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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 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)

[IN-10699]

EPA has received a pesticide petition (IN-10699) 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 amend 40 CFR part 180 to establish an exemption from the requirement of a 

tolerance for 1,2-Propanediol, 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 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. There is no specific crop residue information available 

for 1,2-propanediol, 3-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-1-disiloxanyl]

propoxy]. This information is typically not applicable to this inert ingredient petition.

B. Toxicological Profile

1. Acute toxicity. The proposed inert (CAS RN 70280-68-1) is EPA Toxicity

Category III for acute oral and acute dermal toxicity. Based on the weight of evidence 
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from the bridging/read-across analysis 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, nonirritating to the eyes 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) analysis for in vitro

and in vivo genotoxicity support a lack of genotoxicity. These data are further supported 

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-heptamethyltrisiloxane (HMTS) showed no 

reproductive or developmental toxicity resulting from oral gavage at doses up to and 

including the highest dose level (800 mg/kg bw/day). Parental systemic toxicity was 

reported at 200 mg/kg bw/day with a NOAEL of 50 mg/kg bw/day. The NOAEL for 

reproductive 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 protoporphyrin accumulation in both male and 

female rats and kidney effects are consistent with alpha-2μ-globulin nephropathy in male 

rats. Mechanistic studies 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 analysis 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 LOAEL of 

200 mg/kg bw/day based on protoporphyrin accumulation. These data demonstrate that 

upon chronic exposure (up to 1 one year of dietary exposure) the NOAELs (24 and 27 

mg/kg bw/day) are similar to those identified in the 28-day oral gavage studies for the Si2 to Si-5 related compounds. The strength 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 carcinogenicity or neurotoxicity is anticipated with dietary exposure with the 

proposed inert.

6. Animal metabolism. The combination of ether hydrolysis followed by ßoxidation of the carbon chain followed by methyl oxidation of the silyl methyl groups is 

the plausible favored pathway for Si-3 and higher backbone siloxanes and is expected for 

CAS RN 70280-68-1. Methyl oxidation would result in the formation of a mixture of 
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primary and alcohol metabolites. The more polar primary alcohol functionalities can 

both be conjugated and excreted directly or further oxidized to form a mixture of more 

polar carboxylic 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 designated or potentially designated as endocrine 

disruptors. Although at some future date EPA may screen the proposed inert for potential 

estrogen, androgen and thyroid (EAT) hormonal effects in the EDSP assays, 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 (Si3) 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 uncertainty factor for intra- and inter-species differences is 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 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. The highest 

% 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. Based on the vapor pressure the proposed inert, CAS 

RN 70280-68-1, is likely to have a low potential for inhalation exposure. Subchronic 

dermal toxicity studies resulted in NOAELs of 1000 mg/kg bw/day. The target organ 

relevant to mammalian toxicity for the proposed inert is expected to be the liver, in the 

form of protoporphyrin accumulation upon repeated dose oral exposure. Therefore, it can 

be concluded that non-dietary exposure would be low for occupational and residential 

exposure.
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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 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 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 form the aggregate exposure to 1,2-propanediol, 3-[3-[1,3,3,3-

tetramethyl-1-[(trimethylsilyl)oxy]-1-disiloxanyl]propoxy].

2. Infants and children. The FFDCA Section 408 requires an additional tenfold 

margin of safety for the protection 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 may 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 analysis of a cluster of structurally

similar chemicals, 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 neuropathological 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 the locomotor activity assessments at 5000 ppm, 

delayed 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 systemic toxicity and offspring decreased 

body weight effects (400 ppm or 2.7 mg/L). 
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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 (systemic 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 compounds included in this 

analysis. In the oral combined repeated dose and reproductive and developmental 

screening study 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 tested). 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 Uncertainty in the Exposure Database

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 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

There are no known international tolerances for 1,2-propanediol, 3-[3-[1,3,3,3-

tetramethyl-1-[(trimethylsilyl)oxy]-1-disiloxanyl]propoxy]