### UNITED STATES ENVIRONMENTAL PROTECTION AGE N CY WASHINGTON, D.C. 20460



### MEMORANDUM

Date : April 16, 2014 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Pyraflufen-Ethyl. Human Health Assessment Scoping Documen t in Support of Registration Review.

PC Code: 030090 DP Barcode: 0417684 Decision No.: 487210 Registration No.: NA Petition No.: NA Regulatory Action: Registration Review Scoping Document Risk Assessment Type: NA Case No.: NA TXR No.: NA CAS No.: 129630-17-7 MRID No.: NA 40 CFR: § 180.585


### F R OM: Kristin Rury, Biologist \- 

# Q**~** Myron Ottley , Senior

# Toxic**cl ~i** **~(Q~** Nancy Dodd, Chemist**;J~ ,()~**  

### Risk Assessmen t Branch III / Health E ffects Division (7509P) Office of Pesticide Programs**~** 

### THROUGH: Christine Olinger, Branch Chief /

. Risk Assessmen t Branch III Health Effects Division (7509P) Office of Pesticide Programs


### TO: Steven Snyderman, Chemical Review Manager Pesticide Re-Evaluation Division (7508P) Office of Pesticide Programs

Attached is the Health Effec t s Division's (HED) human health Registration Review scoping document for the herbicide pyraflufen-ethyl.


### Executive Summary

HED has evaluated recent human hea l th assessments for pyraflufen-ethyl, ethyl 2-[2-chloro-5-[ 4- chloro-5-(difluoromethoxy)-1-methyl-lH-pyrazol-3-yl]-4-fluorophenoxy ]acetate, to determine whether sufficient data are available and whether any updates are needed t o support Registration Page 1 of25

### Review. To determine the scope of work necessary to support Registration Review, HED has considered updates to Agency science policy and risk assessment methodologies and to the pyraflufen-ethyl toxicity, exposure , and usage databases. Pyraflufen

- ethyl is a phenyl pyrazole herbicide , registered for agricultural use as a preplant burndown app li cation , and as a pre- and post

- emergent applica t ion

. Based on the currently registered uses, exposures to pyraflufen

- ethyl can be expec t ed to occur via the dietary (food and drinking water), occupational (handler and post

- applica t i on), and r esidential (handler and postapplication) exposure pathways and via the ora l , dermal , and inha l ation routes of exposure.
The registered uses of pyraflufen-ethy l include: pre -pl an t burndown applicat i on to bu l b vegetables , cereal gra i ns, co l e crops, cucurbits, fruiting vegetables, leafy vegetables, legumes, oil seeds, r oot and tuber vegetables, and sugarcane; application t o non-bearing dates , feijoa, figs , kiwi fruit, mango and persimmon; and in

- seaso n application to corn , cotton, g r apes, olives, peanuts, pistachios, pomegranates, pome fruit (Crop Group 11-1 0), potatoes , sma ll grains, soybean, stone fruit (C r op Group 12), tree nuts (Crop Group 14) , and wheat. Pyraflufen

- ethy l is
a l so registered for use in/around non-agricultural areas including : a i rports; athletic fie l ds; barrier strips and fire breaks; Christmas trees; cemeteries; crop stubble; commercial p l ants; equipment
areas ; fa ll ow beds; fue l tank fanns; golf courses; nurseries; ornamental t urf and plantings; rights of way; sod farms; s t orage and lumber yards; pasture and rangeland; and uncul t ivated areas/conse r vation reserve program areas.
The pyraflufen-ethyl tox i city database is complete, and no additiona l toxicity studies a r e required. HED's Hazard and Science Po li cy Counci l ( H ASPOC) determined a subchronic inhala t ion study is not required for pyraflufen-ethyl (D. Smega l , TXR#0054072, 03/02/2012). The Food Qua li ty Protection Act (FQPA) safety factor has been reduced to IX because the toxicity database is comp le te, there is no concern for susceptib ili ty in infants and young children, there are no neurotoxicity concerns, and there are no residual uncertainties regarding exposure

. Pyraflufe n- et h yl is classified as "Likely to be Carcinogenic to Humans" based on the presence of liver tumors (hepatocellular adenomas, carcinomas, and/or h epatoblastomas) in male and female mice

. There was no evidence of carcinogenic i ty in male or fema l e ra t s. There is no mutagenicity/genotoxicity concern. A linear low -d ose extrapo l ation approach (Qt* of3.32 x 10-
2 

### (mg/kg/dayy 1 ) 

### is used to est i ma t e human cancer ri sk. T he toxicity endpoints and points of departure (PO D s) and the FQPA Safety Factor will be evaluated dur i ng Registration Review.

A new dietary exposure and r i sk assessment may be needed dur i ng Registration Review to incorporate updated estimated drinking wa t er concentrations (EDWCs) i nto the chronic and
cancer dietary exposure assessmen t s. At this t i me, analytica l refe r ence standards for the pyraflufen-ethyl metabo li te E-15 must be submitted to the National Pesticide Standards Repository. Additiona ll y, information on sample storage conditions and du r a t i ons for samp le s analyzed in the orange plant metabolism study was required as a condition of registration. Pend in g resolution of these deficiencies, the residue chemistry and dietary expos u re databases support the exist i ng uses of pyraflufen-ethyl.

An 

### updated residential exposure assessment w ill be needed for pyraflufen-ethyl use on turf and ornamenta l s because there are re gistered uses of pyraflufen-ethyl in residential areas with higher

Page 2 of25

### Page 3 of 25

application rates than those previously assessed. At this time, a turf transferrable residue (TTR) study is not required. An updated aggregate risk assessment will be required to support Registration Review to incorporate any new revisions to the drinking water assessment, as well as the findings from the updated residential assessment. The occupational exposure database is complete. Updated occu pational handler exposure assessments may be required during Registration Review for all registered crops based upon revisions to the Agency’s s cenario

- specific surrogate handler and post

- application exposure data and to assess maximum registered single application rates

. At this time, a dislodge able foliar residue (DFR) study is not required.

Introduction Pyraflufen

- ethyl is an herbicide belonging to the phenyl pyrazole class of chemicals. Pyraflufen

ethyl is applied early in the crop growth cycle to control weeds around agricultural crops and
non
- residential areas. Pyraflufen

- ethyl is sold in the United States as liquid (including ready

- to

use) and dry flowable (DF) /water

- dispersible granule (WDG) formulations. For information on the chemical identity of pyraflufen

- ethyl, see Attachment 1.

The most recent risk assessment for pyraflufen

- ethyl was conducted to evaluate the proposed use on hops and peanuts in 2012 ( K

. Rury , D 396779 , 10/01 /20 12 ). Hazard Identification/Toxicology The pyraflufen

- ethyl hazard database w as reviewed in the previous risk assessment and considered complete (K. Rury, D396779, 10/01/2012 ). Toxicity e ndpoint and p rofile t ables are included in Attachments 3 and 4. Pyraflufen

- ethyl exhibits low acute toxicity via the oral (Toxicity Category IV) , dermal (Toxicity Category III), and inhalation (Toxicity Category IV) routes of exposure. It produces moderate eye irritation (Toxicity Category III), and is not a dermal irritant or a dermal sensitizer. Following repeated short

- term and chronic oral d oses , t he liver, kidney, and hematopoietic system are the target organs for pyraflufen

- ethyl in the rat and/or mouse. Adverse effects were not noted in the dog following oral exposure or in the rat following dermal exposure. There was no evidence of incr eased susceptibility following pre

- natal exposure to rats and rabbits in the developmental toxicity studies, or following pre

- and post

- natal exposure to rats in the multi

generation reproduction study. The re was no concern for neurotoxicity or immunotoxi city in the pyraflufen

- ethyl database . Effects seen in the acute neurotoxicity study (transient decrease in body weight gain) and the immunotoxicity study ( decreases of anti

- SRBC AFC response in male rats ) occurred only at the limit dose

. Pyraflufen

- ethyl is classified as “Likely to be Carcinogenic to Humans” based on the presence of liver tumors ( hepatocellular adenomas, carcinomas, and/or hepatoblastomas) in male and female mice. There was no evidence of carcinogenicity in male or female rats. There is n o mutagenicity/genotoxicity concern. A linear low

- dose extrapolation approach (Q 1 

### * of 3.32 x 10
- 2 

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

### ) is used to estimate human cancer risk (J. Kidwell,

### Page 4 of 25

TXR#0050930, 10/08/2002). Based on the available data, toxicity endpoints and PODs have be en selected for chronic dietary, incidental oral (short

- and intermediate term), and inhalation (all time periods) exposure scenarios. The FQPA safety factor (infants and children) has been reduced to 1X for acute, short

- term, intermediate

- term, and chron ic risk assessments, based on the following considerations: 1) the toxicity database for pyraflufen

- ethyl is complete and considered adequate for risk assessment; 2) there are no concerns for neurotoxicity and no need for a developmental neurotoxicity stud y; 3) there are no residual uncertainties for pre

- and/or postnatal exposure since there is no evidence of increased susceptibility following in utero exposure in the developmental studies in the rat and rabbit, or increased susceptibility following pre

- a nd post

- natal exposure in the reproduction study in the rat; and 4) there are no residual uncertainties identified in the exposure databases.

C onclusion : The toxicity database is adequate to support existing registrations. No modifications to the endpoint selections and safety factors are required during Registration Review

. Dietary Exposure At this time, analytical reference standards for the pyraflufen

- ethyl metabolite E

- 15 must be submitted to the National Pesticide Standards Repository. Addi tionally, information on sample storage conditions and durations for samples analyzed in the orange plant metabolism study was required as a condition of registration. Pending resolution of the se deficiencies, the residue chemistry and dietary exposure da tabases will be complete

. Tolerance enforcement methods are available for determining residues of pyraflufen

- ethyl and
m etabolite E

- 1 in/on plant commodities. Field trial data generated using acceptable data collection methods and supported by adequate storage stability data are available for all registered crops. Adequate processing studies are available. Adequate livestock feeding studies have been submitted for pyraflufen

- ethyl. HED has concluded that the residues of concern in plants includ e the parent and pyraflufen ( metabolite E

- 1 ) for purposes of tolerance enforcement and risk assessment. HED previously concluded that the residues of concern in livestock commodities are parent and metabolites E

- 1 and E

- 9 (refer to names and structures in Appen dix 1) , and that all three compounds should be measured in livestock feeding studies. Based on the metabolite E

- 9 results of the livestock feeding study, HED concludes that the tolerance expression for livestock commodities include s parent and m etabolites E

- 1 and E

- 9.

Environmental fate data indicate that metabolites E

- 1 and E

- 2 (refer to Appendix 1) are the major metabolites (> 10% total radioactive residues [TRR]) in photolysis, aerobic soil metabolism, anaerobic aquatic metabolism and aerobic aquatic metabolism studies for parent. Metabolite E

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

- 2.

### Page 5 of 25

There were no adverse effects attributable to a single dose; therefore, an acute dietary exposure assessment was not performed. Pyraflufen

- ethyl is classified as “Likely to be Carcinogenic to Humans” by the oral route; therefore, a cancer di etary risk assessment is required in addition to a chronic dietary assessment.

P artially refined chronic and cancer dietary assessment s were conducted using 100% crop treated and using 1⁄2 the limit of quantification (LOQ) for the residue values because a ll available pyraflufen

- ethyl field trials showed residues less than the LOQ including the metabolites for the following commodities: corn, cottonseed, potato, soybean, wheat, pome fruit, stone fruit, pomegranate, olive, grape, tree nuts, and pistachio. A ll other established and proposed commodities were analyzed using tolerance

- level residues. Anticipated residues were used for livestock commodities. Because the commodity

- specific processing studies did not show pyraflufen

- ethyl concentration after proc essing, only default processing factors were used for dry potatoes (6.5X), peanut butter (1.89X), dried beef (1.92X), and corn syrup (1.5X). An empirical processing factor of 0.6X was used for cotton seed oil. All exposure inputs for the cancer
assessmen t were the same as for the chronic dietary exposure assessment, except the EDWC. The dietary assessments were conducted using the Dietary Exposure Evaluation Model (DEEM

FCID) using food consumption data from the U.S. Department of Agriculture’s (USDA) Na tional Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA). The chronic dietary (food and drinking water) exposure to pyraflufen

- ethyl is below HED’s level of concern (LOC) [i.e., <100% of the chronic population adjusted dose (cPAD)] for the general U.S. population and all population subgroups. The chronic dietary exposure estimates utilize <1% of the cPAD for the general U.S. population and all population subgroups, including children 1

- 2 years old, the most highly exposed po pulation subgroup.

C ancer dietary exposure from drinking water was determined based on a Tier 2 drinking water (surface water) estimate provided by EFED. The EDWC estimate (30

- year average) value of 0.268 ppb for the combined residues of pyraflufen

- eth yl and its metabolic products, E

- 1, E

- 2, and E

- 3 were incorporated directly into the dietary assessment to estimate carcinogenic risk from drinking water containing pyraflufen

- ethyl. The cancer dietary (food and drinking water) risk estimate for pyraflufe n
- ethyl is 2 x 10
- 6



### . Pyraflufen

- ethyl residue estimates on cereal grains, root and tuber vegetables, and tuberous and corm vegetables were the highest contributors to the cancer dietary exposure estimate.

Conclusion: A new dietary exposure assessment may be needed during Registration Review to incorporate any changes to the drinking water exposure estimates. If the EDWCs increase, the cancer dietary exposure estimates are likely to be greater than 2x10
- 6



### . Residential Exposure Pyraflufen

- ethyl is c urrently registered for use by residential and commercial applicators on several residential/non

- agricultural use sites; i.e., established ornamental turf lawns, parks, cemeteries, athletic fields, golf courses, sod farms, nurseries and ornamental planting s, and christmas trees. It is assumed that most residential uses will result in short

- term (1

- 30 day)

### Page 6 of 25

exposures. Residential handlers are assumed to be wearing short

- sleeved shirts, short pants, shoes, and socks during pyraflufen

- ethyl application. Beca use there was no dermal endpoint chosen for pyraflufen

- ethyl, non

- cancer handler risk from exposure to pyraflufen

- ethyl was assessed for the inhalation route only. All residential handler margins of exposure ( MOEs ) were not of concern to HED, and greater than 35,000,000. Post

- Application incidental oral margins of exposure were not of concern to HED and were greater than 270,000. Cancer risk estimates (dermal + inhalation) were assessed for residential handlers only. It was assumed for cancer risk
asses sment that a handler could treat turf only twice per year based on the maximum number of applications recommended on the registered labels

. Residential handler cancer (dermal + inhalation) risk estimates ranged from 2.0x10
- 8 

### to 2.1 x10
- 7



### . Adult p ost

- appli cation cancer risk estimates from contact with treated turf and ornamentals ranged from 1. 5 x10
- 8 

### to 7.6x10
- 7



### . An updated residential exposure assessment will be needed for pyraflufen

- ethyl use on turf and ornamentals because there are registered uses of pyraflufen

- ethyl in residential areas with higher application rates than those previously assessed; therefore, all existing uses will be reevaluated with the upda ted Residential SOPs during Registration Review. Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of pyraflufen

- ethyl. The Agency is in the process of evaluating these typ es of exposures and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate these post

- application exposures into the Agency's risk assessments. The need for spray drift and volatilization ri sk assessments for pyraflufen

- ethyl will be examined during Registration Review

. Conclusions: An updated residential handler and post

- application assessment will be needed for pyraflufen

- ethyl during Registration Review. HED will also consider volatiliza tion exposure, as well as the potential for exposure from spray drift, during R egistration R eview. In accordance with 40CFR158, TTR data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post

- application exposure to turf. In the absence of chemical

- specific TTR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of all TTR data, available at the time, which resulted in the selection of revised liquid and granular default values for the fraction of the application rate available for transfer after a turf application (F AR 

### ). These values are based on an analysis of 59 TTR studies performed with the Modified California Roller Method (36 studies using liquids, 11 studies using wetta ble powders/water dispersible granules, and 12 studies using granules). The liquid results (N=131) indicate a range of F AR 

### values from 0.0005% to 6.1% and the granular results (N=37) indicate a range of 0.00064% to 0.69%. In both the liquid and granular d ata, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify factors. Although witnessed across multiple chemicals, this range in F AR 

### values is not expected when considering TTR data for a single chemical. EPA selected 1% and 0.2% as the reasonable, high

- end default values for liquid and granular products , respectively. Because TTR data are not available for pyraflufen

- ethyl , EPA has used the default value of 1% . Although there may be a small degree of uncertainty in the use of the

### Page 7 of 25

default TTR value for pyraflufen

- ethyl (i.e., there is a small chance that the F AR 

### value may exceed the applicable default value), it is likely that the health

- protective aspects of EPA’s residential post

- application turf assessment methodology will more than compensate for this potential unce rtainty. For example, when assessing residential post

- application turf exposure, EPA assumes the following: exposures occur to zer o
- day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn’t rain, the grass is not mowed, etc); individuals perform the same post

application activities performed in the turf transfer coefficient study day after day (e.g., tumbling, playing on turf with toys, etc.); and individuals engage in these post

- application activities for a high

- end amount of time every day (represented by data reflecting time children spend outdoors and not specifically engaged in activities on turf). In actuality, residues will dissipate to some degree dep ending on the chemical; children do not play on turf every day; children do not spend all of their outdoor time on turf; and high

- end levels of activity will not occur every day even if children are playing on treated turf.

Given the conservatisms disc ussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated. Since the estimated residential turf post

- application exposure u sing default TTR values for pyraflufen

- ethyl is minimal in comparison to the level of concern (i.e., the calculated MOE is greater than 10 times higher than the level of concern, MOE

= 270,000 compared to the LOC of 100 ); EPA is waiving the 40CFR TTR data requirement. In this instance, it is unlikely that chemical

- specific TTR data would be needed to further refine exposure assessments or would add appreciably to our overall understanding of the availability of turf transferable pesticide residues for pyra flufen

- ethyl

. In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has residential or occupational uses that could result in post

application dermal exposure. As part of the recent revi sion to the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment , HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a foliar application (F AR 

### ). This default value is 25 % and is based on an analysis of 19 DFR studies where the F AR 

### value ranged from 2% to 89%. This value is recommended for use in both residential and occupational postapplication assessments. Of the analyzed DFR studies, the maximum F AR 

### value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical

- specific DFR study ( Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodge able Foliar Residue (DFR) Studies . 12/12/2012, Exposure Science Advisory Council ). A DF R study is not required for pyraflufen

- ethyl at this time since the there is no hazard via the dermal route of exposure and a
non
- cancer dermal post

- application risk as sessment was not performed

. Therefore, DFR studies are not needed for pyraflufen

- ethyl at this time . If the PODs change, the need for DFR studies may be reevaluated in the future to refine the post

- application assessment.

### Page 8 of 25

Aggregate Risk Assessment

A ggregate assessments consider exposures from food, drinking water, and residential uses. Since there are residential uses of pyraflufen

- ethyl , aggregate risk for all exposure durations consists of residential handler and post

- application exposures, food , and drinking water. For pyraflufen

- ethyl , no adverse effects attributable to a single dose were observed in oral toxicity studies, including developmental toxicity studies in rats and rabbits. Therefore, an acute reference dose has not been established and an acute aggregate risk assessment is not required. In the most recent human health risk assessment ( K. Rury, D396779, 10/01/2012 ), short

- term aggregate risk estimates resulting from residential, food , and drinking water exposure w ere not of concern. In addition, the aggregate cancer risk assessment considers exposure estimates from dietary consumption of pyraflufen

- ethyl in food and drinking water, and exposure through residential uses. T he aggregate cancer risk estimate for pyraflufen

- ethyl was 2. 6x10
- 6 

### in the previous risk assessment ( K. Rury, D396779, 10/01/2012 )

. Conclusions : Because a new dietary exposure assessment will be needed during Registration Review to incorporate changes to the drinking water exposure estimates, and because the residential exposure estimates will be reevaluated , an updated aggregate risk assessment will be conducted during Registration Review. If the EDWCs increase, the cancer aggregate exposure estimates are likely to be greater than 2.6x10
- 6



### . Occupatio nal Exposure and Risk Pyraflufen

- ethyl is a phenyl pyrazole herbicide, registered for agricultural use as preplant burndown applications, applications after planting but before crop emergence, and post

- emergent applications. Registered agricultural use sites include: bulb vegetables, cole crops, corn, cotton, cucurbits, fallow beds and crop stubble, dates, feijoa, figs, fruiting vegetables, grapes, grasses, kiwi, leafy vegetables, legumes, mango, non

- cr op areas, olives, oil seeds, pasture and rangeland, peanuts, persimmons, pistachios, pomegranates, pome fruit (Crop Group 11

- 10), potatoes, root and tuber vegetables, small grains, soybean, stone fruit (Crop Group 12), sugarcane, tree nuts (Crop Group 14), uncultivated areas/conservation reserve program areas, and wheat. Pyraflufen

- ethyl is also registered for occupational use on the following non

- agricultural use sites: airports, barrier strips and fire breaks, Christmas trees, commercial plants, equipme nt areas, fuel tank farms, golf courses, nurseries, ornamental turf, rights of way, sod farms, and storage and lumber yards. Pyraflufen

- ethyl is formulated as liquids, dry flowable , and as a ready

- to

- use solution. Pyraflufen

- ethyl may be applied using a erial, ground, a nd hand

- held spray equipment. The personal protective equipment ( PPE) required for handlers consists of a single layer of clothing (long sleeve shirt, long pants, and socks plus shoes) , chemical resistant gloves , and in some cases, protect ive eyewear . The restricted entry interval (REI) for pyraflufen

- ethyl is 12 hours. The occupational uses of pyraflufen

- ethyl are expected to result in both short

- and intermediate

term exposures. Occupational exposure assessments have been conducted for pyraflufen

- ethyl liquid and dry flowable formulations.

### Page 9 of 25

Previous occupational handler exposure and risk assessments were conducted for pyraflufen

ethyl use on corn, cotton, grapes, grasses, non
- crop areas, olives, pasture and rangeland, pome fruit, pomegranates, potatoes, soybeans, stone fruit, tree nuts, turf and wheat. All current exposure estimates at baseline PPE (single layer clothing, no gloves, and no respirator) result in both non

- cancer and cancer risk estimates which are not of concern. The occupational handler inhalation MOE s for the uses evaluated were not of concern to HED and were greater than 1 90,000. To assess cancer risk, it is assumed that private growers would be exposed 10 days per year and commercial applicators wou ld be exposed 30 days per year. The term “private grower” means that the grower or one of the workers would apply the pesticides to land owned or operated by the grower. Commercial applicators means the applicators are completing multiple applications fo r multiple clients. Occupational handler cancer (dermal + inhalation) risk estimates at baseline PPE (no gloves) ranged from 3.5 x10
- 8 

### to 6.1 x10
- 5



### . When evaluated,
o ccupational handler cancer (dermal + inhalation) risk estimates with gloves ranged from 2. 2 x10
- 8 

### to 3.3 x10
- 6



### . However, these assessments were not conducted at the maximum registered application rates and using the current occupational exposure inputs; therefore, a new occupational exposure assessment may be conducted for these uses and all the registered occupational uses of pyraflufen

- ethyl during Registration Review. Occupational post

- application exposure can occur via the dermal and/or inhalation route. Post

application non
- cancer dermal exposures to pyraflufen

- ethyl were not evaluated b ecause adverse effects were not seen in the subchronic 28

- day dermal toxicity study up to the Limit Dose (1,000 mg/kg/day). Post

- application cancer (dermal + inhalation) risk was e stimated for use on peanuts (scouting only) and treated lawn s

. HED assumes that post

- application workers would be exposed 30 days per year. These risk estimates ranged from 5.0x10
- 8 

### to 2.2 x10
- 6 

### on the day of application

. H owever, occupational post

- application exposure inputs and policies have changed since the previ ous risk assessments and post

- application exposure from registered uses of pyraflufen

- ethyl may be re

- evaluated during Registration Review. Based on the Agency's current practices, a quantitative non
- cancer post

- application inhalation exposure assessmen t was not performed for pyraflufen

- ethyl at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (1.2x10
- 10 

### mm Hg), and the low registered use rate s

. However, there are multiple potential sources of p ost

- 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. Th e Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation e xposure data generated by the Agricultural Re

- Entry Task Force ( ARTF ) and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need

### Page 10 of 25

for a quantitative occupational post

- application inhalation exposure assessment for pyraflufen

ethyl

. The pyraflufen

- ethyl database lacks DFR studies. In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has residential or occupational uses that could result in post

- application dermal exposure. Because there is no hazard via the dermal route of exposure, a non

- cancer dermal post

- application ris k assessment was not performed for pyraflufen

- ethyl . Therefore, DFR studies are not needed for pyraflufen

ethyl at this time . If the PODs change, the need for DFR studies may be reevaluated in the future to refine the post

- application assessment.

Conc lusions: There is sufficient information available to assess occupational exposure. An up

to

- date occupational assessment may be needed for all existing uses of pyraflufen

- ethyl to account for changes in occupational assessment policies (unit exposures an d transfer coefficients ) and to evaluate the maximum registered single application rate for each use site. Public Health and Pesticide Epidemiology Data Based on the low frequency and severity of incident cases reported for pyraflufen

- ethyl in both th e OPP Incident Data System (IDS) and Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR)

- Pesticides , there does not appear to be a concern at this time that would warrant further investigation

. There were only eight aggregate incidents (minor, unknown, or no effect outcomes) involving pyraflufen

- ethyl reported i n the Aggregate IDS, from January 1, 2009 to January 15, 2014. A query of SENSOR

- Pesticides 1998

- 2010 identifies one case involving pyraflufen

- ethyl which occurred in Washington State in 2005. This case involved multiple active ingredients (the two products implicated are Vanquish Herbicide and ET Herbicide/Defoliant ). The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization The current tolerance expression for pyraflufen

- ethyl is appropriate. Tolerances are established for plant and livestock commodities under 40 CFR §180.585 (a) for residues of the herbicide pyraflufen

- ethyl, including its metabolites and degradates. Compli ance with the plant commodity tolerance levels specified is to be determined by measuring only the sum of the parent pyraflufen

- ethyl, ethyl 2

- [2

- chloro

- 5

- (4

- chloro

- 5

- difluoromethoxy)

- 1

- methyl

- 1 H

- pyrazol

3

- yl]

- 4

- fluorophenoxy] acetate, and its acid metabol ite, E

- 1, 2

- chloro

- 5

- (4

- chloro

- 5

- difluoromethoxy

- 1

- methyl

- 1 H

- pyrazol

- 3

- yl)

- 4

- fluorophenoxyacetic acid, calculated as the stoichiometric equivalent of pyraflufen

- ethyl in or on the commodity. Compliance with the livestock commodity tolerance levels is to b e determined by measuring only the sum of the parent pyraflufen

- ethyl and its acid metabolites: E

- 1 and E

- 9, 2

- chloro

- 5

- (4

- chloro

- 5

- difluoromethoxy

- 1 H

- pyrazol

- 3

- yl)

- 4

- fluorophenoxyacetic acid, both calculated as the stoichiometric equivalent of pyraflufen

- ethyl in or on the commodity.

### Page 11 of 25

The stone fruit and tree nut crop group commodity definitions should be updated from Fruit, stone, group 12 to Fruit, stone, group 12

- 12, and from Nut, tree, group 14 to Nut, tree, group 14

- 12. Since the representative crops for these crop groups have not changed, no additional residue data are needed to update these crop group names.
There are no Codex or Canadian maximum residue limits (MRLs) established for pyraflufen

ethyl ; therefore, there is no harmonization issue at this time.
Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf )

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activ ities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the United States Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey (NHANES), What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas following application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and mod els that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.
Cumulative Risk Assessments Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to pyraflufen

- ethyl and any other substances , and pyraflufen

- ethyl does not ap pear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that pyraflufen

- ethyl has a common mechanism of toxicity with other substances. For information regarding EPA’s eff orts 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/

. Human Studies

### Page 12 of 25

Past pyraflufen

- ethyl risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. These data, which include studies from the Pesticide Handlers Exposure Database V ersion 1.1 (PHED 1.1); the ARTF database; the Outdoor Residential Exposure Task Force (ORETF); and other registrant

- submitted exposure monitoring studies, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler

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

- app
- exposure
- data.html. Data Requirements Residue Chemistry 860.1650 Submittal of Analytical Reference Standards Analytical reference standards for pyraflufen

- ethyl and m etabolite E

- 15 must be submitted to the National Pesticide Standards Repository. ( E

- mail from Theresa Cole, 1/9/14: Pyraflufen

- ethyl is out of stock. Metabolite E

- 15 expired on 10/18/13. Metabolites E

- 1 and E9 are available, with expiration dates of 7/2/16 and 4/3/15, resp ectively. )

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 stud y (MRID 47872706 , discussed in D377359 ).

R eferences
Memoranda Relevant to Registration Review of Pyraflufen

- ethyl
Author DP / TXR# Date Title
Risk Assessment K. Rury D396779 10/ 0 1/ 20 12 Pyraflufen

- ethyl

– Human Health Risk Assessment for a Section 3 Registration of New Food Uses on Hops and Peanuts

. K. Rury D388220 0 3/31/ 20 11 Pyraflufen

- Ethyl: Addendum to Human Health Risk Assessment for a Section 3 Registration of New Food Uses on Tree Nuts (Crop Group 14), Pistachios, Pome Fruit (Crop Group 11

- 10), and Stone Fruits (Crop Group 12), Hops, Grapes, Olives and Pomegranates. K. Rury D377359 0 3/ 0 1/ 20 11 Pyraflufen

- ethyl: Human Health Risk Assessment for a Section 3 Registration of New Food Uses on Tree Nuts (Crop Group 14), Pistachios, Pome Fruit (Crop Group 11

- 10), and Stone Fruits (Crop Group 12), Hops, Grapes, Olives and Pomegranates. K. Rury D361213 0 2/24/ 20 10 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. M. Ottley D337842 0 4/17/ 20 08 Pyraflufen

- ethyl : Human Health Risk Assessment for Pyraflufen

-

### Page 13 of 25

Memoranda Relevant to Registration Review of Pyraflufen

- ethyl
Author DP / TXR# Date Title 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 Ha y (PP#1F6248)

. H. Johnson D299196 0 4/ 0 7/ 20 04 PP#1F06248 Human Health Risk Assessment for Pyraflufen

- ethyl on Wheat. M. Rust D283496 01/24/2003 Pyraflufen

- ethyl. Amendment to PP#1F06248. Human Health Risk Assessment for Uses on Field Corn and Soybeans. M. Rust D286618 11/06/2002 PP#1F06248 Human Health Risk Assessment for Pyraflufen

- ethyl on Cotton and Potatoes. Residue Chemistry A. Acierto D396779 0 9/12/ 20 12 (Amended) Pyraflufen

- ethyl. PP#1F7944. Petition for Establishment of Tolerances on Hops and Peanuts; Multi

- Residue Method (MRM) and Independent Laboratory Validation (ILV); Unconditional Registrations for Use on Pastures, Rangeland and Post Emergence Application to Corn, Soybean and Wheat; and Amended Repo rt for Residues in Bovine Tissues and Milk from a 28

- day Feeding Study Data, Radiovalidation in Goat Liver and Milk and Storage Stability . Summary of Analytical Chemistry and Residue Data. L. Cheng D377361 0 2/ 0 7/ 20 11 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. A. Acierto D364053 06/26/2009 Pyraflufen

- ethyl: Petition for Label Amendments to Add Aerial Application to Pre

- plant Burndown Uses of Pyraflufen

- ethyl on B ulb Vegetables, Leafy Vegetables, Brassica Leafy vegetables, Cole Crops, Cucurbit Vegetables, Fruiting Vegetables, Legume Vegetables, Root and Tuber Vegetables, Cereal Grains, Oil Seed Crops, and Sugarcane. M. Negussie D356829 01/26/2009 Pyraflufen

- ethyl: Petition for a Label amendment for new Non

- Food Uses on Bulb Vegetables, Oil Seed Crops, Cereal Grain Crops, and Sugarcane. B. Cropp

Kohligian D339032 01/30/2008 Pyraflufen

- ethyl. PP#7F7190: Proposed New Use on Pasture and Rangeland Grasses. PP#1F6248: 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. S ummary of Analytical Chemistry and R esidue Data. L. Cheng D320103 10/31/2006 Pyraflufen

- ethyl. Supplemental Data to Support Amended Use on Cotton and Established Use on Wheat (PRIA R35). Summary of Analytical Chemistry and Residue Dat a. Dietary Exposure K. Rury D397422 09/09/2012 Pyraflufen

- ethyl: Chronic and Cancer Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on Hops and Peanuts. A. Acierto D347500 03/25/2008 Pyraflufen

- ethyl. Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for a Section 3 Registration Action to Allow Early Season Postemergence Uses on Corn (Excluding Sweet Corn), Soybeans, and Wheat.

### Page 14 of 25

Memoranda Relevant to Registration Review of Pyraflufen

- ethyl
Author DP / TXR# Date Title
H. Johnson D299196 03/0 1/2004 Pyraflufen

- ethyl Chronic Dietary Exposure Assessment for the Section 3 Registration Action. L. Cheng D285317 10/17/2002 Pyraflufen

- Ethyl Chronic and Cancer Dietary Exposure Assessments for the Section 3 Registration Action. Occupational Residential Exposure M. Rust D278144 09/12/2002 Nonfood Use Risk Assessment to Support Request for a Section 3 Registration for the Use of Pyraflufen Ethyl on Non

- crop Areas. M. Rust D286617 10/23/2002 PYRAFLUFEN

- ETHYL: Occupational and Residential Exposure Assessment to Support Request for Use on Potatoes and Cotton

. M. Rust D287401 12/20/2002 PYRAFLUFEN

- ETHYL: Occupational Exposure Assessment to Support Request for New Uses on Soybeans, Wheat and Corn. M. Dow D299666 03/25/2004 PYRAFLUFEN ETHYL

- Exposure/Risk Assessment for the Proposed Use of Pyraflufen Ethyl on Wheat. M. Dow D339033 08/09/2007 PYRAFLUFEN

- ETHYL

- Occupational Exposure/Risk Assessment for the Proposed Use of Pyraflufen

- ethyl on Pasture and Range Grass and Post

- Emergence Use on Corn, Soybean and Wheat. K. Rury D361213 01/14/2010 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 bermudagrass, centipedegrass, St. Augustinegrass, and zoysiagrass). K. Rury D378642 12/14/2010 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. K. Rury D397423 10/01/2012 Pyraflufen

- ethyl. Occupational and Residential Exposure Assessment for a Proposed Use on Hops and Peanuts and a Reevaluation of Existing Residential Uses with the Updated Residential SOPs. Toxicology D. Smegal TXR

0054072 03/02/2012 Pyraflufen

- ethyl : Summary of Hazard and Science Policy Council (HASPOC) Meeting of February 16, 2012: Recomm endations on a waiver request for a 28

- day inhalation study. Incident Report S. Recore D418062 02/ 12 /2014 Revised: Pyraflufen

- Ethyl: Tier 1 Review of Human Incidents.



### Attachment

s Attachment 1. Chemical Identity Table Attachment 2. International Residue Limit Status Attachment 3

. Pyraflufen

- Ethyl Endpoint Selection Tables Attachment 4

. Pyraflufen

- Ethyl Toxicity Profile s

### Page 15 of 25 Attachment 1

Chemical Identity Table

Table 1. Pyraflufen

- Ethyl and Its Metabolites Nomenclature. Chemical structure

Common name p yraflufen

- e thyl PC Code 030090 Company experimental name ET

- 751 IUPAC name e thyl [ 2

- chloro

- 5

- (4

- chloro

- 5

- difluoromethoxy

- 1

- methylpyrazol

- 3

- yl)

- 4

- fluorophenoxy ] acetate CAS name ethyl 2

- [2

- chloro

- 5

- [4

- chloro

- 5

- (difluoromethoxy)

- 1

- methyl

- 1 H

- pyrazol

- 3

- yl]

- 4

- fluorophenoxy] acetate CAS registry number 129630

- 19

- 9 End

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

- 7; Label Date 02/20/2007 ) 0.17 lb/gal FlC ( 2.0% FlC; ET ® 2%SC Herbicide/Defoliant; EPA Reg. No. 71711

- 25; Label Date 09/06/2007 ) Chemical structure

Common name pyraflufen PC Code 030091 Company experimental name Metabolite E

- 1; Pyraflufen

- ethyl plant and livestock metabolite of concern IUPAC name [ 2

- c hloro

- 5

- (4

- chloro

- 5

- difluoromethoxy

- 1

- methylpyrazol

- 3

- yl)

- 4

- fluorophenoxy ] acetic acid CAS name 2

- [2

- c hloro

- 5

- [4

- chloro

- 5

- (difluoromethoxy)

- 1

- methyl

- 1 H

- pyrazol

- 3

- yl]

- 4

- fluorophenoxy] acetic acid CAS registry number 129630

- 17

- 7 N N Cl

F Cl

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

F Cl

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

O C H F 2

### Page 16 of 25

Table 1. Pyraflufen

- Ethyl and Its Metabolites Nomenclature. Chemical structure

Company experimental name Metabolite E

- 2; 2

- chloro

- 5

- (4

- chloro

- 5

- difluoromethoxy

- 1

- methylpyrazol

- 3

- yl)

- 4

- fluorophenol Chemical structure

C ompany experimental name Metabolite E

- 9; Pyraflufen

- ethyl livestock metabolite of concern; 2

- [2

- chloro

- 5

- [4

- chloro

- 5

- (difluoromethoxy)

- 1 H

- pyrazol

- 3

- yl]

- 4

- fluorophenoxy] acetic acid Chemical structure

Company experimental name GC/MSD Residue Method Analyte E

- 15; methyl ester of Metabolite E

- 1; methyl 2

- [2

- chloro

- 5

- [4

- chloro

- 5

- (difluoromethoxy)

- 1

- methyl

- 1 H

- pyrazol

- 3

- yl]

- 4

- fluorophenoxy] acetate N N Cl

F Cl

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

F Cl

H O C H F 2 O C H 2 C O O H

### Page 17 of 25 Attachment 2

Tolerance/MRL Table Pyraflufen

- ethyl ( 030090 ) Table 2. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : (a) General. Plants : the sum of the parent pyraflufen

- ethyl, ethyl 2

- [2

- chloro

- 5

- (4

- chloro

- 5

- difluoromethoxy)

- 1

- methyl

- 1 H

- pyrazol

- 3

- yl]

- 4

- fluorophenoxy] acetate, and its acid metabolite, E

- 1, 2

- chloro

- 5

- (4

- chloro

- 5

- difluoromethoxy

- 1

- methyl

- 1 H

- pyrazol

- 3

- yl)

- 4

- fluorophenoxyacetic acid, calculated as the stoichiometric equiv alent of pyraflufen

- ethyl

. Livestock : th e sum of the parent pyraflufen

- ethyl and its acid metabolites: E

- 1and E

- 9, 2

- chloro

- 5

- (4

- chloro

- 5

- difluoromethoxy

- 1 H

- pyrazol

- 3

- yl)

- 4

- fluorophenoxyacetic acid, both calculated as the stoichiometric equivalent of pyra flufen

- ethyl. US Canada Mexico 1 Codex [40 CFR §180.585(a)] None None Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex Almond, hulls 0.02 Cattle, fat 0.03 Cattle, meat 0.03 Cattle, meat byproducts 0.03 Corn, field, forage 0.01 Corn, field, grain 0.01 Corn, field, stover 0.01 Cotton, gin byproducts 1.5 Cotton, undelinted seed 0.04 Fruit, pome, group 11

- 10 0.01 Fruit, stone, group 12 0.01 Goat, fat 0.03 Goat, meat 0.03 Goat, meat byproducts 0.03 Grape 0.01 Grass, forage, group 17 1.0 Grass, hay, group 17 1.4 Horse, fat 0.03 Horse, meat 0.03 Horse, meat byproducts 0.03 Milk 0.03 Nut, tree, group 14 0.01 Olive 0.01 Peanut 0.01 Peanut, hay 0.07 Pistachios 0.01 Pomegranate 0.01 Potato 0.02 Sheep, fat 0.03 Sheep, meat 0.03 Sheep, meat byproducts 0.03 Soybean, forage 0.05 Soybean, hay 0.10 Soybean, seed 0.01 Wheat, forage 0.02 Wheat, grain 0.01 Wheat, hay 0.01 Wheat, straw 0.01 Completed: M. Negussie; 01/28/14 1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

### Page 18 of 25 Attachment 3

Toxicity Endpoint and Point of Departure Selections

Table 3.1. Summary of Toxicological Doses and Endpoints for Pyraflufen

- ethyl for Use in Dietary

and Non

- Occupational Human Health Risk Assessments. Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of

Concern for Risk Assessment Study and Toxicological Effects Acute Dietary (General Population, including Infants and Children) None An endpoint attributable to a single dose was not identified for pyraflufen

- ethyl from the available data.

Chronic Dietary (All Populations) NOAEL =

20 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Chronic RfD =

0.20 mg/kg/day

cPAD = 0.2 mg/kg/day Mouse Carcinogenicity Study

LOAEL = 98 mg/kg/day based on liver toxicity

Incidental Oral Short

Term (1

- 30 days) NOAEL =

20 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Residential LOC

for MOE = 100 Developmental Toxicity

- Rabbit

Maternal LOAEL = 60 mg/kg/day based on decrease d food consumption and fecal output , GI lesions , and premature deaths Dermal Short

- (1

- 30 days), Intermediate (1

- 6 months), and Long

- (>6 months) Term None 28

- Day Dermal To xicity

– Rats No dermal or systemic toxicity was seen at the Limit Dose (1000 mg/kg/day)

Inhalation Short

- (1

- 30 days) and Intermediate

and Long

Term (1

- 6 months) NOAEL =

20 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential LOC

for MOE = 100 Developmental Toxicity

- Rabbit

Maternal LOAEL = 60 mg/kg/day based on decrease d food consumption and fecal output , GI lesions , and premature deaths

Cancer (oral, dermal, inhalation) Classification: “Likely to be Carcinogenic to Humans” by the oral route.

Q 1 * = 3.32 x 10

- 2 (mg/kg/day)

- 1 Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. Dermal absorption for cancer assessment assumed to be 100%.

### Page 19 of 25

Tabl e 3.2. Summary of Toxicological Doses and Endpoints for Pyraflufen

- ethyl for Use in

Occupational Human Health Risk Assessments. Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of

Concern for Risk Assessment Study and Toxicological Effects

Dermal Short

- (1

- 30 days), Intermediate (1

- 6 months), and Long

- (>6 months) Term None 28

- Day Dermal Toxicity

– Rats No dermal or systemic toxicity was seen at the Limit Dose (1000 mg/kg/day)

Inhalation Short

- (1

- 30 days) and Intermediate

and Long

Term (1

- 6 months) NOAEL =

20 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential LOC

for MOE = 100 Developmental Toxicity

- Rabbit

Maternal LOAEL = 60 mg/kg/day based on decrease d food consumption and fecal output , GI lesions , and premature deaths

Cancer (oral, dermal, inhalation) Classification: “Likely to be Carcinogenic to Humans” by the oral route.

Q 1 * = 3.32 x 10

- 2 (mg/kg/day)

- 1 Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. Dermal absorption for cancer assessment assumed to be 100%.

### Page 20 of 25 Attachment 4

Toxicology Data Requirements
The requirements (40 CFR 158.500) for food uses of pyraflufen

- ethyl are in Table 4. 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Table 4.1. Toxicology Data Requirements for Pyraflufen

- ethyl. Study Technical Required Satisfied 870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Acute Eye Irritation

................................ ....................... 870.2500 Acute Dermal Irritation

................................ ................. 870.2600 Skin Sensitization

................................ .......................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 90

- Day Oral Toxicity in Rodents

................................ .. 870.3150 90

- Day Oral Toxicity in Nonrodents

............................. 870.3200 21/28

- Day Dermal Toxicity

................................ ........... 870.3250 90

- Day Dermal Toxicity

................................ ................ 870.3465 90

- Day Inhalation Toxicity

................................ ........... yes yes yes no yes yes

yes yes

-- waived 4 870.3700a Prenatal Developmental Toxicity (rodent)

..................... 870.3700b Prenatal Developmental Toxicity (nonrodent)

............... 870.3800 Reproduction and Fertility Effects

................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Carcinogenicity (rat)

................................ ...................... 870.4200b Carcinogenicity (mouse)

................................ ................ 870.4300 Combined Chronic Toxicity/Carcinogenicity

................ yes no yes yes no yes 1

yes 2 yes 1 yes yes 870.5100 Mutagenicity

— Bacterial Reverse Mutation Test

.......... 870.5300 Mutagenicity

— Mammalian Cell Gene Mutation Test

.. 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5395 Mutagenicity

— Other Genotoxic Effects

....................... yes yes yes yes yes

yes yes yes 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Developmental Neurotoxicity

................................ ........ yes yes no yes

yes

-- 870.7485 Metabolism and Pharmacokinetics

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

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

................................ ............................. yes no 3 yes yes

-- yes 1 The chronic (rodent) and carcinogencity (rat) data requirements are satisfied by the Combined Chronic Toxicity / Carcinogenicity study (870.4300). 2 A chronic study in the dog is available, although it is no longer required. 3 A dermal penetration study is not required because a) a dermal endpoint was not identified (no effects in the 21

- day dermal study up to the Limit Dose) and b) there were no effects of concern observed in studies such as the developmental and reproduction oral studies that reveal adverse effects (such as e ffects on the offspring) that the 21

- day dermal study is not designed to detect or measure. 4 The requirement for a subchronic inhalation toxicity study has been waived (TXR#00564072)

### Page 21 of 25

Table 4.2. Acute Toxicity of Pyraflufen

- ethyl.

Guideline No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral 45327615 LD 50 > 5000 mg/kg IV 870.1200 Acute Dermal 45327613 LD 50 > 2000 mg/kg III 870.1300 Acute Inhalation 45282821 LC 50 > 5.03 mg/L IV 870.2400 Primary Eye Irritation 45327614 moderate irritation III 870.2500 Primary Skin Irritation 45282823 no irritation IV 870.2600 Dermal Sensitization 45282824 non
- sensitizing N/A

Table 4.3. Non

- acute Toxicity Profile for Pyraflufen

- Ethyl.

Guideline Number and Study Type MRID (Year)

Dose Levels Results

870.3100 13

- Week Oral Feeding Rat 45282903 (1994)

0, 200, 1000, 5000, 15000 ppm M;0, 17.8, 85.6,456, 1489 mg/kg/day F: 0, 19.4, 95.4, 499, 1503 mg/kg/day Acceptable/guideline NOAEL = 456

- 499 mg/kg/day. LOAEL = 1489

- 1503 mg/kg/day) based on clinical signs, death, effects on erythrocytes, changes in clinical chemicals for liver function and splenomegaly

870.3150 13

- Week Oral Capsule Dog 45282905 (1996)

0, 40, 200 or 1000 mg/kg/day Acceptable/guidelin e NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day. No effects observed at Limit Dose.

870.3200 28

- Day Dermal Rat 45283001 (2000)

0 , 100, 300 or 1000 mg/kg/day Acceptable/guideline NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day. No effects observed at Limit Dose.

870.3700a Developmental Toxicity Rats 45282917 (1995)

0 , 100, 300 or 1000 mg/kg/day Acceptable/guideline Maternal NOAEL = 1000 mg/kg/day. Maternal LOAEL > 1000 mg/kg/day. No effects observed at Limit Dose. Developmental NOAEL = 1000 mg/kg/day. Developmental LOAEL > 1000 mg/kg/day. No effects observed at Limit Dose. 870.3700b Developmental Toxicity Rabbit 45282918 (1996)

0, 20, 60 or 150 mg/kg/day Acceptable/guideline Maternal NOAEL = 20 mg/kg/day. Maternal LOAEL= 60 mg/kg/day based on reduced food intake and fecal output, lesions in the gastrointestinal tract, and premature deaths

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

### Page 22 of 25

Table 4.3. Non

- acute Toxicity Profile for Pyraflufen

- Ethyl.

Guideline Number and Study Type MRID (Year)

Dose Levels Results

870.3800 2

- Generation Reproduction Rat 45282922 (1996)

0, 100, 1000 or 10, 000 ppm 0, 6.84, 70.8 and 721 mg/kg/day (F 0 [M]); 0, 7.78, 80.1 and 813 mg/kg/day (F 0 [F]); 0, 8.10, 82.3 and 844 mg/kg/day (F 1 [M]); 0, 9.06, 91.2 and 901 mg/kg/day (F 1 [F])

Acceptable/guideline Parental NOAEL = 70.8

- 82.3 mg/kg/day [M]; 80.1

- 91.2 [F]. Parental LOAEL = 721

- 844 and 813

- 901 mg/kg/day based on decreased body wt and body wt gains of F 0 and F 1 (M) and F 1 (F), gross a nd microscopic liver lesions of (M) and (F)

- both generations. Reproductive NOAEL = 721

- 844 and 813

- 901 mg/kg/day. Reproductive LOAEL not determined. No effects observed. Offspring NOAEL = 70.8

- 82.3 mg/kg/day [M]; 80.1

- 91.2 [F]. Offspring LOAEL = 721

- 844 and 813

- 901 mg/kg/day based on decreased body weight and body weight gains of the F 1 and F 2 pups. 870.4300 2

- yr Chronic/ Carcino

- genicity Rat 45282911 (1996)

0, 80, 400, 2000 or 10,000 ppm 0, 3.4, 17.2, 86.7 and 468.1 mg/kg/day (M) 0, 4.4, 21.8, 11.5 and 578.5 mg/kg/day (F) Acceptable/guideline NOAEL = 86.7 mg/kg/day (M); 111.5 mg/kg/day (F). LOAEL = 468.1 mg/kg/day(M); 578.5 mg/kg/day (F) based on decreased body weight and body weight gain in males and microcytic anemia, liver lesions and kidney tox icity (both sexes); possible increase pheochromocytomas in females

870.4200b 78

- Week Carcino

genicity Mouse 45282913 (1996)

0, 200, 1000 or 5000 ppm 0, 20.99, 109.7 and 546.8 mg/kg/day (M) 0, 19.58, 98.3, and 523.7 mg/kg/day (F) Acceptable/guideline NOAEL = 20.99 mg/kg/day (M); 19.58 mg/kg/day (F). LOAEL = 109.7 mg/kg/day (M); 98.3 mg/kg/day (F) based on liver toxicity, hepatocellular tumors at 5,000 ppm; possibly hemangioma/ hemangioasarcomas.

870.4100b 52

- Week Oral Feeding Dogs 45282906 (1996)

0, 40, 200 or 1000 mg/kg/day Acceptable/guideline NOAEL = 1000 mg/kg/day. LOAEL > 1000 mg/kg/day; no effects observed.

870.5100 Bacterial Reverse Gene Mutation Assay 45282924 (1994),

0, 156.3, 312.5, 625, 1250, 2500, 5000 μg/plate in the presence and absence of mammalian metabolic activation (S9

- mix) in two independent assays. Acceptable/guideline There was no evidence of induced mutant colonies over background.

870.5300 In Vitro Mammalian Cell Gene Mutation Assay (mouse lymphoma) 45327623 (1994)

0 , 10, 20, 30, 40 or 50 μg/mL for 4 hours in the absence of mammalian metabolic activation (S9

- mix). 0, 150, 200, 250, 300 or 350 μg/mL for 4 hours with S9

- mix. Two independent assays were conducted. Acceptable/guideline There was no evidence of induced mutant colonies over background up to cytotoxic concentrations (50 μ g/ml

- S9; 350 μ g/ml +S9).

### Page 23 of 25

Table 4.3. Non

- acute Toxicity Profile for Pyraflufen

- Ethyl.

Guideline Number and Study Type MRID (Year)

Dose Levels Results

870.5300 In Vitro Mammalian Cell Gene Mutation Assay (mouse lymphoma) 45282928 (1984),

Assay 1 0, 10, 20, 40, 60 or 80 μg/mL for 4 hours in the absence of mammalian metabolic activation (S9

- mix). 0, 20, 40, 80, 120 or 160 μg/mL for 4 hours with S9

- mix. Assay 2 0, 20, 40, 60, 80 or 100 μg/mL without S9

- mix 0, 40, 80, 120, 160 or 200 μg/mL with S9

- mix Acceptable/guideline There was no increase in the number of mutant colonies over background in the absence of S9

- mix but a non

- reproducible dose

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

- mix.

870.5375 In Vitro Mammalian Chromosome Aberration 45282927 (1994)

0, 650, 1300 or 2600 μg/mL for 19 or 43 hours without metabolic activation (S9

- mix) or for three hours with S9

- mix. A second assay was conducted at the same three concentrations but using a 19 hour sampling time only. Acceptable/guideline There was no evidence of chromosomal aberration induction over background.

870.5500 Bacterial DNA Damage and Repair 45282929 (1994)

0, 343.75, 687.5, 1375, 2750 or 5500 μg/disk in the presence and absence of metabolic activation (S9

- mix). Acceptable/guideline There was no evidence of greater growth inhibition or cell killing in repair

defective strains compared to repair competent strains up to the limit of test material solubility.

870.5550 in vivo/in vitro unscheduled DNA Synthesis (UDS) 45282930 (1998)

6 00 and 2000 mg/kg Acceptable/guideline The mean net nuclear grain count was below zero for both doses at both treatment times indicating no induction of UDS as tested in this study.

870.5395 M ouse M icronucleus A ssay 45282931(1994)

a single dose at 0, 1250, 2500 or 5000 mg/kg with sacrifice at 24 hours; a single dose of 5000 mg/kg with sacrifice at 48 and 72 hours; two doses of 2500 or 5000 mg/kg separated by 24 hours with sacrifice 24 hours after the second dose Acceptable/guideline There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any dose or treatment time.

870.6300a Acute Neurotoxicity Rat 48802401 (2012)

0, 125, 500 or 2000, mg/kg Acceptable/guideline NOAEL = 500 mg/kg LOAEL = 2000 mg/kg based on transiently decreased body weight gain in females (↓26%, ns). No neurotoxicity was observed.

### Page 24 of 25

Table 4.3. Non

- acute Toxicity Profile for Pyraflufen

- Ethyl.

Guideline Number and Study Type MRID (Year)

Dose Levels Results

870.6300b Subchronic Neurotoxicity Rat 48802402 (2012)

0, 1000, 2800, 8000 ppm (M) 0, 61, 174, 502 mg/kg/day (F) 0, 80, 222, 625 mg/kg/day Acceptable/guideline NOAEL = 61 mg/kg/day (M), 222 mg/kg/day (F) LOAEL = 174 mg/kg/day (M), 625 mg/kg/day (F) based on transient decrease in body weight gain and changes in hematology parameters. No
n eurotoxicity was observed.

870.7485 Metabolism and Pharmaco

- kinetics Rat 45282932, 45282933, 45282934,

45282935 (1996) 5.0, 500 mg/kg single oral dose 5 mg/kg/day 14

- day repeated oral dose Acceptable/guideline ET

- 751(pyraflufen

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

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

- fold dose differentia l (2.7

- 2.8 μg eq/g for the low

- dose group and 100

- 107 μg eq

hr/g for the high

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

- 751, urinary excretion accounted for 27

- 33% of the administered radioactivity suggesting that a multiple exposure regimen did not affect the absorption/excretion processes. Urinary excretion was reduced to only 5

- 7% following a single 500 mg/kg dose. Excretion via the feces accounted for the remainder of the administered radioactivity in all treatment grou ps. Analysis of biliary excretion following a single 5 mg/kg dose showed that

 36% of the administered dose appeared in the bile. Based upon the excretion data, total bioavailability of a low dose was approximately 56%. Biliary excretion data were not a vailable for a high

dose group which prevented a definitive assessment of bioavailability. Excretory patterns did not exhibit gender

- related variability. However, plasma and blood clearance was more rapid in females than in males as shown by plasma/blood radioactivity time

- course and the greater AUC values for males (32.3 vs 18.4 μg eq

- hr/g for the low

- dose group and 2738 vs 1401 μg eq

- hr/g for the high

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

- 751 nor its metabolites appear to undergo significant sequestration. Tissue burden data following compound administration did not sugges t a specific target beyond those tissues, namely liver and kidney, which are associated with absorption and elimination of orally administered xenobiotics. Both urinary and fecal metabolites were quantified by HPLC and most were identified using HPLC and TLC in conjunction with known standards. The metabolites identified (primarily hydrolysis and subsequent demethylation products) were consistent with Phase I processes. The major metabolic pathway appears to be a sequential hydrolysis and demethylation of the parent compound to metabolites E

- 1 and E

- 9 both of which are quantitatively prominent components detected in the urine and feces from all treatment gro ups. Extraction efficiencies appeared to be excellent and most components in all of the matrices examined (urine, feces, plasma, and bile) were adequately quantified and characterized. The available data, based upon studies using both the pyrazole

- 5 and the uniformly labeled phenyl ring, affirmed the metabolism pathway proposed by the investigators.

### Page 25 of 25

Table 4.3. Non

- acute Toxicity Profile for Pyraflufen

- Ethyl.

Guideline Number and Study Type MRID (Year)

Dose Levels Results

870.7800 Immunotoxicity Rat 48577901 (2011)

0, 750, 3000 or 12,000 ppm 0, 59.4, 236.2, 946.2 mg/kg/day (M) 0, 67.1, 277.5, 1114.0 mg/kg /day (F) Acceptable/guideline Systemic Toxicity NOAEL= 236.2 mg/kg/day (M); 1114.0 mg/kg /day (F) LOAEL = 946.2 mg/kg/day (M) based on decreases in body weight, body weight gain, food consumption and feed efficiency; not established in (F). Immunotoxicity NOAEL= 236.2 mg/kg/day (M); 1114.0 mg/kg /day) (F) LOAEL = 946.2 mg/kg/day (M) based on decreases of anti

- SRBC AFC response; not established in (F).