Hexamethylcyclotrisiloxane

Endpoint summary

Additional information

Introduction 

 

 There are no in vivo data on the toxicokinetics of hexamethylcyclotrisiloxane (D3; CAS no. 541-05-9; EC No. 208-765-4). The majority of the following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and its hydrolysis products. D3 is a low melting point solid with low water solubility and fairly high log Kow. It hydrolyses rapidly, initially to L3-diol (CAS No. 3663-50-1) and finally to dimethylsilanediol (DMSD, CAS No. 1066-42-8; EC No. 213-915-7). Exposure may occur via the inhalation or dermal routes. Exposure may be to either the parent substance or the hydrolysis products.

   

 

 Absorption 

 

 Oral 

 

 Oral exposure is not expected for this industrial 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).

Therefore, if oral exposure did occur, although the molecular weight of hexamethylcyclotrisiloxane (248.4) is above the favourable range, the water solubility of 1.6 mg/l would favour absorption, so some exposure by this route is probable. Similarly, the intermediate hydrolysis product, L3-diol, is water soluble (1700 mg/L at 25°C) and has a molecular weight of approximately 240.48 g/mol, so should oral exposure occur some systemic exposure will occur also.

 

The final hydrolysis product, dimethylsilanediol, meets both of these criteria (solubility 1700 mg/L at 25°C and molecular weight of approximately 92.17 g/mol) so should oral exposure occur it is reasonable to assume systemic exposure will occur also.

 

 Dermal 

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log Kow values. Substances with log Kow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high.

At 35°C and pH 5.5 (relevant for dermal exposure), the hydrolysis half-life for D3 is expected to be between the values for pH 4 (~45 seconds) and pH 7 (~8.5 minutes). Thus, where exposure occurs over the duration of a working day exposure to the parent and hydrolysis products is expected. While the log Kow (4.4) of D3 is potentially favourable for dermal absorption, its water solubility (1.6 mg/l) suggests that there will be limited partitioning from the stratum corneum into the epidermis, and therefore only low dermal absorption. D3 is also likely to evaporate from the skin, thus reducing absorption further. 

The intermediate hydrolysis product, L3-diol, has estimated water solubility (1700 mg/l at 25°C) and log Kow (1.8) values which suggest that it will be moderately absorbed through the skin. 

The very high water solubility (1E+06 mg/l) and low log Kow (-0.38) of the hydrolysis product, DMSD, suggest that it is too hydrophilic to cross the lipid rich stratum corneum. Therefore, dermal uptake is likely to be low. 

 here are no reliable studies to check for signs of dermal toxicity, and skin irritation/corrosion studies did not report any signs of systemic toxicity. 

 

 Inhalation 

 

 Exposure following inhalation of D3 is likely to be to D3 and its hydrolysis products. The log Kow of D3 is favourable for absorption directly across the respiratory tract epithelium by passive diffusion. 

 

 The intermediate hydrolysis product, L3-diol, has estimated water solubility and log Kow values which suggest that it will be moderately absorbed via the lungs. 

 

 The partition coefficient value for the hydrolysis product, DMSD, indicates that it is likely to be absorbed directly across the respiratory tract epithelium by passive diffusion. However, the high water solubility might lead to some of this hydrolysis product being retained in the mucous of the lungs. 

 

   

 

 Distribution 

 

 D3 is a lipophilic molecule and is likely to be widely distributed into cells and the intracellular concentration might be higher than extracellular concentration particularly in fatty tissues. However, D3 will be hydrolysed relatively rapidly once in the blood, so in reality distribution and retention of D3 in fatty tissues is likely to be negligible. The intermediate hydrolysis product, L3-diol, is also moderately lipophilic and distribution into the fatty tissues is expected.

 DMSD is a small molecule, and it can be predicted to be widely distributed, but its hydrophilic nature will limit its diffusion across membranes (including the blood-brain and blood-testes barriers) and its accumulation in fatty tissues. 

 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 (Kow) is described.

   Table1Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
D3	4.4	25119	8.6	5.3	113.4	10.2	6.1
L3-diol	3.2	1585	6.7	4.2	106.3	4.5	3.2
DMSD	-0.38	0.42	0.6	0.7	0.1	0.7	0.8

 

 

 Metabolism 

 

 D3 hydrolyses in the presence of moisture. The half-life of this hydrolysis reaction depends on pH. There are no data regarding the metabolism of D3 or DMSD. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation. 

 

   

 

 Excretion 

 Since the majority of D3 is likely to be hydrolysed to L3-diol and then DMSD once absorbed into the body, it is the hydrolysis products that should be considered for excretion.

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by DeJongh 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 L3-diol in blood is approximately 8% suggesting it is likely that some of it will be effectively eliminated via the kidneys in urine while accumulation is also likely to occur. The soluble fraction of DMSD in blood is approximately 99% suggesting it is likely to be effectively eliminated via the kidneys in urine and accumulation is very unlikely.