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Administrative data

Description of key information

Value used for CSA:

NOAEL (oral, systemic, animal data): >11,000 mg/kg for nickel oxide green (>8,500 mg Ni/kg/day) (EPSL, 2008)                                                                        

          9,990 mg/kg for nickel oxide black (6,200 mg Ni/kg/day) (EPSL, 2009)

NOAEL (oral, systemic, human data): 0.012 mg Ni (Ni ion)/kg bw/day; based on exacerbated existing dermatitis

           (Nielsen et al., 1999)

NOAEC (inhalation, systemic, animal data): >5.08 mg/L for nickel oxide green; >5.15 mg/L for nickel oxide black

                                                                           (>3,900 mg Ni/m3) (EPSL, 2009/2010)

NOAEC (inhalation, local, animal data): 3.9 mg Ni/m3(MMAD =2.9 µm) for local effects(DNEL calculation is based on 16-day repeated dose study-Dunnick et al, 1988; no acute, local effects data available)

 

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50

Acute toxicity: via inhalation route

Endpoint conclusion
Dose descriptor:
LC50

Additional information

Two background documents describing the use of Ni oxide as a source substance for read-across of oral and inhalation toxicity to other nickel compounds has been attached to Sections 7.2.1 and 7.2.2 of IUCLID and included in the CSR asAppendices B1andB2. 

The majority ofin vivostudies characterizing the acute toxicity of nickel oxide were based on intratracheal instillation or oral gavage, though three studies based on inhalation exposures, and one study based on intraperitoneal, intrarenal, and intramuscular routes were identified. Endpoints included assessments of mortality, pulmonary inflammation and lung toxicity. In vivo studies were conducted in mice and rats, whereas a number of animal and human-based cell lines were utilized in in vitro studies characterizing the acute toxicity of nickel oxide.

 

A series of recent studies conducted by Eurofins Product Safety Laboratory (EPSL) and reported in Henderson et al. (2012b) characterized the acute oral LD50 of both black and green nickel oxides in rats. Based on the acute toxicity up and down procedure (carried out according to OECD Test # 425 guidelines and using GLP standards), the acute oral LD50 was found to be greater than 11,000 mg/kg for nickel oxide green (EPSL, 2008a,b ) and equal to 9,990 mg/kg with a 95% CI of 8,775-11,100 mg/kg bw for nickel oxide black, (EPSL, 2009b). Additional studies with black nickel oxide reported acute oral LD50 > 11,000 (EPSL, 2008c,d,e). Another study of black nickel oxide in DMPS vehicle (EPSL 2009a) yielded an LD50 of 8,796 mg/kg; the confidence limits for this LD50 could not be calculated in this study and thus, the LD50 of 9,990 mg/kg from the EPSL (2009b) study is considered the most representative LD50 value for the black nickel oxide sample . Similar findings were reported in an earlier guideline-based study; Food & Drug Research Laboratories, Inc (1983) reported an acute oral toxicity of green nickel oxide LD50 in rats of >5000 mg/kg. This finding was based on both a range test involving a single oral dose ranging from 100 to 5000 mg/kg that resulted in no mortality or other adverse effects, as well as findings of the main test in which rats were administered 5000 mg/kg green NiO orally and observed for fifteen days. Aside from diarrhea, no mortality or other noteworthy findings were reported. The LC50 >2000 mg/kg supports no classification for acute oral toxicity.

Three studies were identified characterizing acute toxicity following inhalation of nickel oxide. All three studies are guideline-based studies conducted in rats and designed to provide information on health hazards likely to arise from short-term exposure to green nickel oxide and black nickel oxide. In the first study and based on information obtained from pre-test trials, rats were exposed to green NiO (0.18 and 5.9 mg/L) for four hours; animals were observed for mortality, signs of gross toxicity, and behavioral changes for up to 14 days following exposure (EPSL, 2009c). There was no incidence of mortality, resulting in a reported LC50 greater than 5.08 mg/L in male and female rats. In the second study, rats were exposed to black NiO for four hours; animals were observed for mortality, signs of gross toxicity, and behavioral changes for up to 14 days following exposure (EPSL, 2010). There was no incidence of mortality, resulting in a reported LC50 greater than 5.15 mg/L in male and female rats. In the third study, rats were exposed to black NiO for four hours at exposure of 8.3 mg/L. Animals were followed for 14 days but no incidence of mortality was observed, confirming previous results and indicating an LC50 for black NiO greater than 8.3 mg/L in male and female rats (EPSL, 2013). The LC50 >5 mg/L supports no classification for acute inhalation toxicity.

Markers of pulmonary inflammation and lung toxicity were examined in a number of studies that exposed animals via intratracheal instillation. Migally et al.(1982) reported changes in the ultrastructure of pulmonary macrophages (PAM) and pulmonary interstitial macrophages one week following a single dose of 10 mg/mL. Similar findings were reported in a series of studies conducted by Benson and colleagues (Benson et al.1984, 1986) in which rats were administered a single dose (0, 0.01, 0.1. or 1 µmol) of NiO via intratracheal intubation and evaluated lung tissue one or seven days following exposure. In the first study, Benson et al.(1984) reported minimal biochemical changes in lavage fluid one day following exposure (e.g., increased total protein), but changes were not dose-dependent, and were not observed at the seven-day timepoint. Benson et al.(1986), a larger study, did not report any significant biochemical changes one day following exposure. Neither study reported tissue damage associated with acute NiO exposure.

As part of a multi-component study comparing the lung toxicity of nickel fumes and their oxidic components (Ni2O3 and NiO powders) in rats, Toya et al.(1997) evaluated growth rate, gross findings, and histopathological examinations of the lungs following a single intratracheal administration, or four intratracheal administrations of the fume or the oxidized components. When NiO was assessed individually, there were no deaths observed following exposure, no impacts on body weight, and no observable gross or histopathological changes (with the exception of a slightly red coloration of the lobes). In contrast, the nickel fumes, as well as exposure to Ni2O3, significantly impacted all endpoints evaluated, thus leading the authors to conclude that a toxic Ni2O3 component and very fine particles of nickel fumes were involved in acute lung toxicity.

Three studies evaluating less relevant routes of exposure were identified. Sunderman et al.(1987) reported decreased bodyweight and a dose-related correlation with erythropoiesis in rats exposed to multiple forms of nickel oxide via intrarenal injection. In this assessment, black nickel oxide, and other forms of nickel oxide calcined at similar temperatures, caused the most severe outcomes for the endpoints evaluated. As part of a study investigating potential effects associated with prosthesis materials, Pizzoferrato et al.(1987) reported that NiO induced a number of changes associated with pulmonary inflammation in mice exposed to a single i. p. injection of NiO. Novelli et al.(1995) administered 7 mg of NiO of unspecified color to rats. After 72 hours, NiO treated rats exhibited biomarkers for oxidative stress such as increased serum lipid peroxidation. These effects were mitigated in animals that also received injections of superoxide dismutase – suggesting that NiO may exert adverse effects through oxidative stress mechanisms. Though these studies provide information following less environmentally relevant routes of exposure, they may be informative as to the mechanism of action associated with NiO toxicity.

In vivo data generally indicated that nickel oxide was not acutely lethal, and was not associated with pulmonary inflammation and lung toxicity in rodents following acute exposure; however exceptions to these trends were noted when exposures involved very small nickel oxide particles (e.g., nanometer sized). Data were sufficient to characterize mortality following oral exposure of green and black nickel oxides, though were insufficient to characterize other acute toxicity endpoints. The available data for acute toxicity via both the oral and inhalation routes does not support an acute toxicity classification.

There are no available data on which to evaluate acute dermal toxicity. However, acute toxicity is expected to be low in view of the poor absorption by this route. As oral and inhalation routes of exposure are more relevant and data for these have been provided, testing for acute dermal toxicity is therefore waived based on this information.

 

The following information is taken into account for any hazard / risk assessment:

ORAL: A series of recent studies conducted by Eurofins Product Safety Laboratory (EPSL/PSL) characterized the acute oral LD50of both black and green nickel oxides in rats. The acute oral LD50was found to be greater than 11,000 mg/kg for nickel oxide green (>8,500 mg Ni/kg/day) and equal to 9,990 mg/kg for nickel oxide black (6,200 mg Ni/kg/day).

INHALATION: Two guideline-based studies conducted in rats, reported an LC50greater than 5.08 mg/L for nickel oxide green and greater than 5.15 mg/L for nickel oxide black (or >3,900 mg Ni/m3), in male and female rats.

DERMAL: No risk characterisation will be conducted for acute dermal toxicity. Acute systemic effects are not relevant due to the very low dermal absorption of nickel. Acute local effects are covered by the long term DNEL based on prevention of dermal sensitization.

Justification for classification or non-classification

Ni oxide does not have harmonized classifications for acute toxicity (oral, inhalation, or dermal) according to the 1st ATP to the CLP regulation. Supporting information can be found in the discussion section for this endpoint.