Trinickel disulphide

Endpoint summary

Description of key information

 

The in vivo toxicokinetic properties of Ni3S2 have been evaluated in rats and mice following various routes of administration (e.g., oral, intratracheal and inhalation), and for various durations of exposure (1 day to 2 years). Collectively, these data indicate that inhaled Ni3S2 can distribute to extrapulmonary organs such as the liver and kidney; distribution throughout the body was also demonstrated following oral exposure. However, nickel is also cleared or eliminated quickly and does not bioaccumulate in rodents. For nickel subsulphide, the inhalation absorption in rats is conservatively estimated to be 50%, compared to 100% for nickel sulphate hexahydrate. The retention half time for nickel subsulphide was twice as long as for nickel sulphate hexahydrate (4 days versus 2 days) in the study by Benson et al., (1994).  The factor of 2 is also conservative based on the relative Ni ion release in synthetic lung fluids (KMHC, 2010).  Though no single study by itself is sufficient to fully characterize the distribution of Ni3S2, the data when considered collectively provide a general understanding of the toxicokinetics following inhalation or intratracheal instillation of Ni3S2. Considering the  data from Ishimatsu et al. (1995) and Nielsen et al. (1999), 1.5% oral absorption of Ni subsulphide is expected under fasting conditions.

 

Additional information

The in vivo toxicokinetic properties of Ni3S2 have been evaluated in rats and mice following various routes of administration (e.g., oral, intratracheal and inhalation), and for various durations of exposure (1 day to 2 years). The majority of toxicokinetic studies evaluated distribution and clearance of Ni3S2 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. Additionally, most studies relied on measurements of total nickel (Ni) to characterize distribution following exposures to Ni3S2. Lung tissue concentrations were well-characterized by Dunnick and colleagues in a series of inhalation studies designed to evaluate the toxicity of multiple nickel compounds, including Ni3S2. These robust studies each included both rats and mice and a range of two or five doses administered over 2 years or 13 weeks, respectively. A dose-dependent increase in the levels of Ni in the lung following Ni3S2 exposure was observed for animals exposed up to 13 weeks. However, at later time points (i.e., 7 months and 2 years), similar levels of Ni were measured in the lungs of animals from all dose groups. Collectively these results indicated that little or no bioaccumulation occurred and thus concluded that continuous inhalation of Ni3S2 did not result in increased lung burden, suggesting no impaired lung particle clearance. The nickel burden in lung following repeated exposure via inhalation was evaluated in a number of other studies. Benson et al. (1995) examined the nickel lung burden in F344 rats exposed to Ni3S2 /m3 for up to 22 days. Over the course of the exposure period, nickel levels tended to rise rapidly over the first seven days, and then rise more slowly thereafter, resulting in an estimated pulmonary clearance half-time of about 4 days. In a subsequent study, these authors (Benson et al. 1987) examined tissue (lung, kidney, and liver) burden of inhaled Ni3S2 in F344/N rats and B6C3F1 mice exposed for 6 hr/d, 5 d/wk, for 12 exposure days (0.6-10 mg/m3). The authors concluded that the lung and kidney were the only organs containing significant quantities of nickel after 12 days of exposure. Additionally, the study demonstrated no significant differences between lung burdens in males and females. Similar findings were reported by Kodama et al. (1993) following inhalation Ni3S2 exposures in male Wistar rats for a duration of 6 months, followed by a 12-month recovery period. Nickel content was significantly elevated in the lung, liver and kidneys in animals sacrificed within one day after the last exposure. After 12 months of recovery, the nickel levels in these tissues returned to levels comparable with untreated animals. Nickel concentrations in the lung following a very short-term exposure have also been evaluated. In a rather robust evaluation, Benson et al. (1994) examined the fate of inhaled radiolabelled 63Ni3S2 in male F344 rats exposed for 120 min and then monitored for up to 32 days after exposure. Nose-only exposures resulted in an estimated 66% of the recovered nickel being deposited in the upper respiratory tract following exposure, and then was rapidly cleared from the lung with an estimated clearance half-time of 4.6 days. However, a biphasic clearance was reported earlier by Finch et al. (1987), based on the findings of a limited analysis of tissue distribution following instillation of 63Ni3S2. The authors reported an initial half-life of 2 hr followed by a longer half-life of 119 hr. Similar responses were reported in kidneys and blood (206 and 122 hr). In contrast the longer phase for the GI tract was only 34 hours. The authors concluded that Ni3S2 lung burden was quickly cleared by the coughing reflex and subsequently by the GI tract. Separately, Mayer et al. (1998) administered a single, 2-hour, nose-only inhalation dose of Ni3S2 to male F344 rats in an effort to determine the distribution of inhaled Ni3S2 particles in the respiratory tract. Relative to control animals, the Ni content (mg/g dry weight) was approximately 40-fold increased in the nasal mucosa and almost 400-fold increased in lung tissues. Similar findings were observed by Valentine and Fisher (1984) in A/J mice exposed to intratracheally instilled particulate 63Ni3S2. Lung clearance was biexponential; at least 90% of the compound was cleared from the lungs within 35 days. Solubilized Ni3S2 was distributed to the liver, kidney, femur, and blood, but was removed from these sites at rates comparable to lung clearance. A single study evaluating the kinetics of Ni3S2 following oral exposure (Ishimatsu et al. 1995) examined both the solubility and distribution in rats. A single dose of Ni3S2 (10 mg Ni in saline) resulted in increased Ni levels in the lung, liver and kidney relative to the control. However, only 0.47% of the administered Ni3S2 was measurable in organs, blood or urine 24 hr after exposure, thus indicating a high solubility and rapid elimination from the body in rats. Collectively, these data indicate that inhaled Ni3S2 can distribute to extrapulmonary organs such as the liver and kidney; distribution throughout the body was also demonstrated following oral exposure. However, nickel is also cleared or eliminated quickly and does not bioaccumulate in rodents. Though no single study is alone sufficient to fully characterize the distribution of Ni3S2, the data when considered collectively provide a general understanding of the toxicokinetics following inhalation or intratracheal instillation of Ni3S2.

For nickel subsulphide, the inhalation absorption in rats is conservatively estimated to be 50%, compared to 100% for nickel sulphate hexahydrate. The retention half time for nickel subsulphide was twice as long as for nickel sulphate hexahydrate (4 days versus 2 days) in the study by Benson et al., (1994). The factor of 2 is also conservative based on the relative Ni ion release in synthetic lung fluids (KMHC, 2010). Though no single study by itself is sufficient to fully characterize the distribution of Ni₃S₂, the data when considered collectively provide a general understanding of the toxicokinetics following inhalation or intratracheal instillation of Ni₃S₂.Considering the data from Ishimatsu et al. (1995) and Nielsen et al. (1999), 1.5% oral absorption of Ni subsulphide is expected under fasting conditions.