Human volunteer study on the influence of exposure duration and dilution of dermally applied N-methyl-2-pyrrolidone (NMP) on the urinary elimination of NMP metabolites

Abstract

N-Methyl-2-pyrrolidone (NMP) is a versatile solvent used in various industrial processes and applications. Apart from its mildly irritating effects on the eyes, the mucous membranes and the skin, NMP has revealed prenatal toxicity in animal experiments after the oral administration of high doses. The dermal absorption of NMP and the urinary elimination of its main metabolites were investigated within an experimental exposure study. Four male volunteers were exposed to liquid NMP under occlusive conditions on the back of one hand with varying exposure times and solvent concentrations. Urine was collected before, during and after the exposure and analysed for the main NMP metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI). The urinary concentration of the metabolites upon exposure to undiluted NMP for 2 h increased rapidly with 5-HNMP reaching a maximum at 4-5 h and 2-HMSI after 26-29 h. The application of aqueous NMP solutions resulted in a delay of the peak time for 5-HNMP of approximately 6 h as compared with the undiluted solvent. An average dermal absorption of 5.4+/-1.5 mg NMP cm(-2) h(-1) was calculated for a 2 h exposure to undiluted NMP (6.5+/-2.0 mg NMP cm(-2) h(-1) for a 30 min exposure). Aqueous dilution of NMP to 50% was followed by a decrease of the absorption to 0.9+/-0.5 mg NMP cm(-2) h(-1). NMP metabolite concentrations in the range of the detection limits were found only in isolated urine samples after exposure to 10% NMP in aqueous dilution. NMP is rapidly absorbed across the skin and the dermal route may contribute significantly to the uptake of the solvent. Therefore, a biomonitoring of NMP exposed workers is essential for occupational-medical surveillance. Both urinary metabolites reflect the internal dose after a dermal absorption of NMP and thus qualify as suitable biomarkers for NMP exposure.