HFO-1234ze(E) is a next-generation medical propellant in development for use in pressurized metered-dose inhalers (pMDIs). The chemical structure of HFO-1234ze(E) has the ‘–CF<sub>3</sub>’ moiety, which makes formation of trifluoroacetic acid (TFA) possible in the atmosphere. To quantify the contribution of these novel pMDIs in forming environmental TFA, we performed an extensive study using a global atmospheric model coupled with detailed watershed modelling. Herein, we included the master-chemical mechanism of HFO-1234ze(E), accounting for all known pathways that may form atmospheric TFA and assumed pMDI usage as the only source of HFO-1234ze(E) emissions. Based on annual pMDI sales data and HFO-1234ze(E) as their sole medical propellant, we estimate annual global propellant emissions of 4.736 Gg/year. Even though pMDI sales are the highest in regions within the northern-temperate zone, model-predicted TFA deposition rates are higher in regions within the tropical zone, suggesting that photolysis reaction of trifluoroacetic aldehyde (TFAA; which does not yield TFA) is dominant in the northern-temperate zone. We used model-predicted TFA deposition rates around the Hudson River, Cauvery River, and Rhine River as an input to our fate-and-transport model of TFA, yielding pMDI usage-based TFA concentrations in surface water, soil and sediments in each of the three modelled watersheds. Our watershed models predict that TFA concentrations in river surface water would vary between 0.8–19.3 ng/L, indicating greater than 500-fold margin-of-exposure for drinking-water TFA. Our results demonstrate that environmental TFA formation due to pMDI usage-based HFO-1234ze(E) emissions do not pose a human health concern.