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Summary and discussion of toxicokinetics

There are no in vivo data on the toxicokinetics of 1,2 -bis[dichloro(methyl)silyl]ethane. 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. 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 1,2-bis[dichloro(methyl)silyl]ethane or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

1,2 -bis[dichloro(methyl)silyl]ethane is low volatility (vapour pressure 11 Pa at 25°C), moisture-sensitive liquid that hydrolyses very rapidly in contact with water (based on read-across from related substance: Half-life < 1 min at 25°C and pH 4, 7 and 9), generating hydrochloric acid and 1,2-bis[dihydroxy(methyl)silyl]ethane. 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 1,2 -bis[dichloro(methyl)silyl]ethane, systemic exposure to this parent substance is not expected. Potential systemic exposure to the hydrolysis product, 1,2 -bis[dihydroxy(methyl)silyl]ethane 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, 1,2 -bis[dihydroxy(methyl)silyl]ethane.

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 1,2 -bis[dihydroxy(methyl)silyl]ethane, with a predicted water solubility of 1,000,000 mg/l and a molecular weight of 182.32, meets both of these criteria, should oral exposure occur it is reasonable to assume systemic exposure will occur also. 

 

Dermal

The fat solubility and therefore 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. Due to the likely very rapid hydrolysis of 1,2 -bis[dichloro(methyl)silyl]ethane on contact with skin, systemic exposure via this route is predicted to be minimal. However, the predicted water solubility (1,000,000 mg/l) and predicted log Kow (-1.6) of the hydrolysis product, 1,2 -bis[dihydroxy(methyl)silyl]ethane, are not favourable for absorption across the skin so systemic exposure via this route is unlikely. 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. 1,2 -bis[dihydroxy(methyl)silyl]ethane has a low predicted vapour pressure (0.000024 Pa) so evaporation is unlikely to affect the potential for dermal absorption.

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

 

Inhalation

Owing to the low vapour pressure, inhalation of vapours of 1,2 -bis[dichloro(methyl)silyl]ethane is likely to be minimal. Inhalation of aerosols could occur.

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 (Koct:air) as independent variables.

The low Henry's Law Constant of the hydrolysis product, 1,2 -bis[dihydroxy(methyl)silyl]ethane, results in a very high blood:air partition coefficient so once hydrolysis of 1,2 -bis[dichloro(methyl)silyl]ethane has occurred, as it would be expected to in the lungs, then significant uptake of the silanol hydrolysis product would be expected into the systemic circulation. However, the water solubility of 1,2 -bis[dihydroxy(methyl)silyl]ethane may lead to some of it being retained in the mucus of the lungs which is likely to slow down absorption.

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 reliable 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 De Jongh 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 the hydrolysis product, 1,2 -bis[dihydroxy(methyl)silyl]ethane, predicts distribution into the main body compartments would be minimal with tissue:blood partition coefficients of less than 1 for all major tissues (zero for fat).

Table 1: tissue:blood partition coefficients

 

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

1,2 -bis[dihydroxy(methyl)silyl]ethane

-1.6

0.0025

0.6

0.7

0

0.7

0.8

 

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

Metabolism

1,2 -bis[dichloro(methyl)silyl]ethane is rapidly hydrolysed in the presence of moisture to 1,2 -bis[dihydroxy(methyl)silyl]ethane 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 1,2 -bis[dihydroxy(methyl)silyl]ethane. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for 1,2 -bis[dichloro(methyl)silyl]ethane.

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSR’s as developed by De Jongh 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 1,2 -bis[dihydroxy(methyl)silyl]ethane in blood is >99% suggesting it is likely to be effectively eliminated via the kidneys in urine and accumulation is 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.

 

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