title: Subchronic (13-week) toxicity studies of intravaginal administration of spermicidal vanadocene acetylacetonato monotriflate in mice.
abstract: Bis-cyclopentadienyl complexes of vanadium(IV) or vanadocenes are rapid and potent inhibitors of human sperm motility with potential as a new class of contraceptive agents. In this study, groups of 10 B(6)C(3)F(1) and 20 CD-1 female mice were exposed intravaginally to a gel-microemulsion containing 0, 0.06, 0.12, or 0.25% of a representative vanadocene, vanadocene acetylacetonato monotriflate (VDACAC), five days per week for 13 consecutive weeks. The doses of VDACAC used were nearly 300- to 1250-fold higher than its in vitro spermicidal EC(50) value. After 13 weeks of intravaginal treatment, B(6)C(3)F(1) mice were evaluated for survival, body weight gain, absolute and relative organ weights, and systemic toxicity. Blood was analyzed for hematological and clinical chemistry profiles. 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. Gel-microemulsion (placebo) control and VDACAC dosed female CD-1 mice were mated with untreated males in order to evaluate if VDACAC has any adverse effects on the reproductive outcome. There were no treatment-related mortalities in either study. Mean body weight gain during the dosing period was not reduced by VDACAC treatment. Hemograms or clinical chemistry profiles did not reveal any toxicologically significant changes attributed to VDACAC treatment. No clinically significant dose-dependent changes in absolute and relative organ weights were noted in VDACAC dose groups. Extensive histopathological examination of tissues revealed no treatment-related abnormalities in any of the three VDACAC dose groups. Vanadium was not incorporated in mouse tissues at levels above 1 microg/g. Repeated intravaginal exposure of CD-1 mice to increasing concentrations of VDACAC for 13 weeks had no adverse effect on their subsequent reproductive capability (100% fertile), neonatal survival (>96%) or pup development. Collectively, these findings demonstrate that repetitive intravaginal administration of VDACAC 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. The spermicidal vanadocene-chelated complex, VDACAC, may be useful as a safe vaginal contraceptive.
authors.affiliation: Department of Reproductive Biology, Parker Hughes Institute, 2665 Long Lake Road, Suite 300, St. Paul, MN 55113, USA. odcruz@ih.org
authors.forename: Osmond J
authors.initials: OJ
authors.lastname: D'Cruz
authors.forename: Barbara
authors.initials: B
authors.lastname: Waurzyniak
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D004655:Emulsions; D005260:Female; D005298:Fertility / Q000187:drug effects; D005782:Gels; D051379:Mice; D008815:Mice, Inbred Strains; D008863:Microspheres; D009929:Organ Size / Q000187:drug effects; D013089:Spermatocidal Agents / Q000008:administration & dosage / Q000633:toxicity*; D014639:Vanadium / Q000032:analysis; D017968:Vanadium Compounds / Q000633:toxicity
chemical_list: D004655:Emulsions; D005782:Gels; D013089:Spermatocidal Agents; D017968:Vanadium Compounds; C445261:vanadocene acetylacetonato monotriflate; D014639:Vanadium