SCIENTIFIC OPINION Scientific Opinion on the safety and efficacy of copper compounds (E4) as feed additives for all animal species (cupric acetate, monohydrate; basic cupric carbonate, monohydrate; cupric chloride, dihydrate; cupric oxide; cupric sulphate, pentahydrate; cupric chelate of amino acids, hydrate; cupric chelate of glycine, hydrate), based on a dossier submitted by FEFANA asbl 1 EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) 2,3 ABSTRACT European Food Safety Authority (EFSA), Parma, Italy The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) has assessed seven copper compounds in the current application: cupric acetate, monohydrate; basic cupric carbonate, monohydrate; cupric chloride, dihydrate; cupric oxide; cupric sulphate, pentahydrate; cupric chelate of amino acids, hydrate; cupric chelate of glycine, hydrate. These compounds are safe sources of copper for all animal species/categories when used up to maximum authorised copper levels in feed. The use of copper compounds in water for drinking is considered unsafe for ovine and certain breeds of dogs and cats; for all other animal species/categories the simultaneous application of copper compounds via feed and water for drinking should be avoided. No concerns for consumer safety are expected from the use of the copper compounds under application in animal nutrition when used up to the maximum EU-authorised levels in feed. The additives under assessment should be treated as irritant to the skin and eye and skin sensitisers, and should be considered as hazardous by inhalation. Copper chelate of amino acids, hydrate, should also be considered a sensitiser by inhalation. The presence of nickel in the additives may induce contact dermatitis in workers; because of its nickel content, cupric sulphate, pentahydrate, would represent an additional hazard by inhalation to users. Potential risks to soil organisms have been identified after the application of piglet manure; there might be a potential concern related to sediment contamination with copper. Drawing final conclusions would need further model validation and refinement to the assessment of copper-based additives in livestock. The use of copper compounds in aquaculture is not expected to pose a risk. The extent to which copper-resistant bacteria contribute to the overall antibiotic resistance situation cannot be quantified at present. The copper compounds under assessment are efficacious in meeting animal requirements. European Food Safety Authority, 2015 KEY WORDS nutritional additive, compounds of trace elements, copper, copper compounds, safety, environment, efficacy 1 On request from the European Commission, Questions No EFSA-Q-2011-00741, adopted on 11 March 2015. 2 Panel members: Gabriele Aquilina, Vasileios Bampidis, Maria De Lourdes Bastos, Lucio Guido Costa, Gerhard Flachowsky, Mikolaj Antoni Gralak, Christer Hogstrand, Lubomir Leng, Secundino López-Puente, Giovanna Martelli, Baltasar Mayo, Fernando Ramos, Derek Renshaw, Guido Rychen, Maria Saarela, Kristen Sejrsen, Patrick Van Beelen, Robert John Wallace and Johannes Westendorf. Correspondence: FEEDAP@efsa.europa.eu 3 Acknowledgement: The Panel wishes to thank wishes to thank the members of the Working Group on Trace Elements, including Noël Albert Dierick, Jürgen Gropp and Alberto Mantovani, for the preparatory work on this scientific opinion. Suggested citation: EFSA FEEDAP Panel (EFSA Panel on Additives and Products or Substances used in Animal Feed), 2015. Scientific Opinion on the safety and efficacy of copper compounds (E4) as feed additives for all animal species (cupric acetate, monohydrate; basic cupric carbonate, monohydrate; cupric chloride, dihydrate; cupric oxide; cupric sulphate, pentahydrate; cupric chelate of amino acids, hydrate; cupric chelate of glycine, hydrate), based on a dossier submitted by FEFANA asbl., 51 pp. doi:10.2903/j.efsa.2015.4057 Available online: www.efsa.europa.eu/efsajournal European Food Safety Authority, 2015
SUMMARY Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of the following copper compounds as feed additives for all animal species: cupric acetate, monohydrate; basic cupric carbonate, monohydrate; cupric chloride, dihydrate; cupric oxide; cupric sulphate, pentahydrate; cupric chelate of amino acids, hydrate; and cupric chelate of glycine, hydrate. All the copper compounds under application are safe sources of copper for all animal species/categories when used up to maximum European Union (EU)-authorised copper levels in complete feed. The use of copper compounds in water for drinking is considered unsafe for ovine and certain breeds of dogs and cats. For all other animal species/categories the simultaneous application of copper compounds via feed and water for drinking should be avoided. No concerns for consumer safety are expected from the use of the copper compounds under application in animal nutrition when used up to the maximum EU-authorised levels in feed. In the absence of specific studies and considering the toxicological profiles of copper and its compounds, the FEEDAP Panel considers that the additives under assessment should be treated as irritant to the skin and eye and as skin sensitisers, and should be considered hazardous by inhalation. In addition, copper chelate of amino acids, hydrate, should be considered a sensitiser by inhalation. The presence of nickel in the additives may induce contact dermatitis in workers; since the high nickel content in cupric sulphate, pentahydrate, may lead to inhalation exposure significantly exceeding the limits set by the occupational exposure limit for nickel, the use of this additive would represent an additional hazard to users. Potential risks to soil organisms have been identified as a result of application of piglet manure. Levels of copper in other types of manure are too low to pose a potential risk within the timescale considered. There might also be a potential environmental concern related to the contamination of sediment owing to drainage and the run-off of copper to surface water. In order to draw a final conclusion, further model validation is needed and some further refinement to the assessment of copper-based feed additives in livestock needs to be considered, for which additional data would be required. The use of copper-containing additives in aquaculture, up to the maximum authorised copper level in feeds, is not expected to pose an appreciable risk to the environment. The extent to which copper-resistant bacteria contribute to the overall antibiotic resistance situation cannot be quantified at present. The copper compounds under application are efficacious in meeting animal copper requirements. The FEEDAP Panel made some recommendations mainly concerning (i) the name of some of the compounds which should be aligned with the most standard naming convention (i.e. IUPAC); (ii) the characterisation of the cupric chelate of amino acids, hydrate; (iii) the use of copper-based additives via premixtures; (iv) measures to avoid risk to users/workers; (v) the use of copper-based additives in water for drinking, which is seen as critical to ensure compliance with the legally established maximum supply of copper to animals. 2
TABLE OF CONTENTS Abstract... 1 Summary... 2 Background... 4 Terms of reference... 5 Assessment... 8 1. Introduction... 8 2. Characterisation... 9 2.1. Cupric acetate, monohydrate... 9 2.2. Basic cupric carbonate, monohydrate... 10 2.3. Cupric chloride, dihydrate... 11 2.4. Cupric oxide... 12 2.5. Cupric sulphate, pentahydrate... 13 2.6. Cupric chelate of amino acids, hydrate... 14 2.7. Cupric chelate of glycine, hydrate... 16 2.7.1. Cupric chelate of glycine, hydrate (solid)... 16 2.7.2. Cupric chelate of glycine, hydrate (liquid)... 17 2.8. Physico-chemical incompatibilities in mixtures... 18 2.9. Conditions of use... 18 2.10. Evaluation of the analytical methods by the European Union Reference Laboratory (EURL). 19 3. Safety... 19 3.1. Safety for the target species... 19 3.1.1. Conclusions on the safety for target species... 21 3.2. Safety for the consumer... 21 3.2.1. Absorption and deposition... 21 3.2.2. Toxicological studies... 23 3.2.3. Assessment of consumer safety... 24 3.2.4. Conclusions on the safety for consumers... 24 3.3. Safety for the users... 24 3.3.1. Skin and eye irritancy and sensitisation... 25 3.3.2. Inhalation toxicity... 25 3.3.3. Conclusions on the safety for users... 26 3.4. Safety for the environment... 26 3.4.1. Conclusions on the safety for the environment... 27 4. Efficacy... 28 5. Post-market monitoring... 28 Conclusions and recommendations... 28 General Remarks... 30 Documentation provided to EFSA... 30 References... 30 Abbreviations... 35 Appendix A. List of Risk Assessment Reports (RARs) on copper and copper compounds... 37 Appendix B. List of authorisations for copper compounds other than as feed additives... 39 Appendix C. Details on the characterisation and identity of the compounds for which more than one company is involved in the application... 41 Appendix D. Copper deposition in liver and muscle... 48 Annex A. Executive Summary of the Evaluation Report of the European Union Reference Laboratory for Feed Additives on the Method(s) of Analysis for Copper... 50 3
BACKGROUND 4 Copper E4 (seven compounds) for all animal species Regulation (EC) No 1831/2003 5 establishes the rules governing the Community authorisation of additives for use in animal nutrition. Article 4(1) of that Regulation lays down that any person seeking authorisation for a feed additive or for a new use of a feed additive shall submit an application in accordance with Article 7. Article 10(2) of that Regulation also specifies that for existing products within the meaning of Article 10(1), an application shall be submitted in accordance with Article 7, at the latest one year before the expiry date of the authorisation given pursuant to Directive 70/524/EEC for additives with a limited authorisation period, and within a maximum of seven years after the entry into force of this Regulation for additives authorised without time limit or pursuant to Directive 82/471/EEC. The European Commission received a request from TREAC EEIG (Trace Elements Authorisation Consortium European Economic Interest Grouping) 6 for (i) authorisation of a new use, and (ii) reevaluation of authorisation, of seven copper-containing additives (cupric acetate, monohydrate; basic cupric carbonate, monohydrate; cupric chloride, dihydrate; cupric oxide; cupric sulphate, pentahydrate; cupric chelate of amino acids, hydrate; cupric chelate of glycine, hydrate) when used as feed additives for all animal species (category: nutritional additives; functional group: compounds of trace elements). According to Article 7(1) of Regulation (EC) No 1831/2003, the Commission forwarded the application to the European Food Safety Authority (EFSA) under Article 4(1) (authorisation of a feed additive or new use of a feed additive) and under Article 10(2) (re-evaluation of an authorised feed additive). EFSA received directly from the applicants the technical dossiers in support of this application. 7 According to Article 8 of that Regulation, EFSA, after verifying the particulars and documents submitted by the applicant, shall undertake an assessment in order to determine whether the feed additive complies with the conditions laid down in Article 5. The particulars and documents in support of the application were considered valid by EFSA as of 21 September 2011. The additives Cupric acetate, monohydrate, Basic cupric carbonate, monohydrate, Cupric chloride, dihydrate, Cupric oxide, Cupric sulphate, pentahydrate, Cupric chelate of amino acids, hydrate and Cupric chelate of glycine, hydrate had been authorised in the EU under the element Copper-Cu (E4) for all animal species Without a time limit (Commission Regulation (EC) No 1334/2003 8 and Commission Regulation (EC) No 479/2006) 9 and amendments. Following the provisions of Article 10(1) of Regulation (EC) No 1831/2003 the compounds were included in the EU Register of Feed Additives under the category Nutritional additives and the functional group Compounds of trace elements. 10 The Scientific Committee on Animal Nutrition (SCAN) delivered reports on the use of copper methionate for pigs (EC, 1981), copper compounds in feedingstuffs (EC, 1982) and in feedingstuffs for pigs (EC, 1983) and the use of copper in feedingstuffs (EC, 2003a). EFSA issued opinions on the safety of the chelated forms of iron, copper, manganese and zinc with synthetic feed grade glycine (EFSA, 2005), on the safety and efficacy of a copper chelate of hydroxy analogue of methionine (Mintrex Cu) as feed additive for all species (EFSA, 2008a; EFSA FEEDAP Panel, 2009), and on the 4 This section has been amended following the confidentiality claims made by the applicant. 5 Regulation (EC) No 1831/2003 of the European Parliament and of the Council of 22 September 2003 on additives for use in animal nutrition. OJ L 268, 18.10.2003, p. 29. 6 On 13/03/2013, EFSA was informed by the applicant that TREAC EEIG was liquidated on 19/12/2012 and their rights as applicant were transferred to FEFANA asbl (EU Association of Specialty Feed Ingredients and their Mixtures), including 14 companies referred to in the text as (a1) to (a14). Avenue Louise, 130A, Box 1, 1050 Brussels, Belgium. 7 EFSA Dossier reference: FAD-2010-0031. 8 Commission Regulation (EC) No 1334/2003 of 25 July 2003 amending the conditions for authorisation of a number of additives in feedingstuffs belonging to the group of trace elements. OJ L 187, 26.7.2003, p. 11. 9 Commission Regulation (EC) No 479/2006 of 23 March 2006 as regards the authorisation of certain additives belonging to the group compounds of trace elements. OJ L 86, 24.3.2006, p. 4. 10 European Union Register of Feed Additives pursuant to Regulation (EC) No 1831/2003. Available online: http://ec.europa.eu/food/food/animalnutrition/feedadditives/comm_register_feed_additives_1831-03.pdf 4
safety and efficacy of di copper chloride tri hydroxide (tribasic copper chloride, TBCC) as feed additive for all species (EFSA FEEDAP Panel, 2011a). In the frame of re-evaluation, EFSA has delivered two opinions on copper-based additives: cupric sulphate pentahydrate (EFSA FEEDAP Panel, 2012a) and cupric chelate of amino acids hydrate (EFSA, 2013). TERMS OF REFERENCE According to Article 8 of Regulation (EC) No 1831/2003, EFSA shall determine whether the feed additive complies with the conditions laid down in Article 5. EFSA shall deliver an opinion on the safety for the target animals, consumer, user and the environment and the efficacy of the Cupric acetate, monohydrate, Basic cupric carbonate, monohydrate, Cupric chloride, dihydrate, Cupric oxide, Cupric sulphate, pentahydrate, Cupric chelate of amino acids, hydrate, Cupric chelate of glycine, hydrate, when used under the conditions described in Table 1. Table 1: Description and conditions of use of the additive as proposed by the applicant 11 Additive Copper Registration number/ec No/No (if appropriate) 3b4.xx Category(-ies) of additive 3. Nutritional additives Functional group(s) of additive b. Compounds of trace elements Description Composition, description Cupric acetate monohydrate 31% Cu Chemical formula Cu(CH 3 COO) 2 H 2 O Purity criteria (if appropriate) Method of analysis (if appropriate) Basic cupric carbonate, monohydrate 55% Cu CuCO 3 Cu(OH) 2 H 2 O Cupric chloride, dihydrate 37%Cu CuCl 2 2H 2 O Cupric oxide 77% Cu Cupric sulphate, pentahydrate 24% Cu Cupric chelate of amino acids, hydrate 10% Cu CuO CuSO 4 5H 2 O Cu (x) 1-3 nh 2 O (x=anion of any amino acid derived from hydrolysed soya protein) Molecular weight not exceeding 1500 dalton Complies with EU law on undesirable substances EN 15510:2007 EN ISO 6869:2000 Cupric chelate of glycine, hydrate 15% Cu (solid)/ 6% Cu (liquid) Cu(x) 1-3 nh 2 O (x= anion of synthetic glycine) Trade name (if appropriate) Not appropriate 11 Table updated as indicated in the Technical Dossier/Supplementary Information (October 2012). 5
Name of the holder of authorisation (if appropriate) TREAC EEIG 12 Conditions of use for the additives in complete feed (Cupric acetate, monohydrate; Basic cupric carbonate, monohydrate; Cupric chloride, dihydrate; Cupric oxide; Cupric sulphate, pentahydrate; Cupric chelate of amino acids, hydrate; Cupric chelate of glycine, hydrate (solid); Cupric chelate of glycine, hydrate (liquid)) Species or category of animal Maximum Age Minimum content Maximum content mg/kg of complete feedingstuffs Withdrawal period (if appropriate) Piglets (up to 12 weeks): 170 (total) Other pigs: 25 (total) All animal species and categories - - Milk replacers: 15 (total) Other complete feedingstuffs: 15 (total) Other bovine: 35 (total) Ovine: 15 (total) Not appropriate Fish: 25 (total) Crustaceans: 50 (total) Other species: 25 (total) Conditions of use for the additives in water for drinking (Cupric acetate, monohydrate; Basic cupric carbonate, monohydrate; Cupric chloride, dihydrate; Cupric sulphate, pentahydrate; Cupric chelate of glycine, hydrate (solid); Cupric chelate of glycine, hydrate (liquid)) Species or category of animal Maximum Age Minimum content Maximum content mg/litre water for drinking Withdrawal period (if appropriate) Piglets (up to 12 weeks): 77.3 (total) Other pigs:11.4 (total) All animal species and categories - - Milk replacers: 2.1 (total) Other complete feedingstuffs: 11.7 (total) Other bovine: 11.7 (total) Ovine: 1.5 (total) Not appropriate Other species: 12.5 (total) Specific conditions or restrictions for use (if appropriate) Specific conditions or restrictions for handling (if appropriate) Post-market monitoring (if appropriate) Other provisions and additional requirements for the labelling - Safety recommendations: * For bovines after the start of rumination: Where the level of copper in feedingstuffs is less than 20 mg/kg: the level of copper in this feedingstuff may cause copper deficiencies in cattle grazing pastures with high contents of molybdenum or sulphur. * For sheep: Where the level of copper in feedingstuffs exceeds 10 mg/kg: the level of copper in this feedingstuff may cause poisoning in certain breeds of sheep. - The additive shall be incorporated in feeds in form of a premixture. For user safety: breathing protection, safety glasses and gloves should be worn during handling. Not appropriate (existing feed additive) 12 EFSA notes that TREAC EEIG was liquidated on 19/12/2012 and their rights as applicant were transferred to FEFANA asbl. 6
Specific conditions for use in complementary feedingstuffs (if appropriate) - The copper feed additive is given continuously during animal rearing. - To supply Cu in final feeds with EU legal limits for each species. - To comply with Regulation (EC) n 767/2009 Marker residue Maximum Residue Limit (MRL) (if appropriate) Species or category of animal Target tissue(s) or food products Maximum content in tissues Not appropriate Not appropriate Not appropriate Not appropriate 7
ASSESSMENT At the time of submission, the application represented 14 companies joint as a Consortium. The opinion is based on data provided by these companies involved in the production/distribution of copper-containing compounds, and on publicly available literature. It should be recognised that these data cover only a fraction of the existing relevant compounds of copper-based additives available on the market. 1. Introduction The biological role of copper, its requirements/recommendations, deficiency and toxicity symptoms in farm animals have been already described in a former Opinion of the Scientific Committee on Animal Nutrition (SCAN) (EC, 2003a); the current maximum levels authorised for total copper in feedingstuffs are derived from that opinion. The additives under assessment are: cupric acetate, monohydrate; basic cupric carbonate, monohydrate; cupric chloride, dihydrate; cupric oxide; cupric sulphate, pentahydrate; cupric chelate of amino acids, hydrate; cupric chelate of glycine, hydrate (powder and liquid form). These compounds are already authorised in the European Union (EU) for use in feed. Additionally, the application requests the use of some of the compounds in water for drinking. Therefore, a re-evaluation of authorisation or an authorisation of a new use of an additive is sought, depending on the compound (see Table 2). Table 2: Details of the applications submitted by the European Commission Compound Request Matrix Feed Water for drinking 1. Cupric acetate, monohydrate Re-evaluation X New use of the additive X 2. Basic cupric carbonate, monohydrate Re-evaluation X New use of the additive X 3. Cupric chloride, dihydrate Re-evaluation X New use of the additive X 4. Cupric oxide Re-evaluation X 5. Cupric sulphate, pentahydrate Re-evaluation X New use of the additive X 6. Cupric chelate of amino acids, hydrate Re-evaluation X 7. Cupric chelate of glycine, hydrate: Re-evaluation X (a) powder or solid (b) liquid New use of the additive X The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) reviewed the potential relation between the copper supply of animals and the development of antibiotic resistance in bacteria. The Panel also considered the Maximum Residue Limits (MRLs) set for copper in products of animal origin resulting from the use of copper as pesticide, 13 in the light of the use of copper in animal nutrition. The risk assessment is presented in a previous opinion of the FEEDAP Panel on copper sulphate pentahydrate (EFSA FEEDAP Panel, 2012a) and, therefore, is not repeated in the current document. A compilation of risk assessments carried out on copper and its compounds, including opinions from EFSA panels other than the FEEDAP Panel, is given in Appendix A. A list of authorisations of copper compounds in the EU, other than as feed additives, is reported in Appendix B. 13 Commission Regulation (EC) No 149/2008 of 29 January 2008 amending Regulation (EC) No 396/2005 of the European Parliament and of the Council by establishing Annexes II, III and IV setting maximum residue levels for products covered by Annex I thereto. OJ L 58, 1.3.2008, p. 1. 8
EFSA commissioned the University of Gent (Belgium) to carry out a study of selected trace and ultratrace elements, including copper. The findings were submitted to the EFSA in the form of a technical report (Van Paemel et al., 2010). Another report on the environmental impact of zinc and copper used in animal nutrition was provided to EFSA following a call for tender (Monteiro et al., 2010). 14 Information from these reports has been used in this opinion. 2. Characterisation 15 For compounds of trace elements, the element itself is considered the active substance. 2.1. Cupric acetate, monohydrate 16 Characterisation and identity Cupric acetate, monohydrate (Chemical Abstracts Service (CAS) No 6046-93-1) has the chemical formula Cu(CH 3 COO) 2 H 2 O (molecular weight 199.65 Da, theoretical copper content 32 %). The product is a solid, dark-green powder, with a typical odour. The solubility in water is 72 g/l at 0 C. The product has a bulk density of about 2 g/cm 3. 17 The company provided analytical data of five batches showing a copper content of 31.8 ± 0.1 % (specification 31 %). 18 Levels of heavy metals (lead (Pb) < 10, and cadmium (Cd) < 1 mg/kg product) and arsenic (As) (< 20 mg/kg product) analysed in four batches of the product 19 comply with the thresholds set in Directive 2002/32/EC for compounds of trace elements. Dioxins were analysed in one batch and showed a content of < 0.17 ng WHO PCDD/F-TEQ (World Health Organization (WHO) polychlorinated dibenzodioxin/dibenzofuran (PCDD/F)-toxic equivalent (TEQ))/kg; 20 this concentration complies with that set in Directive 2002/32/EC (1.0 ng/kg WHO PCDD/F-TEQ/kg). Data on the sum of dioxins plus dioxin-like polychlorinated biphenyls (PCBs) were not provided. The nickel (Ni) content (two batches) was < 3.0 mg/kg. 21 Particle size distribution was characterised in two batches of the product by the sieving technique 22 showing that 3.6 3.9 % (w/w) of particles were < 45 µm diameter. Dusting potential (Stauber- Heubach method) was provided for two batches of the additive, showing an average value of 2.3 g/m 3. 23 Stability and homogeneity Stability data were not provided but not considered necessary for cupric acetate, monohydrate. Homogeneity according to theoretical calculations (Jansen, 1992) was provided for a chicken starter diet (20 g sample) at inclusion rate of 15 mg Cu/kg, resulting in a coefficient of variation (CV) of 2.1 %. 24 However, this method has been developed to test the working accuracy of mixing equipment 14 The FEEDAP Panel notes that this report contains a typographical error when referring to the units of the maximum total copper and zinc authorised in feed (Background and Introduction of the document: it is written mg/day and should be mg/kg complete feedingstuffs). 15 This section has been amended following the confidentiality claims made by the applicant. 16 One company involved in the application: (a11). 17 Technical Dossier/Section II/Annex 2.2.17. 18 Technical Dossier/Section II/Annex 2.1.26. 19 Technical Dossier/Section II/Annex 2.1.46. 20 Technical Dossier/Section II/Annex 2.1.66. 21 Technical Dossier/Supplementary Information (October 2012)/Annexes. Annex_Qiaddendum_Nickel_Cu acetate.pdf. 22 Technical Dossier/Supplementary Information (October 2012)/Annexes. Annex_Qiv_Cu acetate_psd.pdf. 23 Technical Dossier/Supplementary Information (October 2012)/Annexes. Annex_Qiv_Cu acetate_dusting potential.pdf. 24 Technical Dossier/Section II/Annex 2.4.11. 9
and it is not accepted by the FEEDAP Panel as a valid method for assessing the homogeneity of distribution of additives in feeds. Manufacturing process Copper acetate is formed by reacting copper carbonate with acetic acid. The copper acetate solution is concentrated until precipitation occurs. The precipitate is then filtered and dried. The final product is monitored by routine quality control measures. 2.2. Basic cupric carbonate, monohydrate 25 Characterisation and identity Basic cupric carbonate, monohydrate (CAS No 100742-53-8) has the chemical formula CuCO 3 Cu(OH) 2 H 2 O (molecular weight 239.13 Da, theoretical copper content 53.2 %). The product is a solid, green-coloured, odourless powder which is insoluble in water. The product has a bulk density of about 4 g/cm 3. 26 The company provided analytical data of five batches showing a copper content of 55.8 56.3 % (specification 55 %). 27 These values indicate that the additive under application also contains copper species other than basic cupric carbonate, monohydrate. Levels of heavy metals (Pb < 0.05 4.5 mg/kg product and Cd < 0.01 0.37 mg/kg product) and As (< 0.05 0.13 mg/kg product), analysed in eight batches of the product, 28 comply with the thresholds set in Directive 2002/32/EC for compounds of trace elements. 29 Dioxins and the sum of dioxins and dioxin-like PCBs were analysed in four batches, 30 showing compliance with the thresholds set in Directive 2002/32/EC. The nickel content (six batches) showed a high variability with values between 3.6 and 91.8 mg/kg. 31 Three batches of the product were analysed for particle size distribution by sieving technique. 32 The dominant particle fraction in batch 1 (63 % w/w) had a diameter below 45 µm; in contrast, most particles of batch 3 (46 %) were between 63 and 90 µm, and only 6 % of particles were below 45 µm. Batch 2 showed similar fractions of 63 90, 45 63 and < 45 µm (25, 35 and 21 %, respectively). Dusting potential (Stauber Heubach method) was provided for three samples of the additive (two samples from batch 2 and one from batch 3 submitted for particle size analysis), showing values of 2.85, 3.15 and 3.20 g/m 3. 33 25 One company involved in the application: (a11). 26 Technical Dossier/Supplementary Information (October 2012)/Annexes. Annexes to Basic cupric carbonate_identity. 2.5.2.a Company (a11)_cu-carbonate_2.5.2 MSDS.pdf. 27 Technical Dossier/Supplementary Information (October 2012)/Annexes. Annexes to Basic cupric carbonate_identity/2.1.3.a FAD-2010-0031_Company (a11)_cucarb_analyses_of_5_batches.pdf. 28 Technical Dossier/Section II/Annex 2.1.45. Technical Dossier/Supplementary Information (October 2012)/Annexes. Annexes to Basic cupric carbonate_identity/2.1.3.a FAD-2010-0031_ Company (a11)_cucarb_analyses_of_5_batches.pdf. 29 Directive 2002/32/EC of the European Parliament and of the Council of 7 May 2002 on undesirable substances in animal feed. OJ L 140, 30.5.2002, p. 10. 30 Technical Dossier/Section II/Annex 2.1.65. Technical Dossier/Supplementary Information (October 2012)/Annexes. Annexes to Basic cupric carbonate_identity/2-1-65 Company (a11)_cu carbonate_dioxins PCB.pdf. 31 Technical Dossier/Section II/Annex 2.1.45. Technical Dossier/Supplementary Information (October 2012)/Annexes. Annexes to Basic cupric carbonate_identity. 2.1.4.2.a Report_349289_120919100337.pdf; 2.1.4.2.b Report_349291_120919083728.pdf; 2.1.4.2.c. Report_349292_120919083745.pdf. 32 Technical Dossier/Supplementary Information (October 2012)/Annexes. Annexes to Basic cupric carbonate_identity. 2.2.2.1.a Company (a11)_cucarb_flowsheet and particle size distribution.pdf. 33 Technical Dossier/Supplementary Information (October 2012)/Annexes. Annexes to Basic cupric carbonate_identity. 2.4.3.b Final_1230854 Dust Cu-carb.pdf. 10
Stability and homogeneity Stability data are not required for inorganic compounds of trace elements. Homogeneity according to theoretical calculations (Jansen, 1992) was provided for a chicken starter diet (20 g sample) at inclusion rate of 15 mg Cu/kg, resulting in a CV of 1.9 %. 34 However, this method has been developed to test the working accuracy of mixing equipment and it is not accepted by the FEEDAP Panel as a valid method for assessing the homogeneity of distribution of additives in feeds. Manufacturing process Copper sulphate and sodium carbonate are solubilised in water and mixed, upon which copper carbonate is formed. Precipitation takes place and the precipitate is purified and separated. The resulting material is then dried and packed. The final product is monitored by routine quality control measures. 35 2.3. Cupric chloride, dihydrate 36 Characterisation and identity Cupric chloride, dihydrate (CAS No 10125-13-0) has the chemical formula, CuCl 2 2H 2 O (molecular weight 170.45 Da, theoretical copper content 37 %). The product is a solid, blue-coloured, odourless powder. Its solubility in water is 770 g/l at 20 C. The product has a bulk density of about 1 g/cm 3. 37 The company provided analytical data of five batches showing a copper content of 37.0 38.8 % (specification 37 %). 38 Levels of heavy metals (Pb: < 0.5, Cd: < 0.1 and mercury (Hg): < 0.01 mg/kg product) and As (< 0.5 mg/kg product) analysed in three batches of the product 39 comply with the thresholds set in Directive 2002/32/EC for compounds of trace elements or, if not mentioned in the Directive, do not represent a concern. Dioxins and the sum of dioxins plus dioxin-like PCBs were analysed in three batches, showing levels of 0.07 ng WHO PCDD/F-TEQ/kg and 0.12 ng WHO PCDD/F-PCB-TEQ/kg, respectively; 40 these concentrations comply with that set in Directive 2002/32/EC. The nickel content (three batches) was in the range < 0.5 to 1.9 mg/kg. 41 Particle size distribution has been characterised in one batch of the product by laser diffraction showing that 8.8 % (v/v) of the particles had a particle size < 100 µm diameter and 0.23 % < 50 µm. 42 No measurable dust could be produced by the Stauber Heubach method in two batches of the additive. 43 Stability and homogeneity Stability data are not required for inorganic compounds of trace elements. 34 Technical Dossier/Section II/Annex 2.4.10. 35 Technical Dossier/Supplementary Information (October 2012)/Annex_Qiii_Basic cupric carbonate, monohydrate_new section 2.pdf. 36 One company involved in the application: (a6). 37 Technical Dossier/Section II/Annex 2.2.19. 38 Technical Dossier/Section II/Annex 2.1.28. 39 Technical Dossier/Section II/Annex 2.1.48. 40 Technical Dossier/Section II/Annex 2.1.68. 41 Technical Dossier/Supplementary Information (October 2012)/Annex_Qiaddendum_Nickel_Cu chloride.pdf. 42 Technical Dossier/Section II/Annex 2.2.35. 43 Technical Dossier/Supplementary Information (October 2012)/Annexes.Annex_Qv_Cu chloride_dusting potential.pdf. 11
Homogeneity according to theoretical calculations (Jansen, 1992) was provided for a piglet feed based on inclusion rates of 130, 150 and 170 mg Cu/kg, resulting in CVs of 2.5, 2.3 and 2.2 %, respectively. 44 However, this method has been developed to test the working accuracy of mixing equipment and it is not accepted by the FEEDAP Panel as a valid method for assessing the homogeneity of distribution of additives in feeds. Manufacturing process Cupric chloride, dihydrate is formed by reacting elemental copper, as raw material, with hydrochloric acid, using hydrogen peroxide as a catalyst. The saturated solution is crystallised, isolated and dried. 2.4. Cupric oxide 45 Characterisation and identity Cupric oxide (CAS No 1317-38-0) has the chemical formula, CuO (molecular weight 79.54 Da, theoretical copper content 80 %). The product is a solid, black to brownish-black amorphous or crystal odourless powder, insoluble in water. The product has a bulk density (measured in three batches) of about 1.3 g/cm 3. 46 The company provided analytical data of five batches showing a copper content of 77 79.8 % (specification 77 %). 47 Levels of heavy metals (Pb 9.3 20.2 mg/kg and Cd < 0.5 mg/kg product, three batches each) and As (35.2 41.5 mg/kg product, four batches) 48 comply with the thresholds set in Directive 2002/32/EC for compounds of trace elements. Dioxins and the sum of dioxins plus dioxin-like PCBs were analysed in three batches of the product, showing levels of 0.001 0.066 ng WHO PCDD/F-TEQ/kg and 0.112 0.221 ng WHO PCDD/F-PCB-TEQ/kg, respectively; 49 these concentrations comply with those set in Directive 2002/32/EC. The nickel content was analysed in a pooled sample of seven production batches revealing a content of 17.4 mg/kg; in two individual batches the content was of 19.6 and 20.5 mg/kg. 50 Particle size distribution was characterised in three batches of the product by sieve analysis; 99.8 % (w/w) of the particles had a particle size < 50 µm. 51 Dusting potential (Stauber-Heubach method) was provided for one batch of the additive, showing 2.83 g/m 3. Stability and homogeneity Stability data are not required for inorganic compounds of trace elements. Homogeneity according to theoretical calculations (Jansen, 1992) was provided for a piglet feed at the inclusion rate of 170 mg Cu/kg, resulting in a CV of 0.8 %. 52 However, this method has been developed to test the working accuracy of mixing equipment and it is not accepted by the FEEDAP Panel as a valid method for assessing the homogeneity of distribution of additives in feeds. 44 Technical Dossier/Section II/Annex 2.4.12. 45 One company involved in the application: (a13). 46 Technical Dossier/Section II/Annex 2.2.18. 47 Technical Dossier/Section II/Annex 2.1.27. 48 Technical Dossier/Section II/Annex 2.1.47. 49 Technical Dossier/Section II/Annex 2.1.67. 50 Technical Dossier/Supplementary Information (October 2012)/Annexes. Annex_Qiaddendum_Nickel_Cu oxide.pdf. 51 Technical Dossier/Section II/Annex 2.2.34. 52 Technical Dossier/Section II. Technical Dossier/Supplementary Information (October 2012)/Annex _Qvii_Copper oxide_homogeneity. 12
Manufacturing process Cupric oxide is formed by reacting copper chloride tetramine (50 %) and sodium hydroxide (50 %). The saturated solution is filtered and dried. 2.5. Cupric sulphate, pentahydrate 53 Characterisation and identity Cupric sulphate, pentahydrate (CAS No 7758-99-8) has the chemical formula, CuSO 4 5H 2 O (molecular weight 249.68 g/mol, theoretical copper content 25 %). The product is solid and odourless and consists of blue crystals. It has a solubility in water of 200 g/l at 20 C. It has a loose bulk density of about 1.2 g/cm 3. 54 The measured copper content of the product in a total of 25 batches (four to seven batches per company) was 24.6 25.6 % (specification 24 %). For further details regarding characterisation and identity of cupric sulphate, pentahydrate, see Appendix C, Table 4. Levels of heavy metals (Pb < 0.5 83 mg/kg product and Cd < 0.5 6.5 mg/kg product, four to seven batches of the product from each company; Hg < 0.1 mg/kg product, two to seven batches from three companies) and As (< 0.1 52 mg/kg product, four to seven batches from each company) comply with the thresholds set in Directive 2002/32/EC for compounds of trace elements (except for As in one batch) or, if not mentioned in the Directive, do not represent a concern. Dioxins (analysed in two to eight batches per company) and the sum of dioxins plus dioxin-like PCBs (two to five batches from three companies) were 0.05 0.27 ng WHO-PCDD/F-TEQ/kg and 0.07 0.36 ng WHO-PCDD/F-PCB- TEQ/kg, respectively; these concentrations comply with those set in Directive 2002/32/EC. The nickel content was analysed in a total of eight production batches (at least one batch per company), revealing a content ranging from 3.5 to 1 900 mg/kg; the wide range was due to data from one company. Particle size distribution was characterised in 1 to 10 batches from each company (by sieve or laser diffraction) showing that 0 15.4 % of the particles had a size < 53 µm (data from four companies) and 0 6.6 % of the particles had a size < 10.7 µm (data from two companies). Stauber Heubach analysis of a single batch from the product with highest fraction of particles, < 50 µm, indicated a dusting potential of 11.8 g/m 3. Stability and homogeneity Stability data are not required for inorganic compounds of trace elements. Homogeneity according to theoretical calculations (Jansen, 1992) was provided for a broiler feed (120 g sample) based on an inclusion rate of 15 mg Cu/kg, resulting in a CV of 7.4 %. 55 However, this method has been developed to test the working accuracy of mixing equipment and it is not accepted by the FEEDAP Panel as a valid method for assessing the homogeneity of distribution of additives in feeds. Manufacturing process Cupric sulphate pentahydrate can be produced in two ways. 53 Four companies involved in the application: (a5), (a7), (a8) and (a9). 54 Technical Dossier/Section II/Annex 2.2.12 (a5), Annex 2.2.13 (a7), Annex 2.2.14 (a8), Annex 2.2.15 (a9). 55 Technical Dossier/Section II/Annex 2.4.9. 13
In one production method, copper sulphate is reacted from blister copper, copper scrap and copper powder and sulphuric acid by electrolysis. After crystallisation, washing and centrifugation, copper sulphate pentahydrate is dried and sieved. Another method uses copper granules (from copper scraps) which are steam-treated together with sulphuric acid. The resulting highly saturated solution is further filtered, crystallised, washed, centrifuged and dried. The final additive may contain an anticaking agent (usually silicon dioxide). 2.6. Cupric chelate of amino acids, hydrate 56 Characterisation and identity Cupric chelate of amino acids, hydrate is described by the applicant with the generic chemical formula Cu(x) 1 3 nh 2 O, where x= anion of any amino acid derived from hydrolysed soybean protein, molecular weight not exceeding 1500 Da. 57 The product is a solid, blue to green free-flowing powder with a characteristic odour. It is reported to be insoluble in water. The product has a density of 1.3 g/cm 3 and the bulk density ranges from 0.4 to 0.9 g/cm 3. 58 The copper content of 42 batches of the additive (3 to 19 batches from each company) was 11.1 17.25 % (specification 10 %). The applicant was requested to provide data on the proportions of copper chelate and any inorganic copper. The applicant developed an indirect method (based on Fourier Transform Infrared (FTIR) spectroscopy) to estimate the binding of copper to amino acids. The values were quantified by comparison with a calibration curve. The predicted degree of chelation for the products (average of three to five batches of the product from five companies) ranged from 50 to 101 %. The results of this in-house method, although validated, are not considered fully reliable but allow the conclusion that at least 50 % of total copper occurs as chelates. Analytical data was provided for the products of four companies showing the percentage of molecules with a molecular weight < 1500 Da. Considering all values, up to 15 % of the molecules exceeded 1500 Da. The FEEDAP Panel notes that the specification of the applicant on the molecular weight of the compound not exceeding 1500 Da is not met by analytical data, and does not comply with current legislation (Commission Regulation (EC) No 1334/2003). The applicant provided the analysis of five batches of the hydrolysate material before the addition of the copper source for free and total amino acids; the lysinoalanine content was also analysed showing to be below 50 mg/100 g. Proximate analysis of a total of seven batches (one to three per company) of the additive revealed a content of 5.2 11.3 % moisture, and on an as is basis: 26.0 38.9 % crude protein (nitrogen 6.25), 0.2 1.1 % lipids, 0.7 2.9 % crude fibre and 18.1 27.8 % ash; the mineral fraction consists of 0.3 0.8 % calcium, 1.79 9.04 % sulphur, 0.02 0.7 % sodium, 1.1 1.8 % potassium and 0.2 0.7 % phosphorus. 59,60, 61,62,63 For further details regarding characterisation and identity of cupric chelate of amino acids, hydrate, see Appendix C, Tables 5 and 6. 56 Seven companies involved in the application: (a1), (a2), (a3), (a4), (a9), (a10) and (a14). During the course of the evaluation, the applicant notified that companies a3 (Balchem) and a9 (Orffa) are no longer defending this additive within the current application; no Supplementary Information was provided by those companies and therefore they were disregarded from the relevant assessment. 57 Commission Regulation (EC) No 1334/2003 of 25 July 2003. 58 Technical Dossier/Section II/Annex 2.2.1 (a1), Annex 2.2.2 (a2), Annex 2.2.4 (a4), Annex 2.2.6 (a10), Annex 2.2.7 (a14). 59 Technical Dossier/Supplementary Information (October 2012)/COMPANY (A1). Annex_Qii_TREAC_COMPANY (A1)_COPPER_composition1.pdf. 14
Levels of heavy metals (Pb 1 25 mg/kg and Cd < 0.27 6 mg Cd/kg, at least one batch of the product from each company; Hg < 0.005 0.03 mg/kg, three batches from two companies), As (< 0.1 13.9 mg/kg at least one batch from each company) and fluorine (F) (< 0.10 mg/kg, three batches from one company) comply with the thresholds set in Directive 2002/32/EC for compounds of trace elements, or, if not mentioned in the Directive, do not represent a concern. Dioxins (analysed in a total of nine batches from the five companies) and the sum of dioxins plus dioxin-like PCBs (analysed in one to three batches from three companies) were 0.023 0.12 ng WHO-PCDD/F-TEQ/kg and 0.043 0.218 ng WHO-PCDD/F-PCB-TEQ/kg, respectively; these concentrations comply with those set in Directive 2002/32/EC. The nickel content was analysed in a total of six production batches (at least one batch per company) revealing a content ranging from 6.3 to 708 mg/kg; the wide range was due to data from one company. In the batches stored for 6 to 36 months, the content of moulds, yeasts and total coliforms was below 100 CFU (colony-forming units)/g; Salmonella was absent in 25 g. Particle size distribution was characterised in one to four batches per company by laser diffraction. The fraction of particles with diameter below 53 μm ranged from 7.7 % to 84.5 % (v/v), and that below 10 μm ranged from 0.27 % to 27.4 % (v/v). Dusting potential (Stauber Heubach method) was determined only in one batch of the product identified as having the highest percentage of particles < 52.6 m, and was 0.21 g/m³. Stability and homogeneity No stability (including shelf-life) data were provided for the cupric chelate of amino acids, hydrate, in particular concerning the maintenance of the specific bounds of copper in the chelates. The FEEDAP Panel recognises the analytical difficulties to demonstrate stability of these specific bonds and notes that the active substance is also unlikely to disappear in these products. The product was shown to be stable to microbial contamination for 6 to 36 months (see Characterisation and identity). Experimental data on the capacity for homogeneous distribution of the additive were provided by company a1. Copper content was determined in 12 samples of a premixture containing cupric chelate of amino acids, hydrate; the mean concentration was 5 528 mg Cu/kg, the CV was 1.5 %. 64 Further studies from the same company with complementary feed for ruminants 65 (2 050 mg Cu/kg) and horses (195 mg Cu/kg) 66 resulted in CVs of 1.2 % and 1.3 %, respectively, from 15 batches. Manufacturing process The manufacturing process starts with enzymatic hydrolysis of soybean protein (under specific ph conditions). The hydrolysation process is followed by chelation with a source of copper. The slurry is dried. The applicant confirmed that only unblended products are placed on the EU market by the companies participating in this application since no anticaking/carrier or other diluents are added. 67 The applicant provided a generic process flow chart. 60 Technical Dossier/Supplementary Information (October 2012)/COMPANY (A2) Cu AA chelate data Q(ii).pdf. 61 Technical Dossier/Supplementary Information (October 2012)/COMPANY (A4). Annexes. Annex_Qiii_TREAC_COMPANY (A4) COPPER_composition1.pdf. 62 Technical Dossier/Supplementary Information (October 2012)/COMPANY (A10). Annex_Qiii_TREAC_COMPANY (A10)_COPPER_composition1.pdf. 63 Technical Dossier/Supplementary Information (October 2012)/Company (a14). Annexes. Annex_Qii_TREAC_Company (a14)_copper_composition.pdf. 64 Technical Dossier/Section II/Annex 2.4.5. 65 Technical Dossier/Section II/Annex 2.4.7. 66 Technical Dossier/Section II/Annex 2.4.8. 67 Technical Dossier/Supplementary Information (October 2012)/TREAC_ EFSA-SIn reply_copper_fad-2010-0031.pdf. 15
The applicant stated that none of the ingredients including enzymes used to manufacture the additive are derived from genetically modified organisms (GMOs). 68 2.7. Cupric chelate of glycine, hydrate Cupric chelate of glycine, hydrate is derived from synthetic glycine mixed with a copper salt. It has the generic formula Cu (x) 1 3 nh 2 O, where x= anion of glycine. The application is for the additive in two forms, solid and liquid. 2.7.1. Cupric chelate of glycine, hydrate (solid) 69 Characterisation and identity The product is a pale- to dark-blue odourless powder. Its solubility in water is >10 g/l. The product has a density of 1.2 g/cm 3 and the bulk density ranges from 0.8 to 1.2 g/cm 3. 70 The copper content of 21 batches of the additive, at least three batches from each company, ranged from 15.9 to 29.6 % the large range results primarily from the different ratios of copper to glycine (specification 15 %). For further details regarding characterisation and identity of cupric chelate of glycine, hydrate, see Appendix C, Table 7. Upon EFSA s request, the applicant provided data on the composition of a total of ten batches of the copper compound. 71 The copper content ranged from 17 to 25.3 %; extractable glycine from 28.5 to 64.2 %; sulphur from 0.1 to 12.9 %; and moisture from 3.3 to 12.4 %. The molar ratio of glycine to copper in the different products ranged from 2.7 to 0.9. (See also Appendix C, Table 8). Levels of heavy metals (Pb < 1 46 mg/kg, Cd 0.1 5 mg/kg, analysed in at least three batches per company; Hg < 0.002 mg/kg, three batches each from two companies) and As (0.23 15 mg/kg, at least three batches per company) comply with the thresholds set in Directive 2002/32/EC for compounds of trace elements, or, if not mentioned in the Directive, do not represent a concern. Dioxins (analysed in one to five batches from each company) and the sum of dioxins plus dioxin-like PCBs (one batch each from two companies) were 0.020 0.27 ng WHO PCDD/F-TEQ/kg and 0.097 0.156 ng WHO PCB- TEQ/kg, respectively; these concentrations comply with those set in Directive 2002/32/EC. Nickel level was analysed in one or two batches per company, showing a range of < 5 to 59.6 mg/kg. Particle size distribution was characterised in one to three batches per company by laser diffraction. The products differed markedly in their particle size distribution. For one group of additives about 30 % of particles showed a diameter < 50 μm, with up to 5 % of particles < 10 μm. The fraction < 50 μm in the other group of additives amounted to less than 1 %; the fraction < 10 μm was negligibly low, if measurable. Dusting potential (Stauber-Heubach method) was determined only in one batch of the product identified as having the highest percentage of particles < 50 m and was 6.6 g/m³. Stability and homogeneity No stability (including shelf-life) data were provided for the copper chelate of glycine, hydrate (solid), in particular concerning the maintenance of the specific bonds of copper in the chelate. The FEEDAP Panel recognises the analytical difficulties to demonstrate stability of this specific bound and notes that the active substance is also unlikely to disappear in these products. 68 Technical Dossier/Supplementary Information (October 2012)/TREAC_ EFSA-SIn reply_copper_fad-2010-0031.pdf. 69 Four companies involved in this application: (a2), (a4), (a10) and (a12). 70 Technical Dossier/Section II/Annex 2.2.8 (a2), Annex 2.2.9 (a4), Annex 2.2.10 (a10), Annex 2.2.11 (a12). 71 Technical Dossier/Supplementary Information (January 2015). 16