### Page 1 of 8 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 e tofenprox, [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 unde rstood in four diverse crops: rice, grapes, oilseed rape and lettuce. The parent com pound, etofenprox, and the metabolite, α -CO [2-(4-ethoxyphenyl)-2- methylpropyl 3-phenoxybenzoate], accounted for the ma jority 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 to lerances are applicable for the parent compound, etofenprox, only.

2. Analytical method.

Samples were analyzed for etofenprox using a work ing method derived from the Wildlife International, Ltd. method 236C-136, “Analytical Method Valida tion 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 (graphiti zed carbon black for alfalfa, snap bean pods with seed, and leaf lettuce and HAX solid phase extraction fo r pasture grass and snap bean foliage). The purified extract was concentrated to dryness, r econstituted 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 a nd 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, unfor tified 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 Californi a and Florida. Pasture grass and leaf lettuce were grown in all trials, alfalfa in California, and snap b eans in Florida (snap beans were substituted for alfalfa

### Page 2 of 8 in Florida because alfalfa is not a commercial crop in th at state). The test substance was applied in one aerial application by helicopter at a rate of approxi mately 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 substan ce 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 hour s. 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 re moval of the current label restrictions against applying the product on or near cr oplands and pasturelands.

### Page 3 of 8 B. Toxicological Endpoints A summary of the toxicological endpoints for etofe nprox 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 sy stemic 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 hum ans at doses that do not alter rat thyroid hormone

homeostasis.''
UF = uncertainty factor, FQPA SF = any add itional safety factor retained due to c oncerns unique to the FQPA, NOAEL = no observe d adverse effect level, LOAEL = lowest observed adverse effect level, P AD = population adjusted dose (a = acute, c = chronic) RfD = refer ence 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-u se pesticide if a toxicological study has indicated the possibility of an effect of concern occurring as a r esult of a one day or single exposure. An acute risk

### Page 4 of 8 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 Agri culture’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 th e 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 resi due 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 commod ities 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 popula tion 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) %cPAD 1 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 car cinogenic potential of etofenprox. Its objective was to demonstrate a threshold mechanism for the thyroid tumo rs in rats. In 2005, an additional 4-week dietary investigative study on thyroid function and hepatic micr osomal enzyme induction in rats was reviewed by the EPA. In 2005, the Agency considered if the add itional study along with the previously submitted data provided sufficient information to support re-evalu ation of etofenprox's carcinogenicity status. In consideration of these new data, and in accordance w ith the EPA Final Guidelines for Carcinogen Risk

### Page 5 of 8 Assessment, etofenprox was classified as “Not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone homeostasis.” This d ecision was based on the following considerations:

i. Treatment-related thyroid follicular cell tumors we re seen in both male and female rats at 4,900 ppm, which was considered to be adequa te, 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., th yroid growth and thyroid hormonal changes) indicated that etofenprox was inducing a disrupti on in the thyroid-pituitary hormonal status; and

v. Rats are substantially more sensitive than human s to the development of thyroid follicular cell tumors in response to thyroid hormone imba lance. The overall weight-of-the-evidence was considered sufficient to indicate that etofenpr ox induced thyroid follicular tumors through an antithyroid mode of action. The quantificati on 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 u ses on food/feed commodities are to be applied by PCOs only, using ULV aerial applications. The pot ential exposures and associated risks for handlers mixing, loading and applying etofenprox as a mosqu ito adulticide are based on the proposed label for RF2056 OL (etofenprox 20% liquid formulation). The ma ximum 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 inhalati on exposures are predicted for occupational handlers mixing, loading, and applying etofenprox at low volum e 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 th e EPA’s assessment of occupation exposure for etofenprox used as an ULV mosquito adulticide dated 06/09/ 08 (DP Barcode D342643). Th e occupational handler exposure and risk estimates for etofenprox use as a ULV mosquito adulticide are listed below.

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

Short- &

IntermediateTerm Exposure Unit Exposure 1
(mg/lb ai handled) Application

Rate (lb ai/A) Units

Treated 2
(A/day) Average Daily Dose 3

(mg ai/kg bw/day) Short- &

Intermediate-Term

MOE 4

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 (PHE D), Version 1.1, August 1998.

2 Units Treated taken from Science Advisory Council for Exposure, Standard Operating Procedure 9.1, Standard Values for Daily Ac res Treated in Agriculture, Rev. 25, September 2001.

3 Average Daily Dose (ADD) = Unit Exposure x Application Rate x Units Treated x Abso rption Factor (inhalation 100%) ÷ Body Weigh t (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 inhalat ion

exposure.

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

assessment was conducted.

### Page 6 of 8 b. Residential (Non-occupational) exposure and risk Since applications for public health mosquito contro l 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 childre n’s exposures from ULV aerial applications of etofenprox result in MOEs greater than 100 and th erefore do not exceed HED’s level of concern.

D. Cumulative Effects

Cumulative effects from substances with a common mech anism of toxicity: Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to est ablish, modify, or revoke a tolerance, the Agency consider ``available information'' concerning the cumula tive effects of a particular pesticide's residues and ``other substances that have a common mechanism of toxicity.''

Unlike other pesticides for which EPA has followe d 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 tolera nce 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 e ffects 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 deve lopmental toxicity study in rabbits showed no quantitative/qualitative evidence of increased susceptibility in offspri ng. 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 suscep tibility in the offspring was not observed. In the rat developmental study, the maternal LOA EL was equal to the developmental LOAEL.

Reproductive toxicity study: The 2-generation reproduc tion 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 co rresponding pathological changes in pups, and clinical signs of pups during most of the lactation peri od which included body tremors, distended abdomen, lethargy, unsteady gait, and abnormal movements. Howe ver, 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 F 1 and F 2 generations with corresponding centril obular hepatocyte enlargement and increased thyroidal epithelial height in the HDT group of the F 1 generation. At the high dose, parents (F 0 ) had similar effects on their organs as the pups: in creased liver, thyroid, and kidney weights with

### Page 7 of 8 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 indi cation of increased quantitative/qualitative evidence of susceptibility of the offspring in the developmental ra t 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/developmen tal study. In the 2-genera tion reproduction toxicity study, there was no evidence of quantitative and qua litative 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 pare nts). 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 et ofenprox 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 submi ssion 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 Effect s 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 toxico logical 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 resi dential exposure plus chr onic exposure to food and water. Etofenprox is currently registered for use(s) th at could result in short-term residential exposure and it was determined that it is appropriate to aggregat e 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 aggreg ate exposure to food, water, and residential uses. Therefore, short-term aggregate exposure is not exp ected to exceed the Agency's level of concern as per Health Effects Division review (HED: DP Barcode: 343064; J. Arthur; 08/13/08).

### Page 8 of 8 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 curre ntly registered for use(s) that could result in intermediate-term residential exposure, and it was dete rmined 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 residentia l uses (Health Effects Division review [HED: DP Barcode: 343064; J. Arthur; 08/13/08]).Therefore, intermed iate-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, etofe nprox is not expected to pose a cancer risk.

5. Determination of safety Based on these risk assessments, it is concluded that ther e is a reasonable certainty that no harm will result to the general population and to infants and childre n 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).