N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine

Endpoint summary

Additional information

There are no in vitro or in vivo data on the toxicokinetics of N-[3-(dimethoxymethylsilyl)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. The data have been used in algorithms that are the basis of many computer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models. Although these algorithms provide quantitative outputs, for the purposes of this summary only qualitative statements or predictions will be made because of the remaining uncertainties that are characteristic of prediction models. The main input variable for the majority of these algorithms is log K_owso by using this, and where appropriate, other known or predicted physicochemical properties of N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretions (ADME) properties.

N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine is a moisture-sensitive liquid that hydrolyses in contact with water (half-life approximately 15 minutes at pH 7), generating methanol and N-[3-(dihydroxymethylsilyl)propyl]ethylenediamine.

Human exposure can occur via the inhalation or dermal routes. Due to the 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

Significant oral exposure is not expected for N-[3-(dimethoxymethylsilyl)propyl]ethylenediamine.

However, oral exposure to the hydrolysis product N-[3-(dihydroxymethylsilyl)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 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).

N-[3-(Dihydroxymethylsilyl)propyl]ethylenediamine with a predicted water solubility of 1E+06 mg/L and a molecular weight of approximately 178 clearly meets these criteria so should oral exposure occur then systemic exposure is very likely. 

In an oral acute study there were signs of systemic toxicity indicating absorption of test 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_owvalues. 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 (8.6E+05 mg/L) and predicted log K_ow (1.0, unionised form) of the parent substance, N-[3 -(dimethoxymethylsilyl)propyl]ethylenediamine, are potentially favourable for absorption across the skin before hydrolysis occurs, so some systemic exposure to the parent may occur. In the ionised form present when the parent substance is in solution at pH 7, although the water solubility is favourable for absorption across the skin, the predicted log Kow of -2 is not.

Similarly, the predicted water solubility (1E+06 mg/L) of the hydrolysis product, N-[3-(dihydroxymethylsilyl)propyl]ethylenediamine, is favourable for absorption across the skin but the log K_ow of -4 (ionised form) 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.

A skin irritation study did not show any signs of systemic toxicity, and therefore supports low absorption of this hydrolysis product. However, systemic toxicity was observed in male rats in an acute dermal toxicity study with the parent substance at very high doses. The guinea-pig maximisation skin sensitisation study on the parent substance was positive, indicating that a minimal amount of absorption must have occurred.

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 and hydrolysis products results in very high blood:air partition coefficients of approximately 1.8E+06:1 and 5.7E+09:1 respectively, meaning that, if lung exposure occurred there would be significant uptake into the systemic circulation. However, their high water solubility may lead to some of them being retained in the mucus of the lungs therefore limiting absorption.

Inhalation data appear to show local effects of aerosol inhalation and no signs of systemic toxicity.

Distribution

Any absorbed test substance is likely to be in the form of the hydrolysis product N-[3-(dihydroxymethylsilyl)propyl]ethylenediamine.

For blood:tissue partitioning a QSPR algorithm has been developed by DeJongh 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-(dihydroxymethylsilyl)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-(dihydroxysilyl) propyl]ethylenediamine	-4	0.0001	0.6	0.7	0.0	0.7	0.8

 

Metabolism

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

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_owas 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-(dihydroxymethylsilyl)propyl]ethylenediaminein 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.

References:

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

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.

Renwick A. G. (1993) Data-derived safety factors for the evaluation of food additives and environmental contaminants.Fd. Addit. Contam.10: 275-305