Toxicokinetics and Metabolism of N-[c]methylpyrrolidone in Male Sprague-dawley Rats. a Saturable Nmp Elimination Process

This study evaluated the toxicokinetics of N-[C]methylpyrrolidone ([C]NMP) after intravenous administration (0.1, 1, 10, 100, and 500 mg/kg, in saline solution) or topical application (20 and 40 l/cm; 10 cm, neat) in haired male Sprague-Dawley rats. Whatever the dose, unchanged NMP was intensively distributed into the body with a volume of distribution of 69% of body weight. After this phase, unchanged NMP declined almost linearly with time for 3 to 4 h after administration and then followed a mono-exponential function (t1⁄2 0.8 h) for the three lowest doses. The maximal plasma level of 5-hydroxy-N-methylpyrrolidone (5-HNMP), the main metabolite, was reached 4 to 6 h later for the three lowest doses and 8 to 24 h later for the highest doses. These findings indicate that the elimination of NMP is governed by a saturable metabolism process. The Michaelis-Menten parameters estimated from plasma levels of unchanged NMP were 2 mM and 3.8 mg/h, respectively. Between 4 and 10% of the administered doses were excreted in the urine as unchanged NMP. Urinary clearance of NMP (0.03 to 0.07 ml/min) indicates intensive tubular reabsorption. 5-HNMP was the main urinary metabolite and accounted for 42 to 55% of the administered doses. Its maximal urinary excretion occurred between 4 and 6 h after administration of the three lowest doses and between 8 and 24 h for the two highest doses. Urinary clearance (0.9 to 1.3 ml/min) was compatible with renal elimination by simple glomerular filtration. N-Methyl-2-pyrrolidone (NMP) is a widely and increasingly used solvent. It dissolves most monomers and polymers and catalyzes many polymerization reactions. One of its main uses is in the petrochemical industry to extract aromatic oils. It is also used in the microelectronics fabrication industry to manufacture electronic capacitors and batteries. It is a solvent and cosolvent in pharmaceuticals, cosmetics, insecticides, herbicides, or in paint preparations. Finally, NMP is increasingly being used to remove graffiti (Akesson, 1994). A recent study of NMP use in the microelectronics industry indicates that severe eye irritation and headaches can be expected at concentrations as low as 0.7 ppm, even for a short period of exposure (30 min) (Beaulieu and Schmerber, 1991). After two days of working with NMP in a electrotechnical company, 10 of the 12 workers involved displayed acute irritant contact dermatitis of the hands (Leira