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There are no in vivo test data on the toxicokinetics of 2,4,6,8-tetramethylcyclotetrasiloxane (HD4).

The following summary has therefore been prepared based on the physicochemical properties of the substance itself and its hydrolysis products 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 Kow so by using this, and other where appropriate, known or predicted physicochemical properties of 2,4,6,8-tetramethylcyclotetrasiloxane, reasonable predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

In aqueous solution 2,4,6,8-tetramethylcyclotetrasiloxane reacts very rapidly (half life 2.2 min at 22.5°C). The end products of the hydrolysis may vary depending on conditions. Both silanols and polymers may be formed under conditions relevant for human health exposure.Methylsilanetriol is the end product of hydrolysis at low concentrations and is considered representative of other small molecule silanols that could form. The expected intermediate products of hydrolysis are linear siloxanes and methylsilanediol; hydrogen gas is produced as a by-product of the reaction.

Human exposure can occur to the parent substance and hydrolysis products by the inhaled or dermal routes.

Absorption

Oral

Significant oral exposure is not expected for this substance.

In an in vitro study conducted to assess the rate and extent of hydrolysis and condensation reactions of 2,4,6,8-tetramethylcyclotetrasiloxane (HD4) and 2,4,6,8,10–pentamethylcyclopentasiloxane (HD5) in simulated rat gastric conditions (DCC, 2014) no reaction products were observed after up to 4 hours, with >99% of the original concentration of HD4 or HD5 remaining. Although this result would appear to indicate that after oral administration in the rat the substance does not hydrolyse at a the predicted rate, further analysis of the methodology used shows that as the concentrations used far exceed the solubility of the substance (particularly at the high concentration employed), the result is not unexpected. This is because it was noted that the test substance and buffer solutions had formed two distinct layers so only a small proportion of the test substance was in contact with the aqueous medium and therefore subject to hydrolysis. However, regardless of the very low soluble fraction at these concentrations, some hydrolysis would have occurred resulting in the formation of the hydrolysis product, methylsilanetriol. Furthermore, as a result of the lipophilic nature of the substance, intestinal absorption via micellular uptake would occur and once into the more aqueous systemic environment at lower concentrations, hydrolysis would occur.

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. With a log Kow of 5.54 and water solubility of 0.6 mg/l, absorption of 2,4,6,8-tetramethylcyclotetrasiloxaneacross the skin is unlikely as it does not possess the required properties.

The high water solubility (1E+06 mg/l) of the final hydrolysis product, methylsilanetriol, is favourable for absorption across the skin but the log Kow of -2.4 is not. Therefore absorption across the skin is not likely to occur as the substance is likely to be too hydrophilic to cross the lipid-rich environment of the stratum corneum. However, the possible intermediate hydrolysis products have log Kow values in or close to the favourable range and are water soluble so absorption across the skin is potentially possible for them.

There are no dermal studies to check for evidence of absorption.

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.

Using these values for 2,4,6,8-tetramethylcyclotetrasiloxaneresults in a blood:air coefficient of approximately 0.01:1 meaning that, if lung exposure occurred there would be minimal or no uptake in to the systemic circulation of the parent substance. The high water solubility of the final hydrolysis product,methylsilanetriol, results in a very high blood:air partition coefficient (approximately 7.9E+07:1) so once hydrolysis has occurred, as it would be expected to in the lungs, then significant uptake would be expected into the systemic circulation. However, the high water solubility ofmethylsilanetriolmay lead to some of it being retained in the mucus of the lungs so absorption is then likely to slow down. Similarly, the possible intermediate hydrolysis products also have high blood:air partition coefficients so systemic exposure to them is also likely.

In repeat dose inhalation studies systemic effects were noted indicating that absorption had taken place.

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 (Kow) is described. Although systemic exposure to 2,4,6,8-tetramethylcyclotetrasiloxanevia inhaled or dermal routes is unlikely to occur as described above, should it happen then it is predictedit 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 15.7 for the remaining tissues.

For the final hydrolysis product,methylsilanetriol,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). The possible intermediate hydrolysis products would be predicted to distribute primarily into fat but to a lesser extent than the parent substance.

 

Table: Tissue:blood partition coefficients

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

2,4,6,8-tetramethyl
cyclotetrasiloxane


5.54


316228


8.9


5.5


113.9


15.7


7.7

methylsilanetriol

-2.4

0.004

0.6

0.7

0.0

0.7

0.8

 

Metabolism

There are no data on the metabolism of 2,4,6,8-tetramethylcyclotetrasiloxane. 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 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 of 2,4,6,8-tetramethylcyclotetrasiloxane is <0.001% however the corresponding figure for the final hydrolysis product, methylsilanetriol,is >99%. The soluble fraction of the intermediate hydrolysis products range from approximately 5 to 95% but as they are hydrolytically unstable they are expected to be eliminated in the form of the final hydrolysis product, methylsilanetriol. Therefore although systemic exposure to the parent is unlikely, should it occur, it will rapidly hydrolyse and the hydrolysis product will be effectively eliminated via the kidneys in urine so accumulation will not occur. The possible intermediate hydrolysis products also have soluble fractions which indicate that elimination in urine is likely if they have not already further hydrolysed.