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Administrative data

Link to relevant study record(s)

Description of key information

No toxicokinetic studies are available for dimethoxy(methyl)silane. 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, dermal and inhalation routes. Hydrolysis occurs rapidly, and systemic exposure is expected to both the parent substance and the hydrolysis products. Based on the water solubility, the registered substance and its silanol-containing 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 dimethoxy(methyl)silane (CAS 16881-77-9).


The following summary has therefore been prepared based on the predicted and measured physicochemical properties of the registered substance and its hydrolysis products (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 dimethoxy(methyl)silane or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.


Dimethoxy(methyl)silane hydrolyses in contact with water (half-life 0.3 hours at 20-25 °C), generating methylsilanediol, which is further oxidised to methylsilanetriol. Methanol is generated as the non-silanol containing hydrolysis product. 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 products 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


 



Dimethoxy(methyl)silane



Methylsilanediol



Methylsilanetriol



Water solubility



1.7E+04 mg/L at 20°C (QSAR)



1.0E+06 mg/L at 20°C (QSAR)



1.0E+06 mg/L at 20°C (QSAR)



Vapour pressure



7.1E+03 Pa at 25°C (QSAR)



6.5 Pa at 25°C (QSAR)



0.05 Pa at 25°C (QSAR)



Log Kow



1.4 at 20°C (QSAR)



-1.0 at 20°C (QSAR)



-2.4 at 20°C (QSAR)



Molecular weight (g/mol)



106.2



78.15



94.14



Half-life



0.3 h at pH 7, 0.1 h at pH 4 and 0 h at pH 9. at 20-25°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. 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).


If oral exposure to the parent substance did occur, the physicochemical properties of dimethoxy(methyl)silane (M.W. 106.2 g/mol, log Kow 1.4 and water solubility of 17,000 mg/L) are 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 products methylsilanediol and methylsilanetriol within 5 seconds at the temperature of 37.5°C. This suggests that absorption mainly of the hydrolysis product will occur. The hydrolysis products methylsilanediol and methylsilanetriol have a favourable molecular weight and water solubility value for absorption so systemic exposure would be very likely. The predicted water solubility of both silanol hydrolysis products (1E+06 mg/L) suggests that they will readily dissolve in the gastrointestinal fluids. Also, the low molecular weight (≤ 200 g/mol) of the hydrolysis products suggests they will have the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.


In the available acute oral toxicity studies (ASTA Pharma, 1988 and INBIFO, 1979a) narcosis was observed, as well as mortality, indicating that systemic exposure to either the parent or hydrolysis product occurred.


In the available oral 90-day repeated dose toxicity study (Labcorp, 2023), no adverse systemic effects were observed, however, some adaptive changes were observed in the liver, indicating that systemic exposure to either the parent or hydrolysis products occurred.


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 products.


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 high water solubility of 17,000 mg/L, log Kow of 1.4 and molecular weight of 106.2 g/mol of the parent substance suggest that absorption is moderate to high. For the hydrolysis products methylsilanediol and methylsilanetriol, the high water solubility of (1E+06 mg/L) and log Kow values (-1.0 and -2.4, respectively) indicate that the substance may be to hydrophilic to cross the lipid rich environment of the stratum corneum. QSAR based dermal permeability prediction (DERMWIN V2.02a.2015) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 57.5 µg/cm²/h for dimethoxy(methyl)silane. For the hydrolysis products methylsilanediol and methylsilanetriol the dermal penetration rates were 124.0 and 11.8 µg/cm²/h, respectively.


In a non-guideline sub-acute dermal repeated dose toxicity study (Losco, 1996), there were no systemic findings observed, suggesting that the parent substance and/or hydrolysis products have a low dermal absorption rate and/or low toxic potential via the dermal route. However, repeated exposure under the occlusive conditions did cause local effects to the skin, which may enhance the rate of dermal absorption.


 


Inhalation


The vapour pressure of the parent substance (7.1 kPa) indicates that this substance has a moderate volatility, and therefore inhalation as a vapour may occur. The very hydrophilic nature of the hydrolysis products suggest that they may be retained more efficiently within the mucous compared to the parent substance. The moderate log Kow (between -1 and 4) of the parent substance and hydrolysis product methylsilanediol 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 predicted hydrolysis half-life at 20-25 °C and pH 7 (relevant for lungs and blood) is 0.3 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 dimethoxy(methyl)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 dimethoxy(methyl)silane predicts a blood: air partition coefficient of approximately 23:1 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 expected. For the hydrolysis products, (methylsilanediol and methylsilanetriol), the predicted blood: air partition coefficients are approximately 1.0E+06:1 and 1.1E+08:1, respectively, 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 dimethoxy(methyl)silane and its hydrolysis products with respect to dissolving in the mucous of the respiratory tract. The parent is expected to hydrolyse in the aqueous mucous. The hydrolysis products are highly soluble in water and therefore expected to be present in the mucous lining following inhalation of dimethoxy(methyl)silane, from which there is potential for passive absorption.


In an acute inhalation toxicity study in rats, animals were exposed to vapours of the test item via whole body exposure at a concentration of 4600 g/m3 for one single period of 4 hours. No mortality or clinical signs of toxicity were observed, therefore, this study gives little insight into the levels of absorption after inhalation exposure. No repeated dose inhalation toxicity data are available for the registered substance.


 


Distribution


The low molecular weight (78.15 and 94.14 g/mol, respectively) and very high water solubility (1E+06 mg/L) of the hydrolysis products methylsilanediol and methylsilanetriol suggest that they will have the potential to diffuse through aqueous channels, pores and will be widely distributed; however, the log Kow values (-1.0 and -2.4, respectively) indicate they are unlikely to be distributed into cells. Therefore, the extracellular concentration will be higher than the intracellular concentration.


The low molecular weight (106.2) and high water solubility (17,000 mg/L) of dimethoxy(methyl)silane suggests that it will have the potential to diffuse through aqueous channels, pores and will be widely distributed. The log Kow (1.4) suggests that the parent is likely to distribute into cells and so the intracellular concentration may be higher than extracellular concentration. 


For both the parent and hydrolysis products, the water solubility and log Kow values suggest that accumulation in the body is unlikely.


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 dimethoxy(methyl)silane (log Kow = 1.4) predicts that, should systemic exposure occur, distribution would primarily be into fat, with potential distribution into liver, muscle, brain and kidney but to a 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



Dimethoxy(methyl)silane



1.4



25.1


 



1.3



1.1



18.4



1.3



1.1



Methylsilanediol



-1.0



0.1



0.6



0.7



-0.1



0.7



0.8



Methylsilanetriol



-2.4



0.004



0.6



0.7



-0.2



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 dimethoxy(methyl)silane is not expected to accumulate in any organ or tissue. 


 


Metabolism


Dimethoxy(methyl)silane is a moisture-sensitive liquid that hydrolyses in contact with water (estimated half-life of 0.3 h at pH 7 and 25°C), generating methylsilanediol, which is further oxidised to methylsilanetriol. Methanol is generated as the non-silanol containing hydrolysis product. There is no data on the metabolism of dimethoxy(methyl)silane. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.


Dimethoxy(methyl)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, 2013). It is therefore concluded that the substance and its silanol hydrolysis products are not recognised by biological systems containing all the mammalian enzymes and metabolic systems.


 


Excretion


The low molecular weight (below 300 g/mol) and high water solubility of the parent and hydrolysis products 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 dimethoxy(methyl)silane in blood is approximately 85% and of the hydrolysis products 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 slightly 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.


 


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