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EC number: 235-122-5
CAS number: 12070-10-9
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).
carbide is considered to not have a potential for carcinogenicity, and a
classification for carcinogenicity is not believed to be required for
pneumoconiosis and no other signs indicative of allergic inflammation
have been reported for workers manufacturing vanadium carbide.
Furthermore, no pH-related effects
need to be assumed upon contact with respiratory tract epithelia.
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 V2O5 have 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.
local effects on the respiratory tract are not considered relevant for
vanadium carbide for the following reason:
carbide was tested for its potential to become airborne (modified
Heubach procedure, DIN 55992-1:2006) resulting in a total dustiness of
14.54 mg/g and yielding MMADs of 4.76 µm (P = 18%) and 27.20 µm (P =
82%) with GSDs of 1.98 and 1.47, respectively. On the basis of results
of this dustiness test, MPPD modelling was performed and indicates that
the substance does not penetrate to the deep lung tissues
(tracheobronchial: 0.5%; pulmonary: 1.1%), whereas the inhaled material
(Head: 56.4%) is cleared to the GI tract (by swallowing), where oral
bioavailability will determine its uptake. In sum, nearly all of the
inhaled particles are swallowed and do not reach the pulmonary fraction
of the lung. Based on MMAD and MMPD modelling, respiration risk is low
and vanadium carbide can safely be assumed to have a low potential for
human inhalation hazard during handling or application.Therefore, local
effects observed in studies performed with divanadium pentaoxide are not
relevant for vanadium carbide.
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.
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.
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.
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
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
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.
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.
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.
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
multi-generation reproductive toxicity
NTP testing program began with sub-chronic drinking water studies on VOSO4&
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
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
dose-range finding study: gestation day 6 (GD 6) until postnatal day 42
(PND 42) with Harlan Sprague-Dawley rats - ongoing
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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