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There are no in vivo data on the toxicokinetics of 3-chloropropyl(dimethoxy)methylsilane.

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and its hydrolysis productsand 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 3-chloropropyl(dimethoxy)methylsilaneor its hydrolysis products, reasonable predictions or statements may be made about their potential ADME properties.

3-Chloropropyl(dimethoxy)methylsilane is a moisture-sensitive, volatile liquid that hydrolyses rapdily in contact with water (half-life approximately 1.3 hour at pH 7, predicted), generating methanol and 3-chloropropyl(methyl)silanediol. Human exposure can occur via the inhalation or dermal routes. Relevant inhalation exposure would be to the parent and hydrolysis products.

The toxicokinetics of methanol have been reviewed in other major reviews and are not considered further here.

Absorption

Oral

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).

Although significant oral exposure is not expected for 3-chloropropyl(dimethoxy)methylsilane, should it occur then with a solubility of 370 mg/l and a molecular weight of 182.72 g/mol it is reasonable to assume systemic exposure will occur also.

For the hydrolysis product,3-chloropropyl(methyl)silanediol, oral exposure to humans following hydrolysis in the gastro-intestinal tract or via the environment may be relevant. With a higher solubility (60000 mg/l) and lower molecular weight (154.67 g/mol) than the parent, then should oral exposure to 3-chloropropyl(methyl)silanediol occur then it is reasonable to assume systemic exposure will occur also and to a greater extent than the parent.

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.

The water solubility (370 mg/l) and log Kow (3.2) of the parent substance are therefore favourable for dermal absorption, but this will be limited by the hydrolysis of this substance.

The predicted water solubility (60000 mg/l) of the hydrolysis product, 3-chloropropyl(methyl)silanediol, is favourable for absorption across the skin but the log Kow of 0.8 is less so. Therefore some absorption across the skin may occur but possibly to a lesser extent than the parent.

Therefore once hydrolysis has occurred on the skin, absorption is likely to be reduced. The available reliable skin irritation study did not provide evidence of absorption as there were no systemic clinical effects reported. Also, there were no systemic effects observed following a dermal application of the related substance, 3-chloropropyl(diethoxy)methylsilane.

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 3-chloropropyl(dimethoxy)methylsilane results in a blood:air coefficient of approximately 46:1 meaning that, if lung exposure occurred there would be uptake in to the systemic circulation. The high water solubility of the hydrolysis product, 3-chloropropyl(methyl)silanediol, results in a markedly higher 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 would be expected into the systemic circulation. However, the high water solubility of 3-chloropropyl(methyl)silanediol 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 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 3-chloropropyl(dimethoxy)methylsilane predicts that, should systemic exposure occur, distribution would primarily be into fat, with potential distribution into liver, muscle, brain and kidney but to a much lesser extent.

For the hydrolysis product, 3-chloropropyl(methyl)silanediol, it is predicted 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(
dimethoxy)methylsilane

3.2

1585

6.7

4.2

106.3

4.5

3.2

3 -Chloropropyl(
methyl)silanediol

0.8

6.31

0.8

0.9

4.9

1.0

0.9

 

Metabolism

There are no data regarding the metabolism of 3-chloropropyl(dimethoxy)methylsilane. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for 3-chloropropyl(dimethoxy)methylsilane. 3 -Chloropropyl(dimethoxy)methylsilane hydrolyses rapidly to 3-chloropropyl(methyl)silanediol and methanol in the presence of moisture.

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 3-chloropropyl(dimethoxy)methylsilane in blood is approximately 8.0% while the corresponding value for the hydrolysis product, 3-chloropropyl(methyl)silanediol, is approximately 96%. Therefore these figures suggest that thehydrolysis product is likely to be effectively eliminated via the kidneys in urine but the parent substance 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.