Interregional Research Project Number 4 (IR-4)

	

Petition #4E8295

	EPA has received a pesticide petition (4E8295) from Interregional
Research Project Number 4 (IR-4) 500 College Road East, Suite 201 W,
Princeton, NJ  08540,  requesting, 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
Esfenvalerate, ((S)-cyano-(3-phenoxyphenyl)methyl
(S)-4-chloro-alpha-(1-methylethyl) benzeneacetate in or on the Oilseed
Crop Group 20 at 0.5 ppm, and the concurrent deletion of existing
tolerances for cotton, undelinted seed and sunflower seed. 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 metabolism. The metabolism and chemical nature of residues of
fenvalerate in plants and animals is adequately understood.  The fate of
fenvalerate has been extensively studied using radioactive tracers in
plant and animal metabolism/nature of the residue studies previously
submitted to the Agency.  These studies have demonstrated that the
parent compound is the only residue of toxicological significance. EPA
has concluded that the qualitative nature of the residue is the same for
both fenvalerate and esfenvalerate. 

2. Analytical method. There is a practical analytical method utilizing
electron-capture gas chromatography with nitrogen phosphorous detection
available for enforcement with a limit of detection that allows
monitoring food with residues at or above tolerance levels.  The limit
of detection for updated method is the same as that of the current
Pesticide Analytical Manual (PAM) II, which is 0.01 ppm.

3. Magnitude of residues. Fenvalerate is a racemic mixture of four
isomers (S,S; R,S; S,R; and R,R).  Technical Asana® (esfenvalerate) is
enriched in the insecticidally active S,S-isomer (84%).  Tolerance
expressions are proposed for esfenvalerate based on the sum of all
isomers. The following tolerances are proposed: Oilseed Crop Group 20,
at 0.5 ppm. 

Field trials were conducted on the representative commodities for the
Oilseed Group, canola (PP9E5057); sunflower, seed (tolerance previously
established at 0.5 ppm for esfenvalerate); and cotton, undelinted seed
(tolerance previously established at 0.2 ppm for esfenvalerate).

PR#05150 was submitted by IR-4 on February 25, 1999. This submission was
the original Notice of Filing for canola seed and contained the study
“Esfenvalerate: Magnitude of the residue on canola seed and on
processed commodities derived from canola seed” (MRID 44778801). This
report contained crop field trials from three locations; Bowen Mills, GA
(Region 2), Langdon, ND (Region 5), and Moxee/Yakima, WA (Region 11).
Two treatment levels, 1X (0.1 lb ai/A/season) and 2X (0.2 lb
ai/A/season) were used with preharvest intervals (PHI) of 21 to 29 days.
An exaggerated application rate of 5X (0.5 lb ai/A/season) was used for
the processing study. The canola was treated by foliar spray at the
bloom and seed filling stages. The maximum residues in canola treated at
0.1 lb ai/A were 0.289 ppm (WA site).  The maximum residues in canola
treated with 0.2 lb ai/A were 0.561 ppm (ND site).  Concurrent recovery
studies from fortified controls validated the method with recoveries
ranging from 70% to 112%.  The fortification levels ranged from 0.0516
to 1.0 ppm. The LOQ was 0.05 ppm.

Magnitude of residue data on canola have been collected in the new study
(IR-4 PR No. A5150) from three field trials located in NAFTA Regions 5 &
7. At each trial, two foliar broadcast applications of the test
substance 13-14 days apart were made to the treated plots. The
application rates ranged from 0.050 to 0.052 lb ai/A per application for
a total rate range of 0.102 to 0.103 lb ai/A per season. All
applications were made using appropriate spray equipment, and the spray
volume was sufficient to provide adequate dispersal of the test
substance.

Sampling started in the untreated control plot and ended in the treated
plot. At all the field trials, samples were harvested 22-24 days after
the last application. There were no residues of esfenvalerate above the
lowest level of method validation (LLMV) of 0.05 ppm in samples taken at
22-24 days PHI. The nature of the residues of esfenvalerate is
adequately understood, and an acceptable analytical method is available
for enforcement purposes. Results from these trials support the proposed
tolerance. 

B. Toxicological Profile

1. Acute toxicity.  A battery of acute toxicity studies places technical
esfenvalerate in Toxicity Category II for acute oral toxicity (rat LD50
87.2 mg/kg), Category III for acute dermal (rabbit LD50 >2000 mg/kg) and
primary eye irritation (mild irritation in rabbits), and Category IV for
primary skin irritation (minimal skin irritation in rabbits that
reversed within 72 hours after treatment). The acute inhalation LC50 in
male and female rats was between 1270 and 2070 mg/m3. A dermal
sensitization test on esfenvalerate in guinea pigs showed no
sensitization.

2. Genotoxicty. Esfenvalerate was not mutagenic in reverse mutation
assays in S. typhimurium and E. Coli and did not induce mutations in
Chinese hamster V79 cells or chromosome aberrations in Chinese hamster
ovary cells.  Esfenvalerate did not induce micronuclei in bone marrow of
mice given up to 150 mg/kg intraperitoneally.  Esfenvalerate did not
induce unscheduled DNA synthesis in HeLa cells.  Other genetic
toxicology studies submitted on racemic fenvalerate indicate that the
mixture containing equal parts of the four stereoisomers is not
mutagenic in bacteria. The racemic mixture was also negative in a mouse
host mediated assay and in a mouse dominant lethal assay.

3. Reproductive and developmental toxicity. Esfenvalerate was
administered to pregnant female rats by gavage in a pilot developmental
study at doses of  0, 1, 2, 3, 4, 5, and 20 mg/kg/day and a main study
at 0, 2.5, 5, 10, and 20 mg/kg/day.  Maternal clinical signs (abnormal
gait and mobility) were observed at 2.5 mg/kg/day and above.  A 
maternal NOEL of 2 mg/kg/day was established on the pilot study.   The
developmental NOEL was >20 mg/kg/day. A DNT study is no longer required
by EPA as DuPont is among the companies participating in and citing 6
pyrethroid DNT studies that demonstrated offspring were not more
sensitive as compared to adults for the endpoints evaluated.

Esfenvalerate was administered by gavage to pregnant female rabbits in a
pilot developmental study at doses of 0, 2, 3, 4, 4.5, 5, and 20
mg/kg/day and a main study at doses of 0, 3, 10, and 20 mg/kg/day. 
Maternal clinical signs (excessive grooming) were observed at 3
mg/kg/day and above.  A maternal NOEL of 2 mg/kg/day was established on
the pilot study.  The developmental NOEL was > 20 mg/kg/day.

A two-generation feeding study with esfenvalerate was conducted in the
rat at dietary levels of 0, 75, 100, and 300 ppm.  Skin lesions and
minimal (non biologically significant) parental body weight effects
occurred at 75 ppm.  The NOEL for reproductive toxicity was 75 ppm
(4.2-7.5 mg/kg/day) based on decreased pup weights at 100 ppm.

4. Subchronic toxicity. Two 90-day feeding studies with esfenvalerate
were conducted in rats - one at 50, 150, 300, and 500 ppm esfenvalerate,
and a second at 0, 75, 100, 125, and 300 ppm to provide additional dose
levels.  The NOEL was 125 ppm (6.3 mg/kg/day) based on clinical signs
(jerky leg movements) observed at 150 ppm (7.5 mg/kg/day) and above.

A 28-day inhalation study was conducted at exposure concentrations of 0,
6, 16, and 63 mg/m3 in male and female rats. The NOAEL was considered to
be 16 mg/m3 in males and females based on decreased body weight gain,
organ weight changes, and clinical signs of toxicity observed at 63
mg/m3.

A 90-day feeding study in mice was conducted at 0, 50, 150, and 500 ppm
esfenvalerate with a NOEL of 150 ppm (30.5 mg/kg) based on  clinical
signs of toxicity at 500 ppm (106 mg/kg).

Three-month subchronic study in dogs was satisfied by one-year oral
study in dogs, in which the NOEL was 200 ppm (5 mg/kg/day).

A 21-day dermal study in rabbits with fenvalerate conducted at 100, 300,
and 1000 mg/kg/day with an NOAEL of 1000 mg/kg/day.

5. Chronic toxicity. A 1-year study was conducted in which dogs were fed
0, 25, 50 or 200 ppm esfenvalerate with no treatment related effects at
any dietary level.  The NOEL was 200 ppm (5 mg/kg/day).  An effect level
for dietary administration of esfenvalerate for dogs of 300 ppm had been
established earlier in a three week pilot study used to select dose
levels for the chronic dog study.

One chronic study with esfenvalerate and three chronic studies with
fenvalerate have been conducted in mice.

In an 18-month study, mice were fed 0, 35, 150, or 350 ppm
esfenvalerate.  Mice fed 350 ppm were sacrificed within the first two
months of the study after excessive self-trauma related to skin
stimulation and data collected were not used in the evaluation of the
oncogenic potential of esfenvalerate.  The NOEL was 35 ppm (4.29 and
5.75 mg/kg/day for males and females, respectively) based on lower body
weight and body weight gain at 150 ppm.  Esfenvalerate did not produce
carcinogenicity.

In a 2-year feeding study, mice were administered 0, 10, 50, 250 or 1250
ppm fenvalerate in the diet. The NOEL was 10 ppm (1.5 mg/kg/day) based
on granulomatous changes (related to fenvalerate only, not
esfenvalerate) at 50 ppm (7.5 mg/kg/day).  Fenvalerate did not produce
carcinogenicity.

In an 18-month feeding study, mice were fed 0, 100, 300, 1000, or 3000
ppm fenvalerate in the diet. The NOEL is 100 ppm (15.0 mg/kg/day) based
on fenvalerate-related microgranulomatous changes at 300 ppm (45
mg/kg/day).  No compound related oncogenicity occurred.

Mice were fed 0, 10, 30, 100, or 300 ppm fenvalerate for 20 months.  The
NOEL was 30 ppm (3.5 mg/kg/day) based on red blood cell effects and
granulomatous changes at 100 ppm (15 mg/kg/day).  Fenvalerate was not
carcinogenic at any concentration.

In a two-year study, rats were fed 1, 5, 25, or 250 ppm fenvalerate.  A
1000 ppm group was added in a supplemental study to establish an effect
level.  The NOEL was 250 ppm (12.5 mg/kg/day).  At  1000 ppm (50
mg/kg/day), hind limb weakness, lower body weight, and higher
organ-to-body weight ratios were observed.  Fenvalerate was not
carcinogenic at any concentration.

EPA has classified esfenvalerate in Group E - evidence of
noncarcinogenicity for humans.

6. Animal metabolism. After oral dosing with fenvalerate, the majority
of the administered radioactivity was eliminated in the initial 24
hours.  The metabolic pathway involved cleavage of the ester linkage
followed by hydroxylation, oxidation, and conjugation of the acid and
alcohol moieties.

7. Metabolite toxicology. The parent molecule is the only moiety of
toxicological significance appropriate for regulation in plant and
animal commodities.

8. Endocrine disruption. Estrogenic effects have not been observed in
any studies conducted on fenvalerate or esfenvalerate, which include the
amphibian metamorphosis assay, fish short-term reproduction assay, in
vitro estrogen receptor transcriptional activation assay, aromatase
assay, Hershberger assay, steroidogenesis assay, male and female
pubertal assays, ER and AR binding assays, and the Uterotrophic assay. 
In addition, in subchronic or chronic studies there were no lesions in
reproductive systems of males or females.  In the recent reproduction
study with esfenvalerate, full histopathological examination of the
pituitary and the reproductive systems of males and females was
conducted.  There were no compound-related gross or histopathological
effects.  There were also no compound-related changes in any measures of
reproductive performance including mating, fertility, or gestation
indices or gestation length in either generation.  There have been no
effects on offspring in developmental toxicity studies.  

In addition, no test substance-related effects were noted on endocrine
related tissues in the following studies: 90-day rat and mouse studies,
1-year dog study, chronic rat and mouse studies, multigeneration
reproduction studies and developmental toxicity studies, avian
reproduction study, fish full life cycle study, fish sex reversal study,
fish mesocosm study,  and the larval leopard frog study.

Results from the above listed studies demonstrate that esfenvalerate
(and its racemic isomer mixture fenvalerate), provide no clear evidence
of endocrine disruption. Furthermore, the toxicity observed in in vivo
tests is consistent with the known mode of action of esfenvalerate and
fenvalerate. Animals exposed to esfenvalerate continually over 2
generations reproduced and developed normally without any evidence of
adverse effects on endocrine tissues.  Sporadic data from in vitro and
in vivo studies in the open literature have produced positive results in
some study types; however, the methods used preclude the usefulness of
the data for human risk assessment.

C. Aggregate Exposure

1. Dietary exposure. The acute RfD and chronic RfD are the same value of
0.018 mg/kg bw/day based on a NOAEL of 1.75 mg/kg bw/day from the acute
neurotoxicity screen and an uncertainty factor of 100.

i. Food. Acute and chronic dietary exposure resulting from the currently
approved uses and proposed uses of esfenvalerate are within acceptable
limits (<100% RfD) for all sectors of the population.  The Dietary
Exposure Evaluation Model with Food Commodity Intake Database
(DEEM-FCIDTM, version 3.16) was used to conduct the assessments and
incorporates nationwide food consumption data as reported by respondents
in the 2-day food consumption survey (2003-2008) of the National Health
and Nutrition Examination Survey (NHANES).  The acute exposure analysis
used probabilistic assessment using conservative field trial residue
data and monitoring residue data from the USDA Pesticide Data Program,
tolerance values, processing factors, and percent crop treated values;
the chronic exposure analysis used overall mean residue values,
processing factors, and percent crop treated values.  

ii. Drinking water. The impact of esfenvalerate in drinking water on
acute and chronic dietary exposure was assessed. The highest modeled
esfenvalerate water residue values (peak value for acute assessment;
annual average value for chronic assessment) from FIRST Tier 1 surface
water and SCI GROW Tier 1 groundwater models under worst-case conditions
was determined to be in surface water; when these conservative values
for drinking water were included with the food residues in the acute and
chronic exposure assessments, the resultant exposures were within
required limits(< 100% aRfD and < 100% cRfD).

2. Non-dietary exposure. Esfenvalerate is registered for non-crop uses. 
Non-occupational, non-dietary exposure for esfenvalerate must be
considered. 

D. Cumulative Effect 

FQPA requires EPA to consider "available information" concerning the
cumulative effects of a particular pesticide's residues and "other
substances that have a common mechanism of toxicity" when considering
whether to establish, modify, or revoke a tolerance. Esfenvalerate is a
member of the pyrethrins/pyrethroid class of pesticides. A cumulative
risk assessment (CRA) for the pyrethrins/pyrethroid class of pesticides,
which includes esfenvalerate, was released October 4, 2011. The results
of the pyrethrins/pyrethroid cumulative assessment, as well as the
single chemical esfenvalerate assessment, will be considered when
decisions regarding establishing, modifying, or revoking esfenvalerate
tolerances are made.

E. Safety Determination:

1. U.S. population. Based on the completeness and reliability of the
toxicity data and the conservative exposure assessments, there is a
reasonable certainty that no harm will result from the aggregate
exposure of residues of esfenvalerate including all anticipated dietary
exposure and all other non-occupational exposures.  

2. Infants and children. Based on the completeness and reliability of
the toxicity data, the lack of toxicological endpoints of special
concern, the lack of any indication that children are more sensitive
than adults to esfenvalerate, and the conservative exposure assessment,
there is a reasonable certainty that no harm will result to infants and
children from the aggregate exposure of residues of esfenvalerate,
including all anticipated dietary exposure and all other
non-occupational exposures. Accordingly, there is no need to apply an
additional safety factor for infants and children.

F. International Tolerances

Codex maximum residue levels (MRL’s) have been established for
residues of fenvalerate on a number of crops that also have U.S.
tolerances. There are some minimal differences between the section 408
tolerances and certain Codex MRL values for other commodities. These
differences could be caused by differences in methods to establish
tolerances, calculate animal feed, dietary exposure, and as a result of
different agricultural practices.  Therefore, some harmonization of
these maximum residue levels will be required.

Codex has the following for fenvalerate:

Cotton Seed – 0.2 mg/kg

Cotton Seed oil, crude – 0.1 mg/kg

Cotton Seed oil, edible 0.1 mg/kg

Sunflower seed – 0.1 mg/kg

For esfenvalerate:

Rape seed – 0.01 mg/kg

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