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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: David Lieu**  **(703 -**  **305 -**  **0079 )**  **INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In**  **cases where the outline element does not apply, please insert “NA -**  **Remove” and maintain the outline. Please do not change the margins, font, or format in your**  **pesticide petition. Simply re place the instructions that appear in**  **green , i.e., “**  **[ insert**  **company name ]**  **,” with the information specific to your action. TEMPLATE:**  Wellmark International , Central L ife Sciences 2E8031 EPA has received a pesticide petition ( 2E8031 ) from Wellmark International, Central L ife Sciences , 1501 East Woodfield Road, Suite 200 West, Schaumburg, IL 60173 request ing, 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 to establish an ex emption from the requirement of a tolerance for Diisopropyl Adipate (CASRN 6938

- 94

- 9) in or on all raw agricultural commodit ies when used in pesticide formulations applied preharvest (40 CFR 180.920), as a consequence of mosquito treatment in and around growing crops. DIPA is currentl y used in non

- food use pesticide formulations and is now proposed for use in pesticide formulations intended to control mosquitos in agricultural areas where food crops may receive incidental exposure

. 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 Many of the phy sical chemical properties of DI PA were estimated using the EPISuiteTM (EPA Estimati on Programs Interface) modeling programs. The EPI SuiteTM model results predict that DIPA is readily biodegradable and will degrade rapidl y in the environment. B. Toxicological Profile 1. Acute toxicity. DI PA is low in toxicity following acute exposure, with a reported oral LD50 greater than 15g/kg bod y weight. DI PA was not toxic to guinea pigs by the dermal route, and repeated 4

- hour dermal exposures resulted in slight dermal2

irritation. Ey e irritation studies in rabbits indicated ey e irritation was minimal to nonexistent. 2. Genotoxicty. DI PA is readily metabolized by carboxylase enz ym es to form adipic acid and isoprop yl alcohol , and these compounds were both negative in genotoxicity

studies. Three genotoxicity studies conducted on the DIPA surrogate adipic acid were negative; these were : 1) a Host

- Mediated Assay , 2) an in vivo Cytogenetics Assay , and 3) a Dominant L ethal Assay

. In addition, three genotoxicity studies conducted on the surrogat e, isopropy l alcohol were negative; these were: 1) the Ames Assay , 2) an in vitro Mammalian Cell Gene Mutation Assay , and 3) an in vivo Micronucleus Assay

. 3. Reproductive and developmental toxicity. DI PA is readily metabolized by carbox yl ase enzy

mes to form adipic acid and isopropy l alcohol, and these compounds have been evaluated for potential developmental and reproductive toxicity

. The NOAELs from the surrogate studi es can be used as a basis for estimated DIPA NOAEL s . The potential developmental toxicity from exposure to adipic acid was evaluated by administration of adipic acid dail y to rats and mice by gavage from day 6 through day 15 of gestation, and no teratogenic effects or an y adverse effect on maternal or fetal survival were reported. No significant increase in an y adverse effect was identified in rats or mice exposed to the highest dose of adipic acid tested, 263 mg/kg/day in mice, and 288 mg/kg/day

in rats. Isopropy l alcohol administered to pregnant rats via the drinking water from day 6 through 16 of gestation did not cause any gross abnormalities in the offspring or adverse effects on fetal or maternal survival, but did decrease mean fetal body weight in the two high dose groups and increase skeletal variat ions in these groups. The NOAEL identified for this drinking water exposure study for both maternal and fetal toxicity was 596 mg/kg/day

. The developmental toxi city NOAEL in mice is the lower of the two NOAEL s, 256 mg/kg/day , and so this dose may be conve rted to the dose of DI PA that would result in the adipic acid administered. The two isoprop yl groups that are lost in metabolism of DI PA to form adipic acid comprise approximately 19% of the molecular weight of DI PA, so addition of 19% weight to 256 mg/kg/day results in an estimated NOAEL of 305 mg/kg/day . Thus 305 mg/kg of DIPA would provide 256 mg/kg of adipic acid. 4. Subchronic toxicity. To evaluate the potential effects of repeated exposure to the primary

metabolite of DI PA and surrogate compound, adipic acid, rats were exposed to 0, 400 or 800 mg/kg/day adipic acid for 13 weeks. Those exposed to 800 mg/kg/day adipic acid experienced lower weight gains than controls and had higher mortality rat es. In addition, histological evaluation revealed slight changes in the liver and kidney s of the 800 mg/kg/day group . The NOAEL from this 13

- week rat study was 400 mg/kg/day adipic acid. To evaluate the effects of repeated exposure to the second metabol ite of DI PA, and surrogate, isopropy l alcohol, groups of rats and mice were exposed by inhalation to 0, 100, 500, 1500, or 5,000 ppm of isopropanol vapor 6 hours per day , 5 day s per week for 13 weeks. The onl y effect of isopropyl alcohol on organ weight w as an increase in relative liver weight in male and female rats and in female mice, all in the 5,000 ppm group. The only microscopic effect noted was an increase in hy aline droplets in the kidney s of male r ats at the high est dose. The NOAEC was 1,500 ppm.3

5. Chronic toxicity. NA

- Remove 6. Animal metabolism. T he metabolic pathway s of DI PA are proposed based on the molecular structure of DI PA and the known metabolic pathway s for structurally similar compounds. DI PA metabolism can be deduced based on the common structural groups that make up DIPA, the known enzy mes that interact with these structural groups, and the metabolites that result from these interactions. DI PA is a linear fatty acid diester that has an isoprop yl group bound to the oxy gen atom o n eac h end of the molecule

. Given these structural groups, DI PA metabolism is almost certainly catal yz ed by carbox yl esterase enzy

mes that are ubiquitous throughout the bod y, to produce two alcohol atoms plus a carbox yl ate , adipic acid. 7. Metabolite toxicology

. DI PA is readil y metabolized by carbox yl ase enzymes to form adipic acid and isopropyl alcohol, and these compounds have been evaluated for potential developmental and reproductive toxicity

. 8. Endocrine disruption

. Toxicity related to endocrin e disruption was not observed in the DI PA database. When additional screening and/or testing is conducted, DI PA or its metabolites may be the focus of screening and/or testing to better characterize effects related to endocrine disruption. C. Aggregate Exposure 1. Dietary exposure. The estimated chronic dietary exposure to DI PA was determined using EPA methods and assumptions to estimate chronic dietary exposure for a generic inert ingredient as described for the “Alkyl Amines Poly alkox yl ates” (Piper, 2009). The assessment assumes that the inert ingredient is used on all crops, and that 100% of all crops are treated with the inert. DI PA is assumed to be in the formulation at a concentration of 40%, compared to 50% for the default assessment. Chronic dietary exposure estimates were derived for the general US population and sub

- groups of the population

. The estimated chronic dietary exposure to DI PA is expressed as percent of the cPAD for an inert ingredient that makes up 40% of all agricultural formul ations based on the proposal b y Wellmark International to limit the percent of DI PA in the mosquito control formulation that may be applied near agricultural crops to 40 % of the formulation. This dietary exposure assessment is expected to result in a sig nificant overestimate of exposure given that this inert ingredient is proposed for use in a formulation intended to control mosquitoes in agricultural areas, rather than to treat crops. i. Food. The proposed use of DIPA is to treat mosquitoes on an d near cropland, so residues could occur in food. The dietary exposure and risk assessme nt indicates that DI PA exposures via food would be below an y level of potential concern. ii. Drinking water
. The screening level dietary exposure assessment included consideration of drinking water. Potential exposure to DI PA via drinking water from use as an inert ingredient in formulations intended to treat mosquitoes on and around4

cropland is below an y l evel of potential concern. 2. Non

- dietary exposure

. DI PA an d related adipate compounds are ingredients that have been used for many y ears in personal care products including skin cleansers, perfumes and colognes, bath oils, skin fresheners and hair grooming aids. DI PA is ty picall y included in personal care produ cts at concentrations of 0.1 to >10%. D. Cumulative Effects Section 408(b)(2)(D) (9v) 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 .” To our knowledge there are no available data or other re liable information that suggests an y toxic effects produced b y DI PA would be cumulative with those of any other chemical compounds other than the metabolites, adipic acid and isopropyl alcohol

. The potential cumulative effects due to exposure to DI PA, adipic acid, and isopropy l alcohol, are expected to be below any level of potential concern. E. Safety Determination 1. U.S. population. The estimated dietary exposure for the total US population is 5.2% of the chronic Population Adjusted Dose ( cPAD )

. 2. Infants and children

. C hildren age 1 to 2 years old have the highest estimated dietary exposure to DIPA, at 16.2 percent of the cPAD. The fact that all estimated exposures are below 20% of the cPAD indicates there is no toxicological concern for DI PA exposure via the diet from its use in products intended to control mosquitoes in areas on or around cropland. F. International Tolerances There are no international tolerances for DIPA.