Document ID: EPA-HQ-OPP-2014-0449-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-04-06T04:00Z

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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 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,
non-irritating 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
Si-2 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
ß-oxidation 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 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 (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 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.

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 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-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).  

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]

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