Carcinogenic Classifications

In recent years, a number of organizations and international agencies have evaluated the evidence regarding the carcinogenic effects of nickel, all with the intent of delineating the potential differences in the bioavailability and toxicity of various nickel species. Based largely on the 1990 findings of the ICNCM, the IARC concluded that there is sufficient evidence in humans for the carcinogenicity of nickel sulfate and the combinations of nickel sulfides and oxides encountered in the nickel refining industry. Conversely, it concluded that there is inadequate evidence in humans for the carcinogenicity of metallic nickel and nickel alloys. Based upon its evaluation of both human and experimental data, the IARC has classified nickel compounds as Group 1 (carcinogenic to humans) and metallic nickel as Group 2B (possibly carcinogenic to humans) (IARC, 1990).

In a 1986 evaluation, the U.S. Environmental Protection Agency (U.S. EPA) classified nickel subsulfide and nickel refinery dust from pyrometallurgical sulfide nickel matte refineries as Group A carcinogens, indicating that there is sufficient overall evidence that these forms of nickel are carcinogenic to humans (U.S. EPA, 1986). The Agency also classified nickel carbonyl as a Group B2 probable carcinogen. However, this classification was based upon a rodent study showing somewhat questionable statistical results.

The American Conference of Governmental Industrial Hygienists (ACGIH) (a non-legislative organization) published a list of proposed changes to carcinogen classifications and TLVs for nickel compounds in January, 1997. The ACGIH carcinogen classifications for nickel compounds are:

  • A5 (not suspected as a human carcinogen) for metallic nickel,
  • A4 not classifiable as a human carcinogen) for soluble nickel,
  • A1 (confirmed human carcinogen) for insoluble nickel,
  • A1 for nickel subsulfide, and
  • no classification for nickel carbonyl.

In 2008, the Commission of the European Communities will conclude an extensive evaluation of the human health and environmental effects of metallic nickel and a group of nickel compounds including nickel sulfate, nickel chloride, nickel nitrate, nickel carbonate, nickel sulfides (Ni3S2 and NiS) and nickel oxides (NiO, Ni2O3 and NiO2). As a result of this hazard and risk assessment, all these nickel compounds (except metallic nickel) will be classified as human carcinogens (Table 7-1). Category 1 carcinogens are “Substances known to be carcinogenic to man”. The above nickel compounds have been assigned the risk phrase, “May cause cancer by inhalation” which specifically eliminates the potential for carcinogenicity by other routes of exposure (e.g., oral). Nickel metal will be classified as a Category 3 carcinogen, “Substances which cause concern for man owing to possible carcinogenic effects but in respect of which the available information is not adequate for making a satisfactory assessment.”

For more information on the carcinogenicity of nickel, its compounds and alloys, the reader is referred to the Agency for Toxic Substances and Disease Registry August 2005 profile on nickel and nickel compounds (ATSDR, 2005) and the original ICNCM Report (ICNCM, 1990).

 Table 7-1                            

NOTE: This table shows the results of a direct conversion of the 30th ATP EU classifications for  the listed nickel compounds to the GHS system (in blue).  The reference to “BBL” classifications are derived from a project completed by a consulting firm hired by the NI to review the toxicology data in the EU RA and use their own scientific judgment to translate the EU classifications into GHS.  BBL proposed GHS classifications for nickel sulphate, chloride, nitrate and metal. BBL did not look at nickel carbonate, hydroxide, oxide or sulfide. 
^  = By analogy to the BBL interpretation of classification for water soluble nickel compounds since derogation from water soluble compounds was used by the EU for nickel carbonate classification. The nickel hydroxide classification was read-across from nickel carbonate.
^^ = This classification may change based upon a recent negative animal carcinogenicity study and the lack of epidemiological data.
* 0.01% concentration limit
** concentration limit based on release rate of 0.5 µg Ni/cm2/week

Specific Concentration Limits:

Nickel Sulphate: C>25%:  T, N ; R49-61-20/22-38-42/43-48/23-68-50/53; 20%<C≤25%: T, N; R49-61-38-42/43-48/23-68-51/53; 2.5%<C≤20%:  T, N; R49-61-42/43-48/23-68-51/53; 1%<C≤2.5%:  T; R49-61-42/43-48/23-68-52/53; 0,5%<C≤1%: T; R49-61-43-48/20-52/53; 0,25%<C
Nickel Chloride: C>25%: T, N ; R49-61-23/25-38-42/43-48/23-68-50/53; 20%<C≤25%: T, N; R49-61-20/22-38-42/43-48/23-68-51/53; 3%<C≤20%: T, N; R49-61-20/22-42/43-48/23-68-51/53; 2.5%<C≤3%: T, N; R49-61-42/43-48/23-68-51/53; 1%<C≤2.5%: T; R49-61-42/43-48/23-6
Nickel Nitrate: C>25%: T, N ; R49-61-20/22-38-41-42/43-48/23-68-50/53; 20%<C≤25%: T, N; R49-61-38-41-42/43-48/23-68-51/53; 10%<C≤20%: T, N; R49-61-41-42/43-48/23-68-51/53; 5%<C≤10%: T, N; R49-61-36-42/43-48/23-68-51/53; 2.5%<C≤5%: T, N; R49-61-42/43-48/23

R8 = Contact with combustible material may cause fire
R11= Highly flammable
R20 = Harmful by inhalation
R22 = Harmful if swallowed
R23 = Toxic by inhalation
R25 = Toxic if swallowed
R36 = Irritating to eyes
R38 = Irritating to skin
R40 = Limited evidence of a carcinogenic effect
R41 = Risk of serious damage to eyes
R42 = May cause sensitization by inhalation
R43 = May cause sensitization by skin contact
R45 = May cause cancer
R49 = May cause cancer by inhalation
R50 = Very toxic to aquatic organisms
R53 = May cause long term adverse effects in the aquatic environment
R61 = May cause harm to the unborn child
R63 = Possible risk of harm to the unborn child
R68 = Possible risk of irreversible effects
R48/23 = Toxic: Danger of serious damage to health by prolonged exposure through inhalation
O = Oxidizing
Xi  = Irritating
Xn = Harmful
T = Toxic
N = Dangerous for the environment [Note: Currently applies to sulphate, chloride, nitrate, and carbonate (not metal), but are subject to modification by the Environment TC C & L.
S2 = Keep out of the reach of children
S36/37 = Wear suitable protective clothing and gloves.
S45 = In case of accident or if you feel unwell, seek medical advice immediately (show the label where possible).
S53 = Avoid exposure – obtain special instructions before use.
S60 = This material and its container must be disposed of as hazardous waste.
S61 = Avoid release to the environment. Refer to special instructions/safety data sheets.

Note E:

Substances with specific effects on human health (see chapter 4 of Annex V1 of Directive 6715481EEC) that are classified as carcinogenic, mutagenic, and/or toxic for reproduction in categories 1 or 2 are ascribed Note E if they are also classified as very toxic (T+), toxic (T) or harmful (Xn). For these substances, the risk phrases RZO, RZ1, RZZ. R23, R24, R25. R26. R27, R28, R39, R68 (harmful), R48 and R65 and all combinations of these risk phrases shall be preceded by the word 'Also'."

Note U:

is a new note agreed to be included in the foreword to Annex I reading as follows: Alloys containing nickel are classified for skin sensitisation when the release rate of 0.5 μg Ni/cm2/week as specified in the European Parliament and Council Directive 94/27/EC and as measured by the European Standard reference test method, EN 1811 is exceeded.