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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

No substance specific data on fertility is available for the registered substance Divanadyl pyrophosphate is available.

Divanadyl pyrophosphate is a grey-green powder with a melting point > 360°C and a water solubility of ca. 42.2 g/L. For this compound the oxidation state of V(+4). The chemistry of vanadium and inorganic vanadium substances is complex. However, under physiological conditions only the vanadyl ion (VO2+, +4-valent) and the vanadate ion (VO43-, +5-valent) play a significant role. Within tissues of organisms, V(+4) predominate because of largely reducing conditions; in plasma, V(+5) predominates. Under physiological conditions both forms of ions are going to be converted into each other via redox reactions. Therefore, it can be assumed that +4- and +5-valent inorganic vanadium compounds will show the same toxicological profile. Data from soluble +4- and +5-valent vanadium substance were taken into account to address the endpoint of repeated dose toxicity of the registered substance.

Oral exposure:

The reproductive toxicity of sodium metavanadate was studied in male Swiss mice exposed doses of 0, 20, 40, 60 and 80 mg/kg bw per day given in the drinking water for 64 days. To evaluate the fertility of the vanadium-treated animals, males were mated with untreated females for 4 days. A significant decrease in the pregnancy rate was observed at 60 and 80 mg/kg per day. However, the test substance did not reduce fertility in male mice at 20 and 40 mg/kg per day. Decreased body and epididymis weight was only observed in the 80 mg/kg per day group, while testicular weights were not altered by the treatment. Sperm count was significantly decreased at 60 and 80 mg/kg per day, but the sperm motility was unaffected. Histopathological examination revealed that testes were normal and that epididymis of treated male mice contained normal appearing sperm. In this reproduction toxicity study in mice, a NOAEL of 40 mg/kg bw/d was determined for ammonium metavanadate.

However, there is another reproduction toxicity study with ammonium metavanadate in rats available (Morgan et al 2003). Unfortunately, this study was designed to investigate the effects of ammonium metavanadate at only one dose level of 20 mg/kg bw/d. The effects on fertility of male and female rats, as well as on the incidence of teratogenicity and behavioural effects on the offspring were evaluated. Reproductive toxicity was observed in absence of general maternal toxicity. Effects were observed on sexual organs and/or functions in treated males and females, mating and fertility indices were reduced, and implantation losses and dead fetuses were reported. Thus, the dose level of 20 mg/kg bw/d represents an effect level for reproductive toxicity (i.e. 8.71 mg V / kg bw/day).

Inhalation exposure:

Groups of 10 male and 10 female F344/N rats andB6C3F1 micewere exposed to V2O5 aerosols (whole body exposure) at concentrations of 0, 1, 2, 4, 8 or 16 mg/m3 by inhalation, 6 hours/d, 5 d/wk, for 3 months (91-92 days).At the end of the study period, sperm samples were collected from core study male rats and mice of the control and treatment groups for sperm motility evaluations and determination of spermatid heads per testis and per gram testis, spermatid counts, and epididymalspermatozoal motility and concentration. The left cauda,left epididymis and left testis were weighed. Vaginal samples were collected for up to 12 consecutive days prior to the end of the studies from core study female rats and mice exposed to 0, 4, 8, or 16 mg/m3 for vaginal cytology evaluations. The percentage of time spent in the various estrous cycle stages and estrous cycle length were evaluated.

In rats, the results did not indicate effects on male sexual function, but in mice epididymal spermatozoal motility was significantly decreased in males exposed to 8 and 16 mg/m3 V2O5.In contrast, female estrus cycle parameters were not affected in mice, butestrous cycles weresignificantly longer inrats exposed to 8 mg/m3thanin animals of the chamber control group, and the number of cycling females was lower in the 16 mg/m3 group. Considering both, the results in male mice and female rats, an overall NOAEC for effect on fertility in rodents of 4 mg/m3 can be established). These results following inhalative exposure are considered equivocal, and are not considered relevant for human exposure to divanadium pentaoxide (see Section 7.5) .

Read-across:The read-across approach based on dissolved vanadium is based on the assumption that once inorganic vanadium compounds dissolve or become bioavailable, this will be in tetra- or pentavalent vanadium forms.In bioaccessibility tests of tetra- and pentavalent vanadium substances, tetra- and pentavalent forms dissolved completely within 2h in various media selected to simulate relevant human-chemical interactions (i.e. PBSmimickingthe ionic strength of blood, artificial lung, lysosomal, and gastric fluid as well as artificial sweat).Pentavalent vanadium substances are released and retained as pentavalent forms in physiological media, with the exception of artificial lysosomal fluid in which tetravalent V dominates after 2h and is the only form present after 24h.Thus, read-across of reproductive toxicity data from soluble pentavalent vanadium substances is justified.

The National Toxicology Programme (NTP) in the US nominated tetra- and pentavalent vanadium forms(sodium metavanadate, NaVO3(CAS 13718-26-8) and vanadium oxide sulphate, VOSO4(CAS 27774-13-6), i.e. species present in drinking water and dietary supplements in 2007 (http://ntp.niehs.nih.gov/). A comprehensive characterisation via the oral route of exposure of

(i) chronic toxicity,

(ii) carcinogenicity, and 

(iii) multi-generation reproductive toxicity

is planned.

 

The NTP testing program began with sub-chronic drinking water and feed studies on VOSO4& NaVO3as follows:

- Genetic toxicology studies, i.e. the Salmonella gene mutation assays, with NaVO3 and VOSO4 - negative

-14 days with Harlan Sprague-Dawley rats and B6C3F1/N mice (dose: R&M: 0, 125, 250, 500, 1000, 2000 mg/L) - already completed

- 90days with Harlan Sprague-Dawley rats and B6C3F1/N mice (dose: R&M:: 0, 31.3, 62.5, 125, 250, or 500 ppm) - ongoing

- Perinatal dose-range finding study: gestation day 6 (GD 6) until postnatal day 42 (PND 42) with Harlan Sprague-Dawley rats - ongoing

- 28days immunotoxicity study (dosed-water) with female B6C3F1/N mice (dose:0, 31.3, 62.5, 125, 250, or 500 ppm) - ongoing

Effects on developmental toxicity

Additional information

No substance specific data on rdevelopmental toxicity is available for the registered substance Divanadyl pyrophosphate is available.

Divanadyl pyrophosphate is a grey-green powder with a melting point > 360°C and a water solubility of ca. 42.2 g/L. For this compound the oxidation state of V(+4). The chemistry of vanadium and inorganic vanadium substances is complex. However, under physiological conditions only the vanadyl ion (VO2+, +4-valent) and the vanadate ion (VO43-, +5-valent) play a significant role. Within tissues of organisms, V(+4) predominate because of largely reducing conditions; in plasma, V(+5) predominates. Under physiological conditions both forms of ions are going to be converted into each other via redox reactions. Therefore, it can be assumed that +4- and +5-valent inorganic vanadium compounds will show the same toxicological profile. Data from soluble +4- and +5-valent vanadium substance were taken into account to address the endpoint of repeated dose toxicity of the registered substance.

Oral uptake

Vanadyl sulphate was evaluated for its embryotoxic, fetotoxic and teratogenic potential in Swiss mice. The compound was administered by gavage to pregnant mice at doses of 0, 37.5, 75 or 150 mg/kg body weight/day on days 6 -15 of pregnancy. On gestation day 18, all live foetuses were examined for external, visceral and skeletal malformations and variations. Maternal toxicity was observed in all vanadium-treated animals, evident by reduced weight gain, reduced body weight on gestation day 18 (corrected for gravid uterine weight) and decreased absolute liver and kidney weights at 75 and 150 mg/kg body weight/day. The number of total implants, live and dead foetuses, late resorptions, the sex ratio and the post-implantation losses were not significantly different between the vanadium-treated mice and the control. However, there was a significant increase in the number of early resorptions per litter at all dose levels. Fetotoxicity was evidend by lower fetal weights and lengths and the presence of developmental variations. Malformation incidence also increased by administration of vanadium. Thus, the NOEL for maternal toxicity, embryo-/fetotoxicity and teratogenicity for vanadyl sulphate pentahydrate under these test conditions can be expected below 37.5 mg/kg body weight/day (11.72 mg V/kg bw/d) in Swiss mice (Paternain et al. 1990).

Sodium orthovanadate in deionised water was administered once daily by gavage on gestational days 6 -15 to mice at doses of 0, 7.5, 15, 30 and 60 mg/kg body weight/day. Dams were killed on day 18 of pregnancy, and foetuses were examined for external, visceral and skeletal defects. Maternal toxicity was observed at the highest doses levels, as evidenced by a significant number of deaths (60 and 30 mg/kg body weight/day) and reduced weight gain and food consumption (30 and 15 mg/kg body weight/day). Embryolethality and teratogenicity were not observed at maternally toxic doses and below, but fetal toxicity was evidenced by a significant delay in the ossification process of some skeletal districts at 30 mg/kg body weight/day. The NOAEL for maternal toxicity was 7.5 mg/kg body weight/day, and 15 mg/kg body weight/day represented a NOAEL for developmental toxicity in mice under the conditions of this study. However, it needs to be considered that fetal toxicity was observed at maternal toxic dose levels and can thus be regarded as secondary. Thus, the dose level of 30 mg/kg bw/d represents the LOEL for developmental effects and 15 mg/kg bw/d the NOEL for developmental effects at maternally toxic dose levels (reduced body weight gain and food consumption). These values correspond to 8.3 mg V/kg bw/d (LOEL) and 4.2 mg V/kg bw/d (NOEL). In the absence of other reliable information, the lowest NOEL for developmental effects of 15 mg/kg bw/d Na3VO4, corresponding to 7.41 mg V2O5/kg bw/d is used as starting point for this endpoint-specific DNEL derivation, although the effects observed can be considered as secondary due to maternal toxicity (Sanchez et al. 1991).

In the study with sodium metavanadate (Paternain et al. 1987), an oral NOAEL of 20 mg/kg bw/d was determined at the high dose level corresponding to 8.4 mg V/kg bw/d. There is no clear evidence of direct developmental effects in foetuses of dams exposed during gestational day 6-14 to different dose levels. However, no information on maternal toxicity was reported in the study.

Read-across: The read-across approach based on dissolved vanadium is based on the assumption that once inorganic vanadium compounds dissolve or become bioavailable, this will be in tetra- or pentavalent vanadium forms.In bioaccessibility tests of tetra- and pentavalent vanadium substances, tetra- and pentavalent forms dissolved completely within 2h in various media selected to simulate relevant human-chemical interactions (i.e. PBSmimickingthe ionic strength of blood, artificial lung, lysosomal, and gastric fluid as well as artificial sweat).Pentavalent vanadium substances are released and retained as pentavalent forms in physiological media, with the exception of artificial lysosomal fluid in which tetravalent V dominates after 2h and is the only form present after 24h.Thus, read-across of developmental toxicity data from soluble tetra- and pentavalent vanadium substances is justified.

The National Toxicology Programme (NTP) in the US nominated tetra- and pentavalent vanadium forms(sodium metavanadate, NaVO3(CAS 13718-26-8) and vanadium oxide sulphate, VOSO4(CAS 27774-13-6), i.e. species present in drinking water and dietary supplements in 2007 (http://ntp.niehs.nih.gov/). A comprehensive characterisation via the oral route of exposure of

(i) chronic toxicity,

(ii) carcinogenicity, and 

(iii) multi-generation reproductive toxicity

is planned.

 

The NTP testing program began with sub-chronic drinking water and feed studies on VOSO4& NaVO3as follows:

- Genetic toxicology studies, i.e. the Salmonella gene mutation assays, with NaVO3 and VOSO4 - negative

-14 days with Harlan Sprague-Dawley rats and B6C3F1/N mice (dose: R&M: 0, 125, 250, 500, 1000, 2000 mg/L) - already completed

- 90days with Harlan Sprague-Dawley rats and B6C3F1/N mice (dose: R&M:: 0, 31.3, 62.5, 125, 250, or 500 ppm) - ongoing

- Perinatal dose-range finding study: gestation day 6 (GD 6) until postnatal day 42 (PND 42) with Harlan Sprague-Dawley rats - ongoing

- 28days immunotoxicity study (dosed-water) with female B6C3F1/N mice (dose:0, 31.3, 62.5, 125, 250, or 500 ppm) - ongoing

Justification for classification or non-classification

Currently there is no substance specific data on Divanadyl pyrophosphate for fertility and developmental toxicity available. However data from tetra- and pentavalent vanadium compounds (e.g. Divanadium pentoxide (CAS 1314-62 -1)) can be taken into account for hazard assessment.

Based on the available data and according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 Divanadyl pyrophosphate has to be classified as Repro. Cat 2 (H361) for developmental toxicity.