Tetraethyl orthosilicate

Endpoint summary

Additional information

There are no in vivo data on the toxicokinetics of tetraethyl orthosilicate (CAS 78-10-4, EC No. 201 -083-8).

 

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 these 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 predictions are made.

 

The main input variable for the majority of these algorithms is log Kow. So, by using this parameter and, where appropriate, other known or predicted physicochemical properties of tetraethyl orthosilicate or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

 

In contact with water, tetraethyl orthosilicate hydrolyses very rapidly, with a hydrolysis half-life of 0.11 hr (6.6 min), 4.4 hr and 0.22 hr (13 min) at pH 4, 7 and 9 respectively and at 25°C, to form monosilicic acid. Monosilicic acid exists only in dilute aqueous solutions and readily condenses at concentrations above approximately 100 - 150 mg/L as SiO2 to give a dynamic equilibrium between monomer, oligomers and insoluble polysilicic acid. The timing and rate of condensation is regulated by the concentration, pH, ionic strength, temperature etc. The non-silanol product of hydrolysis is ethanol. The toxicokinetics of ethanol have been extensively studied previously and therefore are not discussed further in this summary.

 

Human exposure to tetraethyl orthosilicate can occur via the inhalation or dermal routes.

Some toxicokinetic work may help identify or predict the predominant chemical entity (monosilicic versus polysilicic acid) present in the small intestine, the primary site of gastrointestinal absorption or in the nasal mucosa, the site of respiratory inflammation in the reliable repeat inhalation studies (Omae et al. 1995, Nakashima et al. 2014).

 

Absorption

 

Oral

Significant oral exposure is not expected for tetraethyl orthosilicate.

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 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 g/mol) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

 

If oral exposure of tetraethyl orthosilicate occurs, its molecular weight (208 g/mol) and water solubility (8600 mg/L) favour absorption following oral (neat or aqueous) ingestion. However, tetraethyl orthosilicate will rapidly hydrolyse (hydrolysis half-life at pH 4 is 6.6 minutes; and approximately 5 seconds at pH 2) to monosilicic acid in the stomach, thus making the absorption of tetraethyl orthosilicate following ingestion unlikely. The hydrolysis product monosilicic acid would be absorbed from the gastrointestinal tract (primarily small intestine); whereas absorption of the condensed insoluble polysilicic acid will be insignificant when compared to the absorption of the soluble species (Carlisle, 1986).

 

In the repeated dose oral study with the tetraethyl orthosilicate condensed hydrolysis product polysilicic acid (equivalent to synthetic amorphous silica [SAS], Kim et al. 2014), there were no significant adverse effects identified (author conclusion of a systemic NOAEL at the highest dose tested). Although systemic (renal) findings were observed in the repeated dose oral study with tetraethyl orthosilicate (CIT Safety & Health Laboratories 2005), this result is considered a consequence of the corn oil dosing (see repeated dose endpoint summary).

 

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.

 

With a water solubility of 8600 mg/L and log Kow of 1.4, tetraethyl orthosilicate is in the favourable range for dermal absorption, and therefore could be absorbed prior to hydrolysis in the absence of moisture on the skin. After or during deposition of a liquid on the skin, evaporation of the substance and dermal absorption occur simultaneously such that the vapour pressure of a substance is also relevant. With a vapour pressure of 20 Pa at 20°C, evaporation of tetraethyl orthosilicate is not likely to be a major factor influencing potential dermal absorption.

 

Although the molecular weight of the hydrolysis product monosilicic acid favours absorption across the skin, it is water soluble (approximately 100 - 150 mg/L as ‘SiO2 equivalent’ with condensation to insoluble polysilicic acid occurring at higher concentrations). This solubility suggests that monosilicic acid is too hydrophilic to cross the lipid rich stratum corneum. Thus, absorption of the soluble monosilicic acid and the condensed insoluble polysilicic acid across the skin is unlikely.

 

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.

 

Using these values for tetraethyl orthosilicate results in a blood: air partition coefficient of approximately 910: 1 meaning that if respiratory exposure occurred there could be uptake of tetraethyl orthosilicate into the systemic circulation. However, given the rapid hydrolysis of tetraethyl orthosilicate, it is expected that the entity absorbed across the respiratory (nasal) mucosa would be the monosilicic acid hydrolysis product.

 

Although systemic (renal) effects were identified in reliable repeated-dose inhalation toxicity studies with tetraethyl orthosilicate (Omae et al., 1995, Nakashima et al. 1994), these findings are considered consistent with a physical effect of insoluble polysilicic acid formation within the kidneys, rather than tetraethyl orthosilicate toxicity (see repeated dose endpoint summary).

 

Distribution

As discussed above, the predicted absorbed entity is the monosilicic acid hydrolysis product, rather than tetraethyl orthosilicate or polysilicic acid. Monosilicic acid, is a small polar molecule, and therefore has potential to be widely distributed, but its hydrophilic nature will limit its diffusion across membranes (including the blood-brain and blood-testes barriers) and its accumulation in fatty tissues. Human blood contains 1 mg SiO2/L of monosilicic acid (Iler RK, 1979).

 

For blood: tissue partitioning of the parent substance, 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 (Kow) is described.

 

Tetraethyl orthosilicate quickly hydrolyses to monosilicic acid thus limiting its systemic absorption and therefore distribution. So, the following predicted distribution of tetraethyl orthosilicate to the fatty tissues is not considered likely.

 

Table 5.1.1 Tissue: blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Tetraethyl orthosilicate	1.4	25.12	1.3	1.1	18.4	1.3	1.1

 

Metabolism

Besides the aforementioned hydrolysis, there is no information on the potential metabolism of tetraethyl orthosilicate.

 

Silicon is an essential trace element participating in the normal metabolism of higher animals. It is required in bone, cartilage and connective tissue formation as well as participating in other important metabolic processes. The silicon is present almost entirely as free, soluble monosilicic acid (Carlisle 1986).

 

The available and negative genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.

 

Excretion

As discussed in the repeated dose endpoint summary, all of the tetraethyl orthosilicate would be expected to hydrolyse to monosilicic acid in the gastrointestinal tract after oral exposure or in the nasal mucosa following inhalation. Any absorbed soluble monosilicic acid would either condense to polysilicic acid in the kidneys or be excreted via urine as monosilicic acid. Condensed and insoluble polysilicic acid formed in the gastrointestinal or nasal mucosa would not be absorbed systemically, and thus only excreted in faeces.