Trimethoxy(2,4,4-trimethylpentyl)silane

Endpoint summary

Description of key information

No studies are available. Based on molecular structure, molecular weight, water solubility, 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 by 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. The bioaccumulation potential is expected to be low.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

There are no measured data on the toxicokinetics of trimethoxy(2,4,4-trimethylpentyl)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 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 trimethoxy(2,4,4-trimethylpentyl)silane or its hydrolysis product, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Trimethoxy(2,4,4-trimethylpentyl)silane hydrolyses in contact with water (measured half-life of 5.7 h at pH 7 and at 20-25°C), generating (2,4,4-trimethylpentyl)silanetriol and methanol. Direct exposure of workers and the general population 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 due to the very rapid hydrolysis.

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

 

Table: Physicochemical properties

Physicochemical properties	trimethoxy(2,4,4-trimethylpentyl)silane	(2,4,4-trimethylpentyl)silanetriol
Water solubility	110 mg/L at 20°C (QSAR)	240000 mg/L at 20°C (QSAR)
Vapour pressure	19 Pa at 20°C (OECD 104)	1.2E-04 Pa at 25°C (QSAR)
Log Kow	4 at 20°C (QSAR)	0.9 at 20°C (QSAR)
Molecular weight (g/mol)	234.4	192.3
Half-life	5.7 h at pH 7, 0.3 h at pH 4 and 0.1 h at pH 9 at 20-25°C (QSAR)

 

Absorption

Oral

If oral exposure to parent did occur, the physicochemical properties of trimethoxy(2,4,4-trimethylpentyl)silane (234.4 g/mol, log Kow 4 and 110 mg/L) are still 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 very rapidly into the hydrolysis product (2,4,4-trimethylpentyl)silanetriol within 4 seconds at the temperature of 37.5°C. This suggests that absorption mainly of the hydrolysis product will occur.

The hydrolysis product (2,4,4-trimethylpentyl)silanetriol has a favourable molecular weight and water solubility value for absorption so systemic exposure would be very likely. The predicted water solubility of the hydrolysis product (240000 mg/L) suggests that (2,4,4-trimethylpentyl)silanetriol will readily dissolve in the gastrointestinal fluids. Also, the low molecular weight (≤ 200 g/mol) of the hydrolysis product suggests it will have the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

Signs of systemic toxicity especially effects on the peripheral nervous system and urinary bladder were evident in the oral combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (BSL, 2020), 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, 2017), diethoxy(dimethyl)silane (CAS 78-62-6) was administered repeatedly by oral gavage between 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/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 fat solubility and 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.

The moderate water solubility of 110 mg/L, log Kow of 4 and molecular weight of 234.4 g/mol of the parent substance suggest that absorption is moderate. For the hydrolysis product (2,4,4-trimethylpentyl)silanetriol the high water solubility of 240000 mg/L, log Kow value of 0.9 and molecular weight of 192.3, suggests the substance will have a high potential to be absorbed by the dermal route. QSAR based dermal permeability prediction (DERMWIN V2.02.2022) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 3.8 µg/cm²/h for trimethoxy(2,4,4-trimethylpentyl)silane and 125.1 µg/cm²/h for (2,4,4-trimethylpentyl)silanetriol, respectively. This shows that dermal penetration of the parent substance and the hydrolysis product will be moderate or high, respectively. Therefore, once hydrolysis has occurred, absorption is likely to increase.

 

 

Inhalation

The vapour pressure of the parent substance (19 Pa) indicates that this substance has a low volatility, and therefore inhalation as a vapour is unlikely. 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 lower than 5.7 h. This prediction is based on a validated QSAR estimation 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 uncatalysed 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 trimethoxy(2,4,4-trimethylpentyl)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 trimethoxy(2,4,4-trimethylpentyl)silane predicts a blood: air partition coefficient of approximately 17:1 meaning that, in steady state, approximately 94% of this substance will be in blood and approximately 6% in air, and therefore if lung exposure occurs the vast majority of parent substance available would be absorbed. However, hydrolysis is expected. For the hydrolysis product, (2,4,4-trimethylpentyl)silanetriol, the predicted blood: air partition coefficient is approximately 2.2E+10:1 meaning that systemic exposure is even much 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(2,4,4-trimethylpentyl)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 soluble in water and therefore expected to be present in the mucous lining following inhalation of trimethoxy(2,4,4-trimethylpentyl)silane, from which there is potential for passive absorption. However, hydrolysis of the target substance is considered of minor importance due to the quite long half-life of the parent substance at the physiological pH in the respiratory tract.

 

An acute inhalation toxicity study in rats were carried out, using a test atmosphere containing 11.2 mg/L aerosol of the test item. Following 4 hours of exposure no deaths occurred, but clinical signs (irregular, fitfully and noisy breathing; gasping; salivation; long legged, uncoordinated- and staggering tread; prone position; retracted stomach flanks; sluggished or vanished corneal reflex and positional reflex and paw flick latency; anaesthesia; sneezing) were observed. Repeated exposure of rats to aerosol of the test item for 28 days (6 h/day, 5 days/week) revealed lack of coordination for 2 hours after treatment at 1.54 mg/L air and minimal intense irritation of the alveoli at 2.89 mg/L air. Histopathology, haematology, and clinical chemistry revealed no test material related effects. Taken together, local effects rather than systemic toxicity are considered to be of relevance, indicating a low hazard potential of the substance via the inhalation route.

 

Distribution

The low molecular weight, moderate and high water solubility of the parent and hydrolysis product, respectively, suggest they will both have the potential to diffuse through aqueous channels, pores and will be widely distributed; the log Kow of >0 for trimethoxy(2,4,4-trimethylpentyl)silane and (2,4,4-trimethylpentyl)silanetriol indicates they are likely to be distributed into cells. Therefore, the intracellular concentration will be higher than the extracellular concentration.

The moderate water solubility and a log Kow of 4 of trimethoxy(2,4,4-trimethylpentyl)silane predict a low bioaccumulation potential. In comparison, the high water solubility and the moderate log Kow of the (2,4,4-trimethylpentyl)silanetriol suggest that accumulation of the hydrolysis product in the body is not likely.

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 trimethoxy(2,4,4-trimethylpentyl)silane (log Kow = 4.0) 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 also primarily be into fat. In general, the distribution of the hydrolysis product into the main body compartments is much lower compared to the target substance.

Table: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
trimethoxy(2,4,4-trimethylpentyl)silane	4.0	10000	8.3	5.1	112.7	8.0	5.1
(2,4,4-trimethylpentyl)silanetriol	0.9	7.9	0.9	0.9	6.2	1.0	0.9

 

Also, the available toxicokinetics data on silanes suggest that the silanols with log kow will be rapidly excreted once hydrolysis occurs. In the toxicokinetic test with morpholinotriethoxysilane, CAS 21743-27-1) (described above), for example, 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 (Harlan Laboratories, 2009). Together with excretion data (described later), these findings support the conclusion that trimethoxy(2,4,4-trimethylpentyl)silane might accumulate in fat tissue. However, this is not expected as trimethoxy(2,4,4-trimethylpentyl)silane hydrolyses to (2,4,4-trimethylpentyl)silanetriol and methanol.

 

Metabolism

Trimethoxy(2,4,4-trimethylpentyl)silane is a moisture-sensitive liquid that hydrolyses in contact with water (measured half-life less than 5.7 h at pH 7 and 25°C), generating methanol and (2,4,4-trimethylpentyl)silanetriol. There is no data on the metabolism of (2,4,4-trimethylpentyl)silanetriol. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.

Trimethoxy(2,4,4-trimethylpentyl)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).

No significant biodegradation of the hydrolysis product (2,4,4-trimethylpentyl)silanetriol is expected. 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 and 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 trimethoxy(2,4,4-trimethylpentyl)silane in blood is approximately 2% and of (2,4,4-trimethylpentyl)silanetriol 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