Subchronic (13-week) toxicity studies of intravaginal administration of spermicidal vanadocene dithiocarbamate in mice

Abstract

Spermicidal organometallic complexes of vanadium(IV) with bis(cyclopentadienyl) rings or vanadocenes are a new class of experimental contraceptive agents. In a systematic search for vanadocenes with selective spermicidal activity, we identified vanadocene dithiocarbamate (VDDTC) as the most potent and stable spermicidal compound. In this study, groups of 10 B 6C 3F 1 and 20 female CD-1 mice were exposed intravaginally to a gel-microemulsion containing 0, 0.06, 0.12, and 0.25% VDDTC 5 days per week for 13 consecutive weeks. The doses of VDDTC used were nearly 1250- to 5000-fold higher than its in vitro spermicidal EC 50 value. After 13 weeks of intravaginal treatment, B 6C 3F 1 mice were evaluated for survival, body weight gain, absolute and relative organ weights, and systemic toxicity. Blood was analyzed for hematologic and clinical chemistry parameters. Microscopic examination was performed on hematoxylin and eosin-stained tissue sections from each study animal. Vanadium content in tissues was determined by atomic absorption spectroscopy. Placebo control and VDDTC-dosed female CD-1 mice were mated with untreated males to evaluate whether VDDTC has any deleterious effects on the reproductive performance. There were no treatment-related effects on survival and mean body weight and mean body weight gain during the dosing period. The blood chemistry or hemogram profiles did not reveal any toxicologically significant changes that could be attributed to VDDTC treatment. No clinically significant changes in absolute and relative organ weights were noted in VDDTC dose groups. Extensive histopathological examination of tissues revealed no treatment-related abnormalities in any of the three VDDTC dose groups. The vanadium content of all mouse tissue analyzed was <1 μg/g. Repeated intravaginal exposure of CD-1 mice to increasing concentrations of VDDTC for 13 weeks had no adverse effect on their subsequent reproductive capability (100% fertile), neonatal survival (>90%), or pup development. Collectively, these findings demonstrate that repetitive intravaginal administration of VDDTC to yield effective spermicidal concentrations (<0.1%) in the vagina was not associated with systemic toxicity and did not adversely affect the reproductive performance in mice. VDDTC may have clinical utility as an active ingredient of non-detergent type, safe, vaginal spermicidal contraceptives.