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EPA Registration Division contact: 

Andrew Ertman (703) 308-9367 

PP #1E7925

 EPA has received a pesticide petition (1E7925) from Interregional Research Project 

Number 4 (IR-4), 500 College Road East, Suite 201 W, Princeton, NJ 08540 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 etofenprox, [2-(4-

ethoxyphenyl)-2-methylpropyl 3-phenoxybenzyl ether], in or on food and feed commodities 

at 0.5 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 metabolism. 

The plant metabolism of etofenprox is adequately understood in four diverse crops: rice, grapes, oilseed 

rape and lettuce. The parent compound, etofenprox, and the metabolite, α-CO [2-(4-ethoxyphenyl)-2-

methylpropyl 3-phenoxybenzoate], accounted for the majority of residues extracted in all crops. The 

metabolism of etofenprox in plants is understood for the purposes of the proposed tolerances. Even though 

the parent compound, etofenprox, and the metabolite, α-CO, are the residues of concern for tolerance 

setting purposes, EPA has previously determined tolerances are applicable for the parent compound, 

etofenprox, only. 

2. Analytical method. 

Samples were analyzed for etofenprox using a working method derived from the Wildlife International, 

Ltd. method 236C-136, “Analytical Method Validation for the Determination of Etofenprox and α-CO in 

Rice and Rice Straw”. Modifications were made to improve the performance of the method and are 

included in the analytical summary report. Briefly, 5 g of the sample was extracted with acetone. An 

aliquot was purified by solid phase extraction (graphitized carbon black for alfalfa, snap bean pods with 

seed, and leaf lettuce and HAX solid phase extraction for pasture grass and snap bean foliage). The 

purified extract was concentrated to dryness, reconstituted in acetonitrile:water, and submitted to 

LC/MS/MS analysis. 

Based on recoveries of samples fortified at the LLMV, the limits of detection (LODs) and limits of 

quantitation (LOQs) were calculated as 0.0025 ppm and 0.0075 ppm, respectively, for pasture grass; as 

0.0032 ppm and 0.0095 ppm, respectively, for leaf lettuce; as 0.0011 ppm and 0.0033 ppm, respectively, 

for alfalfa; as 0.0013 ppm and 0.0040 ppm, respectively, for snap bean foliage; and as 0.0014 ppm and 

0.0042 ppm, respectively, for snap bean pods with seed. Treated samples were analyzed the same day as 

extraction. Analytical sets typically consisted of calibration standards, unfortified controls, fortified 

controls, and treated samples. The analytical standard solutions were stored in a refrigerator (~5 °C). 

3. Magnitude of residues. 

Three residue field trials were conducted in California and Florida. Pasture grass and leaf lettuce were 

grown in all trials, alfalfa in California, and snap beans in Florida (snap beans were substituted for alfalfa 
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in Florida because alfalfa is not a commercial crop in that state). The test substance was applied in one 

aerial application by helicopter at a rate of approximately 0.007 lb ai/A. Additional plots in California 

were treated at approximately 0.07 lb ai/A (10X). In the California trial, the tank mixes included test 

substance and BVA Spray 13 oil. The test substance was applied neat in Florida. The California 

applications were made at dusk from an altitude of 50 ft, and samples were collected approximately 13.25 

to 15 hours later. The Florida applications were made in the morning from an altitude of 100 ft, and 

samples were collected within approximately 2.75 hours. Snap bean pods with seed samples were also 

collected in Florida. The proposed tolerance for combined residues of the parent compound, etofenprox, in 

or on food and feed commodities is 0.5 ppm. These proposed tolerances are protective of the U.S. 

population and all subgroups. 

In 1X samples, the highest residues were observed in pasture grass (0.39 ppm) and the lowest in snap bean 

pods with seed (< 0.010 to 0.017 ppm). Residues in 10X samples ranged from 0.57 to 3.2 ppm, with the 

highest residues observed in alfalfa and lowest in leaf lettuce. Data from this study may be used to support 

a tolerance proposal for etofenprox which will allow removal of the current label restrictions against 

applying the product on or near croplands and pasturelands. 
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B. Toxicological Endpoints

A summary of the toxicological endpoints for etofenprox used for human risk assessment is shown in the 

following table: 

Doses and Toxicological Endpoints for Etofenprox 

Exposure/Scenario 

Dose Used in Risk 

Assessment, Interspecies, 

Intraspecies and any 

Traditional UF 

FQPA SF and Level of 

Concern for Risk 

Assessment 

Study and Toxicological Effects 

Acute Dietary (females 13-49 

years of age) 

Not selected NA No toxicological endpoint 

attributable to a single exposure was 

identified in the available toxicology 

studies. 

Acute Dietary (General 

population including infants 

and children) 

Not selected NA No toxicological endpoint 

attributable to a single exposure was 

identified in the available toxicology 

studies. 

Chronic Dietary (All 

populations) 

NOAEL = 3.7 mg/kg/day 

Chronic RfD = 0.037 

mg/kg/day. 

FQPA SF = 1x cPAD = 

Chronic RfD/Special FQPA 

SF = 0.037 mg/kg/ day. 

Combined Chronic Toxicity/ 

Carcinogenicity Study in Rat (MRID 

No. 40449707) 

LOAEL = 25.5 mg/kg/day based on 

increased thyroid weights. Related to 

increased liver weights and 

histopathology changes in liver and 

thyroid that occurred at the higher 

dose. 

Incidental Oral Short-Term 

(1 – 30 days) 

NOAEL =100 mg/kg/day 

UF = 100 

LOC for MOE = 100 Developmental Toxicity in Rabbit 

(MRID No. 45210602) 

LOAEL = 300 mg/kg/day based on 

decreased body weights, body 

weight gains, and food consumption 

(maternal toxicity). 

Incidental Oral IntermediateTerm (1 - 6 months) NOAEL = 20 mg/kg/day 

UF = 100 

LOC for MOE = 100 Subchronic Oral Toxicity in Rat 

(MRID No. 40449703) 

LOAEL = 120 mg/kg/day based on 

decreased body weight gain, 

increased liver and thyroid weights 

with corresponding histopathology, 

changes in hematology and clinical 

chemistry. 

Dermal (All durations) NA NA No systemic toxicity was identified 

in the dermal 28-day study; Highest 

Dose Tested was 1,000 mg/kg/day. 

Inhalation (All durations) NOAEL =10.6 mg/kg/day 

UF = 100 

LOC for MOE = 100 

Residential 

LOC for MOE = 100 

Occupational 

13-Week Inhalation Toxicity in Rat 

(MRID No. 40449705) 

LOAEL = 52.3 mg/kg/day based on 

organ weight changes and 

histopathological changes in liver, 

adrenals and thyroid. 

Cancer (oral, dermal, 

inhalation) 

Classification: ``Not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone 

homeostasis.'' 

UF = uncertainty factor, FQPA SF = any additional safety factor retained due to concerns unique to the FQPA, NOAEL = no observed adverse 

effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE 

= margin of exposure, LOC = level of concern, NA = Not Applicable 

C. Exposure Assessment

1. Dietary Exposure

a. Acute exposure 

Acute dietary risk assessments are performed for a food-use pesticide if a toxicological study has indicated 

the possibility of an effect of concern occurring as a result of a one day or single exposure. An acute risk 
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assessment was not performed. No toxicological endpoint attributable to a single (acute) dietary exposure 

was identified. 

b. Chronic exposure 

A chronic dietary risk assessment was conducted for etofenprox use on food/feed commodities following 

wide-area mosquito adulticide aerial applications by helicopter at a rate of approximately 0.007 lb ai/A 

using the Dietary Exposure Evaluation Model (DEEM-FCIDTM, Version 2.14) which uses food 

consumption data from the US Department of Agriculture’s Continuing Surveys of Food Intakes by 

Individuals (CSFII) from 1994 – 1996 and 1998. Screening level estimates of etofenprox in surface water 

and groundwater from rice and vector control uses were provided by the Environmental Fate and Effects 

Division (EFED: DP Barcode: 342969; G. Orrick; 05/27/08). The vector control rate of 0.007 lb ai/A 

proposed on food/feed commodities was used in the above mentioned EFED assessment. The application 

EFED estimated the maximum chronic (annual average) surface water at 4.7 ppb, and groundwater at 

0.0017 ppm. The estimated 4.7 ppb chronic surface water residue was incorporated directly into the dietary 

assessment; specifically into the DEEM-FCID food categories, “water, direct, all sources” and “water, 

indirect, all sources”. 

The concentration of etofenprox on food/feed commodities is assumed at the proposed tolerance level of 

0.5 ppm and 100 percent of commodities grown are assumed to be treated. The chronic dietary risk 

estimates are below HED’s level of concern (<100% cPAD) for the general U.S. population and all 

population subgroups. The most highly exposed population subgroup (1% of the cPAD) was children 1-2 

years old.

Summary of Chronic Dietary (Food + Drinking Water) Exposure and Risk for Etofenprox 

Population Subgroup Exposure (mg/kg bw/day) %cPAD1 Margin of Exposure 

(MOE) 

US population 0.006616 0.18% 559 

All infants ( < 1 year old) 0.012744 0.34% 290 

Children (1-2 years old) 0.019883 0.54% 186 

Children (3-5 years old) 0.016112 0.44% 230 

Children (6-12 years old) 0.009749 0.26% 380 

Youth (13-19 years old) 0.005840 0.16% 634 

Adults (20-49 years old) 0.004994 0.13% 741 

Adults (50+ years old) 0.004766 0.13% 776 

Females (13-49 years old) 0.004946 0.13% 748 

1

 cPAD = 0.037 mg/kg/day 

c. Cancer 

Etofenprox has been classified as “Not likely to be carcinogenic to humans at doses that do not alter rat 

thyroid hormone homeostasis.” In 1989, the EPA classified etofenprox as a “Group C Possible Human 

Carcinogen” based on thyroid tumors in rats. In 1996, the EPA evaluated additional information submitted 

by the registrant, Mitsui Toatsu, regarding the carcinogenic potential of etofenprox. Its objective was to 

demonstrate a threshold mechanism for the thyroid tumors in rats. In 2005, an additional 4-week dietary 

investigative study on thyroid function and hepatic microsomal enzyme induction in rats was reviewed by 

the EPA. In 2005, the Agency considered if the additional study along with the previously submitted data 

provided sufficient information to support re-evaluation of etofenprox's carcinogenicity status. In 

consideration of these new data, and in accordance with the EPA Final Guidelines for Carcinogen Risk 
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Assessment, etofenprox was classified as “Not likely to be carcinogenic to humans at doses that do not 

alter rat thyroid hormone homeostasis.” This decision was based on the following considerations: 

i. Treatment-related thyroid follicular cell tumors were seen in both male and female rats at 4,900 

ppm, which was considered to be adequate, and not excessive, to assess carcinogenicity; 

ii. No treatment-related tumors were seen in male or female mice when tested at a dose that was 

considered adequate to assess carcinogenicity; 

iii. There is no mutagenicity concern for etofenprox from in vivo or in vitro assays; 

iv. The non-neoplastic toxicological evidence (i.e., thyroid growth and thyroid hormonal changes) 

indicated that etofenprox was inducing a disruption in the thyroid-pituitary hormonal status; and 

v. Rats are substantially more sensitive than humans to the development of thyroid follicular cell 

tumors in response to thyroid hormone imbalance. The overall weight-of-the-evidence was 

considered sufficient to indicate that etofenprox induced thyroid follicular tumors through an 

antithyroid mode of action. The quantification of carcinogenic potential is not applicable. 

Therefore, no risk quantification is required. 

2. Non-dietary exposure 

a. Occupational exposure

Etofenprox 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 etofenprox as a mosquito adulticide are based on the proposed label for 

RF2056 OL (etofenprox 20% liquid formulation). The maximum application rate is 0.007 lb ai/acre. 

Application is not to be made to the same site more than once in three days, and no more than 2 times to a 

single site in any week. A maximum of 25 applications are allowed per year. 

Short- and intermediate-term dermal and inhalation exposures are predicted for occupational handlers 

mixing, loading, and applying etofenprox at low volume by aerial equipment. Since no dermal toxicity 

endpoint was identified for etofenprox, only inhalation exposures are assessed. Since etofenprox-specific 

exposure data are not available, handler scenarios were assessed using surrogate PHED unit exposure data 

(version 1.1, 1998). This strategy was used in the EPA’s assessment of occupation exposure for etofenprox 

used as an ULV mosquito adulticide dated 06/09/08 (DP Barcode D342643). The occupational handler 

exposure and risk estimates for etofenprox use as a ULV mosquito adulticide are listed below. 

Occupational Handler Exposure & Risk Estimates for Etofenprox Use as ULV Mosquito Adulticide 

Short- & 

IntermediateTerm Exposure Unit Exposure1

(mg/lb ai handled) 

Application 

Rate 

(lb ai/A) 

Units 

Treated2

(A/day) 

Average 

Daily Dose3

(mg ai/kg 

bw/day) 

Short- & 

Intermediate-Term 

MOE4

Mixer/Loader – Liquids (ULV) – Open Loading for Aerial Application 

Inhalation 0.0012 0.007 7500 0.0009 12,000 

Applicator – Liquids (ULV) – Aerial 

Inhalation 0.000068 0.007 7500 0.000051 200,000 

Flagger – Liquids (ULV) – Aerial 

Inhalation 0.00035 0.007 350 0.000012 870,000 

1

 Unit Exposure = mg ai/lb ai handled from the Pesticide Handler Exposure Database (PHED), Version 1.1, August 1998. 2

 Units Treated taken from Science Advisory Council for Exposure, Standard Operating Procedure 9.1, Standard Values for Daily Acres Treated in 

Agriculture, Rev. 25, September 2001. 

3

 Average Daily Dose (ADD) = Unit Exposure x Application Rate x Units Treated x Absorption Factor (inhalation 100%) ÷ Body Weight (70 kg). 4

 Margin of Exposure (MOE) = NOAEL (mg/kg/day) ÷ ADD (mg/kg/day); where the NOAEL = 10.6 mg/kg/day for all durations of inhalation 

exposure. 

Since occupational post application activities are not expected with mosquito adulticide applications, no 

assessment was conducted. 
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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 the Health Effects Division review (HED: DP Barcode: 

342643; J. Arthur; 06/09/08), all adult and children’s exposures from ULV aerial applications of 

etofenprox result in MOEs greater than 100 and therefore do not exceed HED’s level of concern. 

D. Cumulative Effects 

Cumulative effects from substances with a common mechanism of toxicity: Section 408(b)(2)(D)(v) of the 

FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency 

consider ``available information'' concerning the cumulative effects of a particular pesticide's residues and 

``other substances that have a common mechanism of toxicity.'' 

 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common 

mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to etofenprox and 

any other substances, and etofenprox does not appear to produce a toxic metabolite produced by other 

substances. Therefore for the purposes of this tolerance action, EPA has not assumed that etofenprox has a 

common mechanism of toxicity with other substances. 

E. Safety Factor for Infants and Children

In general, Section 408 of the FFDCA provides that EPA shall apply an additional ten-fold margin of 

safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity 

and the completeness of the database on toxicity and exposure unless EPA determines that a different 

margin of safety will be safe for infants and children. Margins of safety are incorporated into EPA risk 

assessments either directly through use of a MOE analysis or through using uncertainty (safety) factors in 

calculating a dose level that poses no appreciable risk to humans. 

Developmental toxicity studies: A prenatal developmental toxicity study in rabbits showed no 

quantitative/qualitative evidence of increased susceptibility in offspring. In the rabbit study, the 

developmental effects were seen at doses that resulted in maternal deaths at the high dose. Additionally, 

the rabbit developmental study showed increased abortions, decreased maternal body weights, body 

weight gains and food consumption. In the rabbit study, the maternal LOAEL (300 

milligram/kilogram/day (mg/kg/day)) is equal to the developmental LOAEL. In the 1-

generation/developmental study in rats, increased susceptibility in the offspring was not observed. In the 

rat developmental study, the maternal LOAEL was equal to the developmental LOAEL. 

Reproductive toxicity study: The 2-generation reproduction study in rats did not show evidence of 

quantitative/qualitative susceptibility in offspring. In this study, rats showed decreased pup weights, 

increased thyroid, liver and kidney weights with corresponding pathological changes in pups, and clinical 

signs of pups during most of the lactation period which included body tremors, distended abdomen, 

lethargy, unsteady gait, and abnormal movements. However, except for thyroid weight in female pups, all 

of these effects occurred at the highest dose tested (HDT). The effects on organ weights carried over to the 

adults of both the F1 and F2 generations with corresponding centrilobular hepatocyte enlargement and 

increased thyroidal epithelial height in the HDT group of the F1 generation. At the high dose, parents (F0) 

had similar effects on their organs as the pups: increased liver, thyroid, and kidney weights with 
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pathological changes in the kidney. The parental LOAEL was equal to the offspring LOAEL in the 2-

generation reproduction study in rats. 

Prenatal and postnatal sensitivity: There is no indication of increased quantitative/qualitative evidence of 

susceptibility of the offspring in the developmental rat or rabbit studies or in the 2-generation reproduction 

study in the rat. Developmental effects were seen at doses that caused maternal toxicity. No developmental 

effects were seen in the rat 1-generation/developmental study. In the 2-generation reproduction toxicity 

study, there was no evidence of quantitative and qualitative susceptibility because the presence of toxicity 

in the offspring occurred at the level of parental toxicity (increased organs weights and associated 

pathological changes occurred in both the pups and parents). In the developmental neurotoxicity study in 

rats, the observed eye abnormalities associated with body injuries could not be disassociated from possible 

altered treatment-related maternal behavior that resulted in injury to the pups. 

Conclusion: The toxicology database for etofenprox is essentially complete. The data are sufficient for 

endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements under the 

Food Quality Protection Act (FQPA). Evidence of quantitative and qualitative susceptibility of offspring 

was not observed and therefore, the FQPA 10x safety factor was reduced to 1x. 

F. Aggregate Risks and Determination of Safety 

There are a number of conditionally registered etofenprox products. These include outdoor yard foggers, 

indoor crack and crevice, indoor total-release foggers and cat spot-on products, rice uses and as mosquito 

adulticides. The proposed application in this submission expands the ULV mosquito adulticide use to all 

food/feed commodities. The application rate of 0.007 lb ai/A is identical to the previously approved 

mosquito adulticide use. As per the Health Effects Division review (HED: DP Barcode: 342643; J. Arthur; 

06/09/08), all handler and post-application risks from the ULV mosquito adulticide use were found not to 

exceed HED’s level of concern. 

1. Acute risk 

An acute risk assessment was not performed. No toxicological endpoint attributable to a single (acute) 

dietary exposure was identified. Therefore, acute risk from Etofenprox exposure to is not expected. 

2. Chronic risk 

Using the exposure assumptions described in this unit for chronic exposure, it was concluded that exposure 

to etofenprox from food and water will utilize 0.18% of the cPAD for the U.S. population, and 0.54% of 

the cPAD for children 1-2 years old, the subpopulation at greatest exposure. Based on the use pattern, 

chronic residential exposure to residues of etofenprox is not expected. Therefore, the aggregate exposure is 

not expected to exceed 100% of the cPAD. 

3. Short-term risk 

Short-term aggregate exposure takes into account residential exposure plus chronic exposure to food and 

water. Etofenprox is currently registered for use(s) that could result in short-term residential exposure and 

it was determined that it is appropriate to aggregate chronic food and water and short-term exposures for 

etofenprox. 

EPA has concluded that food, water, and residential exposures aggregated result in combined MOEs that 

do not exceed the Agency's level of concern for aggregate exposure to food, water, and residential uses. 

Therefore, short-term aggregate exposure is not expected to exceed the Agency's level of concern as per 

Health Effects Division review (HED: DP Barcode: 343064; J. Arthur; 08/13/08). 
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4. Intermediate-term risk 

Intermediate-term aggregate exposure takes into account non-dietary, non-occupational exposure plus 

chronic exposure to food and water. Etofenprox is currently registered for use(s) that could result in 

intermediate-term residential exposure, and it was determined that it is appropriate to aggregate chronic 

food and water and intermediate-term exposures for etofenprox. 

EPA has determined intermediate-term aggregate MOEs do not exceed the Agency's level of concern for 

aggregate exposure to food, water, and residential uses (Health Effects Division review [HED: DP 

Barcode: 343064; J. Arthur; 08/13/08]).Therefore, intermediate-term aggregate exposure is not expected to 

exceed the Agency's level of concern. 

Cancer risk 

Etofenprox has been classified as, ``Not likely to be carcinogenic to humans at doses that do not alter rat 

thyroid hormone homeostasis.'' Therefore, etofenprox is not expected to pose a cancer risk. 

5. Determination of safety 

Based on these risk assessments, it is concluded that there is a reasonable certainty that no harm will result 

to the general population and to infants and children from aggregate exposure to etofenprox residues. 

G. International Tolerances

Etofenprox is in the CODEX system with a residue definition of etofenprox for pome fruit (1 mg/kg) and 

potato (0.01 mg/kg).