Tetramethyl orthosilicate

Endpoint summary

Additional information

There are no in vivo data on the toxicokinetics of tetramethyl orthosilicate.

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 of tetramethyl orthosilicate or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Tetramethyl orthosilicate hydrolyses rapidly in water, with a half-life of < 3 minutes at pH 4, 7 and 9. The hydrolysis products are methanol and silicic acid, which rapidly precipitates to insoluble silica (SiO₂) when the concentration is sufficiently high. The toxicokinetics of methanol have been studied previously and therefore will not be discussed further in this summary.

Human exposure can occur via the inhalation or dermal routes. Due to the very rapid hydrolysis, relevant dermal and inhalation exposure would be to the hydrolysis products.

Absorption

Oral

Significant oral exposure is not expected for this substance.

Tetramethyl orthosilicate is likely to be rapidly hydrolysed to silicic acid in the stomach, so minimising absorption of tetrapropyl orthosilicate following ingestion. Silicic acid may be absorbed from the gut before it is precipitated out to insoluble silica.There are no oral studies to check for evidence of absorption. However, in oral studies on the structurally-related substance tetraethylorthosilicate (TEOS) some toxicity, and therefore evidence of absorption, was observed.

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.

Tetramethyl orthosilicate has water solubility (predicted 8.8E+05 mg/l) that would favour dermal penetration but a log K_ow(-0.5) that does not. Therefore predicted dermal absorption is expected to be minimal prior to hydrolysis. 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, tetramethyl orthosilicate is volatile (vapour pressure 1800 Pa) so further reducing the potential for absorption.

Absorption of the silicic acid and silica precipitate across the skin is unlikely.

 

 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 tetramethyl orthosilicate results in a blood:air partition coefficient of approximately 3650:1 meaning that, if lung exposure occurred there would be uptake in to the systemic circulation.

Following hydrolysis the silicic acid may be retained within the mucous of the lungs and thus absorption will be limited. Hydrolysis to silica might lead to some precipitate being retained in the lining of the respiratory tract although this was not noted in the repeat dose inhaled study. In a repeated-dose inhalation toxicity test with the related substance, TEOS, effects including tubulo-interstitial nephritis and haematological changes were observed, indicating systemic uptake.

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 tetramethyl orthosilicate predicts that, should systemic exposure occur, potential distribution into the main body compartments would be minimal with tissue:blood coefficients of all less than 1.

Table 1: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
tetramethyl orthosilicate	-0.5	0.32	0.6	0.7	0.1	0.7	0.8

 

In studies on the structurally-related substance, TEOS, the kidney appears to be a target organ following inhalation and oral exposure; therefore it may be that tetramethyl orthosilicate will be similarly distributed to the kidney.

Metabolism

Besides the already mentioned hydrolysis, there is no information on the potential metabolism of tetramethyl orthosilicate. Silicic acid is not metabolised, but forms a precipitate, as previously described. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.

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 the algorithm, the soluble fraction of tetramethyl orthosilicate in blood is approximately > 99%. Therefore tetramethyl orthosilicate would be effectively eliminated via the kidneys in urine.