A new method for long-term inhalation toxicity studies for bronchospasmolytic aerosol formulations in dogs
✍ Scribed by Jürgen Pauluhn; Georg Kimmerle
- Publisher
- John Wiley and Sons
- Year
- 1989
- Tongue
- English
- Weight
- 456 KB
- Volume
- 9
- Category
- Article
- ISSN
- 0260-437X
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✦ Synopsis
In routine inhalation toxicity studk laboratory anlmala are exposed under dynamk exgosure conditions to diilercat steady-state concentratioas of a test compound. The relevant exposure coaccntration is the analytically determlned time-weighted average Coneentrrtioa in the vicinity of the breathing zone of the animals. If the lotemled use of a bronchospasmdytic a e d is taken into account, a wn-steady-state exposure regimen might be more appropriate. Using this approach loal e f k t s of high a e d concentrations on the respiratory tract were invedgated in dogs by drily W w a e -o n l y expowve for 1 h for 4 weeks. Four groups of four dogs were expo6ed to #),40 and 80 bursts of a bronchodilator formulation using a modieed metered dose inhaler. The analytically determiwd mean concentration of the active ingredient (prostagl.ndia) in the breathing zone was 43.1,92.2 rrad 193.9 p,g C-' air, nspcetively. Maximum concentrations were determined by simulation. The rreroed was in the respirable range (mass median aerodynamic diameter -1.2 pn, geometric standard deviation -1.4). A Liwtie modd was developed to simulate the mean and maximum non-steady-state concentration for an expomre regimen of#), 40 and 80 bursta per hour under dynamic exposure caaditions. The model was based on first-order inhalaticto chamber kinetics. "he kinetic model was validated experimentally by comparing meuwrd mean rrnd simulated mean concentrations. In all exposure groups the simulated maximum concentratiom were ca. 80 mg of test eompwlwl (formulation) per Utre of air. Plasma levels were elevated in a doedependent manner a8 evidence of the validity of the test model employed. m 3 7 x / 8 9 m 9 . 0 0 @ 1989 by John Wiley & Sons, Ltd.