One-month inhalation toxicity study of tulobuterol hydrochloride in rats and dogs

Tulobuterol hydrochloride (HCl) has beta 2-adrenergic agonist activity and is under development for use in the treatment of chronic obstructive lung disease. The purpose of this study was to determine the toxicity of inhaled tulobuterol HCl in rats and dogs. Rats were whole-body exposed to aerosol gravimetric concentrations of 0, 0.03, 0.22, or 1.1 mg/liter of tulobuterol HCl, 60 min/day for 28 days. Dogs were exposed (via insufflation) to estimated daily doses of 0, 0.2, 1.0, or 6.0 mg/kg for an equal period. Plasma levels of tulobuterol were determined following exposure on Days 1, 8, and 28 using a high-pressure liquid chromatographic method developed for this study. Results indicated that plasma tulobuterol levels were highly correlated with tulobuterol doses (p less than 0.001 for rats and dogs). No dose-related changes in body weight food consumption, hematological, or serum chemistry parameters were observed in either species. Anterior nasal cavity lesions were observed by light microscopy in rats exposed to 0.22 and 1.1 mg/liter tulobuterol HCl at an incidence of 14 and 93%, respectively. These lesions involved the nasal septum, turbinates, and/or the dorsolateral wall of the nasal cavity and consisted of suppurative rhinitis and necrosis. The corresponding mean plasma tulobuterol levels on Day 28 in mid- and high-dose rats were approximately 1000 and 15,000 ng/ml. Nasal lesions were not observed in rats allowed to recover for 2 weeks. No gross or microscopic lesions were detected in lungs or other tissues of either species.(ABSTRACT TRUNCATED AT 250 WORDS)