Document ID: EPA-HQ-OPP-2014-0209-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-01-28T05:00Z

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

<EPA Registration Division contact: Mark Suarez (703-305-0120) >

 

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.>

<TEMPLATE:>

<Bayer CropScience LLC>

<[Insert petition number]>

EPA has received a pesticide petition ([insert petition number]) from
Bayer CropScience LLC, 2 T. W. Alexander Drive, Research Triangle Park,
NC 27709 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 of  deltamethrin [(1R,
3R)-3(2,2-dibromovinyl)-2,2-dimethylcyclopropane-carboxylic acid
(S)-alpha-cyano-3-phenoxybenzyl ester] and its major metabolites
trans-deltamethrin [(s)-alpha-cyano-3-phenoxybenzyl-(1R, 3S)
-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate] and
alpha-R-deltamethrin [(R)-alphacyano-3-phenoxybenzyl-(1R,
3R)-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate]: in or on
food and feed commodities at 0.05 ppm following wide-area mosquito
adulticide applications.  EPA has determined that the petition contains
data or information regarding the elements set forth in section 408
(d)(2) of the FDDCA; however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. The metabolism of deltamethrin in plants is well
understood. Deltamethrin metabolism studies in tomatoes, corn, apples,
and cotton demonstrate the same metabolic pathway. The residues of
concern are the parent cis-deltamethrin, and its isomers,
trans-deltamethrin and alpha-R-deltamethrin. 

	2. Analytical method.  Residues of deltamethrin (cis and trans isomers)
were extracted from homogenous 10-g samples of alfalfa forage, lettuce
leaves, and grass forage using acetone/n-hexane/ dichloromethane as the
extraction solvent.   Homogenous 5-g samples of alfalfa hay and grass
hay were soaked in water overnight prior to extraction. Residues of
cis-deltamethrin and trans-deltamethrin were extracted using acetone/
n-hexane/dichloromethane as the extraction solvent with sonication.
Samples were then filtered before an IS solution was added.  After
evaporation of the organic phase to dryness, the dry residue was taken
up with toluene.  An aliquot of the toluene extract was concentrated to
dryness and dissolved in dichloromethane/acetone, followed by solid
phase extraction (SPE) clean up with Varian MEGA BE SCX-2 GM cartridges.
 The extracts were again concentrated to dryness and dissolved in
aqueous acetonitrile/10 mM ammonium acetate before analysis by
HPLC/MS/MS.

HPLC separation was performed with an Ascentis Express C18, 2.7 µm, 150
mm × 3 mm HPLC column.  

Quantitation of each analyte was based on the daughter ion transitions
of the analyte and the respective internal standard analog.  The
responses of LC/MS/MS system to each analyte and its internal standard
were measured in samples and in standards, and a relative response was
calculated (calculated as the ratio of the analyte and the stable
isotopically labeled internal standard responses).  The relative
response of the analyte in each sample was compared to the relative
response of the analyte in the standards.

The total deltamethrin residue is the sum of the individual measured
residue of cis-deltamethrin and trans-deltamethrin.

All applications were made with ULV misters that produced droplets
typical of commercial equipment (≥80% of the droplets were <20 µm in
diameter).   Results:

Alfalfa;  Based on the average residues in alfalfa forage, residues
would be expected to remain below 0.050 ppm following multiple
treatments at either rate.  At the 1.5 g ai/acre/application treatment
rate, total residues varied from  0.0174 ppm to 0.1205 ppm with the
average residues remaining below 0.080 ppm at all time points.  Since
the dried matrix of alfalfa hay is only used for animal feed, secondary
residues in meat milk, and eggs arising from this use at either rate
would be expected to be negligible.

Leaf Lettuce; At both the 0.75 g ai/acre/application and the 1.5 g
ai/acre/application treatment rates, all residues in leaf lettuce at all
time points were below the current food use tolerance (<0.050 ppm). 
Based on the average residues in leaf lettuce, residues would be
expected to remain below 0.050 ppm following multiple treatments at
either rate. 

Grass;  Based on the average residues in grass forage, residues would be
expected to remain at or below 0.050 ppm following multiple treatments
at either rate.  At the 1.5 g ai/acre/application treatment rate, total
residues varied from  0.0298 ppm to 0.1495 ppm with the average residues
remaining below  0.1200 ppm at all time points.  

Since the dried matrix of grass hay forage is only used for animal feed,
secondary residues in meat milk, and eggs arising from this use at
either rate would be expected to be negligible.

B. Toxicological Profile

	1. Acute toxicity.  The acute oral toxic potency of deltamethrin
depends on the vehicle that is used, with an LD50 in rats that ranges
from 66.7 mg/kg (males) when administered in sesame oil to >5000 mg/kg
(both sexes) in an aqueous methylcellulose suspension.  Deltamethrin
technical is classified in Category II for acute oral and inhalation
toxicity, Category III for dermal toxicity and eye irritation and
Category IV for skin irritation.  Deltamethrin is not a skin sensitizer
but can cause transient paresthesia (a local itching, burning or
tingling sensation of the skin) following skin contact to sensitive
individuals.

	2. Genotoxicity.  There was no evidence of mutagenicity in a battery of
in vitro and in vivo studies with technical-grade deltamethrin.
Therefore, deltamethrin is classified as non-mutagenic.

	3. Reproductive and developmental toxicity. A rat development toxicity
study conducted with deltamethrin indicated a maternal NOEL of 3.3
mg/kg/day based on clinical observations, decreased weight gain and
mortality. The developmental NOEL was 11mg/kg/day (HDT).  

In a rabbit development toxicity study with deltamethrin, the maternal
NOEL was considered to be 10 mg/kg/day based on decreased body weights
at 32 mg/kg/day.  The developmental NOEL was > 32 mg/kg/day (HDT).  

In a developmental neurotoxicity study, the maternal NOAEL was 6.8 mg/kg
bw/day, based on decreased body weight, weight gain and food consumption
during gestation and decreased body weight and food consumption during
lactation noted at 16 mg/kg/day. The offspring NOAEL was 6.8 mg/kg
bw/day, based on delayed balanopreputial separation, reduced body weight
and weight gain before weaning for both sexes, with recovery after
weaning. There was no evidence of neurodevelopment effects at any dose
level.

In a two-generation rat reproduction study with deltamethrin the
parental NOAEL was 5.4 mg/kg/day based on clinical signs and increased
mortality. The offspring NOAEL was 5.8 mg/kg/day based on decreased body
weights, body weight gain and increased pup mortality. Deltamethrin was
not a reproductive toxicant.

	4. Subchronic toxicity. A 90-day rat oral toxicity study was conducted
with deltamethrin administered by gavage. The NOEL was 1.0 mg/kg/day
based on reduced body weight gain and slight hypersensitivity. In
another 90-day rat dietary study with deltamethrin, the NOEL was 300 ppm
(23.9 mg/kg/day for males, 30.5 mg/kg/day for females) based on
uncoordinated movement, unsteady gait, tremors, increased sensitivity to
sound, shakes and spasmodic convulsions. The difference in the NOEL
between the two studies is attributed to the different routes of
exposure (gavage in oil vs. administered in diet).

A 12-week study was conducted with deltamethrin in mice. The NOEL was
300 ppm (61.5 mg/kg/day in males and 77.0 mg/kg/day in females) based on
chronic contractions, convulsions, poor condition, decreased weight gain
and mortality. 

Two 13-week dog studies were conducted with deltamethrin. In the first
study, beagle dogs were administered deltamethrin by capsule using PEG
200 as a vehicle.  The NOEL for this study was 1 mg/kg/day based on
tremors, unsteadiness, jerking movements, salivation, vomiting, liquid
feces and/or dilation of the pupils. In the second study, deltamethrin
was administered by capsule without a vehicle to beagle dogs. The NOEL
for this study was 10 mg/kg/day based on unsteady gait, tremors, head
shaking, vomiting and salivation. The difference in toxicity between the
two studies is attributed to the enhanced absorption resulting from the
use of PEG 200 as a vehicle in the first study.  

A 21-day dermal toxicity study was conducted with deltamethrin in rats.
The NOEL for systemic toxicity was determined to be 1000 mg/kg/day.  In
a subchronic inhalation study, rats were exposed to aerosolized
deltamethrin for 6 hours per day, 5 days per week, for a total of 14
days over 3 weeks. Based on slightly decreased body weights and
neurological effects at higher dose levels, it was concluded that 3 pg/L
was the NOEC for systemic effects in this study.

	5. Chronic toxicity.  Deltamethrin was administered in the diet to
beagle dogs for 2 years. No treatment-related effects were observed and
the NOEL was judged to be 40 ppm (1.1 mg/kg/day). In another study,
deltamethrin was administered by capsule (without a vehicle) to beagle
dogs for 1 year. The NOEL in this study was determined at 1 mg/kg/day
based on clinical signs, decreased food consumption and changes in
several hematology and blood chemistry parameters.

Two rat chronic toxicity/oncogenicity studies were conducted with
deltamethrin. In the first study, the test substance was administered
via the diet to rats for 2 years.  The NOEL for this study was 20 ppm (1
mg/kg/day) based on slightly decreased weight gain. In a more recent
study, deltamethrin was administered to rats in the diet for 2 years.
The NOEL for this study was 25 ppm (1.1 and 1.5 mg/kg/day for males and
females, respectively) based on neurological signs, weight gain effects
and increased incidence of histopathological changes to the liver. No
evidence of carcinogenicity was noted in either study.

Two mouse oncogenicity studies were conducted with deltamethrin. In the
first study, deltamethrin was administered in the diet for two years. No
adverse effects were observed and the NOEL was 100 ppm (12 and 15
mg/kg/day, respectively, for males and females). In another study,
deltamethrin was administered in the diet to mice for 97 weeks. The NOEL
was 1000 ppm (15.7 and 19.6 mg/kg/day) based on a higher incidence of
poor physical condition and a slight transient weight reduction.  There
was no evidence of oncogenicity in either study.

6. Neurotoxicity.  Deltamethrin was administered by single gavage in
rats. The NOAEL was 5 mg/kg/day, based on salivation, soiled fur,
impaired mobility, no response to approach or touch in several animals
at 15 mg/kg. There was no evidence of neuropathological effects.  

In a subchronic neurotoxicity study, deltamethrin was administered in
the diet of rats for 13 weeks. The NOAEL was 15 mg/kg/day, based on
mortality, clinical signs of toxicity, FOB findings, and decreased body
weights, body weight gains, and food consumption at 56 mg/kg/day. There
was no evidence of neuropathological effects.

	7. Animal metabolism. The absorption of deltamethrin appears to be
highly dependent upon the route and vehicle of administration. Once
absorbed, deltamethrin is rapidly and extensively metabolized and
excreted, primarily within the first 48 hours, in feces and an
approximately equal amount in urine. Absorbed deltamethrin is cleaved by
hydrolysis at the ester site followed by rapid sulfate and glucuronide
conjugation.

	8. Metabolite toxicology.  N-A Remove

	9.  Endocrine disruption.  No special studies have been conducted to
investigate the potential of deltamethrin to induce endocrine effects.
However, the standard battery of required toxicity studies include an
evaluation of the potential effects on reproduction and development, and
an evaluation of the pathology of the endocrine organs following
repeated or long-term exposure. There is no evidence that deltamethrin
induces endocrine disruption.

C. Aggregate Exposure

	1. Dietary exposure.  As reported in the 2/17/2010 Human Health
Assessment Scoping Document, the dietary exposure database is adequate
to support the registration review of deltamethrin.  Addition of Wide
Area Mosquito Control use of deltamethrin should be covered by existing
food handling area tolerances.  Oral exposure to BES0668 Insecticide
product would be practically non-existent, because the product would not
be applied directly to food crops. Therefore, additional dietary
exposure would be negligible, such that there is no need to include this
use in the dietary assessment for deltamethrin. 

	2. Non-dietary exposure.  

a.  Occupational exposure

Deltamethrin for public health mosquito adulticide uses on food/feed
commodities are to be applied by PCOs only, using ULV aerial
applications. The potential exposures and associated risks for handlers
mixing, loading and applying deltamethrin as a mosquito adulticide are
based on the proposed label for BES0668 Insecticide (deltamethrin 2%
liquid formulation). The maximum application rate is 0.00134 lb ai/acre
per day, or 0.036 lb ai/acre per year.  A maximum of 25 applications are
allowed per year. 

Aerial mixer/loaders are expected to have the highest exposure potential
resulting from the occupational use of BES0668. There will be no
residential non-occupational applications. Unit dermal and inhalation
exposures of 37.6 µg/lb a.i. and 0.219 µg/lb a.i., respectively for a
mixer/loader wearing long pants, a long-sleeved shirt, and protective
gloves were obtained from the EPA Occupational Pesticide Handler Unit
Exposure Surrogate Reference Table March 2013 version. A mixer/loader
preparing spray solution to treat 1200 acres/day will handle 1.6 lb
a.i./day. The dermal and inhalation daily exposures for an 80-kg
individual are calculated as follows with a 1% dermal absorption.

Daily Dermal Exposure: 37.6 µg/lb a.i. x 1.6 lb a.i./day x 0.01 ÷ 80
kg = 0.0075 µg/kg/day

Daily Inhalation Exposure: 0.219 µg/lb a.i. x 1.6 lb a.i./day ÷ 80 kg
= 0.0044 µg/kg/day

The dermal and inhalation toxicity endpoints for risk assessment are 1.0
mg/kg/day and 0.9 mg/kg/day from the 90-day rat oral toxicity and the
21-day rat inhalation toxicity studies, respectively. The MOEs for
dermal and inhalation exposure are 133,000 for dermal exposure and
204,500 for inhalation exposure. Pilots and ground mixer/loaders and
applicators will have larger MOEs.

	b.  Residential (Non-occupational) exposure and risk

Since applications for public health mosquito control are to be made by
professional personnel (i.e., not residential) a residential handler
exposure assessment is not required; however, there are potential post
application exposures to adults and children from the ULV aerial
applications of etofenprox uses in the vicinity of residential
dwellings.  Based on spray drift residue deposition testing submitted
with this application, an adult whole body surface area is approximately
18,000 cm2 so that the spray drift potential exposure to an 80 kg adult
100 feet downwind would range from 6.3 µg/kg to 15 µg/kg.   Based on
the Agency’s 1% dermal absorption factor and the short-term dermal
exposure NOAEL of 1 mg/kg/day the MOEs for bystanders would range from
67,000 to 160,000 showing minimal risk potential from drift. It is
important to note that applications are not supposed to occur in a
manner that could directly exposure someone to the drift.  These
residues would yield MOEs for toddlers in excess of 1000 based on the
Residential SOP defaults.

D. Cumulative Effects

	Deltamethrin is a pyrethroid insecticide. In the cumulative risk
assessment for pyrethroids, the EPA determined that pyrethroids perturb
the kinetics of neuronal voltage-gated sodium ion channels (VGSC)
following an action potential in vertebrates as a common mode of action.
However, exposure to deltamethrin according to the proposed use pattern
is expected to be negligible and therefore would not contribute to
aggregate exposure or cumulative exposure assessment.  The Agency
currently retains a 3x FQPA safety factor for all pyrethroid
insecticides, as per the Cumulative Risk Assessment for Pyrethroids
(2012), based on evidence of underdeveloped clearance mechanisms in
neonatal rats reported in the published literature..

E. Safety Determination

	1. U.S. population. Based on the negligible potential for exposure and
completeness of the toxicology database, it can be concluded that
aggregate exposure to residues of deltamethrin present a reasonable
certainty of no harm.  The proposed mosquito adulticide use pattern will
produce only negligible dietary or drinking water exposures. Thus, there
is a reasonable certainty that the use of deltamethrin in BES0668
Insecticide as a mosquito adulticide will present no harm from aggregate
exposure.

	2. Infants and children.  FFDCA section 408 provides that EPA shall
apply an additional ten-fold safety factor for infants and children in
the case of threshold effects to account for pre  and post natal
toxicity and the completeness of the database, unless EPA determines
there is sufficient evidence to support a different safety.  The
database is complete for FQPA purposes and there are no residual
uncertainties for pre-/post-natal toxicity for deltamethrin, with
submission of the immunotoxicity study (OPPTS 870.7800).  However, the
Agency currently retains a 3x FQPA safety factor for all pyrethroid
insecticides, as per the Cumulative Risk Assessment for Pyrethroids
(2012), based on evidence of underdeveloped clearance mechanisms in
neonatal rats reported in the published literature.  The use pattern for
the mosquito adulticide provides expectation of negligible exposure to
infants or children.  Thus, it can be concluded that there is a
reasonable certainty that no harm will result from aggregate exposure to
deltamethrin residues.

F. International Tolerances

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