Two-week, repeated inhalation exposure of F344N rats and B6C3F(1) mice to ferrocene()

Ferrocene (dicyclopentadienyl iron; CAS No. 102-54-5) is a relatively volatile, organometallic compound used as a chemical intermediate, a catalyst, and as an antiknock additive in gasoline. It is of particular interest because of its structural similarities to other metallocenes that have been shown to be carcinogenic. F344N rats and B6C3F(1) mice were exposed to 0, 2.5, 5.0, 10, 20, and 40 mg ferrocene vapor/m(3), 6 hr/day for 2 weeks. During these exposures, there were no mortality and no observable clinical signs of ferrocene-related toxicity in any of the animals. At the end of the exposures, male rats exposed to the highest level of ferrocene had decreased body-weight gains relative to the weight gained by filtered air-exposed control rats, while body-weight gains for all groups of both ferrocene- and filtered air-exposed female rats were similar. Male mice exposed to the highest level of ferrocene also had decreased body-weight gains, relative to controls, while female mice had relative decreases in body-weight gains at the three highest exposure levels. Male rats had a slight decrease in relative liver weight at the highest level of exposure, whereas no relative differences in organ weights were seen in female rats. Male mice had exposure-relative decreases in liver and spleen weights, and an increase in thymus weights, relative to controls. For female mice, relative decreases in organ weights were seen for brain, liver, and spleen. No exposure-related gross lesions were seen in any of the rats or mice at necropsy. Histopathological examination was done only on the nasal turbinates, lungs, liver, and spleen. The only exposure-related finding was histopathologic lesions in the nasal turbinates of both species. These lesions were primarily centered in the olfactory epithelium and were morphologically diagnosed as subacute, necrotizing inflammation. Nasal lesions were observed in all ferrocene-exposed animals and differed only in severity, which was dependent on the exposure concentration. In vitro metabolism studies of ferrocene showed that nasal tissue, particularly the olfactory epithelium, had ∼ 10 times higher “ferrocene hydroxylating” activity than did liver tissue from the same animals. These results suggest that the mechanism of ferrocene toxicity may be the intracellular release of ferrous ion through ferrocene metabolism, followed by iron-catalyzed lipid peroxidation of cellular membranes.