ABSORPTION AND DISPOSITION KINETICS OF 3,3',4,4'-TETRACHLOROAZOXYBENZENE IN THE MALE FISCHER-344 RAT

3,3',4,4'-Tetrachloroazoxybenzene (TCAOB) is a structural analog of 2, 3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It is formed as a byproduct during the synthesis of industrial products such as herbicides. TCAOB is a ligand for the Ah receptor and, at much higher doses, exhibits to xicities similar to TCDD, Although the reduced in vivo toxicity of TCA OB probably reflects differences in disposition, this study characteri zed its absorption and disposition kinetics, Male Fischer 344 rats wer e administered [C-14]TCAOB (3.4 or 34 mg/kg po, 3.4 mg/kg iv), and the excretion of the radiolabel was monitored over 96 hr, After the low a nd high dose, 35% and 30% of the [C-14]TCAOB were eliminated in the ur ine, with 55% and 54% eliminated in the feces. At 96 hr, the adipose t issue:blood ratios of [C-14]TCAOB equivalents were 8 and 26 for the lo w and high doses, respectively, After the intravenous dose of TCAOB, t he adipose tissue:blood ratio was 21 at 96 hr. Other tissue:blood rati os were of little significance (0.06-3.2). Pharmacokinetic parameters indicate that the parent molecule is cleared from blood with an averag e half-life of 7 hr and an average clearance of 11 ml/min . kg. Absolu te bioavailability was calculated to be similar to 9%. Urine contained a variety of dichlorolaniline conjugates, which support the importanc e of azo reduction in the disposition of TCAOB, When compared with TCD D, the absorption of TCAOB is greatly reduced and the elimination of m etabolites greatly enhanced, Therefore, at equal molar oral doses, TCA OB would express lower levels of Ah receptor-mediated toxicity than th ose defined for TCDD.