1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane

Endpoint summary

Additional information

There are no in vitro or in vivo data on the toxicokinetics of 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane. 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 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane where appropriate. The registered and read-across substances are linear siloxanes with no functional groups present, with 2 (hexamethyldisiloxane, L2), 4 (decamethyltetrasiloxane, L4), 5 (dodecamethylpentasiloxane, L5) and 3 (1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane)silicon atoms linked by oxygen atoms. In L2, L4 and L5, all silicon atoms are fully substituted with methyl groups. In 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane, the central silicon atom has an octyl side group.

1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane is a low volatility (vapour pressure 0.64 Pa at 25°C) liquid that is insoluble in water (predicted water solubility 2.8E-05 mg/l at 20°C). It has a predicted log K_ow of 9.0 at 20°C, indicating that the substance is highly lipophilic. Based on read-across data from a supporting substance, 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane hydrolyses very slowly in contact with water >329 h (13.7 d) at pH 7 and 25°C, >9.76 h at pH 9, >5.09 h at pH 5 and 25°C. At 37.5°C and pH 7, the half-life is approximately 115 hours. The products of hydrolysis are octyl(methyl)silanediol 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 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane, 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).

1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane has a molecular weight (335) unfavourable for absorption and low water solubility, making systemic exposure limited.

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 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane fulfils neither of these criteria, dermal absorption is unlikely to occur as 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane is not sufficiently soluble in water to partition from the stratum corneum into the epidermis.

There was no evidence of absorption in the acute dermal toxicity study or in the skin irritation study.

 

Inhalation

Owing to its low vapour pressure, inhalation of vapours of 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane is likely to be minimal. Inhalation of aerosols could occur. Once inhaled, 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane could be absorbed by micellar solubilisation.

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 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane is approximately 1.7E-4:1 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.

The effects observed in the liver in the repeated dose oral study following unscheduled deaths attributed to aspiration exposure support the possibility of absorption should the substance be inhaled.

 

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 Kow value of 9 for 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane 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
1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane	9	1.0E+09	8.9	5.5	113.9	20.5	8.4

 

The repeated dose toxicity study showed effects in the liver, but only after unscheduled deaths which were attributed to aspiration of the test substance. These effects are therefore considered to indicate that the test substance distributed to the liver after aspiration exposure.

Metabolism

There are no data regarding the metabolism of 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane.

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 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane, corresponding metabolites are likely to be formed following 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane 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 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 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane in blood is <<1%.Therefore, should systemic exposure occur 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane 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 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane (0.64 Pa) compared with hexamethyldisiloxane (4451 Pa), 1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane 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.