4-hydroxymethyl-1,3-dioxolan-2-one

Endpoint summary

Description of key information

For glycerine carbonate, no experimental data are available on toxicokinetics (except data from an in vitro dermal absorption test of glycerine carbonate). Therefore, a qualitative assessment of the absorption, distribution/accumulation, metabolism and elimination is performed on the basis of the physico-chemical properties of the substance. Toxicological data on glycerine carbonate and the read-across substance glycerol are also used to support this assessment.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

0.3

Absorption rate - inhalation (%):

100

Additional information

Glycerine carbonate (CAS 931-40-8) is a liquid substance with a molecular weight (MW) of 118.088 g/mole. It is a very water-soluble substance (1000 g/L) with a low partition coefficient (log P: -1.39) and a low vapour pressure (0.93 Pa at 20°C). The boiling point is 239°C at 102.1 Pa.

Glycerine carbonate is a cyclic carbonate with two functional groups (carbonate ester ring and pendant hydroxyl group). The dissociation constant (pKa) was estimated by calculation to be 13.7.

 

Absorption

Oral/Gastro-intestinal (GI) absorption

Due to its high water solubility, it is expected that glycerine carbonate will readily dissolve into the gastrointestinal fluids and subsequently pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. The water-soluble liquid (1000 g/L) will readily dissolve into the gastrointestinal fluids. An oral absorption of 50% is expected.

 

It is generally thought that ionised substances do not readily diffuse across biological membranes. The intestine is where absorption after oral administration normally takes place. The pKa of glycerine carbonate (13.7) suggests that, at the stomach (assuming pH between 1.0 and 3.5), this substance will be predominantly in its ionised form. In the intestine, the acidity from the stomach will be progressively neutralised: the intraluminal pH is rapidly changed from highly acid in the stomach to about pH 6 in the small intestine and pH 7.4 in the terminal ileum. Although the substance will progressively appear under its non-ionised form, the substance will mainly remain under ionised form and therefore diffusion across membranes will be hampered.

In a dose-range-finding study, the test article was orally administrated to three groups of two rats (one male and one female per group) at dose levels of 500, 2500 and 5000 mg/kg (Mallory VT, 1993). No clinical signs were observed in any animal during this acute toxicity study. None of the animals died at the 500, 2500 or 5000 mg/kg dose levels. Based upon these results, a limit test was performed.

In the limit test, the test article was orally administrated to one group of ten rats (five males and five females), at a dose level of 5000 mg/kg. No clinical signs were observed in any animal during the study. There was an apparent increase in body weight for all animals. None of the animals died. No visible lesions were observed in any of the animals at terminal necroscopy.

Based on the results from the acute oral toxicity study in rats, the estimated acute oral LD50 (combined sexes) for glycerine carbonate was determined to be greater than 5000 mg/kg.

No data are available from repeated toxicity studies by oral administration with glycerine carbonate.

The oral absorption factor is set to 50%, based on the anticipated hampered diffusion of glycerine carbonate because of its high water solubility and moderate log P. In addition, the substance will mainly remain under ionised form in the GI tract. The results of the toxicity studies do not provide reasons to deviate from this proposed value.

 

Respiratory absorption

Given the boiling point of 239°C and the vapour pressure (Vp) of 0.93 Pa, glycerine carbonate is not considered a highly volatile substance (Vp > 25 KPa or boiling point < 50°C) and therefore it is unlikely that the substance is inhaled as a vapour at ambient temperature.

Once in the respiratory tract, glycerine carbonate would deposit on the walls of the airways. Deposited substances may be absorbed directly from the respiratory tract or, through the action of clearance mechanisms, may be transported out of the respiratory tract and swallowed. As glycerine carbonate is a hydrophilic substance, the second mechanisms is expected to be the predominant one, as the substance will be mainly retained by the mucus. After being swallowed, it is expected that the substance undergoes the oral/GI absorption process as described in the above section.

For the deposited material that has not been cleared, similar behaviour as for GI absorption is assumed. Although absorption directly across the respiratory tract epithelium by passive diffusion is favored in view of the low log P value and low MW of glycerine carbonate, the process will be hampered as it is generally thought that ionised substances do not readily diffuse across biological membranes. Indeed the ionised form of glycerine carbonate will be predominant assuming a pH=7.

There are no reliable data on acute or repeated inhalation exposure to glycerine carbonate.

Based on the above considerations and the absence of inhalation toxicity data, the inhalatory absorption factor is set to 100%, as a worst case assumption. It is proposed to use this factor for risk assessment purposes.

 

Dermal absorption

Ward (2002) measured the in vitro absorption of glycerine carbonate through pig epidermis following a method similar to OECD guideline 428 and in compliance with GLP requirements and concluded on the very slow dermal absorption of the test item.

Glycerine carbonate was applied undiluted to 400 µm thick dermatomed membranes at a rate of 10 µl/cm² and left unoccluded. After application of the test material, half the membranes were rinsed off after a 0.5h contact period, with the penetration of glycerine carbonate though the membrane being assessed throughout the entire 24h exposure period, while the rest of the membranes remained in continuous contact with the dose for the entire 24h.

The results obtained in this study indicate that the absorption of glycerine carbonate through dermatomed pig epidermis is extremely slow, when compared with the absorption rates of other penetrants measured through human skin using this in vitro technique.

 

Mean absorption of glycerine carbonate from experiment 1 (contact period 0.5h, exposure period 24) can be regarded as < 0.750 µg/cm²/h (<0.13% of the applied dose at 24h).

The proportions of the dose absorbed at 8, 12 and 24h were 0.14%, 0.14% and 0.28% in experiment 2 (contact period 24h, exposure period 24h), although glycerine carbonate absorption was not detectible for this experiment until 8h after application. The absorption rate between 8 -24h was 2.10 µg/cm²/h, with an average rate over the whole 24h period of 1.5 µg/cm²/h. A mean permeability coefficient (Kp) of 1.54 x 1E-06 was estimated for the 8 -24h period.

 

These data predict that the dermal absorption of glycerine carbonate from potential exposure would be minimal. Based on these data, 0.3% dermal absorption is selected for hazard assessment.

 

Distribution

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules, like glycerine carbonate, will diffuse through aqueous channels and pores.

The high water solubility and low molecular weight predict that the substance will distribute widely through the body after absorption.

Based on the moderate log Kow and the high water solubility, the substance will not likely distribute into cells through the membrane and hence the intracellular concentration is not expected to be higher than the extracellular concentration.

 

Accumulation

In view of the low log Kow and the high water solubility, glycerine carbonate is not expected to accumulate in the body.

 

Metabolism

Once absorbed, hydrolysis to glycerol is expected (Sonnati et al., 2013).

 

Excretion

Given the high water solubility and relatively low molecular weight, glycerine carbonate and glycerol will be mainly excreted via the urine.

 

References

 

ECHA guidance on IR&CSA, R.7c

 

Sonnati MO, Amigoni S, Taffin de Givenchy EP, Darmanin T, Choulet O, Guittard F (2013).Glycerol carbonate as a versatile building block for tomorrow : synthesis, reactivity, properties and applications. Green Chem. 15, 283