Octamethyltrisiloxane

Endpoint summary

Additional information

An in vivo study was carried out to determine a kinetically derived maximum dose (KMD) for octamethyltrisiloxane (L3) in pregnant Sprague-Dawley rats (Dow Corning Corporation, 2017a). The study was based on OECD 414 exposure design. The animals were administered L3 by gavage from Gestational Day (GD) 6 through GDI9. Dosing with non-radiolabelled test article occurred from GD6 - GD 18 and the animals were dosed with ¹⁴C-octamethyltrisiloxane (¹⁴C-L3, solutions contain non-radiolabelled L3 and radiolabelled L3) on GD 19.

Blood was collected at 0.5, 1, 4 and 24 h post-dosing with 14C-L3 and analysed for parent L3 and 14C-activity concentrations and blood AUCs determined. In this repeated dosing study design, steady state blood concentrations of L3 were reached. The AUC analysis showed statistically significant differences in the AUCs for L3 and ¹⁴C-activity at the dose level of 50 mg/kg/day. None of the higher dose groups (150, 450 and 1000 mg/kg/day) had statistically significant differences between the L3 and ¹⁴C-activity AUCs although visual inspection of the graphs showed a difference between ¹⁴C-activity and parent L3 at 24 h indicating the presence of metabolite/degradation products. Based on the statistical method used and the graphical method, the linearity of L3 AUCs vs external dose was observed through 150 mg/kg bw. Therefore, the KMD was determined to be 150 mg/kg bw.

There is a dermal absorption study available on the structurally-related substance decamethyltetrasiloxane (L4, CAS 141-62-8) (Dow Corning Corporation, 2006a). There are also data on the structurally-related substance, hexamethyldisiloxane (L2; CAS 107-46-0) (Dow Corning Corporation, 2001 and Dow Corning Corporation, 2008), which are used to confirm predictions for the kinetics of L3 where appropriate. The registered and read-across substances are siloxanes (alkyl, vinyl, aryl or hydrogen substituted) with 2 (hexamethyldisiloxane), 3 (octamethyltrisiloxane) or 4 (decamethyltetrasiloxane) silicon atoms linked by oxygen atoms.

The following summary has therefore been prepared based on the KMD study (Dow Corning Corporation, 2017a), in vitro data for a structurally-related substance and the physicochemical properties of octamethyltrisiloxane 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 octamethyltrisiloxane reasonable predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

Octamethyltrisiloxane hydrolyses very slowly (half-life of 13.7 days at pH 7 and 25°C). The read-across substances also hydrolyse slowly or very slowly (L2 half-life of 5 days and L4 half-life of 30.3 days, at pH 7 and 25°C). Human exposure to the parent substance can occur via the oral, inhalation or dermal routes.

 

Absorption

Oral

In the KMD study (Dow Corning Corporation, 2017a), L3 was administered by single daily doses by oral gavage for 13 days followed by a radiolabelled dose on the 14th day of dosing and blood samples were then collected at 0.5, 1, 4 and 24 h. Measured blood concentrations data showed that L3 was absorbed and a difference in blood L3 and ¹⁴C-activity AUCs was observed. These data suggest that appreciable levels of metabolites/degradation products were present at the time that the animals were dosed with radiolabel.

 

Based on PBTK prediction models, 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 must 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 octamethyltrisiloxane (approximately 237) is close to the favourable range for absorption but 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. The results of the KMD study confirm that oral absorption does occur but the mechanism of uptake was not studied. There was also evidence of oral absorption in the 7-day repeated dose toxicity study in rats for this substance.

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. Therefore, with a log K_ow of 6.6 (at 24.1 °C)and water solubility of 0.034 mg/l, dermal absorption is unlikely to occur as octamethyltrisiloxane is 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. Octamethyltrisiloxane is volatile so this would further reduce the potential for dermal absorption.

There are no dermal toxicity studies available on octamethyltrisiloxane to check for signs of dermal absorption.

However, there is a dermal absorption study for the structurally related substance, decamethyltetrasiloxane (L4), which has similar relevant physicochemical properties to octamethyltrisiloxane (vapour pressure 57 Pa, water solubility 0.0067 mg/l and log K_ow ca. 8.0).

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- 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, if any (0.001%), of the applied dose penetrated through the skin into the receptor fluid and the total absorbed was estimated to be 0.03% of the applied dose with virtually all of the absorbed test substance retained in the skin. This is consistent with the predicted lack of dermal absorption for octamethyltrisiloxane.

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's Law coefficient and the octanol: air partition coefficient (K_{oct: air}) as independent variables.

 

Using these values for octamethyltrisiloxane results in an extremely low blood: air partition coefficient (approximately 3.3E-04) so absorption across the respiratory tract epithelium is likely to be restricted to micellar solubilisation. The available inhalation toxicity study on L3 showed treatment-related effects therefore indicating that some absorption had occurred.

There is an inhalation toxicokinetics study on L2 (Dow Corning Corporation, 2008) which supports the predictions on L3. 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 K_ow between L2 (log K_ow 5.3) and L5 (log K_ow 9.4) 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 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 (K_ow) is described.

Using this for octamethyltrisiloxane predicts that 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 18.9 for the remaining tissues.

Table 1: tissue: blood partition coefficients

 

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
octamethyltrisiloxane	6.6	4E+06	8.9	5.5	113.9	18.9	8.2

 

The repeated dose toxicity study showed effects in the liver, kidney (oral and inhalation exposure) and spleen (oral exposure) therefore the test substance must have distributed to these organs. 

Metabolism

 

In the KMD study (Dow Corning Corporation, 2017a), the data suggest that appreciable levels of metabolites/degradation products were present at the time that the animals were dosed with radiolabel. With this study design, a repeated non-radiolabelled dosed followed by a radiolabelled dose, and analytical methods used, only total ¹⁴C-activity and parent could be measured, metabolite profiles were not determined in blood. The metabolites although not measured could influence the TK of the dosed radiolabelled L3 via competition for metabolism and elimination processes.

There are no other data regarding the metabolism of L3. It is known to slowly hydrolyse ultimately forming dimethylsilanediol and trimethylsilanol. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for octamethyltrisiloxane.

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 hydroxy silanes may isomerise to silanols and this provides a mechanism by which very polar metabolites may be formed from highly hydrophobic alkyl siloxanes 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 L3, corresponding metabolites are likely to be formed following L3 metabolism. The KMD study (Dow Corning Corporation, 2017a) data confirmed that appreciable levels of metabolites/degradation products were present. However, the metabolite profiles were not determined in blood.

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 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 this algorithm, the soluble fraction of octamethyltrisiloxane itself in blood is <1E-04%. Therefore, octamethyltrisiloxane would not be eliminated via the urine. However, according to data for the related substance, L2 (Dow Corning Corporation, 2008) 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.