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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 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 studies available in which the toxicokinetic properties of trimethoxyphenylsilane have been investigated. Therefore, the toxicokinetic behaviour assessment of the substance and its hydrolysis product was estimated by its physico-chemical properties (see table below) and the available toxicology studies on the substance itself.  

The following summary has been prepared based on validated predictions of the physico-chemical properties oftrimethoxyphenylsilaneand 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 Kow so by using this, and others where appropriate, known or predicted physico-chemical properties of trimethoxyphenylsilane and its silicon-containing hydrolysis product,phenylsilantriol,reasonable predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

 

Trimethoxyphenylsilane hydrolyses rapidly in contact with water (half-life 0.4 hours at pH 7 and 20°C), generating methanol and phenylsilanetriol. This suggests that systemic exposure to both the parent, trimethoxyphenylsilane, and the hydrolysis product, phenylsilanetriol is possible. Hence, this toxicokinetic behaviour assessment will try to predict the behaviour of both these substances. The toxicokinetics of methanol is discussed elsewhere and is not included in this summary.

 

Table: Physicochemical properties

Physicochemical properties

 

Trimethoxy(phenyl)silane

 

Phenylsilanetriol

 

Water solubility

1700 mg/L (QSAR)

1.0E+06 mg/L (QSAR)

Vapour pressure

18.2 Pa at 25°C (EU Method A.4)

0.000053 Pa at 25°C (QSAR)

Log Kow

2.0 (QSAR)

-0.021 at pH7 and 22°C (measured)

Molecular weight (g/mol)

198.29

156.21

Half-life

0.4 hour at pH 7 and at 25°C (measured)

 

 

 

Absorption

Oral:

An acute and a repeated-dose oral toxicity study with trimethoxyphenylsilane showed signs of systemic toxicity, therefore, indicating that absorption via the oral route is possible. If ingestion occurs, the hydrolysis of the parent substance in the low pH of the stomach will be rapid, so any absorption of the parent substance is expected to be minimal and it is more likely to be the hydrolysis product that is absorbed.

 

The predicted water solubility of the parent (1700 mg/L) and hydrolysis product (1E+06 mg/L) suggest that both substances will readily dissolve in the gastrointestinal fluids. Also, the low molecular weight (≤ 198.29 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 of 2 for the parent and -0.021 for the hydrolysis product suggest that both these substances are lipophilic enough to be absorbed by passive diffusion.

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 Cmaxand AUClast, 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 (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:

The vapour pressure of the parent substance (18.2 Pa) indicates that inhalation of the registered substance as a vapour could occur. The predicted moderate water solubility (1700 mg/L) and log Kow (2.0) of the parent substance suggest that absorption from the respiratory tract epithelium by passive diffusion is likely. However, the very high water solubility (1E+06 mg/L) and low log Kow (-0.021) of the hydrolysis product, phenylsilanetriol, might cause retention in the mucous of the lungs. Therefore, once hydrolysis has occurred, absorption is likely to slow down. 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.

As outlined in Section 5.1 the predicted hydrolysis half-life fortrimethoxyphenylsilaneat 37.5ºC and pH 7 (relevant for lungs and blood) is approximately 9 minutes. This prediction is based on a weight of evidence of data from validated QSAR estimation method and measured data. 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]

This chemical reaction is independent of enzymatic involvement. It is reasonable to assume that the parent and hydrolysis products of trimethoxyphenylsilane 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 fortrimethoxyphenylsilanepredicts a blood: air partition coefficient of approximately 250:1 meaning that, in steady state, approximately 99.6% of this substance will be in blood and approximately 0.4% 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, methylsilanetriol, the predicted blood: air partition coefficient is approximately 6.4E+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 trimethoxy(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 trimethoxyphenylsilane, from which there is potential for passive absorption.

 

Dermal:

The moderate water solubility (1700 mg/L), log Kow (2.0) and molecular weight (198.29 g/mol) of the parent substance suggest that absorption via the dermal route is possible. Also 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 g/mol suggest that absorption via the dermal route is also possible. QSAR based dermal permeability prediction (DERWIN V2.00.2009) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 0.004 mg/cm²/h for trimethoxyphenylsilane and 0.204 mg/cm²/h for phenylsilanetriol, respectively. This shows that dermal penetration of the hydrolysis product will be high compared to that of the parent substance which is expected to be moderate. Therefore, once hydrolysis has occurred, absorption is likely to increase.

 

Distribution

The low molecular weight (156.21 g/mol) and very high water solubility of the hydrolysis product suggest it will diffuse through aqueous channels, pores and will be widely distributed. The log Kow of -0.021 indicates it is unlikely to be distributed into cells and therefore the extracellular concentration will be higher than the intracellular concentration. However, the parent substance with the moderate water solubility (1700 mg/L) and log Kow (2.0) 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 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 (Kow) is described. Using this value fortrimethoxyphenylsilanepredicts that, should systemic exposure occur, potential distribution into the main body compartments would be minimal, barring fat.

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

Table1: Tissue:blood partition coefficients

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

trimethoxyphenylsilane

2.0

100

2.5

1.8

50.9

1.9

1.4

phenylsilanetriol

-0.021

0.95

0.6

0.8

0.4

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, 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 trimethoxyphenylsilane is not expected to accumulate in any organ or tissue.

 

Metabolism

Trimethoxyphenylsilane hydrolyses rapidly in contact with water (half-life 0.4 hour at pH 7 and 20°C), generating methanol and phenylsilanetriol. There are no data regarding the enzymatic metabolism of trimethoxyphenylsilane or phenylsilanetriol.

Trimethoxyphenylsilaneis within an analogue group of substances within 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, 0% biodegradation was observed in 28 days/60 days.The other hydrolysis product, hydrochloric acid, is inorganic and therefore biodegradation is not relevant. The alcohol hydrolysis product of the target substance, methanol, is readily biodegradable based on the results of standard tests that show 76 – 82% and 95% removal in standard ready tests after 5 and 20 days, respectively.Thus, there is no evidence of any significant biodegradation of the silanol hydrolysis product phenylsilanetriol. For most organosilicon compounds, little or no degradation is observed in ready biodegradation studies once degradation of any readily biodegradable hydrolysis by-product is accounted for.

Studies with hydroxytrimethylsilane (CAS 1066-40-6) and dimethylsilanediol (CAS 1066-42-8) show no evidence of biodegradation (Clarke, N. (2008); Dow Corning Corporation (1984)).

It is therefore concluded that the registration 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 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 trimethoxyphenylsilane, 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 De Jongh 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 trimethoxymethylsilane in blood is approximately 59%. However, for the hydrolysis product phenylsilanetriol, the figure is >99% meaning that, once absorbed, both the hydrolysis product is likely to be eliminated via the kidneys in urine, and accumulation is 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 (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 Kowcalculation) 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. duct 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 trimethoxyphenylsilane, where effects on the urinary bladder were reported at the lowest test concentration.