Chronic toxicity/carcinogenesis study of temazepam in mice and rats

The benzodiazepine temazepam was given to Charles River CD rats for 2 years in the diet at dosages of 10, 40, and 160 mg/kg day. An 18-month study was performed in Charles River CD-1 mice via dietary admixture at dosages of 10, 80, and 160 mg/kg/day. Mean body weights were significantly decreased for high dose rats of both sexes from Treatment Week 39 until termination. All drug treated male groups had a higher rate of mortality when compared to the male control groups, primarily due to deaths occurring between 19 to 24 months. Compound-related hepatic lipidosis accompanied by an increase in liver weights was observed at the high dose level in the 6- and 12-month and terminal sacrifices, as well as the middle dose level at the 12-month interim sacrifice. No evidence was found of compound induced carcinogenicity at any time period. Mortality for male mice was significantly higher in the two higher dose groups; this resulted from bite wounds associated with a drug-related increase in fighting behavior. An isolated finding of borderline statistical significance (p = 0.0556) was noted for hepatocellular adenomas in high dose female mice (4/100) at the 18-month terminal sacrifice. This incidence is well within the reported historical control range (0-14%). Minimal hepatoproliferative (hyperplastic nodules) and vascular effects (telangiectasis) were seen in the high dose male and female mice at the 18-month terminal sacrifice. Thus, these results were similar to those previously reported for oxazepam although meaningful effects on neoplasia did not occur with temazepam. Unlike in man, temazepam is primarily metabolized to oxazepam in the mouse and thus these results are not adverse with regard to human safety evaluation.