Reaction Mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane

Endpoint summary

Additional information

There are no reliable in vivo data on the toxicokinetics of the registration substance, Reaction mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane.

The submission substance is a multi-constituent substance containing two main constituents, 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane. The reaction mass is a very low volatility liquid (predicted vapour pressure values of 3.6E-03 Pa at 25°C and 1.3E-07 Pa at 25°C for Constituent 1 and Constituent 2 respectively) that is insoluble in water (predicted water solubility values of 2.8E-05 mg/L at 20°C and 1.5E-10 mg/L at 20°C for Constituent 1 and Constituent 2 respectively). Both main constituents have predicted log K_ow values of 9.0, indicating that the substance is highly lipophilic. The constituents of the substance are hydrolytically unstable with a half-life for siloxane degradation of >200 hours at pH 7 and 20-25°C for Constituent 1 and >630 hours at pH 7 and 20-25°C for Constituent 2. At 37.5°C and pH 7, the half-life is >70 h for Constituent 1 and >230 h for Constituent 2. The products of hydrolysis are diphenylsilanediol and trimethylsilanol. Relevant inhalation and dermal exposure would be to the parent, due to the slow hydrolysis rate.

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. Although these algorithms provide a numerical value, for the purposes of this summary only qualitative statements or comparisons will be made. The main input variable for the majority of these algorithms is log K_ow so by using this, and other where appropriate, known or predicted physicochemical properties of the submission substance, reasonable predictions or statements may be made about its potential ADME properties.

 

Absorption

Oral

When oral exposure takes place, it is necessary to assume that except for the most extreme of insoluble substances, that 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 g/mol) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

The constituents of the registered substance have molecular weight values of 360.68 g/mol for Constituent 1 and 558.98 g/mol for Constituent 2; which is unfavourable for absorption and very low water solubility, making systemic exposure limited. There was no evidence of oral absorption in the repeated dose toxicity study in rats with the structurally related substance 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane.

 

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 the registered substance fulfils neither of these criteria, dermal absorption is unlikely to occur as the substance is not sufficiently soluble in water to partition from the stratum corneum into the epidermis.

In an acute dermal toxicity study, no systemic signs of toxicity were observed.

Inhalation

Owing to its low vapour pressure, inhalation of vapours of the submission substance is likely to be minimal. Inhalation of aerosols could occur. Once inhaled, the registered substance could be absorbed by micellar solubilisation.

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.

 

The predicted blood:air partition coefficient for Constituent 1 (3,3-diphenylhexamethyltrisiloxane) and Constituent 2 (3,3,5,5-tetraphenylhexamethyltetrasiloxane) is approximately 0.03:1 and 0.003:1 respectively, meaning that if lung exposure occurs, uptake into the systemic circulation is not likely.

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

 

Distribution

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 (K_ow) is described.

Using a log K_ow value of 9 for both constituents of the submission substance, it is predicted that should systemic exposure occur, the substance will distribute into the main body compartments as follows: fat >> brain > liver ≈ kidney > muscle with tissue:blood partition coefficients of 113.9 for fat and 5.5 to 20.5 for the remaining tissues.

 

Table 5.1.1. Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Reaction mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane	9	1.0E09	8.9	5.5	113.9	20.5	8.4

 

Metabolism

There are no data regarding the metabolism of the submission substance. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation. 

 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 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 the algorithm, the soluble fraction of each component of Reaction mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane in blood is <<1%. Therefore, should systemic exposure occur, the submission substance would not be eliminated via the urine; however, it is possible that it may be partly excreted in urine as water soluble metabolites.

 

References:

 

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

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.

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