Two-Week, Repeated Inhalation Exposure of F344/N Rats and B6C3F Mice to Ferrocene

Two-Week, Repeated Inhalation Exposure of F344/N Rats and B6C3F¹Mice to Ferrocene. SUN, J. D., DAHL, A. R., GILLETT, N. A.,BARR, E. B., CREWS, M. L., EIDSON, A. F., BECHTOLD, W. E., BURT,D. G., DIETER, M. P., AND HOBBS, C. H. (1991). Fundam. ApplToxicol. 17, 150-158. Ferrocene (dicyclopentadienyl iron; CASNo. 102-54-5) is a relatively volatile, organometallic compoundused as a chemical intermediate, a catalyst, and as an antiknockadditive in gasoline. It is of particular interest because ofits structural similarities to other metallocenes that havebeen shown to be carcinogenic. F344/N rats and B6C3F, mice wereexposed to 0, 2.5, 5.0, 10, 20, and 40 mg ferrocene vapor/m3,6 hr/day for 2 weeks. During these exposures, there were nomortality and no observable clinical signs of ferrocene-relatedtoxicity in any of the animals. At the end of the exposures,male rats exposed to the highest level of ferrocene had decreasedbody-weight gains relative to the weight gained by filteredair-exposed control rats, while body-weight gains for all groupsof both ferrocene- and filtered air-exposed female rats weresimilar. Male mice exposed to the highest level of ferrocenealso had decreased body-weight gains, relative to controls,while female mice had relative decreases in body-weight gainsat the three highest exposure levels. Male rats had a slightdecrease in relative liver weight at the highest level of exposure,whereas no relative differences in organ weights were seen infemale rats. Male mice had exposure-relative decreases in liverand spleen weights, and an increase in thymus weights, relativeto controls. For female mice, relative decreases in organ weightswere seen for brain, liver, and spleen. No exposure-relatedgross 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 findingwas histopathologic lesions in the nasal turbinates of bothspecies. These lesions were primarily centered in the olfactoryepithelium and were morphologically diagnosed as subacute, necrotizinginflammation. Nasal lesions were observed in all ferrocene-exposedanimals and differed only in severity, which was dependent onthe exposure concentration. In vitro metabolism studies of ferroceneshowed that nasal tissue, particularly the olfactory epithelium,had 10 times higher "ferrocene hydroxylating" activity thandid liver tissue from the same animals. These results suggestthat the mechanism of ferrocene toxicity may be the intracellularrelease of ferrous ion through ferrocene metabolism, followedby iron-catalyzed lipid peroxidalion of cellular membranes.