4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane

Endpoint summary

Additional information

There are no data on the toxicokinetics of 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane.

The following summary has therefore been prepared based on validated predictions of 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. 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 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane, reasonable predictions or statements can be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

4,4,7,7-Tetraethoxy-3,8-dioxa-4,7-disiladecane hydrolyses at a moderate rate in contact with water (half-life of 36 hours at pH 7, 0.8 hours at pH 4, 0.7 hours at pH 5 and 0.5 hours at pH 9 and 20-25°C), generating 1,1,1,4,4,4-hexahydroxy-1,4-silabutane and ethanol. Human exposure can occur via the inhalation or dermal routes. Relevant inhalation and dermal exposure would be predominantly to the parent substance. Significant oral exposure is not expected for the parent substance 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane. However, oral exposure to the hydrolysis product 1,1,1,4,4,4-hexahydroxy-1,4-silabutane is potentially possible via the environment.

 

The toxicokinetics of ethanol have been reviewed in other major reviews and are not considered further here.

 

Absorption

Oral

When oral exposure takes place, it can be assumed that, except for the most extreme of insoluble substances, 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).

Therefore, if oral exposure did occur, the molecular weight of 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane (354.59 g/mol) is in the favourable range and the water solubility (20 mg/L) means that some absorption would occur. The hydrolysis product, 1,1,1,4,4,4-hexahydroxy-1,4-silabutane has a favourable molecular weight (186.27 g/mol) and water solubility (predicted 1E+06 mg/L, limited to 1000 mg/L by condensation reactions) for absorption, so systemic exposure following oral exposure is likely.

Signs of systemic toxicity were evident in the acute oral toxicity studies with 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane (WIL 2000, Huntingdon Life Sciences 1997, Pharmakon 1993), suggesting that systemic uptake occurs following oral exposure.

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. With a log K_ow of 2.7 and water solubility of 20 mg/l, absorption of 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane across the skin is likely to occur. 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 but as 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane has a low vapour pressure evaporation is not likely to be a factor. The predicted water solubility (1E+06 mg/L) of the hydrolysis product, 1,1,1,4,4,4-hexahydroxy-1,4-silabutane, is potentially favourable for absorption cross the skin but the log K_ow value (-4.0) indicates it is not likely to be sufficiently lipophilic to cross the stratum corneum and therefore dermal absorption into the systemic circulation is likely to be minimal.

The available acute dermal toxicity studies (Pharmakon 1994, WIL 1999, Dow Corning Corporation, 1997) suggest that absorption and systemic exposure does occur via the dermal route.

 Inhalation

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 coefficient and the octanol:air partition coefficient (K_oct:air) as independent variables.

Using these values for 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane results in a blood:air partition coefficient of approximately 90:1 meaning that, if lung exposure occurred, uptake into the systemic circulation would be possible. The high water solubility of the substance may lead to some of it being retained in the mucus of the respiratory tract lining so absorption may slow down although passive absorption is then likely.

Acute inhalation studies (Dow Corning Corporation 1993, Dow Corning Corporation 1995) and repeated dose toxicity inhalation (Dow Corning Corporation 1998) reported local effects only, with no evidence of systemic toxicity. Therefore, there was no evidence of absorption following inhalation.

 

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 this value for 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane predicts that, should systemic exposure occur, distribution into the main body compartments would be primarily into the lipid compartment, and to a much lesser extent to the other tissues.

For the hydrolysis product, 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).

 

Table: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane	2.7	501	4.9	3.2	92.2	3.1	2.3
1,1,1,4,4,4-hexahydroxy-1,4-silabutane	-4.0	0.0001	0.6	0.7	0	0.7	0.8

 

Metabolism

There are no data on the metabolism of 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane. However, once absorbed into the body, it will hydrolyse to form ethanol and 1,1,1,4,4,4-hexahydroxy-1,4-silabutane. In vitro bacterial mutagenicity and mammalian chromosome aberration studies showed no observable differences with and without metabolic activation. However, an in vitro mammalian mutagenicity study in mouse lymphoma L5178Y cells showed a positive result with metabolic activation, and a negative result without metabolic activation. This indicates that 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane might be metabolised by hepatic enzymes. However, the potential for mutagenicity in vivo requires further investigation.

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSR’s 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 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane in blood is approximately 22% indicating that, once absorbed, there is some potential for the substance to be eliminated via the kidneys in urine. The corresponding value for the hydrolysis product, 1,1,1,4,4,4-hexahydroxy-1,4-silabutane, is >> 99% therefore the hydrolysis product is likely to be effectively eliminated via the kidneys in urine and accumulation is unlikely.

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.

 

De Jongh, 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.