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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

An extensive literature/data search and evaluation programme on animal and human data relating to possible adverse effects of vanadium substances on reproductive toxicity has recently been conducted. As an outcome, some data are available for soluble pentavalent substances (V2O5and NaVO3) via the oral and inhalation route.

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 sodium 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.

Inhalation exposure

Groups of 10 male and 10 female F344/N rats and B6C3F1 mice were exposed to V2O5aerosols (whole body exposure) at concentrations of 0, 1, 2, 4, 8 or 16 mg/m3by 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 epididymal spermatozoa 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/m3for vaginal cytology evaluations. The percentage of time spent in the various oestrous cycle stages and oestrous 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/m3V2O5. In contrast, female oestrus cycle parameters were not affected in mice, but oestrous cycles were significantly longer in rats exposed to 8 mg/m3than in animals of the chamber control group, and the number of cycling females was lower in the 16 mg/m3group. Considering both, the results in male mice and female rats, an overall NOAEC for effect on fertility in rodents of 4 mg/m3can be established.

Read-across

Unrestricted read-across from very soluble pentavalent substances to VO2 is not applicable since the bioaccessibility of VO2 is lower (and similar to V2O3 in comparison): in artificial gastric fluid at a loading of 100 mg/L V2O3, only 13% and 15% went into solution after 2h and 24h respectively, whereas other pentavalent substances (V2O5or NaVO3) dissolved completely within 2 h. A similarly low dissolution of V2O3was also observed in artificial lysosomal fluid (11.9% after 2h; 15.7% after 24h) and lung fluid (4.7% after 2h; 5.6% after 24h). Similar bioaccessibility tests are ongoing with VO2. For the time being, the solubility of V2O3 and VO2 in physiological fluids is expected to be similar based on similar intrinsic water solubility and transformation/dissolution characteristics. Thus, the biological uptake of vanadium from V2O3and from VO2 via the oral or inhalation route is expected to be an order of magnitude lower compared to very soluble V substances, such as V2O5or NaVO3. Thus, any read-across from very soluble pentavalent vanadium substances to poorly/less soluble and poorly/less bioavailable for the purpose of classification and labelling of VO2 is not supported.

The registrant is aware that 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 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

- 90-d oral toxicity studies (dosed feed: NaVO3; dosed water: VOSO4) with Harlan Sprague-Dawley rats and B6C3F1/N (dose: rats and mice: 0, 31.3, 62.5, 125, 250, or 500 ppm - ongoing

- Organ systems toxicity, i.e. 28-d immunotoxicity study of NaVO3 (dosed-water) with female B6C3F1/N mice (dose: 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

It can reasonably be anticipated that these studies will be of high quality and relevance, and thus will serve as a more robust basis than the current data base with all its shortcomings.In addition, repeated-dose inhalation toxicity studies (14, 28, and 90 days) with various vanadium substances are planned within the Vanadium Safety Readiness Safety Program. These studies will address issues for which to date equivocal or no data at all exist.Further information on these studies can be found in section 7.5.Only upon availability of the results from these studies, it will be possible to render a more meaningful decision on whether or not testing for reproductive toxicity is required. Therefore for the time being this data requirement should be waived in consideration of animal welfare.


Short description of key information:
Studies via the oral and the inhalation route are available for soluble vanadium substances (NaVO3, NH4VO3, V2O5). Male and female fertility was evaluated in the k_NTP study (2002) in rats and mice at the end of the 90-day inhalation exposure period to V2O5 aerosols. One reproduction toxicity study (k_Loblet 1993) with different dose level ammonium metavanadate administered via drinking water to mice was identified and another study (k_Morgan 2003) with only one dose level of sodium metavanadate in drinking water in rats. Unrestricted read-across from very soluble pentavalent substances to VO2 is not applicable.

Justification for selection of Effect on fertility via oral route:
Data of the reproductive toxicity are available for very soluble pentavalent substances (NH4VO3 and NaVO3) via the oral route.

Justification for selection of Effect on fertility via inhalation route:
Data of the reproductive toxicity are available for very soluble pentavalent substances (V2O5) via the inhalation route.

Justification for selection of Effect on fertility via dermal route:
Data of the reproductive toxicity via the dermal route are not available for any vanadium substance. Following the HERAG guidance for metals and metal salts (see section 7.1.2 of the technical dossier: dermal absorption), negligible percutaneous uptake based on minimal penetration, i.e. a dermal absorption rate in the range of maximally 0.1 - 1.0 %, can be anticipated. Dermal absorption in this order of magnitude is not considered to be “significant”. Thus, regarding reproductive toxicity of vanadium substances, the dermal exposure route is not expected to be the most relevant.

References:
EBRC (2007) HERAG fact sheet - Assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds, EBRC Consulting GmbH, Hannover, Germany, August 2007, 49 pages.

Effects on developmental toxicity

Description of key information
Studies via the oral or inhalation route are available for other soluble vanadium substances. One study (k_Sanchez 1991) with administration of different dose levels of sodium orthovanadate per gavage to pregnant mice was identified. One supportive developmental toxicity study (s_Paternain_1990) with administration of different dose levels of vanadyl sulphate to Swiss mice was identified. Evidence of maternal, embryo-/fetotoxicity and teratogenicity were observed at the lowest dose level investigated. Unrestricted read-across from very soluble pentavalent substances to VO2 is not applicable.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Data of the developmental toxicity are available for very soluble tetra- and pentavalent substances via the oral route.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

An extensive literature/data search and evaluation programme on animal and human data relating to possible adverse effects of vanadium substances on developmental toxicity has recently been conducted. As an outcome, some data are available for very soluble tetra- and pentavalent substances (VOSO4 and Na3VO4) via the oral route.

Oral uptake

Vanadyl sulphate was evaluated for its embryotoxic, foetotoxic 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 evident by lower foetal 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 foetal 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 foetal 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 Na3VO4is 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, information on maternal toxicity was not provided in the study.

Read-across

Unrestricted read-across from very soluble tetra- and pentavalent substances to VO2 is not applicable since the bioaccessibility of VO2 is much lower (and similar to V2O3 in comparison): in artificial gastric fluid at a loading of 100 mg/L V2O3, only 13% and 15% went into solution after 2h and 24h respectively, whereas other tetra- and pentavalent substances (VOSO4, V2O5or NaVO3) dissolved completely within 2 h. Similar bioaccessibility tests are ongoing with VO2. For the time being, the solubility of V2O3 and VO2 in physiological fluids is expected to be similar based on similar intrinsic water solubility and transformation/dissolution characteristics. Thus, the biological uptake of vanadium from V2O3 and from V2O4 via the oral route is expected to be an order of magnitude lower compared to V2O5or NaVO3. Thus, any read-across from very soluble pentavalent vanadium substancesto poorly soluble and poorly bioavailable for the purpose of classification and labelling of VO2 is not supported.

The registrant is aware that 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 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

- 90-d oral toxicity studies (dosed feed: NaVO3; dosed water: VOSO4) with Harlan Sprague-Dawley rats and B6C3F1/N (dose: rats and mice: 0, 31.3, 62.5, 125, 250, or 500 ppm - ongoing

- Organ systems toxicity, i.e. 28-d immunotoxicity study of NaVO3 (dosed-water) with female B6C3F1/N mice (dose: 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

It can reasonably be anticipated that these studies will be of high quality and relevance, and thus will serve as a more robust basis than the current data base with all its shortcomings.In addition, repeated-dose inhalation toxicity studies (14, 28, and 90 days) with various vanadium substances are planned within the Vanadium Safety Readiness Safety Program. These studies will address issues for which to date equivocal or no data at all exist.Further information on these studies can be found in section 7.5.Only upon availability of the results from these studies, it will be possible to render a more meaningful decision on whether or not testing for reproductive toxicity is required. Therefore for the time being this data requirement should be waived in consideration of animal welfare.


Justification for selection of Effect on developmental toxicity: via dermal route:
Data of developmental toxicity via the dermal route are not available for any vanadium substance. Following the HERAG guidance for metals and metal salts (see section 7.1.2 of the technical dossier: dermal absorption), negligible percutaneous uptake based on minimal penetration, i.e. a dermal absorption rate in the range of maximally 0.1 - 1.0 %, can be anticipated. Dermal absorption in this order of magnitude is not considered to be “significant”. Thus, regarding developmental toxicity of vanadium substances, the dermal exposure route is not expected to be the most relevant.

References:
EBRC (2007) HERAG fact sheet - Assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds, EBRC Consulting GmbH, Hannover, Germany, August 2007, 49 pages.

Justification for classification or non-classification

Based on available data for soluble vanadium substances, vanadium dioxide does not classify as reproductive toxicant under Regulation (EC) No 1272/2008.

Additional information

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