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EC number: 215-222-5
CAS number: 1314-13-2
in vitro studies and one in vivo study are available on
the genotoxicity of zinc oxide. Data on other zinc compounds have also
to be taken into account, as the basic assumption is made that after
intake all zinc compounds (including metallic zinc) are changed (at
least in part) to the ionic species and that it is this zinc cation that
is the determining factor for the biological activities of the zinc
of soluble and slightly soluble zinc compounds have been extensively
investigated in a wide range of in vitro and in vivo studies.
The in vitro investigations included non-mammalian and mammalian
test systems covering the endpoints of gene mutation, chromosomal
aberrations, sister chromatide exchange, unscheduled DNA synthesis
(UDS), as well as cell transformation. Availablein vivogenotoxicity
assays included the micronucleus test, sister chromatide exchange (SCE)
and chromosomal aberration test and the dominant lethal mutation assay
in mouse or rat as well as investigations for sex-linked recessive
lethal mutation in drosophila melanogaster.
zinc compounds did not increase the mutation frequencies in the majority
of bacterial or mammalian cell culture systems. For example, zinc
chloride, zinc sulphate, zinc bis(dihydrogen phosphate), zinc oxide or
zinc monoglycerolate were consistently negative in the Ames test. While
zinc chloride was also negative for gene mutations in the mouse lymphoma
assays, there was some evidence that zinc oxide, zinc acetate or zinc
monoglycerolate induced in the absence of metabolic activation the
formation of mutation colonies. Several reviewers noted, however, that
these mutations were observed at cytotoxic concentrations and that the
analysis did not distinguish between big and small colonies which could
be caused by gene mutation or chromosomal aberrations (Thompson et
al.,1989, WHO, 2001; EU RAR, 2004; MAK, 2009).
information was further found when zinc compounds were examined for
their potential to induce chromosomal aberrations or sister chromatide
exchange in mammalian cell systems or when evaluated in the cell
transformation assay. Positive as well as negative results were obtained
in these cell systems with either soluble or slightly soluble zinc
compounds. In those studies where chromosomal aberrations or sister
chromatide exchange has been observed, these were generally considered
to be weak and occurred only at high, often cytotoxic concentrations.
Moreover, these positive in vitro findings have also to be seen
in context of the impact that changes in zinc levels can have on cell
system processes that are controlled by a strict metal homeostasis. A
change of this metal homeostasis due to increased zinc levels, may lead
to a binding of zinc to amino acids like cystein and therefore to an
inhibition of certain enzymes. This can lead to interactions with the
energy metabolism, signal transmission and apoptotic processes which can
lead to the observed clastogenic or aneugenic effects in in vitro systems
(EU RAR, 2004; MAK, 2009).
In addition to
above mentioned in vitro investigations, various soluble and
slightly soluble zinc compounds have also been studied in a range of in
vivo studies including the micronucleus test, SCE and chromosomal
aberration test or dominant lethal mutation assay in mice or rats as
well as in the Drosophila Melanogaster SLRL test. The zinc
compounds were consistently negative in the micronucleus and in the
assay with Drosophila Melanogaster. Zinc sulphate was further negative
in a dominant lethal assay in rats.
Equivocal and sometimes contradicting
results were found for the induction of chromosomal aberrations which
have been studied in bone marrow cells harvest from animals exposed to
zinc compounds zinc chloride, and zinc oxide. Negative findings for
chromosome aberrations have been produced after intraperitoneal
injection of zinc chloride into mice (Vilkina et al., 1978) or
when rats were given zinc sulphate by gavage once or daily for 5
consecutive days (Litton Bionetics, 1974). In contrast, increased
aberrations have been reported in rats after inhalation exposure to zinc
oxide (Voroshilin et al., 1978), in rats after oral exposure to
zinc chloride and in mice after multiple intraperitoneal injections of
zinc chloride (Gupta et al., 1991). Moreover, increased
chromosomal aberrations were found in calcium-deficient mice when fed
zinc (in form of zinc chloride) via the diet (Deknudt, 1982).These
equivocal finding likely a reflection of inter-study differences in
routes, levels, and duration of zinc exposure, the nature of lesions
scored (gaps compared to more accepted structural alterations) and great
variability in the technical rigour of individual studies (WHO, 2001).
The German MAK committee reviewed the existing in vivo evidence
and concluded that particularly those studies indicating clastogenic
effects involved a lot of methodological uncertainties which do not
allow overruling those in vivo studies which did not provide any
evidence for chromosomal aberrations in vivo. Moreover, the Dutch
rapporteur of EU risk assessment of zinc compounds under the EU existing
substance legislation considered the positive in vitro findings
for chromosomal aberration and SCE assays to be overruled by the overall
weight of evidence of negativein vivotests for this endpoint (EU
The only identified publicly available
genotoxicity study in humans related to the identification of
chromosomal aberrations in lymphocytes of 24 workers in a zinc smelting
plant (Bauchinger et al.,1976). This study was, however, not
suitable to draw any conclusions to the association of these effects
with zinc exposure, as the workers displayed also increased blood levels
of lead and cadmium, and the clastogenic effects were predominantly
attributed to cadmium exposure.
There were no further reports in the accessible literature on genotoxic
effects of zinc compounds in human populations.
Zinc oxide nanomaterial:
not increase the mutation frequencies in bacterial cell culture systems:
it was consistently negative in the Ames test. There was some evidence
that nano-ZnO induced the formation of mutation colonies. However,significantly
increased mutation frequencies were always linked to acute cytotoxicity.
For this reason and the limited significance of the test system for
particles, the test results should more likely be judged as
equivocal/questionable in L5178Y/TK cells under the conditions and
restrictions of this assay, implying a possible false positive result.
data have shown that DNA damage was detected in the comet assay in the
absence of a metabolic activation system after exposure to uncoated ZnO
nanoparticles; there was evidence that these effects were mediated by
generation of oxygen species and oxidative stress. Other studies have
of DNA damage but these occurred only at high, often cytotoxic
information was found when nano-ZnO was examined for its potential to
induce chromosomal aberrations or micronucleus induction.A
chromosome aberration test according to OECD Guideline 473 was performed
with V79 cells using Z-COTE® HP1, Z-COTE®, and micronised zinc oxide. No
increase in structural chromosome aberrations and no aneugenic activity
were detected. In contrast, other data revealed clastogenic activity
also below the threshold for cytotoxicity.
clastogenic and aneugenic effects were investigated in a sub-acute
nose-only inhalation toxicity study in male and female Wistar rats using
the bone marrow micronucleus assay (according to OECD Guideline 474). No
systemic chromosome mutagenic activity was detected after inhalation
exposure toZ-COTE® HP1
or uncoated ZnO nanoparticles or micronised ZnO at dose levels inducing
local effects (see section repeated dose toxicity(Bellmann,
2011)) in the
HP1 tested in thein vivomicronucleus test in bone marrow cells of
mouse after single intraperitoneal injection (according
to OECD Guideline 474)
does not induce any chromosome damaging (clastogenic) effect, and there
were no indications of any impairment of chromosome distribution in the
course of mitosis (aneugenic activity) in bone marrow cells in vivo.
administered via intragastric gavage both ZnO nanoparticles and ZnO
microparticles, it was shown that both ZnO nanoparticles and ZnO
microparticles were not considered to be clastogenic in the in vivo
breaks and oxidative DNA damage were analysed ex vivo in BAL cells of
Wistar rats using the hOGG1-modified Comet assay. DNA damage was not
observed 24h after last exposure, but occurred after 14 days of
recovery. The available data on genotoxicity in vitro partly supported
evidence for local genotoxic effects. However, it is questionable,
whether BAL cells are a suitable surrogate for epithelial cells in the
lung, which are the relevant cells for tumour development. No oxidative
DNA damage was detected in epithelial cells of the lung parenchyma using
immunohistochemical methods indicating lack of local genotoxicity in
relevant cells mediated by Reactive oxygen species (ROS). Although an
increase in pro-inflammatory cytokines (coated ZnO) was observed, there
is no evidence of substance specific genotoxic potential.
In conclusion, for nano-ZnO no
nano-specific mutagenic/genotoxic effects could be identified. Zn2+ion
determines the toxicity of ZnO and read across between various forms of
ZnO (micro-scale, nano, coated or not) is fully supported.
Endpoint Conclusion: No adverse effect observed (negative)
The overall weight of the evidence from the
existing in vitro and in vivo genotoxicity assays suggests
that zinc compounds do not have biologically relevant genotoxic
activity. This conclusion is in line with those achieved by other
regulatory reviews of the genotoxicity of zinc compounds (WHO, 2001;
SCF, 2003; EU RAR, 2004, MAK, 2009). Hence, no classification and
labelling for mutagenicity are required.
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