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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Mode of action of the chemical, toxicokinetics and metabolism

Limited toxicokinetic and metabolism data are available for GMA. The metabolism of glycidyl methacrylate in mammals is hypothesized to proceed by at least two different and competing enzyme systems, epoxide hydratase and non-specific carboxylesterases. Metabolism of GMA by carboxylesterase would result in formation of glycidol and methacrylic acid as metabolites, while initial metabolism by epoxide hydrolase would result in the formation of glycerol methacrylate. The relative speed at which the two competing metabolic reactions occur in different tissues and species is likely to be important for understanding the toxicity of glycidyl methacrylate.

 

Species differences in the activity of these enzymes suggest that the carboxylesterase route of metabolism may predominate in the nasal tissue of rabbits (yielding glycidol and methacrylic acid) whereas the epoxide hydratase route would likely predominate in rats and humans (producing glycerol methacrylate, then glycerol and methacrylic acid by carboxylesterase).(Bogdanffy et al.: 1987, Dahl et al.: 1987, Glatt et al.: 1984, Mattes and Mattes: 1992, Pacifici et al.: 1981).

 

Toxicokinetics of glycidyl methacrylate were investigated in rabbits. After an intravenous injection at 200 mg/kg, over 95 % of the parent compound disappeared from the blood within 10 minutes according to a two-compartment open model. Following a subcutaneous injection at 800 mg/kg, the toxicokinetics appeared to fit a first-order absorption one-compartment open model. This chemical was metabolized by incubation with whole blood, plasma, erythrocyte suspension, and homogenates of various tissues. The subcutaneous co-administration of tri-o-cresyl-phosphate (a carboxylesterase inhibitor) with this chemical resulted in about a ten-fold increase in the maximum blood concentrations, compared to those of animals dosed with this chemical alone. (Shi Tao et al.: 1988). This finding suggests a key role of carboxylesterase in glycidyl methacrylate metabolism and although metabolites were not specifically measured, could implicate glycidol as that metabolite.

More definitive work on the metabolism of glycidyl methacrylate (GMA) was studied by Domoradzki et al. (2004)in vitro using liver homogenate and nasal epithelial tissues from humans, rats and rabbits. Radiolabeled GMA [14C 1,3- glycidyl] was used in this study and was 92% radio chemically pure. In vitro incubations of14C GMA with tissue preparations from human, rat and rabbit resulted in the formation of only one metabolite. This metabolite was tentatively identified as glycidol based on retention time match with14C-glycidol. At an initial starting concentration of GMA at 2 mM, half-lives of GMA hydrolysis were faster in incubations with rat and rabbit tissue. Although the biotransformation was faster in rats and rabbits as compared to humans (completed within 30 minutes versus 2 hours), under all circumstances only one metabolite appeared which was tentatively identified as glycidol (EINECS 209 -128 -3).

 

Results indicate that glycidyl methacrylate is rapidly metabolized in vivo in rabbits as measured by disappearance of parent material (95% of intravenous administered dose of 200 mg/kg eliminated within 10 minutes). Maximum blood levels of GMA were increased by 10 fold in rabbits co-administered a carboxylesterase inhibitor indicating that glycidyl methacrylate was likely metabolized by carboxylesterase to glycidol and methacrylic acid. Domoradzki observed similar findings in rat and rabbit liver and respiratory tract epithelium cell fractions in vitro. Gycidol was identified as the metabolite of glycidyl methacrylate in this study.

Metabolism of GMA to glycidol has ramifications for hazard identification. Glycidol has a harmonised classification according to REACH and CLP as carcinogenic (category 1B), germ cell mutagenic (category 2) and toxic to reproduction (category 1B).