Directive 67/548 on classification, packaging  and labelling of dangerous substances –   
 31st ATP  
 
1) Introduction:  
 
 In its 40+ year history, Directive 67/ 548/EEC laying down common provisions for the 
classification, labelling and packaging of dangerous substances has been adapted to technical progress via comitology 30 times in order to take into account scie ntific and technical 
progress to make sure a high le vel of protection of man and the environment, as well as the 
correct functioning of the intern al market is guaranteed.  
 The changes to Directive 67/548/EEC proposed in the 31
st ATP constitute another very 
important step forward in this re gard as it contains a large numb er of substances classified for 
carcinogenicity, mutagenicity or reproductive toxicity. The classifi cations of nearly 22 
existing entries have been revised to include th ese effects. In addition, 96 entries with these 
effects are included in the Annex for the firs t time along with another 110 new entries for 
substances that may cause either sensitisa tion by inhalation and skin  contact or serious 
damage to health from prolonged exposure. Th is information will allow manufacturers, 
importers and downstream users of the substan ces to apply, or recommend, risk reduction 
measures to protect workers, the general pub lic and the environment from these effects. 
 The above changes are contained in th ree annexes to the draft directive: 
Annex 1 A: Revised C&L for existing entries =>  83 entries (6 on nickels covering 12 out of 
100 substances) Annex 1 B: C&L for new entries => 385 entries (45 entries on Nickels covering 97 out of 500 
substances) Annex 1 C: Deleted entries => 4 entries  Due to their commercial importance and a sustained lobbying campaign of the nickel 
industry, the proposed classifi cation of some 110 nickel com pounds has attracted particular 
attention and this paper therefore aims in partic ular to explain the hist ory of and scientific 
rationale for the proposed classifications.    
2) Classification History and Scientific rati onale for classification  of Nickel compounds
 
 
Procedure for harmonised classification:  
 
The determination of the classification of a substance requires specialised knowledge about 
the intrinsic properties of the s ubstance. In order to provide a solid scientific basis for the 
preparation of Commission proposals for harmonised classification and labelling, DG 
Environment has set up a committee of Member State experts and industry observers, called 
the Technical Committee on Classification and Labelling (TC C&L). Meetings of this Technical Committee are organised by the Eu ropean Chemicals Bureau (ECB) at the 
Commission's Joint Research Centre (JRC) Ispra.  All conclusions the TC C&L arrives at are 
recommendations for possible inclusi on in an ATP of Directive 67/548/EEC.  
 
Category/Grouping approach:
  
The category or grouping approach  is a technique for grouping cl osely related ch emicals that 
are then considered as a group, or category, rather than indivi dual chemicals. Under this 
approach, not every chemical needs to be test fo r every effect. The overall data set allows the 
estimation of the hazard for the untested endpoints for the chemicals in the category. The structural similarities may be based on a co mmon functional group (acid, alcohol, specific 
metal ion). The grouping approach is listed in Annex XI of REACH as an alternative method 
to avoid animal testing. The OECD has also  published a detailed guidance on grouping of 
chemicals. The OECD guidance document is  based on the guidance developed by US 
Environmental Protection Agency and expe rience gained within OECD programme on 
chemicals. The category approach is widely used in Annex I (list of classified da ngerous substances) to 
Directive 67/548/EEC. Nearly 100 group entries are already include d in Annex I. Some of the 
entries are defined in quite general terms, such as “arsenic acid and its salts”. Other entries are 
equally general, but do make some exceptions to the general entry. Other entries are more 
specific, such as “Triethyltin compounds, with th e exception of those specified elsewhere in 
this Annex”.   History of Nickel compounds classification:
 
 
- The Danish EPA has reviewed five sel ected nickel compounds under the EU existing 
chemicals programme. The five substances are nickel (metal), nickel sulfate, nickel 
dichloride, nickel dinitrate and nickel  carbonate (i.e., those listed in the 30th ATP). 
- Given that a large number of  other nickel compounds are no t covered by Annex I, in 
2005 the Danish EPA considered that additional pr oposals for classification of relevant nickel 
compounds based on a category approach were required. 
- The category is defined as “nickel and nickel compounds”. “Nickel and nickel 
compounds” includes over 300 identified compounds  of very diverse chemical structure. 
- There are a number of scientific bases underlying any grouping of nickel compounds 
for estimating their biological properties. The main basis is that it is the nickel ion that is 
responsible for the effects to be  assessed. The concentration of th e ion at the site of action is 
the most important factor determining the toxi city of the compound; however this information 
is almost never known and usually di fficult to determine experimentally.  Bioavailability can 
be used as tool to establish categories. Simply defined, bioava ilability is the fraction of the 
metal ion that reaches target sites for toxi city. The bioavailability depends on various 
characteristics of the individual nickel compounds  of which solubility is  considered as being 
particularly important for the release of the nick el ion and thus the syst emic bioavailability of 
the nickel ion.  
- The division into groups acr oss the spectrum of water sol ubility follows the approach 
already widely used for nickel compounds1. The read-across2 within groups of compounds of 
                                                 
1 The NiPERA report prepared for DG V in 1996 (Occ upational exposure limits: Criteria Document for nickel 
and nickel compounds. Volume I: Summary, Conclusions and Recommendations; Volume II: Assessment of 
Occupational Exposures; Volume III: Health Assessment of  various species of Nickel. Prepared by NiPERA in 
collaboration with Eurométaux for the European Commission, Directorate General V. Pub lic health and Safety at 
Work Directorate. Batiment Jean Monnet, Plateau du Kirchberg. L-2920 Luxembourg) considers compounds under the headings of “soluble nickel”, “sulphidic nickel”, “oxidic nickel”, “metallic nickel” and “nickel 
carbonyl”. Other reviews, such as the TERA (1999) (Toxico logical review of soluble ni ckel salts. Prepared for: 
Metal Finishing Association of Southern California, Inc., US Environmental Protection Agency and Health Canada. ) base their conclusion on a common biological effect across a range of water solubilites.  
2 Read-across approach: Human health and environmental effects may be predicted from data for reference 
substances by interpolation to other substances in the group.  similar water solubility is not only justif ied, but provides the possibility of hazard 
identification that would be difficult or impo ssible for certain endpoints (cancer) or would 
involve the use of costly animal  testing and thus the unnecessary use of experimental animals. 
- There is a vast database on the human h ealth effects of nickel compounds. A search 
in Toxline gave 2538 hits for nickel and toxic ity, 5077 hits for "nicke l" and "effects" and 
about 16000 hits for "nickel" and "sensitisati on". However, the data available for any 
individual nickel compound can vary consid erably. The two compounds for which there is 
data that covers most endpoints are the two so luble compounds, nickel dichloride and nickel 
sulfate. Much of the database relating to nickel  metal is linked to sensitisation. On the other 
hand, there is virtually no data at all for most other nickel co mpounds. In particular, data on 
the organic nickel compounds is extremely limited. 
- Due to lack of data for most of the Nickel compounds a grouping approach has been 
proposed by Danish EPA. A matrix has been ela borated on the data ava ilability on selected 
nickel compounds ( <http://cms.mim.dk/NR/rdonlyres/07DB028E-134E-4796-BF6D-
97B9AD5F9E82/0/Nikkel.pdf_>) . There is a good dataset? for some of the water soluble and the 
insoluble compounds on which to base a read-a cross. Read-across for the sparingly soluble 
salts is clearly the group on which there is leas t data. On the other hand, their position in the 
middle of the solubility range with more data rich compounds or greater and less solubility 
compensate for this, at least to some extent. 
 
- In November 2005  there was a wide-ranging discussion in the TC C&L of the 
principle and detail of the proposal. Member States and Industry appeared willing to accept the concept of a group approach. However the number of end point s (acute toxicity, irritation) 
to which it can be applied was identified as an issue for further consid eration. Industry also 
signaled concern that water solubility was not  an appropriate indication of toxicity.  
 
- In March 2006  a modified and reduced proposal  from Denmark was discussed. 
There was MS consensus towards agreemen t on a reduced number of substances (e.g.., 
exclusion of metal-metal substances) and a reduced number of end points. However 
fundamental differences of opini on with the nickel industry rema ined.  The representatives of 
the Industry made clear they did not regard the proposal  as scientifically valid and also that 
they regarded the proposal as not meeting the requirements of the Directive. In the Nickel 
industry’s view the Directive? calls for speci fic substance-based information. MS did not 
regard these concerns as grounds for invali dating the modified proposal. Indeed several 
argued that the work was a clear priority and shou ld be progressed in order to be concluded as 
part of the 31
st ATP.  
The discussion concluded with Member Stat es' agreement to a written procedure for 
the final refinement of the pr oposal based on discu ssions in the meeting. No MS opposed the 
final proposal. 
 - In December 2007 , the recommendation from the MS was placed on the ECB 
website. 
 
Information submitted by Industry:
 
 
- The nickel industry was mainly repres ented in the meeting of the TC C&L by 
Eurométaux, and included ENiG (the Europ ean Nickel Group), ENIA (European Nickel 
Industry Association) and NiPERA (the US ba sed Nickel Producers Environmental Research 
Association). ENIA is the European branch of the Nickel Institute, which itself has also taken 
part in the discussions. - The Nickel industry, while agreeing to the pr inciple of read acro ss, considered this 
approach to be subject to valid ation. The Nickel industry argued that the approa ch using water 
solubility is scientifically invalid as it assumes the mechanism relies on the nickel ion alone and ignores delivery mechanisms. Since 2005 the Ni ckel Institute has sent several letters to 
the Commission claiming that the 31
st ATP is based on flawed sc ience. They also provided 
the Commission with the view of an expert  panel that supported the nickel industry's 
conclusions. However, the nickel industry has as yet not submitted any information or experimental results to substantiate its view. 
- Industry has had the opportunity to put fo rward data disproving this classification. 
One branch of Industry, Eurocolour, a CEFIC sector group, has taken advantage of this 
possibility in close collaboration with the Danish  representatives in the TC C&L. This has led 
to the deletion of a number of  pigments containing nickel compounds from the proposal, as 
the data generated by the CEFIC sector grou p showed that the application of the group 
assessment approach to some pi gments was not justif ied. Both the nickel  industry and other 
Industry groups are free at any time to carry out further testing after a classification has been 
made, if it considers that the data derived from such testing can demonstrate that the 
classification should be changed. 
 
Classification of the Ni compounds in the 31
st ATP proposal:  
 
For the purposes of this evaluation, nickel  compounds are placed in one of eight sub-
categories:   
a) nickel sulfate, nickel di chloride, nickel dinitrate and other soluble compounds with a 
water-solubility greater than 10-2 mol/L (groups of “soluble” compounds). 
 Classification : Carcinogen cat. 1, reproductive t oxicant cat.2, Mutagen cat. 3, chronic 
toxicity by inhalation, sensitisation by inha lation and skin contact , very toxic for the 
environment. 
 b) nickel carbonate, nickel dihydroxide a nd other sparingly soluble compounds with a 
water-solubility in the range 10-4 -10-2 mol/L, (group of “slightly soluble” 
compounds). 
 Classification : Carcinogen cat. 1, chronic toxic ity by inhalation, sensitisation by 
inhalation and skin contact, very  toxic for the environment. 
 
c) nickel sulphide, nickel subsulphide and other ‘insoluble’ compounds with a water 
solubility less than 10-4 mol/L (group of “insoluble” compounds) 
 Classification : Carcinogen cat. 1, chroni c toxicity by inhalation, sensitisation by skin 
contact, very toxic for the environment. 
 d) nickel oxide and mixed nickel oxides  Classification
: Carcinogen cat. 1, chroni c toxicity by inhalation, sensitisation by skin 
contact, possible of long term  effects for the environment. 
 e) metallic nickel and me tallic nickel compounds  
  Not included
. Studies on the inhalational carcinoge nicity of metallic nickel are 
currently in progre ss, and the relevance of incl uding these metal-metal compounds 
can be considered when the results of this study have been evaluated.  
f) nickel carbonyl   No change of the current classification.  g) nickel compounds specifically  excluded from the category  
 see: 
<http://cms.mim.dk/NR/rdonlyres/07DB028E-1 34E-4796-BF6D-97B9AD5F9E82/0/Nikkel.pdf_>  
 h) nickel compounds not included in the category  
 
see: 
<http://cms.mim.dk/NR/rdonlyres/07DB028E-1 34E-4796-BF6D-97B9AD5F9E82/0/Nikkel.pdf_>  
 
Rationale for each endpoint reta ined in the category approach:  
 
- Carcinogen cat. 1:  There is epidemiological evid ence for carcinogenicity of some 
soluble nickel compounds as well as of so me insoluble soluble and nickel oxides. 
Chronic animal studies have shown carcinogenicity for the p oorly water-soluble nickel 
compounds tested. The overall findings indicate  that nickel ions generated in target 
cells are critical determinants for the carcinogenic process.  
The cellular uptake of soluble and insoluble nickel compounds is different as insoluble 
nickel compounds enter the cell via phagocytosis3, while soluble nickel compounds 
enter the cell via metal ion transport sy stems or through membrane diffusion. The 
latter two processes are much less efficien t implicating that the same extracellular 
levels of soluble and insoluble nickel co mpounds lead to lower intracellular nickel 
levels for soluble nickel compounds. Soluble fo rms of nickel interact  with the cell in a 
way that maximises cytotoxicity and mini mises nickel delivery to the nucleus and 
interaction with DNA, while inso luble forms of nickel interact  with cells in a way that 
decreases the cytotoxic potential while increas ing the delivery of nickel to the nucleus . 
Thus, the mechanism for cellular uptake could differ between soluble Nickel 
compounds and insoluble ones. For the gr oup of “slightly soluble" compounds, the 
mechanism for cellular uptake is unknown and coul d be similar either to the one of the 
soluble nickel compounds or to the one of  the insoluble nickel compounds. However, 
since both groups are classified as carci nogens, the group of “slig htly soluble" should 
also be classified in a similar way. This is the logic followed for the 30th ATP in which 
the soluble and slightly soluble compounds lis ted in the ATP have been classified as 
carcinogens. Indeed, it is reasonable to as sume that all nickel compounds that can 
create nickel ions inside or outside the cell are carcinogenic to humans following exposure by inhalation. As a consequence, soluble, slightly and insoluble Nickel 
compounds as well as nickel ox ides are proposed to be clas sified as carcinogens in the 
31
st ATP.  
 - Chronic toxicity by inhalation: 
Inhalation of the inso luble nickel compounds 
(subsulphide and oxide) results in lung infl ammation and fibrosis. Inhalation of the 
soluble nickel sulphate and chloride also affects the l ungs. Chronic lung inflammation 
and lung fibrosis are serious and potentially irreversible  effects. Repeated dose 
toxicity following inhalation is an effect that leads to classification of both soluble 
(nickel sulphate) and insol uble nickel compounds (nicke l subsulphide and nickel 
oxide). The effects are seen at substantially lo wer levels with nickel sulphate than with 
                                                 
3 a cellular  process whereby the cell engulfs solid particles by cell membrane  to form an internal membrane -
bound compartment the insoluble compounds. For this effect, we are in the same situation as for 
carcinogenicity, therefore, a logic similar to carcinogenicity is followed. In other 
words, soluble, slightly and insoluble Ni ckel compounds as well as nickel oxides are 
proposed to be classified as toxic by inha lation following repeated exposure in the 31st 
ATP. 
 - Reproductive toxicity cat.2: 
There are no relevant studies in humans. Only animal 
data on two soluble nickel com pounds are available. In the 30th ATP, based on the 
consistent evidence of developmental toxic ity (stillbirth, post-implantation/perinatal 
lethality) in rats at dose levels not causing  maternal toxicity, some soluble nickel 
compounds have been classified for devel opmental toxicity in Category 2. As the 
available information is limited to solubl e nickel compounds, it is proposed in the 31st 
ATP to classify only the group of soluble nickel compounds as re productive toxicant. 
 
- Mutagen cat. 3: There is considerable evidence of the in vitro genotoxicity of nickel 
compounds. Positive effects are generally seen in studies of chromosomal effects, cell 
transformation tests and tests for DNA damage and repair. In terpretation of the results 
of in vivo studies is more complicated. Most of th e studies have been  carried out with 
the three soluble nickel compounds listed in the 30th ATP. There is little in vivo data 
on other soluble compounds, and data on sparingly soluble nickel compounds and 
insoluble compounds is also very limited. In the 30th ATP, based on the evidence of in 
vivo genotoxicity in somatic cells, after sy stemic exposure, some soluble nickel 
compounds have been classified as muta gens cat.3. As the available information 
demonstrates mutagenicity only for solubl e nickel compounds, it is proposed in the 
31st ATP to classify only the group of so luble nickel compounds as mutagens. 
 - Sensitisation by skin contact: 
Nickel is well known as a skin  sensitizer, and is one of 
the most frequent skin sensit izers in man. Nickel skin sens itisation has been evaluated 
almost entirely on the basis of human studies with very water-soluble nickel 
compounds, and studies on release rates with nickel metal. There is limited data on 
skin sensitisation or nickel release from compounds with lower water-solubility. There 
is however agreement that this  effect also occurs with co mpounds with very low water 
solubility such as nickel oxide. In a similar way as for carcinogenicity and 
reproductive toxicity, soluble,  slightly and insoluble Ni ckel compounds as well as 
nickel oxides are proposed to be classified  as sensitizers by skin contact in the 31st 
ATP.  - Sensitisation by inhalation:
 Respiratory sensitisation is recognised as an effect with 
the soluble and sparingly wa ter-soluble nickel compounds . The TC C&L has agreed 
that (insoluble) nickel sul phide, nickel subsulphide or metallic nickel should not be 
classified for this end-point, although ther e is limited evidence fr om people exposed to 
metallic nickel, and some suggestion that th is effect can also be seen with other 
compounds, as shown by the anecdotal eviden ce that nickel matte also shows this 
effect. The TC C&L agreed to read-across this classification for all the soluble and 
sparingly soluble nickel compounds. It is po ssible that further studies may show that 
this effect occurs across a wider spectru m of water-solubility than is currently 
recognised. 
 - Toxicity for the environment: 
Metal compounds may be toxic in the aquatic 
environment depending on the t oxicity of the metal ion and the rate and extent to which metal compounds can produce soluble ava ilable ionic species in aqueous media . The 
availability of a metal substance means the extent to which the metal ion portion of a 
metal compound can disaggregate from the rest of the compound. To determine the 
classification of a nickel substance, its capac ity to solubilise in water and liberate its 
nickel ion is compared with the refere nce toxic value for the nickel ion. The 
appropriate L(E)C50 value for the evaluation of Nick el compounds is 0.068 mg/L. On 
the basis of this analysis, all the nickel  compounds with the exception of the nickel 
oxides and metallic nickel should be classifi ed as very toxic for aquatic organisms. 
 
Rationale for each endpoint excl uded from the category approach:  
 
- Irritation/corrosivity: The available data that indicates  that soluble nickel compounds 
can cause skin irritation is derived from humans, whilst th e available animal data does 
not support classification for this effect. Unlike nickel sulphate, nickel dinitrate 
showed severe eye irritation. It was suggest ed that the greater severity of this 
compound was due to its oxidising properties. Th is suggests that this  local property is 
more dependent on the counterion4 than other systemic effect s. This endpoint not only 
depends on the water solubility of the nick el compound, but also on the nature of the 
anion5, and that the read-across for nickel salts  must include an ev aluation of not just 
nickel ion availability, but also the irritancy of the an ions. Since the water soluble 
nickel salts are not irritati ng at concentrations below 20%  it will be impossible to 
consider a direct extrapol ation of irritancy data without some knowledge of the 
bioavailable fraction of nickel released  by a particular compound and the potential 
irritancy of the molecule to which it is bound.  - Acute toxicity:
 Most of the available data for both soluble and slightly soluble 
compounds is in the range of or al toxicity are covered by the criteria for "harmful". 
The counter-ions may lead to  increased toxicity, and it  is likely that there are 
additional soluble nickel compounds that, like nickel chloride, show a toxicity in the 
range of oral toxicity covere d by the criteria for "toxic" or  "very toxic". However, the 
uncertainties reflected in the discussion led to deleting acute toxicity from the 
proposals. 
  
                                                
 
4 The ion that accompanies an ionic species in order to maintain electric neutrality 
5 A negatively charged ion, which has more electrons  in its electron shells  than it has protons  in its nuclei