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The nickel slag is a complex metal containing substance. It mainly contains iron silicate and silicates of aluminum and calcium. Traces of metals are present in metal forms, mineral form or included in silicate phases.

The nature of the physical form (solids) and the physico-chemical properties (slag constituents are poorly soluble in water) is therefore expected to limit the solubility of slag-constituents in biological fluids and subsequently to limit the cellular absorption of the slag-constituents The toxicokinetics of nickel slag is therefore primarily related to the degree to which the metal mineral phases in the slag react with biological fluids and release soluble, potentially bio available ionic species. The relevance of such studies to metal absorption and metal hazard profiles has been demonstrated in the past : 

Several in-vitro studies have assessed the release/dissolution of metal ions from a range of metal bearing materials (minerals, soils, substances) in solvents that simulate biological fluids. The resulting value, refered to as ‘bioaccessibility or biosolubility”is defined asthe fraction of a substance that solubilize under physiological conditions and therefore is “potentially available” for absorption into systemic circulation. The fraction that is absorbedin vivois referred to asbioavailabilityThe simulated biological fluids represent relevant exposure routes (e.g. dissolution in sweat is used to estimate bioavailability after dermal exposure, dissolution in gastric fluid is used to estimate bioavailability after oral exposure).The concept of bioaccessibility and relative bioaccessibility (relative to soluble metal compounds) has been applied to assess human exposures to metals and minerals in soils, consumer products, and to the evaluation of sparingly soluble metal substances (e.g. Oomen et al,2002; Van de Wiele et al., 2007; Oswer 2007, Brock and Stopford, 2003; Stopford et al., 2003). 

Biological validation of the results from in-vitro tests (bio-accessibility) in gastric fluid as predictive to in vivo conditions (bioavailability) has been performed for lead in soils. The results are included in U. S. EPA guidance for lead risk assessment (EPA, 2007, Estimation of relative bio-availability of lead in soil and soil like materials using in-vivo and in-vitro methods).

Further biological validation of oral bio-accessibility methods (application of the Barge method, including saliva, gastric and intestine phases) were carried out on As, Cd and Pb in soils. The results showed that gastric relative bio-accessibility for Pb, As and Cd are accurate estimates of in-vivo bioavailability (Van de Wiele et al., 200, Caboche et al.,2010).

Useful to mention that bioaccessibility has already been used in several regulatory frameworks:

-         The standard EN 1811specifies a method for simulating the release of nickel from all articles intended to come into direct and prolonged contact with the skin in order to determine whether such items are in compliance with the European Nickel Directive 94/27/EC

-         TheD5517, identifies metal oral accessibility for Art materials, Results are used under the guideline D 4236 which allows one to take into account the bioavailability of potentially toxic components of an art material in making a determination whether or not the art material would require labeling for a chronic health hazard

-         The standard on safety of toys EN 71-3 specifies requirements for migration of metals from toy materials under conditions which simulate ingestion. 

Bio-accessibility therefore plays a key role in the hazard assessment of nickel slag.

ORAL: Nickel slag is a solid and needs to dissolve before it can be absorbed. Reduced absorption in gastrointestinal tract is therefore expected due to poor water solubility.To assess the potential availability of slags after oral intake, the rate of metal solubilization from slags in solvent mimicking gastric fluid, has been measured.

INHALATION: Nickel slags in massive cannot be inhaled. Granular form contain only 0.22% of inhalable particles less 100 μm

DERMAL: Nickel slag particles have to dissolve into the surface moisture of the skin before dermal uptake can begin. As the nickel slag is poorly soluble in water it is not expected to partition to the epidermis. Therefore dermal uptake is likely to be low. The slag does not have any skin irritant or corrosive properties that could damage the skin surface and enhance penetration. The metals adsorbed after dermal exposure may however contribute to the systemic metal doses and therefore have to be considered for the combined toxicity assessment. 

Trace metals contained in/released from the slag differ in their toxicological properties.The “bio-accessible” metal ions may enter the blood stream and exert its toxic action directly in the blood or in any target tissue or organ to which the circulatory system transports or distributes it. Information on toxicokinetics (absorption, distribution, metabolism and excretion) is available for every single metal in the slag. Most critical for human health hazard assessment is nickel up to 0.44% total metal concentration. As confirmed by mineralogical composition 90% of the total Ni content is present in metallic form and only 10% in the form of NiS. This demonstrates that Ni/NiS are present at catual levels lower that threshold triggering any classification.

Other metals like As, Cd , Pb present at levels much lower than thresholds triggering any classification (Cd up to 0.007%, As in metallic form of < 0.004%, Pb up to 0.002%.

Gastric bio-accessibility

Rodriguez et al, 2010 assessed the relative release/dissolution of metal ions from typical nickel slag sample in biological fluids, simulating oral exposure.

Metal release in human digestive system was estimated through in vitro bio-accessibility test in extraction solvent that resembles gastric fluid (using HCl 0.07N at pH 1.5) in accordance with the ASTM D 5517-07 standard. Metal released to the medium were determined after 1 hour of agitation at 171 rpm and another hour to allow the sample to settle at 37°C. The tests were carried out at loading 200 mg/l and 2 g/l and particle size of <500μm.

The fraction of metals that solubilize under these conditions can be considered as worst case determinant of bio-accessibility of metals contained in the slag, because only solubility in the gastric fluid (pH 1.5) is assessed and the homeostatic mechanisms at the level of the intestine and liver are ignored.

Influence of abrasion on bio-accessibility demonstrated that at the higher loading (2 g/L, small volume of 50ml) abrasion of particles occurred. This was indicated by a relative release at 2g/L being much higher than the relative release at 200 mg/L. The data at 200 mg/L were therefore considered as more reliable.


Results demonstrate reduced relative bio- accessibility of metals. The bio-accessible/total metal ratio’s measured after bio-elution in gastric fluids are :Cu 0.04, Ni 0.05, Co 0.06).Dissolved concentrations of Pb and As were below detection limit.

The results obtained with the ASTM method have been proven to correlate with metal bioavailability concentrations obtained in ingestion assays on animals.


Literature data show that the results from theASTM D 5517-07tests are to be considered as conservative:

-         Oomen et al., 2002 compared the results from different gastric bio-eluiotn tests. They demonstrated that experimental designs of the different digestion systems are distinct, the main differences in test results of bioaccessibility can be explained on the basis of the applied gastric pH. High values are typically observed for a simple gastric method, which measures bioaccessibility in the gastric compartment at low pHs of 1.5. Other methods that also apply a low gastric pH, and include intestinal conditions, produce lower bioaccessibility values.

It can be concluded that the results obtained by in-vitro bio-accessibility test in solution that mimic gastric flied (pH 1.5) provide a conservative estimate of the amounts of metals in nickel slag that are readily available for absorption after ingestion and thus can be used to support the conclusions on hazard classification.

Dermal bio-accessibility

The solubility of Ni was assessed during an in-vitro bio-accessibility test in artificial sweat fluid in accordance with standardized test method (EN 1811).

Results interpreted in the regulatory context of the EU Nickel Directive (94/27/EC) which sets threshold for nickel release in artificial sweat of less than 0.5 µg Ni/cm2/week for products intended to come into direct and prolonged contact with the skin.

The amount of Ni released during the sweat tests of typical nickel slag is below 1.3 % or below 0.018 µg Ni/cm2/week.

This standard method (EN 1811) provides anin-vitrochemical test that correlates as far as possible with the variable human biological reactions that occur when metallic articles containing nickel are in direct and prolonged contact with the skin and pierced parts of the body. The standard provides a measure of the amount of nickel release from an article immersed for one week in artificial sweat.

Clinical patch-testing of a small selection of nickel-containing alloys and coatings on nickel-sensitized persons indicates that high and low results achieved with the present analytical method correspond closely with patch test reactivity.

For copper the dermal absorption of dry copper materials (0.03%) used in the copper VRA is carried forward to the risk characterisation.


It can be concluded that the results obtained by in-vitro bio-accessibility test in artificial sweat provide a reliable measure of the nickel release from nickel slag via dermal contact and thus can be used to support the conclusions on hazard classification.

Inhalation bio-accessability

The inhalation toxicity has relevance to occupational exposures. Relevant occupational exposures to Cd, and As are obtained from biological monitoring and these include inhalation exposures.

For copper and nickel, consistent with the copper risk assessment, in absence of relevant inhalation absorption data, the inhalation absorption will be calculated using the Multiple Path Model of Particle Deposition (MPPD). 

Based on the particle size distribution data, the MPPD model (v1.0) (Asgharian & Freijer, 1999) is then used to predict fractional deposition behaviour in the human respiratory tract for workers. For these calculations, the following model assumptions were used in assessing conditions reflective of workplace conditions:

MPPD model parameters using the Respicon particle size data


Airway morphometry

Human Yeh Schum symmetric model

particle density

1 g/cm³

particle diameter

MMAD = 4 µm (respirable)

10 µm (tracheobronchial)

50 µm (extrathoracic, nominal)

inhalability adjustment




exposure conditions


aerosol concentration

1000 µg/m³

breathing mode

oronasal normal augmenter

shift breathing volume

10 m³/8 h*

breathing frequency

18 breaths/min

tidal volume

1150 ml

*: occup. breathing volume defined by ICRP as 9.6 m³/8-hour shift, composed of 7h light exercise, plus 1 h heavy exercise

From the predicted fractional deposition, inhalation absorption factors were calculated based on the following basic assumptions: copper deposited in the alveolar region was assumed to be 100% absorbed (conservative default). Copper and nickel deposited in the upper respiratory tracts (ET and TB fractions) was assumed to be translocated to the gut. Here it is assumed to be subject to intake-dependent absorption along with dietary copper.