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EC number: 237-272-7 | CAS number: 13718-26-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
A comprehensive literature search was recently conducted for the vanadium category substances, to source relevant information for the hazard and risk assessment. For the group of the soluble vanadium substances, a limited number of studies is available and the different experimental approaches lead to a variety of endpoints measured.
Of the limited effects noted following oral exposure with soluble vanadium substances, it appears most likely that effects on haematological parameters are the most consistently reported among a number of investigators (Mountain et al 1953, Zaporowska et al. 1993, Scibior et al 2006, Scibior, 2005, NTP, 2002). Altogether, haematological effects have been found with a variety of different vanadium compounds including sodium metavanadate, vanadium pentoxide, and ammonium metavanadate supporting the use of this endpoint for risk assessment purposes.
Information on repeated dose toxicity following inhalation exposure to V2O5 is available in a NTP study (k_NTP 2002) with exposure of male and female rats and mice to V2O5 over 16-days, 3-months and 2-years. Pulmonary reactivity to vanadium pentoxide was also investigated following subchronic inhalation exposure in a non-human primate animal model.
The rationale for read-across to sodium metavanadate is summarised below.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- no data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- Well documented study. However, the following deficiencies were noted: test substance insufficiently described, low group sizes (n=8), missing parameters in clinical biochemistry and haematology, FOB was not conducted, only one sex was used, individual body weight data, ophthalmological examination missing, thyroid hormones were not determined, applied doses were not analytically verified, some organ weights were missing and not the complete table of organs were histopathologically examined. Historical control data were not provided and most of the data were presented as graphical overview, thus no raw/individual data were provided. The dose setting was changed during the study.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- This short description is restricted to non-diabetic rats. Investigations on the diabetic rats are not considered here. Four groups of non-diabetic male rats received different concentrations of VOSO4 in drinking water for 52 weeks. The low dose group received 500 mg/L for 52 weeks. The mid dose group received 500 mg/L for 1 week and then 750 mg/L for 51 weeks. The high dose group received 500 and 750 mg/L for 1 week each and then 1250 mg/L for further 50 weeks. Subgroups of 3 animals from each of the four groups were followed for further 16 weeks after cessation of VOSO4 treatment. Various parameters were examined and determined.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Montreal, Quebec, Canada
- Weight at study initiation: 270-320 g
- Diet (ad libitum): standard laboratory food (Purina rat chow)
- Water: ad libitum: vanadyl sulphate hydrate mixed with tap water
ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Vanadyl sulphate hydrate (Fischer Scientific Co., Lair lawn, NJ, USA) was mixed with drinking water.
- Solutions were prepared on alternative days. - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- no data
- Duration of treatment / exposure:
- 52 weeks
- Frequency of treatment:
- continuously (ad libitum in drinking water)
- Dose / conc.:
- 500 mg/L drinking water
- Remarks:
- for 52 weeks (low dose group); nominal in water
- Dose / conc.:
- 500 mg/L drinking water
- Remarks:
- 500 mg/L for 1 week (mid dose group); nominal in water
- Dose / conc.:
- 750 mg/L drinking water
- Remarks:
- for 51 weeks (mid dose group); nominal in water
- Dose / conc.:
- 500 mg/L drinking water
- Remarks:
- for 1 week (high dose group); nominal in water
- Dose / conc.:
- 750 mg/L drinking water
- Remarks:
- for 1 week (high dose group); nominal in water
- Dose / conc.:
- 1 250 mg/L drinking water
- Remarks:
- for 50 weeks (high dose group); nominal in water
- No. of animals per sex per dose:
- 8 male rats per group
- Control animals:
- yes
- Details on study design:
- - Rationale for animal assignment: random
- Positive control:
- no data
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals were examined closely for possible occurrance of diarrhoea, cataract formation or deterioration of their general condition.
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: every 3-5 weeks; every 2-3 weeks during post-exposure observation period.
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: measured every 3-5 weeks; every 2-3 weeks during post-exposure observation period.
FOOD EFFICIENCY: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: regularly, every 3-5 weeks; every 2-3 weeks during post-exposure observation period
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: hematocrit, after 3, 6, 9 and 12 months of treatment as well as 3 months after withdrawal. Other paramenters after 52 weeks of exposure and 3 months of withdrawal.
- How many animals: each rat (haematocrit index).
- Parameters checked: hematocrit index of peripheral blood, haemoglobin, erythrocyte count, leukocyte count and composition, platelet count and reticulocyte percentage.
CLINICAL CHEMISTRY: Yes,
- Time schedule for collection of blood: every 3 months during treatment and 16 weeks after vanadyl withdrawal.
- Animals fasted: for 5 hr
- Parameters checked: aspartate aminotransferase, alanine aminotransferase and urea (for liver and kidney function).
- In addition, determination of non-fasting blood glucose (weekly in the first 4 weeks and then once upon every 2-4 weeks), fasting plasma glucose and insulin, plasma trigycerides and cholesterol throughout the exposure time (every 3 months).
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: Not specified
OTHER:
- Determination of systolic blood pressure, pulse rate after 3, 6, 9 and 12 months of treatment as well as 3 months after withdrawal using tail-cuff method.
- Vanadium levels were determined in the 5-hr fasting plasma samples obtained at the end of the 52 wk-treatment and at weeks 6 and 12 after vanadyl withdrawal.
- V levels were determined in plasma, bone and some of the inner organs after 1 year exposure and after 16 weeks of vanadyl withdrawal - Sacrifice and pathology:
- After treatment for 52 weeks most of the rats were terminated for morphological studies with an overdose of halothane followed by decaptation. 8 rats from the exposed groups and 3 rats from the control group were kept and observed for a further period of 16 weeks (without exposure).
GROSS PATHOLOGY: Yes,
- Brain, thymus, lung, heart, liver, spleen, pancreas, adrenal gland, kidney and testis were weighed.
HISTOPATHOLOGY: Yes,
- Brain, thymus, lung, heart, liver, spleen, pancreas, adrenal gland, kidney and testis were examined. - Other examinations:
- no
- Statistics:
- All results were expressed as mean and standard error of the mean. The data were analyzed using repeated measure or one-way ANOVA, as appropriate, followed by the Newman-Keul’s test, if required. The values of haematological indices of the same rats before and after the withdrawal of vanadyl sulphate were compared using an unpaired Student’s t-test. The level of significance was set at P<0.05. The data from the morphological studies are presented as incidence (%) of the specific morphological abnormalities in each organ and were analyzed with the Chi-Square test. The data of plasma levels of AST; ALT and urea, of organ weight/body weight ratio, and of plasma and tissue concentrations of vanadium are shown as mean and standard error of the mean, and were analyzed with two-way or one-way analysis of variance, as appropriate, followed by the Newman-Keul’s test, if required.
- Clinical signs:
- not specified
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- - one animal died in the high dose group for unknown reasons after 18 weeks of treatment.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - Body weight gain was slightly reduced in the low and mid dose groups indicated by an increasing number of deviations from control values from week 13 onwards reaching occasionally statistical significance.
- Body weight gain was markedly and statistically significantly, at most time points, reduced in the high dose group after week 4.
For details on body weight, please refer to the field "attached background material". - Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Details on results:
- Only data on non-diabetic rats are considered. According to the authors, apart from the body weight changes, intakes of VOSO4 and plasma V concentrations, there were no significant differences in all other parameters among the V treatment groups. Therefore, the pooled results of the 3 treatment groups were used.
FOOD CONSUMPTION
- Food intake was not changed by V exposure compared to the controls.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
- Water intake was not changed by V exposure compared to the controls.
- Average intakes of VOSO4 were reported to be 34, 54 and 90 mg/kg bw/day (corresponding to 0.16, 0.25 and 0.41 mmol/kg/day).
HAEMATOLOGY
- Haematocrit did not show any differences between treatment and control groups.
- No differences between treatment and control groups were observed with respect to the haematological indices.
CLINICAL CHEMISTRY
- Apart from transient fluctuations, data on clinical chemistry were not changed by the treatment.
ORGAN WEIGHTS
- Relative organ weights of brain, thymus, lung, heart, liver, spleen, pancreas, kidney, adrenal, testis did not differ from controls.
GROSS PATHOLOGY
- Gross pathology did not reveal marked differences between treated animals and their controls.
HISTOPATHOLOGY: NON-NEOPLASTIC
- Histopathology did not reveal marked differences between treated animals and their controls.
- Due to the small differences compared to controls, it is difficult to assess whether inflammatory focal cell infiltration of pancreas, interstitual cell hyperplasia in the testis and Leydig cell tumours seen in the groups after 1 year of treatment (1 or 2 animals each) as well as after cessation (1 animal each) was treatment-related. In contrast to the authors’ opinion, no clear recovery of liver and kidney lesions was observed after 16 weeks of cessation.
OTHER FINDINGS
- Systolic blood pressure, and pulse rate did not show any differences between treatment and control groups.
- At the end of the treatment period, plasma samples contained 0.18, 0.31 and 0.46 µg V/ml.
- At weeks 6 and 13 following withdrawal of V, no detectable amounts of V were found.
- Non-fasting blood glucose and fasting plasma glucose were not influenced by VOSO4 treatment, but fasting plasma insulin was reduced compared to the controls.
- VOSO4 treatment had no effect on triglycerides and cholesterol compared to the controls.
- A dose-related increase of V concentrations in various tissues was observed with a ranking bone>kidney testis>liver>plasma>pancreas>brain. After 16 weeks of cessation, small concentrations of V could be detected only in brain and kidney indicating some affinity of V to thes tissues but not in plasma and in the other organs investigated. - Dose descriptor:
- NOAEL
- Effect level:
- 750 mg/L drinking water
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: 54±4.1 mg/kg bw/day (based on fluid intake)
- Dose descriptor:
- NOAEL
- Effect level:
- 16.9 mg/kg bw/day (nominal)
- Based on:
- element
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: based on fluid intake
- Critical effects observed:
- not specified
- Conclusions:
- Four groups of non-diabetic male rats received different concentrations of vanadyl sulfate (VOSO4) in drinking water for 52 weeks. The low dose group received 500 mg VOSO4/L in water for 52 weeks. The mid dose group received 500 mg/L for 1 week followed by 750 mg VOSO4/L in water for 51 weeks. The high dose group received 500 and 750 mg/L for 1 week each followed by 1250 mg VOSO4/L in water for further 50 weeks. Three recovery animals of each group were followed for further 16 weeks after cessation of VOSO4 treatment.
Treatment of male rats with different dose levels of vanadyl sulfate in drinking water corresponding to 34, 54 and 90 mg/kg bw/day over 52 weeks did not indicate severe signs of systemic toxicity under the conditions of this study. Body weights were dose-dependently reduced in treatment groups compared to controls, occasionally reaching statistical significance in the low and mid dose groups and at most time points in the high dose group. At study termination (week 52) significant difference in body weight (>10%) compared to control animals was observed in high dose animals only. Body weights of low and mid dose animals were lower (<10%) but not significantly different and thus considered not biologically relevant.
Based on significant and biologically relevant effects on body weight in high dose animals, the mid dose level of 54 mg/kg bw/day represents a NOAEL. - Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- no data
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- significant methodological deficiencies
- Remarks:
- Well document study, however, beside general toxicity, the investigations were restricted to liver and renal function parameters and histopathology. The following deficiencies were noted: test item insufficiently described, no analytical verification of applied doses, only males were used, haematology missing, clinical biochemistry parameter missing, missing organ weights, several organs were not histopathologically examined, details on gross pathology not given, ophthalmological examination not performed, FOB not conducted, thyroid hormones not determined, historical control data missing and individual/raw data not provided, details on histopathological findings were not provided.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Sodium metavanadate was given to groups of male Sprague-Dawley rats at concentrations of 0, 5, 10 and 50 ppm for three months. Liver and renal function parameters were determined in blood at the end of exposure period and organ weights were taken (liver, kidneys, heart, spleen, lung). Heart, liver, lungs, kidneys, spleen, stomach, small and large intestine were histopathologically examined in three rats of each group.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS (40 males)
- Source: Biocentre (Barcelona, Spain)
- Weight at study initiation: about 91.6 +/- 10.8 g at the start of exposure
- Housing: all animals were placed in individual metabolism cages
- Diet: ad libitum (perfectly balanced Panlab diet, Barcelona, Spain), neglible vanadium concentration
- Water: ad libitum - Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Solutions of sodium metavandate and water were prepared without heating at pH 7.4 and stored at 21-24 °C - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- no data
- Duration of treatment / exposure:
- 3 months
- Frequency of treatment:
- continuous (in drinking water)
- Dose / conc.:
- 5 ppm
- Remarks:
- nominal in water
- Dose / conc.:
- 10 ppm
- Remarks:
- nominal in water
- Dose / conc.:
- 50 ppm
- Remarks:
- nominal in water
- No. of animals per sex per dose:
- 10 males per group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- no data
- Positive control:
- no data
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, measured daily
FOOD EFFICIENCY: Yes
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: protein efficiency coefficient was calculated weekly
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: No data
CLINICAL CHEMISTRY: Yes,
- Time schedule for collection of blood: at the end of exposure
- How many animals: 5 animals per group
- Parameters checked: serum analyses was carried out (GOT, GPT, total protein, bilirubin, urea, uric acid,creatine, glucose and cholesterol)
URINALYSIS: Yes
- Metabolism cages used for collection of urine: Yes
- Parameters checked: volume excreted
NEUROBEHAVIOURAL EXAMINATION: No data
IMMUNOLOGY: Not specified
OTHER
- Vanadium concentration in liver, kidneys, spleen, heart and lungs were determined - Sacrifice and pathology:
- All animals not used for clinical chemistry were killed at the end of exposure.
GROSS PATHOLOGY: Yes
- Necropsy was performed on all animals after exsanguination.
- Organ weights of liver, kidneys, heart, spleen and lungs were determined.
HISTOPATHOLOGY: Yes:
- Histological examination of heart, lungs, liver, kidneys, spleen, stomach and small and large intestine in three rats of each group. - Other examinations:
- no
- Statistics:
- The significance of differences between control and treated groups was calculated by the Student's test. A difference is considered to be significant when p<0.05.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - The amount of total protein was significantly increased in the highest dose group.
- The plasma concentrations of urea and uric acid were increased in the highest exposure group. - Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- on volume of urine
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - Histopathological investigation showed mild, though dose-dependent, lesions in kidneys, lungs and spleen in all dosage groups.
- The changes were more evident in the highest dose group (no further details presented).
- Hyperthrophy and hyperplasia were observed in the white pulp of spleen.
- Corticomedullar micro haemorrhagic foci were seen in kidneys.
- Mononuclear cell infiltration, mostly perivascular, were found in lungs. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
- Appearance, behaviour and mortality of the treated rats of all groups were not affected.
BODY WEIGHT AND WEIGHT GAIN
- Growth of the treated rats of all groups was not affected.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- Food consumption of the treated rats of all groups was not affected.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
- Water consumption of the treated rats of all groups was not affected.
CLINICAL CHEMISTRY
- Enzyme activities (GOT, GPT) and the amounts of bilirubin in the plasma did not indicate effects on the liver function.
- Glucose and cholesterol showed no changes.
URINALYSIS
- No effects on volume of urine.
ORGAN WEIGHTS
- No dose-dependent differences between treated animals and controls.
OTHER FINDINGS
- Vanadium accumulation was first observed at the dose of 10 ppm in the kidneys and spleen and increased dose-dependently.
- At the highest dose, enrichment of V was also observed in liver, heart and lungs compared to the lower doses and the controls. - Dose descriptor:
- NOEL
- Effect level:
- 1.51 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Dose descriptor:
- NOEL
- Effect level:
- 0.62 mg/kg bw/day (nominal)
- Based on:
- element
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Critical effects observed:
- not specified
- Conclusions:
- Sodium metavanadate in drinking water was given to four groups, each consisting of 10 male Sprague-Dawley rats, at concentrations of 0, 5, 10 and 50 ppm. Liver and renal function parameters were determined in blood at the end of exposure period and organ weights were taken (liver, kidneys, heart, spleen, lung). Heart, liver, lungs, kidneys, spleen, stomach, small and large intestine were histopathologically examined in three rats of each group.
Oral administration of NaVO3 via drinking water to groups of male rats over 3 months at concentrations of 0, 5, 10 and 50 ppm caused mild, dose-dependent lesions in kidneys, lungs and spleen with the highest incidence in the 50 ppm group, and increased plasma concentrations of protein, urea and uric acid in the high dose group. Thus, the highest dose level (7.57 mg/kg bw/d NaVO3) represents a clear LOAEL, and the mid dose level (1.51 mg/kg bw/d NaVO3) represents a NOAEL. - Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- significant methodological deficiencies
- Remarks:
- The following deficiencies were noted: test substance insufficiently described, number of animals per group too low for appropriate statistical analysis, only male rats were used, individual body weight data not given, clinical signs were not recorded, complete haematology missing for 100 and 150 ppm group, haematology not performed for remaining groups, clinical biochemistry not conducted, organ weights, necropsy and histopathology not performed/recorded, FOB not performed, thyroid hormones not determined, ophthalmological examination not performed, historical control data not provided, the applied doses were changed during the study.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Measurement of the cystine content of the hair of rats fed diets containing vanadium pentoxide was undertaken to determine if there were changes in cystine content indicative of abnormal metabolism.
Rats were given diets supplemented with vanadium at both high and low levels. In a separate experiment, methionine was also included in the diet of vanadium fed rats to determine whether this sulfur amino acid would counteract the effects of vanadium. - GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 200 to 350 gm (Details for Low Level Vanadium exposure group)
- Diet: Purina Dog Chow Checkers, ground in a Wiley Mill. - Route of administration:
- oral: feed
- Vehicle:
- other: Purina Dog Chow Checkers
- Details on oral exposure:
- Low Level Vanadium exposure:
- One group received a stock diet of Purina Dog Chow Checkers.
- A second group received the stock diet, with 25 ppm of vanadium incorporated in the form of vanadium pentoxide.
- 50 ppm of vanadium was similarly included in the diet of a third group.
- After 35 days, the levels of dietary vanadium were raised to 100 and 150 ppm, respectively, in order to elicit more pronounced differences.
High Level Vanadium exposure:
- A similar study was performed on rats fed the vanadium pentoxide at levels of 500 and 1,000 ppm of vanadium.
- A fourth group of five rats which served as group-paired fed control for those receiving 500 ppm was added.
High Level Vanadium with added methionine:
- dl-methionine in amounts of 1.6 % was added to the diet of one group of rats whose diet further contained 500 ppm V as the pentoxide.
- Another similar group was fed a diet containing 500 ppm V only
- A third similar group served as group-paired fed controls for the latter. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - The metallic composition of the stock and the vanadium-supplemented diets were determined by spectrographic analysis.
- Stock diet of the rats contained an average of 0.7 γ of vanadium per gram. - Duration of treatment / exposure:
- - Low Level Vanadium exposure: 103 days
- High Level Vanadium exposure: 75 days
- High Level Vanadium with added methionine exposure: 63 days - Frequency of treatment:
- Daily
- Dose / conc.:
- 25 ppm
- Remarks:
- (nominal vanadium content in diet; first 35 days; low level vanadium exposure group)
- Dose / conc.:
- 100 ppm
- Remarks:
- nominal vanadium content in diet (36 -103 days; low level vanadium exposure group)
- Dose / conc.:
- 50 ppm
- Remarks:
- (nominal vanadium content in diet; first 35 days; low level vanadium exposure group)
- Dose / conc.:
- 150 ppm
- Remarks:
- nominal vanadium content in diet (36 -103 days; low level vanadium exposure group)
- Dose / conc.:
- 500 ppm
- Remarks:
- vanadium with or without methionine; nominal in diet (High Level Vanadium with added methionine exposure group)
- Dose / conc.:
- 500 ppm
- Remarks:
- nominal vanadium content in diet (High Level Vanadium exposure group)
- Dose / conc.:
- 1 000 ppm
- Remarks:
- nominal vanadium content in diet (High Level Vanadium exposure group)
- No. of animals per sex per dose:
- - Low Level Vanadium exposure: 5 male rats per dose plus one control group of 5 rats
- High Level Vanadium exposure: 5 male rats per dose plus one control group of 5 rats and one group of 5 rats as group-paired fed control for those receiving 500 ppm.
- High Level Vanadium with added methionine: 6 rats in the 500 ppm group, 6 rats in the control-fed group, and 7 rats at 500 ppm + 1.6% dl-methionine. - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No data
- Positive control:
- No data
- Observations and examinations performed and frequency:
- LOW LEVEL VANADIUM EXPOSURE:
CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT GAIN: Yes
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Daily records of food consumption were kept throughout the duration of the experiment.
FOOD EFFICIENCY: No data
WATER CONSUMPTION: No data
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY:
- Red blood cell count and hemoglobin level were determined.
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: Not specified
OTHER:
- Just prior to the introduction of vanadium into the experimental diets, samples of hair were clipped from all the animals.
- Other hair samples were taken at 60 and 103 days (Low Level Vanadium) or 36 and 75 days (High Level Vanadium).
- The hair samples were obtained by first skirting off and discarding about 1 to 1.5 cm of the hair back from the tips. An electric clipper was then used to cut of the hair close to the skin over an area from the shoulder to the base of the tail on the back of the animal. Samples were defatted by placing in evaporating dishes containing benzene for 30 minutes, rinsing with fresh benzene, draining, and air drying (Sullivan, M.X.; Hess, W.C., and Howe, P. E.: A Comparison of the Wool and Skins of Full-Fed and Maintenance-Fed Lambs, J. Agric. Res. 61: 877, 1940).
- Hair samples were stored in a vacuum desiccator over Drierite for 24 hours or until analyzed.
- Samples were analyzed for cystine content. - Sacrifice and pathology:
- GROSS PATHOLOGY: No data
ORGAN WEIGHT: liver-weight to body weight ratio (HIGH LEVEL VANADIUM WITH ADDED METHIONINE EXPOSURE)
HISTOPATHOLOGY: No data - Other examinations:
- No data
- Statistics:
- Analysis of variance was used.
- Clinical signs:
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Details on results:
- LOW LEVEL VANADIUM EXPOSURE:
BODY WEIGHT AND WEIGHT GAIN/FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- Food intake of all groups (total food intake: control: 1,996 gm/rat; 100 ppm group: 2,130 gm/rat; 150 ppm group: 2,019 gm/rat) was nearly the same.
- The vanadium test groups gained more weight than did the controls (average body weight gain: control: 101 gm/rat; 100 ppm group: 156 gm/rat; 150 ppm group: 146 gm/rat); this was not statistically significant.
HAEMATOLOGY
- At 100 and 150 ppm, lower erythrocyte counts were obtained (at study termination: control: 7.7; 100 ppm group: 6.8; 150 ppm group: 6.3)
- Hemoglobin level were decreased (at study termination: control: 15.0; 100 ppm group: 14.5; 150 ppm group: 13.7); this was not statistically significant.
OTHER FINDINGS:
- The cystine content of the hair of the control group increased with time, whereas that of the rats fed the 100 ppm vanadium diet remained nearly constant
- At the 150 ppm level, a decrease in the average hair cystine values occurred.
- The hair cystine of all the individual rats in the control group increased, the smallest increase amounting to 1.15 %.
- Of three rats in the vanadium groups which showed higher hair cystine after, the greatest single increase (0.76%) occurred in those receiving the 100 ppm V.
- The decrease in cystine are considered significant on a relative basis, i.e., comparing the vanadium-fed groups with their corresponding controls.
- The average change in cysteine was statistically significant different from the 100 ppm group and the 150 ppm group (at the 0.5% level).
HIGH LEVEL VANADIUM EXPOSURE:
CLINICAL SIGNS AND MORTALITY
- One rat died in the third week.
BODY WEIGHT AND WEIGHT GAIN
- A decreased rate of body-weight gain occurred in both high level vanadium treated groups, compared with that of controls
- The decreased weight gain was greater in both vanadium groups than in the group-paired fed controls, indicating that food restriction was not the sole factor of growth impairment
- Average body weight gains: control: 125 gm/rat; 500 ppm group: 42 gm/rat; food control group: 90 gm/rat; 1000 ppm group: - 2 gm /rat; this was not statistically significant.
OTHER FINDINGS
- The cystine content of hair of rats fed the higher levels of vanadium, 500 and 1,000 ppm, was depressed in comparison with that of the controls
- Average change in cystine: control: 0.44 +/- 0.20 %, 500 ppm group: -0.19 +/- 0.48%; food control group: -0.26 +/- 0.25%; 1000 ppm group: -0.76 +/- 0.13%; statistically significant at the 5% level).
- This finding corresponded to that at the lower levels, with the difference that the percentage decrease in cystine at the 1,000 ppm level was greater (0.76%) and occurred sooner (75 days) than at the 150 ppm level which required 103 days to produce a 0.41 % average decrease in cystine content.
- The 0.76 % decrease in hair cystine content at the 1,000 ppm level of vanadium feeding is highly significant on an absolute basis, i.e., comparing final and original cystine percentages within the same group.
HIGH LEVEL VANADIUM WITH ADDED METHIONINE EXPOSURE:
BODY WEIGHT AND WEIGHT GAIN
- The weight gain per 100 gm of food consumed by the rats on the methionine-vanadium diets somewhat improved, as compared with those on vanadium diets (5.66 gm. vs. 6.62 gm, not statistically significant).
ORGAN WEIGHTS
- Methionine did not significantly affect either the growth or the relative liver weight in vanadium-fed animals.
- The average values for these suggest a definite tendency toward improvement as a result of the administration of methionine.
- The methionine supplement, however, did not significantly change the liver-weight to body weight rations.
OTHER FINDINGS
- The methionine supplement, however, did not significantly improve the growth of the hair.
- It was noted that the hair growth of the methionine-fed animals was markedly inhibited (10 -90 %).
COMBINED FINDINGS:
- Substantiating evidence for chemical changes found in the hair of vanadium-treated animals were structural changes, both gross and microscopic.
- The regrowth of hair was sparser, coarser, and stiffer compared with the more fleece-like hair of the controls. - Dose descriptor:
- NOEL
- Effect level:
- 4.58 mg/kg bw/day (nominal)
- Based on:
- element
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- Dose descriptor:
- NOEL
- Effect level:
- 150 ppm
- Based on:
- element
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- Critical effects observed:
- not specified
- Conclusions:
- Male rats were treated with vanadium pentoxide for up to 103 days. The experimental setup was split into three phases: 1. animals were exposed to 0, 100 and 150 ppm V for 103 days; 2. animals were exposed to 0, 500 and 1000 ppm V and one group-paired fed control for the 500 ppm group for 75 days; 3. animals were exposed to 0 and 500 ppm V and an additional group was fed with a diet containing 500 ppm V and 1.6% methionine for 63 days.
In all three setups body weight gain and food intake as well as amount of ingested vanadium were recorded. In the first two setups of the study the cysteine content of hair was determined three times (1. setup: day 0, 60 and 103; 2. setup: day 0, 36 and 75). Additionally, in the first setup, red cell count and haemoglobin was determined before study initiation and at study termination. In the third setup liver to body weight ratio was recorded.
According to the author, hair cysteine content decreased dose-dependently in animals exposed to 100, 150, 500 and 1000 ppm vanadium. The food intake was not significantly affected in animals exposed to vanadium. However, animals exposed to 500 and 1000 ppm vanadium showed significantly decreased body weight gains after 75 days (500 and 1000 ppm V) and 63 days (500 ppm V). Animals exposed to 100 and 150 ppm vanadium for 103 days showed slightly decreased red cell counts and haemoglobin levels. No effects on liver to body weight ratios were observed in animals exposed to 500 ppm vanadium for 63 days.
Since the effects on red cell count and haemoglobin in animals exposed to 100 and 150 ppm for 103 days were mild and within historical control ranges of this rat strain and age, the effects were considered to be negligible. Further, cysteine content of rat hair was slightly reduced but the adversity of this effect remains questionable. Since body weight and food consumption in animals exposed to 100 and 150 ppm V were normal and no further adverse effects were observed, mildly decreased values of cysteine in hair is considered not adverse. Consequently, 150 ppm V (equivalent to 4.58 mg V/kg bw/day) represents the NOEL of this study, based on the reduced body weight gain in animals exposed to 500 and 1000 ppm vanadium. - Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- significant methodological deficiencies
- Remarks:
- Well reported study, however, the relevance of the study is limited because only selected parameters were investigated and animals were dosed for only 4 weeks. The test material was insufficiently described, complete haematology, clinical biochemistry, FOB, necropsy, ophthalmological examination, thyroid hormones, organ weights and histopathology were not conducted/evaluated, applied doses were not analytically analysed, historical control data were not provided and only two doses were applied.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Male and female Wistar rats were orally exposed to ammonium metavanadate (0, 10 or 50 mg V/L ) in drinking water for 4 weeks. Body weight gain, food and fluid uptake as well as various haematological and biochemical parameters were determined.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS (46 males and 47 females)
- Age at study initiation: 2 months
- Housing: rats were housed singly in stainless steel cages in a vivarium
- Diet: standard granulated rodent laboratory chow (LSM; CLPP; Motycz, Lublin, Poland)
- Water (ad libitum): deionized water (for control animals)
ENVIRONMENTAL CONDITIONS
- Temperature: 19 -20 °C
- Humidity: 60 +/- 10%;
- Photoperiod (hrs dark / hrs light): natural day-night light cycles - Route of administration:
- oral: drinking water
- Vehicle:
- water
- Remarks:
- sole drinking water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Aqueous solutions of AMV at concentrations of 10 and 50 mg V/L were prepared - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- no data
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- continuously (in drinking water, ad libitum)
- Dose / conc.:
- 10 mg/L drinking water
- Remarks:
- nominal in water
Vanadium intake: males. 1.18 ± 0.01 mg/kg bw/day; females: 1.50 ± 0.23 mg/kg bw/day (calculated based on ingested amount of AMV solution) - Dose / conc.:
- 50 mg/L drinking water
- Remarks:
- nominal in water
Vanadium intake: males. 4.93 ± 0.15 mg/kg bw/day; females: 6.65 ± 0.27 mg/kg bw/day (calculated based on ingested amount of AMV solution) - No. of animals per sex per dose:
- 15 -16 animals each
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Rationale for animal assignment: Animals of each sex were randomly divided into three groups.
- Positive control:
- no data
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: the amount of food consumed was checked daily
FOOD EFFICIENCY: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: amounts of water and AMV solution consumed for the tested rats were checked daily
during of the experimental period.
- The vanadium intake was calculated on the basis of the amount of AMV solution consumed for rats.
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: Yes
- Parameters checked: number of erythrocytes and leukocytes, haemolobin level, haematocrit, percentage composition of leukocytes and polychromatophilic erythrocytes in the peripheral blood, percentage of reticulocytes
CLINICAL CHEMISTRY: No data
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: No data
IMMUNOLOGY: Not specified
OTHER:
- Enzyme measurements were performed from freshly collected blood: erythrocytes enzyme activities: catalse, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, δ-aminolevulinic acid dehydratase
- The level of lipid peroxides in erythrocytes was deteremined (expressed as malonyldialdehyde (MDA) equivalent)
- The L-ascorbic acid concentration in plasma and red blood cells was determined
- The reduced glutathione level (GSH) in blood was estimated - Sacrifice and pathology:
- no data
- Other examinations:
- no data
- Statistics:
- Student's t-test was used for statistical analysis. The value of P < 0.05 was assumed as the level of significance. All results are presented as mean values +/- SEM.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight increases of the animals receiving aqueous AMV solutions were lower than those of controls.
Body weight gain in males: control: 74.77± 5.97 g; low dose: 63.83± 2.86 g; high dose: 67.85 ± 3.10 g
Body weight gain in females: control: 35.03± 2.61 g; low dose: 27.88± 2.80 g; high dose: 31.92± 2.22 g
Overall, body weight gain was slightly reduced in the treatment groups compared to the controls but not in a dose-related manner. - Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Slightly but statistically significant reduced fluid intake in high dose males (control males: 25.65 ± 0.65 cm3/rat, high dose males: 22.04 ± 0.68 cm3/rat). No effects in females.
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- HAEMATOLOGY:
- Haematological examination demonstrated a significant decrease in the erythrocyte count in both treatment groups, whereas haemoglobin levels were significantly reduced only in the high dose group. Hematocrit was reduced in males and females of both treatment groups, but significantly reduced in males only.
- Decrease in the erythrocyte count was associated with a increase in the percentage of reticulocytes, statistically significant in high dose males and females, and a non-statistically significant but dose dependent increase in polychromatophilic erythrocyte percentage in peripheral blood.
- the leukocyte count, including neutrophils, eosinophils, monocytes and lymphocytes, was not changed compared to control animals. - Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
- Treated animals did not show any differences in their external appearance or locomotor behavior as compared with controls.
- No diarrhoe was observed in the treatment groups
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- Food uptake in the experimental groups was similar compared to the control group.
OTHER FINDINGS
- Biochemical analyses demonstrated a decrease of L-ascorbic acid levels in plasma and erythrocytes of males and females exposed to V. But the difference proved to be statistically significant for L-ascorbic acid in plasma of males only (control: 14.09±1.17 µg/cm3; low dose: 10.67±1.16 µg/cm3; high dose: 8.90±1.69 µg/cm3).
- A tendency for the malonyldialdehyde level to increase in the blood was also observed.
- The GSH level in blood was slightly depressed.
- Among the enzymes examined in the erythrocytes (catalase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase and delta-aminolevulinic acid dehydratase [ALA-D]) only the ALA-D activity was depressed, but not statistically significant. - Dose descriptor:
- NOEL
- Effect level:
- 50 other: mg V/L
- Based on:
- element
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects observed
- Dose descriptor:
- NOEL
- Effect level:
- 4.93 mg/kg bw/day (nominal)
- Based on:
- element
- Sex:
- male
- Basis for effect level:
- other: see remarks
- Dose descriptor:
- NOEL
- Effect level:
- 6.65 mg/kg bw/day (nominal)
- Based on:
- element
- Sex:
- female
- Basis for effect level:
- other: see remarks
- Critical effects observed:
- not specified
- Conclusions:
- Male and female Wistar rats were orally exposed to ammonium metavanadate (0, 10 or 50 mg V/L ) in drinking water for 4 weeks. Body weight gain, food and fluid uptake as well as various haematological and biochemical parameters were determined.
Effects on palatability of vanadium containing fluids was observed at 50 mg V/L (significant in males but not in females). Mild and not dose-dependent effects were observed on body weight gain. Additionally, slight but significant effects on erythrocytes, reticulocytes and haemoglobin as well as L-ascorbic acid level in plasma and erythrocytes were observed in both dose groups. As no dose dependency was observed, mild effects on body weight gain were considered negligible. Significant effects on haematological parameters were considered to be mild and within historical control ranges of this rat strain and age (discussed below). Effects on L-ascorbic acid level in erythrocytes and plasma were also not considered relevant since the adversity of this effect is unclear (discussed below) and no further adverse effect was observed. Based on this, the NOEL of this study is considered to be 50 mg V/L drinking water, which is equivalent to 4.93 and 6.65 mg V/kg bw/day in males and females, respectively.
This study is well reported, however, no guideline was followed and only limited parameters were analysed. Erythrocytes and haemoglobin and reticulocytes were slightly but significantly changed in both dose groups and sexes. These changes were not considered to be adverse as they were minor compared to control and within historical control data of this rat strain and age (e.g. Kort, M. et al. (2020) and Giknis, M. & Clifford, C.B. (2008)).
Apart from the above-mentioned minor effects on some haematological parameters, the level of L-ascorbic acid was significantly decreased in plasma of low and high dose males but not in females. The same author reported one year later (please refer to Zaporowska 1994) that male and female rats exposed to doses of up to 0.30 mg V/ml showed clearly reduced L-ascorbic acid values in liver, kidney, adrenals and spleen. Thus, exposure to ammonium metavanadate seems to correlate with decreased L-ascorbic acid values in different tissues and body fluids. However, as no systemic toxicity or any other effect was observed, it remains unclear whether mild to moderate L-ascorbic acid depression is or results in any adverse effects. In a publication of Chan & Reade (1996) Wistar Shionogi rats, unable to synthesize L-ascorbic acid, were supplemented with different doses of L-ascorbic acid to determine the L-ascorbic acid requirements in Wistar rats. After 26 weeks, all animals survived and showed no clinical signs of scurvy. The average weekly body weight gain was normal. A severe L-ascorbic acid deficiency would include perinasal and peri-and intra-oral haemorrhage, joint or intramuscular haemorrhage, weakened or fractured hind limbs, delayed wound healing and a failure to thrive (Clemetson, 1989). As none of these clinical signs were observed in studies reported by Zaporowska (1993, 1994) or Chan & Reade (1996), it is assumed that this mild to moderate L-ascorbic acid depression observed in this study is not an adverse effect.
It has been demonstrated that the toxicity of vanadium increases with its valency. Thus, compounds containing pentavalent V, such as ammonium metavanadate, are most poisonous. It is known that pentavalent V enters cells through anion channels, i.e. phosphate or sulfate channels. In cells, pentavalent V is reduced to divalent VO by some reducing compounds such as L-ascorbic acid and thiol-containing cysteine. Thus, the reported reduction of L-ascorbic acid in plasma and erythrocytes and also in several tissues (Zaporowska, 1994) is most likely the result of an enhanced consumption/reduction activity of this compound. However, in contrast to humans, rodents are able to synthesize L-ascorbic acid. Thus, it can be assumed that this reduction of L-ascorbic acid will induce re-synthesis and reduction of L-ascorbic acid is an adaptive but not an adverse effect. Apart from that, it is also noteworthy that humans are not able to synthesize L-ascorbic acid. Based on this, it is assumed that the protective reduction of pentavalent V to divalent VO is performed by another reducing substance and thus, it remains questionable whether a reduction of L-ascorbic acid in rats is relevant for humans.
References:
Clemetson, I.B. et al. (1975): Synthesis and some major functions of vitamin C in aniamsl. Annals of New York Academy of Science 258, 24 -46
Kort, M. et al. (2020):
Historical control data for hematology parameters obtained from toxicity studies performed on different Wistar rat strains: Acceptable value ranges, definition of severity degrees, and vehicle effects. Toxicology Research and Application, Vol. 4:1 -32
Giknis, M. & Clifford, C.B. (2008):
Clinical Laboratory Parameters for Crl:WI (Han)- Historical control data of studies conducted at Charles River - Executive summary:
Two-months old male and female Wistar rats were dosed with 10 and 50 mg V/L drinking water for 4 weeks. Body weight gain, food and fluid uptake as well as various haematological and biochemical parameters were determined.
According to the author, food intake was not affected, however, fluid intake was statistically significant decreased in high dose males but not in females. Body weight gain showed a tendency to be decreased in low and high dose animals, but not dose dependently and not statistically significant. Erythrocytes were significantly decreased in both dose groups, but not dose dependently in males. Haemoglobin was significantly decreased in high dose males and females, whereas haematocrit was significantly decreased in low and high dose males only. Reticulocytes were significantly decreased in high dose males and females whereas leukocytes were not affected at all. Biochemical analyses demonstrated a decrease of L-ascorbic acid levels in plasma and erythrocytes of males and females exposed to V. But the difference proved to be statistically significant for L-ascorbic acid in plasma of males only. GSH level in blood was slightly depressed and among the enzymes examined in the erythrocytes only the ALA-D activity was depressed, but not statistically significant.
Referenceopen allclose all
After cessation of VOSO4 treatment, no differences between controls and V treatment groups were observed with regards to the biological parameters apart from slightly increasing body weight gain in the treatment groups adapting to normal values of the control group.
Conversion from ppm (mg/L) to mg/kg bw /d based on:
Study Duration: three months/91 d
Average drinking water consumption): 3747.3 mL/rat => 41.2 ml/rat/d
Average body weight: [91.6 (start) + 450.2 (end)]/2 = 272 g (divided by two to use as mean weight during the study)
10 mg NaVO3/L = 1.51 mg/kg bw/d
50 mg NaVO3/L = 7.57 mg/kg bw/d
Conversion of NOEL (ppm in diet) to NOEL (mg/kg bw /d):
NOEL: 150 ppm V
Duration: 103 d
Food intake: 2,019 g/rat
Body weight (kg bw/rat): 0.5 kg
V ingested reported: 236 mg V/rat/103 d= 2.29 mg V/d
NOELcorrected 4.58 mg V/kg bw/d
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 4.58 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Several supportive studies exist. A number of studies are available where vanadium compounds were administered; however, they have involved different experimental approaches and designs as well as different dose regimens, and endpoints. For oral exposure, effects are more limited and the different experimental approaches lead to a variety of endpoints measured.
The NOAEL is expressed as 4.58 mg V/kg bw/d.
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEC
- 0.5 mg/m³
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
- Reliable GLP-conform study with V2O5. Findings in rat model may not be relevant for humans.
The LOAEC is expressed as 0.5 mg V2O5 / m3.
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Initial comment on grouping and read across– oral
The endpoint repeated dose toxicity via the oral route of the vanadium category substance is not addressed by substance-specific information but rather by read-across of data available for soluble tri-, tetra- and pentavalent vanadium substances as well as for insoluble vanadium substances with zero valency, such as vanadium carbide.
All vanadium substances within the read-across concept represent inorganic substances, including salts or oxides and form the vanadium category. For the substances of the inorganic vanadium substances category, it is assumed that the in vivo bioavailability of the vanadium varies in a predictable manner, which is dependent on the in vitro bioaccessibility of the respective vanadium substance, i.e. all members of the category liberate vanadium ions in aqueous media at different rates, inter alia depending on the chemical structure. Thus, this concept is based on the chemistry / composition of all substances and on experimental studies for (i) water solubility and (ii) in-vitro bioaccessibility: assessment of the solubility and speciation of vanadium substances in five different artificial physiological fluids. Robust summaries for these studies are provided in each registration dossier and a detailed evaluation of the relevance, reliability and adequacy of each study is presented in the individual study records. Based on the in vitro bioaccessibility and the available bridging studies, two read-across groups are defined for the systemic effects following oral exposure, i.e. (i) soluble vanadium substances and (ii) poorly soluble vanadium substances. This endpoint summary addresses the hazard data for the soluble read-across group. Further details on the read-across concept are presented in the report attached to IUCLID section 13.
Therefore, the remaining text in this chapter is generic for all vanadium substances of the soluble read-across group and has not been adapted on a substance-specific basis.
Oral - animal data:
A number of studies are available reporting findings observed mainly in rats but also in mice orally exposed to soluble tetra- and pentavalent vanadium substances. However, the studies applied different experimental designs and were targeted at investigating specific endpoints. Thus, the different experimental approaches led to results on a variety of endpoints, which is why the weight of evidence approach is applied.
Based on the available data, the following adverse effects were identified: body weight reduction, haematological effects and reduction of antioxidants in tissues and body fluids. These effects are the most consistently reported among a number of investigators (Mountain et al. 1953, Dai et al. 1985, Roberts et al. 2015 and 2019, Zaporowska et al. 1993, Scibior et al. 2005, 2006, 2012).
A detailed review of the oral repeated dose toxicity studies in animals is presented below.
Mountain et al. 1953: Male rats were treated with vanadium pentoxide for up to 103 days. The experimental setup was split into three phases: 1. animals were exposed to 0, 100 and 150 ppm V for 103 days; 2. animals were exposed to 0, 500 and 1000 ppm V and one group-paired fed control for the 500 ppm group for 75 days; 3. animals were exposed to 0 and 500 ppm V and an additional group was fed with a diet containing 500 ppm V and 1.6% methionine for 63 days. In all three setups body weight gain and food intake as well as amount of ingested vanadium were recorded. In the first two setups of the study the cysteine content of hair was determined three times (1. setup: day 0, 60 and 103; 2. setup: day 0, 36 and 75). Additionally, in the first setup, red cell count and haemoglobin was determined before study initiation and at study termination. In the third setup liver to body weight ratio was recorded. According to the author, hair cysteine content decreased dose-dependently in animals exposed to 100, 150, 500 and 1000 ppm vanadium. The food intake was not significantly affected in animals exposed to vanadium. However, animals exposed to 500 and 1000 ppm vanadium showed significantly decreased body weight gains after 75 days (500 and 1000 ppm V) and 63 days (500 ppm V). Animals exposed to 100 and 150 ppm vanadium for 103 days showed slightly decreased red cell counts and haemoglobin levels. No effects on liver to body weight ratios were observed in animals exposed to 500 ppm vanadium for 63 days. Since the effects on red cell count and haemoglobin in animals exposed to 100 and 150 ppm for 103 days were mild and within historical control ranges of this rat strain and age, the effects were considered to be negligible. Further, cysteine content of rat hair was slightly reduced but the adversity of this effect remains questionable. Since body weight and food consumption in animals exposed to 100 and 150 ppm V were normal and no further adverse effects were observed, mildly decreased values of cysteine in hair is considered not adverse. Consequently, 150 ppm V (equivalent to 4.58 mg V/kg bw/day) represents the NOEL of this study, based on the reduced body weight gain in animals exposed to 500 and 1000 ppm vanadium. This study was rated as RL 3 due to significant methodological deficiencies.
Dai et al. 1994:Four groups of non-diabetic male rats received different concentrations of vanadyl sulfate (VOSO4) in drinking water for 52 weeks. The low dose group received 500 mg VOSO4/L in water for 52 weeks. The mid dose group received 500 mg/L for 1 week followed by 750 mg VOSO4/L in water for 51 weeks. The high dose group received 500 and 750 mg/L for 1 week each followed by 1250 mg VOSO4/L in water for further 50 weeks. Three recovery animals of each group were followed for further 16 weeks after cessation of VOSO4 treatment. Treatment of male rats with different dose levels of vanadyl sulfate in drinking water corresponding to 34, 54 and 90 mg/kg bw/day over 52 weeks did not indicate severe signs of systemic toxicity under the conditions of this study. Body weights were dose-dependently reduced in treatment groups compared to controls, occasionally reaching statistical significance in the low and mid dose groups and at most time points in the high dose group. At study termination (week 52) significant difference in body weight (>10%) compared to control animals was observed in high dose animals only. Body weights of low and mid dose animals were lower (<10%) but not significantly different and thus considered not biologically relevant. Based on significant and biologically relevant effects on body weight in high dose animals, the mid dose level of 54 mg/kg bw/day represents a NOAEL. This study was rated as RL 2, comparable to guideline study with acceptable restrictions.
Domingo et al. 1985:Sodium metavanadate in drinking water was given to four groups, each consisting of 10 male Sprague-Dawley rats, at concentrations of 0, 5, 10 and 50 ppm. Liver and renal function parameters were determined in blood at the end of exposure period and organ weights were taken (liver, kidneys, heart, spleen, lung). Heart, liver, lungs, kidneys, spleen, stomach, small and large intestine were histopathologically examined in three rats of each group. Oral administration of NaVO3 via drinking water to groups of male rats over 3 months at concentrations of 0, 5, 10 and 50 ppm caused mild, dose-dependent lesions in kidneys, lungs and spleen with the highest incidence in the 50 ppm group, and increased plasma concentrations of protein, urea and uric acid in the high dose group. Thus, the highest dose level (7.57 mg/kg bw/d NaVO3) represents a clear LOAEL, and the mid dose level (1.51 mg/kg bw/d NaVO3) represents a NOAEL. This study was rated as RL 3 due to significant methodological deficiencies.
Zaporowska et al. 1993:Male and female Wistar rats were orally exposed to ammonium metavanadate (0, 10 or 50 mg V/L ) in drinking water for 4 weeks. Body weight gain, food and fluid uptake as well as various haematological and biochemical parameters were determined. Effects on palatability of vanadium containing fluids was observed at 50 mg V/L (significant in males but not in females). Mild and not dose-dependent effects were observed on body weight gain. Additionally, slight but significant effects on erythrocytes, reticulocytes and haemoglobin as well as L-ascorbic acid level in plasma and erythrocytes were observed in both dose groups. As no dose dependency was observed, mild effects on body weight gain were considered negligible. Significant effects on haematological parameters were considered to be mild and within historical control ranges of this rat strain and age (discussed below). Effects on L-ascorbic acid level in erythrocytes and plasma were also not considered relevant since the adversity of this effect is unclear (discussed below) and no further adverse effect was observed. Based on this, the NOEL of this study is considered to be 50 mg V/L drinking water, which is equivalent to 4.93 and 6.65 mg V/kg bw/day in males and females, respectively. This study is well reported, however, no guideline was followed and only limited parameters were analysed. Erythrocytes and haemoglobin and reticulocytes were slightly but significantly changed in both dose groups and sexes. These changes were not considered to be adverse as they were minor compared to control and within historical control data of this rat strain and age (e.g. Kort, M. et al. (2020) and Giknis, M. & Clifford, C.B. (2008)). Apart from the above-mentioned minor effects on some haematological parameters, the level of L-ascorbic acid was significantly decreased in plasma of low and high dose males but not in females. The same author reported one year later (please refer to Zaporowska 1994) that male and female rats exposed to doses of up to 0.30 mg V/ml showed clearly reduced L-ascorbic acid values in liver, kidney, adrenals and spleen. Thus, exposure to ammonium metavanadate seems to correlate with decreased L-ascorbic acid values in different tissues and body fluids. However, as no systemic toxicity or any other effect was observed, it remains unclear whether mild to moderate L-ascorbic acid depression is or results in any adverse effects. In a publication of Chan & Reade (1996) Wistar Shionogi rats, unable to synthesize L-ascorbic acid, were supplemented with different doses of L-ascorbic acid to determine the L-ascorbic acid requirements in Wistar rats. After 26 weeks, all animals survived and showed no clinical signs of scurvy. The average weekly body weight gain was normal. A severe L-ascorbic acid deficiency would include perinasal and peri-and intra-oral haemorrhage, joint or intramuscular haemorrhage, weakened or fractured hind limbs, delayed wound healing and a failure to thrive (Clemetson, 1989). As none of these clinical signs were observed in studies reported by Zaporowska (1993, 1994) or Chan & Reade (1996), it is assumed that this mild to moderate L-ascorbic acid depression observed in this study is not an adverse effect. It has been demonstrated that the toxicity of vanadium increases with its valency. Thus, compounds containing pentavalent V, such as ammonium metavanadate, are most poisonous. It is known that pentavalent V enters cells through anion channels, i.e. phosphate or sulfate channels. In cells, pentavalent V is reduced to divalent VO by some reducing compounds such as L-ascorbic acid and thiol-containing cysteine. Thus, the reported reduction of L-ascorbic acid in plasma and erythrocytes and also in several tissues (Zaporowska, 1994) is most likely the result of an enhanced consumption/reduction activity of this compound. However, in contrast to humans, rodents are able to synthesize L-ascorbic acid. Thus, it can be assumed that this reduction of L-ascorbic acid will induce re-synthesis and reduction of L-ascorbic acid is an adaptive but not an adverse effect. Apart from that, it is also noteworthy that humans are not able to synthesize L-ascorbic acid. Based on this, it is assumed that the protective reduction of pentavalent V to divalent VO is performed by another reducing substance and thus, it remains questionable whether a reduction of L-ascorbic acid in rats is relevant for humans. This study was rated as RL 3 due to significant methodological deficiencies.
The following studies reported similar effects on haematological parameters and body weight and also a few other signs of systemic toxicity, but were regarded as supportive, as several shortcomings in study design and reporting led to limited relevance in risk assessment.
Scibior et al. (2012) and Scibior et al. (2018):A group of 16 male Wistar rats received sodium metavanadate (13.03 mg vanadium/kg bw/day) in drinking water for 12 weeks. The following parameters were investigated: clinical signs, mortality, physical appearance, motor behaviour, food/water consumption, haematology, clinical chemistry, and urinalysis (iron concentration only). Furthermore, atomic absorption measurements of vanadium, magnesium, iron, copper and zinc were conducted in selected biological material (liver, spleen, faeces, red blood cells, and urine). Lastly, femoral diaphysis were prepared and analysed for oxidative stress markers (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, total glutathione, glutathione disulfide, lipid peroxidation) and L-ascorbic acid (also in the liver) as well as metal content (vanadium, magnesium, calcium, iron, copper and zinc).
Scibior et al. (2012):After the administration of 13.03 mg/kg bw/day of sodium metavanadate in drinking water some rats had gastrointestinal disturbances. Loose stool/diarrhoea was observed. No mortality was observed in the study. Furthermore, the treatment with sodium metavanadate led i) to a decrease in fluid and food intake and body weight gain, ii) to the development of microcytic-hypochromic anaemia in the animals with excessive iron disposition in liver and spleen, unaltered plasma iron level and enhanced zinc concentration in red blood cells, characterized by a reduced haemoglobin level and haematocrit, unchanged counts of erythrocytes and reticulocytes, lowered total iron-binding capacity and elevated transferrin saturation, iii) disturbed Cu homeostasis, but iv) did not influence the leucocyte count and the plasma total antioxidant status.
Scibior et al. (2018):Vanadium alone did not significantly alter the thiobarbituric reactive substances and the activity of superoxide dismutase compared with the control but reduced slightly the glutathione reductase activity and the L-ascorbic acid level. It also markedly lowered the activity of catalase and glutathione peroxidase but elevated the activity of glutathione transferase and the hepatic L-ascorbic acid level to some degree.
Further, the vanadium concentration in the bone of the treatment group increased, whereas that of magnesium decreased compared with those in the control group. The total content of zinc and calcium did not change markedly in the treatment group compared to the control group.
In conclusion, the results provided evidence that the concentration of vanadium did not enhance the lipid peroxidation in rat bones. Vanadium administered disrupted the antioxidant defence mechanisms and homeostasis of some metals in bone tissue, which may consequently affect the balance in the activities of osteoblastic and osteoclastic cells.
Scibior & Zaporowska 2007:Outbred 2-month old male albino Wistar rats received for a period of 12 weeks vanadium metavanadate in drinking water at a concentration of 0.1 mg V/mL (equivalent to 8.63 mg V/kg bw/day). The control group received deionized drinking water. Food, fluid and water intakes were monitored daily and rats were weighed weekly. After 12 weeks, liver and kidney weights were recorded and the content of L-ascorbic acid in liver and kidney was analysed. Further, GSH and GSSG were determined in liver and kidney. The content of vanadium (V) in feed was analysed by ICP-AES. V, Fe, Zn and Cu were determined in liver and kidney by ICP-AES. Significant effects on GSH and GSSG level and GSH/GSSG ratio were observed in liver and kidney. Moreover, relative weights of liver and kidney were significantly increased. However, the slight effect on organ weights is considered to be small and thus an adaptive but not an adverse effect. Thus, based on the adverse effects on GSH and GSSG level and GSH/GSSG ratio in liver and kidney, the LOAEL of this study is considered to be 8.63 mg V/kg bw/day. This study is well reported, however, no guideline was followed and only limited parameters were analysed. As no details on food and water intake were reported, it remains unclear if the palatability of vanadium containing drinking water was decreased. The author reported that GSH and GSSG level were slightly but significantly decreased in liver and kidney and vanadium levels in both organs were significantly increased. The same author reported a few years before that the levels of L-ascorbic acid were decreased in liver, spleen, kidney and adrenals as well as in plasma and erythrocytes (Zaporowska 1993, 1994). Both, L-ascorbic acid and GSH/GSSG (a disulfide derived from two glutathione molecules), are involved in detoxifying pentavalent vanadium compounds (as discussed in Zaporowska 1993, 1994). As shown in this study, vanadium was present in liver and kidney while in both organs levels of GSH and GSSG were reduced. Thus, the reported reduction of GSH and GSSG was most likley the result of an enhanced consumption/reduction activity of these compounds during detoxification of pentavalent vanadium. The fact that all cells are capable of synthesizing GSH and consumption of GSH initiates re-analysis of GSH most likely explains the slightly increased organ weights of liver and kidney. Thus, it is assumed that slightly affected organs weights were an adaptive but not an adverse effect.
Zaporowska et al. 1994:As reported in several other studies, effects on palatability of vanadium containing fluids were observed in high dose groups. Significant and dose-dependent decreases were observed in L-ascorbic acid levels in spleen, liver, adrenals and kidneys in males exposed to 0.15 and 0.30 mg V/mL and females exposed to 0.05, 0.15 and 0.3 mg V/mL. However, as the adversity of this effect remains questionable (discussed below) and no systemic toxicity was observed, this effect is not considered to be adverse and thus not taken into account for NOAEL setting. Based on this, 0.30 mg V/mL (equivalent to 22.06 mg V/kg bw/day in males and 26.62 mg V/kg bw/day in females) represents the NOEL. This study is well reported, however, no guideline was followed and only limited parameters were analysed. Significant and dose-dependent decreases were observed in L-ascorbic acid levels in spleen, liver, adrenals and kidneys in males exposed to 0.15 and 0.30 mg V/mL and females exposed to 0.05, 0.15 and 0.3 mg V/mL. Zaporwoska et al. (1993) reported already one year before that L-ascorbic acid levels were decreased in plasma and erythrocytes in rats exposed to ammonium metavanadate (see discussion above).
Scibior et al. 2005:Male Wistar rats were exposed to sodium metavanadate in drinking water (0.1 mg V/mL) for 6 weeks. Calculated average uptake of V was 8.35 ± 0.70 mg/kg/day. Food and fluid intake was reduced, which is however most likely a result of reduced palatability. Body weight gain was slightly affected (approx. 14 % reduction) but not significantly different compared to controls. An increase in erythrocyte count, a decrease in the mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin conc. (MCHC) was observed in the treatment group. No statistically significant decrease in the number of leukocytes, haematocrit and haemoglobin was observed in test animals. Based on these results, 8.35 mg V/kg bw/day is considered to be the lowest observed adverse effect level (LOAEL).
Scibior et al. 2006:In this study, vanadium at the dose of 10.7 mg/kg bw/d consumed by rats with their drinking water for 6 weeks caused a significant decrease in food and fluid intakes, body weight gain, RBC count, Hb level, and MCV and MCH values, whereas no significant differences in WBC count were observed in these animals compared to the control group. Additionally, vanadium at the tested dose resulted in a significant decrease in L-ascorbic acid concentration in plasma and caused a significant increase in MDA concentration in RBC, whereas no significant differences in Total Antioxidant Status level in plasma of rats were shown compared to the controls. Moreover, vanadium treated rats had a higher vanadium concentration in the plasma than the control animals. Based on these results, the lowest observed adverse effects level (LOAEL) is considered to be 10.69 mg V/kg bw/day.
Susic et al. 2006:The study was conducted in male rats with sodium metavanadate in the diet for 24 weeks. Groups of rats received 0, 300 or 3000 ppm NaVO3 in the diet. Investigations: systolic blood pressure, heart rate and body weight, renal functions, haematological parameters, cardiac output, total peripheral resistance, determination of plasma V concentration and weight of the right ventricular wall of the heart. Sub-chronic dietary treatment of rats with NaVO3 over 24 weeks (300 or 3000 ppm) did not affect blood pressure, but induced an increase in total peripheral resistance and a decrease in cardiac output in both groups. Haematocrit was significantly increased and plasma, blood and extracellular fluid volumes decreased in the high dose group. Renal function parameters were not affected by treatment of rats with sodium vanadate.
Higashino et al. 1983:Female SD rats either on normal or high potassium intake were exposed to 5 or 25 ppm vanadium metavanadate for 2 weeks. Body weight was recorded weekly and clinical signs as well as food intake were recorded. At study termination blood was collected and organ weights were recorded. Urine was examined twice for endogenous creatine and Na and K fractional excretion. Additionally, the vanadium concentration in different organs were analysed and the plasma concentration of Na and K was determined. Further, the specific activity of Na-K-ATPase in different tissues was determined. Vanadium exposure had no influence on clinical signs and food and water intake and body weight gain was not affected either. Haematological parameters and urinalysis were not affected by vanadium. Despite extremely high tissue levels of vanadium, no effect of the element on the basal activity of Na-K-ATPase could be observed. As no adverse effects, except elevated vanadium levels in different tissues, were observed, the NOAEL of this study is 25 ppm (equivalent to 2129.5 ± 91.2 meq/kg bw/day, highest concentration of rats exposed to normal potassium intake, high potassium concentration/intake was not considered here).
Conclusion
Altogether, available studies on oral tetra- and pentavalent vanadium compound exposure report significant and biological relevant effects on body weight, indicating that vanadium compounds induce systemic toxicity.
In addition, mild but significant effects on haematological parameter were consistently reported. Effects included reduced haemoglobin, reduced haematocrit, reduced mean cell haemoglobin concentrations, reduced mean corpuscular haemoglobin and mean corpuscular volume as well as elevated reticulocyte counts. Erythrocytes were consistently decreased except in the study of Scibior et al. 2005, which reported a slight but significant increase of erythrocytes in sodium metavanadate treated animals. In contrast, white blood cells were consistently unaffected. Although most of the reported effects on haematological parameters were only mild and in most cases within historical control ranges of the respective rat strain and age, the almost consistent reduction of erythrocytes and haematocrit and increase in reticulocytes indicates that tetra- and pentavalent vanadium compounds induce anaemic effects by reducing erythrocytes, which in turn triggers an erythropoietic response.
The fact that evidence of haematological effects was also observed following 90-day inhalation exposure to vanadium pentoxide, in the absence of other remarkable systemic toxicity (NTP, 2002), increases the confidence in this being an appropriate critical effect for oral exposure from the available dataset. Additional support for the reliability of this endpoint comes from a study by Hogan (Comparative erythropoietic effects of three vanadium compounds, 2000), where haematological effects were demonstrated following IV injection of three different vanadium compounds each with a different valence state (vanadium chloride (V-III); vanadyl sulphate (V-IV); and sodium orthovanadate (V-V)).
In addition to the haematological effects, Scibior and Zaporowska reported in several studies with sodium metavanadate or ammonium metavanadate, that the level of L-ascorbic acid and glutathione in plasma and erythrocytes as well as in different tissues is markedly decreased. The adversity of this effect remains unclear, as no other adverse effects were observed. However, a possible explanation for this significant reduction may be, that vanadium, known to be present in several tissues and body fluids, is detoxified by L-ascorbic acid and glutathione. Thus, the reduction is most likely the result of an enhanced consumption of these substances. However, as humans are not capable to synthesize L-ascorbic acid, it is unknown whether or not this effect is relevant for humans.
National Toxicology Programme
It is to be noted, that 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/). The NTP testing program foresees the conduct of animal studies via oral route (drinking water and feed) on VOSO4 & NaVO3 as follows:
- Genetic toxicology studies, i.e. the Salmonella gene mutation assays, with NaVO3 and VOSO4 - negative
-14 days dose-range finding experiments in Sprague-Dawley rats and B6C3F1/N mice (dose rats and mice: 0, 125, 250, 500, 1000, 2000 mg/L) – completed (Roberts et al. 2015)
- 90 days with Sprague-Dawley rats and B6C3F1/N mice (dose rats and mice: 0, 31.3, 62.5, 125, 250, or 500 ppm) – ongoing, first results presented below (Roberts et al. 2019)
- Perinatal dose-range finding study: gestation day 6 (GD 6) until postnatal day 42 (PND 42) with Harlan Sprague-Dawley rats - ongoing, first results presented below (Roberts et al. 2019)
- 28 days immunotoxicity study (dosed-water) with female B6C3F1/N mice (dose: 0, 31.3, 62.5, 125, 250, or 500 ppm) - 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 the study by Roberts et al. 2015, vanadium oxide sulfate was administered in drinking water at concentrations of 83.8, 167.5, 335, 670, and 1340 mg/L (equivalent to 11.7, 23.2, 35.6, 54.5, and 77.2 mg/kg/day for males and 10.0, 16.9, 28.4, 40.7, and 56.0 mg/kg/day for females). No mortality was observed at any dose, no clinical signs were observed in the 83.8, 167.5, and 335 mg/L groups, whereas clinical abnormalities (thin appearance, hunched posture, and ruffled coats) were seen in male and female mice in the 670 and 1340 mg/L groups, which were related to the body weight effects. At the 83.8, 167.5, and 335 mg/L groups group mean body weight of males and females were comparable with the vehicle group. Body weight reductions were observed in the 670 and 1340 mg/L groups, which however were significant only in the 1340 mg/L groups at study termination. Decreases in feed consumption were observed at 1340 mg/L in males and females, and were consistent with body weight effects. Water consumption per kilogram body weight (g/kg/day) decreased with increasing vanadium oxide sulfate concentration for both male and female mice. Although test item intake (mg/kg/day) increased with increasing concentration in drinking water, the increase was not dose proportional due to decreased palatability. Lastly, numerous statistically significant organ weight alterations were evident, although the vast majority of these alterations were proportional to, or at least followed the same trend as, terminal body weights. Reductions in absolute thymus and thymus-to-body weight ratios were apparent for male and female mice in the 1340 mg/L group, and in females in the 670 mg/L group, possibly due to stress associated with substance exposure and reduced water intake.
Overall, a confounding variable in this study is the reduced water consumption, which appears to be a cause of decreased palatability. The reduced water consumption observed in this study was accompanied with reduced body weight at the highest dose levels.
Due to the limited study design typical for a dose-range finding experiment (detailed clinical observations, haematology, clinical chemistry, and histopathology missing; limited organ weight determination) and severe confounder of reduced water intake, the study is used as supplementary information only.
Sodium metavanadate exposure in drinking water resulted in survival of 100 % of males and females in the 0, 125 and 250 mg/L groups, 80 % of males in the 500 mg/L group, and all females in the 500 mg/L group (125, 250 and 500 mg/L are equivalent to 18.364, 36.065, and 58.216 mg/kg/day for males and 15.247, 26.446, and 38.455 mg/kg/day for females, respectively). Due to early deaths, clinical observations, reduced body weights, and decreases in water and food consumption, animals in the 1000 and 2000 mg/L groups (equivalent to 59.587 and 109.377 mg/kg/day for males and 48.750 and 46.736 mg/kg/day for females, respectively) were terminated early on Day 8 (males) and Day 9 (females). Clinical abnormalities were limited to males and females in the 500, 1000 and 2000 mg/L groups, including shallow or rapid breathing, ruffled coat, abnormal gait, hunched posture, lethargy and/or thin appearance.
At study termination, body weight reduction was apparent in males and females in the 500 mg/L group. Reductions in food mean consumption (g/day) were no longer apparent when food consumption was normalized to body weight (g/kg/day) suggesting food intake was proportional to body weight at the 500 mg/L concentration. Effects on water consumption were apparent for males and females in the 500 mg/L groups, but when normalized to body weight, these effects indicated water consumption was proportional to body weight for these groups. Mice in the 1000 and 2000 mg/L groups exhibited more pronounced toxicity (i.e., mortality, moribundity, and clinical abnormalities) related to body weight effects whereas 80 % of males and 100 % of females in the 500 mg/L group survived to study termination. Thus, palatability issues may have contributed to body weight reductions in the 1000 and 2000 mg/L groups.
Organ weight alterations were noted in the heart, lungs, and ovary (right and left) across all exposure concentrations, whereas reductions in thymus and liver weights were noted in the 500 mg/L group only.
Overall, a confounding variable in this study is the reduced water consumption, which might be due to palatability, and the potential dehydration of the animals. Some of the clinical signs can be attributed to dehydration. In addition, lower water consumption might have caused the body weight reduction observed at the 2000 mg/L dose level.
Due to the limited study design, short exposure duration of only 14 days, restricted examination of the animals (detailed clinical observations, haematology, clinical chemistry, and histopathology missing; limited organ weight determination), and lack of reporting the individual data, the study will not be used for hazard and risk assessment purposes but as supplementary information.
In the study by Roberts et al. (2019), time-mated F0 Hsd:Sprague-Dawley rats were exposed to sodium metavanadate and vanadyl sulfate at concentrations of 0, 31, 63, 125, 250, and 500 mg/L and 0, 21, 42, 84, 168, and 335 mg/L, respectively via drinking water on GD 6. Groups of male and female F1 animals were exposed during gestation, lactation and 13-weeks post-weaning (5 animals for biological sampling). Dams/pups exposed to sodium metavanadate at 250 and 500 mg/L in drinking water exhibited moribundity at birth, failure to thrive, and higher moribundity during lactation. Lower body weights were observed in dams during gestation and lactation, and in pups continuing until study termination 13 weeks post-weaning. Vanadyl sulfate, up to 335 mg/L in drinking water, was well tolerated in time-mated rats during gestation and lactation, and their pups during lactation and up to 13-weeks post weaning.
In study by Roberts et al. (2019), groups of 10 male and 10 female B6C3F1/N mice were exposed to sodium metavanadate and vanadyl sulfate at concentrations of 0, 31, 63, 125, 250, and 500 mg/L and 0, 21, 42, 84, 168, and 335 mg/L, respectively via drinking water for a duration of 13 weeks. Sodium metavanadate in drinking water resulted in lower body weights and water consumption at 500 mg/L in adult mice. Mice exposed to higher concentrations of sodium metavanadate also had lower thymus weight. Lastly, mice exposed to higher (125, 150, 500 mg/L) concentrations of sodium metavanadate exhibited increase in erythrocytes and reticulocytes and decreases haematocrit and haemoglobin. Vanadyl sulfate, up to 335 mg/L in drinking water, was well tolerated in adult mice.
The results of NTP studies by Roberts et al presented above are not yet fully accessible or published, since the review process is still ongoing. The results presented above are based on a 2019 congress abstract/poster. A complete robust study summary will be provided in the dossier upon availability of the data.
Inhalation:
Studies via the inhalation route are not available for sodium vanadate, but for other vanadium substances. The registrant is of the opinion that the toxicity of sodium vanadate is driven by the vanadium moiety and that the sodium cation does not contribute to the overall toxicity of the substance sodium vanadate to any relevant extent, for the following reasons:
Sodium cations are abundantly present in the human body in which they play an important role for the ionic balance in body fluids. Based on the above information, one can therefore safely assume that the sodium cation in sodium vanadate does not contribute to the overall toxicity of sodium vanadate. It is concluded that only the effect of “vanadium” is further considered in the human health hazard assessment of sodium vanadate. The rationale for read-across to sodium vanadate can be summarised according to the following relevant routes of exposure:
Animal data:
The most informative study is the standard NTP chronic inhalation study (NTP 2002) using V2O5. In this investigation, there was a statistical increase in lung tumours in mice of both sexes, but not in rats (Starr, 2012). In mice, survival rates of male mice exposed to 4 mg/m³ was less than that of chamber controls, and mean body weights of male mice exposed to 4 mg/m³ and all exposed groups of female mice were generally less than those of the chamber controls throughout the study. As in the 3-month studies, the respiratory tract was the primary site of toxicity. Under the conditions of this 2-year inhalation study there was clear evidence of carcinogenic activity of vanadium pentoxide in male and female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. Exposure to vanadium pentoxide caused a spectrum of non-neoplastic lesions in the respiratory tract (nose, larynx, and lung) including alveolar and bronchiolar epithelial hyperplasia, inflammation, fibrosis, and alveolar histiocytosis of the lung in male and female mice. Hyperplasia of the bronchial lymph node occurred in female mice. The lowest concentration tested (1 mg/m³) represents a LOAEC for local effects in the respiratory tract.
Pulmonary reactivity was also investigated in a sub-chronic inhalation study in cynomolgus monkeys (duration 6 months) with divanadium pentaoxide. The results showed a concentration-dependent impairment in pulmonary function, characterized by airway obstructive changes (pre-exposure challenges) accompanied by a significant influx of inflammatory cells recovered from the lung by bronchoalveolar lavage. Sub-chronic V2O5 inhalation did not produce an increase in V2O5 reactivity, and cytological, and immunological results indicate the absence of allergic response.
Human data:
Regarding the preferential use of human data in risk assessments for human health, a respective statement is attached below. There are several epidemiological studies linking upper respiratory symptoms to vanadium pentoxide exposure (Kiviluoto, 1980; Kiviluoto et al., 1979a; Lewis, 1959, Zenz and Berg, 1967 Zenz et al. 1962). Long-term chronic exposure data of workers in the vanadium industry are reported in several publications. In a factory manufacturing vanadium pentaoxide, 63 workers exposed to V2O5at concentrations of 0.1 to 3.9 mg V/m³ measured as total dust for 11 years (average 0.2-0.5 mg V/m³) did not have an increased prevalence of upper respiratory symptoms in the case study by Kiviluoto et al (1979a,b, 1980, 1981a,b).
Kiviluoto et al. (1979b) did not observe any differences in the anterior and posterior rhinoscopy in the exposed groups after 11 years of exposure to average V2O5levels of 0.2-0.5 mg V/m³ as listed above. Furthermore, there was no difference in the number of blood vessels between the exposed and non-exposed groups. However, the number of neutrophils in the nasal smears and the number of plasma cells in the nasal mucosa were increased indicative of a protective mechanism in the mucosa. Other examined factors of the biopsies and cell findings did not differ between the exposed workers and the controls. Chest radiographs and lung function tests did not reveal any differences. After further 7-11 months of V2O5exposure at concentrations ranging from 0.01 to 0.04 mg V/m³ measured as total dust, a subsequent re-examination revealed that the cell findings did not indicate any further significant changes between the studied exposed groups, and that there were no significant changes in the number of eosinophils of cytological and histological samples.
Altogether, no pneumoconiosis and no other signs indicative of allergic inflammation, including nasal catarrh, cough, phlegm, were observed by Kiviluoto et al. in the exposed subjects working for 11 years under these occupational conditions.
Other epidemiological data support that respiratory symptoms are observed at exposure concentrations of V2O5that are above 0.1 mg/ V/m3, and are summarized in the following table:
Table: Epidemiological studies of V2O5 exposure
Subjects |
V2O5Dose [mg V /m³] |
Exposure duration |
Symptoms |
study |
24 workers |
0.1 - 0.93 mean PS < 5 μm |
|
eye, nose, throat irritation; cough; wheezing, nasal mucosa, rales, rhonchi; injected pharynx and green tongue |
Lewis, 1959 |
2 volunteers |
1 |
8 h |
cough, no eosinophilia, normal white blood cell count & cell patterns, no effects on urinalysis, normal lung function |
Zenz & Berg, 1967 |
5 volunteers |
0.2 (PS: 98 % < 5 μm) |
8 h |
loose cough, no eosinophilia, normal white blood cell count & cell patterns, no effects on urinalysis, normal lung function, no detectable V in the blood |
Zenz & Berg, 1967 |
2 volunteers |
0.1 |
8 h |
formation of mucus |
Zenz & Berg, 1967 |
3 of 18 workers |
> 0.5 mean PS < 5 μm |
24 h |
inflamed throat, dry cough, burning eyes, no wheeze |
Zenz, 1962 |
11 volunteers
|
0.4 condensation aerosol |
|
tickling, itching, dryness of mouth mucosa |
Pazhynic, 1967 |
5 of 11 volunteers |
0.16 |
|
mild signs of irritation |
Pazhynic, 1967 |
11 volunteers |
0.08 |
|
no notice of symptoms |
Pazhynic, 1967 |
8 volunteers (4 workers + 4 trainees) |
0.028 – 0.062 |
8 h/d, 5 d |
no notice of symptoms (i.e. neurobehavioural, neuro-psychological, psychosomatic & psychological effects) |
Hörtnagl et al. 1994 |
The Scientific Committee on Occupational Exposure Limit summarized these studies as follows: „In workers exposed to dust containing vanadium (as vanadium pentaoxide) 0.2-0.5 mg/m³ for about 11 years, irritants effects on the mucous membranes of the upper respiratory tract were reported. After hygienic improvements, the same workers were exposed to VP concentrations in the range of 0.01-0.04 mg/m³ for about 10 months. No worsening of the irritant effects observed as a consequence of the previous exposure was reported for this low-level exposure. In these workers, the exposure did not cause any pathological effects on the blood picture, the cysteine level in the hair, or the respiratory function (Kiviluoto et al., 1979a,b, 1980, 1981a,b; Kiviluoto, 1980)…
Kiviluoto et al (1979a,b, 1980, 1981a,b): in their studies on 63 males exposed in a vanadium factory for 11 years at concentrations in the range of 0.1-3.9 mg/m³ (estimated average concentrations 0.2-0.5 mg/m³) and after a further 7-11 month later when concentrations had been reduced to 0.01-0.04 mg/m³ studied nasal smears and biopsies. The findings were consistent with irritant effects. Eosinophils did not differ between exposed and non-exposed, nor did IgE-antibody levels. Although exposed workers complained significantly more often of wheezing, pulmonary function tests did not differ. There is, thus, little evidence indicating sensitizing effects on the respiratory tract. The known irritant effects of VP can well explain effects on the respiratory tract including rhinitis, bronchial hyper-reactivity, wheeze, asthma as well as bronchitis…
For respiratory tract irritation, and more generally speaking for upper and lower airways effects, dose-response relationships could be obtained in both experimental animals and humans. It can be assumed that 0.04 mg/m³ has to be considered as a NOEL in occupationally exposed subjects (10 months), while in rodents a NOEL could be concluded at an exposure level of 2 mg/m³ (B6C3F1 mice, m. f., inhalation, 6h/day, 5d/w for 16 days) and of 1 mg/m³ (F344/N rats, m. f., inhalation, 6h/day, 5d/w for 14 weeks)…
It appears that exposure to concentrations <0.1 mg/m³ do not induce irritating effects on the respiratory tract.(SCOEL/SUM/62 Final, January 2004)“
Evidence from animal and human data suggests that exposure to elevated V2O5concentrations may result in irritating effects on the respiratory system. However, human data were used as point of departure for the DNEL derivation because long-term chronic data are available from workers exposed to vanadium dust using a sensitive indicator of irritation (cytology), a population similar to the target population (workers of the vanadium industry), and to decrease uncertainty for interspecies differences in sensitivity.
Therefore, the NOAEC of 0.04 mg V/m³ (measured as total dust) for humans exposed occupationally for 11 years to V2O5 dust was used as POD for the DNEL derivation.
Read-across - inhalation:
There is a complete lack of studies that would allow distinguishing whether or not local effects of V2O5 are relevant for other vanadium substances. Based on the assumption that irritancy of a particular V substance is the driver for local effects, read-across of irritating effects of V2O5to other soluble vanadium substances was assessed. Five substance-specific properties are assumed to predominantly account for the observed irritation potential of V2O5: (i) water solubility and potential to become bioavailable, (ii) acidifying properties in aqueous media and potential for related burning, (iii) oxidising properties and potential for oxidative injury, (iv) irritating /corrosive properties (skin and/or eye) and potential for irritation of mucous membranes, and (v) particle size distribution and potential for inhalability. Sodium metavanadate is assessed as follows:
(i) Sodium metavanadate with a water solubility of 215 g/L at 20°C/pH 8.8 is considered very soluble.
(ii) Sodium metavanadate does not have an acidifying effect as in the water solubility test, a pH of 8.8 was measured.
(iii) An oxidising potential is conservatively assumed for all pentavalent V substances, including sodium metavanadate, considering the following bioaccessibility and toxicokinetic data.Upon dissolution, all vanadium substances more or less finally transform to the pentavalent form in artificial body fluids except artificial lysosomal fluid; here, even the pentavalent forms are converted almost completely to the tetravalent species already after a short period of time. Thus, trivalent V species are not stable under these conditions and there appears to be a simultaneous presence of tetra- and pentavalent species in biological media.
(iv) Where available data indicate any irritating effects either to skin, eye or respiratory tract, including mild and reversible effects, it was assumed in a conservative approach that the respective substance may have an irritation potential. Thus, a differentiation between a low-moderate potential (i.e. irritation, reversible effects) and a strong potential (corrosion, irreversible effects as observed with V2O5) was not applied. This approach is likely to overestimate the potential to irritate mucous membranes of several V substances, including sodium metavanadate. However, in the absence of further data, a differentiation cannot be scientifically supported. Hence, in a conservative approach, sodium metavanadate is considered as a substance with irritation potential.
(v) The inhalability as an additional modifying factor was derived from particle size distributions (i.e., granulometry), for which all vanadium substances were subjected to an experimental testing programme. Physical particle size distributions of commercial materials were determined experimentally and are represented by the median particle size diameter (d50).
Since “physical” particle size distributions do not necessarily reflect the particle size of aerosols that may be formed under practically relevant workplace conditions (e.g., during manual operations, including bag filling and emptying, or under mechanical agitation during mixing and weighing), the particle size distribution of the airborne fraction generated during mechanical agitation in the rotating drum according to the method by Heubach (1991) was additionally determined according to DIN 55992 Part 1. Furthermore, using the mass fractions deposited on the impactor stages, mass median aerodynamic diameter (MMAD) of the airborne material and geometric standard deviation (GSD) of the MMAD were determined (Grewe, 2010 & 2013). The Multiple Path Particle Deposition (MPPD) model (CIIT, 2002-2009) was applied to estimate the deposition of particles in the respiratory tract (head, tracheobronchial and pulmonary region) of workers. As a result, sodium metavanadate was assessed as being (at least partly) inhalable based on MPPD model outputs using worker specific input parameters as well as MMAD and GSD estimates.
If a V substance possesses four or more of the five substance-specific properties assumed to predominantly account for the observed irritation of V2O5, read-across of irritating effects of V2O5is considered to be justified in a conservative approach (see Table below).
substance |
potential to become bioavailable |
potential for acidic burning |
potential for inhalability |
potential for oxidative injury |
potential for irritation of mucous membranes |
Read-across of irritation |
NaVO3 |
yes |
no |
yes |
yes |
yes |
yes |
As already stated, the applied approach is likely to overestimate the potential of sodium metavanadate to irritate mucous membranes. However, in the absence of further data, a differentiation cannot be scientifically supported and sodium metavanadate is conservatively assumed to have a potential to irritate the respiratory tract following repeated exposure. Nevertheless, no carcinogenicity, no pneumoconiosis and no other signs indicative of allergic inflammation have been reported for workers manufacturing sodium metavanadate.
Justification for classification or non-classification
Based on read-across of V2O5 data and in a conservative approach, local effects are considered relevant and sodium metavanadate is assumed to irritate the respiratory tract following repeated exposure.
Therefore, sodium metavanadate meets the classification criteria for Specific target organ toxicity-repeated exposure - Category 1 according to Regulation (EC) No 1272/2008.
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