3-(diethoxymethylsilyl)propylamine

Endpoint summary

Additional information

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

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and its hydrolysis productsand 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_owso by using this, and other where appropriate, known or predicted physicochemical properties of3-(diethoxymethylsilyl)propylamineor its hydrolysis products, reasonable predictions or statements may be made about their potential ADME properties.

3-(diethoxymethylsilyl)propylamine is a moisture-sensitive liquid that hydrolyses rapidly in contact with water, generating ethanol and 3-(dihydroxymethylsilyl)propylamine (half-life of 6 hours at pH 7). Human exposure can occur via the inhalation or dermal routes. Due to the rapid hydrolysis, relevant dermal and inhalation exposure would be to the parent and hydrolysis products. Ethanol is not discussed further as its toxicokinetics properties have been extensively reviewed as part of its own REACH submission.

Absorption

Oral

Based on its known use pattern significant oral exposure is not expected for the corrosive parent substance.However, oral exposure to the hydrolysis product3-(dihydroxymethylsilyl) propylamineis potentially possible via the environment.

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 must 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 product3-(dihydroxymethylsilyl)propylaminewith a water solubility of 1000 g/L and a molecular weight of 135.24 clearly meets these criteria so should oral exposure occur then systemic exposure is likely. 

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. The predicted water solubility (5900 mg/L) and log K_owfor the parent3-(diethoxymethylsilyl)propylamine are favourable for absorption across the skin. However, although the water solubility of 1000 g/L of the hydrolysis product 3-(dihydroxymethylsilyl) propylamine is favourable for absorption across the skin the log K_owof -0.9 is not, therefore absorption across the skin is not likely to occur as the substance is likely to be too hydrophilic to cross the lipid-rich environment of the stratum corneum.

Damage to the skin due to the corrosive nature of the parent substance might allow an increase in absorption of the parent and hydrolysis products. Dermal toxicity studies, including skin irritation studies for 3-(diethoxymethylsilyl)propylamine did not show any signs of systemic toxicity, as most observed effects were probably secondary to the corrosive effects.

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 the parent, 3-(diethoxymethylsilyl)propylamine, results in a blood:air partition coefficient of 5269:1 meaning that if lung exposure occurred there would be uptake into the systemic circulation.The high water solubility of the hydrolysis product,3-(dihydroxymethylsilyl)propylamine, results in a markedly higher blood:air partition coefficient 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 of3-(dihydroxymethylsilyl)propylaminemay lead to some of it being retained in the mucus of the lungs so once hydrolysis has occurred, absorption is likely to slow down.

Damage to the respiratory tract due to the corrosive nature of the parent substance might allow an increase in absorption of the parent and hydrolysis products. There are no reliable inhalation data that could be reviewed for signs of systemic toxicity, and therefore absorption.

Distribution

For blood:tissue partitioning a QSPR algorithm has been developed by De Jonghet 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 for3-(diethoxymethylsilyl)propylaminepredicts that it will distribute approximately equally to liver, muscle, brain and kidney and significantly higher to fat.

Using this value for the hydrolysis product3-(dihydroxymethylsilyl)propylaminepredicts that 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 1: tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
3-(diethoxymethylsilyl) propylamine	2.5	316.23	4.2	2.8	82.6	2.7	2.0
3-(dihydroxymethylsilyl) propylamine	-0.9	0.13	0.6	0.7	0.0	0.7	0.8

 

Metabolism

There are no data regarding the metabolism of 3-(Diethoxymethylsilyl)propylamine or 3-(dihydroxymethylsilyl) propylamine. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for 3-(diethoxymethylsilyl) propylamine. 

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSR’s as developed by De Jonghet 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 of3-(Diethoxymethylsilyl)propylaminein blood is approximately 30%. Therefore, taken together with the low molecular weight and water solubility value suggests that elimination via the kidneys in urine is possible.

 

The soluble fraction of the hydrolysis product3-(diethoxymethylsilyl) propylaminein blood is approximately 99%. Therefore, taken together with the low molecular weight and high water solubility suggest that it is likely to be effectively eliminated via the kidneys in urine.