Dimethyl itaconate

Endpoint summary

Description of key information

DMI will be readily absorbed over biological membranes by passive diffusion. This absorption may be enhanced by irritating properties of DMI and altered by ester hydrolysis. DMI will be distributed uniformly throughout the body water in the extracellular compartment. DMI distribution may be limited by skin protein binding. In addition of ester hydrolysis, DMI may induce phase 2 metabolic enzymes. Excretion via urine is the most likely route of excretion for DMI and its metabolites.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Absorption

It is expected that slight lipophilic Dimethyl itaconate (DMI) with a partition coefficient Log P of 0.9 (25 °C), a low molecular weight (158.2 g/mol), no ionisable groups and a high water solubility of 35 g/L (20° C) will be readily absorbed over biological membranes first of all by passive diffusion (alveolar, capillary membranes, etc.). In addition, DMI may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Absorption of DMI may be enhanced as well because of irritating properties (CLP, Category 2) leading to damage to cell membranes. In skin sensitization study (LLNA), DMI was identified as potential skin sensitizer (CLP, Category 1, sub-category 1B); therefore some dermal uptake is possible. However, pH independent DMI for gastrointestinal tract absorption may undergo ester hydrolysis by carboxylesterases to form ionisable (di)carboxylic acid (Smeets and Kieboom, 1992) and so alter the oral bioavailability.

Liquid DMI with the vapour pressure of 4.05 Pa (at 20 °C) and the boiling point of 208 °C (at 1 atm) is considered as a low volatile substance (ECHA Chapter R.14) and has a low potential for intake by inhalation in vapour form. Liquid aerosol building of DMI is not expected, but in the worst case, considering its Log P of 0.9 (25 °C), the compound has a potential to be absorbed directly across the respiratory tract epithelium.

Distribution

Regarding physico-chemical properties of DMI and its hydrolysed forms, it may be expected that the compound and its metabolites will be distributed uniformly throughout the body water in the extracellular compartment with relatively small volume of distribution (Vd). From skin sensitization study (LLNA), where DMI was identified as potential skin sensitizer (CLP, Category 1, sub-category 1B), it may be expected that DMI will bind to skin proteins and limit the amount of the substance available for distribution.

Metabolism

DMI is a relatively potent inducer of phase 2 metabolic enzymes (Talalay et al., 1988) and is susceptible to ester hydrolysis by carboxylesterases (Smeets and Kieboom, 1992). The later reaction is expected to increase the water solubility of the substance and thereby enhances excretion (via the urine).

Excretion

Since DMI is a high water soluble substance with low molecular weight and a probability to be hydrolysed into (di)carboxylic acid (which is almost ionised at the pH of urine), excretion via urine is expected rather than excretion via faeces. As unchanged DMI may be present in blood plasma, excretion via breast milk could be minor but likely route.

References:

Smeets JWH, Kieboom APG (1992) Enzymatic enantioselective ester hydrolysis by carboxylesterase NP. Recl. Tray. Chim. Pays-Bas 38: 490-495.

Talalay P, DeLong M and Prochaska HJ (1988) Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc. Natl. Acad. Sci. USA, 85: 8261-8265.