Document ID: EPA-HQ-OPP-2016-0378-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-12-01T05:00Z

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

EPA Registration Division contact: Mark Dow, 703-305-5533

Jeneil Biosurfactant Company
IN-10851
	EPA has received a pesticide petition (IN-10851) from Technology Sciences Group (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.
	2. to establish an exemption from the requirement of a tolerance for isoamyl acetate, CAS #123-92-2, 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  Isoamyl acetate, which has been identified in nectarines, bananas, kiwi fruit, pork volatiles, cheese products, whiskey, beer, and cognac, metabolizes readily to innocuous, endogenous products. Therefore, oral toxicity resulting from the use of isoamyl acetate as an inert ingredient in pesticides is not expected to be significant. To evaluate this, a number of peer-reviewed data sources were used, including the European Chemicals Agency (ECHA) dataset on isoamyl acetate, the Joint FAO/WHO Expert Committee on Food Additives' (JECFA) evaluation of isoamyl acetate, and the National Toxicology Program (NTP) dataset on isoamyl acetate. In instances where data were unavailable for isoamyl acetate, isoamyl alcohol was used to approximate the response in animals.  This approach is justified by the fact that both the acetate and alcohol are rapidly absorbed after exposure by any route and the acetate is subsequently and quickly hydrolyzed in vivo to the alcohol. (The other primary metabolite is acetic acid, which is exempt from the requirement of a tolerance under 40 CFR 180.1258).
	1. Acute toxicity.  The National Toxicology Program (1994) reported an oral LD50 value of 16,600 mg/kg bw in the rat and 7400 mg/kg bw in rabbits. A dermal study, which was ranked as "unreliable" by the European Chemical Agency (ECHA) because it was a secondary source of data and the primary source could not be corroborated, determined an LD50 of >5000 mg/kg bw in rabbits (ECHA 2013).  No other studies of dermal acute toxicity could be identified. 
There were no guideline acute toxicity studies identified for the inhalation route of exposure, but lethality is not predicted at low concentrations. Pentyl acetates have LCLo values greater than 5000 ppm.  Narcotic effects are seen at high exposure concentrations across species. For example, dogs exposed to 5,000 ppm isoamyl acetate for 1 hour exhibited drowsiness and nasal irritation but did not die.
	2. Genotoxicty. Isoamyl acetate produced negative results in bacteria cell and in vitro genotoxicity assays, as well as one in vivo study. It did not induce reverse mutations in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 at concentrations ranging from 10-10,000 μg/plate in the absence or presence of metabolic activation. Isoamyl acetate was also negative in S. typhimurium strains TA92 and TA94 when tested up to 5 mg/plate both with and without metabolic activation. Isoamyl acetate was not mutagenic in the mouse lymphoma forward mutation assay in the absence and presence of metabolic activation.  There was also no evidence of preferential inhibition of repair-deficient strains in Escherichia coli or Bacillus subtilis in a microsuspension assay for DNA repair following treatment with isoamyl acetate. Doses up to 2 mg/mL isoamyl acetate did not induce chromosomal aberrations in Chinese hamster lung cells. Finally, exposure to 0.15-0.24% isoamyl acetate failed to induce mitotic chromosomal malsegregation, mitotic recombination or point mutation in Saccharomyces cerevisiae strain D61.M.
The National Toxicology Program tested isoamyl acetate and found it negative for mutagenicity at feeding and injection doses of 4,800 ppm and 14,000 ppm, respectively, in the Drosophila melanogaster sex-linked recessive lethal (SLRL) assay.
	3. Reproductive and developmental toxicity.  A Hydra developmental toxicity assay was carried out for isoamyl acetate itself. Adult and developmental minimal affective concentrations of isoamyl acetate were both established as 0.2 mL/L. Because it was equally toxic to adults and embryos, isoamyl acetate was considered by the NTP to have a low-priority for more elaborate developmental testing.
In an OECD guideline 414 developmental toxicity study of isoamyl alcohol, pregnant SPF-Wistar, Chbb:THOM rats (25/group) and Himalayan rabbits (15/group)  were whole body exposed to 500, 2500, or 10,000 mg/m[3] isoamyl alcohol (136, 681 and 2,725 ppm), 6 hours/day, on gestational days 6 - 15 (rat) or 7 - 19 (rabbits). The following parameters were evaluated: body weight, behavior, uterus and ovary endpoints (weight, number corpora lutea, number implants, early and late resorptions, dead fetuses), and pre- and post-implantation loss. Fetuses were weighed, sexed, and assessed for malformation or variations in skeleton, soft tissue, or external parameters. Inhalation of up to 10,000 mg/m[3] in Wistar rats and Himalayan rabbits produced no developmental effects, although maternal effects at the high dose included reduced body weight gain in both species and eye irritation in rabbits. The NOAEL for maternal effects was 2500 mg/m[3] (681 ppm)  and the developmental NOAEL was 10,000 mg/m[3] isoamyl alcohol.
No effects on reproductive parameters, including uterine and ovarian weights, number of corpora lutea, number of implants, incidence of early and late resorptions, sex ratio, and fraction of viable fetuses, were noted in the study described above on prenatal toxicity of isoamyl alcohol. In the 90-day gavage study described above, there were no effects observed on gonad weights in rats. Male rats dosed with 1000 or 500 mg/kg bw for 3 weeks had significantly lower absolute testes weights compared to controls. The rats dosed with 500 mg/kg for three weeks also had lower relative testes weights than controls; this was not seen at the higher dose. Rats dosed for six weeks and 17 weeks showed none of these effects.  The pair feeding study described above strongly suggested that absolute organ weight changes seen in male rats could be attributed to reduced food intake due to localized irritation or unpalatable food and not systemic toxicity.   
	4. Subchronic toxicity.  No repeat-dose toxicity studies were identified for isoamyl acetate. However, based on toxicity of a structurally similar chemical/metabolite isoamyl alcohol and based on the widespread occurrence of this compound 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 isoamyl acetate is not expected to be significant. 
In a 4-week preliminary drinking water study, SPF-Wistar rats (n=3/sex/group) received >98% pure isoamyl alcohol doses of 360 mg/kg bw for two weeks and 1160 mg/kg bw for the next 2 weeks (20,000 and 16,000 ppm, respectively). The higher concentration was unpalatable to rats. Isoamyl alcohol exposure did not affect body weight gain or food consumption and no effects were observed upon gross post-mortem examination. The subsequent 90-day drinking water study followed OECD test guideline 408. Rats (10/sex/group) received 0, 1000, 4000, or 16,000 ppm isoamyl alcohol, with daily renewals of doses. Doses were equivalent to 73, 295, and 1068 mg/kg bw/day in males and 91, 385, 1657 mg/kg bw/day in females. No effects were noted on mortality, body weight, various clinical chemistry parameters, organ weights or any abnormality at gross and microscopic examination. There was a slight decrease in mean corpuscular volume and hemoglobin content in high dose males and an increase in red blood cell count in males receiving the mid and high dose. However, the Dutch Committee on Updating of Occupational Exposure Limits considered the NOAEL from this study to be the highest dose tested for both sexes: 1068 and 1657 mg/kg/day for males and females, respectively.
In a gavage study, Ash/CSE rats received 0, 500, or 1000 mg/kg bw for 3 or 6 weeks (5/sex/group), or 0, 150, 500, or 1000 mg/kg bw for 17 weeks (15/sex/group). Parameters monitored included clinical observations, body weight, food and water consumption, hematology, clinical chemistry, urinalysis, organ weights (brain, heart, liver, spleen, stomach, small intestine, caecum, adrenals, gonads, pituitary, and thyroid), and macroscopic and microscopic evaluation. Changes in body weight gain in the 17-week study and in absolute organ weights in the 3-week study were determined by a subsequent pair-feeding study to be the result of reduced food uptake due to local irritation rather than a systemic toxic response. Study authors and the Dutch Committee on Updating of Occupational Exposure Limits agreed that the NOAEL was the highest dose tested, 1000 mg/kg/day.
	5. Chronic toxicity. The European Chemicals Bureau (2000) and Health Council of the Netherlands (HCN)(2003) reported on one non-guideline chronic carcinogenicity study of isoamyl alcohol. Fifteen Wistar rats were administered approximately 80 mg/kw bw isoamyl alcohol by gavage two times per week for an estimated 135 weeks (approximately 23 mg/kg bw/day). The average survival time in treated rats was 527 days, significantly shorter than the 643-day survival of the control group. Four of the 15 orally treated animals developed malignant tumors: two liver cell carcinomas, one gastric carcinoma, and one myeloid leukemia. Three treated rats had benign tumors and three of the 25 control animals developed benign tumors. Other effects noted in treated rats were cirrhosis and possibly other adverse effects on the liver, metaplasia and hyperplasia of the hematopoietic bone marrow parenchyma, spleen metaplasia, and inflammatory pancreatic changes. These effects, plus the appearance and distribution of tumors suggest the systemic maximum tolerated dose was exceeded, and evidence for a specific toxic mode of action for isoamyl alcohol is difficult to elucidate. Based on the absence of a full study and on methodological shortcomings such as the irregular dosing, exceeding of the MTD, and the small sample sizes, it is difficult to draw useful conclusions from this study. 

	6. Animal metabolism. Inhaled or ingested isoamyl acetate is readily absorbed. Metabolism of aliphatic esters such as isoamyl acetate proceeds rapidly through hydrolysis to form an alcohol and carboxylic acid. The initial metabolites are isoamyl alcohol and acetic acid. Ultimately isoamyl alcohol is oxidized via alcohol dehydrogenase and aldehyde dehydrogenase to isovaleric acid. Isovaleric acid would then be metabolized in amino acid and fatty acid pathways.  These metabolic products are endogenous and innocuous.  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 lung.  
	7. Metabolite toxicology. NA Remove
	8. Endocrine disruption. Toxicity data related to endocrine disruption were not identified in the isoamyl acetate or isoamyl alcohol 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, isoamyl 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 isoamyl 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, and that 100% of all crops are treated with the inert.  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).  The estimated chronic exposure for the total US population is 0.189 mg/kg/day, 1.28% of the chronic Population Adjusted Dose (cPAD).  Children age 1 to 2 years old have the highest estimated exposure at 0.706 mg/kg/day, or 4.78% of the cPAD.
	i. Food. Dietary exposures of concern are not anticipated for isoamyl acetate due to its lack of persistence in the environment and low general toxicity.  A significant source of dietary isoamyl acetate comes from natural food sources and its use as a food additive. JECFA (1997) estimated the level of intake of isoamyl acetate as a flavoring agent to be 10,000 μg/person/day in the U.S., or about 0.143 mg/kg bw/day, and reported that there was no safety concern at the current level of intake. Residues from this compound's use as an inert pesticide ingredient will be minimal and not a concern in the diet.
	ii. Drinking water. Isoamyl acetate exposure via drinking water from use as an inert ingredient is not expected to be significant. Isoamyl acetate is inherently biodegradable and it will volatilize moderately 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 isoamyl 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 isoamyl acetate would be cumulative with those of any other chemical compounds. EPA has not made a common mechanism of toxicity finding as to isoamyl acetate and other compounds. Isoamyl 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 isoamyl 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 isoamyl acetate, there is a reasonable certainty that no harm to any population subgroup will result from the use of isoamyl acetate as an inert ingredient in pesticide products.  The oral Reference Dose (RfD) and chronic Population Adjusted Dose (cPAD) were derived using the oral NOAEL of 1477 mg/kg/day calculated above divided by uncertainty factors totaling 100 (10 each for intraspecies and interspecies extrapolations). Therefore, the oral RfD and cPAD are both 14.8 mg/kg/day.  For the total US population, the estimated chronic dietary exposure from food and drinking water for isoamyl acetate, calculated as 50% of all agricultural formulations, is 1.28% of the cPAD, well below any level of potential concern.
	2. Infants and children. There is a reasonable certainty that no harm to infants and children will result from the use of isoamyl acetate as an inert ingredient in pesticide products. In the Hydra developmental toxicity assay, the adult and developmental minimal affective concentrations of isoamyl acetate were both established as 0.2 mL/L. Because it was equally toxic to adults and embryos, isoamyl acetate was considered to have a low-priority for more elaborate developmental testing. Isoamyl alcohol, the metabolic product of isoamyl acetate, was not a developmental toxin in rats or rabbits following inhalation exposure. Based on available information, isoamyl acetate is of low toxicity for human health endpoints at doses expected from its inert use in pesticide formulations.  Therefore, there is no concern for increased sensitivity to infants and children to isoamyl acetate when used as an inert ingredient in pesticide formulations. 

F. International Tolerances
NA Remove