Registration Dossier

Administrative data

Description of key information

ORAL: A 2-year oral carcinogenicity study reported a NOAEL of 2.2 mg Ni/kg b.w./day and a LOAEL of 6.7 mg Ni/kg b.w./day (Heim et al. 2007). The LOAEL of 6.7 mg Ni/kg bw/day based on reduced body weight and increased mortality together with a NOAEL of 2.2 mg Ni/kg bw/day is taken forward to the risk characterisation. According to read across statement Nickel fluoride belongs to the group of Nickel sulfate. These values leads to a NOAEL of 3.6 mg/Kg bw/day of NiF2 and 6.28 mg/Kg bw/day of NiF2*4H2O
DERMAL: It was not possible to determine a NOAEL/LOAEL for the dermal route based on the available information. Testing by the dermal route has been waived as Nickel is already classified as skin sensitisers and data are available for a second route of exposure, i.e. inhalation
INHALATION: Chronic lung inflammation including lung fibrosis results from long-term exposure via inhalation to a LOAEC of 0.056 mg/Ni/m3. and a NOAEC of 0.027 mg/Ni/m3 This corresponds to a LOAEC of 0.092 mg/m3 and a NOAEC of 0.044 mg/m3 for nickel fluoride and 0.77 mg/m3 for nickel difluoride tetrahydrated. This value is much lower than the minimum concentration of NiF2 that could induce tissue inflammation.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
3.6 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
0.044 mg/m³
Study duration:
chronic
Species:
rat

Additional information

ENDPOINT SUMMARY INFORMATION FROM THE 2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT.

When nickel compounds are inhaled, the main target is the respiratory system, where serious effects are induced in the form of chronic inflammation and fibrosis. The most sensitive study was the 2-year rat study by NTP. The data from this study do not allow identification of a clear NOAEC due to the difficulties with a definitive interpretation of the biological significance of the observed effects at the lowest exposure level (0.027 mg Ni/m3). Therefore, a LOAEC of 0.056 mg Ni/m3 (0.25 mg nickel sulphate hexahydrate/m3) for lung inflammation and fibrosis is used in the risk characterisation. It should be noted that data indicates that adverse effects possibly occur at lower levels. This is in line the CSTEE evaluation of non-cancer effects of nickel and nickel compounds in relation to the Ambient Air Position Paper (European Commission, 2000).

The TERA review concluded that the kidney is the most sensitive target organ following oral exposure. No studies have shown marked histopathological kidney damage. The occurrence of albuminuria in rats indicates kidney effects, but histopathology did not confirm the presence of lesions. However, a mouse study showed mild tubular nephropathy at higher dose levels. The rapporteur agrees that nickel sulphate does seem to induce adverse effects on the kidney, but that marked kidney toxicity has not been demonstrated. A weight reduction of the thymus and various effects on immunological cells indicates interference with the immune system. The effects on the immune system have been demonstrated at dose levels above those causing body weight loss, while the increased urinary albumin occurs at approximately the same dose level as the reduction in body weight.

In the study by Obone et al. (1999), the 13-week LOAEL for nickel sulphate hexahydrate given in the drinking water was 11 mg Ni/kg bw/day based on the 4% reduction in body weight and increased relative organ weights. The NOAEL was 4.5 mg Ni/kg bw/day. Another 90-day study, using gavage, showed 8% body weight reduction at 7-11 mg Ni/kg bw/day (SLI, draft not dated, submitted 2002). In the 3-6-month drinking water study by Vyskocil et al. (1994b), increased urinary albumin was found at 7.6 mg Ni/kg bw/day. In the 2-year rat study by Ambrose et al. (1976) where nickel sulphate hexahydrate was administered in the diet, similar effects on body weight were induced, since a NOAEL of 10 mg Ni/kg bw/day and a LOAEL of 100 mg Ni/kg bw/day was determined for 18% decreased body weight in females. In the 2-year dog study by Ambrose et al. (1976), a NOAEL of 75 mg Ni/kg bw/day and a LOAEL of 188 mg Ni/kg bw/day was determined for decreased body weight, lung granulomas, and bone marrow hyperplasia, but because of the small group size (3 dogs/sex) of this study it is possible that effects at the lower dose levels were missed. In a 2- year OECD 451 carcinogenicity study, decreased body weight gain ranging from 4% to 12% was recorded (males and females combined) following oral gavage of 2.2 to 11 mg Ni/kg bw/day. A dose-related reduced survival achieving statistical significance at the two highest dose levels was seen in females (CRL 2005).

The LOAEL of 6.7 mg Ni/kg bw/day based on reduced body weight and increased mortality together with a NOAEL of 2.2 mg Ni/kg bw/day from the CRL (2005) study is taken forward to the risk characterisation for oral repeated dose toxicity. However, uncertainties remain whether this NOAEL should actually be considered as a NOAEL, as reduced body weight gain (both sexes) and increased mortality (females) occurred to a statistically non-significant extent.

It was not possible to determine a NOAEL/LOAEL for the dermal route based on the available information.

Nickel fluoride was classified as T:R48/23 and STOT RE 1;H372 in the 1st ATP to the CLP (group 028 -029 -00 -4)

Please note the following in regards to REACH endpoint requirements identified in Column 2 of the REACH Annexes VIII and IX:

Repeated dose toxicity: oral (Chronic Toxicity/STOT-RE:oral) -

The rules for adaptation in Column 2 of the REACH Annex VIII state that,“the short-term toxicity study (28 days) does not need to be conducted if:a reliable sub-chronic (90 days) or chronic toxicity study is available, provided that an appropriate species, dosage, solvent and route of administration were used”. Therefore, the requirement for a short-term study has been waived based on the availability of a 90-day.

Repeated dose toxicity: dermal (Chronic Toxicity/STOT-RE:dermal)-

The rules for adaptation in Column 2 of the REACH Annexes VIII and IX state that,“Testing by the dermal route is appropriate if…(1) inhalation of the substance is unlikely…”.  It also states that, “Testing by the dermal route is appropriate if: (1) skin contact in production and/or use is likely; and (2) the physicochemical properties suggest a significant rate of absorption through the skin; and (3) one of the following conditions is met:  toxicity is observed in the acute dermal toxicity test at lower doses than in the oral toxicity test, or  systemic effects or other evidence of absorption is observed in skin and/or eye irritation studies, orin vitro tests indicate significant dermal absorption, or significant dermal toxicity or dermal penetration is recognised for structurally-related substances”. As these conditions are not met and the inhalation route of exposure is considered most likely, testing for chronic dermal toxicity has been waived. It should also be considered that Nickel fluoride is already classified as skin sensitiser. Risk measures to protect workers from exposure cover also the risk of dermal contact

Repeated dose toxicity: inhalation (Chronic Toxicity/STOT-RE:inhalation)-

The rules for adaptation in Column 2 of the REACH Annex VIII state that,“the short-term toxicity study (28 days) does not need to be conducted if:a reliable sub-chronic (90 days) or chronic toxicity study is available, provided that an appropriate species, dosage, solvent and route of administration were used”. Therefore, the requirement for a short-term study has been waived based on the availability of a 90-day.

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)



Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Justification for classification or non-classification

Classification is valid for both the anhydrous and hydrated forms

Nickel fluoride fulfils the criteria for classification as T; R48/23 since chronic lung inflammation including lung fibrosis results from long-term exposure via inhalation to a concentration of 0.092 mg/m3. Nickel fluoride is classified as T; R48/23 with a specific concentration limit of > 1% for T; R48/23 and > 0.1 % for Xn; R48/20 in the 30th ATP. Ni fluoride is classified as T:R48/23 and STOT RE 1;H372 in the 1st ATP to the CLP Regulation.