Document ID: EPA-HQ-OPP-2012-0469-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-08-22T04:00Z

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 replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

Wellmark International, Central Life Sciences

2E8031

	EPA has received a pesticide petition (2E8031) from Wellmark International, Central Life Sciences, 1501 East Woodfield Road, Suite 200 West, Schaumburg, IL 60173 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 to establish an exemption from the requirement of a tolerance for Diisopropyl Adipate (CASRN 6938-94-9)	in or on all raw agricultural commodities when used in pesticide formulations applied preharvest (40 CFR 180.920), as a consequence of mosquito treatment in and around growing crops.   DIPA is currently 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 physical chemical properties of DIPA were estimated using the EPI Suite(TM) (EPA Estimation Programs Interface) modeling programs.  The EPI Suite(TM) model results predict that DIPA is readily biodegradable and will degrade rapidly in the environment.           

B. Toxicological Profile

	1. Acute toxicity.  DIPA is low in toxicity following acute exposure, with a reported oral LD50 greater than 15g/kg body weight.  DIPA was not toxic to guinea pigs by the dermal route, and repeated 4-hour dermal exposures resulted in slight dermal irritation.  Eye irritation studies in rabbits indicated eye irritation was minimal to nonexistent.

	2. Genotoxicty. DIPA is readily metabolized by carboxylase enzymes to form adipic acid and isopropyl 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 Lethal Assay.  In addition, three genotoxicity studies conducted on the surrogate, isopropyl 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. DIPA is readily metabolized by carboxylase enzymes to form adipic acid and isopropyl alcohol, and these compounds have been evaluated for potential developmental and reproductive toxicity. The NOAELs from the surrogate studies can be used as a basis for estimated DIPA NOAELs. The potential developmental toxicity from exposure to adipic acid was evaluated by administration of adipic acid daily to rats and mice by gavage from day 6 through day 15 of gestation, and no teratogenic effects or any adverse effect on maternal or fetal survival were reported.   No significant increase in any 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.  Isopropyl 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 variations 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 toxicity NOAEL in mice is the lower of the two NOAELs, 256 mg/kg/day, and so this dose may be converted to the dose of DIPA that would result in the adipic acid administered.  The two isopropyl groups that are lost in metabolism of DIPA to form adipic acid comprise approximately 19% of the molecular weight of DIPA, 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 DIPA 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 rates.  In addition, histological evaluation revealed slight changes in the liver and kidneys 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 metabolite of DIPA, and surrogate, isopropyl 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 days per week for 13 weeks.  The only effect of isopropyl alcohol on organ weight was 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 hyaline droplets in the kidneys of male rats at the highest dose.  The NOAEC was 1,500 ppm.  

	5. Chronic toxicity. NA-Remove

	6. Animal metabolism. The metabolic pathways of DIPA are proposed based on the molecular structure of DIPA and the known metabolic pathways for structurally similar compounds.  DIPA metabolism can be deduced based on the common structural groups that make up DIPA, the known enzymes that interact with these structural groups, and the metabolites that result from these interactions. DIPA is a linear fatty acid diester that has an isopropyl group bound to the oxygen atom on each end of the molecule.  Given these structural groups, DIPA metabolism is almost certainly catalyzed by carboxylesterase enzymes that are ubiquitous throughout the body, to produce two alcohol atoms plus a carboxylate, adipic acid. 

	7. Metabolite toxicology. DIPA is readily metabolized by carboxylase 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 endocrine disruption was not observed in the DIPA database.  When additional screening and/or testing is conducted, DIPA 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 DIPA was determined using EPA methods and assumptions to estimate chronic dietary exposure for a generic inert ingredient as described for the "Alkyl Amines Polyalkoxylates" (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.  DIPA 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 DIPA is expressed as percent of the cPAD for an inert ingredient that makes up 40% of all agricultural formulations based on the proposal by Wellmark International to limit the percent of DIPA 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 significant 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 and near cropland, so residues could occur in food.  The dietary exposure and risk assessment indicates that DIPA exposures via food would be below any level of potential concern. 

	ii. Drinking water. The screening level dietary exposure assessment included consideration of drinking water.  Potential exposure to DIPA via drinking water from use as an inert ingredient in formulations intended to treat mosquitoes on and around cropland is below any level of potential concern. 

	2. Non-dietary exposure. DIPA and related adipate compounds are ingredients that have been used for many years in personal care products including skin cleansers, perfumes and colognes, bath oils, skin fresheners and hair grooming aids.   DIPA is typically included in personal care products 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 reliable information that suggests any toxic effects produced by DIPA 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 DIPA, adipic acid, and isopropyl 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. Children 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 DIPA 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.