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EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: [insert name and telephone number with area code]

INSTRUCTIONS: Please utilize this outline in p reparing the pesticide petition. In

cases where the outline element does not apply, please insert “NA-Remove” and

maintain the outline. Please do not chan ge the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green , i.e., “ [insert company name] ,” with the information specific to your action.

TEMPLATE:

ISK Biosciences Corporation (ISK)

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from ISK Biosciences Corporation, 7470 Aubur n Road, Suite A, Concord, OH 44077 requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to establish an exemption from the requirement of a tolerance for dimethyl sulfoxide (DMSO) under 40 CFR part 180.920 for post-emergence pre-harvest

use in Cyclaniliprole 50 SL Formulations

(Options (pick one)

2. to establish an exemption from the requirement of a tolerance for:

Dimethyl Sulfoxide (DMSO) (CAS RN 67-68- 5), for use as an in ert ingredient in pre-harvest applications in cluding post-emergence use in Cyclaniliprole 50 SL formulations in accordance with 40 CFR §180.920 . EPA has determined that the petition contains data or information regarding the el ements set forth in se ction 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 gran ting 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. While no specific food use residue information was2

located for DMSO, based on the physical, ch emical and environmental properties of DMSO, significant crop residues are not likely. DMSO is readily biodegradable and environmental persis tence is not likely.

B. Toxicological Profile

1. Acute toxicity. Based on the toxicological database, DMSO is of low acute toxicity (EPA Toxicity Category III or IV) via acute oral, dermal and inhalation exposures, is slightly irritati ng to the eyes, non-irritating to the skin and is not a skin

sensitizer.

2. Genotoxicity. DMSO is used worldwide as a solvent for poorly water-soluble substances in the genotoxicity tests and it ha s been tested in a large number of assays using a wide range of methods. The data pr esented support a lack of genotoxicity for DMSO. In studies performed with methods compliant to OECD guidelines, no genotoxic activity was observed for DMSO in gene mutations assays in Salmonella typhimurium

, and in vitro cytogenetic assays in Chinese hamster ovary (CHO) cells and an in vivo micronucleus assay in rats.

3. Reproductive and developmental toxicity. Results of reproductive and developmental toxicity studies do not indicat e any fetal or embryo toxicity, teratogenic effects, fertility effects, systemic effects on reproductive organs or offspring toxicity. The NOAEL for reproductive effects, offspring effects, embryo- and feto-toxicity is 1000 mg/kg bw/day and the NOAEL for maternal toxicity in rabbits was 300 mg/kg bw/day with a LOAEL of 1000 mg/kg bw/day based on maternal body weight gain. Ocular toxicity was not evaluated in these studies; however, no vis ceral effects, which would include eyes, were reported in the offspring in these studies.

4. Subchronic toxicity. DMSO is considered to be we ll absorbed orally, dermally and via inhalation. Other than ocular toxicity, only slight systemic t oxicity at dose levels

at or above the limit dose of 1000 mg/kg bw/day have been re ported in the toxicological

literature in animals. These effects include decreased body weight gain and effects that may be secondary to the diuretic effect of DMSO (hematological effects, urinalysis effects). A NOAEL of 1000 mg/kg bw/day w ould also be protective of the ocular toxicity in humans based on the av ailable testing data in humans.

5. Chronic toxicity. DMSO is of low toxicity upon subchronic and chronic repeated oral administration. Indications of systemic toxicity (not including ocular toxicity) include body weight and hematological finding at dose leve ls at or above the limit dose of 1000 mg/kg bw/day. Although not relevant to humans, a NOAEL for ocular toxicity of 500 mg/kg bw/day is also available. The strength and c onsistency of the data lead to a high level of confidence for th e use of 1000 mg/kg bw/day as the NOAEL for chronic dietary risk assessment.

No neurobehavioral or neuropa thological effects were repor ted from oral, dermal or inhalation exposures in the toxi cological database for DMSO.3

6. Animal metabolism. Upon dermal and oral exposures, in humans and animals, DMSO is quickly biotransformed from an e ssentially odorless liqui d to a highly volatile metabolite, dimethyl sulfide (DMS). DMSO metabolism to DMS is mediated by sulfoxide reductases, primarily in the liv er and kidneys, and then DMS is rapidly

reoxidized to DMSO 2 by mixed-function oxidases. Excr etion of DMSO is 1% in exhaled air, and 85% in urine (50%) and feces (50%). No accumulation of DMSO in tissues has been reported after prolonged administ ration. Upon topical administration, DMSO enhances skin permeability. An in vitro permeability rate of 176 g/m 2 h has been reported for human skin. No data are available on the absorption of DMSO by inhalation exposure. However, its physico-chemical pr operties (low molecular size, high polarity and water solubility) suggest that DMSO is si gnificantly absorbed by the inhalation route.

Peak plasma concentration of DMSO was atta ined at 4 h after oral dosing in humans and at 0.5 h in rats. DMSO is widely distributed to all body tissues. Highest concentrations of DMSO were found in the kidney, spleen, lung, heart and testes of rats given an oral dose, while highest levels of DMSO were noted in the spleen, liver and lungs following a dermal dose. In humans, the plasma DMSO clearance half-life was about 11 to 14 h, and 20 h after dermal and oral dosing, respectivel y. A shorter clearance half-life of 6 hours

was observed in rats after bot h routes of exposure. Me tabolism of DMSO takes place primarily in the liver and kidneys. The principal metabolite is dimethyl sulfone (DMSO 2 ). Peak plasma levels of DMSO 2 in humans were observed at 72 to 96 h after dosing, and then declined with a half-life of about 60 to 72 h. DMSO is excreted unchanged or as the metabolite DMSO 2 in the urine. In humans, about 13 and 18% of a dermal dose, and 51% and 10% of an oral dose were accounted for by urinary excretion

of DMSO and DMSO 2 , respectively.

7. Metabolite toxicology

. DMSO does not produce a toxi c metabolite(s) that may have a common mechanism of toxicity with other substances.

8. Endocrine disruption

. DMSO, the proposed inert, doe s not belong to a class of chemicals designated or potentially designate d as an endocrine di sruptor. Although at some future date EPA may screen the propos ed inert for potential EAT hormonal effects in the EDSP assays, the current repeat dose database of mammalia n toxicology studies, which include reproductive and developmen tal toxicity testin g, does not indicate potential adverse EAT hormonal effects.

DMSO is used at concentrations up to 0.01% (v /v) as a solvent (vehic le) control in EDSP

Tier I in vitro assays. In the meeting minutes from the FIFRA SAP Meeting held January 29-31, 2013, it was stated that DMSO can be weakly estrogenic in in vitro testing.

C. Aggregate Exposure

1. Dietary exposure. For the dietary risk assessment of the proposed inert, the 100X uncertainty factor for intra- and inter-spe cies differences are a pplicable. There are no residual FQPA concerns and the FQPA uncertainty factor can be reduced to 1X. Therefore, the recommended reference dos e (RfD) for risk assessment is 10 mg/kg4

bw/day (NOAEL of 1000 mg/kg bw/day / 100X ) for the general population and 3 mg/kg bw/day (NOAEL of 300 mg/kg bw/day / 100X) for females 13-49.

The I-DEEM assessment used a chronic refere nce dose (cRfD) of 10 mg/kg bw/day with a maximum percentage of the proposed inert of 61.82% as a d iluent in the Cy claniliprole 50 SL formulations according to 40 CFR 180.920 pr e-harvest applications including postemergence. The highest % chronic populati on adjusted dose (cPAD) using the cRfD and a cap of 61.82% is approximately 8.7% 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 on the I-DEEM assessment of the proposed inert, exposure to humans (adults and children) vi a potential residues in drinking water is

below EPA’s established level of concern for all U.S. subpopulations.

2. Non-dietary exposure

. DMSO is considered to be well absorbed orally, dermally and via inhalation. No data ar e available on the absorption of DMSO by inhalation exposure. However, its physico-ch emical properties (low molecular size, high polarity and water solubility) suggest that DMSO is significantly absorbed by the

inhalation route.

D. Cumulative Effects

Unlike pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not conducted a common mechanism evaluation for DMSO. Moreover, DMSO doe s not produce a toxic metabolite(s) that may have a common mechanism of t oxicity 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 the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures fo r cumulating effects from substances found to have a common mechanism ( http://www.epa.gov/pesticides/cumulative ).

E. Safety Determination

1. U.S. population. A dietary exposure assessment using current EPA inert screening level methodology (I-DEEM) was co nducted. Based on the conservative IDEEM dietary exposure estimates, there is a reasonable certainty th at no harm will result to the U.S. population from the aggregate exposure to Dimethyl Sulfoxide. For the proposed use of 61.82% maximum of the inert in a pesticide formulation, the % cPAD is a maximum of 2.3% for the U.S. population.5

2. Infants and children

. A preliminary chronic dietary exposure assessment was conducted for DMSO utilizing I-DEEM using the default 50% and the actual 61.82% percentages of the inert in the formulation. The reference value utilized for the general population was 10 mg/kg/day based on an or al NOAEL of 1000 mg/kg bw/day with 100X in safety factors. A reference valu e of 3.0 mg/kg bw/day for females 13-49 was also used based on the oral NOAEL of 300 mg /kg bw/day in the rabbit developmental toxicity study with 100X in safety factors. For the proposed use of 61.82% maximum of the inert in a pesticide formulation, the % cPAD is a maximum of 8.7% for children 1-2 years of age.

Completeness of the Toxicological Database

A complete toxicological database is availa ble for DMSO. The toxicological database consists of studies in humans, primates, ra ts, rabbits, dogs and pigs via oral, dermal and/or inhalation exposures fo r subchronic and chronic durati ons. The database consists of both guideline and non-guide line studies. Guideline reproductive and developmental toxicity studies are available for DMSO . The dose levels used throughout the toxicological database are at or well above the limit dose of 1000 mg/kg bw/day. Ocular

effects demonstrated in oral and dermal repeated dose te sting in dogs, ra ts, rabbit and pigs, were not seen in humans and were ques tionable in primates. Systemic effects were limited to dose levels >1000 mg /kg bw/day and included body weight effects and effects possibly due to the secondary diuretic e ffect of DMSO (mild hematological and urinalysis parameters). No reproductive or developmental toxicity was reported in the database, maternal toxicity in rabbits was reported at a dose level of 300 mg/kg bw/day.

Evidence of Neurotoxicity

No neurobehavioral or neuropa thological effects were repor ted from oral, dermal or inhalation exposures in the t oxicological database for DM SO. The non-guideline oral

and dermal studies include evaluations of c linical effects as well as gross and histopathology assessment of relevant neurological organs with no effects. In addition, the 90-day guideline study with DMSO via nose- only inhalation included functional observations battery (FOB) eval uations as well as full hist opathology and no effects were reported.

Neurotoxicological effects of DMSO reported in the literature are li mited to non-relevant exposure pathways (intravenous or in vitro exposures) (see Attachment 2, literature search DMSO and neurotoxicity). DMSO has been reported to mildly inhibit acetylcholinesterase (AChE) activity (EPA, 2006) and in vitro AChE in the literature was reported in Carr and Nail (2008). In the st udy by Carr and Nail (2008), the cholinesterase inhibition of DMSO in late preweanling rats was evaluated at dos e levels of 0.5 ml/kg administered subcutaneously for 7 days from post-natal days 10 th rough 16. No effect on brain ChE was reported in this study and no i nhibition of serum ChE was reported in the DMSO only treated groups in this study.

Based on the weight of the evidence, the result s of these studies indicate that there are no qualitative or quantitative differences in the sensitivity of offspring and that no6

neurotoxicological effects are seen in the toxicological database for DMSO for which other toxicological endpoints (maternal 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 to the following in utero exposure to DMSO.

Residual Uncertainty in the Exposure Database

There are no residual uncertainties for pre- an d/or postnatal toxicity because the observed effects are well characterized. Furthermore, the dietary risk assessments for inert ingredients are very conserva tive as they are based on hi gh-end assumptions regarding dietary exposures. As such, the exposure as sessment is unlikely to underestimate actual exposures. No other residual uncertainties were identified with resp ect to susceptibility. The endpoints selected for the proposed inert are protective of adverse effects in both offspring and adults.

F. International Tolerances

No known international tolerances have been established for DMSO.