Safety of propellants

Abstract

Chlorofluorocarbon (CFC) propellants used in metered dose inhalers (MDI) must be replaced under the terms of the Montreal Protocol. Following a review of the available data, HFA134a (1,1,1,2 tetrafluoroethane) was selected as a potential alternative propellant. However, because this data was insufficient to satisfy the stringent requirements for pharmaceuticals, additional toxicological assessments were performed. These included genotoxicology, animal inhalation studies, reproductive toxicology, local tolerability and safety pharmacology studies. A special grade of HFA134a, containing relatively high concentrations of all likely impurities, was used for all pivotal studies. HFA134a was devoid of genotoxicity and had exceptional low acute toxicity. No toxicity was seen in rats or dogs exposed to concentrations of up to 5% or 12% respectively for up to one year. No fetotoxicity, effects on reproductive performance, peri- or postnatal development was demonstrated. HFA134a was devoid of oncogenic potential in rats and mice. There was no evidence of sensitisation or local irritation to the skin or eyes. All species demonstrated high systemic HFA134a concentrations. An extensive toxicological evaluation, at very high multiples of the likely patient exposure, has indicated that HFA134a is a suitable alternative to CFC propellants for MDIs.