Ethylene carbonate

Endpoint summary

Description of key information

For ethylene carbonate, no experimental in vivo studies are available where absorption, distribution, metabolism and/or excretion are evaluated. Therefore, a qualitative assessment is performed on the basis of the physicochemical properties of the substance, an in vitro hydrolysis/degradation study (Ehmer, 2015) and the publication of Hanley et al. (1989). It can be concluded that ethylene carbonate hydrolysis in blood is fast and occurred with maximum degradation rates of 0.14 μmol/(ml x min). Under the incubation conditions used in the study, nearly complete hydrolysis and stoichiometric formation of ethylene glycol was observed after 30 min.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Absorption

Oral absorption:

As ethylene carbonate is a small molecule (MW 88 g/mol), it will be absorbed easily. Moreover, the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. The water-soluble solid (778 g/L) will readily dissolve into the gastrointestinal fluids. Also the moderate log Kow value is favourable for absorption by passive diffusion. An oral absorption of 50 % is expected.

Respiratory absorption:

As the substance is liquid at room temperature, with a high boiling point (247 °C) and a low vapour pressure (0.01 hPA), no or only a limited number of airborne particles are expected. The substance is water soluble and will be readily soluble in blood. When the substance is airborne, a high amount will be absorbed per breath. Since the substance has a moderate Log KoW (0.11) absorption might occur. When exposure occurs, 100% respiratory absorption is proposed as a worst case.

Dermal absorption:

The substance is a solid and therefore not readily taken up by the skin in comparison to liquid products. The product will have to dissolve into the surface moisture of the skin before uptake can take place. The low molecular weight of ethylene carbonate (88 g/mol) favours dermal uptake. Based on its high water solubility, dermal uptake is expected to be moderate to high. Moreover, ethylene carbonate has a low vapour pressure. These parameters favour dermal uptake. On the other hand, the substance might be too hydrophilic to cross the lipid rich environment of the stratum corneum. Similar to the oral route, an absorption of 50% is expected.

Distribution/Accumulation:

Wide distribution throughout the body is expected as the substance is relatively small and water-soluble. It is likely to diffuse through aqueous channels and pores. Based on the results of the (eco)toxicological studies included in this dossier, no bioaccumulation is expected.

Metabolism:

Ethylene carbonate follows the documented metabolic pathway where cyclic organic carbonates are metabolized to their respective glycols. Yang et al. (1998) identified a rat liver enzyme capable the biotransformation of certain cyclic alkyl carbonates to CO2 and the respective alkyl glycols. In particular, Yang et al. concluded that “The mechanism previously outlined for the hydrolysis of imides appears to apply equally to the activity toward cyclic organic carbonates. The reaction would be expected to take the form of protonation of the carbonyl group of the carbonate, thereby providing a strong electrophilic center for the addition of water. Upon such addition, ring opening would be followed by elimination of CO2. The finding of this enzyme in rat liver provides a metabolic pathway for the conversion of cyclic organic carbonates to their respective glycols.” One of the substances used by Yang et al. to describe this phenomenon was the registered substance ethylene carbonate.

An in vivo toxicokinetic study (Hanley et al., 1989) using radiolabeled ethylene carbonate (200 mg/kg bw) supports the conclusions drawn by Yang et al., since ethylene carbonate was shown to be primarily excreted via exhalation as CO2 (57%), to a lower amount via the urine (27%) and only marginally via feces (2%). In urine, only a single major peak was identifiable, representing one single metabolite: ethylene glycol. The identity of this major metabolite was further confirmed by GC/MS analyses. These experiments have unequivocally proven that ethylene glycol is the major systemically available metabolite of ethylene carbonate. To get an impression about the elimination half-life of ethylene carbonate, Hanley and co-workers further analyzed rat blood samples at various time points after test material application and concluded by estimation that the half-life of ethylene carbonate is approximately 0.25 h. However, it should be noted that 15 min was the first time point at which blood samples were taken and that the half-life could be even lower than 0.25 h. Briefly, after application of 200 mg ethylene carbonate/kg bw the peak concentration of ethylene carbonate itself was 0.028 μmol/g blood reached within 15 min, whereas the peak concentration of ethylene glycol was 2.3 μmol/g blood reached after 45 min. Hence, the levels of the metabolite ethylene glycol were approximately 100-fold higher as compared to the parent compound ethylene carbonate. This huge difference in blood concentrations strongly suggest, that most of the ethylene carbonate was already metabolized to ethylene glycol well before blood samples were taken for the first time (15 min). Thus, the reported half-life could be considered an overestimation and the real half-life will be much shorter. To support this hypothesis, a further in vitro hydrolysis study was performed (Ehmer, 2015). In this study, originally the hydrolysis of propylene carbonate was studied and ethylene carbonate was used as a positive control. Both compounds were incubated in Wistar rat blood over a time span of 30 min. Concerning ethylene carbonate, 35.5% of the start concentration remained after 5 min of incubation. After 30 min 15.5% of the start concentration was observed. The hydrolysis product ethylene glycol was shown to be formed simultaneously from the reference item at concentrations that corresponded to its turnover/hydrolysis. The calculated half-life value for ethylene carbonate was 3.53 min and therefore much shorter than the half-life as derived by Hanley and co-workers. These data strongly suggest that the systemic toxicity observed following oral administration of ethylene carbonate results only from the rapid conversion of the parent compound to ethylene glycol both in vivo as well as in vitro.

In the endpoint summary on developmental toxicology, further information is included on the mebatolism of ethylene glycol by oxidative pathways (Corley et al., 2005): At low doses, metabolism is extensive, and the major elimination products are exhaled carbon dioxide and urinary parent glycol and metabolites. However, the oxidation of glycolic acid (GA) to glyoxylic acid becomes saturated at doses in the range 125–500 mg/kg bw, resulting in accumulation of GA in the blood and increased excretion in the urine of female rats (Corley et al., 2005; Pottenger et al., 2001).

Excretion:

Based on the physicochemical characteristics of ethylene carbonate, excretion via urine is expected, as the substance is relatively small and water soluble. Hanley et al. (1989) conducted a toxicokinetic study using ethylene carbonate, and demonstrated that ethylene carbonate is primarily excreted via exhalation as carbon dioxide (57%), to a lower amount via the urine (27%) and only marginally via feces (2%).