Review of kidney sections from a subchronic d-limonene oral dosing study conducted by the National Cancer Institute.
d-Limonene administered by oral gavage at 150-2400 mg/kg/day in a subchronic (91-day) study conducted for the National Cancer Institute induced renal alterations in male rats at all dose levels, whereas kidneys of male mice, female rats and female mice were unaffected. The renal alterations were dose responsive, and were similar to changes observed as sequelae to oral or inhalation exposure to decalin, a model compound used in a volatile hydrocarbon toxicology programme. Decalin induces a nephrotoxic response unique to the male rat, but the primary response associated with decalin exposure--hyaline droplet formation within the cytoplasm of the epithelial cells of the proximal convoluted tubule--was not recognized in the kidneys of d-limonene-exposed male rats. A possible explanation for the absence of this primary response from kidneys of the d-limonene-treated male rats could be the 4-5-day interval between administration of the final dose and the killing of the animals.