Acute, repeated inhalation toxicity, respiratory system irritation, and mutagenicity studies of 1,1,2,2-tetrafluoroethane (HFC-134) as the impurity in the pharmaceutical propellant 1,1,1,2-tetrafluoroethane (HFA-134a)

Abstract

HFC-134 is the main impurity of HFA-134a. In order to verify the rationality of HFC-134 limits in HFA-134a and ensure the safety of HFA-134a as propellant in pharmaceutical metered-dose inhalers, acute inhalation toxicity, seven-day repeat dose inhalation irritation study, 21-day repeat dose inhalation toxicity study and reverse mutation assay of HFC-134 were tested to evaluate its inhalation safety. In acute inhalation studies, Sprague-Dawley rats were exposed nose-only to HFC-134 at levels of 100 000, 200 000, 400 000, 600 000, and 800 000 ppm for 4 h. Based on the mortality incidence, the calculated four-hour LC₅₀ value for HFC-134 is 532 069 ppm for males and 502 058 ppm for females and acute inhalation toxicity is manifested as the lung lobes turn dark red. Exposures to 836 ± 67 ppm for 4 hours/day 7 days/week continuously did not induce local irritation of the respiratory system in Sprague-Dawley rats. Sprague-Dawley rats were exposed nose-only to HFC-134 at levels of 0 (control), 203 929 ppm and 394 871 ppm 2 h/day for 21 consecutive days, no significant treatment-related adverse effects was noted. Results from Ames studies demonstrated that HFC-134 was not mutagenic. Although HFC-134 has a very low acute inhalation toxicity, considering that its acute inhalation toxicity is higher than that of HFA-134a, and due to the high frequency of use of MDI by asthma patients, acceptance criteria of HFC-134 as the impurity in aerosol propellant HFA-134a should be lower than 8-h TWA WEEL value of 1000 ppm to ensure the safety of the MDI.

Keywords:

• Metered-dose inhaler
• propellant
• inhalation toxicology
• HFC-134a
• HFC-134

Disclosure statement

There are no conflicts to declare.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was funded by Research and Establishment of Pharmaceutical Grade Substitute: Safety, Toxicity and Method of Quality Control of HFC-134a under the Sector Plan for Phase-Out of CFCs in MDI Pharmaceutical Aerosol Sector in China (MDI-LC-4-01).