Nickel difluoride

Endpoint summary

Description of key information

Skin sensitization: Based on a guinea pig maximization study performed according to the OECD guideline 406 with the related substances NiSO4 (FDRL, 1986; K2), the test substance Nickel fluoride is considered to be a skin sensitizer.

Respiratory sensitization: The available data were not sufficient to fully address each research objective.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vitro

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin sensitisation study does not need to be conducted because adequate data from an in vivo skin sensitisation study are available

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

January to April 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Principles of method if other than guideline:

According to the Guinea pig maximization test

GLP compliance:

yes

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

The LLNA is not applicable for use in evaluating skin sensitization since this methodology provides false negative results for nickel as a known human skin sensitizer (due to differences in the toll receptors in mice used in the LLNA and humans).

Species:

guinea pig

Strain:

Hartley

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, MA, USA.
- Age at study initiation: young adult
- Weight at study initiation: 345-350 g
- Housing: individually housed in wire mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS: controlled, details not reported

IN-LIFE DATES: not reported

Route:

intradermal

Vehicle:

propylene glycol

Concentration / amount:

0.1 ml of 1.0% w/v NiSO4 in distilled water
0.1 ml of Freunds Complete adjuvant (FCA)
0.1 ml of 1.0% w/w NiSO4 in 50% w/v (FCA)
0.3 ml of 5.0% NiSO4 in distilled water for 48 hours

Route:

intradermal

Vehicle:

propylene glycol

Concentration / amount:

0.1 ml of 1.0% w/v NiSO4 in distilled water
0.1 ml of Freunds Complete adjuvant (FCA)
0.1 ml of 1.0% w/w NiSO4 in 50% w/v (FCA)
0.3 ml of 5.0% NiSO4 in distilled water for 48 hours

No. of animals per dose:

10 per dose

Details on study design:

MAIN STUDY
A. INDUCTION EXPOSURE
0.1 ml of 1.0% w/v NiSO4 in distilled water
0.1 ml of Freunds Complete adjuvant (FCA)
0.1 ml of 1.0% w/w NiSO4 in 50% w/v (FCA)
0.3 ml of 5.0% NiSO4 in distilled water and occluded for 48 hours

B. CHALLENGE EXPOSURE
Challenge performed on both flanks and ventral surface and occluded for 24 hours at concentrations of
0.2 ml of 1.0% w/v NiSO4 in distilled water

Erythema and edema scored according to Draize et al. 1944.

Challenge controls:

Induction: 0.1 ml of propylene glycol, 0.1 ml of FCA in distilled water, or 0.1 ml of 1.0% w/v proylene glycol in 50% w/v FCA.
Challenge: 0.2 ml of propylene glycol

Positive control substance(s):

yes

Remarks:

1-chloro-2,4-dinitrobenzene

Positive control results:

1-chloro-2,4-dinitrobenzene did cause dermal contact sensitization in female albino guinea pigs.

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.2 ml of 1.0% w/v nickel sulfate in distilled water

No. with + reactions:

10

Total no. in group:

10

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

0.2 ml of 1.0% w/v nickel sulfate in distilled water

No. with + reactions:

10

Total no. in group:

10

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

negative control

No. with + reactions:

1

Total no. in group:

10

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

negative control

No. with + reactions:

0

Total no. in group:

10

Reading:

1st reading

Hours after challenge:

24

Group:

positive control

Dose level:

positive control

No. with + reactions:

6

Total no. in group:

6

Reading:

2nd reading

Hours after challenge:

48

Group:

positive control

Dose level:

positive control

No. with + reactions:

6

Total no. in group:

6

Mean erythema score at 24 and 48 hours for NiSO4 were 1.1 and 1.0, respectively

Interpretation of results:

Category 1 (skin sensitising) based on GHS criteria

Conclusions:

No reliable data with the test substance is available. Data generated with the related substance nickel sulfate is used for endpoint coverage.
Nickel sulfate did cause dermal contact sensitization in female albino guinea pigs.
Mean erythema score at 24 and 48 hours for NiSO4 were 1.1 and 1.0, respectively. It is assumed that the test substance is therefore to be classified as skin sensitizing category 1 according to CLP criteria.

Executive summary:

STUDY RATED BY AN INDEPENDENT REVIEWER.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

ENDPOINT SUMMARY INFORMATION FROM THE 2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT. Data from human studies are reported under Section 7.10.4 of this IUCLID file.

 

In a guinea pig maximization test conducted in accordance OECD guideline 406, the skin sensitising effect was examined on 10 female guinea pigs. Positive, solvent and negative controls were included in the study. The animals were injected intradermally on study day one with 0.1 ml of 1.0% w/v test substance in distilled water and 1.0% w/v test substance in Freund’s complete adjuvant. On study day eight, a 48-hour topical application was made with 0.3 ml of 5.0% w/v aqueous test substance after a two-week rest period, the animals were challenged with topical applications of 1.0% w/v aqueous test substance, nickel oxide moistened with propylene glycol, CT-243-85C moistened with propylene glycol, and 25% w/v CT-243-85F moistened with propylene glycol. The exposure duration for challenge was 24 hours. An additional ten females served as the vehicle control group and were exposed to propylene glycol during induction. These animals were challenged with the test articles in the same manner as the test group. Another six animals served as the positive control group and were exposed to 1-chloro-2,4-dinitrobenzene during the induction and challenge applications. The challenge sites were examined and evaluated for irritation at 24 and 48 hours following binder removal.

All test group animals challenged with the test substance exhibited very slight or well-defined erythema after treatment. Nickel oxide, CT-243-85C and CT-243-85F produced no irritation to the test group animals following challenge. the test substance and CT-242-85F caused very slight erythema in on vehicle control group. DNCB cause slight or well-defined erythema in all positive control group animals after challenge. Under the conditions of this study, CT-243-85C, Ct-242-85F and nickel oxide failed to cause sensitization, however the test substance and DNCB did cause dermal contact sensitization in female albino guinea pigs. Furthermore all controls showed expected results, resulting in a valid assay. Based on this study, it was concluded that the substance did cause contact hypersensitivity in guinea pigs and is therefore considered sensitizing.

No in vitro skin sensitisation studies were performed as adequate data from an in vivo study are available.

This conclusion is extrapolated for Nickel fluoride, as it was demostrated that the sensitisation activity is due to the presence of Nickel and is assumed valid for all soluble Nickel compounds as reported in the European Risk Assessment Report on Nickel soluble compounds. Data suggest that nickel fluoride is a skin sensitiser in humans and in experimental animals.

FOR AN EXTENSIVE DISCUSSION, REFER TO THE NICKEL SULFATE DOSSIER WHICH IS BASED ON THE CONCLUSIONS EXPLAINED IN THE 2008/2009 EUROPEAN UNION EXISITING SUBSTANCE RISK ASSESSMENT OF NICKEL (EU RAR) (EEC 793/93)

K1 and K2 studies included in the current version of the nickel sulphate dossier were reviewed and included. K3 and K4 studies from the NiSO4 dossier were not included in the NiF2 dossier if new studies were included in the last update of the NiSO4 dossier.

Respiratory sensitisation

Link to relevant study records

Reference

Endpoint:

respiratory sensitisation

Adequacy of study:

supporting study

Rationale for reliability incl. deficiencies:

other: A comprehensive review of the available literature regarding the potential of soluble Ni compounds to induce respiratory sensitization can be found in the attached background document.(see attached .pdf document)

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Some data suggest that nickel soluble compounds are respiratory sensitisers in humans (see Section 7.10.4 for data on human studies). No data regarding respiratory sensitisation in animals have been located. A comprehensive review of the available literature regarding the potential of soluble Ni compounds to induce respiratory sensitization can be found in the attached background document entitled, "Background-Soluble Nickel Respiratory Sensitization" (Section 7.4.2 of IUCLID)

Some data suggest that nickel soluble compounds are respiratory sensitisers in humans. No data regarding respiratory sensitisation in animals have been located.

Justification for classification or non-classification

Based on the available data and according to the criteria laid down in the CLP Regulation (EC) 1272/2008, the test substance should be classified as Skin sensitizer, Category 1 (H317) and Respiratory sensitizer Category 1 (H334).

 

A comprehensive review of the available literature regarding the potential of soluble Ni compounds to induce respiratory sensitization can be found in the attached background document entitled, "Background-Soluble Nickel Respiratory Sensitization".