tert-butylchlorodimethylsilane

Endpoint summary

Additional information

Summary and discussion of toxicokinetics

There are no in vivo data on the toxicokinetics of tert-butyl(chloro)dimethylsilane. The following summary has therefore been prepared based on measured physicochemical data and validated predictions of the physicochemical properties of the substance itself and its hydrolysis products, using this data in algorithms that are the basis of many computer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models. Although these algorithms provide quantitative outputs, for the purposes of this summary only qualitative statements or predictions will be made.

The main input variable for the majority of these algorithms is log K_ow so by using this, and, where appropriate, other known or predicted physicochemical properties of tert-butyl(chloro)dimethylsilane or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

tert-Butyl(chloro)dimethylsilane is moisture-sensitive liquid that hydrolyses very rapidly in contact with water (based on read-across from related substance: Half-life < 1 minute at 25°C and pH 4, 7 and 9), generating hydrochloric acid and tert-butyl(dimethyl)silanol. Human exposure can occur via the inhalation or dermal routes. Relevant inhalation exposure would be to the hydrolysis products (hydrolysis would occur rapidly when inhaled, even if a mixture of parent and hydrolysis products were present in air). The substance would also hydrolyse rapidly in contact with moist skin. The resulting hydrochloric acid hydrolysis product would be severely irritating or corrosive.

Therefore, due to the very rapid hydrolysis of tert-butyl(chloro)dimethylsilane, systemic exposure to this parent substance is not expected. Potential systemic exposure to the hydrolysis product, tert-butyl(dimethyl)silanol is discussed below. Potential systemic exposure to the other hydrolysis product, hydrochloric acid, is not discussed.

Absorption

Oral

Significant oral exposure is not expected for this corrosive parent substance. However, oral exposure to humans via the environment may be relevant for the hydrolysis product, tert-butyl(dimethyl)silanol.

When oral exposure takes place, it can be assumed that, except for the most extreme of insoluble substances, 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).

As tert-butyl(dimethyl)silanol, with a predicted water solubility of 970 mg/l and a molecular weight of 132.28, meets both of these criteria, should oral exposure occur it is reasonable to assume systemic exposure will occur also. There was no evidence of oral absorption in the acute oral study with the registration substance (LPT, 2002).

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log K_owvalues. Substances with log K_owvalues between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Due to the likely very rapid hydrolysis of tert-butyl(chloro)dimethylsilane on contact with skin, systemic exposure via this route is predicted to be minimal. However, the predicted water solubility (970 mg/l) and predicted log K_ow(2.5) of the hydrolysis product, tert-butyl(dimethyl)silanol, are within the favourable range. Therefore, absorption across the skin may occur as the substance is likely to be sufficiently hydrophilic to cross the lipid-rich environment of the stratum corneum.

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. tert-Butyl(dimethyl)silanol has a predicted vapour pressure of 60 Pa, so evaporation may affect the potential for dermal absorption.

Since the other hydrolysis product, hydrochloric acid is corrosive to the skin, damage to the skin may increase penetration. There are no dermal studies to check for signs of systemic availability.

 

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's Law Constant and the octanol:air partition coefficient (K_oct:air) as independent variables.

Using these values for tert-butyl(dimethyl)silanol results in a blood:air partition coefficient of 82:1 so once hydrolysis of tert-butyl(chloro)dimethylsilane has occurred, as it would be expected to in the lungs, then uptake of the silanol hydrolysis product into the systemic circulation would be likely. However, the water solubility of tert-butyl(dimethyl)silanol 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.

As with dermal exposure, damage to membranes caused by the corrosive nature of the hydrochloric acid hydrolysis product might enhance the uptake. There are no available studies on the silanol hydrolysis product to check for signs of inhalation toxicity.

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 the hydrolysis product, tert-butyl(dimethyl)silanol, predicts that, should systemic exposure occur, potential distribution into the main body compartments would be predominately to the fat.

Table 1: tissue:blood partition coefficients  

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
tert-butyl(dimethyl)silanol	2.5	316	4.2	2.8	82.6	2.7	2.0

 

Hydrogen and chloride ions will enter the body’s natural homeostatic processes.

Metabolism

tert-Butyl(chloro)dimethylsilane is rapidly hydrolysed in the presence of moisture to tert-butyl(dimethyl)silanol and hydrogen chloride. Most if not all of this will have occurred before absorption into the body. There are no data regarding the metabolism of tert-butyl(dimethyl)silanol. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for tert-butyl(chloro)dimethylsilane.

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_owas 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 tert-butyl(dimethyl)silanol in blood is approximately 30% meaning that once absorbed there is some potential for the substance to be eliminated via the kidneys in urine.

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.