2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane

Endpoint summary

Additional information

There are no data on the toxicokinetics of 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane (CAS 3388-04-3).

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. 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 K_ow so by using this, and other where appropriate, known or predicted physicochemical properties 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane hydrolyses in contact with water, and has hydrolysis half-lives of 0.2 hours at pH 4, 0.3 hours at pH 5, 4 hours at 7 and 0.1 hours at 9 at 20-25°C, generating [2-(3,4-epoxycyclohexyl)ethyl]silanetriol and methanol. The half-life at 37.5°C and pH 7 is 1.5 hours, and at pH 2 it is 5 seconds.

Human exposure can occur via the inhalation or dermal routes. Relevant exposure would be to the parent substance and the hydrolysis products, due to the hydrolysis rate at body temperature.

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 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).

In the acidic environment of the stomach, the parent substance hydrolyses very rapidly (hydrolysis half-life at 37.5°C and pH 2 is 5 seconds). The parent substance has a molecular weight of 246.38 and water solubility of 1400 mg/l, so some systemic exposure would be expected. Similarly, the hydrolysis product, [2-(3,4-epoxycyclohexyl)ethyl]silanetriol has a favourable molecular weight (204.3) and water solubility (1.0E+06 mg/l) for absorption so systemic exposure is likely.

Dermal

Dermal exposure would be to the parent and the hydrolysis products, as at 25°C and pH 5 the hydrolysis rate is 0.3 hours.

The fat solubility and therefore potential dermal penetration of the parent and the hydrolysis product [2-(3,4-epoxycyclohexyl)ethyl]silanetriol 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 parent substance is water soluble (1400 mg/l) and has a log Kow value (2.5) in the favourable range so absorption into the systemic circulation is likely. However, for the hydrolysis product, [2-(3,4-epoxycyclohexyl)ethyl]silanetriol, although it is highly soluble (1.0E+06 mg/l), the log Kow value (-0.6) indicates it is not likely to be sufficiently lipophilic to cross the stratum corneum and therefore dermal absorption into the blood is likely to be minimal. Therefore absorption of substance-related material will slow down as hydrolysis progresses.

Inhalation

There is a Quantitative Structure-Property Relationship (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.

For the hydrolysis product [2-(3,4-epoxycyclohexyl)ethyl]silanetriol the predicted blood:air partition coefficient is approximately 7.4E+11:1 meaning that significant uptake in to the systemic circulation is likely. However, the 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. Similarly, for the parent, the blood:air coefficient is approximately 1.4+04:1, and uptake is likely.

Distribution

For blood:tissue partitioning a QSPR algorithm has been developed by De Jongh 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 (K_ow) is described.

For the parent compound, distribution into fat tissue is likely, but distribution to other compartments is likely to be minimal.

For the hydrolysis product [2-(3,4-epoxycyclohexyl)ethyl]silanetriol, distribution into the main body compartments is predicted to be minimal and zero for fat.

Table 5.1: Tissue:blood partition coefficients

 

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
2-(3,4-epoxycyclohexyl) ethyltrimethoxysilane	2.5	316.23	4.2	2.8	82.6	2.7	2.0
[2-(3,4-epoxycyclohexyl) ethyl]silanetriol	-0.6	0.25	0.6	0.7	0.0	0.7	0.8

Metabolism

There are no data on the metabolism of 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane. However, it will hydrolyse when in contact with moisture to form methanol and [2-(3,4-epoxycyclohexyl)ethyl]silanetriol. 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 Jongh 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 the algorithm, the soluble fraction of the parent in blood is 31% and the hydrolysis product [2-(3,4-epoxycyclohexyl)ethyl]silanetriol >99% meaning that once absorbed and hydrolysed it is likely to be eliminated via the kidneys in urine and accumulation is unlikely