One-Month Inhalation Toxicity Study of Tulobuterol Hydrochloride in Rats and Dogs

Tulobuterol hydrochloride (HCl) has ß₂-adrenergicagonist activity and is under development for use in the treatmentof chronic obstructive lung disease. The purpose of this studywas to determine the toxicity of inhaled tulobuterol HCl inrats and dogs. Rats were whole-body exposed to aerosol gravimetricconcentrations of 0, 0.03, 0.22, or 1.1 mg/ liter of tulobuterolHCl, 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 anequal period. Plasma levels of tulobuterol were determined followingexposure on Days 1, 8, and 28 using a high-pressure liquid chromato-graphicmethod developed for this study. Results indicated that plasmatulobuterol levels were highly correlated with tulobuterol doses(p < 0.0001 for rats and dogs). No dose-related changes inbody weight food consumption, hematological, or serum chemistryparameters were observed in either species. Anterior nasal cavitylesions were observed by light microscopy in rats exposed to0.22 and 1.1 mg/liter tulobuterol HCl at an incidence of 14and 93%, respectively. These lesions involved the nasal septum,turbinates, and/or the dorsolateral wall of the nasal cavityand consisted of suppurative rhinitis and necrosis. The correspondingmean plasma tulobuterol levels on Day 28 in mid- and high-doserats were approximately 1000 and 15,000 ng/ml. Nasal lesionswere not observed in rats allowed to recover for 2 weeks. Nogross or microscopic lesions were detected in lungs or othertissues of either species. These results indicate that the insufflationof high doses of tulobuterol HCl aerosol for 1 month was generallywithout toxicity in dogs and that the local nasal ussue injuryobserved in rats exposed to high concentrations of aerosolizedtulobuterol HCl was reversible.