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Description of key information

Based on physico-chemical characteristics, particularly water solubility and octanol-water partition coefficient absorption via oral, inhalation and dermal route is likely to occur. Intracellular concentration is likely to be higher than extracellular due to the moderate lipophilicity of the test substance. A conjugation reaction may increase hydrophilicity and metabolites are considered to be not more toxic than the parent molecule. Excretion via urine is assumed to be the main excretion pathway of metabolites formed due to their low molecular weight. Bioaccumulation is not likely to occur based on physico-chemical properties.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicological profile of the test substance

Acute toxicity studies via oral, via inhalation and via dermal route are available. The acute oral toxicity study with rats showed adverse effects. The LD50 value was determined to be 3600 mg/kg bw. The animals showed color changes in the liver and the kidneys. Adverse effects were also observed in the acute inhalation study. The LD50 was determined to be 10500 mg/m3. Effects were observed in behavior, appearance and breathing. All animals exposed to 22.0 mg/L air died within 3 hours after exposure start. The acute dermal toxicity study showed no adverse effects up to 2000 mg/kg bw. In a skin irritation test with rabbits according to OECD guideline 404 the test item showed irritating effects. The mean erythema (24/48/72 h) of animal one and two was 2, of animal three 1.3. The erythema effect was fully reversible. The edema score (24/48/72 h) was 2.3 for animal one and 0.6 for animal two and three. The edema effect was fully reversible for animal one and for animal three. The effect of animal 2 was not reversible. In an eye irritation test with white Vienna rabbits according to OECD guideline 405 no or only slightly irritating effects were observed. In a Local Lymph Node Assay (LLNA) in mice DPM (disintegrations per minute) values were neither significantly increased compared to vehicle control group nor did any dose group produce a S.I. of 3 or higher compared to vehicle values. The test item was thus not a skin sensitizer under the test conditions of this study. No experimental data on animals are available for repeated dose toxicity. The potential of the test substance to cause genotoxic effects was determined in a bacterial reverse mutation assay, in an in-vitro micronucleus test and in an in-vitro Mammalian Cell Gene Mutation Test (HPRT). The Salmonella typhimurium and Escherichia coli strains showed neither mutagenic nor cytotoxic effects in the absence and presence of metabolic activation. In the micronucleus test no chromosome-damaging clastogenic effect and no induction of numerical chromosomal aberrations under in vitro conditions were observed (with and without metabolic activation). The cell count or proliferation index indicated also no cytotoxicity. The HPRT test supports the results of the two other tests. No increase of mutants was found after treatment with the test item. In contrast to the other two studies cytotoxic effects were found in this test.

Toxicokinetic analysis of the test substance

2-(2-ethoxyethoxy)-2-methylpropane is a clear liquid with a molecular weight of 146.2273 g/mol. The melting point is below -20 °C. The boiling point is determined to be 146.8 °C. Density is 0.831 g/mL at 20 °C. The vapour pressure is determined to be 36.96 hPa. The partition coefficient between octanol and water (log Kow) is 2.2 and water solubility is 37 g/L at 21 °C. The soil adsorption coefficient (log Koc) was calculated to be 1.23. Due to the log Kow value no BCF was determined because accumulation of the substance in organisms is not expected. Based on chemical structure, no surface activity is to be expected.

Absorption

Substances with a molecular weight below 500 g/mol are favoured for oral absorption. This characteristic combined with the moderate lipophilic log Kow value and high water solubility allow dissolution of 2-(2-ethoxyethoxy)-2-methylpropane in the gastro-intestinal fluids and contact with the mucosal surface. In one oral toxicity study a LD50 of 3600 mg/kg bw was determined.

Additionally, readily absorption through the GIT epithelium is assumed after oral intake due to the low log Kow value of the test substance. Furthermore, the low molecular weight (below 200 g/mol) combined with the high water solubility (> 10 g/L) may allow the direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across the membrane with the bulk passage of water.

Based on the vapour pressure of approximately 36.96 hPa the test substance may reach the respiratory system. If the substance would reach the lungs in its vapour or gaseous state, absorption directly across the respiratory tract epithelium by passive diffusion is likely to occur due to its log Kow value and water solubility. An acute inhalation toxicity study performed on rats with the test substance in its aerosol form revealed a LC50 of 10500 mg/m3.

Similarly, based on physico–chemical properties of the test substance, it may be able to penetrate skin as the log Kow value and water solubility allow dermal penetration. As the compound´s water solubility is very high with 37 g/L and the log Kow is 2.2 absorption can be anticipated to be moderate to high. Moreover, for substances with a log Kow between 1 and 4, both penetration into stratum corneum and partition into the epidermis are likely to occur. In addition, the test substance caused slight skin irritation, which may enhance penetration.

Distribution

Assuming that the test substance is absorbed into the body following oral, dermal or inhalation intake, it may be distributed into the interior part of cells due to its moderate lipophilic properties and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. As mentioned above, the physico-chemical properties, especially the lower molecular weight and relatively high water solubility, favour systemic absorption. Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. Based on the relatively low log Kow and the log Koc values, it can be expected that the test substance has no potential to bioaccumulate in the human body.

Metabolism

Based on the structure of the molecule it may be metabolized by Phase I enzymes while undergoing functionalization reactions aiming to increase the compound’s hydrophilicity. The substance is most likely not enzymatically activated (toxified) during metabolism. This assumption is supported by the result of an Ames test as well as an in vitro micronucleus assay in V79 Cells in which cytotoxicity of the parent substance was not higher as compared to metabolic activated test substance.

Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the parent compound or the Phase I metabolite in order to ultimately facilitate excretion.

Excretion

As the molecule has a low molecular weight (146.2273 g/mol) and is miscible in water renal excretion may be the major route of elimination. The compound may either directly excreted by urine or further metabolised by Phase II enzymes before excretion.

References

ECHA (2012), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

Marquardt H., Schäfer S. (2004). Toxicology. Academic Press, San Diego, USA, 2nd Edition 688-689.