Document ID: EPA-HQ-OPP-2019-0138-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2019-10-03T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
			WASHINGTON, D.C.  20460

							OFFICE OF CHEMICAL SAFETY 								AND POLLUTION PREVENTION

MEMORANDUM  

DATE:		September 9, 2019

SUBJECT:      IN-11248; Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-
            ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-: Human Health Risk and Ecological Effects Assessment of a Food Use Pesticide Inert Ingredient 
 
		CAS Reg. No. 67674-67-3; 	 
                  PC Code:  811641;     
                  Decision 544557

FROM:	Deirdre Sunderland, MHS, Industrial Hygienist
		Chemistry, Inerts & Toxicology Assessment Branch (CITAB)
		Registration Division (RD); 
	

TO:		Kerry B. Leifer, Branch Chief
		CITAB/RD 

 EXECUTIVE SUMMARY

In September 2018 Exponent Inc., on behalf of LNouvel, Inc., submitted a petition (IN-11248) to the Environmental Protection Agency (herein referred to as EPA or the Agency) requesting an exemption from the requirement of tolerance for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- (CAS Reg. No. 67674-67-3) as an inert ingredient for use under 40 CFR § 180.930 for use as a surfactant in pesticide formulations used on animals. Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy is currently approved for use as a food use inert ingredient in pesticide products under 40 CFR 180.910 for use pre- and post-harvest. According to the submitter, it is also use in various other non-pesticidal food and consumer products, including fermentation processes, instant coffee production, paper coatings and sizing, diet soft drinks, waste yeast tanks, food washing solutions, adhesives, textiles, deasphalting, boiler treatments, detergents, cleaning solutions, surfactants, cosmetic products, and polishes. 

No metabolism or pharmacokinetic data was provided; however, based on its molecular weight it was previously concluded by the EPA that absorption of compounds with large molecular weights, such as methylated silicones, by any route would be "poor to nil"

Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy exhibits low levels of acute toxicity. Acute studies in rats showed oral LD50 of >1,600 mg/kg. The dermal LD50 in rats was >3,200 mg/kg. No acute inhalation studies were available. Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- is considered to be an eye irritant and a mild skin irritant. However, it was not found to be a dermal sensitizer. 

Repeat dose studies on poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- are limited. In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats, effects were seen at the highest dose tested (1000 mg/kg/day of the test substance and once adjusted for percent in formulation, 800 mg/kg/day poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-)) and included decreased body weight, body weight gain, and food consumption and reduced body temperature in males. No developmental/reproductive adverse effects attributed to the test substance were observed in the study. 

There is no evidence that exposure to poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- suppresses or otherwise harms immune function in humans. No signs of neurotoxicity were reported in acute or repeat-dose oral studies. There were also no signs of carcinogenicity in the database. Similarly, all tests were negative for genotoxicity and mutagenicity. The available data suggests that poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- is not carcinogenic.

In the 2006 Reassessment of Fifteen Exemptions from the Requirement of a Tolerance for Twelve Poorly Absorbed Chemicals, EPA concluded that absorption of compounds with large molecular weights, such as methylated silicones, by any route would be "poor to nil". At that time the combined repeated dose toxicity study was not available. The decrease in food consumption and the resultant reduced body weights seen in the study were thought by the study author to be due to esophageal irritation caused by direct contact of the test substance. In the second part of the study the test substance was mixed with 5ml/kg of water before administration. The effects seen in the second part of the study were similar and therefore; the Agency is taking the conservative approach of treating these as treatment related. The Point of Departure (POD) for all durations of oral, dermal, and inhalation exposure is based on this study. The No Observed Adverse Effect Level (NOAEL) was 300 mg/kg/day (240 mg/kg/day poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- when adjusted for percent inert ingredient in the test substance) based on effects seen at the Lowest Observed Adverse Effect Level (LOAEL) of 1000 mg/kg/day (800 mg/kg/day poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- when adjusted for percent inert ingredient in the test substance). 
The current and proposed use in pesticide formulations applied to crops pre- or post-harvest and use on animals may result in possible dietary (oral) and residential (dermal, inhalation, and incidental oral in children) exposure. No acute endpoint was determined therefore, an acute assessment was not done. The dietary assessment showed that children 1-2 years old would be the highest exposed subgroup at 29.4% of the 2.4 mg/kg/day chronic Population Adjusted Dose (cPAD). Based on a review of current pesticide product labels containing this inert ingredient, a residential exposure assessment was conducted for pesticides applied to lawns and turf. All exposure scenarios were within acceptable limits and were considered safe. 
When aggregating residential and dietary exposure EPA determines whether pesticide exposures are safe by comparing aggregate exposure estimates to the cPAD. Risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the Margin of Exposure (MOE) called for by the product of all applicable Uncertainty Factors (UFs) are not exceeded. The Agency is concerned with MOEs <100 (10X inter- and 10X intra-species extrapolation safety factors). The FQPA safety factor was reduced to 1X.  When an aggregated exposure assessment was conducted for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- the risk to adults and children were considered safe.  
These products could also be used in commerce and therefore, the use of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- in pesticide formulations may result in dermal and inhalation exposures to workers. The Agency found that when used as proposed, the risk to occupational workers would not exceed the Agency's level of concern. 
Various ecotoxicity and environmental fate studies were conducted with poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-. Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- is dispersible in water and has a octanol-water partition coefficient of 3.31. Available studies classify it as not readily biodegradable.
Available data on the toxic effects of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- to aquatic organisms showed that it is moderately toxic to fish and slightly toxic to aquatic invertebrates. It was practically nontoxic to earthworms and honey bees. 
Based upon the factors summarized above, the Agency approves the expansion of the tolerance of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- to include use on animals under 40 CFR § 180.930 as an inert ingredient in food use pesticide formulations.

 BACKGROUND

In September 2018, Exponent, Inc. on behalf of LNouvel, Inc. submitted a petition (IN-11248) requesting an exemption from the requirement of tolerance for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- (CAS Reg. No. 67674-67-3) as an inert ingredient under 40 CFR § 180.930 for use as a surfactant in pesticide formulations intended for use on animals. Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- is currently approved by the EPA under 40 CFR 180.910 for use pre- and post-harvest.  It was reassessed in June 2006 by the EPA under the chemical grouping of methylated silicones. 

According to the document "Methylated silicones" is general description of large silicone-based polymers. The "Reassessment of Fifteen Exemptions from the Requirement of a Tolerance for Twelve Poorly Absorbed Chemicals" outlined the determination by the EPA's Structural Activity Team (SAT) that while data was limited for methylated silicones, "Absorption of the low molecular weight fraction (MW<1000) is expected to be poor all routes. Nil absorption for the fraction with a molecular weight greater than 1000...low concern for potential health effects."

According to the submitter, methylated silicones "have widespread use in a variety food and consumer products, including fermentation processes, instant coffee production, paper coatings and sizing, diet soft drinks, waste yeast tanks, food washing solutions, adhesives, textiles, deasphalting, boiler treatments, detergents, cleaning solutions, surfactants, cosmetic products, and polishes".
         
 PHYSICAL/CHEMICAL PROPERTIES 

Below are the available physical and chemical properties of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-. Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)
propyl)-omega-hydroxy- is a polyether-modified trisiloxane, with the polyalkyleneoxide portion of the molecule varying in the number of repeat units. According to the submitter, the number of polyalkyleneoxide repeat units is typically either 7 or 8.

Table 1: Physical/Chemical Properties of Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-
Characteristic
Value
Source
Chemical Names
Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)
propyl)-omega-hydroxy- 

3-(Polyoxyethylene)propylheptamethyltrisiloxane

https://chem.nlm.nih.gov/chemidplus/rn/67674-67-3
CAS Reg. No. 
67674-67-3
https://chem.nlm.nih.gov/chemidplus/rn/67674-67-3
Structure

Submitter
Molecular Formula
(C2H4O)nC10H28O3Si3 

Submitter
Molecular Weight 
648.3 (For 8 repeating units of polyalkyleneoxide)
Submitter
Density
1.02 g/cm[3] at 25 °C
Submitter
Vapor Pressure
< 1 mmHg 
Submitter
Melting point
<(-60)- (-8) °C 
Submitter
Boiling point
149-205 °C 
Submitter
Flash Point 
87-118°C
Submiter
Water Solubility
"Dispersible in water"
Submitter
Octanol/Water Coefficient (Log Kow)
3.31 at pH 7 and 9
Submitter

 METABOLISM
No specific study data are available on the toxicokinetics, metabolism or distribution of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-. However, according to the submitter, due to the physical and chemical properties of methylated silicones, limited to nil absorption is expected upon ingestion, inhalation or dermal exposure. 
This conclusion has also been previously made by EPA in the Reassessment of Fifteen Exemptions from the Requirement of a Tolerance for Twelve Poorly Absorbed Chemicals. (EPA 2006). In this reassessment, EPA's Structural Activity Team (SAT) indicated that "The molecular weight of a chemical can affect the human body's ability to absorb it after exposure.". They concluded that absorption of compounds with large molecular weights, such as methylated silicones, by any route would be "poor to nil".

 TOXICOLOGY
        
Available data for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- are summarized below. The majority of data used in this risk assessment was conducted on a mixture that contains ~80% poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-, and 20% of another chemical. This mixture is referred to as "the test substance" in this risk assessment. Subsequently, the dosing values provided in the study were adjusted to account for this percentage. 

 Acute Toxicity

Data on acute oral and dermal toxicity, as well as, data on eye and skin irritation and skin sensitization are discussed in this section. 

 Acute Oral Toxicity 
                                             
The test substance was administered, according to Organization for Economic Cooperation and Development (OECD) Test Guideline 401 (MRID 50657501), by gavage to five male and five female Sprague-Dawley rats at a dose of 2,000 mg/kg. One male rat was found dead two days after dosing. All other animals survived and were observed for 14 days. The LD50 for the test substance was determined to be greater than 2,000 mg/kg (1,600 mg/kg poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega- hydroxy- when adjusted for percent in the test formulation).
 Acute Dermal Toxicity
The test substance was applied to the clipped intact skin of five male and five female Sprague-Dawley rats and maintained in contact for 24 hours under a semi-occlusive dressing according to OECD Test Guideline 402 (MRID 50657502). Skin reactions included desquamation and slight erythema or small superficial scattered scabs. By Day 9 all skin effects were resolved. No mortality or signs of systemic toxicity was seen. The LD50 of the test substance was determined to be greater than 4,000 mg/kg (3,200 mg/kg poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl) propyl)- omega- hydroxy- when adjusted for percent in the test formulation).

 Acute Inhalation Toxicity
           
No acute inhalation toxicity studies are available for poly(oxy-1,2-ethanediyl),alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-.
 Skin Irritation 
Undiluted test substance (0.5 ml) was applied to the clipped skin of 3 New Zealand white rabbits and maintained under a semi­occlusive dressing for 4 hours according to OECD Test Guideline 404 (MRID 50657504). One rabbit showed transient and very slight erythema and edema up to 48 hours post-dosing. No effects were seen at 72-hours. Under the Draize classification scheme the test substance was classified as a mild skin irritant. 
 Eye Irritation 
Eye irritation potential was evaluated after 0.1 ml of the test substance it was instilled in the conjunctival sac of the right eye of one New Zealand white rabbit as described in OECD Test Guideline 405 (MRID 50657503). The left eye remained untreated and was used for control purposes. Corneal opacity, iridial inflammation and moderate conjunctival irritation persisted for 7 days. Circumcorneal vascularization was also noted. Minimal conjunctival irritation was still present on day 14 of observation. Symptoms resolved by day 21 of observation. These findings indicate that the test substance is an eye irritant.
 Skin Sensitization 
The skin sensitizing potential of the test substance was evaluated using a guinea pig maximization test following OECD Test Guideline 406 (MRID 50657505). The study consisted of three phases: a range-finding study, the induction phase (intradermal and topical administration) and the challenge phase (topical exposure). The test substance was classified as a non-sensitizer to guinea pig skin.

 Repeat Dose Toxicity
        
 Combined Repeated Dose Range-Finding Toxicity Study (Oral Toxicity Study in Rats) 

In a  range-finding combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (MRID 50657507, OCSPP Test Guideline 870.3650, OECD Test Guideline 422), the test substance (~80% poly(oxy-1,2-ethanediyl),alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-) was administered to three Han Wistar rats/sex/dose by gavage undiluted at dose levels of 0, 100, 300, or 1000 mg/kg/day (~0, 80, 240, or 800 mg/kg/day poly(oxy-1,2-ethanediyl),alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- when adjusted for percent inert ingredient in the test substance) for at least 14 days prior to mating, throughout mating (up to 14 days), and 13 days after mating for females, for a total of approximately 4 weeks of treatment for males and 6 weeks of treatment for females. Directly after administration of the test item, and without withdrawing the gavage tube, the rats were given 5 mL/kg/day of purified water; control animals were treated with 5 mL/kg/day of purified water only. Terminal sacrifices took place on day 14 post coitum for females, and for males, after necropsy of the first females. Evaluated parameters in included mortality/clinical signs, body weight, food consumption, and gross pathology with special attention to the GI tract and trachea. The necropsy of females included records of the number and distribution of implantation sites, live or dead embryos, and early and late resorptions, and the number of corpora lutea.  Based on recorded data, the following means were calculated: body weight gain and daily food consumption; precoital interval; mating, fertility, conception, and gestation indices; and pre- and post-implantation losses.  

Effects were only noted in high-dose animals as follows. After the mating period, two animals were found dead: one male (on day 11) and one female (on GD 7). No abnormal clinical signs were noted in either animal beforehand. In this same dose group, mean food consumption, body weight and body weight gain were reduced in both males and females during the study. Mean food consumption in males was decreased during the first week of the pre-mating period (17-30%, p<0.01 during days 4-8 only) and during the post-mating period "((20.8%, not statically significant (n.s.)).  Correspondingly, mean body weight gains also were significantly decreased during most of the pre-mating period (p<0.05 for days 4-9,11-12); relative to initial body weight, mean weight increased by 3% in the high-dose group, compared to the 11.3% gain in control males, and mean absolute body weight remained slightly but not significantly lower (3-6%, n.s.) during this time period.  In the high-dose females, mean food consumption also was reduced compared to controls from day 4 of the pre-mating period through gestation (13.8% and 31.2% lower than controls during pre-mating and gestation, respectively).  Statistical significance was achieved during days 11-14 of the pre-mating period and during gestation.  Mean body weight and body weight gain also were reduced in these females.  The lower absolute body weights achieved statistical significance on GDs 9-14, and the mean body weight increase (as a percentage of GD 0 value) was only 21.3% compared to the 31.6% gain in the controls over the gestation period.  There were no macroscopic findings noted in any animal.  
  
Accidental aspiration, rather than a toxic effect of the test item, was considered the likely cause of mortality for the two animals found dead.  Further, the decrease in food consumption and the resultant reduced body weights were thought to be due to esophageal irritation caused by direct contact of the test substance; however, no evidence was provided to support this assumption.  Based on the results of this dose range-finding study, it was determined that the administration method should be altered so that water is administered concurrently with the test substance, at dose levels of 0, 100, 300, or 1000 mg/kg/day.

There was no treatment-related effect on precoital interval, despite the slightly increased interval in groups receiving the test substance (2.7, 3.0. 4.0, and 3.7 days, in the control, 100, 300, and 1000 mg/kg/day groups, respectively).  All females mated within 5 days. There were no treatment-related effects on reproductive performance parameters, including fertility, number of implantations, and pre- and post-implantation losses.  

The parental systemic NOAEL for the test substance was 300 mg/kg/day. The parental systemic LOAEL for the test substance was 1000 mg/kg/day and was based on decreased body weight, body weight gain, and food consumption. No developmental/reproductive adverse effect were seen in the study therefore, the reproductive NOAEL for the test substance was greater than or equal to 1000 mg/kg/day (highest dose tested). When adjusted for percent poly(oxy-1,2-ethanediyl),alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega- hydroxy- in the test substance the parental systemic NOAEL and LOAEL were 240 mg/kg/day and 800 mg/kg/day, respectively and no developmental/reproductive adverse effects were seen at the limit dose tested, so the  NOAEL was 800 mg/kg/day once adjusted for the percent in the test substance. 
      
 Reproductive and Developmental Toxicity
In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (MRID 50657508, OCSPP Test Guideline 870.3650, OECD Test Guideline 422), the test substance containing ~80% poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- was administered to Han Wistar rats (10/sex/dose) by gavage in purified water (5 mL/kg) at dose levels of 0, 100, 300, or 1000 mg/kg/day (~0, 80, 240, or 800 mg/kg/day poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-) for at least 14 days prior to mating, throughout mating (up to 14 days), and after mating, up to and including the day prior to sacrifice. Terminal sacrifices took place following at least 28 days of treatment for males, on lactation day (LD) 5 for females that littered, on day 25 post coitum for females that did not litter, and on postnatal day (PND) 4 for offspring. Evaluated parameters in the parental animals included mortality/clinical signs, body weight, food consumption, functional observational battery (FOB), motor activity assessment, hematology, clinical chemistry, reproductive performance, organ weights, and histopathology. Dose selection was based on a previously conducted range-finding study (MRID 50657507).   

At the high dose, one male and two females died or were sacrificed moribund prior to scheduled sacrifice. The male had no clinical signs prior to death on day 6 of the pre-mating period, but both females exhibited clinical signs prior to death on post coitum day 3 and gestation day (GD) 17, including rales and labored respiration, and ruffled fur. Among survivors, rales were noted in two additional high-dose males (labored respiration was also noted in one of these), and two additional high-dose females (for one day in one female). The mortalities, and likely the respiratory signs, were attributable to accidental respiratory uptake of the test substance and were not considered treatment-related. Body temperature was significantly lower (37.5 ºC vs. 38.4 ºC) and outside the range of historical controls in high-dose males. High-dose males also had significantly reduced absolute body weights (5-8%) throughout most of the study that were related to significantly lower body weight gains (6% gain versus 12% gain) and food consumption (-14%) during the pre-mating period. Food consumption remained reduced after mating (without statistical significance), and this was correlated with a significantly decreased mean terminal body weight for this group (-10%; p<0.05). There were no treatment-related effects on clinical pathology, or macroscopic or microscopic findings. 

There were no treatment-related effects on the reproductive indices, gestation lengths, mean numbers of corpora lutea and implantations per dam, pre- and post-implantation losses, mean litter size, numbers of live and dead pups born, sex ratio, or the birth index. Relative to controls, the following differences were noted in the high-dose group. Pup body weight was decreased on PND 4 (10-11%, p<0.05 in females only). The viability index was significantly lower than control (95.5% vs. 100%; p<0.05) due to increased pup deaths during PNDs 0-4, with three litters affected. The mean precoital interval was longer than that of the control group (4.4 vs. 2.5 days, respectively). Respiratory clinical signs noted in the parental animals (and attributable to misdosing) very likely contributed to these differences. For precoital interval, unusually long intervals (8 and 14 days) were noted where one animal in each pair was morbid during mating; pup deaths and lower body weights also were noted in the litter from the affected female.

Under the conditions of this study, the parental systemic NOAEL for the poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega- hydroxy- in rats was 240 mg/kg/day (i.e., 300 mg/kg/day of the test substance). The parental systemic LOAEL was 1000 mg/kg/day (~800 mg/kg/day poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-), based on decreased body weight and terminal body weight, body weight gain, and food consumption, and reduced body temperature in males.    

Misdosing in the high-dose group complicated interpretation of results, and exclusion of the data from the surviving misdosed dam results in an inadequate number of litters available for analysis; however, the reproductive effects seen are most likely attributable to maternal toxicity. 
 Genotoxicity and Mutagenicity
        
 Bacterial Reverse Mutation Test 
           
Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl) propyl)-omega-hydroxy- (80%) was evaluated for mutagenicity (MRID 40657506) at concentrations of up to 5000 ug/plate in Salmonella typhimurium strains, TA 98, TA100, TA 1535, TA 1537 and Escherichia coli strain WP2 uvrA. No significant increases in the numbers of revertant were found in any of the test strains at any concentrations, with or without metabolic activation.
In a second study (MRID 40657509), the test substance (85% poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-) was tested in a Salmonella typhimurium reverse mutation assay (TA1535, TA1537, TA100 and TA98) and in an Escherichia coli reverse mutation assay (WP2uvrA) at concentrations of up to 5000 ug/plate. The test was performed in two independent experiments in the presence and absence of S9-mix (rat liver S9-mix induced by a combination of phenobarbital and B-naphthoflavone). No significant increases in the numbers of revertant were found in any of the test strains at any concentrations, with or without metabolic activation.
 In Vitro Mammalian Chromosome Aberration Test
The test substance (~80 % poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-) was tested in a chromosome aberration assay (MRID 40657510) using Chinese hamster ovary (CHO) cells in both the absence and presence of an Aroclor-induced S9 activation system. A preliminary toxicity test was performed to establish the dose range for the chromosome aberration assay. In the preliminary toxicity assay, the maximum dose tested was 5000 ug/mL. Based on the findings of this study, poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy) disiloxanyl)propyl)-omega-hydroxy-) was concluded to be negative for the induction of structural and numerical chromosome aberrations in CHO cells in both non-activated and S9-activated test systems.
 Carcinogenicity
No cancer or long-term studies were available to evaluate the carcinogenic potential of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega- hydroxy-. No target organ toxicity was seen in the repeat dose study. In addition, because of the lack of any genotoxic or mutagenic effects in the bacterial reverse mutation test and the in vitro mammalian chromosome aberration test (Section 5.4), the EPA would consider that poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega- hydroxy- is unlikely to be carcinogenic.
 Neurotoxicity

No neurotoxicity studies are available for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy. Functional Observational Battery (FOB) tests were carried out in rats during the OCSPP 870.3650 study (MRID 50657508). The decreased mean body temperature of the high-dose males was considered to be a treatment-related adverse effect. The statistically significant lower body temperatures in high-dose females and mid-dose males may have been treatment-related but were not considered adverse since they were within the range of historical control means (males: 37.9 to 38.5ºC; females: 38.5 to 39.1ºC). The decreased mean body temperature is most likely a result of the decreased food consumption and not a neurological effect. Landing foot splay was increased in males in the low- and mid-dose groups, but since no difference was noted in the high-dose group, this effect was not considered treatment-related.
 Immunotoxicity
No immunotoxicity studies are available for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-(trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-; however, no evidence of immunotoxicity was seen in any of the studies. 

 TOXICITY ENDPOINT SELECTION

Limited data is available for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-. In the 2006 Reassessment of Fifteen Exemptions from the Requirement of a Tolerance for Twelve Poorly Absorbed Chemicals (EPA 2006), EPA concluded that absorption of compounds with large molecular weights, such as methylated silicones, by any route would be "poor to nil". At that time the OCSPP 870.3650 study was not available. 

In this study, the decrease in food consumption and the resultant reduced body weights were thought by the study author to be due to esophageal irritation caused by direct contact of the test substance. In the second part of the study the test substance was mixed with 5mL/kg of water before administration. The effects seen in the second part of the study were similar and therefore; the Agency is taking the conservative approach of treating these effects as treatment related. Therefore, the Point of Departure (POD) for all durations of oral, dermal, and inhalation exposure is based on the NOAEL of 300 mg/kg/day and the LOAEL of 1000 mg/kg/day in the OCSPP 870.3650 study. Once adjusted for the percent inert ingredient in the test formulation, the NOAEL was 240 mg/kg/day and the LOAEL was 800 mg/kg/day poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-. 
A 100-fold uncertainty factor was used (10X interspecies extrapolation, 10X for intraspecies variability, and 1X FQPA safety factor (SF)). The FQPA SF is reduced to 1X because the reproductive and developmental toxicity database is complete and there is no evidence of increased risk to infants and children. See Section 7 below for more information on the FQPA SF. 
EPA determines whether acute and chronic pesticide exposures are safe by comparing exposure estimates to the aPAD and cPAD. The aPAD and cPAD represent the highest safe exposures, taking into account all appropriate safety factors (SFs). No acute endpoint was determined therefore, an acute assessment was not done. EPA calculates the cPAD by dividing the POD by all applicable UFs. Risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the Margin of Exposures (MOE) called for by the product of all applicable UFs is not exceeded.  

When the 100X uncertainty or safety factor is applied, the chronic reference dose (cPAD) is 2.4 mg/kg/day. The residential and aggregate level of concern (LOC) is for MOEs that are less than 100 and is based on 10X interspecies extrapolation, 10X for intraspecies variability and 1X FQPA factor.
 	SPECIAL CONSIDERATION for INFANTS and CHILDREN

FFDCA Section 408(b)(2)(c) provides that EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure unless EPA determines based on reliable data that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the FQPA safety factor (SF). In applying this provision, EPA either retains the default value of 10X, or uses a different additional safety factor when reliable data available to EPA support the choice of a different factor. Based on the reasons listed below the Agency has used a FQPA SF of 1X. 

 The database for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- is considered adequate for FQPA assessment.
 A combined repeated dose toxicity study with a reproduction/developmental toxicity screening test showed no effect on reproductive parameters of fertility in the absence of maternal toxicity. 
 Although no neurotoxicity studies are available, no clinical signs of neurotoxicity were observed. Therefore, there is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity.
 Immunotoxicity studies were not available. However, there were no test-item related signs of immunotoxicity noted in the repeat-dose study.

Taking into consideration all available information including potential exposure, there is no concern, at this time, for increased sensitivity to infants and children to poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- when used as inert ingredient in pesticides formulations. Therefore, it is appropriate to reduce the FQPA SF to 1X as this will not underestimate the risk to infants and children. 

 EXPOSURE

Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy) disiloxanyl)propyl)-omega-hydroxy- is currently approved under 40 CFR §180.910 for use as an inert ingredient pre- and post-harvest. LNouvel, Inc. is requesting that EPA establish an exemption from the requirement of a tolerance for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- under 40 CFR §180.930 for use on animals. 
Based on the current and proposed use pattern of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-, dietary and residential exposure from pesticidal uses are expected. The endpoint used for all durations of oral, dermal, and inhalation exposure is based on the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OCSPP 870.3650). Once corrected for the percent in formulation, the NOAEL was 240 mg/kg/day poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-. 

 Dietary Exposure
A dietary exposure assessment (including drinking water) was conducted using the Dietary Exposure Evaluation Model-DEEM-FCID[TM], Version 3.16, which uses food consumption information from the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, "What we eat in America", (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. A complete description of the general approach taken to assess inert ingredient risks in the absence of residue data is contained in the memorandum entitled "Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for the Inerts." (D361707, S. Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number EPA-HQ-OPP-2008-0738.

In the absence of actual residue data, the highly conservative inert ingredient dietary exposure model assumes that the residue level of the inert ingredient would be no higher than the highest established tolerance for an active ingredient on a given commodity. For drinking water, the default of 100 ppb is assumed. Although sufficient information to quantify actual residue levels in food is not available, the compounding of the conservative assumptions will lead to a significant exaggeration of actual exposures. EPA does not believe that this approach underestimates exposure in the absence of residue data. The results of the dietary exposure assessment have been summarized in Table 2. The full DEEM report can be found in Appendix A. 
 
Table 2: Summary of Chronic Dietary Exposure and Risk
Population Subgroup
cPAD (mg/kg/day)
Exposure (mg/kg/day)
% cPAD
General U.S. Population
                                       
                                      2.4
                                       
                                    0.1893
                                      7.9
All Infants (<1 year old)
                                       
                                    0.3944
                                     16.4
Children 1-2 years old
                                       
                                    0.7062
                                     29.4
Children 3-5 years old
                                       
                                    0.4856
                                     20.2
Children 6-12 years old
                                       
                                    0.2506
                                     10.4
Youth 13-19 years old
                                       
                                    0.1348
                                      5.6
Adults 20-49 years old
                                       
                                    0.1447
                                      6.0
Adults 55+ years old
                                       
                                    0.1527
                                      6.4
Females 13-19 years old
                                       
                                    0.1359
                                      5.7

The chronic dietary exposure estimates for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- are below the Agency's level of concern for the general U.S. population and various population subgroups. The highest exposed population subgroup, children 1-2 years old, is 29.4% of the chronic population adjusted dose (cPAD). The chronic dietary exposure estimate for the general U.S. population is 7.9% of the cPAD.

 Residential Exposure

The term "residential exposure" is used in this document to refer to non-occupational, non-dietary exposure. Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl) oxy)disiloxanyl)propyl)-omega-hydroxy- is currently approved as an inert ingredient under 40 CFR §180.910. A review of residential pesticide products containing this inert ingredient revealed that it is currently used in fungicides, herbicides, and insecticides applied to residential setting, mainly on lawns and turf. 

In a conservative effort to assess exposure, the EPA has conducted a screening level assessment using high-end exposure scenarios for pesticidal use on lawns/turf. The Agency used actual data from current products containing the inert ingredient along with default assumptions from EPA's Office of Pesticide Programs (OPP), Health Effect Division (HED) 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, herein referred to as HED's 2012 Residential SOP. 

In addition to the proposed and current pesticidal uses of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-, it is also used in various non-pesticidal products as stated by the submitter. However, no reliable data is available to quantify the exposure to poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- from its use in non-pesticidal residential products. A search of the chemical in U.S. Department of Health and Human Services' Household Products Database did not result in any products containing poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-.
 Lawn and Turf
                  
The Agency conducted an assessment to represent residential exposure to poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- by assessing residential handler/applicator and post-application exposures and risk from poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy) disiloxanyl)propyl)-omega-hydroxy in pesticide formulations applied to lawn/turf. The three exposure scenarios: Hose-End Sprayer, Manually-Pressurized Handwand, and Backpack Sprayer were selected from Section 3 (Lawn/Turf) of HED's 2012 Residential SOP. Current pesticide products registered for application to lawn and turf containing poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy were reviewed. Based on this review, a 5% concentration (default) in pesticide formulations was used to evaluate this inert ingredient in pesticides applied to lawns/turf. This more conservative value for exposure is expected to be protective of potential uses of this inert ingredient in pesticide products applied to lawns and turf as well as currently registered products.   

    Handler 
Consumer pesticide handlers are assumed to wear short-pants, short-sleeved shirts and shoes plus socks but no protective gloves. As stated in HED's 2012 Residential SOP, this activity is generally considered to be short-term in duration and therefore, only short-term applicator exposure is assessed. The application rate is based on default assumption based on a review of various product labels and supplemental information provided by the submitter. 
In addition to HED's 2012 Residential SOP, further details of the assumptions used in the residential exposure and risk analysis can be found in the memorandum entitled ``JITF Inert Ingredients. Residential and Occupational Exposure Assessment Algorithms and Assumptions Appendix for the Human Health Risk Assessments to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations D364751", (5/7/09, Lloyd/LaMay in docket ID number EPA - HQ - OPP - 2008 - 0710) found at http://www.regulations.gov. The Agency believes that the handler scenarios assessed represent worse-case short-term exposures and risks. The results of these model predictions are provided in Table 3.  

Table 3: Short-term Exposure and Risks for Residential Handlers to Lawns and Turf
Exposure Scenario (Formulation/ Application)
Application Rate1 
Quantity Handled/ Treated per day[2]
Dermal Unit Exposure[3] (mg/lb inert)
Inhalation Unit Exposure[3] (mg/ lb inert)[3]
Dermal Dose[4] (mg/kg/day)[2]
Inhalation Dose[4] (mg/kg/ day)[2]
 Dermal MOE[5]
 Inhalation MOE[5]
Liquids/ Manually-Pressurized Handwand 
0.0105 lb/gal
5 gallons
63
0.018
0.0415
0.000012
5,800
20,000,000
Liquids/ 
Hose End Sprayer

0.45 lb/half acre**
0.5 acre
13.4
0.022
0.0753
0.000124
3,200
1,935,000
Liquids/ Backpack Sprayer

0.0105 lb/gal
5 gallons
130
0.14
0.0857
0.000092
2,800
2,608,000
1 Application rate (AR) Hand-wand and Backpack= Product Density (PD) * % in Formulation (%) * Dilution Factor (DF)
      PD= 9 lbs/gallon (Assumed, 2009 JITF Inert Ingredients. Residential and Occupational Exposure Assessment and Algorithms and Assumptions Appendix for the Human Health Risk Assessments to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations D364751)
      %= 5% max expected in formulation 
      DF= Assumed 0.0234 (3 oz product in 1 gallon (128 oz) of water), From Benzyl Acetate www.regulations.gov (Docket # EPA-HQ-OPP-2014-0783-004)
[1]Application rate (AR) Hose-End= Product Density (PD) * 1 gallon** * % in Formulation (%) 
** Based on reviews of currently available pesticide products, the expected use rate is 32 fl oz of product to cover approximately 5000 sq ft. A residential user is expected to use 4 x 32oz bottles (128 fl oz or 1 gallon) to treat (1/2) acre (21780 sq ft) based on the approximated used rate of 32 fl oz per 5000 sq ft. 
[2] Default Assumption from HED's 2012 Residential SOP Table 3-2
[3] From HED's 2012 Residential SOP Table 3-1
[4] Average Daily Dose (HED's 2012 Residential SOP Equation 3.2) = Daily exposure (=Application rate * Quantity Treated) * Unit Exposure * Absorption Factor / Body Weight (80 kg).  A Dermal Study was not provided therefore, dermal absorption factor was 100%. 
[5]MOE = POD (NOAEL mg/kg/day)/ Daily dose (mg/kg/day); 
      NOAELs: Dermal and Inhalation = 240 mg/kg/day

Risks were calculated using the Margin of Exposure (MOE) approach. This is a ratio of the body burden to the toxicological Point of Departure (POD). For these chemicals a MOE greater than 100 indicates that the exposure scenario does not demonstrate a risk of concern. For all residential handler scenarios, risk estimates are not of concern for both the dermal and inhalation assessment. These exposure models are highly conservative and therefore, the true risk of the anticipated exposure to these chemicals is believed to be less than what is illustrated in Table 3. 

    Post-application
Product specific data was not available; therefore, EPA applied default assumptions for this risk assessment. Post-application exposure to poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- was calculated using the scenarios outlined in HED's 2012 Residential SOP. As stated in the 2012 SOP "Post-application inhalation exposure while engaged in activities on or around previously treated turf is generally not assessed and should be handled on a case-by-case basis." The Agency did not assess post-application inhalation exposure to treated lawn and turf for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-. 

Pesticide residues can be transferred to the skin of adults and children who enter treated lawns for play, recreation, yardwork, or other home activities on the day the pesticide is applied. Dermal exposure to treated lawns were calculated for adults and children (1-2 years). It is assumed that individuals come in contact with treated lawns/turf the same day the pesticide is applied. Post-application dermal exposure following applications to lawns and turf is generally considered short-term in duration therefore, only short-term exposure was assessed. 
Table 4: Short-term Post-Application Dermal Exposure and Risks from Treated Lawns and Turf
Exposure Scenario
Application Rate[1]

Turf Transferable Residue[2]
Transfer Coefficients[3] (cm2/hr)

Exposure Time[3]
Dose (mg/kg/day)
MOE

AR
TTR
TC
ET

Adults
0.9 (lbs inert/acre)
0.1018(ug/cm[2])
180000
1.5
0.3436
700
Children (1-2 years)

49000
1.5
0.6563
365

1 AR= 0.9 lbs inert ingredient/acre (Hose-end sprayer-Table 3) 
[2]TTR=AR * F* (1-FD)[t] *CF2 *CF3   
Using the Default Values from HED's 2012 Residential SOP: 
      F= Fraction of Transferable Residue (0.01); 
      FD=Fraction of Residue that Dissipates per Day (0.1); 
      t= Post-Application Day (0) EPA assessed exposure on the day of application 
      CF2 4.58 x 108 ug/lb; 
      CF3 2.47 x 10[-8] acre/cm[2]
[3]Default HED's 2012 Residential SOP
[4]Dose= TTR * CF1 * TC *ET * Dermal Adsorption Factor / BW; 
      CF1= 0.001 mg/ ug, 
      TC and ET see Table
      Dermal Absorption= 100% or 1, No Dermal Study provided. 
      BW= adult 80 kg, child 11.4 kg
[5]MOE = POD (NOAEL 240 mg/kg/day)/ Daily dose (mg/kg/day)

In addition, post-application oral exposure (i.e., hand-to-mouth (HTM)) for children 1-2 years old was also determined and use in the risk assessment. While post-application exposure to children exposed to treated lawns is possible via object-to-mouth (OTM) transfer and soil ingestion, based on the conservatisms of all post-application exposure scenarios for exposure to treated lawns/turf, the Agency typically combines dermal and hand-to-mouth post-application exposure (Table 6). This combination is considered a protective estimate of children's exposure to pesticides use on turf. 

 

Table 5: Short-term Post-Application Hand-to-Mouth Exposure and Risks from Treated Lawns and Turf in Children 1-2 years old
Hand Residue[1] (mg/cm2)
(HR)
Area Mouthed/Event[2] 
(cm2/
event)
(AM)
Exposure time[3] (hrs/day)
(ET)
Replenishment Interval[3]
(intervals/hr)
(N-Replen)
Saliva Extraction Factor[3]
(SE)
Frequency[3]
(events/hr)
(Freq)
Dose[4]
(mg/kg/day)
MOE[5]
Rounded
0.00013
19.05
1.5
4
0.48
13.9
0.0012
200,000
1 HR=Fraction on Hand * Dermal Exposure / (2 * Surface Area of 1 hand)
      Defaults from HEDs 2012 Residential SOP, Dermal exposure based on Table 4
      Fraction on Hand = 0.06
      Dermal Exposure= 0.6563 mg from Table 4
      Surface Area of 1 hand= 150 cm[2]
2 AM=fraction hand surface mouthed (0.127) *surface area of one hand (150 cm2); Defaults from HED 2012 Residential SOP
3 Default HED 2012 Residential SOP
[4] Dose = [HR * (AM) * (ET * N_Replen) * (1- (1- SE)[(][Freq_HtM][/N-][Replen][)])]/BW 11.4kg
5 MOE = PD (ORAL NOAEL 240 mg/kg/day)/ Daily dose (mg/kg/day)

Table 6: Aggregate Short-term Post-Application Exposure and Risks from Treated Lawns and Turf in Children 1-2 years old
Exposure
                                     Dose
                                  (mg/kg/day)
                                      MOE
                                    Rounded
Post-Application: Dermal (Table 4)
                                    0.6563
                                      365
Post-Application: Hand-to-mouth (Table 5)
                                    0.0012
                                    200,000
Combined
                                    0.6575
                                      365

All MOEs for residential dermal and hand-to-mouth post-application exposures to treated lawns for both adults and children were greater than or equal to 365. In addition, the combined post-application exposure in children 1-2 years old resulted in a MOE of 365. The level of concern is for MOEs that are lower than 100; therefore, post-application exposure to treated lawn in each scenario are not of concern.
  Combined Exposure to Treated Lawns and Turf

The aggregate exposure to adults and children from exposure to treated lawns and turf are illustrated in Table 7

 Table 7: Residential Exposures: Aggregate Risk Assessment

 Population

    Handler Exposure (mg/kg/day)[1]
 Post-application Exposure (mg/kg/day)[2]
Residential Exposure (mg/kg/day)[3]
 Adult
                  0.0857
 0.3436
                   0.4297
 Child
         N/A
 0.6575
0.6575
[1]Handler exposure, from Table 3, combines high end dermal and inhalation handler exposure. Liquids/ Backpack Sprayer  scenario was used because it resulted in the greatest exposure to handlers. 
[2] Post-application exposure for adults, includes high end dermal exposure to treated lawns and turf.  Post-application exposure for children combines post-application exposures from dermal and incidental oral exposure from exposure to treated lawn and turf. 
3Residential exposure is the sum of the handler (adults only) and post application exposures.

 Occupational Exposure/Risk
The representative occupational scenarios selected by the Agency for assessment incorporate the likely maximum application rates for products which may contain the inert ingredient for the short-term exposure assessment, and average application rates for products likely to contain the inert ingredient for the intermediate-term exposure durations. Active ingredient application rates are corrected for the maximum amount of inert ingredient likely to be in the final formulations to determine exposure and risk from exposure to the inert ingredient by fungicide/insecticide or herbicide. These models use high exposure scenarios and would likely overestimate risk; however, they have been chosen to represent a worst-case scenario for the potential use of this inert ingredients.

The Agency considers a level of concern (LOC) for these risk assessments to be an MOE of 100 based on the standard 10X inter and 10X intra species extrapolation safety factors.  
 Occupational Handler Risk
Dermal and inhalation exposure are estimated using the Pesticide Handlers Exposure Database (PHED) and Outdoor Residential Exposure Task Force (ORETF) data. The analytical techniques were developed by the Science Policy Council on Exposure (ExpoSAC), Heath Effects Division, Office of Pesticide Programs, US Environmental Protection Agency. The quantitative exposure assessment developed for occupational handlers exposed to the inert ingredient is based on scenarios that represent the highest potential exposure. 

Occupational exposures are presented for aerial applicators, ground applicators and for mixer/loaders preparing and applying liquid formulations diluted for use in applications. These are the occupational activities believed to be associated with the highest exposures use patterns. The occupation exposure assessment utilized the values for the highest exposure herbicide, insecticide and fungicide, however, only the herbicide data is provided below because, in general, it provided the lowest and most conservative MOEs. A 5% concentration in pesticide formulations was used as a protective value for occupational exposure to pesticides. 
      
Table 8: Exposure and Risks for Occupational Handlers at Baseline* Dermal and Inhalation PPE
Exposure Scenario (Formulation/ Application/ Crop)
Application Rate1 (lb inert/ A)
Area Treated Daily2 (acres)
Dermal Unit Exposure[3] (mg/lb inert)
Inhalation Unit Exposure[3] (ug/ lb inert)

Baseline Dermal Dose4 (mg/kg /day)

Baseline Inhalation Dose4 (mg/kg/ day)
Baseline Dermal MOE[5]
Baseline Inhalation MOE[5]
                      Combined Dermal and Inhalation MOE
                            Mixer/Loader Scenarios

Liquids/ Aerial Application/ High Acreage Crops (ST)
                                     0.52
                                     1200
                                     0.22
                                     0.219
                                     1.716
                                    0.00171
                                      140
                                    140000
                                      140
Liquids/ Aerial Application/ High Acreage Crops (IT)
                                      0.1
                                       
                                       
                                       
                                     0.330
                                    0.00033
                                      730
                                    730000
                                      730
Liquids/ Groundboom/ High Acreage Crops (ST)
                                     0.52
                                      200
                                       
                                       
                                     0.286
                                    0.00028
                                      840
                                     84000
                                      840
Liquids/ Groundboom/ High Acreage Crops (IT)
                                      0.1
                                       
                                       
                                       
                                     0.055
                                    0.00005
                                     4400
                                    4400000
                                     4400
Wettable Powder/ Groundboom/ High Acreage Crops (ST)
                                     0.08
                                      200
                                    0.0777
                                     2.75
                                    0.01554
                                    0.00055
                                     15000
                                    440000
                                     1500
Wettable Powder/ Groundboom/ High Acreage Crops (IT)
                                     0.05
                                       
                                       
                                       
                                    0.00971
                                    0.00034
                                     25000
                                    700000
                                     24000
                             Applicator Scenarios
                                       
Liquid/ Aerial Application/ High Acreage Crops (ST)[9]
                                     0.52
                                     1200
                           Eng control only: 0.0028
                           Eng control only: 0.0049
0.0162
0.000038
15000
6300000
                                     15000
Liquid/ Aerial Application/ High Acreage Crops (IT)[9]
                                      0.1
                                       
                                       
                                       
0.0031
0.000007
77000
33000000
                                     77000
Groundboom/ High Acreage Crops (ST)
                                     0.52
                                      200
                                    0.0786
                                     0.34
0.1022
0.00044
2300
540000
                                     2300
Groundboom/ High Acreage Crops (IT)
                                      0.1
                                       
                                       
                                       
0.0197
0.00009
12000
2800000
                                     12000
                       Mixer/Loader/Applicator Scenarios
                                       
Liquid/ Low Pressure Handwand/ Ornamentals (ST)
                                     0.36
                                       5
                                      100
                                      30
2.25
0.00068
110
36000
                                      110
Liquid/ Low Pressure Handwand/ Ornamentals (IT)
                                     0.36
                                       
                                       
                                       
2.25
0.00068
110
36000
                                      110
                               Flagger Scenarios
                                       
Liquid/ Flagger/ High Acreage Crops (ST)
                                     0.52
                                     1200
                                     0.011
                                     0.35
0.0858
0.00273
2800
88000
                                     2700
Liquid/ Flagger/ High Acreage Crops (IT)
0.1

0.0165
0.00053
15000
460000
                                     14000
* Baseline Dermal PPE = single layer clothing, no gloves. Baseline Inhalation PPE= no respirator. 
[1].Default maximum application rates from Table 3.1.2 "JITF Inert Ingredients. Residential and Occupational Exposure Assessment Algorithms and Assumptions Appendix for the Human Health Risk Assessments to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations,'' (D364751, 5/7/09, Lloyd/LaMay in docket ID number EPA - HQ - OPP - 2008 - 0710 and adjusted for 5 % inert ingredient in formulation. Application rates for Short-term (ST) exposure risk estimates are based on maximum application rates.  Application rates for Intermediate-term (IT) exposures are based on average application rates.  
[2]Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern.
[3]Unit Exposure values are reported in EPA's Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (OPHUE) dated June 2018.  All exposure scenarios assess baseline dermal PPE plus baseline inhalation exposure except for aerial applicator scenarios, which assess inhalation and dermal exposures with engineering controls.
4 Average Daily Exposure (**) = Unit Exposure * Application Rate * Units Treated * Absorption Rate (100%)
                        80 kg Body Weight
      (** = Conversion Factor (1 mg /1000 ug) for inhalation exposure calculations)
[5] Margin of Exposure = POD (Dermal and Inhalation NOAEL: 240 mg/kg/day) / Dose

The assessment for occupational handlers was conducted assuming baseline personal protective equipment (PPE) (i.e., long pants, a long-sleeved shirt, shoes, socks, no chemical-resistant gloves, and no respiratory protection). In the absence of additional dermal or inhalation PPE, all exposure scenarios indicated an acceptable level of risk (i.e., MOEs greater than 100). Therefore, the Agency believes occupational handler risk is acceptable. 

 Post-application Exposure Scenarios
           
Post-application exposures occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions such as scouting for pests or harvesting. Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure. Inhalation exposures are also not typically calculated for occupational post-application scenarios because inhalation exposures generally account for a negligible percentage of the overall body burden for most pesticide chemicals. 
      
The Agency expects post-application agricultural exposures to workers would typically be short-term (1-30 days for 8 hrs/day). Therefore, only short-term post-application exposure was assessed for the day of treatment (Day 0). Risks were calculated using the Margin of Exposure (MOE) approach, which is a ratio of the body burden to the toxicological POD. The three occupational scenarios assessed are for post-application activities associated with:

 Tall field/row crops (including scouting, weeding, hand harvesting sweet corn)
 Turf (golf course/sod farm) (including mowing, transplanting, hand weeding)
 Vine/Trellis crops (including scouting, training, tying, thinning, and grape girding and cane turning)
Table 9.  Summary of Exposure & Risk from Occupational Post-Application Exposure to Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-
Exposure Potential
Transfer Coefficients[1]
cm[2]/hr
Application Rate[1]
lb inert/Acre
DFR Levels[2]
ug/cm[2]
Short-term Dose[3]
mg inert/kg /day
MOE[4]

                      Herbicide Short-term Tall Field Row
Low: scouting, weeding immature/low foliage plants
100
0.52 lb inert/A
1.167
0.0117
21000
Medium: scouting, weeding more mature/foliaged plants
400

0.0467
5100
High: scouting, irrigation, weeding mature/full foliage plants
1000

0.1167
2100
Very high: hand harvest or detasseling
17000

1.9835
120
                           Herbicide Short-term Turf
Low: mowing
500
0.52 lb inert/A
0.292
0.015
16000
High: transplanting, hand weeding
6800

0.198
1200
                      Insecticide Short-term Vinetrellis
Low: hedging, irrigation, scouting, hand weeding, training/tying blueberries
500
0.35 lb inert/A
0.785
0.0393
6100
Medium: scouting, training, tying
1000

0.0785
3100
High: hand harvest, leaf pulling, thinning, pruning, training/tying grapes
5000

0.3927
610
Very high: grape girdling and cane turning
10000

0.7853
310
[1.] Default values are taken from Occupational Post-application Risk Assessment Calculator Version 2 (12/2008). 
[2.] Dislodgeable Foliar Residue = AR * F * (1-D)[t] * CF2 * CF3 
		AR = Application rate (lb inert/A)
      F = fraction of inert retained on foliage (unitless) (default 20%)
      D = fraction of residue that dissipates daily (unitless) (default 10%)
      t = post application day on which exposure is being assessed (day 0)
      CF2 = weight unit conversion factor to convert the lbs inert in the application rate to ug for the DFR value (4.54E8 ug/lb)
      CF3 = Area unit conversion factor to convert the surface area units (ft[2]) in the application rate to cm[2] for the DFR value (1.08E-3 ft[2]/cm[2] or 2.47E-8 acre/cm[2])
[3]. Average Daily Dose (ADD) = DFR * TC * hours of daily exposure (8 hrs/day) * CF (0.001 mg/ug)
							80 kg body weight
[4.] Margin of Exposure = POD (Dermal NOAEL 240 mg/kg/day) / Dose

The post-application occupational MOEs for all scenarios were above 100. As the level of concern is for MOEs that are lower than 100, post-application occupational worker exposure is not of concern.

 AGGREGATE EXPOSURE

EPA determines whether acute and chronic pesticide exposures are safe by comparing aggregate exposure estimates to the aPAD and cPAD. The aPAD and cPAD represent the highest safe exposures, taking into account all appropriate safety factors (SFs). No acute endpoint was identified in the database; therefore, EPA did not conduct an acute aggregate assessment. EPA calculates the cPAD by dividing the Point of Departure (POD) by all applicable UFs. Risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the MOE called for by the product of all applicable UFs is not exceeded.  

Consumer exposure to poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl) oxy)disiloxanyl)propyl)-omega-hydroxy can occur through dietary exposures to poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy in food and drinking water resulting from pesticidal uses and from DIY pesticides for lawn/turf. Exposure to poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl) oxy)disiloxanyl)propyl)-omega-hydroxy is also possible through non-pesticidal uses; however, quantifiable data is not available and therefore, these uses were not incorporated into the aggregate assessment. 
A POD of 240 mg/kg/day (i.e., 300 mg/kg/day test substance) was used for all durations of oral, dermal, and inhalation exposure. A 100-fold uncertainty factor was used (10X interspecies extrapolation, 10X for intraspecies variability, and 1X FQPA safety factor (SF)). The FQPA SF is reduced to 1X because the reproductive and developmental toxicity database is complete and there is no evidence of increased risk to infants and children in the absence of maternal toxicity. 

 Table 10: Short-Term Aggregate Risk 

 Population

  POD mg/kg/day

 LOC[1]
  Max Allowable Exposure[2] mg/kg/day
  Average Food & Water Exposure mg/kg/day

  Residential Exposure[3] mg/kg/day
 Aggregate MOE
 (food and residential)[4]
 Adult
                                                                            240
 100
  2.4
  0.1893
 0.4297
                                                                            390
 Child (1-2 yrs)
                                                                            240
 100
  2.4
  0.7062
 0.6575
                                                                            175
        1 The LOC (Level of Concern) is based on the standard inter- and intra-species uncertainty factors totaling 100.
        2 Maximum Allowable Exposure (mg/kg/day) = POD (Point of Departure)/LOC
        3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure] from Table 7
        4 Aggregate MOE = [POD/ (Avg Food & Water Exposure + Residential Exposure)]

This aggregate risk assessment is highly conservative since it is based on a combination of several conservative assumptions:
 Dietary exposures assume use on all crops, assumes that residues will be high in these crops, and assumes that poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- will be used at 50 % of the formulation.
 Dermal absorption was assumed to be 100% as worst-case for all scenarios.

EPA considers a LOC for this risk assessments to be an MOE of 100 based on 10X inter- and 10X intra-species extrapolation safety factors. The aggregate MOEs for both adults and children/toddlers exceed the LOC of 100. Therefore, the Agency believes levels of concern are not exceeded for aggregate risk for persons involved in consuming and handling pesticide products containing poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl) oxy)disiloxanyl)propyl)-omega-hydroxy-.  

    CUMULATIVE EXPOSURE

Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity."

EPA has not found poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl) oxy)disiloxanyl)propyl)-omega-hydroxy- to share a common mechanism of toxicity with any other substances, and poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl) oxy)disiloxanyl)propyl)-omega-hydroxy- does do not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA assumed that poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl) propyl)-omega-hydroxy- does not 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 EPA's website at http://www.epa.gov/pesticides/cumulative.

    ENVIRONMENTAL FATE & EFFECTS 
        
 Environmental Fate

Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy) disiloxanyl)propyl)-omega-hydroxy- has a reported vapor pressure of <1mmHg and a log Kow of 3.31. 
    Biodegradation
Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy) disiloxanyl)propyl)-omega-hydroxy- was evaluated according to OECD 301 B to determine the biodegradability by the CO2 Evolution Modified Sturm Test. The test material showed 7.97% degradation by 11 days and 24.63% degradation by day 28. Based on the CO2 analysis results from this study, the test material was not "readily biodegradable" according to the OECD 301 B guideline because it did not reach 60% biodegradation within a 10-day window. 
    Hydrolysis
In a preliminary (Tier 1) test (MRID 50657515), the half-lives at 50 ºC were estimated to be less than 0.02 days, 2.34 days, and 0.03 days at pH 4, 7, and 9, respectively. Based on these results,
the test substance was determined to be hydrolytically unstable at pH 4, 7 and 9 and required further testing.

During the definitive (Tier 2) test, the hydrolysis of the test substance in pH 4, 7 and 9 sterile buffers was assessed at temperatures of 20 +- 0.5 and 35 +- 0.5 ºC continuously in the dark for a period of 34 days. During the 34-day definitive test, the concentration of the test substance decreased rapidly over time at both 20 and 35 ºC. The half-lives were determined to be 1.80 and 0.65 hours, respectively, at pH 4 at 20 and 35 ºC; 23.3 and 5.36 days, respectively, at pH 7 at 20 and 35 ºC; and 22.8 and 3.76 hours, respectively, at pH 9 at 20 and 35 ºC.

Based on the results of this study, hydrolysis would be a major route of elimination of the test substance from the environment.   

 Ecotoxicity Data
        
    Fish: Rainbow Trout
                                                                               
The acute toxicity of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl) oxy)disiloxanyl)propyl)-omega-hydroxy was evaluated in an OECD 203 study (MRID 50657512) with rainbow trout. Fish were exposed to 1.8, 3.2, 5.6, 10 and 18 mg/L of the test substance (~80% poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl) oxy)disiloxanyl)propyl)-omega-hydroxy-) for 96-hours. The LC50 for rainbow trout for the test substance, based on nominal concentrations, was determined to be 4.5 mg/L, and the 96-hour No-Observed-Effect-Concentration (NOEC) was 3.2 mg/L. The test substance was moderately toxic to aquatic organisms in this study. 
    Aquatic Invertebrates: Water Flea
The 48-hour EC50, based on immobilization, for Daphnia magna was determined in an OECD 202 Acute Immobilization Test and Reproduction Test (MRID 50657511). Animals were exposed to 1, 1.8, 3.2, 5.6, 10, 18, 32, 56, and 100 mg/L of the test substance (~80% poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-) for 48 hours under static conditions. The 48-hour EC50 for the test substance was 24 mg/L, and the NOEC was 5.6 mg/L. The test substance was slightly toxic to aquatic organisms in this study. 

    Soil organisms-Earthworm
           
The toxicity of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl) oxy)disiloxanyl)propyl)-omega-hydroxy to earthworms (Eisenia fetida) was tested according to OECD Test Guideline 207 (MRID 50657514). Following a preliminary range-finding test, 60 earthworms (six replicates of 10 worms) were exposed to a single concentration of the test substance at 1000 mg/kg (dry weight) of soil (~80% poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-) for a period of 14 days at approximately 21 °C. The number of mortalities were determined at 7- and 14-days post-exposure. The 14-day LC50, based on nominal test concentrations, was >1000 mg/kg. The NOEC was 1000 mg/kg (~800 mg/kg when correct for percent in formulation). There was no effect on earthworms at the highest dose tested. 
 
    Honey Bees

The acute toxicity of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy to honey bees (Apis mellifera) was evaluated according to OECD Guidelines 213 and 214 (MRID 50657513). Based on the results of the range finding phase, contact tests were run at 6.25, 12.5, 25, 50 and 100 ug test product/bee and for the oral administration a limit test at 100 ug test product/bee. The 48-hour contact and oral LD50 was estimated to be >100 ug test product/bee. The test substance is ~80% poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy) disiloxanyl)propyl)-omega-hydroxy-. There was no effect on honey bees at the highest dose tested. 

    RISK CHARACTERIZATION

No metabolism or pharmacokinetic data was provided; however, based on its molecular weight it was previously concluded by the EPA that absorption of compounds with large molecular weights, such as methylated silicones, by any route would be "poor to nil"

Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl) propyl)-omega-hydroxy exhibits low levels of acute toxicity. Acute studies in rats showed oral LD50 of >1,600 mg/kg. The dermal LD50 in rats was >3,200 mg/kg. No acute inhalation studies were available. Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy) disiloxanyl)propyl)-omega-hydroxy- is considered to be an eye irritant and a mild skin irritant. However, it was not found to be a dermal sensitizer. 

Repeat dose studies on poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- are limited. In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats, effects seen at 1000 mg/kg/day, the highest dose tested (i.e., 800 mg/kg/day to poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-) included decreased body weight, body weight gain, and food consumption and reduced body temperature in males. No developmental/reproductive adverse effect attributed to the test substance were observed in the study. 

There is no evidence that exposure to poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- suppresses or otherwise harms immune function in humans. No signs of neurotoxicity were reported in acute or repeat-dose oral studies. There were also no signs of carcinogenicity in the database. Similarly, all tests were negative for genotoxicity and mutagenicity. The available data suggests tha poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1-((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- is not carcinogenic.

In the 2006 Reassessment of Fifteen Exemptions from the Requirement of a Tolerance for Twelve Poorly Absorbed Chemicals, the EPA concluded that absorption of compounds with large molecular weights, such as methylated silicones, by any route would be "poor to nil". At that time the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was not available. The decrease in food consumption and the resultant reduced body weights seen in the study were thought by the study author to be due to esophageal irritation caused by direct contact of the test substance. In the second part of the study the test substance was mixed with 5ml/kg of water before administration. The effects seen in the second part of the study were similar and therefore; the Agency is taking the conservative approach of treating these as treatment related. Therefore, the Point of Departure (POD) for all durations of oral, dermal, and inhalation exposure is based on this study. The adjusted No Observed Adverse Effect Level (NOAEL) was 240 mg/kg/day based on effects seen at the Lowest Observed Adverse Effect Level (LOAEL) of 800 mg/kg/day. 
Based on the current and proposed use in pesticide formulations applied to crops pre- or post-harvest and use on animals, dietary (oral) and residential (dermal and incidental oral in children) exposure is possible. The dietary assessment showed that children 1-2 years old would be the highest exposed subgroup at 29.4% of the 2.4 mg/kg/day chronic Population Adjusted Dose (cPAD). Based on a review of current pesticide product labels containing this inert ingredient, a residential exposure assessment was conducted for pesticides applied to lawns and turf. All exposure scenarios were within acceptable limits and were considered safe. 
When aggregating residential and dietary exposure EPA determines whether pesticide exposures are safe by comparing aggregate exposure estimates to the cPAD. Risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the MOE called for by the product of all applicable uncertainty factors are not exceeded. The Agency is concerned with MOEs <100 (10X inter- and 10X intra-species extrapolation safety factors). The FQPA safety factor was reduced to 1X. When an aggregated exposure assessment was conducted for poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl) oxy)disiloxanyl)propyl)-omega-hydroxy- the risk to adults and children was considered safe.  
In addition, these products could be used in commerce and therefore, the use of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- in pesticide formulations could result in dermal and inhalation exposures to workers. The Agency found that when used as proposed, the risk to occupational workers would not exceed the Agency's level of concern. 
Various ecotoxicity and environmental fate studies were conducted with poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy-. Poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy) disiloxanyl)propyl)-omega-hydroxy- is dispersible in water and has an octanol-water partition coefficient of 3.31. Available studies classify it as not readily biodegradable.
Available data on the toxic effects of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl)propyl)-omega-hydroxy- to aquatic organisms show that it is moderately toxic to fish and slightly toxic to water flea. It was practically nontoxic to earthworms and honey bees. 
Based upon the factors summarized above, the Agency approves the expansion of the tolerance of poly(oxy-1,2-ethanediyl), alpha-(3-(1,3,3,3-tetramethyl-1- ((trimethylsilyl)oxy)disiloxanyl) propyl)-omega-hydroxy- to include 40 CFR § 180.930 as an inert ingredient in food use pesticide formulations.

                                 Bibliography

MRID 50657501 Driscoll, R. (1995) (Inert Ingredient): Acute Oral Toxicity (Limit Test) in the Rat. Project Number: 771/2. Unpublished study prepared by Safepharm Laboratories, Ltd. 17p. 

MRID 50657502 Driscoll, R. (1995) (Inert Ingredient): Acute Dermal Toxicity (Limit Test) in the Rat. Project Number: 771/3. Unpublished study prepared by Safepharm Laboratories, Ltd. 17p. 

MRID 50657503 Driscoll, R. (1995) (Inert Ingredient): Acute Eye Irritation Test in the Rabbit. Project Number: 771/5. Unpublished study prepared by Safepharm Laboratories, Ltd. 16p. 

MRID 50657504 Driscoll, R. (1995) (Inert Ingredient): Acute Dermal Irritation Test in The Rabbit. Project Number: 771/4. Unpublished study prepared by Safepharm Laboratories, Ltd. 15p. 

MRID 50657505 Driscoll, R. (1995) (Inert Ingredient): Magnusson & Kligman Maximisation Study in the Guinea Pig. Project Number: 771/6. Unpublished study prepared by Safepharm Laboratories, Ltd. 31p. 

MRID 50657506 Wagner, V.; Twardzok, S. (1999) Bacterial Reverse Mutation Assay with an Independent Repeat Assay (Inert Ingredient): Final Report. Project Number: AA09YC/504001/BTL. Unpublished study prepared by BioReliance. 75p. 

MRID 50657507 Whitlow, S. (2018) Dose Range Finding Study for a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in the Han Wistar Rat (Inert Ingredient). Project Number: B67544. Unpublished study prepared by RCC, Ltd. 171p. 

MRID 50657508 Ceccatelli, R. (2009) Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in the Han Wistar Rat (Inert Ingredient). Project Number: B67555. Unpublished study prepared by Harlan Laboratories, Ltd. 516p. 

MRID 50657509 Verspeek-Rip, C. (2005) Evaluation of the Mutagenic Activity of (Inert Ingredient) in the Salmonell Typhirium Reverse Mutation Assay and the Escherichia Coli Reverse Mutation Assay (with Independent Repeat). Project Number: 436365. Unpublished study prepared by Notox B.V. 26p. 

MRID 50657510 Gudi, R.; Rao, M. (2007) In vitro Mammalian Chromosome Aberration Test (Inert Ingredient): Final Report. Project Number: AB42RZ/331/BTL. Unpublished study prepared by Bioreliance. 45p.

MRID 50657511 Sewell, I.; Grant-Salmon, D.; Bartlett, A. (1995) (Inert Ingredient): Acute Toxicity to Daphnia Magna. Project Number: 771/7. Unpublished study prepared by Safepharm Laboratories, Ltd. 36p. 

MRID 50657512 Sewell, I.; Grant-Salmon, D.; Bartlett, A. (1995) (Inert Ingredient): Acute Toxicity to Rainbow Trout (Oncorhynchus mykiss). Project Number: 771/8. Unpublished study prepared by Safepharm Laboratories, Ltd. 42p. 

MRID 50657513 Taylor, K. (2015) Acute Toxicity to Honeybees (Inert Ingredient): Final Report. Project Number: TMR0026. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 43p. 

MRID 50657514 Harris, S. (2015) (Inert Ingredient): Earthworm, Acute Toxicity Test: Report. Project Number: 41403783. Unpublished study prepared by Harlan Laboratories, Ltd. 23p. 

MRID 50657515 Turk, R. (2009) (Inert Ingredient): Determination of the Abiotic Degradation of the Test Substance by Hydrolysis at Three Different pH Values. Project Number: 12023/6179. Unpublished study prepared by Springborn Smithers Laboratories. 101p. 

MRID 50657516 McLaughlin, S. (2009) (Inert Ingredient): Determination of the Biodegradability by the (Carbon Dioxide) Evolution Modified Sturm Test. Project Number: 12023/6189. Unpublished study prepared by Springborn Smithers Laboratories. 39p.

US EPA's Office of Pesticide Programs (OPP), (2006) Reassessment of Fifteen Exemptions from the Requirement of a Tolerance for Twelve Poorly Absorbed Chemicals. 6/1/12006.
US EPA's Office of Pesticide Programs (OPP), Health Effect Division (HED) (2012) Standard Operating Procedures for Residential Pesticide Exposure Assessment, https://www.epa.gov/sites/production/files/2015-08/documents/usepa-opp-hed_residential_sops_oct2012.pdf

                                  Appendix A

U.S. EPA                                                        Ver. 3.16, 03-08-d
DEEM-FCID Chronic analysis for INERTS- IN-11248               NHANES 2003-2008 2-day
Residue file name: C:\Users\dsunderl\OneDrive - Environmental Protection Agency (EPA)\Inert Models\11248 INERTS_57ACTIVE_100PPBH2OREV.R08
                                                 Adjustment factor #2 NOT used.
Analysis Date 07-22-2019/13:22:54     Residue file dated: 07-22-2019/12:53:15
Reference dose (RfD, Chronic) = 2.4 mg/kg bw/day
COMMENT 1: Inert 57 active ingredients + drinking water (100ppb)
===============================================================================
                    Total exposure by population subgroup
-------------------------------------------------------------------------------

                                                    Total Exposure
                                         -----------------------------------
          Population                           mg/kg                  Percent of   
           Subgroup                          body wt/day                 Rfd       
--------------------------------------   -------------       ----------------
Total US Population                        0.189343                 7.9%
Hispanic                                           0.206762                 8.6%
Non-Hisp-White                              0.185800                 7.7%
Non-Hisp-Black                               0.175951                 7.3%
Non-Hisp-Other                               0.223356                 9.3%
Nursing Infants                                0.248204                10.3%
Non-Nursing Infants                        0.459734                19.2%
Female 13+ PREG                           0.165239                 6.9%
Children 1-6                                     0.546673                22.8%
Children 7-12                                   0.227410                 9.5%
Male 13-19                                       0.133762                 5.6%
Female 13-19/NP                             0.135932                 5.7%
Male 20+                                          0.140996                 5.9%
Female 20+/NP                                0.153162                 6.4%
Seniors 55+                                      0.152687                 6.4%
All Infants                                        0.394428                16.4%
Female 13-50                                   0.146403                 6.1%
Children 1-2                                     0.706242                29.4%
Children 3-5                                     0.485634                20.2%
Children 6-12                                   0.250554                10.4%
Youth 13-19                                     0.134797                 5.6%
Adults 20-49                                    0.144740                 6.0%
Adults 50-99                                    0.151788                 6.3%
Female 13-49                                   0.146333                 6.1%