In chronic exposure studies, lung tumours were produced in rats under conditions of particle overload. In a 2-year inhalation study in male and female rats, exposures to titanium dioxide particles (rutile type) at concentrations of 10, 50, or 250 mg/m3 produced lung tumours only at the highest concentration (Lee et al, 1985). With one exception, the tumours produced were ultimately characterised as primarily benign pulmonary keratin cysts (Warheit and Frame, 2006). In a study reported by Muhle et al (1991), TiO2 was used as a negative control dust in a two-year inhalation study with toner particles. Male and female rats were exposed (6 hr/day, 5 days/week) to 5 mg/m3 TiO2 (rutile form) of 1.1 mm MMAD with a respirable fraction of 78%. There were no significant increases in lung tumours vs. control rats exposed for up to 24 months by whole body inhalation to TiO2 in this study.