Search

The carcinogenic potential of muraglitazar, a dual human peroxisome proliferator-activated receptor alpha/gamma agonist, was evaluated in 2-year studies in mice (1, 5, 20, and 40 mg/kg) and rats (1, 5, 30, and 50 mg/kg). Benign gallbladder adenomas occurred at low incidences in male mice at 20 and 40 mg/kg (area under the curve [AUC] exposures > or = 62 times human exposure at 5 mg/day) and were considered drug related due to an increased incidence of gallbladder mucosal hyperplasia at these doses. There was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder in male rats at 5, 30, and 50 mg/kg (AUC exposures > or = 8 times human exposure at 5 mg/day). At 30 and 50 mg/kg, the urinary bladder tumors were accompanied by evidence of increased urine solids. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Incidences of subcutaneous liposarcoma in male rats and subcutaneous lipoma in female rats were increased at 50 mg/kg (AUC exposures > or = 48 times human exposure at 5 mg/day) and attributed, in part, to persistent pharmacologic stimulation of preadipocytes. Toxicologically relevant nonneoplastic changes in target tissues included thinning of cortical bone in mice and hyperplastic and metaplastic adipocyte changes in mice and rats. Considering that muraglitazar is nongenotoxic, the observed tumorigenic effects in mice and rats have no established clinical relevance since they occurred at either clinically nonrelevant exposures (gallbladder and adipose tumors) or by a species-specific mechanism (urinary bladder tumors).

The inhalation toxicity of 25-, 100-, and 250-ppm morpholine was investigated by 6 hr/day, 5 day/week exposures to Sprague-Dawley rats for 13 weeks. Irritant effects of morpholine exposures were evident mostly in the high exposure group; a reddish discharge was observed around the nose and mouth in the 250-ppm group rats after the first week; salivation was also observed. Ten rats/sex/dose level were sacrificed after 7 weeks. The high-level (250-ppm) exposure resulted in focal erosion and focal squamous metaplasia of the maxilloturbinates; effects were observed in 6 10 male rats and 2 10 female rats. There was also a sporadic increase of secretions in the Harderian gland sections. Almost all high-level rats sacrificed after 13 weeks demonstrated comparable effects; the lesions, which were increased in incidence and severity, involved the nasal septum and anterior nasal cavities in addition to the nasoturbinates and maxilloturbinates. Lesions of chronic murine pneumonia were increased in severity in the 250-ppm group. The only compound-related histomorphologic alterations observed in the 100-ppm group consisted of focal necrosis and necrotic cell debris in the nasal cavity of two female rats at terminal sacrifice. No exposure related effects were observed in the 25-ppm group. No significant compound-related effects on body weight, clinical chemistry, hematology, or organ weight data were observed.