N-(3-(trimethoxysilyl)propyl)ethylenediamine

Endpoint summary

Additional information

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

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

N-(3-(trimethoxysilyl)propyl)ethylenediamine is a moisture-sensitive liquid that hydrolyses very rapidly in contact with water (half-life 1.5 minutes at pH 7), generating methanol and N-(3-(trihydroxysilyl)propyl)ethylenediamine. Human exposure can occur via the inhalation or dermal routes. Due to the very rapid hydrolysis, relevant dermal and inhalation exposure would be to the hydrolysis products. 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 N-(3-(trimethoxysilyl)propyl)ethylenediamine. However, oral exposure to the hydrolysis product N-(3-(trihydroxysilyl)propyl)ethylenediamine is 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).

N-(3-(trihydroxysilyl)propyl)ethylenediamine with a water solubility of 1000 g/L and a molecular weight of 180.28 clearly meets these criteria so should oral exposure occur then systemic exposure is very likely. 

In oral acute and repeat dose studies there were signs of systemic toxicity indicating absorption of test substance-reacted 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 (1000 g/L) of the hydrolysis product, N-(3-(trihydroxysilyl)propyl)ethylenediamine, is favourable for absorption across the skin but the log K_ow of -3.4 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. Skin irritation and acute dermal toxicity studies did not show any signs of systemic toxicity, and therefore did not show any 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 N-(3-(trihydroxysilyl)propyl)ethylenediamine (vapour pressure 0.4 Pa) results in a very high blood:air coefficient meaning that, if lung exposure occurred there would be significant uptake in to the systemic circulation. However, the high water solubility of N-(3-(trihydroxysilyl)propyl)ethylenediamine 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.

In an acute inhaled study there were signs of systemic toxicity indicating absorption of test substance-reacted material had occurred.

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 N-(3-(trihydroxysilyl)propyl)ethylenediamine predicts 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
N-(3-(trihydroxysilyl) propyl)ethylenediamine	-3.4	0.0004	0.6	0.7	0.0	0.7	0.8

 

Metabolism

There are no data regarding the metabolism of N-(3-(trihydroxysilyl)propyl) ethylenediamine. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for N-(3-(trimethoxysilyl)propyl)ethylenediamine.

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QSPRs 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 N-(3-(trihydroxysilyl)propyl) ethylenediamine in blood is >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.