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Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published literature study: read across from similar compound

Data source

Reference
Reference Type:
publication
Title:
Spermicidal Activity of Metallocene Complexes Containing Vanadium(IV) in Humans
Author:
D'Cruz OJ, Ghosh P & Uckun FM
Year:
1998
Bibliographic source:
Biology of Reproduction 58, 1515-1526

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Computer-assisted sperm analysis was used to evaluate the spermicidal activity of 8 metallocene dihalides, 5 vanadocene di-pseudohalides and 3 disubstituted derivatives.
GLP compliance:
no
Remarks:
: published literature study
Type of method:
in vitro

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
8 metallocene dihalides(vanadocene dichloride [VDC], titanocene dichloride [TDC], zirconocene dichloride [ZDC], molybdocene dichloride [MDC], hafnocene dichloride [HDC], vanadocene dibromide [VDB], bis[methylcyclopentadienyl] vanadium dichloride [VMDC] and vanadocene diiodide [VDI]); 5 vanadocene di-pseudohalides (vanadocene diazide [VDA], vanadocene dicyanide [VDCN], vanadocene dioxycyanate [VDOCN], vanadocene dithiocyanate [VDSCN] and vanadocene diselenocyanate [VDSeCN]); and 3 disubstituted derivatives (vanadocene ditriflate [VDT], vanadocene monochloro oxycyanate [VDCO] and vanadocene monochloroacetonitrilo tetrachloro ferrate [VDFe]).

Test animals

Species:
other: not applibale, in vitro study
Details on test animals and environmental conditions:
Semen was provided by 12 healthy volunteers who had been repeatedly found to have normospermic semen according to World Health Organization criteria for normal donor specimen. Semen samples were allowed to liquefy for 30 min at 37C, after which an aliquot was removed for analysis.

Administration / exposure

Route of administration:
other: in vitro
Vehicle:
other: sperm were exposed to the test material in appropriate culture media
Details on exposure:
Motile fractions of sperm were isolated prior to a sperm immobilisation assay with exposure to the test compound for 3 hours. In experiments investigating sperm acrosome reactions, exposure time was 3 hours.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
3 hour incubation of sperm with the test material
Frequency of treatment:
Single exposure
Duration of test:
3 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
1.9-250 uM
Basis:
nominal conc.
: serial dilutions of all test substances
No. of animals per sex per dose:
Not applicable
Details on study design:
No further details.
Statistics:
Results for the various numerical sperm function parameters were presented as mean + SD values. Comparisons between VDC-treated sperm relative to sperm motility parameters and acrosomal loss were performed using a paired, two-tailed Student's t-test. A p value of < 0.05 was considered
significant. Nonlinear regression analysis was used to find the EC50 values.

Results and discussion

Observed effects

Metallocene complexes containing titanium, zirconium, molybdenum and hafnodium were inactive, however all 12 of the vanadocene complexes investigatd elicited potent spermicidal activity at nanomolar to micromolar concentrations. The order of efficacy was VDSeCN > VDSCN > VDB > VMDC > VDCN > VDA > VDC > VDOCN > VDI > VDT > VDFe > VDCO. No disruption of the acrosomal membrane was noted , as determined by high-resolution low-voltage scanning electron microscopy. The sperm-immobilizing activity of the vanadocene complexes was rapid and irreversible, since the
treated sperm underwent apoptosis as determined by the flow cytometric annexin V binding assay, DNA nick end-labeling and confocal laser scanning microscopy.

Any other information on results incl. tables

No further details.

Applicant's summary and conclusion

Conclusions:
Potent spermicidal activity in vitro was demonstrated for metallocene compounds containing vanadium, whereas this activity was not seen for complexes of other metals investigated. The authors conclude that metallocene complexes containing vanadium (IV), especially vanadocene diselenocyanate may be useful as contraceptive agents.
Executive summary:

Computer-assisted sperm analysis was used to evaluate the spermicidal activity of eight metallocene dihalides (vanadocene dichloride [VDC], titanocene dichloride [TDC], zirconocene dichloride [ZDC], molybdocene dichloride [MDC], hafnocene dichloride [HDC], vanadocene dibromide [VDB], bis[methylcyclopentadienyl] vanadium dichloride [VMDC] and vanadocene diiodide [VDI]); five vanadocene di-pseudohalides (vanadocene diazide [VDA], vanadocene dicyanide [VDCN], vanadocene dioxycyanate [VDOCN], vanadocene dithiocyanate [VDSCN] and vanadocene diselenocyanate [VDSeCN]); and three disubstituted derivatives (vanadocene ditriflate [VDT], vanadocene monochlorooxycyanate [VDCO] and vanadocene monochloro acetonitrilo tetrachloroferrate [VDFe]). The metallocene complexes containing titanium, zirconium, molybdenum, and hafnodium were inactive, however all 12 vanadocene complexes elicited potent spermicidal activity at nanomolar or micromolar concentrations with an order of efficacy VDSeCN > VDSCN > VDB > VMDC > VDCN > VDA > VDC > VDOCN > VDI > VDT > VDFe > VDCO. This activity was achieved without disruption of the acrosomal membrane, as determined by high-resolution low-voltage scanning electron microscopy. The sperm-immobilising activity of the vanadocene complexes was rapid and irreversible, since the treated sperm underwent apoptosis as determined by the flow cytometric annexin V binding assay, DNA nick end-labeling, and confocal laser scanning microscopy. The authors conclude that metallocene complexes containing vanadium (IV), especially VDSeCN, may be useful as contraceptive agents.