Ammonium trioxovanadate

Endpoint summary

Description of key information

Studies via the oral and inhalation route are not available for ammonium trioxovanadate, but for other vanadium substances. Of the limited effects noted following oral exposure of soluble vanadium substances, it appears most likely that effects on haematological parameters are the most consistently reported among a number of investigators.
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 ammonium trioxovanadate is summarised below (see discussion).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEL

6.88 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Several supportive studies exist.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1997-01-06 (first exposure) to 1999-01-04/08 (necropsy date)

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well reported study. Test procedure in accordance with generally accepted scientific standards and described in sufficient detail.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of 50 male and 50 female F344/N rats (approx. 6-7 weeks old) were exposed to V2O5 aerosols at concentrations of 0, 0.5, 1 or 2 mg/m3 by inhalation, 6 hours/d, 5 d/wk, for 104 weeks. The body weight was controlled initially and body weight and clinical finding were recorded every 4 weeks (until week 89) and every 2 weeks from week 92 on. Animals were observed twice daily. Necropsy was performed at study end.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Inc. (Germantown, NY)
- Age at study initiation: average age: 6 or 7 weeks old on the first day of the study
- Weight at study initiation: average body weight for week 1: 134-136 g (males) and 130-105 g (females)
- Housing: housed individually; stainless steel wire bottom (Hazleton Systems, Inc., Aberdeen, MD); cages and racks were rotated weekly.
- Diet: ad libitum, except during exposure periods; NTP-2000 pelleted diet (Zeigler Brothers, Inc., Gardeners, PA), changed weekly
- Water: ad libitum; tap water (Richland, WA, municipal supply water used) via automatic watering system
- Acclimation period: quarantined for 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 23.9± ca.2°C (75° ± 3° F)
- Humidity (%): 55% ± 15%
- Air changes (per hr): 15/hour
- Photoperiod (hrs dark / hrs light): 12 hours/day

IN-LIFE DATES: From: 1997-01-06 (first exposure) to 1999-01-4/8 (necropsy date)
- No further information on test material was stated.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: MMAD = 1.0-1.3 µm, GSD = 2.3-2.8

Details on inhalation exposure:

- The generation and delivery system used in the 16-day special studies and the 2-year studies consisted of a linear dust feeder, a particle attrition chamber, and an aerosol distribution system. The linear dust feeder, a slide-bar dust-metering device, was composed of a shuttle bar, body, outlet port, and hopper. As the compressed-air-driven shuttle bar slid back and forth during generation, the metering port aligned with the hopper, which served as a reservoir for the bulk chemical, and was filled with a small amount of vanadium pentoxide powder. As the shuttle bar slid to the dispersing position, the metering port aligned with a compressed-air port in the body and a puff of air from this port dispersed the vanadium pentoxide into the particle attrition chamber. Generator output was regulated by adjusting the cadence of the shuttle bar. The particle attrition chamber used low fluid energy from an air jet tangential to the chamber to deagglomerate the vanadium pentoxide particles. After deagglomeration, the particles were swept into a classification zone where smaller particles exited to the distribution line; larger particles were thrown to the perimeter of the classifier by centrifugal force and were reentrained into the impacting air jet, and the process was repeated until the particles were sufficiently deagglomerated. The aerosol passed through the distribution lines to the exposure chambers. A pneumatic pump designed by the study laboratory was located at each chamber inlet and drew aerosol from the distribution line into the chamber inlet, where it was diluted with conditioned air to the appropriate concentration. Flow through the distribution line was controlled by Air-Vac pumps (Air-Vac Engineering, Milford, CT), and pressure was monitored by photohelic differential pressure gauges (Dwyer Instruments, Inc., Michigan City, IN).
- The stainless steel chambers (Lab Products, Inc., Harford Systems Division, Aberdeen, MD), were designed so that uniform aerosol concentrations could be maintained throughout the chambers when catch pans were in place. The total active mixing volume of each chamber was 1.7 m³.

CHAMBER ATMOSPHERE CHARACTERIZATION
- The particle size distribution in each chamber was determined prior to the start of all studies, during the first week of the 16-day and 3-month studies, during the first 2 weeks of the 2-year studies, and monthly during the 3-month and 2-year studies.
- For the 16-day special studies and the 2-year studies, a Mercer-style seven-stage impactor was used. The stages (glass coverslips lightly sprayed with silicon) were analyzed by ICP/AES, and the relative mass collected on each stage was analyzed by probit analysis.

OTHER
- The uniformity of aerosol concentration in the inhalation exposure chambers without animals was evaluated before each of the studies began; concentration uniformity with animals present in the chambers was also measured. During the 16-day and 3-month studies, minor excursions in chamber uniformity values were observed in one or more exposure chambers, but these excursions had no impact on the studies. Chamber concentration uniformity was acceptable throughout the 16-day special studies and 2-year studies.
- The stability of vanadium pentoxide in the exposure system was tested with XRD analysis. XRD analyses indicated no detectable build-up of degradation products at a detection limit of approximately 1%.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

- During all studies, chamber aerosol concentrations were monitored with real-time aerosol monitors (RAMs) that used a pulsed-light-emitting diode in combination with a silicon detector to sense light scattered over a forward angular range of 45° to 95° by particles traversing the sensing volume. The instruments respond to particles 0.1 to 20 μm in diameter.
- For the 16-day special studies and the 2-year studies, the sampling system consisted of a valve that multiplexed each RAM to two or three exposure chambers and to a HEPA filter and/or the control chamber or room; selection of sampling streams and data acquisition from each RAM was remotely controlled by a computer. Equations for calibration curves were stored in the computers and were used to convert the measured voltages to exposure concentrations.
- Each RAM was calibrated daily during the 16-day and 3-month studies by correlating the measured voltage with vanadium pentoxide concentrations determined by gravimetric analysis of glass fiber filters and one to two times per week during the 2-year studies by ICP/AES or ICP/mass spectrometry analysis of Pallflex® TX40H120WW glass fiber filters.

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

6 hours per day, 5 days per week

Remarks:

Doses / Concentrations:
0.5 mg/m³ V2O5
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
1 mg/m³ V2O5
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
2 mg/m³ V2O5
Basis:
nominal conc.

No. of animals per sex per dose:

core study: groups of 50 male and 50 female rats
tissue burden analyisis: 40 female rats per exposed group; separate control groups of 15 female rats were used as chamber controls

Control animals:

yes

Details on study design:

- Dose selection rationale: based on the incidences and severities of respiratory lesions and increased lung weights in male and female rats, concentrations of 4 mg/m3 or greater were considered to be too high for use in a 2-year study. The exposure concentrations selected for the 2-year inhalation study in rats were 0.5, 1, and 2 mg/m3.
- Rationale for animal assignment (if not random): randomly into groups of approximately equal initial mean body weights.
- No further information on test material was stated.

Positive control:

not stated

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- The health of the animals was monitored during the studies according to the protocols of the NTP Sentinel Animal Program

DETAILED CLINICAL OBSERVATIONS: Yes
- Clinical findings were recorded every 4 weeks from week 5 through 89 and every 2 weeks from week 92 until the end of the studies

BODY WEIGHT: Yes
- Time schedule for examinations: body weights were recorded on day 1 and every 4 weeks from week 5 through 89 and every 2 weeks from week 92 until the end of the studies

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

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 data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
- Tissue Burden Studies: groups of five female rats were evaluated on days 1, 5, 12, 26, 54, 173, 360, and 542;
- Total lung weight, right lung burden, and left lung histopathology were measured in exposed animals at all time points.
- Blood vanadium concentration was measured in all animals at all time points after day 12. Groups of five chamber control animals were bled at each of these time points and returned to their chambers and used for subsequent bleedings. Blood was obtained by cardiac puncture from exposed animals or from the retroorbital sinus of chamber control animals.

Sacrifice and pathology:

Method of sacrifice: CO2 asphyxiation.

PATHOLOGY: Yes
- Necropsy was performed at study end on all core study animals.
- All organs and tissues were examined for grossly visible lesions, and all major tissues were prepared for microscopic examination.

HISTOPATHOLOGY:
- Complete histopathology was performed on all core study animals. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, gallbladder (mice only), heart and aorta, large intestine (cecum, colon, and rectum), small intestine (duodenum, jejunum, and ileum), kidney, larynx, liver, lung and mainstem bronchi, lymph nodes (mandibular, mediastinal, mesenteric, and bronchial), mammary gland (except male mice), nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis (with epididymis and seminal vesicle), thymus, thyroid gland, trachea,
urinary bladder and uterus.

Other examinations:

Five male and five female rats were randomly selected for parasite evaluation and gross observation of disease.

Statistics:

Survival Analyses:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958) and is presented in the form of graphs. Animals found dead of other than natural causes were censored from the survival analyses; animals dying from natural causes were not censored. Statistical analyses for possible doserelated effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses are two sided.

Analysis of Continuous Variables:
Two approaches were employed to assess the significance of pairwise comparisons between exposed and control groups in the analysis of continuous variables. Organ and body weight data, which historically have approximately normal distributions, were analyzed with the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972). Hematology, clinical chemistry, urinalysis, urine concentrating ability, cardiopulmonary, immunotoxicologic, cell proliferation, tissue concentrations, spermatid, and epididymal spermatozoal data, which have typically skewed distributions, were analyzed using the nonparametric multiple comparison methods of Shirley (1977) and Dunn (1964). Jonckheere’s test (Jonckheere, 1954) was used to assess the significance of the dose-related trends and to determine whether a trend-sensitive test (Williams’ or Shirley’s test) was more appropriate for pairwise comparisons than a test that does not assume a monotonic dose-related trend (Dunnett’s or Dunn’s test). Average severity values were analyzed for significance with the Mann-Whitney U test (Hollander and Wolfe, 1973). Treatment effects were investigated by applying a multivariate analysis of variance (Morrison, 1976) to the transformed data to test for simultaneous equality of measurements across exposure concentrations. (for more information see publication)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

only marginally less for the 2 mg/m3–exposed females

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Based on the analysis of Starr et al. (2012), effects oberved in the male rat are not significant.

Details on results:

CLINICAL SIGNS AND MORTALITY
- Survival of the animals were similar to the controls

BODY WEIGHT AND WEIGHT GAIN
- Body weights of the animals were similar to the controls except body weight of the 2 mg/m3–exposed females which was less

HISTOPATHOLOGY: NON-NEOPLASTIC
- Non-neoplastic lesions occurred in respiratory system of males and females (lung, larynx, and nose) , and the severities of these lesions generally increased with increasing exposure concentration.

LUNGS:
- Effects in males: alveolar epithelium, hyperplasia (7/50, 24/49, 34/48, 49/50); bronchiole, epithelium hyperplasia (3/50, 17/49, 31/48, 49/50); alveolar epithelium, metaplasia, squamous (1/50, 0/49, 0/48, 21/50); bronchiole, metaplasia, squamous (0/50, 0/49, 0/48, 7/50); inflammation, chronic active (5/50, 8/49, 24/48, 42/50); interstitial, fibrosis (7/50, 7/49, 16/48, 38/50); alveolus, infiltration cellular, histiocyte (22/50, 40/49,45/48, 50/50).
- Effects in females: alveolar epithelium, hyperplasia (4/49, 8/49, 21/50, 50/50); bronchiole, epithelium hyperplasia (6/49, 5/49, 14/50, 48/50); alveolar epithelium, metaplasia, squamous (0/49, 0/49, 0/50, 6/50); inflammation, chronic active (10/49, 10/49, 14/50, 40/50); interstitial, fibrosis (19/49, 7/49, 12/50, 32/50); alveolus, infiltration cellular, histiocyte (26/49, 35/49, 44/50, 50/50).
- Incidences of minimal to mild chronic active inflammation and interstitial fibrosis in the lungs were significantly increased in males exposed to 1 or 2 mg/m3 and females exposed to 2 mg/m3, and the incidences of histiocytic cellular infiltrate of the alveolus were increased in all exposed groups of males and females. The inflammatory lesions were primarily minimal to mild and consisted of interstitial and perivascular infiltrates of mostly mononuclear inflammatory cells that were occasionally within alveoli. Alveolar septa were occasionally thickened by thin strands of eosinophilic fibrillar material (fibrosis). The histiocytic infiltrate was also minimal to mild, consisting of scattered intraalveolar macrophages that contained large amounts of foamy intracytoplasmic material, interpreted as pulmonary surfactant. Additionally, scant amounts of eosinophilic material (surfactant) similar to that observed within alveolar macrophages was also free within alveoli; however, a separate diagnosis was not made. A brownish pigment (pigmentation) was visible in alveolar macrophages in some males and females exposed to 2 mg/m3 and in females exposed to 1 mg/m3; it was a mild change considered of little biological significance and was not further characterized.

LARYNX:
- Effects in males: inflammation, chronic (3/49, 20/50, 17/50, 28/49); respiratory epithelium, epiglottis degeneration (0/49, 22/50, 23/50, 33/49); respiratory epithelium, epiglottis, hyperplasia (0/49, 18/50, 34/50, 32/49); respiratory epithelium, epiglottis, metaplasia, squamous (0/49, 9/50, 16/50, 19/49).
- Effects in females: inflammation, chronic (8/50, 26/49, 27/49, 37/50); respiratory epithelium, epiglottis degeneration (2/50, 33/49, 26/49, 40/50);
respiratory epithelium, epiglottis, hyperplasia (0/50, 25/49, 26/49, 33/50); respiratory epithelium, epiglottis, metaplasia, squamous (2/50, 7/49, 7/49, 16/50).
- There were increased incidences of minimal to mild lesions of the larynx in exposed males and females. The incidences generally increased with increasing exposure concentration and included chronic inflammation of the larynx and degeneration, hyperplasia, and squamous metaplasia of the respiratory epithelium of the epiglottis. The inflammation consisted of a mixture of mononuclear and granulocytic inflammatory cells in the submucosa beneath the epithelium lining the base of the epiglottis, ventral pouch, and caudal larynx. The degeneration of the respiratory epithelium was characterized by a loss or decrease in the height of cilia and shortening of the normally columnar to cuboidal surface epithelial cells lining the laryngeal surface of the base of the epiglottis. Squamous metaplasia was diagnosed when the ciliated cells were replaced by one or more layers of flattened squamous epithelium. In the same area, the respiratory epithelium was mildly thickened in many animals; this change was diagnosed as hyperplasia. These changes are relatively minimal, commonly occur in rats in NTP inhalation studies, and represent a common response to laryngeal injury.

NOSE:
- Effects in males: goblet cell, respiratory epithelium, hyperplasia (4/49, 15/50, 12/49, 17/48)
- Effects in females: goblet cell, respiratory epithelium, hyperplasia (13/50, 18/50, 16/50, 30/50)
- There were increased incidences of mild goblet cell hyperplasia of the nasal respiratory epithelium in all groups of exposed male rats and in females exposed to 2 mg/m3. Increased numbers of goblet cells were most notable in the respiratory epithelium lining the median septum adjacent to the area of the vomeronasal organ.

KIDNEY:
- The incidences of nephropathy were significantly increased in male rats exposed to 1 or 2 mg/m3. Nephropathy is a common lesion in aged rats, particularly males, and has been diagnosed in virtually all males in NTP 2-year studies that used the NIH-07 diet. In those studies, chemical exacerbation of nephropathy was identified by increased severity. With the NTP-2000 diet, the severity of spontaneous nephropathy has been reduced. In this study, the severity of nephropathy was not increased in exposed groups of males. Also, exposed females were not affected. Although the NTP doesn’t have a formal historical control database for nonneoplastic lesions, a review of recent studies indicates that the incidence in the male chamber control group in the current study is low. It is not clear if the increased incidences in this study were related to exposure to vanadium or were a reflection of the low incidence in the control group. Regardless, nephropathy was a relatively weak response and was likely of marginal biological significance.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)

Please note that the following carcinogenic effects as reported in the original study are not statistically significant according to Starr et al. (2012).

LUNG:
- Effects in males: alveolar/ bronchiolar adenoma (4/50, 8/49, 5/48, 6/50); alveolar/bronchiolar carcinoma (0/50, 3/49, 1/48, 3/50); alveolar/ bronchiolar adenoma or carcinoma (4/50, 10/49, 6/48, 9/50)
- Effects in females: none (equivocal findings: alveolar/bronchiolar adenoma (0/49, 3/49, 1/50, 0/50); alveolar/bronchiolar adenoma or carcinoma (0/49, 3/49, 1/50, 1/50)
- Alveolar/bronchiolar neoplasms with incidences often exceeding the historical control ranges, were present in exposed groups of males and one 2 mg/m3 female. Alveolar/bronchiolar adenomas were present in 0.5 and 1 mg/m3 females; incidence in the 0.5 mg/m3 group was at the upper end of historical ranges. Additionally, one female exposed to 2 mg/m3 had an alveolar/bronchiolar carcinoma. There were no statistically significant increases in the incidences of lung neoplasms in rats.
- There were increased incidences of alveolar epithelial hyperplasia and bronchiole hyperplasia in the lungs of males exposed to 0.5 mg/m3 or greater and females exposed to 1 or 2 mg/m3. The severities of these lesions were increased in 2 mg/m3 males and females. In affected animals, this was essentially a diffuse change with proliferation of epithelium in the distal terminal bronchioles and immediately associated alveolar ducts and alveoli. Normally flattened epithelium was replaced with cuboidal epithelium.
- Increased incidences of squamous metaplasia of the alveoli occurred in male and, to a lesser extent, in female rats exposed to 2 mg/m3. There were a spectrum of changes ranging from minimal to severe. Minimal lesions were characterized by a single alveolus with the thin type I cells which normally line alveoli replaced by one to several layers of squamous epithelium. Severe lesions were much larger, often involving an area approximately 1 cm in diameter. Many alveoli were involved and there was apparent coalescence of the metaplasia. There were also lesions of intermediate severity. Keratin production was a prominent feature of the squamous metaplasia observed in this study. Keratin often filled the affected alveoli, and in some of the lesions, cyst-like structures filled with keratinous material were formed. In a few animals (predominantly males), the squamous metaplasia extended into the distal airways and was diagnosed as bronchiole squamous metaplasia. Commonly dispersed within the squamous lesions were areas of respiratory epithelial metaplasia in which the alveolar epithelium was replaced by tall cuboidal to columnar epithelium with cilia often present and with mucous material filling the alveolar lumen.

UTERUS:
- The incidences of stromal polyp occurred with a positive trend in female rats (chamber control, 6/50; 0.5 mg/m3, 3/50; 1 mg/m3, 7/50; 2 mg/m3, 13/50). However, the incidence in the 2 mg/m3 group was within the historical range in controls. Endometrial stromal polyps are common neoplasms in the F344/N rat in NTP studies. They are benign neoplasms and generally do not progress to malignancy; however, they occasionally do progress to stromal sarcoma. In this study, when the incidences of stromal polyp were combined with the single incidence of stromal sarcoma, the combined incidence in 2 mg/m3 females was significantly increased. The marginal increase in the incidence of stromal polyp and stromal sarcoma (combined) in females exposed to 2 mg/m3 was not considered related to exposure to vanadium pentoxide.

OTHER FINDINGS
LUNG BURDEN STUDIES:
- Histopathology: the left lung lobe from each animal was infused with 10% neutral buffered formalin, and sections were examined microscopically. The purpose was to follow progression of the lung lesions. Following day 1 of exposure, there was an infiltrate of alveolar macrophages in the lungs. With continued exposure, increased numbers of alveolar macrophages, interstitial mononuclear inflammatory cell infiltrates, and hyperplasia of alveolar and bronchiolar epithelium were observed. In rats exposed to 2 mg/m3, there was an increase in severity of the hyperplasia between days 54 and 173. An increase in severity was not obvious between days 173 and 360, but hyperplasia appeared more severe on day 542. Hyperplasia was observed in only a few animals exposed to 1 mg/m3 and only on day 542. The minimal fibrosis observed in the 2-year study was not readily apparent on day 542 or earlier.
- Lung weights from exposed female rats increased throughout the study. Although there appeared to be an exposure concentration-related increase in lung weights after day 26 of the study, it was primarily due to increases in lung weights of female rats exposed to 2 mg/m3. In general, lung weights of 0.5 or 1 mg/m3 females were similar.
- Lung burden data appeared proportional to exposure concentration in rats.
- Though deposition patterns were similar between rats and mice, the maximum lung burdens occurred at day 173 in rats. The lung burdens appeared to reach steady state at the lowest exposure concentrations (0.5 mg/m3). A decline in lung burdens was observed. The retention of vanadium in the lungs at 18 months was ca. 13% to 15% in rats. The total lung doses for rats exposed to 0.5, 1, or 2 mg/m3 were estimated to be 130, 175, and 308 μg vanadium, respectively.
- Lung clearance half-times were considerably longer than those observed in the 16-day special studies.

BLOOD:
- Vanadium was detected in the blood at concentrations several orders of magnitude lower than those measured in the lungs of exposed rats, and blood vanadium concentrations in exposed groups were only marginally increased over that of the chamber control group. Overall, blood vanadium concentrations appeared to increase with increasing exposure concentration; however, this proportionality was less clear when the 0.5 and 1 mg/m3 groups were compared.
- Blood vanadium concentrations in all exposed groups appeared to peak on days 26 or 54 after which there was a decline throughout the rest of the study. This response was similar to that seen in lung burdens. However, these changes in concentrations were small, making it difficult to determine if there was an increase in elimination of vanadium from the blood or a decreased absorption from the lung due to reduced deposition, especially at the higher exposure concentrations.

Dose descriptor:

LOAEC

Remarks:

local

Effect level:

0.5 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: non-neoplastic changes (epithelial hyperplasia, squamous metaplasia, chronic inflammation, degeneration) in the respiratory system (lung, larynx, and nose) of male and female rats

Critical effects observed:

not specified

Chamber concentration uniformity was acceptable throughout the 16-day special studies and 2-year studies.

Conclusions:

Survival rates and body weights were not affected in rats exposed to vanadium pentoxide for 2 years. As in the 3-month studies, the respiratory tract was the primary site of toxicity in rats. Under the conditions of this 2-year inhalation study, some evidence of carcinogenic activity of vanadium pentoxide in male F344/N rats and equivocal evidence of carcinogenic activity of vanadium pentoxide in female F344/N rats was reported. Based on the analysis of Starr et al. (2012), the observed carconogenic effects are statistically not significant as follows:
(1) there are not any statistically significant differences in tumor incidence between vanadium pentoxide-treated and concurrent control group male and female rats,
(2) there is weakened evidence from comparisons with the widened historical control tumor incidence ranges that result from use of updated historical control data, and
(3) there is a likelihood that all of the male rats utilized in the vanadium pentoxide bioassay may have had elevated risks of developing alveolar/bronchiolar adenoma even in the absence of vanadium pentoxide exposure.
The genetic toxicology studies ( Salmonella typhimurium gene mutations and Micronucleated erythrocytes Mouse peripheral blood in vivo) show negative results for mutagenic effects.
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 rats and an unusual squamous metaplasia of the lung in male and female rats. The lowest concentration tested (0.5 mg/m3) represents a LOAEC for local effects in the respiratory tract.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

0.64 mg/m³

Study duration:

chronic

Species:

rat

Quality of whole database:

Findings in rat model may not be relevant for humans.

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

Ammonia/ammonium (i) is ubiquitous in the environment (air, soil and water) and as part of the natural nitrogen cycle intrinsically present in the human body due to a natural background in all dietary sources, and (ii) ammonia/ammonium is a normal constituent of all body fluids. The sources of endogenous ammonium include bacterial hydrolysis of urea and other nitrogenous compounds in the intestine, the purine-nucleotide cycle, amino acid transamination in skeletal muscle, and other metabolic processes in kidneys and liver. At physiological pH, it exists mainly as ammonium ion with reference serum levels just below 35 µmol/L. Any excess ammonia is excreted as urea, which is synthesised in the liver through the urea cycle. In consequence, because of its intrinsic nature as an endogenous physiological compound, repeated-dose toxicity effects of ammonium are not expected.Therefore, only the potential of the respective vanadium anion is addressed.

Studies via the oral and inhalation route are not available for ammonium trioxovanadate, but for other vanadium substances. The rationale for read-across to ammonium trioxovanadate can be summarised according to the following relevant routes of exposure:

Oral:

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. The most consistent effect of exposure to V2O5, i.e. pulmonary irritation and inflammation, is associated with the inhalation route. For oral exposure to vanadium substances, effects are more limited and the different experimental approaches lead to a variety of endpoints measured. Of the limited effects noted following oral exposure, 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).

In a study (treatment of male rats for 103 days) with the focus on reduction of the cysteine content in rat hair (Mountain et al. 1953), reduced erythrocyte counts and levels of hair cysteine were observed dose-dependently at dose levels of 100 and 150 ppm in the diet. Effects on hair cysteine levels and on red blood cell parameters may correlate with erythropenia and anaemia. Similar haematological effects were observed by Zaporowska et al. (1993) in a 4-week toxicity study. Rats received NH₄VO₃at dose levels of 1.5 and 5-6 mg V/kg bw/d via drinking water.

Haematological examinations showed a decrease in erythrocyte counts (associated with increased reticulocyte counts), haemoglobin and haematocrit levels in both groups. Effects of vanadium and chromium on body weight gain and selected haematological and blood parameters in rats were also investigated by Scibior (2005) following administration of NaVO₃to rats via drinking water for a period of 6 weeks. Treatment of rats with about 8 mg V/kg bw/d resulted in effects on body weight and erythrocytes (increased no. of erythrocytes, haemoglobin, and decrease of MCV, MCH, MCHC and leucocytes).

Altogether, effects noted have included reduced haemoglobin, reduced haematocrit, reduced mean cell haemoglobin concentrations, while effects on red blood cells have included both reductions and increases depending on dose levels used and duration of treatment, perhaps compensating for the haemoglobin effect. Haematological effects have been found with a variety of different vanadium compounds including sodium metavanadate, vanadium pentoxide, and ammonium trioxovanadate supporting the use of this endpoint.

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 the appropriate critical effect for oral exposure from the available dataset. Additional support for the reliability of this endpoint comes from a study by Hogan (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)).

Few other signs of systemic toxicity following oral ingestion of vanadium compounds have been reported in other studies, but they do not show a consistent picture. In a study conducted by Domingo et al. (1985), some evidence for renal effects were reported following exposure for 3 months to sodium metavanadate however the effects (increased plasma protein, urea and uric acid) were limited to the top dose with the mid and low dose not being affected. Organ weights, including kidneys, were not affected, and histopathology data were not reported (Domingo et al. (1985). Other studies (Susic and Kentera 1988; NTP 2002) including some assessment of renal function have not shown similar effects although only limited information is available. However, in a study in rats with chronic dietary administration (24 wks) of vanadate (Susic & Kentera, 1988), changes were seen in cardiac output and total peripheral resistance at dose levels of 300 and 3000 ppm NaVO₃in the diet. In addition, there was an effect on haematocrit (increase), plasma and blood volume (decrease) as well as extracellular fluid in the high dose group. In another subchronic study (2 months) by Susic & Kentera (1986), 300 ppm represents an effect level for pulmonary function. In this study, no effects were observed on haematocrit levels. The results of a study reported by Jadhav and Jandhyala (1983) suggest that the cardiovascular system responded to vasoconstrictor agents in a dose-dependent manner after subchronic (6 weeks) oral vanadate exposure (drinking water) favouring the development of high blood pressure.In a subchronic study (8 weeks) on behavioural effects of orally administered NaVO₃in rats, effects on general activity and learning were observed already at the lowest dose level of 4.1 mg/kg bw/d(Sanchez et al. 1998).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. Based on these effects, the lowest dose level of 34 mg/kg bw/d represents a LOAEL.

Based on the available limited data on repeated dose toxicity following oral exposure of soluble tetra- and pentavalent vanadium substances, effects on red blood cell parameters can be regarded as the most robust effect of systemic toxicity. This is further backed by results from a 90-day NTP study (2002) with inhalation exposure of rats. Of the studies showing haematological effects, several of the studies measured the effect with one dose of vanadium compound while other treatment groups received vanadium combined with other substances. These studies are regarded as supportive. Results from the Mountain et al. study (1953) were selected as the starting point for derivation of the DNEL for oral exposure, because it represents the study with the longest duration (103 days) and included several dosage groups. Although the effects observed at the low dose level of 100 ppm V in the diet are only minimal, this dose level is regarded to represent a LOEL in order to protect for potential other toxicological effects. Almost similar results were obtained by Zaporowska et al. (1993) in a 4-week toxicity study, but as the study is only of short-term duration, it is considered as supportive.

Conversion of LOEL (ppm in diet) to LOEL (mg/kg bw /d):

LOEL:             100 ppm V                  Duration:                                 103 d

Food intake:    2,130 g/rat                   Body weight (kg bw/rat):          0.5 kg

V ingested reported:                           155 mg V/rat/103 d= 1.5 mg V/kg

LOEL_corrected= 3.0 mg V/kg bw/d based on exposure to soluble vanadium forms

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

Inhalation:

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 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.

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/m³measured 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/m³as 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/m³measured as total dust, a subsequent reexamination 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 ofV₂O₅exposure

Subjects	V2O5Dose [mg V /m^3]	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 et al. (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/m³for 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/m³for 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/m³studied 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/m³do 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 V₂O₅dust was used as POD for the DNEL derivation.

Read-across: There is a complete lack of studies that would allow distinguishing whether or not local effects of V₂O₅are 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. Ammonium trioxovanadate is assessed as follows: 

(i) Ammonium trioxovanadate with a water solubility of 7.8 g/L at 20°C/pH6 is considered soluble.

(ii) Ammonium trioxovanadate does not have an acidifying effect as in the water solubility test, a pH of 6.0 was measured. 

(iii) An oxidising potential is conservatively assumed for all pentavalent V substances, including ammonium trioxovanadate, 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 indicates 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 ammonium trioxovanadate. However, in the absence of further data, a differentiation cannot be scientifically supported. Hence, in a conservative approach ammonium trioxovanadate 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, ammonium trioxovanadate 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).

 

	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
NH4VO3	yes	no	yes	yes	yes	yes

As already stated, the applied approach is likely to overestimate the potential of ammonium trioxovanadate to irritate mucous membranes. However, in the absence of further data, a differentiation cannot be scientifically supported and ammonium trioxovanadate is conservatively assumed to have a potential to irritate the respiratory tract. Nevertheless, no carcinogenicity, no pneumoconiosis and no other signs indicative of allergic inflammation have been reported for workers manufacturing ammonium trioxovanadate.

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:
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.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
reliable GLP-conform study with V2O5

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. In addition, ammonium trioxovanadate does not have any potential for skin irritation as indicated by the lack of any effects in the respective in vivo skin irritation test.

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

Justification for classification or non-classification

Based on read-across of V2O5 data and in a conservative approach, local effects are considered relevant and ammonium trioxovanadate is assumed to irritate the respiratory tract following repeated exposure.

Therefore, ammonium trioxovanadate meets the classification criteria for Specific target organ toxicity-repeated exposure - Category 1 according to Regulation (EC) No 1272/2008.