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Sensitisation data (human)

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Endpoint:
sensitisation data (humans)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Meets generally accepted scientific methods with sufficient documentation. Relevant exposure to submission substance, adequate detail on study methods. (A detailed description of the scoring criteria can be found in the .pdf document attached to the 'Sensitisation Scoring Rationale Document' record at the beginning of Section 7.10.4).

Data source

Reference
Reference Type:
review article or handbook
Title:
Experimental nickel elicitation thresholds - a review focusing on occluded nickel exposure
Author:
Fischer, L.A., Menne, T., Johansen, J.D.
Year:
2005
Bibliographic source:
Contact Dermatitis 2005: 52: 57-64

Materials and methods

Type of sensitisation studied:
skin
Study type:
other: review article for risk assessment (DNEL for elicitation threshold))
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Experimental open exposure to Ni can be done as a single or repeated application, and to mimic the effect of Ni on irritated skin, the experimental
exposure can be done with or without an irritant. Studies have tried to visualize the dose-response characteristics of open and occluded exposure to Ni under these different conditions.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent

Method

Type of population:
general
Ethical approval:
not specified
Subjects:
Sensitized individuals from the general population
Clinical history:
Not available
Controls:
Use of controls was dependent on the studies reviewed
Route of administration:
dermal
Details on study design:
OCCLUDED EXPOSURE STUDIES
Reviewing the literature, it is found that there are several dose-response studies made with Ni. However, the studies are often not directly comparable, as materials, substances, methods and details of the study conditions vary, and in some cases, the information given on the said issues are insufficient or lacking. Occluded exposure to Ni is the most common method in experimental studies used to define the thresholds for elicitation. 13 studies were identified and of these, 8 studies were selected for further analysis based on the following criteria:

(1) at least 5 dilutions (including vehicle) had been used for the patch test;
(2) at least 10 patch-tested Ni-sensitized persons;
(3) the patch-test method was similar to the Finn Chamber method and 2 days of occlusion were used;
(4) a fair description of the study details was available in the articles chosen.

Criteria (1) and (2) were chosen based on statistical considerations to obtain results that were reliable. The details of the studies are summarized inTable 1. It was assumed that all concentrations were given as the hydrated salt, e.g. NiS04 6H20. Based on these data, the statistical analysis was
performed. One study (18) was excluded, because the TRUE Test™ was used. This study, using a vehicle other than that of the Finn Chamber
method and known to give more positive reactions to Ni, was clearly displaced to the left when analysing the dose-response curves (results not
shown).

OPEN EXPOSURE STUDIES
The 2 single open application studies performed gave remarkable similar results. Ni applied in a single open application at a dose of 6.84 ug Ni/cm2 gave a response in 7.8% of Ni-sensitive individuals. This is a dose that is around x 6 higher than the weighted average for the occluded exposure where 10% of sensitized persons will react. Interestingly, Christensen and Wall found that 24 h after the application of 2.5% Nickel chloride, there were nonsignificantly more positive reactions to an open test compared with the same concentration in an occluded patch test (even though the dose per cm2
was higher in the occluded than in the open test). At the 48-hr reading, this was reversed. The open test is not directly comparable to the patch-test
situation unless both the tests are done under standardized conditions on the same subjects.

Results and discussion

Results of examinations:
The thresholds for elicitation of Ni allergy are dependent on the conditions under which the Ni exposure occurs, e.g. open/closed/penetrating exposure, single or repeated applications, the presence of an irritant or irritated skin, the selection of the study group, the definition of a positive reaction and the vehicle used for testing. The patch-test data presented in this analysis show that the elicitation thresholds determined differ by a factor of 10 between studies. This is a limited variation considering that the studies have been performed in different geographical regions, at different time periods and probably with other differences among the test subjects. According to the weighted average, 5% of a sensitized population will react to a dose of 0.44/µg Ni/cm2 and 10% of a sensitized population will react to a dose of 1.04/µg Ni/cm2. The elicitation threshold for single open exposure is around x 6 higher than the elicitation threshold for single occluded exposure. The sensitization and elicitation thresholds for penetrating exposure are lower than the elicitation threshold for single occluded exposure. The thresholds from open testing are not directly comparable to the thresholds from occluded exposure, because the testing is done in different populations. The studies which include an irritant are also not comparable, because the exposures to the irritant are done very differently, and therefore, the results are also divagating. When we look at the results from this review, we see that they are dependent on factors within each study, which makes it difficult to make comparisons of thresholds for open, closed and penetrating exposure across the studies. However, a comparison of the thresholds on different kinds of exposure could be made by a systematic study that compares the threshold for patch testing with, e.g., repeated open exposure within the same individuals at the same time.

Any other information on results incl. tables

Table2. Results of logistic regression analyses performed on the data from each of the chosen occluded nickel dose-response studies

 

Reference

Dose (µg/cm2)

Agreement

Estimated doses (µg/cm2)

Minimum

Maximum

X2

P value

ED1%

ED5%

ED10%

ED25%

ED50%

ED75 %

ED90%

ED95%

ED99%

(12)

0.067

335

0.2

0.91

0.15

0.43

0.7

1.4

2.8

5.7

11.5

18.5

53

(17)

0.0063

558

0.31

0.96

0.Q28

0.124

0.24

0.64

1.72

4.6

12.2

24

104

(19)

0.17

335

24.3

0.0068

0.054

0.36

0.85

3

10.8

38

135

320

2148

(20)

3.9

495

8.57

0.2

0.38

1.37

2.5

5.8

13.5

32

74

132

476

(21)

0.087

335

13.3

0.1

0.29

1.6

3.5

10.8

34

106

330

715

3956

(22)

0.23

254

3.18

0.67

0.05

0.3

0.67

2.2

7.2

24

77

173

1030

(15)

0.087

838

6.74

0.24

0.0175

0.172

0.48

2.2

10.1

46

210

590

5783

(16)

0.087

838

4.76

0.31

0.165

0.9

1.94

6

18.5

57

177

382

2083

Table 3. Studies investigating the elicitation of nickel allergy on different exposures to nickel: open, occluded, single, repeated, with and without an irritant

Open

Occluded

Single

Repeated

Single

Repeated

without an irritant

 

(10) Menne and Calvin

4/51 = 7.8 % positive to 6.8 µg Ni/cm218/51 = 35.3% positive to 27.37 µg Ni/cm2

 

(11) Christensen and Wall

6/15 = 40% positive to 37.1 µg Ni/cm2

10/15=67% positive to 74.1 µg Ni/cm213/15 = 87% positive to 148.2-222.4 µg Ni/cm2

14/15 = 93% positive to 296.5 µg Ni/cm2

 

with an irritant*

 

(10) Menne and Calvin

1/51 = 2% positive to 6.84 µg Ni/cm2

1/51 = 2% positive to 27.37 µg Ni/cm2

 

without an irritant

 

(12) Nielsen et al. - increased blood-flow in finger exposed to:

1stweek: 10ppm NiCl2x 10 minutes

2ndweek: 100 ppm NiCl2x 10 minutes 4/17 = 23.5% follicular reaction on forearm exposed to 1stweek:

10 ppm 2nd week 100 ppm

 

with an irritant*

 

(12) Nielsen et al.

8/17 = 47% follicular reaction on arm exposed to: 1stweek: 10 ppm NiCl2

2nd week: 100 ppm NiCl2

(compared to 1/17 = 6% follicular reaction when exposed to vehicle combined with SLS)

with an irritant*

 

(13) Allenhy and Basketter - An arm immersed daily into SLS until erythema. Following patch test:

2/20 = 10% positive to 0.5 ppm = 0.0049 µg Ni/cm2(compared to no positives when patch testing at this concentration on normal skin)

 

(14) Agner et al. - 4 fold increase of inflammatory response when patch testing with SLS and NiCl2(compared to NiCl2alone)

 

(15) Hindsen and Braze - lowered test-score when pretreating the patcht test site with SLS one month prior to exposure to nickel, (compared to the site with no SLS pre-treatment)

without an irritant

 

(15) Hindsen and Braze - patch test on an area treated with nickel 1 month earlier:

12/20 = 63% positive to 3.43 µg Ni/cm2(compared to 15% at this concentration when no pre-exposure to nickel (p = 0.08))

 

(16) Hindsen et al. patch test on area treated with nickel 1 month earlier:

2/23 = 8.7% positive to 0.0871 µg Ni/cm2(compared to 0% at this concentration when no pre-exposure to nickel (p = 0.03))

 

with an irritant* No studies

*the irritant was SLS

10.  Menne T, Calvin G. Concentration threshold of nonoccluded nickel exposure in nickel-sensitive individuals and controls with and without surfactant. Contact Dermatitis 1993: 29: 180-184.

11.  Christensen 0 B, Wall L M. Open, closed and intradermal testing in nickel allergy. Contact Dermatitis 1987: 16: 21-26.

12.  Nielsen N H, Menne T, Kristiansen J, Christensen J M, Borg L, Poulsen L K. Effects of repeated skin exposure to low nickel concentrations: A model for allergic contact dermatitis to nickel on the hands. Br J Dermatol 1999: 141: 676-682.

13.  Allenby C F, Basketter D A. An arm immersion model of compromised skin (II). Influence in minimal eliciting patch test concentrations of nickel. Contact Dermatitis 1993: 28: 129-133.

14.  Agner T, Johansen J D, Overgaard L, Volund A, Basketter D, Menne T. Combined effects of irritants and allergens. Synergistic effects of nickel and sodium lauryl sulfate in nickel-sensitised individuals. Contact Dermatitis 2002: 47: 21-26.

15.  Hindsen M, Bruze B. The significance of previous contact dermatitis for elicitation of contact allergy to nickel. Acta Derm Venereal 1998: 78: 367-370.

16.  Hindsen M, Bruze M, Christensen 0 B. The significance of previous allergic contact dermatitis for elicitation of delayed hypersensitivity to nickel. Contact Dermatitis 1997: 37: 101-106.

Table 4. Studies investigating the sensitization and elicitation of nickel allergy during penetrating exposure (ear piercing)

 

Penetrating

 

Sensitization

Elicitation

Rasanen et al. investigated 9 persons with symptoms related to ear piercing, 6/9=67% had a positive patch test to nickel, the studs the 67% were pierced with had the following nickel-release:

(a: in plasma, b: in water)

A1: 22.44 ug Ni/cm2/week

B1: 0.46 ug Ni/cm2/week

A2: 0.15 ug Ni/cm2/week

B2: 0.02 ug Ni/cm2/week

A3: 104.59 ug Ni/cm2/week

B3: O.79 ug Ni/cm2/week

A4: 10.06 ug Ni/cm2/week

B4: 0.04 ug Ni/cm2/week

A5: 0.17 ug Ni/cm2/week

B5: 0.01 ug Ni/cm2/week

A6: 2.03 ug Ni/cm2/week

B6: 0.03 ug Ni/cm2/week

Fischer et al. investigated 10 nickel sensitive persons with pierced ears who were wearing nickel containing ear-rings with different release of nickel for a maximum of 1 week.

(Release in synthetic sweat).

Positive symptoms: itching, redness and dermatitis

4/10=40% positive to 0.05 ug Ni/week

3/11=27% positive to 2.3 ug Ni/week

4/6=67% positive to 7.7 ug Ni/week

6/6=100% positive to 15 ug Ni/week

 

Ingber et al. investigated 25 nickel sensitive persons whose ears were pierced with piercing-studs with a nickel content of 11.5-12.9%

2/25=8% had a transient itch and erythema 48 h after piercing with studs releasing 0.11-0.2 ug Ni/cm2/week

35.  Rasanen L, Lehto M, Mustikka-Miiki U P. Sensitization to nickel from stainless steel ear-piercing kits. Contact Dermatitis 1993: 28: 292-294.

36.  Fischer T, Fregert S, Gruvberger B,Nickel release from ear piercing kits and earrings. Contact Dermatitis 1984: 10: 39--41.

37.  Ingber A, Hershko K, Horev L AISI 316L Stainless steel ear piercing post assembly does not cause dermatitis in nickel-sensitive subjects. Exog Dermatol 2003: 2: 195-200.

Applicant's summary and conclusion