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There are no in vivo data on the toxicokinetics of N,N’,N’’-tricyclohexyl-1-methylsilanetriamine. N,N’,N’’-Tricyclohexyl-1-methylsilanetriamine is a moisture-sensitive liquid that hydrolyses very rapidly in contact with water, generating cyclohexylamine and methylsilanetriol. In a reliable hydrolysis study conducted according to an appropriate guideline, a half-life result at 25 °C of 5.1 minutes at pH 9 was reported. Half-life times of <3 min at pH 5 and 25 °C and <2 min at pH 7 and 25 °C were estimated, as the substance was concluded to be fully hydrolysed prior to test measurements commencing.

For N,N’,N’’-tricyclohexyl-1-methylsilanetriamine human exposure can occur via the inhalation or dermal routes. Due to the very rapid hydrolysis, relevant dermal and inhalation exposure would be to the hydrolysis products.

In vivo data are available for some routes of exposure for the toxicokinetics of the hydrolysis product cyclohexylamine, and these are discussed below. No in vivo data are available for the toxicokinetics of the hydrolysis product methylsilanetriol.

The following summary for methylsilanetriol has therefore been prepared based on validated predictions of the physicochemical properties of the hydrolysis products and using these 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 where appropriate, other known or predicted physicochemical properties of the hydrolysis products of N,N’,N’’-tricyclohexyl-1-methylsilanetriamine, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Absorption

Oral

Significant oral exposure is not expected for this substance. However, oral exposure to humans via the environment may be relevant for the hydrolysis products, cyclohexylamine and methylsilanetriol. When oral exposure takes place it is necessary to assume, except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood takes place. 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) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

As cyclohexylamine, which is reported to be miscible with water and has a molecular weight of 99.18, meets both of these criteria, should oral exposure occur it is reasonable to assume systemic exposure will occur also. The hydrolysis product methylsilanetriol also has favourable molecular weight and water solubility values for absorption so exposure to this is also likely.

Oral administration of radiolabelled cyclohexylamine demonstrated that absorption is rapid and almost complete in animals and humans. Peak concentration in blood and plasma was between one and two hours following oral administration to human volunteers at doses of 2.5, 5 or 10 mg/kg bw, and the half-life value was three to five hours (Wiley, 2012 citing: Bopp et al., 1986; Eichelbaum et al., 1974; Renwick and Williams, 1972).

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by 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. Due to the very rapid hydrolysis of N,N’,N’’-tricyclohexyl-1-methylsilanetriamine on contact with skin, systemic exposure via this route is predicted to be minimal. Although the hydrolysis products, cyclohexylamine and methylsilanetriol, are highly soluble, the log Kow values (-1.52 at pH 7.4 (calculation by KOWWIN v1.68) and -2.36 (QSAR prediction) respectively) indicate they are not likely to be sufficiently lipophilic to cross the stratum corneum and therefore dermal absorption into the blood is likely to be minimal. Damage to the skin due to the corrosive property of the hydrolysis product cyclohexylamine might be such that dermal absorption of the parent and hydrolysis products increases.

After or during deposition of a liquid on the skin, evaporation of the substance and dermal absorption occur simultaneously so the vapour pressure of a substance is also relevant. Cyclohexylamine has a high vapour pressure (1.43 kPa at 20°C) so evaporation will further limit the potential for dermal absorption.

Dermal toxicity studies, including skin irritation studies for N,N’,N’’-tricyclohexyl-1-methylsilanetriamine, did not show any signs of systemic toxicity, as most observed effects were considered to be secondary to the corrosive effects.

Inhalation

There is a 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 coefficient and the octanol:air partition coefficient (Koct:air) as independent variables.

The high water solubility of the hydrolysis products cyclohexylamine and methylsilanetriol, results in very high blood:air partition coefficients so once hydrolysis has occurred, as it would be expected to in the lungs, then significant uptake of both hydrolysis products would be expected into the systemic circulation. However, the high water solubility of the hydrolysis products also suggests that they could be dissolved in the mucous of the respiratory tract lining, so may also be passively absorbed from the mucous, further increasing the potential for absorption.

There are no inhalation data that could be reviewed for signs of systemic toxicity, and therefore absorption.

Distribution

All absorbed test substance is likely to be in the form of the hydrolysis products.

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 for the hydrolysis product, cyclohexylamine, predicts that, should systemic exposure occur, distribution into the main body compartments would be minimal with tissue:blood partition coefficients of less than 1 for all major tissues (zero for fat).

Published in vivo data showed highest concentrations of cyclohexylamine in the lungs, spleen, liver, adrenal glands, heart, gastrointestinal tract and kidneys of rats. The calculated distribution volume in rats was 2.7 l/kg, which is in agreement with the apparent distribution volume in humans of 2.1 to 2.9 l/kg. Measurement of binding to plasma protein revealed differences between rats and humans: binding to human serum albumin was 33%, whereas in the rat 8% of cyclohexylamine was bound to plasma protein (Wiley, 2012 citing: Bopp et al., 1986; Eichelbaum et al. 1974).

Studies in pregnant rhesus monkeys have shown that cyclohexylamine diffuses freely across the placental barrier, so foetal exposure is possible (Wiley, 2012 citing: Filer, 1974; Pitkin et al., 1969).

For the hydrolysis product methylsilanetriol, distribution into the main body compartments is also predicted to be minimal.

Table 1: Tissue:blood partition coefficients

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

Cyclohexylamine

-1.52

0.03

0.6

0.7

0

0.7

0.8

Methylsilanetriol

-2.36

3.98E-03

0.6

0.7

0.0

0.7

0.8

 

Metabolism

N,N’,N’’-Tricyclohexyl-1-methylsilanetriamine is hydrolysed into cyclohexylamine and methylsilanetriol before absorption. Species differences in metabolic rates and pathways for cyclohexylamine have been reported. In humans, 24 hours after oral administration of 25 or 200 mg [¹⁴C]cyclohexylamine, 1% to 2% was metabolised; the deaminated metabolites found were cyclohexanol and transcyclohexane-1,2-diol. In rats and female guinea pigs, 24 hours after oral administration of 50-500 mg/kg bw of [¹⁴C]cyclohexylamine, <10% was metabolised; in rabbits approximately 30% metabolism occurred. In rats, isomers of 3- or 4-aminocyclohexanol are produced by ring hydroxylation; in guinea pig and rabbit deamination and ring hydroxylation occur. Metabolites identified in dog include cyclohexanone and cyclohexanol; in rabbit urine N-hydroxycyclohexylamine was identified, but this was not present in rat, guinea pig or human urine. Deamination of cyclohexylamine is mediated by CYP450. A diagram of the metabolism of cyclohexylamine is attached (Bopp et al.,1986, as presented in Wiley, 2012).

Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for N,N’,N’’-tricyclohexyl-1-methylsilanetriamine .

 Excretion

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 this algorithm, the soluble fraction for both cyclohexylamine and methylsilanetriol in blood is >99% meaning that, once absorbed, the hydrolysis products are likely to be eliminated via the kidneys in urine and accumulation is unlikely.

Administration of cyclohexylamine to humans and animals resulted in approximately 90% or more of the dose being eliminated in the urine. Both elimination via glomerular filtration and tubular secretion in humans demonstrated that clearance of cyclohexlamine exceeded that of creatinine. An inverse relationship between dose and clearance was indicated by a low-level saturability in the secretion process.

Absorption and elimination of cyclohexylamine is more rapid in mice than in rats, and the plasma clearance rate was therefore lower in rats than in mice. This meant that in rats the secretion via renal tubules was at saturation and this resulted in some differences between the two species in effects observed in repeated dose studies (Wiley, 2012 citing Roberts and Renwick, 1989).

Bopp BA, Sonders RC, Kesterson JW (1986) Toxicological aspects of cyclamate and cyclohexylamine. Crit Rev Toxicol 16: 213–306, as cited in Wiley, 2012.

DeJongh, J., H.J. Verhaar, and J.L. Hermens (1997). 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.

Eichelbaum M, Hengstman JH, Rost H, Brecht T, Dengler HJ (1974). Pharmacokinetics, cardiovascular and metabolic actions of cyclohexylamine in man. Arch Toxicol 31: 243–263, as cited in Wiley, 2012.

Filer Jr LJ (1974). Placental transmission of chemicals in the subhuman primate. Pediatrics 53: 823–824, as cited inWiley, 2012.

Meulenberg, C.J. and H.P. Vijverberg, (2000). Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol, 2000. 165(3): p. 206-16.

Pitkin RM, Reynolds WA, Filer LJ (1969). Cyclamate and cyclohexylamine: transfer across the hemochorial placenta. Proc Soc Exp Biol Med 132: 993–995, as cited in Wiley, 2012.

Renwick AG, Williams RT (1972). The metabolites of cyclohexylamine in man and certain animals. Biochem J 129: 857–867, as cited in Wiley, 2012.

Renwick A. G. (1993). Data-derived safety factors for the evaluation of food additives and environmental contaminants. Fd. Addit. Contam. 10: 275-305.

Roberts A, Renwick AG (1989). The pharmacokinetics and tissue concentrations of cyclohexylamine in rats and mice. Toxicol Appl Pharmacol 98 : 230–242,as cited in Wiley, 2012.

Wiley, 2012. Cyclohexylamine [MAK Value Documentation, 2006]. The MAK Collection for Occupational Health and Safety. 74–100. Published online 31 Jan 2012.

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