Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

ENDPOINT SUMMARY INFORMATION FROM THE 2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT. Data from human studies are reported under Section 7.10.4 of this IUCLID file.

A number of studies on skin sensitisation in guinea pigs have been performed with nickel sulphate. The dose-response relationship for nickel sulphate hexahydrate has been studied in the guinea pig maximization test. Six intradermal (0.01%-3.0% solutions in water) and six topical (0.25%-10.0% pet.) concentrations were chosen for induction and nickel sulphate hexahydrate 1% in petrolatum was used for challenge in the first instance. At 48 h, a linear relationship was obtained between the intradermal induction dose (but not topical dose) and the response, resulting in a maximum sensitisation rate of 40% after intradermal induction with 3% nickel sulphate. The reactivity disappeared at re-challenge 1 week later. Following a booster closed patch on day 35, using 10% nickel sulphate in petrolatum, the animals were challenged with nickel sulphate 2% in petrolatum and statistical analyses of 72-h readings revealed a non-linear dose-response relationship, giving a maximum response frequency of 40% after initial induction with nickel sulphate 3% intradermally and 2% after topical application. (Rohold et al. 1991).

As the maximum response rate of 40%, found in the study cited above was found to be low, an open epicutaneous application method was tried, and found to be more efficient. Immediately after pre-treatment with 1% aqueous sodium lauryl sulphate, the upper back skin was treated daily for 4 weeks with 0.3%-3% nickel sulphate in either a 1% lanolin cream (Vaseline, pH 5 SAD cream) or hydroxypropyl cellulose. Weekly intradermal injections with aluminium potassium sulphate were used as adjuvant. The animals were challenged twice with a one-week interval, with nickel sulphate 2% in water and 1% in petrolatum, respectively. Considering both readings at both challenges concentrations, the frequency of sensitisation was 57-93% (8 /14 to 13/14 animals) in the group treated with 1% in the lanolin cream, 60-100% (9/15 to 15/15 animals) in the group treated with 3% in the lanolin cream, and 67-75% (8/12 to 9/12 animals) in the group treated with 1% in hydroxypropyl cellulose. Rechallenge of initially sensitised animals 10 weeks later confirmed that a lasting contact allergy had been obtained. (Nielsen et al. 1992). Basketter & Scholes (1992) tested nickel sulphate in the local lymph node assay (LLNA) in mice at concentrations of 0.5, 1 and 2.5%. Nickel sulphate was negative in the LLNA.

Several studies have demonstrated that immunological tolerance to nickel can be achieved in animals (Vreeburg et al., 1984; van Hoogstraten et al., 1992a and b; van Hoogstraten et al., 1993; Ishii et al., 1993; van Hoogstraten et al., 1994; Troost et al., 1995; and Artik et al. 1999). In a number of experiments on mice and guinea pigs, persistent immune tolerance to nickel was induced by oral dosing with nickel prior to cutaneous exposure (Ishii et al., 1993; van Hoogstraten et al., 1992; Vreeburg et al., 1984). It was observed that intragastric priming with nickel sulphate prior to sensitisation successfully reduced the cutaneous delayed type hypersensitivity response to cutaneous application of the same antigen in mice in a dose-dependent manner, as measured by ear swelling (van Hoogstraten et al., 1993). Although the objective of these studies was to investigate the possibility to induce immunological tolerance to nickel, indirectly they provide evidence that nickel sulphate can induce skin sensitisation in mice.

These conclusions are extrapolated for Nickel fluoride, as it was demostrated that the sensitisation activity is due to the presence of Nickel and is assumed valid for all soluble Nickel compounds as reported in the European Risk Assessment Report on Nickel soluble compounds.

FOR AN EXTENSIVE DISCUSSION, REFER TO THE NICKEL SULFATE DOSSIER WHICH IS BASED ON THE CONCLUSIONS EXPLAINED IN THE 2008/2009 EUROPEAN UNION EXISITING SUBSTANCE RISK ASSESSMENT OF NICKEL (EU RAR) (EEC 793/93)


Migrated from Short description of key information:
Data suggest that nickel fluoride is a skin sensitiser in humans and in experimental animals.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Some data suggest that nickel soluble componds are respiratory sensitisers in humans (see Section 7.10.4 for data on human studies). No data regarding respiratory sensitisation in animals have been located. A comprehensive review of the available literature regarding the potential of soluble Ni compounds to induce respiratory sensitization can be found in the attached background document entitled, "Background-Soluble Nickel Respiratory Sensitization" (Section 7.4.2 of IUCLID)


Migrated from Short description of key information:
Some data suggest that nickel soluble compounds are respiratory sensitisers in humans. No data regarding respiratory sensitisation in animals have been located.

Justification for classification or non-classification

Classification is valid for both the anhydrous and hydrated forms. Due to the high sensitisation potential of Ni, the same specific concentration limits are maintained for both forms.

Ni fluoride is classified as R42/R43; H334 and H317 in the 1st ATP to the CLP Regulation with specific concentration limit C>= 0.01%. A comprehensive review of the available literature regarding the potential of soluble Ni compounds to induce respiratory sensitization can be found in the attached background document entitled, "Background-Soluble Nickel Respiratory Sensitization". In summary, criteria associated with classification of a given compound as a respiratory sensitizer are not yet well defined. However, the peer-reviewed literature generally indicate that soluble nickel compounds meet the common criteria shared between respiratory and contact allergens as these compounds can both act as haptens, gain access to the target tissue, and engage an immune response via cytokines and chemokines. Regarding criteria that set the respiratory and contact sensitization apart, which are generally accepted to be associated with the type of immunological responses that they induce, soluble nickel compounds have been associated with Type I reactions involving IgE in case studies of workers with occupational asthma. This is the response pathway associated with respiratory hypersensitivity.