Nickel sulphate

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, well documented and acceptable for publication.

Data source

Reference

Reference Type:

publication

Title:

Evaluation of the effect of the specific CCRI antagonist CP-481715 on the clinical and cellular responses observed following epicutaneous nickel challenge in human subjects

Author:

Borregaard J, Skov L, Wang L, Ting N, Wang C, Beck LA, Sonne J, Clucas A.

Year:

2008

Bibliographic source:

Contact Dermatitis 59, 212-19.

Materials and methods

Type of study / information:

Phase 1/2 placebo-controlled, randomized, double-blind, parallel group, multi-dose study

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The investigators conducted a phase 1/2 placebo-controlled, randomized, double-blind, parallel group, multi-dose study to evaluate the effects of CP-481715 (a specific CC-chemokine receptor 1 antagonist) on clinical responses and cellular infiltration following Ni challenge in allergic subjects. 40 subjects were randomized to 5 days of treatment in 4 parallel groups (placebo three times daily, placebo once daily, 1000 mg CP-481715 three times daily, 3000 mg CP-481715 once daily). Nickel sulphate patch tests were conducted and biopsies were used to quantify cellular influx into the dermis by immunohistology.

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

Results and discussion

Any other information on results incl. tables

EXPOSURE
- Number of measurements: Three Ni sulphate patches applied on the back of all subjects.
- Other: 24 hours after the first drug administration (placebo three times daily, placebo once daily, 1000 mg CP-481715 three times daily, or 3000 mg CP-481715 once daily), Ni sulphate patches were applied on all subjects’ backs and removed 48 hours later.

FINDINGS: Pretreatment with 1000 mg CP-481715 three times daily resulted in significant, clinical reductions in the visual scores of the nickel patch test reactions. None of the subjects experienced total inhibition of the allergic reactions to nickel. No significant change from pooled placebo was observed for the CP-48l715 3000 mg once daily group for clinical visual scores. Similarly, pretreatment with 1000 mg CP-481715 three times daily also showed signs of reducing erythema reactions to nickel when assessed with the chromameter. No significant change observed in erythema reactions between pooled placebo and the 3000 mg CP-481715 once daily group. There were no significant differences observed between either CP-481715 treatment group and pooled placebo for any of the immunohistological end-points. However, whereas the numbers of inflammatory cells tended to increase in biopsies after the second nickel challenge in the placebo groups, the cell counts tended to remain stable or even decrease for the CP481715
1000 mg three times daily group, particularly for CD4+ and CD8+ cells.

STATISTICAL RESULTS
- Clinical visual scores: Difference in mean change from baseline (change in area under the curve of patched vs. nonpatched sites) between treatment with 1000 mg CP-48175 three times daily and pooled placebo: -50.13 (90% confidence interval -82.17 to -18.09, p =0.01). No significant change from pooled placebo was observed for the CP-48l715 3000 mg once daily group (P = 0.80).
-Instrumental measurement of erythema: Difference in mean change from baseline (area under the curve of patched site minus area under the curve of non-patched site) between treatment with 1000 mg CP-48175 three times daily and pooled placebo: -186.97 (95% confidence interval -349.01 to -24.92, p=0.06). No significant change from pooled placebo was observed for the 3000 mg CP-481715 once daily group (P = 0.13).
- Immunohistological cell counts: No significant differences observed between either CP-481715 treatment group and pooled placebo for any of the immunohistological end-points (p ≥ 0.13).

Applicant's summary and conclusion

Conclusions:

The authors concluded that the blocking of CCR1 only partly inhibited clinical manifestations of allergic contact dermatitis (ACD) as induced by nickel sulphate. Several chemokine receptors are likely relevant for the cellular influx observed in ACD lesions.

Executive summary:

Study rated by an independent reviewer.