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There are no in vivo data on the toxicokinetics of 3-(triethoxysilyl)propanethiol.

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 Kowso by using this, and other where appropriate, known or predicted physicochemical properties of 3-(triethoxysilyl)propanethiol or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

3-(Triethoxysilyl)propanethiol hydrolyses in contact with water to form 3-(trihydroxysilyl)propanethiol and ethanol (predicted half-life approximately 18 hours at pH7).

Human exposure can occur via the oral, inhalation or dermal routes.

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

Absorption

Oral

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).

Although the molecular weight of 3-(triethoxysilyl)propanethiol (approximately 238) is a little above the favourable range, the substance is water soluble so should oral exposure occur then it is reasonable to assume systemic exposure to 3-(triethoxysilyl)propanethiol will occur also.

For the hydrolysis product,3-(trihydroxysilyl)propanethiol, oral exposure to humans following hydrolysis in the gastro-intestinal tract or via the environment may be relevant. With a significantly higher solubility and lower molecular weight than the parent, then should oral exposure to 3-(trihydroxysilyl)propanethioloccur then it is reasonable to assume systemic exposure will occur also and to a greater extent than the parent.

In an acute oral toxicity study with 3-(triethoxysilyl)propanethiol clinical signs such as sluggishness, incoordination and tremor indicated that absorption of test substance-related material had occurred. 

Dermal

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

The water solubility (82 mg/l) and log Kow(2.7) of 3-(triethoxysilyl)propanethiol are therefore favourable for dermal absorption. The water solubility (1E+06 mg/l) of the hydrolysis product, 3-(trihydroxysilyl)propanethiol, is favourable for absorption across the skin but the log Kowof -1.4 is not. Therefore potential absorption of the hydrolysis product is unlikely.

In an acute dermal toxicity study there were indications (pale livers and congested kidneys) that absorption had occurred. However, absorption might have been enhanced by the severe local effects observed in this study, or the observed effects might have been secondary to the 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 (Koct:air) as independent variables.

Using these values for 3-(triethoxysilyl)propanethiol results in a blood:air coefficient of approximately 370:1 meaning that, if lung exposure occurred there would be uptake in to the systemic circulation. The high water solubility of the hydrolysis product, 3-(trihydroxysilyl)propanethiol, results in a markedly higher blood:air partition coefficient (approximately 6.6E+10:1) 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 3-(trihydroxysilyl)propanethiol may lead to some of it being retained in the mucus of the lungs so once hydrolysis has occurred, absorption is likely to slow down.

There are no reliable inhalation studies to check for signs of absorption.

Distribution

For blood:tissue partitioning a QSPR algorithm has been developed by De Jonghet 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 3-(triethoxysilyl)propanethiol 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 product, 3-(trihydroxysilyl)propanethiol,it is predicted there would minimal distribution into the main body compartments with tissue:blood partition coefficients of less than 1 (zero for fat).

Table 1: Tissue:blood partition coefficients

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

3-(triethoxysilyl)
propanethiol

2.7

501.19

4.9

3.2

92.2

3.1

2.3

3-(trihydroxysilyl)
propanethiol

-1.4

0.04

0.6

0.7

0.0

0.7

0.8

 

Metabolism

3-(triethoxysilyl)propanethiol is rapidly hydrolysed to 3-(trihydroxysilyl)propanethiol and ethanol in the presence of moisture. There are no data regarding the metabolism of the 3-(triethoxysilyl)propanethiol or 3-(trihydroxysilyl)propanethiol. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for 3-(triethoxysilyl)propanethiol.

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSR’s as developed by De Jonghet al. (1997) using log Kowas 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 3-(triethoxysilyl)propanethiol in blood is approximately 22% while the corresponding value for the hydrolysis product, 3-(trihydroxysilyl)propanethiol, is > 99%. 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 to a lesser extent. However, as the parent is hydrolysed, the hydrolysis product will be excreted via urine, and accumulation is therefore unlikely.