Registration Dossier

Administrative data

Description of key information

A study via the oral route is available for vanadium carbide nitride. The NOAEL results in a discriminating dose of ≥ 1000 mg/kg bw/d VCN, corresponding to a NOAEL of ≥ 937.5 mg/kg bw/d VC based on vanadium-content conversion.
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. However, local effects on the respiratory tract are not considered relevant for vanadium carbide (see discussion below).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011-04-07 to 2011-07-29
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Version / remarks:
adopted 1995-07-27
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
signed 2010-01-26
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: 44 to 50 days
- Weight at study initiation: males: 238 to 294 g; females: 165 to 242 g
- Housing: the animals were housed five of one sex per cage. The cages were made of a polycarbonate body with a stainless steel mesh lid. Wood based material was used as bedding and was sterilised by autoclaving
- Diet (ad libitum, except when urine was being collected and overnight before routine blood sampling): a standard rodent diet (Rat and Mouse No. 1 Maintenance Diet)
- Water (ad libitum, except when urine was being collected): potable water
- Acclimation period: 15 days

Each cage of animals was provided with an Aspen chew block for environmental enrichment. Chew blocks were provided throughout the study. Each
cage of animals was provided with a plastic shelter for environmental enrichment.

ENVIRONMENTAL CONDITIONS
- Temperature: 19 to 23°C
- Relative humidity: 40 to 70%
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test substance was prepared for administration as a series of suspensions in the vehicle. For each test formulation the required amount of test material was weighed and transferred to a suitably sized mortar to be ground into a fine powder. Small amounts of the pre-weighed vehicle were added and mixed with the test material using a pestle, ensuring any agglomerates were broken down to produce a smooth paste. The suspension was poured into a measuring cylinder which had been wetted with vehicle. The mortar was thoroughly rinsed with vehicle and this was added to the cylinder. The required volume was achieved with the remaining vehicle. The suspension was transferred into a beaker and mixed using a high shear homogeniser until it was homogenous. Finally, the suspension was transferred into containers, via syringe, whilst magnetically stirring.
The test substance was used as supplied. All formulations were prepared weekly and stored refrigerated (approximately 2-8°C) until use.
Formulations were stirred using a magnetic stirrer before and throughout the dosing procedure.
30 mg/kg/day: concentration: 6 mg/mL; volume dose: 5 mL/kg
300 mg/kg/day: concentration: 60 mg/mL; volume dose: 5 mL/kg
1000 mg/kg/day: concentration: 200 mg/mL; volume dose: 5 mL/kg
The volume administered to each animal was calculated from the most recently recorded bodyweight.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Before treatment commenced, the suitability of the proposed mixing procedure was determined and specimen formulations were analysed to assess the homogeneity and stability of the test substance in the liquid matrix.
Samples of each formulation prepared for administration in Week 1 of treatment were analysed for achieved concentration and homogeneity of the test substance.

Methods:
1) Homogeneity and stability in corn oil formulations
The homogeneity and stability of vanadium carbide nitride in corn oil formulations was assessed at nominal concentrations of 2 mg/mL and 200 mg/mL, during ambient and refrigerated storage. Freshly prepared specimen formulations (400 mL) were equally sub-divided (4 × 100 mL) into four amber glass screw top bottles and submitted for analysis.
- Ambient temperature storage (nominally +21ºC): on receipt, the contents of one bottle of each formulation were mixed by 20-fold inversion followed by vigorous shaking (30 seconds) and magnetic stirring. After stirring for 5 minutes (representing 0 hour), 1 hour and 2 hours, single samples (nominally 1 mL) were removed for analysis from approximately one quarter, one half and three quarters the depth (representing the top, middle and bottom) of the continuously stirred formulation.
The remainder of the bottle was stored at ambient temperature and after 1 day storage the contents were remixed and sampled as detailed above.
- Refrigerated storage (nominally +4ºC): the remaining bottles were refrigerated on receipt and on Days 1, 8 and 14, the appropriate bottle was removed from storage and equilibrated to ambient temperature. The contents of the bottle were mixed by 20-fold inversion followed by vigorous shaking (30 seconds) and
magnetic stirring for 5 minutes and single samples (nominally 1 mL) were removed for analysis from the top, middle and bottom of the stirred formulation.

2) Concentration in test formulations
At Week 1 of treatment, freshly prepared test formulations were sampled (1 mL, accurately weighed from the top, middle and bottom strata) and submitted for
analysis. The concentrations of vanadium carbide nitride was analysed by atomic absorption spectroscopy technique using the graphite furnace.

Results:
The homogeneity and stability was confirmed for vanadium carbide nitride in corn oil formulations at nominal concentrations of 2 mg/mL and 200 mg/mL for ambient temperature storage for 1 day and refrigerated storage for up to 8 days. The storage times represented the maximum time from preparation to completion of administration.
The mean concentrations of vanadium carbide nitride in test formulations analysed for Week 1 of the study were within +10%/-15% of nominal concentrations, confirming accurate formulation.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
once daily, seven days per week
Remarks:
Doses / Concentrations:
0, 30, 300 and 1000 mg/kg /day
Basis:
actual ingested
No. of animals per sex per dose:
Main study and recovery groups:
0 mg/kg/day: 5 males / 5 females (plus 5 males / 5 females as recovery group)
30 mg/kg/day: 5 males / 5 females
300 mg/kg/day: 5 males / 5 females
1000 mg/kg/day: 5 males / 5 females (plus 5 males / 5 females as recovery group)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The results of a preliminary study conducted be the laboratory (Study number IVY0008) at doses of 250, 500 or 1000 mg/kg/day showed that the test substance was well tolerated, with no findings considered to be related to treatment at any dose. It was therefore considered that a high dose of 1000 mg/kg/day would be appropriate for the present study, with low and intermediate doses at 30 and 300 mg/kg/day, respectively.

- Post-exposure recovery period in satellite groups: animals assigned to the recovery phase completed a further two weeks without treatment.
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of ill-health amongst the occupants.
Daily during the study detailed observations were recorded at the following times in relation to dose administration:
Week 1 of treatment: immediately before dosing, on completion of dosing of each group, between one and two hours after completion of dosing of all groups, and as late as possible in the working day
Weeks 2 to 4 of treatment: immediately before dosing and between one and two hours after completion of dosing of all groups
Week 1 and 2 of recovery: at approximately the same time each day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: before treatment commenced and during each week of treatment and recovery, detailed physical examination and arena observations were performed on each animal. On each occasion, the examinations were performed at approximately the same time of day (before dosing during the treatment period).
After removal from the home cage, animals were assessed for physical condition and behaviour during handling and after being placed in a standard arena. Particular attention was paid to possible signs of neurotoxicity, such as convulsions, tremor and abnormalities of gait or behaviour.

BODY WEIGHT: Yes
- Time schedule for examinations: the weight of each rat was recorded before treatment commenced (Day -7), on the day that treatment commenced (Day 1), on Days 8, 15, 22 and 28 of the treatment period and on Days 1, 8 and 14 of the recovery period and before necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
The weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded for each week throughout the treatment and recovery periods. From these records the mean weekly consumption per animal (g/rat/week) was calculated for each cage.

FOOD EFFICIENCY:
- 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: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: fluid intake was assessed by daily visual observation. No effect was observed and, consequently, quantitative measurements were not performed.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on Day 29 of treatment (after the 28th dose), blood samples were obtained from all main study animals. On Day 15 of recovery blood samples were obtained from all recovery phase animals. The blood samples were withdrawn from the sublingual vein.
- Anaesthetic used for blood collection: Yes, light general anaesthesia induced by isoflurane
- Animals fasted: Yes, the samples were taken after overnight withdrawal of food.
- How many animals: all main study and all recovery phase animals
- Parameters examined: haematocrit, haemoglobin concentration, erythrocyte count, reticulocyte count, mean cell haemoglobin, mean cell haemoglobin concentration, mean cell volume, total white cell count, differential WBC count (neutrophils, lymphocytes, eosinophils, basophils, monocytes and Large unstained cells), platelet count, prothrombin time and activated partial thromboplastin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on Day 29 of treatment (after the 28th dose), blood samples were obtained from all main study animals. On Day 15 of recovery blood samples were obtained from all recovery phase animals. The blood samples were withdrawn from the sublingual vein.
- Animals fasted: Yes, the samples were taken after overnight withdrawal of food.
- How many animals: all main study and all recovery phase animals
- Parameters examined: alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, creatinine, glucose, total cholesterol, total bile acids, triglycerides, sodium, potassium, chloride, calcium, inorganic phosphorus, total protein and albumin
Albumin/globulin ratio was calculated from total protein concentration and analysed albumin concentration.

URINALYSIS: Yes
- Time schedule for collection of urine: during Week 4 of treatment overnight urine samples were collected from all main study animals and during Week 2 of recovery overnight urine samples were collected from all recovery phase animals.
- Metabolism cages used for collection of urine: Yes, animals were placed in an individual metabolism cage.
the following day.
- Animals fasted: Yes
- Parameters examined: appearance, volume, pH, specific gravity, protein, glucose, ketones, bile pigments, and blood pigments
A microscopic examination of the urine sediment was performed (epithelial cells, leucocytes, erythrocytes, crystals, spermatozoa, casts and abnormalities).

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: sensory reactivity and grip strength assessments were performed (before dosing), during Week 4 of treatment.
During Week 4 of treatment (before dosing), the motor activity was measured and In addition, all recovery phase animals were tested during Week 2 of recovery.
- Dose groups that were examined: 30 and 300 mg/kg/day (main study) and all recovers phase animals
- Battery of functions tested:
The following measurements, reflexes and responses were recorded:
1) Sensory reactivity: approach response, touch response, auditory startle reflex, tail pinch response,
2) Grip strength
3) Motor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Animals surviving until the end of the scheduled treatment or recovery period were killed by carbon dioxide asphyxiation followed by subsequent exsanguination. The sequence in which the animals were killed after completion of treatment or recovery was selected to allow satisfactory inter-group comparison.
All animals were subject to a detailed necropsy.
After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. The cranial roof was removed to allow observation of the brain, pituitary gland and cranial nerves. After ventral mid-line incision, the neck and associated tissues and the thoracic, abdominal and pelvic cavities and their viscera were exposed and examined in situ. Any abnormal position, morphology or interaction was recorded.
The requisite organs were weighed and external and cut surfaces of the organs and tissues were examined as appropriate. Any abnormality in the appearance or size of any organ and tissue was recorded and the required tissue samples preserved in appropriate fixative.

ORGAN WEIGHTS:
The following organs were taken from each animal killed after four weeks of treatment or two weeks of recovery and weighed: adrenals, brain, epididymides, heart, kidneys, liver, ovaries, prostate, seminal vesicles, spleen, testes, thymus and uterus with cervix
Prostate and seminal vesicles with coagulating gland were weighed together.
Bilateral organs were weighed together. Organ weights were also adjusted for terminal bodyweight, using the weight recorded before necropsy.

HISTOPATHOLOGY: Yes
Microscopical examination of the following organs: adrenals, ovaries, brain, Peyer’s patches, caecum, pituitary, colon, prostate, duodenum, rectum, epididymides, eyes, seminal vesicles, heart, ileum, spinal cord, jejunum, spleen, kidneys, sternum, stomach, liver, testes, lungs, thymus, lymph nodes (mandibular, mesenteric, left axillary), thyroid with parathyroids, trachea, urinary bladder, uterus and cervix, and vagina
Microscopic examination was performed as follows:
- all tissues preserved for examination were examined for all animals of vehicle control group and the 1000 mg/kg/day dose level group sacrificed on completion of the scheduled treatment period.
- tissues reported at macroscopic examination as being grossly abnormal were examined for main and recovery animals in line with current practice.
Those tissues subject to histological processing included the following regions:
- adrenals: cortex and medulla
- brain: cerebellum, cerebrum and midbrain
- femur with joint: longitudinal section including articular surface, epiphysial plate and bone marrow
- heart: included auricular and ventricular regions
- kidneys: included cortex, medulla and papilla regions
- liver: section from two main lobes
- lungs: section from two major lobes, to include bronchi
- spinal cord: transverse and longitudinal section at the cervical, lumbar and thoracic levels
- stomach: included keratinised, glandular and antrum in sections
- thyroid: included parathyroids in section where possible
- uterus: uterine body with cervix section
For bilateral organs, sections of both organs were prepared. A single section was prepared from each of the remaining tissues required for microscopic pathology
Statistics:
All statistical analyses were carried out separately for males and females. All analyses were carried out using the individual animal as the basic experimental unit.
The following data types were analysed at each time point separately: grip strength and motor activity, bodyweight (using gains over appropriate study periods), blood chemistry, haematology and urinalysis, organ weights.
The following statistical tests were used for grip strength, motor activity, bodyweight, organ weight and clinical pathology data: Bartlett's test for variance homogeneity, t-tests, F1 approximate test, Williams’ test, Dunnett's test, Wilcoxon’s rank sum tests, H1 approximate test, Shirley's test, Steel's test, Fisher’s Exact tests and analysis of covariance
Significant differences between Control and treated groups were expressed at the 5% (p<0.05) or 1% (p<0.01) level.
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:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no deaths.
The appearance and behaviour of the animals were unaffected by treatment.

BODY WEIGHT AND WEIGHT GAIN
Overall bodyweight gain was unaffected by treatment.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Overall food consumption was unaffected by treatment.

WATER CONSUMPTION AND COMPOUND INTAKE
Visual assessment of water intake did not identify an effect of treatment.

HAEMATOLOGY
The haematological investigation on Day 29 revealed, when compared to the controls, slightly low total white cell counts (associated with slightly low lymphocyte counts) for females at 300 or 1000 mg/kg/day. Basophil and monocyte counts were also slightly low for females at 1000 mg/kg/day. These differences from controls were still apparent on Day 15 of the recovery period for females previously treated at 1000 mg/kg/day.
Activated partial thromboplastin times were also slightly reduced, when compared to the controls, for females at 300 or 1000 mg/kg/day. This difference from controls was not apparent on Day 15 of the recovery period for females previously treated at 1000 mg/kg/day.
Minor changes seen in blood parameters were considered to be of minor toxicological importance and not adverse in nature.

CLINICAL CHEMISTRY
The biochemical examination of the blood plasma on Day 29 revealed, when compared to the controls, slightly low bile acid levels for males at 300 or 1000 mg/kg/day. Phosphorus levels were also slightly low for males at 1000 mg/kg/day. These differences from controls were no longer apparent on Day 15 of the recovery period for males previously treated at 1000 mg/kg/day.
Minor changes seen in blood parameters were considered to be of minor toxicological importance and not adverse in nature.

URINALYSIS
The appearance and composition of urine was not affected by treatment.

NEUROBEHAVIOUR
There were no effects on sensory reactivity or grip strength that were considered to be related to treatment.
There were no effects on motor activity that were considered to be clearly associated with treatment.

ORGAN WEIGHTS
The assessment of organ weights after 4 weeks of treatment revealed, when compared to the controls, slightly high adrenal weight and slightly low spleen weight for females at 1000 mg/kg/day. These inter-group differences were not apparent in females previously treated at 1000 mg/kg/day killed after 2 weeks of recovery.
Minor changes seen in organ weights were considered to be of minor toxicological importance and not adverse in nature.

GROSS PATHOLOGY
There were no treatment-related macroscopic findings seen at necropsy.

HISTOPATHOLOGY: NON-NEOPLASTIC
There were no treatment-related histopathology changes seen at 1000 mg/kg/day.
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
NOAEL (rats): ≥1000 mg/kg bw
The oral administration of vanadium carbide nitride to Crl:CD(SD) rats for 4 weeks at doses up to 1000 mg/kg/day was generally well tolerated. There were no target organs identified at histopathological examination. Minor changes seen in blood parameters and organ weights were considered to be of minor toxicological importance and not adverse in nature. Consequently, the No Observed Adverse Effect Level (NOAEL) was considered to be ≥ 1000 mg/kg/day.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
937.5 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The GLP-study is reliable without restrictions.
Remark: The NOAEL is a discriminating dose, i.e. ≥ 937.5 mg VC/kg bw/d.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Speciation:

Upon dissolution, vanadium substances transform in artificial body fluids, including PBS, sweat, gastric juice and lung fluid, predominantlyto the pentavalent form, except in artificial lysosomal fluid; here, even pentavalent forms are converted almost completely to tetravalent species already after a short period of time (for more information on in vitro bioaccessibility testing,please refer IUCLID section 7).Thus, it can be assumed that vanadium speciation in body fluids is controlled by the conditions of the respective medium but not by the vanadium source.

Read-across concept:

The toxicity of vanadium carbide may reasonably be considered to be determined by the bioavailability of vanadium. As a first surrogate for bioavailability, the solubility of a test substance may be used. Under conditions of the transformation/dissolution test (T/D, OECD Series 29) with vanadium carbide powder at a loading of 1 mg/L, dissolved vanadium concentrations after 28d were 41.7 and 27.8 µg V /L at pH 8 and pH 6, respectively. Under similar conditions of the T/D test with vanadium carbide nitride, dissolved vanadium concentrations after 28d at pH 8 and pH 6 were below 1.8 µg V /L.Vanadium carbide (2.1 mg/L; 20°C/pH 5.2) and vanadium carbide nitride (0.01 mg/L; 20°C/pH 6.8) are substances that are also poorly / sparingly soluble in water. In sum, read-across from a vanadium compound with similar water solubility, i.e. vanadium carbide nitride, is considered acceptable because kinetic data indicate a similar solubility potential. Vanadium carbide nitride is non-toxic if swallowed repeatedly as the 28-d NOAEL is a discriminating dose, i.e. ≥ 1000 mg/kg bw/d. By read-across based on similar solubility potentials, vanadium carbide is considered to be also non-toxic.

Repeated dose inhalation:

The most informative study is the standard NTP chronic inhalation carcinogenicity 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 subchronic 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. Subchronic V2O5 inhalation did not produce an increase in V2O5 reactivity, and cytological, and immunological results indicate the absence of allergic response.

However, local effects on the respiratory tract are not considered relevant for vanadium carbide for the following reason:

Based on dustiness testing and MMAD and MPPD modelling, vanadium carbide can safely be assumed to have a very low potential for human inhalation hazard during handling or application. Vanadium carbide was tested for its potential to become airborne (modified Heubach procedure, DIN 55992-1:2006) resulting in a total dustiness of 14.5 mg/g and yielding MMADs of 4.76 µm (P = 18%) and 27.20 µm (P = 82%) with GSDs of 1.98 and 1.47, respectively. On the basis of results of this dustiness test, MPPD modelling was performed and indicates that the substance does not penetrate to the deep lung tissues (tracheobronchial: 0.5%; pulmonary: 1.1%), whereas the inhaled material (Head: 56.4%) is cleared to the GI tract (by swallowing), where oral bioavailability will determine its uptake. Based on MMAD and MMPD modelling, respiration risk is low and nearly all of the inhaled particles are swallowed and do not reach the pulmonary fraction of the lung. Therefore, local effects observed in studies performed with divanadium pentaoxide are not relevant for vanadium carbide.

No carcinogenicity,no pneumoconiosis and no other signs indicative of allergic inflammation have been reported for workers manufacturing vanadium carbide. Furthermore, no pH-related effects need to be assumed upon contact with respiratory tract epithelia. Therefore, the local respiratory effects of V2O5 are not relevant for read-across to vanadium carbide.

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

(i) chronic toxicity,

(ii) carcinogenicity, and 

(iii) multi-generation reproductive toxicity

is planned.

 

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

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

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

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

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

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

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


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
key study; conducted with vanadium carbide nitride

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

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

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

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

Justification for classification or non-classification

The currently available and reliable toxicity data does not justify classification of vanadium carbide for specific target organ toxicity - repeated exposure.