2-ethyl-2-oxazoline

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Description of key information

Based on considerations of the physicochemical properties and the toxicologically insignificant gross pathological findings following acute exposure 2-ethyl-2-oxazoline would be expected to be absorbed following oral, dermal and inhalation exposure. Conservative absorption rates for this substance are set at 100% for all routes of exposure.

Gross pathological observations and the physicochemical properties of the substance suggest that there will be distribution of the substance throughout the body. The substance is expected to rapidly transform via hydrolysis and metabolism to its aliphatic amine and corresponding fatty acid components. Ultimately the majority of excretion is expected to be urinary but might also be faecal following oral dosing. Based on the available data, in particular the log P value of 0.198, the water solubility of >97.87 g/L, the substance is expected to have a no potential to bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

To date, no relevant analytical toxicokinetic testing data has been generated for 2-ethyl-2-oxazoline. However, toxicological information following oral, dermal, and inhalation exposure of 2-ethyl-2-oxazoline and information on the physicochemical properties can be used as a basis for the assessment of toxicokinetics.

Absorption

The diffusion of a substance across biological membranes in a test species is governed by the physicochemical properties of the substance, particularly its molecular size, Log P, and water solubility (ECHA, 2017).

Oral

Due to its small molecular size of 99 g/mol, very hydrophilic nature with a water solubility of >97.87 g/L and a Log P of 0.198 there is the possibility of passive absorption of 2-ethyl-2-oxazoline following oral exposure through aqueous pores or through the epithelial barrier by bulk transport of water. Following oral exposure, 2-ethyl-2-oxazoline is expected to undergo hydrolysis to 2 -aminoethanol and propionic acid; as these products of hydrolysis are smaller molecules, have similar water solubility and Log P values, they too are anticipated to be passively absorbed.

There are two acute oral studies included within this REACH dossier. Both indicate the substance may be harmful is swallowed (LD50 > 2000 mg/kg bw and less than 5000 mg/kg bw). While no toxicologically significant effects were reported during the gross pathological investigations, one study reported pale kidneys and the other pale livers in the mid to high dose level groups. These pathological findings suggest systemic absorption followed oral exposure. Based on a consideration of the substance’s physicochemical properties and the available oral toxicity studies, a conservative default value for oral absorption of the substance is set as 100%.

Inhalation

The low measured vapour pressure (1.31 kPa at 37.8°C) and measured boiling point (131°C) of the substance would suggest it possesses moderate to low volatility and thus likely not readily available for inhalation as a vapour. However, the hydrophilic nature of the substance (low Log P value, high water solubility) would suggest it is favourable for absorption directly across the respiratory tract epithelium by passive diffusion. 2-Ethyl-2-oxazoline is expected to undergo hydrolysis to 2-aminoethanol and propionic acid; as these products of hydrolysis are smaller molecules, have similar water solubility and Log P values, they too are anticipated to be passively absorbed.

While the available acute inhalation toxicity study in rats indicated a low acute vapour inhalation toxicity value (7h LC50 > 635 ppm) and no toxicologically significant gross pathological findings were report, the kidneys were described as pale. These pathological findings suggest systemic absorption followed inhalation exposure. Based on a consideration of the physicochemical properties and the available oral and inhalation toxicity studies, a conservative default value for inhalation absorption of the substance is set as 100%.

Dermal

The very hydrophilic nature of the substance would suggest that 2-ethyl-2-oxazoline would not cross the lipid rich environment of the stratum corneum. However, 2-ethyl-2-oxazoline is CLP classified as a Category 1B Skin Corrosive substance. Dermal exposure to the substance could damage the lipid rich stratum corneum allowing for passive diffusion directly through the epidermis.

An acute dermal toxicity study with a 10% aqueous solution of 2-ethyl-2-oxazoline supports the assumption of passive diffusion through damaged skin as deaths were reported in following exposure of animals with abraded skin while no deaths were reported following exposure of animals with unabraded skin. Based on a consideration of the substance’s physicochemical properties and the results of the available skin toxicity study, a conservative value of 100% skin absorption is chosen.

Distribution

As 2-ethyl-2-oxazoline is a small water-soluble molecule it is anticipated to diffuse through the aqueous channels and pores of cellular membranes following absorption. While there were no toxicologically significant gross pathological findings following oral and inhalation exposure; the reports of pale liver and/or kidneys support distribution throughout the animal system. No significant signs of systemic toxicity were reported following dermal exposure with animals with unabraded skin while deaths were reported in animals with abraded skin. The findings reported following acute exposure suggest that the substance dose distribute in animal systems.

Metabolism

The substance is expected to undergo initial hydrolysis into its secondary amide which will then be metabolized by amidase enzymes such as  fatty acid amide hydrolase (FAAH) [Fiume, et al., 2015] into its aliphatic amine (ethanolamine) and corresponding fatty acid (propionic acid) components. FAAH, an enzyme responsible for the hydrolysis of a number of primary and secondary fatty acid amides, is widely distributed throughout the human body.

Excretion

Following metabolism to the aliphatic amine and corresponding fatty acid, ultimate excretion is expected to be primarily urinary, although a minor amount of faecal excretion may also occur following oral dosing. 

Based on the available data, in particular the log P value and high water solubility the substance is expected to have a no potential to bioaccumulate in animals and humans.

References

 

ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. Volume 3.0, July 2017. Available at:https://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf/e2e23a98-adb2-4573-b450 -cc0dfa7988e5

 

Fiume, M.M., Heldreth, B.A., Bergfeld, W.F., Belsito, D.V., Hill, R.A., Klaassen, C.D., Liebler, D.C., Marks Jr, J.G., Shank, R.C., Slaga, T.J. and Snyder, P.W., 2015. Safety Assessment of Ethanolamides as Used in Cosmetics. International journal of toxicology, 34(1_suppl), pp.18S-34S.