3-(triethoxysilyl)propanethiol

Endpoint summary

Additional information

There are no in vivo or in vitro data on the toxicokinetics of 3-(triethoxysilyl)propanethiol (CAS No. 14814-09-6, EC No. 238-883-1).

 

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and its silanol hydrolysis product and using these 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 log K_ow, and where appropriate, other known or predicted physicochemical properties of 3-(triethoxysilyl)propanethiol or its silanol hydrolysis product, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

 

3-(Triethoxysilyl)propanethiol hydrolyses moderately rapidly in contact with water to form 3-(trihydroxysilyl)propanethiol (CAS / EC Nos. not available) and ethanol with a half-life of 32.1 h at pH 7 and 20 °C (OECD Test Guideline 111).

 

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, uptake through intestinal walls into the blood takes place. Uptake from intestines can be assumed 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 (Renwick, 1993).

 

Although the molecular weight of 3-(triethoxysilyl)propanethiol (approximately 238 g/mol) is a little above the favourable range, the substance is water soluble (predicted value of 82 mg/l at 20°C). So should oral exposure occur, it is reasonable to assume that systemic exposure to 3-(triethoxysilyl)propanethiol would occur also.

 

For the hydrolysis product, 3-(trihydroxysilyl)propanethiol, oral exposure to humans following hydrolysis in the gastrointestinal tract or via the environment may be relevant. With a significantly higher solubility (1E+06 mg/l) and lower molecular weight (approximately 154 g/mol) than the parent, it is reasonable to assume systemic exposure would occur following oral exposure and to a greater extent than for the parent.

 

Signs of systemic toxicity and therefore oral absorption of 3-(triethoxysilyl)propanethiol and/or the silanol hydrolysis product 3-(trihydroxysilyl)propanethiol were evident in the repeated dose oral study (Charles River Laboratories, 2021a) at ≥100 mg/kg bw/day and the supporting acute oral toxicity study (Carnegie-Mellon Institute of Research, 1976) at approximately 6000 mg/kg bw. No mortality or signs of acute oral toxicity were observed in the key acute oral toxicity study (Eurofins / BSL Bioservice Scientific Laboratories, 2019) at 2000 mg/kg bw.

 

Dermal

 

The fat solubility and therefore 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.

 

The water solubility (82 mg/l) and log K_ow (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 K_ow of -1.4 is not. Therefore, potential dermal absorption of the hydrolysis product is unlikely.

 

After or during deposition of a liquid on the skin, evaporation of the substance and dermal absorption occur simultaneously such that the vapour pressure of a substance is also relevant. Substances with a vapour pressure >100 Pa may readily partition into the stratum corneum, but uptake would be limited by the rate at which evaporation would occur. 3-(Triethoxysilyl)propanethiol and its hydrolysis product 3-(trihydroxysilyl)propanethiol have vapour pressures of 2.9 Pa and 1.1E-04 Pa at 25°C respectively, therefore, evaporation from the skin surface is not considered a factor in the extent of potential uptake from the skin.

 

Signs of systemic toxicity and therefore dermal absorption of 3-(triethoxysilyl)propanethiol were evident in the acute dermal toxicity study (Carnegie-Mellon Institute of Research, 1976) at approximately 680 mg/kg bw or higher. However, absorption might have been enhanced by the severe local skin effects observed in this study.

 

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 81 : 1 meaning that, if lung exposure occurred, there would be uptake into the systemic circulation. The high water solubility of the hydrolysis product, 3 –(trihydroxysilyl)propanethiol, results in a markedly higher blood: air partition coefficient (approximately 2.7E+10: 1). So once hydrolysis of the parent has occurred, as would be expected in the lungs, then significant uptake of 3-(trihydroxysilyl)propanethiol into the systemic circulation would be expected. However, the high water solubility of 3-(trihydroxysilyl)propanethiol may lead to some of it being retained in the mucus of the lungs, thus acting to slow down the absorption process.

 

Although there are no reliable inhalation studies for 3-(triethoxysilyl)propanethiol, there is some indication of absorption for the oral and dermal routes (see above).

 

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 3-(triethoxysilyl)propanethiol predicts that, should systemic exposure occur, distribution would primarily be into fat, with much lower potential distribution into liver, muscle, brain and kidney.

 

For the hydrolysis product, 3-(trihydroxysilyl)propanethiol, it is predicted there would be 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

Substance	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
3-(Triethoxysilyl) propanethiol	2.7	501.2	4.9	3.2	92.2	3.1	2.3
Hydrolysis product: 3-(Trihydroxysilyl) propanethiol	-1.4	0.04	0.6	0.7	0.0	0.7	0.8

 

Metabolism

 

3-(Triethoxysilyl)propanethiol hydrolyses moderately rapidly 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. For 3-(triethoxysilyl)propanethiol, the genetic toxicity tests in vitro were primarily negative and showed no observable differences in effects with and without metabolic activation. In the mammalian mutagenicity test (BSL Bioservice Scientific Laboratories, 2012b), 3-(triethoxysilyl)propanethiol was mutagenic without metabolic activation; however, this finding may have been falsely positive as the comet assay did not confirm the result.

 

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 assuming 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 unhydrolysed parent substance would be subject to less urinary excretion. However, as 3-(triethoxysilyl)propanethiol is hydrolysed, the hydrolysis product 3-(trihydroxysilyl)propanethiol will be excreted via urine, and accumulation of the parent or hydrolysis product is therefore unlikely.

 

DeJongh, J., H.J. Verhaar, and J.L. Hermens, A quantitative property-property relationship (QPPR) approach to estimatein vitrotissue-blood partition coefficients of organic chemicals in rats and humans. Arch Toxicol, 1997. 72(1): p. 17-25.

 

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.