Triethoxy(phenyl)silane

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 and dermal routes rather than via inhalation. Hydrolysis occurs rapidly, 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 expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no measured data on the toxicokinetics of triethoxy(phenyl)silane.

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

Triethoxy(phenyl)silane hydrolyses rapidly in contact with water (predicted half-life approximately 1.5 hours at pH 7 and at 20-25°C), generating phenylsilanetriol and ethanol. Direct exposure of workers and the general population to the parent substance or its hydrolysis products might occur via the 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 due to the rapid hydrolysis.

 

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

 

Table: Physicochemical properties

Physicochemical properties	Triethoxy(phenyl)silane	Phenylsilanetriol
Water solubility	50 mg/L (QSAR)	1.0E+06 mg/L (QSAR)
Vapour pressure	0.03 Pa at 20°C (EU Method A.4)	0.000053 Pa at 25°C (QSAR)
Log Kow	3.4 (QSAR)	-0.021 at pH7 and 22°C (measured)
Molecular weight (g/mol)	240.38	156.21
Half-life	1.5 hour at pH 7 and at 20°C (QSAR)

 

 

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. 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 parent did occur, molecular weight of triethoxy(phenyl)silane (240.38 g/mol) is in the favourable range and 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 phenylsilanetriol within 5 seconds at the temperature of 37.5°C. Phenylsilanetriol has a favourable molecular weight and water solubility values for absorption so systemic exposure to this would also be likely.

Signs of systemic toxicity were evident in the repeated dose toxicity (Eurofins, 2019) oral studies, which indicates systemic exposure to either the parent or hydrolysis product.

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, 2018), 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 C_maxand AUC_last, was generally noted over the used dose range of 100 to 1000 mg/kg/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 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 (Harlan, 2009). Three male and three female animals were sacrificed one and four hours after test substance administration, and terminal blood, femur, stomach, combined gastrointestinal (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.

 

Dermal

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

The water solubility of 50 mg/L, log Kow of 3.4 and molecular weight of 240.38 g/mol of the parent substance suggest that absorption will be low. For the hydrolysis product (phenylsilanetriol) the water solubility of 1E+06 mg/L, log Kow value of -0.021 and molecular weight of 156.21 suggests the substance will also have a low potential to be absorbed by the dermal route, as it may be too hydrophilic to cross the lipid rich environment of the stratum corneum. QSAR based dermal permeability prediction (DERMWIN V2.00.2009) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 0.626 µg/cm²/h for triethoxy(phenyl)silane and 204.82 µg/cm²/h for phenylsilanetriol, respectively.

The acute dermal toxicity study (Mellon Institute, 1972) showed evidence of systemic toxicity at high doses (approx. 4000 mg/kg bw) of parent test substance, implying that dermal absorption of substance-related material had occurred.

 

Inhalation

The vapour pressure of the parent substance (0.03 Pa) indicates that this substance has a low volatility, and therefore inhalation as a vapour is unlikely to occur. The very hydrophilic nature of the hydrolysis product suggest that it may be retained more efficiently within the mucus compared to the parent substance, however the moderate log kow (between -1 and 4) of the parent substance and hydrolysis product indicate 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 predicted hydrolysis half-life at 20-25 °C and pH 7 (relevant for lungs and blood) is approximately 1.5 hours. This prediction is based on a validated QSAR estimation method and the following principle. 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.

k_obs= k₀+ k_H3O+[H3O⁺] + k_OH-[OH^-] + k_a[acid] + k_b[base]

This chemical reaction is independent of enzymatic involvement. It is reasonable to assume that the parent and hydrolysis products of triethoxy(phenyl)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(phenyl)silane predicts a blood: air partition coefficient of approximately 2600:1 meaning that, in steady state, more or less 100% 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, phenylsilanetriol, the predicted blood: air partition coefficient is approximately 6.4 E+10:1 meaning that systemic exposure is even 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(phenyl)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 also expected to be present in the mucous lining following inhalation of triethoxy(phenyl)silane, from which there is potential for passive absorption.

 

Distribution

The low molecular weight (156.21) and very high water solubility of the hydrolysis product suggest it will diffuse through aqueous channels and pores more easily than the parent substance. The log Kow of -0.021 (at pH 7) indicates it is likely to be distributed into cells and therefore the intracellular concentration will be higher than the extracellular concentration. Also, the parent substance with the low to moderate water solubility (50 mg/L) and Log Kow (3.4) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration. 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(phenyl)silane (log Kow = 3.4) 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 into the main body compartments is predicted to be minimal.

Table: Tissue: blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Triethoxy(phenyl)silane	3.4	2512	7.3	4.5	109	5.3	3.6
Phenylsilanetriol	-0.021	0.95	0.6	0.8	0.6	0.8	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(phenyl)silane is might accumulate in fat tissue. However, this is not expected as triethoxy(phenyl)silane hydrolyses fast to phenylsilantriol and ethanol.

 

Metabolism

Triethoxy(phenyl)silane is a moisture-sensitive liquid that hydrolyses rapidly in contact with water (predicted half-life 1.5 hour at pH 7 and 20°C), generating ethanol and phenylsilanetriol. There is no data on the metabolism of phenylsilanetriol. In the Ames test no difference was observed in the tests performed with or without metabolic activation. Due to the high water solubility no further metabolism is expected.

Triethoxy(phenyl)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). In the ready biodegradation study with the structurally related substance trichloro(phenyl)silane, respectively, the biodegradation observed is attributable to the non-silanol hydrolysis product (ethanol). Mass-balance calculation has been undertaken to determine the percentage by weight of the parent substance that is associated with the biodegradable by-product. Once the biodegradation of the hydrolysed ethoxy- groups is taken into account, there is no evidence of any biodegradation of the silanol hydrolysis product, phenylsilanetriol. This observation is supported by studies with silanols that are structurally similar to phenylsilanetriol. Studies with hydroxytrimethylsilane (CAS 1066-40-6) and dimethylsilanediol (CAS 1066-42-8) show no evidence of biodegradation (Clarke, 2008; Dow Corning Corporation, 1984). 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 (below 300 g/mol) and moderate to high water solubility of the parent and hydrolysis product suggest that they are likely to be excreted by the kidneys into urine. This is further compounded by the repeated-dose oral toxicity study with triethoxyphenylsilane, where effects on the urinary bladder were reported at the lowest test concentration.

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(phenyl)silane in blood is approximately 5.4%. 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 hydrolysis product will be excreted via urine, and accumulation is therefore unlikely.

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                                                  

Charles River (2017) Single Dose Pharmacokinetics of Diethoxy(dimethyl)silane after Oral Administration in Male and Female Wistar Rats (non-GLP) (ReachCentrum/Charles River, 2017) (Single Dose Pre-Study; final study report not yet available).

Clarke, N (2008). Trimethylsilanol (CAS No. 1066-40-6) Assessment of Ready Biodegradability; CO2 in Sealed Vessels (CO2 Headspace Test). Safepharm Laboratories Limited, Shardlow Business Park, Shardlow, Derbyshire, DE72 2GD. Report number: 2581/0002. Report date: 2008-10-14.

 

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.

 

Dow Corning Corporation (1984) Twenty Day Biochemical Oxygen Demand of Dimethylsilanediol with Bacterial Isolates Previously Exposed to Silicones

 

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