Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Text was truncated. The full text is available in the migration report.

Key value for chemical safety assessment

Additional information

There is no data on inhalation absorption of nickel oxide (green or black) but it is expected to be low. To estimate the difference between the inhalation absorption of nickel from nickel oxide and from nickel sulphate, the relative retention half times in rats are considered (T1/2 = 2 days for nickel sulphate and 120 days for nickel oxide, Benson et al., 1994). The value of 60 is conservative compared to the relative Ni ion release in synthetic alveolar and interstitial lung fluids after 72 hours:  0.1% alveolar-0.1% interstitial for nickel oxide-green, 0.7% alveolar -0.8% interstitial for nickel oxide-black, 48% alveolar -57% interstitial for nickel sulphate, KMHC, 2010].

For the purpose of risk characterisation, a value of 1.7% is taken forward for the risk characterisation as the absorbed fraction of nickel from the respiratory tract following inhalation exposure to nickel oxide (respirable size) in rats. The oral absorption of nickel oxide is very low (0.04% for nickel oxide compared to 11.12% for nickel sulphate in rats; Ishimatsu et al., 1995). Therefore, a 278-fold difference in oral absorption between nickel oxide and nickel sulphate was carried over to the risk characterization based on human data from Nielsen et al. (1999) where approximately 30% of nickel ion was absorbed under fasting conditions. Dividing this value by the 278-fold lower absorption of nickel oxide results in 0.1% oral absorption under fasting conditions.

Discussion on bioaccumulation potential result:

The in vivo toxicokinetic properties of NiO have been evaluated in multiple species (hamsters, rats, and mice) following various routes of administration (oral, intramuscular, intratracheal and inhalation), and for various durations of exposure (<1 day to 2 years). Only a single study was identified that directly compared the toxicokinetic characteristics of green and black nickel oxide. The majority of toxicokinetic studies evaluated distribution and clearance of NiO to and from the lung following inhalation (and often only evaluated a single dose and compared tissue concentrations to control animals); fewer studies comprehensively evaluated tissues other than the lung or evaluated excretion.

Evaluation of tissue distribution over time following a single inhalation exposure was reported in several studies. Benson et al (1994) exposed rats (nose-only) to 10 mg green 63NiO/m3 for 70 minutes and distribution monitored in many tissues (including excreta) between 1 hr to 180 days post exposure. Within 1 hr post exposure, 82% of the deposited 63Ni was found in the GI tract, 16% in lungs, and 6% in skull (measured tissue concentrations of Ni were not reported by the authors). At 4 days post-exposure, 63Ni was only found in the lung, and persisted for as long as 180 days. Within four days of exposure, Ni activity was only reported in the lung, where it appeared to be only slowly cleared. Similar findings were reported by English et al (1981), where rats were exposed to a single dose of radiolabelled black NiO via intratracheal administration and Ni distribution was monitored over time in several organs. The highest levels were in the lung followed by the kidney; lung concentrations remained greatly elevated throughout the 90 days following NiO exposure. Only about 30% of the NiO dose was excreted by 3 days (with roughly equal amounts of nickel in urine and feces). The concentration of nickel in blood remained constant for 60 days, indicating a consistent release from the lung. Wehner et al (1975) and Kodama et al (1985) also reported that tissue distribution was primarily limited to lung and only small amounts of nickel reached other tissues following a 61-day and 3-month exposure to NiO aerosol, respectively.

Tanaka and colleagues conducted a series of studies evaluating the toxicokinetics of green NiO in rats (Tanaka et al 1986, 1988, 1992). In a study evaluating distribution following 3-, 6- or 12-month inhalation exposure (control, low- and high- dose groups), the concentrations of nickel in lungs were much higher than controls in all exposure groups whereas nickel concentrations in other organs (liver, kidney, spleen and blood) were slightly higher in high exposure group only (Tanaka et al 1986). In what appears to be a follow up report, Tanaka et al (1988) reported on tissue concentrations in rats exposed to a low or high dose of green NiO for up to 12 months and monitored up to 8 months post exposure. Nickel concentrations in the lungs of the exposed and the exposed-clearance rats were much higher than those of control. The amount of nickel in the lungs after 12 months of exposure was 2.6 and 0.6 mg in high and low exposure groups; clearance of the nickel from the lungs was very slow and the biological half time was determined 7.7 months. In a separate study, nickel distribution was determined immediately after a 1-month exposure to a single dose of green NiO, or after a 12-month clearance period following a 1-month exposure to green NiO (Tanaka et al 1992). Collectively, these data generally indicated that in animals exposed for one month, the nickel concentrations in the exposed rat lungs were much higher than those in controls in all animals evaluated. Based on their series of kinetic studies, these authors concluded that the clearance rate of nickel following exposure to green NiO increased with decreasing particle diameter, but that the clearance ratio may not be affected by the exposure concentration.

Clearance rates were also evaluated by Benson et al. (1995). Benson et al. (1995) examined the fate and effects of inhaled green NiO in male rats and mice exposed 6 hr/day, 5 d/wk, for up to 6 months. The authors reported nickel accumulation in lung following repeated inhalation exposure to NiO, but also showed that prior exposure to unlabelled green NiO reduced the clearance rate of 63NiO from the lung (as compared to rates without pre-exposure).

Lung tissue concentrations were well-characterized by Dunnick and colleagues in a series of studies designed to evaluate the toxicity of multiple nickel compounds, including NiO. These robust studies each included both rats and mice and a range of five doses. Dose dependent increases in nickel concentrations in the lung were reported following 12-day, 13-week and 2-year inhalation studies in both rats and mice (Dunnick et al 1988, 1989, 1995). Relative to the other compounds tested (NiSO4 and Ni3S2), NiO had the greatest retention in the lung. A dose- and time-dependent increase in nickel concentrations in the lung were also reported by Cho et al (1992) associated with up to 12 months of exposure to NiO (lung burden evaluated at 3, 6, and 12 months, as well as 8 months following the termination of exposure). Similar trends in disposition were noted in hamsters by Wehner et al (1972); nearly 20% of the inhaled NiO was retained in the lungs after initial clearance, and 45% was present after 45 days following 3 months of exposure (2-day and 3-week exposures were also evaluated).

Limited information was identified evaluating distribution following oral exposure. Ishimatsu et al. (1995) examined the solubility and distribution of several nickel compounds (including both green and black NiO) following a single oral exposure (10 mg). 24 hours after exposure, stark differences in distribution were noted as black NiO was much more readily distributed than green NiO as demonstrated by higher tissue concentrations. However, the authors reported that only 0.04% of black NiO was absorbed. Wehner et al. (1972) exposed unfasted hamsters to 5 mg NiO of unspecified color via oral gavage and found that Ni levels were not significantly elevated in the lungs, liver, kidneys or carcass relative to control animals.

A single study evaluating distribution following intramuscular injection of NiO was identified; Novelli et al., 1995 reported that a single dose (7 mg/kg) NiO (unspecified color) led to 3- to 5-fold increases in nickel content in the pancreas and liver respectively. The authors did not specifically comment on the distribution finding, though the elevated levels of Ni measured in tissues following intramuscular injection suggest that nickel was distributed to other tissues within the 72 hours (note: data on excretion was not provided).

The data indicates that relatively little NiO is absorbed from the GI tract. The oral absorption of nickel oxide is very low (0.04% for nickel oxide compared to 11.12% for nickel sulphate in rats; Ishimatsu et al., 1995). Therefore, a 278-fold difference in oral absorption between nickel oxide and nickel sulphate was carried over to the risk characterization based on human data from Nielsen et al. (1999) where approximately 30% of nickel ion was absorbed under fasting conditions. Dividing this value by the 278-fold lower absorption of nickel oxide results in 0.1% oral absorption under fasting conditions.

However, given that data are very limited (and no information was identified characterizing the toxicokinetics following dermal exposure, which is not considered to be a relevant route of exposure), more data are required to fully characterize the toxicokinetics associated with exposure routes other than inhalation. Data from inhalation studies are more robust and clearly indicate that, in laboratory species, concentrations of nickel in the lung increase with both dose and time, and that once nickel is deposited following exposure to NiO, it is slowly cleared from the lung. Though no single study is alone sufficient to fully characterize the distribution of NiO, the data when considered collectively provide a general understanding of the toxicokinetics following inhalation of NiO.