Page 1 of 34 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date:**  08 - MAY - 2013 **SUBJECT: Fenpyroximate**  . Human - Health Risk Assessment for Proposed Section 3 Uses

on Stone Fruits (Group 12 - 12), Tuberous and Corm Vegetables (Subgroup 1C), and Small Vine Climbing Fruits Except Kiwifruit (Subgroup 13 - 07F). **PC Code:** 129131 **DP Barcode**  **:** D 404839 **Decision No.:** 468635 **Registration Nos. :**  71711 - 4 and 71711 - 19 **Petition No.:** 2E8072 **Regulatory Action:** Section 3 Registration **Risk Assessment Type:** Single Chemical/Aggregate **Case No.:** 7432 **T XR No.:**  NA **CAS No.:** 134098 - 61 - 6 (E - isomer) **MRID No.:** NA **40 CFR:** §180.566 **FROM:** Jennifer R. Tyler, Chemist

George F. Kramer, Ph.D., Senior Chemist Chester E. Rodriguez, Ph.D., Toxicologist Risk Assessment Branch 1 (RAB1) Health Effects Division (7509P) **THROUGH:** Charles W. Smith III , Acting Branch Chief

RAB1/HED ( 7509P) **TO:** Sydney

Jackson/Barbara Madden, RM 05 Registration Division (RD; 7505P) The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The RD of OPP has requested that 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 the registered a nd proposed uses of the insecticide/miticide fenp yroximate (( E ) - 1,1 - dimethylethyl 4 - [[[[(1,3 - dimethyl - 5 - phenox y- 1 H

- py razol - 4 - yl)methylene]amino]ox y] methyl]benzoate). A summary of the estimated human health risks resulting from the registered and requested fenpy roximate uses are provided in this document. The risk assessment and occupational/residential exposure assessment were provided b y J ennifer T yl er (RAB1); the residue chemistry data review and dietary

exposure assessment by

George Kramer (RAB 1); the hazard characterization by Chester Rodriguez (RAB1); and the drinking water assessment b y Greg Orrick of the Environmental Fate and Effects Division (EFED).Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 2 of 34 **TABLE OF CONTENTS** 1.0 Executive Summary ................................ ................................ ................................ ............. 3 2.0 HED Recommendations ................................ ................................ ................................ ....... 7 2.1 Data Deficiencies ................................ ................................ ................................ ............. 7 2.2 Tolerance Considerations ................................ ................................ ................................ . 7 2.2.2 Recommended Tolerances ................................ ................................ ............................ 8 2.3 Label Recommendations ................................ ................................ ................................ .. 8 3.0 Introduction ................................ ................................ ................................ .......................... 9 3.1 Chemical Identity ................................ ................................ ................................ ............. 9 3.2 Phy sical/Chemical Characteristics ................................ ................................ ................... 9 3.3 Pesticide Use Pattern ................................ ................................ ................................ ........ 9 3.4 Anticipated Exposure Pathway s ................................ ................................ ..................... 11 3.5 Consideration of Environmental Justice ................................ ................................ ........ 11 4.0 Hazard Characterization and Dose - Response Assessment ................................ ................ 11 4.1 Hazard Profile ................................ ................................ ................................ ................ 11 4.4 Safety

Factor for Infants and Children (FQPA Safety Factor) ................................ ....... 13 5.0 Dietary

Exposure and Risk Assessment ................................ ................................ ............ 17 5.1 Residues of Concern Summary and Rationale ................................ ............................... 17 5.2 Food Residue Profile ................................ ................................ ................................ ...... 18 5.3 Water Residue Profile ................................ ................................ ................................ .... 18 5.4 Dietary

Risk Assessment ................................ ................................ ................................ 19 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ .... 20 6.1 Residential By stander Post - Application Inhalation Exposure ................................ ....... 20 6.2 Spray

Drift ................................ ................................ ................................ ...................... 21 7.0 Aggregate Exposure/Risk Characterization ................................ ................................ ....... 21 7.1 Acute Aggregate Risk ................................ ................................ ................................ .... 21 7.2 Chronic Aggregate Risk ................................ ................................ ................................ . 22 8.0 Cumulative Exposure/Risk Characterization ................................ ................................ ..... 22 9.0 Occupational Exposure/Risk Characterization ................................ ................................ .. 22 9.1 Handler Exposure/Risk Estimates ................................ ................................ ................. 22 9.2 Post - Application Exposure/Risk Estimates ................................ ................................ ... 26 10.0 References ................................ ................................ ................................ .......................... 28 Appendix A. Toxicology Profile Tables. ................................ ................................ ..................... 30 Appendix B. Phy sical/Chemical Properties ................................ ................................ ................. 34Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 3 of 34 **1.0 Executive Summary**  Fenp yroximate is a contact insecticide/miticide used for the control of leafhoppers, meal ybugs, and mites. Fenp yroximate is a mitochondrial electron - transport inhibitor (METI) which acts by targeting proton - translocating NADH:Q oxidoreductase and blocking ubiquinone reduction. The Interregional Project No. 4 (IR - 4) has proposed a Section 3 Registration for application of fenp yroximate to stone fruits (group 12 - 12), small vine climbing fruits except ki wifruit (subgroup 13 - 07F), and tuberous and corm vegetables (subgroup 1C) . IR - 4, on behalf of the Agricultural Experiment Stations of CA, MI , MT, PA, TX, and UT, requests the establishment of tolerances for the combined residues of the insecticide fenp yr o ximate, 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 b y measuring onl y the sum of fenpy roximate, (

E ) - 1,1 - dimethylethyl 4 - [[[[(1,3 - dimethyl - 5 - phenoxy- 1 H - py razol - 4 - yl ) meth yl ene] amino]ox y] methyl] benzoate and its Z-isomer, (Z ) - 1,1 - dimethylethyl 4 - [[[[(1,3 - dimethyl - 5 - phenoxy- l H - py razol - 4 - yl ) meth yl ene]amino]oxy] methyl]benzoate, calculated as the stoichiometric equivalent of fenp yroximate, in/o n the following raw agricultural commodities (RACs): fruit, stone, group 12 at 2.0 ppm; vegetable, tuberous and corm, subgroup 1C at 0.10 ppm; and fruit, small, vine climbing, except fuzzy

kiwifruit, subgroup 13 - 07F at 1.0 ppm. Fenp yroximate tolerances h ave been established in 40 CFR §180.566. Tolerances for plant commodities are expressed in terms of combined residues of fenp yroximate and its Z - isomer. Permanent tolerances for plant commodities, under §180.566(a)(1) range from 0.10 ppm for cotton undel inted seed to 20 ppm for tea. Tolerances for milk and the fat, meat, and meat by products (excluding liver and kidney) of cattle, goat, horse, and sheep are listed in 40 CFR §180.566(a)(2) and are expressed in terms of the combined residues of fenpy roximat e and its metabolites (

E) - 4 - [(1,3 - dimethyl - 5 - phenoxy py razol - 4 - yl ) - methylene aminooxy methyl]benzoic acid and ( E) - 1,1 - dimethylethyl - 2 - hydroxyeth yl4 - [[[[(1,3 - dimethyl - 5 - phenoxy- 1 H - py razol - 4 - yl )meth yl ene]amino]oxy]methyl]benzoate, calculated as the parent compound. Tolerances for cattle, goat, horse, and sheep liver and kidney are listed under 40 CFR §180.566(a)(3) at 0.25 ppm and are expressed in terms of fenp yr oximate and its metabolite ( E) - 4 - [(1,3 - dimethyl - 5 - phenox yp yr azol - 4 - yl ) - methylene aminooxy methyl]be nzoic acid, calculated as the parent compound . A time - limited tolerance for residues in/on honey at 0.10 ppm with a 12/31/13 expiration date is listed in 40 CFR §180.566(b) under a Section 18 Emergency Exemption. Fenp yroximate has no uses that result in residential exposure. **Toxicity Profil**

**e** : Fenp yr oximate was classified as Category II for acute toxicity

via the oral and inhalation routes of exposure. It exhibited low dermal acute toxicity (Category

I II) and was neither a skin nor eye irritant. Fenp yroximate is considered to be a slight to moderate skin sensitizer. The effects following repeated oral exposures to fenpy roximate were based on sy stemic toxicity (no specific target organ/tissue identified). The most sensitive species tested was the dog . The effects reported in the dog included slight bradyc ardia, deficits in food consumption, body weight, body- weight gain, and an increased incidence of emesis and diarrhea. Emaciation and torpor (sluggish inactivity) were reported in female dogs at low er dose levels than males. The highest dose tested in the dog (50 mg/kg bw/day) resulted in first - and second - degree heartFenpyroximate Human - Health Risk Assessment DP No. 404839

Page 4 of 34 block, increased urea concentration, decreased glucose, and altered plasma electrol yt e levels among other signs of toxicity . In sub chronic and chronic studies with rats, the primary effect was decreased body- weight gain in both sexes with hematological changes (e.g., higher counts of red blood cells) at higher doses. In a rat prenatal developmental toxicity study , a dose level that m arginall y affected maternal body weight and food consumption also resulted in an increased litter incidence of increased thoracic ribs, indicating increased prenatal (qualitative) susceptibility . In the rabbits, there were no developmental effects reporte d at the levels tested. In the rat two - generation rep roductive toxicity study ; maternal toxicity

(decreased body weight) and offspring toxicity (decreased lactational weight gain in both generations) occurr ed at the same dose. There is no evidence that fenp yroximate specifically targets the nervous or immune sy stem based on the results of recentl y submitted studies. In the acute neurot oxicity study , neurotoxicity

signs such as decreases in motor activity occurred in the presenc e of other effects including decreases in body weight and food consumption, and in the absence of neuropathology . Similar results were noted in a delayed acute neurotoxicity study in the hen where no effects (neurotoxic or otherwise) were reported. The results of the rat subchronic neurotoxicity study did not indicate any neurotoxicity- specific effects; deficits in body weight and food consumption were the main effects reported. Similarly , the effects reported in a rat immunotoxicity study were limited t o decreased body- weight gain . In a 21 - day

dermal toxicity

study in rats, there were clinical signs in females consisting of red nose and mouth/nasal discharge, decreased body weights, body- weight gains, and food consumption in males and females. There were also increased liver weights and hepatocellular necrosis reported in females. In a 4 - week rat inhalation study , treatment - related effects included clinical observations (labored breathing and rales), increased lung weights, decreases in body- weight gai n and food consumption, and changes in hematology parameters (increased counts of ery throcy tes and leukocy tes). There were also histopathology findings in the nasal passage mucosa consisting of atrophy and squamous metaplasia. Fenp yroximate was classified as “not likel y to be carcinogenic to humans” based on the results of rat and mouse carcinogenicity studies. Genotoxicity studies including mutagenicity did not demonstrate an y genotoxic potential associated with fenpy roximate. **Dose -** **response and Food Quality Protection Act (FQPA) Assessment** : The existing toxicology database for fenp yroximate is complete and adequate for FQPA evaluation, risk assessment, and tolerance setting. Appropriate endpoints were identified for exposure s to fenpy roximate. For the acute dietary

risk assessment of females 13 - 49 years old, the acute population - adjusted dose (aPAD) of 0.05 mg/kg/day was selected based on the no - observed - adverse - effect level (NOAEL) of 5.0 mg/kg/day

in the rat prenatal devel opmental toxicity study where an increased incidence of additional thoracic ribs was observed at 25.0 mg/kg/day . For the acute dietary risk assessment f o r the general population, the aPAD of 0.375 mg/kg/day was selected based on the NOAEL of 37.5 mg/kg/day in the rat acute neurotoxicity study where decreases in motor activity and auditory startle response were observed. The chronic dietary endpoint for all populations wasFenpyroximate Human - Health Risk Assessment DP No. 404839

Page 5 of 34 based on a chronic population - adjusted dose (cPAD) of 0.05 mg/kg/day based on the N OAEL of 5.0 mg/kg/day

in a chronic dog study

where an increased incidence of bradycardia and diarrhea was observed along with decreases in cholesterol, body- weight gain, and food consumption at 15.0 mg/kg/day . For occupational exposure scenarios involving dermal exposure (short - and intermediate - term), a route - specific study

was selected where decreases in body weight, body- weight gain, and food consumption were noted along with increased absolute liver weight and a possible increase in hepatocellular necrosis . T he dermal NOAEL was chosen as 300 mg/kg/day and the level of concern (LOC) is 100. A route - specific inhalation study was used for assessing inhalation occupational exposures (short - and intermediate - term). The effects report ed included clinical o bservations (labored breathing and rales), increased lung weights, decreases in body- weight gain and food consumption, and changes in hematology parameters (increased counts of erythrocy tes and leukocytes) , and histopathology changes. The i nhalation NOAEL was chosen as 0.002 mg/L and the LOC is 30 because the animal inhalation exposure POD was converted to a human - equivalent concentration (HEC) which includes a dosimetry adju stment factor for duration of exposure and species differences in respiration and respiratory tract surface area. The fenp yroximate risk assessment team has evaluated the hazard and exposure data; and, b ased on these data, recommended that the FQPA S afety F actor (SF) be reduced to 1x for all exposure scenarios . The recommendation is b ased on the following: (1) the existing toxicology database for fenp yr oximate is complete and adequate for FQPA evaluation; (2) there is no concern for neurotoxicity ; (3) although there was evidence for increased (qualitative) prenatal susceptibility foll owing oral exposures in the rat developmental toxicity study , the concern is low because there was clear NOAEL established; and (4) there are no residual uncertainties with respect to exposure data. **Residue Chemistry and Drinking Water Assessments:** The r esidue chemistry and drinking water databases are adequate to assess potential human exposure to fenpy roximate. Adequate residue chemistry

data have been submitted to support the proposed uses. No new residue data were submitted to support the tolerance on small vine climbing fruits except kiwifruit (subgroup 13 - 07F) . IR - 4 has requested that the established tolerance for residues in/on grape be expanded to its respective crop group. EFED provided Tier 1 estimated drinking water concentrations (EDWCs) fo r fenp yr oximate and its isomer s /degradate s , M1 and M3. The ground water EDWC was determined using the Screening Concentration In Ground Water (SCI - GROW) model; and surface water EDWCs were determined using the FQPA Index Reservoir Screening Tool (FIRST) m odel and a Provisional Cranberry Model. Surface water EDWCs of 0.043 ppm and 0.0086 ppm were used in the acute and chronic analy ses, respectivel y, as these values were the highest and provided a more conservative approach. **Dietary Risk Estimates (Food + Drinking Water**  ) : Acute and chronic aggregate dietary (food + drinking water) exposure and risk assessments were conducted for fenp yro ximate using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM - FCID, ver. 3.16) which incorpo rates consumption data from United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA; 2003 - 2008). The acute and chronic analy ses employed tolerance - level residues for all commodities; 100% crop treated ( CT ) information; DEEM (ver. 7.81) defaultFenpyroximate Human - Health Risk Assessment DP No. 404839

Page 6 of 34 processing factors (as necessary); and empirical processing factors for several commodities . Drinking water was incorporated directly into the dietary

assessments using the EDWCs for surface water. Separate acute dietary

exposure and risk anal ys es were conducted for females 13 - 49 years old and for the general U.S. population as separate endp oints of concern attributable to a single dose were identified. The acute dietary risk est imate is not of concern to HED ( <100% of the aPAD) for females 13 - 49 years old, or the general U.S. population. The resulting acute risk estimate is 13% of the aPAD at the 95 th percentile of the exposure distribution for females 13 - 49 years old. The highest acute exposure estimate for the U.S. population or population subgroup is children 1 - 2 years old, which resulted in a risk estimate of 6.2% of the aPAD. A chron ic dietary

exposure and risk assessment was conducted for the general U.S. population and various population subgroups. The chronic dietary risk estimates are below HED’s LOC (<100% of the cPAD) for the general U.S. population and all population subgroups . The most highl y exposed population subgroup is children 1 - 2 years old with a risk estimate of 15% of the cPAD. **Residential Exposure** : The proposed use is on agricultural crops; therefore, a quantitative residential exposure assessment was not conducted . In addition, there are no proposed or existing fenpy

roximate products registered for residential use sites. **Aggregate Exposure Assessment** : Aggregate exposure risk assessments were assessed b y incorporating the drinking water directl y into the dietary exposure assessment for the following scenarios: acute and chronic aggregate exposures (food + drinking water). Short - , intermediate - , and long - term aggregate risk assessments were not performed because there are no registered or proposed uses of fenp y

roximate that result in residential exposures. A cancer aggregate risk assessment was not performed because fenp yroximate is not carcinogenic. The acute and chronic aggregate risk estimates do not exceed the HED’s LOC for the general U.S. population and all population subgroups. **Occupational Exposure** : Short - and intermediate - term inhalation and dermal risk estimate s for handlers were assessed for mixer/loaders and applicators involved in occupational use of fenp yroximate. Post - application dermal risk e stimate s were assessed for workers involved in post - application activities. Surrogate data were used to estimate mixer/loader and applicator exposure. For handlers, HED has determined that risk estimate s are not of concern [margin of exposure (MOE) >100 for dermal exposure and >30 for inhalation exposure] at baseline and with the addition of gloves (required on the label). HED has also determined that the risk estimate s are not of concern (i.e., MOE >100) on the day of treatment for all post - application activities. Therefore, occupational risk estimate s for handlers and post - application workers are not of concern. The proposed labels have a 12 - hour restricted - entry interval (REI). Fenpy

roximate is classified as Toxicity

Category II for acute dermal, an d Toxicity Category IV for primary

eye irritation and primary dermal irritation. It is a slight to moderate dermal sensitizer by the maximization test method. Therefore, while an assessment of sy stemic toxicity from post - application exposure would indicate acceptable MOEs on the day of treatment, the acute toxicity categories for thisFenpyroximate Human - Health Risk Assessment DP No. 404839

Page 7 of 34 chemical require a 24 - hour RE I for this product under the Worker Protection Standard (WPS). **RD should ensure that all fenpyroximate labels have the appropriate REI listed.** The Akari ® 5SC label should be amended to specify the use of “chemical - resistant gloves” instead of “waterproof gloves.” **RD should ensure the appropriate personal protective equipment (PPE) is listed on the label.**  **Review of Human Research** : This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from Pesticide Handler Exposure Database (PHED), Version 1.1 (August, 1998), the AH ETF database, the Outdoor Residential Exposure Task Force (ORETF) database, and the Agricultural Reentry Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics req uirements. For certain studies, that review may have included review s by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/pestici des/science/post - app - exposure - data.html . **2.0 HED**  **Recommendations** Provided revised Sections B and F are submitted, HED concludes that the toxicological, residue ch emistry and occupational/residential databases support a Section 3 registration and establis hment of the tolerances listed in Section 2.2.2. HED is not recommending for any additional data in conjunction with this petition. **2.1 Data Deficiencies**  No additional data are required to support the proposed use. **2.2 Tolerance Considerations**  **2.2.1 E**  **nforcement Analytical Method** An adequate enforcement method is available for determination of fenp yr oximate residues of concern in the proposed/registered crops. A gas chromatograph y method with nitrogen/phosphorus detection (GC/NPD), Method S19, has pas sed an Agency validation (DP# 269410, 10/10/00, G. Kramer). Method S19 has a limit of quantitation (LOQ) of 0.05 ppm for the combined residues of fenp yroximate and M - 1 in snap beans and avocados. A data - gathering liquid chromatograph y/mass spectroscop y/m ass spectroscop y ( LC /MS/MS) method is also available. This method was used for the anal ys is of the samples from submitted field and processing studies.Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 8 of 34 **2.2.2 Recommended Tolerances**  **Table 2.2.2. Tolerance Summary for Fenpyroximate. Comm**  **odity Proposed** 

**Tolerance (ppm) HED**  **- Recommended** 

**Tolerance (ppm) Correct Commodity**  **Definition/Comments** Fruit, stone, group 12 2.0 2.0 Fruit, stone, group 12 - 12 Vegetable, tuberous and corm, subgroup lC 0.10 0.10 Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13 - 07F 1.0 1.0 **Rem ove from** **40 CFR §180.566 (a)(1):** Grape **2.2.3 Revisions to Petitioned**  **- For Tolerances**  A summary

of recommended tolerances for the current petition is listed in Table 2.2.2. **A revised Section F specifying the HED**  **- recommended tolerances should be submitted.**  **2.2.4 International Harmonization**  Codex and Mexican maximum residue limits (MRLs) are established for residues of fenp yroximate per se in/ grapes (fresh and dried). Har monization with the Codex and Mexican MRL s is not possible because the U.S. tolerance expression includes an additional isomer and the U.S. use pattern requires a higher numerical value. There are currently no established Canadian MRL s. **2.3 Label Recomme**  **ndations 2.3.1**  **Recommendations from Occupational Assessment**

 The Akari ® 5SC label should be amended to specify the use of “chemical - resistant gloves” instead of “waterproof gloves.” RD s hould ensure the appropriate PPE is listed on the label.  T he acute toxicity

categories indicate that a 24 - hour REI is appropriate for this product under the WPS . The proposed labels list a 12 - hour REI . RD should ensure that all fenp yroximate labels have the appropriate REI listed.Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 9 of 34 **3.0 In**  **troduction 3.1**  **Chemical Ident ity**  **Table 3.1. Fenpyroxim ate Nom**  **enclature.** Chemical structure

Common name Fenpyroximate Company experimental name NNI - 850 IUPAC name tert- butyl(E) - alpha - (1,3 - dimethyl - 5 - phenoxypyrazol - 4 - yl methyleneamino - oxy) - p - toluate CAS name 1,1 - dimethylethyl 4 - [[[( E) - [(1,3 - dimethyl - 5 - phenoxy1 H - py razol - 4 - yl)methylene] - amino]oxy]methyl]benzoate CAS registry number 134098 - 61 - 6 (E isomer); 111812 - 58 - 9 (unspecified stereochemistry) End - use products (EPs) FujiMite ®/P ortal ® Miticide/Insecticide 0.4 lb ai/gal EC f ormulation (5% ai; EPA Reg. No. 71711 - 19) Akari ® 5SC Miticide/Insecticide 0.42 lb ai/gal SC formulation (5% ai; EPA Reg. No. 71711 - 4) Chemical structure of fenpyroximate Z isomer metabolite 1,1 - dimethylethyl 4 - [[[(Z ) - [(1,3 - dimethyl - 5 - phenoxy1 H - py razol - 4 - yl)methylene] - amino]oxy]methyl]benzoate Metabolite M1 **3.2 Physical/Chemical Characteristics**  The phy sical and chemical properties, as well as a summary of relevant environmental fate parameters, are detailed in Appendix B. Fenp yroximate has a low vapor pressure (10 - 8 mmHg) and environmental fate data indicate that it is not likely to volatilize. **3.3 Pesticide Use Pattern**  Fenp yroximate is a contact insecticide/miticide used for the control of leafhoppers, meal ybugs, and mites. U.S. registrat ions are currentl y held b y Nichino America, Inc., and include registrations for nonfood uses on ornamental, floral, and foliage crops, and for several food uses. The EPs associated with this registration action are Fujimite ® 5EC Miticide/Insecticide (EPA Reg. No. 71711 - 19), an EC formulation containing 5% ai (equivalent to 0.4 lb ai/gal); Portal ® Miticide/Insecticide (EPA Reg. No. 71711 - 19), an EC formulation containing 5% ai (equivalent to 0.4 lb ai/gal); and Akari ® 5SC Miticide/Insecticide (EPA Reg. No. 71711 - 4), an SC formulation containing 5% ai (equivalent to 0.42 lb ai/gal). Summaries of the proposed end - use products and crop use patterns are presented in Tables 3.3.1 and 3.3.2, respectivel y. The proposed FujiMite ® 5EC and Portal ® label s require applicators and other handlers to wear a long - sleeved shirt and long pants, chemical - resistant gloves, protective eyewear, shoes plus O C H 2 N N C H 3 C H 3 C N

O C O O C ( C H 3 ) 3 H

C O O C ( C H 3 ) 3 H

N N C H 3 C H 3 C N

O O C H 2Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 10 of 34 socks, chemical resistant apron (for mixing and loading), and chemical - resistant headgear (for overhead exposure). The p roposed Akari ® 5SC label requires applicators and other handlers to wear a long - sleeved shirt and long pants, waterproof gloves, protective eyewear, and shoes plus socks. **The label should be amended to specify the use of “chemical -**  **resistant gloves” instea**  **d of “waterproof gloves.” RD should ensure the appropriate PPE is listed on the label.**  **Table 3.3.1. Summary of Proposed End -**  **Use Product .**  **Trade Name EPA** 

**Reg. No. ai (%**  **of**

**formulation) Formulation** 

**Type Target Crops**  **Target Pests Label Date**  Fujimite ® 5EC Miticide/ Insecticide 71711 - 19 5% (equivalent to 0.4 lb ai/gal) Emulsifiable

Concentrate stone fruits (group 12 -

12), small vine climbing fruits except kiwifruit (subgroup 13 - 07F), and tuberous and corm vegetables (subgroup 1C) Mites Undated draft label Portal ® Miticide/ Insecticide Akari ® 5SC Miticide/ Insecticide 71711 - 4 5% (equivalent to 0.42 lb ai/gal) Soluble

Concentrate stone fruits (group 12 -

12), and tuberous and corm vegetables (subgroup 1C) **Table 3.3.2. Summary of Directions for Use of Fenpyroxim**  **ate. Application**  **Timing, Type, and**  **Equipment Form**  **ulation**

**[EPA Reg. No.]**  **Maximum**

**Application Rate (lb**  **ai/A) Maximum #** 

**Applications per Season**  **Max.**

**Seasonal Application**  **Rate (lb ai/A)**  **PHI 1** 

**(days) Use Directions and** 

**Limitations Sm**  **all Fruit Vine Climbing (Except Fuzzy Kiwifruit) (Crop Subgroup 13**  **- 07F)**  Airblast Fujimite ® EC

[71711 - 19] 0.05 - 0.1 2 0.1 14 RTI 3 = 14 days; Min. GPA2 = 50; Do not apply by air; Do not apply through any type of irrigation system. **Tuberous and Corm Vegetables (Crop Subgroup 1C)**  Groundboom, Aerial Fujimite ®

EC/Portal ® [71711 - 19] Akari ® SC [71711 - 4] 0.1 2 0.2 7 RTI = 7 days; Min. GPA

= 20 (ground) and 5 (air); Do not apply through any type of irrigation system. **Stone Fruit (Crop Group 12 -**  **12)** Airblast Fujimite ® EC/

Portal ® [71711 - 19] Akari ® SC [71711 - 4] 0.1 2 0.2 7 RTI = 14 days; Min. GPA = 80; Do not apply by air; Do not apply through any type of irrigation system. 1. PHI = pre - harvest interval. 2. GPA = gallons of water per acre. 3. RTI = retreatment interval. The following rotational crop restriction appears on the proposed labels: “Do not plant rotational crops other than those listed on the label for 30 day s following the last application of this product.”Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 11 of 34 **3.4 Anticipated Exposure Pathways**  RD has requested an assessment of human health risk to support the proposed new use of fenp yroximate on stone fruits (group 12 - 12), small vine climbing fruits except kiwifruit (subgroup 13 - 07F), and tuberous and corm vegetables (subgroup 1C) . Humans may b e exposed to fenpy roximate in food and drinking water, since it may be applied directly

to growing crops, and application may

result in fenpy

roximate reaching surface and ground water sources of drinking water. As there are no residential uses of fenp yrox imate, there is not likely to be exposure in residential or non - occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a lso potential for po st - application exposure for workers re - entering treated fields. Risk assessments have been previousl y conducted for fenp yr oximate, but no new toxicity data have been received since the previous risk assessment. This risk assessment considers all of the aforementioned exposure pathway s based on the proposed new uses of fenpy roximate, but also considers the existing uses as well, for the dietary and aggregate exposure assessments. **3.5 Consideration of Environmental Justice**  Potential areas of environme ntal 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 L ow - Income Populations," (http://www.hss.energy .gov/nuclearsafety/ env/guidance/justice/eo12898.pdf ) . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgrou ps 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 NHANES/WWEIA; 2003 - 2008 and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country . Additionall y, 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 by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **4.1 Hazard Profile**  **4.1.1 Mode of Action**  Fenp yroximate is a contact insecticide/miticide used for the control of leafhoppers, meal ybugs, and mites. The proposed pesticidal mode of action involves inhibition of mitochondrial function.Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 12 of 34 More specificall y, fenp yr oximate is a mitochondrial electron transport inhibitor that targets the enzy me NADH:ubiquinone oxidoreductase and blocks electron transfer to ubiquinone. **4. 2**  **Toxicology Studies Available for Analysis** The toxicological database for fenpy roximate is adequate for characterization of its hazard, toxicity endpoint selection, and FQPA SF consideration . In the last risk assessment ( Memo, J. Tyler et al. , 16 - APR - 2012 , D P# 391430 ) , immunotoxicity and neurotoxicity

studies ( acute and subchronic ) previously

noted as data gaps were included in the hazard characterization along with a 4 - week inhalation toxicity rat study previously

submitted to the Agency . **4. 2.1**  **Absorption, Distribution, Metabolism, & Elimination (ADME)** Following oral administratio n in the rat, radiolabeled fenp yroximate was slowly absorbed into the sy stemic circulation reaching maximum blood levels at 7 - 11 hours post dose. The elimination half

- life in blood was estimated at 6.1 - 8.9 hours at the dose of 2 mg/kg bw. The liver contained up to 9.77% of the administered radioactivity after 6 hours, but decreased to 0.61 - 0.78% at 12 hours. The majority of radioactivity was excreted in feces within the first 24 hours post - dosing. Feces accounted for 75.1 - 91.6% of the radioactivity , whi le the contribution of urine was 9.21 - 17.8%. The parent compound detected in feces accounted for only a small fraction (6.32 - 8.68%) of the administered dose. At least 20 different metabolites were characterized from excreta (urine and feces). The low le vels of the parent chemical and the presence of different metabolites in feces is indicative of extensive absorption, metabolism, and biliary excretion. No sex - dependent differences were reported in ADME behavior. **4. 2.1**  **Dermal Absorption** A dermal - absorption factor of 5% was previousl y estimated for fenp yroximate based on the results of a rat dermal penetration study . In addition, a route - specific dermal rat toxicity study can be used to assess hazard associated with the dermal route of expo sure. **4. 3**  **Toxicological Effects** Fenp yroximate induced moderate acute lethality i n rats (Category I I) via the oral and inhalation routes of exposure. It exhibited low dermal acute toxicity (Category

I II) and was neither a skin nor eye irritant. Fenp yr ox imate was classified as a skin sensitizer by the maximization method, but not by

the method of Buehler. HED considers fenpy roximate to be a slight to moderate sensitizer by

the maximization test method. The effects following repeated oral exposures to f enpy roximate resulted in overall s ys temic toxicity (no specific target organ/tissue identified). The most sensitive species tested was the dog. The effects reported in subchronic and chronic studies in the dog included slight bradycardia, deficits in foo d consumption, body weight, body- weight gain, and an increased incidence of emesis and diarrhea. Emaciation and torpor (sluggish inactivity) were reported in female dogs at lower dose levels than males. The highest dose tested in the dog (50 mg/kg bw/day) resulted in first - and second - degree heart block, increased urea concentration, decreased glucose, and altered plasma electrol yt e levels among other signs of toxicity . In subchronic andFenpyroximate Human - Health Risk Assessment DP No. 404839

Page 13 of 34 chronic studies with rats, the primary effect was decreased body- we ight gain in both sexes; there were hematological changes (e.g., higher counts of red blood cells) at higher doses. The rat and rabbit developmental toxicity studies were performed at dose levels that produced no or minimal maternal toxicity . In the rat study , a dose level that marginall y affected maternal body weight and food consumption also resulted in an increased litter incidence of increased thoracic ribs, indicating increased prenatal (qualitative) susceptibility . In the rabbit prenatal developme ntal toxicity , there were no effects (maternal or developmental) reported at the levels tested. In the rat two - generation reproductive toxicity study , there was no indication of increased pre - or post - natal susceptibility ; maternal toxicity (decreased body- weight) and offspring toxicity (decreased lactational weight gain in both generations) occurred at the same dose. Reproductive parameters were not affected. There is no evidence that fenp yroximate specifically targets the nervous s ys tem based on the r esults of recently

submitted acute and subchronic neurotoxicity studies in the rat. In the acute neurotoxicity

study , neurotoxicity

signs such as decreases in motor activity occurred in the presence of other effects including decreases in body weight and food consumption, and in the absence of neuropathology . Similar results were noted in a delayed acute neurotoxicity study in the hen where no effects (neurotoxic or otherwise) were reported at the limit dose (5000 mg/kg bw). The results of the rat subchronic neurotoxicity study did not indicate any

neurotoxicityspecific effects; deficits in body weight and food consumption were the main effects reported. In a recentl y submitted immunotoxicity study in rats, there were no immunotoxic effects reported at the dose levels tested. The treatment - related effects were limited to decreased body- weight gains in both sexes. In a 21 - day

dermal toxicity

study in rats, there were clinical signs in females consisting of red nose and mouth/nasal discharge, decreased b ody weights, body- weight gains, and food consumption in males and females. There were also increased liver weights and hepatocellular necrosis reported in females. In a 4 - week rat inhalation study , treatment - related effects included clinical observations (labored breathing and rales), increased lung weights, dec reases in body- weight gain and food consumption, and changes in hematology parameters (increased counts of ery throcy tes and leukocy tes). There were also histopathology findings in the nasal passag e mucosa consisting of atrophy and squamous metaplasia. **4. 4**  **Safety Factor for Infants and Children (FQPA Safety Factor)** The RAB1 risk assessment team recommends that the FQPA SF be reduced to 1X for all exposure scenarios for the following reasons: the toxicological database is complete and adequate for FQPA consideration, there is no evidence of neurotoxicity , there was some evidence for qualitative susceptibility in the developing/young animals, however, there are no resi dual uncertainties for pre - and post - natal susceptibility for infants and children , and there is no uncertainty in the exposure database. The rationale is provided below.Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 14 of 34 **4. 4**  **.1 Completeness of the Toxicology Database**  The existing toxicology

database for fenp yroximate is complete and adequate for FQPA evaluation. The re are acceptable developmental rat and rabbit toxicity studies, an acceptable rat two - generation reproduction study , and acceptable acute and subchronic neurotoxicity studies available fo r FQPA consideration . **4. 4**  **.2 Evidence of Neurotoxicity**  There is no concern for neurotoxicity with fenpy

roximate. Both acute and subchronic neurotoxicity

studies in the rat did not indicate neurotoxicity- specific effects; reductions in body weight and foo d consumption were the main effects reported. Further, both studies attained clear NOAELs. **4. 4**  **.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  There was evidence for increased (qualitative) prenatal susceptibility following or al exposures in the rat developmental toxicity study . However, the concern is low because (1) there was a clear NOAEL established for the developmental effect consisting of an increased incidence of additional thoracic ribs; (2) the rat developmental toxi city study was selected as the critical study for the acute dietary

endpoint of the population of concern: females 13 - 49 years old; and (3) there is no other indication of increased pre - or post - natal susceptibility in the database. **4. 4**  **.4 Residual Uncerta**  **inty in the Exposure Database** There are no residual uncertainties with respect to exposure data. The dietary food exposure assessment utilizes tolerance - level residues (established or recommended) and 100% CT for all proposed/established commodities. By using these assumptions, the acute and chronic exposures/risks will not be underestimated. The dietary drinking water assessment utilizes water concentration values generated b y models and associated modeling parameters, which are designed to provide con servative, health - protective, high - end estimates of water concentrations that will not likely

be exceeded. There are no registered or proposed residential uses. **4. 5**  **Toxicity Endpoint and Point of Departure Selections 4.5**  **.1 Dose**  **- Response Assessment**  Acute Dietary - Females Age 13 - 49 Years Old : The acute dietary endpoint is based on an increased incidence of additional thoracic ribs in the rat developmental toxicity study at the lowest - observed - adverse - effect level (LOAEL) of 25 mg/kg bw (NOAEL = 5 mg/kg bw). The developmental effects were reported in the presence of mild maternal toxicity (marginal decrease in body- weight gain and food consumption). The standard combined uncertai nty factor (UF) of 100X is being applied to account for interspecies (10 X) and intraspecies (10X) extrapolation. The FQPA SF was not retained for this exposure scenario since the toxicology database is complete and there were no residual uncertainties for pre - and or post - natal susceptibility . Thus, the acute reference dose ( aRfD) and aPAD are e quivalent at 0.05 mg/kg bw.Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 15 of 34 Acute Dietary - General U.S. Population : This acute dietary endpoint is based on the results of the acute neurotoxicity

study . The effects at the LOAEL of 150 mg/kg bw (NOAEL=37.5 mg/kg bw) were based on d ecreased motor activity (total activity counts and total time spent in movement) in both sexes, and a reduction in auditory startle response in females at 24 hours post dose, and mild dehydration in males. The standard combined UF of 100X is being applied to account for interspecies (10X) and intraspecies (10X) extrapolation. The FQPA SF was not retained for this exposure scenario since the toxicology database is complete and there were no residual uncertainties for pre - and or post - natal susceptibility . Thus, the aRfD and aPAD are e quivalent at 0.375 mg/kg bw. Chronic Dietary - All Populations : A dog chronic toxicity study was selected for this exposure scenario since the dog is the most sensitive species. The LOAEL of 15 mg/kg bw/day (NOAEL

= 5 .0 mg/kg bw/day) was based on an increased incidence of bradyc ardia, diarrhea, and emesis and decreases in body- weight gain, food consumption, and cholesterol. The standard combined UF of 100X was applied to account for interspecies (10X) and intraspecies (10 X) extrapolation. The FQPA SF was not retained for this exposure scenario since the toxicology database is complete and there were no residual uncertainties for pre - and or post - natal susceptibility . Thus, the chronic reference dose (cRfD) and cPAD are equivalent, estimated at 0.05 mg/kg bw. Dermal Exposure (Short - and Intermediate - Term) : This endpoint is based on the results of a rat 21 - day dermal toxicity

study . The effects at the LOAEL of 1000 mg/kg bw/day (NOAEL = 300 mg/kg bw/day) consisted of cli nical signs in females, decreased body weights, body- weights gains, and food consumption in both sexes, increased absolute liver weights and a possible increase in hepatocellular necrosis in the females. An LOC of 100 which includes interspecies (10X) and intraspecies (10X) extrapolation is adequate for this scenario. Inhalation Exposure (Short - and Intermediate - Term) : This endpoint is based on the results of a rat 4 - week inhalation toxicity study . The effects at the L OAEL of 10 mg/m 3 (NOAEL= 2 mg/m 3 ) consisted of increased lung weights, changes in hematology parameters (increased counts of ery

throcy tes), and histopathology

findings in the nasal passage mucosa consisting of atrophy and squamous metaplasia. The methods and dosimetry equations described in EPA’s reference concentration (RfC) guidance (1994) are suited for calculating HECs based on the inhalation toxicity N OAEL for use in MOE calculations. The regional - deposited - dose ratio (RDDR), which accounts for the particulate diameter (mass median a erodyn amic diameter [MMAD] and geometric standard deviation [  g ] of aerosols), can be used to estimate the different dose fractions deposited along the respiratory

tract. The RDDR is also based on interspecies differences in ventilation and respiratory- tract surface areas. Thus, the RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the predicted inhalation exposure for a human. For the 4 - week inhalation study with fenpyroximate, an RDDR wa s estimated at 1.2 based on the reported MMAD of 3.00 μm and standard deviation (  g ) of 2.20 and the respiratory - tract surface area of the rat relative to the human (see Appendix for detailed calculations). Since the rat inhalation study was carried out for 6 hr/day for 5 days/week, the only exposure adjustment made was in the assumption of 8 hrs/day for human occupational exposures. The resulting HEC is 0.002 mg/L. The LOC for this scenario is 30, which includes interspecies (3X) and intraspecies (10X)Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 16 of 34 extrapolation. The interspecies factor was reduced from 10X to 3X due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) interspecies differences. **4.5 .2**  **Recommendation for Combining Routes of Exposures for Risk Assessment** Exposures (dermal, oral, and inhalation) can be combined if the toxicological effects are the same. The dermal POD was selected from a 21 - day dermal - toxicity

study in rats in which clinical signs in females, decreased body weights, body- weights gains, and food consumption in both sexes, increased absolute liver weights and a possible increase in hepatocellular necrosis in the females were observed, The inhalation POD was selected from an inhalation toxicity study in rats in which increased lung weights, changes in hematology parameters (increased counts of erythrocy tes), and histopathology

findings in the nasal passage mucosa consisting of atrophy and squamous metaplasia were observed . Therefore, for fenp yroximate , the dermal and inhalation routes cannot be combined for risk asse ssment since a common endpoint was not observed. **4.5 .3**  **Cancer Classification and Risk Assessment Recommendation** There is no evidence of carcinogenic potential for fenp yroximate based on the results of carcinogenicity

studies via the oral route in either the rats or mice resulting in the carcinogenicity classification of “not likel y” to be carcinogenic to humans.” **4.5 .4**  **Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment**  Table 4. 5 . 4 summarizes the toxicological doses and endpoints selected for human - health risk assessment . **Table 4.5.4 . Summary of Toxicology Endpoints and P**  **O Ds for Fenpyroximate in Dietary and Occupational Risk**  **Assessment. Exposure**  **Scenario POD**  **Uncertainty/ FQPA Safety Factors or LOC for Risk**  **Assessment Study and Toxicological Effects**  Ac ute Dietary (Females 13 - 49 years old) NOAEL = 5.0 mg/kg bw UF = 100X

(for inter - and intra - species extrapolation) FQPA SF = 1X aRfD = aPAD = 0.05 mg/kg bw Prenatal Developmental Toxicity Study - Rat LOAEL = 25 mg/kg/day based on increase in the fetal incidence of additional thoracic ribs. Ac ute Dietary (General Population) NOAEL = 37.5 mg/kg bw UF = 100X

(for inter - and intra - species extrapolation) FQPA SF = 1X aRfD = aPAD = 0.375 mg/kg bw Ac ute Neurotoxicity Study - Rat LOAEL = 150 mg/kg bw based on decreased motor activity (total activity counts and total time spent in movement) in both sexes, and a reduction in auditory startle response in females at 24 hours post dose, and mild dehydration in males. Chronic Dietary (All populations) NOAEL = 5.0 mg/kg/day UF = 100X

(for inter - and intra - species extrapolation) FQPA SF = 1X cRfD = cPAD = 0.05 mg/kg/day Chronic toxicity - Dogs LOAEL = 15 mg/kg/day based on an increased incidence of bradycardia, diarrhea, and decrease s in cholesterol, body weight gain, and food consumption (M); vomiting, diarrhea, excess salivation andFenpyroximate Human - Health Risk Assessment DP No. 404839

Page 17 of 34 **Table 4.5.4 . Summary of Toxicology Endpoints and P**  **O Ds for Fenpyroximate in Dietary and Occupational Risk**  **Assessment. Exposure**  **Scenario POD**  **Uncertainty/ FQPA Safety Factors or LOC for Risk**  **Assessment Study and Toxicological Effects**  decrease cholesterol in females. Dermal (Short - and Intermediate - Term) NOAEL = 300 mg/kg bw/day LOC = 100

(for inter - and intra - species extrapolation) 21 - day Dermal toxicity study LOAEL = 1000 (limit dose) based on clinical signs in the females, decreased body weights, body - weights gains, and food consumption in both sexes, increased absolute liver weights and a possible increase in hepatocellular necro sis in the females. Short - and Intermediate - Term Inhalation Rat NOAEL =

0.002 mg/L LOC = 30

(3X interspecies, 10X intraspecies ) Inhalation toxicity study - Rat LOAEL = 0.01 mg/L based on increased lung weights, changes in hematology parameters (increased counts of erythrocytes), and histopathology findings in the nasal passage mucosa consisting of atrophy and squamous metaplasia. HEC = 0.002 mg/L HED = 0.10 mg/kg bw /day Cancer (Oral, dermal, inhalation) Classification: “Not likely to be carcinogen,” cancer risk assessment is not required. NOAEL = no - observed adverse - effect level, LOAEL = lowest - observed adverse - effect level, PAD = population - adjusted dose (a = acute, c = chronic), MOE = margin of exposure, HEC = human - equivalent concentration; HED = human - equivalent dose. HEC = rat NOAEL*(daily duration adjustment)*weekly daily duration adjustment *RDDR* = 0.002 mg/L * (6hr/8hr)*(1)*1.2 = 0.0018 or 0.002 mg/L HED = HEC*human - specific conversion factor*daily duration = 0.002 mg/L * 6.0 L/hr/kg*8hr = 0.096 or 0.10 mg/kg bw/day **5.0 Dietary Exposure and Risk Assessment**  The residue chemistry

data submitted in support of the proposed petitions were evaluated b y HED (Memo , G. Kramer, 08 - MAY - 2013 , DP# 405715 ). The drinking water assessment was comp leted b y EFED on 20 - SEP - 2012 (Memo, G. Orrick, DP# 404840). The dietary exposure assessment was completed in a HED memorandum (Memo , G. Kramer, 08 - MAY - 2013 , DP# 405 718 ) . **5.1 Residues of Concern Summary and Rationale**  The nature of the residue in crops is understood based on acceptable plant metabolism studies with fenp yroximate on snap beans, apples, citrus, cotton, and grapes. The HED Metabolism Assessment Review Committee (MARC) has determined that the residues of c oncern for purposes of tolerance enforcement and risk assessment are the parent compound plus its Z isomer (M - 1) (Memo, J. Stokes, 12 - JUL - 2003; DP# 292639). The nature of the residue in ruminants is adequatel y understood based on an acceptable metabolism study in goats. The MARC reviewed these data and determined that the residues of concern for purposes of tolerance enforcement and risk assessment are parent, Fen - OH [( E) - 1,1 - dimethylethyl - 2 - hydroxyeth yl4 - [[[[(1,3 - dimethyl - 5 - phenoxy- 1 H - py razol - 4 - yl )methylene]amino]oxy]methyl]benzoate], and M3 [( E) - 4 - [(1,3 - dimethyl - 5 - phenox yp yr azol - 4 - yl ) - methylene aminooxy methyl]benzoic acid] inFenpyroximate Human - Health Risk Assessment DP No. 404839

Page 18 of 34 milk, meat, and fat; and parent and M3 in liver and kidney . For drinking water, the residues of concern for risk assessment include the parent, M - 1 and M - 3. **5.2 Food Residue Profile**  No new residue data were submitted to support the tolerance on small vine climbing fruits except kiwifruit (subgroup 13 - 07F) . IR - 4 has requested that the established tolerance for residues in/on grape be expanded to its respective crop group. The submitted field trial residue data for stone fruit and potatoes are adequate. The field trial data reflect the proposed use pattern; an adequate number of trials were conducted in the appropriate geogra

phic regions; and samples were anal yz ed for the residue of concern using validated data - collection methods. The storage intervals were also validated. Using the Organization for Economic Co - operation and Development (OECD) tolerance calculation procedure s for the residue data sets indicate that the requested tolerance levels are appropriate. However, a revised Section F with corrected commodity definitions is requested ( see Table 2.2.2 ). The submitted plum and potato processing studies are also adequate. Separate tolerances are not required for residues in/on any of the processed fractions. No new livestock feeding studies were submitted with this petition. The only cattle feed commodities associated with this petition are potato culls and pro cessed waste. The additional fenp yroximate uses are not expected to result in an increase in the maximum reasonabl y balanced diets (MRBDs). The existing tolerances on ruminant commodities are thus adequate to support registration of the proposed new uses of fenpy roximate. There are no swine or poultry feedstuffs associated with this petition. An adequate confined rotational crop study is available. [ 14 C] - Fenp yroximate was applied to sandy loam soil at 0.20 lb ai/A (1X the maximum seasonal rate to annua l crops addressed in this petition). Crops of radish, lettuce, and wheat were planted at 30, 120, and 365 days after treatment. Residues were too low to allow for metabolite identification. A field rotational crop study and rotational crop tolerances wi ll, therefore, not be needed to support the proposed and registered uses. The proposed 30 - day plant - back interval (PBI) is appropriate. **5.3 Water Residue Profile**  Drinking water residues were incorporated directly into the acute and chronic dietary analy ses (“water, direct, all sources” and “water, indirect, all sources”) and were provided by EFED . The EDWCs were screening - level estimates generated with the FIRST and a Provisional Cranberry Model for fenp yr oximate and its metabolites (M - 1 and M - 3) in surface water and with SCI GROW for ground water. Although the current and proposed end - use labels that result in the highest exposure are for ornamentals (an application rate to ornamentals of 0.343 lbs ai/A with a maximum application of 0.686 lbs ai/A), the use scenario with the highest acute and chronic EDWCs are for the cranberry scenario (see Table 5.3).Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 19 of 34 **Table 5.3. Maxim um** **Screening EDWCs of Fenpyroximate for Current and Proposed Uses. 1**  **Drinking Water Source (m odel)**  **Use (Maxim um** **Annual Rate) EDWC**  **(ppb) Acute (peak**  **exposure) Chronic (annual** 

**mean exposure)** Surface Water (FIRST) Ornamentals (0.69 lb ai/A) 29 1.9 Surface Water (Cranberry model) Cranberries (0.20 lb ai/A) **43 8.6**  Groundwater (SCI - GROW) Ornamentals (0.69 lb ai/A) < 0.27 1. Maximum values in bold. Surface water EDWCs of 43 ppm and 8 . 6 ppm were used in the acute and chronic anal ys es, respectivel y, as these values were the highest and provided a more conservative approach. **5.4 Dietary Risk Assessment**  Acute and chronic aggregate dietary (food + drinking water) exposure and risk assessments were conducted for fenp yr oximate using DEEM - FCID, ver. 3.16 which incorporates consumption data from USDA NHANES/WWEIA (2003 - 2008). A cancer dietary (food + drinking water) exposure and risk as sessment w as not performed because fenp yroximate is not carcinogenic. **5.4.1 Description of Residue Data Used in Dietary Assessment**  The acute and chronic dietary exposure assessments were unrefined, using tolerance - level residues and assuming 100% CT for all registered and proposed commodities. Exposure to drinking water was incorporated directly in the acute and chronic dietary assessments using the acute (peak) and chronic (annual average) concentrations for surface water generated by the Provisional Cranberry

Model, respectively . **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The acute and chronic dietary exposure assessments assumed 100% CT for all registered and proposed uses. **5.4.3 Acute Dietary Risk Assessment**  Separate acute dietary

expos ure anal ys es were conducted for females 13 - 49 years old and for the general U.S. population as separate endpoints of concern attributable to a single dose were identified. Both acute analy ses assumed 100% CT, tolerance - level residues for all commodities, DEEM (ver. 7.81 ) default processing factors for all commodities excluding apple, pear, and grape juice (0.11x); grape, raisin (2.7x); orange, grapefruit, tangerine, lemon and lime juice (0.06x); tomato paste (1.0x) and puree (1.0x); and peppermint and spearmint oil (0.08x). The acute anal ys es incorporated the EDWCs provided by EFED. An EDWC of 0.043 ppm was used in the acute analy ses, as this was the highest (i.e., most conservative) estimate. The resulting acute food plus drinking water risk estimates are not of concern to HED (<100% of the aPAD) at the 95 th percentile of the exposure distribution for females 13 - 49 years old or the general U.S. population. The resulting acute risk estimate is 13% of the aPAD at the 95 th percentile of the exposure distribution for females 13 - 49 years old. The highest acute exposureFenpyroximate Human - Health Risk Assessment DP No. 404839

Page 20 of 34 estimate for the U.S. population or population subgroup is children 1 - 2 years old, which resulted in a risk estimate of 6.2% of the aPAD. **5.4.4 Chronic Dietary Risk Assessment**  The chronic anal ys is assumed 100% CT, tolerance - level residues for all commodities, and DEEM (ver. 7.81) default processing factors for most commodities (see above). The chronic anal ys is also incorporated EDWCs provided by EFED ( an EDWC of 0.0086 ppm was used in the chronic analy sis ). The resulting chronic risk estimates are not of concern to HED (<100% of the cPAD). The most highl y exposed population was children 1 - 2 years old with a risk estimate of 15 % of the cPAD. **5.4.5 Summary Table**  **Table 5.4.5. Summary of D ietary**  **(Food and Drinking Water) Exposure and Risk for Fenpyroximate.**  **Population Subgroup 1**  **Acute Dietary (95 th**  **Percentile) 2**  **Chronic Dietary 3**  **Dietary Exposure (m**  **g/kg/day) % aPAD**  **Dietary Exposure (m**  **g/kg/day) % cPAD**  General U.S. Population 0.008312 2.2 0.002208 4.4 All Infants (<1 year old) 0.022585 6.0 0.004700 9.4 **Children 1 -**  **2 years old 0.023191**  **6.2 0.007336**  **15** Children 3 - 5 years old 0.016596 4.4 0.005098 10 Children 6 - 12 years old 0.009835 2.6 0.002723 5.4 Youth 13 - 19 years old 0.005336 1.4 0.001394 2.8 Adults 20 - 49 years old 0.006565 1.8 0.001712 3.4 Adults 50 - 99 years old 0.006917 1.8 0.002013 4.0 Females 13 - 49 years old **0.006685 13**  0.001693 3.4 1. The values for the highest exposed population for each type of risk assessment are bolded. 2. Separate acute toxicity endpoints were determined for females 13 - 49 years old and the general U.S. population and all population subgroups. 3. Chronic dietary endpoint of 0.05 mg/kg/day applies to the general U.S. population and all population subgroups. **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  The proposed use is on agricultural crops; therefore, a quantitative residential exposure assessment was not conducted. In addition, there are no proposed or existing fenpy roximate products registered for residential use sites. **6.1 Residential Bystander Post**  **- Application Inhalation Exposure**  Based on the Agency's current practices, a quantitative residential b ys tander post - application inhalation exposure assessment was not performed for fenp yr oximate at this time primarily because it has a low vapor pressure ( 5.6 x 10 - 8 mmHg), and it is applied at a low use rate (0.1 lb ai/A). However, volatilization of pesticides may be a potential source of post - application inhalation exposure to individuals nearb y to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency

received the SAP’s final report on March 2, 2010Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 21 of 34 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures, to identify

the need for and, subsequently , the way to incorporate post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative post - appli cation inhalation exposure assessment for fenp yr oximate . **6.2 Spray Drift**  Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from ground application. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State L ead Agencies for pesticide regulation and other parties to develop the best spray drift man agement practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a memb ership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply the data and the AgDRIFT ® computer model to its risk assessments for pesticides applied b y air, orchard air - blast, and ground h ydraulic methods. After the polic y is in place, the Agency

may impose further refinements in spray- drift - management practices to reduce off

- target drift and risks associated with aerial as well as other application ty pes where appropriate. Although a quantitative r esidential post - application inhalation - exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhal ation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post - application inhalation exposure scenarios. **7.0 Aggregate Exposure/Risk Characterization**  The Agency

conducts aggregate exposure assessments by summing dietary (food and water) and residential exposures (residential or other non - occupational exposures). Since there are no registered/proposed uses of fenp yroximate that result in residential exposure, the acute and chronic aggregate risk assessment s are equal to the acute dietary and chronic dietary

estimates (food and water onl y), respectively (see Table 5.4.5). Short - , intermediate - , and long - term aggregate - risk assessments were not performed because there are no registered or proposed uses of fe npy roximate that result in residential exposures. A cancer aggregate - risk assessment was not performed because fenpy roximate is not carcinogenic. **7.1 Acute Aggregate Risk**  No acute residential/recreational exposures are expected. In the case of fenpy roxi mate, the acute aggregate risk is composed of exposures to fenp yr oximate residues in food and drinking water and is equivalent to the acute dietary risk discussed in Section 5.4.5. The acute risk estimates do not exceed the HED’s LOC for the general U.S. population and all population subgroups.Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 22 of 34 **7.2 Chronic Aggregate Risk**  A long - term aggregate risk assessment was not performed, because long - term residential exposure to fenp yroximate (i.e., >6 months) is unlikely to occur based upon the use patterns. Spec ificall y, in the case of fenp yroximate, the chronic aggregate risk is composed of exposures to fenpy roximate residues in food and drinking water and is equivalent to the chronic dietary risk discussed in Section 5.4.5. The chronic risk estimates do not ex ceed the HED’s LOC for the general U.S. population and all population subgroups. **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity , EPA has not made a common mechanism of toxicity finding as to fenpy roximate and any

other substances and fenpy roximate does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that fenpy roximate has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to de termine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 Occupational Exposure/Risk Characterization**  Based on the propos ed application scenarios and toxicological considerations, non - cancer occupational handler (dermal and inhalation) and post - application (dermal) assessments were conducted for the proposed uses. The occupational exposure assessment was completed by J. Tyl er ( Memo, 08 - MAY - 2013 , DP#404839 ), and reviewed b y the Exposure Science Advisory Committee (ExpoSAC) on 21 - FEB - 2013 . **9.1 Handler Exposure/Risk Estimates**  HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used b y a handler can cause exposure levels to differ in a manner specific to each application event. Based on the anticipated use patterns and current labeling, typ es of equipment and techniques that can potentially

be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: Mixer/L oaders  mixing/loading liquids in support of aerial applications,Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 23 of 34  mixing/loading liquids in support of groundboom applications,  mixing/loading liquids in support of airblast applications, Applicators  applying with enclosed cockpit aerial equipment,  applying with open - cab groundboom equipment  applying with airblast equipment, and Flaggers  flagging to support aerial applications. It is the policy

of HED to use the best available data to as sess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical - specific data, include PHED 1.1, the AHETF database, the ORETF database, or other registrant - submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures , ” are outlined in the “Occup ational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler - exposure - table.pdf ) , which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website (http://www.epa.gov/pesticides/science/handler - exposure - data.html ) . Estimates of dermal and inhalation exposure were calculated for various levels of PPE . Results are presented for “baseline,” defined as a single layer of clothing consisting of a long - sleeved shirt, long pants, shoes plus socks, no protectiv e gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc ). See Section 3.3 for a detailed description of the required PPE for proposed labels. Handler exposure is expected to be short - and intermediate - term based on information provided on the label for the proposed uses (e.g., maximum of two spray applications per season at a maximum rate of 0.1 lb ai/A with 14 day s between applications). Ty picall y, HED completes short - and intermediate - te rm assessments for occupational scenarios in all cases because these kinds of exposures are likely , and acceptable use/usage data are not available to justify deleting intermediate - term scenarios. Based on use data and label instructions, HED believes that occupational exposures may occur over a single day

or up to weeks at a time for many of the use - patterns and that intermittent exposure over several weeks may also occur. Some applicators may apply these products over a period of weeks, because they are commercial applicators who are completing multiple pesticide applications for multiple clients. L ong - term exposures are not expected; therefore, a long - term assessment was not conducted. The Agency

matches quantitative occupational exposure assessment with appropriate characterization of exposure potential . While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades. According to the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of Global Positioning Sy stem (GPS) for swath guidance in agricultural aviation has grown steadil y from the mid 1990s . Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadil y from ~15% in the late 1990s to only

1% in the most recent (2012) NAAA survey . The Agency will continue to monitorFenpyroximate Human - Health Risk Assessment DP No. 404839

Page 24 of 34 all available information sources to best assess and characterize the exp osure potential for human flaggers in agricultural aerial applications. Table 9 .1.1 provides a summary of the estimated exposures and risk estimate s to occupational pesticide handlers. A MOE ≥ 100 is adequate to protect occupational pesticide handlers from dermal exposures, and a MOE ≥ 30 is adequate to protect occupational handlers from inhalation exposures. For the scenarios where baseline data are available, all dermal and inhalation risk estimate s for occupational handlers are above the LOC (MOE ≥ 10 0 for dermal and MOE ≥ 30 for inhalation ) with baseline protection (i.e., long - sleeve shirt, long pants, shoes, and socks) . Only engineering - control data (i.e., enclosed cockpits) are available for aerial application scenarios. All dermal and inhalation risk estimate s for occupational aerial applicators are above the L OC (MOE ≥ 100 for dermal and MOE ≥ 30 for inhalation) with baseline clothing and enclosed cockpits .Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 25 of 34 **Table 9 .1.1. Short**  **- and Interm**  **ediate -**  **Term Occupational Exposure and Risk Estimates for Fenpyroxim ate**  . **Exposure Scenario**  **Crop or Target Dermal Unit**  **Exposure (ug/lb ai)**  **1 Inhalation**  **Unit**

**Exposure (ug/lb ai) 1**  **Ma xim**  **um**

**Application Rate**  **2 Area Treated** 

**or Amount Handled Daily**  **3 Dermal**  **Inhalation Mitigation Level**  **Mitigation Level Dose**  **(m g/k** **g/day) 4**  **MOE 5**  **Dose (m**  **g/k g/day)**  **4 MOE**  **5** Mixer/Loader Liquids

– Aerial Applications Tuberous and Corm Vegetables

(Crop Group 1C) Baseline 6 : 220 Baseline: 0.219 0.1 1200 0.33 910 0.000329 300 Liquids

– Groundboom Applications Tuberous and Corm Vegetables

(Crop Group 1C) Baseline: 220 Baseline: 0.219 0.1 200 0.055 5500 0.0000548 1800 Liquids

– Airblast Applications Small Fruit Vine Climbing

(Except Fuzzy Kiwifruit) (Crop Group 13 - 07F) Baseline: 220 Baseline: 0.219 0.1 40 0.011 27000 0.000011 9100 Stone Fruit (Crop Group 12 - 12) Applicator Aerial Applications Tuberous and Corm Vegetables

(Crop Group 1C) Eng. Controls 7 : 5 Eng. Controls: 0.068 0.1 1200 0.0075 40000 0.000102 980 Groundboom Applications Tuberous and Corm Vegetables

(Crop Group 1C) Baseline: 78.6 Baseline: 0.34 0.1 200 0.0196 15000 0.000085 1200 Airblast Small Fruit Vine Climbing

(Except Fuzzy Kiwifruit) (Crop Group 13 - 07F) Baseline: 1770 Baseline: 4.71 0.1 40 0.0885 3400 0.000235 430 Stone Fruit (Crop Group 12 - 12) Flagger Flagger Tuberous and Corm Vegetables

(Crop Group 1C) Baseline: 11 Baseline: 0.35 0.1 350 0.00481 62000 0.000154 650 1. Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table,” September 2012 . 2. Application Rate = 0.1 lb ai/A. Taken from proposed Fujimite ® EC/Portal ® [71711 - 19] and Akari ® SC [71711 - 19] labels. 3. Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1, revised 25 Se ptember 2001. 4. Average Daily Dose = Unit Exposure (μg/lb ai) × Conversion Factor (0 .001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A) ÷ BW (kg). 5. MOE = m argin of e xposure = NOAEL  ADD. NOAEL = 300 mg/kg bw/day (dermal), 0.10 mg/kg bw/day (inhalation). 6. Baseline = l ong - sleeve shirt, long pants, and no gloves (dermal); no respirator (inhalation). 7. Engineering Control = en closed cockpit and baseline attire (long - sleeve shirt, long pants, shoes, and socks).Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 26 of 34 **9.2 Post**  **- Application Exposure/Risk Estimates**  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 (also referred to as re entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, i ncluding activities related to crop production, such as scouting for pests or harvesting. Post - application exposure levels vary over time and depend on such things as the ty pe of activity , the nature of the crop or target that was treated, the ty pe of pes ticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatl y reduce the potential for post - application exposure. **9.2.1 Dermal Post**  **- application Risk**  HED expe cts that post - application exposure will occur since fenpy roximate is applied as a foliar spray . Post - application exposure is expected to be short - term based on information provided on the label (a maximum of two applications per crop cycle). However, the short - and intermediate term toxicological endpoints are the same; therefore, the estimates of risk for short - term duration exposures are protective of those for intermediate - term duration exposures. It is the policy

of HED to use the best available data to assess post - application exposure. Sources of generic post - application data, used as surrogate data in the absence of chemical specific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data protect ion provisions of FIFRA. The standard values recommended for use in predicting post - application exposure that are used in this assessment, known as “transfer coefficients,” are presented in the “Science Advisory Council for Exposure (ExpoSAC) Policy 3” (http://www.epa.gov/pesticides/science/exposac_policy 3.pdf), which, along with additional information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post app - exposure - data.html . A summary

of the post - application MOEs and respective reentry intervals is provided in Table 9.2.1. The short - term post - application assessments for sugarcane resulted in MOEs of 100 or greater on “day

0” (immediately

after a pplication) for all exposure activities, and are not of concern. **Table 9.2.1. Summary of Short -**  **and Interm ediate**  **- term** **Occupational/Commercial Post -**  **application Risk Estimates for Fenpyroximate.**  **Crop/Site Activities**  **Transfer Coefficient**  **(cm 2**  **/hr) DFR** 

**(μg/cm 2**  **) 1**  **Dermal Dose**

**(m g/k** **g/day) 2**  **MOE 3**  Tuberous and Corm Vegetables (Crop Group 1C) Irrigation (hand set) 1,900 0.28 0.0532 5,600 Scouting 210 0.28 0.00588 5,100 Weeding, hand 70 0.28 0.00196 150,000 Small Fruit Vine Climbing (Except Fuzzy Kiwifruit) (Crop Group 13 - 07F) Girdling; Turning 19,300 0.28 0.54 560

Grapes (wine) : Tying/training; Harvesting, hand; Leaf pulling 10,100 0.28 0.283 1,100 Grapes (table and raisin) Tying/training; Harvesting, hand; Leaf

pulling 5,500 0.28 0.154 1,900 Irrigation (hand set) 1,900 0.28 0.0532 5,600Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 27 of 34 **Table 9.2.1. Summary of Short -**  **and Interm ediate**  **- term** **Occupational/Commercial Post -**  **application Risk Estimates for Fenpyroximate.**  **Crop/Site Activities**  **Transfer Coefficient**  **(cm 2**  **/hr) DFR** 

**(μg/cm 2**  **) 1**  **Dermal Dose**

**(m g/k** **g/day) 2**  **MOE 3**  Scouting; Pruning, hand; Weeding, hand; Bird control; Trellis repair 640 0.28 0.0179 17,000 Stone Fruit (Crop Group 12 - 12) Thinning fruit 3,600 0.8 0.101 3,000 Harvesting, hand 1,400 0.28 0.0392 7,700 Scouting; Pruning, hand; Training 580 0.28 0.0162 19,000 Weeding, hand; Orchard maintenance; Bird control; Propping 100 0.28 0.0028 110,000 1. DFR (μg/cm2 ) = Application Rate (lb ai/A) x (1 - Daily Dissipation Rate) t x CF (4.54E+8 μg/lb) x CF (2.47E - 8 A/cm2 ) x 25 % DFR after initial treatment. 2. Daily Dose = [DFR (μg/cm2 ) x TC (cm2/hr) x 0.001 mg/μg x 8 hrs/day] ÷ Body Weight (80 kg). 3. MOE = NOAEL (Short - and I ntermediate - term NOAEL 300 mg/kg/day)/Daily Dose (L OC=100). REI : The proposed FujiMite ® , Portal ® , and Akari ® labels list 12 - hour REIs. Fenp yroximate is classified as Toxicity

Category II for acute dermal toxicity and Toxicity

Category IV for primary eye irritation and primary dermal irritation. Therefore, while an assessment of sy stemic toxicity from post - application exposure would indicate acceptable MOEs on the day of treatment, the acute toxicity

categories for this chemical require a 24 - hour REI for this product under the WPS. **RD should ensu re that all fenpyroximate labels have the appropriate REI listed.**  Dislodgeable Foliar Residue (DFR) : In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has residential or occupational u ses that could result in post - application dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment , HED anal yz ed 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 anal ysis of 19 DFR studies where the F AR value ranged from 2% to 89%. This value is reco mmended for use in both residential and occupational post - application 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 calculat ed MOE of approximately 4 times higher than the LOC (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for an y potentiall y higher residues seen in a chemical - specific DFR study ( Guida nce for Requiring/W

aiving Turf Transferrable Residue (TTR) and DFR Studies . 6/7/2012, Exposure Science Advisory

Council). A DFR study

is not required for fenp yroximate at this time since the dermal MOEs are greater than 400 (i.e., 4x higher than the LOC) based on default values for the fraction of application rate available for transfer after a foliar application. **9.2.2 Inhalation Post**  **- application Risk**  Based on the Agency's current practices, a quantitative occupational post - application inhalation exposure assessment was not performed for fenp yr oximate at this time primarily because it has a low vapor pressure ( 5.6 x 10 - 8 mmHg ) and is applied at a low use rate (0.1 lb ai/A). However, there are multiple potential sources of post - application inhalation exp osure to individuals performing post - application activities in previously treated areas. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that containFenpyroximate Human - Health Risk Assessment DP No. 404839

Page 28 of 34 pesticides. The Agency

sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipol y/ SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluat ing 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, subsequentl y, 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 fenpy roximate. Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesti cides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. **10.0 References**  G. Kramer, 08 - MAY - 2013 , DP# 405715, Petition for the Establishment of Permanent Tolerances for Residues in/on Stone Fruits (Group 12 - 12), Tuberous and Corm Vegetables (Subgroup 1C), and Small Vine Climbing Fruits Except Kiwifruit (Subgroup 13 - 07F). Summary of Anal yt ical Chemistry

and Residue Data. G. Kramer, 08 - MAY - 2013 , DP# 405718, Petition for the Establishment of Permanent Tolerances for Residues in/on Stone Fruits (Group 12 - 12), Tuberous and Corm Vegetables (Subgroup 1C), and Small Vine Climbing Fruits Except Kiwifruit (Subgroup 13 - 07F). Acute and Chronic Dietary Exposure and Risk Assessments. G. Orrick, 20 - SEP - 2012, DP# 404840, Drinking Water Exposure Assessment for Proposed New Uses on Stone Fruits (Crop Group 12 - 12), Tuberous and Cor m Vegetables (Crop Subgroup 1C), and Small Vine Climbing Fruits Except Kiwifruit (Crop Subgroup 13 - 07F). J. Stokes, 12 - JUL - 2003, DP# 292639, Conclusion and Briefing Memorandum for 07/09/03 Meeting of the HED MARC . J. Tyler et al. , 16 - APR - 2012, DP# 39143 0, Human - Health Risk Assessment for 1) Proposed Section 3 Uses on Cucumber, Snap Bean, Avocado, Black Sapote, Canistel, Mamey Sapote, Mango, Papaya, Sapodilla, Star Apple, Corn (Field, Pop, Silage, and Grown for Seed); 2) Updated Tolerances for Citrus Frui t - Group 10 - 10, Pome Fruit Group 11 - 10, and Fruiting Vegetable Group 8 - 10; 4) the Establishment of a Tolerance on Imported Tea; 3) Increase I n Maximum Seasonal Application Rate on Mint; and 4) Proposed Label Amendment to Include Aerial Applications to Exi sting Uses on Citrus in Texas, Melons, Fruiting Vegetables, and Snap Beans.Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 29 of 34 J. Tyler, 08 - MAY - 2013 , DP# 404839, Occupational and Residential Exposure Assessment for a Proposed Use on Stone Fruit Group 12 - 12; Small Fruit Vine Climbing, Except Fuzzy Kiwifrui t, Subgroup 13 - 07F; and Tuberous and Corm Subgroup 1C.

cc: J. Tyler (RAB1), G. Kramer (RAB1), C. Rodriquez (RAB1) RDI : Risk Assessment Team (2/27/13); RAB1 (2/27/13); G. Kramer (5/8/13); D. Vogel (5/8/13) J. Tyler:S10943:PY - S:(703)305 - 5564:7509P:RAB1Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 30 of 34 **Appendix A. Toxicology Profile Tables. Table A1. Toxicity Testing Requirements for Fenpyroximate.**  **Test Technical**  **Required Satisfied**  870.1100 Ac ute Oral Toxicity 870.1200 Ac ute Dermal Toxicity 870.1300 Ac ute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation 870.2600 Dermal Sensitization yes yes yes yes yes yes yes

yes yes yes yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (nonrodent) 870.3200 21 - Day

Dermal 870.3250 90 - Day

Dermal 870.3465 28 - Day

Inhalation yes yes yes no yes yes

yes yes

- yes 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (non - rodent) 870.3800 Reproduction yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (non - rodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial 870.5300 Mutagenicity

—Gene Mutation - mammalian 870.5400 Mutagenicity

— Structural Chromosomal Aberrations 870.5500 Mutagenicity

—Other Genotoxic Effects yes yes yes yes yes

yes yes yes 870.6100a Ac ute Delayed Neurotox. (hen) 870.6100b 90 - Day

Neurotoxicity (hen) 870.6200a Ac ute Neurotox. Screening Battery (rat) 870.6200b 90 - Day

Neuro. Screening Battery (rat) 870.6300 Develop. Neurotoxicity no no yes yes no -

- yes yes

- 870.7485 General Metabolism 870.7600 Dermal Penetration yes yes yes

yes Special Studies for Ocular Effects

Ac ute Oral (rat) ................................ ........................... Subchronic Oral (rat) ................................ .................. Six - mo nth Oral (dog) ................................ .................. no no no -

-

-Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 31 of 34 **Table A2 . Acute Toxicity of Fenpyroximate.**  **Guideline No. Study Type**  **MRID #s Results**  **Toxicity Category**  870.1100 Ac ute oral - rat 43560501 LD 50 = 450 mg/kg males LD 50 = 245 mg/kg females LD 50 = 350 mg/kg combined II 870.1200 Ac ute dermal - rat 44847901 LD 50 >2,000 mg/kg II I 870.1300 Ac ute inhalation - rat 44847902 LC 50 = 0.24 mg/L (male) LC 50 = 0.37 mg/L (female) LC 50 = 0.35 mg/L (combined) II 870.2400 Ac ute eye irritation - rabbit 44781004 Not an ocular irritant. IV 870.2500 Ac ute dermal irritation rabbit 44781005 Not a dermal irritant. IV 870.2600 Skin sensitization - guinea pig 44781006 Slight to moderate dermal sensitizer by the maximization test method. N/A 1. MRID 44781007 indicates that the technical is not dermal sensitizer by the Buehler method. **Table A3 . Toxicity Profile for Fenpyroxim**  **ate Technical. Guideline No./ Study**  **Type MRID No. (year)/ Classification**  **/Doses Results**  870.3100 90 - Day oral toxicity rodents (rats) 43429501 (1987) **Acceptable/guideline** 0, 20, 100, or 500 ppm M & F: 1.5, 7.4, or 37 mg/kg/day NOAEL = 1.5 mg/kg/day (20 ppm). LOAEL = 7.4 mg/kg/day (100 ppm) for rats, based on decreased body- weight gains in both sexes. 870.3150 90 - Day dog oral toxicity (nonrodents) 43429502 (1988) **Acceptable/guideline** 0, 2, 10, 50 mg/kg/day (capsule) NOAEL <2 mg/kg/day. LOAEL = 2 mg/kg/day, based on slight bradycardia and an increased incidence of diarrhea in both sexes; and reduced fo od consumption, body weight, body - weight gain, emaciation, and torpor in females. 870.3200 21 - Day dermal toxicity (rats) 44781012 (1992) **Unacceptable/guideline** 0 or 1000 mg/kg/day 6 hr/day, 5 d/week NOAEL <1000 mg/kg/day (HDT). LOAEL = 1000 mg/kg/day (the limit dose and the only dose tested) based on decreased body - weight gains in males and females and increased liver weights in the females. 870.3200 21 - Day dermal toxicity (rats) 44781013 (1992) **Acceptable/guideline** 0, 100, 300, or 1000 mg/kg/day NOAEL = 300 mg/kg/day. LOAEL = 1000 mg/kg/day (limit dose) based on clinical signs in the females, decreased body weights, body - weights gains, and food consumption in both sexes, increased absolute liver weights and a possible increase in hepatocellular ne crosis in the females. 870.3465 28 - Day inhalation toxicity (rats) 45323302 (1991) Acceptable/guideline 0, 2, 10, or 50 mg/m3 NOAEL = 2 mg/m3 LOAEL = 10 mg/m3 based on treatment related effects with hematology (increased erythrocyte count), organ weights (increased lung weights) and microscopic pathology (squamous metaplasia of nasal passage mucosa) . 870.3700a Prenatal developmental toxicity (rats) 43429505 & 44519906 (1989) **Acceptable/guideline** F: 0, 1, 5, or 25 mg/kg/day **Maternal** NOAEL = 5 mg/kg/day. LOAEL = 25 mg/kg/day based on marginal decrease in bodyweight gain and food consumption. **Developmental** NOAEL = 5 mg/kg/day. LOAEL = 25 mg/kg/day based on increased incidence of additional thoracic ribs. 870.3700b Prenatal developmental toxicity (rabbits) 43429504, 44519903 - 44519905 (1989) **Acceptable/guideline** ; **how ever,**  **the study cannot be used for establishing RfD.**  F: 0, 1, 2.5, or 5 mg/kg/day **Maternal** NOAEL = 5 mg/kg/day. LOAEL >5. **Developmental** NOAEL = 5 mg/kg/day. LOAEL >5 mg/kg/day. 870.3800 Reproduction and fertility effects (rats) 43429506 (1989) **Acceptable/guideline** 0, 10, 30, or 100 ppm F 0 (M/F): 0/0, 0.67/0.83, 2.0/2.4, or 6.6/8.6 mg/kg/day **Parental/Systemic** NOAEL = 1.99 mg/kg/day for males 2.44 mg/kg/day for and females. LOAEL = 6.59 and 8.60 mg/kg/day for males and females, respectively, based on decreased body - weights during the premating period.Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 32 of 34 **Table A3 . Toxicity Profile for Fenpyroxim**  **ate Technical. Guideline No./ Study**  **Type MRID No. (year)/ Classification**  **/Doses Results**  F 1 (M/F): 0/0, 0.78/0.96, 2.3/2.8, or 8.4/9.9 mg/kg/day **Reproductive** NOAEL = 6.59 and 8.60 mg/kg/day for males and females, respectively. LO AE L was not established. **Offspring** NOAEL = 2.44 mg/kg/day. LOAEL = 8.60 mg/kg/day, based on decreased lactational weight gain in both generations of pups. 870.4100a Chronic toxicity (rodents) NA; see 870.4300 NA 870.4100b Chronic toxicity (dogs) 43429503 (1989) **Acceptable/guideline** 0, 0.5, 1.5, 5, or 15 mg/kg/day (capsule) NOAEL = 5 mg/kg/day. LOAEL = 15 mg/kg/day in both sexes, based on diarrhea, bradycardia, and decrease cholesterol, body - weight gain, and food consumption (M); vomiting, diarrhea, excess salivation, and decrease cholesterol in females. 870.4200a Carcinogenicity (rats) NA; see 870.4300 NA 870.4200b Carcinogenicity (mice) 43560503 (1989) **Acceptable/guideline** 0, 25, 100, 400, or 800 ppm M: 0, 2.4, 9.5, 38, or 69.6 mg/kg/day F: 0, 2.5, 10, 41.5, or 73 mg/kg/day NOAEL = Males: 2.4 mg/kg/day; Females: 2.5 mg/kg/day. LOAEL = Males: 9.5 mg/kg/day; Females: 10 mg/kg/day based on decreased body weights, and food consumption. **No evidence of carcinogenicity.** 870.4300 Combined Chronic/ carcinogenicity (rats) 43560502 (1989) Acceptable/guideline 0, 10, 25, 75, or 150 ppm M: 0, 0.4, 0.97, 3.0, or 6.2 mg/kg/day F: 0, 0.49, 1.21, 3.81, or 6.18 mg/kg/day NOAEL = Males: 0.97 mg/kg/day; Females: 1.16 mg/kg/day. LOAEL = Males: 3.08 mg/kg/day; Females: 3.79 mg/kg/day based on decreased mean body- weight gain. **No evidence of carcinogenicity.** 870.5100 Bacterial reverse mutation 43429507 (1989) Acceptable/guideline S. typhimurium strains and Escherichia coli WP2uvrA were exposed to NNI - 850 technical (97.3% ai) in DMSO at 50, 158, 500, 1580, and 5000 μg/plate ± S9 metabolic activation. At limit concentration (5000 μg/plate) inhibition of growth was observed in strains TA98, TA1537, TA1538 and WP2uvrA. The p ositive controls induced the appropriate responses in the corresponding strains. **There w as no evidence of induced**  **mutant colonies over background** . 870.5300 In vitro mammalian cell gene mutation 43429508 (1988) Acceptable/guideline Chinese hamster V79 cel ls were exposed at concentrations of 3, 10, 30, 100, and 330 μg/ml ± S9 activation. Not cytotoxic up to 330 μg/ml, the limit of solubility. **There wa**  **s no evidence of mutagenic effect at any dose level with or without metabolic activation.**  The positive controls induced the appropriate response. 870.5375 In vitro mammalian chromosome aberration (HL) 43429509 (1989) Acceptable/guideline The preliminary test was conducted at 3 - 330 μg/ml with and without S - 9 activation. In the main study, human lymphocytes were exposed at 1.25 - 20 μg/ml ± S9 activation. Tested up to limit of solubility (up to 330 μg/ml). For metaphase analysis, the highest concentration (20 μg/ml) produced moderate toxicity (mitotic index ~57% of solvent control). Two lower concentrations p roduces mitotic indices 25% and 12.5% of the high concentration. Positive controls induced the appropriate response. **The results of this study provide sufficient evidence to consider NNI**  **- 850 negative in this assay**  . 870.5395 Mammalian micronucleus (mous e) 43429510 (1989) **Acceptable/guideline** Male and female CD - 1 mice received a single dose of 80 - 2000 mg/kg. There was suggestive evidence that NNI - 850 was cytotoxic to the target cell at the highest dose level. The positive control induced significant inc reases in micronucleated polychromatic erythrocytes (MPCEs) . **There was no significant increase in the frequency of**  **MPCEs in bone marrow after any NNI -**  **850 treat**  **me nt time. Fenpyroxim**  **ate is considered negative in this mi**  **cronucleus assay.** 870.5500 43429511 (1988) **Did not cause any inhibitory zone in either strain at any dose**Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 33 of 34 **Table A3 . Toxicity Profile for Fenpyroxim**  **ate Technical. Guideline No./ Study**  **Type MRID No. (year)/ Classification**  **/Doses Results**  DNA damage/repair REC assay **Acceptable/guideline** Cultures were exposed at 10 - 500 μg/disk ± S9 activation. **level in the presence or absence of metabolic activation.** The negative and positive controls induced the appropriate responses. 870.5550 Unscheduled DNA sy nthesis (RPH) 43429512 (1989) **Acceptable/guideline** Primary rat hepatocyte cultures were exposed at 0.025 - 1.02 μg/mL. **Fenpyroxim ate was negative.**  The positi ve control induced the appropriate response. 870.6100 Acute delayed neurotoxicity - hen 44847904 (1989) **Acceptable/guideline** 5000 mg/kg/day (Limit Test) NOAEL  5000 mg/kg/day. LOAEL was not observed. 870.6200 Acute Neurotoxicity

- Rat 48441401 (2011) 0, 37.5, 75, 150, 300 mg/kg bw Acceptable/guideline NOAEL = 150 mg/kg bw. LOAEL = 300 mg/kg bw based on decreased motor activity [total activity counts (males ↓46%; females ↓38%); total time spent in movement ( ↓54%; females ↓49%)]. 870.6200 Subchronic neurotoxicity

- Rat 48537704 (2011) 0, 30, 100, or 300 ppm M: 0, 1.8, 6.1, 16.4 mg/kg/day F: 0, 2.0, 6.6, 18.4 mg/kg/day Acceptable/guideline NOAEL = 1.8 mg/kg bw/day. LOAEL = 6.1 mg/kg bw/day based on deficits in body weight and food consumption. 870.7485 Metabolism and pharmacokinetics rat 43560504 and 43560505 (1991) 43429513 (1990) **Acceptable/guideline** In a metabolism study, doses ranged from 2 - 400 mg/kg. In a separate blood pharmacokinetics study (MRID 43429513), five rats/sex/dose were given single oral doses of [pyrazole 14 C] or [benzyl 14 C] fenpyroximate at 2 or 400 mg/kg. The majority of the radioactivity from the single and repeated low doses was excreted in the feces within 24 hours of dosing. In contrast, fecal excretion of the majority of the high dose was delayed until 96 - 144 hours; and, at 24 hours, the major portion of the single high dose (53.4 - 63.9%) remained in the stomach contents. The maximum concentration in blood (tma x) was reached at 7 - 11 hours following a single low dose compared with 29 - 101 hours after a single high dose. The low doses were eliminated from blood within 96 hours, whereas the high dose persisted through 168 hours. A total of 20 metabolites, each accounting for <10% of the dose, were characterized f

rom excreta (urine and feces) of low - dose rats. The preponderance of metabolites and low levels of parent in the feces at the 2 mg/kg dose indicates absorption from the digestive tract, extensive metabolism by the liver, and biliary excretion of the low dose (2 mg/kg). The high dose of 400 mg/kg causes as a toxic effect delayed excretion and decreased absorption and metabolism. 870.7600 Dermal penetration

– Rat 45734204 (1993) **Acceptable/guideline** Test material was applied to a 10 cm2 area at nominal dose levels of 10, 100 and 520 ug/cm2 (actual 10.6, 103 and 52.3 ug/cm2)

. Exposure durations were 0.5, 1, 2, 4, 10 or 24 hours. Mean absorption based on urinary/fecal excretion, blood, carcass, and cage wash ranged from 0 to 5.3% (0.0 to 5.3% low dose, 0.5 to 2.5% mid dose and 0.52 to 1.5% high dose). **Dermal -**  **absorption factor is 5%.** 870.7800 Immunotoxicity 48441402 (2011) Acceptable/guideline M: 0, 2.2, 7.1, 18.4 mg/kg/day F: 0, 2.6, 7.9, 21.4 mg/kg/day Immunotoxicity NOAEL = 18.4 mg/kg bw/day (highest dose tested). LOAEL = not identified. Systemic toxicity NOAEL = 2.2 mg/kg bw . LOAEL = 7.1 mg/kg bw based on dose - related reduction in body weight in both sexes (21.3% decrease).Fenpyroximate Human - Health Risk Assessment DP No. 404839

Page 34 of 34 **Appendix B. Physical/Chemical Properties**  **Table B1. Physicochem** **ical Properties of Fenpyroxim ate.**  Parameter Value Reference Melting range 99.3 - 101.7 ° C D301316, 5/3/04, L. Kutney pH 5.63 - 6.10 D301316, 5/3/04, L. Kutney Density 1.247 - 1.257 g/mL at 20 ° C D301316, 5/3/04, L. Kutney Water solubility Water, pH 5 - 21.4 ppb Water, pH 7 - 23.1 ppb Water, pH 9 - 29.8 ppb D257640, 8/20/99, G. Kramer Solvent solubility Acetone 15.0 g/100 mL Chloroform 119.7 g/100 mL DMSO 2.86 g/100 mL Ethanol 1.65 g/100 mL Ethyl acetate 20.1 g/100 mL Hexane 0.35 g/100 mL Methanol 1.53 g/100 mL Methylene chloride 130.7 g/100 mL Tetrahydrofuran 73.7 g/100 mL Toluene 26.8 g/100 mL Xylene 19.3 g/100 mL D301316, 5/3/04, L. Kutney

Vapor pressure 5.6 x 10 - 8 Pa at 25 ° C D257640, 8/20/99, G. Kramer Dissociation constant, pKa Not applicable; nearly insoluble in water D301316, 5/3/04, L. Kutney Octanol/water partition coefficient, Log(KOW) log P ow = 5.01 (PAI) D301316, 5/3/04, L. Kutney