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 o f E sfenvalerate, ((S)
- cyano - (3
-phenoxyp henyl)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 c otton, 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 full y 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 m etabolism. The metabolism and chemical nature of residues of fenvalerate in plants and animals is adequatel y understood. The fate of fenvalerate has been extensively s tudied 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 o f 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 anal ytical 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 Analy tical 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 (PP 9E5057) ; sunflower, seed (tolerance previousl y establishe d 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

2 5, 1999. This submission was2 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/s eason) 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

f oliar 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). C oncurrent recovery s tudies from fortified controls validated the method with recoveries ranging from 70% to 1 12%. 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 fol iar 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 e quipment, 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 acc eptable anal ytical 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 I I for acute oral toxicity

(rat LD50 87.2 mg/kg), Category III for acute dermal (rabbit LD50 >2000 mg/kg) and primary e ye 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 LC 50 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 c ells. Esfenvalerate did not induce micronuclei in bone marrow of mice given up to 150 mg/kg3 intraperitoneall y. E sfenvalerate did not induce unscheduled DNA sy nthesis in HeLa cells. O ther genetic toxicology s tudies 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

g avage 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
. M aternal clinical signs (abnormal gait and mobility) were observed at 2.5 mg/kg/day and above. Amaternal NOELo f 2 mg/kg/day was established on the p ilot study . The developmental NOELw as >20 mg/kg/day
. A DNT study

is no longer required by

EPA as DuPont is among the companies participating in and citing 6 py rethroid DNT studies that demonstrated offspring were not more sensitive as compared to adults for the endpoints evaluated. Esfenvalerate was administered by g avage 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 do s es of 0, 3, 10, and 20 mg/kg/day
. M aternal clinical s igns (excessive grooming) were observed at 3 mg/kg/day and above. Am aternal NOELo f 2 mg/kg/day

w as 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 l evels of 0, 75, 100, and 300 ppm. S kin lesions and minimal (non biologicall y significant) parental body w eight effects occurred at 75 ppm. The NOEL for reproductive toxicity w as 75 ppm (4.2
- 7.5 mg/kg/day) based on decreased pup weights at 100 ppm . 4. Subchronic toxicity. Two 90
- day f eeding 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 NOELwas 12 5 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

w as 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 w eight gain, organ weight changes, and clinical signs of toxicity observed at 63 mg/m3. A 90
- day f eeding study

in mice was conducted at 0, 50, 150, and 500 ppm esfenvalerate with a NOELo f 150 ppm (30.5 mg/kg) based on c linical signs of toxicity

at 500 ppm (106 mg/kg). Three
- month subchronic study in dogs was satisfied by

one - ye ar oral study

in dogs, in which the NOEL was 200 ppm (5 mg/kg/day).4

A 21
- day d ermal 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
- ye ar study w as conducted in which dogs were fed 0, 25, 50 or 200 ppm esfenvalerate with no treatment related effects at any dietary level. The NOELw as 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. Inan 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 f or males and females, respectively) based on lower body

w eight and body

w eight gain at 150 ppm. E sfenval erate did not produce carcinogenicity
. In a 2
- ye ar 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
. Inan 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). F envalerate was not carcinogenic at any concentration. In a two - ye ar study, rats were fed 1, 5, 25, or 250 ppm fenvalerate. A1 000 ppm group was added in a supplemental study to establish an effect level. The NOEL was 250 ppm (12.5 mg/kg/day). At 1 000 ppm (50 mg/kg/day), hind limb weakness, lower body w eight, and higher organ - to -body w eight ratios were observed. Fenvalerate was not carcinogenic at any concentration
. EPA has classified esfenvalerate in Group E
- evidence of noncarc inogenicity for humans. 6. Animal metabolism. After oral dosing with fenvalerate, the majority of the5 administered radioactivity w as eliminated in the initial 24 hours. The metabolic pathway

involved cleavage of the ester linkage followed by hydroxyl ation, 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 substanc e - 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, multi generation reproduction studies and developmental toxicity

s tudies, avian reproduction s tudy, 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 evidenc e 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 o ver 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 typ es; 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

b ased on a NOAEL of 1.75 mg/kg bw/day f rom the acute neurotoxicity

screen and an uncertainty factor of 100. i. Food. Acute and chronic dietary exposure resulting from the currentl y approved uses and proposed uses of esfenvalerate are within acceptable6 limits (<100% RfD) for all sectors of the population. The Dietary Exposure Evaluation Model with Food Commodity Intake Datab ase (DEEM
- FCID TM , 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 (NHANE S). 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 anal ys is 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 value s (peak value for acute assessment; annual average value for chronic assessment) from FIRST Tier 1 surface water and SCIGROW 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 "oth er substances that have a common mechanism of toxicity" when considering whether to establish, modify, or revoke a tolerance. Esfenvalerate is a member of the py rethrins/py

rethroid class of pesticides. A cumulative risk assessment (CRA) for the py rethrins/ py rethroid class of pesticides, which includes esfenvalerate, was released October 4, 2011. The results of the p yrethrins/py rethroid 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 o f the toxicity

d ata 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 .7

2. Infants and children
. Based on the completeness and reliability o f 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 e xposure and all other non occupational exposures. Accordingl y, there is no need to appl y 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