risk was 1.4x10[-][7] at baseline and with a single layer and gloves.

Occupational agricultural post-application cancer risks were not evaluated based on the proposed pyraflufen-ethyl use pattern.  Pyraflufen-ethyl is applied to crop foliage as a burndown treatment only.  In all other cases, the target sites of pyraflufen-ethyl are broadleaf weeds and grasses.  Therefore, a post-application risk assessment is not needed.  

Pyraflufen-ethyl is classified as acute toxicity category III for acute dermal and primary eye irritation.  It is classified as category IV for primary skin irritation and it is not a dermal sensitizer.  Therefore, the interim Worker Protection Standard (WPS) restricted entry interval of 12 hours (as stated on the label) is adequate to protect agricultural workers from post-application exposures to pyraflufen-ethyl.

The minimum level of PPE for handlers is based on acute toxicity for the end-use product.  RD is responsible for ensuring that PPE listed on the label is in compliance with the WPS.

Regulatory Recommendations
The proposed agricultural uses have been assessed and no risks of concern were identified.  HED has no objection to the registration of this new use pattern provided that the registration be made conditional pending submission of the newly required Part 158 toxicology data and well as additional residue chemistry data (see Section 2.0 for details).  

Environmental Justice Considerations
Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

Review of Human Research
This risk assessment relies in part on data from Pesticide Handlers Exposure Database (PHED) studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies have been determined to require a review of their ethical conduct and have received that review.

2.0	HED RECOMMENDATIONS

HED has examined the toxicology and residue chemistry database for pyraflufen-ethyl.  There are no residue chemistry issues that would preclude granting a conditional registration for use of pyraflufen-ethyl on the requested crops except for hops.  The deficiencies below must be resolved before granting an unconditional registration.  For hops, detailed field trial information such as the location of the trials, formulation type, application rate, application method, if an adjuvant was used, and the soil characteristics (if pyraflufen-ethyl is directed to the soil) must be provided.  Therefore, registration for the requested use on hops cannot be granted at this time. 

The proposed uses and the submitted data support the following tolerances for residues of pyraflufen-ethyl in/on the following raw agricultural commodities.  In accordance with HED's Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09), the tolerance expression for pyraflufen-ethyl should be revised to state:

"Tolerances are established for residues of pyraflufen-ethyl, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring pyraflufen-ethyl, ethyl 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]acetate, and its acid metabolite, 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]acetic acid, in or on the commodity."

            Almond, hulls	0.02 ppm
            Nut, tree, group 14	0.01 ppm
            Pistachio	0.01 ppm
            Fruit, pome, group 11	0.01 ppm
            Fruit, stone, group 12	0.01 ppm
            Pomegranate	0.01 ppm
            Olive	0.01 ppm
            Grape	0.01 ppm

The proposed uses and the submitted data support the following tolerances for residues of pyraflufen-ethyl in the following livestock commodities:

"Tolerances are established for residues of pyraflufen-ethyl, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring pyraflufen-ethyl, ethyl 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]acetate, and its acid metabolites, 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]acetic acid and 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1H-pyrazol-3-yl]-4-fluorophenoxy]acetic acid, in or on the commodity."

            Cattle, fat	0.03 ppm
            Cattle, meat	0.03 ppm
            Cattle, meat byproducts	0.03 ppm
            Goat, fat	0.03 ppm
            Goat, meat	0.03 ppm
            Goat, meat byproducts	0.03 ppm
            Horse, fat	0.03 ppm
            Horse, meat	0.03 ppm
            Horse, meat byproducts	0.03 ppm
            Milk	0.03 ppm
            Sheep, fat	0.03 ppm
            Sheep, meat	0.03 ppm
            Sheep, meat byproducts	0.03 ppm
            
Table 2 shows the proposed and recommended tolerances by commodity. 

Table 2. 	Tolerance Summary for Pyraflufen-ethyl.
Commodity
                          Established Tolerance (ppm)
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
Comments; Correct Commodity Definition
Grapes
                                      --
                                     0.01
                                     0.01
Grape
Adequate residue data are available.
Hop cones, dried
                                      --
                                     0.01
                                     None
Hop, dried cones
Registration cannot be granted at this time since additional information is needed regarding the proposed use and field trial data.
Fruit, Pome group 11

                                      --
                                     0.01
                                     0.01
Fruit, pome, group 11

Fruit, Stone group 12
                                      --
                                     0.01
                                     0.01
Fruit, stone, group 12
Adequate residue data are available by translation.
Nuts, tree group 14
                                      --
                                     0.01
                                     0.01
Nut, tree, group 14
Adequate residue data are available.
Almond, hulls
                                      --
                                     0.02
                                     0.02
Adequate residue data are available.
Pistachio
                                      --
                                     0.01
                                     0.01
Adequate residue data are available by translation.
Pomegranates
                                      --
                                     0.01
                                     0.01
Pomegranate
Adequate residue data are available by translation.
Olives
                                      --
                                     0.01
                                     0.01
Adequate residue data are available by translation.
Cattle, fat
                                     None
                                     None
                                     0.03

Cattle, meat
                                     None
                                     None
                                     0.03

Cattle, meat byproducts
                                     0.02
                                      --
                                     0.03

Goat, fat
                                     None
                                     None
                                     0.03
                                       
Goat, meat
                                     None
                                     None
                                     0.03
                                       
Goat, meat byproducts
                                     0.02
                                      --
                                     0.03
                                       
Horse, fat
                                     None
                                     None
                                     0.03
                                       
Horse, meat
                                     None
                                     None
                                     0.03
                                       
Horse, meat byproducts
                                     0.02
                                      --
                                     0.03
                                       
Milk
                                     0.02
                                      --
                                     0.03
                                       
Sheep, fat
                                     None
                                     None
                                     0.03
                                       
Sheep, meat
                                     None
                                     None
                                     0.03
                                       
Sheep, meat byproducts
                                     0.02
                                      --
                                     0.03
                                       

            
      2.1	Data Deficiencies/Conditions of Registration

RESIDUE CHEMISTRY

The following must be provided prior to a tolerance being established or registration allowed on hops:

860.1200  Directions for Use

	::	Detailed field trial information for the hop study (MRID#47872705) was not provided; therefore, it is uncertain if the crop field trials are representative of the proposed label. 

	::	The label does not provide a pre-harvest interval (PHI); therefore, it could be assumed that hops can be collected immediately after application.  Hop samples were collected at a PHI of 29 to 38 days.  The crop field trials should reflect the proposed use directions; therefore, the label should be revised to reflect a 30-day PHI, or new crop field trials should be conducted using a PHI of 0 days. 

860.1500 Crop Field Trials

   oo Detailed field trial information for the hop study (MRID#47872705) was not provided.  The petitioner needs to submit detailed field trial information for MRID#47872705, including the location of the trials, formulation type, application rate, application method, if an adjuvant was used, meteorological data, and the soil characteristics.

The following data are required as a condition of registration on pome fruit (crop group 11), stone fruit (crop group 12), pomegranates, olives, grapes, tree nuts (crop group 14), and pistachios:

RESIDUE CHEMISTRY

860.1300  Nature of the Residue - Plants

	::	The petitioner should submit information on sample storage conditions and durations for samples analyzed in the orange plant metabolism study. 

860.1340  Residue Analytical Methods  

	::	Method validation data for the method development of Metabolite E-9 (PTRL West Study 1837W) should be submitted for confirming its limit of quantification (LOQ).

860.1360 Multiresidue Methods

	::	Data are required reflecting recovery of pyraflufen-ethyl and Metabolite E-1 through the FDA Protocols C and D with and without the use of Florisil cleanup.  These data remain outstanding.

	::	Since Metabolite E-9 should also be included in the tolerance definition for livestock commodities, data will be required reflecting recovery of Metabolite E-9 through the FDA multiresidue methods.

860.1380 Storage Stability

	::	No storage stability data were submitted for Metabolite E-9.  A storage stability study for Metabolite E-9 in milk and liver under frozen conditions for 3 months is required.

860.1480 Meat, Milk, Poultry, and Eggs

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

860.1650 Submittal of Analytical Reference Standards

	::	Analytical standards for Metabolites E-1 and E-9 must be submitted to the National Pesticide Standards Repository.
      
TOXICOLOGY

870.3465  28 Day Inhalation - Rat

   * Since the proposed use pattern will result in repeated inhalation exposure, a 28-day inhalation toxicity study is being required.  

870.6200  Acute and Subchronic Neurotoxicity Studies

   * Acute and subchronic neurotoxicity studies are now required under the revised 40 CFR §158.340 guidelines.

870.7800  Immunotoxicity Study

●	An immunotoxicity study in rats and/or mice is now required under the revised 40 CFR §158.340 guidelines.

EPA expects to receive reports from the conduct of these four studies for detailed review by late 2011.

3.0	INGREDIENT PROFILE

Pyraflufen-ethyl is a herbicide that is currently registered for use as a harvest aid in cotton and potatoes; for a single preplant or preemergence burndown use in field corn, cotton, deciduous fruit and nut trees and vines, soybeans, and wheat; for postemergence use in cotton, corn (except sweet corn), and soybeans, for weed control in non-crop land and uncultivated agricultural areas (nonfood producing); and as a nonselective herbicide for control of broadleaf weeds in non-crop areas, including recreational and residential areas, established ornamental turf lawns, parks, cemeteries, athletic fields, golf courses, sod farms, and similar turf areas.    

	3.1	Summary of Proposed Uses

Pyraflufen-ethyl is a herbicidal active ingredient (ai).  The proposed formulated end-use products are labeled under the trade names ET(R) Herbicide/Defoliant which contains 2.5% (0.208 lb ai/gallon) pyraflufen ethyl, and ET(R) 2% SC Herbicide/Defoliant which contains 2% (0.17 lb ai/gallon) pyraflufen-ethyl.  Pyraflufen-ethyl is proposed for use on post-harvest, dormant, pre-bloom, and in-season tree nuts, pome fruits, hops, grapes, olives, stone fruits, and pomegranates for control of broadleaf weeds.  Pyraflufen-ethyl may be applied at a single application rate of 0.0013 to 0.0053 lb ai per acre via ground application.  Pyraflufen-ethyl may not be applied via chemigation or aerially to the proposed use sites.  Up to 3 applications may be made per year to post-harvest, dormant, or pre-bloom use sites, and up to 2 applications may be made per year to in season crops.  The maximum seasonal application rate is 0.01 lb ai per acre (0.007 for ET 2% Herbicide/Defoliant and 0.01 for ET Herbicide/defoliant (2.5%).  

The proposed use profile is summarized in Table 3.1.  

Table 3.1. Use Profile for Pyraflufen-Ethyl
                                     Crop
                               Application Type
                            Methods of Application
                       Single Application Rate (lb ai/A)
                    Maximum Number of Applications (fl oz)
                  Maximum Seasonal Application Rate (lb ai/A)
                          Retreatment Interval (RTI)
      ET 2% Herbicide/Defoliant (EPA Reg. No.  71711-25) (0.17 lb ai/gal)
Grapes, Olive Trees, Pomegranates, Pome Fruit (Apple, Crabapple, Loquat, Mayhaw, Pear, Pear (oriental), Quince), Stone Fruits (Apricot, Cherry, Nectarine, Peach, Plum, Plumcot, Prune), Tree Nuts , Hops
                        Post-Harvest, Dormant, Prebloom
                                  Groundboom
                                0.0013 - 0.0053
                                   3 
(5.5)
                                     0.009
                                    30 days

                                   In Season

                                   2 
(5.5)

         ET Herbicide/Defoliant EPA Reg. No. 71711-7 (0.208 lb ai/gal)
Grapes, Olive Trees, Pomegranates, Pome Fruit (Apple, Crabapple, Loquat, Mayhaw, Pear, Pear (oriental), Quince), Stone Fruits (Apricot, Cherry, Nectarine, Peach, Plum, Plumcot, Prune), Tree Nuts  Hops
                        Post-Harvest, Dormant, Prebloom
                                  Groundboom
                                0.0013 - 0.0053
                                   3 
(6.8)
                                     0.009
                                    30 days

                                   In Season

                                   2 
(6.8)

      3.2	Structure and Nomenclature

Table 3.2. Pyraflufen-Ethyl Nomenclature
Chemical structure
                                       N
N
Cl
F
Cl
C
H
3
O
C
H
2
C
O
O
C
2
H
5
O
C
H
F
2
Common name
Pyraflufen-Ethyl
PC Code
030090
Company experimental name
ET-751
IUPAC name
Ethyl [2-chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxy]acetate
CAS name
Ethyl 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]acetate
CAS registry number
129630-19-9
End-use product (EP)
0.208 lb/gal EC (2.5%EC; ET(R) Herbicide/Defoliant; EPA Reg. No. 71711-7;
Label Date 02/20/2007)
0.17 lb/gal FlC (2.0%FlC; ET(R) 2%SC Herbicide/Defoliant;  EPA Reg. No. 71711-25;
Label Date 09/06/2007)
Chemical structure 
                                       N
N
Cl
F
Cl
C
H
3
O
C
H
F
2
O
C
H
2
C
O
O
H
Common name
Pyraflufen
PC Code
030091
Company experimental name
Metabolite E-1; Pyraflufen-ethyl plant and livestock metabolite of concern
IUPAC name
[2-chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxy]acetic acid
CAS name
2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]acetic acid
CAS registry number
129630-17-7
Chemical structure 
                                       N
N
Cl
F
Cl
H
O
C
H
F
2
O
C
H
2
C
O
O
H
Company experimental name
Metabolite E-9; Pyraflufen-ethyl livestock metabolite of concern
Chemical structure 
                                       N
N
Cl
F
Cl
C
H
3
O
C
H
F
2
O
C
H
2
C
O
O
CH3
Company experimental name
GC/MSD Residue Method Analyte E-15; methyl ester of Metabolite E-1
      
      3.3	Physical and Chemical Properties
      
For a detailed description, refer to Section 2.3, Physical and Chemical Properties of the previous risk assessment document (D339360, M. Ottley, 04/17/2008). 
 
4.0	HAZARD CHARACTERIZATION
 
		4.1 	Hazard Profile

Studies Available 
The toxicology database for pyraflufen-ethyl is of high quality and complete except for acute and subchronic neurotoxicity and immunotoxicity studies which are now included under 40 CFR Part §158.500 as part of the toxicology data requirements for registration of a pesticide (food and non-food uses).  Additionally, because the proposed use pattern will result in repeated inhalation exposure, a 28-day inhalation toxicity study is required.

Although and acute and subchronic neurotoxicity and immunotoxicity studies are needed to complete the database, there are no concerns for immunotoxicity or neurotoxicity based on the results of the existing studies.  Further, in the absence of a route specific inhalation toxicity study, a PoD for inhalation exposure risk assessment has been extrapolated from an oral study.

Absorption, Distribution, Metabolism, and Excretion
Radiolabeled kinetic studies in the rat show that pyraflufen-ethyl is rapidly absorbed in a 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 GI tract, liver and excretory organs.  There was no evidence of accumulation.  Excretion of residues was essentially complete 24 hours after dosing with <1% of the absorbed dose eliminated unchanged.

The metabolic pathway in plants and animals involves ester hydrolysis and N-demethylation. Compounds of toxicological significance in rats, plants, and livestock included parent and metabolites E1 and E9.  Other environmental transformation products (E-1, E-2, and E-3), predicted to be present in water, are also considered of toxicological significance.

 Acute, Short-, and Long-Term Toxicity
 Pyraflufen-ethyl exhibits relatively low toxicity following single oral, dermal, and inhalation exposure.  It is moderately irritating to the eye, but is not a skin irritant or a dermal sensitizer. Following repeated short-term and chronic oral doses, the liver, kidney, and possibly the hematopoietic system are the target organs for pyraflufen-ethyl in the rat and/or mouse.  No adverse toxic effects were noted in the dog following oral exposure or in the rat following dermal exposure.  There was no evidence of increased susceptibility following pre-natal exposure to rats and rabbits and pre-and post-natal exposures to rats.  Although not mutagenic or carcinogenic in the rat, pyraflufen-ethyl is classified as a likely human carcinogen based increased incidence of hepatocellular tumors (adenomas, carcinomas and/or hepatoblastomas) in male and female mice.
   
 Points of Departure and Uncertainty Factors Used for Risk Assessment 
An acute dietary risk assessment was not conducted as there was no indication of an adverse effect attributable to a single dose.  Short-term inhalation and incidental oral risk assessments utilized the most sensitive dose and endpoint in the database, a maternal NOAEL of 20 mg/kg/day based on decreased body weight and food consumption observed in the rabbit developmental toxicity study.  The chronic dietary risk assessment utilized the most sensitive chronic dose and endpoint in the database, a NOAEL of 20 mg/kg/day based on liver toxicity observed in the 18-month mouse carcinogenicity study.  Although neurotoxicity and immunotoxicity studies are needed to complete the database, there are no concerns for neurotoxicity or immunotoxicity based on the results of the existing studies and no need for a database uncertainty factor.  The FQPA factor was reduced to 1X because pyraflufen-ethyl showed no evidence of increased susceptibility of the young.  The standard 100-fold safety factor for combined human variability and interspecies differences has been applied to the points of departure selected for all non-cancer risk assessment scenarios.  A linear low-dose extrapolation (Q1* of 3.32 x 10[-2] (mg/kg/day)[-1]) is used for quantification of human cancer risk from oral, dermal and inhalation routes. In the absence of dermal absorption data, dermal absorption is assumed to be 100%  and inhalation absorption is assumed to be equivalent to oral (100%).
 
		4.2	FQPA Considerations
 
 HED recommends that the default 10X FQPA safety factor be reduced to1X for the following reasons: 
  
    1. The database is complete with the exception of acute and subchronic neurotoxicity, immunotoxicity, and inhalation toxicity studies.
    2. There is no evidence of increased susceptibility of rat or rabbit fetuses following in utero exposure in the developmental studies with pyraflufen-ethyl.  There is no evidence of increased susceptibility of young rats in the reproduction study with pyraflufen-ethyl and there are no residual uncertainties for pre- and/or postnatal exposure. 
    3. There are no concerns for neurotoxicity and no need for a developmental neurotoxicity study (DNT).
    4. There are no residual uncertainties identified in the exposure databases.  The dietary food exposure assessment, although somewhat refined, is conservative assuming 100% crop treated information.  Dietary drinking water exposure is based on conservative modeling estimates.  HED Residential SOPs were used to assess post-application exposure to children as well as incidental oral exposure of children (age 3 to <6).  These assessments will not underestimate the exposure and risks posed by pyraflufen-ethyl.

      		4.3 	Dose-Response Assessment

 HED has evaluated the toxicology database of pyraflufen-ethyl, established reference doses (RfD) and selected the toxicological endpoints for dietary as well as occupational and residential exposure risk assessments.  A summary of the endpoints identified for risk assessment is presented below in Table 4.3.1.

Table 4.3. Summary of Toxicological Doses and Endpoints for Pyraflufen-Ethyl for Use in Dietary, Residential (Non-Occupational) and Occupational Human Health Risk Assessments.
                                   Exposure/
                                   Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary 
(all popula-tions)
None
None
None
An endpoint attributable to a single dose was not identified from the available data.
Chronic Dietary (all populations)
NOAEL = 20
UFA=10X
UFH=10X
FQPA SF = 1X
Chronic
RfD = 0.20 mg/kg/day

cPAD = 0.2 mg/kg/day
Mouse Carcinogenicity
LOAEL = 98 mg/kg/day based on liver toxicity
Incidental Oral Short-Term
(1-30 days)
Maternal NOAEL = 20 mg/kg/day 
UFA=10X
UFH=10X
FQPA SF = 1X
MOE = 100 (residential)
Developmental Toxicity-Rabbit
LOAEL = 60 mg/kg/day based on decreases in body weight and food consumption, GI observations, and abortions
Incidental Oral Intermediate-Term
(1-6 months)
Maternal NOAEL = 20 mg/kg/day
UFA=10X
UFH=10X
FQPA SF = 1X
MOE = 100 (residential)
Mouse Carcinogenicity
LOAEL = 98 mg/kg/day based on liver toxicity at interim sacrifice
Dermal  (All Durations)
None
None
None
In a 28-dermal toxicity study in rats, no dermal or systemic toxicity was seen at the Limit Dose (1000 mg/kg/day).
Inhalation (All Durations)
Maternal NOAEL = 20 mg/kg/day 
UFA=10X
UFH=10X
FQPA SF = 1X
MOE = 100 (occupational)

MOE = 100 (residential)
Developmental Toxicity-Rabbit
LOAEL = 60  mg/kg/day based on decreases in body weight and food consumption, GI observations, and abortions
Cancer (oral, dermal, inhalation)

Classification: "Likely to be Carcinogenic to Humans" by the oral route.
Q1* = 3.32 x 10[-2] (mg/kg/day)[-1]
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

HED identified endpoints for chronic dietary exposure assessment (chronic reference dose), short- and intermediate-term incidental oral exposure assessment and short- and intermediate-term inhalation exposure assessment.  Endpoints for short- and intermediate-term dermal exposure assessment were not identified, because in a 28-day dermal toxicity study in rats, no effects were seen at the limit dose (1000 mg/kg/day).  Long-term or chronic exposure through dermal or inhalation routes is not expected based on the use pattern (intermittent use).
 
 To quantify cancer risk, the Q1* is multiplied by the estimated lifetime average daily doses from occupational or residential exposure.  In the absence of dermal absorption data, 100% dermal absorption was assumed, in spite of the fact that the octanol/water partition coefficient (Kow) is low, which indicates that dermal absorption is expected to be low.  Therefore, non-dietary cancer risk estimates in this document are considered very conservative.  Lifetime average daily dermal and inhalation exposures were summed, because cancer risk is based on total exposure over a lifetime.
 
 	4.4	Residual Uncertainty in the Exposure Database
 
 Although the registrant has been requested to conduct a cattle feeding study at the 10X dose of 18 ppm to meet a guideline requirement, the existing feeding study results at the 5X dose are sufficient to establish meat and milk tolerances and do not underestimate the exposure to cattle commodities. Although partially refined with average field trials, the dietary exposure estimates assumed 100% crop treated.  This conservative approach will not underestimate dietary exposure to pyraflufen-ethyl in the proposed agricultural commodities.  HED Residential SOPs were used to assess post-application exposure to children as well as incidental oral exposure of children (toddlers).  These assessments will not underestimate the exposure and risks posed by pyraflufen-ethyl.
 
		4.5	Endocrine Disruption
 
 As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate."  The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems.  Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.
 
 Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients.  This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post-application agricultural scenarios.  This list should not be construed as a list of known or likely endocrine disruptors.
 
 Pyraflufen-ethyl is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP.  Under FFDCA Sec. 408(p) the Agency must screen all pesticide chemicals.  Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all pesticide active ingredients. 
 
 For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website:  http://www.epa.gov/endo/.
 
5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION
		
HED has concluded that the residues of concern in plants include the parent and Metabolite E-1 for purposes of tolerance enforcement and risk assessment.  The residues of concern in livestock commodities are parent, Metabolite E-1, and Metabolite E-9 2-[2-chloro-5-[4-chloro-5-difluoromethoxy)-1H-pyrazol-3-yl]-4-fluorophenoxy]acetic acid].  

      5.1 	Pesticide Metabolism and Environmental Degradation
      
      	5.1.1	Summary of Plant and Animal Metabolism Studies
 
The qualitative nature of the residue in plants is adequately understood based on a submitted mandarin orange study and previously submitted cotton, potato, and wheat metabolism studies.  HED has concluded that the residues of concern in primary and rotational crops for the tolerance expression and risk assessment are the parent and Metabolite E-1.  The qualitative nature of the residue in livestock is adequately understood based on adequate ruminant and poultry metabolism studies.  HED has concluded that the residues of concern in livestock commodities for the tolerance expression and risk assessment are parent, Metabolite E-1, and Metabolite E-9.  

      5.1.2	Metabolism in Rotational Crops

A confined rotational crop study on radish, lettuce, and barley was previously submitted reflecting a soil application of [[14]C-pyrazole]pyraflufen-ethyl at 0.0127 lb ai/A (0.9x the maximum seasonal rate on cotton).  Detectable residues (0.001-0.003 ppm) were observed in 30-day mature radish roots and tops, and barley chaff and straw, 120-day immature radish roots, and 150-day barley forage.  No pyraflufen-ethyl was identified on analysis of 30-day radish tops and barley straw; however, metabolites E-1, E-2, and E-3 were tentatively identified in radish tops at <3% TRR each.  No residues were identified in barley straw.  Pyraflufen-ethyl breaks down in the soil to its metabolites E-1, E-2, and E-3, and uptake of pyraflufen-ethyl and its soil metabolites by rotational crops only occurs at very low levels. 

Although the HED originally concluded that the confined rotational crop study was insufficient due to [14]C-labeling in only the pyrazole ring, the Agency (ChemSAC minutes, 12/3/03) concluded that an additional confined rotational crop study with pyraflufen-ethyl radiolabeled in the phenyl ring would not be required, as the metabolic pathways in soil, plants, and animals were similar and there was no evidence of cleavage of the bond between the phenyl and pyrazole rings.  The available confined study supports the 30-day plantback interval specified on the label for all crops without primary uses of pyraflufen-ethyl.  

There are no rotational crop data requirements associated with the use on tree nuts (crop group 14), pistachios, pome fruits (crop group 11), stone fruits (crop group 12), pomegranates, olives, and grapes; therefore, this guideline is not applicable to these crops.  However, other crops may be planted following hops.

		5.1.3	Analytical Methodology

Plant Commodities 
An adequate gas chromatography-mass spectrometry (GC/MS) method is available for tolerance enforcement, and similar GC/MS methods used for data collection in the apple, grape, tree nut, and hop field trials were adequately validated in conjunction with the analysis of field trial samples.

Livestock Commodities 
An adequate GC/MS method is available for collecting data on residues of parent and Metabolite E-1 (determined as E-15) in livestock commodities.  The method has a validated LOQ of 0.01 ppm for each analyte in milk and tissues, for a combined LOQ of 0.03 ppm.  Method validation data for the method development of metabolite E-9 (PTRL West Study 1837W) should be submitted.  

The method has undergone a successful independent laboratory validation (ILV) for parent and metabolite E-1 and has been radiovalidated. There is an analytical method available for enforcement (D352195, C. Stafford, 02/03/2011).

Multiresidue Methods
No adequate multiresidue methods testing data have been submitted for pyraflufen-ethyl.  Nichino previously submitted a method description and supporting data for an EEC (European) multiresidue enforcement method.  This submission was not adequate to fulfill EPA's multiresidue method requirement.

Data are required reflecting recovery of pyraflufen-ethyl and its metabolite E-1 through the FDA multiresidue methods according to Protocols C and D in the Pesticide Analytical Manual, Volume I, Appendix II.  Evaluations should be performed with and without Florisil cleanup.  Since Metabolite E-9 should also be included in the tolerance definition for livestock commodities, data will be required reflecting recovery of Metabolite E-9 through FDA multiresidue methods.

		5.1.4	Environmental Degradation

Due to its low persistence and mobility pyraflufen-ethyl should not be available for runoff or leaching.  However, three metabolites were identified as major transformation products (E-1, E-2 and E-3). HED concluded that the parent, E-1, E-2, and E-3 should all be included in the drinking water assessment. See appendix for metabolite structures.  The metabolite E-1 is moderately persistent, making it available for runoff during rain events occurring shortly after application.  E-3, the most persistent of the three terminal degradates, generally appears at lower concentrations, later in time, and binds more strongly to soils.  E-3 should also be available for runoff in rain events accompanied with erosion.

		5.1.5	Toxicity Profile of Major Metabolites and Degradates
 
 Pyraflufen-ethyl degrades into similar metabolites in plants, livestock, water and soil.  HED considered the metabolites and concluded that none of them is likely to be more toxic than pyraflufen-ethyl itself.  While there are no data specific to the toxicity of the metabolites, E-1, E-2 and E-3 are structurally similar to the parent pyraflufen-ethyl and as such are assumed to be of equal or lesser toxicity (MARC Decision memo, 07/19/02 and personal communication with A. Protzel and J. Doherty, 9/19/02).  See the Appendix B for metabolite structures.  The metabolites were included in the risk assessment (E-1 in the food-source dietary assessment and E-1, E-2 and E-3 in the drinking water assessment).
 
 The conclusion that pyraflufen-ethyl metabolites are not expected to be more toxic than the parent compound was confirmed by HED's Derek Analysis program which conducted structure activity analyses on the chemicals in question.
 
			5.1.6	Pesticide Metabolites and Degradates of Concern

The nature of the residue in plants, rotational crops and livestock is adequately understood. HED has concluded that the residues of concern in plants and rotational crops include the parent and metabolite E-1 for purposes of tolerance enforcement and risk assessment.  Although not relevant to the proposed non-food uses, the HED has concluded that the residues of concern in livestock commodities for the risk assessment are parent and metabolites E-1 and E-9, and that all three compounds should be measured in livestock feeding studies.  HED also previously concluded in connection with food petitions that time-limited tolerances could be established for parent and metabolite E-1 pending results of the requested cattle feeding study.  

Environmental fate data indicate that metabolites E-1 and E-2 are the major metabolites (>10% total radioactive residues [TRR]) in photolysis, aerobic soil metabolism, anaerobic aquatic metabolism and aerobic aquatic metabolism studies for parent.  E-3 is the major metabolite (>10% TRR) in aerobic soil metabolism resulting from E-2.  Although U1 (2-fluoro-5-hydroxy-5-(N-methylcarbamoyl)-4-oxo-2-pentenoic acid) was observed at 21% TRR under photolysis in soil, soil photolysis is not a major route of environmental degradation, and with the fact that the application rate is so low (<0.02 lbs ai/A), HED concluded that U1 is not a residue of concern in drinking water (MARC Decision memo, 07/19/02).  Although PD-1 (parent compound with the chlorine on the phenyl ring replaced by hydroxyl) is a major degradate in aqueous photolysis, it is relatively unstable in water based on its short half-life (32.2% at 36 hours to 18.7% at 48 hours).  Therefore, HED concluded that the residues for risk assessment in drinking water include parent, E-1, E-2, and E-3 (MARC Decision memo, 07/19/02).

Table 5.1.6.  Summary of Metabolites and Degradates To Be Included in the Risk Assessment and Tolerance Expression
                                    Matrix
                     Residues Included in Risk Assessment
                   Residues Included in Tolerance Expression
                                    Plants
                                 Primary Crop
                                  parent, E-1
                                  parent, E-1
                                       
                                Rotational Crop
                                  parent, E-1
                                  parent, E-1
                                   Livestock
                                   Ruminant
                               parent, E-1, E-9
                               parent, E-1, E-9*
                                       
                                    Poultry
                               parent, E-1, E-9
                               parent, E-1, E-9*
                                Drinking Water
                             parent, E-1, E-2, E-3
                                Not Applicable
* Metabolite E-9 has been included in permanent tolerance for livestock commodities, based on the results of the cattle feeding study requested in connection with food uses.

      5.1.7	Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by EFED in the following memorandum:  "Tier I Estimated Environmental Concentrations of Pyraflufen for the Use in the Human Health Risk Assessment" (D337845, M. Barrett, 2/29/2008).  

Due to its low persistence, pyraflufen-ethyl should not be available for runoff or leaching.  However, three metabolites were identified as major transformation products and are included in the drinking water assessment. The metabolite E-1 is moderately persistent, making it available for runoff during rain events occurring shortly after application.  E-3, the most persistent of three terminal degradates, generally appears at lower concentrations, later in time, and binds more strongly to soils.  E-3 should also be available for runoff in rain events accompanied with erosion.  There are no data available on the toxicity of the metabolites.  E-1, E-2 and E-3 are structurally similar to the parent pyraflufen-ethyl and as such are assumed to be of equal or lesser toxicity (MARC Decision memo, 07/19/02 and personal communication with A. Protzel and J. Doherty, 9/19/02).

Monitoring data for drinking water estimates are not available.  Models were used to calculate drinking water estimates.  Upper-bound Tier 1 EDWCs were calculated for pyraflufen-ethyl and its major residues E-1, E-2, and E-3, calculated using the FIRST model (surface water) and SCIGROW model (ground water).  Based on the highest application rate, the acute surface water EDWC value is 1247 ppt of total residues of pyraflufen-ethyl and its major degradates and the annual average surface water value is 281 ppt.  The ground water screening concentration from SCIGROW is 1.8 ppt.  These values generally represent upper-bound conservative estimates of the total residue concentrations that might be found in surface water and ground water due to the use of pyraflufen-ethyl.

Table 5.1.7.  Summary of Estimated Surface Water and Ground Water Concentrations for Pyraflufen-
Ethyl and Metabolites

                               Pyraflufen-Ethyl

                         Surface Water Conc., ppt [1]
                          Ground Water Conc., ppt[2]
                      Acute (maximum single-day exposure)
                                     1247
                                      1.8
                 Chronic (non-cancer, one in 10-year average)
                                      281
                                      1.8
[1] From the Tier I FIRST (FQPA Index Reservoir Screening Tool) model.  Input parameters are based on wheat, soybean, corn, pastures, sod farms, Christmas trees, nurseries, ornamental plantings, non-crop weed control; and for preplant burndown on root and tuber vegetables, cole crops, legumes, fruiting vegetables, cucurbits and small grains
[2] From the SCI-GROW model assuming a maximum seasonal use rate of 0.00325 lb ai/A for pasture and range, and 0.00122 lb ai/A for post-emergence use on corn, soybean and wheat, a Koc of approx. 2000.

EFED provided HED with Tier 2 EDWCs for crops associated with this action as well as updated EDWCs for existing crop uses (e:mail dated 3/10/11 from Michael Barrett to Paula Deschamp).  Tier 2 analysis for total residues of pyraflufen ethyl and it's metabolites/degradates E1, E2, and E3 shows that potatoes remain the highest exposure site with a maximum EDWC of 268 ppt for the long-term mean.

      5.1.8	Food Residue Profile

Crop Field Trials
The submitted field trial data for pome fruit, grapes and tree nuts are adequate.  There is sufficient geographic representation of residue data, and the field trials were conducted according to the proposed use pattern for flowable concentrate (FlC) and/or emulsifiable concentrate (EC) formulations of pyraflufen-ethyl.  Residues for apples, pears, grapes, almond nutmeat and pecan nutmeat were all below the combined LOQ for both the parent and metabolite; therefore, the recommended tolerances are 0.01 ppm in pome fruit (crop group 11), grapes, and tree nuts (crop group 12).  The recommended tolerance for almond hulls was calculated using the maximum residue limit (MRL)/maximum likelihood estimation (MLE) tolerance spreadsheets.  The calculated tolerance for almond hulls is 0.02 ppm.  The submitted field trial data for hops is not adequate because the report did not provide enough field trial information, including the location of the trials, the application rate, application method, if an adjuvant was used, meteorological data, and the soil characteristics. Residue data were not submitted for stone fruit (crop group 12), pistachios, olives, or pomegranates. However,  ChemSAC concluded that bridging the submitted data for pome fruit, tree nuts, and grapes to stone fruit (crop group 12), olives, and pomegranates was acceptable since the following criteria are met: 1) the pesticide is directed at the ground when applied, resulting in <LOQ residues in the edible RACs; 2) the application rate is low; and 3) uptake is low as demonstrated by results of rotational crop studies; and recommended tolerances of 0.01 ppm  for stone fruit (crop group 12), olives, and pomegranates(minutes, 1/13/2010). Currently, HED recommends the tolerance for the tree nut crop group be extended to pistachio.
                                       
Table 5.1.8.1.  Summary of Tree Nut Residue Data from Crop Field Trials with Pyraflufen-Ethyl (SC).
                                   Commodity
                              Total Applic. Rate
                                    lb ai/A
                                  (kg ai/ha)
                                  PHI (days)
                               Residue Levels[1]
                          (ppm in parent equivalents)
                                       
                                       
                                       
                                       n
                                     Min.
                                     Max.
                                    HAFT[2]
                                    Median
                                    (STMdR)
                                     Mean
                                    (STMR)
                                   Std. Dev.
                               Pyraflufen-Ethyl
                                 Pecan Nutmeat
                         0.0088-0.0090 (0.0099-(0.010)
                                      0-1
                                      10
                                   <0.005
                                   <0.005
                                   <0.005
                                   <0.005
                                   <0.005
                                      --
                                Almond Nutmeat
                                 0.0086-0.0089
                                (0.0096-0.010)
                                       0
                                      10
                                   <0.005
                                   <0.005
                                   <0.005
                                   <0.005
                                   <0.005
                                      --
                                 Almond Hulls
                                 0.0086-0.0089
                                (0.0096-0.010)
                                       0
                                      10
                                   <0.005
                                    0.0074
                                    0.0062
                                    0.0051
                                     0.005
                                    0.0008
                                      E-1
                                 Pecan Nutmeat
                         0.0088-0.0090 (0.0099-(0.010)
                                      0-1
                                      10
                                   <0.005
                                   <0.005
                                   <0.005
                                   <0.005
                                   <0.005
                                      --
                                Almond Nutmeat
                                 0.0086-0.0089
                                (0.0096-0.010)
                                       0
                                      10
                                   <0.005
                                   <0.005
                                   <0.005
                                   <0.005
                                   <0.005
                                      --
                                 Almond Hulls
                                 0.0086-0.0089
                                (0.0096-0.010)
                                       0
                                      10
                                   <0.005
                                   <0.005
                                   <0.005
                                   <0.005
                                   <0.005
                                      --
                            Pyraflufen-Ethyl + E-1
                                 Pecan Nutmeat
                         0.0088-0.0090 (0.0099-(0.010)
                                      0-1
                                      10
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      --
                                Almond Nutmeat
                                 0.0086-0.0089
                                (0.0096-0.010)
                                       0
                                      10
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      --
                                 Almond Hulls
                                 0.0086-0.0089
                                (0.0096-0.010)
                                       0
                                      10
                                   <0.01
                                    0.0124
                                    0.0112
                                     0.010
                                     0.011
                                    0.0008
1  The LOQ (0.005 ppm for each analyte) was used for all values reported as ND and <LOQ to determine the minimum, maximum, and HAFT and for the calculation of the median, mean and standard deviation.
2   HAFT = Highest Average Field Trial.

Processing Studies 
The submitted apple and grape processing studies are adequate.  The combined residues of pyraflufen-ethyl and Metabolite E-1 following a 5X application were <LOQ in/on apples and its processed fractions (juice and wet pomace) and grapes and its processed fractions (juice and raisins).  These data indicate that quantifiable pyraflufen-ethyl residues are unlikely to occur in apple or grape processed commodities following applications at the maximum proposed use rate. Therefore, tolerances for the processed commodities of apple and grape are not required for the purpose of this petition request.

Storage Stability
The available storage stability data on apples, grapes, and almond hulls adequately support the storage conditions and intervals for the apple, pear, grape, and almond hull samples from the current field trials.  No storage stability data are available for hops; however, the stability of pyraflufen-ethyl and Metabolite E-1 has been demonstrated in a variety of other crops, including wheat, and can be translated to hops.  Additionally, no storage stability data are available for pecan and almond nutmeat, but data can be translated from soybean and cotton seeds (oily seeds).  No storage stability data are required for the processed fractions from each of the processing studies, as all processed commodities were stored frozen for <1 month prior to analysis.  

The submitted storage stability data for pyraflufen-ethyl and Metabolite E-1 in milk and cattle tissues are adequate and support the stability of the combined residues in milk and all tissues for the intervals incurred during the feeding study. 

No storage stability data were submitted for Metabolite E-9.  A storage stability study for Metabolite E-9 in milk and liver under frozen conditions for 3 months is required. 

Meat, Milk, Poultry and Eggs
The additional cattle feeding study data adequately depict the levels of parent, Metabolite E-1 and Metabolite E-9 in cattle milk and tissues following 29 days of dosing with pyraflufen-ethyl at levels equivalent to 1.0, 3.1 and 9.8 ppm in the diet.  

Because quantifiable residues of Metabolite E-1 and Metabolite E-9 were found in all kidney samples from the 9.8 ppm dose group (5.4X the maximum reasonably balanced dietary (MRBD) burden; ranging from 0.019-0.045 ppm for Metabolite E-1 and ranging from 0.012-0.030 ppm for Metabolite E-9) and in one kidney sample (Metabolite E-1 at 0.012 ppm) from the 3.1 ppm dose group (1.7X MRBD burden), tolerances are required for the combined residues of pyraflufen-ethyl, Metabolite E-1, and Metabolite E-9 in meat byproducts from cattle, goats, horses and sheep.  Likewise, because detectable residues of Metabolite E-1 (maximum of 0.01 ppm) and Metabolite E-9 (maximum of 0.012 ppm) were found in some milk samples from the 9.8 ppm dose group (5.4X MRBD burden) and pyraflufen-ethyl was found in one milk sample (0.0107 ppm) from the 1.0 ppm dose group (0.56X MRBD burden), tolerances are required for the combined residues of pyraflufen-ethyl, Metabolite E-1, and Metabolite E-9 in milk.  These tolerances should be set at the combined LOQ (0.03 ppm) for the analytical method.  Furthermore, tolerances are also required for residues in meat and fat of cattle, goats, horses or sheep since there are no residue data reflecting nonquantifiable residues of pyraflufen-ethyl, E-1 and E-9 in meat and fat at the 18 ppm (10X dietary burden) feeding level to support a no reasonable expectation of finite residues situation.  

With regards to poultry and hog commodities, tolerances for residues in these commodities are not required for this petition.  Based on the data from the poultry and goat metabolism studies and the current cattle feeding study, and considering the low levels of dietary exposure for poultry and hogs (0.01 ppm), there is no reasonable expectation of finite residues occurring in poultry or hog commodities.

		5.1.9	International Residue Limits

There are no MRLs in Codex or Canada. There are currently no established Codex or Canadian maximum residue limits (MRLs) or tolerances for pyraflufen-ethyl on the proposed use sites (see Appendix B, Table B1).

	5.2	Dietary Exposure and Risk

          5.2.1 	Acute Dietary Exposure/Risk
          
 An acute dietary risk assessment was not performed as no adverse effect attributable to a single exposure (dose) was observed in oral toxicity studies; therefore, pyraflufen-ethyl has no acute toxicological endpoint.

       5.2.2	Chronic Dietary Exposure/Risk

Reference: Pyraflufen-ethyl. Chronic and Cancer Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action for Uses on Pome Fruit (crop group 11), Stone Fruit (crop group 12), Pomegranates, Olives, Grapes, Tree Nuts (crop group 14) and Pistachios.  DP#378643, L. Cheng, 2/8/2011.

A chronic aggregate (food and drinking water) dietary exposure and risk assessment was conducted using the DEEM-FCID, which uses food consumption data from the USDA's Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.  The analyses were performed to support Section 3 requests for the use of pyraflufen-ethyl on pome fruit, stone fruit, pomegranates, olives, grapes, tree nuts, and pistachios. 

The chronic dietary (food and drinking water) analysis was conducted for pyraflufen-ethyl, assuming tolerance level residues in the established and proposed commodities except corn, cottonseed, potato, soybean, wheat, pome fruit, stone fruit, pomegranate, olive, grape, tree nuts and pistachio for which (1/2) of the combined LOQs for the parent and the metabolite were used since all field trial data were <LOQ.  All processed commodities derived from the treated corn grain, soybean seeds, wheat grain, apple and grape had nondetectable residues; therefore, no processing factors were applied to those commodities.  A default processing factor of 6.5X was used for dry potato and a default processing factor of 1.5X was used for corn syrup.  An experimental processing factor of 0.6X was used for cotton seed oil.  One hundred percent crop treated (%CT) was assumed for all crop commodities. The anticipated residue value in milk was calculated to be 0.001 ppm. This analysis incorporates all current and proposed tolerances for the combined residues of pyraflufen-ethyl and Metabolite E-1 in plants and residues of pyraflufen-ethyl, Metabolite E-1 and Metabolite E-9 in animals.

Chronic (non-cancer) dietary exposure from drinking water was determined based on a Tier I model (surface water) estimate provided by EFED.  The estimate for drinking water was incorporated directly into the dietary assessment using the EDWC value of 281 parts per trillion (ppt) for the combined residues of pyraflufen-ethyl and its metabolic products, E-1, E-2, and E-3. 

The non-cancer chronic dietary (food and drinking water) exposure to pyraflufen-ethyl is below HED's level of concern [i.e., <100% Chronic Population Adjusted Doses (cPAD)] for the general U.S. population and all population subgroups.  The chronic dietary exposure estimates are <1% of cPAD for the general U.S. population and all population subgroups, including children 1-2 years old, the most highly exposed population subgroup. 

5.3	Cancer Dietary Risk

The cancer dietary exposure assessment was conducted using DEEM software, which incorporates consumption data from USDA's Continuing Surveys of Food Intake by Individuals (CSFII), 1994-1996, 1998.  Estimated cancer risk is determined for the general U.S. population only.  

HED is generally concerned when the cancer risk is no longer considered negligible, typically when the risk exceeds 10[-6].  The aggregate (food and water) cancer risk estimates associated with exposure to pyraflufen-ethyl for the general U.S. population is 2.7x10[-6].  Although some inputs into this assessment are refined, other inputs are very conservative, as high-end tolerance levels were used for some commodities, as well as the assumption of 100% crop treated. This result is conservative since the mean 0.281 ppt value EDWC determined for a  non-cancer model (1 in 10 year annual mean ) was used in the absence of an exposure estimate for cancer  risk (1 in 30 year annual mean EDWC). 

 Table 5.3.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Pyraflufen-Ethyl
                              Population Subgroup
                                       
                               cPAD (mg/kg/day)
                                Chronic Dietary
                                     Cancer
                                        
                                        
                                Dietary Exposure
                                  (mg/kg/day)
                                     % cPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
                               Q* = 3.32 x 10[-2]
                            General U.S. Population
                                       
                                      0.2
                                    0.000081
                                     <1
                                    0.000081
                                  2.7 x 10[-6]
                         All Infants (< 1 year old)
                                       
                                      0.2
                                    0.000119
                                     <1
                                     NA[2]
                                       NA
                             Children 1-2 years old
                                       
                                      0.2
                                    0.000228
                                     <1
                                        
                                        
                             Children 3-5 years old
                                       
                                      0.2
                                    0.000191
                                     <1
                                        
                                        
                            Children 6-12 years old
                                       
                                      0.2
                                    0.000122
                                     <1
                                        
                                        
                             Youth 13-19 years old
                                       
                                      0.2
                                    0.000080
                                     <1
                                        
                                        
                             Adults 20-49 years old
                                       
                                      0.2
                                    0.000064
                                     <1
                                        
                                        
                              Adults 50+ years old
                                       
                                      0.2
                                    0.000052
                                     <1
                                        
                                        
                            Females 13-49 years old
                                       
                                      0.2
                                    0.000059
                                     <1
                                        
                                        
[1]The population subgroup with the highest estimated chronic dietary (food + drinking water) 
exposure and risk is indicated by bold text.
[2]NA = not applicable
	
	5.4	Anticipated Residue and Percent Crop Treated (%CT) Information

The chronic dietary exposure analysis is partially refined in that one-half the combined LOQs of the parent and metabolite are used as the residue values rather than the tolerances (for corn, wheat, soybeans, cottonseed, potatoes, pome fruit, stone fruit, pomegranates, olives, grapes, tree nuts and pistachios).  However, the assessment assumed that 100% of crops are treated with pyraflufen-ethyl. In addition, drinking water exposure estimates were based on screening level estimates using Tier 1 estimates generated by the FIRST (surface water) and SCI-GROW (ground water) models.  Dietary estimates could be further refined through the use of percent crop treated data, as well as Tier II estimated drinking water concentrations.
 
6.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION
REFERENCE: Pyraflufen-ethyl:  Occupational and Residential Exposure Assessment for proposed non-food uses of pyraflufen-ethyl on cool season grasses (bluegrass, fescue, and ryegrass) and warm season grasses (Bahia grass, common Bermuda grass, centipede grass, St. Augustine grass, and zoysia grass), DP#361213, K.Rury, 01/14/2010. 

Pyraflufen-ethyl is registered for use on turf at residential and recreational use sites, and therefore, may result in residential handler exposure from mixing/loading and applying pyraflufen-ethyl, as well as post-application exposure to adults and children involved in recreational activities.  Exposure to adults and children from the use of pyraflufen-ethyl at recreational use sites are assumed to be the same as those assessed for residential use sites, and therefore, a separate recreational exposure assessment was not included.  Residential turf exposure assessment results in what are considered upper bound risk estimates.  Therefore, it is not expected that the upper bound residential exposure scenario would occur on the same day as an upper bound recreational exposure scenario.  Therefore, exposures from the residential and recreational scenarios are not aggregated.  Rather, the residential risk estimate should serve as an upper bound for both residential and recreational exposure.

	6.1	Residential Handler Exposure and Risk
      
Residential handlers may be exposed from mixing, loading and applying liquid pyraflufen-ethyl for spot treatment and/or broadcast control of weeds on ornamental lawns.  Mixing/loading and spot application of a liquid formulation with a low pressure hand sprayer for spot treatment of grasses, and mixing/loading and application via broadcast with a hose end sprayer was assessed. Exposure duration is expected to be short-term only and only inhalation risks are assessed because no dermal hazard was identified.  Although a point of departure from an oral study was used to assess residential handler inhalation risks for pyraflufen-ethyl, HED does not believe this assessment is under-protective of adult handlers.  MOEs calculated for residential handlers were all >35,000,000, thus providing an ample margin of safety to account for any uncertainties in route-to-route extrapolation.  Cancer risk was determined by multiplying a Q1* = 3.32 x 10[-2] mg/kg/day[-1] by the handler's combined dermal and inhalation exposures; dermal and inhalation exposures were assumed to be 100%.  Calculation inputs and results of this assessment are presented in Table 6.1.  Short-term inhalation MOEs range from 35,000,000 to 430,000,000.  These risks are not of concern to HED.  Cancer risks range from 2.8x10-8 to 4.7x10-8 and are not of concern to HED. 

Table 6.1.  Short-Term Exposure and Risk Estimates (MOE) and Cancer Risks for Homeowner Lawn/Garden Application with Pyraflufen-Ethyl 
                               Exposure Scenario
                                Crop or Target
                             App Rate (lb ai/A)[1]
                            Acres Treated Daily[2]
                        Dermal Unit Exposure (ug/lb ai)
                    Inhalation Unit Exposure (ug/lb ai)[3]
                             Dose Baseline Dermal
                          Dose Baseline Inhalation[4]
                           MOE5 Baseline Inhalation
                           Total LADD[6]
(mg/kg/day)
                                Cancer Risk[7]

                            Mixer/Loader/Applicator
Mixing/Loading and Spot application of Liquid Formulation with Low Pressure Hand Sprayer
                   Cool Season Grasses, Warm Season Grasses
                                     0.004
                                     0.023
                                      100
                                      30
                                    0.00015
                                  0.000000046
                                  430,000,000
                                    6.0E-07
                                    2.0E-08
Mixing/Loading and Broadcast Application of liquid formulation with (Hose-End Sprayer)
                   Cool Season Grasses, Warm Season Grasses
                                     0.004
                                      0.5
                                      11
                                      17
                                    0.00037
                                  0.00000057
                                  35,000,000
                                    1.4E-06
                                    4.7E-08
1 Application rate is based on maximum values found in proposed label: ET (2.5%)(EPA Reg. No. 71711-7) and ET (2%)(EPA Reg. No. 71711-25).
2 Area treated is based on the area that can be reasonably treated in a single day based on the application method (standard EPA/OPP/HED values  -  Policy 12).
3 Inhalation unit exposure values represent no respirator.  
4 Daily Dose (mg/kg/day) = (Unit Exposure x Application rate x Area treated) / 60 kg.
5 Short-Term MOE = NOAEL (20 mg/kg/day) / Daily Dose.  The LOC is 100.
[6] LADD= (Dermal Dose+Inhalation Dose) x average days of exposure (2 days /365 days)*(50 years/70 years)
[7] Cancer Risk Estimates = LADD * Q1*, where Q1*=3.32E-2 (mg/kg/day)

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

Toxicity endpoints were chosen by HED for short- and intermediate-term inhalation and oral exposures.  Post-application inhalation exposure is considered to be negligible.  However, non-dietary, incidental ingestion of residues from treated turfgrass and contaminated soil are possible for children (hand-to-mouth, object-to-mouth and soil ingestion).  While the NOAEL (20 mg/kg/day) is the same for both short- and intermediate-term oral toxicity, the standard assumptions (input values) for intermediate-term exposure are less conservative than those for short-term (e.g., short-term hand-to-mouth events = 20/hr; intermediate-term= 9.5/hr).  Therefore, only short-term exposure/risk is assessed as a worst-case for all children's post-application scenarios.  Intermediate-term risk is expected to be lower than that for short-term.  Post-application exposure assessments are summarized in Tables 6.2.1, 6.2.2, 6.2.3, 6.2.4, and 6.2.5.  All MOEs for each scenario are above 100, and therefore, are not of concern. 

Post-application dermal exposure is only estimated for adults for use in estimating adult cancer risk.  Intermediate-term standard assumptions (input values for transfer coefficients), are used instead of the more conservative short-term assumptions for cancer assessments, because the effect is determined for a life-time of exposure (50 years).

The residential exposure estimates for adult dermal and three children's incidental oral scenarios are assessed for the day of application (day "0") because it is assumed that residential contact with the lawn can occur immediately after application.  Chronic exposure is not expected (i.e., these activities are not expected to occur continuously for more than 6 months).  
        
Adult cancer risk from dermal contact with treated lawn (summarized in Table 6.2.5) is estimated as 7.6x10[-7] and is not of concern to HED.  Adult golfer cancer risk from dermal contact with treated turf (also summarized in Table 6.2.5) is estimated as 1.4x10[-7] and is not of concern to HED.

Table 6.2.1.  Oral Hand-to-Mouth Exposure and Risk for Children From Treated Lawns
                        Application Rate (AR) (lb ai/A)
                         Fraction of ai Available (F)
                 Turf Transferable Residue (TTR)[1] (ug/cm[2])
                            Exposure Time (hrs/day)
                           Extraction by Saliva (EX)
                     Hand Surface Area (SA) (cm[2]/event)
                          Frequency (FQ) (events/hr)
                               Body Weight (kg)
                            Daily Dose2 (mg/kg/day)
                               Short Term MOE[3]
                                     0.004
                                     0.05
                                    0.0022
                                       2
                                      0.5
                                      20
                                      20
                                      15
                                   5.98E-05
                                    330,000
   1     Turf Transferable Residue = TTR = AR*F*CF2(4.54E08 ug/lb)*CF3(2.47E-8 acre/cm[2]).
   2     Potential Dose Rate (PDR) on Day '0' (mg/kg/day)=TTR*SA*EX*FQ*ET*CFI1 (0.001mg/ug). 
   3     MOE = NOAEL/Daily Dose where the NOAEL = 20 mg/kg/day.

Table 6.2.2.     Exposure and Risk for Children from Object-to-Mouth (Turfgrass) from Treated Lawns
                         Application Rate (AR) lb ai/A
                         Fraction of ai available (F)
                        Grass Residue (GR) (ug/cm2)[1]
                         Mouthing Rate (IgR) (cm2/day)
                               Body Weight (kg)
                           Daily Dose[2] (mg/kg/day)
                               Short Term MOE[3]
                                     0.004
                                      0.2
                                    0.0090
                                      25
                                      15
                                   1.50E-05
                                   1,300,000
1    GR = AR*F*CF2 (4.54E8 ug/lb)*CF3 (2.47E-8 acre/cm2).
2     Potential Dose Rate on Day `0' (mg/kg/day) = GR*IgR*CF1 (.001 mg/ug).
3     MOE = NOAEL/Daily Dose where the NOAEL = 20 mg/kg/day.

Table 6.2.3.     Exposure and Risk for Children from Ingestion of Soil from Treated Lawns
                       Application Rate (AR)
 (lb ai/A)
                         Fraction of ai Available (F)
                          Soil Residue (SR) (ug/g)[1]
                         Ingestion Rate (IgR) (g/day)
                               Body Weight (kg)
                           Daily Dose[2] (mg/kg/day)
                               Short Term MOE[3]
                                     0.004
                                       1
                                     0.030
                                      100
                                      15
                                   2.00E-07
                                  100,000,000
   1 SR =AR*F*CF2(4.54E8 ug/lb)*CF3(2.47E-8 acre/cm2)*CF4(0.67 cm3/g soil).
   2 PDR for incidental ingestion of soil = SR*IgR*CF1 (1E-6 g/ug) and 
   3 MOE = NOAEL/Daily Dose where the NOAEL = 20 mg/kg/day.

Table 6.2.4.     Combined Short Term MOE[1]

                                   Scenario
                                     Dose
                                 Combined MOE
                              Oral Hand-to-Mouth
                                   5.98E-05
                                    270,000
                                Object to Mouth
                                   1.50E-05
                                       
                               Ingestion of Soil
                                   2.00E-07
                                       
 1 Total MOE=[1/(Oral Hand-to-Mouth Dose+Object-to-mouth Dose+Ingestion of Soil Dose)]*NOAEL (20 mg/kg/day)
 

Table 6.2.5.     Adult Residential Post Application Exposure and Cancer Risk from Dermal Contact with Treated Lawns
                                   Scenario
                          Application Rate (lb ai/A)
                           Fraction of ai Available
                      Turf Transferrable Residue (ug/cm)
                            Exposure Time (hrs/day)
                         Transfer Coefficient (cm2/hr)
                               Body Weight (kg)
                            Daily Dose[1] (mg/kg/d)
                                    Dermal
                                    LADD[2]
                                Cancer Risk[3]
                    Residential Contact with Treated Turf 
                                     0.005
                                     0.05
                                    0.0028
                                       2
                                     7300
                                      70
                                    0.00058
                                   2.29E-05
                                   7.60E-07
                                 Adult Golfer 
                                     0.005
                                     0.05
                                    0.0028
                                       4
                                      500
                                      70
                                   0/0000801
                                   3.13E-06
                                   1.04E-07
1   Daily Dose = unit exposure*Application Rate*Area treated)/body weight
2    LADD= (Dermal Cancer Dose)*average days of exposure (1)/year x 50 years of expected exposure/(365 days/year x 70 year lifetime)
3    Cancer Risk = LADDxQ1*; where Q1*=3.32E-2 (mg/kg/day)

7.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  For pyraflufen-ethyl, potential exposures from food, drinking water, and residential scenarios were aggregated.

	7.1 	Acute Aggregate Risk

No adverse effect attributable to a single exposure (dose) was observed in oral toxicity studies, including the developmental toxicity studies in rats and rabbits.  Therefore, an acute reference dose was not established and an acute aggregate risk assessment was not conducted.

	7.2	Short- and Intermediate-Term Aggregate Risk

 The short-term aggregate risk assessment estimates risks likely to result from 1- to 30-day exposure to pyraflufen-ethyl residues from food, drinking water, and residential pesticide uses.  High-end estimates of residential exposure are used in the short-term assessment, while average values are used for food and drinking water exposure (i.e., chronic exposures).
 
 The same endpoints were identified for short-term incidental oral and inhalation risk assessment. No hazard via the dermal route was identified, therefore this route of exposure is not included in the aggregate assessment. 
 
Short-term aggregate risk is based on residential handler exposure, children's incidental oral exposure (from residential post-application treatment) and dietary exposure (food and drinking water).  The anticipated exposure level for children, 1-2 years old (the highest exposed population) is below HED's LOC, with an MOE of 66,000.  

An intermediate-term aggregate risk assessment was not conducted for adults because exposure duration is expected to be short-term only.  In addition, an intermediate-term aggregate risk assessment was not conducted for children (post-application exposure) because standard assumptions (input values) for intermediate-term exposure are less conservative than those for short-term exposure.  

Estimated aggregate (food + water + residential) exposure to adults and children from pyraflufen-ethyl residues is below HED's LOC.

Table 7.2.  Short- and Intermediate-Term Aggregate Risk Calculations.
                                       
                                  Population
                     Short- or Intermediate-Term Scenario
                                       
                                     NOAEL
                                   Mg/kg/day
                                    LOC[1]
                                 Max Allowable
                                  Exposure[2]
                                   mg/kg/day
                                    Average
                               Food & Water
                                   Exposure
                                   mg/kg/day
                            Residential Exposure[3]
                                   mg/kg/day
                                 Aggregate MOE
                                   (food and
                                residential)[4]
                                  Adult Male
                                      20
                                      100
                                      0.2
                                   0.000081
                                  0.00000057
                                    250,000
                                 Adult Female
                                      20
                                      100
                                      0.2
                                   0.000081
                                  0.00000057
                                    250,000
                            Children, 1-2 years old
                                      20
                                      100
                                      0.2
                                   0.000228
                                   0.000075
                                    66,000
[1] Interspecies variability = 10x, Intraspecies variability = 10x, FQPA Factor = 1x
[2] Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC
[3] Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure].  Dermal Exposure is not a concern since no effects were observed at the Limit Dose in a 28-day dermal study.
[4] Aggregate MOE = [NOAEL/(Avg Food & Water Exposure + Residential Exposure)]

	7.3	Chronic Aggregate Risk

Chronic exposure from the residential pathway is not anticipated based on the current/proposed use pattern. The chronic aggregate risk (food and drinking water) is below HED's LOC (i.e., <100% cPAD for the general U.S. population and all population subgroups).   Using the DEEM-FCID software, dietary exposure is estimated at 0.000081 mg/kg/day for the general U.S. population (<1% of the cPAD) and 0.000228 mg/kg/day (<1% of the cPAD) for children one - two years old, the population subgroup with the highest estimated chronic dietary exposure to pyraflufen-ethyl.   See Section 5.2 for details.

	7.4	Aggregate Cancer Risk

The aggregate cancer risk assessment for the general U.S. population takes into account exposure estimates from dietary consumption of pyraflufen-ethyl from food, residential and drinking water sources.  Exposures from residential uses are based on the lifetime average daily dose and assume an exposure period of 5 days per year and 50 years of exposure in a lifetime (70 years).  Average food+water source dietary exposure was used.  Estimated cancer risk for the general U.S. population includes infants and children; therefore, in accordance with HED Policy, a children's cancer risk estimate was not reported separately.

HED is concerned when the cancer risk is no longer considered negligible, typically when the risk exceeds 10[-6].   The aggregate cancer risk estimate for pyraflufen-ethyl is 2.8 x 10[-][6].  Therefore, aggregate cancer risk estimate from pyraflufen-ethyl residues in food and drinking water is not of concern to HED for the general U.S. population.

Table 7.4.  Aggregate Cancer Calculations. 
                                  Population
                                      Q*
                                  Negligible
                                  Risk Level
                           Chronic Food & Water
                              Exposure mg/kg/day
                                  Residential
                                   Exposure
                                    (LADD)
                                   mg/kg/day
                                   Aggregate
                                  Cancer Risk
                               (food, water and
                                residential)[1]
                                   U.S. Pop
                                    0.0332
                                    10[-6]
                                   0.000081
                                  2.29x10[-5]
                                 2.8 x 10[-6]
1 Aggregate MOE Cancer = Q* x [Chronic Food & Water Exposure + Residential Exposure (Lifetime Average Daily Dose).

8.0	CUMULATIVE RISK

 Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for pyraflufen-ethyl and any other substances, and pyraflufen-ethyl does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA assumed that pyraflufen-ethyl does not have a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

9.0	OCCUPATIONAL EXPOSURE AND RISK

Reference: Pyraflufen-Ethyl:  Occupational and Residential Exposure Assessment for proposed uses of pyraflufen-ethyl on the tree nut, pome fruit, and stone fruit crop groups, hops, grapes, olives and pomegranates, DP#378642, K.Rury, 12/14/2010. 

Pyraflufen-ethyl may be applied to post-harvest, dormant, pre-bloom, and in-season tree nuts, pome fruits, hops, grapes, olives, stone fruits, and pomegranates for control of broadleaf weeds.  Pyraflufen-ethyl may be applied at a rate of 0.0013 to 0.0053 lb pyraflufen-ethyl per acre via ground application.  Pyraflufen-ethyl may not be applied via chemigation or aerially to the proposed use sites.  Up to 3 applications may be made per year to post-harvest, dormant, or pre-bloom use sites, and up to 2 applications may be made per year to in season crops.  The maximum seasonal application rate is 0.009 lb pyraflufen-ethyl per acre.  

	9.1	Occupational Handler

There is a potential for exposure to pyraflufen-ethyl during mixing, loading and application activities.  An exposure/risk assessment using applicable endpoints selected by HED was performed. Handler's exposure and risk were estimated for the following scenarios: 
            * Mixing and loading liquid formulation 
            * Applying with a groundboom 

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

Table 9.1.1. Exposure and Risk Estimates (MOE) for Occupational Application of Pyraflufen-Ethyl 
                               Exposure Scenario
                             App Rate (lb ai/A)[1]
                            Acres Treated Daily[2]
                      Inhalation Unit Exposure (mg/lb ai)
                          Inhalation Dose Baseline[3]
                          Inhalation MOE Baseline[4] 

                                 Mixer/Loader
             Mixing and Loading a Liquid Formulation (Groundboom)
                                    0.0053
                                      80
                                    0.0012
                                   0.0000085
                                   2,400,000
                                  Applicator
                  Applying with Groundboom - Open Cab (PHED)
                                    0.0053
                                      80
                                    0.00074
                                   0.0000052
                                   3,800,000
   1.  Application rate is based on maximum values found in proposed label: ET (2% ai, EPA Reg. No 71711-25) and ET (2.5% ai, EPA Reg. No. 71711-7).
   2.  Area treated is based on the area that can be reasonably treated in a single day based on the application method (standard EPA/OPP/HED values)
   3.  Daily Dose (mg/kg/day) = (Unit Exposure x Application rate x Area treated) / 60 kg.
   4.  Short- and Intermediate-Term MOE = NOAEL (20 mg/kg/day) / Daily Dose.  The LOC is 100.

A MOE of 100 is adequate to protect occupational pesticide handlers from short-term and intermediate-term exposures to pyraflufen-ethyl.  The proposed use patterns do not exceed HED's LOC for non-cancer risks.  Intermediate-term exposures are not expected.  However, the intermediate-term inhalation NOAEL is also 20 mg ai/kg bw/day.  Therefore, the estimates of short-term risk are adequate to describe the risks from intermediate-term exposures should they occur.

Tables 9.1.2 and 9.1.3 show the estimated cancer risk for workers in baseline clothing, engaged in open mixing/loading liquids to support groundboom application is 2.8x10[-5] for commercial applicators (assumed to apply pyraflufen-ethyl 30 days per year) and 9.3x10[-6] for private applicators (assumed to apply pyraflufen-ethyl 10 days per year).  The estimated cancer risks for mixer/loaders in baseline clothing plus gloves is 2.3x10[-7] for commercial workers and 7.8x10[-3] for private workers.  The estimated cancer risks is 1.4x10[-7] for commercial applicators in baseline clothing plus gloves and is 4.7x10[-8] for private applicators in baseline clothing plus gloves.

                                       
Table 9.1.2. Cancer Risk Estimates for Commercial Application of Pyraflufen-Ethyl 
                               Exposure Scenario
                             App Rate (lb ai/A)[1]
                            Acres Treated Daily[2]
                        Dermal Unit Exposure (mg/lb ai)
                     PPE-G Dermal Unit Exposure (mg/lb ai)
                    Inhalation Unit Exposure (mg/lb ai)[3]
                            Dose Baseline Dermal[4]
                              PPE Dermal Dose[4]
                          Dose Baseline Inhalation[4]
                        Commercial LADD[5]
(mg/kg/day)
                      Commercial LADD PPE[6] (mg/kg/day)
                      Commercial Baseline Cancer Risk[7]
                         Commercial PPE Cancer Risk[8]

                                 Mixer/Loader
             Mixing and Loading a Liquid Formulation (Groundboom)
                                    0.0053
                                      80
                                      2.9
                                     0.023
                                    0.0012
                                    0.0205
                                   0.000163
                                   0.0000085
                                   8.43E-04
                                  7.0279E-06
                                    2.8E-05
                                    2.3E-07
                                  Applicator
                  Applying with Groundboom - Open Cab (PHED)
                                    0.0053
                                      80
                                     0.014
                                     0.014
                                    0.00074
                                   0.000099
                                   0.000099
                                   0.0000052
                                    4.3E-06
                                    4.3E-06
                                    1.4E-07
                                    1.4E-07
1 Application rate is based on maximum values found in proposed label: ET (2%) (EPA Reg. NO 71711-25) and ET (2.5%) (EPA Reg. No. 71711-7) . 
                                       
                                       
2 Area treated is based on the area that can be reasonably treated in a single day based on the application method (standard EPA/OPP/HED values).
3 Inhalation unit exposure values represent no respirator.  
4 Daily Dose (mg/kg/day) = (Unit Exposure x Application rate x Area treated) / 60 kg.
                                       
                                       
                                       
                                       
                                       
                                       
5 LADD= (Dermal Dose+Inhalation Dose) x average days of exposure (30/365) x (35 years/70 years).
                                       
                                       
                                       
                                       
                                       
6 LADD =(Dermal PPE Dose+Inahaltion Dose) x average days of exposure (30/365) x (35 years/70 years).
7 Cancer Risk Estimates = LADD x Q1*, where Q1*=3.32E-2 (mg/kg/day).
                                       
                                       
                                       
                                       
                                       
                                       
                                       
8 Cancer Risk PPE Estimates = LADD PPE x Q1*, where Q1*=3.32[-2] (mg/kg/day).

	
Table 9.1.3. Cancer Risk Estimates for Private Application of Pyraflufen-Ethyl 
                               Exposure Scenario
                             App Rate (lb ai/A)[1]
                            Acres Treated Daily[2]
                        Dermal Unit Exposure (mg/lb ai)
                     PPE-G Dermal Unit Exposure (mg/lb ai)
                    Inhalation Unit Exposure (mg/lb ai)[3]
                            Dose Baseline Dermal[4]
                              PPE Dermal Dose[4]
                          Dose Baseline Inhalation[4]
                          Private LADD[5]
(mg/kg/day)
                        Private LADD PPE[6] (mg/kg/day)
                        Private Baseline Cancer Risk[7]
                          Private PPE Cancer Risk[8]

                                 Mixer/Loader
             Mixing and Loading a Liquid Formulation (Groundboom)
                                    0.0053
                                      80
                                      2.9
                                     0.023
                                    0.0012
                                    0.0205
                                   0.000163
                                   0.0000085
                                   0.0002808
                                   2.34E-06
                                    9.3E-06
                                    7.8E-08
                                  Applicator
                  Applying with Groundboom - Open Cab (PHED)
                                    0.0053
                                      80
                                     0.014
                                     0.014
                                    0.00074
                                   0.000099
                                   0.000099
                                   0.0000052
                                   1.427E-06
                                   1.43E-06
                                    4.7E-08
                                    4.7E-08
1 Application rate is based on maximum values found in proposed label: ET (2%) (EPA Reg. NO 71711-25) and ET (2.5%) (EPA Reg. No. 71711-7) .

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

3 Inhalation unit exposure values represent no respirator.  
4 Daily Dose (mg/kg/day) = (Unit Exposure x Application rate x Area treated) / 60 kg.
                                       
                                       
                                       
                                       

5 LADD= (Dermal Dose+Inhalation Dose) x average days of exposure (10/365) x (35 years/70 years).
                                       
                                       
                                       

6 LADD =(Dermal PPE Dose+Inahaltion Dose) x average days of exposure (10/365) x (35 years/70 years).
                                       
                                       
                                       

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

8 Cancer Risk PPE Estimates = LADD PPE x Q1*, where Q1*=3.32[-2] (mg/kg/day).

	9.2	Occupational Post-Application

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide.  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on the type of activity, the nature of the crop or target that was treated, the type of pesticide application, or the pesticide's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.  

HED believes that the potential for dermal post-application worker exposure is low, provided the 24 hour restricted entry interval (REI) stated on the proposed label is observed.  As there is no dermal endpoint, dermal non-cancer post-application risks were not assessed.  Occupational post-application cancer risks were also not evaluated based on the proposed pyraflufen-ethyl use pattern.  Pyraflufen-ethyl is applied to crop foliage as a burndown treatment only, minimizing potential for worker post-application exposure.  In all other cases, the proposed target sites of pyraflufen-ethyl are broadleaf weeds and grasses.  Therefore, a post-application risk assessment was not performed.  

Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment was not performed for pyraflufen-ethyl at this time.  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for pyraflufen-ethyl.

      9.3	Restricted Entry Interval (REI)

Pyraflufen-ethyl is classified as Acute Toxicity Category III for acute dermal toxicity and for primary eye irritation.  It is classified as Toxicity Category IV for acute inhalation toxicity and primary skin irritation.  It is not a dermal sensitizer.   Therefore the interim worker protection standard (WPS) restricted entry interval (REI) of 12 hours is adequate to protect agricultural workers from post-application exposures to pyraflufen-ethyl as might result from the proposed new use pattern.  

Appendix A. Toxicology Profile 

A.1. 	Toxicity Profile of Pyraflufen-Ethyl
 
 Table A.1.1.  Acute Toxicity of Pyraflufen-ethyl.
                                   Guideline
                                      No.
                                  Study Type
                                    MRID #
                                    Results
                               Toxicity Category

                                   870.1100
                                     81-1

                                  Acute Oral

                                   45327615

                             LD50 > 5000 mg/kg

                                      IV

                                   870.1200
                                     81-2

                                 Acute Dermal

                                   45327613

                             LD50 > 2000 mg/kg

                                      III

                                   870.1300
                                     81-3

                               Acute Inhalation

                                   45282821

                              LC50 > 5.03 mg/L

                                      IV

                                   870.2400
                                     81-4

                            Primary Eye Irritation

                                   45327614

                              moderate irritation

                                      III

                                   870.2500
                                     81-5 

                            Primary Skin Irritation

                                   45282823

                                 no irritation

                                      IV

                                   870.2600
                                     81-6

                             Dermal Sensitization

                                   45282824

                                non-sensitizing

                                      N/A
 
 
Table  A.1.2.     Non-acute Toxicity Profile for Pyraflufen-Ethyl.
                        Guideline Number and Study Type
                                    Results

870.3100
13-Week Feeding in Rats; 1994; 
Dose Levels: 0, 200, 1000, 5000 or 15,000 ppm (representing 0, 17.8, 85.6,455.5 and 1489.4 mg/kg/day (M); 0, 19.4, 95.4, 499.0 and 1502.9 mg/kg/day (F); 10 rats/sex/group

NOAEL = 5000 ppm (456-499 mg/kg/day).
LOAEL = 15,000 ppm (1489-1503 mg/kg/day) based on clinical signs, death, effects on erythrocytes, changes in clinical chemicals for liver function and splenomegaly

870.3150
13-Week Feeding Study in Dogs-capsule; 1996;
Dose Levels: 0, 40, 200 or 1000 mg/kg/day
4 dogs/sex/group

NOAEL = 1000 mg/kg/day.
LOAEL not established.  No effects observed.

870.3200
28-Day Dermal Toxicity in Rats; (2000);
Dose Levels: 0, 100, 300 or 1000 mg/kg/day; 10 rats/sex/group;
Application: 6-7 hr/day, 7 days/week for 29 days

NOAEL = 1000 mg/kg/day.
LOAEL not established.  No effects observed.

870.3700a
Developmental Toxicity Study in Rats; 1995;
Dose Levels: 0, 100, 300 or 1000 mg/kg/day; 22 females/sex/group 

Maternal NOAEL > 1000 mg/kg/day.
Maternal LOAEL not determined; no effects observed.

Developmental NOAEL  > 1000 mg/kg/day.
Developmental LOAEL not determined; no effects observed.

870.3700b
Developmental Toxicity in Rabbits; 1996;
Dose Levels: 0, 20, 60 or 150 mg/kg/day; 15 females/group

Maternal NOAEL = 20 mg/kg/day. 
Maternal LOAEL= 60 mg/kg/day based on mortality.

Developmental = 60 mg/kg/day.
Developmental LOAEL = 150 mg/kg/day based on increased incidence of abortion.

870.3800
2-Generation Reproduction Study in Rats; 1996; 
Dose Levels: 0, 100, 1000 or 10, 000 ppm (representing 0, 6.84, 70.8 and 721 mg/kg/day (F0[M]); 0, 7.78, 80.1 and 813 mg/kg/day (F0[F]); 0, 8.10, 82.3 and 844 mg/kg/day (F1[M]); 0, 9.06, 91.2 and 901 mg/kg/day (F1[F])
24 rats/sex/group

Parental NOAEL = 1000 ppm (70.8-82.3 mg/kg/day [M]; 80.1-91.2 [F].
Parental LOAEL = 10,000 ppm (721-844 and 813-901 mg/kg/day) based on decreased bwt and bwt gains of F0 and F1(M) and F1(F), gross and microscopic liver lesions of (M) and (F)-both generations.

Reproductive NOAEL > 10,000 ppm (721-844 and 813-901 mg/kg/day).
Reproductive LOAEL not determined. No effects observed.

Offspring NOAEL = 1000 ppm (70.8-82.3 mg/kg/day [M]; 80.1-91.2 [F].
Offspring LOAEL = 10, 000 ppm (721-844 and 813-901 mg/kg/day) based on decreased bwt and bwt gains of the F1 and F2 pups.

870.4100a/870.4200
2-year Feeding Study/Carcinogenicity in Rats; 1996;
Dose Levels: 0, 80, 400, 2000 or 10,000 ppm (representing 0, 3.4, 17.2, 86.7 and 468.1 mg/kg/day (M); 0, 4.4, 21.8, 11.5 and 578.5 mg/kg/day (F)
70 rats/sex/group

NOAEL = 2000 ppm (86.7 mg/kg/day (M); 111.5 mg/kg/day (F).
LOAEL = 10,000 ppm (468.1 mg/kg/day(M); 578.5 mg/kg/day (F) based on decreased bodyweight (bwt) and bodyweight gain in males and microcytic anemia, liver lesions and kidney toxicity (both sexes); possible increase pheochromocytomas in females

870.4100a/870.4300
78-Week Carcinogenicity Study in Mice; 1996;
Dose Levels: 0, 200, 1000 or 5000 ppm (representing 0, 20.99, 109.7 and 546.8 mg/kg/day (M); 0, 19.58, 98.3, and 523.7 mg/kg/day (F)
60 mice/sex/group

NOAEL = 200 ppm (20.99 mg/kg/day (M); 19.58 mg/kg/day (F).
LOAEL = 1000 ppm (109.7 mg/kg/day (M); 98.3 mg/kg/day (F) based on liver toxicity, hepatocellular tumors at 5,000 ppm; possibly hemangioma/ hemangioasarcomass.

870.4100b
52-Week Feeding in Dogs-capsule; 1996;
Dose Levels: 0, 40, 200 or 1000 mg/kg/day
4 dogs/sex/group

NOAEL > 1000 mg/kg/day.  LOAEL not determined; no effects observed.

A.2.	Toxicology Data Requirements

875.1300  Inhalation Exposure

●	Since the proposed use pattern will result in repeated inhalation exposure, a 28-day inhalation toxicity study is being required.  Pyraflufen-ethyl may qualify for a waiver from the requirement of the 28-day inhalation toxicity study (see SOP 2002.01- HED Standard Operating Procedure: Guidance: Waiver Criteria for Multiple-Exposure Inhalation Toxicity Studies, 08/15/02).

870.6200  Acute and Subchronic Neurotoxicity Studies

●	Acute and subchronic neurotoxicity studies are now required under the revised 40 CFR §158.340 guidelines.

870.7800  Immunotoxicity Study

●	An immunotoxicity study in rats and/or mice is now required under the revised 40 CFR §158.340 guidelines.

Appendix B.	 Residue Chemistry

B.1.	US and International Tolerances and MRLs 

Table B1. Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition:
US
Canada
Mexico[2]
Codex[3]
40 CFR 180.585:
Plant:  Pyraflufen-ethyl, ethyl 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenoxyacetate, and its acid metabolite, E-1, 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenoxyacetic acid, expressed in terms of the parent 
Livestock:  Pyraflufen-ethyl  and its metabolites E-1 and E-9 (2-chloro-5-(4-chloro-5-difluoromethoxy-1H-pyrazol-3-yl)-4-fluorophenoxyacetic acid), expressed in terms of the parent
None

None
Commodity[1]
Tolerance (ppm) /Maximum Residue Limit (mg/kg)

                                      US
Canada
Mexico[2]
Codex
Grape
                                     0.01
                                                                               

                                                                               
Fruit, pome, group 11
                                     0.01
                                                                               

                                                                               
Fruit, stone, group 12
                                     0.01
                                                                               

                                                                               
Nut, tree, group 14
                                     0.01
                                                                               

                                                                               
Almond, hulls
                                     0.02
                                                                               

                                                                               
Pistachio
                                     0.01
                                                                               

                                                                               
Pomegranate
                                     0.01
                                                                               

                                                                               
Olive
                                     0.01
                                                                               

                                                                               
Milk
                                     0.03
                                                                               

                                                                               
Cattle, meat byproducts
                                     0.03
                                                                               

                                                                               
Goat, meat byproducts
                                     0.03
                                                                               

                                                                               
Horse, meat byproducts
                                     0.03
                                                                               

                                                                               
Sheep, meat byproducts
                                     0.03
                                                                               

                                                                               
Completed:  M. Negussie; 11/02/2010

REFERENCES:

Pyraflufen-ethyl:  Occupational and Residential Exposure Assessment for proposed non-food uses of pyraflufen-ethyl on cool season grasses (bluegrass, fescue, and ryegrass) and warm season grasses (Bahia grass, common Bermuda grass, centipede grass, St. Augustine grass, and zoysia grass), DP#361213, K. Rury, 01/14/2010. 

Pyraflufen-Ethyl:  Occupational and Residential Exposure Assessment for proposed uses of pyraflufen-ethyl on the tree nut, pome fruit, and stone fruit crop groups, hops, grapes, olives and pomegranates, DP#378642, K. Rury, 12/14/2010. 

Tier I Estimated Environmental Concentrations of Pyraflufen for the Use in the Human Health 
Risk Assessment; DP#337845, M. Barrett, 2/29/2008.  
 
Pyraflufen-ethyl: Human Health Risk Assessment for Pyraflufen-ethyl: Proposed New Use on Pasture and Rangeland Grasses (PP#7F7190) and Amendment to Allow Early Season Postemergence Broadcast Uses to Corn (excluding sweet corn), Soybeans, and Wheat and Proposed Increased Tolerances on Soybean Forage and Hay (PP#1F6248); DP#339360, M. Ottley, 04/17/2008.

Pyraflufen-ethyl.  Chronic and Cancer Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action for Uses on Pome Fruit (crop group 11), Stone Fruit (crop group 12), Pomegranates, Olives, Grapes, Tree Nuts (crop group 14) and Pistachios; DP#378643, L. Cheng, 02/08/2011. 

Pyraflufen-ethyl: Proposed New Use on Pome Fruit (crop group 11), Stone Fruit (crop group 12), Pomegranates, Olives, Hops, Grapes, Tree Nuts (crop group 14), and Pistachios.  Summary of Analytical Chemistry and Residue Data; DP#377361, 377365, L. Cheng, 02/07/2011.  

Pyraflufen-ethyl: Human Health Risk Assessment for a Section 3 Registration of New Non-Food Uses on Established Ornamental Turf Lawns (Residential, Industrial, and Institutional), Parks, Cemeteries, Athletic Fields, Golf Courses (Fairways, Aprons, Tees and Roughs), Sod farms, and Similar Turf Areas; DP#361213, 361214, M. Negussie, 02/24/2010.