Naphthenic acids, nickel salts

Endpoint summary

Description of key information

No skin sensitisation study with naphthenic acids, nickel salts is available, thus the skin sensitisation potential will be addressed with existing data on the individual moieties nickel and naphthenate.

Naphthenic acids, nickel salts is expected to show signs of dermal and respiratory sensitisation, since both moieties have shown skin sensitisation potential and the moiety nickel displayed respiratory sensitisation potential.

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Nickel

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.

 

A number of studies using different protocols showed that nickel sulphate is a skin sensitiser in guinea pigs and mice.

 

In addition to these animal data, copious information on human dermal sensitization is documented in the Nickel and nickel compounds Background Document in support of individual RISK ASSESSMENT REPORTS of nickel compounds prepared in relation to Council Regulation (EEC) 793/93 and is summarized in this report. Additional studies are summarized in the Nickel Sulphate IUCLID dossier Section 7.10.4.

 

Naphthenate

Both data from published experimental studies and QSAR prediction for sensitisation were used in a Weight of Evidence approach:

- A Guinea pig maximisation test (GPMT) test in 6-week-old female Hartley guinea pigs was performed with Naphthenic acids and salts (copper, zinc and cobalt naphthenate) (Yamano et al, 2006). The first induction dose was set at 1%, while the second induction dose was 25%. Two weeks after the second induction, 0.1 ml aliquots of the 7 chemicals in vehicles (0.5% in petroleum ether for CuN, CoN. ZnN and NA) were applied to a shaved area of the flank for challenge. Each site was scored 48 hours after challenge. Naphthenic acid resulted in 4/5 animals with clear reactions at 48 hours, therefore it is considered to be sensitizing for skin.

- In an LLNA test, 6- to 8-week-old female mice were exposed to Naphthenic acids and salts (copper, zinc and cobalt naphthenate ) in a petroleum ether and olive oil (4 : 1) through application to the dorsum of both ears for 3 consecutive days (Yamano et al, 2006). On the 5° & 6° day, 4, 5- bromo-7-deoxyuridine (BrdU) was administered intraperitoneally to each mousse to measure the LLNA stimulation index. At the time of lymph node excision, the thickness of the ears was measured at the edge of the right pinna. There was an increase of the stimulation index, which was accompanied with an increase in the irritation index, therefore the results are not conclusive about the sensitizing properties of naphthenic acid under the conditions of the LLNA test, however a positive reaction is not excluded.

- Finally, skin sensitisation was predicted using the VEGA QSAR sensitisation model which is an extension of the original CAESAR model. Since naphthenic acids do not have a fixed composition, the prediction was performed on a broad selection of different possible structures in accordance with the substance identification. As can be seen from the results, almost of the molecules in Naphthenic acids were indicated to be sensitisers. Only two molecules were indicated to be a non-sensitiser with a low applicability domain index (ADI). Most molecules fell in the applicability domain (with ADI >=0.8) and thus the prediction can be assumed to be reliable.

 

Naphthenic acids, nickel salts

Naphthenic acids, nickel salts is expected to show signs of dermal and respiratory sensitisation, since both moieties have shown skin sensitisation potential and the moiety nickel displayed respiratory sensitisation potential.

Thus, naphthenic acids, nickel salts is to be classified according to regulation (EC) 1272/2008 as skin sensitising Cat. 1 (H317) and respiratory sensitising Cat. 1 (H334). Further testing is not required. For further information on the toxicity of the individual assessment entities, please refer to the relevant sections in the IUCLID and CSR.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

No respiratory sensitisation study with naphthenic acids, nickel salts is available, thus the respiratory sensitisation potential will be addressed with existing data on the individual moieties nickel and naphthenate.

Evidence for respiratory sensitisation was identified for the moiety nickel:

A few case reports in the 1970s and 1980s suggest that nickel sulphate may be a respiratory sensitiser in humans. Considering the number of workers that have been exposed to soluble nickel compounds in the refining and metal finishing industry over the years, the number of reported cases is very small. No data regarding respiratory sensitisation in animals have been located.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.

Justification for classification or non-classification

Naphthenic acids, nickel salts is expected to show signs of dermal and respiratory sensitisation, since both assessment entities have shown skin sensitisation potential and the assessment entity nickel displayed respiratory sensitisation potential.

Thus, naphthenic acids, nickel salts is to be classified according to regulation (EC) 1272/2008 as skin sensitising Cat. 1 (H317) and respiratory sensitising Cat. 1 (H334).