2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate

Endpoint summary

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate has been investigated.

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008), assessment of the toxicokinetic behaviour of the substance 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate was conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008) and taking into account further available information on the breakdown products of ester hydrolysis.

The substance 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate contains Acetic acid bound to Triethylene glycol. 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate is an organic liquid at 20°C and has a molecular weight of 234.25 g/mol and a water solubility of > 1000 g/L (Villa, 2011). The log Pow is 0.03 (Villa, 2011) and the vapour pressure is calculated to be 0.0394 Pa at 20 °C (Nagel, 2011).

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2008).

Oral

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2008). As the molecular weight of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate is 234.25 g/mol, absorption of the intact molecule in the gastrointestinal (GI) tract can be anticipated.

Absorption after oral administration is also expected when the “Lipinski Rule of Five” ((Lipinski, 2001), refined by Ghose (1999)) is applied to the substance 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate. However, when assessing the potential 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate to be absorbed in the GI tract, it has to be considered that esters will undergo to a high extent hydrolysis by ubiquitous expressed GI enzymes (Long, 1958; Lehninger, 1970; Mattson and Nolen, 1972). Thus, due to the anticipated hydrolysis the predictions based upon the physico-chemical characteristics of the intact parent substance alone may no longer apply but also the physico-chemical characteristics of the breakdown products of the ester; the alcohol component Triethylene glycol and Acetic acid (ECHA, 2008). As 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate is highly water-soluble, the substance will readily dissolve into GI fluids. The molecular weight of the parent substance 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (234.25 g/mol) does suggest absorption as described above. Furthermore, when considering the hydrolysis products Triethylene glycol and Acetic acid, both are highly water-soluble and have low molecular weights and can therefore dissolve into GI fluids, as well (Acetic acid: miscible; Triethylene glycol: miscible). The respective molecular weights of Triethylene glycol (150.17g/mol) and Acetic acid (60.05 g/mol) do favour absorption, as well. Due to their low molecular weights, the hydrolysis products may pass through aqueous pores or may be carried through the epithelial barrier by the bulk passage of water. Furthermore, the moderate log Pow of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate and Acetic acid (-0.17) and to a lesser extent of Triethylene glycol (-1.98) favours absorption by passive diffusion. Thus, 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate, Triethylene glycol and Acetic acid will be readily absorbed through the GI tract (SRC database; SCOEL, 2012; No. 2000/15OSH/113, 2004). This is supported by the results of an in-vivo study in rats administering 1.2 g/kg bw Triethylene glycol or 3.5 g/kg bw Triethylene glycol diacetate. The study showed that 59% and 64.4% of the administered dose of Triethylene glycol and Triethylene glycol diacetate were excreted as Triethylene glycol via the urine after 1 day. The unchanged ester Triethylene glycol diacetate was not found in urine or faeces and the authors concluded that large doses of Triethylene glycol diacetate were completely absorbed, metabolised to the parent glycol and rapidly excreted in the urine (NTIS, 1984).

Studies in rats and guinea pigs investigating the acute oral toxicity of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate are available resulting in a LD50 value of > 2000 mg/kg bw (e.g. Smith, 1969). The lack of short- term systemic toxicity of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate cannot be equated with a lack of absorption or with absorption but rather with a low toxic potential of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate and the breakdown products themselves.

Dermal

On the basis of the following considerations, the dermal absorption of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate is considered to be high. Regarding the molecular weight of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (234.25 g/mol) dermal uptake of the substance is possible. Due to the octanol/water partition coefficient of 0.03 (Villa, 2011) together with the very high water solubility, the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum and dermal uptake might be low. However, QSAR calculation using EPIwebv4.1 resulted in a Dermal Flux of 2.49E-1 mg/cm² per h and QSAR calculation using DERMWIN showed a high dermal absorption potential of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetatewith a permeability constant of 8.09E-05 cm/h, as well. Furthermore, available data on acute dermal toxicity 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate did show signs of systemic toxicity, although in very high doses of 16000 mg/kg bw, indicating dermal absorption as well (Smyth, 1967).

Overall, taking into account the physico-chemical properties of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate, the QSAR calculation and available toxicological data on 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate, the dermal absorption potential of the test substance is anticipated to be high.

Inhalation

2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate has a very low vapour pressure of 0.0394 Pa at 20 °C thus being of low volatility (Nagel, 2011). Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not significant. However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the formulated substance is sprayed. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2008).

Due to the high hydrophilicity of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate, deposition in the mucus is possible. Due to the moderate log Pow value 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate and also of the predicted products of ester hydrolysis Triethylene glycol and Acetic acid, direct absorption across the respiratory tract epithelium by passive diffusion is favoured. Absorption of deposited material is anticipated to be high, due to the low molecular weight and the moderate log Pow of the parent substance and the hydrolysis products as discussed in the oral absorption section above.

Data from acute studies via inhalation and oral route from 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate did not show systemic toxicity. However, this lack of short-term systemic toxicity cannot be equated with a lack of absorption or with absorption but rather with a low toxic potential of the test substance and the breakdown products themselves. Based on the physicochemical properties of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate and the possible breakdown products of hydrolysis absorption via the lung is expected to be high.

Distribution and accumulation

Distribution of a compound within the body depends on the physicochemical properties of the substance especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution (ECHA, 2008). As the parent compound 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate can be hydrolysed to a substantial extent before absorption or thereafter in the liver, the distribution of intact 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate is not solely relevant but also the distribution of the breakdown products of hydrolysis. 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate and the products of hydrolysis, Acetic acid and Triethylene glycol can be distributed within the body. Both the parent substance and Triethylene glycol and Acetic acid have low molecular weights and high water solubilities. Based on the physico-chemical properties, 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate, Triethylene glycol and Acetic acid will be distributed within the body (ATSDR, 2010; ICPS, 2001; SRC database). Substances with high water solubility like 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate, Triethylene glycol and Acetic acid do not have the potential to accumulate in adipose tissue due to their low log Pow. In addition, the intact parent compound 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate is not assumed to be accumulated as hydrolysis to Triethylene glycol and Acetic acid is anticipated to take place before absorption or during metabolism (see below).

Metabolism

Metabolism of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate is expected to occur initially via enzymatic hydrolysis of the ester by ubiquitous expressed esterases before absorption.

In an in-vivo study, 1.2 g/kg bw Triethylene glycol or 3.5 g/kg bw 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (Triethylene glycol diacetate) were administered to rats. The study showed that 59% and 64.4% of the administered dose of Triethylene glycol and Triethylene glycol diacetate were excreted as Triethylene glycol via the urine after 1 day. The unchanged ester Triethylene glycol diacetate was not found in urine or faeces and the authors concluded that large doses of Triethylene glycol diacetate were completely absorbed, metabolised to the parent glycol and rapidly excreted in the urine (NTIS, 1984). McKennis et al. (1962) administered single oral doses of labelled 14C-Triethyleneglycol to rats for a period of 5 days. The radioactivity recovered, measured as percent of the administered dose, was 0.8% to 1.2% in expired air, 2.0% to 5.3% in faeces, and 86.1% to 94.0% in urine (total recovery 90.6-98.3%).

The fraction of ester absorbed unchanged will undergo enzymatic hydrolysis by ubiquitous esterases, primarily in the liver (Fukami and Yokoi, 2012). In addition, simulation of intestinal metabolism of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate, using the OECD QSAR ToolBox v.2.3.0, resulted in 13 intestinal metabolites including, Triethylene glycol monoacetate, Acetic acid and oxidized Triethylene glycol derivates supporting the metabolism pathway of a stepwise ester hydrolysis, as well. Similarly, liver metabolism simulation resulted in 11 metabolites including Triethylene glycol monoacetate and Acetic acid. The second product of hydrolysis, Acetic acid and the respective acetate ion are normally-occurring metabolites in catabolism or in anabolic synthesis, e.g. in the formation of Glycogen, Cholesterol synthesis and degradation of fatty acids (SCOEL, 2012).

Excretion

Based on the metabolism described above, 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate will be hydrolysed and the breakdown product Acetic acid will be metabolised in the body to a high extent. Acetic acid will be metabolised in the citric acid cycle and mainly excreted via exhaled air as CO2 (Lehninger, 1970; Stryer, 1994).In-vivo studies with Triethylene glycol diacetate showed, that no unchanged ester was found in urine or faeces whereas a large dose was converted to the parent glycol Triethylene glycol, and was excreted via the urine (NTIS, 1984). In a further study with radiolabelled Triethylene glycol in rats and rabbits a high degree of urinary excretion of the unchanged Triethylene glycol is described. The total elimination via urine, faeces and expired air during a 5-day period following a single oral dose of 22.5 mg was 91-98% (McKennis, 1962).

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.