2-(2-ethoxyethoxy)ethyl acetate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of 2-(2-Ethoxyethoxy)ethyl acetate 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-Ethoxyethoxy)ethyl acetate 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-Ethoxyethoxy)ethyl acetate contains Acetic acid bound to Diethyleneglycol ethyl ether (CAS 111-90-0). 2-(2-Ethoxyethoxy)ethyl acetate is an organic liquid at 20°C and has a molecular weight of 176.21 g/mol and a water solubility of > 1000 g/L (Villa, 2011). The log Pow is 0.32 (Villa, 2011) and the vapour pressure is 13.19 Pa at 20 °C (SRC database).

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 favorable for oral absorption (ECHA, 2008). As the molecular weight of 2-(2-Ethoxyethoxy)ethyl acetate is 176.21 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-Ethoxyethoxy)ethyl acetate. However, when assessing the potential 2-(2-Ethoxyethoxy)ethyl acetate 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 glycol ether Diethyleneglycol ethyl ether and Acetic acid (ECHA, 2008). As 2-(2-Ethoxyethoxy)ethyl acetate is highly water-soluble, the substance will readily dissolve into GI fluids. The molecular weight of the parent substance 2-(2-Ethoxyethoxy)ethyl acetate (176.21 g/mol) does suggest absorption as described above. Furthermore, when considering the hydrolysis products Diethyleneglycol ethyl ether 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; Diethyleneglycol ethyl ether: 1 x 10E6 mg/L; SRC database). The respective molecular weights of Diethyleneglycol ethyl ether (134.18 g/mol) and Acetic acid (60.05 g/mol) do favour absorption, as well. In addition, due to its low molecular weight, Acetic acid 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-Ethoxyethoxy)ethyl acetate, Acetic acid (-0.17) and Diethyleneglycol ethyl ether (-0.54) favours absorption by passive diffusion, as well. Thus, 2-(2-Ethoxyethoxy)ethyl acetate, Diethyleneglycol ethyl ether and Acetic acid will be readily absorbed through the GI tract (SRC database; SCOEL, 2012; No. 2000/15OSH/113, 2004). Studies on acute oral toxicity of the parent substance 2-(2-Ethoxyethoxy)ethyl acetate did not show systemic toxicity, resulting in LD50 values greater than 2000 mg/kg bw (Smyth, 1941). However, in an oral repeated dose study with 2-(2-Ethoxyethoxy)ethyl acetate, systemic toxicity was apparent and thus absorption has occurred (Smyth, 1948). Overall, taking into account the physico-chemical properties of 2-(2-Ethoxyethoxy)ethyl acetate and all available experimental data, the oral absorption potential of the test substance is anticipated to be high.

Dermal

On the basis of the following considerations, the dermal absorption of 2-(2-Ethoxyethoxy)ethyl acetate is considered to be high. Regarding the molecular weight of 2-(2-Ethoxyethoxy)ethyl acetate (176.21 g/mol) dermal uptake of the substance is possible. Due to the octanol/water partition coefficient of 0.74 (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. However, QSAR calculation using EPIwebv4.1 resulted in a Dermal Flux of 4.52x10E-1 mg/cm² per h and QSAR calculation using DERMWIN showed a high dermal absorption potential of 2-(2-Ethoxyethoxy)ethyl acetatewith a permeability constant of 2,66E-04 cm/h, as well. However, available data on acute dermal toxicity of 2-(2-Ethoxyethoxy)ethyl acetate did not show signs of systemic toxicity (Smyth, 1991). Overall, taking into account the physico-chemical properties of 2-(2-Ethoxyethoxy)ethyl acetate and the QSAR calculation, the dermal absorption potential of the test substance is anticipated to be high.

Inhalation

2-(2-Ethoxyethoxy)ethyl acetate has low vapour pressure of 13.19 Pa at 20 °C, thus being of low volatility (SRC database, 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-Ethoxyethoxy)ethyl acetate, deposition in the mucus is possible. Due to the moderate log Pow value 2-(2-Ethoxyethoxy)ethyl acetate and also of the predicted products of ester hydrolysis Diethyleneglycol ethyl ether 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 an acute study via the inhalation route in rats and guinea pigs from 2-(2-Ethoxyethoxy)ethyl acetate did not show systemic toxicity in saturated vapour (Smyth, 1991). However, in a repeated dose toxicity study via inhalation in rats, systemic effects were observed and thus absorption via inhalation has occurred (Anonymous, 1992). Based on the physicochemical properties of 2-(2-Ethoxyethoxy)ethyl acetate and the possible breakdown products of hydrolysis and the available data, 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-Ethoxyethoxy)ethyl acetate can be hydrolysed before absorption or thereafter in the liver, the distribution of intact 2-(2-Ethoxyethoxy)ethyl acetate is not solely relevant but also the distribution of the breakdown products of hydrolysis. 2-(2-Ethoxyethoxy)ethyl acetate and the products of hydrolysis, Acetic acid and Diethyleneglycol ethyl ether can be distributed within the body. Both the parent substance and Diethyleneglycol ethyl ether and Acetic acid have low molecular weights and high water solubilities. Based on the physico-chemical properties, 2-(2-Ethoxyethoxy)ethyl acetate, Diethyleneglycol ethyl ether and Acetic acid will be distributed within the body (ATSDR, 2010; ICPS, 2001; SRC database).

Substances with high water solubility like 2-(2-Ethoxyethoxy)ethyl acetate, Diethyleneglycol ethyl ether 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-Ethoxyethoxy)ethyl acetate is not assumed to be accumulated as hydrolysis to Diethyleneglycol ethyl ether and Acetic acid is anticipated to take place before absorption or during metabolism (see below).

Metabolism

Metabolism of 2-(2-Ethoxyethoxy)ethyl acetate is expected to occur initially via enzymatic hydrolysis of the ester by ubiquitous expressed esterases before absorption. The fraction of ester absorbed unchanged will undergo enzymatic hydrolysis by ubiquitous esterases, primarily in the liver (Fukami and Yokoi, 2012). This metabolism pathway is supported by experimental data of a structurally related analogue substance, Diethylene glycol monobutyl ether acetate (CAS 124-17-4). In an in-vitro hydrolysis study in rat blood, 5 mM Diethylene glycol monobutyl ether acetate were hydrolysed to Diethylene glycol monobutyl ether with a half-life of less than 3 min. In addition, the in-vivo metabolism of 14C-Diethylene glycol monobutyl ether acetate after oral administration was studied in male Sprague-Dawley rats. The test material was rapidly absorbed from the GI tract and excreted with the urine within 24 h. The major urinary metabolite was 2-(2-butoxyethoxy)acetic acid and no unchanged ester or Diethylene glycol monobutyl ether was detected (Deisinger, 1989). In addition, simulation of intestinal metabolism of 2-(2-Ethoxyethoxy)ethyl acetate, using the OECD QSAR ToolBox v.2.3.0, resulted in 21 intestinal metabolites including Diethyleneglycol ethyl ether and Acetic acid supporting the metabolism pathway of ester hydrolysis, as well. Similarly, liver metabolism simulation resulted in 35 metabolites including Acetic acid and Diethyleneglycol ethyl ether and its oxidized derivates. 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-Ethoxyethoxy)ethyl acetate 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). The second metabolite Diethyleneglycol ethyl ether is expected to follow a similar metabolism and excretion pattern as the structurally related substance Diethylene glycol monobutyl ether acetate. After oral administration, Diethylene glycol monobutyl ether acetate was excreted with the urine within 24 h with the major urinary metabolite being 2-(2-butoxyethoxy)acetic acid. Furthermore, no unchanged ester was observed in the urine (Deisinger, 1989). Thus, it is expected that the cleavage product of ester hydrolysis Diethyleneglycol ethyl ether will be excreted via the urine as its oxidized metabolites.