Toxicological evaluations of the benzodiazepine doxefazepam.
1-(2-Hydroxyethyl)-3-hydroxyl-7-chloro-1,3-dihydro-5-(O-fluorophenyl)-2H - 1,4-benzodiazepin-2-one (doxefazepam, SAS 643, Doxans) was investigated in a series of toxicological studies. Oral LD50 values were greater than 2000 mg/kg in mice, rats and dogs, while endoperitoneal LD50 values were 746 and 544 mg/kg in the mice and rats, respectively, and greater than 1000 mg/kg in the dogs. Subacute and chronic studies in rats and dogs evidenced a transient ataxia after administration of the test compound, which was dose-dependent in the subacute experiment, and occurred only at the highest dose in the chronic studies. No pathological findings were registered at necropsy or in microscopic observations, except an increase of liver weight at the highest dosage in the chronic study in the rat. Doxefazepam did not exert any teratogenic effects in rats and rabbits. Moreover in rats it did not alter the reproductive performance. The mutagenic studies did not reveal any mutagenic potential. In the cancerogenicity study in rats doxefazepam did not show positive carcinogenic potential.
Bertoli
D
D
Research Division, Alfa Wassermann S.p.a., Bologna, Italy.
Borelli
G
G
Carazzone
M
M
D000818:Animals; D014151:Anti-Anxiety Agents / Q000633:toxicity*; D001569:Benzodiazepines; D002273:Carcinogens; D004285:Dogs; D005260:Female; D005298:Fertility / Q000187:drug effects; D005479:Flurazepam / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D051379:Mice; D009153:Mutagens; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013723:Teratogens
D014151:Anti-Anxiety Agents; D002273:Carcinogens; D009153:Mutagens; D013723:Teratogens; D001569:Benzodiazepines; C008020:doxefazepam; D005479:Flurazepam