Distribution, elimination, and test for carcinogenicity of 2,6‐dinitrotoluene after intraperitoneal and oral administration to strain a mice

Abstract

After intraperitoneal (ip) and oral (po) administration of 2,6‐dinitrotoluene (2,6‐DNT), the distribution, elimination, and lung tumor response were determined in strain A mice. In a 30‐wk bioassay and at total ip doses of 600, 1500, or 3000 mg/kg, or total po doses of 1200, 3000, or 6000 mg/kg, 2,6‐DNT did not produce an increase in lung adenomas when compared to vehicle‐treated controls. The urine was the major route of elimination of both ip and po administered ³ H‐labeled 2,6‐DNT, with 87.6, 55.2, and 49.1% of ip doses of 1, 10, and 100 mg/kg, respectively, excreted within 4 h. The corresponding amounts excreted after po administration were 33.6, 25.2, and 24.3%, which increased to 53.7, 53.5, and 48.6% after 8 h. The distribution of 2,6‐DNT in various tissues (blood, liver, kidneys, lungs, small and large intestine) showed no evidence for preferential uptake or retention at any of the ip or po doses. Terminal half‐lives of radioactive material in the liver were 1.11, 0.95, and 1.16 h after ip doses of 1, 10, and 100 mg/kg, respectively. At all ip doses (1, 10, and 100 mg/kg), rapid and extensive metabolism of ³ H‐labeled 2,6‐DNT was observed, as judged by the low amounts (<2% of the total ³ H/tissue) of unchanged ³ H‐labeled 2,6‐DNT that could be reisolated from blood, liver, small intestine, or lungs at 2 h after administration. The extent of ³ H‐labeled 2,6‐DNT metabolism by these tissues after po administration was similar, except for the relatively high amounts of unchanged ³ H‐labeled 2,6‐DNT (approximately 50% of the total ³ H/tissue between 1 and 8 h after 100 mg/kg) present in the small intestine. At these times, negligible (<2%) unchanged ³ H‐labeled 2,6‐DNT was present in the large intestine. It is concluded that ip or po administered 2,6‐DNT is not carcinogenic in the strain A mouse lung‐tumor bioassay. Excretion in the urine is the major mode of elimination after either ip or po administration, but is slower after po than after ip dosing. It is likely that the liver and small intestine are major sites of 2,6‐DNT metabolism, and it is possible that po administered 2,6‐DNT is also metabolized by the microflora of the large intestine.