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Inhalation Absorption

After inhalation, the deposition of particles in the various regions of the respiratory tract depends on the particle size distribution of the aerosols (MMAD, GSD) as well as on other characteristics of the particles. The absorption of nickel from the respiratory tract into the blood stream depends on the solubility of the nickel substance inhaled and the deposited and/or retained dose. Dosimetric models can estimate the fraction of the inhaled dose that will be deposited in each region.  The particles retained in the airways are removed by the mucociliary escalator and translocated into the gastrointestinal tract; particles deposited on the nose region are swallowed as well. Particles deposited in the pulmonary region can be cleared by dissolution or via macrophages. A 90-day inhalation study with Ni metal powder in rats (WIL Research Laboratories 2004), showed that nickel lung burdens increased with increasing exposure concentrations and so did the blood nickel levels indicating absorption of nickel from the retained nickel particles in the lungs.

To assess the extent of absorption of Ni after repeated inhalation of Ni metal powder it can be anticipated that after a 13-week exposure period the daily amount of nickel eliminated from the blood primarily via urine and faeces is equal to the amount absorbed. However since the retention T1/2 for Ni metal was estimated as 30-60 days it is not known whether a steady state was reached after 13 weeks. If this is not the case, the absorbed amount may be underestimated. After 13 weeks of exposure at 1 mg/m3 6h/d 5d/w a nickel level in blood of 16.7 ng Ni/ml is reached (average for males and female Wistar rat in the WIL Research Laboratories 2004 study). When the background level of the control groups (4.4 ng/ml) is subtracted, it can be estimated that the exposure resulted in an increase of 12.3 ng Ni/ml. IPCS (1991 has described a two-compartment model for the toxicokinetics of nickel in the Wistar rat. A total excretory clearance of 8.14 ml/h has been calculated (urinary clearance of 6.39 ml/h + faecal clearance of 1.28 + clearance into sink (body tissues)).

Using this model, together with a blood level of 12.3 ng/ml and a daily clearance of 8.14 ml/h the daily absorbed amount can be estimated (12.3 ng/ml x 8.14 ml/h x 24 h = 2403 ng/d or 0.0024 mg/d). With an average rat body weight of 208 g (corresponding to the clearance value) this corresponds to an absorbed (and eliminated) dose of 0.0116 mg/kg/d.

This internal dose can be compared to the external exposure at 1 mg/m3. During the 13-week exposure period a rat inhaling 0.22 m3 per day will be subjected to an average daily exposure of:  1mg/m3 x 0.22 m3/d x 6h/24 h x 5d//7d / 0.208 kg bw = 0.189 mg/kg bw/d. Thus 0.0116 mg/kg bw/d x100/ 0.189 mg/kg bw/d = 6.1 % or approximately 6% of the inhaled dose is absorbed. Although a steady state with respect to nickel lung burden and nickel blood level may not have been reached, the calculated absorption figure represents a rough upper estimate of inhalation absorption as additional oral exposure to deposited nickel particles in the fur by grooming occurs. This may influence the absorbed amount of nickel although the gastrointestinal absorption is very low (~0.1%).

For the purpose of risk characterisation, a value of 6% is taken forward as the absorbed fraction of nickel from the respiratory tract following inhalation exposure to nickel metal powder (respirable size) in rats. Data on the bioaccessibility of Ni metal in biological fluids can be found in Section 7.1.1 of the IUCLID file.

Oral absorption

There are no studies of absorption and retention of nickel following oral administration of nickel metal powder in humans. A study in rats showed an absorption of 0.09% when nickel metal was administered in a 5% starch saline solution  (Ishimatsu et al. 1995).

Insoluble nickel compounds, such as nickel metal, are expected to be absorbed from the gastrointestinal tract following oral exposure to a limited extent compared to water soluble compounds.

The study in rats by Ishimatsu et al. (1995) indicates, by direct comparisons of the absorbed fractions, a 100-fold lower absorption of nickel following administration of nickel metal than for soluble nickel compounds.

The Nielsen et al. (1999) oral study with soluble nickel is included here because a value for oral absorption of nickel from nickel metal in humans could be derived using knowledge from the oral absorption of soluble nickel in humans together with information on relative oral absorption of nickel from nickel metal and soluble nickel in rats. The Nielsen et al. (1999) study value for soluble nickel exposure under fasting conditions was approximately 30%.  With the 100-fold adjustment for lower absorption for nickel metal (from Ishimatsu et al. 1995), the value for nickel metal oral absorption is 0.3%.  

A value of 0.3% is taken forward for the risk characterisation as the absorbed fraction of nickel from the gastrointestinal tract in humans following oral exposure to nickel metal powder under fasting conditions. For absorption of nickel from nickel metal consumed with food, the Nielsen study indicated 5% could be used as a conservative value for soluble nickel; therefore, a value of 0.05% will be used for absorption from nickel metal (100-fold lower).

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 recent human in vivo study, a large part of the administered dose remained on the surface of the skin after 96 hours and a minor part (around 0.2%) was absorbed into the stratum corneum (Hostynek et al. 2001).

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 data are too limited for an exact valuation of the absorbed fraction of nickel following dermal contact to nickel metal.

For the purpose of risk characterisation, a value of 0.2% is taken forward for the absorbed fraction of nickel following dermal contact to nickel metal based on the data from the in vivo study in humans (Hostynek et al., 2001).

Distribution and Elimination

The information on distribution and elimination of nickel following exposure to nickel metal is very limited. Inhalation of nickel particles (1-2 μm MMAD) resulted in accumulation of particles in the lungs of rats. The data indicate that steady state levels of nickel in the lung were reached by 12 months of exposure at 0.1 and 0.4 mg/m3 (Oller et al., 2008). Absorbed nickel from Ni metal exposure (or any other Ni substance) is expected to be distributed systemically (lung, pancreas, liver) and be eliminated through the kidneys (Ishimatsu et al., 1995; Nielsen et al., 1999).