3-(trimethoxysilyl)propiononitrile

Endpoint summary

Additional information

There are no in vivo or in vitro data on the toxicokinetics of 3-(trimethoxysilyl)propiononitrile.

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of 3-(trimethoxysilyl)propiononitrile 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. 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)propiononitrile, reasonable predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

3-(Trimethoxysilyl)propiononitrile is a moisture-sensitive non-volatile liquid that hydrolyses in contact with water (predicted half-life approximately 1.1 hour at pH 7 and 25°C) generating methanol and 3-(trihydroxysilyl)propiononitrile. Human exposure can occur via the inhalation or dermal routes. Relevant inhalation and dermal exposure would be to the parent substance and the hydrolysis product.

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

Absorption

Oral

Significant oral exposure is not expected for this substance.

However, oral exposure to humans via the environment may be relevant for the hydrolysis product, 3-(trihydroxysilyl)propiononitrile. When oral exposure takes place, it is necessary to assume that except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood takes place. 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).

3-(Trihydroxysilyl)propiononitrile is highly water soluble and has a molecular weight of 133.18 so fulfils both of these criteria. Therefore, it is considered that should oral exposure occur it is reasonable to assume that resulting systemic exposure will occur also. 

Available oral toxicity tests show adverse systemic effects. Therefore, these tests support the conclusion that the parent or hydrolysis product is absorbed following oral exposure.

Dermal

Dermal exposure would be predominantly to the parent and potentially to the hydrolysis products.

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. Although the predicted water solubility of 3-(trimethoxysilyl)propiononitrile is potentially favourable, the predicted log K_ow (0.2) is not. Taken together this suggests that that 3-(trimethoxysilyl)propiononitrile will have minimal absorption through the skin. Similarly, for the hydrolysis product, 3-(trihydroxysilyl)propiononitrile, although highly water soluble the log K_ow is far from the ideal range for dermal absorption meaning that it is not likely to be sufficiently lipophilic to cross the stratum corneum and therefore dermal absorption into the blood is likely to be low.

Therefore, any absorption of the test substance might be expected to be reduced once hydrolysis has occurred, but overall dermal absorption is expected to be poor. Dermal studies on this substance do not provide convincing evidence of absorption.

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 3-(trimethoxysilyl)propiononitrile results in a high blood:air coefficient of approximately 1.8E+05:1 meaning that, if lung exposure occurred there would be uptake into the systemic circulation. The high water solubility of the hydrolysis product, 3-(trihydroxysilyl)propiononitrile, results in a markedly higher blood:air partition coefficient (approximately 1.2E+11:1) so once hydrolysis has occurred, as it would be expected to in the lungs, then significant uptake would be expected into the systemic circulation. However, the high water solubility of 3-(trihydroxysilyl)propiononitrile may lead to some of it being retained in the mucus of the lungs.

There are no reliable inhalation studies to check for signs of systemic toxicity.

Distribution

For blood:tissue partitioning 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 (K_ow) is described. Using this value for the parent and hydrolysis product predicts that distribution into the major body compartments is unlikely.

Table 1: tissue:blood partition coefficients

 

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
3-(trimethoxysilyl) propiononitrile	0.2	1.58	0.7	0.8	1.1	0.8	0.8
3-(trihydroxysilyl) propiononitrile	-2.9	0.00126	0.6	0.7	0.0	0.7	0.8

  

Metabolism

There are no data on the metabolism of 3-(trimethoxysilyl)propiononitrile. However, it will hydrolyse to form methanol and 3-(trihydroxysilyl)propiononitrile once absorbed into the body. Genetic toxicity tests in vitro 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 De Jongh 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 3-(trimethoxysilyl)propiononitrile and 3-(trihydroxysilyl)propiononitrile in blood are both >98% indicating they will be effectively eliminated via the kidneys in urine.