[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

Endpoint summary

Additional information

There are no reliable in vivo data on the toxicokinetics of [3-(2,3-epoxypropoxy)propyl]trimethoxysilane.

The following summary has therefore been prepared based on 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_ow so by using this, and where appropriate, other known or predicted physicochemical properties of [3-(2,3-epoxypropoxy)propyl]trimethoxysilane, reasonable predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

[3-(2,3-epoxypropoxy)propyl]trimethoxysilane is a moisture-sensitive liquid that has a measured hydrolysis half-life of 6.5 hours at pH 7 and 25°C, generating 3-(2,3-epoxypropoxy)propylsilanetriol and methanol. Hydrolysis of the alkoxy and epoxy groups occur independently. Human exposure can occur via the inhalation or dermal routes. Relevant inhalation and dermal exposure would be predominantly to the parent substance.

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, 3-(2,3-epoxypropoxy)propylsilanetriol. 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 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).

3-(2,3 -Epoxypropoxy)propylsilanetriol is highly water soluble (1E+06 mg/l) and has a  molecular weight of 194.26 in the favourable range. Should oral exposure occur, based on its known properties it is reasonable to assume that systemic exposure is likely. However, an available toxicokinetic study (WIL, 2000) reports little or no absorption of the test article 30 minutes following oral administration. This is likely to be due to “limited by condensation” solubility properties of the hydrolysis substance, the high dose in the study would had led to the formation of a siloxane wax upon hydrolysis. This behaviour might not be expected at lower concentrations, so it is possible that oral exposure to low doses will result in uptake.

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log K_ow values. Substances with log K_ow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. With a log K_ow of 0.5 and water solubility of 1.1 E+05 mg/l, absorption of [3-(2,3-epoxypropoxy)propyl]trimethoxysilane across the skin is unlikely. 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 but as [3-(2,3-epoxypropoxy)propyl]trimethoxysilane has a low vapour pressure evaporation is not likely to be a factor.

The high water solubility 1.0E+06 mg/l of the hydrolysis product, 3-(2,3-epoxypropoxy)propylsilanetriol, is favourable for absorption across the skin but the log K_ow of -2.6 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 absorption might be expected to be significantly reduced once hydrolysis has occurred. The available acute dermal toxicity studies (Mellon, 1962, Dow Corning Corporation, 1963) suggest that absorption and systemic exposure does occur via the dermal route, with death and gross pathology recorded in animals exposed to the test material.

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 substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane, results in a blood:air partition coefficient of approximately 2.2E+05:1 meaning that if lung exposure occurred there would be uptake into the systemic circulation, though the high water solubility of the parent substance may lead to some of the substance being retained in the mucus of the lungs. The high difference in log K_ow between the parent substance and hydrolysis product, 3-(2,3-epoxypropoxy)propylsilanetriol, results in a markedly higher blood:air partition coefficient (approximately 21.5E+11:1) of the hydrolysis product 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 the hydrolysis product 3-(2,3-epoxypropoxy)propylsilanetriol may lead to this substance being retained in the mucus of the lungs so absorption may be lower than the blood:air partition coefficient would suggest.

There available inhalation studies (Allied Corporation, 1982, Dow Corning Corporation, 1982) show evidence of absorption, including dose related toxicity and body weight changes, indicating systemic exposure.

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 (K_ow) is described. Using this value for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane predicts that, should systemic exposure occur, distribution would be slight into fat, liver, muscle, brain and kidney.

For the hydrolysis product, 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 5.1.2: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
[3-(2,3-epoxypropoxy)propyl]trimethoxysilane	0.5	3.16	0.7	0.8	2.5	0.9	0.9
3-(2,3-epoxypropoxy)propylsilanetriol	-2.6	0.0025	0.6	0.7	0.0	0.7	0.8

An in vivo bioavailability study for another trialkoxysilane, 4-((triethoxysilyl)methyl)morpholine (CAS 21743-27-1) shows evidence for systemic exposure following IP administration (Harlan 2009). This study is included to support the need for more data on genetic toxicity.

Metabolism

There are no data on the metabolism of [3-(2,3-epoxypropoxy)propyl]trimethoxysilane. However, it will hydrolyse to form 3-(2,3-epoxypropoxy)propylsilanetriol and methanol once absorbed into the body. 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. QPSRs as developed by DeJongh et al. (1997) using log K_ow 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-(2,3-epoxypropoxy)propyl]trimethoxysilane in blood is approximately 98% while the corresponding value for the hydrolysis product, 3-(2,3-epoxypropoxy)propylsilanetriol, 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 therefore unlikely.

 

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.

De Jongh, 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.