Urinary excretion of
N-nitrosodibutylamine (NDBA) and of two omega-fluorinated analogues [N-nitroso-4,4,4-trifluorobutyl-butylamine, NDBA-F3; N-nitroso-bis(4,4,4-trifluorobutyl)-amine, NDBA-F6] was studied in male Sprague-Dawley (SD) rats. After oral application of equimolar doses (0.44 and 1.32 mmol/kg body wt.) urines were collected (48 h) and analyzed for parent compounds, and for
nitrosamine metabolites by gas chromatography/Thermal Energy Analyzer (GC/
TEA) and gas chromatography/mass spectrometry (GC/MS). After administration of NDBA the known major metabolites N-nitroso-3- hydroxybutylbutylamine (3-OH-NDBA) and N-nitroso-3-carboxypropylbutylamine (
BCPN) were excreted in urine. After application of the omega-fluorinated analogue NDBA-F6, however, urinary and biliary
nitrosamine metabolites were detected only in trace amounts. This finding demonstrates a strong inhibitory effect of
fluorine substitution on oxidations at omega, (omega-1) and beta-positions. Confirmation of this inhibitory effect of omega-
fluorine substitution is given from the excretion profiles of NDBA-F3 which shows metabolic oxidations only at the nonfluorinated chain: N-nitroso-3-hydroxybutyl-4,4,4-trifluorobutylamine (3-OH-NDBA-F3) and N-nitroso-3-carboxypropyl-4,4,4-trifluorobutylamine (BCPN-F3) were excreted as main metabolites. Our results on metabolism together with the available data on carcinogenicity of the compounds in the rat strongly support the hypothesis that omega-oxidation of one butyl-chain is a prerequisite for the induction of urinary bladder
tumors with NDBA. For the induction of liver
tumors, alpha-C-hydroxylation appears to be the crucial event.