Triethoxy(3-thiocyanatopropyl)silane

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

There are no in vitro or in vivo data on the toxicokinetics of triethoxy(3-thiocyanatopropyl)silane (CAS No. 34708-08-2, EC No. 252-161-3).

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 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 the log of the n-octanol:water partition coefficient (log K_ow). So, by using this parameter and others, as known or predicted for triethoxy(3-thiocyanatopropyl)silane, reasonable predictions or statements may be made about its potential absorption, distribution, metabolism, and elimination (ADME) properties.

In contact with water, triethoxy(3-thiocyanatopropyl)silane reacts moderately to form (3-thiocyanatopropyl)silanetriol and ethanol (half-life: < 0.1 hours at pH 4 at 20°C, and approximately 23 hours at pH 7 and 0.8 hours at pH 9 and 25°C). Human exposure can occur via the oral, inhalation or dermal routes. Relevant exposure would be to the parent and hydrolysis products. The toxicokinetics of ethanol have been reviewed in other major reviews and are not considered further here.

Absorption

Oral

Human exposure to the parent and hydrolysis products can occur via the oral route. When oral exposure occurs, uptake through intestinal walls into the blood is likely to take place. Uptake from intestines is 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).

Triethoxy(3-thiocyanatopropyl)silane has a predicted water solubility of 140 mg/L at 20°C and a molecular weight of 263.43 g/mol. Thus if oral exposure occurs, systemic exposure also will occur, although the molecular weight is above the ideal range.

The hydrolysis product (3-thiocyanatopropyl)silanetriol with a predicted water solubility of 1E+06 mg/l at 20°C and a molecular weight of 179.27 g/mol clearly meets both of the above criteria. So should oral exposure occur, then systemic exposure is very likely.

In the acute oral toxicity study (ASTA Pharma AG, 1987), clinical signs and mortality were observed which confirm evidence of absorption from the gastrointestinal tract.

Dermal

The fat solubility and the potential dermal penetration of a substance can be estimated by 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. With a predicted log Kow of 3.1 and a predicted water solubility of 140 mg/l at 20°C, absorption of triethoxy(3-thiocyanatopropyl)silane across the skin is likely. The predicted water solubility of the hydrolysis product, (3-thiocyanatopropyl)silanetriol (1E+06 at 20°C), is favourable for absorption across the skin, although the log Kow (-1.5) is less so. However, overall systemic exposure of (3-thiocyanatopropyl)silanetriol via the dermal route is considered likely. The available acute dermal toxicity study with triethoxy(3-thiocyanatopropyl)silane (Harlan Laboratories Ltd, 2011) showed clinical signs of toxicity and therefore, evidence for dermal absorption.

After or during deposition of a liquid on the skin, evaporation of the substance and dermal absorption occur simultaneously which is why the vapour pressure of a substance is also relevant. Triethoxy(3-thiocyanatopropyl)silane and its hydrolysis product (3 -thiocyanatopropyl)silanetriol are considered to be minimally volatile, with vapour pressures of <100 Pa at 20°C (measured; Value for CSA: 0.38 Pa at 25°C, predicted) and 2E-06 Pa at 25°C (predicted), respectively. Therefore, evaporation from the skin surface is not considered a factor in the extent of potential uptake of either substance from the skin..

Inhalation

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 coefficient and the octanol:air partition coefficient (Koct:air) as independent variables; Collectively calculated for this assessment based on molecular weight (see oral absorption above), and on water solubility, log K_ow, and vapour pressure (see dermal absorption above), as estimated for 37.5°C.

Using these values for triethoxy(3-thiocyanatopropyl)silane results in a blood:air coefficient of 951: 1. Thereby, if lung exposure occurs, some uptake into the systemic circulation would occur. In comparison, the high water solubility and low vapour pressure of the hydrolysis product (3-thiocyanatopropyl)silanetriol results in a markedly higher blood:air partition coefficient of 1.8E+12: 1. Consequently, when hydrolysis has occurred (as expected in the lungs), significant uptake of this hydrolysis product would be expected into the systemic circulation. However, the high water solubility of (3-thiocyanatopropyl)silanetriol may lead to some of it being retained in the mucus of the lungs, likely slowing down its systemic absorption.

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 value for K_ow is described. Using this value for triethoxy(3-thiocyanatopropyl)silane predicts that it will distribute into the main body compartments as follows: fat >> liver > brain ≈ muscle ≈ kidney with tissue:blood partition coefficients of 104.4 for fat and 3.0 to 6.4 for the remaining tissues. For the hydrolysis product, distribution would be minimal with tissue:blood partition coefficients of less than 1 for all tissues (zero for fat).

Table 1: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Triethoxy(3-Thiocyanatopropyl) silane	3.1	1258.93	6.4	4.0	104.4	4.2	3.0
(3-Thiocyanatopropyl) silanetriol (silanol hydrolysis product)	-1.5	0.03	0.6	0.7	0.0	0.7	0.8

 

Metabolism

No data regarding the metabolism of triethoxy(3-thiocyanatopropyl)silane is available. Genetic toxicity tests in vitro showed no observable effect differences with and without metabolic activation for triethoxy(3-thiocyanatopropyl)silane.

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 that human blood contains 0.7% lipids.

 

Using this algorithm, the soluble fraction of triethoxy(3-thiocyanatopropyl)silane in blood is approximately 10% and for (3-thiocyanatopropyl)silanetriol is >99%. The low molecular weight, high water solubility, and low log K_owof the hydrolysis product (3-thiocyanatopropyl)silanetriol suggest that it is likely to be effectively eliminated via the kidneys in urine. Any unhydrolysed parent substance (higher molecular weight, lower water solubility, and higher log K_ow) would be predicted to be not as readily eliminated from the body. However, since the parent substance is expected to be hydrolysed in the body, the hydrolysis product will be excreted via urine and its accumulation is therefore unlikely.

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

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.

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.