DataSheet1_Pressurized metered-dose inhalers using next-generation propellant HFO-1234ze(E) deposit negligible amounts of trifluoracetic acid in the environment.docx

Pressurized metered-dose inhalers (pMDIs) deliver life-saving medications to patients with respiratory conditions and are the most used inhaler delivery device globally. pMDIs utilize a hydrofluoroalkane (HFA), also known as an F-gas, as a propellant to facilitate the delivery of medication into the lungs. Although HFAs have minimal impact on ozone depletion, their global warming potential (GWP) is more than 1,000 times higher than CO2, bringing them in scope of the F-Gas Regulation in the European Union (EU). The pharmaceutical industry is developing solutions, including a near-zero GWP “next-generation propellant,” HFO-1234ze(E). At the same time, the EU is also evaluating a restriction on per-and polyfluoroalkyl substances (PFAS) under the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation. Trifluoroacetic acid (TFA) is a persistent PFAS and a potential degradation product of HFO-1234ze(E). We quantified yield of TFA from HFO-1234ze(E) using a computational model under Europe-relevant atmospheric conditions. The modeling suggests that most HFO-1234ze(E) degrades into formyl fluoride within 20 days (≥85%) even at the highest examined altitude. These results suggest that TFA yield from HFO-1234ze(E) varies between 0%–4% under different atmospheric conditions. In 2022, France represented the highest numbers of pMDI units sold within the EU, assuming these pMDIs had HFO-1234ze(E) as propellant, we estimate an annual rainwater TFA deposition of ∼0.025 μg/L. These results demonstrate negligible formation of TFA as a degradation product of HFO-1234ze(E), further supporting its suitability as a non-persistent, non-bioaccumulative, and non-toxic future propellant for pMDI devices to safeguard access for patients to these essential medicines.

加压定量吸入器（pressurized metered-dose inhalers, pMDIs）可为呼吸系统疾病患者递送救命药物，是全球应用最为广泛的吸入给药装置。此类装置以氢氟烷烃（hydrofluoroalkane, HFA，又称F气体）作为抛射剂，实现药物向肺部的递送。尽管氢氟烷烃对臭氧层的破坏影响微乎其微，但其全球变暖潜能值（global warming potential, GWP）是二氧化碳的1000倍以上，因此被纳入欧盟（European Union, EU）的F气体监管范围。制药行业目前正在开发各类解决方案，其中包括全球变暖潜能值近乎为零的"下一代抛射剂"HFO-1234ze(E)。与此同时，欧盟也正依据《化学品注册、评估、授权和限制（Registration, Evaluation, Authorization, and Restriction of Chemicals, REACH）法规》，评估对全氟和多氟烷基物质（per-and polyfluoroalkyl substances, PFAS）的限制举措。三氟乙酸（trifluoroacetic acid, TFA）属于持久性全氟和多氟烷基物质，同时也是HFO-1234ze(E)的潜在降解产物。本研究采用计算模型，在符合欧洲相关的大气条件下，对HFO-1234ze(E)降解生成三氟乙酸的产率进行了定量分析。模型分析结果显示，即便在最高测试海拔下，≥85%的HFO-1234ze(E)可在20天内降解为甲酰氟。研究表明，在不同大气条件下，HFO-1234ze(E)降解产生的三氟乙酸产率介于0%至4%之间。2022年，法国是欧盟境内加压定量吸入器销量最高的成员国。假设该类吸入器均以HFO-1234ze(E)作为抛射剂，我们估算其对应的年雨水三氟乙酸沉降浓度约为0.025 μg/L。本研究结果证实，HFO-1234ze(E)降解产生的三氟乙酸生成量可忽略不计，进一步佐证其可作为非持久性、非生物累积性、无毒性的下一代抛射剂，应用于加压定量吸入器，以保障患者能够获取这类必需的治疗药物。