Document ID: EPA-HQ-OPP-2008-0556-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-08-03T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES, AND

TOXIC SUBSTANCES

MEMORANDUM

  SEQ CHAPTER \h \r 1 Date:		12/23/2008

Subject:	Fenpyroximate.  Petition for the Establishment of Permanent
Tolerances for Residues on Fruiting Vegetable (Crop Group 8), Melon
(Crop Subgroup 9A), Cucumber, and Okra.  Human-Health Risk Assessment.  

PC Code:  129131	DP Barcode:  354305

Decision No.:  394796	Registration Nos.:  71711-4 and 71711-19

Petition No.:  8E7365	Regulatory Action:  Amended Sec. 3 Registration

Risk Assessment Type:  Single Chemical/Aggregate	Case No.:  NA

TXR No.:  NA	CAS No.:  134098-61-6 (E-isomer)

MRID No.:  None	40 CFR:  §180.566

FROM:	William D. Wassell, Risk Assessor

		George F. Kramer, Ph.D., Senior Chemist

Lata Venkateshwara, Environmental Scientist

Kelly M. Lowe, Environmental Scientist

Robert Mitkus, Ph.D., Toxicologist

Registration Action Branch 1 (RAB1)/Health Effects Division (HED, 7509P)

Through:		Dana Vogel, Branch Chief

	RAB1/HED (7509P)

To:				Daniel Rosenblatt/Sidney Jackson, 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
requested fenpyroximate use is provided in this document.  The risk
assessment and dietary exposure assessment were provided William Wassell
(RAB1); the residue chemistry data review were provided by George Kramer
(RAB1); the occupational/residential exposure assessment by Lata
Venkateshwara and Kelly M. Lowe, (RAB1), the hazard characterization by
Robert Mitkus (RAB1); and the drinking water assessment by William
Shaughnessy of the Environmental Fate and Effects Division (EFED).

NOTE:  HED recently completed a Section 3 risk assessment for the use of
fenpyroximate on citrus fruits, hops, mint, pistachio, and tree nuts
(Memo, 5/26/2006, G. Kramer et al., DP# 317905).  This document contains
only those aspects of the risk assessment which are affected by the
addition of these new uses of fenpyroximate on fruiting vegetables (crop
group 8), melon (crop subgroup 9A), okra, and cucumber.

Table of Contents

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc217810280"  1.0  EXECUTIVE
SUMMARY	  PAGEREF _Toc217810280 \h  4  

  HYPERLINK \l "_Toc217810281"  2.0  PHYSICAL/CHEMICAL PROPERTIES
CHARACTERIZATION	  PAGEREF _Toc217810281 \h  9  

  HYPERLINK \l "_Toc217810282"  3.0  HAZARD CHARACTERIZATION	  PAGEREF
_Toc217810282 \h  10  

  HYPERLINK \l "_Toc217810283"  3.1  Hazard Profile	  PAGEREF
_Toc217810283 \h  10  

  HYPERLINK \l "_Toc217810284"  3.2  FQPA Considerations	  PAGEREF
_Toc217810284 \h  11  

  HYPERLINK \l "_Toc217810285"  3.3  Dose-Response Assessment	  PAGEREF
_Toc217810285 \h  12  

  HYPERLINK \l "_Toc217810286"  3.4  Endocrine Disruption	  PAGEREF
_Toc217810286 \h  13  

  HYPERLINK \l "_Toc217810287"  4.0  EXPOSURE ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc217810287 \h  14  

  HYPERLINK \l "_Toc217810288"  4.1  Summary of Registered Uses	 
PAGEREF _Toc217810288 \h  14  

  HYPERLINK \l "_Toc217810289"  4.2  Summary of Proposed Uses	  PAGEREF
_Toc217810289 \h  14  

  HYPERLINK \l "_Toc217810290"  4.3  Dietary Exposure/Risk Pathway	 
PAGEREF _Toc217810290 \h  16  

  HYPERLINK \l "_Toc217810291"  4.4  Water Exposure/Risk Pathway	 
PAGEREF _Toc217810291 \h  25  

  HYPERLINK \l "_Toc217810292"  4.5  Residential/Non-Occupational
Exposure Pathway	  PAGEREF _Toc217810292 \h  26  

  HYPERLINK \l "_Toc217810293"  5.0  AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc217810293 \h  26  

  HYPERLINK \l "_Toc217810294"  6.0  CUMULATIVE RISK	  PAGEREF
_Toc217810294 \h  26  

  HYPERLINK \l "_Toc217810295"  7.0  OCCUPATIONAL EXPOSURE AND RISK
ASSESSMENT	  PAGEREF _Toc217810295 \h  27  

  HYPERLINK \l "_Toc217810296"  7.1  Handler Exposure and Risk
Assessment	  PAGEREF _Toc217810296 \h  27  

  HYPERLINK \l "_Toc217810297"  7.2  Post-Application Exposure and Risk
Assessment	  PAGEREF _Toc217810297 \h  31  

  HYPERLINK \l "_Toc217810298"  7.3  REIs	  PAGEREF _Toc217810298 \h  33
 

  HYPERLINK \l "_Toc217810299"  8.0  DATA DEFICIENCIES	  PAGEREF
_Toc217810299 \h  33  

  HYPERLINK \l "_Toc217810300"  8.1  Residue Chemistry	  PAGEREF
_Toc217810300 \h  33  

  HYPERLINK \l "_Toc217810301"  8.2  Occupational Exposure	  PAGEREF
_Toc217810301 \h  35  

  HYPERLINK \l "_Toc217810302"  8.3  Toxicology	  PAGEREF _Toc217810302
\h  35  

  HYPERLINK \l "_Toc217810303"  Appendix 1:  Acute Toxicity Profile	 
PAGEREF _Toc217810303 \h  36  

  HYPERLINK \l "_Toc217810304"  Appendix 2:  Toxicity Profile	  PAGEREF
_Toc217810304 \h  37  

 

1.0  EXECUTIVE SUMMARY

Fenpyroximate is a contact insecticide/miticide used for the control of
leafhoppers, mealybugs, and mites.  The mode of action is similar to
that of pyridaben and acequinocyl.  Fenpyroximate is a mitochondrial
electron-transport inhibitor (METI) which acts by targeting
proton-translocating NADH:Q oxidoreductase and blocking ubiquinone
reduction.

U.S. registrations are currently held by Nichino America, Inc. and
include a 0.42 lb/gal (5%) suspension-concentrate (SC; equivalent to a
flowable-concentrate, FlC) formulation (Akari 5SC Miticide -
Insecticide, EPA Reg. No. 71711-4), registered for nonfood use on
ornamental, floral, and foliage crops, and a 0.40 lb/gal (5%)
emulsifiable-concentrate (EC) formulation (FujiMite 5 EC
Miticide/Insecticide; EPA Reg. No. 71711-19) registered for foliar
application to pome fruit, cotton, grapes, and nonbearing deciduous
fruit and nut trees and vines.  In conjunction with the subject
petition, the Interregional Research Project No. 4 (IR-4) proposes to
amend the labels for these products to incorporate new uses on the crops
addressed in this petition.  Fujimite® is proposed for foliar spray
applications of fruiting vegetables, okra, and melons at a maximum
seasonal rate of 0.2 lb ai/A with preharvest intervals (PHIs) of 1 day
(fruiting vegetables and okra) or 3 days (melons).  Akari® is proposed
for foliar spray applications of greenhouse-grown cucumbers at a maximum
seasonal rate of 0.1 lb ai/A with a PHI of 7 days.

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)(2) range from 0.10 ppm for cotton
undelinted seed to 10 ppm for cotton gin byproducts.  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)(3)
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)(4) 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. 
Fenpyroximate has no uses that result in residential exposure.  

Hazard Assessment 

FQPA SF for Infants and Children

HED Hazard Identification and Assessment Review Committee (HIARC)
concluded, based upon the lack of residual uncertainties for pre-and
post-natal toxicity, the Food Quality Protection Act (FQPA) safety
factor (SF) should be reduced to 1x.  The FQPA SF was reduced based upon
toxicological considerations by HIARC, the conservative residue
assumptions used in the chronic dietary-exposure risk assessment, the
completeness of the residue chemistry and environmental fate databases
and the lack of the potential for residential exposures (evaluated by
the risk assessment team).

There was no evidence of adverse effects on the organs of the immune
system at the lowest-observed adverse-effect level (LOAEL) in submitted
toxicology studies with fenpyroximate.  In addition, fenpyroximate does
not belong to a class of chemicals (e.g., the organotins, heavy metals,
or halogenated aromatic hydrocarbons) that would be expected to be
immunotoxic.  Based on the above considerations, HED does not believe
that conducting a special series 870.7800 immunotoxicity study will
result in a point of departure less than the cRfD with a NOAEL of 0.97
mg/kg/day already set for fenpyroximate; therefore, an additional
uncertainty factor for database uncertainties (UFDB) does not need to be
applied.

Dose-Response Assessment

The doses and toxicological endpoints selected for various exposure
scenarios as per our previous risk assessment are summarized in the
following table.

Exposure Scenario	Dose	FQPA SF and Level of Concern for Risk Assessment
Study/Effect

Acute Dietary (females 13-50 only)	NOAEL = 5 mg/kg/day

UF = 100

Acute RfD = 0.05 mg/kg/day	FQPA SF = 1x

aPAD = aRfD

              FQPA SF

= 0.05 mg/kg/day	Prenatal developmental-toxicity study in rats.  LOAEL =
25 mg/kg/day based on an increase in the fetal incidence of additional
thoracic ribs.

Chronic Dietary	NOAEL = 0.97 mg/kg/day

UF = 100

Chronic RfD = 0.01 mg/kg/day	FQPA SF = 1x

cPAD = cRfD

             FQPA SF

= 0.01 mg/kg/day	Combined oral chronic toxicity/carcinogenicity study in
rats.  LOAEL = 3.1 mg/kg/day based on decreased body-weights accompanied
by reduced food efficiency and a slight decrease in mean food
consumption.

Short-term inhalation

(1-30 days)	NOAEL = 2 mg/kg/day	Occupational LOC for MOE = 100

LOC for MOE =100 )	2-generation reproductive-toxicity study in rats. 
Parental LOAEL = 6.59 mg/kg/day, based on decreased body-weights during
premating.

Short-term dermal

(1-30 days)	Dermal NOAEL = 300 mg/kg/day	Occupational LOC for MOE = 100 

LOC for MOE = 100	21-day dermal-toxicity study in rats.  LOAEL = 1000
mg/kg/day based on clinical signs in females, decreased body-weights,
body-weight gains, and food consumption in both sexes, and increased
absolute liver weights and hepatocellular necrosis in females.

UF = uncertainty factor, NOAEL = no-observed adverse-effect level, LOAEL
= lowest-observed adverse-effect level, PAD = population-adjusted dose
(a = acute, c = chronic), RfD = reference dose, LOC = level of concern,
MOE = margin-of-exposure.

Exposure Assessment

Residential Exposure:  The proposed use is on agricultural crops;
therefore, there is no potential for residential exposure.  In addition,
there are no proposed or existing fenpyroximate products registered for
residential use sites.  

Dietary Risk Estimates (Food + Water):  Acute (for females 13-49 years
old) and chronic dietary risk assessments were conducted using the
Dietary Exposure Evaluation Model software with the Food Commodity
Intake Database (DEEM-FCID(, Version 2.03), which incorporates food
consumption data from the U.S. Department of Agriculture's (USDA’s)
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996
and 1998.  The acute and chronic analyses employed tolerance-level
residues for all commodities, 100% crop-treated and DEEM( (ver. 7.81)
default processing factors (as necessary), and empirical processing
factors for apple, pear, grape, orange, grapefruit, lemon, tangerine,
and lime juice; grape, raisin; tomato paste and puree; and peppermint
and spearmint oil.  Drinking water was incorporated directly into the
dietary assessments using the estimated drinking water concentrations
(EDWCs) for surface water.  The EDWCs were Tier 1 estimates for ground
water using the SCI-GROW model (Screening Concentration In GROund Water)
and surface water using the FIRST model (FQPA Index Reservoir Screening
Tool) for fenpyroximate and its degradates, M1 and M3.  The models
utilized an application rate of 0.2 lb ai/A with 2 applications per
season.  EDWCs of 0.00874 ppm and 0.00051 ppm were used in the acute and
chronic analysis, respectively. 

An acute dietary-exposure assessment was conducted for females 13-49
years old.  Since an effect of concern attributable to a single dose in
toxicity studies was not identified for the general U.S. population, an
acute dietary-exposure assessment was not performed for subgroups other
than females 13-49 years old.  This assessment (see Table 4.3.2.1.1)
concludes that the acute dietary-exposure estimate is below HED’s
level of concern (<100% aPAD) for females 13-49 years old (6.6 % aPAD).

A chronic dietary-exposure assessment was conducted for the general U.S.
population and various population subgroups.  This assessment (see Table
4.3.2.1.2) concludes that the chronic dietary-exposure estimates are
below HED’s level of concern (<100% cPAD) for the general U.S.
population (12% cPAD) and all population subgroups.  The most
highly-exposed population subgroup is children 1-2 years old at 38%
cPAD.

Occupational Exposure Estimates:  Short-term inhalation and dermal risks
for handlers were assessed for mixer/loaders and applicators involved in
occupational use of fenpyroximate.  Postapplication dermal risks were
assessed for workers involved in post-harvest activities. 
Chemical-specific exposure data were not available to assess pesticide
handler exposure.  Therefore, surrogate data from the Pesticide Handler
Exposure Database (PHED), Version 1.1 (August, 1998) were used to
estimate mixer/loader and applicator exposure.  For handlers, HED has
determined that risks are not a concern (i.e., margin of exposure (MOE)
>100) at baseline and with the addition of gloves (required on the
label).  HED has also determined that the risks are not of concern (i.e.
MOE >100) on the day of treatment for all post application activities. 
Therefore, occupational risks for handlers and post application workers
are not of concern.

Fenpyroximate is classified as Toxicity Category II for acute oral,
acute dermal and acute inhalation; 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 postapplication exposure
would indicate acceptable MOEs on the day of treatment, the acute
toxicity categories for this chemical require a 24 hour restricted-entry
interval (REI) for this product under the Worker Protection Standard
(WPS).  HED recommends that all fenpyroximate labels have an REI of 24
hours.  

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 which result in
residential exposures.  A cancer aggregate risk assessment was not
performed because fenpyroximate is not carcinogenic.  

Recommendation for Tolerances and Registration: 

  SEQ CHAPTER \h \r 1 Pending submission of revised Sections B and F
(see below), this risk assessment supports the establishment of
permanent tolerances for the combined residues of fenpyroximate and its
Z-isomer as follows:

Vegetable, fruiting, group 8	0.20 ppm

Okra	0.20 ppm

Melon subgroup 9A	0.10 ppm

Cucumber	0.10 ppm

The registrations on fruiting vegetables (crop group 8), okra, melon
subgroup 9A, and cucumber should be made conditional pending the
submission of an analytical reference standard for fenpyroximate, the
resolution of the data gap pertaining to residue analytical methods and
submission of a immunotoxicity study (see below). 

  SEQ CHAPTER \h \r 1 Residue Chemistry Deficiencies

Revised Sections B and F:

A revised Section B (Directions for Use) is required to clarify the
proposed use on greenhouse-grown cucumbers.  The maximum seasonal rate
of 0.1 lb ai/A is inconsistent with the label specification that two
applications may be made at 0.1 lb ai/A per application.  The submitted
data will support only one application at 0.1 lb ai/A per growing
season.  In addition, the label directions regarding use of ultra-low
volume equipment on greenhouse cucumbers should be deleted since data
reflecting this type of application were not submitted.  Also, the
labels should be revised to prohibit use of adjuvants on the subject
crops as residue data were not provided to support their use.

The petitioner is required to submit a revised Section F (proposed
tolerances) to amend the proposed tolerances for residues in/on:  (i)
melon subgroup 9A, from 0.03 ppm to 0.10 ppm; and (ii) cucumber, from
0.05 ppm to 0.10 ppm.

Deficiencies To Be Satisfied Prior To Granting Permanent Registrations:

Toxicology:

As a result of the 2007 revisions to 40 CFR §158, the following
guideline toxicology studies are required:  immunotoxicity study and
acute and subchronic neurotoxicity studies in rats.

Residue Chemistry:

  SEQ CHAPTER \h \r 1 860.1340 Residue Analytical Method - Plant
Commodities

The available enforcement analytical method data should be upgraded to
support the expanded uses of fenpyroximate proposed under the current
petition.  The method should be rewritten to include instructions for
the analysis of fruiting vegetables, okra, melon, and cucumber.

The requirement for an interference study demonstrating the specificity
of the enforcement method, or a specific confirmatory method (e.g., use
of mass spectroscopy (MS) detection) remains outstanding.  If the
petitioner can validate the liquid chromatograph equipped with tandem
mass spectrometers (LC/MS/MS) Method AJW/03/01 on the registered crops
and the crops addressed in this petition, then this requirement will be
fulfilled.

Clarifications are required for the analytical methods used for pepper
and cantaloupe.  Due to the potential for isomerization between
fenpyroximate and its Z-isomer in peppers and cantaloupes, the results
were reported as combined residues (with both analytes determined as the
Z-isomer).  Although the method used for peppers and cantaloupes did not
differ significantly in procedure from the original enforcement
analytical method, the petitioner stated that for analysis of the
subject commodities, fenpyroximate was converted to the Z-isomer in the
injector area of the gas chromatograph (GC); however, it is noted that
this conversion was not always complete, as shown by the presence of a
double peak in several of the sample chromatograms.  The petitioner
should provide further explanation for this observation, addressing
whether conversion to the Z isomer is specific to certain crop
commodities such as cantaloupe and pepper or was the result of the
instrument conditions used for analysis of subject commodity samples.

  SEQ CHAPTER \h \r 1 860.1650 Submittal of Analytical Reference
Standards

Analytical standards for fenpyroximate (with expiration date of 12/6/08)
and its Z-isomer (with expiration date of 6/21/10) are currently
available in the EPA National Pesticide Standards Repository.  Since the
standards for fenpyroximate are about to expire, the petitioner is
requested to provide a new supply to the Repository.  The reference
standards should be sent to the Analytical Chemistry Lab, which is
located at Fort Meade, to the attention of Theresa Cole at the following
address:

	USEPA

	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

	701 Mapes Road

	Fort George G. Meade, MD  20755-5350

(Note that the mail will be returned if the extended zip code is not
used.)

2.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

The chemical structure and nomenclature of fenpyroximate and its
metabolite M1 and the physicochemical properties of the technical grade
of fenpyroximate are presented in Tables 2.0.1 and 2.0.2

 

Common name	Fenpyroximate

Company experimental name	NNI-850

IUPAC name
tert-butyl(E)-alpha-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-ox
y)-p-toluate

tert-butyl(E)-alpha-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-ox
y)-p-toluate

CAS name	1,1-dimethylethyl
4-[[[(E)-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)methylene]-amino]oxy]methy
l]benzoate

CAS registry number	134098-61-6 (E isomer);

111812-58-9 (unspecified stereochemistry)  

End-use product (EP)	FujiMite® 5% EC (EPA Reg. No. 71711-19)

 

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	  SEQ CHAPTER \h \r 1 Acetone                15.0
g/100 mL

Chloroform    SEQ CHAPTER \h \r 1          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

3.0  HAZARD CHARACTERIZATION

3.1  Hazard Profile

Reference: Human-Health Risk Assessment, 5/26/2006, G. F. Kramer et al.,
DP# 317905 

A complete toxicology database for this chemical has been submitted. 
Fenpyroximate technical is in Toxicity Category II for oral and
inhalation toxicity.  It has low dermal toxicity (Category III) and is
not an eye or skin irritant.  Fenpyroximate is a sensitizer by the
maximization method but not by the method of Buehler.  Overall, HED
considers fenpyroximate to be a slight to moderate sensitizer by the
maximization test method. 

For subchronic toxicity, the primary oral effects in the rat included
decreased body-weight and weight gain at the LOAEL, while there were
hematological effects at higher doses.  In the 21-day dermal toxicity
study in rats, there were clinical signs in the females (including red
nose/mouth/nasal discharge); decreased body-weights, body-weight gains,
and food consumption in males and females; and increased liver weights
and hepatocellular necrosis in the females.  In the subchronic oral dog
study, there was bradycardia observed at the LOAEL.  This effect was
present at 6 weeks (first time point measured) and did not appear to
increase in severity with time.  Also observed at this dose level were
diarrhea, decreased body-weight, body-weight gain, and food consumption.
 At higher doses, there was also emesis.  The highest dose resulted in
first- and second-degree heart block, increased urea concentration,
decreased glucose and altered plasma electrolyte levels among other
signs of toxicity. 

In the chronic oral rat and mouse studies, signs of toxicity were
similar to those in the oral subchronic rat study.  The chronic dog
study also had signs, including bradycardia, diarrhea, decreased
body-weight gain, and food consumption.  There was no evidence of
carcinogenic potential in either the rat or mouse study resulting in the
carcinogenicity classification of “not likely” to be carcinogenic to
humans (1999 Proposed Carcinogenicity Guidelines).

The rat and rabbit developmental toxicity studies were tested at doses
that produced minimal maternal toxicity.  These doses were supported
partly by range-finding data.  The two-generation reproductive toxicity
study indicated that maternal (decreased body-weight) and offspring
toxicity (decreased lactational weight gain) occurred at the same dose,
suggesting no evidence of sensitivity or susceptibility.  Reproductive
parameters were not affected in this two-generation reproduction study.

There are no neurotoxicity studies other than a negative delayed acute
neurotoxicity study in the hen.  There was no indication of
neurotoxicity present in any of the existing subchronic or chronic
toxicity studies.

There was no concern for mutagenic activity in several studies
including:  Salmonella, E. Coli, in vitro mammalian cell gene mutation
assay at the HGPRT locus, mammalian cell chromosome aberration assay, in
vivo mouse bone marrow micronucleus assay, DNA repair disk diffusion
assay, and an unscheduled DNA synthesis assay.

In the rat, fenpyroximate is absorbed from the digestive tract and
extensively metabolized by the liver.  In low-dose studies, it is
rapidly excreted in the feces (within 24 hours).  The blood T1/2 was 6-9
hours.  There was also biliary excretion at the low dose.  There was
almost complete recovery in the feces, and to a lesser extent, in the
urine by 7 days.  Parent was only recovered in the feces (about 8-20% of
the label).  The high-dose metabolism profile was different.  There was
a delay of 3-4 days for fecal excretion, as well as a longer blood T1/2
(1-2 days).  Parent was again only found in the feces, but it was about
50% of the fecal label.  There was low tissue uptake for either dose,
with fat having the highest uptake.

3.2  	FQPA Considerations

3.2.1  FQPA SF for Infants and Children

The HED HIARC met on July 8, 2003 to select endpoints for risk
assessment and to evaluate the potential for increased susceptibility of
infants and children from exposure to fenpyroximate according to the
February 2002 OPP 10x guidance document.  

HIARC concluded, based upon the lack of residual uncertainties for
pre-and post-natal toxicity, the FQPA SF should be reduced to 1x.  The
FQPA SF was reduced based upon toxicological considerations by HIARC,
the conservative residue assumptions used in the chronic
dietary-exposure risk assessment, the completeness of the residue
chemistry and environmental fate databases and the lack of the potential
for residential exposures (evaluated by the risk assessment team).

There was no evidence of adverse effects on the organs of the immune
system at the LOAEL in submitted toxicology studies with fenpyroximate. 
In addition, fenpyroximate does not belong to a class of chemicals
(e.g., the organotins, heavy metals, or halogenated aromatic
hydrocarbons) that would be expected to be immunotoxic.  Based on the
above considerations, HED does not believe that conducting a special
series 870.7800 immunotoxicity study will result in a point of departure
less than the cRfD with a NOAEL of 0.97 mg/kg/day already set for
fenpyroximate, and therefore, an additional uncertainty factor for
database uncertainties (UFDB) does not need to be applied.

Endpoints were selected for acute and chronic dietary, short- and
intermediate-term incidental- oral, dermal, and inhalation risk
assessment.  Long-term inhalation and dermal endpoints were also
identified.  Based upon uncertainty factors for inter- and intra-species
variation, the level of concern for human health risk assessment is an
MOE <100.  Endpoints selected for risk assessments that are pertinent to
this action are summarized below.  Since the FQPA SF for fenpyroximate
is 1x, the population-adjusted doses (PADs) are the same as the
reference doses (RfDs).

3.3  Dose-Response Assessment

The doses and toxicological endpoints selected for various exposure
scenarios as per HED’s previous risk assessment are summarized in
Table 3.3.1.

Table 3.3.1. Fenpyroximate Endpoints Selected for Risk Assessment.

Exposure

Scenario	Dose Used in Risk Assessment,

UF	FQPA SF and Level of Concern for Risk Assessment	Study and
Toxicological Effects

Acute Dietary

females 13-50 years of age	NOAEL = 5.0 mg/kg/day

UF = 100

Acute RfD = 0.05 mg/kg/day	FQPA SF = 1x

aPAD = aRfD

              FQPA SF

= 0.05 mg/kg/day	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 including infants and children	N/A	N/A	N/A

Chronic Dietary

all populations	NOAEL= 0.97 mg/kg/day

UF = 100

Chronic RfD = 0.01 mg/kg/day	FQPA SF = 1x

cPAD = cRfD

             FQPA SF

= 0.01 mg/kg/day	Combined Oral Chronic Toxicity/carcinogenicity Study -
rat

LOAEL = 3.1 mg/kg/day based on decreased body-weights, accompanied by
reduced food efficiency and a slight decrease in mean food consumption.

Short-Term Dermal (1-30 days)

(Occupational/

Residential)	dermal study NOAEL= 300 mg/kg/day	Occupational LOC for MOE
= 100 

Residential LOC 

for MOE = 100 	21-Day Dermal-Toxicity Study – Rat

LOAEL = 1000 mg/kg/day based on clinical signs in the females, decreased
body-weights, body-weights gains, and food consumption in both sexes,
and increased absolute liver weights and hepatocellular necrosis in the
females.

Intermediate-Term

Dermal (1 - 6  months)

(Occupational/

Residential)	dermal study NOAEL= 300 mg/kg/day	Occupational LOC for MOE
= 100 

Residential LOC 

for MOE = 100 	21-Day Dermal-Toxicity Study – Rat

LOAEL = 1000 mg/kg/day based on clinical signs in the females, decreased
body-weights, body-weights gains, and food consumption in both sexes,
and increased absolute liver weights and hepatocellular necrosis in the
females.

Long-Term Dermal (> 6 months)

(Occupational/

Residential)	dermal study NOAEL= 300 mg/kg/day	Occupational LOC for MOE
= 100 

Residential LOC 

for MOE = 100 	21-Day Dermal-Toxicity Study – Rat

LOAEL = 1000 mg/kg/day based on clinical signs in the females, decreased
body-weights, body-weights gains, and food consumption in both sexes,
and increased absolute liver weights and hepatocellular necrosis in the
females.

Short-Term Inhalation (1-30 days)

(Occupational/

Residential)	oral study NOAEL= 2 mg/kg/day

(inhalation absorption rate = 100%)	Occupational LOC for MOE = 100 

Residential LOC 

for MOE = 100 	2-Generation Reproductive-Toxicity Study – Rat

Parental toxicity LOAEL = 6.59 mg/kg/day, based on decreased
body-weights during premating.

Intermediate-Term Inhalation (1 - 6 months)

(Occupational/

Residential)	oral study NOAEL= 1.5 mg/kg/day

(inhalation absorption rate = 100%)	Occupational LOC for MOE = 100 

Residential LOC 

for MOE = 100 	90-Day Oral Toxicity Study – Rat

LOAEL = 7.4 mg/kg/day based on decreases in body-weight gains in both
sexes.

Cancer (oral, dermal, inhalation)	(not likely( to be carcinogenic to
humans	N/A	No evidence of carcinogenic potential in adequate
carcinogenicity studies in both rat and mouse.

1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL =
no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect
level, PAD = population-adjusted dose (a = acute, c = chronic) RfD =
reference dose, LOC = level of concern.

3.4  Endocrine Disruption

EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA), as
amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate.  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there are scientific
bases for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) and, to the
extent that effects in wildlife may help determine whether a substance
may have an effect in humans, FFDCA has authority to require the
wildlife evaluations.  As the science develops and resources allow,
screening of additional hormone systems may be added to the Endocrine
Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, fenpyroximate may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0  EXPOSURE ASSESSMENT AND CHARACTERIZATION

The residue chemistry data submitted in support of proposed petitions
were evaluated by HED (Memo, pending, G. Kramer, DP# 354703).  The
drinking water assessment was completed by EFED on 11/3/2008 (Memo, W.
Shaughnessy, DP# 354306).  The dietary exposure assessment was completed
in a HED memorandum (Memo, pending, W. Wassell, DP# 357391).  The
occupational exposure assessment was completed by L. Venkateshwara and
K. Lowe (Memo, 11/21/2008, D354305).

4.1  Summary of Registered Uses

The end-use products (EPs) associated with this registration action are
Fujimite® 5EC Miticide/Insecticide (EPA Reg. No. 71711-19) and Akari®
5SC Miticide/Insecticide (EPA Reg. No. 71711-4).  The U.S. registrations
of these EPs are currently held by Nichino America, Inc.  Fujimite® is
formulated as an EC formulation containing 5% ai (equivalent to 0.4 lb
ai/gal) and is registered for foliar application to pome fruit, cotton,
grapes, and nonbearing deciduous fruit and nut trees and vines.  Akari®
is formulated as a SC (equivalent to FlC) formulation containing 5% ai
(equivalent to 0.42 lb ai/gal) and is registered for nonfood use on
ornamental, floral, and foliage crops.

4.2  Summary of Proposed Uses t \l2 "4.2  Summary of Proposed Uses
Error! Bookmark not defined. 

In conjunction with the subject petition, IR-4 has submitted an
application for an amended Section 3 registration for the 5% EC
formulation to add uses on fruiting vegetables (crop group 8), melon
(crop subgroup 9a), cucumber, and okra.



Table 4.2.1.  Summary of Proposed End-Use Products.

Trade Name	EPA

Reg. No.	ai (% of formulation)	Formulation Type	Target Crops	Target
Pests	Label Date

Fujimite® 5EC Miticide/

Insecticide	71711-19	5% (equivalent to 0.4 lb ai/gal)	Emulsifiable 

Concentrate	Fruiting vegetables except cucurbits, melon subgroup 9A,

and okra	Leafhoppers, mealybugs, mites or psylla	Undated draft label

Akari® 5SC Miticide/

Insecticide	71711-4 	5% (equivalent to 0.42 lb ai/gal)	Suspension
concentrate	Greenhouse cucumbers	Mites including spider mites	Undated
draft label

Table 3B.  Summary of Proposed Directions for Use of Fenpyroximate.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	

Applic. Rate 	Max. No. Applic. per Season	Max. Seasonal Applic. Rate	PHI

(days)

Fruiting Vegetables, Crop Group 8 (Field and Greenhouse) [Including: 
Eggplant; Ground Cherry (Physalis spp.); Pepino; Peppers including Bell
Pepper, Chili Pepper, Cooking Pepper, Pimento, and Sweet Pepper;
Tomatillo; and Tomato]; and Okra1

Foliar spray

Ground or airblast	Fujimite® 5EC;

0.4 lb/gal EC

[71711-19]	0.1 lb ai/A	2	0.2 lb ai/A	1

	Use Directions and Limitations:  Apply in a minimum of 20 gallons per
acre (GPA) of water for ground applications (or 100 GPA on greenhouse
tomatoes).  Use of higher carrier volume is recommended for heavy
infestations and in situations where thorough coverage is difficult to
achieve.  Do not apply through any type of irrigation system.  The
product should be used in a rotational program with other products with
alternative modes of action to provide resistance management.  A 12-hour
restricted entry interval (REI) is proposed.

Melon Subgroup 9A (Including Cantaloupe, Citrus Melon, and Watermelon)

Foliar spray

Ground or airblast	Fujimite® 5EC;

0.4 lb/gal EC

[71711-19]	0.1 lb ai/A	2	0.2 lb ai/A	3

	Use Directions and Limitations:  Apply in a minimum of 20 GPA for
ground applications.  Use of higher carrier volume is recommended for
heavy infestations and in situations where thorough coverage is
difficult to achieve.  The product should be used in a rotational
program with other products with alternative modes of action to provide
resistance management.  Do not apply through any type of irrigation
system.  A 12-hour REI is proposed.

Greenhouse Cucumbers

Foliar spray

Ground	Akari® 5SC

0.42 lb/gal SC

[71711-4]	0.1 lb ai/A	2	0.1 lb ai/A	7

	Use Directions and Limitations:  Apply in a minimum of 100 GPA for
ground applications.  Use of higher carrier volume is recommended for
heavy infestations and in situations where thorough coverage is
difficult to achieve.  Apply using backpack sprayer equipment. 
Applications may also be made with high volume, low volume, or ULV
(thermal and non-thermal foggers, misters, etc.)  Do not apply through
any type of irrigation system.  Do not use Akari® 5SC in successive
miticide applications per resistance management statements on the label.
 A 12-hour REI is proposed.

1  Based on the minutes of the Chemistry Science Advisory Council
(ChemSAC) meeting of 10/18/06, HED has approved adding okra to the
fruiting vegetable crop group.  

The proposed label for Fujimite® 5EC Miticide/Insecticide (EPA Reg. No.
71711-19) specifies that application by air is prohibited on the
proposed crops; application by air is recommended only for cotton, a
registered crop.  In addition, the following rotational crop restriction
appears on the label:  “Do not plant rotational crops other than those
listed on the label for 30 days following the last application of this
product.”  

Conclusions.  The proposed use patterns on fruiting vegetables, melons,
and okra are adequate to allow evaluation of the residue data submitted
in support of this petition.  However, the proposed use on
greenhouse-grown cucumber must be clarified as the maximum proposed
seasonal rate of 0.1 lb ai/A is inconsistent with the label
specification that two applications may be made at 0.1 lb ai/A per
application.  The submitted data will support one application at 0.1 lb
ai/A per growing season.  In addition, the label direction regarding use
of ULV equipment on greenhouse cucumbers should be deleted since no data
reflecting this application equipment was conducted on any cucumber
trials.  Also, the labels should be revised to prohibit use of adjuvants
on the subject crops as residue data were not provided to support their
use.

4.3  Dietary Exposure/Risk Pathway

4.3.1  Residue Profile

Nature of the Residue in Plants  

  SEQ CHAPTER \h \r 1 No plant metabolism studies were submitted with
the subject petition.  Acceptable plant metabolism studies with
fenpyroximate on apples, citrus, cotton, and grapes were previously
submitted in support of tolerance petitions for uses on imported wine
grapes and hops (PP#5E04435) and pome fruit, cotton, and grapes (PP#s
0F06437 and 0E06519).  HED has determined (Memo, 07/12/03, J. Stokes,
DP# 292639) that the residues of concern for purposes of tolerance
enforcement and risk assessment are the parent compound plus its
Z-isomer (M1).  The available plant metabolism data are adequate to
support the proposed uses on fruiting vegetables, melons, cucumbers, and
okra.  The residues of concern in these commodities are fenpyroximate
and its Z-isomer.

Nature of the Residue in Livestock

The nature of residue in lactating goat is understood.  The HED
Metabolism Assessment Review Committee (MARC) concluded that for milk
and the fat, meat, and meat byproducts (excluding liver and kidney) of
cattle, goat, horse, and sheep, the residues of concern are the parent
compound, 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 (Memo, J. Stokes, 8/12/03;
DP# 292639).  Additionally, the residues of concern for cattle, goat,
horse, and sheep liver and kidney are fenpyroximate and its metabolite
(E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)-methylene
aminooxymethyl]benzoic acid, calculated as the parent compound.

As fenpyroximate is not currently registered for use on crops which are
used as poultry feed items, the nature of the residue in poultry is not
of concern for this risk assessment.

Residue Analytical Method for Crops and Livestock 

  SEQ CHAPTER \h \r 1 Plant Commodities

An acceptable enforcement method, GC/nitrogen-phosphorus detector (NPD)
method DFG S19, is available for enforcement of tolerances for residues
in/on plant commodities.  This method has undergone a petition method
validation (Memo, 10/10/00, G. Kramer, DP# 269410) and is listed in the
U.S. EPA Index of Residue Analytical Methods under fenpyroximate, Method
ID 2000_109M, “Quantitation of Fenpyroximate Residues in Raw
Agricultural and Processed Commodities.”  

In conjunction with PP#s0F06437, PP#0E06519, and PP#5E04435 (Memo,
8/20/03, G. Kramer, DP# 291925 and Memo, 8/20/03, G. Kramer, DP#
292394), HED required the submission of an interference study
demonstrating the specificity of Method S19, or a specific confirmatory
method (e.g., use of MS detection).  This data requirement remains
outstanding.

Livestock Commodities

In conjunction with PP#5E6943 (Memo, 6/19/08, G. Kramer, DP# 338871),
HED has requested that the petitioner develops a new method for
determination of residues of fenpyroximate and its metabolites Fen-OH
and M3 in ruminant commodities based on the comments from the Analytical
Chemistry Branch/Biological and Economics Analysis Division (ACB/BEAD)
and have this method validated by an independent laboratory.  

Magnitude of the Residue in Crops

IR-4 has submitted crop field trials supporting the use of fenpyroximate
on fruiting vegetables (crop group 8), melon (crop subgroup 9a),
cucumber, and okra.  The results from these studies are discussed and
summarized below.

Vegetable, Fruiting, Crop Group 8

Pepper (47439602.der.doc):  IR-4 has submitted magnitude of the residue
data for fenpyroximate on bell and non-bell pepper from supervised
trials conducted under field and greenhouse conditions.  The results see
Table 4.3.1.1) show that following two foliar applications of Fujimite®
5EC Miticide/Insecticide at a target rate of ~0.10 lb ai/A per
application for a total rate of ~0.20 lb ai/A, the maximum combined
residues of fenpyroximate and its Z-isomer in/on samples collected at a
1-day PHI were:  0.075 ppm for bell peppers grown in the field, 0.069
ppm for bell peppers grown in greenhouse, 0.12 ppm for non-bell peppers
grown in the field, and 0.056 ppm for non-bell peppers grown in
greenhouse.

The residue decline trial indicated that the combined residues generally
remained steady in/on bell peppers and decreased in/on non-bell peppers
with increasing sampling intervals.  In the bell pepper decline trial,
maximum combined residues were 0.095 ppm at the 0-day PHI and were 0.094
ppm at the 12-day PHI; in the non-bell pepper decline trial, maximum
combined residues declined from 0.12 ppm at the 1-day PHI to <0.05 ppm
at the 14-day PHI.



Table 4.3.1.1.  Summary of Residue Data from Pepper Trials with
Fenpyroximate.

Commodity	Total Applic. Rate (lb ai/A)	PHI (days)	Combined Residue
Levels (ppm)1

	n	Min.	Max.	HAFT	Median	Mean	Std. Dev.

Proposed Use Pattern = Maximum seasonal rate of 0.2 lb ai/A with a 1-day
PHI

Pepper, bell

(field trials)	0.201-0.203	1	12	<0.05	0.075	0.066	0.050	0.057	0.010

	0.298-0.313	0	2	0.093	0.095	0.094	0.094	0.094	--

1	4	<0.05	0.133	0.127	0.085	0.088	0.044

3	2	0.098	0.110	0.104	0.104	0.104	--

7	2	0.096	0.099	0.098	0.098	0.098	--

12	2	0.070	0.094	0.082	0.082	0.082

	Pepper, bell

(greenhouse trials)	0.202-0.206	1	4	<0.05	0.069	0.069	0.059	0.059	0.011

Pepper, non-bell

(field trials)	0.200-0.206	1	10	<0.05	0.12	0.12	0.050	0.064	0.027

3	2	<0.05	<0.05	0.05	0.05	0.05	--

7	2	<0.05	<0.05	0.05	0.05	0.05	--

14	2	<0.05	<0.05	0.05	0.05	0.05	--

Pepper, non-bell

(greenhouse trials)	0.204	1	2	0.052	0.056	0.054	0.054	0.054	--

1  Combined residues of fenpyroximate and its Z-isomer (Metabolite M1). 
In the calculation of the median, mean, and standard deviation, the
combined limit of quantification (LOQ) of 0.05 ppm was used for residues
reported as less than the LOQ.

Tomato (47439604.de1.doc):  IR-4 has submitted magnitude of the residue
data for fenpyroximate on tomatoes from supervised trials conducted
under field and greenhouse conditions.  The tomato trials (see Table
4.3.1.2) show that following two foliar applications of Fujimite® 5EC
Miticide/Insecticide at a target rate of ~0.10 lb ai/A per application
for a total rate of ~0.20 lb ai/A, the maximum combined residues of
fenpyroximate and its Z-isomer in/on samples collected at a 1-day PHI
were 0.185 ppm for tomatoes grown in the field and 0.174 ppm for
tomatoes grown in greenhouse.  Lower combined residues of <0.055 ppm
were obtained for field-grown tomatoes treated with three foliar
applications of the test formulation.  The residue decline trials
indicated that the combined residues of fenpyroximate generally
decreased with increasing sampling intervals; residues of M1 were
nonquantifiable in/on all samples at all sampling intervals.



Table 4.3.1.2.  Summary of Residue Data from Tomato Trials with
Fenpyroximate.

Commodity	Total Applic. Rate

(lb ai/A)	PHI (days)	Analyte	Residue Levels (ppm)1

n	Min.	Max.	HAFT2	Median	Mean	Std. Dev.

Proposed Use Pattern = Maximum seasonal rate of 0.2 lb ai/A with a 1-day
PHI

Tomato, field-grown	0.198-0.248	0	Fenpyroximate	2	0.046	0.053	0.050
0.050	0.050	--

	M1	2	<0.032	<0.032	0.032	0.032	0.032	--

	Combined	2	0.078	0.085	0.082	0.082	0.082	--

1	Fenpyroximate	30	<0.023	0.123	0.115	0.052	0.059	0.025

	M1	30	<0.032	0.062	0.055	0.032	0.033	0.006

	Combined	30	<0.055	0.185	0.170	0.084	0.092	0.029

3	Fenpyroximate	4	0.026	0.043	0.042	0.038	0.036	0.008

	M1	4	<0.032	<0.032	0.032	0.032	0.032	--

	Combined	4	0.058	0.075	0.074	0.070	0.068	0.008

7	Fenpyroximate	4	0.023	0.049	0.047	0.035	0.035	0.014

	M1	4	<0.032	<0.032	0.032	0.032	0.032	--

	Combined	4	0.055	0.081	0.079	0.066	0.067	0.014

13-14	Fenpyroximate	4	0.023	0.054	0.042	0.027	0.033	0.015

	M1	4	<0.032	<0.032	0.032	0.032	0.032	--

	Combined	4	0.055	0.086	0.074	0.058	0.065	0.015

21	Fenpyroximate	2	<0.023	<0.023	0.023	0.023	0.023	--

	M1	2	<0.032	<0.032	0.032	0.032	0.032	--

	Combined	2	<0.055	<0.055	0.055	0.055	0.055	--

	0.303	1	Fenpyroximate	2	<0.023	<0.023	0.023	0.023	0.023	--

	M1	2	<0.032	<0.032	0.032	0.032	0.032	--

	Combined	2	<0.055	<0.055	0.055	0.055	0.055	--

Tomato, greenhouse-grown	0.195-0.208	1	Fenpyroximate	6	0.066	0.142	0.108
0.076	0.085	0.028

	M1	6	<0.032	<0.032	0.032	0.032	0.032	--

	Combined	6	0.098	0.174	0.140	0.107	0.117	0.028

1  For calculation of the median, mean, and standard deviation, the LOQs
(0.02339 ppm for fenpyroximate, 0.03174 ppm for M1, and 0.05513 ppm for
combined residues) were used for residues reported as less than the LOQ.

Conclusions:  The submitted residue data for bell pepper, non-bell
pepper, and tomato, which are the representative commodities of fruiting
vegetables, crop group 8, are adequate to fulfill data requirements. 
The number and locations of trials conducted are in accordance with
OPPTS Guideline 860.1500.  The trials reflect the proposed use pattern.

The residue data for the representative commodities were separately
entered into the Agency’s tolerance spreadsheet as specified by the
Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP
to determine appropriate tolerance levels.  The spreadsheet recommends
tolerances of 0.20 ppm for tomato, 0.10 ppm for bell pepper, and 0.20
ppm for non-bell pepper.  Since the recommended tolerances differ by
less than 5x, a crop group tolerance of 0.20 ppm will be appropriate for
fruiting vegetables, crop group 8.  This recommendation is identical to
the tolerance level proposed by the petitioner for fruiting vegetables.

Okra:  Residue data for fenpyroximate in/on okra were not submitted in
support the proposed use.  IR-4 has proposed to translate the existing
fruiting vegetable data (peppers and tomatoes) to okra.  According to
the ChemSAC decision of 10/18/06, HED has approved adding okra to the
fruiting vegetable crop group.  Until 40 CFR §180.41 is updated, a
separate tolerance must be established for residues in/on okra.

Melon Subgroup 9A

Cantaloupe (47439603.der.doc):  IR-4 has submitted magnitude of the
residue data for fenpyroximate on cantaloupe.  The field trials (see
Table 4.3.1.3) indicate that following two foliar applications of
Fujimite® 5EC Miticide/Insecticide at a target rate of ~0.10 lb ai/A
per application for a total rate of ~0.20 lb ai/A, the maximum combined
residues of fenpyroximate and its Z-isomer in/on cantaloupe samples
collected at a 2- to 3-day PHI were below the method limit of
quantification (LOQ, 0.05 ppm).  The decline trial also showed that the
combined residues were nonquantifiable (<0.05 ppm) in/on all samples of
cantaloupe fruits harvested 1, 3, 7, 13, or 21 days following the second
of two foliar spray applications.

Table 4.3.1.3.  Summary of Residue Data from Cantaloupe Field Trials
with Fenpyroximate.

Commodity	Total Applic. Rate

(lb ai/A)	PHI (days)	Combined Residue Levels1 (ppm)

	N	Min.	Max.	HAFT	Median	Mean	Std. Dev.

Proposed Use Pattern = Maximum seasonal rate of 0.2 lb ai/A with a 3-day
PHI

Cantaloupe, fruit	0.197-0.202	1	2	<0.05	<0.05	0.05	0.05	0.05	--

2-3	16	<0.05	<0.05	0.05	0.05	0.05	--

7	2	<0.05	<0.05	0.05	0.05	0.05	--

13	2	<0.05	<0.05	0.05	0.05	0.05	--

21	2	<0.05	<0.05	0.05	0.05	0.05	--

1  Combined residues of fenpyroximate and its Z-isomer (Metabolite M1). 
In the calculation of the median and mean, the combined LOQ of 0.05 ppm
was used for residues reported as less than the LOQ.

Conclusions:  The submitted residue data for cantaloupe, the
representative commodity of melon subgroup 9A, are adequate to fulfill
data requirements.  The number and locations of trials conducted are in
accordance with OPPTS Guideline 860.1500.  The trials reflect the
proposed use pattern.  The residue data were not entered into the
Agency’s tolerance spreadsheet because all treated samples bore
combined residues below the LOQ of 0.05 ppm.  The available data for
cantaloupe will support a tolerance of 0.10 ppm (the combined LOQs of
the enforcement method) for melon subgroup 9A.  A revised Section F is
required to amend the proposed tolerance for residues in/on melon
subgroup 9A from 0.03 ppm to 0.10 ppm.

Cucumber (47439605.der.doc (Includes MRID 47439606)):  IR-4 has
submitted two studies which depict magnitude of the residue data for
fenpyroximate on cucumbers grown under greenhouse (MRID 47439605) or
polytunnel conditions (MRID 47439606).  The results (see Table 4.3.1.4)
show that following one application of a 5% SC formulation of
fenpyroximate at 0.08-0.10 lb ai/A, the maximum combined residues of
fenpyroximate and its Z-isomer in/on cucumbers were <0.05 ppm at 0-day
PHI, <0.04 ppm at 3-day PHI, <0.03 ppm at 7-day PHI, and <0.02 ppm at
10-day PHI.  The maximum individual residue of fenpyroximate was 0.04
ppm at 0-day PHI; individual residue of the Z-isomer was <0.01 ppm in/on
all treated samples.



Table 4.3.1.4.  Summary of Residue Data from Greenhouse Cucumber Trials
with Fenpyroximate.

Commodity	Total Applic. Rate

 (lb ai/A)	PHI (days)	Analyte	Residue Levels (ppm)1

n	Min.	Max.	HAFT	Median	Mean	Std. Dev.

Proposed Use Pattern = Maximum seasonal rate of 0.1 lb ai/A with a 7-day
PHI

Cucumber, fruit	0.09-0.10	0	Fenpyroximate	4	0.03	0.04	0.04	0.04	0.04
0.006

	M1	4	<0.01	<0.01	0.01	0.01	0.01	--

	Combined	4	<0.04	<0.05	0.05	0.05	0.05	0.006

3	Fenpyroximate	4	<0.01	0.03	0.03	0.02	0.02	0.008

	M1	4	<0.01	<0.01	0.01	0.01	0.01	--

	Combined	4	<0.02	<0.04	0.04	0.03	0.03	0.008

	0.08-0.10	7	Fenpyroximate	9	<0.01	0.02	0.02	0.01	0.01	0.005

	M1	9	<0.01	<0.01	0.01	0.01	0.01	--

	Combined	9	<0.02	<0.03	0.03	0.02	0.02	0.005

10	Fenpyroximate	9	<0.01	<0.01	0.01	0.01	0.01	--

	M1	9	<0.01	<0.01	0.01	0.01	0.01	--

	Combined	9	<0.02	<0.02	0.02	0.02	0.02	--

1  In the calculation of median, mean, and standard deviation, the LOD
(0.01 ppm for each analyte) was used for residues reported below the
LOD.

Conclusions:  The submitted residue data for cucumber are adequate to
fulfill data requirements. The trials reflect the proposed use pattern,
but were conducted in Europe under greenhouse or polytunnel conditions. 
ChemSAC decision of 3/26/08 approved use the of European residue data to
support the use of fenpyroximate on greenhouse-grown cucumbers in the
U.S.  The residue data for cucumber were entered into the Agency’s
tolerance spreadsheet as specified by the Guidance for Setting Pesticide
Tolerances Based on Field Trial Data SOP to determine an appropriate
tolerance level.  Although the spreadsheet recommends a tolerance of
0.06 ppm for residues in/on cucumber, the appropriate raw agricultural
commodity (RAC) tolerance is 0.10 ppm (the combined LOQs of the
enforcement method).  A revised Section F is required to amend the
proposed tolerance for residues in/on cucumber from 0.05 ppm to 0.10
ppm.

Magnitude of the Residue in Livestock

No new livestock feeding studies were submitted with this petition and
no livestock feed items are derived from the subject crops of this
petition.  Thus, the existing tolerances for secondary residues in
ruminant commodities are adequate to support registration of the
proposed new uses of fenpyroximate.

Magnitude of the Residue in Processed Food and Feed

Tomato (47439604.de2.doc):  IR-4 has submitted a tomato processing study
with fenpyroximate.  The test formulation was a 0.4 lb/gal EC
formulation of fenpyroximate (Fujimite® 5EC Miticide/Insecticide, EPA
Reg. No. 71711-19) which was sprayed twice (foliar applications) to
established tomato plants at a target rate of 0.2 lb ai/A per
application, with a 12- to 14-day retreatment interval (RTI), for a
total of ~0.4 lb ai/A (2x the maximum proposed seasonal rate). 
Commercially mature tomatoes were harvested from the treatment and
control plots one day following the second application.  The harvested
tomatoes were processed into paste and puree using simulated commercial
processing procedures.

Individual residues of fenpyroximate and Metabolite M1 in/on treated
tomato RAC samples ranged 0.065-0.094 ppm and <0.032-0.035 ppm,
respectively, with combined residues ranging <0.097-0.129 ppm.  The
processing data indicate that residues of fenpyroximate per se did not
concentrate in tomato paste or puree as all processing factors were
<1.0x.  Residues of Metabolite M1 did not concentrate in tomato puree;
however, residues of M1 concentrated slightly in tomato paste
(processing factor of <1.3x from the NY sample).  When residues are
combined, the average processing factors were <0.89x for tomato paste
and <0.57x for tomato puree; see Table 4.3.1.5.

The calculated processing factors do not exceed the theoretical
concentration factors of 1.4x for tomato paste and 5.5x for tomato puree
(OPPTS 860.1520, Table 2).

Table 4.3.1.5.  Average Processing Factors from Tomato Processing Study
with Fenpyroximate.

Processed Commodity	Fenpyroximate	M1	Fenpyroximate + M1

Tomato paste	<0.69x	NC	<0.89x

Tomato puree	<0.41x	NC	<0.57x

Conclusions:  The submitted tomato processing data are adequate to
satisfy data requirements.  The processing data indicate that residues
of fenpyroximate per se did not concentrate in tomato paste or puree as
all processing factors were <1.0x.  Residues of the Z-isomer (Metabolite
M1) did not concentrate in tomato puree; however, residues of M1
concentrated slightly in tomato paste (processing factor of <1.3x from
the NY sample).  When residues are combined, the average processing
factors were <0.89x for tomato paste and <0.57x for tomato puree.  Based
on these data, tolerances are not needed for tomato processed
commodities.

Confined Accumulation in Rotational Crops

The crops (fruiting vegetables, melons, cucumbers, and okra) proposed
under the current petition may be rotated.  No new confined rotational
crop data were submitted with this petition.  An acceptable confined
rotational crop study was previously submitted in support of the
tolerance petition for uses on pome fruits, cotton, and grapes (PP#s
0F06437 and 0E06519; DP#s 291925 and 291926, 8/20/03, G. Kramer;
45649913.der.wpd).  In the study, lettuce, radish, and wheat were
planted 30, 120, and 365 days following treatment of sandy loam soil at
0.2 lb ai/A.  The application rate used in the study is 1-2x the
proposed maximum seasonal rate to the crops addressed in this petition. 

The rotational crop data indicated that fenpyroximate-related residues
were <0.01 ppm in all samples of rotated lettuce, radish, and wheat
planted at 30-, 120-, and 365-day plant-back intervals (PBIs) except
wheat straw from the 120-day PBI.  The proposed 30-day plant-back
interval on the product labels is appropriate.

International Considerations

Codex and Mexican maximum residue limits (MRLs) are established for
residues of fenpyroximate per se in/on several crop commodities but not
for the crops requested.  Harmonization with the other Codex and Mexican
MRLs is not possible because the U.S. tolerance expressions include
additional metabolites/isomers.  There are currently no established
Canadian MRLs.

Summary of Proposed and Recommended Tolerances:  

The submitted residue data for fruiting vegetables (bell pepper,
non-bell pepper, and tomato) and cucumbers were entered into the
tolerance spreadsheet as per Agency’s Guidance for Setting Pesticide
Tolerances Based on Field Trial Data in order to determine appropriate
tolerance levels.  The submitted residue data for cantaloupe were not
entered into the tolerance spreadsheet because all treated samples bore
combined residues below the LOQ of 0.05 ppm.

For the representative members of the fruiting vegetables, the
spreadsheet recommends tolerances of 0.20 ppm for tomato, 0.10 ppm for
bell pepper, and 0.20 ppm for non-bell pepper.  Since the recommended
tolerances differ by less than 5x, a crop group tolerance of 0.20 ppm
will be appropriate for fruiting vegetable, crop group 8.  This
recommendation is identical to the tolerance level proposed by the
petitioner for fruiting vegetables.

For okra, the submitted residue data for pepper and tomato will be
translated to support the proposed tolerance of 0.20 ppm for residues
in/on okra.

For cucumber, the spreadsheet recommends a RAC tolerance of 0.06 ppm. 
However, the appropriate RAC tolerance is 0.10 ppm (the LOQ of the
enforcement method for combined residues).  A revised Section F is
required to amend the proposed tolerance for residues in/on cucumber
from 0.05 ppm to 0.10 ppm.

For cantaloupe, a revised Section F is required to amend the proposed
tolerance residues in/on melon subgroup 9A, from 0.03 ppm to 0.10 ppm.

A summary of recommended tolerances for the current petition is listed
in Table 4.3.1.6.

Table 4.3.1.6.  Tolerance Summary for Fenpyroximate.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;

Correct Commodity Definition

Vegetable, fruiting, group 8	0.20	0.20

	Okra	0.20	0.20

	Melon subgroup 9A	0.03	0.10	A revised section F is required.

Cucumber	0.05	0.10	A revised section F is required.

4.3.2	Dietary-Exposure Analyses

Dietary risk assessment incorporates both exposure and toxicity of a
given pesticide.  For acute and chronic assessments, the risk is
expressed as a percentage of a maximum acceptable dose.  This is the
PAD, which HED has concluded will result in no unreasonable adverse
health effects. The PAD is the RfD divided by the FQPA SF.  Dietary risk
is expressed as a percentage of the PAD.  HED is concerned when
estimated dietary risk exceeds 100% of the PAD.  References which
discuss the acute and chronic risk assessment in more detail are
available on the EPA/pesticides web site:  Available Information on
Assessing Exposure from Pesticides, A User’s Guide, 6/21/2000, web
link:  http://www.epa.gov/fedrgstr/EPA-PEST/2000/July/Day-12/6061.pdf ;
or see Standard Operating Procedure (SOP) 99.6 (8/20/99).

The acute and chronic dietary-exposure assessments were conducted using
the DEEM-FCID(, Version 2.02, which incorporates consumption data from
USDA’s CSFII, 1994-1996 and 1998.  The 1994-96, 98 data are based on
the reported consumption of more than 20,000 individuals over two
non-consecutive survey days.  Foods “as consumed” (e.g., apple pie)
are linked to EPA-defined food commodities (e.g. apples, peeled fruit -
cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S,
baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA.  For chronic-exposure assessment,
consumption data are averaged for the entire U.S. population and within
population subgroups, but for acute exposure assessment are retained as
individual consumption events.  Based on analysis of the 1994-96, 98
CSFII consumption data, which took into account dietary patterns and
survey respondents, HED concluded that it is most appropriate to report
risk for the following population subgroups: the general U.S.
population, all infants (<1 year old), children 1-2, children 3-5,
children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+
years old.

For chronic dietary-exposure assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form.  The resulting residue
consumption estimate for each food/food form is summed with the residue
consumption estimates for all other food/food forms on the commodity
residue list to arrive at the total average estimated exposure. 
Exposure is expressed in mg/kg body-weight/day and as a percent of the
cPAD.  This procedure is performed for each population subgroup.

For acute exposure assessment, individual one-day food consumption data
are used on an individual-by-individual basis.  The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or matched in multiple random
pairings with residue values and then summed in a probabilistic
assessment.  The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., those who reported eating
relevant commodities/food forms) and a per-capita (i.e., those who
reported eating the relevant commodities as well as those who did not)
basis.  In accordance with HED policy, per capita exposure and risk are
reported for all Tiers of analysis.  However, for Tiers 1 and 2,
significant differences in user vs. per capita exposure and risk are
identified and noted in the risk assessment.

4.3.2.1  Acute and Chronic Dietary-Exposure Analyses

HED’s level of concern is when the exposure is greater than 100% of
the PAD.  That is, estimated exposures above this level are of concern,
while estimated exposures at or below this level are not of concern. 
The DEEM-FCID( analysis estimates the dietary exposure of the U.S.
population and 26 population subgroups.  The results reported in Table
4.3.2.1.1 and 4.3.2.1.2 are for the U.S. Population, all infants (<1
year old), children 1-2, children 3-5, children 6-12, youth 13-19,
females 13-49, males 20-49, and adults 50+ years, when appropriate.

The acute and chronic analyses employed tolerance-level residues for all
commodities, 100% CT and DEEM( (ver. 7.81) default processing factors
were assumed 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).

An acute dietary-exposure assessment was conducted for females 13-49
years old.  Since an effect of concern attributable to a single dose in
the toxicity studies was not identified for the general U.S. population,
an acute dietary-exposure assessment was not performed for subgroups
other than females 13-49 years old.  This assessment (see Table
4.3.2.1.1) concludes that the acute dietary-exposure estimate is below
HED’s level of concern (<100% aPAD) for females 13-49 years old (6.6 %
aPAD).

A chronic dietary-exposure assessment was conducted for the general U.S.
population and various population subgroups.  This assessment (see Table
4.3.2.1.2) concludes that the chronic dietary-exposure estimates are
below HED’s level of concern (<100% cPAD) for the general U.S.
population (12% cPAD) and all population subgroups.  The most
highly-exposed population subgroup is children 1-2 years old at 38%
cPAD.

Table 4.3.2.1.1.  Summary of Acute Dietary Exposure and Risk for
Fenpyroximate at the 95th Percentile.

Population Subgroup	aPAD (mg/kg/day)	Exposure (mg/kg/day)	%aPAD

Females 13-49 years old	0.05	0.003299	6.6

Table 4.3.2.1.2.  Summary of Chronic Dietary Exposure and Risk for
Fenpyroximate.

Population Subgroup	cPAD (mg/kg/day)	Exposure (mg/kg/day)	%cPAD

General U.S. Population	0.01	0.001157	12

All Infants (< 1 year old)

0.001940	19

Children 1-2 years old

0.003761	38

Children 3-5 years old

0.002922	29

Children 6-12 years old

0.001511	15

Youth 13-19 years old

0.000691	6.9

Adults 20-49 years old

0.000881	8.8

Adults 50+ years old

0.000991	9.9

Females 13-49 years old

0.000824	8.2

** The values for the highest exposed population are bolded.

4.4  Water Exposure/Risk Pathway

The MARC Committee decided that in addition to the parent compound,
metabolites M1 and M3 should be included in the drinking water
assessment for fenpyroximate.  Based on the proposed application rates
and the environmental fate properties of fenpyroximate, some surface and
ground water contamination may occur.  However, the risk of water
contamination from parent compound is relatively low, based on its high
sorption potential.  Unlike parent compound, the sorption of the M3
metabolite is much less, and it may move into water resources more
readily.  

Ground and Surface Water EDWCs

The estimated drinking water concentrations (EDWCs) were Tier 1
estimates for ground water using the SCI-GROW model and surface water
using the FIRST model for fenpyroximate and its degradates, M1 and M3. 
The models utilized an application rate of 0.2 lb ai/A with 2
applications per season.  EDWCs of 0.00874 ppm and 0.00051 ppm were used
in the acute and chronic analysis, respectively. 

Table 4.4.1.  Modeling Results for Use of Fenpyroximate, M1, and M3 on
Fruiting Vegetables.

Chemical	Surface Water (ppb)	Groundwater (ppb)

	Acute	Chronic	Acute and Chronic

Fenpyroximate, M1 and M3	8.74	0.51	0.001

4.5  Residential/Non-Occupational Exposure Pathway

The proposed use is on agricultural crops; therefore, there is no
potential for residential exposure. In addition, there are no proposed
or existing fenpyroximate products registered for residential use sites.
 However, 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( 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.

5.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

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 which result in residential exposures.  A
cancer aggregate-risk assessment was not performed because fenpyroximate
is not carcinogenic.  

6.0  CUMULATIVE RISK

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
(available information( concerning the cumulative effects of a
particular pesticide's residues and other substances that have a common
mechanism of toxicity. 

EPA does not have, at this time, available data to determine whether
fenpyroximate has a common mechanism of toxicity with other substances. 
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/.

7.0  OCCUPATIONAL EXPOSURE AND RISK ASSESSMENT

7.1  Handler Exposure and Risk Assessment

This risk assessment relies in part on data from the PHED studies, in
which adult human subjects were intentionally exposed to a pesticide or
other chemical.  These studies have been reviewed and have been
determined to be ethical.

Table 7.1.1 summarizes the proposed use patterns and formulations
specified in the end-use products containing fenpyroximate.  The label
directions for the FujiMite® Miticide/Insecticide

(EPA Reg. No. 71711-19) recommend an application rate of 2 pints per
acre or 0.1 lb ai/A for cantaloupe, tomato, pepper, eggplant, and okra. 
The label does not provide an application interval and states to apply
no more than two applications per crop season.  The label directions for
Akari ®5SC Miticide/ Insecticide (EPA Reg. No. 71711-4) also recommend
an application rate of 2 pints per acre or 0.105 lb ai/A for greenhouse
cucumbers.  The label does not provide an application interval and
states to apply no more than two applications per crop season. 
Application by airblast was assessed because it is on the proposed
label; however, this is not a typical application for these types of
crops.

Table 7.1.1.  Proposed Use Patterns and Formulations

Product	Formulation	Use Sites	Application Rates	Application Equipment
PHI	Max App Rate per crop season	Proposed Label REI

FujiMite®

Miticide/

Insecticide

EPA Reg. No. 71711-19	Emulsifiable Concentrate	Cantaloupe	0.1 lb ai/A
Airblast, Groundboom	3 day	0.2 lb ai/A	12 hours

Tomato, pepper, eggplant, okra	0.1 lb ai/A	Airblast, Groundboom	1 days
0.2 lb ai/A

	Akari ®5SC Miticide/

Insecticide EPA Reg. No. 71711-4	Soluble Concentrate	Greenhouse
cucumbers	0.1 lb ai/A	Backpack sprayer, High pressure handwand	7 days
0.1 lb ai/A	12 hours

There is potential for occupational handler and postapplication exposure
from the proposed uses on agricultural crops. It is anticipated that the
following scenarios could result in handler exposure:

	Mixer/Loaders:

		1a) 	Mixing/Loading Liquids for Airblast Applications (PHED);

		1b) 	Mixing/Loading Liquids for Groundboom Applications (PHED);

Applicators:

		2)   	Applying Sprays via Airblast Equipment (PHED);

		3)   	Applying Sprays via Groundboom Equipment (PHED); 

Mixer/Loader/Applicator

4)   	Mixing/Loading/Applying Liquid with a high Pressure Handwand (only
study in PHED is for greenhouse use); and

		5)   	Mixing/Loading/Applying Liquid with a Backpack (PHED).

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED
(August, 1998). For pesticide handlers, HED presents estimates of dermal
exposure for “baseline” (i.e., workers wearing a single layer of
work clothing consisting of a long-sleeved shirt, long pants, shoes plus
socks, and no protective gloves), as well as for “baseline” and the
use of protective gloves or other personal-protective equipment (PPE),
as might be necessary. The fenpyroximate product labels direct
applicators and other handlers to wear a long-sleeve shirt, long pants,
protective eyewear, chemical-resistant gloves, and shoes plus socks. 
For overhead exposure, the product label directs the applicator and
other handlers to wear chemical-resistant headgear.

Handler exposure is expected to be short- and intermediate-term based on
information provided on proposed labels.  The average adult body-weight
of 70 kg was used for estimating inhalation and dermal dose.  Long-term
exposures are not expected; therefore, a long-term assessment was not
conducted.

Daily dermal or inhalation handler exposures are estimated for each
applicable handler task with the application rate, the area treated in a
day, and the applicable dermal or inhalation unit exposure using the
following formula:

Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x
Application Rate (lbs ai/area) x Daily Area Treated (area/day)

Where:  

Daily Exposure		=	Amount (mg ai/day) deposited on the surface of the
skin that is available for dermal absorption or amount inhaled that is
available for inhalation absorption;

Unit Exposure 		=	Unit exposure value (mg ai/lb ai) derived from August
1998 PHED data;

Application Rate		=	Normalized application rate based on a logical unit
treatment, such as acres; and

	Daily Area Treated 	=	Normalized application area based on a logical
unit treatment such as acres (A/day). 

The daily dermal or inhalation dose is calculated by normalizing the
daily exposure by body-weight and adjusting, if necessary, with an
appropriate dermal or inhalation absorption factor using the following
formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x
(Absorption Factor (%/100)) / Body-weight (kg)

Where:

Average Daily Dose 		= 	Absorbed dose received from exposure to a
pesticide in a given scenario (mg ai/kg body-weight/day);

Daily Exposure 			=	Amount (mg ai/day) deposited on the surface of the
skin that is available for dermal absorption or amount inhaled that is
available for inhalation absorption;

Absorption Factor 		= 	A measure of the amount of chemical that crosses
a biological boundary such as the skin or lungs (% of the total
available absorbed); and

Body-weight 			= 	Body-weight determined to represent the population of
interest in a risk assessment (kg).

Non-cancer dermal and inhalation risks for each applicable handler
scenario are calculated using a MOE, which is a ratio of the NOAEL to
the daily dose.  All MOE values were calculated using the formula below:

MOE= NOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

Table 7.1.2 presents the estimated risks for workers based on the short
and intermediate-term dermal and inhalation exposures at baseline and
with additional PPE.  HED has determined that risks are not of concern
(i.e., MOEs>100). 



Table 7.1.2.  Occupational Handler Dermal and Inhalation Exposures and
Risks.

Dermal and

Inhalation Unit Exposures

(mg/lb ai)	Application rate

(lb ai/A)a	Area Treated Daily (A)b	Short- and Intermediate-term Doses
(mg/kg/day)c	Short- and Intermediate-term MOEsd

Short	Intermediate

Mixer/Loader – Airblast Application

Dermal

Baselinee: 2.9 (HC)h

Inhalation

Baselinef   0.0012 (HC)	0.1	40	Dermal

Baseline: 0.17	Dermal

Baseline: 1800

	Inhalation

Baseline: 0.000069	Inhalation

Baseline: 29,000	Inhalation

Baseline: 22,000

Mixer/Loader – Groundboom Application

Dermal

Baseline: 2.9 (HC)

Inhalation

Baseline: 0.0012 (HC)	0.1	80	Dermal

Baseline: 0.33	Dermal

Baseline: 910

	Inhalation

Baseline: 0.000137	Inhalation

Baseline: 15,000	Inhalation

Baseline: 11,000

Applicator –Airblast Application

Dermal

Baseline: 0.36 (HC)

Inhalation

Baseline: 0.0045 (HC)	0.1	40	Dermal

Baseline: 0.020	Dermal

Baseline: 15,000

	Inhalation

Baseline: 0.00026	Inhalation

Baseline: 7,800	Inhalation

Baseline: 5,800

Applicator –Groundboom Application

Dermal

Baseline: 0.014 (HC)

Inhalation

Baseline: 0.00074 (HC)	0.1	80	Dermal

Baseline: 0.0016	Dermal

Baseline: 187,500

	Inhalation

Baseline: 0.000085	Inhalation

Baseline: 24,000	Inhalation

Baseline: 18,000

Mixer/Loader/Applicator – High Pressure Handwand

Dermal

Baseline: No Data

Single layer w/glovesg 2.5 (LC)

Inhalation

Baseline: 0.12 (LC)	0.105	10 i	Dermal

Single layer w/gloves: 0.038	Dermal

Single layer w/gloves: 7,900

	Inhalation

Baseline: 0.0018	Inhalation

Baseline: 1,100	Inhalation

Baseline: 830

Mixer/Loader/Applicator – Backpack

Dermal

Baseline: No Data

Single layer w/gloves 2.5 (LC)

Inhalation

Baseline: 0.3 (LC)	0.105	0.4ij	Dermal

Single layer w/gloves: 0.0015	Dermal

Single layer w/gloves: 200,000

	Inhalation

Baseline: 0.000018	Inhalation

Baseline: 110,000	Inhalation

Baseline: 8,300

a	Application rates are the maximum (single) recommended rates provided
on the fenpyroximate product labels.

b	Area treated per day and amount handled values are HED estimates based
on ExpoSAC Policy #9 “Standard Values for Daily Acres Treated in
Agriculture,” industry sources, and HED estimates.

c	Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre) x
Area Treated (acres/day) x %Absorption (100% dermal and 100% inhalation
assumed) / Body-weight.  The body-weight is 70 kg for the inhalation and
dermal dose. 

d	MOE = NOAEL/Dose; where the short- and intermediate-term dermal NOAEL
= 300 mg/kg/day.  The short-term inhalation NOAEL = 2 mg/kg/day and the
intermediate-term inhalation NOAEL = 1.5 mg/kg/day.

e	Baseline Dermal:  Long-sleeve shirt, long pants, and no gloves.

f	Baseline Inhalation: no respirator.

g	Single layer w/gloves: Single layer baseline attire plus
chemical-resistant gloves.

h	Data Confidence for PHED unit exposures: LC = Low Confidence, MC =
Medium Confidence, HC = High Confidence.

i.	1000 gal/day ÷ 100 gal/A = 10 A/day

j.	40 gal/day ÷ 100 gal/A = 0.4 A/day

7.2  Post-Application Exposure and Risk Assessment

HED expects that postapplication exposure will occur since fenpyroximate
is applied as a foliar spray.  Since no postapplication data were
submitted in support of this registration action, exposures during
postapplication activities were estimated using dermal transfer
coefficients from HED’s Exposure Science Advisory Council (ExpoSAC,
Policy Number 3.1) “Agricultural Transfer Coefficients” (August,
2000).  Table 7.2.1 summarizes the scenarios assessed.  In addition, the
following assumptions were used in the calculations: 

Assumptions:

Exposure Duration			=	8 hours per day

Body-weight				=	70 kg

Dermal Absorption			= 	100% 

Fraction of ai retained on foliage		=	assumed to be 20% on day zero (= %

dislodgeable foliar residue, DFR, after initial treatment).  This
fraction is assumed to further dissipate at the rate of 10% per day on
following days.  These are default values established by ExpoSAC.

Table 7.2.1: Anticipated Postapplication Activities and Dermal Transfer
Coefficients.

Proposed Crops	Policy Crop Group Category	Application Rate (lb ai/acre)
Transfer Coefficients (cm2/hr)	Activities

Cantaloupe	Vegetable cucurbit	0.1	500	Irrigation, scouting, thinning,
hand weeding

	1500	Irrigation, scouting, hand weeding

	2500	Hand harvest, hand pruning, thinning

Tomato, pepper, eggplant, okra	Vegetable, fruiting	0.1	500	Hand weeding,
hand pruning, irrigation

	700	Irrigation, scouting, thinning, hand weeding

	1000	Hand harvest, hand pruning, staking, thinning, training, tying

Greenhouse cucumbers	Vegetable cucurbit	0.105	500	Irrigation, scouting,
thinning, hand weeding

	1500	Irrigation, scouting,  hand weeding

	2500	Hand harvest, hand pruning, thinning

The information in the table is based on proprietary and non-proprietary
data.



Equations/Calculations:

The following equations were used to calculate risks for workers
performing post application activities:

DFRt( µg/cm2) = Application Rate (lb ai/acre) x F x (1-D)t  x 4.54E8
µg/lb X 2.47E-8 acre/cm2

Where:	

		DFRt 	=	dislodgeable foliage residue on day "t" (ug/cm2)

		Rate	=	application rate (lb ai/acre)

		F	=	fraction of ai retained on foliage (unitless)

		D	=	fraction of residue that dissipates daily (unitless)

Daily dermal exposures were calculated on each postapplication day after
application using the following equation:

		

Daily Dermal Doset  =  [DFRt (µg/cm2) x 0.001 mg/µg x Tc (cm2/hr) x DA
x ET (hrs)]  /  BW (kg)

		

Where,

		t	= 	number of days after application day (days)

		DFRt 	=	dislodgeable foliage residue on day "t" (ug/cm2)

		Tc	=	transfer coefficient (cm2/hr)	

		DAF	=	dermal absorption factor (100%)	

		ET	=	exposure time (8 hr/day)

		BW	=	body-weight (70 kg)

Note that the (TR(t)) input may represent levels on the day of
application in the case of short-term risk calculations.  Once daily
exposures are calculated, the calculation of daily absorbed dose and the
resulting MOEs use the same algorithms that are described above for the
handler exposures.  These calculations are completed for each day or
appropriate block of time after application.

HED has determined that risks are not of concern (i.e., MOEs>100) on the
day of treatment (i.e., Day 0) for all postapplication exposure
activities.  Table 7.2.2 presents a summary of occupational
postapplication risks associated with use of fenpyroximate. 

Table 7.2.2.  Postapplication Risks for Fenpyroximate

Crop	Application  Rate

(lb ai/A)	Contact Potential	Transfer Coefficient

(cm2/hr)	DFR (ug/cm2)	Days After Treatment	Daily Dose1

(mg/kg/ay)	MOE2

Vegetable, cucurbit

(Cantaloupe)	0.1	Low	Irrigation, scouting, thinning, hand weeding (500)
0.22	0

(12 hours)	0.013	23,000

Medium	Irrigation, scouting, thinning, hand weeding (1500)

	0.038	7,900

High	Hand harvest, hand pruning, thinning (2500)

	0.062	4,800

Vegetable, fruiting	0.1	Low	Hand weeding, hand pruning, irrigation (500)
0.22	0

(12 hours)	0.013	23,000

Medium	Irrigation, scouting, staking, tying, irrigation (700)

	0.018	17,000

High	Hand harvest, hand pruning, staking, thinning, training, tying
(1000)

	0.025	12,000

Vegetable curcurbit (Greenhouse cucumber)	0.105	Low	Irrigation,
scouting, thinning, hand weeding (500)	0.24	0

(12 hours)	0.013	23,000

Medium	Irrigation, scouting, hand weeding (1500)

	0.041	7,300

High	Hand harvest, hand pruning, thinning (2500)

	0.068	4,400

The information in the table is based on proprietary and non-proprietary
data.

1:  Daily Dose = [DFR (ug/cm2) x Tc (cm2/hr) x 0.001 mg/µg x Dermal
Absorption (100) x 8 hrs/day] ÷ Body-weight (70 kg)

2:  NOAEL/Daily Dose (Short- and Intermediate-term NOAEL = 300
mg/kg/day)

7.3  REIs

Fenpyroximate is classified as Toxicity Category II for acute oral,
acute dermal and acute inhalation; 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 postapplication 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.  HED recommends that all
fenpyroximate labels have an REI of 24 hours.  

8.0 DATA DEFICIENCIES

8.1  Residue Chemistry

Revised Sections B and F:

A revised Section B (Directions for Use) is required to clarify the
proposed use on greenhouse-grown cucumbers.  The maximum seasonal rate
of 0.1 lb ai/A is inconsistent with the label specification that two
applications may be made at 0.1 lb ai/A per application.  The submitted
data will support only one application at 0.1 lb ai/A per growing
season.  In addition, the label directions regarding use of ultra-low
volume equipment on greenhouse cucumbers should be deleted since no data
reflecting this application equipment was conducted on any cucumber
trials.  Also, the labels should be revised to prohibit use of adjuvants
on the subject crops as residue data were not provided to support their
use.

The petitioner is required to submit a revised Section F to amend the
proposed tolerances for:  (i) melon subgroup 9A, from 0.03 ppm to 0.10
ppm; and (ii) cucumber, from 0.05 ppm to 0.10 ppm.

Deficiencies To Be Satisfied Prior To Granting Permanent Registrations:

  SEQ CHAPTER \h \r 1 860.1340 Residue Analytical Method - Plant
Commodities

The available enforcement analytical method data should be upgraded to
support the expanded uses of fenpyroximate proposed under the current
petition.  The method should be rewritten to include instructions for
the analysis of fruiting vegetable, okra, melon, and cucumber.

The requirement for an interference study demonstrating the specificity
of the enforcement method, or a specific confirmatory method (e.g., use
of MS detection) remains outstanding.  If the petitioner can validate
LC/MS/MS Method AJW/03/01 on the registered crops and the crops
addressed in this petition, then this requirement will be fulfilled.

Clarifications are required for the analytical methods used for pepper
and cantaloupe.  Due to the potential for isomerization between
fenpyroximate and its Z-isomer in peppers and cantaloupes, the results
were reported as combined residues (with both analytes determined as the
Z-isomer).  Although the method used for peppers and cantaloupes did not
differ significantly in procedure from the original enforcement
analytical method, the petitioner stated that for analysis of the
subject commodities, fenpyroximate was converted to the Z-isomer in the
injector area of the GC; however, it is noted that this conversion was
not always complete, as shown by the presence of a double peaks in
several of the sample chromatograms.  The petitioner should provide
further explanation for this observation, addressing whether conversion
to the Z isomer is specific to certain crop commodities such as
cantaloupe and pepper or was the result of the instrument conditions
used for analysis of subject commodity samples.

  SEQ CHAPTER \h \r 1 860.1650 Submittal of Analytical Reference
Standards

Analytical standards for fenpyroximate (with expiration date of 12/6/08)
and its Z-isomer (with expiration date of 6/21/10) are currently
available in the EPA National Pesticide Standards Repository.  Since the
standards for fenpyroximate are about to expire, the petitioner is
requested to provide a new supply to the Repository.  The reference
standards should be sent to the Analytical Chemistry Lab, which is
located at Fort Meade, to the attention of Theresa Cole at the following
address:

		USEPA

		National Pesticide Standards Repository/Analytical Chemistry
Branch/OPP

		701 Mapes Road

		Fort George G. Meade, MD  20755-5350

(Note that the mail will be returned if the extended zip code is not
used.)

8.2  Occupational Exposure

860.1200 Directions for Use

Fenpyroximate is classified as Toxicity Category II for acute oral,
acute dermal and acute inhalation; 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 postapplication 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.  HED recommends that all fenpyroximate labels have an REI
of 24 hours.  

8.3  Toxicology

As a result of 2007 revisions to 40 CFR §158):

Immunotoxicity study

Acute neurotoxicity study (in rats)

Subchronic neurotoxicity study (in rats)

RDI: RAB1:  12/17/2008

Petition Number:  PP#8E7365

DP Number:  354305

PC Code:  129131

WDWassell:S10316:Potomac Yard:703-305-6135:7509P:RAB1

Appendix 1:  Acute Toxicity Profile

Table A.2  Acute Toxicity of Fenpyroximate.

Guideline

No.	Study Type	MRID #s	Results	Toxicity Category

81-1	Acute oral—rat	43560501	LD50 = 450 mg/kg males

LD50 = 245 mg/kg females

LD50 = 350 mg/kg combined	II

81-2	Acute dermal—rat	44847901	LD50 > 2,000 mg/kg	III

81-3	Acute inhalation–rat	44847902	LC50 = 0.24 mg/L (male)

LC50 = 0.37 mg/L (female)

LC50 = 0.35 mg/L (combined)	II

81-4	Acute eye irritation—rabbit	44781004	Not a ocular irritant.	IV

81-5	Acute dermal irritation—rabbit	44781005	Not a dermal irritant.	IV

81-6	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

Appendix 2:  Toxicity Profile

Table A.2.  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 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.

870.3700a

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 can not 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

 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 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

萘

 

I

o

p

’

“

·

Ð

Ó

Õ

Ù

Ú

Ý

æ

ò

I

p

“

Ü

Ý

਀Ý

j

␃ഃࣆȀᥐ᪸

@

¶

¶

$

b	8

$

b	8

$

b	8

$

b	8

H*  h

 h

  h

 h

 h

 h

 h

 h

 h

 h

  h

H*

 h

  h

 h

 h

 h

 h

h

h

  h

 h

 h

 h

h

  h

 h

 h

H*

 h

h

  h

 h

h

h

 h

 h

 h

 h

 h

 h

Q

S

^

_

㄀Ĥ摧偬ßЀ_

a

¢

¹

º

¿

Ì

Í

Î

Ý

Þ

$

%

<

I

J

b

o

p

†

“

”

«

¬

*u

†

›

¡

¢

@

¢

º

¿

È

Ì

@

@

@

@

@

a

b

k

o

p

摧偬ßЀp

…

†

“

¶

º

»

ø

@

@

º

»

÷

ø

ù

ˆÿ"

š

ˆÿ"

š

阂x혅ȘāȀāȀāȀāȀāȀāࠀ峖Ѐﾈ"

š

@

@

@

  h

 h

 h

”ÿÑ	I

©

 h

 h

”ÿÑ	I

©

$

”ÿÑ	I

©

”ÿÑ	I

©

”ÿÑ	I

©

 h

 h

”ÿÑ	I

©

”ÿÑ	I

©

 h

  h

 h

 h

”ÿÑ	I

©

”ÿÑ	I

©

  h

 h

@

$

h>

h>

h>

h>

옍)

@

@

@

@

$

@

@

옍)

h>

550

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.

870.7485

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), 5 rats/sex/dose were given
single oral doses of [pyrazole-14C] or [benzyl-14C] 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 dosed 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

摧s Ԁ

Risk Assessment		DP# 354305

Page   PAGE  1  of   NUMPAGES  39