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EPA REGISTRATION DIVISION COMPANY 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 preparing 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 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 Auburn 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 inert ingredient in 

pre-harvest applications including 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 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. While no specific food use residue information was 
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located for DMSO, based on the physical, chemical and environmental properties of 

DMSO, significant crop residues are not likely. DMSO is readily biodegradable and 

environmental persistence 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 irritating 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 has been tested in a large number of assays 

using a wide range of methods. The data presented 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 indicate 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 visceral effects, which would 

include eyes, were reported in the offspring in these studies. 

 4. Subchronic toxicity. DMSO is considered to be well absorbed orally, dermally 

and via inhalation. Other than ocular toxicity, only slight systemic toxicity at dose levels 

at or above the limit dose of 1000 mg/kg bw/day have been reported 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 would also be protective of the ocular 

toxicity in humans based on the available 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 levels 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 consistency of the data 

lead to a high level of confidence for the use of 1000 mg/kg bw/day as the NOAEL for 

chronic dietary risk assessment. 

No neurobehavioral or neuropathological effects were reported from oral, dermal or 

inhalation exposures in the toxicological database for DMSO. 
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 6. Animal metabolism. Upon dermal and oral exposures, in humans and animals, 

DMSO is quickly biotransformed from an essentially odorless liquid to a highly volatile 

metabolite, dimethyl sulfide (DMS). DMSO metabolism to DMS is mediated by 

sulfoxide reductases, primarily in the liver and kidneys, and then DMS is rapidly 

reoxidized to DMSO2 by mixed-function oxidases. Excretion 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 administration. Upon topical administration, DMSO 

enhances skin permeability. An in vitro permeability rate of 176 g/m2 h has been 

reported for human skin. No data are available on the absorption of DMSO by inhalation 

exposure. However, its physico-chemical properties (low molecular size, high polarity 

and water solubility) suggest that DMSO is significantly absorbed by the inhalation route. 

Peak plasma concentration of DMSO was attained 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, respectively. A shorter clearance half-life of 6 hours 

was observed in rats after both routes of exposure. Metabolism of DMSO takes place 

primarily in the liver and kidneys. The principal metabolite is dimethyl sulfone 

(DMSO2). Peak plasma levels of DMSO2 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 DMSO2 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 DMSO2, respectively. 

 7. Metabolite toxicology. DMSO does not produce a toxic metabolite(s) that may 

have a common mechanism of toxicity with other substances.

 8. Endocrine disruption. DMSO, the proposed inert, does not belong to a class of 

chemicals designated or potentially designated as an endocrine disruptor. Although at 

some future date EPA may screen the proposed inert for potential EAT hormonal effects 

in the EDSP assays, the current repeat dose database of mammalian toxicology studies, 

which include reproductive and developmental toxicity testing, does not indicate 

potential adverse EAT hormonal effects. 

DMSO is used at concentrations up to 0.01% (v/v) as a solvent (vehicle) 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-species differences are applicable. There 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 10 mg/kg 
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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 reference dose (cRfD) of 10 mg/kg bw/day with 

a maximum percentage of the proposed inert of 61.82% as a diluent in the Cyclaniliprole 

50 SL formulations according to 40 CFR 180.920 pre-harvest applications including postemergence. The highest % chronic population 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) via 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 are available on the absorption of DMSO by 

inhalation exposure. However, its physico-chemical 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 does not produce a toxic 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 the 

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 Determination

 1. U.S. population. A dietary exposure assessment using current EPA inert 

screening level methodology (I-DEEM) was conducted. Based on the conservative IDEEM dietary exposure estimates, there is a reasonable certainty that 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.
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 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 oral NOAEL of 1000 mg/kg bw/day with 

100X in safety factors. A reference value 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 available for DMSO. The toxicological database 

consists of studies in humans, primates, rats, rabbits, dogs and pigs via oral, dermal 

and/or inhalation exposures for subchronic and chronic durations. The database consists 

of both guideline and non-guideline 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 testing in dogs, rats, rabbit and 

pigs, were not seen in humans and were questionable 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 effect 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 neuropathological effects were reported from oral, dermal or 

inhalation exposures in the toxicological database for DMSO. The non-guideline oral 

and dermal studies include evaluations of clinical 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) evaluations as well as full histopathology and no effects were 

reported. 

Neurotoxicological effects of DMSO reported in the literature are limited 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 study by Carr and Nail (2008), the cholinesterase 

inhibition of DMSO in late preweanling rats was evaluated at dose levels of 0.5 ml/kg 

administered subcutaneously for 7 days from post-natal days 10 through 16. No effect on 

brain ChE was reported in this study and no inhibition of serum ChE was reported in the 

DMSO only treated groups in this study. 

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 
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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- and/or postnatal toxicity because the observed 

effects are well characterized. Furthermore, the dietary risk assessments for inert 

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

No known international tolerances have been established for DMSO.