Triethoxypropylsilane

Endpoint summary

Description of key information

No studies are available. Based on molecular structure, molecular weight, water solibility, and octanol-water partition coefficient it can be expected that the submission substance is likely to be absorbed via the oral, dermal, and inhalation routes. Hydrolysis occurs in contact with water, and systemic exposure is expected to both the parent substance and the hydrolysis product. Based on the water solubility, the registered substance and its silanol-containig hydrolysis product are likely to be distributed in the body, and excretion via the renal pathway can be expected. Bioaccumulation is not favourable.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic properties of triethoxy(propyl)silane have been investigated.

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 which 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 triethoxy(propyl)silane or its hydrolysis product, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

 

Triethoxy(propyl)silane hydrolyses in contact with water (half-life is 4.3 min and 3.6 minutes at pH4 and 20°C and 35°C, respectively and 1.4 days at pH7 and 20°C), generating ethanol and propylsilanetriol. This suggests that systemic exposure to both the parent, triethoxy(propyl)silane, and to the hydrolysis product, propylsilanetriol, is possible. Hence, this toxicokinetic behaviour assessment will try to predict the behaviour of both these substances. The toxicokinetics of ethanol is discussed elsewhere and is not included in this summary.

Triethoxy(propyl)silane is characterised by the following physico-chemical parameters:

 

Physicochemical properties	Triethox(propyl)silane	Propylsilanetriol
Water solubility	382 mg/L (measured)	1E+06 (QSAR)
Vapour pressure	80 Pa at 20°C (measured)	4.6E-03 Pa at 25°C (QSAR)
Log Kow	3.1 (measured)	-1.4 (QSAR)
Molecular weight (g/mol)	206.35	122.19

 

Absorption

Oral: An acute oral limit test with triethoxy(propyl)silane showed no signs of mortality or systemic effects. Thus, indicating that the registered substance is of low toxicity and/or has low potential to be absorbed by the oral route.

Due to the fast hydrolysis rate at pH4 and 35°C it can be assumed that the test substance will hydrolyse quickly in the stomach. This suggests that absorption mainly of the hydrolysis product will occur.

The predicted water solubility (382 mg/L) of the parent and the hydrolysis product (1E+06 mg/L) suggests that both substances will readily dissolve in the gastrointestinal fluids. Also, the low molecular weight (≤ 206.35 g/mol) of the substances suggests they will have the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Furthermore, the moderate log Kow value of 3.1 for the parent and -1.4 for the hydrolysis product suggest that both substances are likely to be absorbed by passive diffusion with the parent substance being more efficient. 

There are supporting toxicokinetic data on two related alkoxysilane substances that show rapid absorption of alkoxysilanes following oral administration.

In a toxicokinetic test (Charles River, 2017), diethoxy(dimethyl)silane (CAS 78-62-8) was administered repeatedly by oral gavage of 100 and 1000 mg/kg bw to male and female as well as pregnant rats (3/sex). Blood samples were collected at 0.5, 1, 2, 4, 6 and 24 hours after dosing on Day 29 for males, premating for females and on gestation day 18 for females. The peak plasma concentration was reached rapidly, at the first blood collection point, just half an hour after dosing.A dose proportional increase in exposure, in terms of Cmax and AUClast, was generally noted over the used dose range of 100 to 1000 mg/kg bw/day in both males and females (pre-mated and pregnant (GD18)). After absorption diethoxy(dimethyl)silane was rapidly eliminated with individual apparent terminal half-lives ranging between 0.6 to 1.0 hours in males, 0.6 to 1.5 hours in pre-mated females and between 0.7 to 1.3 hours in pregnant females on GD18.

In a toxicokinetic test (Harlan, 2009) on morpholinotriethoxysilane (CAS 21743-27-1), the radiolabelled test substance was administered by oral gavage to mice (12/sex) as a single dose of 2000 mg/kg bw. Three male and three female animals were sacrificed one and four hours after test substance administration, and terminal blood, femur, stomach, combined GI tract contents, small intestine, large intestine, liver and kidney were collected. Terminal blood, femur, stomach, small intestine, large intestine, combined GI tract contents, liver, kidney as well as urine and faeces were collected from the remaining animals 24 hours after administration. Overall, significant mean levels of the test item were found in blood and plasma as early as 1 hour after application. This indicates that after oral administration the test item was rapidly absorbed in significant amounts. 

 

Inhalation:  In a subchronic inhalation study the registered substance showed no adverse effects. Therefore, the registered substance is deemed to be of low toxicity and/or having low potential to be absorbed by the inhalation route, too. The predicted vapour pressure of the parent substance (80 Pa) indicates that inhalation of the registered substance as a vapour could occur. 

The predicted moderate water solubility (382 mg/L) and log Kow (3.1) of the parent substance suggest that absorption from the respiratory tract epithelium by passive diffusion is likely. However, the high water solubility (1E+06 mg/L) and log Kow (-1.4) of the hydrolysis product, propylsilanetriol, might cause retention in the mucous of the lungs. Therefore, once hydrolysis has occurred, absorption is likely to slow down. However, the hydrolysis rate at pH7 is quite long with 1.4 days suggesting that the absorption of the hydrolysis product will rather be secondary. Particles deposited on the mucociliary blanket will be elevated into the laryngeal region and ultimately be swallowed (ingestion).

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 1.4 days. 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 triethoxy(propyl)silane 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 triethoxy(propyl)silane predicts a blood: air partition coefficient of approximately 5:1 meaning that, in steady state, more or less 83% of this substance will be in blood and very little in air, and therefore if lung exposure occurs the majority of parent substance available would be absorbed. However, hydrolysis is expected. For the hydrolysis product, propylsilanetriol, the predicted blood: air partition coefficient is approximately 9.3E+8:1 meaning that systemic exposure is more likely. 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 triethoxy(propyl)silane and its hydrolysis product with respect to dissolving in the mucous of the respiratory tract. The parent is expected to hydrolyse in the aqueous mucous. The hydrolysis product is highly soluble in water and therefore expected to be present in the mucous lining following inhalation of triethoxy(propyl)silane , from which there is potential for passive absorption.

 

Dermal: The moderate water solubility (382 mg/L) and log Kow (3.1) of the parent substance suggest that absorption via the dermal route is possible. For the hydrolysis product, propylsilanetriol, the high water solubility (1E+06 mg/L) and log Kow value of -1.4 suggest that the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum; however, the low molecular weight of 122.19 g/mol may favour some dermal uptake. QSAR-based dermal permeability prediction (DERMWIN V2.00.2009) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 0.00550 mg/cm²/h for triethoxy(propyl)silane and 0.0347 mg/cm²/h for propylsilanetriol, respectively. This shows that dermal penetration of the hydrolysis product is expected to be moderate compared to that of the parent substance, which is expected to be low. Therefore, once hydrolysis has occurred, absorption is likely to increase.

 

Distribution

The low molecular weight (122.19 g/mol) and very high water solubility (1E+06 mg/L) of the hydrolysis product suggest that it will have the potential to diffuse through aqueous channels, pores and will be widely distributed; however, the log Kow of -1.4 indicates it is unlikely to be distributed into cells. Therefore, the extracellular concentration will be higher than the intracellular concentration. Conversely, the parent substance, with moderate water solubility (382 mg/L) and log Kow (3.1), is likely to distribute into cells and so the intracellular concentration may be higher than extracellular concentration. The high water solubility and the moderate log Kow of both the parent and hydrolysis product suggest that accumulation in the body is not favourable for both substances.

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 triethoxy(propyl)silane (log Kow = 3.1) predicts that, should systemic exposure occur, distribution would primarily be into fat, with potential distribution into liver, brain, muscle and kidney but to a much lesser extent.

For the hydrolysis products, distribution into the main body compartments is predicted to be minimal.

Table: Tissue: blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Triethoxy(propyl)silane	3.1	1259	6.4	4.0	104.4	4.2	3.0
Propylsilanetriol	-1.4	0.06	0.6	0.7	-0.1	0.7	0.8

 

Additionally, there is a supporting study on a structurally-related substance (morpholinotriethoxysilane, CAS 21743-27-1) which show that there is no bioaccumulation in any organ (Harlan Laboratories, 2009). In this test (described above) mean plasma concentrations declined during the 24 h observation period to approximately 6.8% of the peak value in male mice and to 6.0% of the peak value in female mice. A comparable effect was seen in all tissues analysed. Together with excretion data (described later) these findings provide supporting evidence for the conclusion that triethoxy(propyl)silane is not expected to accumulate in any organ or tissue. 

 

Metabolism

Triethoxy(propyl)silane hydrolyses in contact with water (half-life is 1.4 days at pH 7 and 20°C), generating ethanol and propylsilanetriol. There are no data regarding the enzymatic metabolism of triethoxy(propyl)silane or propylsilanetriol.

Triethox(propyl)silane is within an analogue group of substances for which, in general, there is no evidence of any significant biodegradation once hydrolysis and subsequent biodegradation of alkoxy/acetoxy groups has been taken into account (PFA, 2013f). A biodegradation rate of 54% in 28 days was reported for the analogue substance trimethoxy(propyl)silane. The results from this study are likely to reflect the biodegradation of methanol, which would biodegrade rapidly (three of the six carbons in trimethoxy(propyl)silane are converted to methanol in a rapid hydrolysis reaction). Propylsilanetriol is not expected to biodegrade to any significant extent. This is supported by evidence that within a category of small molecule silicon-dominated organosilicon compounds, without reactive functional groups in the side chain, there is no evidence of any significant biodegradation in ready biodegradation tests. The second hydrolysis product ethanol is known to be readily biodegradable. It is therefore concluded that the substance and its silanol hydrolysis product are not recognised by biological systems containing all the mammalian enzymes and metabolic systems.

 

Excretion

The low molecular weight and moderate to high water solubility of the parent and hydrolysis product, respectively, suggest that they are likely to be excreted by the kidneys into urine.

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 triethoxy(propyl)silane in blood is approximately 60% and of propylsilanetriol is approximately 100%. 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 be eliminated from the body to a lesser extent via the kidneys.

This prediction is supported by in vivo toxicokinetic data on two related substances (morpholinotriethoxysilane and diethoxy(dimethyl)silane). The details of these tests are described above. With regard to excretion it has been demonstrated that both of these substances are rapidly absorbed, but also rapidly excreted.

In the test conducted by Harlan Laboratories (2009), morpholinotriethoxysilane peak concentration to radioactivity in the blood, plasma, femur, liver and kidney were found after just one hour. However, by 24 hours after administration concentrations had declined to 6-7% of the peak concentrations in plasma and tissues. After 24 hours 24.9% and 17.4% of the applied dose was detected in urine, 3.4% and 9.8% of the applied dose in cage wash of male and female mice, respectively. Also, 63.8% and 64.2% of the applied dose was excreted via faeces in male and female mice, respectively.

In the test conducted by Charles River (2018), the maximum plasma concentration of diethoxy(dimethyl)silane was reached rapidly. After absorption diethoxy(dimethyl)silane was rapidly eliminated with individual apparent terminal half-lives ranging between 0.6 to 1.0 hours in males, 0.6 to 1.5 hours in pre-mated females and between 0.7 to 1.3 hours in pregnant females on GD18.

In conclusion, rapid absorption into the blood and fast elimination from the blood via urine was observed with related alkoxysilane substances.

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, 2013f, Peter Fisk Associates, Biodegradation Main Analogue Group report, PFA.300.005.007