Dichloro(3-chloropropyl)methylsilane

Endpoint summary

Additional information

There are noin vivo data on the toxicokinetics of dichloro(3-chloropropyl)methylsilane.

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 K_owso by using this, and other where appropriate, known or predicted physicochemical properties ofdichloro(3-chloropropyl)methylsilaneor its hydrolysis products, reasonable predictions or statements may be made about their potential ADME properties.

Dichloro(3-chloropropyl)methylsilane is a moisture-sensitive liquid that hydrolyses very rapidly in contact with water (half-life <5 seconds at 25°C and pH 4, 7 and 9

), generating hydrochloric acid and (3-chloropropyl)methylsilanediol. 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 very rapidly in contact with moist skin.

The resulting hydrochloric acid hydrolysis product would be severely irritating or corrosive, and the critical health effect for the registered substance is corrosion.Potential systemic exposure to hydrochloric acid is not discussed.

Absorption

Oral

Significant oral exposure is not expected for this corrosive substance.

However, oral exposure to humans via the environment may be relevant for the hydrolysis product,(3-chloropropyl)methylsilanediol.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). As(3-chloropropyl)methylsilanediol, with a water solubility of 6.0E+04 mg/land a molecular weight of 154.67, 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 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 dichloro(3-chloropropyl)methylsilane on contact with skin, systemic exposure via this route is predicted to be minimal. However, although the log K_ow(0.8) of the hydrolysis product,(3-chloropropyl)methylsilanediol, is just below the lower end of the favourable range for absorption across the skin, it has high water solubility so systemic exposure via this route is considered probable. 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 but as(3-chloropropyl)methylsilanediolhas a low vapour pressure evaporation is not likely to be a factor.

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

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 (K_oct:air) as independent variables.

The high water solubility of the hydrolysis product,(3-chloropropyl)methylsilanediol, results in a very high blood:air partition coefficient (approximately 2.1E+07:1) so once hydrolysis has occurred, as it would be expected to in the lungs, then significant uptake of(3-chloropropyl)methylsilanediolwould be expected into the systemic circulation. However, its high water solubility 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 (K_ow) is described. Using this value for the hydrolysis product,(3-chloropropyl)methylsilanediol,predicts there may be some distribution into fat but minimal distribution into the other main body compartments with tissue:blood partition coefficients of less than 1.

Table 1: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
(3-chloropropyl) methylsilanediol	0.8	6.31	0.8	0.9	4.9	1.0	0.9

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

Metabolism

Dichloro(3-chloropropyl)methylsilane is very rapidly hydrolysed to (3-chloropropyl)methylsilanediol and hydrochloric acid in the presence of moisture. Most if not all of this will have occurred before absorption into the body. There are no data regarding the metabolism of (3-chloropropyl)methylsilanediol. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for dichloro(3-chloropropyl)methylsilane.

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 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 the hydrolysis product, (3-chloropropyl)methylsilanediol, in blood is approximately 96% suggesting itis likely to be effectively eliminated via the kidneys in urine. As the parent is hydrolysed and the hydrolysis product will be excreted via urine, accumulation is therefore unlikely.