Nickel difluoride

Sensitisation data (human)

Administrative data

Endpoint:

sensitisation data (humans)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not reported

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:

publication

Title:

Effects of repeated skin exposure to low nickel concentrations: a model for allergic contact dermatitis to nickel on the hands.

Author:

Nielsen, N.H., T. Menné, J. Kristiansen, J.M. Christensen, L. Borg, and L.K. Poulsen.

Year:

1999

Bibliographic source:

British Journal of Dermatology. 141:676-682.

Materials and methods

Type of sensitisation studied:

skin

Study type:

study with volunteers

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

No standard guideline followed. Details of test methods provided in the following sections.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Nickel sulphate

EC Number:

232-104-9

EC Name:

Nickel sulphate

Cas Number:

7786-81-4

Molecular formula:

NiSO4

IUPAC Name:

nickel(2+) sulfate

Details on test material:

- Name of test material (as cited in study report): Nickel sulphate
- Molecular formula (if other than submission substance): not different than submission substance
- Molecular weight (if other than submission substance): not different than submission substance
- Smiles notation (if other than submission substance): not different than submission substance
- InChl (if other than submission substance): not different than submission substance
- Structural formula attached as image file (if other than submission substance): not different than submission substance
- Substance type: Pure product
- Physical state: liquid
- Analytical purity:5%
- Other details on test material not reported or not applicable

Method

Type of population:

general

Ethical approval:

confirmed and informed consent free of coercion received

Subjects:

- Number of subjects exposed: 35 (17 exposed, 18 control)
- Sex: Male and female
- Age: 23-68 years (Mean = 45)
- Race: not reported
- Demographic information: not reported
- Other: none

Clinical history:

- History of allergy or casuistics for study subject or populations: had hand eczema for >3 months
- Symptoms, onset and progress of the disease: hand eczema was mild to moderate (erythema, hyperlinearity and/or scaling)
- Other: tested positive in a patch test to 5% NiSO4 prior to study

Controls:

Yes, mean age = 42 years

Route of administration:

dermal

Details on study design:

TYPE OF TEST(S) USED: skin immersion (fingers and forearm)

ADMINISTRATION
- Type of application: skin immersion in test substance, 10 minutes daily
- Description of patch: not applicable
- Vehicle / solvent: aqua purificata or ethanol (20%)
- Concentrations: 0, 10, 100, 200 ppm Ni
- Volume applied: 100 mL for finger exposure,
- Testing/scoring schedule: Day 0, 7 and 14
- Removal of test substance: washing not conducted for at least 30 min.
- Other: followed up on day 14 with a standard patch test using 5% NiSO4 in petrolatum and 10, 100, 200 ppm NiCl2

EXAMINATIONS
- Grading/Scoring system: Homogeneous erythema on the exposed finger was graded on a scale of 0 to 3. Scaling was reported as present or not
present. A semiquantitative scale (0, 1-10, 11-20, 21-30, 31-40, 41-50, >50) was used for scoring the number of vesicles (intact or broken) on
the exposed finger or forearm. Homogeneous erythema and infiltration and homogeneous erythema, infiltration, and vesicles were recorded as
present or not present.
- Statistical analysis: Mann-Whitney U-test and Wilcoxon's Rank Sum Test, and Student's T-test as appropriate (p<0.05)
- Other: none

Results and discussion

Results of examinations:

SYMPTOMS/NO. REACTIONS:
On Day 7, 7 of the 35 test subjects (7/35) had vesicles scored 1-10, 6/35 had vesicles scored 11-20, and 2/35 had vesicles scored 31-40. The
remaining subjects (20/35) had vesicles scored 0.

On Day 14, 3/35 test subjects had vesicles scored 1-10, 8/35 had vesicles scored 11-20, 4/35 had vesicles scored 21-30, 2/35 had vesicles
scored 31-40, 2/35 had vesicles scored 41-50, and 3/35 had vesicles scored >50. The remaining 13/35 subjects had vesicles scored 0.

At Day 14, there was a significantly higher score (p=0.05) of vesicles on the exposed finger of subjects exposed to nickel than those subjects
exposed only to water (vehicle).

There was significantly higher blood flow (p=0.05) at Day 14 of subjects exposed to nickel, relative to the water only exposed control subjects.

Results of the nickel patch test conducted at Day 14:

5% Nickel sulfate (nickel exposed subjects): 6 subjects with 1+ reactions, 10 subjects with 2+ reactions, and 0 subjects with 3+ reactions
5% Nickel sulfate (vehicle exposed subjects): 2 subjects with 1+ reactions, 15 subjects with 2+ reactions, and 1 subject with 3+ reactions
10 ppm Nickel chloride (nickel exposed subjects): 1 subject with 1 + reactions, 0 subjects with 2+ or 3+ reactions
10 ppm Nickel chloride (vehicle exposed subjects): no 1+, 2+, or 3+ reactions
100 ppm Nickel chloride (nickel exposed subjects): 2 subjects with 1+ reactions, 2 subjects with 2+ reactions, and 0 subjects with 3+ reactions
100 ppm Nickel chloride (vehicle exposed subjects): 2 subjects with 1 + reactions, no subjects with 2+ or 3+ reactions
200 ppm Nickel chloride (nickel exposed subjects): 1 subject with 1+ reactions, 3 subjects with 2+ reactions, and 0 subjects with 3+ reactions
200 ppm Nickel chloride (vehicle exposed subjects): 4 subjects with 1+ reactions, no subjects with 2+ or 3+ reactions

Exposure resulted in a significant increase in local vesicle formation and blood flow in subjects exposed to Ni, compared to controls. In a
secondary test, the nickel concentrations used provoked significant inflammation on forearm skin treated with sodium lauryl sulfate. The
authors suggested that the changes observed were "specific to nickel exposure."

Applicant's summary and conclusion

Conclusions:

In a study of 35 patients with hand eczema immersion of a finger in 10 ppm Ni as nickel chloride 10 min/day for one week followed by immersion in 100 ppm Ni the next week resulted in statistically significant increase in eczema symptoms.

Executive summary:

STUDY RATED BY AN INDEPENDENT REVIEWER.

(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).

 

ROBUST SUMMARY DEVELOPED BY AN INDEPENDENT REVIEWER.

 

Robust summary for Nielsen et al. (1999):

  

Study was conducted to evaluate the effects of trace-to-moderate occupational nickel exposure. 35 test subjects with current hand eczema (>3 months) and nickel allergy were studied. The study was double-blind and vehicle controlled.

 

The 35 test subjects exposed one finger and two areas on the ventral aspect of one forearm. The patient group (n=35) and 7 control subjects were treated with a closed patch test using Finn Chambers with 15 ul of 0.5% aqueous sodium lauryl sulfate (SLS) for 24 hours on one of the two forearm areas. Exposures to nickel were at concentrations of 10 and 100 ppm during the first and second week, respectively, or to the vehicle during both weeks.

 

The 35 test subjects immersed the finger in solution for 10 minutes. Two drops of solution were placed on the two forearm areas. The exposed areas were allowed to air dry, and could be washed after at least 30 minutes. 30 control subjects exposed an area of the forearm to the nickel concentrations or to the vehicle only. Another group of 7 control subjects exposed one area of the SLS-treated forearm skin to two drops of 

nickel solution, while the other area was exposed to the vehicle only.

 

Clinical evaluations and blood flow measurements (using the laser Doppler technique) were made on Days 0, 7 and 14. At Day 14, a standard patch test using 5% nickel sulfate in PET and patch tests with 10, 100 and 200 ppm of 15 ul nickel chloride in aqua purifacata were performed on all subjects.

 

Data were analyzed statistically using non-parametric tests (i.e., Wilcoxon matched-pairs signed-ranks test, Mann-Whitney U-test, and Wilcoxon's rank sum paired data test) and the Student's t-test as appropriate. The level of significance was 0.05.

 

Homogeneous erythema on the exposed finger was graded on a scale of 0 to 3. Scaling was reported as present or not present. A semiquantitative scale (0, 1-10, 11-20, 21-30, 31-40, 41-50, >50) was used for scoring the number of vesicles (intact or broken) on the exposed finger or forearm. Homogeneous erythema and infiltration and homogeneous erythema, infiltration, and vesicles were recorded as present or not present.

 

On Day 7, 7 of the 35 test subjects (7/35) had vesicles scored 1-10, 6/35 had vesicles scored 11-20, and 2/35 had vesicles scored 31-40. The remaining subjects (20/35) had vesicles scored 0. On Day 14, 3/35 test subjects had vesicles scored 1-10, 8/35 had vesicles scored 11-20, 4/35 had vesicles scored 21-30, 2/35 had vesicles scored 31-40, 2/35 had vesicles scored 41-50, and 3/35 had vesicles scored >50. The remaining 13/35 subjects had vesicles scored 0. At Day 14, there was a significantly higher score (p=0.05) of vesicles on the exposed finger of subjects exposed to nickel than those subjects exposed only to water (vehicle). There was significantly higher blood flow (p=0.05) at Day 14 of subjects exposed to nickel, relative to the water only exposed control subjects.

 

Results of the nickel patch test conducted at Day 14:

 

-5% Nickel sulfate (nickel exposed subjects): 6 subjects with 1+ reactions, 10 subjects with 2+ reactions, and 0 subjects with 3+ reactions

-5% Nickel sulfate (vehicle exposed subjects): 2 subjects with 1 + reactions, 15 subjects with 2+ reactions, and 1 subject with 3+ reactions

-10 ppm Nickel chloride (nickel exposed subjects): 1 subject with 1+ reactions, 0 subjects with 2+ or 3+ reactions

-10 ppm Nickel chloride (vehicle exposed subjects): no 1+, 2+, or 3+ reactions

-100 ppm Nickel chloride (nickel exposed subjects): 2 subjects with 1 + reactions, 2 subjects with 2+ reactions, and 0 subjects with 3+ reactions

-100 ppm Nickel chloride (vehicle exposed subjects): 2 subjects with 1+ reactions, no subjects with 2+ or 3+ reactions

-200 ppm Nickel chloride (nickel exposed subjects): 1 subject with 1+ reactions, 3 subjects with 2+ reactions, and 0 subjects with 3+ reactions

-200 ppm Nickel chloride (vehicle exposed subjects): 4 subjects with 1 + reactions, no subjects with 2+ or 3+ reactions

 

Exposure resulted in a significant increase in local vesicle formation and blood flow in subjects exposed to Ni, compared to controls. In a secondary test, the nickel concentrations used provoked significant inflammation on forearm skin treated with sodium lauryl sulfate. The authors suggested that the changes observed were "specific to nickel exposure."