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Summary and discussion of toxicokinetics

There are no in vitro or in vivodata 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 Kowso 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 watertriethoxy(3-thiocyanatopropyl)silanereacts 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 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 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)silanehas a water solubility of 140 mg/L and although the molecular weight of 263.43 is above the ideal range, should oral exposure occur it is reasonable to assume systemic exposure will occur also. 

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.

There were many clinical signs of toxicity and some deaths in the acute oral toxicity study therefore confirming evidence of absorption from the gastrointestinal tract.

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. With a log Kowof 3.1 and 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)silanetriolvia this route is considered likely. The acute dermal toxicity study available on 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 so the vapour pressure of a substance is also relevant. Triethoxy(3-thiocyanatopropyl)silaneand its hydrolysis product(3-thiocyanatopropyl)silanetriolare considered to be minimally volatile, therefore evaporation from the skin surface is considered not to 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)silaneresults in a blood:air coefficient of 57000:1 meaning that, if lung exposure occurred there would be uptake in to the systemic circulation. The high water solubility of the hydrolysis product,(3-thiocyanatopropyl)silanetriol, results in a markedly higher blood:air partition coefficient 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-thiocyanatopropyl)silanetriol 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.

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 triethoxy(3-thiocyanatopropyl)silanepredicts 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

There are no data regarding the metabolism of triethoxy(3-thiocyanatopropyl)silane. Genetic toxicity testsin vitroshowed no observable differences in effects 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. 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 oftriethoxy(3-thiocyanatopropyl)silanein 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, of(3-thiocyanatopropyl)silanetriol, suggest that it is likely to be effectively eliminated via the kidneys in urine. The parent substance however, with a lower water solubility and higher log Kowwould 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.