Biotransformation and toxicokinetics of musk xylene in humans

Musk xylene (1-tert-butyl-3,5-dimethyl-2,4,6-trinitrobenzene, MX) is widely used as a fragrance ingredient in detergents and toiletries and is an environmental contaminant. High concentrations of MX have been found in fish, and humans are constantly exposed to MX as a result of its stability in the environment. We investigated the biotransformation and toxicokinetics of MX in humans. A single dose of 0.3 mg/kg body wt of 15N-labeled MX (15N-MX) was given to six volunteers (three male and three female) by the oral route and to another six volunteers (three males and three females) by the dermal route. Urine was collected for 96 h after exposure. Blood samples were taken at intervals for up to 140 days after administration. The metabolite 1-tert-butyl-3,5-dimethyl-15N-4-amino-2,6-dinitrobenzene in urine and 15N-MX in plasma were quantified by gas chromatography/electron-capture mass spectrometry (GC-MS/NCI). Peak plasma concentrations of 15N-MX after oral administration were 36-262 and 1.6-5.5 ng/ml plasma after dermal administration. The toxicokinetics of 15N-MX in plasma can be described by a two-compartment kinetic model with an initial rapid decrease, due to the distribution from the blood into a second compartment (likely fat tissue) and a terminal elimination phase with an average half-life of 70 days for both routes of administration. The amount of 1-tert-butyl-3,5-dimethyl-15N-4-amino-2,6-dinitrobenzene (15N-4-A-MX) in recovered urine represented 0.1-0.5% of the oral applied dose of 15N-MX, respectively, 0.02-0.16% of dermal dose. After a short time of invasion the concentrations of 15N-4-A-MX in urine reached a maximum 18-24 h after administration. The further elimination of the metabolite occurred by first-order kinetics with an average elimination half-life of 11.8 h. After the single oral or dermal dose of 15N-MX, 15N-4-A-MX was not detected in hemoglobin. However, hemoglobin samples contained 1-tert-butyl-3, 5-dimethyl-4-amino-2,6-dinitrobenzene (4-A-MX) (11.4-18.9 fmol/mg Hb), likely derived from chronic environmental exposures.