Comparative Toxicity and Metabolism of Tetrachlorobenzene Isomers

Abstract

LD50 values for 1,2,3,4-, 1,2,4,5- and 1,2,3,5-tetrachloro- benzene (TCB) were found to be 1470, 3105 and 2297 mg·kg^-1, respectively, in male rats. In females the LD50 values were found to be 1167 and 1727 mg·kg^-1 for 1,2,3,4- and 1,2,3,5-TCB, respectively. Clinical signs of toxicity included depression, flaccid muscle tone, prostration, piloerection, loose stool, hypothermia, dacryorrhea, coma and death. In a subacute study, rats were fed diets containing 0, 0.5, 5.0, 50 or 500 ppm 1,2,3,4-, 1,2,4,5- or 1,2,3,5-TCB for 28 days. At 500 ppm 1,2,4,5-, but not 1,2,3,4- or 1,2,3,5-TCB, caused a significant increase in the liver weight, and serum cholesterol of male and female rats. Hepatic microsomal aniline hydroxylase was induced by 500 ppm 1,2,4,5-TCB. Hepatic microsomal aminopyrine demethylase activity was increased by the administration of this compound at 50 ppm and higher in males and at 500 ppm in the females. Rats fed 1,2,3,4- and 1,2,3,5-TCB at 500 ppm also showed a significant increase in aminopyrine demethylase activity. Moderate to severe histological changes were found in the liver, thyroid, kidney and lungs of rats fed 500 ppm 1,2,4,5-TCB. Histological changes in the tissues produced by the administration of the 1,2,3,4- and 1,2,3,5- isomer were mild even at the highest dose levels. Similar results were observed in rats fed TCB isomers for 90 days. However, histopathological changes in the kidney of rats fed 1,2,4,5-TCB were more severe than those of the subacute study. Tissue residue data showed that 1,2,4,5-TCB accumulated in a dose-dependent manner and at much higher concentrations than the other two isomers. In a separate study adult male rats were given orally single doses of ¹⁴C-l, 2,3,4-, or 1,2,4,5-TCB at 10 mg·kg^-1 body weight, and were housed in individual metabolism cages to collect urine and feces for radio- assay. The fat, skin and liver of rats dosed with 1,2,4,5-TCB contained the highest levels of radioactivity, whereas little ¹⁴C was detected in 1,2,3,4- and 1,2,3,5-TCB treated animals. For 1,2,3,4- and 1,2,3,5-TCB, approximately 46% to 51% of the administered compound were excreted in urine and feces within 48 hours after administration. During the same period only 8% of the administered 1,2,4,5- Tetrachlorobenzene was excreted. Analysis of urine indicated that the tetrachlorobenzenes were biotransformed to a number of polar metabolites. The metabolites for each of the three TCB’s in decreasing order of quantities were as follows; for 1,2,3,4-TCB: 2,3,4,5- and tetrachlorophenol and a trace of tetrachlorothiophenol and 2, 3,4-trichlorophenol; for 1,2,3,5-TCB: 2, 3, 4, 6-tetrachlorophenol, isomeric mercaptotrichlorophenols and a trichlorophenol; for 1,2,4,5-TCB: 2,3,5,6-tetrachlorophenol, tetrachloroquinol and a trichlorophenol. Data indicate that 1,2,4,5-TCB was much more toxic than the other two TCB isomers, and that the differences in toxicity were associated with a higher degree of bioaccumulation and slower metabolic degradation of this compound.