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EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: William Cutchin 703-305-7990

Jeneil Biosurfactant Company

IN-10850

EPA has received a pesticide petition (IN-10850) from Jeneil Biosurfactant Company, 400 N. Dekora W oods Blvd. Saukville, WI 53080 requesting, pursuant to section 408(d) of the Federal Food, Drug, a nd 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 isobutyl isobutyrate, CAS #97-85-8,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 petiti on contains data or informati on 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 tim e or whether the data supports granting of the petition. Additional data may be need ed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. NA

2. Analytical method. NA

3. Magnitude of residues. NA

B. Toxicological Profile

Isobutyl isobutyrate, which is a natura l component of many fruits, essential oils, and fragrances, metabolizes readily to i nnocuous products. Therefor e, oral toxicity resulting from the use of isobutyl isobutyrate as an inert ingr edient in pesticides is not expected to be significant. To further evaluate the toxicity of isobutyl isobutyrate the

OECD SIDS dataset on isobut yl isobutyrate was consul ted. In addition, data on

isobutanol from the US EPA's IRIS database is referenced. Isobuta nol is one of the primary metabolic products of isobutyl isobut yrate, and therefore these data can be bridged to assess the toxicity of the ester.

1. Acute toxicity. Acute toxicity data categorize isobutyl isobutyrate into Acute Toxicity Category IV for oral, inhalation, and dermal exposure. The acute oral LD 50 value in rats and mice was >6,400 mg/kg/bw. More re cent studies of isobutanol, a metabolite of isobutyl isobutyrate, derived si milarly high values for the acute oral median lethal dose,2

around 3000 mg/kg/bw in rats. Acute inhalation toxicity is likewise low, with a 6-hour

LC 50 between 3.88 and 31.94 mg/L isobutyl is obutyrate in rats. The dermal LD 50 value in guinea pigs was >8550 mg/kg/bw.

2. Genotoxicty. Isobutyl isobutyrate did not i nduce reverse mutations in Salmonella typhimurlum strains TA98, TAIOO, TA1535, and TA1537, or in Escherichia

coli strain WP2 uvrA at concentrations as hi gh as 5000 pg/mL in the absence or presence

of metabolic activation. In vivo genotoxicity studies of isobutanol are all negative.

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 postcoitum days 6-15. No mortalit y or significant diffe rences in clinical signs, body weight development, or gross path ology between controls and treated groups were observed. No effects on development we re 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 lowe r body weight gain, par ticularly during the first phase of exposure. The maternal NOAEL for rabbits was 758 ppm. Fetuses exhibited no signs of developmental changes in res ponse to isobutanol. Therefore, the rabbit developmental NOAEL was 3030 ppm, the highest dose (OECD 2004).

Reproductive Toxicity

In a 2-generation reproductive i nhalation study isobutanol (99.9%) was administered to 30 Crl:CD(SD)IGS BR ra ts/sex/dose by whole body exposure at 0, 500,1000 and 2500 ppm (0, 1476, 2952, and 7380 mg/m 3 ) 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 e nded after weaning of the pups (F0 generation postnatal day 28, F1 generation postnatal da y 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 significan t spermatogenic or macroscopic findings, changes in primordial follicle or corpora lu tea counts, changes in mean organ weights or histopathologic lesions in th e F0 or F1 rats at any dose. Pup endpoints were not significant for either F1 or F2 generations, including survival, ge neral physical condition, and mean body weights. Ther e were no macroscopic findings , changes in mean organ weights, or maturation of F1 pups. The NOA EL of isobutanol for parental systemic, reproductive and neonatal toxi city is 2500 ppm (7380 mg/m 3 the maximum applied dose) in males and females of the F0, F1 and F2 generations. The study was rated "reliable without restriction" by the Eur opean Chemicals Agency (ECHA).

4. Subchronic toxicity. Isobutyl isobutyrate (purity >98%) had a low toxicity profile in the one subchronic toxicity study identified: an 18-week oral gavage study in3

rats. Wistar rats (15/sex/ dose) received doses of 0, 10, 100, or 1,000 mg/kg bw/day. No lasting significant effects were noted in blood or urin e parameters, histological examination, behavior, appearance, body wei ght, or food/water consumption. There were no significant changes in organ weights rela ted to treatment of animals with isobutyl isobutyrate. The NOAEL was repor ted to be 1000 mg/kg/day.

Studies of isobutanol, the metabolite produ ced rapidly from isobutyl isobutyrate, further support that isobutyl is obutyrate is low in toxicity. In a 90-day oral r odent toxicity study on isobutanol, which serves as the scie ntific basis for US EPA's RfD for that compound, the test compound was administered to 30 Sprague-Dawley (Crj: CD(SD)) rats/sex/dose by gavage for 90 days at dos e 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 ra ts) 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. In addition, serum potassium levels were 11-15% lower in both sexes compared to controls on day 29, but group mean serum potassium con centrations were similar for treated and control groups at the final cl inical pathologic evaluation. No other significant differences between dosed groups and controls were found for ophthalmoscopic examination, hematology, urinalysis, organ weights, gr oss pathology and hist opathology. 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 isobutanol by applying uncertainty factors totaling 1000 to this NOEL.

Wistar rats (10/sex/group) were exposed to isobuta nol 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 incl uded full hematology, urinalysis, and ophthalmological endpoints as well as postsac rifice 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, clin ical observation, c linical chemistry,

neurobehavioral observations , organ weights, pathol ogy, and histopathology. The NOAEL for repeat-dose effects was the highest dose 2500 ppm.4

5. Chronic toxicity. No chronic studies were iden tified for isobutyl or its metabolites. Based on negative results in genotox icity assays and an extensive history of exposure to isobutyl isobutyrate, carcinogenic potential of th is compound is likely to be

low.

6. Animal metabolism. Esters of short-chain alcohols are hydrolyzed rapidly in the intestines, liver and kidneys of experimental animals and form an alcohol and carboxylic

acids which in this case would be isobutanol and isobutyric acid. Th ese are reactions of the carboxylesterases or esterases, which pre dominate in hepatocyte s but are present in most tissues throughout the body, including sm all intestine, col on, kidney, trachea and lung. In male rats injected intravenously w ith isobutyl isobutyrate , the parent compound decreased rapidly in blood and was undete cted after 166 seconds. The half-life was

calculated at 11.1 seconds. Isobut anol and isobutyric acid leve ls increased rapidly, with the acid consistently higher than the alcohol , suggesting that the former is a metabolic product of the alcohol in addition to th e parent compound. Isobutyric acid will be conjugated and excreted or will undergo β -oxidation in the fatty acid metabolic pathway.

7. Metabolite toxicology

. NA

8. Endocrine disruption

. Toxicity data related to e ndocrine disruption were not identified in the isobutyl isobutyrate databa se. As the scientific knowledge develops, screening of additional compounds may be a dded to the Endocrine Disruptor Screening Program (EDSP). When additi onal screening and/or test ing is conducted, isobutyl isobutyrate may be the focus of screening and/ or testing to better characterize effects

related to endocri ne disruption.

C. Aggregate Exposure

1. Dietary exposure. The estimated dietary exposure to isobutyl isobutyrate was determined using methods to estimate ch ronic dietary exposure for a generic inert ingredient. This assessment considers drinki ng water and crop-specific residues from preharvest applications of agricu ltural insecticides, herbicides and fungicides, assuming the highest established tolerance level residue for each commodity. The assessment assumes that the inert ingredient is us ed on all crops. The inert ingredie nt 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 deri ved for the general US population and subgroups of the population using the Dietar y Exposure Evaluation Model, DEEMTM. The inert ingredient is assumed to be in the fo rmulation at a concentr ation of S0% for the

default assessment. Chronic di etary exposure estimates were derived for the general US population and subgroups of the population. Th e estimated exposure for the total US population is 0.1893 mg/kg bw/day, or 1.89% of the cPAD. Children age 1 to 2 years old have the highest estimated exposure at 0.7062 mg/kg bw/day, or 7.06% of the cPAD.

i. Food. Dietary exposures of concern are not anticipated for isobutyl isobutyrate due to its lack of persistence in the envi ronment and low general toxicity. A significant source of dietary isobutyl isobutyrate comes fr om natural food sources and its use as a5

food additive, JECFA (1999) estimated that in the U.S. the consumption of isobutyrate esters of aliphatic acyclic pr imary alcohols with branched-c hain aliphatic acyclic acids from food additives is equivalent to that from natural sources. JECFA (1999) further

estimated the current levels of intake of isobutyl isobutyrate from its use as a food flavoring agent to be 2.3 ug/ person/day in the U.S., equi valent to approximately 0.033 pg/kg bw/day (0.000033 mg/kg/day). Residues fr om 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. Isobutyl isobutyrate exposure via drinking water from use as an inert ingredient is not expected to be significant. The physical and chemical properties of isobutyl isobutyrate indicate it will volatili ze, readily biodegrade , and therefore not persist in the water environment. Exposure via the drinking water was estimated in the DEEM dietary exposure assessment a ssuming a concentration of 100 ppb.

2. Non-dietary exposure

. Residential exposures of con cern are not anticipated for isobutyl isobutyrate due to its inherent ability to biodegr ade 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 consid er "available information" concerning the cumulative effects of a part icular 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 isobutyrate would be cumulative with those of any other chemical compounds.

EPA has not made a common mechanism of t oxicity finding as to isobutyl isobutyrate and other compounds, isobutyl isobutyrate doe s not produce toxic metabolites in common with other substances of potential concer n. For the purpose of the tolerance exemption proposed, it is assumed that isobutyl isobutyr ate does not share a common mechanism of toxicity with ot her substances

E. Safety Determination

1. U.S. population. Taking into consideration all av ailable information on isobutyl isobutyrate, there is a reasonable certainty that no harm to any population subgroup will result from dietary and ot her nonoccupational exposures to isobutyl isobutyrate when used as an inert ingredient in an inert mixt ure intended for use in pesticide formulations. The toxicity profile of isobut yl isobutyrate indicates a low hazard from all routes of exposure, and a lack of genotoxicity. Isobut yl isobutyrate metabolizes rapidly and completely to isobutanol, which displays lo w repeat-dose toxicity and an absence of developmental and reproductive toxicity in two rodent species. The NOAEL of 1000 mg/kg/day isobutyl isobutyrate derived by Drake et al. (1977) was considered to be the point of departure for this risk assessme nt. Although this was an older study, the high NOAEL is supported by studies of isobuta nol, a primary metabolite of isobutyl6

isobutyrate, indicating low toxi city for that compound too. Adjusting for uncertainty of inter- and intraspecies extrap olations (l0x each), the RfD for isobutyl isobutyrate was determined to be 1000/100 = 10 mg/kg/day. The chronic Population Adjusted Dose (cPAD) was considered equivalent to th e RfD because no effects of isobutanol, on development or reproduction were observe d, suggesting that isobut yl isobutyrate too would not increase susceptibility of sensitiv e populations. Therefor e, 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 isobut yl isobutyrate, 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 isobutyl isob utyrate as an inert i ngredient in pesticide products. An evaluation of susceptibility and unc ertainty Issues asso ciated with isobutyl isobutyrate has been performed. The structur ally similar and metabolically related compound isobutanol was not a developmenta l toxin to rats or rabbits following inhalation. Therefore, there is no concern for increased sensitivity to Infants and children to isobutyl isobutyrate when used as an inert in gredient in pesticide formulations. 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.

F. International Tolerances

NA