Reaction mass of 1,1,1,5,5,5-hexamethyl-3-phenyl-3-((trimethylsilyl)oxy)trisiloxane and 1,1,1,7,7,7-hexamethyl-3,5-diphenyl-3,5-bis[(trimethylsilyl)oxy]tetrasiloxane and 1,1,1,9,9,9-hexamethyl-3,5,7-triphenyl-3,5,7-tris((trimethylsilyl)oxy)pentasiloxane

Endpoint summary

Additional information

There are no in vivo or reliable in vitro data on the toxicokinetics of phenyl silsesquioxanes. Due to technical difficulties in the in vitro dermal absorption study (TNO, 2001) no reliable analysis of the samples for the presence of test material was possible and the study was terminated. Therefore, results from this study are disregarded.

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and using this 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 K_ow so by using this and, where appropriate, other known or predicted physicochemical properties of phenyl silsesquioxanes reasonable predictions or statements may be made about its potential ADME properties.

Phenyl silsesquioxanes is a multiconstituent substance, which is insoluble in water, and is not hydrolysed. Human exposure can occur via the inhalation or dermal routes.

Absorption

Oral

When oral exposure takes place it is necessary to assume that except for the most extreme of insoluble substances, uptake through intestinal walls into the blood takes place. Uptake from intestines must 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).

Although significant oral exposure is not expected for phenyl silsesquioxanes, its lack of solubility (3.7E-15 to 6.6E-03 mg/ml) and high molecular weight ( >314.6) mean that even if oral exposure did occur, uptake into the systemic circulation would be very unlikely.

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log K_ow values. Substances with log K_ow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Therefore as phenyl silsesquioxanes fulfils neither of these criteria (log K_ow of 9 and solubility < 6.6E-03 mg/ml) absorption across the skin is unlikely.

In an acute dermal toxicity study (Dow Corning Corporation, 1997a) there were no signs of systemic toxicity.

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 (K_oct:air) as independent variables.

Using these values for Silsesquioxanes, Phenyl results in very low to extremely low blood:air partition coefficients for the constituents (0.41:1 for phenyltris(trimethylsiloxy)silane, 1.6E-05 for 1,3-diphenyl-1,1,3,3-tetra(trimethylsiloxy)disiloxane and even lower for the remaining constituents) so it is predicted that systemic exposure via the inhalation route would almost certainly not occur. However, in an acute inhalation toxicity study (Dow Corning Corporation, 2000) there was evidence of systemic effects indicating absorption of test substance-related material may have occurred.

 

Distribution

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 (K_ow) is described.

Although systemic exposure to phenyl silsesquioxanes via inhaled or dermal routes is unlikely to occur as described above, should it happen then using a log K_ow value of 9 a qualitative comparison of the resulting predicted coefficients suggests that it will distribute primarily into fat and to a much lesser extent into the other main body compartments.

 

Table 1: tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Phenyl silsesquioxanes	9	1.0E09	8.9	5.5	113.9	20.5	8.4

 

Metabolism

There are no data regarding the metabolism of phenyl silsesquioxanes. However, it is likely that this substance would be metabolised to more water soluble metabolites. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for phenyl silsesquioxanes.

 Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by DeJonghet al. (1997) using log K_ow 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 of phenyl silsesquioxanes, in blood is <0.01%. Therefore, should systemic exposure occur phenyl silsesquioxanes would not be eliminated via the urine, however, it is possible that it may be partly excreted in urine as water soluble metabolites.

References:

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

Meulenberg, C. J. and Vijverberg, H. P. (2000). Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds.Toxicol Appl Pharmacol.165, 206-216.

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