Toxicokinetics and metabolism of pseudocumene (1,2,4-trimethylbenzene) after inhalation exposure in rats.

The objective of this study was to evaluate the toxicokinetics and metabolism of pseudocumene after inhalation exposure. Male Wistar rats were exposed to pseudocumene vapors at nominal concentrations of 25,100 or 250 ppm in the dynamic inhalation chambers for 6 h. Blood samples were collected during (between 1st and 6th h) and after exposure (betwen 6th min and 6th h). Blood concentrations of pseudocumene were estimated by gas chromatography using the headspace technique. During a six-hour exposure, the concentration of pseudocumene in blood increased rapidly within the first 2 h reaching then a plateau. The elimination of pseudocumene from blood followed an open two-compartment model. Urine samples were collected from the exposed animals, and metabolites were analyzed by gas chromatography with a flame ionization detector. Three metabolites were measured in the rat urine after hydrolysis: 3,4-dimethylbenzoic acid (3,4-DMBA), 2,4-dimethylbenzoic acid (2,4-DMBA) and 2,5-dimethylbenzoic acid (2,5-DMBA). A significant linear correlation was found between the level of exposure and the concentration of dimethylbenzoic acids. The enzyme kinetics of pseudocumene biotransformation was calculated by Lineweaver-Burk equation. Metabolic constants, Km (mg/l) and Vmax (mg/h/kg), the parameters for pseudocumene biotransformation by rats were estimated (3,4-DMBA - Km = 28, Vmax = 96; 2,4-DMBA - Km = 7, Vmax = 25; 2,5-DMBA - Km = 7, Vmax = 23).