Document ID: EPA-HQ-OPP-2015-0728-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-11-30T05:00Z

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-10849]
	EPA has received a pesticide petition (IN-10849]) from 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
	Isoamyl alcohol, CAS #123-51-3, 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 alcohol is moderately acutely toxic and irritating to eyes and skin in animal studies. Humans exposed to dilutions of this compound have not shown evidence of irritation or sensitization. An endpoint of concern for isoamyl alcohol appears to be respiratory irritation.  Central nervous system depression can occur at very high inhaled or ingested acute doses. Repeat-dose animal toxicity studies of isoamyl alcohol suggest that there is no subchronic hazard, including developmental hazard, resulting from the presence of isoamyl alcohol as an inert ingredient in pesticide formulations at the concentrations described in this petition. Oral toxicity studies of isoamyl alcohol identified NOAELs of 1000 to 1657 mg/kg/day in rats. The inhalation NOAEL for maternal effects was 2500 mg/m[3] (681 ppm).
	1. Acute toxicity.  Isoamyl alcohol is low in toxicity by the oral route of exposure. Acute oral toxicity values in rats and rabbits were all greater than 2000 mg/kg except for one LD50 for male rats that was 1300 mg/kg bw. Sublethal effects observed at 5000 mg/kg bw included dyspnea, apathy, staggering, atonia, pareses of rear extremities, and poor general condition (HCN 2003). The weight of evidence suggests that this substance can be considered Acute Toxicity Category III for the oral route of exposure.  An acute dermal toxicity value of 3210 mg/kg bw was reported for isoamyl alcohol in rabbits. No other details were identified for this study. The LD50 of 3210 mg/kg bw categorizes this compound as dermal Acute Toxicity Category III. No guideline animal studies were identified that assessed the acute inhalation toxicity of isoamyl alcohol. Rats exposed to concentrated vapors of isoamyl alcohol for 8 hours did not die within the 14 day observation period. Rats exposed to an "enriched atmosphere" of isoamyl alcohol for seven hours also did not die, but had significant panting and loss of pain reflex.  In mice, the concentration associated with a 50% decrease in respiration rate (RD50) was 2624  -  16,339 mg/m[3].
	2. Genotoxicty. Isoamyl alcohol produced negative results for bacteria cell and in vitro genotoxicity assays. It did not induce reverse mutations in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 in the absence or presence of metabolic activation; no significant forward mutations at the HPRT locus were observed in V79 Chinese hamster lung fibroblast cells in the presence or absence of metabolic activation; and isoamyl alcohol did not induce DNA damage in human blood cells in the Comet assay (HCN 2003).  
	3. Reproductive and developmental toxicity.  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.  
	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. Metabolism of alcohols such as isoamyl alcohol proceeds rapidly via hydrolysis to corresponding aldehydes (isovaleraldehyde) then carboxylic acids (isovaleric acid) via alcohol and aldehyde dehydrogenases. This takes place primarily in the liver, but also in kidneys, lungs, and gastric mucosa. Isovaleric acid would then be metabolized in amino acid and fatty acid pathways. Some conjugation of isoamyl alcohol will also occur, which will then be excreted; in rabbits given a single oral dose of 2200 mg isoamyl alcohol, 9% was excreted in the urine within 24 hours as the glucuronide conjugate.
Hepatic oxidation of isoamyl alcohol is rapid in humans and animals.  One hour after oral administration of 2 g/kg bw isoamyl alcohol, a maximum of 17 mg isoamyl alcohol /100 mL was found in blood, with less than 1 mg/mL detectable after 4 hours; no parent compound was detected in the urine.  A similar pattern was noted following a series of intraperitoneal injections of 1000 mg/kg bw to rats. The maximum (initial) blood concentrations were approximately 36 mg/100 mL, and in less than 5 hours the alcohol had disappeared from the blood. Only small amounts of the parent compound left the body in air or urine (0.97% and 0.27% of total dose, respectively). 
Four male volunteers were exposed to 92 mg/m[3] isoamyl alcohol in air for 10 minutes. A quasi-steady state absorption was reached after a few minutes and the mean absorption during that time was 63%. Absorption following nasal exposure in rats was estimated to be 80%. 
	7. Metabolite toxicology. NA Remove
	8. Endocrine disruption. Toxicity data related to endocrine disruption were not identified in the 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 alcohol 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 alcohol 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, 1.89% 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 7.06% of the cPAD.
	i. Food. FDA permits the addition of isoamyl alcohol to foods as a flavoring substance and adjuvant. JECFA (1997) estimated the current level of intake of isoamyl alcohol as a flavoring agent to be 1600 μg/person/day in the U.S., or about 0.023 mg/kg bw/day. There are natural sources of dietary isoamyl alcohol including peanut oil, blue cheese, filberts, meat, chickpeas, oranges, bananas, Concord grapes, and nectarines. It is also the main ingredient in fusel oil, a by-product of alcoholic fermentation, and is therefore found in some alcoholic beverages and vinegar.  The average percentage isoamyl alcohol in fusel oil is 60-65%. Residues from this compound's use as an inert pesticide ingredient will be minimal and, particularly in relation to background dietary consumption, not an important dietary source. 
	ii. Drinking water. Isoamyl alcohol exposure via drinking water from use as an inert ingredient is not expected to be significant. Isoamyl alcohol is biodegradable and 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 alcohol 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 alcohol would be cumulative with those of any other chemical compounds. EPA has not made a common mechanism of toxicity finding as to isoamyl alcohol and other compounds. Isoamyl alcohol 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 alcohol 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 alcohol, there is a reasonable certainty that no harm to any population subgroup will result from dietary and other nonoccupational exposures to isoamyl alcohol when used as an inert ingredient in Flavorzon, an inert mixture intended for use in pesticide formulations. The oral Reference Dose (RfD) and chronic Population Adjusted Dose (cPAD) were derived using the oral NOAEL of 1000 mg/kg/day from the 17-week gavage study in rats, divided by uncertainty factors totaling 100 (10 each for intraspecies and interspecies extrapolations). An additional safety factor was not considered necessary to derive the cPAD because effects on development were not observed in a guideline experiment and because the database is adequate and increased susceptibility is not predicted. Therefore, the oral RfD and cPAD are both 10 mg/kg/day. 
For the total US population, the estimated chronic dietary exposure from food and drinking water for isoamyl alcohol, calculated as 50% of all agricultural formulations, is 1.89% 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 alcohol as an inert ingredient in pesticide products. An evaluation of susceptibility and uncertainty issues associated with isoamyl alcohol has been performed. Based on available information, isoamyl alcohol is of low toxicity for human health endpoints at doses expected from its inert use in pesticide formulations.  It is not a developmental toxin to rats or rabbits following inhalation. Therefore, there is no concern for increased sensitivity to infants and children to isoamyl alcohol when used as an inert ingredient in pesticide formulations. 
F. International Tolerances
NA Remove