Nickel di(acetate)

Endpoint summary

Additional information

      

Information characterizing the toxicokinetics of nickel acetate was limited.  The majority of the data come fromin vitrostudies evaluating the dissolution rates of nickel acetate in different synthetic fluids. Data on the bioaccessibility of Ni acetate in six biological fluids as a surrogate for bioavailability are reported within Section 7.1.1 of the IUCLID file (KMHC, 2010). One additional study was identified that investigated the dermal absorption of nickel acetate. Additional information regarding the toxicokinetics of Ni acetate can be read across from Ni sulphate, based on similar dissolution rates in synthetic fluids and other information, as described in Henderson et al. (2012a).

Inhalation Absorption

No studies providing specific information about the absorbed fraction of nickel following inhalation or intratracheal instillation of nickel acetate or other water soluble nickel compounds have been located. There are two studies in experimental animals that provide some information on the inhalation absorption of Ni from nickel sulphate. No human data are available.

The study by Benson et al. (1995) showed that clearance of nickel after inhalation of nickel sulphate hexahydrate (MMADs ranging from 2.0 to 2.4 µm) from the lungs of rats and mice is extensive with 99% of inhaled nickel sulphate being cleared with a half-time of 2 to 3 days in rats and with 80-90% being cleared with a half-time of less than one day in mice. Nickel levels in blood and urine were not measured, so this study does not provide evidence for whether clearance was via absorption from the lungs into the blood stream or by clearance from the respiratory tract via the mucociliary mechanisms and subsequent oral absorption. Repeated inhalation of nickel sulphate hexahydrate aerosol did not result in accumulation of nickel in the lungs of either rats or mice and did not affect the clearance of⁶³NiSO₄inhaled after either 2 or 6 months of nickel sulphate hexahydrate exposure. No nickel sulphate particles were observed histologically in the lungs of nickel sulphate exposed animals. Benson et al. (1988) indicate that lung nickel burdens increase with increasing concentrations of nickel sulphate (at least up to about 0.8 mg Ni/m³) in the inhaled air as well as with duration of exposure.

The intratracheal instillation study by Medinsky et al. (1987) showed that nickel sulphate (administered as a solution in isotonic saline) is rapidly absorbed from the lungs into the blood in a dose dependent manner as the urinary excretion of nickel increased with increasing dose levels (50% at the two lower dose levels and 80% at the high dose level). Studies in rats using intratracheal instillation of nickel chloride (Carvalho & Ziemer 1982, English et al. 1981, Clary 1975) showed that up to approximately 97% of a dose of nickel chloride can be absorbed from the respiratory tract. These intratracheal studies are expected to overestimate the systemic absorption after inhalation.

Soluble nickel compounds, such as nickel sulphate or nickel acetate, are expected to be absorbed from the respiratory tract following inhalation exposure (dose and time dependent) but the exact amount cannot be quantified unless detailed aerosol and animal data is available. Using dosimetric models like the MPPD (multiple path particle dosimetry model) it is possible to calculate the deposition fraction of aerosols (< 5µmd_ae) in the various regions of the respiratory tract after single or repeated exposures. The fraction of particles deposited in the extrathoracic and tracheo-bronchial regions can be expected to be cleared by swallowing and to be absorbed through the gastrointestinal tract (11% absorption). As a worst case scenario, the fraction deposited in the pulmonary region can be considered to be 100% absorbed. These calculations provide a realistic estimate of nickel absorption after inhalation. Aerosols of d_ae> 5µmwill not be deposied in the pulmonary region and can be considered to be absorbed mostly through the gastrointestinal tract.

 

 

Oral Absorption

A study of male volunteers (Nielsen et al. 1999), receiving a single dose of 100% soluble Ni(II) ion solution, showed that 25.8% of the administered dose was excreted in the urine following administration in drinking water to fasting individuals compared with 2.5% when nickel was mixed with food. Based on experimental data from various human studies, Diamond et al. (1998) used a biokinetic model to estimate nickel absorption; the results showed that estimated nickel absorption ranged from 12-27% of the dose when nickel was ingested after a fast, to 1-6% when nickel was administered either in food, in water, or in a capsule during (or in close proximity to) a meal.

In conclusion, the available data indicate that the absorption of nickel following administration in the drinking water to fasting individuals might be as high as up to about 25-27% and about 1-6% when administered to nonfasting individuals and/or together with (or in close proximity to) a meal.

The 2008/2009 European Union Risk Assessment for Nickel Sulphate, selected a value of 30% as the absorbed fraction of nickel from the gastrointestinal tract following oral exposure to nickel ion (100% bioaccessible) under fasting conditions. Therefore, this same value is used for Ni acetate based on similar nickel ion release. For absorption of nickel from food, soil, dust and from water consumed with food, a value of 5% will be used. This value is very conservative as absorption of Ni mixed with food is <5% and is expected to be even lower for absorption of Ni in food (Ni present in complex organic molecules) or in dust-soil. When extrapolating rat exposures from the oral route to the inhalation route, a value of 11% is used for absorption by the oral route (Ishimatsu et al., 1995) and 100% for the inhalation route (assumes that a respirable size fraction aerosol will have 100% deposition in the respiratory tract of rats and that 100% absorption of the deposited dose will be absorbed). This is quite conservative as only 50% of the aerosol is expected to be deposited (mostly in the nose and conducting airways) with the highest deposited fraction being absorbed though the gastrointestinal tract (11%).

Dermal Absorption

 

In the case of dermal absorption, it is important to distinguish between penetration of nickel into the skin (relevant for local effects such as irritation or sensitization) and percutaneous transport into the blood stream (relevant for systemic effects).

 

In a human study with nickel sulphate (Hostýnek et al. 2001), a large part of the administered dose remained on the surface of the skin or in the uppermost layers of the stratum corneum, even after 24hs. In an in vitro study using human skin (stratum corneum from cadaver leg skin) and a variety of water soluble compounds (including Ni acetate), about 97% of the dose was recovered in the donor solution after 96 hours, with about 1% in the receptor fluid and 0.6% in the stratum corneum (Tanojo et al. 2001); absorption following dermal contact may have a lag time. Studies in experimental animals have yielded mixed results. Some studies indicate that some nickel can be absorbed through the skin of rats (Mathur et al. 1977), guinea-pigs and rabbits (Norgaard 1957). Another study in guinea pigs showed that nickel only penetrated into the stratum corneum (Lindberg et al. 1989).

 

In conclusion, the available data indicate that absorption of nickel following dermal contact to various nickel compounds can take place, but to a limited extent with a large part of the applied dose remaining on the skin surface or in the stratum corneum. The in vitro study of soluble nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, and nickel acetate) using human skin showed about 98% of the dose remained in the donor solution (Tanojo et al. 2001). For the purpose of risk characterisation, a value of 2% is taken forward for the systemically absorbed fraction of nickel following dermal contact to nickel acetate.