Dialuminium nickel tetraoxide

Endpoint summary

Description of key information

Oral:
LD50 > 2000 g/kg bw nickel aluminate
LD50 cut-off > 5000 g/kg bw nickel aluminate
Read-across from nickel oxide:
ORAL: A series of recent studies conducted by Eurofins Product Safety Laboratory (EPSL) 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 and equal to 9,990 mg/kg for nickel oxide black.
INHALATION: Two guideline-based studies conducted in rats, reported an LC50 greater than 5.08 mg/L for nickel oxide green and greater than 5.15 mg/L for nickel oxide black, in male and female rats.

Additional information

Oral:

The oral acute toxicity study has been performed according to OECD guideline 423 (Colas, 2009). 6 female rats received a single oral dose of 2000 mg/kg bw nickel aluminate. All animals survived and no test substance-related clinical signs were observed. Macroscopical examination of the animals did not reveal treatment-related changes. The LD50 cut-off was determined as 5000 mg/kg bw nickel aluminate.

There are no further data available on the acute toxicity of nickel aluminate. However, there are reliable data available for the structurally related substance nickel oxide. Thus, read-across was conducted based on an analogy approach.

Two background documents describing the use of Ni oxide as a source substance for read-across oral and inhalation toxicity to other nickel compounds has been included in the CSR as Appendices B1 and B2. 

 

The majority of in vivo studies 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) 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 and equal to 9,990 mg/kg for nickel oxide black. However, additional studies reported an acute oral LD50 of 8,796 mg/kg (95% PL confidence interval of 0 mg/kg to 20 mg/kg) and >11,000 mg/kg for black nickel oxide using a vechicle other than water. 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.

Three studies were identified characterizing acute toxicity following inhalation of nickel oxide. The most robust studies was a guideline-based studies conducted in rats, designed to provide information on health hazards likely to arise from short-term exposure to green nickel oxide and black nickel oxide. 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. The incidence of mortality was low, 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. The incidence of mortality was low, resulting in a reported LC50 greater than 5.15 mg/L in male and female rats. A separate study characterized acute toxicity associated with exposure to NiO (no sample color or further characterization provided) and reported that no significant changes in pulmonary inflammation markers (e.g., PMN cell count, cell viability, percent of neutrophils) were observed in bronchial lavage samples taken from mice after 6, 24, 48, or 72 hours of exposure at a concentration of 340 µg/m3 (Leikauf et al 2001).

However, 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. In contrast to other acute toxicity studies identified, Lu et al (2009) reported an increase in polymorphonuclear neutrophils (PMN) 24 hours after exposure to an area equivalent dose of 500 cm2/mL in mice.

The effect of particle size on pulmonary inflammation markers was evaluated in two studies identified. Consistent with most acute studies, no significant changes in pulmonary inflammation markers (e.g., PMN cell count, viability, percent neutrophils) were observed in mice exposed to either a single dose of NiO (300 µg/kg) administered as varying particle size (40 to 1000 nm), or multiple doses of NiO (3 to 3000 µg/kg) as a single particle size (40 nm) (Leikauf et al 2001). In a more recent study, Ogami et al (2009) evaluated various markers of inflammation in BALF, as well as tissue damage, 3 days, 1 week, 3 month, and 6 months after a single intratracheal instillation of 2 mg of nano- (27 nm) or micro- (2.7 µm) particle size NiO. The percent of PMN in BALF was significantly elevated at all time points in animals exposed to nanometer sized NiO (nNiOm), whereas no significant change was noted for this endpoint in animals exposed to the larger, micrometer sized NiO. A similar trend was reported for tissue damage as significantly more severe lesions and markers of cellular damage were observed in the animals exposed to nNiOm, thus indicating that the smaller particles were clearly associated with greater toxicity than micrometer-size nickel oxide.

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.

Data from in vivo studies were generally sufficient to characterize potential acute inhalation toxicity following exposure to nickel oxide; however, the most robust data were reported to be associated with routes of exposure that are not environmentally relevant. Thus, in order to fully characterize acute inhalation toxicity, and primary responses associated with pulmonary toxicity, additional inhalation studies are needed. Following intratracheal instillation or inhalation, 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.

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. In addition, please note the following in regards to REACH endpoint requirements identified in Column 2 of the REACH Annex VIII which state,

"in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 [inhalation and dermal acute toxicity] shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. If there is only one route of exposure, information for only that route need be provided”.  The rules for adaptation also state that, “Testing by the dermal route is appropriate if…(1) inhalation of the substance is unlikely…”.  

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.

Justification for classification or non-classification

The available data on the acute oral toxicity of nickel aluminate are conclusive but not sufficient for classification.

Based on analogy approach, there are conclusive data available on acute oral, dermal and inhalative toxicity which are not sufficient for classification.