Tetradecamethylhexasiloxane

Endpoint summary

Additional information

There are no in vitro or in vivo data on the toxicokinetics of tetradecamethylhexasiloxane, L6. There is an in vivo toxicokinetics study on the structurally-related substance, dodecamethylpentasiloxane (L5, CAS 141-63-9) (Dow Corning Corporation, 1985), and a dermal absorption study available on the structurally-related substance, decamethyltetrasiloxane (L4, CAS 141-62-8) (Dow Corning Corporation, 2006). There are also data on the structurally-related substance, hexamethyldisiloxane (L2, CAS 107-46-0) (Dow Corning Corporation, 2008), which are used to confirm predictions for the kinetics of tetradecamethylhexasiloxane where appropriate. The registered and read-across substances are linear siloxanes with no functional groups present, with 2 (hexamethyldisiloxane), 4 (decamethyltetrasiloxane), 5 (dodecamethylpentasiloxane) and 6 (tetradecamethylhexasiloxane) silicon atoms linked by oxygen atoms.

Tetradecamethylhexasiloxane is a low volatility (vapour pressure 0.27 Pa at 20°C) liquid that is insoluble in water (predicted water solubility 2.3E-06 mg/l at 20°C). It has a log K_ow of >9.41 (read across from L5), indicating that the substance is highly lipophilic. Tetradecamethylhexasiloxane hydrolyses very slowly in contact with water 6300 h at pH 7, 5.8 h at pH 5, and 36.5 h at pH 9 and 20 -25°C. At 37.5°C and pH 7, the half life is approximately 1600 hours. The products of hydrolysis are dimethylsilanediol and trimethylsilanol. 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.

The following summary has therefore been prepared based on in vitro data for a structurally-related substance and 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 tetradecamethylhexasiloxane, reasonable predictions or statements can be made about their 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).

Tetradecamethylhexasiloxane has a molecular weight (459 g/mol) unfavourable for absorption and low water solubility, making systemic exposure limited.

A study conducted with the structurally-related substance, dodecamethylpentasiloxane, by Dow Corning Corporation (1985) showed that absorption following an oral gavage dose of 600 mg/kg bw to two Sprague-Dawley rats was approximately 25%. This is in agreement with predictions based on physicochemical properties, which would suggest that, due to its highly lipophilic nature and extremely low water solubility, the likely means by which absorption from the gastrointestinal tract could occur is via micellar solubilisation. 

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 tetradecamethylhexasiloxane fulfils neither of these criteria, dermal absorption is unlikely to occur as tetradecamethylhexasiloxane is not sufficiently soluble in water to partition from the stratum corneum into the epidermis.

There are no dermal toxicity data that can be checked for signs of systemic availability. However, there is a dermal absorption study for the structurally related substance, decamethyltetrasiloxane (L4, CAS 141-62-8) which has similar relevant physicochemical properties (vapour pressure 73 Pa at 25°C, water solubility 0.0067 mg/l at 23°C and log K_ow 8.21 at 25.1°C). In the in vitro dermal penetration study (Dow Corning Corporation, 2006) 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 the 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, if any (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. The results of this study therefore confirm the predicted dermal absorption of tetradecamethylhexasiloxane. 

Inhalation

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

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.

The predicted blood:air partition coefficient for tetradecamethylhexasiloxane is approximately 1.7E-5:1 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. However, there is an inhalation toxicokinetics study on hexamethyldisiloxane, (Dow Corning Corporation, 2008), which supports the predictions on tetradecamethylhexasiloxane. After a 6 hour inhalation exposure of female rats to 5000 ppm hexamethydisiloxane, approximately 3% of the achieved dose was retained. Due to the difference in log K_ow between hexamethyldisiloxane (log K_ow 5.06 at 20°C) and tetradecamethylhexasiloxane (log K_ow >9.41) the results 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 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 K_ow value of 9.41 for tetradecamethylhexasiloxane 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
tetradecamethylhexasiloxane	9.41	2.57E+09	8.9	5.5	113.9	20.5	8.4

 Metabolism

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

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, 2008) 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 L6, corresponding metabolites are likely to be formed following L6 metabolism.

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 K_ow 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 tetradecamethylhexasiloxane in blood is <<1%. Therefore, should systemic exposure occur, tetradecamethylhexasiloxane would not be eliminated via the urine; however, it is possible that it may be partly excreted in urine as water soluble metabolites.

A toxicokinetics study was conducted with the structurally-related substance, dodecamethylpentasiloxane (Dow Corning Corporation, 1985), in two male rats. Approximately 74% of the dose was recovered from the faeces, while 23% was eliminated through the expired air. Only 2.2% was recovered in urine. About 65 and 97% of the applied dose was eliminated within 24 and 48 hours, respectively. Therefore, elimination was rapid.

Kinetics following inhalation might differ to kinetics following oral exposure according to data for the related substance, hexamethyldisiloxane (Dow Corning Corporation, 2008). The majority of systemically absorbed hexamethyldisiloxane (3% of applied dose) was eliminated in the urine or expired volatiles. 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 substance with the remainder as metabolites. It might be expected that, due to the much lower vapour pressure of tetradecamethylhexasiloxane (0.27 Pa at 20°C) compared with hexamethyldisiloxane (5500 Pa at 25°C), tetradecamethylhexasiloxane elimination as expired volatiles is less than that of hexamethyldisiloxane.

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.