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EC number: 236-068-5 | CAS number: 13138-45-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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Carcinogenicity
Administrative data
Description of key information
ORAL: Data are read-across from a negative oral carcinogenicity in rats with Ni sulphate. A well-conducted OECD 451 study in rats (Heim et al 2007) did not show any carcinogenic potential of nickel sulphate following oral administration. A summary document on this topic can be found in the attached document entitled, " Background-Oral Carcinogenicity for all Nickel Compounds" (Section 7.7 of IUCLID) and in AppendixB1 of the CSR.
INHALATION: Data for nickel nitrate are read-across from Ni sulphate. Data on respiratory carcinogenicity associated with inhalation exposure to nickel chloride and/or Ni sulphate (in mixed nickel exposures) from multiple human studies are considered (e.g., Oller et al., 2014; Grimsrud et al., 2002).
DERMAL: As oral exposure to nickel sulphate does not show any carcinogenic potential, and systemic dermal absorption of nickel is lower than oral absorption, cancer via dermal exposure is not a concern for Ni sulphate or any other nickel compound including nickelnitrate.
Value used for CSA (route: oral):
NOAEL:11 mg Ni/kg bw/day (as nickel sulphate hexahydrate)
Value used for CSA (route: inhalation):
NOAEC: 0.11 mg Ni/m3 (as nickel sulphate hexahydrate)
Key value for chemical safety assessment
Justification for classification or non-classification
Ni nitrate is classified as Carc. 1A; H350i via inhalation route of exposure according to the 1st ATP to the CLP Regulation. Background information can be found in the discussion section. In addition, a background document summarizing the potential of Ni compounds to cause cancer via the oral route of exposure can be found in the attached document entitled, "Background-Oral Carcinogenicity for all Nickel Compounds" (Appendix B1 to CSR). In summary, absence of oral carcinogenicity of the nickel (II) ion demonstrates that the possible carcinogenic effects of nickel-containing substances in humans are limited to the inhalation route of exposure and the associated organ of entry (i. e., the respiratory tract). After inhalation, respiratory toxicity limits the systemic absorption of Ni (II) ion to levels below those that can be achieved via oral or dermal exposure.
Additional information
Data regarding the carcinogenic potential of Ni nitrate by oral or inhalation routes of exposure are lacking. However, based on the expected similar toxicological behavior of nickel in compounds that have similar nickel ion release (e.g., nickel chloride hexahydrate, nickel acetate tetrahydrate, nickel sulphamate tetrahydrate, and nickel sulphate hexahydrate), it seems apparent that we can read across from nickel sulphate to very water soluble nickel compounds such as nickel dinitrate. Based on water solubility of nickel dinitrate and bioaccessibily and toxicity data for other similarly soluble nickel compounds we can read across to nickel dinitrate from Ni sulphate (KMHC, 2010 and Appendices B1 and B2).
Animal Data
Inhalation studies with nickel sulphate hexahydrate (MMAD = 2.1-2.5 µm; GSD ~ 2) have been performed in rats and mice (NTP 1996a). No exposure related neoplasms were observed in rats (F344/N) or in mice (B6C3F1) after exposure for two years at concentrations up to 0.11 mg Ni/m3 or 0.22 mg Ni/m3, respectively. These results are in contrast to those obtained with crystalline nickel subsulphide and green (high calcining temperature) nickel oxide. Inhalation studies with nickel oxide (NTP, 1996b) and nickel subsulphide (NTP, 1996c) showed some evidence and clear evidence, respectively, for carcinogenic activity following inhalation exposure in rats, and there was equivocal evidence for nickel oxide in female mice.
The different results obtained with nickel sulphate, nickel oxide, and nickel subsulphide raise questions as to whether these compounds differ in their mode of action or carcinogenic potency. The role of respiratory toxicity on carcinogenicity is also an important consideration. Water soluble nickel compounds are the most toxic compounds for the respiratory tract but by themselves did not induce tumors even at exposure levels corresponding to the maximum tolerated dose. A possible model based on the Ni bioavailability at critical intracellular sites has been described to help reconcile all these possibilities (Goodman et al., 2009, 2011). It is postulated that there are many factors that can affect the bioavailability of nickel at key intracellular sites and that if these factors preclude Ni to be available at nuclear sites in sufficient amounts, no tumors will be induced.This could be the case for soluble nickel compounds that are very toxic to the lungs, and this toxicity limits the exposure levels that can be tolerated. In addition, these compounds are cleared from the lungs very quickly, and the Ni ion released extracellularly is very poorly taken up by the cells. The possibility that exposure to soluble nickel compounds may enhance the development of tumors initiated by other carcinogens cannot be excluded based on the data from animals experiments with single exposures.
The carcinogenicity of nickel sulphate (a water soluble nickel compound) following oral administration has been studied in several studies with rats and dogs and no neoplasms were observed. The most recent 2-year carcinogenicity study in rats by oral gavage was performed according to OECD 451 guidance and did not show a carcinogenic potential for exposure to nickel sulphate following oral administration (Heim et al., 2007). 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. In conclusion, there is sufficient oral carcinogenicity data to show that nickel sulphate (as a surrogate for water soluble nickel compounds) does not show a carcinogenic potential in experimental animals following oral administration. The negative results from the oral study are consistent with the negative results from the inhalation study. These results can be read across to nickel nitrate. A background document summarizing the potential of Ni compounds to cause cancer via the oral route of exposure can be found in the attached document entitled, " Background-Oral Carcinogenicity for all Nickel Compounds" (Section 7.7) and in Appendix B1 of the CSR.
No data regarding carcinogenicity following dermal contact to nickel nitrate or nickel sulphate in experimental animals have been located. However, toxicokinetic data indicates that systemic absorption of nickel from water soluble nickel compounds through the skin is very low (≤ 2%). As oral exposure does not show systemic carcinogenicity, it seems reasonable to assume that cancer is not a relevant endpoint for dermal exposure.
Epidemiology Data
As discussed in the European Union Risk Assessment for Nickel Sulphate report (2008/2009), epidemiological studies from three nickel refineries processing sulphidic nickel ores have demonstrated elevated risk of lung and nasal cancer in workers exposed to dust containing nickel sulphate and/or nickel chloride in the presence of variable amounts of water insoluble nickel compounds. These refineries were: the Clydach refinery in Wales, UK; the Kristiansand refinery in Norway; and the Harjavalta refinery in Finland. Among electrolysis workers at the Port Colborne refinery in Canada the association between respiratory cancer and exposure to nickel sulphate and/or nickel chloride was not observed.
In Clydach (Doll et al., 1990; Easton et al., 1992; Sorahan and Williams, 2005, Grimsrud and Peto, 2006), elevated risk for death from lung or nasal cancer was found in workers employed in the hydrometallurgy department. Exposure to water soluble nickel also took place in other departments and there was evidence of a dose-response between soluble nickel exposure and increased cancer risk in workers with high oxidic and/or sulfidic exposure but not when oxidic and sulfidic exposures were low. At the Kristiansand refinery, both lung and nasal cancer mortality risks were elevated (Doll et al., 1990; Andersen et al., 1996; Grimsrud et al., 2002; 2003). A dose-response was demonstrated for lung cancer according to duration of work in the electrolysis departments. In a regression analysis, a dose-response for lung cancer and cumulative exposure to water-soluble nickel (nickel sulphate and nickel chloride) was observed after adjustment for age, smoking (ever smoker versus never smokers), and cumulative exposure to oxidic nickel. The effect from sulphidic nickel was not addressed but for oxidic nickel a modest increase in risk was also observed. The study suggested a multiplicative effect of smoking and nickel exposure. A 2002 case-control study within the same cohort, also demonstrated a dose-response between lung cancer and water-soluble nickel after adjustment for smoking (life-time habits). An increase in risk from exposures to other forms of nickel irrespective of dose could not be excluded.
The refinery in Harjavalta also treated a sulphidic nickel concentrate, as did the two refineries in Clydach and Kristiansand. Elevated risk for lung and nasal cancers was demonstrated in the group of workers with nickel sulphate exposures (Doll et al., 1990; Anttila et al., 1998). No adjustment for smoking could be performed in the analyses of lung cancer risk. No dose-response was found, but the number of cancer cases was low. The electrolysis workers at the Port Colborne refinery were exposed mainly to nickel sulphate until 1942 and from that year exposures contained a mixture of sulphate and chloride. In contrast to the three cohorts described above, lung cancer mortality risks were not elevated among the electrolysis workers with no exposure in leaching, calcining or sintering plant (Roberts et al., 1989a,b; Doll et al., 1990). In addition, there were no nasal cancer cases among these workers.
The epidemiological evidence (without the animal data) was reviewed by the Specialised Experts in April, 2004. The Specialised Experts concluded that the epidemiological evidence was sufficient to classify nickel sulphate in Category 1, known to be carcinogenic to man. The Specialised Experts considered the data to be sufficient to establish a causal association between the human exposure to the substances and the development of lung cancer and they considered that there was supporting evidence for this conclusion from more limited data on nasal cancer. Likewise, the European Union Risk Assessment for Nickel Sulphate (2008/2009) concluded that the epidemiological data demonstrated “a positive association in a dose-dependent manner between exposureto soluble nickel compounds (e.g., nickel sulphate and nickel chloride) and increased respiratory cancer risk in at least three separate cohorts.”
A recent review of the carcinogenicity data for soluble nickel compounds applied the Bradford Hill criteria of causality to the epidemiological evidence in support of the carcinogenicity of soluble nickel compounds. (Goodman et al.,2009). A weight of evidence analysis was also applied to the epidemiological, animal and mode of action data. Based on their evaluation, the authors considered that certain epidemiological data, but not all, suggest that soluble nickel exposure leads to increased cancer risk in the presence of certain insoluble nickel compounds. In the authors’ opinion, there was only limited evidence for its carcinogenicity in humans. They noted that although there is no evidence that soluble nickel acts as a complete carcinogen in animals, there is some evidence from the animal data that soluble nickel may act as a tumor promoter. Goodman et al.(2009) go on to state: “Finally, the mode-of-action data suggest that soluble nickel compounds are not able to cause genotoxic effectsin vivobecause they cannot deliver sufficient nickel ion to nuclear sites of target cells. Although the data do suggest several possible non-genotoxic effects of the nickel ion, it is unclear whether soluble nickel compounds can elicit these effectsin vivoor whether these effects, if elicited, would result in tumor promotion. Overall, the mode-of-action data equally support soluble nickel as a promoter or as not being a causal factor in carcinogenesis at all.” Goodman and coworkers concluded: “The weight of evidence does not clearly support a role for soluble nickel alone in carcinogenesis.”
However, as discussed above, the Specialized Experts had concluded in 2004 that the epidemiological evidence (from workers with mixed exposures) alone was sufficient to classify nickel sulphate and nickel nitrate in Category 1, known to be carcinogenic to man. Hence, Ni nitrate carries the carcinogenicity classification of Carc. 1A; H350i via inhalation.
The following information is taken into account for any hazard / risk assessment:
ORAL: Data are read-across from a negative oral carcinogenicity in rats with Ni sulphate. A well-conducted OECD 451 study in rats (Heim et al 2007) did not show any carcinogenic potential of nickel sulphate following oral administration. A summary document on this topic can be found in the attached document entitled, " Background-Oral Carcinogenicity for all Nickel Compounds" (Section 7.7 of IUCLID) and in Appendix B1 of the CSR.
INHALATION: Data for nickel nitrate are read-across from Ni sulphate. Data on respiratory carcinogenicity associated with inhalation exposure to nickel chloride and/or Ni sulphate (in mixed nickel exposures) from multiple human studies are considered (e.g., Oller et al., 2014; Grimsrud et al., 2002).
DERMAL: As oral exposure to nickel sulphate does not show any carcinogenic potential, and systemic dermal absorption of nickel is lower than oral absorption, cancer via dermal exposure is not a concern for Ni sulphate or any other nickel compound including nickelnitrate.
Value used for CSA (route: oral):
NOAEL:11 mg Ni/kg bw/day (as nickel sulphate hexahydrate)
Value used for CSA (route: inhalation):
NOAEC: 0.11 mg Ni/m3 (as nickel sulphate hexahydrate)
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