Trichloro(hexadecyl)silane

Endpoint summary

Description of key information

No studies are available. Hydrolysis occurs very rapidly, and systemic exposure is expected to the silanol-containing hydrolysis product. Based on molecular structure, molecular weight, water solubility, and octanol-water partition coefficient it can be expected that the hydrolysis product is likely to be absorbed via the oral, inhalation and dermal routes, however, absorption via the dermal route is expected to be relatively low. The molecular weight (304.6 g/mol) and relatively low water solubility (4.74 mg/L) of the hydrolysis product suggests it will be taken up by micellular solubilisation and will not diffuse through aqueous channels, pores and will not be widely distributed in the body. Excretion via the bile is considered favoured, and test material deposited in the stratum corneum is expected to be sloughed off with the skin cells. Thus, bioaccumulation 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 trichloro(hexadecyl)silane (CAS 5894-60-0). 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 trichloro(hexadecyl)silane or its hydrolysis product, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Trichloro(hexadecyl)silane hydrolyses rapidly in contact with water, generating hydrochloric acid (HCl) and hexadecylsilanetriol. A hydrolysis study could not be performed due to the very fast rate of hydrolysis. Half-lives are considered to be very rapid (<< 2 minutes) across all physiologically relevant pH and temperature ranges. Trichloro(hexadecyl)silane will also hydrolyse rapidly in contact with moist skin; the resulting HCl hydrolysis product would be severely irritating or corrosive. It is therefore likely that any systemic exposure to the substance will be to the hydrolysis product, hexadecylsilanetriol, rather than the parent substance, trichloro(hexadecyl)silane. Therefore, this toxicokinetic behaviour assessment will try to predict the behaviour of the hydrolysis product hexadecylsilanetriol.

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

Table: Physicochemical properties

Physicochemical properties	Trichloro(hexadecyl)silane	Hexadecylsilanetriol
Water solubility	hydrolyses rapidly	4.7 mg/l at 20 °C (QSAR)
Vapour pressure	0.007 Pa at 20°C (measured)	8.23E-08 Pa at 25°C (QSAR)
Log Kow	hydrolyses rapidly	5.0 (QSAR)
Molecular weight (g/mol)	359.9	304.5
Half-life	<< 2 minutes

 

Absorption

Oral:

If ingestion occurs, the hydrolysis of the parent substance at the low pH of the stomach will be very rapid (<<2 min), so any absorption of the parent substance is expected to be negligible and it is more likely to be the hydrolysis product that is absorbed.

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. The absorption of highly lipophilic substances (log P of 4 or above) may be limited by the inability of such substances to dissolve into GI fluids and hence make contact with the mucosal surface. However, the absorption of such substances will be enhanced if they undergo micellular solubilisation by bile salts. Substances absorbed as micelles (aggregate of surfactant molecules, lowering surface tension) enter the circulation via the lymphatic system, bypassing the liver. (ECHA, 2017).

The molecular weight of hexadecylsilanetriol (304.54 g/mol) is in the range that would favour absorption. The log Kow of 5.0 indicates that the test substance is highly lipophilic. Moreover, the substance has relatively low water solubility (4.7 mg/L) and thus micellular solubilisation is of particular importance for hexadecylsilanetriol to be absorbed orally.

In an acute oral toxicity study according to OECD TG 423 and to GLP, all animals died shortly after dosing with 2000 mg/kg bw of the registered substance (LPT 2002). No abnormalities were found at macroscopic post mortem examination of the animals. In the available repeated dose toxicity studies (OECD 408: BSL, 2022 & OECD 414: BSL, 2022), limited evidence of test item-related toxicity was observed, with local irritant effects associated with the formation of HCl as the predominant findings.

Dermal

If dermal exposure were to occur, in practice, this would be to 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 log Kow value of hexadecylsilanetriol (5.0, QSAR) is outside the favourable range for dermal absorption. Likewise, the water solubility (4.76 mg/L) and molecular weight (304.54 g/mol) are not in the favourable range, therefore, dermal absorption is expected to be relatively low.

QSAR based dermal permeability prediction (DERMWIN V2.02.2012) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 0.302 µg/cm²/h for hexadecylsilanetriol. This is an indicator for a medium low dermal absorption. Since the other hydrolysis product, HCl is corrosive to the skin; damage to the skin might increase penetration. There is no dermal toxicity data available for trichloro(hexadecyl)silane, with the acute dermal toxicity study waived due to the corrosive nature of the substance.

Inhalation

Trichloro(hexadecyl)silane has a very low vapour pressure (0.007 Pa at 20°C), therefore, inhalation exposure of vaporised substance is unlikely. Hydrolysis is expected to occur rapidly in the respiratory tract, therefore, it will be the hydrolysis product that is available for absorption. Hexadecylsilanetriol has a Log Kow of 5.0, therefore, lipophilic compounds such as this may be taken up by micellular solubilisation, particularly as the water solubility is relatively low (4.7 mg/L).

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 hydrolysis half-life at pH 7 (relevant for lungs and blood) is rapid (<< 2 min) and is likely to be in the order of seconds at physiologically relevant temperatures. 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]

Hydrolysis is a chemical reaction that is independent of enzymatic involvement. It is reasonable to assume that the hydrolysis products 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 the hydrolysis product hexadecylsilanetriol predicts a very high blood: air partition coefficient of approximately 1.5E+09:1 meaning that, high levels of systemic exposure are expected, therefore, if exposure occurs the majority of the hydrolysis product would be absorbed. Again, this prediction is based on physicochemical properties and is not expected to vary between individuals.

As with dermal exposure, damage to membranes caused by the corrosive nature of the HCl hydrolysis product might enhance the uptake. There are no reliable studies to check for signs of inhalation toxicity.

In conclusion, inhalation exposure to trichloro(hexadecyl)silane is considered to be negligible, due to its low vapour pressure. However, should exposure occur, the hydrolysis product hexadecylsilanetriol is likely to be readily absorbed.

Distribution

As the log Kow of the hydrolysis product hexadecylsilanetriol is > 0 (5.0, QSAR) it is likely to distribute into cells and intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

It is generally the case that substances with high log Kow values have long biological half-lives. On this basis, daily exposure to a substance with a log Kow value of around 4 or higher could result in a build up of that substance within the body (ECHA, 2017).

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 hexadecylsilanetriol (log Kow = 5.0) 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.

Table: Tissue: blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Hexadecylsilanetriol	5.0	1.0E+5	8.8	5.4	113.8	13.4	7.1

Hydrogen and chloride ions will enter the body’s natural homeostatic processes.

Metabolism

Trichloro(hexadecyl)silane hydrolyses very rapidly to form hexadecylsilanetriol and HCl in the presence of moisture. Most if not all of this will have occurred before absorption into the body. There are no data regarding the enzymatic metabolism of trichloro(hexadecyl)silane or hexadecylsilanetriol.

Excretion

Based on the molecular weight (>300 g/mol) and relatively low water solubility (4.7 mg/L) of hexadecylsilanetriol, excretion via bile seems to be favoured. Remaining substance in the stratum corneum may be sloughed off with the skin cells. Thus, the bioaccumulation potential is expected to be low.

Since the abiotic 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.