Trimethoxy(methyl)silane

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no measured data on the toxicokinetics of trimethoxy(methyl)silane.

 

The following summary has therefore been prepared based on the predicted and measured physicochemical properties of the registered substance and its hydrolysis product. The data have been used in algorithms which 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 trimethoxy(methyl)silane or its hydrolysis product, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Trimethoxy(methyl)silane hydrolyses in contact with water (half-life approximately 2.2 hours at pH 7 and at 20°C), generating methylsilanetriol and methanol. Direct exposure of workers and the general population to the parent substance or its hydrolysis products might occur via the 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 rapid hydrolysis.

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

Absorption

Oral

Direct oral exposure is not expected for this substance. However, oral exposure to the hydrolysis product is potentially possible via the environment.

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) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

Therefore, if oral exposure to parent did occur, molecular weight of trimethoxy(methyl)silane (136.2) is in the favourable range and the water solubility (9.1E+04 mg/ml) 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 methylsilanetriol within 5 seconds at the temperature of 37.5°C. Methylsilanetriol has a favourable molecular weight and water solubility values for absorption so systemic exposure to this would also be likely.

Signs of systemic toxicity were evident in the acute toxicity (Mellon Institute, 1963) and repeat dose toxicity (Dow Corning Corporation, 2005) oral studies, which indicates exposure to substance-related material.

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

In the first toxicokinetic test (Charles River, 2017) diethoxy(dimethyl)silane was administered as a single oral gavage dose (1000 mg/kg bw) to male and female rats (2/sex). Blood samples were collected at 0.5, 1, 2, 4, 6 and 24 hours after dosing. The peak plasma concentration was reached rapidly, at the first blood collection point, just half an hour after dosing. A full repeated dose toxicokinetic test is ongoing.

In a toxicokinetic test (Harlan Laboratories, 2009) 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. Three male and three female animals were sacrificed one and four hours after test substance administration, and terminal blood, femur, stomach, combined 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 by using the water solubility and log K_ow values. Substances with log K_ow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal), particularly if water solubility is high. Although the water solubility of trimethoxy(methyl)silane (9.1E+04 mg/L) is potentially favourable for dermal absorption, the log K_ow (0.7) is not; therefore, absorption by this route isn’t impossible but it’s not likely. Although the hydrolysis product methylsilanetriol is highly soluble, the log K_ow value indicates it is not likely to be sufficiently lipophilic to cross the stratum corneum and therefore dermal absorption into the blood is likely to be minimal.

An acute dermal toxicity study (Mellon Institute, 1963) showed no indication of systemic toxicity at a dose level of 10 ml/kg (equivalent to ca. 9500 mg/kg bw). Since clear evidence of systemic toxicity was observed via the oral and inhalation routes, this does not contradict the conclusion that there is no or very little dermal absorption of trimethoxy(methyl)silane.

Inhalation

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

As outlined in Section 5.1 the predicted hydrolysis half-life for trimethoxy(methyl)silane at 37.5ºC and pH 7 (relevant for lungs and blood) is approximately 0.8 hours. This prediction is based on a weight of evidence of data from validated QSAR estimation method and measured data. 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 uncatalyzed reaction as well as catalysis by hydronium, hydroxide, and general acids or bases.

k_obs = k₀ + k_H3O+[H₃O⁺] + k_OH^-[OH^-] + k_a[acid] + k_b[base]

This chemical reaction is independent of enzymatic involvement. It is reasonable to assume that the parent and hydrolysis products of trimethoxy(methyl)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 trimethoxy(methyl)silane predicts a blood: air partition coefficient of approximately 82:1 meaning that, in steady state, approximately 99% of this substance will be in blood and approximately 1% in air, and therefore if lung exposure occurs the majority of parent substance available would be absorbed. However, hydrolysis is expected. For the hydrolysis product, methylsilanetriol, the predicted blood: air partition coefficient is approximately 2.3 E+08:1 meaning that systemic exposure is even 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 trimethoxy(methyl)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 highly soluble in water and therefore also expected to be present in the mucous lining following inhalation of trimethoxy(methyl)silane, from which there is potential for passive absorption.

The key inhalation study on trimethoxy(methyl)silane (Dow Corning Corporation, 2008) showed adverse systemic effects, specifically involving the kidneys and bladder. These findings are reliable evidence that the test substance was absorbed following inhalation exposure.

 

Distribution

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 (K_ow) is described. Using this value for trimethoxy(methyl)silane (1.1) predicts that, should systemic exposure occur, potential distribution into the main body compartments would be minimal.

Similarly, for the hydrolysis products, distribution into the main body compartments is predicted to be minimal.

Table X: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
trimethoxy(methyl)silane	0.7	5.01	0.8	0.8	3.9	1.0	0.9
methylsilanetriol	-2.36	3.98E-03	0.6	0.7	0.0	0.7	0.8

 

Additionally, there is a supporting study on a structurally-related substance (morpholinotriethoxysilane, CAS 21743-27-1) which show that there is no bioaccumulation in any organ (Harlan Laboratories, 2009). In this test (described above) 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. Together with excretion data (described later) these findings provide supporting evidence for the conclusion that trimethoxy(methyl)silane is not expected to accumulate in any organ or tissue.

 

Metabolism

There are no data on the metabolism of trimethoxy(methyl)silane. However, it will hydrolyse to form methanol and methylsilanetriol once absorbed into the body. Genetic toxicity testsin vitroshowed no observable differences in effects with and without metabolic activation.

Trimethoxy(methyl)silane is within an analogue group of substances within 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 ready biodegradation study with the structurally related substance trimethoxy(propyl)silane, the biodegradation observed is attributable to the non-silanol hydrolysis product (methanol). Mass-balance calculation has been undertaken to determine the percentage by weight of the parent substance that is associated with the biodegradable by-product. Once the biodegradation of the hydrolysed methoxy- groups is taken into account, there is no evidence of any biodegradation ofthe silanol hydrolysis product, propylsilanetriol. This observation is supported by studies with silanols that are structurally similar to propylsilanetriol. Studies with hydroxytrimethylsilane (CAS 1066-40-6) and dimethylsilanediol (CAS 1066-42-8) show no evidence of biodegradation (Clarke, N. (2008); Dow Corning Corporation (1984)).

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

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by De Jongh et al. (1997) using log K_ow 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 trimethoxy(methyl)silane in blood is approximately 97%. Similarly, for the hydrolysis product methylsilanetriol, the figure is >99% meaning that, once absorbed, both the parent substance and hydrolysis product are likely to be eliminated via the kidneys in urine, and accumulation is unlikely.

This prediction is supported byin vivotoxicokinetic 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% and17.4% 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 (2017), the maximum plasma concentration of diethoxy(dimethyl)silane was measured at 1 hour after dosing (the first sampling point). The test substance was also rapidly eliminated with an individual half-life ranging between 1.06 to 1.27 hours for males and females, respectively.

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 K_ow 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:                                                                                  

Charles River (2017) Single Dose Pharmacokinetics of Diethoxy(dimethyl)silane after Oral Administration in Male and Female Wistar Rats (non-GLP) (ReachCentrum/Charles River, 2017) (Single Dose Pre-Study; final study report not yet available).

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.

Renwick A. G. (1993) Data-derived safety factors for the evaluation of food additives and environmental contaminants.Fd. Addit. Contam.10: 275-305.

Dow Corning Corporation (1984) Twenty Day Biochemical Oxygen Demand of Dimethylsilanediol with Bacterial Isolates Previously Exposed to Silicones

Clarke, N (2008). Trimethylsilanol (CAS No. 1066-40-6) Assessment of Ready Biodegradability; CO2 in Sealed Vessels (CO2 Headspace Test). Safepharm Laboratories Limited, Shardlow Business Park, Shardlow, Derbyshire, DE72 2GD. Report number: 2581/0002. Report date: 2008-10-14.