Ethoxytrimethylsilane

Endpoint summary

Description of key information

No studies are available. Based on molecular structure, molecular weight, water solubility and octanol-water partition coefficient it can be expected that the submission substance is likely to be absorbed via the oral and dermal routes. The vapour pressure of the submission substance suggests that inhalation as a vapour is likely. Hydrolysis is expected to occur very rapidly, and based on the physico-chemical parameters of the silanol containing degradation product, absorption via the gastrointestinal tract, inhalation and the dermal routes are expected. Due to the low molecular weight and moderate water solubility, the submission substance and its hydrolysis product is expected to be widely distributed in the body. Excretion via the urine is considered favoured. No bioaccumulation is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no measured data on the toxicokinetics of ethoxy(trimethyl)silane.

The following summary has therefore been prepared based on the predicted and measured physicochemical properties of the registered substance and its hydrolysis product (see Table below). The data have been used in algorithms that are the basis of many physiologically based pharmacokinetic and toxicokinetic (PBTK) prediction models. Although these algorithms provide quantitative outputs, for the purposes of this summary, only qualitative statements or predictions will be made because of the remaining uncertainties that are characteristic of prediction models.

The main input variable for the majority of the algorithms is the log Kow. By using this and, where appropriate, other known or predicted physicochemical properties of ethoxy(trimethyl)silane or its hydrolysis product, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Ethoxy(trimethyl)silane hydrolyses very rapidly in contact with water (measured half-life of 2.2 min at pH 7 and at 25°C), generating trimethylsilanol (CAS 1066-40-6) and ethanol. Direct exposure of workers and the general population to the parent substance or its hydrolysis products might occur via inhalation and dermal routes. Exposure of the general population via the environment might occur via the oral route but would be limited to the hydrolysis product due to the very rapid hydrolysis.

The toxicokinetics of ethanol have been reviewed in other major reviews and are not considered further here.

 

Table: Physicochemical properties

Physicochemical properties	ethoxy(trimethyl)silane	trimethylsilanol
Water solubility	302 mg/L at 20-25°C (QSAR)	995 mg/L at 20°C (OECD 105)
Vapour pressure	11800 Pa at 20°C (EU Method A.4)	1900 Pa at 25°C (OECD 104)
Log Kow	3.7 at 20°C(QSAR)	1.19 at 25 ± 0.5°C and pH 7.1 (OECD 107)
Molecular weight (g/mol)	118.1	90.2
Half-life	2.2 min at pH 7, <2 min at pH 4 and 6.1 min at pH 9 at 25 °C (EU Method C.7)

 

Absorption

Oral

When oral exposure takes place, it can be assumed, except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood occurs. Uptake from intestines can be assumed to be possible for all substances that have appreciable solubility in water or lipid. Other mechanisms by which substances can be absorbed in the gastrointestinal tract include the passage of small water-soluble molecules (molecular weight up to around 200 g/mol) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (ECHA, 2017).

Therefore, if oral exposure to parent did occur, molecular weight of ethoxy(trimethyl)silane (118.1 g/mol) is in the favourable range and would favour absorption, so systemic exposure by this route is likely. At pH 2 in the stomach, the parent compound is predicted to hydrolyse into the hydrolysis product trimethylsilanol within 1 second at the temperature of 37.5°C. Trimethylsilanol has a favourable molecular weight and water solubility values for absorption so systemic exposure to this would also be likely. Furthermore, the moderate log Kow value of the parent and hydrolysis product suggests that they are both likely to be absorbed by passive diffusion.

Signs of systemic toxicity especially effects on the urinary system were evident in the oral combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (Citoxlab, 2019), which indicates systemic exposure to either the parent or hydrolysis product.

There are supporting toxicokinetic data on two related alkoxysilane substances that show rapid absorption of alkoxysilanes following oral administration.

In a toxicokinetic test (Charles River, 2017), diethoxy(dimethyl)silane (CAS 78-62-6) was administered repeatedly by oral gavage between 100 and 1000 mg/kg bw to male and female as well as pregnant rats (3/sex). Blood samples were collected at 0.5, 1, 2, 4, 6 and 24 hours after dosing on Day 29 for males, premating for females and on gestation day 18 for females. The peak plasma concentration was reached rapidly, at the first blood collection point, just half an hour after dosing. A dose proportional increase in exposure, in terms of Cmax and AUClast, was generally noted over the used dose range of 100 to 1000 mg/kg/day in both males and females (pre-mated and pregnant (GD18)). After absorption diethoxy(dimethyl)silane was rapidly eliminated with individual apparent terminal half-lives ranging between 0.6 to 1.0 hours in males, 0.6 to 1.5 hours in pre-mated females and between 0.7 to 1.3 hours in pregnant females on GD18.

In a toxicokinetic test on morpholinotriethoxysilane (CAS 21743-27-1), the radiolabelled test substance was administered by oral gavage to mice (12/sex) as a single dose of 2000 mg/kg bw (Harlan, 2009). Three male and three female animals were sacrificed one and four hours after test substance administration, and terminal blood, femur, stomach, combined gastrointestinal (GI) tract contents, small intestine, large intestine, liver and kidney were collected. Terminal blood, femur, stomach, small intestine, large intestine, combined GI tract contents, liver, kidney as well as urine and faeces were collected from the remaining animals 24 hours after administration. Overall, significant mean levels of the test item were found in blood and plasma as early as 1 hour after application. This indicates that after oral administration the test item was rapidly absorbed in significant amounts.

Dermal

If dermal exposure were to occur, in practice, this would be to the parent compound as well as the hydrolysis product.

The fat solubility and the potential dermal penetration of a substance can be estimated using the water solubility and log Kow values. Substances with log Kow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal), particularly if water solubility is high.

The moderate water solubility of 302 mg/L, log Kow of 3.7 and molecular weight of 118.1 g/mol of the parent substance suggest that absorption is high. For the hydrolysis product (trimethylsilanol) the water solubility of 995 mg/L, log Kow value of 1.19 and molecular weight of 90.2, suggests the substance will have a medium-high potential to be absorbed by the dermal route. QSAR based dermal permeability prediction (DERMWIN V2.00.2009) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 28.83 µg/cm²/h for ethoxy(trimethyl)silane and 3.01 µg/cm²/h for trimethylsilanol, respectively. This shows that dermal penetration of the parent substance and the hydrolysis product will be high or medium-high, respectively.

Inhalation

The vapour pressure of the parent substance (11800 Pa) indicates that this substance has a high volatility, and therefore inhalation as a vapour is likely to occur. The moderate log Kow (between -1 and 4) of the parent substance and hydrolysis product indicate that absorption directly across the respiratory tract epithelium by passive diffusion is possible.

The pH of the airway surface liquid has been determined to be in the range 6.7-7 (Jayaraman et al., 2000), without significant inter- or intraspecies variation.

The measured hydrolysis half-life at 20-25 °C and pH 7 (relevant for lungs and blood) is lower than 2.2 min. This prediction is based on a validated QSAR estimation and the following principle. As the hydrolysis reaction may be acid or base catalysed, the rate of reaction is expected to be slowest at around pH 7 and increase as the pH is raised or lowered. For an acid-base catalysed reaction in buffered solution, the measured rate constant is a linear combination of terms describing contributions from the uncatalysed reaction as well as catalysis by hydronium, hydroxide, and general acids or bases.
kobs= k0+ kH3O+[H3O+] + kOH-[OH-] + ka[acid] + kb[base]

This chemical reaction is independent of enzymatic involvement. It is reasonable to assume that the parent and hydrolysis products of ethoxy(trimethyl)silane will be present in the airway surface liquid, without significant variation between individuals.

Proving the hydrolysis rate in the lungs of experimental animals in vivo would present many complicated (possibly insurmountable) technical difficulties, and therefore the presence of parent and hydrolysis product is assumed as a worst-case scenario.

There is a Quantitative Structure-Property Relationship (QSPR) to estimate the blood: air partition coefficient for human subjects as published by Meulenberg and Vijverberg (2000). The resulting algorithm uses the dimensionless Henry’s Law coefficient and the octanol: air partition coefficient (Koct: air) as independent variables.

Using these values for ethoxy(trimethyl)silane predicts a blood: air partition coefficient of approximately 0.22:1 meaning that, in steady state, approximately 18% of this substance will be in blood and approximately 82% in air, and therefore if lung exposure occurs the majority of parent substance available would not be absorbed. However, hydrolysis is expected. For the hydrolysis product, trimethylsilanol, the predicted blood: air partition coefficient is approximately 12.6:1 meaning that systemic exposure is much more likely. Again, this prediction is based on physicochemical properties and is not expected to vary between individuals.

It is also important to consider the water solubility of ethoxy(trimethyl)silane and its hydrolysis product with respect to dissolving in the mucous of the respiratory tract. The parent is expected to hydrolyse in the aqueous mucous. The hydrolysis product is soluble in water and therefore expected to be present in the mucous lining following inhalation of ethoxy(trimethyl)silane, from which there is potential for passive absorption.

 

Distribution

The low molecular weight, moderate water solubility of the parent and hydrolysis product, respectively, suggest they will both have the potential to diffuse through aqueous channels, pores and will be widely distributed; the log Kow of >0 for ethoxy(trimethyl)silane and trimethylsilanol indicates they are likely to be distributed into cells. Therefore, the intracellular concentration will be higher than the extracellular concentration.

The moderate water solubility and the moderate log Kow of both the parent and hydrolysis product suggest that accumulation in the body is not likely for both substances.

For blood: tissue partitioning a QSPR algorithm has been developed by DeJongh et al. (1997) in which the distribution of compounds between blood and human body tissues as a function of water and lipid content of tissues and the n-octanol: water partition coefficient (Kow) is described. Using this value for ethoxy(trimethyl)silane (log Kow = 3.7) predicts that, should systemic exposure occur, distribution would primarily be into fat, with potential distribution into liver, muscle, brain and kidney but to a much lesser extent. For the hydrolysis products, distribution would also primarily be into fat. In general, the distribution of the hydrolysis product into the main body compartments is much lower compared to the target substance.

Table: Tissue: blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
ethoxy(trimethyl)silane	3.7	5012	7.9	4.9	111.5	6.6	4.4
trimethylsilanol	1.19	15.5	1.1	1.0	11.9	1.2	1.0

Also, the available toxicokinetics data on silanes suggest that the silanols with log kow will be rapidly excreted once hydrolysis occurs. In the toxicokinetic test with morpholinotriethoxysilane, CAS 21743-27-1) (described above), for example, mean plasma concentrations declined during the 24 h observation period to approximately 6.8% of the peak value in male mice and to 6.0% of the peak value in female mice. A comparable effect was seen in all tissues analysed (Harlan Laboratories, 2009). Together with excretion data (described later), these findings support the conclusion that ethoxy(trimethyl)silane might accumulate in fat tissue. However, this is not expected as ethoxy(trimethyl)silane hydrolyses fast to trimethylsilanol and ethanol.

Metabolism

Ethoxy(trimethyl)silane is a moisture-sensitive liquid that hydrolyses rapidly in contact with water (measured half-life less than 2.2 min at pH 7 and 25°C), generating ethanol and trimethylsilanol. There is no data on the metabolism of trimethylsilanol. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.

Ethoxy(trimethyl)silane is within an analogue group of substances for which, in general, there is no evidence of any significant biodegradation once hydrolysis and subsequent biodegradation of alkoxy/acetoxy groups has been taken into account (PFA, 2013f).

In a biodegradation study with trimethylsilanol (CAS 1066-40-6) according to OECD 310, there was no evidence of biodegradation (Safepharm, 2008). It is, therefore, concluded that the substance and its silanol hydrolysis product are not recognised by biological systems containing all the mammalian enzymes and metabolic systems.

Excretion

The low molecular weight (below 300 g/mol) and moderate water solubility of the parent and hydrolysis product suggest that they are likely to be excreted by the kidneys into urine.

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by DeJongh et al. (1997) using log Kow as an input parameter, calculate the solubility in blood based on lipid fractions in the blood assuming that human blood contains 0.7% lipids.

Using the algorithm, the soluble fraction of ethoxy(trimethyl)silane in blood is approximately 6% and of trimethylsilanol is approximately 100%. Therefore, these figures suggest that the hydrolysis product is likely to be effectively eliminated via the kidneys in urine but the parent substance would be predicted to be eliminated from the body to a lesser extent via the kidneys.

This prediction is supported by in vivo toxicokinetic data on two related substances (morpholinotriethoxysilane and diethoxy(dimethyl)silane). The details of these tests are described above. With regard to excretion it has been demonstrated that both of these substances are rapidly absorbed, but also rapidly excreted.

In the test conducted by Harlan Laboratories (2009), morpholinotriethoxysilane peak concentration to radioactivity in the blood, plasma, femur, liver and kidney were found after just one hour. However, by 24 hours after administration concentrations had declined to 6-7% of the peak concentrations in plasma and tissues. After 24 hours 24.9% and 17.4% of the applied dose was detected in urine, 3.4% and 9.8% of the applied dose in cage wash of male and female mice, respectively. Also, 63.8% and 64.2% of the applied dose was excreted via faeces in male and female mice, respectively.

In the test conducted by Charles River (2018), the maximum plasma concentration of diethoxy(dimethyl)silane was reached rapidly. After absorption diethoxy(dimethyl)silane was rapidly eliminated with individual apparent terminal half-lives ranging between 0.6 to 1.0 hours in males, 0.6 to 1.5 hours in pre-mated females and between 0.7 to 1.3 hours in pregnant females on GD18.

In conclusion, rapid absorption into the blood and fast elimination from the blood via urine was observed with related alkoxysilane substances.

These findings support the hypothesis that after hydrolysis, a water-soluble silanol is formed (supported by log Kow calculation) which is rapidly excreted from the body. Since, this hydrolysis occurs without enzymatic involvement it is appropriate to reduce the intraspecies assessment factor from 5 to 2.2 for workers and from 10 to 3.2 for the general population, by exclusion of the toxicokinetic element of this assessment factor.

References:

ECHA (2017). Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7c: Endpoint specific guidance. Version 3.0. June 2017                                                  

DeJongh, J., H.J. Verhaar, and J.L. Hermens, A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans. Arch Toxicol, 1997.72(1): p. 17-25.

Jayaraman, S.; Song, Y.; Vetrivel, L.; Shankar, L. & Verkman, A. Noninvasive in vivo fluorescence measurement of airway-surface liquid depth, salt concentration, and pH Journal of Clinical Investigation, American Society for Clinical Investigation, 2000, 107, 317-324.

Meulenberg, C.J. and H.P. Vijverberg, Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol, 2000. 165(3): p. 206-16.

PFA, 2013f, Peter Fisk Associates, Biodegradation Main Analogue Group report, PFA.300.005.007