Tris(pentane-2,4-dionato-O,O')vanadium

Respiratory sensitisation

Administrative data

Endpoint:

respiratory sensitisation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: peer-reviewed data

Data source

Reference

Reference Type:

publication

Title:

Pulmonary Reactivity to Vanadium Pentoxide Following Subcrhonic Inhalation Exposure in a Non-human Primate Animal Model

Author:

Knecht E.A. et al.

Year:

1992

Bibliographic source:

Journal of Applied Toxicology 12(6), 427-434

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

- Short description of test conditions: A total of 24 adult, male cynomolgus monkeys (Macaca fascicularis) were exposed to vanadium pentoxide dust by inhalation for 6 h per day, 5 days per week, for 26 weeks.
- Parameters analysed / observed: Impact of vanadium pentoxide on pulmonary function, number of immune cells and level of inflammatory mediators in broncho-alveolar lavage fluid as well as cutaneous reactivity was studied prior to and after the repeated exposure for 26 weeks.

GLP compliance:

not specified

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:

O5V2

IUPAC Name:

dioxovanadiooxy(dioxo)vanadium

Test material form:

aerosol dispenser: not specified

Specific details on test material used for the study:

Average vanadium pentoxide aerosol concentrations and particle sizes:
At the completion of the 26 weeks of inhalation exposure, the overall C x t values were within 10.2 % for the two vanadium pentoxide-exposed groups. Particle sizes measured during the vanadium pentoxide challenges and subchronic exposure were generally within the 1-5 µm range, producing tracheobronchial deposition. Pre-exposure particle sizes for both challenge concentrations were lower than those measured during the post-exposure challenges. However, these pre- vs. post-differences in particle size did not impair the ability to test for treatment-related changes in vanadium pentoxide challenge reactivity, because a concurrent control group was included in the experimental design.

Test animals

Species:

monkey

Strain:

Macaca fascicularis

Sex:

male

Details on test animals or test system and environmental conditions:

Adult, male cynomolgus monkeys (Macaca fascicularis) were purchased from Charles River Research Primate Corp. (Port Washington, NY). Monkeys were caged individually in stainless-steel mesh cages and were fed a standard diet (Monkey Chow Jumbo; Ralston Purina Co., St. Louis, MO) with fresh fruit (apples and bananas). Water was available ad libitum.

Test system

Route of induction exposure:

inhalation

Route of challenge exposure:

inhalation

Vehicle:

other: filtered, conditioned air

Concentration:

Two vanadium pentoxide-exposed groups received equal weekly vanadium pentoxide-exposures (concentration x time) with different exposure profiles:
constant group: 0.5 mg vanadium pentoxide/m3 on 5 days per week
peak group: 0.1 mg vanadium pentoxide/m3 on 3 days (Mon., Wed., Fri.) and 1.1 mg vanadium pentoxide/m3 on 2 days (Tue., Thu.) per week

No. of animals per dose:

8 per group

Details on study design:

Two different exposure profiles were tested: one group received a constant daily concentration of 0.5 mg vanadium pentoxide/m3, while the other group received 0.1 mg vanadium pentoxide/m3 on 3 days (Mon., Wed., Fri.) and 1.1 mg vanadium pentoxide/m3 on 2 days (Tue., Thu.) per week.
Pulmonary function tests (provocation challenge with metacholine) as well as cytological and immunological analyses were conducted prior to and post-exposure.

Challenge controls:

Methacholine

Positive control substance(s):

none

Negative control substance(s):

none

Results and discussion

Results:

Pulmonary response in post-exposure provocation tests:
Post-eposure reactivity was not significantly different between the three exposure groups at either challenge concentration. However, a trend (not statistically significant) toward decreased post-exposure challenge reactivity in the two pulmonary function variables RL (pulmonary flow resistance) and FEF50/FVC (forced expiratory flow/forced vital capacity) was noted in the vanadium pentoxide-exposed groups as compared to the control group at the 3.0 mg vanadium pentoxide/m3 level.
The respiratory system was highly reactive to provocation challenges with methacholine. Dramatic increases in RL (P <0.001) and decreases in FEF50/FVC (P < 0.001) were measured at the 6.25 mg/mL methacholine concentration. Methacholine reactivity was not significantly increased by subchronic vanadium pentoxide exposure; however, a trend toward a post-exposure decrease in RL was observed in the vanadium pentoxide-exposed groups that was similar to that observed for post-exposure vanadium pentoxide reactivity.

Regarding the cytological and immunological investigations, a post-exposure trend (statistically significant for eosinophils) toward decreased responses was observed in the vanadium pentoxide-exposed groups as compared to the control group.
The number of circulating neutrophils and eosinophils in venous blood was not affected by subchronic vanadium pentoxide exposure. The number of circulating neutrophils during pre-exposure testing was 6.6 ± 0.5, and 6.6 ± 0.8, 6.1 ± 1.2 and 8.6 ± 2.6 x 10E3 cells/mm3 for the Control, Peak and Constant groups, respectively, during post-exposure testing. The number of eosinophils was 0.22 ± 0.05, and 0.24 ± 0.09, 0.14 ± 0.06 and 0.26 ± 0.09 x 10E3 cells/mm3, respectively. Similarly, serum immunoglobulins were unchanged throughout the study, averaging 1070 ± 61, and 1107 ± 81, 1095 ± 122 and 1159 ± 111 mg/dL for IgG; and 37.4 ± 1.5. and 42.7 ± 3.5. 43.0 ± 3.7 and 44.5 ± 2.4 ng/mL for IgE.

Positive control results:

not applicable

Any other information on results incl. tables

Animal Observations:

Respiratory distress developed in three monkeys from the Peak group during the subchronic vanadium pentoxide exposures. The pattern of effect was characterized by audible wheezing and coughing, and occurred only on peak exposure days during the first few weeks of exposure. Responses developed within 3-4 h of exposure, and occasionally required early removal of the affected monkeys from the exposure chamber. Through careful animal monitoring, these three monkeys continued to receive daily exposures for the entire study.

Pre-exposure provocation challenges:

The pre-exposure provocation challenges with vanadium pentoxide (V₂O₅) produced statistically significant impairments in pulmonary function at an aerosol concentration of 3.0 mg V₂O₅/m³, but not at 0.5 mg V₂O₅/m³. Significant changes in the hypothesis-testing variables (RL and FEFSU/FVC) were observed. The increase in RL and the decrease in FEF50/FVC were accompanied by a significant increase in RV and a significant decrease in FVC, thereby demonstrating an obstructive pattern of impaired pulmonary function.

Pre-exposure challenge also produced a cellular response characterized by a significant increase in the total number of respiratory cells recovered from the lung by bronchoalveolar lavage (BAL). The increase in the total number of cells occurred through a highly significant increase (P < 0.001) in the number of PMNs. The number of eosinophils recovered from the lung was also increased, while the numbers of lymphocytes, macrophages and mast cells were not. Significant challenge responses were not observed for total protein, albumin, LTC4 or the immunoglobulins, despite the significant cellular response to vanadium pentoxide challenge.

Pulmonary responses during subchronic exposure:

The pattern of pulmonary function observed when the monkeys were rechallenged following subchronic exposure resembled the obstructive pattern measured in response to the pre-exposure V₂O₅ challenges. In addition, the pattern of the cellular and immunological response observed after subchronic exposure was similar to the responses to the pre-exposure challenges.

Beside pulmonary function, skin sensitivity tests were also performed. Skin sensitivity to both skin test solutions, i.e. sodium vanadate and vanadium pentoxide-MSA conjugate, averaging < 1 was observed for both the immediate and delayed responses, and remained unchanged after subchronic exposure, supporting the indicated absence of allergic sensitisation.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

No increase in pulmonary reactivity as well as no skin response was found in monkeys after subchronic inhalation exposure to vanadium pentoxide for 26 weeks. This indicates that under these conditions, vanadium pentoxide did not induce allergic sensitisation in monkeys upon inhalation exposure.

Executive summary:

No regulatory accepted test guideline exists for the determination of a respiratory sensitisation potential of chemicals. The potential of the test item vanadium pentoxide to induce sensitisation upon subchronic inhalation exposure was studied in monkeys. Groups of 8 monkeys were exposed to vanadium pentoxide for 26 weeks. Pulmonary responses as well as cytological and immunological parameters measured after the subchronic exposure period were compared with measurements conducted prior to exposure. Here, no increased but a rather decreased pulmonary reactivity was found after subchronic inhalation exposure. In addition, cytological and immunological parameters as well as the negative skin test results indicate the absence of allergic sensitisation. Overall, the test item vanadium pentoxide was not found as a respiratory sensitiser after subchronic inhalation exposure in monkeys.