Octaphenylcyclotetrasiloxane

Endpoint summary

Additional information

There are no in vitro or in vivo data on the toxicokinetics of octaphenylcyclotetrasiloxane.

However, octaphenylcyclotetrasiloxane is a very low volatility (predicted vapour pressure 1.0E-6 Pa at 25°C) solid that is insoluble in water (predicted water solubility <1E-05 mg/l at 20°C). It has a predicted log K_ow of 9.0, indicating that the substance is highly lipophilic. Hydrolysis is likely to be negligible due to the highly lipophilic nature of the substance.

Human exposure can occur via the inhalation or dermal routes. Relevant inhalation and dermal exposure would be to the parent, due to the negligible hydrolysis. The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself, 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, where appropriate, other known or predicted physicochemical properties of octaphenylcyclotetrasiloxane, reasonable predictions or statements can be made about potential absorption, distribution, metabolism and excretion (ADME) properties.

Absorption

Oral

Significant oral exposure is not expected for this substance.

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. 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).

Octaphenylcyclotetrasiloxane has a molecular weight (approximately 793 g/mol) unfavourable for absorption and low water solubility, making systemic exposure limited. Furthermore, uptake into systemic circulation is expected to be hindered by the large molecular diameter (D_max16.9 Å). There was no evidence of oral absorption in the acute oral toxicity or repeated dose toxicity study in rats for this substance.

Dermal

The fat solubility and the 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 octaphenylcyclotetrasiloxane fulfils neither of these criteria, dermal absorption is unlikely to occur as it is not sufficiently soluble in water to partition from the stratum corneum into the epidermis.

There was no evidence of absorption in the in vivo skin sensitisation study on octaphenylcyclotetrasiloxane.

 

Inhalation

Owing to its low vapour pressure, inhalation of vapours of octaphenylcyclotetrasiloxane is likely to be negligible. Inhalation of aerosols could occur.

Once inhaled, octaphenylcyclotetrasiloxane could be absorbed by micellar solubilisation. 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 (K_oct:air) as independent variables.

The predicted blood:air partition coefficient for octaphenylcyclotetrasiloxane is approximately 0.03:1 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 Kow value of 9 for octaphenylcyclotetrasiloxane the algorithm predicts that, should systemic exposure occur, it 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: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Octaphenylcyclotetrasiloxane	9	1.0E+09	8.9	5.5	113.9	20.5	8.4

Metabolism

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

The metabolism of silanes and siloxanes is influenced by the chemistry of silicon, and it is fundamentally different from that of carbon compounds. These differences are due to the fact that silicon is more electropositive than carbon; Si-Si bonds are less stable than C-C bonds and Si-O bonds form very readily, the latter due to their high bond energy. Functional groups such as -OH, -CO₂H, and -CH₂OH are commonly seen in organic drug metabolites. If such functionalities are formed from siloxane metabolism, they will undergo rearrangement with migration of the Si atom from carbon to oxygen.

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 the algorithm, the soluble fraction of the octaphenylcyclotetrasiloxane in blood is <<1%. Therefore, should systemic exposure occur octaphenylcyclotetrasiloxane 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.