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Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

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

Nickel is well known as a skin sensitiser. It is one of the most frequent skin sensitisers in man. Approximately 10–20% of the general population is sensitized to nickel. The Ni2+ ion is considered exclusively responsible for the immunological effects of nickel (Menné, 1994).

Nickel allergy is a Type IV allergic reaction. Characteristic for this type of reaction is that it is cell mediated (mediated by T-lymphocytes) and delayed (the reaction appears 24-72 hours after exposure). Nickel allergy manifests itself as allergic contact dermatitis, which is an inflammatory reaction in the upper part of the skin (epidermis) with erythema, infiltrations, and vesicles. Since the recognition of nickel dermatitis as a common disease in workers in the 1920’s and 1930’s, occupational sensitisation is still very common, and also now as a disease in the general population following skin contact with metallic items such as ear ornaments, jewellery, jeans buttons and other nickel releasing items.

Development of nickel allergy includes two steps, induction (also called sensitisation) and elicitation. Nickel allergy is induced by direct and prolonged skin exposure to elemental nickel, which is corroded (release of ions) by contact with sweat, or by skin exposure to other nickel compounds where Ni ions penetrate into the skin. In order to induce an allergic response, the nickel ion as a hapten must react with a protein in the skin to form a complete allergen, which is then taken up by a macrophage for antigen presentation to a T-lymphocyte. The Langerhans cells of the skin are believed to be responsible for transporting the allergen to the T-lymphocytes in the peripheral lymph node, where antigen presentation takes place. Here, the nickel will be presented to naive T-lymphocytes, and a sensitisation specific to nickel will take place, resulting in clones of specific sensitive memory- and effector-T cells. This process lasts about 14 days. The next time the individual is exposed to nickel, the specific sensitised T-lymphocytes will elicit an inflammatory response in the epidermis (elicitation) at the site of exposure and possibly elsewhere.

Experimentally, a human maximisation test was established with the purpose to test whether a given substance was able to induce skin sensitisation and to what degree (Kligman, 1966). The test was designed to yield allergenicity ratings depending on the frequency of sensitisation in a group of 25 test persons. The grading of sensitization reactions is detailed in Table I below. The test was carried out using nickel sulphate, and the induction procedure consisted of 5 sequences of 48 hours treatment with 10% nickel sulphate. The treatments were performed on the same place on one extremity (forearm or calf of the leg) under occlusion. Whether the subjects became sensitised or not were tested with the challenge concentration of 2.5% nickel sulphate. Twelve out of 25 attempts were successful. The author therefore categorised nickel sulphate as a moderate human sensitiser (grade 3), in the same category as other industrial contactants, such as mercaptobenzothiazole, chromium trioxide or chromium sulfate.

Table I: Maximization test grading (Kligman, 1966)

Sensitization rate

Grade

Classification

0-2 / 25

1

Weak

3-7 / 25

2

Mild

8-13 / 25

3

Moderate

14-20 / 25

4

Strong

21-25 / 25

5

Extreme

There are no data from skin exposure to nickel sulphate or chloride to allow an estimate of the dose of these salts that may cause skin sensitisation. A literature review of epidemiological data by T. Menné deals with the quantitative aspects of primary nickel sensitisation and elicitation of nickel dermatitis in already sensitised individuals (Menné, 1994). Based on a wide range of studies, an arbitrary non-sensitising nickel concentration of 0.5 µg/cm2/week has been suggested for consumer items made of nickel alloys. As detailed in Table II below, nickel release from nickels alloy clinically known to induce nickel sensitisation seems to be 10 to 100 times higher compared to alloys never or rarely inducing primary nickel sensitisation in nickel-sensitised patients. Eliciting of nickel dermatitis is unlikely for concentrations < 0.1-1 µg/cm2 during occluded exposure and 15 µg/cm2 when non-occluded. The lowest eliciting threshold concentration of non-occluded nickel exposure has been studied in 51 nickel-sensitive patients, as detailed in Table III. Simultaneous open testing with nickel chloride and a surfactant increase the eliciting threshold concentration, likely because of bioavailability decrease by the surfactant. With crude nickel chloride, 18 out of 51 patients reacted to 4000 ppm, 4 out of 51 patients to 1000 ppm (equivalent to 15 µg/cm² nickel) and none to 100 ppm or lower. Highly sensitized individuals might react to 0.5 ppm (0.0075 µg/cm2) nickel when exposed on inflamed skin under occlusion. The effects of skin inflammation on nickel elicitation threshold concentration in 20 nickel-sensitive patients are detailed in Table IV below.

It is not possible to set a scientifically based threshold for skin elicitation and sensitisation caused by nickel salts after direct and prolonged exposure. For use in the risk characterisation of occupational exposure, the empirical elicitation threshold of 0.3 μg nickel/cm2 is suggested to be used as the best estimate of a threshold for sensitisation by the Danish legislation (NB. Danish Environmental Protection Agency is the Rapporteur for the EU risk assessment reports of metallic nickel, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate prepared in relation to EEC Council Regulation 793/93, see final version of the Background Document, dated March 2008). As sensitisation is assumed to require higher doses than elicitation this estimate for sensitisation is more conservative than the estimate for elicitation.

Table II: Reactivity to different nickel alloys and nickel release measured in synthetic sweat (Menné, 1994)

Alloy

Nickel release (µg/cm²/week)*

% reactivity in nickel-sensitised patients

Safe alloys

Stainless steel

0.01

3

White gold

0.02

11

Nickel tin

0.1

23

Sensitising alloys

Nickel silver

20

81

Nickel chemical (2)

32

56

Nickel electrochemical

40

76

Nickel chemical (1)

45

79

Nickel iron

65

79

* Release after three weeks of exposure

Table III: Concentration thresholds of non-occluded nickel exposure in nickel-sensitive individuals with or without surfactant (Menné, 1994)

Nickel concentration (ppm)

Nickel chloride*

Nickel chloride + 4% Sodium Lauryl Sulphate*

0.1

0

0

1

0

0

10

0

0

100

0

0

1000

4

1

4000

18

1

* Number of positive patients (out of 51 in total) is indicated

Table IV: Concentration thresholds of nickel exposure in nickel-sensitive individuals with or without inflammation (Menné, 1994)

Nickel concentration (ppm)

Back*

Forearm* (normal)

Forearm* (immersed §)

0.5

Not tested

Not tested

1

1

0

0

3

5

1

3

6

10

3

3

12

* Number of positive patients (out of 20 in total) is indicated

§ Volunteers repeatedly immersed their forearms twice daily in a dilute surfactant solution until a moderate degree of inflammation was induced

Literature references:

  • Kligman AM. The identification of contact allergens by human assay. III. The maximization test: a procedure for screening and rating contact sensitizers. J Invest Dermatol. 47(5): 393-409, 1966.
  • Menné T. Quantitative aspects of nickel dermatitis. Sensitization and eliciting threshold concentrations. Sci Total Environ. 148 (2-3): 275-81, 1994


Migrated from Short description of key information:
PBN1 mixture is considered a skin sensitiser due to the presence of nickel fluoride and nickel chloride. Skin sensitisation testing has been waived based on classification as corrosive.

Respiratory sensitisation

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

Cases of work related asthma due to exposure to nickel sulphate in electro- or metal plating have been reported. In all cases, the diagnosis was based on clinical picture and specific bronchial inhalation test with nickel sulphate. Nickel sulphate is a respiratory sensitiser in humans. Nickel fluoride and nickel chloride are also classified as respiratory sensitisers. It is not possible to set a threshold for induction or elicitation in the case of respiratory sensitisation.


Migrated from Short description of key information:
PBN1 mixture is considered a respiratory sensitiser due to the presence of nickel fluoride and nickel chloride.

Justification for classification or non-classification

According to the Annex I of Directive 67/548/EEC, nickel fluoride (CAS No.: 10028 -18 -9) and nickel chloride (CAS No.: 7718 -54 -9) are classified R42/43 (skin and respiratory sensitisers). A specific concentration limit of 0.01% for R43 has been set. As they are present at 9.5 and 4.5% respectively in the mixture, PBN1 mixture should be classified as R42/43 taking into account the classification criteria of Directive 1999/45/EC for sensitisation or skin sensitiser cat. 1 (H317) and respiratory sensitiser cat. 1 (H334) taking into account the classification criteria of Directive 1272/2008/EC (CLP) for sensitisation.