Introduction : Increased use of nanomaterials has raised concerns about the potential for undesirable human health and environmental effects. Releases into the air may occur and, therefore, the inhalation route is of specific interest. Here we tested copper oxide nanoparticles (CuO NPs) after repeated inhalation as hazard data for this material and exposure route is currently lacking for risk assessment. Methods : Rats were exposed nose-only to a single exposure concentration and by varying the exposure time, different dose levels were obtained (C × T protocol). The dose is expressed as 6 h-concentration equivalents of 0, 0.6, 2.4, 3.3, 6.3, and 13.2 mg/m 3 CuO NPs, with a primary particle size of 10 9.2–14 nm and an MMAD of 1.5 μm. Results : Twenty-four hours after a 5-d exposure, dose-dependent lung inflammation and cytotoxicity were observed. Histopathological examinations indicated alveolitis, bronchiolitis, vacuolation of the respiratory epithelium, and emphysema in the lung starting at 2.4 mg/m 3 . After a recovery period of 22 d, limited inflammation was still observed, but only at the highest dose of 13.2 mg/m 3 . The olfactory epithelium in the nose degenerated 24 h after exposure to 6.3 and 13.2 mg/m 3 , but this was restored after 22 d. No histopathological changes were detected in the brain, olfactory bulb, spleen, kidney and liver. Conclusion : A 5-d, 6-h/day exposure equivalent to an aerosol of agglomerated CuO NPs resulted in a dose-dependent toxicity in rats, which almost completely resolved during a 3-week post-exposure period.