抛射剂四氟乙烷中杂质CFC115和HFC1243zf的吸入毒理安全性评价

Inhalation toxicity and safety of impurities CFC115 and HFC1243zf in the pharmaceutical HFA-134a

目的:对抛射剂四氟乙烷中杂质五氟氯乙烷(CFC115)和3,3,3-三氟丙烯(HFC1243zf)进行吸入毒性和安全性评价。方法:用CFC115和HFC1243zf混合气体(体积比为7∶3)作为受试样品进行体外空气暴露的小鼠成纤维细胞(L929)细胞毒性及Ames试验,SD大鼠口鼻暴露4 h的急性吸入毒性、7 d重复吸入局部刺激性、21 d重复吸入亚慢毒性试验和Hartley豚鼠全身主动过敏性试验,为控制四氟乙烷中CFC115和HFC1243zf杂质限度提供依据。结果:大鼠急性吸入毒性半数致死浓度(LC50)CFC115>3115 g/m^(3),HFC1243zf>832 g/m^(3);未见重复吸入局部刺激性;未见豚鼠全身致敏反应;无细胞毒性作用;Ames试验未见致突变作用。大鼠21 d重复吸入CFC115(3205 g/m^(3))和HFC1243zf(856 g/m^(3))混合气体后,与对照组相比,摄食量减少(P<0.05或P<0.01)、体质量增长缓慢(P<0.05),血液白细胞分类嗜碱性粒细胞(Bas)、单核细胞(Mon)百分数升高,血生化丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、尿素氮(UREA)、碱性磷酸酶(ALP)、总胆红素(TBil)平均值升高(P<0.05或P<0.01),尿液亚硝酸盐(NIT)、酮体(KET)、个别尿蛋白(PRO)和白细胞(LEU)平均值升高(P<0.05或P<0.01),脑系数升高和卵巢湿质量降低(P<0.05或P<0.01),组织病理学发现心内膜灶性或多灶性坏死、单核细胞浸润的改变,另外雄性大鼠肺脏湿质量和肺系数降低(P<0.01)。结论:CFC115和HFC1243zf混合气体的体外试验或短期动物试验在高浓度接触或吸入未见明显毒性,较长期反复高浓度吸入对大鼠存在多器官损伤,但产生毒性的浓度远高于临床最大暴露量。

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 CFC115and 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 LC50value was higher than 3115 g/m^(3)for CFC115 and 832 g/m^(3)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 of3205 g/m^(3)for CFC115 and 856 g/m^(3)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<0.05or P<0.01).Brain coefficient values increased and ovarian wet weight values decreased.Histopathologicalchanges of focal or multifocal endocardial necrosis and monocyte infiltration in 5 SD rats which had atreatment-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 HFC1243zfshowed no safety risk under high concentration of exposure or inhalation exposure.Long-term repeatedhigh-concentration inhalation exposures showed a variety of toxic target organ effects in rats.However,thesetoxic concentrations were well above the clinical maximum exposure.