Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
26.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Several reliable studies are available. Results are not considered relevant for human exposure.
Effect on fertility: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
6.8 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
One reliable study is available. Results are considered equivocal, and are not considered relevant for human exposure. The route of exposure may not be relevant for vanadium, oxalate complexes solution.
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 foetuses 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/m3 than 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:

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 tri-, tetra- and pentavalent vanadium substances, tri-, tetra- and pentavalent forms dissolved within 2h in various media selected to simulate relevant human-chemical interactions (i.e. PBS mimicking the ionic strength of blood, artificial lung, lysosomal, and gastric fluid as well as artificial sweat). Tri-, tetra- and pentavalent vanadium substances are 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.

The registrant is of the opinion that the toxicity of vanadium, oxalate complexes is driven by the vanadium moiety for the following reasons: Oxalic acid is a dicarboxylic acid occurring in many plants and vegetables and as such part of the daily diet. It is produced in the body by metabolism of glyoxylic acid or ascorbic acid and is not metabolized but excreted in the urine. Based on the lack of any identified systemic human health effect at relevant exposure levels, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) does not specify an ADI for oxalic acid. Further, oxalic acid is unlikely to raise public health concerns because any use in food-producing animals is generally regarded as safe by many national authorities (JECFA).

Based on the above information, one can therefore safely assume that the oxalate anion in vanadium, oxalate complexes is not the driver of reproductive toxicity of vanadium, oxalate complexes. It is concluded that only “vanadium” is further considered in the assessment of human health effects of vanadium, oxalate complexes. Thus, read-across of reproductive toxicity data from soluble pentavalent vanadium substances is justified.

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 levels of 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.

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. However, inhalation may not be a relevant route of exposure for vanadium, oxalate complexes solution.

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 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 vanadium oxide sulphate to Swiss mice was identified. Evidence of maternal, embryo-/foetotoxicity and teratogenicity were observed at the lowest dose level investigated.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
12.7 mg/kg bw/day
Species:
mouse
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

Vanadium oxide 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. Foetotoxicity 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-/foetotoxicity 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: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 tri-, tetra- and pentavalent vanadium substances, tri-, tetra- and pentavalent forms dissolved within 2h in various media selected to simulate relevant human-chemical interactions (i.e. PBS mimicking the ionic strength of blood, artificial lung, lysosomal, and gastric fluid as well as artificial sweat). Tri-, tetra- and pentavalent vanadium substances are 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.

The registrant is of the opinion that the developmental toxicity of vanadium, oxalate complexes is driven by the vanadium moiety for the following reasons: Oxalic acid is a dicarboxylic acid occurring in many plants and vegetables and as such part of the daily diet. It is produced in the body by metabolism of glyoxylic acid or ascorbic acid and is not metabolized but excreted in the urine.

Based on the lack of any identified human health effect at relevant exposure levels, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) does not specify an ADI for oxalic acid. Further, oxalic acid is unlikely to raise public health concerns because any use in food-producing animals is generally regarded as safe by many national authorities (JECFA).

Based on the above information, one can therefore safely assume that the oxalate anion in vanadium, oxalate complexes is not the driver of developmental toxicity of vanadium, oxalate complexes. It is concluded that only “vanadium” is further considered in the assessment of human health effects of vanadium, oxalate complexes. Thus, read-across of developmental toxicity data from soluble tetra- and pentavalent vanadium substances is justified.

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 oral route:
In the absence of other reliable information, the lowest NOEL for developmental effects at a maternal toxic dose level was selected.

Justification for selection of Effect on developmental toxicity: via inhalation route:
Inhalation may not be a relevant route of exposure for vanadium, oxalate complexes solution.

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

An extensive literature/data search and evaluation programme on animal and human data relating to possible adverse effects of relevant vanadium substances on fertility and developmental toxicity has been conducted. Based on read-across of data available for other very soluble vanadium substances, vanadium, oxalate complexes classifies as reproductive toxicant category 2 according to commission Regulation (EC) No 1272/2008. The placing in Category 2 is proposed on the basis of evidence in animal studies, which is not sufficiently convincing to place the substance in Category 1A or 1B.