Acute toxicity study of 7432-S and 7432-S-trans in rats and dogs

Abstract

We studied the acute toxicity of 7432-S, an oral cephalosporin antibiotic, by giving the compound to Sprague-Dawley rats and to beagle dogs by a single oral administration. We also studied the acute toxicity of sodium salts of trans-isomer-rich 7432-S (7432-Strans·Na) and of 7432-S (7432-S·Na) by given orally and intravenously. 1. Oral administration of 10g/kg of 7432-S, which is the technically applicable maximum dose, caused slight inactivity, weakness, loose stools, diarrhea and abdominal distention due to cecal dilatation, but no death attributable to intoxication occurred in rats. There were no findings suggesting visceral disorder and 7432-S was classified as “practically non-toxic” 2. As with 7432-S, no death occurred after oral administration of 7432-S-trans·Na to rats at a dose of 10 g/kg, and the rats recovered from loose stools or diarrhea quickly. The LD50 value of 7432-S·Na after oral administration to rats was about 10 g/kg for males and 8.3g/kg for females, indicating very low toxicity in both sexes. 3. The findings after intravenous administration of 7432-S-trans·Na and 7432-S·Na to rats included toxic signs considered attributable to acute circulatory disorder and shock such as tonic convulsion immediately after administration, bleeding in various organs and tissues, increased hydrothorax and ascites, pale kidney accompanying tubular dilatation histopathologically, and centrilobular hepatocyte necrosis. Administration of a large volume of hypertonic solution was considered mainly responsible for these changes. Death occurred within 15 minutes after dosing, and the LD50 value for 7432-S-trans·Na was 4.0g/kg for males and 4.5g/kg for females, and that for 7432-S·Na was 3.3 g/kg for males and 3.6 g/kg for females. 4. 7432-S was administered orally to male and female beagle dogs at doses of 2.5 or 5.0g/kg. With the exception of vomiting and diarrhea within 24 hours after dosing, there were no changes considered attributable to the administration of this compound in other parameters. These results indicate that oral administration of 7432-S dose not induce any definite toxicity in beagle dogs and the maximum tolerable dose is assumed to be 5.0 g/kg or more. © 1989, Japanese Society of Chemotherapy. All rights reserved.