Decamethyltetrasiloxane

Endpoint summary

Additional information

There are no in vivo data on the toxicokinetics of decamethyltetrasiloxane (L4). There is an in vitro dermal absorption study available for L4 (Dow Corning Corporation, 2006c). There are also data on the structurally-related substance, hexamethyldisiloxane (L2; CAS 107-46-0) (Dow Corning Corporation, 2001 and Dow Corning Corporation, 2008a), which are used to confirm predictions for the kinetics of L4 where appropriate. The registered and read-across substances are siloxanes (alkyl, vinyl, aryl or hydrogen substituted) with 2 (hexamethyldisiloxane), or 4 (decamethyltetrasiloxane) silicon atoms linked by oxygen atoms.

The following summary has therefore been prepared based on in vitro data for a structurally-related substance and the physicochemical properties of decamethyltetrasiloxane 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 Kow so by using this, and other where appropriate, known or predicted physicochemical properties of decamethyltetrasiloxane reasonable predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

Decamethyltetrasiloxane hydrolyses very slowly in contact with water (half-life of 30.3 days at pH 7 and 25°C), generating dimethylsilanediol (2 moles) and trimethylsilanol (2 moles). The read-across substance L2 also hydrolyses very slowly (half-life of 5 days at pH 7 and 25°C). Human exposure can occur via the inhalation or dermal routes. Relevant inhalation and dermal exposure would be to the parent, due to the slow hydrolysis rate.

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).

The molecular weight of decamethyltetrasiloxane (MW 310) is unfavourable 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. Pathological changes in the liver in the repeated dose toxicity study in rats (Dow Corning Corporation, 2010b) provide evidence of absorption for this substance.

 

Dermal

In the in vitro dermal penetration study (Dow Corning Corporation, 2006c) using human skin, conducted using a study comparable to OECD 428 and to GLP almost all (99.9%) of the recovered 14C-decamethyltetrasiloxane (L4) volatilised from the skin surface and was captured in the charcoal baskets placed above the exposure site. Only a small amount of applied dose (0.06%) was found on the skin surface after 24 hours exposure or remained in the skin after washing and tape stripping (0.03%). Little (0.001%), of the applied dose penetrated through the skin into the receptor fluid. The total percent dose absorbed was estimated to be 0.03% of applied dose with virtually all of the absorbed test substance retained in the skin.

 

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 decamethyltetrasiloxane results in an extremely low blood:air partition coefficient (approximately 6.7E-04) so absorption across the respiratory tract epithelium is likely to be restricted to micellar solubilisation.

There is an inhalation toxicokinetics study on L2 (Dow Corning Corporation, 2008a) which supports the predictions on L4. After a 6 hour inhalation exposure of female rats to 5000 ppm L2, approximately 3% of the achieved dose was retained. Due to the difference in log Kow between L2 (log Kow 5.3) and L4 (log Kow 8.21) the results for L2 can only be used to confirm qualitatively that absorption following inhalation is low.

 

Distribution

 

For blood:tissue partitioning a QSPR algorithm has been developed by DeJongh 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 for decamethyltetrasiloxane predicts that it will distribute into the main body compartments as follows: fat >> brain > liver ≈ kidney > muscle.

 

Table 5.1: Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
decamethyltetrasiloxane	8.21	1.62E+08	8.9	5.5	113.9	20.3	8.4

 

Metabolism

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

 

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. Consequently, alpha hydroxysilanes may isomerise to silanols and this provides a mechanism by which very polar metabolites may be formed from highly hydrophobic alkylsiloxanes in relatively few metabolic steps.

Urinalysis conducted in the inhalation toxicokinetics study (Dow Corning Corporation, 2008a) on L2 demonstrated that several peaks were present, but none corresponded to the retention time of the parent. Primary metabolites detected were 1,3-bis(hydroxymethyl)tetramethyldisiloxane combined with an unknown metabolite with retention time of 26.6 minutes (61%; 6-12 h sample). Other metabolites that were detected at greater than 5% were hydroxymethyldimethylsilanol (14%), dimethylsilanediol (14%) and trimethylsilanol (6%).

Also, following oral exposure to L2 the following are among the major metabolites identified in urine (Dow Corning Corporation, 2001): Me2Si(OH)2; HOMe2SiCH2OH; HOCH2Me2SiOSiMe2CH2OH (predominant); HOCH2Me2SiOSiMe3; HOMe2SiOSiMe3; Me3SiOH. Besides these there were also three other metabolites: HOMe2SiOSiMe2CH2OH; 2,2,5,5-tetramethyl-2,5-disila-1,3-dioxalene and 2,2,5,5-tetramethyl-1,4-dioxa-2,5-disilacyclohexane inferred from GC-MS analyses. Their presence in the HPLC metabolite profile was not established. No parent L2 was present in urine.

Based on the structural similarity between L2 and L4, corresponding metabolites are likely to be formed following L4 metabolism.

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 decamethyltetrasiloxane in blood is <1%. Therefore, decamethyltetrasiloxane itself would not be eliminated in urine. However, according to data for the related substance, L2 (Dow Corning Corporation, 2008a) the majority of systemically absorbed L2 (3% of applied dose) was eliminated in the urine or expired volatiles and urinary excretion consisted of entirely polar metabolites. The primary route of elimination was in expired volatiles and 71% of this radioactivity was attributed to parent L2 with the remainder as 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.

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.