(chloromethyl)triethoxysilane

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 (chloromethyl)triethoxysilane is likely to be absorbed. However, hydrolysis is expected to occur rapidly, and data from the silanol containing degradation product indicate a less favourable absorption. Due to the high water solubility, distribution in the body is likely, and a fast excretion via the renal route can be expected. The bioaccumulation potential is expected to be negligible.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic properties of (chloromethyl)triethoxysilane have been investigated. Therefore, the toxicokinetic behaviour assessment of the substance and its hydrolysis product was estimated by its physico-chemical properties and the available toxicology studies on the substance itself.  

 

(Chloromethyl)triethoxysilane hydrolyses in contact with water (predicted half-life 2.5 h at pH 7), generating (chloromethyl)silanetriol and ethanol. Acid environment is hereby known to catalyse this abiotic and enzyme-independent reaction and enhance the reaction rate, further increased by the body temperature of approximately 37°C present in mammals (predicted half-life 5 s at pH 2 and 37.5°C). This suggests that systemic exposure to both the parent, (chloromethyl)triethoxysilane, and to the hydrolysis product, (chloromethyl)silanetriol, is possible. Hence, this toxicokinetic behaviour assessment will try to predict the behaviour of both these substances. The toxicokinetic of ethanol is discussed elsewhere and is not included in this summary.

 

The molecular weight and the predicted water solubility of (chloromethyl)triethoxysilane are 212.75 g/mol and 1100 mg/l at 20°C, respectively. In contrast, the molecular weight and predicted water solubility of the hydrolysis product, (chloromethyl)silanetriol, are 128 g/mol and 1E+06 mg/L at 20°C. The hydrolysis product is smaller in size and more water soluble, and thereby suggests that it will have greater potential to be absorbed through biological membranes than the parent substance. Furthermore, the predicted moderate log Kow of 2.5 for the parent substance indicates that this substance is lipophilic enough to efficiently pass through biological membranes by passive diffusion. However, the hydrolysis product chloromethylsilanetriol is less lipophilic (log Kow of -2.1) and therefore, passing of biological membranes by passive diffusion is less likely, but due to its low molecular weight and its high water solubility, it still has the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

 

Absorption

Oral: An acute oral toxicity study in rats with (chloromethyl)triethoxysilane given by gavage did show signs of systemic toxicity (dragging of limbs, decreased activity, hunched posture, ruffled fur and/or swaying gait on test day 1 which persisted up to test day 3) and reported an LD50 between 2000 and 5000 mg/kg body weight. Therefore, indicating that absorption via the oral route is possible. If ingestion occurs, the parent substance hydrolyses in the low pH of the stomach and absorption of the parent substance is expected to be low. It is more likely to be the hydrolysis product that is absorbed.

The predicted water solubility of the parent (1100 mg/L) and hydrolysis products (1E+06 mg/L) suggest that both substances will readily dissolve in the gastrointestinal fluids. Additionally, the low molecular weight (≤212 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 2.5 for the parent substance suggests that it is lipophilic enough to be absorbed by passive diffusion.

 

Inhalation: The vapour pressure of the parent substance (6.5 Pa) indicates that inhalation of the registered substance as a vapour is not likely to occur. Additionally, an acute inhalation toxicity limit test (rats, vapour, whole body exposure, LD50>4.7 mg/L was conducted, which did not result in any signs of systemic toxicity. The predicted moderate water solubility (1100 mg/L) and log Kow (2.5) 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 the high hydrophilicity (log Kow and -2.1) of the hydrolysis product, chloromethylsilanetriol, 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). Since inhalation exposure did result in systemic toxicity, absorption via the respiratory tract may therefore be a possibility.

 

Dermal: The moderate water solubility (1100 mg/lL, log Kow (2.5) and molecular weight (212 g/mol) of the parent substance suggest that absorption via the dermal route is possible. Hydrolysis is considered to be of minor importance due to the low presence of water on the skin surface. Additionally, for the hydrolysis product, chloromethylsilanetriol, the high water solubility of 1E+06 mg/L and a log Kow<-1 (-2.1) suggest that the substance would be too hydrophilic to cross the lipid rich environment of the stratum corneum. Since skin sensitising study using (chloromethyl)triethoxysilane showed sensitising potential, some dermal absorption of the substance must have occurred.

 

Distribution

The low molecular weight (<128.6 g/mol) and very high water solubility (1E+06 mg/L) of the hydrolysis product suggests it will diffuse through aqueous channels and pores and will be widely distributed. The log Kow of -2.1 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 (1100 mg/L) and log Kow (2.5) is lipophilic and therefore 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.

 

Metabolism

There are no data regarding a in vivo transformation of (chloromethyl)triethoxysilane except via abiotic hydrolysis. The predicted hydrolysis half-life at pH 7 (20°C) is 4.6 h. At physiological temperature (37°C), this half-life will be substantially shortened. Likewise, under gastric conditions (pH 2), the hydrolysis is predicted to be quantitative within a few minutes. Gastric transit half-life in the rat is about 2 h, so that there is little likelihood that appreciable amounts of parent enter the duodenum (Enck et al., 1989).

The hydrolysis product could theoretically be subject to further metabolism, e.g., via monooxygenases. However, after the initial hydrolysis step has occurred, the reaction product, (chloromethyl)triethoxysilane, already possesses an appreciable water solubility of 1E+06 mg/L at 20°C (predicted by QSAR) which qualifies the molecule for immediate urinary excretion. Thus, further enzymatic oxidation of (chloromethyl)silanetriol is rather unlikely to occur. It is therefore assumed that abiotic hydrolysis is the only significant route of metabolism. Phase-II metabolism by conjugation with glucuronic acid or sulphate is often seen in molecules bearing hydroxyl groups. However, these conjugates are either not formed at all or very short-lived, because such conjugates could not be detected in ADME studies with the siloxanes D4, D5, and HMDS. In all cases, non-conjugated silanol metabolites were detected in urine. It is therefore concluded that the primary hydrolysis product, (chloromethyl)silanetriol, is the only significant metabolite of (chloromethyl)triethoxysilane.

The reactivity of (chloromethyl)triethoxysilane towards water suggests high reactivity to other biological nucleophils like protein-bound amino acids with hydroxyl groups. (Chloromethyl)silanetriol lacks this reactivity and has a much lower tendency to be taken up into potential target tissues in the first place, judged by the reduced tissue-blood partition coefficients (see table below). Therefore, hydrolysis is considered a very efficient detoxification step.

Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
(chloromethyl)triethoxysilane	2.5	316.22	3.80	2.64	102	2.93	2.05
chloromethylsilanetriol	-2.1	7.94E-03	0.52	0.74	0.10	0.78	0.77

This has direct implications for human risk assessment since assessment factors for toxicokinetic interspecies differences are per default set as the allometric scaling (AS) factor which in turn reflects the different caloric demand of different species. However, abiotic hydrolysis is clearly independent of caloric demand. It is a quasi-first order reaction since the reaction partner, water, is available in great excess. The hydrolysis rate therefore depends only on the concentration of the parent molecule. Hence, the metabolism of the parent does not underlie the AS principle when extrapolating dose descriptors from rodent studies to DNELs.

 

Excretion

(Chloromethyl)triethoxysilane is known to undergo hydrolysis with a predicted half-life of 5 s (pH 2) to 2.5 h (pH 7). The hydrolysis product named above is far more water soluble than the parent chemical and has a molecular weight lower than 300 g/mol. Therefore, it is expected to be excreted predominantly via the renal route. 

Enck, P. et al. (1989) Stress effects on gastrointestinal transit times in the rat. Gut 30, 455-459