Bis(triethoxysilylpropyl)amine

Endpoint summary

Description of key information

Based on the molecular structure, molecular weight, water solubility, and octanol-water partition coefficient it can be expected that 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine is likely to be absorbed via the oral and inhalation route, however, the low vapour pressure means that inhalation exposure is likely to be negligible. Dermal absorption is considered to be low.

Hydrolysis occurs rapidly, and exposure is expected to both the parent substance and its hydrolysis products ethanol and 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine. Due to the very high water solubility, the silanol hydrolysis product is expected to be widely distributed in the body. Excretion via the renal route is considered favoured, and test material deposited in the stratum corneum is expected to be sloughed off with the skin cells. Thus no bioaccumulation is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no measured data on the toxicokinetics of 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine.

The following summary has therefore been prepared based on the predicted and measured physicochemical properties of the registered substance and its hydrolysis product (see Table below). The data have been used in algorithms that are the basis of many physiologically based pharmacokinetic and 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 the algorithms is the log Kow. By using this and, where appropriate, other known or predicted physicochemical properties of 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine or its hydrolysis product, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

3-(Triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine hydrolyses in contact with water (measured half-life of 11.9 h at pH 7 and at 20°C), generating 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine and ethanol. Direct exposure of workers to the parent substance or its hydrolysis products might occur via inhalation and dermal routes. Exposure of the general population via the environment might occur via the oral route but would be limited to the hydrolysis product.

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

Table: Physicochemical properties

Physicochemical properties	3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine	3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine
Water solubility	23 mg/L at 20-25°C (QSAR)	1.0E+06 mg/L at 20-25°C (QSAR)
Vapour pressure	1.8E-04 Pa at 25°C (QSAR)	2.2E-10 Pa at 25°C (QSAR)
Log Kow	3.1 at 20°C (QSAR)	-4.0 at 20°C (QSAR)
Molecular weight (g/mol)	425.7	257.4
Half-life	11.9 h at pH 7, 7.7 min at pH 4 and 5.62 min at pH 9 at 20 °C (OECD 111)

Absorption

Oral

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. Generally, the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption. 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 g/mol) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (ECHA, 2017).

Therefore, if oral exposure to the parent did occur, the molecular weight of 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine (425.7 g/mol) would favour absorption, so systemic exposure by this route is likely. At pH 2 in the stomach, the parent compound is predicted to hydrolyse into the hydrolysis product 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine within two seconds at the temperature of 37.5°C, therefore, the hydrolysis product is the predominant species that will be available for absorption. The molecular weight of 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine (257.4 g/mol) is in the favourable range for absorption, however, due to its high water solubility (1.0E+06 mg/l at 20-25°C) the rate of passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid.

Signs of systemic toxicity especially effects on the liver (markedly increased levels ALT and AST) and skeletal muscle (myofiber degeneration) were evident in the oral combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (Charles River Laboratories , 2022), which indicates systemic exposure to either the parent or hydrolysis product.

In conclusion, both 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine and its hydrolysis product 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine will be absorbed after oral exposure. Given the rapid rate of hydrolysis that will occur at pH 2 in the stomach, the predominant species that will be available for absorption is 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine.

Dermal

If dermal exposure were to occur, in practice, this would be to the parent compound as well as the hydrolysis product.

The potential dermal penetration of a substance can be estimated using the water solubility and log Kow values. Substances with log Kow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal), particularly if water solubility is high.

Although the log Kow value (3.1 at 20°C) of the parent substance is in the favourable range for dermal absorption, the low water solubility (23 mg/L) and relatively high molecular weight (425.7 g/mol) indicate that the rate of dermal absorption is likely to be low. For the hydrolysis product, the high water solubility (1.0E+06 mg/L at 20-25°C) and low log Kow of (-4.0 at 20°C) indicate the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Therefore, dermal uptake is expected to be low.

QSAR based dermal permeability prediction (DERMWIN V2.02.2012) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 0.0169 µg/cm²/h for 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine and 0.124 µg/cm²/h for 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine, respectively. This supports the overall assertion that dermal uptake of the parent and hydrolysis product are expected to be low.

There is limited dermal toxicity data available for 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine. In an acute dermal toxicity study (LPT, 2009), no mortality and no clinical signs of toxicity were observed. The body weight gain was not influenced by the test item administration. The macroscopic examination did not reveal any changes. This data supports the conclusion that dermal uptake of 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine and its hydrolysis product (3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine) will be low.

Inhalation

3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine has a low vapour pressure of 1.8E-04 Pa at 25°C. Therefore, inhalation exposure of vaporised substance is unlikely. The moderate log Kow (between -1 and 4) of the parent substance indicates that absorption directly across the respiratory tract epithelium by passive diffusion is possible.

The pH of the airway surface liquid has been determined to be in the range 6.7-7 (Jayaraman et al., 2000), without significant inter- or intraspecies variation.

The measured hydrolysis half-life at 20-25 °C and pH 7 (relevant for lungs and blood) is 11.9 h. As the hydrolysis reaction may be acid or base catalysed, the rate of reaction is expected to be slowest at around pH 7 and increase as the pH is raised or lowered. For an acid-base catalysed reaction in buffered solution, the measured rate constant is a linear combination of terms describing contributions from the uncatalyzed reaction as well as catalysis by hydronium, hydroxide, and general acids or bases.

kobs= k0+ kH3O+[H3O+] + kOH-[OH-] + ka[acid] + kb[base]

Hydrolysis is a chemical reaction that is independent of enzymatic involvement. It is reasonable to assume that the parent and hydrolysis products of 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine will be present in the airway surface liquid, without significant variation between individuals.

Proving the hydrolysis rate in the lungs of experimental animals in vivo would present many complicated (possibly insurmountable) technical difficulties, and therefore the presence of parent and hydrolysis product is assumed as a worst-case scenario.

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’s Law coefficient and the octanol: air partition coefficient (Koct: air) as independent variables.

Using these values for 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine predicts a blood: air partition coefficient of approximately 3.0E+5:1 meaning that, high levels of systemic exposure are expected, therefore, if lung exposure occurs the majority of parent substance available would be absorbed. However, hydrolysis is also expected to occur. For the hydrolysis product, 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine, the predicted blood: air partition coefficient is approximately 8.8E+15:1 meaning that systemic exposure is predicted to be even higher. Again, this prediction is based on physicochemical properties and is not expected to vary between individuals.

It is also important to consider the water solubility of 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine and its hydrolysis product with respect to dissolving in the mucous of the respiratory tract. The parent has a relatively low water solubility, therefore, solubility in the mucous of the respiratory tract is expected to be low. The hydrolysis product is highly soluble in water and therefore expected to be present in the mucous lining following inhalation of 3-(Triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine. Therefore, there is potential for passive absorption.

There are no inhalation toxicity studies for 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine or its hydrolysis product 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine, therefore, no further assessment of absorption following inhalation exposure can be made.

In conclusion, inhalation exposure to 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine is considered to be negligible, due to its low vapour pressure. However, should exposure occur, the parent substance and hydrolysis product 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine are likely to be absorbed.

Distribution

As the log Kow of 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine is > 0 (3.1 at 20°C) it is likely to distribute into cells and intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. However, the predominant species available in the body will be the hydrolysis product 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine. The molecular weight (257.4 g/mol) and high water solubility (1E+06 mg/L) of the hydrolysis product suggests it will diffuse through aqueous channels, pores and will be widely distributed in the body. However, the log Kow of -4.0 indicates the hydrolysis product is not lipophilic enough to distribute into cells and the extracellular concentration may be higher than the intracellular concentration.

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 (Kow) is described. Using this value for 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine (log Kow = 3.1) predicts that, should systemic exposure occur, distribution would primarily be into fat, with potential distribution into liver, muscle, brain and kidney but to a much lesser extent. For the hydrolysis products, distribution would be equally low within all tissues. Distribution of the hydrolysis product into the main body compartments is predicted to be much lower compared to the parent substance.

Table: Tissue: blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
3-(Triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine	3.1	1259	6.4	4.0	104.4	4.2	3.0
3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine	-4.0	0.0001	0.6	0.7	-0.2	0.7	0.8

 In conclusion, data for the hydrolysis product is considered to be the most relevant when assessing distribution and overall bioaccumulation potential, as 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine is expected to undergo hydrolysis to 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine in the body. The log Kow of the hydrolysis product (-4.0) demonstrates that it is not lipophilic enough to distribute into fatty tissue, therefore, there is no bioaccumulation potential.

Metabolism

No data are available describing the metabolism of 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine. However, metabolism of the target substance is considered negligible, since abiotic and enzyme independent hydrolysis is the prominent degradation reaction, leading to the highly water soluble products ethanol and 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine.

This is demonstrated in the available biodegradation studies for 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine, where there is no evidence of any significant biodegradation once hydrolysis and subsequent biodegradation of alkoxy groups has been taken into account (PFA, 2021).

It cannot be excluded, that amine containing compounds underlie multiple metabolic reactions such as N-oxidation or N-dealkylation, but this is considered to be insignificant and would only enhance renal excretion.

Excretion

3-(Triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine is known to undergo hydrolysis. The hydrolysis product 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine is far more water soluble than the parent chemical and has a molecular weight lower than 300 g/mol. Therefore, it is expected to be excreted predominantly via the renal route.

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by DeJongh et al. (1997) using log Kow 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 fraction of 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine in blood is approximately 8% and of 3-(trihydroxysilyl)-N-[3-(hydroxysilyl)propyl]-1-propanamine is >99%. Therefore, these figures suggest that the hydrolysis product is likely to be effectively eliminated via the kidneys in urine but the parent substance would be predicted to not be as readily eliminated from the body. However, as the parent is hydrolysed, the silanol hydrolysis product will be excreted via urine, and accumulation is therefore unlikely.

 

These findings support the hypothesis that after hydrolysis, a water-soluble silanol is formed (supported by log Kow calculation) which is rapidly excreted from the body. Since, this hydrolysis occurs without enzymatic involvement it is appropriate to reduce the intraspecies assessment factor from 5 to 2.2 for workers and from 10 to 3.2 for the general population, by exclusion of the toxicokinetic element of this assessment factor.

 

References

ECHA (2017). Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7c: Endpoint specific guidance. Version 3.0. June 2017

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.

Jayaraman, S.; Song, Y.; Vetrivel, L.; Shankar, L. & Verkman, A. Noninvasive in vivo fluorescence measurement of airway-surface liquid depth, salt concentration, and pH Journal of Clinical Investigation, American Society for Clinical Investigation, 2000, 107, 317-324.

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.

PFA, 2021, Peter Fisk Associates, Background to persistence assessment of organosilicon compounds, PFA.923.001.001