Miscellaneous: P17: Lethal rhinitis/sinusitis in rodents by aspiration of formulation in gavage studies: Importance of evaluation of the nose

• Published in: Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie Vol. 61; no. 4; p. 410
• Main Authors: De Jonghe, S., Lammens, L., Raoof, A., Steemans, K., Broeckaert, F., Verbeeck, J., Van Goethem, F., Hanton, G.
• Format: Journal Article
• Language: English
• Published: Elsevier GmbH 2009
• ISSN: 0940-2993; 1618-1433
• DOI: 10.1016/j.etp.2009.02.103

For repeated dose oral gavage studies in rodents, OECD guidelines do not include the nasal turbinates in the list of recommended tissues for histopathologic examination. During the past few years, unexpected high mortality was noted with two different compounds in rodents for which the cause of death was mainly based on histological evaluation of the nose. For compound A (a solution in PEG 400), unexpected high mortality was encountered early in the carcinogenicity studies. The dose-related increase in mortality correlated with an increase in inflammatory and necrotic or ulcerative changes within the respiratory tract of the preterminal deaths, often involving the nose and sinuses. For several animals rhinitis/sinusitis (mainly involving the lower half of the nose and most prominently affecting the respiratory epithelium) was the most important finding. The respiratory tract findings were consistent with irritation. The irritant nature of the formulation was confirmed in a BCOP-test. It was concluded that a part of the irritant formulation entered into the nose/airways via aspiration during gavage-dosing. This was considered to be related to the high viscosity of the vehicle (PEG400). The problem was further prevented by adapting the gavage procedure and by reducing the volume and/or concentration of the formulation. Compound B (also a solution in PEG 400) resulted in high mortality at the high dose in the 3 m mouse study, from the 1st week onwards. At necropsy, the preterminally dead/sacrificed animals showed gastrointestinal dilatation with test formulation being present in the stomach. Acute, necrotizing rhinitis/sinusitis was the cause of death for the majority of these mice. Only a minority of these animals showed lesions in other parts of the respiratory tract. The test article and PEG 400 (to a lesser extent) were demonstrated to delay gastric emptying in a separate pharmacology study. This effect, together with the high viscosity of the vehicle and the irritant nature of the compound formulation resulted in entry of the formulation in the respiratory tract (probably due to regurgitation/aspiration) with subsequent inflammatory/necrotizing changes. For the majority of mice, the cause of death would not have been evident without evaluation of the nose. In conclusion, evaluation of the nose can be valuable to determine the cause of death in rodents.