Trimethoxy(2-methylpropyl)silane

Endpoint summary

Additional information

There are no in vivo data on the toxicokinetics of trimethoxy(2-methylpropyl)silane.

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and its silanol hydrolysis productand 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 oftrimethoxy(2-methylpropyl)silane or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Trimethoxy(2-methylpropyl)silane is a moisture-sensitive liquid that hydrolyses rapidly in contact with water (half-lifeapproximately 4.1 hours at pH 7,0.2 hours at pH 4, 0.3 hours at pH 5, 0.1 hours at pH 9 and 20 - 25°C), generating methanol and (2-methylpropyl) silanetriol.

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

Significant oral exposure is not expected for this substance.

However, oral exposure to humans via the environment may be relevant for the hydrolysis product,(2-methylpropyl) silanetriol.When oral exposure takes place it can be assumed, except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood occurs. 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).

(2-methylpropyl) silanetriolis very water soluble and has a molecular weight of approximately 136 so fulfils both criteria. Therefore, it is considered that should oral exposure take place it is reasonable to assume that resulting 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. With a log K_owof 2.1 and water solubility of 4900 mg/l, absorption oftrimethoxy(2-methylpropyl)silaneacross the skin is likely to occur. 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 and astrimethoxy(2-methylpropyl)silane is volatile this may limit the potential for dermal absorption.

The high water solubility of the hydrolysis product,(2-methylpropyl) silanetriol, is favourable for absorption across the skin but the log K_owof -1.0 is not. Therefore absorption across the skin is not likely to occur as the substance is likely to be too hydrophilic to cross the lipid-rich environment of the stratum corneum.Therefore once hydrolysis has occurred on the skin, absorption is likely to be substantially decreased. The available reliable skin irritation study did not report systemic effects. There are no other 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.

Using these values for the parent,trimethoxy(2-methylpropyl)silane, results in a blood:air partition coefficient of approximately 170:1 meaning that if lung exposure occurred there would be uptake into the systemic circulation.The high water solubility of the hydrolysis product, (2-methylpropyl) silanetriol, results in a markedly higher blood:air partition coefficient (approximately 2.9E+06:1, if a water solubility of 1000 mg/L is used) 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 (2-methylpropyl) 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.

The acute inhalation study showed signs of narcosis during exposure, indicating uptake had occurred.

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 fortrimethoxy(2-methylpropyl)silanepredicts that, should systemic exposure occur, distribution would primarily be into fat, with potential slight distribution into liver, muscle, brain and kidney.

For the hydrolysis product,(2-methylpropyl) silanetriol,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
trimethoxy(2-methylpropyl)silane	2.1	125.9	2.8	2.0	57.6	2.0	1.5
(2-methylpropyl) silanetriol	-1.0	0.10	0.6	0.7	0.0	0.7	0.8

Metabolism

There are no data regarding the metabolism of trimethoxy(2-methylpropyl)silane. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for trimethoxy(2-methylpropyl)silane.

In a 28-day ready biodegradation test there was no evidence for biodegradation other than could be accounted for by biodegradation of the non-silanol hydrolysis product, ethanol, which is readily biodegradable (see Section 4). This suggests that the substance and its silanol hydrolysis product are not recognised by biological systems containing all the mammalian enzymes and metabolic systems.

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 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 trimethoxy(2-methylpropyl)silane in blood is approximately 53% while the corresponding value for the hydrolysis product, (2-methylpropyl) silanetriol, is > 99%. Therefore these figures suggest that both the parent and the hydrolysis product are likely to be effectively eliminated via the kidneys in urine and accumulation is unlikely.