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There are no data on the toxicokinetics of 2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane (Vi4-D4).

The following summary has therefore been prepared based on measured toxicokinetic data for the closely related substance octamethylcyclotetrasiloxane (D4), and the physicochemical properties of Vi4-D4 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 Kowso by using this, and other where appropriate, known or predicted physicochemical properties of Vi4-D4 reasonable predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties. Although these algorithms provide a numerical value, for the purposes of this summary only qualitative statements or comparisons will be made.

In contact with water Vi4-D4 hydrolyses very slowly (half-life of 63 hours at pH 7 and 25°C) to form methylvinylsilanediol. Relevant human exposure would be to the parent substance and can occur via the oral, inhalation or dermal routes.

Absorption

Oral

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).

The molecular weight ofVi4-D4 (approximately 345)is above to the favourable range for absorption and due to its highly lipophilic nature and low water solubility the only means by which absorption from the gastrointestinal tract is likely to occur is via micellar solubilisation.

Absorption of the closely related substance D4 was studied in female Fischer rats following a single oral dose of 300 mg/kg14C-D4 in corn oil, Simethicone fluid or undiluted. Absorption of radioactivity, expressed as percentage of total recovered radioactivity from urine, carcass, expired volatiles and expired CO2was 52%, 12% and 28% with14C-D4 in corn oil, Simethicone or neat, respectively. The area under the curve (AUC) generated from blood data also indicated D4 was most readily absorbed when delivered in corn oil and least available in Simethicone fluid (Dow Corning Corporation, 1998). This study shows that D4 is most readily absorbed following oral administration in corn oil (as compared with other vehicles). This result supports the above predictions for Vi4-D4 as micellar solubilisation relies on dietary lipids to occur.

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log Kowvalues. Substances with log Kowvalues between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Therefore with a log Kowof 6.47 and water solubility of 0.0073 -0.0088 mg/l, dermal absorption is unlikely to occur asVi4-D4is not sufficiently soluble in water to partition from the stratum corneum into the epidermis.Furthermore, 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.Vi4-D4is volatile so this would further reduce the potential for dermal absorption.

In a human volunteer study in which three men and three women were dermally (axilla) exposed to13C-D4 (open application, 1.4 and 1.0 g/person, respectively),13C-D4 was detectable in blood, plasma and exhaled air (Dow Corning Corporation, 2000). The plasma and blood levels of13C-D4 after dermal application were low, <10 ng/g of blood or plasma. The peak levels of13C-D4 were 3.8 ng/g at 1 hour and 0.95 ng/g at 6 hours post exposure. The percentage absorption was not calculated, but from the concentrations detected in blood and plasma, absorption was low, and the weight-of-evidence for dermal absorption of D4 suggested a dermal absorption of 0.5% to be realistic.

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 Vi4-D4 results in an extremely low blood:air partition coefficient (approximately 0.17:1) so absorption across the respiratory tract epithelium is likely to be restricted to micellar solubilisation.

In three nose only inhalation studies, male F344 rats were exposed to14C-D4 at 700 ppm for 6 hours (Dow Corning Corporation, 1996a),male and female F344 rats were exposed to14C-D4 at 7, 70 or 700 ppm for 3 or 6 hours (Dow Corning Corporation, 1996b),and male and female F344 rats were exposed to unlabelled D4 at 7 or 700 ppm for 14 consecutive days followed by a single 6-hour exposure of14C-D4 at 7 or 700 ppm (Dow Corning Corporation, 1997). After 6 hours exposure, the percent of14C-D4 retained by males ranged from 4.99 to 5.47 % and in females from 5.19 to 5.52% of the delivered radioactivity (Dow Corning Corporation, 1996b). Similar retention levels (males: 4.38 -5.96%; females: 4.50 -6.14%) were achieved in males and females exposed to 7 or 700 ppm for 14 consecutive days. Plasma values of14C-D4 at the three concentrations (7, 70 and 700 ppm) showed an increase that was approximately proportional to increasing dose. Overall, the data show that approximately 8% of an inhaled D4 dose is absorbed in rats.

Distribution

For blood:tissue partitioning a QSPR algorithm has been developed by De Jonghet 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 forVi4-D4predicts that should systemic exposure occur potential distribution into the main body compartments would primarily be into fatty tissues with significantly less distribution into the remaining tissues.

Table 1: tissue:blood partition coefficients

 

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

Vi4-D4

6.47

2.95E+06

8.9

5.5

113.9

18.6

8.2

 

The predicted Vi4-D4 tissue:blood partition coefficients are supported by studies with D4 (described above), which showed that this substance is preferentially taken up into fatty tissues (Dow Corning Corporation 1996a, 1996b, 1997).

Metabolism

There are no data regarding the metabolism of Vi4-D4. Genetic toxicity testsin vitroshowed no observable differences in effects with and without metabolic activation for Vi4-D4. Once absorbed, Vi4-D4 is expected to continue to hydrolyse, thus formingmethylvinylsilanediol. From data on the read-across substance D4 (Dow Corning Corporation, 1998), it can be predicted that Vi4-D4, and its hydrolysis product are likely to be extensively metabolised to form a number of more water soluble metabolites.

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSR’s as developed by De Jonghet al. (1997) using log Kowas 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 ofVi4-D4in blood is <1E-04%. ThereforeVi4-D4would not be eliminated via the urine.

 

Data on D4 suggest that the primary route of elimination for D4 and D4 metabolites by rats is via the urine (only metabolites found in urine), followed by expired volatiles and faeces. Elimination was rapid during the first 12/24 hours after inhalation exposure (Dow Corning Corporation, 1996a and b). Following oral exposure most D4 was excreted in faeces (Dow Corning Corporation, 1998). The excretion of Vi4-D4 is expected to be comparable to the excretion of D4 i.e. metabolites in urine.