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Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of 2-(1-Methylethoxy)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, 2012), assessment of the toxicokinetic behaviour of the substance 2-(1-Methylethoxy)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, 2012) and taking into account further available information on the breakdown products of ester hydrolysis.

The substance 2-(1-Methylethoxy)ethyl acetate contains acetic acid bound to 2-isopropoxyethanol. 2-(1-Methylethoxy)ethyl acetate is an organic liquid at 20°C and has a molecular weight of 146.18 g/mol and a water solubility of 99.8 g/L (Renzi, 2011; Villa, 2011). The log Pow is 1.28 (Villa, 2011) and the vapour pressure is 700 Pa at 20 °C (Holzschuh, 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, 2012).

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, 2012). As the molecular weight of 2-(1-Methylethoxy)ethyl acetate is 146.1 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-(1-Methylethoxy)ethyl acetate. However, when assessing the potential 2-(1-Methylethoxy)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). Rapid hydrolysis of the substance 2-(1-Methylethoxy)ethyl acetate was confirmed in an in vitro hydrolysis test in rat plasma, resulting in a calculated half-time for hydrolysis of the parent substance of 8.85 min (Tarran, 2013). Furthermore, 2-(1-methylethoxy) ethanol, the expected metabolite of the substance after ester hydrolysis, was identified in rat plasma. Based on these results, rapid ester hydrolysis of the parent substance by plasma esterases and formation of the respective hydrolysis products are also expected after the substance is absorbed from the GI tract. 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 2-isopropoxyethanol and acetic acid (ECHA, 2012). As 2-(1-Methylethoxy)ethyl acetate is highly water-soluble, the substance will readily dissolve into GI fluids. The molecular weight of the parent substance 2-(1-Methylethoxy)ethyl acetate (146.1 g/mol) does suggest absorption as described above. Furthermore, when considering the hydrolysis products 2-isopropoxyethanol 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; 2-isopropoxyethanol:1x10E6 mg/L; SRC database). The respective molecular weights of 2-isopropoxyethanol (104.15 g/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-(1-Methylethoxy)ethyl acetate, acetic acid (-0.17) and 2-isopropoxyethanol (0.05) favours absorption by passive diffusion, as well. Thus, 2-(1-Methylethoxy)ethyl acetate, 2-isopropoxyethanol 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 acute oral toxicity study with the parent substance 2-(1-Methylethoxy)ethyl acetate. In the study, systemic toxicity was apparent, thus absorption has occurred (Pooles, 2012).

Dermal

On the basis of the following considerations, the dermal absorption of 2-(1-Methylethoxy)ethyl acetate is considered to be high. Regarding the molecular weight of 2-(1-Methylethoxy)ethyl acetate (146.1 g/mol) dermal uptake of the substance is possible. Due to the octanol/water partition coefficient of 1.28 (Villa, 2011) together with the very high water solubility, dermal absorption is favoured. QSAR calculation using EPIwebv4.1 resulted in a Dermal Flux of 2.54E-1 mg/cm² per h and QSAR calculation using DERMWIN showed a high dermal absorption potential of 2-(1-Methylethoxy)ethyl acetate with a permeability constant of 1.68E-03 cm/h, as well. However, available data on acute dermal toxicity of 2-(1-Methylethoxy)ethyl acetate did not show signs of systemic toxicity (Pooles, 2012). Overall, taking into account the physico-chemical properties of 2-(1-Methylethoxy)ethyl acetate, the QSAR calculation and available toxicological data on 2-(1-Methylethoxy)ethyl acetate and applying a worst case assumption, the dermal absorption potential of the test substance is anticipated to be high.

Inhalation

2-(1-Methylethoxy)ethyl acetate has boiling point above 150°C (164.5 °C) and a low vapour pressure of 700 Pa at 20 °C, thus being of low volatility (Villa, 2011; Holzschuh, 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, 2012).

Due to the high hydrophilicity of 2-(1-Methylethoxy)ethyl acetate, deposition in the mucus is possible. Due to the moderate log Pow value 2-(1-Methylethoxy)ethyl acetate and also of the expected products of ester hydrolysis, 2-isopropoxyethanol 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 oral route from 2 2-(1-Methylethoxy)ethyl acetate did show systemic toxicity (Pooles, 2012). However, data from an acute inhalation study did not show systemic toxicity (Griffiths, 2012). Thus, based on the physicochemical properties of 2-(1-Methylethoxy)ethyl acetate and the possible breakdown products of hydrolysis, and applying a worst case assumption, 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, 2012). As the parent compound 2-(1-Methylethoxy)ethyl acetate can be hydrolysed to a substantial amount before absorption or thereafter in the liver, the distribution of intact 2-(1-Methylethoxy)ethyl acetate is not solely relevant but also the distribution of the breakdown products of hydrolysis. 2-(1-Methylethoxy)ethyl acetate and the products of hydrolysis, acetic acid and 2-isopropoxyethanol can be distributed within the body. Both the parent substance and 2-isopropoxyethanol and acetic acid have low molecular weights and high water solubilities. Based on the physico-chemical properties, 2-(1-Methylethoxy)ethyl acetate, 2-isopropoxyethanol and acetic acid will be distributed within the body (ATSDR, 2010; ICPS, 2001; SRC database). Substances with high water solubility like 2-(1-Methylethoxy)ethyl acetate, 2-isopropoxyethanol 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-(1-Methylethoxy)ethyl acetate is not assumed to be accumulated as hydrolysis to 2-isopropoxyethanol and acetic acid is anticipated to take place before absorption or during metabolism (see below).

Metabolism

Metabolism of 2-(1-Methylethoxy)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). Rapid hydrolysis of the substance 2-(1-Methylethoxy)ethyl acetate was confirmed in an in vitro hydrolysis test in rat plasma, resulting in a calculated half-time for hydrolysis of the parent substance of 8.85 min (Tarran, 2013). Furthermore, 2-(1-methylethoxy) ethanol, the expected metabolite of the substance after ester hydrolysis, was identified in rat plasma. In addition, simulation of intestinal metabolism of 2-(1-Methylethoxy)ethyl acetate, using the OECD QSAR ToolBox v.2.3.0, resulted in 9 intestinal metabolites including, 2-isopropoxyethanol and acetic acid supporting the metabolism pathway of ester hydrolysis, as well. Similarly, liver metabolism simulation resulted in four metabolites including 2-isopropoxyethanol and acetic acid, as well. Intraperitoneal injection into rats of the predicted hydrolysis product 2-isopropoxyethanol in doses of 1 mg/animal, resulted in 87% excretion of the 14C-labelled substance within 2 h. The majority was excreted via the urine (73%) and 14% were excreted as CO2 in the exhaled air. The excreted metabolites comprised Isopropoxyacetic acid in free and glycine-conjugated form together with acetone and ethylene glycol (MAK, 2012). 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-(1-Methylethoxy)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). In-vivo studies with 2-isopropoxyethanol showed a high percentage of excretion via the urine (73%) and a further 14% as CO2 in the exhaled air (MAK, 2012).