Methylsilanetriyl triacetate

Endpoint summary

Additional information

There are no in vivo data on the toxcokinetics of methylsilanetriyl triacetate.

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and its hydrolysis products and using this data in algorithms that are the basis of many computer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models. The main input variable for the majority of these algorithms is log K_ow so by using this, and other where appropriate, known or predicted physicochemical properties of methylsilanetriyl triacetate or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Methylsilanetriyl triacetate is a moisture-sensitive substance that hydrolyses very rapidly in contact with water (half-life <12 seconds at pH 7), generating acetic acid and methylsilanetriol. Human exposure can occur via the inhalation or dermal routes. Due to the very rapid hydrolysis, relevant dermal and inhalation exposure would be to the hydrolysis products. The resulting acetic acid hydrolysis product would be severely irritating or corrosive.

Potential systemic exposure to acetic acid is not discussed.

Absorption

Oral

Significant oral exposure is not expected for this corrosive substance. A gastric juice simulation study (Yinget al., 2002; see Section 4.1.1.1) is available. In this study when methylsilanetriyl triacetate, at concentrations approximately equal to three times the highest doses used in the key acute oral toxicity study, was added to simulated gastric juice, relatively high molecular weight polymers were found after 1 and 4 hours. This finding indicates that at very high gavage doses polymerisation could occur in the stomach. Thus absorption might be reduced following polymerisation.

Oral exposure to humans via the environment may be relevant for the hydrolysis product, methylsilanetriol. When oral exposure takes place it is necessary to assume that except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood takes place. 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).

Methylsilanetriol is highly water soluble (1E+06 mg/l) and has a molecular weight of 94.14 so fulfils both of these criteria so it is considered that should oral exposure occur it is reasonable to assume that resulting systemic exposure will occur also.

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log K_owvalues. 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. Due to the likely very rapid hydrolysis ofmethylsilanetriyl triacetateon contact with skin, systemic exposure via this route is predicted to be minimal. After or during deposition of a liquid on the skin, evaporation of the substance and dermal absorption occur simultaneously so the vapour pressure of a substance is also relevant and becausemethylsilanetriyl triacetate is volatile this would further limit the potential for absorption.

The high water solubility (1E+06 mg/l) of the hydrolysis product, methylsilanetriol, is favourable for absorption across the skin but the log K_ow of -2.4 is not. Therefore absorption across the skin is not likely to occur as the substance is likely to be too hydrophilic to cross the lipid-rich environment of the stratum corneum.

However, where contact with the skin occurs, the corrosive effects of methylsilanetriyl triacetate will damage the skin and penetration of the parent and hydrolysis product may be enhanced. Skin irritation studies did not show any signs of systemic toxicity that could be differentiated from effects secondary to the extreme local effects.

Inhalation

There is a 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 coefficient and the octanol:air partition coefficient (K_oct:air) as independent variables.

Using these values for the hydrolysis product, methylsilanetriol, results in a very high blood:air partition coefficient (approximately 7.9E+07:1) so once hydrolysis has occurred, as it would be expected to in the lungs, then significant uptake would be expected into the systemic circulation. However, the high water solubility of methylsilanetriol may lead to some of it being retained in the mucus of the lungs so absorption is then likely to slow down.

Absorption may be increased following corrosive effects on the respiratory epithelium. In an acute inhalation study (Dow Corning Corporation, 1961) signs of systemic toxicity were observed, and provide evidence that absorption following inhalation does occur.

Distribution

All absorbed test substance is likely to be in the form of the hydrolysis product methylsilanetriol. 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 formethylsilanetriolpredicts that distribution into the main body compartments would be minimal with tissue:blood partition coefficients of less than 1 for all major tissues (zero for fat).

Table 1: tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
methylsilanetriol	-2.4	0.004	0.6	0.7	0.0	0.7	0.8

  

Metabolism

There are no data regarding the metabolism of methylsilanetriol. Genetic toxicity tests in vitro of the read-across substance, ethylsilanetriyl triacetate, showed no observable differences in effects with and without metabolic activation. 

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by DeJongh 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 this algorithm, the soluble fraction of the hydrolysis product, methylsilanetriol, in blood is approximately >99% suggesting it is likely to be effectively eliminated via the kidneys in urine and accumulation is very unlikely.