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					                    ECBI/69/03 Add. 38




               Nickel carbonate

             CAS-No.: 3333-67-3


            EINECS-No.: 222-068-2


         RISK ASSESSMENT
        Revised Draft of February, 2004

Chapter 4 Human Health: Mutagenicity and Cancer
     and part of Chapter 6 References - only


    Danish Environmental Protection Agency
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Information on the Rapporteur.
The Danish Environmental Protection Agency is the Rapporteur for the risk assessment report of nickel carbonate. The
Rapporteur is responsible for the risk evaluation and for the contents of this report.

Contact persons:
Lotte Kau Andersen, Henrik Søren Larsen & Henrik Tyle
Chemicals Division
Danish Environmental Protection Agency
Strandgade 29
DK-1401 Copenhagen K
DENMARK

Tel: +45 32 66 01 00
Fax: +45 32 66 02 61
E-mail: LKA@mst.dk / HEL@mst.dk / HTY@mst.dk / DEPA-ESR@mst.dk


Acknowledgements.
The scientific assessments included in this report have been prepared by the following organisations by order of the
Rapporteur:

        The Danish National Working Environment Authority (Occupational Exposure, Chapter 4)
        Danish Technological Institute (Chapter 3 and assistance with Chapters 1 & 2)
        Institute of Food Safety and Nutrition, The Danish Veterinary and Food Administration, (Consumer and
         Indirect Exposure, Human health effects, Chapter 4)
        National Environmental Research Institute, Denmark (Terrestrial effects Assessment, Chapter 3).

The Rapporteur would also like to acknowledge the contributions from the following individuals:
     Professor Aage Andersen and Dr. Tom K. Grimsrud of the Cancer Registry of Norway, Institute of Population-
       based Cancer Research, for their assistance in the preparation of the section on cancer epidemiology in Chapter
       4,
     Drs. Hudson Bates, Adriana Oller, Katherine Heim, Lisa Ortego and Chris Schlekat, NiPERA, Durham, North
       Carolina, USA, for providing information on the health and environmental effects of nickel carbonate,
     Jim Hart, Sherborne, Dorset, UK, for the preparation of Chapters 1 & 2, and sections of Chapter 4,
     Leila Laine, OMG, Finland, for providing information on the production and use of nickel carbonate and nickel
       hydroxycarbonate,
     Prof. Tore Sanner, Institute of Cancer Research, Montebello, Oslo, Norway, for providing the calculation of the
       quantitative risk assessment of the carcinogenicity of nickel and nickel compounds
     Dr. Sally Pugh Williams, Inco, Wales, UK for general information on nickel.




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4.1.2.6 Mutagenicity
The genotoxicity of nickel carbonate and other nickel compounds have been reviewed by several organisations
including IPCS (1991), IARC (1990), UK HSE (1987), ECETOC (1989), US ATSDR (1997), NiPERA (1996)1 and
TERA (1999). The following tables give a summary of the in vitro and in vivo data on the mutagenic and genotoxic
effects of nickel carbonate. These tables and the discussions are based primarily on the summaries given in the above-
mentioned published reviews and other information submitted by Industry.

4.1.2.6.1 In vitro studies

4.1.2.6.1.1       DNA Damage and Repair.
There are no studies in vitro on effects on DNA.

4.1.2.6.1.2       Gene mutations
There is no data available on the effects of nickel carbonate on gene mutation in vitro.

4.1.2.6.1.3       Chromosomal effects
The studies on nickel carbonate on chromosomal effects in vitro are summarised in table 4.1.2.6.1.A.

Nickel carbonate has been tested for sister chromatid exchanges (SCE) in two studies, both carried out by Montaldi et
al. (1985, 1987 - reviewed by NiPERA and TERA). Positive effects were seen in both studies.

In the Montaldi et al. (1987) study referred to above, chromosome aberrations were also studied, with a positive result.
Table 4.1.2.6.1.A: In vitro studies with nickel carbonate in mammalian cells.

Species (Test           Endpoint              Result          Reference               Review
system).
Hamster CHO             SCE                   Positive        Montaldi et al.         NiPERA,
                                                              (1985, 1987)            TERA
Hamster CHO             CA                    Positive        Montaldi et al.         NiPERA,
                                                              (1987)                  TERA

4.1.2.6.1.4       Discussion and conclusion, in vitro studies.
The data on in vitro genotoxicity of nickel carbonate is very limited. The positive results seen for chromosomal
aberrations and SCE in hamster CHO cells in vitro are consistent with effects seen for other nickel compounds.

4.1.2.6.2 In vivo studies

4.1.2.6.2.1       DNA Damage and Repair.
Nickel carbonate has been tested in two in vivo studies for effects on DNA strand breaks, X links and alkaline elution in
rats at doses from 5 – 40 mg Ni/kg intraperitoneally. The two studies by Ciccarelli et al. (1981, 1985) which were
reviewed by IPCS, IARC, NiPERA, 1996) showed single strand breaks in lung and kidney nuclei. The damage
correlated with the nickel concentration (quoted from NiPERA 1996). Whilst not direct evidence of mutagenicity, these
studies indicate that effects seen with nickel salts in vitro can also be seen in vivo. NiPERA (2003) regards the meaning
of these studies for in vivo mutagenicity as unclear.

4.1.2.6.2.2       Gene mutations
There is no in vivo data available on the effects of nickel carbonate on gene mutation in vivo.



1
 NiPERA has pointed out that this review was produced by independent scientists for NiPERA and that the conclusions
of the report do not necessarily reflect the current position of NiPERA.



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4.1.2.6.2.3       Chromosomal effects.
There is no in vivo data available on the effects of nickel carbonate on chromosomal aberrations or sister chromatid
exchange.

4.1.2.6.2.4       Discussion and conclusion, in vitro studies.
There is practically no data on the in vivo genotoxicity of nickel carbonate. The two Ciccarelli studies provide evidence
that effects similar to those seen with other nickel compounds can also occur in vivo.

4.1.2.6.3 Conclusions
The data on the in vitro and in vivo genotoxicity of nickel carbonate is very limited indeed. The two studies showing
effects in vitro on chromosome aberrations and sister chromatid exchanges with nickel carbonate are consistent with the
effects seen with other better studied nickel compounds. In vivo studies on DNA damage suggest that effects can also be
seen in vivo. The genotoxicity of nickel compounds has been reviewed by NiPERA (1996) and TERA (1998). TERA
concludes that soluble nickel salts produce chromosomal effects in mammalian cells both in vitro and in vivo. The
NiPERA (1996) report concludes “that it is clear that most Ni compounds are clastogenic in vitro and in vivo as
measured by chromosomal aberrations and micronuclei induction, although in general the elicited responses are weak.”
The Rapporteur considers that there is a concern for the genotoxic effects of the substance, and that this requires that the
carcinogenicity risk characterisation is carried out using a non-threshold approach.

There is no evidence concerning possible hereditable effects on germ cells.

NiPERA (2003) considers that the mutagenicity assessment for nickel carbonate could be derogated to the overall
mutagenicity assessment for either soluble or insoluble nickel compounds (worst-case). The Rapporteur considers that
there is sufficient evidence to consider that soluble nickel salts should be classified as Muta. Cat. 3; R68. On the basis
of the derogation suggested above, the Rapporteur feels that it is reasonable to propose the classification of nickel
carbonate as Muta. Cat. 3; R68.

The opinion of the Specialised Experts is being sought with regard to the possible effects on germ cells. Section 4.2.2.3
of Annex VI (Comments regarding the classification of mutagenic substances) notes that “substances are classified as
mutagens with specific reference to inherited genetic damage. However, the type of results leading to classification of
chemicals in category 3 [….] is generally also regarded as an alert for possible carcinogenic activity.” As discussed in
Chapter 4.1.2.7 (below) the Rapporteur considers that nickel carbonate should be classified as a known human
carcinogen (Carc. Cat. 1; R49). In the absence of specific effects on germ cells, the Rapporteur could consider
classification as a mutagen in category 3 “as an alert for possible carcinogenic activity” as redundant.

The Rapporteur considers that, whether or not the substance is classified as Muta. Cat. 3, there is a concern for the
genotoxic effects, and that this requires that the carcinogenicity risk characterisation is carried out using a non-threshold
approach. This is consistent with the opinion of the CSTEE (2001) on the Commission Ambient Air paper. The CSTEE
finds that “a genotoxic component in the mode of carcinogenic action is possible”.

At the same time, the Rapporteur acknowledges the uncertainties in the interpretation of the genotoxicity of nickel
compounds with respect to the role of genotoxicity in the induction of cancer. To provide additional information, the
Rapporteur proposes that nickel carbonate (with a soluble nickel compound, either nickel sulphate, nickel chloride or
nickel nitrate, metallic nickel and other selected nickel compounds) is tested in an in vivo comet assay in lung cells after
inhalational exposure of at least 13 weeks duration. In view of the absence of data on this substance in general,
inclusion of other endpoints (such as a comet assay in germ cells or guideline MN or CA assays) in the study may be
relevant.

4.1.2.7 Carcinogenicity

4.1.2.7.1 Animal data

4.1.2.7.1.1       Inhalation
No studies regarding carcinogenicity of nickel carbonate following inhalation exposure or intratracheal instillation in
experimental animals have been located.




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4.1.2.7.1.2        Oral
No data regarding carcinogenicity of nickel carbonate following oral administration in experimental animals have been
located.

4.1.2.7.1.3        Dermal
No data regarding carcinogenicity following dermal contact to nickel carbonate in experimental animals have been
located.

4.1.2.7.1.4        Other routes of administration
Studies on the carcinogenicity of nickel carbonate following intramuscular implants or intraperitoneal injections have
been performed in rats; these studies are summarised in Table 4.1.2.7.1.A. Tumours were observed following both
routes of administration.
Table 4.1.2.7.1.A: Summary of carcinogenicity studies of nickel carbonate in experimental animals by other
routes of administration than inhalation, oral administration, and dermal contact.

 Route of             Species, group      Concentration,               Results                  Reference
 administration       size and sex        exposure duration
 Intramuscular        NIH black rats, 35 3 implants (interval          Implantation-site        Payne (1964 –
 implants (in         animals per group unspecified) of 7 mg of        sarcomas in 6/35 rats    quoted from IARC
 sheep fat pellets)                      nickel carbonate                                       1990, TERA
                                                                                                1999). Reported as
                                          Observation for 18           No tumours in            an abstract.
                      Vehicle controls    months                       controls (0/35)
 Intraperitoneal      Wistar rats         25 or 50 injections of 1     Abdominal tumours in Pott et al. (1989,
 injections                               mg nickel as nickel          1/35                 1992)
                      35 females          carbonate twice weekly
                                                                       (1 sarcoma) or 3/33 (2 (Pott et al. 1992
                                          Observation for 132          mesothelioma, 1        cited in IARC
                      Controls:           weeks                        sarcomas)              1990 and TERA
                                                                                              1999 as Pott et al.
                      1 ml saline x 3                                  1/33 (sarcoma)         1990)
                      1 ml saline x 50                                 0/34

                      2 ml saline x 4                                  3/66 (1 mesothelioma,
                                                                       2 sarcomas)


4.1.2.7.1.5        Promoter studies
No data regarding the promoting effect of nickel carbonate in experimental animals have been located.

4.1.2.7.1.6        Discussion and conclusions, carcinogenicity in experimental animals

4.1.2.7.1.6.1 Inhalation
No studies regarding carcinogenicity of nickel carbonate following inhalation exposure or intratracheal instillation in
experimental animals have been located.

Inhalation studies on nickel oxide (NTP 1996b) and nickel subsulphide (NTP 1996c) showed some evidence and clear
evidence, respectively, for carcinogenic activity following inhalation in rats, and there was equivocal evidence for
nickel oxide in female mice. In contrast, similar inhalation studies on nickel sulphate (NTP 1996a) showed no evidence
of carcinogenic activity following inhalation of nickel sulphate hexahydrate in rats and mice.

The results of the NTP studies on nickel sulphate, nickel oxide, and nickel subsulphide raise the question of whether
soluble forms of nickel differ from insoluble forms of nickel in carcinogenic potential or in potency in experimental
animals following exposure by inhalation; however, the available data are not sufficient for an evaluation of this
question. For further details, the reader is referred to the Background document in support of the individual Risk
Assessment Reports.




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No other data considered as being relevant for the conclusion on the carcinogenicity of nickel carbonate in experimental
animals following inhalation have been located.

In conclusion, the available data on carcinogenicity of various nickel compounds is considered as being insufficient for
a conclusion on the carcinogenic potential of nickel carbonate in experimental animals following inhalation.

4.1.2.7.1.6.2 Oral
No data regarding carcinogenicity of nickel carbonate following oral administration in experimental animals have been
located.

The carcinogenicity of nickel sulphate following oral administration has been studied in rats and dogs; no neoplasms
were revealed in either rats or dogs. Data on other nickel compounds are limited to a drinking water study of nickel
acetate in rats and mice in which no exposure-related neoplasms was observed. However, these studies suffer from
several limitations and are therefore not conclusively negative.

In conclusion, the available data are too limited for an evaluation of the carcinogenic potential in experimental animals
following oral administration of nickel carbonate.

4.1.2.7.1.6.3 Dermal
No data regarding carcinogenicity following dermal contact to nickel carbonate in experimental animals have been
located.

Data on other nickel compounds are limited to a study in male hamsters in which no tumours developed in the buccal
pouch, oral cavity, or intestinal tract following painting on the mucosa of the buccal pouches with -nickel subsulphide.

In conclusion, the available data are too limited for an evaluation of the carcinogenic potential in experimental animals
following dermal contact to nickel carbonate.

4.1.2.7.1.6.4 Other routes of administration
Studies on the carcinogenicity of nickel carbonate following intramuscular implants or intraperitoneal injections have
been performed in rats; tumours were observed following both administration routes.

Data on other nickel compounds show that these compounds, with a few exceptions, produce local tumours following
injection at various sites to experimental animals.

In conclusion, the available data show that nickel compounds, with a few exceptions, produce local tumours following
injection at various sites to experimental animals. It should be noted that these routes of administration are irrelevant for
human beings who will only be exposed via inhalation, oral intake or dermal contact to nickel carbonate. However, the
positive findings in these studies might be considered as part of the weight of the evidence when evaluating the
carcinogenic potential of nickel carbonate to human beings.

4.1.2.7.1.6.5 Promoter studies
No data regarding the promoting effect of nickel carbonate in experimental animals have been located.

Data on nickel sulphate, nickel chloride, and nickel metal indicate that these compounds might have a promoting effect.

In conclusion, the available data indicate that nickel sulphate, nickel chloride, and nickel metal might have a promoting
effect in combination with selected initiators. However, based on the available studies, it is not possible to draw any
conclusion regarding a promoting potential of the five prioritised nickel compounds (nickel sulphate, nickel chloride,
nickel nitrate, nickel carbonate, and nickel metal). Furthermore, such information is difficult to use with respect to
evaluating the carcinogenic potential of nickel carbonate.

4.1.2.7.1.7       Conclusion
The data in experimental animals on nickel carbonate as reported here as well as data on other nickel compounds are
considered as being insufficient for an evaluation of the carcinogenic potential of nickel carbonate in experimental




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animals and thus, do not clearly indicate whether nickel carbonate should be regarded as a carcinogenic substance in
experimental animals.




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4.1.2.7.2 Human studies
Since 1990, starting with the report of the International Committee on Nickel Carcinogenesis in Man (Doll et al., 1990),
many of the epidemiological cancer studies among nickel exposed workers have addressed four groups of nickel
species: sulphidic, oxidic, and metallic nickel, and water soluble nickel salts. In order to improve the quality of the
exposure data, the nickel industry has developed a sequential leaching technique that identifies these four forms of
nickel in dust and aerosols (Zatka et al., 1992). Nickel carbonate is generally considered to form part of the oxidic
fraction (NiPERA, 1996). For further details of the behaviour of nickel hydroxycarbonate in this leaching process, see
Chapter 4.1.1.2.1.2.

No epidemiological study has addressed the potential carcinogenic effect of nickel carbonate specifically.

A single case of nasal cancer has been reported among nickel-refinery workers engaged in a high-temperature process
where nickel carbonate was decomposed to nickel oxide (Enterline et al., 1982). Results from the same refinery cohort
were included in the report of the International Committee on Nickel Carcinogenesis in Man (Doll et al., 1990), but
there was no strong evidence for nickel related increased risk of respiratory cancer.

In the report from the International Committee on Nickel Carcinogenesis in Man (Doll et al., 1990), nickel carbonate
was classified as an insoluble form of nickel for most of the nickel refineries, while for the Norwegian one it was
classified as water soluble. The contribution from nickel carbonate to the inhalation exposure in these cohorts was
probably rather low compared to the other forms of nickel.

An evaluation of the carcinogenicity to humans of nickel carbonate could possibly be based on the toxico-kinetic
properties of nickel carbonate compared to other nickel compounds such as nickel sulphides and nickel oxides.

4.1.2.7.2.1       Overall conclusion for carcinogenicity
Nickel carbonate should be classified in Category 1, known to be carcinogenic to man. The Industry derogation
statement (Laine, 2003d) indicates that the carcinogenicity should be evaluated using the worst-case comparison with
data for soluble and insoluble nickel compounds.

The Rapporteur considers that nickel carbonate should be classified as Carc. Cat. 1; R49. The relevance of possible
classification with R45 should be reconsidered when results of the on-going two-year oral carcinogenicity study of
nickel sulphate are available.




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REFERENCES.
   Ciccarelli RB, Hampton TH, Jennette KW (1981): Nickel carbonate induces DNA-protein crosslinks and DNA
    strand breaks in rat kidney. Cancer Lett. 12(4): 349-354.
   Ciccarelli RB, Wetterhahn KE (1985): In Vitro Interaction of 63-Nickel (II) with Chromatin and DNA from rat
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   ECETOC, (1989): Technical Report N° 33, Nickel and Nickel compounds : Review of Toxicology and
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   Enterline PE, Marsh GM (1982): Mortality among workers in a nickel refinery and alloy manufacturing plant in
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   IARC (1990): IARC Monographs on the evaluation of carcinogenic risks to humans, Volume 49, Chromium, nickel
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   IPCS (1991): Environmental Health Criteria 108: Nickel. World Health Organisation, Geneva. 383 p.
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   Montaldi A , Zentalin L, Zordan M, Bianchi V, Levis AG, Clonfero E, Paglialunga S (1987): Chromosomal effects
    of heavy metals (Cd, Cr, Hg, Ni and Pb) on cultured mammalian cells in the presence of nitrilotriacetic acid (NTA).
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   NiPERA (1996) (in collaboration with Eurométaux for DG V): Occupational exposure limits: Criteria Document
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   NTP [National Toxicology Program] (1996a): Technical Report on the toxicology and carcinogenesis studies of
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   NTP [National Toxicology Program] (1996b). Technical Report on the toxicology and carcinogenesis studies of
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   NTP [National Toxicology Program] (1996c). Technical Report on the toxicology and carcinogenesis studies of
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   Payne WW (1964): Carcinogenicity of nickel compounds in experimental animals (Abstract No. 197). Proc. Am.
    Assoc. Cancer Res., 5:50.
   Pott, F., Rippe, R. M., Roller, M., Csicsaky, M., Rosenbruch, M. Huth F. (1989): Tumours in the abdominal cavity
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   Pott, F., Rippe, R. M., Roller, M., Csicsaky, M., Rosenbruch, M. and Huth F. (1992): Carcinogenicity of nickel
    compounds and nickei alloys in rats by intraperitoneal injection. In Nickel in Human Health: Current Perspectives
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   TERA (1999): Toxicological review of soluble nickel salts. Prepared for: Metal Finishing Association of Southern
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    EPA Contract #68-C7-0011. March 1999.




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   UK-HSE [Health & Safety Executive] (1987): Toxicity Review 19. The toxicity of nickel and its organic
    compounds. Health and Safety Executive. HMSO. ISBN 0 11 883961 6
   US ATSDR [Agency for Toxic Substances and Diseases Registry] (1997): Toxicological Profile for Nickel.
    September 1997. US Department of Health and Human Services, Public Health Service.
   Zatka VJ, Warner JS, Maskery D (1992): Chemical speciation of nickel in airborne dusts: analytical methods and
    results of an interlaboratory test program. Env Sci Tech 26,138-144.




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