
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           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:  D404839
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
TXR 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 and proposed uses of the insecticide/miticide fenpyroximate ((E)-1,1-dimethylethyl 4-[[[[(1,3-dimethyl-5-phenoxy-1H-pyrazol-4-yl)methylene]amino]oxy]methyl]benzoate).  A summary of the estimated human health risks resulting from the registered and requested fenpyroximate uses are provided in this document.  The risk assessment and occupational/residential exposure assessment were provided by Jennifer Tyler (RAB1); the residue chemistry data review and dietary exposure assessment by George Kramer (RAB1); the hazard characterization by Chester Rodriguez (RAB1); and the drinking water assessment by Greg Orrick of the Environmental Fate and Effects Division (EFED).


                               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	Physical/Chemical Characteristics	9
3.3	Pesticide Use Pattern	9
3.4	Anticipated Exposure Pathways	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 Bystander 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.  Physical/Chemical Properties	34


1.0	Executive Summary

Fenpyroximate is a contact insecticide/miticide used for the control of leafhoppers, mealybugs, and mites.  Fenpyroximate 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 fenpyroximate to stone fruits (group 12-12), small vine climbing fruits except kiwifruit (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 fenpyroximate, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only the sum of fenpyroximate, (E)-1,1-dimethylethyl 4-[[[[(1,3-dimethyl-5-phenoxy-1H-pyrazol-4-yl) methylene] amino]oxy]methyl] benzoate and its Z­isomer, (Z)-1,1-dimethylethyl 4-[[[[(1,3-dimethyl-5- phenoxy-lH-pyrazol-4-yl) methylene]amino]oxy] methyl]benzoate, calculated as the stoichiometric equivalent of fenpyroximate, in/on 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.

Fenpyroximate tolerances have been established in 40 CFR §180.566.  Tolerances for plant commodities are expressed in terms of combined residues of fenpyroximate and its Z-isomer.  Permanent tolerances for plant commodities, under §180.566(a)(1) range from 0.10 ppm for cotton undelinted seed to 20 ppm for tea.  Tolerances for milk and the fat, meat, and meat byproducts (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 fenpyroximate and its metabolites (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)-methylene aminooxymethyl]benzoic acid and (E)-1,1-dimethylethyl-2-hydroxyethyl 4-[[[[(1,3-dimethyl-5-phenoxy-1H-pyrazol-4-yl)methylene]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 fenpyroximate and its metabolite (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)-methylene aminooxymethyl]benzoic 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.  Fenpyroximate has no uses that result in residential exposure.  

Toxicity Profile:  Fenpyroximate was classified as Category II for acute toxicity via the oral and inhalation routes of exposure.  It exhibited low dermal acute toxicity (Category III) and was neither a skin nor eye irritant.  Fenpyroximate is considered to be a slight to moderate skin sensitizer.

The effects following repeated oral exposures to fenpyroximate were based on systemic toxicity (no specific target organ/tissue identified).  The most sensitive species tested was the dog.  The effects reported in the dog included slight bradycardia, 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 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 electrolyte levels among other signs of toxicity.  In subchronic 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 marginally 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 reported at the levels tested.  In the rat two-generation reproductive toxicity study; maternal toxicity (decreased body weight) and offspring toxicity (decreased lactational weight gain in both generations) occurred at the same dose. 

There is no evidence that fenpyroximate specifically targets the nervous or immune system based on the results of recently submitted studies.  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.  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 to 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 gain and food consumption, and changes in hematology parameters (increased counts of erythrocytes and leukocytes).  There were also histopathology findings in the nasal passage mucosa consisting of atrophy and squamous metaplasia.

Fenpyroximate was classified as "not likely to be carcinogenic to humans" based on the results of rat and mouse carcinogenicity studies.  Genotoxicity studies including mutagenicity did not demonstrate any genotoxic potential associated with fenpyroximate.

Dose-response and Food Quality Protection Act (FQPA) Assessment:  The existing toxicology database for fenpyroximate is complete and adequate for FQPA evaluation, risk assessment, and tolerance setting.  Appropriate endpoints were identified for exposures to fenpyroximate.  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 developmental toxicity study where an increased incidence of additional thoracic ribs was observed at 25.0 mg/kg/day.  For the acute dietary risk assessment for 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 was based on a chronic population-adjusted dose (cPAD) of 0.05 mg/kg/day based on the NOAEL 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.  The 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 reported included clinical observations (labored breathing and rales), increased lung weights, decreases in body-weight gain and food consumption, and changes in hematology parameters (increased counts of erythrocytes and leukocytes), and histopathology changes.  The inhalation 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 adjustment factor for duration of exposure and species differences in respiration and respiratory tract surface area.

The fenpyroximate risk assessment team has evaluated the hazard and exposure data; and, based on these data, recommended that the FQPA Safety Factor (SF) be reduced to 1x for all exposure scenarios.  The recommendation is based on the following:  (1) the existing toxicology database for fenpyroximate is complete and adequate for FQPA evaluation; (2) there is no concern for neurotoxicity; (3) although there was evidence for increased (qualitative) prenatal susceptibility following 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 residue chemistry and drinking water databases are adequate to assess potential human exposure to fenpyroximate.  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) for fenpyroximate and its isomers/degradates, 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) model and a Provisional Cranberry Model.  Surface water EDWCs of 0.043 ppm and 0.0086 ppm were used in the acute and chronic analyses, respectively, 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 fenpyroximate using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM-FCID, ver. 3.16) which incorporates 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 analyses employed tolerance-level residues for all commodities; 100% crop treated (CT) information; DEEM (ver. 7.81) default 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 analyses 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.  The acute dietary risk estimate 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 chronic 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 highly 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 fenpyroximate products registered for residential use sites.  

Aggregate Exposure Assessment:  Aggregate exposure risk assessments were assessed by incorporating the drinking water directly 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 fenpyroximate that result in residential exposures.  A cancer aggregate risk assessment was not performed because fenpyroximate 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 estimates for handlers were assessed for mixer/loaders and applicators involved in occupational use of fenpyroximate.  Post-application dermal risk estimates 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 estimates 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 estimates are not of concern (i.e., MOE >100) on the day of treatment for all post-application activities.  Therefore, occupational risk estimates for handlers and post-application workers are not of concern.

The proposed labels have a 12-hour restricted-entry interval (REI).  Fenpyroximate is classified as Toxicity Category II for acute dermal, and 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 systemic 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 Worker Protection Standard (WPS).  RD should ensure that all fenpyroximate labels have the appropriate REI listed. 

The Akari[(R)] 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 AHETF 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 requirements.  For certain studies, that review may have included reviews by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

2.0	HED Recommendations

Provided revised Sections B and F are submitted, HED concludes that the toxicological, residue chemistry and occupational/residential databases support a Section 3 registration and establishment 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	Enforcement Analytical Method

An adequate enforcement method is available for determination of fenpyroximate residues of concern in the proposed/registered crops.  A gas chromatography method with nitrogen/phosphorus detection (GC/NPD), Method S19, has passed 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 fenpyroximate and M-1 in snap beans and avocados.  A data-gathering liquid chromatography/mass spectroscopy/mass spectroscopy (LC/MS/MS) method is also available.  This method was used for the analysis of the samples from submitted field and processing studies.


2.2.2	Recommended Tolerances

Table 2.2.2.  Tolerance Summary for Fenpyroximate.
                                   Commodity
                           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

                     Remove 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 fenpyroximate per se in/ grapes (fresh and dried).  Harmonization with the Codex and Mexican MRLs 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 MRLs.

2.3	Label Recommendations

2.3.1	Recommendations from Occupational Assessment

   * The Akari[(R)] 5SC label should be amended to specify the use of "chemical-resistant gloves" instead of "waterproof gloves."  RD should ensure the appropriate PPE is listed on the label.
   * The 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 fenpyroximate labels have the appropriate REI listed.


3.0	Introduction

3.1	Chemical Identity

Table 3.1.  Fenpyroximate Nomenclature.
Chemical structure
                                       
Common name
Fenpyroximate
Company experimental name
NNI-850
IUPAC name
tert-butyl(E)-alpha-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxy)-p-toluate
CAS name
1,1-dimethylethyl 4-[[[(E)-[(1,3-dimethyl-5-phenoxy1H-pyrazol-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[(R)]/Portal[(R)] Miticide/Insecticide 0.4 lb ai/gal EC formulation (5% ai; EPA Reg. No. 71711-19)
Akari[(R)] 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-phenoxy1H-pyrazol-4-yl)methylene]-amino]oxy]methyl]benzoate
                                 Metabolite M1

3.2	Physical/Chemical Characteristics

The physical and chemical properties, as well as a summary of relevant environmental fate parameters, are detailed in Appendix B.  Fenpyroximate 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

Fenpyroximate is a contact insecticide/miticide used for the control of leafhoppers, mealybugs, and mites.  U.S. registrations are currently held by 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[(R)] 5EC Miticide/Insecticide (EPA Reg. No. 71711-19), an EC formulation containing 5% ai (equivalent to 0.4 lb ai/gal); Portal[(R)] Miticide/Insecticide (EPA Reg. No. 71711-19), an EC formulation containing 5% ai (equivalent to 0.4 lb ai/gal); and Akari[(R)] 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, respectively.

The proposed FujiMite(R) 5EC and Portal[(R)] labels require applicators and other handlers to wear a long-sleeved shirt and long pants, chemical-resistant gloves, protective eyewear, shoes plus socks, chemical resistant apron (for mixing and loading), and chemical-resistant headgear (for overhead exposure).  The proposed Akari[(R)] 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" instead 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[(R)] 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[(R)] Miticide/
                                  Insecticide
                                       
                                       
                                       
                                       
                                       
                                       
                            Akari[(R)] 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 Fenpyroximate.
                   Application Timing, Type, and  Equipment
                          Formulation [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
   Small Fruit Vine Climbing (Except Fuzzy Kiwifruit) (Crop Subgroup 13-07F)
                                   Airblast
                           Fujimite(R) EC [71711-19]
                                   0.05-0.1
                                       2
                                      0.1
                                      14
RTI[3] = 14 days; Min. GPA[2] = 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(R) EC/Portal(R) [71711-19]
                             Akari(R) 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(R)EC/ Portal(R)  [71711-19]
                             Akari(R) 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 days following the last application of this product."  

3.4	Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new use of fenpyroximate on stone fruits (group 12-12), small vine climbing fruits except kiwifruit (subgroup 13-07F), and tuberous and corm vegetables (subgroup 1C).  Humans may be exposed to fenpyroximate in food and drinking water, since it may be applied directly to growing crops, and application may result in fenpyroximate reaching surface and ground water sources of drinking water.  As there are no residential uses of fenpyroximate, 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 also potential for post-application exposure for workers re-entering treated fields.  

Risk assessments have been previously conducted for fenpyroximate, but no new toxicity data have been received since the previous risk assessment.  This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of fenpyroximate, but also considers the existing uses as well, for the dietary and aggregate exposure assessments.  

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the NHANES/WWEIA; 2003-2008 and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

4.1	Hazard Profile

4.1.1	Mode of Action

Fenpyroximate is a contact insecticide/miticide used for the control of leafhoppers, mealybugs, and mites.  The proposed pesticidal mode of action involves inhibition of mitochondrial function. More specifically, fenpyroximate is a mitochondrial electron transport inhibitor that targets the enzyme NADH:ubiquinone oxidoreductase and blocks electron transfer to ubiquinone. 

4.2	Toxicology Studies Available for Analysis

The toxicological database for fenpyroximate 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, DP#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 administration in the rat, radiolabeled fenpyroximate was slowly absorbed into the systemic 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, while 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 levels 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 previously estimated for fenpyroximate 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 exposure.

4.3	Toxicological Effects

Fenpyroximate induced moderate acute lethality in rats (Category II) via the oral and inhalation routes of exposure.  It exhibited low dermal acute toxicity (Category III) and was neither a skin nor eye irritant.  Fenpyroximate was classified as a skin sensitizer by the maximization method, but not by the method of Buehler.  HED considers fenpyroximate to be a slight to moderate sensitizer by the maximization test method. 

The effects following repeated oral exposures to fenpyroximate resulted in overall systemic 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 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 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 electrolyte levels among other signs of toxicity.  In subchronic and chronic studies with rats, the primary effect was decreased body-weight 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 marginally 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 developmental 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 fenpyroximate specifically targets the nervous system based on the results 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 neurotoxicity-specific effects; deficits in body weight and food consumption were the main effects reported.

In a recently 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 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 gain and food consumption, and changes in hematology parameters (increased counts of erythrocytes and leukocytes).  There were also histopathology findings in the nasal passage 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 residual 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.


4.4.1	Completeness of the Toxicology Database

The existing toxicology database for fenpyroximate is complete and adequate for FQPA evaluation.  There are acceptable developmental rat and rabbit toxicity studies, an acceptable rat two-generation reproduction study, and acceptable acute and subchronic neurotoxicity studies available for FQPA consideration.

4.4.2	Evidence of Neurotoxicity

There is no concern for neurotoxicity with fenpyroximate.  Both acute and subchronic neurotoxicity studies in the rat did not indicate neurotoxicity-specific effects; reductions in body weight and food 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 oral 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 toxicity 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 Uncertainty 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 by models and associated modeling parameters, which are designed to provide conservative, 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 uncertainty factor (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 acute reference dose (aRfD) and aPAD are equivalent at 0.05 mg/kg bw. 

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 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.  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 equivalent 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 bradycardia, 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 (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 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 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.  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 LOAEL of 10 mg/m[3] (NOAEL = 2 mg/m[3]) consisted of 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.

The methods and dosimetry equations described in EPA's reference concentration (RfC) guidance (1994) are suited for calculating HECs based on the inhalation toxicity NOAEL for use in MOE calculations.  The regional-deposited-dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic 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 was estimated at 1.2 based on the reported MMAD of 3.00 um 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) 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 erythrocytes), and histopathology findings in the nasal passage mucosa consisting of atrophy and squamous metaplasia were observed.  Therefore, for fenpyroximate, the dermal and inhalation routes cannot be combined for risk assessment since a common endpoint was not observed. 

4.5.3	Cancer Classification and Risk Assessment Recommendation

There is no evidence of carcinogenic potential for fenpyroximate based on the results of carcinogenicity studies via the oral route in either the rats or mice resulting in the carcinogenicity classification of "not likely" 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 PODs for Fenpyroximate in Dietary and Occupational Risk Assessment.
                                   Exposure
                                   Scenario
                                      POD
          Uncertainty/ FQPA Safety Factors or LOC for Risk Assessment
                        Study and Toxicological Effects
Acute 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.
Acute 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
Acute 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 decreases in cholesterol, body-weight gain, and food consumption (M); vomiting, diarrhea, excess salivation and 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 necrosis 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 by HED (Memo, G. Kramer, 08-MAY-2013, DP# 405715).  The drinking water assessment was completed by 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# 405718).  

5.1	Residues of Concern Summary and Rationale

 The nature of the residue in crops is understood based on acceptable plant metabolism studies with fenpyroximate on snap beans, apples, citrus, cotton, and grapes.  The HED Metabolism Assessment Review Committee (MARC) has determined that the residues of concern 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 adequately 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-hydroxyethyl 4-[[[[(1,3-dimethyl-5-phenoxy-1H-pyrazol-4-yl)methylene]amino]oxy]methyl]benzoate], and M3 [(E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)-methylene aminooxymethyl]benzoic acid] in 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 geographic regions; and samples were analyzed 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 procedures 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 processed waste.  The additional fenpyroximate uses are not expected to result in an increase in the maximum reasonably balanced diets (MRBDs).  The existing tolerances on ruminant commodities are thus adequate to support registration of the proposed new uses of fenpyroximate.  There are no swine or poultry feedstuffs associated with this petition.

An adequate confined rotational crop study is available.  [[14]C]-Fenpyroximate was applied to sandy loam soil at 0.20 lb ai/A (1X the maximum seasonal rate to annual 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 will, 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 analyses ("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 fenpyroximate 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).


Table 5.3.  Maximum Screening EDWCs of Fenpyroximate for Current and Proposed Uses.[1]
                         Drinking Water Source (model)
                           Use (Maximum 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 analyses, respectively, 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 fenpyroximate 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 assessment was not performed because fenpyroximate 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 exposure analyses 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 analyses 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 analyses incorporated the EDWCs provided by EFED.  An EDWC of 0.043 ppm was used in the acute analyses, 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 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.

5.4.4	Chronic Dietary Risk Assessment

The chronic analysis assumed 100% CT, tolerance-level residues for all commodities, and DEEM (ver. 7.81) default processing factors for most commodities (see above).  The chronic analysis also incorporated EDWCs provided by EFED (an EDWC of 0.0086 ppm was used in the chronic analysis).

The resulting chronic risk estimates are not of concern to HED (<100% of the cPAD).  The most highly 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 Dietary (Food and Drinking Water) Exposure and Risk for Fenpyroximate.
                             Population Subgroup[1]
                      Acute Dietary (95[th] Percentile)[2]
                               Chronic Dietary[3]
                                        
                          Dietary Exposure (mg/kg/day)
                                     % aPAD
                                Dietary Exposure
                                  (mg/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 fenpyroximate products registered for residential use sites.

6.1	Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative residential bystander post-application inhalation exposure assessment was not performed for fenpyroximate 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 nearby 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, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for fenpyroximate.

6.2	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from ground application.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices.  The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT[(R)] computer model to its risk assessments for pesticides applied by air, orchard air-blast, and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray-drift-management practices to reduce off-target drift and risks associated with aerial as well as other application types where appropriate.

Although a quantitative residential post-application inhalation-exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation-exposure assessment was performed for flaggers.  This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios.   

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 fenpyroximate that result in residential exposure, the acute and chronic aggregate risk assessments are equal to the acute dietary and chronic dietary estimates (food and water only), 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 fenpyroximate that result in residential exposures.  A cancer aggregate-risk assessment was not performed because fenpyroximate is not carcinogenic.
7.1	Acute Aggregate Risk

No acute residential/recreational exposures are expected.  In the case of fenpyroximate, the acute aggregate risk is composed of exposures to fenpyroximate 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.

7.2	Chronic Aggregate Risk

A long-term aggregate risk assessment was not performed, because long-term residential exposure to fenpyroximate (i.e., >6 months) is unlikely to occur based upon the use patterns.  Specifically, in the case of fenpyroximate, the chronic aggregate risk is composed of exposures to fenpyroximate 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 exceed 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 fenpyroximate and any other substances and fenpyroximate does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that fenpyroximate has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

9.0	Occupational Exposure/Risk Characterization

Based on the proposed 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. Tyler (Memo, 08-MAY-2013, DP#404839), and reviewed by 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 task.  Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by 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, types 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/Loaders
   * mixing/loading liquids in support of aerial applications,
   * 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 assess 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 "Occupational 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 protective 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 days between applications).  Typically, HED completes short- and intermediate-term 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.  Long-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 System (GPS) for swath guidance in agricultural aviation has grown steadily from the mid 1990s.  Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990s to only 1% in the most recent (2012) NAAA survey.  The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

Table 9.1.1 provides a summary of the estimated exposures and risk estimates 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 estimates for occupational handlers are above the LOC (MOE >= 100 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 estimates for occupational aerial applicators are above the LOC (MOE >= 100 for dermal and MOE >= 30 for inhalation) with baseline clothing and enclosed cockpits.



Table 9.1.1.  Short- and Intermediate-Term Occupational Exposure and Risk Estimates for Fenpyroximate.
                               Exposure Scenario
                                Crop or Target
                      Dermal Unit Exposure (ug/lb ai)[1]
                    Inhalation Unit Exposure (ug/lb ai)[1]
                                    Maximum
                              Application Rate[2]
                    Area Treated or Amount Handled Daily[3]
                                    Dermal
                                  Inhalation
                                       
                                       
                               Mitigation Level
                               Mitigation Level
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/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[(R)] EC/Portal[(R)] [71711-19] and Akari(R) 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 September 2001.
 4.  Average Daily Dose = Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Area Treated (A) / BW (kg).
 5.  MOE = margin of exposure = NOAEL  ADD.  NOAEL = 300 mg/kg bw/day (dermal), 0.10 mg/kg bw/day (inhalation).
 6.  Baseline = long-sleeve shirt, long pants, and no gloves (dermal); no respirator (inhalation).
 7.  Engineering Control = enclosed cockpit and baseline attire (long-sleeve shirt, long pants, shoes, and socks).

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, including 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 type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1	Dermal Post-application Risk

HED expects that post-application exposure will occur since fenpyroximate 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 protection 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_policy3.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 application) for all exposure activities, and are not of concern.

Table 9.2.1.  Summary of Short- and Intermediate-term Occupational/Commercial Post-application Risk Estimates for Fenpyroximate.
                                   Crop/Site
                                  Activities
                        Transfer Coefficient (cm[2]/hr)
                                      DFR
                                (ug/cm[2])[1]
                                 Dermal Dose 
                                (mg/kg/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
                                     5,600
                                       
     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 (ug/cm[2]) = Application Rate (lb ai/A) x (1-Daily Dissipation Rate)[t] x CF (4.54E+8 ug/lb) x CF (2.47E-8 A/cm[2]) x 25% DFR after initial treatment.
2.  Daily Dose = [DFR (ug/cm[2]) x TC (cm[2]/hr) x 0.001 mg/ug x 8 hrs/day] / Body Weight (80 kg).
3.  MOE = NOAEL (Short- and Intermediate-term NOAEL 300 mg/kg/day)/Daily Dose (LOC=100).

REI:  The proposed FujiMite[(R)], Portal[(R)], and Akari[(R)] labels list 12-hour REIs.  Fenpyroximate 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 systemic 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 ensure 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 uses 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 analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a foliar application (FAR).  This default value is 25% and is based on an analysis of 19 DFR studies where the FAR value ranged from 2% to 89%.  This value is recommended for use in both residential and occupational post-application assessments.  Of the analyzed DFR studies, the maximum FAR value seen was 89% or 3.6 times higher than the default residue transfer value.  Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the LOC (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical-specific DFR study (Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and DFR Studies. 6/7/2012, Exposure Science Advisory Council).  A DFR study is not required for fenpyroximate 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 fenpyroximate 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 exposure 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 contain 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/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for fenpyroximate.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

10.0	References

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 Analytical 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 Corm 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# 391430, 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 Fruit- 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 Existing Uses on Citrus in Texas, Melons, Fruiting Vegetables, and Snap Beans.

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 Kiwifruit, 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:RAB1
Appendix A.  Toxicology Profile Tables.

Table A1.  Toxicity Testing Requirements for Fenpyroximate.
                                     Test
                                   Technical

                                   Required
                                   Satisfied
870.1100	Acute Oral Toxicity
870.1200	Acute Dermal Toxicity
870.1300	Acute 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	Acute Delayed Neurotox. (hen)
870.6100b	90-Day Neurotoxicity (hen)
870.6200a	Acute 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
         Acute Oral (rat)	
         Subchronic Oral (rat)	
         Six-month Oral (dog)	
                                       
                                      no
                                      no
                                      no
                                       
                                       -
                                       -
                                       -


Table A2.  Acute Toxicity of Fenpyroximate.
                                 Guideline No.
                                  Study Type
                                    MRID #s
                                    Results
                               Toxicity Category
                                   870.1100
                                Acute oral-rat
                                   43560501
                            LD50 = 450 mg/kg males
                           LD50 = 245 mg/kg females
                           LD50 = 350 mg/kg combined
                                      II
                                   870.1200
                               Acute dermal-rat
                                   44847901
                             LD50 >2,000 mg/kg
                                      III
                                   870.1300
                             Acute inhalation-rat
                                   44847902
                            LC50 = 0.24 mg/L (male)
                           LC50 = 0.37 mg/L (female)
                          LC50 = 0.35 mg/L (combined)
                                      II
                                   870.2400
                          Acute eye irritation-rabbit
                                   44781004
                            Not an ocular irritant.
                                      IV
                                   870.2500
                        Acute 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 Fenpyroximate 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 food 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 necrosis in the females.
870.3465
28-Day inhalation toxicity
(rats)
45323302 (1991)
Acceptable/guideline
0, 2, 10, or 50 mg/m[3]
NOAEL = 2 mg/m[3]
LOAEL = 10 mg/m[3] 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 body-weight 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; however, 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
F0 (M/F):  0/0, 0.67/0.83, 2.0/2.4, or 6.6/8.6 mg/kg/day
F1 (M/F):  0/0, 0.78/0.96, 2.3/2.8, or 8.4/9.9 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.
Reproductive NOAEL = 6.59 and 8.60 mg/kg/day for males and females, respectively.
LOAEL 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 positive controls induced the appropriate responses in the corresponding strains.  There was no evidence of induced mutant colonies over background.
870.5300
In vitro mammalian cell gene mutation
43429508 (1988)
Acceptable/guideline
Chinese hamster V79 cells 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 was 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 produces 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 (mouse)
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 increases in micronucleated polychromatic erythrocytes (MPCEs).  There was no significant increase in the frequency of MPCEs in bone marrow after any NNI-850 treatment time.  Fenpyroximate is considered negative in this micronucleus assay. 
870.5500
DNA damage/repair REC assay
43429511 (1988)
Acceptable/guideline
Cultures were exposed at 10-500 μg/disk +- S9 activation. 
Did not cause any inhibitory zone in either strain at any dose level in the presence or absence of metabolic activation.  The negative and positive controls induced the appropriate responses.
870.5550
Unscheduled DNA synthesis (RPH)
43429512 (1989)
Acceptable/guideline
Primary rat hepatocyte cultures were exposed at 0.025-1.02 μg/mL.
Fenpyroximate was negative.  The positive 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 (tmax) 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 from 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 cm[2] area at nominal dose levels of 10, 100 and 520 ug/cm[2] (actual 10.6, 103 and 52.3 ug/cm[2)].  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). 

Appendix B.  Physical/Chemical Properties

Table B1.  Physicochemical Properties of Fenpyroximate.
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	21.4 ppb 
Water, pH 7-23.1 ppb 	23.1 ppb
Water, pH 9-29.8 ppb	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 Pow = 5.01 (PAI)
D301316, 5/3/04, L. Kutney

