2-Propenoic acid, tris(1-methylethyl)silyl ester

Endpoint summary

Additional information

There are no in vivo data on the toxicokinetics of tri(isopropyl)silyl acrylate.

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_ow so by using this, and other where appropriate, known or predicted physicochemical properties of tri(isopropyl)silyl acrylate or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Tri(isopropyl)silyl acrylate is a moisture-sensitive liquid that hydrolyses very rapidly in contact with water (half-life <1 hour at pH 4, 7 and 9 at 25^oC), generating acrylic acid and tris(1-methylethyl)silanol. 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. Acrylic acid is not discussed further as its toxicokinetic properties have been extensively reviewed as part of its own REACH submission.

Absorption

Oral

Significant oral exposure is not expected for this substance.

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).

The molecular weight of tri(isopropyl)silyl acrylate (228.41) is beyond the favourable range for absorption, however when in contact with water the parent substance hydrolyses very rapidly and expected exposure would be to the hydrolysis product tris(1-methylethyl)silanol. Tris(1-methylethyl)silanol has favourable molecular weight (174.36) but low water solubility (60 mg/l at 20°C) for absorption so systemic exposure via the oral route is likely to be minimal.

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. Due to the likely very rapid hydrolysis of tri(isopropyl)silyl acrylate on contact with skin, systemic exposure via this route is predicted to be minimal. The water solubility (60 mg/l) and the log K_ow (3.9) of the hydrolysis product tris(1-methylethyl)silanol, are not favourable for absorption across the skin. Skin irritation studies did not show any signs of systemic toxicity.

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 hydrolysis product, tris(1-methylethyl)silanol, results in a blood:air partition coefficient of approximately 103.1 so once hydrolysis of the registered substance has occurred, as it would be expected to in the lungs, some uptake would be expected into the systemic circulation.

Distribution

All absorbed test substance is likely to be in the form of the hydrolysis product tris(1-methylethyl)silanol. 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 tris(1-methylethyl)silanol predicts that 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
tris(1-methylethyl)silanol	3.9	7943.28	8.2	5.1	112.4	7.5	4.9

 

Metabolism

There are no data regarding the metabolism of tri(isopropyl)silyl acrylate or tris(1-methylethyl)silanol. The available genetic toxicity tests 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 the hydrolysis product, tris(1-methylethyl)silanol, in blood is <2% suggesting that urinary excretion will not be the significant route of excretion.

 

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.

DeJongh, 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.