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Description of key information

Key value for chemical safety assessment

Absorption rate - dermal (%):
0.098

Additional information

There are no in vivo data on the toxicokinetics of 2,4,6 -trimethyl-2,4,6-tris(3,3,3-trifluoropropyl)cyclotrisiloxane (F-D3), although an in vitro dermal penetration study is available.

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and its hydrolysis products and 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 predictions will be made.

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 2,4,6 -trimethyl-2,4,6-tris(3,3,3-trifluoropropyl)cyclotrisiloxane or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretions (ADME) properties.

Hydrolysis half-lives of >7.5 days at pH 5, 6 days at pH 7 and 11 minutes at pH 9 and 25°C were determined for F-D3. The half-lives described are for the removal of parent substance. Complete reaction to the ultimate end products would take longer.1,5-Dihydroxy-1,3,5-trimethyl-1,3,5-tris(3,3,3-trifluoropropyl)trisiloxane and 3,3,3-trifluoropropylmethysilanediol are the postulated intermediate and final hydrolysis products respectively.

Human exposure can occur via the inhalation or dermal routes.

Absorption

Oral

Significant oral exposure is not expected for F-D3.

When oral exposure takes place, it is necessary to assume that except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood takes place. 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).

With a molecular weight of 468.5 and a water solubility of 1.3E-06 mg/l virtually no systemic exposure to F-D3 would be expected following oral exposure. However, in an oral acute (TNO, 1986) and repeat dose (Dow Corning Corporation, 2002a) studies there were signs of systemic toxicity indicating absorption of test substance-related material had occurred.

 

Dermal

In an in vitro dermal penetration study using 14C-F-D3 conducted to a design comparable to OECD 428 and in compliance with GLP (Dow Corning, 2015), only 0.098% of the applied dose was found to penetrate through rabbit skin. Only 0.629% of the applied dose volatilised, meaning the majority of the applied dose, remained either in or on the skin.

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.

The water solubility (1.3E-06 mg/l) and predicted log Kow (9.0) of the parent substance, F-D3, are far from favourable for absorption across the skin. The predicted dermal absorption for the parent substance is therefore consistent with the data from the in vitro study. However, systemic toxicity was observed in rabbit acute (Cannon Labs, 1979) and repeat dose dermal toxicity (Siddiqui and Hobbs, 1982) studies indicates absorption of test substance-related material had occurred.

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 coefficient and the octanol:air partition coefficient (Koct:air) as independent variables.

Using these values for F-D3 results in an extremely lowblood:air partition coefficient of approximately 7.2E-08:1, meaning that even if lung exposure occurred there would be no uptake into the systemic circulation.

No signs of systemic toxicity were reported in an acute inhalation study.

Distribution

Absorbed test substance may be in the form of the parent substance, the intermediate hydrolysis product, 1,5 -dihydroxy-1,3,5-trimethyl-1,3,5-tris(3,3,3-trifluoropropyl)trisiloxane or the final hydrolysis product, 3,3,3-trifluoropropylmethysilanediol.

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 (Kow) is described.

Using this value for F-D3 predicts that, should systemic exposure occur, potential distribution into the main body compartments would be primarily into the lipid compartment, and to a lesser extent to the other tissues.

Table 5.1.1: tissue:blood partition coefficients

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

F-D3

9.0

1.00E+09

8.9

5.5

113.9

20.5

8.4

 

Metabolism

There are no data regarding the metabolism of 2,4,6 -trimethyl-2,4,6-tris(3,3,3-trifluoropropyl)cyclotrisiloxane. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation. 

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 this algorithm, the soluble fraction of the parent F-D3 is <0.001% meaning that it is unlikely to be eliminated via the kidneys.