Nickel compounds – a category approach for metals in EU legislation

Jim Hart, Consultant

prepared on behalf of the Danish Environmental Protection Agency

January 2008

PREFACE:

This report was commissioned by the Danish EPA, and describes the use of a categories approach to the classification and labelling of a group of nickel compounds.

The Danish EPA is the Rapporteur for the risk assessment of nickel and four nickel compounds (nickel sulphate, nickel dichloride, nickel dinitrate and nickel carbonate) under the EU Existing Chemicals Regulation (EEC) 793/93. Part of this work included data collection and evaluation of a number of other nickel compounds such as the nickel oxides and sulphides.

As a result of this work, classification and labelling proposals for the five nickel compounds evaluated under the EU Existing Chemicals Regulation have been prepared by the Danish EPA, and, after discussion in the EU Technical Committee for Classification and Labelling, new and revised entries for the five compounds have been included in Annex I to Directive 67/548/EEC (List of Dangerous Substances), which was adopted by a Technical Progress Committee in February 2007 as part of the 30th Adaptation to Technical Progress of the Directive (ECB, 2007a).

In addition, proposals for updating the existing entries for some of the other nickel compounds in Annex I to Directive 67/548/EEC (nickel hydroxide, nickel oxides and nickel sulphides) were also prepared by the Danish EPA, and agreed by the EU Technical Committee for Classification and Labelling for inclusion in the 31st Adaptation to Technical Progress of the Directive.

Based on the agreed classification for these individual substances, the Danish EPA then prepared a classification proposal covering more than 100 nickel compounds. This proposal reflected the group approach already used for a number of metals in Annex I, but refined the approach by proposing classifications based on a number of different subgroups. After discussion and further refinement, this proposal was also agreed by the EU Technical Committee for Classification and Labelling in 2006 for inclusion in the 31st Adaptation to Technical Progress of the Directive (ECB, 2007b).

This report describes these proposals and the discussions in the EU Technical Committee. The experience of this discussion, and the relevance of the approach used here for a Category approach to metals has formed part of the development of guidance for the use of a Category approach in both the EU and the OECD.

This report is an updated version of Example F in Chapter 3.2 “Guidance on the Development and Use of Chemical Categories in the HPV Chemicals Programme”, in the OECD “Manual For Investigation of HPV Chemicals”. This guidance document was prepared by the OECD Secretariat based on the agreements reached in the OECD Existing Chemicals Programme up to May 2005.

The experience in the development of these proposals is also reflected in the EU Technical Guidance Document to Industry on the Information Requirements for REACH (RIP 3.3 project).

This report reflects the status of the discussion of the classification and labelling of these nickel compounds at the time of publication in December 2007. The report reflects the proposals for the Annexes to the 31st ATP as shown on the ECB website.

The subheadings used in this document reflect the stepwise procedure described in the OECD 2005 guidance, but do not necessarily reflect the stepwise approach proposed in the latest (2007) OECD or guidance or the draft RIP 3.3 guidance.

2

INDEX

PREFACE:...... 2

INTRODUCTION ...... 4

IDENTIFICATION OF STRUCTURE-BASED CATEGORY AND ITS MEMBERS:...... 6

GATHER PUBLISHED AND UNPUBLISHED DATA FOR EACH CATEGORY MEMBER...... 8

EVALUATE DATA FOR ACCURACY...... 8

CONSTRUCT A MATRIX OF DATA AVAILABILITY...... 8

PERFORM AN INTERNAL ASSESSMENT OF THE CATEGORY...... 10

THE NEED FOR FURTHER TESTING...... 17

FILL DATA GAPS BY READ-ACROSS, EXTRAPOLATION, INTERPOLATION ETC...... 17

REFINEMENT OF THE CATEGORY...... 18

REFINEMENT OF THE READ-ACROSS...... 23

ADVICE WHEN READ-ACROSS IS NOT NECESSARILY APPLICABLE...... 29

CONCLUSIONS...... 31

REFERENCES ...... 32

TABLE 1: INVENTORY OF NICKEL COMPOUNDS...... 36 TABLE 1.1: Nickel and Nickel Compounds in Einecs...... 36 TABLE 1.2: Nickel compounds included in Elincs...... 48 TABLE 1.3: Additional Nickel compounds, and complex substances containing nickel included in TSCA (through 08/2000) but not included in Einecs...... 49 TABLE 1.4: Additional Nickel compounds listed in ECICS (European Customs Inventory of chemical substances), but not included in Einecs or the TSCA Inventory...... 51 TABLE 1.5: Additional Nickel compounds in Annex I to Directive 67/548/EEC but not in Einecs or TSCA...... 51 TABLE 1.6: Additional nickel compound found in the course of compiling the inventory of nickel compounds...... 51 TABLE 1.7: Additional nickel hydroxycarbonate compounds not included in the lists above...... 52 TABLE 1.8: Nickel containing minerals (from IARC, 1990 and NiPERA, 1996)...... 52

3 INTRODUCTION

1. A category approach for compounds of concern is widely used in Annex I to Directive 67/548/EEC. Annex I is a list of dangerous substances with a harmonised classification and labelling agreed by the Members States according to the classification criteria adopted by formal EU legislative procedures. A list of the nearly 100 group entries already included in Annex I is given in the RIP 3.3. scoping study in the TAPIR final report Appendix 9. These entries are called “group” entries, and the term “category” is not used in the EU legislation.

2. Many of these group entries date from very early versions of Annex I and reflect the general concern for metal compounds, irrespective of the precise chemical composition of the actual compound. The concern for the hazard of these metal compounds is also reflected in the often very low concentration limits for certain metals to be considered as “Toxic” or “Harmful” included in the Paints and Varnishes Directive (EEC, 1977). These specific concentration limits were carried over into Annex I of Directive 67/548/EEC in the 12th ATP (EEC, 1991) with the introduction of the Preparations Directive in 1988 (EEC, 1988). Many of these limits still apply today.

3. 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. An example is “antimony compounds, with the exception of the tetroxide (Sb2O4), pentoxide (Sb2O5), trisulfide (Sb2S3), pentasulfide (Sb2S5) and those specified elsewhere in this Annex”. The wording indicates that whilst the entry is considered generally applicable, certain compounds (in this case the oxides and sulfides) are excluded. Other entries are more specific. “Triethyltin compounds, with the exception of those specified elsewhere in this Annex” is a narrowly defined group of compounds. Finally, the elemental metal may be included as a separate entry.

4. Prior to the establishment of Einecs and other inventories of chemicals on the market, it was often impossible to develop comprehensive lists of the compounds covered by these group entries. In some cases (e.g. the proposals for a group entry for inorganic nickel compounds proposed by Norway and for chrom(VI) compounds proposed by Germany) the proposals were accompanied by a list of the compounds that were intended to be covered by the group entry. Now, increasing ease of carrying out computerised searches has made it possible to list the specific individual compounds included in these group entries. One source of this information is the N-Class database developed by Sweden and accessed from the ECB Classification and Labelling home page. This shows that in some cases the group entry includes a very heterogeneous group of compounds. As an example, N-Class identifies 464 individual compounds covered by the group entry 082- 001-00-6 for “lead compounds with the exception of those specified elsewhere in this Annex”. This includes the twelve lead compounds covered by the Voluntary Risk Assessment carried out by Industry in collaboration with the Netherlands. In addition to a large number of other lead(II) salts, the group also includes a range of organic lead compounds (not including the lead alkyls which have separate entries in the Annex), spinels, slags, wastes and other residues.

5. The Danish EPA has reviewed five selected HPV nickel compounds under the EU existing chemicals programme. The five substances are nickel (metal), nickel sulfate, nickel dichloride, nickel dinitrate and nickel carbonate. This has led to the classification of these five substances in Annex I based on the conclusions of the hazard assessment. Apart from metallic nickel, the four nickel compounds considered are all classified for hazards that are regarded with particular concern in the EU. These classifications include concern for carcinogenicity (Category 1), mutagenicity (Category 3) and Reproductive toxicity (Category 2) according to the EU criteria1. These revised classifications are included in the 30th Adaptation to Technical

1 References to the EU classification criteria refer in all cases to Annex VI to Directive 67/548/EEC, and not to the implementation of GHS criteria in EU legislation.

4 Progress of Directive 67/548/EEC2. This review has also led to the revision of the classification of the other nickel compounds already included in Annex I. Revised classifications for the nickel sulfides and nickel oxides have been agreed for inclusion in the 31st ATP currently in preparation (ECB, 2007b). No change in the existing classification for nickel carbonyl was considered necessary.

6. Given that a large number of other nickel compounds that are not covered by these entries in Annex I may also be on the market, the Danish EPA considered that additional proposals for classification of relevant nickel compounds based on a category approach was required (Danish EPA, 2005a). If only some nickel compounds are included in Annex I as Category 1 carcinogens this might lead to market distortions, since if nickel compounds with similar properties are not included in Annex I, they could be perceived to be safer than those with a harmonised classification, and lead to unjustified substitution of nickel compounds currently in use by others not included in Annex I. This would not be beneficial for either the regulatory community or the industries concerned.

7. Two earlier classification proposals for group entries for nickel compounds have been made by Norway and Sweden but were not discussed in the relevant EU Technical Committees. A Norwegian proposal (W031) (ECB1/46/95 – Add. 12.) for a group classification of inorganic nickel compounds in Einecs included a list of approximately 125 inorganic nickel compounds in Einecs. More recently, Sweden has made a proposal for the environmental classification of metals which includes an entry for “Inorganic compounds of nickel” (ECBI/89/04). The Danish category approach to classification was presented as a refinement of these earlier, less specific, category approaches to metals classification, in a deliberate attempt to avoid the heterogeneity seen in some of the group entries described above.

8. The Danish EPA classification proposal (2005a) listed the nickel compounds that would potentially be included in the category approach individually, and includes a rationale for the classification proposed for each entry. The proposal also included additional background information, including a modified version of the OECD Example F and information on the current provisional classification of nickel compounds. The revised Danish EPA proposal (2006a) includes a revised rationale for the classification proposed for each entry.

9. In developing these classification proposals, MSDS from a number of different suppliers of nickel compounds were found on the Internet. The approach taken in this proposal is consistent with the approach taken by Industry in compiling Material Safety Data Sheets, in that, for a number of nickel compounds, most MSDS identify hazards on the basis of read-across rather than on the basis of actual data.

10. The five individual HPV nickel compounds reviewed by the Danish EPA were discussed by the OECD at SIAM 243. The health part of the SIAP for the five specific nickel compounds was discussed and revised at the meeting, and no comments to these SIAPs have been received by the OECD by the deadline for final endorsement. The description below is based on the work of the Danish EPA under the EU existing chemicals programmes and, in particular, the discussions held in the EU Classification and Labelling Technical Committees. This work has led to the adoption of proposals for a legally binding harmonised classification and labelling of a large number of nickel compounds using a category approach. These proposals have been agreed by the TC C&L and are being considered by the Commission for inclusion in the 31st ATP of the EU Classification and Labelling Directive 67/548/EEC currently under preparation. Some modifications to a number of the individual entries have been suggested by the Commission and the resulting proposals have been posted on the ECB website (ECB, 2007b).

2 The 30th ATP received a favourable opinion at a meeting of the Committee on the Adaptation to Technical Progress of the Directives for the Elimination of Technical Barriers to Trade with Dangerous Substances and Preparations held on 16 February 2007. The Directive has not yet been adopted by the Commission. The relevant classification proposals are available on the ECB website (ECB, 2007a). 3 One HPV pigment, CI Pigment Yellow 53 has been assessed by the OECD previously. This compound is further discussed in paragraph 64 below.

5 IDENTIFICATION OF STRUCTURE-BASED CATEGORY AND ITS MEMBERS:

11. The category is defined as “nickel and nickel compounds”. This description is a category already widely used in EU legislation. Table 1 shows a list of the nickel compounds identified. “Nickel and nickel compounds” includes over 300 compounds of very diverse chemical structure.

12. The list was primarily based on compounds in the European Inventory of Existing commercial Chemical Substances, Einecs (EU Commission, 1990). A number of different searches were made. Whilst the majority of the substances shown in the final list were found as the result of a single search, different searches identified a number of compounds not included in other searches (Table 1.1). There are also three nickel compounds included in Elincs with agreed classifications in Annex I to Directive 67/548/EEC up to the 30th ATP (Table 1.2). These lists were supplemented by a search in TSCA (up to and including August, 2000) (Table 1.3) which identified an additional forty compounds on the US market which are not reported to be on the EU market. Additional compounds were identified in ECICS (Table 1.4) as well as in the Swedish N- Class database and other data sources (Table 1.5) and in the course of the discussions (Table 1.6). In discussions on the identity of the HPV “nickel carbonate”, a number of nickel hydroxycarbonate compounds were identified (Table 1.7). Finally, a number of nickel ores have been identified from the IARC monograph (Table 1.8).

13. Whilst Table 1 probably includes most of the nickel compounds actually on the market, this cannot be considered a definitive list4.

14. Numerically, organic nickel compounds outnumber inorganic nickel compounds. The category also includes a number of complex nickel-containing compounds, many of which are waste products.

15. A second type of grouping of nickel compounds is also used administratively. This divides nickel compounds into five groups: Metallic nickel, oxidic nickel, sulfidic nickel, soluble nickel and nickel carbonyl. These groups reflect the main nickel compounds seen during nickel refinery production, rather than the wider range of nickel chemicals on, or potentially on, the market. These different categories have been used in some countries as the basis for different Occupational Limit Values (OELs) based on differences in the types and potency of different mammalian toxicological effects.

16. The wide diversity of chemical types suggests that whilst “nickel and nickel compounds” is useful as a category in identifying compounds that contain nickel and may therefore potentially be a source of nickel release, it requires further refinement in order to provide a basis for a read-across approach that can identify hazards that may be common to all members of the (sub-)category. This refinement step, identifying firstly appropriate sub-categories and secondly nickel compounds that can reasonably be considered as members of these different sub-categories is an essential part of this category approach.

17. There are a number of assumptions underlying any grouping of nickel compounds for estimating their biological properties. The main assumption is that it is the nickel ion that is responsible for the effects to be assessed. This is considered to be a reasonable assumption for the majority of the inorganic anions of nickel compounds and for some organic anions. This implies that in the case of inorganic metal salts, the hazard assessment is based on the known toxicity of the hydrated cation.

18. The primary basis of any grouping would therefore be the water solubility of the nickel salt. Two reports prepared for the Danish EPA have collected and assessed the available data for water solubility of inorganic nickel compounds (Carlsen, 2001a) and organic compounds (Carlsen, 2001b).

19. In the table below, a grouping of the inorganic nickel ligands with Group 13, 14, 15, 16 and 17 ligands is suggested. The term ‘insoluble’ means that the solubility of the species is less than 10-4 mol/L,

4 This is confirmed by the fact that the ECB have carried out further searches since the conclusion of the discussions and have found additional nickel-containing compounds. These have not been included in this document.

6 ‘slightly soluble’ covers the solubility range 10-4 - 10-2 mol/L, ‘soluble’ the range 10-2 - 5·10-1 mol/L and ‘very soluble’ refers to solubility above 5·10-1 mol/L.

20. It should be noted that the group of “insoluble” compounds, with solubility < 10-4 mol/L covers a range of solubility. Nickel oxides and mixed metal oxides are in general characterised as insoluble. Nickel metal and nickel metal compounds are also characterised by their very limited solubility. Nickel sulfide and subsulfide are normally also considered as insoluble. However, as the following discussion shows, substances conventionally thought of as “insoluble” by chemists or toxicologists may still be sufficiently soluble to produce effects on the aquatic environment and human health that can lead to hazard classification.

Grouping of nickel species based on inorganic ligands in water (from Carlsen, 2001a).

Group 13 Group 14 Group 15 Group 16 Group 17 Misc.

Insoluble NiXB NiXSi NiXPY NiXSY Ni2Fe(CN)6

NiXAs NiXSe

NiXSbY NiXTe

Ni2P2O7

Ni3(AsO3)2

Ni3(AsO4)2

Ni(AsO3)2 a Slightly Ni(CO)4 Ni3(PO4)2 NiSO3 Ni(IO3)2 Ni2Fe(CN)5NO soluble Ni(CN)2 Ni[NiP2O7] NiSeO3

NiCO3

Ni(HCO3)2

Soluble NiK2(SO4)2 NiF2

Very NiB6O10 Ni(SCN)2 Ni(NO3)2 NiSO4 NiCl2 soluble a Ni(BF4)2 NiSiF6 Ni(H2PO2)2 Ni(SO3NH2)2 Ni(ClO3)2

NiSeO4 Ni(ClO4)2

NiBr2

Ni(BrO3)2

NiI2

21. No comparable grouping of organic ligands has yet been carried out (Carlsen, 2001b). In contrast to the inorganic nickel compounds it is not obvious how to group the organically based species based on solubility alone. Aqueous solubility is not unexpectedly seen to decrease with increasing molecular weight and increasing carbon content of the ligand. On the other hand, the introduction of hydrophilic and/or polar - - functional groups, such as OH, C=O, COO , NH, SH and SO3 cause increased solubility. Further it should be emphasized that the solubility of the complexes cannot immediately be related to the solubility of the single ligands. Hence, it seems more appropriate to group organically based nickel complexes based on the stability of the complexes.

22. The organic nickel compounds have been reviewed, and a number of organic nickel compounds have been included in the group of compounds for which classification has been agreed. These compounds are considered to a) have a solubility similar to comparable inorganic compounds and b) to be compounds where the nickel is not significantly complexed to the organic part of the molecule to invalidate comparison with the data obtained from the inorganic reference compounds.

7 GATHER PUBLISHED AND UNPUBLISHED DATA FOR EACH CATEGORY MEMBER.

23. There is a vast database on the human health effects of nickel compounds. A search in Toxline gave 2538 hits for nickel and toxicity, 5077 hits for nickel and effects and about 16000 hits for nickel and sensitisation. However, the data available for any individual nickel compounds can vary considerably. The two compounds for which there is data that covers most endpoints are the two soluble 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 nickel compounds. In particular, data on the organic nickel compounds is extremely limited.

EVALUATE DATA FOR ACCURACY.

24. Much of these human health data have been reviewed in good quality reviews including UK HSE (1987), IARC (1990), Environment Canada and Health Canada, (1994), IPCS (1991, 1996), US ATSDR (1997) and a Nordic Expert Group (Aitio, 1995). NiPERA in collaboration with Eurométaux have also produced a criteria document for nickel and nickel compounds for the European Commission (NiPERA 1996). Toxicology Excellence for Risk Assessment (TERA) has prepared a toxicological review of soluble nickel salts for Metal Finishing Association of Southern California Inc., US-EPA and Health Canada (TERA 1999).

25. In depth reviews of health effects of metallic nickel, nickel sulfate, nickel chloride, nickel nitrate and nickel (hydroxy)carbonate and a background report in support of the individual have been prepared by the Danish EPA (Danish EPA 2005b, 2005c, 2005d, 2005e, 2005f and 2006d). Reports covering the environmental aspects of these five compounds are currently being finalised.

CONSTRUCT A MATRIX OF DATA AVAILABILITY.

26. A matrix of available data included in the draft risk assessment reports prepared under the OECD SIDS and the EU existing chemicals programmes is shown below for nickel metal, nickel sulfate, nickel chloride, nickel nitrate and nickel carbonate5.

27. Data is also available for the other nickel compounds included in Annex I. One of these is another HPV substance, nickel oxide and another, nickel sulfide, is an LPVC substance. Data has been included from the reviews quoted above, in particular from the Background report is support of the individual risk assessment reports (Danish EPA, 2006d). This data is summarised in the matrix of available data shown below.

5 The compound reported as a HPV chemical to IUCLID was nickel carbonate (CAS No. 3333-67-3). In the course of subsequent discussions with the Industry, it became clear that the marketed product was in fact a nickel hydroxycarbonate and not nickel carbonate. For administrative purposes, the commercial product is considered to be the 1:2 hydroxycarbonate, [carbonato(2-)] tetrahydroxytrinickel, (CAS No. 12607-70-4, EC No. 222-068-2) which is also included in the TSCA Inventory. The evaluation also covers the 2:3 basic carbonate (CAS No. 12122-15-5). As it is not always clear from the study reports which precise carbonate has been tested, the results are shown as “nickel carbonate”.

8

MATRIX OF DATA AVAILABILITY ON SELECTED NICKEL COMPOUNDS. Nickel Environ- Ecological effects* Human Health effects compound mental fate

Fish acute acute Fish Daphnid acute Daphnid chronic Acute Irritation Skin Sensitisation Repeated dose Mutagenicity Carcino- genicity Reproductive Toxicity nickel dissolution - - - √ √ √ √ (√) (√) - metal** protocol nickel oxide transforma- √ √ - √ - - √ √ √ - tion test nickel screening - √ - √ - - √ √ √ - sulfide / test subsulfide nickel screening - √ - √ - - - (√) - - dihydroxide test “nickel dissolution - - - √ (√) - (-) (√) - - carbonate” protocol. nickel soluble √ √ √ √ √ √ √ √ √ √ sulfate nickel soluble √ √ √ √ (√) √ √ √ √ √ dichloride nickel soluble √ √ √ √ √ (√) - √ - - dinitrate nickel soluble - √ - √ ------carbonyl Key: “√” denotes that sufficient data are available for the substance/endpoint for hazard identification. “(√)” indicates that there is some data, but this is not sufficient to draw a conclusion directly. In some cases additional data may be needed. “(-)” indicates only very limited data from which no conclusions can be drawn. “-” denotes no data available. In all cases except for “√” and for the carcinogenicity of nickel metal, read across has been performed to varying extents as described in more detail below. Shaded areas show six possible subcategories (the five subcategories shown in paragraph 15 and a sixth sub-category which includes sparingly soluble nickel hydroxide and carbonate). *: data concerning other endpoints and species are available and are being considered. **: nickel metal powder (INCO123) and nickel granules have been tested. Only the powder has been tested in the 28 d dissolution test.

28. The nickel compounds for which most data is available are the three soluble nickel salts, nickel oxides and nickel sulfides. Less information is available for nickel metal, the semi-soluble compounds nickel carbonate and nickel hydroxide, and for nickel carbonyl. Whilst the soluble and semi-soluble salts tested are all in the Ni(II) oxidation state, some of the sulfides and oxides may be in mixed formal oxidation states of nickel and/or complex coordination in the solid form (IARC, 1990). Nickel metal and nickel carbonyl are both in the Ni(0) oxidation state.

29. The nickel compounds included in the matrix of available data are mainly those directly associated with the (refinery) production of metallic nickel, and nickel alloys. There is a IUCLID file available of one of the intermediate products (nickel matte) but this contains no data. The other main intermediate product, ferro- nickel, is not included in Einecs, as at the time Einecs was compiled it was agreed that this was an alloy.

30. The data on “downstream” nickel compounds not directly associated with the production processes, and in particular, the organic nickel compounds, is very limited. The EU provisional classification supplied by the producer/importer in the IUCLID file is available for a number of other nickel compounds, including a number of organic compounds and complex waste products such as slimes and sludges. However, there is no actual data in these IUCLID submissions, and it is not clear whether these provisional classifications have been based on experimental evidence or on assumptions about the properties of the compounds (i.e. application of a category approach). In some cases Safety Data Sheets are available, and there is a very limited amount of original information available from these. In most cases, the hazards have been identified using read-across from the hazards considered to be relevant for nickel compounds.

9 PERFORM AN INTERNAL ASSESSMENT OF THE CATEGORY.

31. The following paragraphs evaluate the classifications for the compounds listed in the matrix of data availability as assessed against the EU classification criteria and included either the 28th. ATP (EC, 2001b) or the 30th ATP6, or agreed by the EU TC NES for possible inclusion in 31st. ATP (currently in preparation).

The corresponding hazard statements based on the GHS classification criteria are shown in footnotes. The conversion between EU and GHS hazard statements is based on the Table of Equivalence included in a report for the EU Commission on GHS (Milieu, 2005b). The hazards of the five HPV nickel compounds have also been reviewed directly against the GHS criteria as part of the preparation for the workshop on experience in applying the GHS criteria for classification and labelling using SIDS documents (Danish EPA, 2007). It should be noted that whilst the EU classification proposals have been reviewed and agreed by an EU Technical Committee, this is not the case for the GHS classifications which are those proposed by the Danish EPA.

32. In applying the aquatic hazard classification rules for nickel compounds, the evaluation is based on the values of an EC50 of 0.068 mg/L for the acute aquatic toxicity of the nickel ion and an EC10 of 2.4 μg/L for the chronic toxicity. For the soluble compounds, no Transformation/Dissolution (T/D) protocol is required. For less soluble compounds, the use of the T/D protocol, i.e. solubility dependency of pH at environmentally realistic pHs has been used.

The soluble nickel compounds, including nickel carbonyl, are classified as N; R50-537.

Nickel carbonate and nickel hydroxide were both tested in a T/D protocol screening test, and classified as N; R50-53 in the 28th. ATP (EC, 2001b).

Nickel sulfide and nickel subsulfide were both tested in a T/D protocol screening test. Nickel sulfide was classified as N; R50-53 and nickel subsulfide as N; R51-538 in the 28th ATP (EC, 2001b). Following agreement on the values for the acute and chronic toxicity, it was agreed that both should now be classified as N; R50-53.

The nickel oxides are substantially less soluble and are classified with R539. Although this classification was adopted in the 28th ATP (EC, 2001b), NiPERA (2006) pointed out that the average concentration for nickel oxide from the T/D protocol was 2 μg/L and, as such, below the figure for chronic toxicity. Hence, nickel oxide and analogous substances should not be classified as causing long-term adverse effects to the aquatic environment. The Danish EPA (2006b) noted that for this escape clause to be applied, data from a 28-day dissolution protocol was needed, and this data was not available. At the TC C&L Environment meeting in April 2006, other Member States supported this view and the default classification with R53 remained unchanged.

It has been agreed that metallic nickel does not fulfil the criteria for classification for hazards to the aquatic environment. However, there is agreement that fine metal powders prepared by the Mond process do fulfil the criteria for classification as R52-5310. The fine metal powders have been defined on the basis of particle size

6 Whilst adopted by the Technical Committee, this has not yet been adopted by the Commission or published in the Official Journal. 7 Classification with N; R50-53 corresponds to the GHS Chronic Category 1. This classification also corresponds to the GHS Acute Category 1, this is not used as an additional classification in the EU classification system. 8 Classification with N; R51-53 corresponds to the GHS Chronic Category 2. This classification also corresponds to the GHS Acute Category 2, this is classification is not included in the EU classification system. 9 Classification with R53 corresponds to the GHS Chronic Category 4. 10 Classification with R52-53 corresponds to the GHS Chronic Category 3. This classification also corresponds to the GHS Acute Category 3, this is classification is not included in the EU classification system.

10 diameter < 1 mm in the Annex I entry in the 31st ATP currently in preparation (ECB, 2007b). In the Danish GHS proposal, these powders are defined on the basis of an average specific surface area ≥ 0.1 m2/g.

33. There is data for acute oral toxicity for all the reference compounds with exception of nickel carbonyl. The acute oral toxicity decreases with decreasing water solubility and is of concern for soluble and slightly soluble compounds, whilst less soluble compounds (e.g. sulfides, oxides and the metal) do not give rise to concern for this effect.

Whilst most of the figures for the soluble and sparingly soluble compounds lie in the range of the criteria for 11 12 Xn; R22 (GHS Category 4), nickel dichloride has been classified separately as T; R25 as the LD50 is < 200 mg/kg. Nickel sulfate has been classified as Xn; R22 according to the EU criteria, whilst the LD50 of < 300 mg/kg leads to a more stringent classification in the GHS Category 3 together with nickel dichloride.

However, there is no direct correlation between the acute toxicity values and water solubility. The approximate value of the LD50 for nickel dinitrate, one of the most soluble nickel compounds, is closer to the values for the slightly soluble carbonate and hydroxide than the other, more soluble compounds.

34. There is data for acute inhalational toxicity for nickel carbonyl, and this is classified as T+; R2613.

This appears to be no acute inhalational toxicity (LC50) data available for any of the other nickel compounds considered here. However, there is evidence from sub-acute inhalational studies as well as from toxicokinetic considerations that indicates that this route of administration is of concern for those nickel compounds where there is concern for acute toxicity by the oral route. Nickel hydroxide is already classified for acute toxicity in the EU by both oral and inhalation routes of administration.

With the exception of nickel carbonyl, the EU TC C&L agreed that the concern for oral and inhalational toxicity should be considered as comparable14. In applying the GHS criteria, classification is also proposed in the same toxicity category for both the oral and inhalation routes15.

35. There is no data for acute dermal toxicity for any of the compounds reviewed. There is however no grounds for concern for this effect, due to the low systemic uptake of these compounds by this route.

36. Whilst animal studies with nickel sulfate show no significant irritating effect on the skin, human data shows that solutions of nickel sulfate at concentrations > 20% are irritating. A similar effect in humans is also seen with nickel dichloride (Environment Canada and Health Canada, 1994). An Annex V animal study with nickel nitrate shows irritation which fulfils the criteria for classification as Xi; R3816. There is no human or animal data for nickel carbonate on irritation, but information on the pH of its solutions is available that shows that the pH is not so extreme that this would in itself lead to classification for irritation.

11 Classification with Xn; R22 corresponds approximately to the GHS Acute toxicity Cat. 4 (oral). There is however a difference in the criteria where the EU cut-off for the LD50 is 200 mg/kg, and the GHS cut-off is 300 mg/kg. 12 Classification with T; R25 corresponds approximately to the GHS Acute toxicity Cat. 3 (oral). See comment above concerning the difference in cut-off. 13 The range of classification with T+; R26 corresponds to either the GHS Acute toxicity Cat. 1 or 2 (inhalation), depending on the actual data. Based on the data for nickel carbonyl toxicity, the appropriate GHS classification is Acute toxicity Category 1. 14 Classification with T; R25 is accompanied by classification with T; R23; classification with Xn; R22 with Xn; R20.. 15 It should be noted that Section 3.1.3.6 Classification of mixtures based on ingredients of the mixture (Additivity formula) of the GHS criteria explicitly allows for extrapolation between oral, dermal and inhalation acute toxicity estimates where data is lacking. However, this extrapolation is not included in the actual criteria for substance evaluation. An Industry proposal for the GHS classification of nickel sulfate makes the same extrapolation, although to a lower classification category for acute inhalation toxicity (Acute category 4). 16 Classification with Xi; R38 corresponds to the GHS Skin irritant category 2.

11 The EU TC C&L has agreed that the soluble and sparingly soluble salts should be classified as Xi; R38.

A specific concentration limit of 20% for this effect has been set for the three soluble compounds based on the human data for nickel sulfate.

There is no concern for skin irritation for nickel carbonyl or the less soluble sulfide, subsulfide, oxides or metal.

37. There is a marked difference in the results of animal studies on eye irritation with nickel sulfate and nickel dinitrate. Whilst there is little sign of irritation with nickel sulfate, animal data shows severe eye irritation with nickel nitrate. It has been suggested that this is related to the oxidising potential of the compound.

The EU TC C&L Technical Committee has agreed that nickel nitrate should be classified as Xi; R4117. None of the other compounds have been classified for eye irritancy.

38. Nickel is a well-known skin sensitiser. The soluble salts show considerable potency as initiators of this effect. Skin sensitisation appears to occur across a very wide range of water solubility, and the even the insoluble nickel oxides are considered to meet the criteria for classification as skin sensitisers. Release of nickel from nickel-containing metal surfaces is related to direct and prolonged skin contact and to the rate of nickel release to the skin.

The EU TC C&L has agreed that all the nickel compounds specifically discussed, with the exception of nickel carbonyl, should be classified as R4318.

A specific concentration limit of 0.01% for this effect has been set for the three soluble compounds based on human data, reflecting the high potency of the nickel ion in inducing skin sensitisation.

39. Unlike the extensive documentation for skin sensitisation, the data for respiratory sensitisation is very limited. Nickel sulfate is considered to be a respiratory sensitiser in humans, based on a limited number of cases. There are no data for nickel dichloride, nickel dinitrate or nickel carbonate. There are a limited number of case reports associated with exposure to nickel metal, and the IUCLID file for nickel matte, which consists mainly of nickel subsulfide, includes a statement (but no data) that this effect may be of concern. The Ni2+ ion is considered exclusively responsible for the immunological effects of nickel. As nickel sulfate is considered to induce respiratory sensitisation it must be assumed that nickel chloride, nickel dinitrate, nickel carbonate and nickel hydroxide also may have the potential to induce respiratory sensitisation and thus, should be regarded as respiratory sensitisers.

The EU C&L Technical Committee has agreed to classify soluble and slightly soluble compounds with the exception of nickel carbonyl as R4219. but agreed that the data for metallic nickel is not sufficient to lead to classification with R42. The nickel oxides and sulfides were not classified for this effect.

40. There is data showing repeated dose toxicity following inhalation for nickel sulfate, nickel chloride, nickel subsulfide, nickel oxide and metallic nickel. Inhalational repeated dose toxicity is shown by both soluble and insoluble nickel compounds. The available studies show that the effects seen on the lung occur at lower levels in nickel sulfate than with nickel subsulfide or nickel oxide.

The EU C&L Technical Committee has agreed that all the nickel compounds specifically discussed, with the exception of nickel carbonyl, should be classified as T; R48/23.

17 Classification with Xi; R41 corresponds to the GHS Serious eye damage category 1 18 Classification with R43 corresponds to the GHS Skin Sensitiser 19 Classification with R42 corresponds to the GHS Respiratory Sensitiser

12 A specific concentration limit of 1% for this effect has been set for the three soluble compounds based on the data for nickel sulfate.

41. There is evidence of in vitro mutagenicity for a number of soluble and insoluble compounds. There is much less data from in vivo studies. The three soluble compounds have been extensively tested in vivo, and there are also in vivo data for nickel sulfide. There is very limited data for metallic nickel, nickel carbonate or nickel hydroxide. There is some human data on chromosome aberrations in humans, mainly based on studies carried out on refinery workers. In general, the evidence for insoluble compounds is much less than for soluble compounds.

The in vitro data shows positive results across the range of solubility, particularly in tests that show effects on chromosomes. The in vivo data is conflicting. The data has been extensively discussed in both the context of the EU existing chemicals assessment with respect to possible additional testing, and in the EU TC C&L with respect to classification. The mutagenicity of the soluble compounds and nickel carbonate was discussed by the EU Specialised Experts in April, 2004 (European Commission, 2004). The Specialised Experts concluded that nickel sulfate, nickel chloride and nickel nitrate should be classified as Muta. Cat. 3; R6820. This conclusion is based on evidence of in vivo genotoxicity in somatic cells, after systemic exposure, and, hence the possibility that the germ cells are affected cannot be excluded. However further testing of effects on germ cells was not considered practicable. Concerning nickel carbonate, the experts concluded that there was insufficient evidence for classification for this substance.

In the subsequent discussions, the EU TC C&L agreed to classify the soluble nickel compounds as Muta. Cat. 3; R68. The semi-soluble compounds, nickel carbonate and nickel hydroxide were also classified as Muta. Cat. 3; R68, taking into account a derogation statement from Industry for nickel carbonate (Laine, 2003). Nickel sulfide and nickel subsulfide were also classified as Muta. Cat. 3; R68 on the basis of data, not least the results of positive in vivo Comet assays in the lung.

In the absence of adequate data on which to make a proposal, classification of metallic nickel, nickel oxides and nickel carbonyl was not considered. There is agreement that further testing for nickel metal may be required, depending on the result of inhalational carcinogenicity studies currently being carried out.

It should be noted that the acute oral toxicity of both nickel carbonate and nickel hydroxide shows that there is systemic uptake of both these compounds, and that therefore, like the more soluble compounds, the nickel ion may be systemically available to the germ cells, and that for nickel carbonate and nickel hydroxide the possibility that the germ cells are affected cannot be excluded. There is no evidence of similar systemic uptake for the less soluble nickel sulfides, subsulfides, oxides and metallic nickel. Concern for genotoxicity in these cases is more related to concerns for carcinogenicity at the target cells than for concern for effects on germ cell mutagenicity.

42. Nickel sulfide, subsulfide and the nickel oxides have long been recognised as human carcinogens, and classified as Carc. Cat. 1; R4921. A positive effect has been seen in animals with nickel subsulfide and nickel oxide, but not with nickel sulfate. The available data for inhalational carcinogenicity is not adequate to assess the effects of the metal. The data following other routes of administration is very limited but there is a recent study on nickel sulfate following oral administration which is negative.

The cancer epidemiology was discussed by the EU Specialised Experts in April, 2004 (European Commission, 2004). The Specialised Experts concluded that nickel sulfate and nickel chloride should be considered as human carcinogens (Carc. Cat. 1). The data was considered to be sufficient to establish a causal association between the human exposure to the substances and the development of lung cancer. There was supporting evidence for this conclusion from more limited data on nasal cancer.

20 Classification with Muta. Cat. 3; R68 for effects on germ cells corresponds to the GHS Germ cell mutagen Category 2. 21 Classification with Carc. Cat. 1; R49 corresponds to the GHS Carcinogen Category 1 (“by inhalation”)

13 In drawing this conclusion regarding lung cancer, it was recognised that the epidemiological data showed a clear exposure response relationship for water-soluble compounds, consistency across and within studies and time periods, and high strength of association. Improved exposure characterisation based on personal air sampling and improved analysis of the water-soluble fractions added to the reliability of the findings. Confounding factors such as co-exposure to insoluble nickel compounds and smoking were adequately addressed, and did not lower the level of confidence in reaching the conclusion.

The Specialised Experts also agreed that nickel nitrate and nickel carbonate should be classified as Carc. Cat. 1. In reaching this conclusion for nickel nitrate the Specialised Experts recognised that the water solubility of this compound was sufficiently similar to that of nickel sulfate and nickel chloride to justify the same classification. Since both the water soluble nickel compounds considered at this meeting and the insoluble inorganic nickel compounds already classified in Annex I are considered as human carcinogens consequently also the nickel carbonate was considered to be a human carcinogen.

In the subsequent discussions, the EU TC C&L initially agreed to classify all the nickel compounds under discussion with the exception of nickel metal and nickel carbonyl as Carc. Cat. 1.

It was also agreed that R49 rather than R4522 was appropriate, as the human evidence on which the conclusion was based was following inhalational exposure, and the oral study with nickel sulfate was negative. It was also noted that the tumours seen were local rather than systemic. As a result of further discussion (see paragraph 80), it was agreed to classify the nickel compounds covered by the group proposal as Carc. Cat. 2; R49.

Discussion of the current classification for metallic nickel as Carc. Cat. 3; R4023 was postponed until the results of inhalational carcinogenicity studies currently in progress are available24.

Possible revision of the current classification for nickel carbonyl as Carc. Cat. 3; R40 was not discussed.

43. Nickel carbonyl is already classified as Repr. Cat. 2; R6125. Studies on both fertility and development are available for nickel sulfate and nickel dichloride, but no relevant studies on nickel carbonate, nickel nitrate, nickel sulfide, nickel oxide or metallic nickel have been found. The data for nickel sulfate and nickel chloride fulfil the criteria for classification as Repr. Cat. 2; R61.

In the subsequent discussions, the EU TC C&L agreed to classify the soluble nickel compounds as Repr. Cat. 2; R61. Although there is no data available for the other nickel compounds, this classification was also considered appropriate for the sparingly soluble compounds (nickel carbonate and nickel hydroxide) but not for the compounds of lower solubility (nickel sulfide, subsulfide, oxides or metal). As for mutagenicity, it should also be noted that the acute oral toxicity of both nickel carbonate and nickel hydroxide shows that there is systemic uptake of both these compounds, and that therefore, like the more soluble compounds, the nickel ion may be systemically available. There is no evidence of similar systemic uptake for the less soluble nickel sulfides, subsulfides, oxides and metallic nickel.

44. The conclusions of these discussions in the EU TC C&L was that classification proposals were agreed for all endpoints discussed above for all the nickel compounds listed in the matrix of data availability. The conclusion for nickel sulfate and metallic nickel was to revise the entries for these two substances in Annex I and to include new entries for nickel dichloride and nickel dinitrate in the 30th. ATP (ECB, 2007a).

22 Classification with Carc. Cat. 1; R45 corresponds to the GHS Carcinogen Category 1 but without any limitation on the route of administration. 23 Classification with Carc. Cat. 3; R40 corresponds to the GHS Carcinogen Category 2. This classification in the EU system does not include any possibility of including a particular route of administration. 24 These results are expected in 2007. 25 Classification with Repr. Cat. 2; R61 corresponds to the GHS Reproductive toxicant Category 1 (“May damage the unborn child”)

14 No change in the current classification of nickel carbonyl was considered necessary. For the other compounds, (nickel hydroxide, nickel sulfides, nickel subsulfide, and the nickel oxides) there was agreement in the EU TC C&L on a revision of the current Annex I entries in the 31st ATP currently under preparation (ECB, 2007b).

45. The agreed classifications for the substances listed in the matrix of data availability are shown in the Table below:

Substance (1) EU Classification GHS Classification (2) nickel sulfate Carc. Cat. 1; R49; Carcinogen Category 1 by inhalation Repr. Cat. 2; R61; Reproductive toxicant Category 1 (“May damage the unborn child”) Muta. Cat. 3; R68; Germ cell mutagen Category 2 Xn; R20 Acute toxicity Cat. 3 (inhalation) Xn; R22; Acute toxicity Cat. 3 (oral) (3) T; R48/23; (SCL of 1%). STOST (Repeated exposure) Category 1 (inhalation) Xi; R38; (SCL of 20%) Skin irritant category 2 R42 Respiratory Sensitiser R43 (SCL of 0.01% Skin Sensitiser N; R50-53 Hazards to the aquatic environment: Acute and Chronic Category 1 (4) nickel dichloride Carc. Cat. 1; R49; Carcinogen Category 1 by inhalation Repr. Cat. 2; R61; Reproductive toxicant Category 1 (“May damage the unborn child”) Muta. Cat. 3; R68; Germ cell mutagen Category 2 T; R23 Acute toxicity Cat. 3 (inhalation) T; R25 Acute toxicity Cat. 3 (oral) T; R48/23; (SCL of 1%). STOST (Repeated exposure) Category 1 Xi; R38; (SCL of 20%) Skin irritant category 2 R42 Respiratory Sensitiser R43 (SCL of 0.01%) Skin Sensitiser N; R50-53 Hazards to the aquatic environment: Acute and Chronic Category 1 (4) nickel dinitrate O; R8 Oxidizing solid Cat. 2 Carc. Cat. 1; R49; Carcinogen Category 1 by inhalation Repr. Cat. 2; R61; Reproductive toxicant Category 1 (“May damage the unborn child”) Muta. Cat. 3; R68; Germ cell mutagen Category 2 Xn; R20 Acute toxicity Cat. 4 (inhalation) Xn; R22; Acute toxicity Cat. 4 (oral) T; R48/23; (SCL of 1%). STOST (Repeated exposure) Category 1 Xi; R38 (SCL of 20%) Skin irritant category 2 Xi; R41; Serious eye damage category 1 R42 Respiratory Sensitiser R43 (SCL of 0.01%) Skin Sensitiser N; R50-53 Hazards to the aquatic environment: Acute and Chronic Category 1 (4) nickel carbonate Carc. Cat. 1; R49; Carcinogen Category 1 by inhalation Repr. Cat. 2; R61; Reproductive toxicant Category 1 (“May damage the unborn child”) Muta. Cat. 3; R68; Germ cell mutagen Category 2 Xn; R20 Acute toxicity Cat. 4 (inhalation) Xn; R22; Acute toxicity Cat. 4 (oral) T; R48/23; STOST (Repeated exposure) Category 1 Xi; R38; Skin irritant category 2 R42 Respiratory Sensitiser R43 Skin Sensitiser N; R50-53 Hazards to the aquatic environment: Acute and Chronic Category 1 (4)

15 nickel dihydroxide Carc. Cat. 1; R49; Carcinogen Category 1 by inhalation Repr. Cat. 2; R61; Reproductive toxicant Category 1 (“May damage the unborn child”) Muta. Cat. 3; R68; Germ cell mutagen Category 2 Xn; R20 Acute toxicity Cat. 4 (inhalation) Xn; R22; Acute toxicity Cat. 4 (oral) T; R48/23; STOST (Repeated exposure) Category 1 Xi; R38; Skin irritant category 2 R42 Respiratory Sensitiser R43 Skin Sensitiser N; R50-53 Hazards to the aquatic environment: Acute and Chronic Category 1 (4) nickel sulfide Carc. Cat. 1; R49; Carcinogen Category 1 by inhalation /nickel subsulfide Muta. Cat. 3; R68; Germ cell mutagen Category 2 T; R48/23; STOST (Repeated exposure) Category 1 R43 Skin Sensitiser N; R50-53 Hazards to the aquativ environment: Acute and Chronic Category 1 (4) nickel oxide Carc. Cat. 1; R49; Carcinogen Category 1 by inhalation /nickel dioxide T; R48/23; STOST (Repeated exposure) Category 1 /nickel trioxide R43 Skin Sensitiser R53 Hazards to the aquatic environment: Chronic Category 4 metallic nickel Carc. Cat. 3; R40; Carcinogen Category 2 (inhalation) T; R48/23 STOST (Repeated exposure) Category 1 R43 Skin Sensitiser R52-53(5) Hazards to the aquativ environment: Acute and Chronic Category 3 (4) (6) nickel carbonyl F; R11 Flammable liquid Cat. 2 Carc. Cat. 3; R40; Carcinogen Category 2 Repr. Cat. 2; R61; Reproductive toxicant Category 1 (“May damage the unborn child”) T+; R26; Acute toxicity Cat. 1 (inhalation) (7) N; R50-53 Hazards to the aquatic environment: Acute and Chronic Category 1 (4) Notes: 1. Following the Einecs rules, an entry for an inorganic salt covers both the anhydrous compound as well as all hydrates unless hydrates are mentioned specifically in a separate entry. 2. Taken from Danish EPA (2007) and Milieu (2005b). 3. As the LD50 for female rats is 275 mg/kg, the classification for acute toxicity is more stringent in GHS classification system than in the EU. 4. In the GHS system separate classifications are given for both Acute and Chronic effects.. 5. There is agreement that metallic nickel should not be classified for hazards to the aquatic environment. However, nickel metal products with diameter less than 1 mm should be classified as R52-53. 6. There is agreement that metallic nickel should not be classified for hazards to the aquatic environment. However, nickel metal products with average specific surface area ≥ 0.1 m2/g should be classified as Acute and Chronic Category 3. 3 7. Estimated on the basis of the LC50 values of 67 – 1900 mg/m (30 minute exposure), UK HSE (1987)

46. As the available data for metallic nickel for a key endpoint, carcinogenicity, is not adequate to assess the effects of the metal, it was recognised that the Annex I classification might need further revision when the results of the current inhalational carcinogenicity study become available.

47. The extent of the available data varies for the different endpoints discussed above. Whilst for some endpoints the conclusions are based on human or experimental data for most of the individual compounds discussed, these decisions in themselves are based, to a varying extent, on read-across.

16 In some cases, like skin sensitisation, the evidence for an effect is extensive. In other cases, such as respiratory sensitisation, the database is limited to data on a few cases seen with nickel sulfate, nickel metal and anecdotal evidence for nickel matte.

In some cases, such as skin sensitisation, carcinogenicity and repeated inhalational toxicity, there is clear evidence that the effect occurs over the whole of the solubility range considered. This does not necessarily mean that the mechanism of action is identical across the solubility spectrum, and Industry has argued that the mechanisms of carcinogenicity may be different in the soluble nickel compounds and the less soluble sulfidic and oxidic compounds. The evidence for the sparingly soluble compounds (nickel carbonate and nickel dihydroxide) is particularly limited, and the classification for there two compounds is based on a higher degree of read-across than has been necessary for the other compounds considered.

48. The recognition that read-across is appropriate within this partial category of nickel compounds considered specifically is an important consideration in extending the same considerations to a larger group of comparable compounds.

THE NEED FOR FURTHER TESTING.

49. Additional testing is currently underway to evaluate metallic nickel following inhalational administration.

50. Industry has initiated a research programme concerning the influence of abiotic factors on the (chronic) ecotoxicological effects of nickel using the BLM theory26.

51. Apart from the inhalational carcinogenicity study and the BLM studies, the Danish EPA is not aware of any plans at the present time for specific testing aimed at providing additional data that would be expected to modify the classification agreed for any of the substances discussed above.

52. With the exception of the availability studies that have been carried out on the spinels and rutiles (see discussion below), no further testing on compounds in the additional extended category is envisaged.

53. NiPERA have argued that a minimum of test data is required for any individual substance to be included in the category. Information such as basic toxicokinetic data and/or acute and irritation studies would provide a minimum of scientifically supportable criteria for the inclusion of individual chemical compounds into a group (NiPERA, 2006).

54. Provision of additional information was not considered to be necessary by the EU TC C&L, and the Danish proposal was agreed without provision of further data. An external assessment of the category was not considered necessary for agreement on this approach.

55. Since the potential candidates for a read-across approach are listed individually, the potential eligibility of individual compounds has been evaluated on a case-by-case approach. This is described below.

FILL DATA GAPS BY READ-ACROSS, EXTRAPOLATION, INTERPOLATION ETC.

56. The use of read-across for specific endpoints within the limited group of substances for which data is available is clearly acceptable. This being the case, it seems reasonable to consider to what extent the same approach can be applied to the much larger group of “nickel and nickel compounds”.

26 Biotic Ligand Model

17 57. In cases where there are clear similarities to the compounds considered above, the use of read- across to evaluate the hazards of these compounds would seem justified. For example, soluble nickel(II) salts would be expected to show the same effects as the other soluble nickel(II) salts evaluated on the basis of their measured data.

58. For the purposes of this evaluation, nickel compounds are placed in one of eight sub-categories: a) nickel sulfate, nickel dichloride, nickel dinitrate and other soluble compounds with a water- solubility greater than 10-2 mol/L (corresponding to the groups of “soluble” and “very soluble” compounds in the Table in paragraph 20 above). b) nickel carbonate, nickel dihydroxide and other sparingly soluble compounds with a water-solubility in the range 10-4 - 10-2 mol/L, (corresponding to the group of “slightly soluble” compounds in the Table in paragraph 20 above), but excluding nickel carbonyl (group (f) below). c) nickel sulfide, nickel subsulfide and other ‘insoluble’ compounds with a water solubility less than 10-4 mol/L (corresponding to the group of “insoluble” compounds in the Table in paragraph 20 above) but excluding the oxides and metallic compounds (groups (d) and (e) below). d) nickel oxide and mixed nickel oxides e) metallic nickel and metallic nickel compounds f) nickel carbonyl g) nickel compounds specifically excluded from the category h) nickel compounds not included in the category

59. The distinction between groups (g) and (h) reflects the fact that in group (g) compounds have been considered individually and excluded from the category for specific reasons. In additional there are a number of compounds in group (h) that, whilst they form part of the initial category, are not considered relevant for inclusion for a specific classification proposal. It is possible that for some compounds in this sub-category, additional data would indicate whether or not they should be included.

REFINEMENT OF THE CATEGORY.

60. Read-across is used for inorganic compounds, some organic compounds and for relevant complex substances where possible. This approach has been carried out following a process of refinement of the initial list of nickel compounds in order to ensure that compounds for which read-across is not relevant are excluded from the category.

61. Whilst it is not always easy to distinguish between nickel(I) and nickel (II) compounds27, compounds known to be nickel(I) compounds have been excluded.

62. Nickelates have also been systematically excluded, as there is no data on which to assess the validity of a read-across from the other nickel compounds for which data is available.

63. Tetraammine and hexaammine compounds have also been excluded as the read-across from the hexaammine nickel complex to a hydrated nickel ion is not necessarily appropriate.

64. Following additional information provided by Industry, a number of complex nickel oxide compounds have been deleted from the category.

27 An example is nickel(II)chloride which is often described as nickel chloride and not by its more correct name nickel dichloride. There is however a nickel(I)chloride that has not been included in the proposal.

18 Industry has argued that the nickel availability from these compounds, which are complex nickel-containing oxides with either a rutile or a spinel structure, is significantly different from that of nickel oxide.

One nickel-containing mixed oxide has been studied in the OECD SIDS programme (UNEP, 2005). The compound, C.I.Pigment Yellow 53 is a rutile pigment. Based on a nickel category approach, the main potential hazards would be expected to be a) carcinogenicity, b) repeated dose inhalational toxicity and c) sensitisation. Carcinogenicity was not studied in the SIDS evaluation. Repeated dose inhalational toxicity was studied in a rat inhalation study with exposure to 60 mg/m3 for 6 hr/day for 5 days. The study produced no clinical signs of toxicity. However, the absence of histological examination prevented identification of a reliable NOAEC. No data are available on sensitisation. However, the substance was not considered likely to produce this effect as the nickel has been shown to be not biologically available following repeated inhalation and oral exposure in rats.

Following discussions with Industry, it was agreed that the concerns for carcinogenicity, repeated dose toxicity or skin sensitisation could not be dismissed on the basis of lack of systemic absorption following oral or repeated inhalational exposure alone. Nickel is a potent skin sensitiser and the rate set for the maximum acceptable release from metallic nickel or nickel alloys in products intended to come into direct and prolonged contact with the skin in the so-called Nickel Directive (EC, 1994) is 0.5 μg/cm²/week as measured by EN 1811 (CEN, 1998).

Industry has measured the nickel release from some spinels and rutiles and compared this with the release from bunsenite. Studies have been performed using the CEN assay used to assess the nickel release from nickel-containing alloys for conformity with the Nickel Directive dealing with skin sensitisation as well as the OECD 29 test method (Eurocolour, 2006). These studies have shown a different pattern of nickel release from the spinels and rutiles compared to nickel oxide, and this justifies the exclusion of these compounds from the category.

The Eurocolour comments (Eurocolour, 2005) suggested that in addition to the substances discussed above cobalt nickel grey periclase should also be excluded from the proposal. Industry has subsequently shown that the similarity of the X-ray diffraction spectrum of the periclase to bunsenite, the naturally occurring form of nickel oxide, and the ready solubility of the periclase in concentrated hydrochloric acid indicates that it should not be excluded from the category.

Finally, it is possible that there are other nickel-containing mixed oxides that could also be removed from this proposal. These include a number of pigments which are no longer on the market. In the absence of further information suggesting that these entries should be excluded, the EU TC C&L group decided that it is most appropriate to keep these entries in the proposal.

The following spinel and rutile compounds have been excluded from the category:

CAS No. Substance name Crystal type

68187-10-0 Nickel-ferrite-brown-spinel; CI Pigment Brown 34 spinel

12168-54-6 Iron nickel oxide (Fe2-NiO4) spinel (1)

71631-15-7 Nickel-iron-chromite-black-spinel; CI Pigment Black 30 spinel

68611-43-8 Nickel-niobium-titanium-yellow-rutile; CI Pigment Yellow 161 rutile

69011-05-8 Nickel titanium oxide tungstate (NiTi20-O35-(WO6)2) rutile

68186-85-6 CI Pigment Green 50 spinel

8007-18-9 Antimony-nickel-titanium-oxide-yellow-; C.I. Pigment Yellow 53 rutile 73892-02-1 Antimony oxide (Sb203), solid soln. with nickel oxide (NiO) and titanium oxide rutile 54576-53-3 Antimony-nickel-titanium-oxide rutile

19 71077-18-4 Rutile, antimony nickel yellow rutile 12018-18-7 Chromium nickel oxide (Cr2-NiO4) spinel 97435-21-7 Iron nickel zinc oxide (Fe2-NiZnO4) spinel 99749-23-2 Cassiterite, cobalt manganese nickel grey cassiterite 12645-50-0 Iron-nickel-zinc-oxide- spinel 95046-47-2 Spinels, cobalt nickel zinc grey spinel Notes: 1. According to Eurocolour, this compound is identical with CI Pigment Brown 34 (Eurocolour, 2002). Iron nickel oxide with CAS No. 12168-54-6 is placed on the market separately, and one supplier has given this a provisional classification with R49-43 (Alfa Aesar, 2005). In this case, the provisional classification applied by the supplier is more stringent than the result of the category approach. 2. See also UNEP, 2005.

65. Nickel forms metal-metal compounds with a number of elements. These compounds are substances and not alloys, and the compounds with aluminium, niobium, lanthanum, dysprosium and bismuth are known to be on the market. The classification of metallic metal has been based on data for the compound and not on read-across from any of the other nickel compounds under review. In particular, the classification for cancer has been based on the limited data available rather than on read-across. Studies on the inhalational carcinogenicity of metallic nickel are currently in progress, and the relevance of including these metal-metal compounds can be considered when the results of this study have been evaluated.

The following metal-metal compounds have therefore been provisionally excluded from the category:

EC No. CAS No. Substance name 234-827-5 12035-52-8 Antimony, compd. with nickel (1:1) 235-676-8 12503-49-0 Antimony, compd. with nickel (1:3) 234-439-6 12003-78-0 Aluminum, compd. with nickel (1:1) 235-261-1 12142-92-6 Nickel, compd. with zirconium (1:2) 234-807-6 12034-55-8 Nickel, compd. with niobium (1:1) 235-034-7 12059-23-3 Nickel, compd. with tin (3:1) 235-372-5 12196-72-4 Lanthanum, compd. with nickel (1:5) 235-341-6 12175-27-8 Dysprosium, compd. with nickel (1:2) 235-773-5 12688-64-1 Bismuth, compd. with nickel (1:1) 257-510-3 51912-52-8 Copper, compd. with lanthanum and nickel (4:1:1)

66. There are a number of nickel containing compounds on the market listed as high production volume chemicals or, in some cases, as low production volume chemicals, which are not considered as relevant for consideration in a category approach, as their effects are not considered to be adequately described by their nickel content.

Asphalt (EC No: 232-490-9, CAS No. 8052-42-4) is obtained as the non-volatile residue from distillation of crude oil or by separation as the raffinate from a residual oil in a deasphalting or decarbonisation process. Asphalt is a very complex combination of high molecular weight organic compounds containing a relatively high proportion of hydrocarbons having carbon numbers predominantly greater than C25 with high carbon-to- hydrogen ratios. Asphalt also contains small amounts of various metals such as nickel, iron or vanadium (European Commission, 1990).

The Einecs entries for “Glass, oxide” (EC No: 266-046-0, CAS No: 65997-17-3) and “Ceramic materials and wares” (EC No: 266-340-9, CAS No: 66402-68-4) list the various chemicals manufactured in the production of inorganic glasses and in the production of ceramics. The elements listed in these Einecs entries are principally present as components of oxide systems, but some may be present in other forms (European Commission, 1990).

20

The Einecs entries for “Frits, chemicals” (EC No.: 266-047-6, CAS No.: 65997-18-4), describes the production of frits as a mixture of chemicals substances produced by rapidly quenching a molten, complex combination of materials, confining the chemical substances thus manufactured as non-migratory components of glassy solid flakes or granules. This category includes all of the chemical substances specified in the entry (Einecs includes a list of 35 elements, including nickel) when they are intentionally manufactured in the production of frit. The primary members of this category are oxides of some or all the listed elements. Fluorides of these elements may also be included in combination with these primary substances (European Commission, 1990). Eurocolour, an umbrella organisation under CEFIC, has described the production of nickel-containing frits from nickel oxide and nickel hydroxide. The group of “frits” as such is considered to be too poorly defined in terms of the content of nickel oxide to justify a classification proposal based on the effects of nickel and its compounds. The IUCLID file recognises that the classification will depend on the composition of the individual product. Whilst frits with concentrations of nickel oxide above 0.1% should be classified as Category 1 carcinogens according to EU legislation, not all frits will contain nickel oxide.

Copper matte (EC No.: 266-967-8, CAS No.: 67711-91-5) is defined in Einecs as the product of smelting roaster calcines concentrates or cement copper with flux in reverberatory or electric furnaces. The matte is composed primarily of copper and copper, iron and lead sulphides with minor sulphides of other metals (European Commission, 1990). Copper matte produced from nickel-containing copper ores can contain some nickel sulphide. Whilst copper mattes with concentrations of nickel sulphide or subsulfide above 0.1% should be classified as Category 1 carcinogens according to EU legislation, not all copper mattes will contain nickel sulphide at these concentrations.

Copper smelting slags (EC No.: 266-968-3, CAS No.: 67711-92-6) are slags resulting from the smelting of a heterogeneous mixture of copper and precious metals from primary and secondary sources and plant reverts. Major constituents are iron-calcium-aluminium silicates, with minor amounts of copper, lead, nickel and various non-ferrous metals and oxides (European Commission, 1990). Whilst slags with concentrations of nickel oxide above 0.1% should be classified as Category 1 carcinogens according to EU legislation, not all slags will contain nickel oxide at these concentrations.

Ashes (residues) (EC No.: 268-627-4, CAS No.: 68131-74-8) are the residues from the burning of a combination of carbonaceous materials. The following elements may be present as oxides: aluminium, calcium, iron, magnesium, nickel, phosphorous, potassium, silicon, sulfur, titanium and vanadium (European Commission, 1990). A similar compound, Ashes (residues), heavy fuel oil fly (EC No.: 297-402-3, CAS No.: 93571-76-7) is a LPVC. Whilst ashes with concentrations of nickel oxide above 0.1% should be classified as Category 1 carcinogens, not all ashes will contain nickel oxide.

Lead alloy, base, Pb, Sn, dross (EC No.: 273-701-4, CAS No.: 69011-60-5) are the oxides formed during melting, refining, and casting of solders. Major constituents are oxides of tin, lead and antimony; minor constituents are iron, nickel, sulfur, arsenic, copper and silver (European Commission, 1990). A similar compound, Lead alloy, base, dross (EC No.: 273-700-9, CAS No.: 69011-59-2) is a LPVC. Whilst drosses with concentrations of nickel oxide above 0.1% should be classified as Category 1 carcinogens, not all drosses will contain nickel oxide. The high concentration of lead oxide (included in Annex I No. 082-001-00- 6) in the dross could provide a basis for the evaluation of this compound.

Waste solids, copper electrolyte purifn. cathodes (EC No.: 273-720-8, CAS No.: 69012-20-0) are impure copper cathodes formed during the electrolytic demetallizing of spent copper refining electrolyte. They consist primarily of copper with varying levels of antimony, arsenic, bismuth, lead and nickel (European Commission, 1990). The Einecs description suggests the nickel is present in metallic form, but does not indicate the concentration. Whilst cathodes with concentrations of nickel above 1% should be classified as Category 3 carcinogens, it is not clear that all cathodes will contain nickel at this concentration. Classification should also reflect the presence of other metals such as antimony and lead.

Leach residues, zinc ore-calcine, cadmium-copper ppt. (EC No.: 293-311-8, CAS No.: 91053-46-2) is an insoluble material precipitated by hydrolysis during hydrometallurgical treatment of crude zinc sulfate

21 solution. It consists primarily of cadmium, cobalt, copper, lead, manganese, nickel, thallium, tin and zinc (European Commission, 1990). The Einecs description does not make clear the form of the nickel in the compound or indicate the concentration. Classification should also reflect the presence of other metals such as cadmium, thallium and lead.

Leach residues, zinc ore-calcine, iron-contg. (EC No.: 293-312-3, CAS No.: 91053-47-3) is an insoluble material precipitated by hydrolysis during hydrometallurgical treatment of crude zinc sulfate solution. It consists primarily of ferric oxide and, as impurities, arsenic, cadmium, cobalt, copper, lead, nickel, thallium, tin and zinc (European Commission, 1990). The Einecs description does not make clear the form of the nickel in the compound or indicate the concentration. Classification should also reflect the presence of other metals such as arsenic, cadmium, thallium and lead.

The production of ferro-nickel slags (EC No.: 273-729-7, CAS No.: 69012-29-9) is described in the risk assessment report for nickel metal. According to EU waste legislation (EC, 2001a) nickel slag from primary production is classified as non-hazardous waste (10 08 09). Section C.5 of the IUCLID file for “ferronickel manufacturing slags” (EC No. 273-729-7) considers the substance fulfils the criteria for classification as Carc. Cat 3; R40 and R43. Whilst slags with concentrations of nickel oxide above 0.1% should be classified as Category 1 carcinogens, the composition data indicates that not all slags will contain concentrations of nickel oxide above this limit. NiPERA (2005) has stressed that all ferro-nickel slags contain a negligible concentration of nickel oxide.

It should be noted that ferronickel and slags from nickel matte production are not included in Einecs, and so are not included in the category, even though the quantities involved are also likely to qualify them as HPVCs.

67. Read-across is also used for certain organic nickel compounds in cases where these are expected to behave similarly to soluble inorganic compounds. Organic compounds (largely soluble compounds) have been included on the basis of an evaluation of the solubility and the association constants. Organic nickel compounds where the nickel is sufficiently soluble and sufficiently dissociated from the organic moiety are considered as being comparable to inorganic nickel compounds of similar water solubility. This selection was made on the basis of expert judgement.

68. The UK has pointed out that for the following compounds initially included in the category (Danish EPA, 2005), the presence of a double bond makes the molecule more likely to be biologically active (Danish EPA, 2006a):

CAS No Chemical Name 60700-37-0 2-Propenoic acid, nickel(2+) salt 51222-18-5 2-Propenoic acid, nickel salt 13001-15-5 9-Octadecenoic acid (Z)-, nickel(2+) salt 6283-67-6 2-Butenedioic acid (E)-, nickel(2+) salt (1:1) 52496-91-0 2-Propenoic acid, 2-methyl-, nickel(2+) salt 94275-78-2 2-Propenoic acid, 2-methyl-, nickel salt 67952-41-4 Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-, nickel(2+) salt (2:1)

Deletion of the tartrate (CAS number 67952-41-4) has also led to deletion of the other two entries for tartrates shown in the proposal (CAS Nos. 52022-10-3 and 10471-42-8).

In addition, for the following compounds, the UK considers that the contribution of the organic moiety to the overall hazard profile should be considered (Danish EPA, 2006a):

22 CAS No Chemical Name 14100-15-3 Nickel, bis(8-quinolinolato-N(1)-,O(8))- 71767-12-9 Uranate(2-), tetrakis(acetato-O)dioxo-, nickel(2+) (1:1), (OC-6-11)- 68958-89-4 Nickel(2+), bis(1,2-ethanediamine-N,N’)-, bis[bis(cyano-C)aurate(1-)] 12794-26-2 Nickel, bis(1-nitroso-2-naphthalenolato)- 14406-66-7 Nickel, bis(1-nitroso-2-naphthalenolato-N(1)-,O(2))-, (T-4)-

Whilst it is possible that for some endpoints, a category approach for these compounds might be appropriate, these compounds have been deleted from the category.

69. There is uncertainty about the identity of nickel metaborate shown in ECICS (Table 1.4). The CAS number does not correspond to this compound. Given the uncertainty concerning the identity of this compound, this has not been included in the category.

70. The compounds described in paragraphs 61 – 69 above have been excluded from the category.

71. Organonickel compounds that are likely to behave as largely or entirely organonickel complexes were not included in the category.

72. Among the organonickel compounds not included in the category are a number that are listed as LPVCs. These include substances used as nickel colorants, as well as other compounds where the use is not clear from the information in IUCLID.

CAS No Chemical Name 70833-37-3 Nickel, bis(3-amino-4,5,6,7-tetrachloro-1H-isoindol-1-one oximato-N(2)-,O(1))- 13927-77-0 Nickel, bis(dibutylcarbamodithioato-S,S')-, (SP-4-1)- 29204-84-0 Nickel, bis[2,3-bis(hydroxyimino)-N-phenylbutanamidato-N(2)-,N(3)-]- 42739-61-7 Nickel, bis[2,3-bis(hydroxyimino)-N-(2-methoxyphenyl)butanamidato]- 14055-02-8 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-,N(32)-]-, (SP-4-1)- 14516-71-3 Nickel, (1-butanamine)[[2,2'-thiobis[4-(1,1,3,3-tetramethylbutyl)phenolato]](2-)-O,O',S]- 68511-62-6 Nickel, 5,5'-azobis-2,4,6(1H,3H,5H)-pyrimidinetrione complexes 90459-30-6 Nickel, acetate carbonate C8-C10-branched fatty acids C9-C11-neofatty acids complexes

Some of these compounds have provisional classifications in the HEDSET files included in IUCLID. As these compounds fall outside the category, this category approach is not appropriate to evaluate the potential hazards of these compounds. ETAD has offered its cooperation to assess the proper classification of nickel based organic pigments and dyes (ETAD, 2005).

REFINEMENT OF THE READ-ACROSS.

73. In the read-across shown below, the read-across has been based on the classifications agreed for the individual nickel compounds shown in the Table in paragraph 45 above. The read-across is shown using the EU classifications agreed by the TC C&L. The GHS equivalents are shown in the Table in paragraph 45.

a) Soluble nickel(II) compounds, with a water-solubility greater than 10-2 mol/L (corresponding to the groups of “soluble” and “very soluble” compounds in the Table shown in paragraph 20 above) are

23 classified based on the classification for nickel sulfate shown in paragraph 45 above: Carc. Cat. 228; R49; Repr. Cat. 2; R61; Muta. Cat. 3; R68; T; R48/23; R42/43 and N; R50-53, with specific concentration limits for R43 of 0.01% and for T; R48/23 of 1%. Read-across has not been used for the classification for acute toxicity or for irritation.

b) Sparingly soluble nickel(II) compounds, with a water-solubility in the range 10-4 - 10-2 mol/L (corresponding to the group of “slightly soluble” compounds in the Table shown in paragraph 20 above) are classified based on the classification for nickel carbonate shown in paragraph 45 above: Carc. Cat. 2; R49; Repr. Cat. 2; R61; Muta. Cat. 3; R68; T; R48/23; R42/43 and N; R50-53. Unlike the soluble compounds, no specific concentration limits are included. Read-across has not been used for the classification for acute toxicity or for irritation. The Commission has subsequently suggested that the classification for the systemic effects reproductive toxicity (Repr. Cat. 2; R61) and mutagenicity (Muta. Cat. 3; R68) should not be applied to this group of compounds.

c) Insoluble nickel compounds, with a water-solubility less than 10-4 mol/L but excluding nickel oxides and metallic metal compounds (corresponding to the group of “insoluble” compounds in the Table shown in paragraph 20 above) are classified based on the classification for nickel sulfide: Carc. Cat. 2; R49; T; R48/23; R43 and N; R50-53. No specific concentration limits are included. Read-across has not been used for mutagenicity.

d) Mixed nickel oxides are classified based on the classification for nickel oxide: Carc. Cat. 2; R49; T; R48/23 and R43 and R53. Read-across has not been used for classification for environmental hazards.

e) Read-across for nickel metal compounds has not been carried out. This is discussed in paragraph 65 above.

f) Nickel tetracarbonyl is included in the Table shown in paragraph 20 above by Carlsen (2001), although this is not a typical inorganic nickel compound. Its low solubility is caused by its hydrophobic character, rather than by a low dissociation constant. Whilst the environmental effects appear to be consistent with the results expected from its water solubility, apart from its effects on reproductive toxicity, its effects on human health are not immediately comparable to any of the other nickel compounds studied. The data from this compound has not been used as the basis for any read- across.

74. In cases where other metals or anions are present that have known significant toxic effects as shown by other Annex I group entries for these metals or anions, these effects are included in the classification using the Guidance under Note A in the Foreword to Annex I in Directive 67/548/EEC.

“For substances belonging to more than one group of substances included in Annex I, the symbols, indications of danger, R- and S-phrases to be used for each substance shall be those shown in both the appropriate entries given in Annex I. In cases where two different classifications are given in the two entries for the same hazard, the classification reflecting the more severe hazard classification is used.

Example:

for substance AB - no individual entry in Annex I:

Annex I group entry for compounds of A: Repr. Cat. 1; R61 Repr. Cat. 3; R62 Xn; R20/22 R33 N; R50-53

Annex I group entry for compounds of B: Carc. Cat.1; R45 T; R23/25 N; R51-53

Classification of substance AB thus becomes: Carc. Cat. 1; R45 Repr. Cat. 1; R61 Repr. Cat. 3; R62 T; R23/25 R33 N; R50-53”

28 For discussion of classification as category 1 or 2 carcinogens, see paragraph 80.

24 This guidance assumes an additive effect of the different effects due to the different components of the compound.

75. Acute toxicity This endpoint was discussed at some length, both under the discussion of the individual compounds reviewed initially and in the subsequent discussion of the category approach. In the initial Danish proposals for classification of the three soluble ESR nickel compounds, nickel sulfate, nickel dichloride and nickel dinitrate, the possibility was raised of a common classification for all three compounds, rather than basing the classification on the specific LD50 data for each. This suggestion was based on the assumption that the measured LD50 values for these compounds could be seen as different point estimates of the acute oral toxicity of the Ni2+ ion. This approach found some sympathy with some members of the EU TC C&L, but was finally not accepted. Nickel dichloride was classified as T; R2529, whilst the sulfate30 and dinitrate were classified as Xn; R22. Whilst the LD50 data for nickel acetate is very similar to that of nickel sulfate, nickel dinitrate has an LD50 substantially higher than either of the other two compounds. Whilst nickel dinitrate is the most water soluble of the individual nickel compounds studied, the LD50 is closer to that of the slightly soluble compounds, nickel carbonate and nickel dihydroxide, which have LD50 values around 840 – 1700 mg/kg.

NiPERA (2005) recognised that even though the proposal to classify all the soluble nickel compounds as Xn; R20/22 may prove to be acceptable at this time, there are too many unknowns for this approach to be considered valid.

The uncertainties reflected in the discussion led to the Danish EPA deleting proposals for acute toxicity based on read-across31 from the proposals. Note H was added instead32.

There was however agreement that where acute oral toxicity is identified as a hazard, in the absence of further information, acute inhalational toxicity should also be identified as a hazard at the same level of concern as the acute oral toxicity.

76. Irritation/ corrosivity This endpoint was also discussed at some length. The available data that indicates that soluble nickel compounds can cause on skin irritation is derived from humans, whilst the available animal data does not support classification for this effect. Unlike the results for eye irritation of nickel sulfate, nickel dinitrate showed severe eye irritation. It was suggested that the greater severity with this compound was due to its oxidising properties. This suggests that this local property is more dependent on the counterion than other systemic effects. NiPERA (2005) pointed out that this endpoint not only depends on the water solubility of the nickel compound, but on the nature of the anion, and that the read-across for nickel salts must include an evaluation of not just nickel ion availability, but also the irritancy of the anions. NiPERA (2005) also pointed out that, since the water soluble nickel salts are not irritating at concentrations below 20% it will be impossible to consider a direct extrapolation 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.

29 Although not included as a specific entry in either the UN Recommendations on the Transport of Dangerous Goods (UN, 2001) ADN (UN ECE 2001a) or in the ADR (UN ECE, 2001b), both solid and liquid nickel chloride meet the criteria under ADR/RID/IMDG for Class 6.1 “Toxic Substances”. The agreed classification for nickel dichloride reflects this UN Transport classification. 30 As noted above, under the GHS criteria, nickel sulfate is classified for acute toxicity in the same category as nickel dichloride, based on the LD50 value of 275 mg/kg. 31 Classification for acute toxicity is included where data is available. 32 Note H is described in more detail in paragraph 83 below. This is a Note that indicates that the classification agreed is a partial classification, and that other hazards not included in the harmonised classification need to be addressed by the supplier of the chemical.

25 The uncertainties reflected in the discussion led to the Danish EPA deleting proposals for irritation / corrosivity based on read-across33 from the proposals. Note H was added instead.

77. Skin Sensitisation Nickel skin sensitisation 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. Animal studies have contributed little to the understanding of this effect. 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 compounds with very low water solubility such as nickel oxide. The studies carried out by Industry with the nickel-containing spinels are interesting in that they demonstrate that there is in fact an additional group of compounds where the nickel availability is even less than that seen with the nickel oxides. These studies have identified nickel compounds which show the same, very limited, nickel release that that has previously been demonstrated for certain nickel-containing alloys such as certain stainless steels, and which does not give rise to concern for skin sensitisation.

NiPERA (2005) have expressed concerns about read-across for this effect, particularly for the organonickel compounds, where the possibility of lipophilicity of insoluble compounds creates the possibility that some insoluble organonickel compounds could penetrate the skin and be metabolised in the basal layer to release nickel. However, it is just as likely that the nickel ion may not be released from water-soluble organonickel compounds, raising the possibility that they may not be sensitising at any concentration. Once again, some determination of the bioavailability (not just water solubility) of the nickel ion from the compound is required for an accurate read-across.

This argument was not supported by the EU TC C&L, and it was agreed to read-across this classification for all the nickel compounds finally included in the category. The specific concentration limits for this effect agreed for nickel sulfate were also applied to the other soluble nickel compounds considered.

78. Respiratory sensitisation. Respiratory sensitisation is recognised as an effect with the soluble and sparingly water-soluble nickel compounds, although this conclusion is based on a limited number of cases with nickel sulfate. The TC C&L has agreed that R42 is not appropriate for nickel sulphide, nickel subsulphide or metallic nickel, although there is limited evidence from people exposed to metallic nickel, and some suggestion that this effect can also be seen with other compounds, as is shown by the anecdotal evidence from the IUCLID file that nickel matte also shows this effect.

NiPERA (2005) commented that although the mechanisms are different, the issue of bioavailability of nickel ion from the compound will be the determinant in the read-across of the respiratory sensitisation of soluble inorganic nickel salts to other nickel containing compounds.

The EU TC C&L agreed to read-across this classification for all the soluble and sparingly soluble nickel compounds. It is possible that further studies may show that this effect occurs across a wider spectrum of water-solubility than is currently recognised.

79. Repeated dose toxicity Repeated dose toxicity following inhalation is an effect that leads to classification in both soluble (nickel sulfate) and insoluble nickel compounds (nickel subsulfide and nickel oxide). The effects are seen at substantially lower levels with nickel sulfate than with the insoluble compounds.

NiPERA (2005) commented that, as already noted the issue of ion availability from the water-soluble organometallic compounds further complicates the read-across on the basis of water solubility alone. Consequently, even though the proposal to classify all the nickel compounds as T; R48/23 may prove to be acceptable at this time there are too many unknowns for this approach to be considered as validated.

33 Classification for corrosivity/irritation is included where data is available.

26 The EU TC C&L agreed to read-across this classification for all the soluble and sparingly soluble nickel compounds.

The use of the approach given in Note A in the Foreword to Annex I means that R33 needs to be assigned for some entries. In the EU classification and labelling system, R33 is used to identify concerns due to bioaccumulation, but where the concerns are less than those covered by classification with R48. This R- phrase is now largely redundant, following development of the improved criteria for R48, and within GHS cumulative effects are clearly covered by the criteria for STOST – repeat exposure (Milieu, 2005a). Since the concern that gave rise to the application of R33 may be covered by other possible classifications, R33 has not been included and is covered by Note H.

80. Germ cell mutagenicity Agreement on the use of read-across for this endpoint was only obtained after much discussion. In their comments to the proposal, Belgium (2005) questioned whether it was necessary to include the Muta. Cat. 3; R68 classification given that the compounds are already classified Carc. Cat. 1; R49. They also took into account the fact that the evidence for mutagenicity is conflicting, and that the Specialized Experts concluded that there was insufficient evidence for the classification of nickel carbonate, a sparingly soluble compound. In these circumstances, Belgium did not consider that performing a read-across classification for such a conflicting endpoint seems justified. NiPERA (2005) has also expressed concern about the use of read-across for this endpoint, in particular with respect to the organic compounds included in the proposal.

In their evaluation, the Specialised Experts concluded that concluded nickel sulfate, nickel chloride and nickel nitrate should be classified as Muta. Cat. 3; R68. This conclusion is based on evidence of in vivo genotoxicity in somatic cells, after systemic exposure, and, hence the possibility that the germ cells are affected cannot be excluded. The Specialised Experts also concluded that further testing of effects on germ cells was not considered practicable. This conclusion is reflected in the agreement to classify nickel sulfate, nickel dichloride and nickel dinitrate as Muta. Cat. 3; R68 and the “conclusion (i) on hold”34 for this endpoint for these three compounds under the Existing Substances Regulation (Danish EPA, 2005b, 2005e, 2005f). In reaching their conclusion concerning nickel carbonate, the Specialised Experts did so based on the data for this substance alone, and were not asked to look at the data for the less soluble nickel sulphide. The TC C&L subsequently accepted classification as Muta. Cat. 3; R68 (in the 30th. ATP) on the basis of a derogation request from Industry made in the context of the risk assessment evaluation. The EU TC C&L subsequently agreed to classify both the sulphide and the subsulphide as Muta. Cat. 3; R68 on the basis of data.

In the following discussions, a distinction was made between possible effects on the germ cells and other genotoxic effects. Consideration was also given to the fact that for soluble nickel compounds, further testing was not considered practicable. The EU TC C&L agreed that read-across for classification as Muta. Cat. 3; R68 for germ cell mutagenicity was reasonable for the soluble compounds, but was not appropriate for the non-soluble nickel compounds. Note H was added to cover this effect for the less water-soluble compounds.

The conclusions of the discussions in the EU TC C&L for the sparingly soluble compounds have been discussed further within the Commission. The discussion at the March 2006 distinguished between “soluble” nickel compounds for which read-across was agreed and “non-soluble” nickel compounds for which read- across was not considered appropriate. It is unclear whether "non-soluble" nickel compounds include the sparingly soluble nickel compounds. The Commission has concluded on the basis of their understanding of the discussion and having in mind the last Danish proposal (ECBI/96/04 Add. 2 Rev 1) that "non-soluble" should include the "sparingly soluble".

Whilst there is evidence of systemic availability of the nickel ion for nickel carbonate and nickel hydroxide as shown by the acute toxicity of these compounds, and hence, effects on germ cells cannot be excluded, for the other semi-soluble compounds included in the proposal, information demonstrating systemic availability is

34 Whilst conclusion (i) under the Existing Substances Regulation means that further data is required, a conclusion (i) on hold means that whilst there is agreement that additional data is needed, there is also an agreement that no further testing should actually be carried out.

27 not available. Given the differences in water-solubility between the slightly soluble compounds (with water solubility in the range 10-4 - 10-2 mol/L) and the soluble compounds (from 10-2 to over 5·10-1 mol/L), the assumption that the nickel ion is systemically available for the slightly soluble compounds is not necessarily justified, and the read-across for this systemic effect is not used, and Note H can be used to cover this endpoint for the slightly-soluble compounds.

81. Carcinogenicity There is epidemiological evidence for carcinogenicity of soluble nickel compounds as well as for nickel sulfide, nickel subsulfide and nickel oxides (Danish EPA 2005a, 2005b, 2005c, 2005d, 2005e, 2005f). IARC (1990) concluded that “nickel compounds are carcinogenic to humans (Group 1)”. Chronic animal studies have shown carcinogenicity for the poorly water-soluble nickel compounds tested, but the NTP studies with nickel sulfate failed to show a positive result.

NiPERA (2005) has argued that while it would appear that the carcinogen classification of nickel sulfate, nickel subsulfide, and nickel monoxide can be read-across to all the inorganic and organic compounds in the Danish proposal, the very fact that all these compounds are classified as Carc. Cat. 1; R49 demonstrates a fallacy in the use of water solubility for extrapolation. Since all these compounds have different water solubilities, but have each been deemed to be Category 1 carcinogens it is obvious that the determinant of carcinogenic potential has nothing to do with water solubility. In fact, it appears that there are two separate modes of action by which exposure to nickel substances may increase the appearance of tumors. For water insoluble nickel compounds the likely determinant of carcinogenicity is the bioavailability of the nickel ion released from these compounds to the critical site in the target cells in the lung. Nickel substances with very low bioavailability may not cause tumors at all. For inorganic water soluble salts of nickel, the mode of action may be secondary to localized toxicity. In this case, the solubility is high but the bioavailability is low due to poor uptake of the nickel ion into the cells. This is demonstrated in the fact that there is no evidence of systemic carcinogenicity at the oral MTD which occurs at exposures that are higher than can be achieved through inhalation (hence the R49 classification for nickel compounds). Since it is clear that simple water solubility is not the determining factor in the carcinogenicity of these compounds it is not possible to predict how all of the compounds proposed by the Danes for classification will behave biologically. This is particularly true of the organic compounds where it is not certain how they will be metabolized or whether “nickel” will be bioavailable at all.

The EU TC C&L agreed that read-across for classification for carcinogenicity was reasonable for all the compounds in the revised category. However, following a lengthy discussion, a majority of Member States agreed that the classification should be in Category 2 rather than in Category 1, as the classification was based on read-across. This view was not supported by a number of Member States that argued that Category 1 classification was appropriate since it was the nickel ion that was the basis for the classification. The conclusions of the discussions in the EU TC C&L have been discussed further within the Commission, who have proposed classification in Category 1, with reference to the SCHER opinion on the risk assessment of the nickel compounds in which the classification is based on the effects of the nickel ion (SCHER, 2006), adopted subsequent to the discussions in the EU TC C&L.

82. Reproductive toxicity Reproductive toxicity is identified as a hazard with the soluble and sparingly water-soluble nickel compounds evaluated as reference compounds.

NiPERA (2005) commented that reproductive toxicity is a threshold based toxicity. Therefore, the nickel ion will have to be made bioavailable to the target organs in sufficient concentration to cause the effect. This requires the reproductive toxicity threshold to be reached before the Maximum Tolerated Dose of the maternal animal prevents higher exposure. In the case of water soluble nickel salts this scenario can occur. It is unclear if it can occur with the sparingly soluble compounds and it is unlikely to occur with the insoluble compounds. In addition, the systemic bioavailability of the nickel ion would have to be ascertained for all the organonickel compounds in order to ascertain whether the reproductive toxicity hazard could exists from exposure to these compounds. Consequently, NiPERA did not agree on relying on solubility as the sole

28 decision criteria and considered that some toxicokinetic data on the absorption, bioavailability, and metabolism of each compound must be included to make an informed extrapolation.

The EU TC C&L agreed to read-across classification as Repr. Cat. 2; R61 for all the soluble and sparingly soluble nickel compounds.

The conclusions of the discussions in the EU TC C&L for the sparingly soluble compounds have been the discussed further within the Commission. As for mutagenicity, there is evidence of systemic availability of the nickel ion for nickel carbonate and nickel hydroxide as shown by the acute toxicity of these compounds, and hence, effects on reproductive toxicity cannot be excluded. For the other semi-soluble compounds included in the proposal, information demonstrating systemic availability is not available. Given the differences in water-solubility between the slightly soluble compounds (with water solubility in the range 10-4 - 10-2 mol/L) and the soluble compounds (from 10-2 to over 5·10-1 mol/L), the assumption that the nickel ion is systemically available for the slightly soluble compounds is not necessarily justified, and the read-across for this systemic effect is not used, and Note H is used to cover this endpoint for the slightly-soluble compounds.

83. Hazards to the aquatic environment. The TC C&L Environment group has agreed that the appropriate L(E)C50 value for the evaluation of these compounds is 0.068 mg/L. The TC C&L Environment group has agreed that all the nickel compounds with the exception of the nickel oxides and metallic nickel should be classified as N; R50-53. Since the classification is based on the toxicity of the nickel ion, the molecular weights of the different compounds have been checked to see whether this classification requires modification (to e.g. N; R51-53). No correction for molecular weight is necessary.

In accordance with the metal classification strategy agreed by the TC C&L Environment group, nickel monoxide was originally classified as R53 by default because of lack of data. According to data subsequently provided by Industry, the greatest Ni2+ ion concentration achieved in dissolution testing of nickel oxide is 4µg/L and the average value was 2 µg/L (NiPERA, 2006). NiPERA (2006) argued that since no significant amounts of nickel ion were released, the R53 value is not merited and should not be used for any substances analogous to nickel oxide. The Danish EPA (2006b) pointed out in reply that since the chronic toxicity EC10 value is less than 4 µg/l, the classification should remain as R53. This was agreed by the EU TC C&L Environment group at the meeting in April 2006.

Where there is a clear analogy to nickel oxide, these compounds are classified as R53. In other cases, where there is uncertainty about the contribution of other metal constituents to the environmental classification, no environmental classification has been given and Note H has been added for this effect.

ADVICE WHEN READ-ACROSS IS NOT NECESSARILY APPLICABLE.

84. In cases where read-across has not been applied, the classification for certain endpoints is covered by Note H.

The wording of Note H in the Foreword to Annex I is shown in the 28th ATP (EC 2001b).

“Note H: The classification and label shown for this substance applies to the dangerous property(ies) indicated by the risk phrase(s) in combination with the category(ies) of danger shown. The requirements of Article 6 of this Directive on manufacturers, distributors and importers of this substance apply to all other aspects of classification and labelling. The final label shall follow the requirements of section 7 of Annex VI of this Directive.

This note applies to certain coal- and oil-derived substances and to certain entries for groups of substances in Annex I.”

29 Whilst this category approach for the nickel compounds could be considered as a group entry, as the nickel compounds covered by the Danish proposal are shown individually, the EU TC C&L has agreed to delete the last sentence in Note H in the 31st ATP currently in preparation in order to avoid any ambiguity.

85. Inclusion of Note H imposes a duty on the manufacturers, distributors and importers of a substance where this label is included to evaluate the hazards not specifically addressed in the harmonised classification shown in Annex I. The following paragraphs indicate possible ways to do this for the hazards that have not been specifically covered on the basis of read-across.

86. Acute toxicity NiPERA (2006) has suggested that the biological information already available in the scientific literature can be combined with in vitro test data to provide an empirical means of future extrapolation of the acute toxicity potential by untested nickel containing materials. Specifically, in vivo determination of the LD50 values for multiple nickel compounds has been published in the scientific literature. Determination of nickel release rates for each of the tested compounds in in vitro gastric and lung fluid dissolution tests will establish a range of nickel concentrations in these tests for nickel ion induced LD50 values from < 200 mg/kg bw to > 5000 mg/kg bw. Comparison of the equivalent dissolution test nickel ion concentration of a nickel compound for which the LD50 is unknown to the known values will permit an estimation of the in vivo LD50 value for both oral and inhalation exposure. A final evaluation of the potential impact of the counter-ion will have to be made for the material with an “unknown” LD50 (NiPERA, 2006).

For acute toxicity, most of the available data for both soluble and slightly soluble compounds is in the range of oral toxicity currently covered by the criteria for “Harmful” (200 mg/kg bw < LD50 < 2000 mg/kg bw). As a default position, soluble and sparingly soluble nickel compounds included in this category should be classified as Xn; R20/22. However, counter-ions and the presence of other metal ions may lead to increased toxicity, and it is likely that there are additional soluble nickel compounds that, like nickel chloride, show an LD50 < 200 mg/kg (e.g. nickel cyanide). Use of the additivity formula given in Note A can be used. In vivo testing should only be considered as a last resort.

It should also be noted that the data on inhalational toxicity is very limited, and consideration should be given to this endpoint in evaluating the substance.

87. Irritation/ corrosivity The evidence for skin irritation for nickel sulfate and nickel chloride comes from human experience, and the results of the available animal studies are negative. There is evidence that the effect is more severe in the case of some counter-ions, e.g. the oxidising counter-ions nitrate and chlorate. It would probably be difficult to prove convincingly that a soluble nickel salt was not skin irritating, as a negative animal study would be consistent with the effects seen with nickel sulfate. This would appear to be supported by the fact that Material Safety data sheets for a number of nickel compounds already include skin and eye irritation as potential health hazards, without any apparent data to support this.

As a default position, soluble and sparingly soluble nickel compounds included in this category should be classified as Xi; R38. If there is reason to believe that the counter-ion would lead to a greater effect, a more stringent classification for skin and eye should also be considered. If necessary, this can be supplemented by relevant in vitro tests. In vivo testing should only be considered as a last resort.

88. Mutagenicity For the compounds for which Note H has been recommended, there is very little data for this effect. The group of “sulfidic compounds” are a fairly limited group of compounds with very similar water solubility (e.g. borides, phosphides, selenides, arsenides). The data on which the classification for mutagenicity is based (Comet assay) reflects concerns for genotoxicity rather than for germ cell mutagenicity.

Since the Comet assay is a non-standard test, it is difficult to recommend this as a basis for further testing. The evaluation of this group of compounds for this effect is unlikely to be easy, and is probably best approached by systematic development of relevant data for this effect for this group of compounds.

30

89. Hazards to the aquatic environment. For nickel oxides where no environmental classification is shown, either a screening or a full 28-day 2+ transformation/dissolution protocol test should be carried out. For Ni concentrations exceeding 0.068 (EC50) mg/L, classification with N; R50-53 is appropriate. For Ni2+ concentrations between 0.068 mg/L and 0.0024 mg/L classification with R53 is appropriate. For Ni2+ concentrations below 0.0024 mg/L derived from a full 28-day transformation/dissolution protocol test, no hazard classification for this effect is required.

CONCLUSIONS.

90. The discussions reported above describe the arguments used in

a) initiating a discussion for a category approach (Danish EPA, 2005a), including a rationale for the proposed classification for each entry b) refining the approach (Danish EPA 2006a) including a revised rationale for the proposed classification for each entry and finally c) agreeing a category approach.

These discussions resulted in the two relevant EU Working groups, the TC C&L for Human Health and for Environmental Effects agreeing to the Danish proposal, as modified as a result of the discussions in these Technical Committees.

Following the discussions in the Technical Committees, a modified version of these proposals (including the use of Note H to cover mutagenicity and reproductive toxicity for the group of semi-soluble nickel compounds and classification as a Category 1 carcinogen) has been circulated by the Commission DG ENV for comments. A draft of the classification proposals for including classifications for 117 compounds has been posted by the ECB on its website (ECB, 2007).

31 REFERENCES

Aitio (1995): Nickel and nickel compounds. The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals. Arbete och Hälsa vetenskaplig skriftserie 1995:26, no 119. Solna: Arbetslivsinstitutet, 1995: pp. 1-61.

Alfa Aesar (2005): MSDS for iron nickel oxide. Available at: http://www.alfa.com/CGI- BIN/LANSAWEB?WEBEVENT+L0B5CAE8B28478200287606U+ALF+ENG

Belgium (2005): Comments from Belgium on the Danish proposal for an approach to a group classification for Nickel compounds. May, 2005. ECBI/96/04 – Add 8. Document available on the ECB website as: http://ecb.jrc.it/classlab/9604a8_B_nickel.doc

Carlsen L (2001a): Aqueous Solubilities and Complex Stabilities of Ni(II) Species. Part I: Inorganic Ligands. Draft report to the Danish EPA35.

Carlsen L (2001b): Aqueous Solubilities and Complex Stabilities of Ni(II) Species. Part II: Organic Ligands. Draft report to the Danish EPA36.

CEN [Comité Européen de Normalisation] (1998): Reference test method for release of nickel from products intended to come into direct and prolonged contact with the skin. EN 1811:1988.

Danish EPA (2005a): Classification of nickel compounds: Danish proposal for an approach to a group classification. 20. April, 2005. ECBI/96/04 Add 2. Document available on the ECB website as: http://ecb.jrc.it/classlab/9604a2_DK_ nickel

Danish EPA (2005b): Nickel (CAS-No.: 7440-02-0, EINECS-No.: 231-111-4) Risk Assessment: Draft for final written approval of JuneNovember 2005, Chapters 0, 1, 2, 4, 5, 6 & 7 – human health only. R311_1105_hh_chapter0124567

Danish EPA (2005c): Nickel sulfate (CAS-No.: 7786-81-4, EINECS-No.: 232-104-9) Risk Assessment: Draft for final written approval of JuneNovember 2005, Chapters 0, 1, 2, 4, 5, 6 & 7 – human health only. R312_1105_hh_chapter0124567

Danish EPA (2005d): Nickel carbonate (CAS-No.: 3333-67-3, EINECS-No.: 222-068-2) Risk Assessment: Draft for final written approval of JuneNovember 2005, Chapters 0, 1, 2, 4, 5, 6 & 7 – human health only. R419_1105_hh_chapter0124567

Danish EPA (2005e): Nickel dihloride (CAS-No.: 7718-54-9, EINECS-No.: 231-743-0) Risk Assessment: Draft for final written approval of JuneNovember 2005, Chapters 0, 1, 2, 4, 5, 6 & 7 – human health only. R420_1105_hh_chapter0124567

Danish EPA (2005f): Nickel dinitrate (CAS-No.: 13138-45-9, EINECS-No.: 236-068-5) Risk Assessment: Draft for final written approval of JuneNovember 2005, Chapters 0, 1, 2, 4, 5, 6 & 7 – human health only. R424_1105_hh_chapter0124567

Danish EPA (2006a): Classification of nickel compounds: Revised Danish proposal for classification of nickel compounds. 6. February, 2006. ECBI/96/04 – Add 2 – Rev. 1. Document available on the ECB website as: http://ecb.jrc.it/classlab/9604a2r1_DK_%20nickel.doc.

35 This draft reports is available on request from the Danish EPA 36 This draft reports is available on request from the Danish EPA.

32

Danish EPA (2006b): Danish comments on the comments of the nickel producers February 27, 2006: “Comments on Toxicity Categories Regarding the “Classification of Nickel Compounds: Revised Danish Proposal for Classification of Nickel Compounds””, environmental classification. March 7 2006. ECBI/26/95 – Add. 84. Document available on the ECB website as: http://ecb.jrc.it/classlab/2695a84_DK_nickel.doc

Danish EPA (2006c): Danish proposal for grouping nickel entries agreed at the meeting of the TC C&L 03/2006. 27. March, 2006. ECBI/96/04 – Add. 25. Document available on the ECB website as: http://ecb.jrc.it/classlab/9604a25_draft%20Annex%20I%20entries.doc.

Danish EPA (2006d): Nickel and nickel compounds: Background Document in support of individual risk assessment reports of nickel compounds prepared in relation to Council Regulation (EEC) 793/93: Draft for final written approval of November 2006, Chapters 0, 1, 2, 4, 5, 6 & 7 – human health only. R_NickelBackground_1105_hh_chapter0124567

Danish EPA (2007): Danish proposal for classification of 5 nickel compounds in preparation for the workshop on experience in applying the GHS criteria for classification and labelling using SIDS documents. Email from Lena Marianne Höglund (Danish EPA) to Anne Gourmelon (OECD Secretariate), 2. May, 2007 and available on the OECD restricted access website.

EC (1994): European Parliament and Council Directive 94/27/EC of 30 June 1994 on the 12th amendment of Directive 76/769/EEC on the approximation of the laws, regulations and administrative provisions relating to the marketing and use of certain dangerous substances and preparations. OJ. L188, 22.7.1994, p. 1-2.

EC (2001a): Commission Decision 2001/118/EC of 16 January 2001 amending Decision 2000/532/EC as regards the list of wastes. OJ. L47, 16.2.2001, p. 1 – 31

EC (2001b): Commission Directive 2001/59/EC of 6 August 2001 adapting to technical progress for the 28th time Council Directive 67/548/EEC on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances. O.J. L225. 21.8.2001, p.1 – 333.

ECB (2007a): Final TC C&L proposal for the 30th ATP. Available on the ECB Classification & Labelling homepage: http://ecb.jrc.it/classification-labelling/.

ECB (2007b): Final TC C&L proposal for the 31st ATP. Available on the ECB Classification & Labelling homepage: http://ecb.jrc.it/classification-labelling/.

ECICS [European Customs Inventory of Chemical Substances] (1997): European Customs Inventory of Chemical Substances – A guide to the classification of chemicals in the Combined Nomenclature. Volume 1 – Alphabetical list of chemical products. Volume 2 – Numerical list (by CUS-Number) Correlation between CAS- and CUS-Numbers. Office for Official Publications of the European Communities. ISBN 92-828-0637- 5. Also available online at: http://europa.eu.int/comm./taxation_customs/dds/en/ecicau.databases/ecis_en.htm.

EEC (1977): Council Directive 77/728/EEC of 7. November, 1977 on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of paints, varnishes, adhesives and similar products. OJ L303, 28.11.1977, p. 23.

EEC (1988): Council Directive 88/379/EEC of 7. June, 1988 on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous preparations. OJ L187, 16.07.1988, p. 14.

EEC (1991):Commission Directive 91/326/EEC of 29. July, 1983 adapting to Technical Progress for the twelfth time Council Directive 67/548/EEC on the approximation of the laws, regulations and administrative

33 provisions relating to the classification, packaging and labelling of dangerous substances. OJ L180 & OL L180A, 8.07.1991, p. 1.

Environment Canada and Health Canada (1994): PSL1 Report on Nickel and its Compounds. Cat. No.: En 40- 215/43E

ETAD (2005): ETAD Position onClassification of nickel compounds: Danish proposal for an approach to a Group classification. 12 October 2005. ECBI/96-04 – Add. 18. Also available online at: http://ecb.jrc.it/classlab/9604a18_IND_nickel.doc.

Eurocolour (2002): Letter and document from Eurocolour to Danish rapporteur, 1. August, 2002. From Danish EPA, 2006d.

Eurocolour (2005): Comments on Danish Proposal for Classification of Inorganic Poigments containing Nickel. ECBI/96/04 – Add. 17

Eurocolour (2006). Report on nickel leaching from Rutile and Spinel Pigments. 4. May 2006. ECBI/42/06 Add. 10. Detailed study results are shown in documents ECBI/42/06 Add. 11 parts I- XVII which are available to governmental authorities only.

European Commission (1990): Commission communication pursuant to Article 13 of Council Directive 67/548/EEC of 27 June 1967 on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances, as amended by Directive 79/831/EEC (90/C146A/01). EINECS (European inventory of existing commercial chemical substances). O.J. C146A, 15.6.1990, p. 1.

European Commission (2004): Document ECBI/74/04 Rev. 2. Summary Record: Commission Working Group of Specialised Experts in the fields of Carcinogenicity and Mutagenicity. Meeting held at Arona, April 20-21, 2004. Ispra, August 2, 2004.

IARC (1990): IARC Monographs on the evaluation of carcinogenic risks to humans, Volume 49, Chromium, nickel and welding. IARC, Lyon, France, 1990. pp. 257-446.

IPCS (1991): Environmental Health Criteria 108: Nickel. World Health Organisation, Geneva. 383 p.;

IPCS (1996): Guidelines for drinking water quality. Volume 2. Health criteria and other supporting information. World Health Organisation, Geneva, 1996 p. 308-313.

Laine L (2003): Nickel Carbonate Derogation Statement, 29.04.2003.

Milieu (2005a): Project Report from Milieu on Technical support for the preparation of the Annexes for the draft EU legislation implementing GHS. Available at: http://ecb.jrc.it/classlab/Final_GHS_Report.doc

Milieu (2005b): Part 1: Tables of Equivalence from Project Report from Milieu on Technical support for the preparation of the Annexes for the draft EU legislation implementing GHS Annex VI. Available at: http://ecb.jrc.it/classlab/Equivalence_tables-Milieu.doc

N-CLASS Database on Environmental Hazard Classification: http://www.kemi.se/nclass/:

NiPERA (1996): Occupational 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. Public health and Safety at Work Directorate. Batiment Jean Monnet, Plateau du Kirchberg. L-2920 Luxembourg.

34 NiPERA (2005): Comments on Toxicity Categories and compounds regarding the “Classification of Nickel Compounds and Complex Materials: DEPA Proposal for an approach to group classification”. Comments of the Nickel Producers Environmental Research Association (NiPERA). Submitted by the European Nickel Industry Association (ENIA). February 8 2005. ECBI/96/04 – Add. 20. Document available on the ECB website as: http://ecb.jrc.it/classlab/9604a20_IND-nickel.pdf

NiPERA (2006): Comments on Toxicity Categories regarding the “Classification of Nickel Compounds: revised Danish Proposal for Classification of Nickel compounds”. Comments of the Nickel Producers Environmental Research Association (NiPERA). Submitted by the European Nickel Industry Association (ENIA). February 23 2006. Document available on the ECB website as: http://ecb.jrc.it/classlab/9604a23_IND_nickel.doc

SCHER opinion on risk assessment report on nickel compounds, Human health part, Adopted by the SCHER during the 11th plenary of 4 May 2006. http://ec.europa.eu/health/ph_risk/committees/04_scher/docs/scher_o_034.pdf

TAPIR - Final Report Appendix 9. Information Working Group 3 (IWG-3). Non-Testing Considerations. 25th February, 2005 – Editorial changes May 2005. Appendix 2.4.1.B Group entries in Annex I to Directive 67/548/EEC (up to and including the 29th. ATP). Available at the ECB website: http://ecb.jrc.it/reach/rip/

TERA (1999): Toxicological review of soluble nickel salts. Prepared for: Metal Finishing Association of Southern California, Inc., US Environmental Protection Agency and Health Canada. Prepared by Toxicology Excellence for Risk Assessment (TERA) under subcontract in part with Science Applications International Corporation (SAIC). EPA Contract #68-C7-0011. March 1999.

UK HSE (1987): Toxicity Review 19. The toxicity of nickel and its organic compounds. Fairhurst & Illing. London. HMSO. ISBN 0 11 883961 6

US ATSDR (1997): Toxicological Profile for Nickel. September 1997. US Department of Health and Human Services, Public Health Service.

UNEP (2005): Chemicals Screening Information datraset for High Volume Chemicals. C.I. Pigment Yellow 53. http://www.chem.unep.ch/irptc/sids/OECDSIDS/8007189.pdf

35 TABLE 1: INVENTORY OF NICKEL COMPOUNDS

In the following inventory, compounds reviewed by the Danish EPA review of HPV chemicals under the EU Existing Chemicals Regulation are shown with green shading. The classification for these entries is included in the 30th ATP.

Other nickel compounds already in Annex I with Annex I numbers starting with 028 (nickel) are also shown with green shading. Where relevant, revisions to the classification of these entries has been agreed for inclusion in the draft 31st. ATP (ECB, 2007b).

Compounds for which classification proposals based on a group approach have been agreed for inclusion in the draft 31st ATP are shaded in yellow.

Compounds explicitly excluded from the category approach using read-across are shaded in red.

Unshaded nickel containing compounds were not included in the category approach using read-across for a variety of reasons and are not considered further in this review. It should be noted that further analysis might show that some of these compounds may in fact be suitable for this approach.

TABLE 1.1: Nickel and Nickel Compounds in Einecs.

The nickel compounds in Einces are divided into four groups in this Table: nickel and compounds with nickel metals; inorganic nickel compounds, organic nickel compounds and diverse nickel-containing compounds.

Nickel and compounds with nickel metal. EC Number CAS Annex I No. Chemical Name HPVC / CUS 37 Number LPVC Number 231-111-4 7440-02-0 028-002-00-7 Nickel HPVC 11024 234-439-6 12003-78-0 Aluminum, compd. with nickel (1:1) 235-261-1 12142-92-6 Nickel, compd. with zirconium (1:2) 234-807-6 12034-55-8 Nickel, compd. with niobium (1:1) 235-034-7 12059-23-3 Nickel, compd. with tin (3:1) 234-827-5 12035-52-8 [051-003-00-9] Antimony, compd. with nickel (1:1) 235-676-8 12503-49-0 [051-003-00-9] Antimony, compd. with nickel (1:3) 235-372-5 12196-72-4 Lanthanum, compd. with nickel (1:5) 235-341-6 12175-27-8 Dysprosium, compd. with nickel (1:2) 235-773-5 12688-64-1 Bismuth, compd. with nickel (1:1) 257-510-3 51912-52-8 Copper, compd. with lanthanum and nickel (4:1:1)

37 The EU CUS number is a five-digit number in the European Customs Inventory of Chemical Substances (ECICS). The list shows the correlation between the CUS number and the CAS number

36 Inorganic nickel compounds. EC Number CAS Annex I No. Chemical Name HPVC / CUS Number LPVC Number 215-215-7 1313-99-1 028-003-00-2 Nickel monooxide (NiO) HPVC 20749 215-217-8 1314-06-3 028-005-00-3 Nickel trioxide (Ni2O3) 20765 234-323-5 11099-02-8 (028-003-00-2) Nickel oxide 234-823-3 12035-36-8 028-004-00-6 Nickel dioxide (NiO2) 234-454-8 12004-35-2 Aluminum nickel oxide (Al2-NiO4) 234-825-4 12035-39-1 Nickel titanium oxide (NiTiO3) 235-752-0 12653-76-8 Nickel-titanium-oxide- 257-970-5 52502-12-2 Nickel vanadium oxide (NiV2-O6) 234-636-7 12018-18-7 Chromium nickel oxide (Cr2-NiO4) 235-335-3 12168-54-6 Iron nickel oxide (Fe2-NiO4) 306-902-3 97435-21-7 Iron nickel zinc oxide (Fe2-NiZnO4) 261-346-8 58591-45-0 Cobalt nickel oxide (CoNiO2) 269-051-6 68186-89-0 Cobalt-nickel-gray-periclase- LPVC 268-169-5 68016-03-5 Cobalt molybdenum nickel oxide (CoMo2-NiO8) 274-755-1 70692-93-2 Nickel zirconium oxide (NiZrO3) 305-835-7 95046-47-2 Spinels, cobalt nickel zinc grey 238-034-5 14177-55-0 Molybdenum nickel oxide (MoNiO4) 234-824-9 12035-38-0 Nickel tin oxide (NiSnO3) 20760 238-032-4 14177-51-6 Nickel tungsten oxide (NiWO4) 239-876-6 15780-33-3 [092-002-00-3] Nickel uranium oxide (NiU3-O10) 277-627-3 73892-02-1 [051-003-00-9] Antimony oxide (Sb2-O3), solid soln. with nickel oxide (NiO) and titanium oxide (TiO2) 232-353-3 8007-18-9 [051-003-00-9] Antimony-nickel-titanium-oxide-yellow- LPVC 269-071-5 68187-10-0 Nickel-ferrite-brown-spinel- LPVC 271-112-7 68515-84-4 Olivine, nickel green 271-853-6 68610-24-2 [056-002-00-7] Nickel-barium-titanium-primrose-priderite-; C.I. Pigment Yellow 157 271-892-9 68611-43-8 Nickel-niobium-titanium-yellow-rutile- 275-738-1 71631-15-7 Nickel-iron-chromite-black-spinel- LPVC 309-018-6 99749-23-2 Cassiterite, cobalt manganese nickel grey 273-686-4 69011-05-8 Nickel titanium oxide tungstate (NiTi20-O35-(WO6)2) 269-047-4 68186-85-6 C.I.Pigment Green 50 234-348-1 11113-74-9 028-008-00-X Nickel hydroxide 235-008-5 12054-48-7 028-008-00-X Nickel dihydroxide (Ni(OH)2) LPVC 20745 234-493-0 12007-00-0 Nickel boride (NiB) 234-494-6 12007-01-1 Nickel boride (Ni2-B) 234-495-1 12007-02-2 Nickel boride (Ni3-B) 235-723-2 12619-90-8 Nickel-boride-

37

Inorganic nickel compounds (continued). 235-033-1 12059-14-2 Nickel silicide (Ni2-Si) 235-379-3 12201-89-7 Nickel silicide (NiSi2) 234-828-0 12035-64-2 Nickel phosphide (Ni2-P) 234-349-7 11113-75-0 028-006-00-9 Nickel sulphide 234-829-6 12035-72-2 028-007-00-4 Nickel subsulphide (Ni3S2) 25517 240-841-2 16812-54-7 028-006-00-9 Nickel sulphide (NiS) LPVC 25516 235-103-1 12068-61-0 [033-002-00-5] Nickel arsenide (NiAs2) 248-169-1 27016-75-7 [033-002-00-5] Nickel arsenide (NiAs) 215-216-2 1314-05-2 [034-002-00-8] Nickel selenide (NiSe) 233-263-7 10101-96-9 [034-002-00-8] Selenious acid, nickel(2+) salt (1:1) 239-125-2 15060-62-5 [034-002-00-8] Selenic acid, nickel(2+) salt (1:1) 20757 235-260-6 12142-88-0 Nickel telluride (NiTe) 20758 271-512-1 68583-44-8 Cadmium sulfide (CdS), solid soln. With zinc sulfide, nickel and silver-doped 271-539-9 68584-42-9 Cadmium sulfide (CdS), solid soln. With zinc sulfide, copper and nickel-doped 270-961-0 68512-22-1 Zinc sulfide (ZnS), nickel and silver-doped 271-601-5 68585-93-3 Zinc sulfide (ZnS), copper and nickel-doped 272-277-8 68784-84-9 Zinc sulfide (ZnS), copper and nickel and silver-doped 236-669-2 13463-39-3 028-001-00-1 Nickel carbonyl (Ni(CO)4), (T-4)- 20730 209-160-8 557-19-7 [006-007-00-5] Nickel cyanide (Ni(CN)2) 20734 254-261-2 39049-81-5 Nickelate(2-), tris(cyano-C)-, dipotassium 238-082-7 14220-17-8 Nickelate(2-), tetrakis(cyano-C)-, dipotassium, (SP-4-1)- 238-946-3 14874-78-3 Ferrate(4-), hexakis(cyano-C)-, nickel(2+) (1:2), (OC-6- 20738 11)- 222-068-2 3333-67-3 028-010-00-0 Carbonic acid, nickel(2+) salt HPVC 20729 240-408-8 16337-84-1 028-010-00-0 Carbonic acid, nickel salt 235-715-9 12607-70-4 028-010-00-0 [carbonato(2-)]tetrahydroxytrinickel LPVC (25626)38 265-748-4 65405-96-1 028-010-00-0 [μ-[carbonato(2-)-O:O’]]dihydroxy trinickel 233-071-3 10028-18-9 Nickel fluoride (NiF2) LPVC 20739 231-743-0 7718-54-9 028-012-00-1 Nickel dichloride (NiCl2) HPVC 2073139 253-399-0 37211-05-5 Nickel-chloride- {a nickel[1] compound} 267-897-0 67952-43-6 Chloric acid, nickel(2+) salt 237-124-1 13637-71-3 Perchloric acid, nickel(2+) salt 20754 236-665-0 13462-88-9 Nickel bromide (NiBr2) LPVC 20728 238-596-1 14550-87-9 Bromic acid, nickel(2+) salt 236-666-6 13462-90-3 Nickel iodide (NiI2) 20747

38 The CUS Number shown is for the tetrahydrate, CAS No. 39430-27-8. 39 Also nickel (II) chloride hexahydrate, CAS No.: 7791-20-0, CUS No.: 39096

38

Inorganic nickel compounds (continued). 231-827-7 7757-95-1 Sulfurous acid, nickel(2+) salt (1:1) 232-104-9 7786-81-4 028-009-00-5 Nickel sulphate HPVC 20762 237-563-9 13842-46-1 Sulfuric acid, nickel(2+) potassium salt (2:1:2) 20756 239-793-5 15699-18-0 Sulfuric acid, ammonium nickel(2+) salt (2:2:1) 11026 275-897-7 71720-48-4 Sulfuric acid, monoethyl ester, nickel(2+) salt 237-396-1 13770-89-3 Sulfamic acid, nickel(2+) salt (2:1) LPVC 20761 239-967-0 15851-52-2 Telluric acid (H2-TeO3), nickel(2+) salt (1:1) 239-974-9 15852-21-8 Telluric acid (H2-TeO4), nickel(2+) salt (1:1) 236-068-5 13138-45-9 028-013-00-7 Nickel dinitrate HPVC 2075040 238-076-4 14216-75-2 028-013-00-7 Nitric acid, nickel salt 238-278-2 14332-34-4 Phosphoric acid, nickel(2+) salt (1:1) 242-522-3 18718-11-1 Phosphoric acid, nickel(2+) salt (2:1) 233-844-5 10381-36-9 Phosphoric acid, nickel(2+) salt (2:3) 20751 268-585-7 68130-36-9 Molybdenum-nickel-hydroxide-oxide-phosphate- 238-426-6 14448-18-1 Diphosphoric acid, nickel(2+) salt (1:2) 238-511-8 14507-36-9 Phosphinic acid, nickel(2+) salt 20746 252-840-4 36026-88-7 Phosphinic acid, nickel salt 236-771-7 13477-70-8 [033-005-00-1] Arsenic acid (H3-AsO4), nickel(2+) salt (2:3) 20724 244-578-4 21784-78-1 Silicic acid (H2-SiO3), nickel(2+) salt (1:1) 237-411-1 13775-54-7 Silicic acid (H4-SiO4), nickel(2+) salt (1:2) 20759 250-788-7 31748-25-1 Silicic acid (H2-SiO3), nickel(2+) salt (4:3) 253-461-7 37321-15-6 Silicic acid, nickel salt 235-688-3 12519-85-6 Nickel hydroxide silicate (Ni3-(OH)4-(Si2-O5)) 238-766-5 14721-18-7 [024-017-00-8] Chromic acid (H2-CrO4), nickel(2+) salt (1:1) 20732 239-646-5 15586-38-6 [024-017-00-8] Dichromic acid (H2-Cr2-O7), nickel(2+) salt (1:1) 237-595-3 13859-60-4 Nickelate(2-), tetrafluoro-, dipotassium, (T-4)- 308-989-3 99587-11-8 Nickelate(2-), tetrachloro-, diammonium, (T-4)- 246-378-2 24640-21-9 Nickelate(1-), trichloro-, ammonium 11021 237-597-4 13859-65-9 Nickel, tetrakis(phosphorous trifluoride)-, (T-4)- 238-753-4 14708-14-6 Borate(1-), tetrafluoro-, nickel(2+) (2:1) 20740 237-638-6 13877-20-8 Nickel(2+), hexaammine-, (OC-6-11)-, bis[tetrafluoroborate(1-)] 247-430-7 26043-11-8 [009-013-00-6] Silicate(2-), hexafluoro-, nickel(2+) (1:1) 20741 250-370-4 30868-55-4 Zirconate(2-), hexafluoro-, nickel(2+) (1:1), (OC-6-11)- 235-531-9 12263-13-7 Molybdate(3-), tetracosa-mu-oxododecaoxo[mu12- [phosphato(3-)- O:O:O:O':O':O':O'':O'':O'':O''':O''':O''']]dodeca-, nickel(2+) (2:3)

40 Also nickel(II) nitrate hexahydrate, CAS No.: 13478-00-7, CUS No. 39097.

39 Organic nickel compounds (listed in order of increasing carbon number). EC Number CAS Chemical Name HPVC / Number LPVC 222-101-0 3349-06-2 Formic acid, nickel(2+) salt 20742 239-946-6 15843-02-4 Formic acid, nickel salt 268-755-0 68134-59-8 Formic acid, copper nickel salt 272-149-1 68758-60-1 Nickel(2+), hexaammine-, (OC-6-11)-, diformate 237-205-1 13689-92-4 [615-032-00-6] Thiocyanic acid, nickel(2+) salt 208-933-7 547-67-1 [607-007-00-3] Ethanedioic acid, nickel(2+) salt (1:1) 20752 243-867-2 20543-06-0 [607-007-00-3] Ethanedioic acid, nickel salt 206-761-7 373-02-4 Acetic acid, nickel(2+) salt LPVC 2072341 239-086-1 14998-37-9 Acetic acid, nickel salt LPVC 240-235-8 16083-14-0 Acetic acid, trifluoro-, nickel(2+) salt 262-383-2 60700-37-0 2-Propenoic acid, nickel(2+) salt 257-066-0 51222-18-5 2-Propenoic acid, nickel salt 267-961-8 67968-22-3 Nickelate(4-), [[[nitrilotris(methylene)]tris[phosphonato]](6-)]-, triammonium hydrogen, (T-4)- 264-338-2 63588-33-0 Nickelate(4-), [[[nitrilotris(methylene)]tris[phosphonato]](6-)]-, tetrapotassium, (T-4)- 268-296-6 68052-00-6 Nickelate(4-), [[[nitrilotris(methylene)]tris[phosphonato]](6-)- N,O,O'',O''']-, tetrasodium, (T-4)- 222-102-6 3349-08-4 Propanoic acid, nickel(2+) salt 267-923-0 67952-69-6 1,2,3-Propanetriol, mono(dihydrogen phosphate), nickel(2+) salt (1:1) 269-946-1 68391-37-7 1,2,3-Propanetriol, 1-(dihydrogen phosphate), nickel(2+) salt (1:1) 264-136-4 63427-32-7 [006-007-00-5] Copper(2+), bis(1,2-ethanediamine-N,N’)-, (SP-4-1)- tetrakis(cyano-C)nickelate(2-) (1:1) 273-379-5 68958-89-4 [006-007-00-5] Nickel(2+), bis(1,2-ethanediamine-N,N’)-, bis[bis(cyano- C)aurate(1-)] 244-300-1 21264-77-7 Nickel(2+), bis(ethylenediamine)-, sulfate (1:1) 287-849-2 85586-46-5 Nickel, bis(1H-1,2,4-triazole-3-sulfonato-N(2)-,O(3))- 228-501-1 6283-67-6 2-Butenedioic acid (E)-, nickel(2+) salt (1:1) 237-618-7 13869-33-5 Nickel, [N-(carboxymethyl)glycinato(2-)-N,O,O(N)-]- 268-711-0 68133-84-6 Nickel, [(2-amino-2-oxoethoxy)acetato(2-)]- 268-195-7 68025-40-1 Nickelate(3-), [N,N-bis(phosphonomethyl)glycinato(5-)]- , triammonium, (T-4)- 264-360-2 63597-34-2 Nickelate(3-), [N,N-bis(phosphonomethyl)glycinato(5-)]- , tripotassium, (T-4)- 268-196-2 68025-41-2 Nickelate(3-), [N,N-bis(phosphonomethyl)glycinato(5-)]- , trisodium, (T-4)-

41 Also nickel(II) acetate tetrahydrate, CAS No.: 6018-89-9, CUS No. 39093.

40 Organic nickel compounds (continued). 257-963-7 52496-91-0 2-Propenoic acid, 2-methyl-, nickel(2+) salt 304-466-9 94275-78-2 2-Propenoic acid, 2-methyl-, nickel salt 267-894-4 67952-41-4 Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-, nickel(2+) salt (2:1) 257-610-7 52022-10-3 Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-, nickel salt 237-877-6 14038-85-8 [006-007-00-5] Nickelate(2-), tetrakis(cyano-C)-, disodium, (SP-4-1)- 273-375-3 68958-86-1 Nickelate(6-), [[[1,2- ethanediylbis[nitrilobis(methylene)]]tetrakis[phosphonat o]](8-)]-, pentaammonium hydrogen, (OC-6-21)- 273-376-9 68958-87-2 Nickelate(6-), [[[1,2- ethanediylbis[nitrilobis(methylene)]]tetrakis[phosphonat o]](8-)]-, pentapotassium hydrogen, (OC-6-21)- 273-377-4 68958-88-3 Nickelate(6-), [[[1,2- ethanediylbis[nitrilobis(methylene)]]tetrakis[phosphonat o]](8-)]-, pentasodium hydrogen, (OC-6-21)- 257-953-2 52486-98-3 Nickel, bis[(2-hydroxyethyl)carbamodithioato-S,S’]-, (SP-4-1)- 239-560-8 15521-65-0 Nickel, bis(dimethylcarbamodithioato-S,S’)-, (SP-4-1)- 20737 252-235-5 34831-03-3 Nickelate(1-), [N,N-bis(carboxymethyl)glycinato(3-)- N,O,O’,O’’]-, hydrogen, (T-4)- 264-377-5 63640-18-6 Nickelate(1-), [N,N-bis(carboxymethyl)glycinato(3-)- N,O,O’,O’’]-, potassium, (T-4)- 254-642-3 39819-65-3 Benzenesulfonic acid, nickel(2+) salt 303-972-7 94232-44-7 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, cobalt(2+) nickel(2+) salt (2:1:2) 227-873-2 6018-92-4 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, nickel(2+) 20733 salt (2:3) 304-013-5 94232-84-5 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, cobalt(2+) nickel(2+) salt (2:2:1) 268-176-3 68025-13-8 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, ammonium nickel(2+) salt (2:2:1) 242-533-3 18721-51-2 Citric acid, nickel(2+) salt (1:1) 242-161-1 18283-82-4 Citric acid, ammonium nickel salt 245-119-0 22605-92-1 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, nickel salt 209-046-8 553-71-9 Benzoic acid, nickel(2+) salt 20726 254-210-4 38951-94-9 Nickel, bis[2-butene-2,3-dithiolato(2-)-S,S’]-, (SP-4-1)- 275-994-4 71767-12-9 [092-002-00-3] Uranate(2-), tetrakis(acetato-O)dioxo-, nickel(2+) (1:1), 20766 (OC-6-11)- 236-782-7 13478-93-8 Nickel, bis[(2,3-butanedione dioximato)(1-)-N,N’]-, (SP- 16135 4-1)- 224-699-9 4454-16-4 Hexanoic acid, 2-ethyl-, nickel(2+) salt 231-480-1 7580-31-6 Hexanoic acid, 2-ethyl-, nickel salt 301-323-2 93983-68-7 Hexanoic acid, dimethyl-, nickel salt 225-656-7 4995-91-9 Octanoic acid, nickel(2+) salt LPVC 249-555-2 29317-63-3 Isooctanoic acid, nickel(2+) salt 248-585-3 27637-46-3 Isooctanoic acid, nickel salt

41 Organic nickel compounds (continued). 284-349-6 84852-37-9 Isononanoic acid, nickel(2+) salt 300-094-6 93920-10-6 Neononanoic acid, nickel(2+) salt 215-039-0 1271-28-9 Nickelocene- 274-912-4 70824-02-1 Nickel, bis(5-oxo-L-prolinato-N(1)-,O(2))- 285-069-7 85026-81-9 Nickel, bis(5-oxo-DL-prolinto-N(1)-,O(2))- 247-019-2 25481-21-4 Nickelate(2-), [[N,N'-1,2-ethanediylbis[N- (carboxymethyl)glycinato]](4-)-N,N',O,O',O(N)-,O(N')- ]-, dihydrogen, (OC-6-21)- 267-686-3 67906-12-1 Nickelate(1-), [[N,N'-1,2-ethanediylbis[N- (carboxymethyl)glycinato]](4-)-N,N',O,O',O(N)-,O(N')- ]-, potassium, (OC-6-21)- 221-875-7 3264-82-2 Nickel, bis(2,4-pentanedionato-O,O')-, (SP-4-1)- 223-463-2 3906-55-6 Cyclohexanebutanoic acid, nickel(2+) salt 20735 257-954-8 52486-99-4 Nickel, bis[bis(2-hydroxyethyl)carbamodithioato-S,S']-, (SP-4-1)- 278-504-7 76625-10-0 Nickel, bis[N-(2-hydroxyethyl)-N-methylglycinato- N,O,O(N)-]- 238-157-4 14267-17-5 Nickel, bis(diethylcarbamodithioato-S,S')-, (SP-4-1)- 258-044-3 52610-81-8 Nickel, bis(diethylcarbamodithioato-S,S')- 287-468-1 85508-43-6 Isodecanoic acid, nickel(2+) salt 287-469-7 85508-44-7 Neodecanoic acid, nickel(2+) salt 257-447-1 51818-56-5 Neodecanoic acid, nickel salt 239-028-5 14949-69-0 Nickel, bis(1,1,1,5,5,5-hexafluoro-2,4-pentanedionato- O,O')-, (SP-4-1)- 300-093-0 93920-09-3 Neoundecanoic acid, nickel(2+) salt 235-339-5 12170-92-2 Nickel, di-mu-carbonylbis(eta(5)-2,4-cyclopentadien-1- yl)di-, (Ni-Ni) 255-387-0 41476-75-9 Nickel, bis(1-piperidinecarbodithioato-S,S')- 20753 276-205-6 71957-07-8 Nickel, bis(D-gluconato-O(1)-,O(2))- 258-051-1 52625-25-9 Benzoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, nickel(2+) salt (2:1) 215-072-0 1295-35-8 Nickel, bis[(1,2,5,6-eta)-1,5-cyclooctadiene]- 32526 238-536-4 14522-99-7 Nickel, bis(6-methyl-2,4-heptanedionato-O,O')- 284-350-1 84852-38-0 Nickel, (2-ethylhexanoato-O)(isooctanoato-O)- 237-138-8 13654-40-5 Hexadecanoic acid, nickel(2+) salt 274-916-6 70833-37-3 Nickel, bis(3-amino-4,5,6,7-tetrachloro-1H-isoindol-1- LPVC one oximato-N(2)-,O(1))- 250-401-1 30947-30-9 Phosphonic acid, [[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]methyl]-, monoethyl ester, nickel(2+) salt (2:1) 287-470-2 85508-45-8 Nickel, (2-ethylhexanoato-O)(isononanoato-O)- 287-471-8 85508-46-9 Nickel, (isononanoato-O)(isooctanoato-O)- 265-022-7 64696-98-6 Nickel, [2,3'-bis[[(2-hydroxyphenyl)methylene]amino]- 2-butenedinitrilato(2-)-N(2)-,N(3)-,O(2)-,O(3)-]-, (SP-4- 2)-

42 Organic nickel compounds (continued). 237-950-2 14100-15-3 Nickel, bis(8-quinolinolato-N(1)-,O(8))- 239-841-5 15751-00-5 Nickel(2+), hexakis(1H-imidazole-N(3))-, dichloride, (OC-6-11)- 284-347-5 84852-35-7 Nickel, (isooctanoato-O)(neodecanoato-O)- 284-351-7 84852-39-1 Nickel, (2-ethylhexanoato-O)(isodecanoato-O)- 285-698-7 85135-77-9 Nickel, (2-ethylhexanoato-O)(neodecanoato-O)- 285-909-2 85166-19-4 Nickel, (isodecanoato-O)(isooctanoato-O)- 235-832-5 13001-15-5 9-Octadecenoic acid (Z)-, nickel(2+) salt 237-696-2 13927-77-0 Nickel, bis(dibutylcarbamodithioato-S,S')-, (SP-4-1)- LPVC 20736 239-354-8 15317-78-9 Nickel, bis[bis(2-methylpropyl)carbamodithioato-S,S']-, (SP-4-1)- 218-744-1 2223-95-2 Octadecanoic acid, nickel(2+) salt 27634 288-967-7 85958-80-1 Nickel, [2-hydroxybenzoic acid [3-[1-cyano-2- (methylamino)-2-oxoethylidene]-2,3-dihydro-1H- isoindol-1-ylidene]hydrazidato(2-)]- 284-348-0 84852-36-8 Nickel, (isodecanoato-O)(isononanoato-O)- 287-592-6 85551-28-6 Nickel, (isononanoato-O)(neodecanoato-O)- 235-829-9 12794-26-2 Nickel, bis(1-nitroso-2-naphthalenolato)- 238-380-7 14406-66-7 Nickel, bis(1-nitroso-2-naphthalenolato-N(1)-,O(2))-, (T- 4)- 249-503-9 29204-84-0 Nickel, bis[2,3-bis(hydroxyimino)-N- LPVC phenylbutanamidato-N(2)-,N(3)-]- 287-467-6 85508-42-5 Nickel, (isodecanoato-O)(neodecanoato-O)- 300-092-5 93920-08-2 Nickel, (neononanoato-O)(neoundecanoato-O)- 256-331-8 47726-62-5 Nickel, [[2,2'-(4,8-dichlorobenzo[1,2-d:4,5- d']bisoxazole-2,6-diyl)bis[4,6-dichlorophenolato]](2-)]- 255-924-9 42739-61-7 Nickel, bis[2,3-bis(hydroxyimino)-N-(2- LPVC methoxyphenyl)butanamidato]- 252-937-1 36259-37-7 Nickel, bis(dipentylcarbamodithioato-S,S')-, (SP-4-1)- 286-563-5 85269-39-2 Nickel, bis[N-(2,4-dimethoxyphenyl)-2,3- bis(hydroxyimino)butanamidato-N(2)-,N(3)-]-, (SP-4-1)- 279-314-7 79817-91-7 Nickelate(3-), [5-[(4,5-dihydro-3-methyl-5-oxo-1- phenyl-1H-pyrazol-4-yl)azo]-4-hydroxy-3-[(2-hydroxy- 3-nitro-5-sulfophenyl)azo]-2,7-naphthalenedisulfonato(5- )]-, trisodium 243-820-6 20437-10-9 Nickel, [[1,1'-[1,2- phenylenebis(nitrilomethylidyne)]bis[2- naphthalenolato]](2-)-N,N',O,O']- 249-353-4 28984-20-5 Nickel, bis[1,2-diphenyl-1,2-ethenedithiolato(2-)-S,S']-, (SP-4-1)- 248-536-6 27574-34-1 Nickel, [[2,2'-thiobis[4-(1,1,3,3- tetramethylbutyl)phenolato]](2-)-O,O',S]- 251-715-1 33882-09-6 Nickel, [[2,2'-thiobis[3-octylphenolato]](2-)-O,O',S]- 240-485-8 16432-37-4 Nickel, [[2,2'-sulfonylbis[4-(1,1,3,3- tetramethylbutyl)phenolato]](2-)-O(1)-,O(1')-,O(2)-]- 262-703-0 61300-98-9 Nickelate(1-), [3,4-bis[[(2-hydroxy-1- naphthalenyl)methylene]amino]benzoato(3-)-N(3)-,N(4)- ,O(3)-,O(4)-]-, hydrogen

43 Organic nickel compounds (continued). 255-965-2 42844-93-9 Nickel, [1,3-dihydro-5,6-bis[[(2-hydroxy-1- naphthalenyl)methylene]amino]-2H-benzimidazol-2- onato(2-)-N(5)-,N(6)-,O(5)-,O(6)-]-, (SP-4-2)- 257-521-3 51931-46-5 Nickel, bis[3-[(4-chlorophenyl)azo]-2,4(1H,3H)- quinolinedionato]- 267-045-8 67763-27-3 Nickel, (2-propanol)[[2,2'-thiobis[4-(1,1,3,3- tetramethylbutyl)phenolato]](2-)-O,O',S]- 249-155-8 28680-76-4 Nickel, [29H,31H-phthalocyaninetetrasulfonyl tetrachloridato(2)-N(29)-,N(30)-,N(31)-,N(32)-]- 237-893-3 14055-02-8 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)- LPVC ,N(31)-,N(32)-]-, (SP-4-1)- 254-212-5 38951-97-2 Nickel, bis[1,2-bis(4-methoxyphenyl)-1,2- ethenedithiolato(2-)-S,S']-, (SP-4-1)- 253-958-9 38465-55-3 Nickel, bis[1-[4-(dimethylamino)phenyl]-2-phenyl-1,2- ethenedithiolato(2-)-S,S']- 238-523-3 14516-71-3 Nickel, (1-butanamine)[[2,2'-thiobis[4-(1,1,3,3- LPVC tetramethylbutyl)phenolato]](2-)-O,O',S]- 276-364-1 72139-08-3 Nickelate(8-), bis[3-[(2-amino-8-hydroxy-6-sulfo-1- naphthalenyl)azo]-2-hydroxy-5-sulfobenzoato(5-)]-, hexasodium dihydrogen 281-282-4 83898-70-8 Nickel, dimethoxy[29H,31H-phthalocyaninato(2-)- N(29)-,N(30)-,N(31)-,N(32)-]-, (OC-6-12)- 274-027-3 69524-96-5 Nickel, bis(4-benzoyl-2,4-dihydro-5-methyl-2-phenyl- 3H-pyrazol-3-onato-O,O')- 238-400-4 14428-08-1 Nickel, bis[bis(2-ethylhexyl)carbamodithioato-S,S']- 238-154-8 14264-16-5 Nickel, dichlorobis(triphenylphosphine)- 32583 279-060-7 79102-62-8 Nickelate(4-), [[[(3-amino-4- sulfophenyl)amino]sulfonyl]-29H,31H- phthalocyaninetrisulfonato(6-)-N(29)-,N(30)-,N(31)- ,N(32)-]-, tetrahydrogen 300-365-9 93939-76-5 Nickelate(4-), [[[(3-amino-4- sulfophenyl)amino]sulfonyl]-29H,31H- phthalocyaninetrisulfonato(6-)-N(29)-,N(30)-,N(31)- ,N(32)-]-, tetrasodium 235-851-9 13007-90-4 Nickel, dicarbonylbis(triphenylphosphine)-, (T-4)- 32582 283-380-2 84604-95-5 Nickel, bis[bis(3,5,5-trimethylhexyl)carbamodithioato- S,S’]- 260-258-7 56557-00-7 Nickel, bis[2,4-dihydro-5-methyl-4-(1-oxodecyl)-2- phenyl-3H-pyrazol-3-onato-O,O’]- 276-491-2 72229-81-3 Nickelate(3-), [[[[3-[(4-amino-6-chloro-1,3,5-triazin-2- yl)amino]phenyl]amino]sulfonyl]tris(aminosulfonyl)- 29H,31H-phthalocyaninetrisulfonato(5-)-N(29)-,N(30)- ,N(31)-,N(32)-]-, trisodium 275-295-4 71243-96-4 Nickelate(3-), [22-[[[3-[(5-chloro-2,6-difluoro-4- pyrimidinyl)amino]phenyl]amino]sulfonyl]-29H,31H- phthalocyanine-1,8,15-trisulfonato(5-)-N(29)-,N(30)- ,N(31)-,N(32)-]-, trisodium, (SP-4-2)- 276-168-6 71889-22-0 Nickel, [mu-(piperazine-N(1)-:N(4))]bis[3-[1-[(4,5,6,7- tetrachloro-1-oxo-1H-isoindol-3-yl)hydrazono]ethyl]- 2,4(1H,3H)-quinolinedionato(2-)]di- 239-949-2 15843-91-1 Nickel, bis[[2-hydroxy-4- (octyloxy)phenyl]phenylmethanonato]-

44 Organic nickel compounds (continued). 306-462-2 97280-68-7 Nickelate(4-), [bis[[[4-[[2- (sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl]- 29H,31H-phthalocyaninedisulfonato(6)-N(29)-,N(30)- ,N(31)-,N(32)-]-, tetrasodium 245-028-6 22484-07-7 Nickel, [mu-[[1,1’,1’’,1’’’-[1,2,4,5- benzenetetrayltetrakis(nitrilomethylidyne)]tetrakis[2- naphthalenolato]](4-)]]di- 272-095-9 68698-80-6 Nickelate(6-), [4-[[5-[[(3,6-dichloro-4- pyridazinyl)carbonyl]amino]-2-sulfophenyl]azo]-4,5- dihydro-5-oxo-1-[5-[[(trisulfo-29H,31H- phthalocyaninyl)sulfonyl]amino]-2-sulfophenyl]-1H- pyrazole-3-carboxyla 299-467-3 93891-86-2 Nickelate(6-), [4-[[5-[[(3,6-dichloro-4- pyridazinyl)carbonyl]amino]-2-sulfophenyl]azo]-4,5- dihydro-5-oxo-1-[2-sulfo-5-[[(trisulfo-29H,31H- phthalocyaninyl)sulfonyl]amino]phenyl]-1H-pyrazole-3- carboxyla 272-799-6 68912-08-3 Nickel, bis(2-heptadecyl-1H-imidazole- N(3))bis(octanoato-O)- 279-067-5 79121-51-0 Nickel, bis(4-benzoyl-2,4-dihydro-5-methyl-2-phenyl- 3H-pyrazol-3-onato-O,O’)(2,2,4,4-tetramethyl-7-oxa- 3,20-diazadispiro[5.1.11.2]heneicosan-21-one-O(21))- 276-399-2 72152-45-5 Nickelate(6-), [22-[[[3-[[4,5-dihydro-3-methyl-5-oxo-1- [3-sulfo-4-[2-[2-sulfo-4-[(2,5,6-trichloro-4- pyrimidinyl)amino]phenyl]ethenyl]phenyl]-1H-pyrazol- 4-yl]azo]-4-sulfophenyl]amino]sulfonyl]-29H,31H- 306-784-3 97404-21-2 Nickel, [[N,N’,N’’-[29H,31H- phthalocyaninetriyltris(sulfonylimino-3,1- phenylene)]tris[3-oxobutanamidato]](2-)-N(29)-,N(30)- ,N(31)-,N(32)-]- 269-684-8 68309-97-7 Nickel(2+), tris(4,7-diphenyl-1,10-phenanthroline-N(1)- ,N(10))-, (OC-6-11)-, bis[tetrafluoroborate(1-)] 254-127-3 38780-90-4 Nickel(2+), tris(4,7-diphenyl-1,10-phenanthroline-N(1)- ,N(10))-, (OC-6-11)-, dinitrate 277-174-1 72986-45-9 Nickel, [N,N’,N’’,N’’’-tetrakis[4-(4,5-dihydro-3-methyl- 5-oxo-1H-pyrazol-1-yl)phenyl]-29H,31H- phthalocyaninetetrasulfonamidato(2-)-N(29)-,N(30)- ,N(31)-,N(32)-]- 306-785-9 97404-22-3 Nickel, [[N,N’,N’’,N’’’-[29H,31H- phthalocyaninetetrayltetrakis(sulfonylimino-3,1- phenylene)]tetrakis[3-oxobutanamidato]](2-)-N(29)- ,N(30)-,N(31)-,N(32)-]- 252-777-2 35884-66-3 Nickel, tetrakis[tris(methylphenyl) phosphite-P]- 262-934-7 61725-51-7 Nickel, 3-[(4-chlorophenyl)azo]-4-hydroxy-2(1H)- quinolinone complex 263-000-1 61788-71-4 Naphthenic acids, nickel salts 269-826-9 68334-36-1 Resin acids and Rosin acids, nickel salts 271-764-2 68607-31-8 Resin acids and Rosin acids, calcium nickel salts 270-174-2 68412-18-0 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)- ,N(31)-,N(32)-]-, sulfo [[4-[[2- (sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl derivs. 270-944-8 68511-62-6 Nickel, 5,5'-azobis-2,4,6(1H,3H,5H)-pyrimidinetrione LPVC complexes

45 Organic nickel compounds (continued). 276-877-0 72828-53-6 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)- ,N(31)-,N(32)-]-, [[3-[(1,3- dioxobutyl)amino]phenyl]amino]sulfonyl derivs. 294-302-1 91697-41-5 Fatty acids, C6-C19-branched, nickel salts 283-972-0 84776-45-4 Fatty acids, C8-C18 and C18-unsatd., nickel salts 287-356-2 85480-75-7 Nickel, 2,2'-thiobis[4-nonylphenol] complexes 291-676-8 90459-33-9 Nickel, isooctanoate naphthenate complexes 287-801-0 85585-98-4 Nickel, isononanoate naphthenate complexes 287-800-5 85585-97-3 Nickel, isodecanoate naphthenate complexes 287-802-6 85585-99-5 Nickel, naphthenate neodecanoate complexes 291-673-1 90459-30-6 Nickel, acetate carbonate C8-C10-branched fatty acids LPVC C9-C11-neofatty acids complexes 291-674-7 90459-31-7 Nickel, borate C8-C10-branched carboxylate complexes 291-675-2 90459-32-8 Nickel, C5-C23-branched carboxylate octanoate complexes 291-677-3 90459-34-0 Nickel, acetylacetone 6-methyl-2,4-heptanedione complexes 291-678-9 90459-35-1 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)- ,N(31)-,N(32)-]-, [[3-[(5-chloro-2,6-difluoro-4- pyrimidinyl)amino]phenyl]amino]sulfonyl sulfo derivs., sodium salts 291-679-4 90459-36-2 Nickelate(4-), [bis[[[3-[[4,5-dihydro-3-methyl-5-oxo-1- [4-[[2-(sulfooxy)ethyl]sulfonyl]phenyl]-1H-pyrazol-4- yl]azo]phenyl]amino]sulfonyl]-29H,31H- phthalocyaninedisulfonato(6-)-N(29)-,N(30)-,N(31)-,N(3 295-925-1 92200-98-1 Nickel, C5-C23-branched carboxylate naphthenate complexes 295-926-7 92200-99-2 Nickel, C5-C25-branched carboxylate naphthenate octanoate complexes 296-343-0 92502-55-1 Nickel, borate neodecanoate complexes 297-548-8 93573-14-9 Nickel, C5-C23-branched carboxylate C4-C10-fatty acids naphthenate complexes 297-549-3 93573-15-0 Nickel, C4-C10 fatty acids naphthenate complexes 297-550-9 93573-16-1 Nickel, C4-C10 fatty acids octanoate complexes 297-774-7 93762-59-5 Nickel, C5-C23-branched carboxylate C4-C10 fatty acids complexes 297-551-4 93573-17-2 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)- ,N(31)-,N(32)-]-, chlorosulfonyl derivs., reaction products with 2-[(4-aminophenyl)sulfonyl]ethyl hydrogen sulfate monosodium salt, potassium sodium 305-643-3 94891-42-6 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)- ,N(31)-,N(32)-]-, chlorosulfonyl derivs., reaction products with 2-[(4-aminophenyl)sulfonyl]ethyl hydrogen sulfate monosodium salt, potassium salts 305-644-9 94891-43-7 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)- ,N(31)-,N(32)-]-, chlorosulfonyl derivs., reaction products with 2-[(4-aminophenyl)sulfonyl]ethyl hydrogen sulfate monosodium salt, sodium salts

46 Diverse Nickel compounds. EC Number CAS Annex I No. Chemical Name HPVC / CUS Number LPVC Number 307-554-5 97660-42-9 Copper, bis(8-quinolinolato-N(1)-,O(8))-, reaction products with C8-C10-branched fatty acids, tert-decanoic acid, nickel(2+) diacetate, nickel(2+) carbonate (1:1) and nickel hydroxide (Ni(OH)2) 283-945-3 84776-20-5 Bentonite, nickeloan 232-490-9 8052-42-4 Asphalt HPVC 266-046-0 65997-17-3 Glass, oxide, chemicals HPVC 266-047-6 65997-18-4 Frits, chemicals HPVC 266-048-1 65997-19-5 Steel manufacture, chemical 266-340-9 66402-68-4 Ceramic materials and wares, chemicals HPVC 266-965-7 67711-89-1 Calcines, copper roasting 266-967-8 67711-91-5 Matte, copper HPVC 266-968-3 67711-92-6 Slags, copper smelting HPVC 268-627-4 68131-74-8 Ashes, residues HPVC 273-700-9 69011-59-2 Lead alloy, base, dross LPVC 273-701-4 69011-60-5 Lead alloy, base, Pb,Sn, dross HPVC 273-704-0 69011-64-9 Babbitt, dross 273-720-8 69012-20-0 Waste solids, copper electrolyte purifn. cathodes HPVC 273-729-7 69012-29-9 Slags, ferronickel-manufg. HPVC 273-749-6 69012-50-6 Matte, nickel HPVC 273-795-7 69029-51-2 Lead, antimonial, dross 282-214-6 84144-92-3 Leach residues, nickel-vanadium ore 293-311-8 91053-46-2 Leach residues, zinc ore-calcine, cadmium-copper ppt. HPVC 293-312-3 91053-47-3 Leach residues, zinc ore-calcine, iron contg. HPVC 293-796-6 91082-81-4 Waste solids, chromium-nickel steel manuf. 293-799-2 91082-84-7 Waste solids, nickel-manuf. 295-859-3 92129-57-2 Slimes and Sludges, copper electrolyte refining, HPVC decopperised, Ni sulfate 297-402-3 93571-76-7 Ashes (residues), heavy fuel oil fly LPVC 305-433-1 94551-87-8 Slimes and Sludges, copper electrolyte refining, LPVC decopperised 308-765-5 98246-91-4 [082-001-00-6] Speiss, lead, nickel-contg. 310-050-8 102110-49-6 [082-001-00-6] Residues, copper-iron-lead-nickel matte, sulfuric acid- insol.

Note: Einecs entries that include a reference to nickel as e.g. a catalyst rather than as a constituent have not been included.

47 TABLE 1.2: Nickel compounds included in Elincs.

EC Number CAS Annex I No. Chemical Name HPVC / CUS Number LPVC Number 410-160-7 148732-74-5 607-288-00-2 Tetrasodium (c-(3-(1-(3-(e-6-dichloro-5-cyanopyrimidin- f-yl(methyl)amino)propyl)-1,6-dihydro-2-hydroxy-4- methyl-6-oxo-3-pyridylazo)-4- sulfonatophenylsulfamoyl) phtalocyanine-a,b,d- trisulfonato(6-))nickelato II, where a is 1 or 2 or 3 or 4,b is 8 or 9 or 10 or 11, c is 15 or 16 or 17 or 18, d is 22 or 23 or 24 or 25 and where e and f together are 2 and 4 or 4 and 2 respectively 407-110-1 - 611-103-00-0 Trisodium (1-(3-carboxylato-2-oxido-5- sulfonatophenylazo)-5-hydroxy-7-sulfonatophthalen-2- amido)nickel(II) 417-250-5 151436-99-6 611-122-00-2 Hexasodium (di(N-(3-(4-[5-(5-amino-3-methyl-1- phenylpyrazol-4-yl-azo)-2,4-disulfo-anilino]-6-chloro- 1,3,5-triazin-2-ylamino)phenyl)-sulfamoyl](disulfo)- phthalocyaninato)nickel

48 TABLE 1.3: Additional Nickel compounds, and complex substances containing nickel included in TSCA (through 08/2000) but not included in Einecs.

EC No. CAS Number Annex I No. Chemical Name HPVC/ CUS LPVC Number 12031-65-1 Lithium nickel oxide (LiNiO2) 12645-50-0 Iron-nickel-zinc-oxide- 12673-58-4 Molybdenum-nickel-oxide- 12737-30-3 Cobalt-nickel-oxide- 14221-00-2 Nickel, tetrakis(triphenyl phosphite-kappaP)-, (T-4)- 14406-71-4 Nickel, [[2,2'-[1,2-phenylenebis[(nitrilo- kappaN)methylidyne]]bis[phenolato-kappaO]](2-)]- 14434-67-4 Nickel, bis(hexahydro-1H-azepine-1-carbodithioato- kappaS,kappaS')-, (SP-4-1)- 17169-61-8 Phosphoric acid, calcium nickel salt 18824-79-8 1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, nickel(2+) salt (1:1) 18972-69-5 [006-007-00-5] Nickel(2+), bis(1,2-propanediamine- kappaN,kappaN')-, bis[bis(cyano-kappaC)aurate(1-)] 19372-20-4 Diphosphoric acid, nickel(2+) salt 34109-80-3 Titanate(2-), hexafluoro-, nickel(2+), (1:1), (OC-6- 11)- 36545-21-8 Nickel, bis[(phenyldiazenecarbothioic acid-kappaS) 2-phenylhydrazidato-kappaN2]- 51449-18-4 Nickel, bis[1-[4-(diethylamino)phenyl]-2-phenyl- 1,2-ethenedithiolato(2-)-kappaS,kappaS']- 53199-85-2 Nickel(1+), [1-[2-amino-4-(imino-kappaN)-5(4H)- thiazolylidene]-N-[1-[2-amino-4-(imino-kappaN)- 5(4H)-thiazolylidene]-1H-isoindol-3-yl-kappaN]- 1H-isoindol-3-aminato-kappaN2]-, chloride 54576-53-3 [051-003-00-9] Antimony-nickel-titanium-oxide- 55868-93-4 Benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)- 4-hydroxy-, nickel(2+) salt (2:1) 65229-23-4 Nickel-boron-phosphide- 68189-15-1 Nickel, bis[[2-(hydroxy-kappaO)-4- octylphenyl]phenylmethanonato-kappaO]- 68412-19-1 Nickel, [29H,31H-phthalocyaninato(2-)- N29,N30,N31,N32]-, [(3- aminophenyl)amino]sulfonyl sulfo derivs. 68412-20-4 Nickel, dextrin complexes 68585-48-8 Sulfuric acid, nickel(2+) salt (1:1), reaction products with nickel and nickel oxide (NiO) 69012-51-7 Copper cake, zinc-refining 70776-98-6 Nickel, (2-ethylhexanoato-kappaO)(trifluoroacetato- kappaO)- 71050-57-2 Acetic acid, nickel(2+) salt, polymer with formaldehyde and 4-(1,1,3,3-tetramethylbutyl)phenol

49

Additional Nickel compounds in TSCA (continued) 71215-73-1 Nickel, [[2,2'-[methylenebis(thio- kappaS)]bis[acetato-kappaO]](2-)]- 71215-97-9 Nickel(2+), tris(1,2-ethanediamine- kappaN,kappaN')-, (OC-6-11)-, salt with dimethylbenzenesulfonic acid (1:2) 71215-98-0 Nickel(2+), bis(1,2-ethanediamine- kappaN,kappaN')-, salt with dimethylbenzenesulfonic acid (1:2) 71605-83-9 Nickel, bis[N-hydroxy-3-(hydroxyimino-kappaN)- N'-(2-methoxyphenyl)butanimidamidato-kappaN']- 71889-20-8 Nickel, [N-(4-chlorophenyl)-3-[[[1-(4- chlorophenyl)-4,5-dihydro-3-methyl-5-(oxo- kappaO)-1H-pyrazol-4-yl]methylene]hydrazino- kappaN2]-alpha-cyano-1H-isoindole-3- acetamidato(2-)-kappaN2,kappaO3]- 72162-32-4 Sulfuric acid, nickel salt, reaction products with sulfurized calcium phenolate 72252-57-4 Nickel, [N,N',N''-tris[4-(4,5-dihydro-3-methyl-5- oxo-1H-pyrazol-1-yl)phenyl]-29H,31H- phthalocyanine-C,C,C-trisulfonamidato(2-)- kappaN29,kappaN30,kappaN31,kappaN32]- 72319-19-8 2,7-Naphthalenedisulfonic acid, nickel(2+) salt (1:1) 79357-65-6 Aluminum, triethyl-, reaction products with nickel(2+) bis(2-ethylhexanoate) 83864-02-2 Nickel, bis[(cyano-C)triphenylborato(1-)- N]bis(hexanedinitrile-N,N')- 91845-72-6 Fatty acids, C3-22, nickel salts, basic 106316-55- Nickel, aqua[2-[[4,5-dihydro-3-methyl-5-(oxo- 6 kappaO)-1H-pyrazol-4-yl]azo-kappaN1]benzoato(2- )-kappaO]- 108818-89- Nickel(2+), hexakis(1H-imidazole-kappaN3)-, (OC- 9 6-11)-, 1,2-benzenedicarboxylate (1:1) 113894-88- Nickel, [29H,31H-phthalocyaninato(2-)- 5 N29,N30,N31,N32]-, sulfo [[4-[[2- (sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl derivs., potassium sodium salts 131866-99- Nickel, [29H,31H-phthalocyaninato(2-)- 4 N29,N30,N31,N32]-, sulfo [[4-[[2- (sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl derivs., sodium salts

50 TABLE 1.4: Additional Nickel compounds listed in ECICS (European Customs Inventory of chemical substances), but not included in Einecs or the TSCA Inventory.

EC No. CAS No. Annex I No. Name HPVC/ CUS LPVC Number 10471-42-8 Nickel tartrate 20764 10534-88-0 Hexaamminenickel dichloride 18196 12137-12-1 Trinickel tetrasulfide 20763 12758-25-7 Nickel metaborate42 20727 13601-55-3 Hexaamminenickel dibromide 11020 15651-35-1 Tetraamminenickel dinitrate 11025 16039-61-5 Nickel dilactate 20748 74195-78-1 Diammonium nickel hexacyanoferrate 11023 74646-29-0 033-002-00-5 Trinickel bis(arsenite) 20725

TABLE 1.5: Additional Nickel compounds in Annex I to Directive 67/548/EEC but not in Einecs or TSCA.

EC No. CAS No. Annex I No. Name HPVC/ CUS LPVC Number

12256-33-6 033-002-00-5 nickel arsenide, Ni11As8

12255-80-0 033-002-00-5 nickel arsenide, Ni5As2 12255-10-6 033-002-00-5 nickel arsenide sulfide, NiAsS

12137-13-2 033-002-00-5 nickel selenide, Ni3Se2 71077-18-4 051-003-00-9 Rutile, antimony nickel yellow 68130-19-8 082-001-00-6 Silicic acid, lead nickel salt

TABLE 1.6: Additional nickel compound found in the course of compiling the inventory of nickel compounds.

EC No. CAS No. Annex I No. Name HPVC/ CUS LPVC Number 11132-10-8 nickel potassium fluoride

391864-36-1 nickel potassium cyanide (NiK2(CN)4) 55465-44-6 potassium nickel cyanide nickel calcium cyanide43 131344-56-4 cobalt lithium nickel oxide 162004-08-2 cobalt lithium nickel oxide (Co,Li,Ni)O2 510727-46-5 cobalt lithium nickel oxide (Co,Li)NiO2

42 The CAS number shown corresponds to boron nickel oxide and not to “nickel metaborate”. 43 Marketed without CAS No.

51 TABLE 1.7: Additional nickel hydroxycarbonate compounds not included in the lists above.

EC No. CAS No. Annex I No. Name, formula HPVC/ CUS LPVC Number

152008-07-6 4NiCO3.Ni(OH)2

128024-15-7 3NiCO3.Ni(OH)2

342774-56-5 Ni(CO3)0-1.5(OH)0-3

148522-90-1 3NiCO3.4Ni(OH)2 12122-15-5 pentanickel dicarbonate hexahydroxide, 2NiCO3.3Ni(OH)2

12274-86-1 NiCO3.3Ni(OH)2

404866-99-5 NiCO3.13Ni(OH)2

TABLE 1.8: Nickel containing minerals (from IARC, 1990 and NiPERA, 1996).

CAS Number Name Chemical composition 1 1 53809-86-2, 12174-14-0 Pentlandite (Fe,Ni)9S8 1314-04-1 Millerite NiS

12035-71-1 Heazlewoodite Ni3S2

Polydymite Ni3S4

Siegenite (Co,Ni)3S4

Violarite Ni2FeS4 2 12035-50-6 Vaesite NiS2

Pyrrhotite, nickeliferous (Fe,Ni)1-xS 1303-13-5 Niccolite, nickeline NiAs

12044-65-4 Maucherite Ni11As8

Rammelsbergite NiAs2 12255-11-7 Gersdorffite NiAsS 12201-85-3 Makinenite, Maekinenite NiSe 12125-61-0 Breithauptite NiSb 24270-51-7 Imgreite NiTe

Garnierite (Ni, Mg)SiO3.nH2O

Nickeliferous limonite (Fe,Ni)O(OH).nH2O 34492-97-2 Bunsenite NiO

39430-27-8 Zaratite (basic nickel carbonate, tetrahydrate) NiCO3.2Ni(OH)2.4H2O

Morenosite (nickel sulphate heptahydrate) NiSO4.7H2O Notes: 1) CAS No. 53809-86-2 corresponds to Fe9Ni9S16; CAS No. 12174-14-0 corresponds to (Fe0.4-0.6Ni0.4-0.6)9S8 (NiPERA, 1996). 2) IARC also lists pure nickel sulphide (NiS2), CAS No. 12035-51-7. Both compounds are in the +4 oxidation state. Minerals are exempted from registration under REACH. However, minerals should be classified if they fulfill the classification criteria. The chemical composition of some of these compounds could justify the use of read-across for relevant endpoints.

52