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There are no in vitro or in vivo data on the toxicokinetics of triethoxy(3-thiocyanatopropyl)silane.

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 Kow so by using this, and other where appropriate, known or predicted physicochemical properties of triethoxy(3-thiocyanatopropyl)silane, reasonable predictions or statements may be made about its potential ADME properties.

In contact with water, (3-thiocyanatopropyl)silanetriol reacts moderately to form (3-thiocyanatopropyl)silanetriol and ethanol (half-life: approximately 23 hours at pH 7, < 0.1 hours at pH 4 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, 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 must 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).

Triethoxy(3-thiocyanatopropyl)silane has a predicted water solubility of 140 mg/L and a molecular weight of 263.43. If oral exposure would occur, it is reasonable to assume that systemic exposure will also occur, although the molecular weight is above the ideal range.

The hydrolysis product (3-thiocyanatopropyl)silanetriol with a water solubility of 2000 g/L and a molecular weight of 179.27 clearly meets both of these criteria so should oral exposure occur then systemic exposure is very likely.

In the acute oral toxicity study, 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, absorption of Triethoxy(3-thiocyanatopropyl)silane across the skin is likely. The predicted water solubility (2000 g/L) of the hydrolysis product, (3-thiocyanatopropyl)silanetriol, is favourable for absorption across the skin although the log Kow is less so. However, overall systemic exposure of (3-thiocyanatopropyl)silanetriol via this route is considered likely. The available acute dermal toxicity study with triethoxy(3-thiocyanatopropyl)silane, 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 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. Therefore, evaporation from the skin surface is considered to not be a factor in the extent of potential uptake from the skin.

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 triethoxy(3-thiocyanatopropyl)silane results in a blood:air coefficient of 57000:1. Thereby, if lung exposure occurs, uptake into the systemic circulation would occur. The high water solubility of the hydrolysis product, (3-thiocyanatopropyl)silanetriol, results in a markedly higher blood:air partition coefficient. Consequently, when hydrolysis has occurred (as it would be expected to in the lungs), significant uptake 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 and therefore, when hydrolysis has occurred, absorption is likely to slow down.

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 (Kow) 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

-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 Kow 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 triethoxy(3-thiocyanatopropyl)silane in blood is approximately 10% and for (3-thiocyanatopropyl)silanetriol is >99%. Therefore, these figures taken together with the low molecular weight and high water solubility of the hydrolysis product, (3-thiocyanatopropyl)silanetriol, suggest that it is likely to be effectively eliminated via the kidneys in urine. However, the parent substance with a lower water solubility and higher log Kow, would be predicted to not be as readily eliminated from the body. However, as the parent is hydrolysed, the hydrolysis product will be excreted via urine, and 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.