3-chloropropyltrimethoxysilane

Endpoint summary

Additional information

There are no in vivo or in vitro data on the toxicokinetics of (3-chloropropyl)trimethoxysilane.

The following summary has therefore been prepared based on 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 a numerical value, for the purposes of this summary only qualitative statements or comparisons will be made. The main input variable for the majority of these algorithms is log Kow so by using this and, where appropriate, other known or predicted physicochemical properties of (3-chloropropyl)trimethoxysilane or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

(3-Chloropropyl)trimethoxysilane is a moisture-sensitive, volatile liquid that hydrolyses in contact with water with a hydrolysis half-life of <0.083 hour at pH 4, 3.1 hours at pH 7 and <0.1 hour at pH 9 and 25oC, generating methanol and (3-chloropropyl)silanetriol.

Human exposure can occur via the inhalation or dermal routes. Relevant inhalation and dermal exposure would be to the parent substance and hydrolysis products. The toxicokinetics of methanol is discussed elsewhere and is not included in this summary.

Absorption

Oral

Significant oral exposure is not expected for this substance.

However, oral exposure to humans via the environment may be relevant for the hydrolysis product, (3-chloropropyl)silanetriol. 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 can 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)silanetriol is very water soluble (1.0E+06 mg/L at 20°C (QSAR)) and has a molecular weight of approximately 156.64 it meets both of these criteria, so should oral exposure occur it is reasonable to assume systemic exposure will also occur.

In an acute oral toxicity study, there was no evidence of systemic toxicity, and therefore no evidence of absorption.

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 likelihood that hydrolysis of (3-chloropropyl)trimethoxysilane might occur during contact with skin, exposure via this route is predicted to be to the parent and hydrolysis products. 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.  However, both (3-chloropropyl)trimethoxysilane and its hydrolysis product (3-chloropropyl)silanetriol have low vapour pressure, so it is considered that volatilisation would be minimal therefore it would not limit dermal absorption potential.

The predicted log Kow (2.0) of (3-chloropropyl)trimethoxysilane suggest that the parent substance could be absorbed very effectively through the skin.

The very high predicted water solubility (1E+06 mg/L) and low predicted log Kow (-1.1) of the hydrolysis product, (3-chloropropyl)silanetriol, suggest that it is too hydrophilic to cross the lipid rich stratum corneum. Therefore, dermal uptake is likely to be low.

Therefore, absorption of the test substance might be expected to be significantly reduced once hydrolysis has occurred.

In an acute dermal toxicity study, there was no evidence of systemic toxicity, and therefore no evidence of absorption.

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 the parent substance (3-chloropropyl)trimethoxysilane, the QSPR predicts a blood:air partition coefficient of approximately 2.3E+02:1 meaning that, if lung exposure occurred there would be some uptake into the systemic circulation. For the hydrolysis product (3-chloropropyl)silanetriol the predicted blood:air partition coefficient is very high (approximately 1.66E+10:1) 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)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.

Repeated dose studies on (3-chloropropyl)trimethoxysilane showed signs of systemic toxicity, and therefore were evidence of absorption via the inhalation route. It must also be considered that some of the absorbed effects could be a result of oral exposure resulting from transport of mucus out of the respiratory tract.

Distribution

The absorbed material may be in the form of the parent and hydrolysis products. The log Kow of the parent substance means that it is likely to distribute into cells and the intracellular concentration might be higher than the extracellular concentration, particularly in fatty tissues. The hydrophilic nature of (3-chloropropyl)silanetriol will limit its diffusion across membranes (including the blood-brain and blood-testes barriers) and its accumulation in fatty tissues.

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 the parent substance and the silanol hydrolysis product predicts that distribution of the parent substance is likely to occur while distribution of the hydrolysis product would be minimal.

Toxicity studies provide evidence for distribution to the bladder and kidneys.

Table 1 Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
(3-chloropropyl)trimethoxysilane	2	100	2.5	1.8	50.9	1.9	1.4
(3-chloropropyl)silanetriol	-1.1	0.1	0.6	0.7	0	0.7	0.8

Metabolism

There are no data on the metabolism of (3-chloropropyl)trimethoxysilane. However, it will hydrolyse to form methanol and (3-chloropropyl)silanetriol once absorbed into the body. There were no observable differences in effects with and without metabolic activation in bacterial mutagenicity tests, which were positive; however in vitro mammalian mutagenicity tests gave positive results with metabolic activation, but negative results without metabolic activation, indicating possible potential for metabolism by hepatic enzymes in vivo. The potential for genetic toxicity observed in vitro was not confirmed when the substance was tested in an in vivo micronucleus assay.

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)trimethoxysilane in blood is approximately 58% suggesting it is likely that some of it will be effectively eliminated via the kidneys in urine while accumulation is also likely to occur. The soluble fraction of the hydrolysis product, (3-chloropropyl)silanetriol, in blood is approximately 99% suggesting it is likely to be effectively eliminated via the kidneys in urine and accumulation is very unlikely.

References

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