 

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  >

Docket ID No.: EPA-HQ-OPP-2008-0556

<EPA Registration Division contact: Sidney Jackson (703) 305-7610) >

 

<Interregional Research Project Number 4(IR-4) >

<[Pesticide Petition # 8E7365]>

<	EPA has received a pesticide petition (PP# 8E7365) from Interregional
Research Project Number 4  (IR-4) 500 College Road East, Suite 201 W,
Princeton, NJ 08540,  proposing, pursuant to section 408(d) of the
Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to
amend 40 CFR part 180 by establishing a tolerance for residues residues
of the insecticide fenpyroximate, (E)-1,1-dimethylethyl
4-[[[[(1,3-dimethyl-  5-phenoxy-1H-pyrazol-4-yl)  methylene]
amino]oxy]methyl]  benzoate and its Z-isomer, (Z)-1,1-dimethylethyl
4-[[[[(1,3-dimethyl-5-
phenoxy-1H-  pyrazol-4-yl)methylene]  amino]oxy]  methyl]benzoate
in or on the following raw agricultural commodities:  vegetables,
fruiting, group 8 at 0.20 parts per million (ppm), okra at 0.20 ppm,
melon subgroup 9A 0.03 ppm, and cucumber at 0.05 ppm. EPA has determined
that the petition contains data or information regarding the elements
set forth in section 408 (d)(2) of  FDDCA; however, EPA has not fully
evaluated the sufficiency of the submitted data at this time or whether
the data support granting of the petition. Additional data may be needed
before EPA rules on the petition.  This summary has been prepared by
Nichino America, Inc., Wilmington, DE 19808, the registrant.>

<A. Residue Chemistry>

<	1. Plant metabolism. The metabolism of fenpyroximate and z-isomer has
been studied in cotton, apples, grapes, and citrus and is well
understood. The major residue in plants is fenpyroximate and z-isomer,
with very low levels of several degradates. Metabolism in plants
involves hydrolysis of the ester and methyleneamino ether links,
N-demethylation, oxidation, and conjugation of the polar metabolites.

	2. Analytical method. Based upon the metabolism of fenpyroximate in
plants and the toxicology of the parent and metabolites, quantification
of the parent, fenpyroximate and the z-isomer, combined as fenpyroximate
is sufficient to determine toxic residues in plants. As a result an
enforcement method has been developed which involves extraction of
fenpyroximate from crops with acetone, filtration, partitioning and
cleanup, and analysis by gas chromatography using a nitrogen/phosphorous
detector. The method has undergone independent laboratory validation as
required by PR Notice 88-5 and 96-1. 

>

<	3. Magnitude of residues. Magnitude of residues in crops-

Field residue trials meeting EPA study requirements have been conducted
at the maximum label rate for tomato, peppers, and melons.  Residue
analysis from cucumbers growing in the polytunnels/greenhouse from
several locations have been conducted at the maximum label rate and
requested PHI.  Results from these trials demonstrate that the highest
fenpyroximate and z-isomer residues found will not exceed the proposed
tolerances when the product is applied following the proposed use
directions. 

	4. Magnitude of the residue in animals--a. Ruminants. Maximum residues
of fenpyroximate, z-isomer, and acid metabolite in a cattle feeding
study demonstrate that the highest fenpyroximate, z-isomer, and acid
metabolite, combined as fenpyroximate will not exceed the proposed
tolerances in or on milk 0.01ppm; meat 0.02 ppm, fat 0.8 ppm, kidneys
and liver 0.5 ppm, and meat by-products 0.01 ppm in cattle, goats, hogs,
horses, sheep. After work-up, analysis of tissue and milk samples was by
GC/NPD. Additionally, liver and kidney extracts were analyzed by
LC/MS/MS.  GC/NPD Limits of Quantitation (LOQ) were 0.005 ppm in milk
and 0.01 ppm in other tissues.  LC/MS/MS limits of detection (LOD) were
0.003 ppm.   >

<B. Toxicological Profile>

<Acute toxicity.   “NA-Remove”>  

  

<	2. Genotoxicity. “NA-Remove”>

<	3. Reproductive and developmental toxicity. “NA-Remove”>

<	4. Subchronic toxicity. “NA-Remove”>

<	5. Chronic toxicity. “NA-Remove”>

1.  An extensive battery of toxicology studies has been conducted with
fenpyroximate.  EPA has evaluated the available toxicity data and
considered its validity, completeness, and reliability as well as the
relationship of the results of the studies to human risk  The nature of
the toxic effects caused by fenpyroximate is discussed in Unit III.A. of
the Final Rule on Fenpyroximate Pesticide Tolerance published in the
Federal Register on April 10, 2001 (66 FR 18561) (FRL-6773-2).   An
assessment of toxic effects caused by fenpyroximate including the
toxicological endpoints of concern is also discussed in Unit III.A. and
Unit III B. of the Federal Register dated June 10, 2004   (FRL-7362-9)
(89 FR 32457).

<	6. Animal metabolism. The qualitative nature of the residues of
fenpyroximate and its z-isomer, in animals is adequately understood.
Fenpyroximate was not metabolized to volatiles to any significant
degree.  The majority of either benzyl or pyrazole labels (approximately
70 % to 92 %) is excreted in the feces. Urinary excretion accounts for
less (approximately 9 % to 18 %) of the label.  Thus, feces and urine
are the major routes of excretion for fenpyroximate.  Tissue did not
accumulate fenpyroximate or its metabolites to any great extent.  The
greatest levels of label were in liver, kidneys, adrenals, and fat (to a
lesser degree).  In blood, nearly all of the label is in the plasma.   

	7. Metabolite toxicology. No toxicologically significant 

metabolites were detected in plant or animal metabolism studies for 

cotton, apples, or or grapes.    

8. Endocrine disruption. Chronic, lifespan, and multigenerational
bioassays in mammals and acute and subchronic studies on aquatic
organisms and wildlife did not reveal any endocrine effects for
fenpyroximate.  Any endocrine related effects would have been detected
in this comprehensive series of required tests.  The probability of any
such effect due to agricultural uses of fenpyroximate is negligible.

>

<C. Aggregate Exposure>

using LifeLine™ version 4.3.  Residue estimates for water consumption
were based on PRZM3/EXAMs and SCIGROW models and exposure assessments
using LifeLineTM version 4.3.  

	i. Food. The acute dietary exposure was based on the following
assumptions: residues at tolerance levels, 100% crop treated, and
DEEM™ (ver. 7.76) default processing factors for all
registered/proposed commodities (Tier 1).  The acute dietary aPAD (acute
population adjusted dose) was set at 0.05 mg/kg/day for females aged
13-50 years old based on a developmental toxicity study in rats that had
an oral NOEL of 5 mg/kg/day.  The chronic dietary exposure was based on
the following assumptions:  Residues at tolerance levels, 100% crop
treated, and using UDDA survey data where available.  The chronic
dietary cPAD (chronic Population Adjusted Dose) was determined to be
0.01 mg/kg/day for the general population, based on an oral NOAEL of
0.97 mg/kg/day in the two-year rat chronic/oncogenicity study.  An
additional 10x database uncertainty factor was applied.  The resultant
safety factor used to establish the cPAD was 100.  There was not likely
any evidence of carcinogenicity. 

Using tolerance values for exposure and a default value of 100% crop
treated, the resulting food exposure estimate for females 13-49 years
old was 11.3% of the acute RfD. No acute endpoint was identified for the
remaining population subgroups.  

	ii. Drinking water. The residue of concern in drinking water was
determined to be fenpyroximate and its z-isomer.  There are no
established maximum contaminant levels or health advisory levels for
residues of fenpyroximate in drinking water.  In the absence of
comprehensive water monitoring data, the Agency uses the FQPA Index
Reservoir Screening Tool or the Pesticide Root ZoneModel/Exposure
Analysis Modeling System (PRZM/EXAMS) to produce estimates of pesticide
concentrations in an index resevoir.   The SCI-GROW model is used to
predict pesticide concentrations in shallow ground water. For a
screening-level assessment for surface water EPA will use FIRST (a tier
1 model) before using PRZM/EXAMS (a tier 2 model). The FIRST model is a
subset of the PRZM/EXAMS model that uses a specific high-end runoff
scenario for pesticides. Both FIRST and PRZM/EXAMS incorporate an index
reservoir environment, and both models include a percent crop area
factor as an adjustment to account for the maximum percent crop coverage
within a watershed or drainage basin.

None of these models include consideration of the impact processing
(mixing, dilution, or treatment) of raw water for distribution as
drinking water would likely have on the removal of pesticides from the
source water. The primary use of these models by the Agency at this
stage is to provide a screen for sorting out pesticides for which it is
unlikely that drinking water concentrations would exceed human health
levels of concern.

The estimated drinking water concentrations (EDWCs) in surface water
were determined using the Tier II PRZM (Pesticide Root Zone Model) and
EXAMS (Exposure Analysis Modeling System (PE4-PL, version 01).  PRZM is
used to simulate pesticide transport as a result of runoff and erosion
and spray drift from an agricultural field and EXAMS estimates
environmental fate and transport of pesticides in surface water.  The
EPA estimated that based on the maximum use pattern of two applications
to Georgia pecans for the acute and the chronic and long-term estimates.
 The acute EDWCs are 12.9 ppb, and for chronic 1.8 ppb.  In ground
water, using Tier I SCI-GROW, the acute level and chronic level is 0.059
ppb. Concentrations in actual drinking water would be much lower than
the levels predicted in the hypothetical, small, stagnant farm pond
model since drinking water derived from surface water would normally be
treated before consumption. Based on these analyses, the contribution of
water to the dietary risk estimate is negligible. Therefore, based on
the dietary and drinking water assessments, aggregate exposure to
residues of fenpyroximate and its z-isomer in food and water can be
considered to be negligible.

 >

<	2. Non-dietary exposure.  The term residential exposure is used in
this document to refer to non-occupational, non-dietary exposure (e.g.
for lawn and garden pest control, indoor pest control, termiticides, and
flea and tick control on pets). Fenpyroximate is not registered for use
on any sites that would result in residential exposure. 

>

<D. Cumulative Effects 

Fenpyroximate is a mitochondrial electron transport inhibitor acting at
Site I, which is similar to pyridaben, but quite different than other
established acaricides.  All relevant toxicological data has been
provided to the EPA.  A determination has not been made that
fenpyroximate has a common mechanism of toxicity with other substances. 
Fenpyroximate does not appear to produce a common toxic metabolite with
other substances. Therefore, for the purposes of this notice of filing,
there should be no consideration of cumulative risk that would require
assessment.  

>

<E. Safety Determination>

<	1. U.S. population.

 i. Acute risk.  Using the conservative assumptions discussed above,
based on the completeness and reliability of the toxicity data, it is
concluded that aggregate exposure to the proposed uses of fenpyroximate
are estimated at 0.007 mg/kg/day and will utilize at most 11.3% of the
acute reference dose of females (13-49).  This estimate is likely to be
much less, as more realistic data and models are developed.  Drinking
water and other water consumption (EDWC of 12.9 ppb) scenarios were
included in the dietary risk assessment modeling.  

>

ii. Chronic Risk.  Based on the toxicology data base and available
information on anticipated residues, the chronic dietary exposure to the
U.S. Population (total) was estimated to be 0.00168 mg/kg/day and was
16.8 % of the estimated chronic population adjusted dose (cPAD).
Drinking water and other potential water consumption scenarios (EDWC of
1.8 ppb) were included in the dietary risk assessment modeling. Based on
these assessments, it can be concluded that there is reasonable
certainty of no harm to the U.S. Population or any population subgroup
from exposure to fenpyroximate.

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o be protective of infants and children.  EPA generally has no concern
for exposures below 100% of the cPAD. The Agency has considered the
potential aggregate exposure from food, water and non-occupational
exposure routes and has concluded aggregate exposure is not expected to
exceed 100% of the chronic reference dose, and consequently, has
determined there is a reasonable certainty that no harm will occur to
infants and children from aggregate exposure to residues of
fenpyroximate.

>

<F. International Tolerances>

<Canada, Codex, and Mexico do not have maximum residue limits for
residues of fenpyroximate in/on the proposed crops.  Therefore,
harmonization is not an issue. >

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