3-(triethoxysilyl)propyl methacrylate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no measured in vitro or in vivo data on the toxicokinetics of 3-(triethoxysilyl)propyl methacrylate.

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 of 3-(triethoxysilyl)propyl methacrylate or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

3-(Triethoxysilyl)propyl methacrylate contains two types of hydrolysable groups: three ethoxysilane groups (which react rapidly to the corresponding silanols plus ethanol) and one methacrylate ester group (which has the potential to react to the corresponding alcohol plus methacrylic acid).

The half-lives for hydrolysis of the ethoxysilane groups are predicted to be 0.6 h at pH 4, 23.9 h at pH 7 and 0.3 h at pH 9 and 20-25°C, generating 3-(trihydroxysilyl) propyl methacrylate and ethanol. This corresponds to hydrolysis half-lives of approximately 8.8 hours at 37.5°C and pH 7 (relevant for lungs and blood), approximately 8 seconds at 37.5°C and pH 2 (relevant for conditions in the stomach following oral exposure), and 0.2 - 8.8 hours at 37.5°C and pH 5.5 (relevant for dermal exposure).

Hydrolysis of the methacrylate ester group is predicted to be very slow (>1 year) and therefore the hydrolysis product is not considered for the chemical safety assessment (WHO CICAD summary citing Howard, 1989).

Human exposure can occur via the inhalation or dermal routes. Relevant inhalation and dermal exposure would be to the parent substance predominantly, although some exposure to the hydrolysis products is likely following hydrolysis in the lungs or in contact with moist skin.Significant oral exposure is not expected for the parent substance 3-(triethoxysilyl)propyl methacrylate. However, oral exposure to the hydrolysis product 3-(trihydroxysilyl) propyl methacrylateis potentially possible via the environment.

The toxicokinetics of ethanol have been reviewed in other major reviews and are not considered further here.

Absorption

Oral

Significant oral exposure is not expected for this substance. Oral exposure to the hydrolysis products 3-(trihydroxysilyl)propyl methacrylate is potentially possible via the environment.

When oral exposure takes place, it can be assumed that, 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).

Therefore, if oral exposure did occur, although the molecular weight of 3-(triethoxysilyl)propyl methacrylate (290.4) is above the favourable range, the water solubility of 63 mg/L would favour absorption, so some exposure by this route is probable. The hydrolysis product, 3-(trihydroxysilyl)propyl methacrylate has favourable molecular weight (206.27) and water solubility values (1E+06 mg/L, limited to 1000 mg/L by condensation reactions) for absorption so systemic exposure to this is also likely.

There were no systemic effects observed in the key acute oral toxicity study (WIL (1995)).

 

Dermal

Dermal exposure would be to the parent and hydrolysis products.

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_ow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high.

Based on the predicted water solubility of 63 mg/l and log K_ow of 3.6, 3-(triethoxysilyl)propyl methacrylate is in the favourable range for dermal absorption, and is therefore expected to be absorbed prior to hydrolysis. After or during deposition on the skin, evaporation of the substance and dermal absorption occur simultaneously so the vapour pressure of a substance is also relevant. With a vapour pressure of 0.05 Pa at ambient temperature, evaporation of 3-(triethoxysilyl)propyl methacrylate is expected to be insignificant in respect of impact on potential dermal absorption.

Based on the predicted water solubility (1E+06 mg/L) of the hydrolysis product, 3-(trihydroxysilyl)propyl methacrylate, is potentially favourable for absorption across the skin but the log K_ow value (-0.9) indicates it is not likely to be sufficiently lipophilic to cross the stratum corneum and therefore dermal absorption into the systemic circulation is likely to be minimal. Therefore absorption of substance-related material will slow down as hydrolysis progresses.

Inhalation

The uptake of substances into the lungs requires that the substance should be sufficiently water soluble to dissolve in the mucous of the respiratory tract lining. In addition, the substance needs to have a log Kow which is favourable to absorption, i.e. between -1 and 4.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’s Law coefficient and the octanol: air partition coefficient (K_{oct: air}) as independent variables.

Using these values for 3-(triethoxysilyl)propyl methacrylate predicts a blood: air partition coefficient of approximately 2980:1 meaning that, if lung exposure occurred there would be uptake into the systemic circulation. The water solubility of 3-(triethoxysilyl)propyl methacrylate (63 mg/L) also suggests that it could be dissolved in the mucous of the respiratory tract lining to a limited extent, so it may also be passively absorbed from the mucous, further increasing the potential for absorption.

For the hydrolysis product 3-(trihydroxysilyl) propyl methacrylate the predicted blood: air partition coefficient is approximately 2.6E+11:1 meaning that significant uptake into 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.

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 algorithm for 3-(triethoxysilyl)propyl methacrylate predicts that, should systemic exposure occur, potential distribution into the main body compartments would primarily be into fatty tissues with similar but much lower proportions into the other tissues.

For the hydrolysis product 3-(trihydroxysilyl) propyl methacrylate, distribution into the main body compartments is predicted to be minimal.

Tissue: blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
3-(triethoxysilyl)propyl methacrylate	3.6	3980	7.7	4.8	111	6.1	4.1
3-(trihydroxysilyl) propyl methacrylate	-0.9	0.13	0.6	0.7	0.0	0.7	0.8

 

Metabolism

There are no data on the metabolism of 3-(triethoxysilyl)propyl methacrylate. However, it will hydrolyse to form ethanol and 3-(trihydroxysilyl) propyl methacrylate once absorbed into the body. An in vitro bacterial mutagenicity study with the registration substance and a bacterial reverse mutation study with the analogous substance 3-trimethoxysilylpropyl methacrylate (CAS 2530-85-0) showed no observable differences in effects with and without metabolic activation. However, an in vitro chromosome aberration study with the analogous substance 3-trimethoxysilylpropyl methacrylate (CAS 2530-85-0) showed a positive result for clastogenicity, and a difference in potency with and without metabolic activation, possibly indicating metabolism by hepatic enzymes. Further investigation is therefore required, and the substance is being tested in an in vivo comet assay.

 

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 the algorithm, the soluble fraction of 3-(triethoxysilyl)propyl methacrylate in blood is approximately 3.4%. For the hydrolysis product 3-(trihydroxysilyl)propyl methacrylate the figure is >99% meaning that once absorbed the hydrolysis product is likely to be eliminated via the kidneys in urine.The parent substance would be predicted to not be as readily eliminated from the body, however, as the parent is hydrolysed, the hydrolysis product will be excreted via urine and accumulation is therefore unlikely.

References:

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.

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.

Renwick A. G. (1993) Data-derived safety factors for the evaluation of food additives and environmental contaminants.Fd. Addit. Contam.10: 275-305.