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 electroncapture 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 
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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 (IR4 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 
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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).
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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 
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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 
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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. Nonoccupational, 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. 
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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 nonoccupational 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