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EC number: 208-933-7
CAS number: 547-67-1
Where data are not available for the
nickel oxalate, data for other inorganic nickel compounds (i.e.
structurally related substances) that are expected to have similar or
higher bioavailability can be used for read across. For human health
endpoints, it is the bioavailability of Ni2+at target
site(s) that in most cases determines the potential occurrence and
severity of the systemic effects to be assessed for the read across of
nickel substances. Therefore, similarity of toxicity is estimated by
comparing data for solubility in simulated human body fluids (e.g.
gastric, lysosomal, and interstitial fluids) as well as in vivo and
human data, where available. For mutagenicity, data for inorganic
nickel substances of similar release of the nickel ion for the
relevant route of exposure can be used for read across. For nickel
substances, the read-across strategy is predicated on the assumed
presence and bioavailability of a common metal anion (e.g., Ni2+)
in biological fluids after exposure to nickel compounds. This is a
reasonable assumption for the majority of inorganic compounds and some
organic compounds (e.g., metal salts of some organic acids) (ICCM,
2007; OECD, 2007; and ECHA, 2008), provided no significant effect of
the other constituents is expected. The oxalate ion is not of concern
since oxalate (i.e. oxalic acid) has not been demonstrated to be
mutagenic (Sayato et al., 1987; Ishidate et al., 1984).
Data for inorganic nickel substances of
higher bioavailability (i.e. higher nickel ion release) can be used as
a worst-case approach. This approach is not considered to be as
representative of the mutagenicity potential for nickel oxalate as
read across from an inorganic nickel substance of a similar
bioavailability and mode of action, but in the absence of access to data
on nickel oxalate the higher nickel ion concentration generated by the
higher nickel ion-releasing substance for read across results in
higher nickel ion bioavailability and associated mutagenicity
potential. The substance used for read across is nickel sulfate
hexahydrate. Because of the higher solubility (and bioavailability of
nickel ions) of nickel sulfate compared to nickel oxalate, the
worst-case approach is used for read across. Since data for nickel
sulfate hexahydrate demosntrate that it is mutagenic, nickel oxalate
is also considered to be mutagenic using read-across data as the
ECHA. 2008. Guidance on Information
Requirements and Chemical Safety Assessment, Chapter R.6: QSARs and
Grouping of Chemicals (Available from ECHA
ICMM [International Council on Mining and
Metals]. 2007. Health Risk Assessment Guidance for Metals (HERAG)
(available from ICMM
Ishidate M Jr, Sofuni T, Yoshikawa K,
Hayashi M, Nohmi T, Sawada M, Matsuoka A. 1984. Primary mutagenicity
screening of food additives currently used in Japan. Food Chem
Kirby Memorial Health Center. 2010.
Bioaccessibility of nickel oxalate (soluble nickel analyses in
simulated gastric, interstitial, and lysosomal fluids). Study Sponsor:
Metallo-Chimique. Report Date: 2010-06-30.
OECD [Organisation for Economic
Co-operation and Development]. 2007. Guidance on Grouping of
Chemicals. Series on Testing and Assessment Number 80 (Available from
Sayato, Y., Nakamuro, K., Ueno, H. 1987.
Mutagenicity of products formed by ozonation of naphthoresorcinol in
aqueous solutions. Mutation Research. Vol. 189, no. 3. p. 217-222.
No data are available for nickel oxalate;
therefore, read-across to more soluble nickel species is used. From the
data reviewed above there is clear evidence indicating that nickel
sulphate is genotoxic in vitro, and in particular, is clastogenic. There
are also a number of in vivo studies.
For nickel sulphate hexahydrate, Larramendy
et al. (1981) conducted a Sister Chromatid Exchange Assay (SCE) with
Syrian Hamster Embryos and a chromosome aberration assay with human
lymphocyte cultures. In the SCE assay, treatment increased the frequency
of SCEs in hamster embryo cells in a dose dependent manner. Nickel
sulphate hexahydrate also increased the number of chromosomal
aberrations in human lymphocytes relative to the control. In another SCE
assay, Wulf (1980) also found that nickel sulfate produced a significant
increase in the number of sister chromatid exchanges. In the only gene
mutation information identified for nickel sulphate, treatment with
nickel sulfate failed to produce a statistically significant increase in
the number of reverse mutations in S. typhimurium strains TA98, TA100,
TA1535, TA1537, and TA1538 and E.Coli strain (DG1153) in the absence of
For nickel sulphate hexahydrate, Oller and
Erexson (2007) performed an in vivo micronucleus assay according to OECD
Test Guideline 474. In this study, male Sprague-Dawley rats received 3
daily gavage doses up to 500 mg/kg day. Treatment failed to induce a
significant increase in the percent of micronucleated erythrocytes in
either bone marrow or peripheral blood.
The study by Benson et al. (2002) shows that
nickel sulphate given by inhalation seems to induce inflammation and
genotoxicity in lung cells at approximately the same concentrations. The
results from some of the other animal studies are conflicting. Results
of two recent micronucleus studies, one after oral and one after
intraperitoneal administration are negative. Evidence from human studies
There are no definitive studies on germ
cells, and little evidence concerning hereditable effects. Whilst there
is evidence that the nickel ion reaches the testes, no effect on
spermatogonial cells was seen in the Mathur et al. (1978) study. The
effects seen in the Sobti & Gill (1989) study may reflect toxic effects
on germ cells rather than chromosomal damage.
The opinion of the Specialised Experts has
been sought with regard to the classification of nickel sulphate as
Muta. Cat. 3; R68 at their meeting in April 2004. The Specialised
Experts concluded that nickel sulphate, nickel chloride and nickel
nitrate should be classified as Muta. Cat. 3; R68. This conclusion is
based on evidence of in vivo genotoxicity in somatic cells, after
systemic exposure. Hence the possibility that the germ cells are
affected cannot be excluded. The Specialised Experts did not consider
that further testing of effects on germ cells was practicable (European
Further testing in an in vivo comet assay in
lung cells after inhalational exposure is also considered to be
unnecessary for the purposes of risk characterisation. A positive result
would not alter the conclusions for the classification as a mutagen, and
a negative result would not be regarded as sufficient evidence to
justify the use of a threshold approach in the carcinogenicity risk
characterisation. Hence, further testing for this effect would not
produce additional information that would significantly change the
outcome of this risk assessment.
Using a weight of evidence approach nickel
sulphate is classified as Muta. Cat. 3; R68 and Muta. 2:H341 in the 1st
ATP to the CLP.
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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