3-(trimethoxysilyl)propyl isocyanate

Endpoint summary

Additional information

There are no in vivo data on the toxicokinetics of 3-(trimethoxysilyl)propyl isocyanate.

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 3-(trimethoxysilyl)propyl isocyanate or its hydrolysis products, reasonable predictions or statements may be made about their potential ADME properties.

3-(Trimethoxysilyl)propyl isocyanate is a moisture-sensitive liquid that hydrolyses very rapidly in contact with water initially expected to generate 3-(trimethoxysilyl)propylamine (CAS 13822-56-5) and carbon dioxide, followed by less rapid formation of methanol and 3-aminopropylsilanetriol from the silane intermediate. Relevant human exposure would be via the inhalation or dermal routes. However, due to the high reactivity of the isocyanate and methoxysilane groups with water, producing amine and hydroxyl groups respectively, relevant inhalation exposure would be to the hydrolysis products, primarily to 3-(trimethoxysilyl)propylamine (hydrolysis would occur rapidly when inhaled, even if a mixture of parent and hydrolysis products were present in air). The substance would also be expected to hydrolyse rapidly in contact with moist skin. At the local site of contact severe effects can be expected that trigger the hazard classification of the substance. Relevant systemic exposure by inhalation or dermal contact is to the primary and secondary hydrolysis products only. The parent substance is a respiratory sensitiser, and this is the critical health effect for the registered substance.

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

Absorption

Oral

Based on the known use pattern, significant oral exposure is not expected for the corrosive parent substance 3-(trimethoxysilyl)propyl isocyanate. However, oral exposure to the final hydrolysis product 3-aminopropylsilanetriol is potentially possible via the environment.

Following oral exposure, it is assumed that uptake through the intestinal walls into the blood occurs, except for the most extreme of insoluble substances. All substances with an appreciable solubility in water or lipid are assumed to have an uptake from the intestines. 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-(Trimethoxysilyl)propylamine and 3-aminopropylsilanetriol with predicted water solubility values of 5.7E+05 mg/l and 1000 g/L respectively and molecular weights of 179.29 and 137.21 clearly meet these criteria so should oral exposure occur then systemic exposure is very likely. 

Dermal

By using the water solubility and log Kow values, the fat solubility as well as the potential of dermal penetration of a substance can be estimated. 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.

The water solubility of the intermediate hydrolysis product 3-(trimethoxysilyl)propylamine (5.7E+05 mg/l) is favourable for absorption across the skin, however, the log K_ow (0.2) is not. Therefore, absorption across the skin is not likely to occur due to the hydrophilicity of the substance. Similarly, the predicted water solubility (1000 g/l) and the log K_ow of -2.9 of the final hydrolysis product 3-aminopropylsilanetriol mean it is unlikely to be absorbed.

Once hydrolysis has occurred absorption is likely to be significantly reduced. It is also possible that the damage caused by the corrosive properties of the test substance might increase the overall absorption.

Inhalation

Evidence of a Quantitative Structure Property Relationship (QSPR) to estimate the blood:air partition coefficient for human subjects has been 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 products, 3-aminopropylsilanetriol and 3-(trimethoxysilyl)propylamine result in high blood:air partition coefficients. Consequently, when hydrolysis has occurred, e.g. as in the lungs, the significant uptake into the systemic circulation would be expected. However, the high water solubility may also lead to the hydrolysis products being partly retained in the mucus of the lungs and therefore, 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). 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.

For 3-(trimethoxysilyl)propylamine and 3-aminopropylsilanetriol, 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 in the case of the final hydrolysis product, 3-aminopropylsilanetriol).

Table 1: tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
3-aminopropylsilanetriol	-2.9	0.0013	0.6	0.7	0.0	0.7	0.8
3-(trimethoxysilyl)propylamine	0.2	1.58	0.7	0.8	1.1	0.8	0.8

 

Metabolism

There are no data regarding the metabolism of 3-(trimethoxysilyl)propyl isocyanate or the intermediate and final hydrolysis products. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for 3-(trimethoxysilyl)propyl isocyanate. 

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. DeJongh et al., (1997) developed QPSRs using log

K_ow as an input parameter to calculate the solubility in blood based on lipid fractions in the blood assuming that human blood contains 0.7% lipids.

 

The substance will be hydrolysed to 3-(trimethoxysilyl)propylamine and 3-aminopropylsilanetriol in vivo. Using the algorithm, the soluble fraction of both hydrolysis products in blood is >99%. Therefore, taken together with the low molecular weight and high water solubility, it is likely to be effectively eliminated via the kidneys in urine.

 

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.