 

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

EPA Registration Division contact: Maggie Rudick, (703) 347-0257

TEMPLATE:

Bayer CropScience

(5E8431)

EPA has received a pesticide petition (5E8431) from Bayer CropScience,
P.O. Box 12014, 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:

1.  Establishing a tolerance for residues of Deltamethrin, IUPAC
chemical name:

(S)-α-cyano-3-phenoxybenzyl
(1R,3R)-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate in or
on the raw or processed agricultural commodity orange, dried pulp at 3
parts per million (ppm), orange, oil at 50 parts per million (ppm)

2.	Amending existing tolerance for residues of Deltamethrin, IUPAC
chemical name: (S)-α-cyano-3-phenoxybenzyl
(1R,3R)-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate in or
on the raw or processed agricultural commodity orange, fruit at 0.3
parts per million (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 supports granting of the petition.
Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant and livestock metabolism.  The metabolism of deltamethrin in
plants is adequately understood for purposes of establishing these
proposed tolerances.  In plants, cis-deltamethrin undergoes
isomerization to form trans- and α-R-deltamethrin.  Each of these
isomers can undergo cleavage at the ester linkage to yield
3-phenoxybenzaldehyde and cis- or trans-Br2CA metabolites that can be
further oxidized, reduced, and/or conjugated.  Deltamethrin is also
directly hydroxylated to 4(-hydroxydeltamethrin or the nitrile group can
be hydrolyzed to form an amide metabolite.  Deltamethrin
(cis-deltamethrin) and its isomers alpha-R-deltamethrin, and
trans-deltamethrin were the major residues found in all crops.  Smaller
amounts of several minor components were present at <0.01 mg/kg and <10%
of the TRR.  Deltamethrin (cis-deltamethrin) and its isomers
alpha-R-deltamethrin, and trans-deltamethrin are the relevant residues
of concern for tolerance enforcement in crop commodities.

The nature of residues in animal commodities is also adequately
understood.  The metabolism of deltamethrin in rats, lactating cows and
laying hens dosed orally shows similar pathways.  Deltamethrin is
readily metabolized and excreted with half-lives of less than 24 hours. 
The basic metabolic reactions involve cleavage of the ester bond by
oxidation and/or hydrolysis, followed by oxidation of the released acid
and alcohol moieties. The acid moiety (Br2CA) is transformed into
conjugates, chiefly the glucuronide, and excreted in urine. It can also
be hydroxylated at one of the gem-methyl groups, which is in turn
conjugated and excreted. The unstable alcohol moiety is transformed via
the aldehyde into the acid (mPB acid), which undergoes further oxidation
by hydroxylation on aromatic rings and then is extensively excreted in
urine, mainly as the 4'OH sulfate conjugate.

Deltamethrin (cis-deltamethrin) and its isomers alpha-R-deltamethrin,
and trans-deltamethrin are the relevant residues of concern for
tolerance enforcement in livestock commodities.

	2. Analytical method.  Analytical methods based on a gas chromatography
equipped with an electron capture detector (GC/ECD) are available for
enforcing tolerances for residues of deltamethrin.  These methods are
used for the determination of cis-deltamethrin, alpha-R-deltamethrin,
and trans-deltamethrin in crop and animal matrices.  The total residue
reported is the sum of residues of three isomers.

3. Magnitude of residues.  Residue trials were conducted on orange in
the United States and Brazil in accordance with the EPA and PMRA
guidelines for crop field trials (OCSPP 860.1500; OCSPP 860.1520;
OCSPP-170005; FRL-6559-3 Import Tolerance Guidance; DACO 7.4.1; DACO
7.4.2; DACO 7.4.5) to support the tolerances requested.

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 signs, decreased weight gain and mortality.
The developmental NOEL was 11 mg/kg/day (HDT).

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

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. The reproductive
NOAEL was 24.9 mg/kg/day (HDT). Deltamethrin was not a developmental or
reproductive toxicant. 

4. Subchronic toxicity.  A 90-day rat oral toxicity study was conducted
with deltamethrin administered by gavage. The NOEL was 2.5 mg/kg/day
based on reduced body weight gain and slight hypersensitivity to
sound.  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 means of exposure
(oral gavage as a bolus dose vs. dietary administration). 

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
clonic 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
(HDT).  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 weight
and neurological signs at 2.5 mg/kg/day, it was concluded that 0.003
mg/L (0.783 mg/kg/day) was the NOEC (NOEL) 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 neurologic 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 in a single dose by
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 the time of peak effect at 15 mg/kg. There was no evidence of
neuropathology at any dose.   

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 neuropathology at any dietary level. 

7. Animal metabolism.  The absorption of deltamethrin is 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. 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 includes 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.  The proposed new import tolerance use of
deltamethrin on oranges and processed orange commodities has minor
effects on the previous dietary aggregate risk assessment conducted for
all existing registered uses (EPA, D423638, December 4, 2014).  Residues
for the additional crop group were based on field trials on orange
fruit.  Assessments, using the DEEM FCID Version 4.02 software, were
conducted to evaluate potential risks due to chronic and acute dietary
exposure of the U.S. population and selected population subgroups to
residues of deltamethrin.  Consumption data used in this program were
taken from NHANES WWEIA 2005-2010.

The acute toxicity endpoint used in the acute assessment was the Bench
Mark Dose Level of 1.49 mg/kg/day from the deltamethrin acute
neurotoxicity study as described in the Agency’s HED risk assessment
(EPA, D417556, February 24, 2015).  A 100X uncertainty factor was
applied for all populations > 6 yrs. old results in an acute population
reference dose (aPAD) of 0.015 mg/kg/day.  An additional FQPA Safety
Factor of 3X was applied to children under 6 yrs. resulting in a aPAD of
0.005 mg/kg/day.

EPA determined that a chronic dietary endpoint is not required because
repeated exposure to deltamethrin does not result in a lower point of
departure. Therefore, the acute dietary endpoint is protective of
chronic exposure scenarios.  Chronic dietary exposure was estimated in
order to address aggregate exposure.

The acute dietary assessment for combined food and water exposure shows
96% of the aPAD for Children 1-2 years old (most sensitive) and 16% of
the aPAD for US Population.  Results from the dietary exposure
assessments demonstrate a reasonable certainty that no harm to the
overall U.S. population or any population subgroup will result from the
use of deltamethrin on the proposed crops.

i. Food.  A partially refined acute dietary (food only) risk assessment
was conducted.  For the population subgroup Children 1-2 years old, the
acute analysis indicates an exposure of 95% of the aPAD at the 99.9th
percentile.  Acute exposure to the overall U.S. population is 16% of the
aPAD.

ii. Drinking water.   In order to address drinking water, water was
included in the dietary analysis for food.  DEEM analyses were performed
using surface water estimates based on sweet corn application at 0.45
lbs ai/A.  The EDWC for the acute and chronic dietary assessment was 0.2
ppb.  EFED determined there was no need to conduct a PRZM-GW assessment
since groundwater values are at the limit of solubility of 0.2 ppb.  For
the population subgroup Children 1-2 years old, the acute analysis
results in an exposure of 96% of the aPAD.  Acute exposure to the
overall U.S. population is 16% of the aPAD.  Drinking water was not a
significant contributor to the overall dietary exposure.

2. Non-dietary exposure.

a. Occupational exposure.  

The newly proposed use of deltamethrin on oranges and process orange
commodities as import tolerance would have no change to previous
estimates of occupational exposure.  A previous residential handler
exposure assessment for indoor, outdoor, turf, pet and paint uses was
conducted by EPA (D418867, 6/11/2014).  The residential handler
scenarios resulted in inhalation risk estimates (Margin of Exposure)
ranging from 4,300 to 850,000.  The lowest MOE of 4,300 was associated
with the use of a backpack sprayer to treat lawns with a wettable powder
formulation.  These risk estimates were well above the Level of Concern
of 100.

	b. Residential (Non-occupational) exposure and risk

The newly proposed use of deltamethrin on oranges and process orange
commodities as import tolerance would have no change to previous
estimates of residential exposure.  A previous residential
post-application exposure assessment for indoor, outdoor, turf, pet and
paint uses was conducted by EPA (D418867, 6/11/2014).  The residential
post-application scenarios resulted in incidental oral (hand-to-mouth)
risk estimates (Margin of Exposure) ranging from 630 to 400,000.  The
lowest MOE of 630 was associated with exposure to children from indoor
bed bug scenario.  These risk estimates were well above the Level of
Concern of 300 for children younger than 6 yrs. old.  

All post-application inhalation and incidental oral exposure estimates
for the mosquito control scenarios resulted in MOEs greater than their
respective LOCs and are not of concern.

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 minimal 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 short-term aggregate risk estimation
combining residential exposure with background exposure from dietary
(chronic food and water exposure) for the US population has a Margin of
Exposure (MOE) of 2,200.  This MOE is well above the Level of Concern of
100.  The proposed import tolerance for orange use pattern will produce
minor dietary exposures. Thus, there is a reasonable certainty that the
use of deltamethrin will present no harm from aggregate exposure.

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The short-term aggregate risk estimation combining residential exposure
with background exposure from dietary (chronic food and water exposure)
for the Children 1-2 yrs. old has a Margin of Exposure (MOE) of 510. 
This MOE is well above the Level of Concern of 300.  The use pattern for
deltamethrin on orange fruit and process commodities of oranges will
have minimal 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

Deltamethrin is a broad spectrum insecticide used throughout the world
to control pests of livestock, crops, ornamentals plants and turf, and
household, commercial, and industrial food use areas. As a consequence a
large number of CODEX MRLs exist for deltamethrin.  US and Canadian
petitions seek to harmonize MRLs at the proposed 0.3 ppm.  

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