Subchronic intravenous toxicity studies with gamma-cyclodextrin in rats.

The toxicity of gamma-cyclodextrin (gamma-CD), a cyclic polymer of 8 alpha-1,4-linked glucopyranosyl units with potential applications in food and pharmaceutical preparations, was examined in two toxicity studies in rats with intravenous administration of gamma-CD for 1 and 3 months, respectively. Each study comprised four groups of 15 rats/sex each. In the 1-month study, gamma-CD was administered to the four groups at daily doses of 0 (controls), 200, 630, or 2000 mg/kg body wt, respectively. In the 3-month study, dose levels of 0, 60, 120, and 600 mg/kg body wt were tested. gamma-CD was administered by injection of an aqueous solution in the tail vein. At the end of the treatment period, 10 rats/sex/group were killed. The remaining 5 rats continued the study without treatment (recovery period) for 4 weeks (1-month study) or 5 weeks (3-month study). The treatment was generally well tolerated and there were no mortalities in either study. Mean body weights tended to be slightly reduced during the first and second week in the groups receiving gamma-CD at doses of >/=600 mg/kg body wt. Thereafter, body weights did not differ between treated groups and controls. Examination of standard hematological parameters at the end of the treatment period revealed decreased erythrocyte counts, hemoglobin, hematocrit values, and thrombocyte counts in both studies at gamma-CD doses of >/=600 mg/kg body wt. Concomitantly, the relative weight of the spleen was increased. In the high-dose group of the 1-month study, hemoglobin was detected in the urine. It is likely that a direct interaction of the injected gamma-CD with blood cells accounts for these effects. Examination of standard clinicochemical parameters at the end of the treatment period did not reveal any changes that would point to the liver as a target organ for gamma-CD toxicity. This was confirmed by the absence of histopathological changes in the liver. The only noteworthy observation was an increase of serum urea in the high-dose group (either sex) of the 1-month study and in males of the high-dose group of the 3-month study, suggesting a slight impairment of the renal function. On histopathological examination, reabsorptive vacuolation was seen in the renal tubular epithelium of some rats receiving gamma-CD at doses of 630 or 600 mg/kg body wt in the 1- and 3-month study, respectively. In the high-dose group of the 1-month study, all animals exhibited this morphological effect. However, degenerative changes were not observed in the kidneys, and the vacuolation was fully reversible on cessation of the treatment. The occurrence of absorptive vacuolation was attributed to the presence of gamma-CD in urine (parenterally administered gamma-CD is excreted unchanged in the urine). Simple or focal hyperplasia of the urinary bladder epithelium was observed in some animals of the high-dose group of the 3-month study. This hyperplasia was not seen at the end of the recovery period and, therefore, was considered to be a reactive response to the treatment. The most prominent morphological effect was an accumulation of phagocytosing alveolar macrophages (histiocytosis) in the lungs of rats receiving gamma-CD at a dose of >/=600 mg/kg body wt. This effect was associated with an increase of relative lung weights. However, degenerative changes (fibrosis) were not seen, and at the end of the recovery period only some small residual changes were noted in the lungs of a few animals. In conclusion, daily intravenous gamma-CD doses of 120-200 mg/kg body wt were tolerated without adverse effects. The changes observed at higher dose levels (>/=600-630 mg/kg body wt) were reversible on cessation of the treatment and are considered to be biochemical responses, without toxicological relevance, to the presence of transiently high concentrations of gamma-CD in the circulating blood.