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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: [**  **P. V. Shah, 703**  **- 308**  **- 1846**  **] INSTRUCTIONS:**  **Please utilize this outline in preparin g 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 g**  **reen , i.e., “**  **[ insert**  **company name ]**  **,” with the information specific to your action. TEMPLATE:**  ISK Biosciences Corporation (I SK) [ IN - 10699 ] EPA has received a pesticide petition ( IN - 10699 ) from IS K Biosciences Corporation , 7470 Auburn Road, Suite A, Con cord, OH 44077 request ing, 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 1,2 - P ropanediol, 3 - [3 - [1,3,3,3 - tetramethyl - 1 - [(trimethylsilyl)oxy] - 1 - disiloxanyl]propoxy] (CAS RN 70280 - 68 - 1 ), for use as an inert ingredient antifoaming agent in pre - harvest food - use formulations in accordance with 40 CFR §180.920 , with a maximum use rate of 10% . EPA has determined that the p etition 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 1. Plant metabolism. Not applicable to this inert ingredient petition . 2. Analytical method. Not applicable to this inert ingredient petition . 3. Magnitude of residues. There is no specific crop residue information available for 1,2 - propanediol, 3 - [3 - [1,3,3,3 - tetrameth yl - 1 - [(trimethylsilyl)ox y] - 1 - disiloxanyl] propox y] . This information is ty picall y n ot applicable to this inert ingredient petition . B. Toxicological Profile 1. Acute toxicity. T he proposed inert (CAS RN 70280 - 68 - 1) is EPA Toxicity Category III for acute oral and acute dermal toxicity . Based on the weight of evidence2

from the bridging/read - across anal ys is of the linear short chain siloxane cluster (Si - 2 to Si - 5), the proposed inert is expected to be non - toxic via acute inhalation exposure, non irritating to the ey es and skin, and not result in skin sensitization. 2. Genotoxicty. 1,2 - propanediol, 3 - [3 - [1,3,3,3 - tetramethyl - 1 - [(trimethylsilyl)oxy] - 1 - disiloxanyl] propoxy] has been shown to be without effect in the Ames assay . The available data for the linear short chain siloxane cluster (Si - 2 to Si - 5) anal ysis for in vitro and in vivo genotoxicity

support a lack of genotoxicity . These data are further suppo rted by the DEREK assessment . 3. Reproductive and developmental toxicity. The OECD 422 oral gavage combined repeated dose and reproductive/developmental screening study conducted with CAS RN 1873 - 88 - 7, 1,1,1,3,5,5,5 - heptameth yl trisiloxane (HMTS) showed n o reproductive or developmental toxicity resulting from oral gavage at doses up to and including the highest dose level (800 mg/kg bw/day). Parental s ys temic toxicity was reported at 200 mg/kg bw/day with a NOAEL of 50 mg/kg bw/day . T he NOAEL for reprodu ctive and developmental toxicity is estimated to be 800 mg/kg bw/day for the proposed inert ingredient, CAS RN 70280 - 68 - 1, based on the combined oral repeated dose and reproductive and developmental toxicity testing available for the Si - 3 compound, CAS RN 1873 - 88 - 7, 1,1,1,3,5,5,5 - heptamethyltrisiloxane (HMTS). 4. Subchronic toxicity. The repeated dose toxicity data available on the linear short chain siloxane cluster support a NOAEL of 25 mg/kg bw/day . Evaluation of the data set indicates that the target organs for this cluster of compounds are the liver and kidney . Liver effects are consistent with protoporphy rin accumulation in both male and female rats and kidney

effects are consistent with alpha - 2μ - globulin nephropathy in male rats. Mechanistic stud ies have been conducted with this cluster of compounds that confirm the alpha - 2μ - globulin nephropathy mode of action in male rats, which EPA has determined to be not relevant to humans. The identification of kidney and liver as the target organs is also supported by the DEREK analy sis for the proposed inert. 5. Chronic toxicity. The recommended NOAEL for chronic oral exposure for the proposed inert, CAS RN 70280 - 68 - 1, is 25 mg/kg bw/day with an associated L OAEL of 200 mg/kg bw/day

based on protoporphy

ri n accumulation. These data demonstrate that upon chronic exposure (up to 1 one y ear of di etary exposure) the NOAELs (24 and 27 mg/kg bw/day) are similar to those identified in the 28 - day oral gavage studies for the Si 2 to Si - 5 related compounds. The str ength and consistency of the data lead to a high level of confidence for the use of 25 mg/kg bw/day as the NOAEL for chronic dietary risk assessment . No carcinogenicit y or neurotoxicity is anticipated with dietary exposure with the proposed inert. 6. An imal metabolism. T he combination of ether hydrol ys is followed b y ß oxidation of the carbon chain followed b y meth yl oxidation of the silyl methyl groups is the plausible favored pathway for Si - 3 and higher backbone siloxanes and is expected for CAS RN 7028 0 - 68 - 1. Methyl oxidation would result in the formation of a mixture of3

primary and alcohol metabolites. The more polar primary alcohol functionalities can both be conjugated and excreted directl y or further oxidized to form a mixture of more polar carbox yl ic acid metabolites that could be readily conjugated and excreted. 7. Metabolite toxicology . There are no metabolites of toxicological concern. 8. Endocrine disruption . The proposed inert, CAS RN 70280 - 68 - 1, does not belong to a class of chemicals de signated or potentially designated as endocrine disruptors. Although at some future date EPA may screen the proposed inert for potential estrogen, androgen and thy roid ( EAT ) hormonal effects in the EDSP assay s, the current repeat dose database of mammalian toxicology studies, that includes reproductive and developmental toxicity

testing, does not indicate potential adverse EAT hormonal effects. Two uterotrophic studies conducted with the linear short chain cluster compounds are available; CAS RN 107 - 46 - 0 (Si - 2) via oral gavage exposure and CAS RN 107 - 51 - 7 (Si 3) via inhalation exposure reported no effects for either study . C. Aggregate Exposure 1. Dietary exposure. For the dietary risk assessment of the proposed inert, the 100X uncertaint y factor for intra - and inter - species differences is applicable. T here are no residual FQPA concerns and the FQPA uncertainty factor can be reduced to 1X. Therefore, the recommended reference dose (RfD) for risk assessment is 0.25 mg/kg/day (NOAEL of 25 mg/kg bw/day / 100X). The I - DEEM assessment used a chronic reference dose (cRfD) of 0.25 mg/kg bw/day with a maximum percentage of the proposed inert of 10% as an antifoaming agent in formulated pesticides according to 40 CFR 180.920 pre - harvest applications. T he highe st % chronic population adjusted dose (cPAD) using the cRfD and a cap of 10% is approximately 15.8% for the U.S. population and 57.5% for children (1 - 2 yr), the most sensitive population. i. Food. The available data demonstrate that the I - DEEM screening level chronic dietary (food and drinking water) exposures are below 100% of the cPAD, and are therefore below EPA’s established level of concern for all U.S. subpopulations . ii. Drinking water. Based the I - DEEM assessment of the proposed inert, exposure to humans (adults and children) via potential residues in drinking water is below EPA’s established level of concern for all U.S. subpopulations. 2. Non - dietary exposure . B ased on the vapor pressure the proposed inert, CAS RN 70280 - 68 - 1, is likely to hav e a low potential for inhalation exposure. Subchronic dermal toxicity

studies resulted in NOAEL s of 1000 mg/kg bw/day . T he target organ relevant to mammalian toxicity for the proposed inert is expected to be the liver, in the form of protoporph yrin accumulation upon repeated dose oral exposure. Therefore, it can be concluded that non - dietary exposure would be low for occupational and residential exposure.4

D. Cumulative Effects Unlike pesticides for which EPA has followed a cumulative risk approach bas ed on a common mechanism of toxicity , EPA has not conducted a common mechanism evaluation for 1,2 - propanediol, 3 - [3 - [1,3,3,3 - tetramethyl - 1 - [(trimethylsilyl)oxy] - 1 - disiloxanyl]propoxy] (CAS RN 70280 - 68 - 1). Moreover the proposed inert does not produce a tox ic metabolite(s) that may have a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity

and to evaluate the cumulative effects of such chemicals, see th e policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism (http://www.epa.gov/pesticides/cumulative). E. Safety Dete rmination 1. U.S. population. A dietary exposure assessment using current EPA inert screening level methodology (I - DEEM) was conducted. Based on the conservative I DEEM dietary

exposure estimates, there is a reasonable certainty that no harm will result to the U.S. population form the aggregate exposure to 1,2 - propanediol, 3 - [3 - [1,3,3,3 - tetrameth yl - 1 - [(trimethylsilyl)oxy] - 1 - disiloxanyl]propoxy] . 2. Infants and children . The FFDCA Section 408 requires an additional tenfold margin of safety

for the prote ction of infants and children to account for prenatal and postnatal toxicity , and an inadequate toxicity database. Where an adequate and reliable database is available, and there is a lack of evidence for increased susceptibility , the FQPA safety

factor m ay

be reduced or removed. Completeness of the Toxicological Database Although a complete toxicological database is not available for the proposed inert, CAS RN 70280 - 68 - 1, based on bridging/read - across analy sis of a cluster of structurally similar chemic als, the toxicological database is adequate for characterizing the toxicity of linear short chain siloxane compounds and assessing the risk from dietary exposure to the proposed inert ingredient. Evidence of Neurotoxicity No neurobehavioral or neuropathol ogical effects were reported from oral exposures. The two - generation reproduction study via whole - body inhalation with CAS RN 107 - 46 - 0 reported the developmental neurobehavioral NOAEC at 10.6 mg/L (1600 ppm), based on a lack of habituation exhibited in th e locomotor activity assessments at 5000 ppm, delay ed attainment of the surface righting response in the 5000 ppm group F2 females, and decreases in average and peak acoustic startle response on PND 20 in the 5000 ppm group F2 males and females. However, these effects were noted at exposure concentrations above the NOAEC for parental s ys temic toxicity and offspring decreased body weight effects (400 ppm or 2.7 mg/L).5

Based on the weight of the evidence, the results of these studies indicate that there are no qualitative or quantitative differences in the sensitivity of offspring and that no neurotoxicological effects are seen in the bridging/read - across database for which other toxicological endpoints (sy stemic parental and offspring body weight effects) would not be protective. Evidence of Sensitivity

/Susceptibility

in the Developing or Young Animal There is no evidence of increased quantitative or qualitative susceptibility of rat fetuses following in utero exposure to the linear short chain siloxane c ompounds included in this anal ys is. In the oral combined repeated dose and reproductive and developmental screening stud y with Si - 3 compound CAS RN 1873 - 88 - 7, the NOAEL for reproductive and developmental toxicity was 800 mg/kg bw/day

(the highest dose tes ted). Because the oral route of exposure is most applicable to the dietary risk assessment, this study is the most relevant to the assessment of risk resulting from dietary exposure to the proposed inert ingredient. Residual Uncertaint y in the Exposure D atabase There are no residual uncertainties for pre - and/or postnatal toxicity because the observed effects are well characterized and there are clear NOAELs/LOAELs determined for the toxic effects observed. Furthermore, the dietary risk assessments for i nert ingredients are very conservative as they are based on high - end assumptions regarding dietary exposures. As such, the exposure assessment is unlikely to underestimate actual exposures. No other residual uncertainties were identified with respect to susceptibility . The endpoints selected for the proposed inert are protective of adverse effects in both offspring and adults. F. International Tolerances There are no known international tolerances for 1,2 - propanediol, 3 - [3 - [1,3,3,3 - tetrameth yl - 1 - [(tri methylsilyl)oxy] - 1 - disiloxanyl]propoxy]