Vanadium, oxalate complexes

Repeated dose toxicity: inhalation

Administrative data

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.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2002

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Divanadium pentaoxide

EC Number:

215-239-8

EC Name:

Divanadium pentaoxide

Cas Number:

1314-62-1

Molecular formula:

V2O5

IUPAC Name:

divanadium pentaoxide

Test material form:

other: solid

Details on test material:

- Name of test material (as cited in study report): Vanadium pentaoxide
- Substance type: technical product
- Physical state: solid
- Analytical purity: ca. 99 %
- Impurities (identity and concentrations): XRD analyses of both lots indicated the presence of vanadium pentoxide with no detectable contaminants. No impurities > 1% .
- Lot/batch No.: Lot 1210490 was used in the 16-day and 3-month studies. Lot 1210140 was used in the 16-day special studies and the 2-year studies.
- Stability under test conditions: stability was monitored throughout the study. No degradation of the bulk chemical was detected.
- Other:
Vanadium pentoxide was obtained from Shieldalloy Metallurgical Corporation (Newfield, NJ) in two lots (1210490 and 1210140).
Lot 1210490, was identified as vanadium pentoxide using X-ray diffraction (XRD) analyses and infrared and ultraviolet/visible spectroscopy and by the study laboratory using infrared spectroscopy.
Lot 1210140 was identified using infrared and ultraviolet/visible spectroscopy and by the the study laboratory using XRD analysis.
The purity of lot 1210490 was determined using elemental analyses, weight loss on drying, spark source mass spectrometry, energy-dispersive X-ray (EDX) spectroscopy, and potentiometric titration.
The purity of lot 1210140 was determined using weight loss on drying, potentiometric titration, and ICP/AES.
- No further information on test material was stated.

Test animals

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.

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Remarks:

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

Doses / concentrations 2

Remarks:

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

Doses / concentrations 3

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

Examinations

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)

Results and discussion

Results of examinations

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.

Effect levels

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

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.