Document ID: EPA-HQ-OPP-2016-0007-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-04-25T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: PV Shah, 703-308-1846

Jeneil Biosurfactant Company
[IN-10846]
	EPA has received a pesticide petition (IN-10846) from Technology Sciences Group Inc. (1150 18[th] Street, Suite 1000 Washington, DC 20036) on behalf of Jeneil Biosurfactant Company, 400 N. Dekora Woods Blvd. Saukville, WI  53080 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.
(Options (pick one)
	2. to establish an exemption from the requirement of a tolerance for
	Isobutyl acetate, CAS #110-19-0, when used as an inert solvent applied to growing crops or harvested crops under 40 CFR 180.910 in pesticide formulations.  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 NA remove
	1. Plant metabolism.
	2. Analytical method. NA remove
	3. Magnitude of residues. NA remove
B. Toxicological Profile  Isobutyl acetate, which has been identified as one of the primary fragrance compounds in bananas and is also a product of yeast fermentation processes, metabolizes readily to innocuous, endogenous products. Therefore, oral toxicity resulting from the use of isobutyl acetate as an inert ingredient in pesticides is not expected to be significant. To further evaluate the toxicity of isobutyl acetate the European Chemicals Bureau (ECB) IUCLID dataset on isobutyl acetate acid was consulted. In addition, data on isobutyl alcohol from the US EPA's IRIS database and the European Chemical Agency's dossier are referenced. Isobutyl alcohol is one of the primary metabolic products of isobutyl acetate, and therefore these data can be bridged to assess the toxicity of the acetate form.
	1. Acute toxicity.  Acute toxicity tests categorize isobutyl acetate into acute toxicity category IV for oral, inhalation, and dermal exposure. Oral LD50 values range from 4763 mg/kg bw in rabbits to 13,400 mg/kg bw in rats. Acute inhalation toxicity is likewise low, with a 6-hour LC50 of >13.24 mg/L calculated for rats. The dermal LD50 in rabbits was determined to be >17,400 mg/kg bw in the 24-hour Draize cuff method. Another acute dermal study derived an LD50 of >5000 mg/kg bw in rabbits.

	2. Genotoxicty. Isobutyl acetate did not induce reverse mutations in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 at concentrations as high as 5000 μg/mL in the absence or presence of metabolic activation.
	3. Reproductive and developmental toxicity.  In two prenatal developmental toxicity inhalation studies, mated female Wistar rats and Himalayan rabbits were exposed to isobutanol (99.8%) at vapor concentrations of  0, 151, 758 or 3030 ppm (0, 500, 2,500 or 10,000 mg/m[3]) for six hours/day. The rats were dosed on post-coitum days 6-15. No mortality or significant differences in clinical signs, body weight development, or gross pathology between controls and treated groups were observed. No effects on development were noted. The maternal and developmental rat NOAELs were 3030 ppm.  Rabbits (15/dose) were dosed on post-insemination days 7-19. High-dose rabbit dams had a slightly lower body weight gain, particularly during the first phase of exposure.    The maternal NOAEL for rabbits was 758 ppm. Fetuses exhibited no signs of developmental changes in response to isobutanol. Therefore, the rabbit developmental NOAEL was 3030 ppm, the highest dose.
In a 2-generation reproductive inhalation study isobutanol (99.9%) was administered to 30 Crl:CD(SD)IGS BR rats/sex/dose by whole body exposure at 0, 500, 1000 and 2500 ppm (0, 1476, 2952, and 7380 mg/m³) for 6 hours per day 7 days per week. Exposure began at the commencement of the study for the F0 generation, and on postnatal day 28 for the F1 generation. It ended after weaning of the pups (F0 generation postnatal day 28, F1 generation postnatal day 21). For dams, exposure was discontinued after day 20 of gestation through lactation day 5. No exposure-related effects were observed on F0 and F1 parental survival or on F0 and F1 reproductive performance, body weights, food consumption and food efficiency in males or females.  There were no significant spermatogenic or macroscopic findings, changes in primordial follicle or corpora lutea counts, changes in mean organ weights or histopathologic lesions in the F0 or F1 rats at any dose. Pup endpoints were not significant for either F1 or F2 generations, including survival, general physical condition, and mean body weights. There were no macroscopic findings, changes in mean organ weights, or maturation of F1 pups. The NOAEL of isobutanol for parental systemic, reproductive and neonatal toxicity is 2500 ppm (7380 mg/m³, the maximum applied dose) in males and females of the F0, F1 and F2 generations (ECHA 2014b). The study was rated "reliable without restriction" by the European Chemicals Agency (ECHA). 
	4. Subchronic toxicity.   No repeat-dose toxicity studies were identified for isobutyl acetate. However, based on the toxicity profile of isobutyl alcohol (isobutanol), which is one of the primary metabolic products of isobutyl acetate, and based on the widespread occurrence of isobutyl acetate in food, both as a synthetic food additive and natural component of many plant species and food-related fermentation processes, the long-term toxicity of isobutyl acetate is not expected to be significant. A 90-day oral rodent toxicity study on isobutyl alcohol served as the scientific basis for US EPA's oral Reference Dose (RfD) for that compound.  Isobutyl alcohol was administered to 30 Sprague-Dawley (Crj: CD(SD)) rats/sex/dose by gavage for 90 days at dose levels of 0, 100, 316, or 1000 mg/kg bw/day. Treatment related effects were seen only at 1000 mg/kg bw/day, and included hypoactivity, which was significant during week one and decreased markedly after week 4, and lower body weight gain (18% below that of control rats) in males during week one. Food consumption averages were below those of the controls for both males and females during weeks 1 and 2. Clinical signs and effects on body weight and food consumption were all transient and were considered as adaptive and therefore as not adverse. Serum potassium levels were 11-15% lower in both sexes compared to controls on day 29 , but group mean serum potassium concentrations were similar for treated and control groups at the final clinical pathologic evaluation. No other significant differences between dosed groups and controls were found for ophthalmoscopic examination, hematology, urinalysis, organ weights, gross pathology and histopathology. The NOEL was determined to be 316 mg/kg bw/day and the NOAEL was 1000 mg/kg/day. U.S. EPA derived an oral RfD of 0.3 mg/kg/day for isobutyl alcohol by applying uncertainty factors totaling 1000 to this NOEL.
In another study, Wistar rats (10/sex/group) were exposed to isobutanol in drinking water at concentrations of 0, 1000, 4000, or 16,000 ppm, equivalent to approximately 0, 80, 340, or 1450 mg/kg bw/day isobutanol actually ingested. The 90-day study was carried out under OECD Test Guideline 408 and included full hematology, urinalysis, and ophthalmological endpoints as well as post-sacrifice histological exam.  Body weight, food and water consumption, and clinical signs of toxicity were monitored throughout the study.  There were no significant dose-dependent signs of toxicity in any of these parameters. Study authors concluded that the NOAEL for isobutanol was the highest dose, 1450 mg/kg/day.
In a 90-day guideline study (Guideline: 82-7, Subdivision F (Neurotoxicity Screening Battery)), 99% pure isobutanol was administered by dynamic whole-body exposure to 10-20 Sprague-Dawley rats/sex/dose at 0, 250, 1000, or 2500 ppm for 6 hours per day, 5 days/week  (~ 0.75, 3.0, 7.5 mg/L). In high dose females, total erythrocyte count, hemoglobin, and hematocrit were slightly elevated compared to controls (p <= 0.05). The European Chemicals Agency (ECHA), which reviewed the study, considered this to be not biologically significant. No differences were found in body weight, food consumption, ophthalmoscopic examination, clinical observation, clinical chemistry, neurobehavioral observations, organ weights, gross pathology, and histopathology. The NOAEL for repeat-dose effects was the highest dose, 2500 ppm.
	5. Chronic toxicity. No chronic studies were identified for isobutyl acetate or its metabolites.
	6. Animal metabolism. Metabolism of aliphatic esters such as isobutyl acetate proceeds rapidly through hydrolysis to form an alcohol and carboxylic acid. These are reactions of the carboxylesterases or esterases, which predominate in hepatocytes but are present in most tissues throughout the body, including small intestine, colon, kidney, trachea and lungs.  The initial metabolites of isobutyl acetate are isobutyl alcohol and acetic acid. Isobutyl alcohol is oxidized via alcohol dehydrogenase and aldehyde dehydrogenase to isobutyric acid. The acids will be conjugated and excreted or will undergo β-oxidation in the fatty acid metabolic pathway. The metabolic products are endogenous in mammals and innocuous at levels produced from the typical diet.
	7. Metabolite toxicology. NA Remove
	8. Endocrine disruption. Toxicity data related to endocrine disruption were not identified in the isobutyl acetate database. As the scientific knowledge develops, screening of additional compounds may be added to the Endocrine Disruptor Screening Program (EDSP). When additional screening and/or testing is conducted, isobutyl acetate 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 dietary exposure to isobutyl acetate was determined using methods to estimate chronic dietary exposure for a generic inert ingredient. This assessment considers drinking water and crop-specific residues from pre-harvest applications of agricultural insecticides, herbicides and fungicides, assuming the highest established tolerance level residue for each commodity.  The assessment assumes that the inert ingredient is used on all crops.  The inert ingredient is assumed to be present in all commodities treated with 57 of the most significant active ingredients at the maximum tolerance level as identified by the U.S. EPA for the default assessment.  Chronic dietary exposure estimates were derived for the general US population and sub-groups of the population using the Dietary Exposure Evaluation Model, DEEM(TM).  Assuming all crops are treated with formulated products containing 10% isobutyl acetate by weight, the estimated chronic exposure for the total US population is 0.038 mg/kg/day, 7.7% of the chronic Population Adjusted Dose (cPAD).  Children age 1 to 2 years old have the highest estimated exposure at 0.141 mg/kg/day, or 28.5% of the cPAD.
	i. Food. Dietary exposures of concern are not anticipated for isobutyl acetate due to its lack of persistence in the environment and low general toxicity.  A significant source of dietary isobutyl acetate comes from natural food sources and its use as a food additive. JECFA (1999) estimated the current level of intake of isobutyl acetate as a food-flavoring agent to be 1300 μg/day in the U.S., equivalent to approximately 0.0186 mg/kg bw/day and reported that there was no safety concern at the current level of intake.
	ii. Drinking water. Isobutyl acetate exposure via drinking water from use as an inert ingredient is not expected to be significant. Isobutyl acetate is inherently biodegradable and will volatilize relatively quickly from water.  Exposure via the drinking water was estimated in the DEEM dietary exposure assessment assuming a concentration of 100 ppb.
	2. Non-dietary exposure. Residential exposures of concern are not anticipated for isobutyl acetate due to its inherent ability to biodegrade in the environment, low projected use-level in pesticides, and low general toxicity. 
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 isobutyl acetate would be cumulative with those of any other chemical compounds. EPA has not made a common mechanism of toxicity finding as to isobutyl acetate and other compounds. Isobutyl acetate does not produce toxic metabolites in common with other substances of potential concern. For the purpose of the tolerance exemption proposed, it is assumed that isobutyl acetate does not share a common mechanism of toxicity with other substances
E. Safety Determination
	1. U.S. population. Taking into consideration all available information on isobutyl acetate, there is a reasonable certainty that no harm to any population subgroup will result from dietary and other nonoccupational exposures to isobutyl acetate when used as an inert ingredient in an inert mixture intended for use in pesticide formulations.  Adjusting for relative molecular weight, EPA's oral RfD of 0.3 mg/kg/day for isobutanol was used to derive an RfD for isobutyl acetate of 0.495 mg/kg/day, which added uncertainty factors totaling 1000 for interspecies extrapolation, intraspecies variability, and for extrapolating subchronic exposure to chronic exposure. The chronic Population Adjusted Dose (cPAD) was determined to be the same as the RfD because no effects of isobutanol on development or reproduction were observed, suggesting that isobutyl acetate too would not increase susceptibility of sensitive populations.  Therefore, the oral RfD and cPAD are both 0.495 mg/kg/day. For the total US population, the estimated chronic dietary exposure from food and drinking water for isobutyl acetate, calculated as 10% of all agricultural formulations, is 7.7% of the cPAD, well below any level of potential concern.
	2. Infants and children. An evaluation of susceptibility and uncertainty issues associated with isobutyl acetate has been performed and there is a reasonable certainty that no harm to infants and children will result from the use of isobutyl acetate as an inert ingredient in pesticide products. The structurally similar and metabolically related compound isobutyl alcohol was not a developmental toxin to rats or rabbits following inhalation.  For this reason, a safety factor analysis has not been implemented to assess risk and the additional tenfold safety factor for the protection of infants and children is also unnecessary. The estimated chronic dietary exposure from food and drinking water was highest (28.5% of cPAD) for children aged 1 to 2 years old.  This estimated exposure to isobutyl acetate is well below any level of potential concern. 
F. International Tolerances
NA Remove