acrylic acid, 3-(trimethoxysilyl)propyl ester

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no in vivo or in vitro data on the toxicokinetics of 3-(trimethoxysilyl)propyl acrylate (CAS No. 4369 -14-6, EC No. 419-560-6). 

The following summary has therefore been prepared based on the physicochemical properties of the substance itself and its silanol hydrolysis product 3-acryloxypropylsilanetriol 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 comparisons are made. The main input variable for the majority of the algorithms is log K_ow, so by using this parameter and, where appropriate, other known or predicted physicochemical properties of 3-(trimethoxysilyl)propyl acrylate (and 3-acryloxypropylsilanetriol), reasonable predictions and statements may be made about their potential absorption, distribution, metabolism, and excretion (ADME) properties.

3-(Trimethoxysilyl)propyl acrylate is a relatively low molecular weight (234.32 g/mol), moderately water soluble (4300 mg/l, predicted, at 20°C), somewhat volatile (vapour pressure of 20.5 Pa at 25°°C, measured), and moisture sensitive liquid that hydrolyses in contact with water and has a predicted log K_owof 1.6 at 20°C. At 20-25°C, its hydrolysis half-life is predicted to be 0.2 hours at pH 4, 2.9 hours at pH 7, and 0.1 hours at pH 9, with each mole of 3-(trimethoxysilyl)propyl acrylate generating one mole of 3 -acryloxypropylsilanetriol and 3 moles methanol (CAS No. 67-56-1, EC No. 200-659-6). In comparison to the registered substance, the silanol hydrolysis product 3 -acryloxypropylsilanetriol has a lower molecular weight (192.25 g/mol), is miscible in water (water solubility of 1E+06 mg/l at 20°C, predicted), has a very low vapour pressure (2.3E-05 Pa at 25°C, predicted), and has a low log K_ow(-1.5 at 20°C, predicted).

Human exposure to the parent substance can occur via the dermal, and inhalation routes. Relevant inhalation exposures likely would be to 3-(trimethoxysilyl)propyl acrylate and its silanol hydrolysis product 3 -acryloxypropylsilanetriol, while dermal exposure primarily would be to registered substance. No direct oral exposure to humans is anticipated but indirect exposure via the environment may occur from the silanol hydrolysis product.

The toxicokinetics of methanol (non-silanol hydrolysis product) are discussed elsewhere and are not included in this summary.

 

Absorption

Oral

When oral exposure takes place, it can be assumed, except for the most extreme of insoluble substances, that uptake through the intestinal walls into blood takes place. 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).

 

Although the molecular weight of 3-(trimethoxysilyl)propyl acrylate (234.32 g/mol) is a little above the favourable range (<200 g/mol), the substance is moderately water soluble (4300 mg/l, predicted, at 20°C). So should oral exposure occur, it is reasonable to assume that some systemic exposure to the registered substance may take place before its hydrolysis. At relevant conditions for the stomach following oral exposure (37.5ºC and pH 2), the half-life for 3-(trimethoxysilyl)propyl acrylate is approximately 3 seconds. However, it is not appropriate or necessary to attempt to predict half-life accurately when itis less than 5-10 seconds. As a worst case, it can therefore be considered that the half-life of the substance in the stomach is approximately 5 seconds. Thus, oral exposure would be predominantly to the silanol hydrolysis product. Noting that some substances used as dosing vehicles (e.g., corn oil) may decrease the rate of parent hydrolysis such that some exposure to the parent substance could occur.

 

For the hydrolysis product, 3-acryloxypropylsilanetriol, oral exposure to humans following hydrolysis in the gastrointestinal tract or in the environment may be relevant. With a significantly higher solubility (1E+06 mg/l at 20°C, predicted) and lower molecular weight (192.25 g/mol) than the parent, it is reasonable to assume systemic exposure would occur following oral exposure and to a much greater extent than for the parent.

 

In the acute oral study in rats (OECD Test Guideline 401, Hita Research Laboratories, 1994a), a tendency toward decreased body weight gain in males on day 1 may indicate some oral absorption. However, a similar effect was not seen in the surviving females. In the oral repeated dose study in rats (OECD Test Guideline 407, Hita Research Laboratories, 1994b), the clinical signs observed may indicate oral absorption, but there were no systemic effects considered adverse or toxicologically relevant in this study. Since 3-(trimethoxysilyl)propyl acrylate is hydrolytically unstable, it is considered that the animals would have been exposed systemically to the hydrolysis products, 3 -acryloxypropylsilanetriol and methanol following oral absorption, and that any systemic effects observed would reflect the properties of these products following hydrolysis in the body.

 

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. Higher octanol solubility and lower water solubility result in higher log K_owvalues. Hydrolysis on moist skin may also occur, therefore exposure via this route is predicted to be to a mixture of a parent substance and its hydrolysis products. 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.

 

For 3-(trimethoxysilyl)propyl acrylate, the predicted log K_ow (1.6 at 20°C) is in the favourable range for dermal absorption. The registered substance is also only moderately water soluble (4300 mg/l, predicted, at 20°C). Further, it is corrosive to the skin (Category 1B), with skin damage potentially increasing dermal penetration. As potentially moderating processes, the registered substance is somewhat volatile (20.5 Pa at 25°C, measured), but not volatile enough (a vapour pressure >100 Pa) to limit dermal absorption. In addition, on moist skin and at relevant physiological conditions (pH 5.5 and 37.5°C), the hydrolysis half-life of the registered substance would be expected to be in the range from 4.4 minutes (predicted half-life at pH 4 and 37.5°C) to 64 minutes (predicted half-life at pH 7 and 37.5°C). Thus overall, uptake of unhydrolysed 3-(trimethoxysilyl)propyl acrylate through the skin is expected to occur and to a greater extent than its silanol hydrolysis product. However, dermal absorption of the registered substance would be expected to be significantly reduced once hydrolysis has occurred.

 

The very high predicted water solubility (1E+06 mg/l at 20°C) and low predicted log K_ow(-1.5 at 20°C) of the silanol hydrolysis product, 3-acryloxypropylsilanetriol, suggest that it is too hydrophilic to cross the lipid rich stratum corneum. Although it has a very low vapour pressure (2.3E-05 Pa at 25°C, predicted) such that volatilisation from skin would be minimal, dermal uptake of this silanol hydrolysis product is likely to be low based on its hydrophilicity.

 

No dermal acute or repeated dose data are available for 3-(trimethoxysilyl)propyl acrylate (not required as the substance is classified as corrosive to the skin. Thus, the potential for its absorption through the skin in an in vivo study cannot be assessed. However, since 3-(trimethoxysilyl)propyl acrylate is hydrolytically unstable, it is considered that study animals would be exposed systemically to the hydrolysis products, 3 -acryloxypropylsilanetriol and methanol following dermal absorption, and that any systemic effects observed would reflect the properties of these products following hydrolysis in the body.

 

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 predicted dimensionless Henry’s Law Constant (air: water partition coefficient, Kaw) and the octanol: air partition coefficient (Koa) as independent variables which are based on molecular weight, vapour pressure (predicted at 37°C), and water solubility (also predicted at 37°C). Higher molecular weight and vapour pressure will tend to decrease the blood: air partition coefficient, while higher water solubility will tend to increase this coefficient.

 

Using the above values, 3-(trimethoxysilyl)propyl acrylate is predicted to have a blood: air partition coefficient of approximately 5.99E+02:1. Thus, if lung exposure occurs, moderate absorption directly across the respiratory tract epithelium by passive diffusion is predicted to take place. At conditions relevant for the lungs (37.5ºC and pH 7), the hydrolysis half-life for 3-(trimethoxysilyl)propyl acrylate is approximately 1.1 hours.

 

For the silanol hydrolysis product 3-acryloxypropylsilanetriol, the predicted blood: air partition coefficient is very high (approximately 1.46E+11:1). So, once hydrolysis of the parent has occurred, as expected in the lungs, then significant uptake from the lungs would be expected into the systemic circulation. As a moderating factor, 3 -acryloxypropylsilanetriol is miscible in water (predicted water solubility of 1E+06 mg/l at 20°C), therefore some of it may be retained in the mucus of the lungs, a process that would slow down absorption through the lungs. Overall and based on the very high predicted blood: air partition coefficient, significant uptake of 3-acryloxypropylsilanetriol via inhalation is anticipated.

 

In the acute inhalation study in rats with 3-(trimethoxysilyl)propyl acrylate (OECD Test Guideline 403, SafePharm Laboratories, 1995c), the decreased body weight gain during the first week of observation and the gross pathology noted in organs other than the lungs indicate absorption via the inhalation route. Since 3 -(trimethoxysilyl)propyl acrylate is hydrolytically unstable, it is considered that the animals would have been exposed systemically to the hydrolysis products, 3-acryloxypropylsilanetriol and methanol following absorption through the lungs, and that any systemic effects observed would reflect the properties of these products following hydrolysis in the body.

 

Distribution

For blood: tissue partitioning, a QSPR algorithm has been developed by DeJonghet al. (1997) in which the distribution of compounds between blood and human body tissues (tissue: blood partition coefficients) as a function of water and lipid content of tissues and the n-octanol: water partition coefficient (K_ow, calculated from the log K_ow) is described.

 

The absorbed material may be in the form of parent 3-(trimethoxysilyl)propyl acrylate and its silanol hydrolysis product 3-acryloxypropylsilanetriol, with higher tissue: blood partition coefficients predicted for the parent. The log K_owof the parent substance (1.6 at 20°C, predicted) means that it is likely to distribute into fatty tissues to a much greater extent than other tissues. In contrast, the hydrophilic nature of 3 -acryloxypropylsilanetriol (log K_owof -1.5 at 20°C, predicted) will limit its diffusion across tissue membranes (including the blood-brain and blood-testes barriers) and especially limit its accumulation in fatty tissues.

 

Using the K_owvalues for the parent substance and the silanol hydrolysis product, the tissue: blood partition coefficients shown in Table 5.1.1 are predicted, with greater tissue distribution expected for unhydrolysed parent substance than the hydrolysis product. Noting that the parent estimates are relevant to the extent that some parent substance is absorbed into blood and then tissues prior to its hydrolysis following oral, dermal (on moist skin), or inhalation exposure.

Table 5.1.1 Tissue: blood partition coefficients

	log Kow	Kow(a)	Liver	Muscle	Fat	Brain	Kidney
3-(Trimethoxysilyl)propyl acrylate	1.6	39.8	1.6	1.3	27.0	1.4	1.2
3-Acryloxypropyl-silanetriol (silanol hydrolysis product)	-1.5	3.16E-02	0.6	0.7	0	0.7	0.8

 

(a) Calculated from the log K_ow

 

Metabolism

There are no data on the metabolism of 3-(trimethoxysilyl)propyl acrylate. However, it will hydrolyse to form the silanol 3-acryloxypropylsilanetriol and the non-silanol methanol during absorption (via ingestion, dermal contact on moist skin, or inhalation) or once absorption into the body has taken place. At physiologically relevant temperature (37.5ºC), the hydrolysis half-life for 3-(trimethoxysilyl)propyl acrylate in the body is predicted to vary from a worst case of 5 seconds at pH 2 (stomach) to 1.1 hours at pH 7 (lungs and blood). Inin vitrogenetic toxicity tests with registered substance (OECD Test Guideline 471, Hita Research Laboratories, 1994c; OECD Test Guideline 473, Hita Research Laboratories, 1994 d), there were 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 DeJonghet al. (1997) using log K_owas an input parameter, calculate the solubility in blood assuming that human blood contains 0.7% lipids.

 

Using this algorithm, the soluble fraction of 3-(trimethoxysilyl)propyl acrylate in blood is approximately 78% suggesting it is likely that some of it will be effectively eliminated via the kidneys in urine while accumulation is also likely to occur, both processes assuming that some of the parent remains unhydrolysed. At physiologically relevant temperature (37.5ºC), the hydrolysis half-life for 3-(trimethoxysilyl)propyl acrylate in the body is predicted to vary from a worst case of 5 seconds at pH 2 (stomach) to 1.1 hours at pH 7 (lungs and blood).

 

The soluble fraction of the silanol hydrolysis product 3-acryloxypropylsilanetriol in blood is approximately 100% suggesting it is likely to be effectively eliminated via the kidneys in urine, with accumulation very unlikely. The latter is consistent with the low predicted tissue: blood partition coefficients for this silanol, as presented under “Distribution.”  

 

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.