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Effects on fertility

Description of key information
A number of non-standard studies are available, which further investigate the mechanism of the testicular toxicity of vanadium and the potential for the use of vanadium-containing complexes as spermicidal agents.
Additional information

Toxicity to reproduction

 

The toxicity to reproduction of various vanadium compounds has been investigated by a number of authors in the rat and mouse.

 

Altimirano-Lozano et al (1996) investigated the effects of single and repeated intraperitoneal injections of vanadium (V) pentoxide on the testicular function and reproductive capacity of male mice. Single administrations of vanadium pentoxide in this study were shown (using the Comet assay) to cause DNA damage to testicular germ cells; repeated administration caused adverse effects on sperm numbers, motility and morphology and resulted in reduced fertility of the treated males. The study reports increased numbers of resorbed foetuses and lower numbers of smaller foetuses born to untreated females which had been mated with the treated males. The same group (Aragon & Altimirano-Lozano, 2001) also investigated the effects of the intraperitoneal injection of vanadium (IV) tetraoxide in male mice. Repeated administration over the study period of 60 days resulted in reduced testes weight with disruption and degeneration of the seminiferous tubule epithelium. Findings were associated with reduced sperm count, reduced sperm viability and motility and increased numbers of morphologically abnormal sperm. Another paper from the same group (Aragon et al, 2005) further investigates the effects of the repeated intraperitoneal injection of vanadium (IV) tetraoxide on the testicular ultrastructure. Treatment was shown to increase the proportion of apoptotic testicular germ cells; inclusion structures were noted in the testicular germ and Sertoli cells. Serum testosterone and progesterone cells were unaffected by treatment. The route of administration used in these studies (intraperitoneal injection) is not of direct relevance to the human risk assessment; however the study does indicate an intrinsic hazard of both vanadium pentoxide and vanadium tetraoxide for male fertility. 

 

Domingo et al (1986) investigated the reproductive toxicity of sodium metavanadate (vanadium (V)) in male and female rats following oral administration to both sexes at dose levels of up to 20 mg/kg bw/d. Males were treated for 60 days prior to mating; females were treated for 14 days prior to mating and throughout gestation and lactation. No effect was observed on reproductive performance; however the weight and size of the resulting offspring were lower from birth and throughout the lactation period. Effects were seen in the absence of overt maternal toxicity and may result from exposure in utero and/or during lactation. However it is also noted that the study of Altimirano-Lozano et al (1996) reports that the treatment of parental male mice with vanadium (V) pentoxide resulted in smaller offspring when these animals were mated with untreated females. In a further study from this group (Llobet et al, 1993), the effects of the oral administration of sodium metavanadate were investigated in male mice. Males were administered dose levels of up to 80 mg/kg bw/d for 64 days prior to mating with untreated females. Reduced fertility was seen at dose levels of 60 and 80 mg/kg bw/d. No effect was seen on testes weight or histopathology; however sperm counts (but not motility) were reduced at these dose levels. Sperm morphology was unaffected by treatment in this study.

 

A comprehensive investigation of the reproductive toxicity of ammonium metavanadate (vanadium (V)), Morgan & El-Tawil (2003) treated male and female rats for 70 and 14 days prior to mating (respectively) by oral administration. Treated rats were mated with untreated rats to assess the effects of treatment on fertility in both sexes. Oestrus cyclicity was reported to be ‘disturbed’ in treated females. Prolonged gestation and dystocia were noted in treated females and the untreated females mated with treated males. The fertility of treated males and females was adversely affected by treatment; lower numbers of implantation sites, increased resorption, pre and post-implantation loss was seen in treated females and in untreated females mated with treated males. Weights of pups at birth were adversely affected by the treatment of females but were also apparently affected by the treatment of parental males, as reported in other studies.

 

Literature reviews of the effects of vanadium on fertility have been performed by Domingo (1996) and more recently by Strother (1998). It is noted (Domingo, 1996) that vanadium is able to cross the blood-testis barrier and may accumulate in the testis; this may account for the effects noted on testicular structure, sperm parameters and male fertility. Strother (2008) considers that the oral NOAEL for the reproductive toxicity of vanadium cannot be established with confidence.


Short description of key information:
No studies are available for the substance, however a number of published studies are available for read-across substances. The weight of evidence information available therefore demonstrates that vanadium compounds are likely to be reproductive toxins. The studies are more than sufficient to address the reproductive toxicity endpoints required at this tonnage level. No additional testing is therefore required for the substance and none is proposed, on scientific grounds and for reasons of animal welfare.

Effects on developmental toxicity

Description of key information
No studies are available for the substance, however a number of published studies are available for read-across substances. The weight of evidence information available therefore demonstrates that vanadium compounds are likely to be developmental toxins.  The studies are more than sufficient to address the developmental toxicity endpoints required at this tonnage level.  No additional testing is therefore required for the substance and none is proposed, on scientific grounds and for reasons of animal welfare.
Additional information

Developmental toxicity / teratogenicity

 

The developmental toxicity of various vanadium compounds has been investigated in a number of studies using the mouse, rat and hamster as experimental models. Carlton et al (1982) investigated the effects of ammonium metavanadate (vanadium (V)) in the hamster, using intraperitoneal injection. The study suffers from limited reporting, therefore the authors conclusions that there is no definitive evidence for teratogenicity but that there is some evidence for mild developmental toxicity based on an increased incidence of minor skeletal anomalies cannot be independently verified. The developmental toxicity of sodium orthovanadate (vanadium (V)) at dose levels of up to 30 mg/kg bw/d was investigated in the mouse (Sanchez et al, 1991) in a study comparable to OECD Test Guideline 414. No evidence of teratogenicity was seen in this study. Embryofoetal survival was unaffected by treatment (despite marked maternal toxicity); evidence of developmental toxicity was limited to reduced/delayed foetal skeletal ossification at 30 mg/kg bw/d. The authors considered the skeletal effects to be secondary to maternal toxicity.

Paternain et al (1987) investigated the developmental toxicity of sodium metavanadate in the rat in a study comparable to OECD Test Guideline 414. Some evidence of teratogenicity was seen in this study; a low incidence of hydrocephaly was reported at the highest dose level of 20 mg/kg bw/d. The association of this finding with maternal toxicity cannot be assessed as maternal effects were either not investigated or reported. The total incidence of foetal variations (haemorrhage of various body areas) was increased in all treated groups; the total incidence was highest at 20 mg/kg bw/d but otherwise did not exhibit a dose-response relationship. Similarly, the individual incidences of haemorrhage of different body areas did not consistently exhibit a dose-response relationship.  In contrast to other studies, no effects are reported on the foetal skeleton. The results of this study are difficult to interpret due to poor mating performance and in the absence of any data on maternal toxicity.  Nevertheless, there is some indication of a teratogenic effect of sodium metavanadate at the highest dose level in this study. The same authors (Paternain et al, 1990) also investigated the developmental toxicity of vanadyl (IV) sulphate in the mouse in a study using oral administration and comparable to OECD Test Guideline 414. Evidence of maternal toxicity was seen in all treatment groups in this study. The numbers of implantations in all groups were comparable, however litter sizes in the treated groups were slightly lower than controls as a consequence of slightly (but significantly) increased early resorption. Numbers of late resorptions and dead foetuses were slightly elevated at 75 and 150 mg/kg bw/d. Incidences of external malformations and variations and skeletal variations were significantly increased in all treated groups. The incidence of cleft palate in particular was notably increased at the highest dose level.  Tissue levels of vanadium were also measured in this study; levels of vanadium in the placenta were relatively low, but foetal concentrations were higher than the placental and maternal tissue concentrations in all groups. It is unclear from the dosing pattern whether vanadium is preferentially distributed to the foetus or if elimination from the foetus is relatively slow compared to maternal tissues.

The developmental toxicity of ammonium metavanadate in the rat using oral administration was investigated as part of a wider assessment of the reproductive toxicity of this substance (Morgan & El-Tawil, 2003). Males and females were treated in this study; animals were mated with untreated males or females and the developmental toxicity investigated. Increased resorptions, pre-and post-implantation loss were seen in both treated groups. Foetuses from both treated groups showed higher incidences of stunted growth, subcutaneous haemorrhage and micrognathia. The proportion of foetuses exhibiting visceral malformations and anomalies was significantly increased on both treated groups; findings included hydrocephaly, dilated nares, anophthalmia, renal hypoplasia and cerebral hypoplasia. The incidences of skeletal anomalies including reduced ossification were also increased in both treated groups. While the sensitivity of this study to detect foetal malformations and variations is somewhat limited by the low numbers of foetuses from the treated groups available for investigation, the study clearly indicates the potential for teratogenicity and other developmental toxicity. While male-mediated effects on foetal size are consistent with those reported in other studies, the concordance of the other findings between the offspring of treated females (mated with untreated males) and the offspring of treated males (mated with untreated females) is remarkable.

Literature reviews of the developmental toxicity of vanadium have been performed by Domingo (1996) and more recently by Strother (1998). Domingo (1996) postulates that the known potent inhibition by vanadium of DNA and protein synthesis and other metabolic processes may be responsible for its developmental toxicity.  The potential for developmental toxicity is noted to be influenced by the chemical form of the vanadium compound, the oxidation state of the vanadium ion, the route of exposure, the timing of exposure and the dose level administered.  Developmental toxicity was associated inconsistently with maternal toxicity in the studies reviewed; however the author considers that the pattern of developmental effects seen in these studies is more consistent with a direct effect of the test material rather than an effect secondary to maternal toxicity.

Toxicity to reproduction: other studies

Additional information

Other studies

Poggiolli et al (2001) investigated the behavioural and developmental outcomes in the offspring of female rats. The pregnant rats were administered vanadyl sulphate (300 mg/L) and sodium chloride (5 g/L) in the drinking water for the last three days of gestation and throughout lactation; treatment of the offspring continued following weaning up to Day 100 post partum. Control groups were exposed to drinking water only or drinking water containing 5 g/L sodium chloride (rats administered vanadyl sulphate were also administered sodium chloride in order to reduce gastrointestinal toxicity).  Exposure to vanadyl sulphate reduced survival to weaning of offspring; rats were potentially exposed for three days prior to birth (via maternal administration), potentially exposed during lactation (via breast milk) and during late lactation (directly from the drinking water).  It is unclear which exposure (if any) was responsible for the reduced survival, or whether this was secondary to maternal toxicity (which is not detailed).  There is also some indication of retarded growth in offspring following weaning, which is attributable to direct exposure to vanadyl sulphate in the drinking water; however some effects were also seen in the group administered sodium chloride alone (rats administered vanadyl sulphate were also administered sodium chloride in order to reduce gastrointestinal toxicity).  No convincing evidence of an effect on locomotor activity was apparent in either sex.  Some evidence of reduced activity was seen in males open-field observations, however a similar effect was not seen in females.  Food and water consumption were not affected by treatment with vanadyl sulphate. An apparent impairment of memory was reported for rats administered vanadyl sulphate at Day 100 post partum, however this effect is not considered to be of significance given the even greater apparent impairment in rats administered sodium chloride alone.

The effects of vanadium compounds on the testes have been investigated in further detail by a number of authors. In male mice exposed by inhalation to vanadium pentoxide for periods of up to 12 weeks, the proportion of gamma-tubulin positive cells in the testicular germ, Sertoli and Leydig cells decreased in the treated groups with increasing exposure (Mussali-Galante et al, 2005).  The authors suggest that the effects of exposure on the levels of gamma-tubulin implies an effect of vanadium on microtubule function, which may lead to effects on spermatogenesis. The same group investigated the effects of the inhalation of vanadium pentoxide for periods of up to 12 weeks on testicular structure (Fortoul et al, 2007). Exposure did not affect testes weight, but resulted in the necrosis of testicular germ and Sertoli cells and spermatogonia; nuclear changes were also apparent in spermatids. Testosterone levels were highly variable and did not reveal any effects of exposure. Vanadium concentration in the testes increased markedly after Week 1, but notably remained relatively constant thereafter. The authors suggest that the proteins of the blood-testis barrier are a possible target of vanadium toxicity, and that the generation of ROS may be involved in the mechanism of vanadium toxicity.  Leopardi et al (2005) assessed the effects of oral exposure to sodium orthovanadate on the testes of male mice. Mean testis weight was unaffected by treatment; no effects were seen on testis cell subpopulations (investigated using flow cytometry) or sperm chromatin structure. A comet assay did not demonstrate any effect of treatment on testis cells, in contrast to splenocytes. The authors suggest that the absence of effects on the testes in this study may be due to poor oral bioavailability of the test material. A series of studies (D’Cruz et al, 1998, 1999, 2002) investigates the spermicidal activity of complexes of vanadium. Studies with human sperm in vitro demonstrated that metallocene compounds containing vanadium have potent spermicidal activity, in contrast to complexes of a number of other metals investigated. Sperm appeared to be rapidly immobilised and underwent apoptosis. Further results demonstrate that the spermicidal and apoptosis-inducing activities of vanadium (IV) complexes are influenced by the oxidation state of vanadium as well as their structural geometry. The repeated intravaginal exposure of CD-1 mice to increasing concentrations of one spermicidal vanadium complex, vanadocene acetylacetonato monotriflate (VDACAC) for 13 weeks had no adverse effect on their subsequent reproductive capability, neonatal survival or pup development. The authors conclude that VDACAC may be useful as a vaginal contraceptive.

Justification for classification or non-classification

The potential reproductive toxicity of vanadium compounds is clearly demonstrated by the available published data. The effects of vanadium on reproduction appear to be primarily male-mediated; adverse effects on the testes and sperm parameters are reported in a number of studies. Studies of teratogenicity / developmental toxicity are also available for a number of vanadium compounds, and demonstrate teratogenic and other developmental effects. Vanadium pyrophosphate contains vanadium in the valency states V4+and V5+, therefore read-across to the various (V4+and V5+vanadium compounds) which have been investigated for reproductive toxicity in the cited literature studies is scientifically valid.

Screening studies for reproductive and developmental toxicity appropriate guidelines (OECD 421, OECD 422) are required at this tonnage level (10-100 tpa). However it is considered that the investigations of reproductive toxicity of vanadium compounds reported in the literature adequately address the endpoints covered by the screening studies. Studies have been performed with a number of different vanadium compounds and in a number of species and include investigation of the effects of pre-mating exposure of male and female animals for adequate periods. Detailed investigations of the effects of vanadium exposure on the male gonads have been undertaken in these studies, far beyond the requirements of the relevant OECD guidelines. Taken as a whole, the parameters investigated in these studies more than adequately address the potential for effects onfertility, pregnancy, maternal and suckling behaviour, growth and development of the resulting offspring from conception to Day 4post partum. In a number of areas, the basic requirements of OECD 421 are exceeded. The developmental toxicity of vanadium compounds has been adequately addressed in a number of studies in different species, including three studies comparable to OECD 414. The data provided by these studies are sufficient to conclude that vanadium compounds are likely developmental toxins. The information available therefore demonstrates that vanadium compounds are likely to be reproductive and developmental toxins. The studies are more than sufficient to address the reproductive and developmental toxicity endpoints required at this tonnage level. No additional testing is therefore required for the substance and none is proposed, on scientific grounds and for reasons of animal welfare.

Classification of the substance for reproductive toxicity is proposed. Based on the harmonised classification of the read-across substance vanadium pentoxide, classification for reproductive toxicity in Category 2 (H361d) according to CLP and classification for reproductive toxicity in Category 3 (R63) according to DSD is proposed.