Abstract: OBJECTIVE: To evaluate inhalation toxicity and safety of impurities CFC115 and HFC1243zf in the pharmaceutical HFA-134a as propellant in pharmaceutical metered-dose inhalers. METHODS: Cytotoxicity assay, Reverse mutation assay, acute inhalation toxicity, 7-day repeat dose inhalation irritation study,21-day repeat dose inhalation toxicity study and active systemic anaphylaxis of the mixture of CFC115 and HFC1243zf (7:3,V/V) were tested to provide a basis for HFA 134a to control the impurity limit of CFC115 and HFC1243zf. RESULTS: Result from acute inhalation studies demonstrated that the 4-hour LC₅₀ value was higher than 3 115 g/m³ for CFC115 and 832 g/m³ for HFC1243zf. Results from 7-day repeat dose inhalation irritation,active systemic anaphylaxis,Ames and cytotoxicity studies demonstrated that the mixture of CFC115 and HFC1243zf was not irritative, allergenic, mutagenic nor cytotoxic. 21-day repeat dose inhalation toxicity study were exposed, nose-only, to the mixture of CFC115 and HFC1243zf at levels of 3 205 g/m³ for CFC115 and 856 g/m³ for HFC1243zf 2 h/d,compared with the control group. Among these exposed rats,food intakes were decreased,body weight increased slowly. Values of Bas and Mon%,ALT, AST,ALP,T-BIL and UREA,and the urinary nitrite,ketone,PRO and LEU were mostly increased (P<0.05 or P<0.01). Brain coefficient values increased and ovarian wet weight values decreased. Histopathological changes of focal or multifocal endocardial necrosis and monocyte infiltration in 5 SD rats which had a treatment-related adverse effect. In addition,the lung wet weight and coefficient values of male rats decreased (P<0.01). CONCLUSION: In in vitro or short-term animal tests,the mixed gas of CFC115 and HFC1243zf showed no safety risk under high concentration of exposure or inhalation exposure. Long-term repeated high-concentration inhalation exposures showed a variety of toxic target organ effects in rats. However,these toxic concentrations were well above the clinical maximum exposure.

Key words: aerosol, propellant, HFA-134a, CFC115, HFC1243zf, inhalation toxicity