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Carcinogenicity

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Description of key information

There is no evidence of systemic carcinogenicity in a study with V2O5, which is a suitable surrogate regarding systemic effects. The marginal evidence for carcinogenicity in the animal lung in the study with V2O5 is considered a substance specific local effect and is without relevance for the substance under consideration in this dossier (see discussion).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Vanadium dioxide is considered to not have a potential for carcinogenicity, and a classification for carcinogenicity is not believed to be required for vanadium dioxide.

Additional information

No carcinogenicity, no pneumoconiosis and no other signs indicative of allergic inflammation have been reported for workers manufacturing vanadium dioxide. Furthermore, no pH-related effects need to be assumed upon contact with respiratory tract epithelia.

There is, however, marginal evidence for carcinogenicity in the animal lung in the study with V2O5, which is considered a substance specific local effect (see below). Severe irritant properties of V2O5have been identified for eye (cat 1) and in lungs, and the redox potential of V2O5 as well as the sharp decline on pH in contact with aqueous media is hypothesised to either mediate this mechanism or at least propagate this mechanism.

In contrast, there is no indication whatsoever of any potential for irritation of the respiratory tract for V2O3and VO2. With regard to substance-specific properties assumed to predominantly account for an irritation potential, V2O3 and VO2 are different from V2O5as follows:

- A low dissolution of V2O3was observed in artificial lysosomal fluid (11.9% after 2h; 15.7% after 24h) and lung fluid (4.7% after 2h; 5.6% after 24h)while pentavalent substances (V2O5or NaVO3) dissolved completely within 2 h. Thus, the bioavailability and reactivity of V2O3in tissues of the respiratory tract is assumed to be far less than that of V2O5. Based on similar water solubility and transformation/dissolution characteristics, a similar low bioavailability in the lung is assumed for VO2.

- V2O3and VO2upon contact with water do not cause such significant pH decrease as in the case of V2O5, thus indicating a lack of acidifying properties in aqueous media and any potential for tissue injury associated therewith of V2O3and VO2.

- V2O3and VO2are completely void of oxidising properties and the potential for oxidative injury.

- While VO2lacks any irritation potential to skin and eye in vivo, some very mild but reversible effects have been observed in vivo in the eye after exposure to V2O3.

Regarding the potential for respiratory irritation, a comprehensive histopathological evaluation of lung tissue was performed within 14-d inhalation studies conducted both with V2O3and V2O5. Severe lung effects including hyperplasia in alveolar and bronchial epithelia, inflammation or fibrosis could not be observed at exposure levels up to 250 mg/m3 with V2O3, whereas these effects are reported as severe for all animals exposed to V2O5already at a level of 2 mg/m3. In conclusion, the onset of marked irritation effects with V2O5 occurs at exposure levels approx. 100-fold lower than with V2O3; on the other hand, given the low solubility and the high exposures, the onset of overload phenomena cannot be completely excluded for V2O3. Based on available evidence, a similar lack of a potential for respiratory irritation (i.e. local effects) can be expected for VO2. Hence, vanadium dioxide is considered to not have a potential for carcinogenicity, and a classification for carcinogenicity is not believed to be required for vanadium dioxide.

 

Divanadium pentaoxide-conclusion

A two year carcinogenicity study (NTP 2002) is available, in which the substance V2O5 was administered to rats and mice via inhalation. Considerable thought has been given to the possible classification of vanadium pentaoxide as a carcinogen based upon the available scientific data. There is in fact no credible human epidemiological evidence for carcinogenicity, and we must thus rely upon the experimental studies and anyin vitromechanistic information that is available for an assessment. Workers (63) exposed at 0.1 to 3.9 mg V/m3(average 0.2-0.5 mg V/m3) measured as total dust for 11 years in a factory manufacturing vanadium pentaoxide did not have an increased prevalence of upper respiratory symptoms in the human case study by Kiviluoto et al (1979a,b, 1980, 1981 a, b).No carcinogenicity,no pneumoconiosis and no other signs indicative of allergic inflammation, including nasal catarrh, cough, phlegm, were observed in the exposed subjects working for 11 years under these occupational conditions.

The most informative study is the standard NTP chronic inhalation carcinogenicity study (NTP 2002) using V2O5. In this investigation, there was a statistical increase in lung tumours in mice of both sexes, but not in rats (Starr, 2012). There was clear evidence of a carcinogenic activity of vanadium pentoxide in the 2-year study in male and female mice based on increased incidences of alveolar/bronchiolar neoplasms. The genetic toxicology studies (Salmonella typhimurium gene mutations and micronucleated erythrocytes of mouse peripheral blood in vivo) show negative results for mutagenic effects. No increase in tumours was seen at any other target site in rats or mice. There is a reasonable weight of evidence fromin vivoandin vitroinvestigations (Assem & Levy, 2009) that the mode of action underlying the lung tumours in mice in the NTP 2002 study is by (a) non-DNA reactive mechanism(s) and that, consequently, there is likely to be an identifiable threshold of exposure of vanadium pentaoxide for this critical effect.

The NTP study was conducted over a very narrow and high dose range (1-4 mg/m3in mice, and 0.5 to 2 mg/m3in rats), and as a result, it does not provide sufficient data to draw conclusions regarding thresholds or modes/mechanisms. More helpfully, the recent study in mice conducted by Harlan (Schuler, 2010), and submitted as part of this dossier, provides further evidence for the non-genotoxic mode of action for vanadium pentaoxide and further supports our contention, as well as providing information on thresholds of early lung inflammatory effects which are likely to be the trigger for the carcinogenicity effects seen in the mice in the NTP 2002 study.

In addition, a recently published study (Rondini et al. 2010) adds further evidence to the contention that the lung tumours seen in mice in the NTP 2002 study are induced by a non-DNA (non-genotoxic) mechanism. Whereas some vanadium compounds have been shown to produce a range of chromosome damages. On the other hand, guideline-conform, state-of-the-art in-vitro gene mutation studies performed with all three valency states of vanadium have unequivocally demonstrated an absence of effects, thus ruling out direct DNA interactions (Loyd, 2010a,b,c).

The lack of significant induction of cII mutant frequencies on the lungs of BB mice exposed to tumorigenic concentrations of divanadium pentaoxide by inhalation for up to 8 weeks suggests that divanadium pentaoxide is unlikely to act via a mutagenic mode of action (Manjanatha et al. 2015). Further, the lack of significant changes in levels of Kras codon 12 GAT or GTT mutation supports the idea that the accumulation of additional Kras mutants is not an early event, and/or that the proliferative advantage of Kras mutant clones requires either longer expression times or larger cumulative divanadium pentaoxide exposures (Banda et al. 2015). Furthermore, the data do not provide support for either a direct genotoxic effect of divanadium pentaoxide on Kras in the context of the exposure conditions used, or early amplification of preexisting mutation as being involved in the genesis of divanadium pentaoxide-induced mouse lung tumours.

Further evidence that genotoxicity is not a driving force in lung tumor formation by V2O5 comes from the study of biological perturbations following 90-day V2O5 exposure at tumorigenic levels by Black et al. (2015). The study assessed if any of these perturbations were consistent with genotoxicity or oxidative stress and compared V2O5 responses with those of 13 other lung tumorigens and non-tumorigens. Differential gene expression varied greatly among the compounds. V2O5 had 1,026 differentially expressed genes, 483 of which were unique to V2O5. Functional ontology enrichment indicated several possible effects on lipid metabolism as well as ontology categories associated with inflammation. These functional ontology results are consistent with evidence of epithelial hyperplasia, degeneration and inflammation in mice, but were not indicative of processes traditionally related to tumor initiation. There was not any evidence for enrichment of pathways associated with changes in cell cycle/proliferation, DNA-damage, or oxidative stress related pathways with the V2O5 differentially expressed genes.Given that vanadium pentaoxide in contact with aqueous media yields a strongly acidic pH (Klawonn, 2010), due to chronic inflammation promoted by this pH effect vanadium pentaoxide may act through an increase in inflammatory-related oxidative stress. 

An evaluation of the data base for vanadium pentaoxide by the Scientific Committee on Occupational Exposure Limits (SCOEL, 2004) concluded that considering the available genotoxicity data on vanadium pentaoxide and other vanadium compounds it is not possible to clearly identify a threshold level below which there is no concern. Regarding the carcinogenic potential it was concluded that vanadium pentaoxide was found to be carcinogenic in rats and mice, but the biological mechanism underlying the initiation and promotion of pulmonary disease and lung cancer induced by vanadium pentaoxide is not understood. In consequence, a health based occupational exposure limit (OEL) was not derived by SCOEL. In order to gain more insight into the mechanism of the carcinogenic potential, a 16-day inhalation toxicity study was conducted in female mice with the evaluation of specific endpoints (Schuler, 2010). However, the results of the first study suggest that further investigations are necessary to identify mouse-rat differences that might suggest a mode of action, to investigate the lack of effects in a comet assay seen in this in vivo study in a further in-vitro test on BAL/pulmonary cells, and to investigate the 8-oxodGua-specific lesions observed with respect to induction or repair inhibition. 

Because the data base is regarded as insufficient for the derivation of an Occupational Exposure Limit with respect to the endpoints carcinogenicity and genotoxicity by various committees and for these above reasons including the fact that human data reporting a carcinogenic potential do not exist, classification for carcinogenicity should be examined once the needed data will be generated.

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 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

-90-d oral toxicity studies (dosed feed: NaVO3; dosed water: VOSO4) with Harlan Sprague-Dawley rats and B6C3F1/N (dose: rats and mice: 0, 31.3, 62.5, 125, 250, or 500 ppm - ongoing

- Organ systems toxicity, i.e. 28-d immunotoxicity study of NaVO3 (dosed-water) with female B6C3F1/N mice (dose: 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

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 section 7.5.Only upon availability of the results from these studies, it will be possible to render a more meaningful decision on whether or not testing forcarcinogenicityis required. Therefore for the time being this data requirement should be waived in consideration of animal welfare.


Justification for selection of carcinogenicity via inhalation route endpoint:
Data of the carcinogenicity are available for V2O5 via the inhalation route but are not relevant for VO2.

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