3-(trimethoxysilyl)propylamine

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

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

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-(trimethoxysilyl)propylamine or its hydrolysis products, reasonable predictions or statements can be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

3-(Trimethoxysilyl)propylamine. hydrolyses in contact with water (half-life 2.6 hours at pH 7, 5 seconds at pH 2, 0.2 hours at pH 4 and 0.1 hours at pH 9 and 20-25°C), generating 3-aminopropylsilanetriol and methanol. Human exposure can occur via the inhalation or dermal routes. Due to the hydrolysis at relevant physiological pH values inhalation and dermal exposure would be to the parent and hydrolysis products. Oral exposure to the hydrolysis product 3-aminopropylsilanetriol may occur in humans via the environment.

The ADME properties of methanol have been reviewed in other major reviews (OECD SIDS, 2004) and are not considered further here.

Absorption

Oral

Significant oral exposure is not expected for 3-(trimethoxysilyl)propylamine. However, should it occur, due to the very rapid hydrolysis at pH 2 relevant exposure would be to the hydrolysis product 3-aminopropylsilanetriol.

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 hydrolysis product 3-aminopropylsilanetriolwith a predicted water solubility of 1000 g/L and a molecular weight of 137.21 clearly meets these criteria so should oral exposure occur then systemic exposure is very likely. 

Clinical signs were recorded in the key acute oral study with 3-(trimethoxysilyl)propylamine (BRRC, 1980) indicating systemic exposure of substance-related material had occurred.

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.

The predicted water solubility of 3-(trimethoxysilyl)propylamine (5.7E+05 mg/L) is favourable for absorption across the skin but the predicted log K_ow of -2.8 at pH 7 is not.Therefore absorption across the skin is not likely to occur as the substance is too hydrophilic to cross the lipid-rich environment of the stratum corneum. Similarly the predicted water solubility (1000 g/L) of the hydrolysis product, 3-aminopropylsilanetriol, is favourable for absorption across the skin but the log K_ow of -4 at pH 7 is not.

However, as the parent substance is irritant, the resulting damage to the skin may increase potential for dermal penetration of 3-(trimethoxysilyl)propylamine and its hydrolysis products.

Inhalation

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 coefficient and the octanol:air partition coefficient (K_oct:air) as independent variables.

Using these values for 3-(trimethoxysilyl)propylamine predicts a blood:air partition coefficient of approximately 2E+05:1 meaning that, if lung exposure occurred there would be significant uptake into the systemic circulation.

 

The high water solubility of the hydrolysis product, 3-aminopropylsilanetriol, results in a markedly higher blood:air partition coefficient so once hydrolysis has occurred, as it would be expected to in the lungs, then uptake would be expected into the systemic circulation to an even greater extent that the parent. However, the high water solubility of 3-aminopropylsilanetriol 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 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 3-(trimethoxysilyl)propylamine and the hydrolysis product3-aminopropylsilanetriol predicts that, should systemic exposure occur, 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 5.1.1: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
3-(trimethoxysilyl)propylamine	-2.8	0.002	0.6	0.7	0.0	0.7	0.8
3-aminopropylsilanetriol	-4	0.0001	0.6	0.7	0.0	0.7	0.8

Metabolism

There are no data regarding the metabolism of 3-(trimethoxysilyl)propylamine. However, it will hydrolyse to form 3-aminopropylsilanetriol and methanol 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 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 fractions of 3-(trimethoxysilyl)propylamine and the hydrolysis product 3-aminopropylsilanetriol in blood are both >99% meaning they are likely to be eliminated via the kidneys in urine and accumulation would not occur.

References

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.

OECD (2004): SIDS Initial Assessment Report for SIAM 19, Berlin, Germany, 18-20 October 2004, Methanol, CAS 67-56-1.