efsa reglementation

EFSA Journal 2013;11(2):3107

Suggested citation: EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP); Scientific

Opinion on the safety and efficacy of copper compounds (E4) as feed additives for all species: cupric chelate of amino acids

hydrate, based on a dossier submitted by Zinpro Animal Nutrition Inc.. EFSA Journal 2013;11(2):3107. [26 pp.].

doi:10.2903/j.efsa.2013.3107. Available online: www.efsa.europa.eu/efsajournal

© European Food Safety Authority, 2013

SCIENTIFIC OPINION

Scientific Opinion on the safety and efficacy of copper compounds (E4) as

feed additives for all species: cupric chelate of amino acids hydrate, based

on a dossier submitted by Zinpro Animal Nutrition Inc.1

EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP)2,3

European Food Safety Authority (EFSA), Parma, Italy

This scientific output, published on 10 January 2014, replaces the earlier version published on 21

February 2013.4

ABSTRACT

Cupric chelate of amino acids hydrate is safe for all animal species/categories up to the authorised maximum of

total copper content in complete feed. Consumption surveys include copper from foodstuffs of animal origin.

Since the supplementation of animal feed with copper-containing compounds has not essentially changed over

the last decade, no change in the contribution of foodstuffs originating from supplemented animals to the overall

copper intake of consumers is expected. No concerns for consumer safety are expected from the use of cupric

chelate of amino acids hydrate in animal nutrition, which would substitute for other copper sources. The additive

should be considered as a skin and eye irritant and, owing to its amino acid/peptide component, as a

skin/respiratory sensitiser. Potential risks to soil organisms have been identified as a result of the application of

piglet manure. Levels of copper in other types of manure are too low to create a potential risk within the

timescale considered. There might also be a potential environmental concern related to the contamination of

sediment resulting from 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 authorised maximum of total copper content in complete 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. Cupric chelate of amino acids hydrate is

recognised as an efficacious source of copper to meet animal requirements.

© European Food Safety Authority, 2013

KEY WORDS

Nutritional additive, compounds of trace elements, cupric chelate of amino acids hydrate, safety, environment,

efficacy

1 On request from the European Commission, Question No EFSA-Q-2011-00742, adopted on 31 January 2013. 2 Panel members: Gabriele Aquilina, Alex Bach, Vasileios Bampidis, Maria De Lourdes Bastos, Gerhard Flachowsky, Josep

Gasa-Gasó, Mikolaj Antoni Gralak, Christer Hogstrand, Lubomir Leng, Secundino López-Puente, Giovanna Martelli,

Baltasar Mayo, Derek Renshaw, Guido Rychen, Maria Saarela, Kristen Sejrsen, Patrick Van Beelen, Robert John Wallace

and Johannes Westendorf. Correspondence: [email protected] 3 Acknowledgement: The Panel wishes to thank the members of the Working Group on Trace Elements, including Noël

Albert Dierick, Jürgen Gropp, Alberto Mantovani, Joop de Knecht and the late Reinhard Kroker, for the preparatory work

on this scientific opinion. 4 Revision 1: erratum. The recommendation concerning the molecular weight of the compound has been redefined.

Cupric chelate of amino acids for all species

2 EFSA Journal 2013;11(2):3107

SUMMARY

Following a request from the European Commission, the 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 cupric chelate of amino acids hydrate when used as feed additive for all animal species.

Cupric chelate of amino acids hydrate is safe for all animal species/categories up to the authorised

maximum of total copper content in complete feed.

Consumption surveys include copper from foodstuffs of animal origin. Since the supplementation of

animal feed with copper-containing compounds has not essentially changed over the last decade, no

change in the contribution of foodstuffs originating from supplemented animals to the overall copper

intake of consumers is expected. No concerns for consumer safety are expected from the use of cupric

chelate of amino acids hydrate in animal nutrition, which would substitute for other copper sources.

The additive should be considered as a skin and eye irritant and, owing to its amino acid/peptide

component, as a skin/respiratory sensitiser.

Potential risks to soil organisms have been identified as a result of the application of piglet manure.

Levels of copper in other types of manure are too low to create a potential risk within the timescale

considered. There might also be a potential environmental concern related to the contamination of

sediment resulting from 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 authorised maximum of total

copper content in complete 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.

Cupric chelate of amino acids hydrate is recognised as an efficacious source of copper to meet animal

requirements.


3 EFSA Journal 2013;11(2):3107

TABLE OF CONTENTS

Abstract .................................................................................................................................................... 1 Summary .................................................................................................................................................. 2 Table of contents ...................................................................................................................................... 3 Background .............................................................................................................................................. 4 Terms of reference.................................................................................................................................... 5 Assessment ............................................................................................................................................... 8 1.Introduction ........................................................................................................................................... 8 2.Identity and characterisation ................................................................................................................. 8

2.1. Manufacturing process .................................................................................................................. 8 2.2. Characterisation of the copper compound ..................................................................................... 9 2.3. Characterisation of the additive .................................................................................................... 9 2.4. Physical state of the additive ......................................................................................................... 9 2.5. Stability ......................................................................................................................................... 9 2.6. Homogeneity ............................................................................................................................... 10 2.7. Physico-chemical incompatibilities in feed ................................................................................ 10 2.8. Conditions of use ........................................................................................................................ 10 2.9. Evaluation of the analytical methods by the European Union Reference Laboratory (EURL) .. 10

3.Safety ................................................................................................................................................... 10 3.1. Safety for the target species ........................................................................................................ 10

3.1.1. Tolerance of target animals ............................................................................................ 10 3.1.2. Microbial studies ............................................................................................................ 11 3.1.3. Conclusions on safety for the target species ................................................................... 11

3.2. Safety for the consumer .............................................................................................................. 11 3.2.1. Metabolic and residue studies ........................................................................................ 11 3.2.2. Assessment of consumer safety ...................................................................................... 13 3.2.3. Conclusions on the safety for the consumer ................................................................... 14

3.3. Safety for the users/workers ........................................................................................................ 14 3.4. Safety for the environment .......................................................................................................... 14

3.4.1. Conclusions on safety for the environment .................................................................... 15 4.Efficacy ............................................................................................................................................... 16 5.Post-market monitoring ....................................................................................................................... 16 Conclusions and recommendations ........................................................................................................ 16 General remark ....................................................................................................................................... 17 Documentation provided to EFSA ......................................................................................................... 17 References .............................................................................................................................................. 17 Appendices ............................................................................................................................................. 21


4 EFSA Journal 2013;11(2):3107

BACKGROUND

Regulation (EC) No 1831/20035 establishes the rules governing the Community authorisation of

additives for use in animal nutrition. 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 the company Zinpro Animal Nutrition Inc.6 for re-

evaluation of authorisation of the copper-containing additive cupric chelate of amino acids hydrate

(Availa®Cu) when used as a feed additive 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 10(2) (re-evaluation of an

authorised feed additive). EFSA received directly from the applicants the technical dossier 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 additive cupric chelate of amino acids hydrate had been authorised in the EU under the element

Copper-Cu for all animal species ―Without a time limit‖ (Commission Regulation (EC) No

1334/2003)8 and amendments. Following the provisions of Article 10(1) of Regulation (EC) No

1831/2003 the compound was included in the EU Register of Feed Additives under the category

―Nutritional additives‖ and the functional group ―Compounds of trace elements‖.9

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).10

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, 2009a), and on the safety and

efficacy of di copper chloride tri hydroxide (tribasic copper chloride, TBCC) as feed additive for all

species (EFSA, 2011). EFSA has issued an opinion concerning the re-evaluation of cupric sulphate

pentahydrate (EFSA, 2012).

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 Zinpro Animal Nutrition Inc.. Gerard Doustraat 4a. 5831-Boxmeer. The Netherlands. 7 EFSA Dossier reference: FAD-2010-0070. 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 European Union Register of Feed Additives pursuant to Regulation (EC) No 1831/2003. Available from

http://ec.europa.eu/food/food/animalnutrition/feedadditives/comm_register_feed_additives_1831-03.pdf 10 Available from http://ec.europa.eu/food/fs/sc/scan/out115_en.pdf

http://ec.europa.eu/food/food/animalnutrition/feedadditives/comm_register_feed_additives_1831-03.pdf

http://ec.europa.eu/food/fs/sc/scan/out115_en.pdf


5 EFSA Journal 2013;11(2):3107

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

chelate of amino acids hydrate, when used under the conditions described in Table 1.


6 EFSA Journal 2013;11(2):3107

Table 1: Description and conditions of use of the additive as proposed by the applicant Zinpro

Animal Nutrition Inc.

Additive Availa®

Cu

Registration number/EC

No/No (if appropriate)

Category(-ies) of additive Nutritional additive

Functional group(s) of additive 3(b)

Description

Composition, description Chemical formula Purity criteria

(if appropriate)

Method of analysis

(if appropriate)

Copper Amino Acid

Chelate, Hydrate

Cu (x)1-3· nH2O

(x = anion of any amino

acid derived

from hydrolysed soya

protein)

Molecular weight not

exceeding 1 500.

10% Copper Copper assay using

CEN/TS 15621:

Animal feeding stuffs-

Determination of

calcium, sodium,

phosphorus,

magnesium, potassium,

sulphur, iron, zinc,

copper, manganese,

cobalt and

molybdenum after

pressure digestion by

ICP-AES.

Trade name (if appropriate) Availa®

Cu

Name of the holder of

authorisation (if appropriate)

Zinpro Animal Nutrition Inc.,

The Netherlands

Conditions of use

Species or

category of

animal

Maximum

Age

Maximum content Withdrawal

period

(if appropriate) mg/kg of complete feedingstuffs

All species

See

specifics

by species

Pigs

- piglets up to 12 weeks:

- other pigs:

170 (total)

25 (total)

Not relevant

Bovine

1. Bovine before the start of

rumination:

- milk replacers

- other complete feedingstuffs

2. Other bovine:

15 (total)

15 (total)

35 (total)

Ovine 15 (total)

Fish 25 (total)

Crustaceans 50 (total)

Other species 25 (total)


7 EFSA Journal 2013;11(2):3107

Other provisions and additional requirements for the labelling

Specific conditions or restrictions for

use (if appropriate)

The following declarations shall be inserted in the labeling and

accompanying documents:

— 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.‘

— 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.‘

Specific conditions or restrictions for

handling (if appropriate)

For user safety: gloves, respiratory and eye protection

recommended. (see MSDS)

Post-market monitoring

(if appropriate)

Tracking & tracing will be in full place, all remarks during the use

of Availa®Cu will be noticed and recorded.

Specific conditions for use in

complementary feedingstuffs

(if appropriate)

Availa®

Cu can be mixed in feeds, to supply Cu in final feed within

EU legal limits for each species.

Maximum Residue Limit (MRL) (if appropriate)

Marker residue Species or category of

animal

Target tissue(s) or food

products

Maximum content in

tissues

Non applicable Non applicable Non applicable Non applicable


8 EFSA Journal 2013;11(2):3107

ASSESSMENT

This opinion is based in part on data provided by an applicant involved in the production/ distribution

of copper-containing compounds. It should be recognised that these data covers only a fraction of the

existing cupric chelate of amino acids hydrate.

1. Introduction

The biological role of copper, its requirements/recommendations, and its deficiency and toxicity

symptoms in farm animals have already been described in a previous opinion of the Scientific

Committee on Animal Nutrition (SCAN) (EC, 2003a); the maximum levels authorised for total copper

in feedingstuffs are derived from that opinion. To the knowledge of the FEEDAP Panel, there is no

additional relevant information that may lead it to modify the SCAN opinion.

Cupric chelate of amino acids hydrate is currently authorised as a nutritional additive under the

functional group ―Compounds of trace elements‖ to be used in feed for all animal species/categories.

The applicant is asking the re-evaluation of that compound.

The FEEDAP Panel 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 origin11

resulting from the use of copper as

pesticide, 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, 2012), and therefore

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, can be found in Appendix B. A list of authorisations of

copper compounds in the EU, other than as feed additive, is reported in Appendix C.

EFSA commissioned two studies, from which technical reports have been delivered; information from

these reports has been used in this opinion. One of the studies was on selected trace and ultratrace

elements in animal nutrition by the University of Gent (Belgium) (Van Paemel et al., 2010); copper

was included in this study. The other study concerned the pre-assessment of the environmental impact

of zinc and copper used in animal nutrition (Monteiro et al., 2010).

2. Identity and characterisation

For compounds of trace elements, the element itself is considered the active substance.

Cupric chelate of amino acids hydrate has the chemical formula Cu(x)1–3·nH2O, where x = anion of

any amino acid derived from hydrolysed soybean protein, molecular weight not exceeding 1500 Da.

2.1. Manufacturing process

The manufacturing process comprises an acid hydrolysis of soybean protein under heat, followed by

chelation with copper (from cupric oxide). The process is optimised to maximise the release of free

amino acids.12

The final additive is obtained by adding cellulose (44 45 %) and calcium carbonate

(18 19 %) to the slurry and drying.

11 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. 12 Supplementary Information January 2013.


9 EFSA Journal 2013;11(2):3107

The applicant stated that the source soybean is of conventional, non-genetically modified, origin,

either contractually sourced, or based on an approved geographic region, is used in the production of

the additive.13

2.2. Characterisation of the copper compound

The copper content of five batches of the slurry14

ranged from 8.95 to 9.17 % (w/v).15

The applicant

estimated the molecular weight of the additive to be 236 335 Da. Analytical data on one sample

showed that 98 % of the chelated material had a molecular weight <1500 Da and 2 % a molecular

weight >1500 Da.16

The lysinoalanine content of five batches of the hydrolysate was below 5 mg/100

g protein.17

The content of heavy metals (lead, cadmium and mercury), fluorine and arsenic analysed

in the slurry complied with EU legislation, as did the dioxins and the sum of dioxins plus dioxin-like

PCBs (all values derived from three batches).18

2.3. Characterisation of the additive

The final product is specified to contain a minimum of 10 % copper, as confirmed by analysis of five

batches (10.1 10.4 %).19

Proximate analysis of the same five batches revealed a content of 3.5 %

moisture, 21.1 % crude protein, 1.4 % lipids, 11.9 % crude fibre and 37 % ash.20

The product also

contains per kilogram additive: 56.5 g calcium, 4.7 g sodium, 3.3 g potassium, 1.25 g sulphur and

0.08 g phosphorous (one batch). Heavy metals (lead, cadmium and mercury), fluorine and arsenic

complied with the limits set in EU legislation, as did dioxins and the sum of dioxins plus dioxin-like

PCBs (all values derived from five batches).21

The nickel content (five batches) was between 3.05 and

11.57 mg/kg.22

In five batches Escherichia coli O157.H7 and Salmonella (25 g sample of the product)

were absent.23

2.4. Physical state of the additive

The product is a coarse granular powder with a slight characteristic odour. It is reported to be insoluble

in water. Bulk density is 600 620 kg/m3.

Sieve analysis of three batches identified that 1 2 % (w/w) of particles had a diameter below

180 µm.24

At the request of the FEEDAP Panel sieve analysis was repeated in three other batches, and

revealed the fraction below 75 µm to be 0.2–0.9 % (w/w).25

No data on dusting potential were

provided.

2.5. Stability

No data were provided for the cupric chelate amino acids hydrate, an organic copper compound.

Information on the maintenance of the specific copper bonds in the chelates would be valuable. The

FEEDAP Panel recognises the analytical difficulties in demonstrating stability of this specific bond

and notes that the active substance is also unlikely to disappear in these products.

13 Supplementary Information/March 2012. 14 Slurry means the intermediate product of copper chelation with the protein hydrolysate. 15 Supplementary Information/January 2013. 16 Supplementary Information/January 2013. 17 Supplementary Information/June 2012. 18 Supplementary Information/January 2013. 19 Technical Dossier/Section II/Annex II_2. 20 Technical Dossier/Section II/Annex II_2a and Annex II_2b. 21 Technical Dossier/Section II/Annex II. 22 Supplementary Information/March 2013. 23 Technical Dossier/Section II. 24 Technical Dossier/Section II/Annex II and Supplementary Information/March 2012. 25 Supplementary Information/March 2012.


10 EFSA Journal 2013;11(2):3107

Microbial decomposition could be excluded since Enterobacteriaceae, moulds and yeasts were present

at <10 CFU/g and Salmonella was absent in 25 g after 10, 15 and 18 months‘ storage.26

2.6. Homogeneity

The potential homogeneous distribution of the additive was predicted using a statistical approach

(Jansen, 1992) in the case of a complete feed for chickens for fattening. The coefficient of variation

was 11%.27

However, the FEEDAP Panel notes that this method has been developed to test the

working accuracy of mixing equipment and its applicability to test homogeneity has not been

demonstrated.

2.7. Physico-chemical incompatibilities in feed

Based on current knowledge, no incompatibilities resulting from the use of copper in compound feed

are expected, other than those widely known and considered by feed manufacturers when formulating

diets.

2.8. Conditions of use

The copper compound under application, cupric chelate of amino acids hydrate, is intended to supply

copper in final feed for all animal species/categories up to a maximum total content of 170 mg Cu/kg

complete feedingstuffs for piglets (up to 12 weeks) and 25 mg Cu/kg for other pigs; 15 mg Cu/kg

complete feedingstuffs for bovine before the start of rumination (milk replacers and other complete

feedingstuffs) and 35 mg Cu/kg for other bovine; 15 mg Cu/kg complete feedingstuffs for ovine; 50

mg Cu/kg complete feedingstuffs for crustaceans; 25 mg Cu/kg complete feedingstuffs for fish; and 25

mg Cu/kg complete feedingstuffs for other species.

2.9. Evaluation of the analytical methods by the European Union Reference Laboratory

(EURL)

EFSA has verified the EURL report as it relates to the methods used for the control of the copper

(seven compounds, including cupric chelate of amino acids hydrate) in animal feed. The Executive

Summary of the EURL report can be found in the Appendix A.

3. Safety

3.1. Safety for the target species

3.1.1. Tolerance of target animals

Huge differences in the maximum tolerable copper concentrations between animal species exist (e.g.

500 mg/kg for rodents; 250 mg/kg for poultry, pigs and horses; 100 mg/kg for fish; 40 mg/kg for

cattle, 15 mg/kg for sheep) (NRC, 2005). Therefore, considering the maximum copper content in feed

set by Regulation (EC) No 1334/2003, it cannot be expected that all animal species would share the

same margin of safety for a copper-containing additive. Consequently, the theoretical margin of safety

(maximum tolerable concentration/maximum content authorised) of a safe copper-containing additive

could be 10 in poultry and pigs (250/25), 4 in fish (100/25), 1.1 in cattle (40/35) and 1 in ovines

(15/15). Since these margins of safety are not substance-specific, this consideration neglects the

influence of potential differences in the bioavailability of copper from different sources. However,

according to a literature review comparing the relative bioavailabilities of different sources of copper,

including copper lysine and copper methionine, in poultry, pigs and ruminants, there was no evidence

that the bioavailability of copper from organic forms is higher than the bioavailability from copper

sulphate (Jongbloed et al. 2002). The conclusions of this review are supported by more recent

publications cited in Section 3.2.1.1. Consequently, the FEEDAP Panel does not expect the tolerance

26 Supplementary Information/March 2012. 27 Technical Dossier/Section II.


11 EFSA Journal 2013;11(2):3107

of target animals to cupric chelate of amino acids hydrate to differ from tolerance to copper sulphate,

when used up to the maximum authorised content in feed.

3.1.2. Microbial studies

The antimicrobial resistance to copper from the additive was tested against five tetracycline-sensitive

microbial strains as recommended by the FEEDAP Guidance on Microbial Studies (EFSA, 2008). The

minimum inhibitory concentration for all five strains was above 50 mg Cu/L, the highest tested copper

concentration.28

The influence of copper in animal nutrition on the development of antibiotic resistance in bacteria has

been reviewed and discussed in the scientific opinion on copper sulphate pentahydrate (EFSA, 2012).

3.1.3. Conclusions on safety for the target species

The FEEDAP Panel concludes that the source of copper under application is safe for all animal

species/categories up to the maximum total copper content authorised in feed.

3.2. Safety for the consumer

3.2.1. Metabolic and residue studies

Copper is absorbed from the diet in the upper jejunum by active and passive processes, stored in the

liver and kidney, secreted in the bile and excreted in faeces. Copper excretion via the kidneys is

quantitatively insignificant if complex-forming substances are not administered (thiomolybdate from

oral molybdenum in ruminants, dimethyl cysteine). Copper status is not easy to determine, and the

homeostatic mechanisms that control copper distribution and metabolism are not completely

understood. Copper interacts with other divalent cations, such as calcium, iron and zinc, for

gastrointestinal absorption and metabolism. Absorption and availability may be influenced by the

carbohydrate content of the diet, with reduced availability by phytate containing diets or those

containing fructose (EC, 2003b).

The SCAN delivered an opinion on copper (EC, 2003a) in which the metabolism and tissue deposition

of copper were reviewed. Other reviews are available from McDowell (2003) and Suttle (2010). The

distribution of total copper in the body varies with species, age and copper status of the animal. In

general, levels in newborn and suckling animals are higher, then a steady decline during growth until

adult values are reached. The main target organ for copper deposition is the liver. Other edible tissues

containing high concentrations of copper are the heart, brain and kidney. Lower levels are found in

muscle. Liver and kidney copper concentrations are related to dietary intake, whereas muscle is less

affected. Copper is generally present in very low amounts in milk and this is not influenced by dietary

supplementation levels. Clearance is higher in poultry than in mammals; the copper concentration in

eggs is generally low. In fish, copper is primarily stored in the liver.

3.2.1.1. Organic vs. inorganic copper compounds

The effects of trace mineral fortification of the diet in dairy cattle were studied by Nocek et al. (2006).

This study included 573 cows, which were balanced by parity and 305-day mature equivalent at dry-

off. Zinc, manganese, copper and cobalt in organic form, in the form of sulphates and as a

combination of organic and inorganic forms with zinc and copper were supplied at dose levels up to

100 % of the NRC (2001) recommendations. Liver biopsies were collected from the same 30 cows per

treatment at three times. Liver copper concentration increased with time (P< 0.01) and was higher in

cows supplemented with organic copper and the combination of organic and inorganic copper sources

than in those receiving the sulphate form, indicating that the liver responds to copper source.

In a study with 300 multiparous dairy Holstein cows, treatments with different forms of dietary copper

were given from 21 days prior to calving until 250 days of lactation (Ballantine et al., 2002). Diets

28 Technical Dossier/Section III/Annex III-1.


12 EFSA Journal 2013;11(2):3107

either contained only inorganic copper levels, or part of the copper was replaced by organic copper.

Liver samples were taken by biopsy prior to initiation of treatments and at approximately 18 weeks

post calving. No significant differences could be found.

In another study in dairy cows (Siciliano-Jones et al., 2008), 250 multiparous and primiparous cows

were assigned to groups receiving different forms of trace elements from approximately 70 days pre-

partum. Treatments consisted of supplemental zinc, manganese, copper and cobalt provided in

sulphate form and 360 mg zinc, 200 mg manganese, 125 mg copper per animal and day in organic

form. There was no effect of treatment on copper content of the liver.

A study was conducted by supplementing the diet of laying hens with a combination of zinc,

manganese and copper from organic and inorganic sources (Mabe et al., 2003). Addition of zinc,

manganese and copper did not increase their concentrations in egg yolk irrespective of source.

3.2.1.2. Copper deposition in tissues and products of animal origin

Following a request from EFSA, the applicant performed a literature search for peer-reviewed articles

published between 2003 and November 2011 on potential differences in the deposition in edible

tissues and products of copper from inorganic and organic sources.29

The databases used for this

research were Medline, Food Science and Technology, Agricola, Biological Abstracts, Embase,

Medline preprints and Life science collections, and included the applicant‘s own database. The

keywords applied were reported. Since the bioavailability and retention of copper can vary between

different organic forms, only the studies in which copper chelate of amino acids hydrate was

administered were considered to compare the copper edible tissue/animal products deposition with that

of copper sulphate as standard inorganic copper source.

In the case of liver copper deposition, data from three studies on cows, two studies on steers, one on

pigs and four on poultry were submitted. In cattle for fattening, the supplementation of feed with

copper (10 mg/kg DM) from 50 % sulphate and 50 % chelated amino acid hydrate did not result in

different copper liver levels than those obtained after supplementation with the equivalent dose of

copper sulphate only (Ahola et al., 2004). A study on dairy cows showed that oral doses of solutions

containing the equivalent of 150 mg Cu/day, either from sulphate or from chelated amino acid hydrate,

resulted in significantly different copper deposition in liver compared with control; however, there was

no difference in copper liver concentration between cows treated with copper sulphate pentahydrate or

copper amino chelate; the rate of copper deposition in liver was influenced by the initial copper

concentration in liver (Balemi et al., 2010). In ovariectomised beef cows the supplementation of feed

with copper (10 mg/kg DM) from chelated amino acid hydrate or copper sulphate did not lead to

significantly different liver levels of copper (Ahola et al., 2005). No significant differences in liver

levels of copper were found between cows given an inorganic source (copper sulphate or tribasic

copper chloride) and those given copper from a chelated amino acid hydrate at either 5 mg Cu/kg

(Mullis et al., 2003) or 10 mg Cu/kg (Arthington et al., 2003).

No significant differences in the levels of copper in liver were reported in pigs for fattening given

copper from copper sulphate or from chelated amino acid hydrate (0, 10, 30 and 50 mg/kg feed)

(Hernandez et al., 2009).

In laying hens fed diets supplemented 150 or 250 mg Cu/kg from either copper sulphate or chelated

amino acid hydrate, the response in terms of liver copper levels was not significantly different (Idowu

et al., 2006). Similarly, studies using a copper dose of 8 mg/kg feed (Ao et al., 2009; Aksu et al., 2010)

from copper sulphate or from chelated amino acid hydrate did not result in a different pattern of

copper liver deposition in chickens for fattening. Only in the study of Jegede et al. (2011), in which

broilers‘ diet was supplemented with copper at with copper supplementation levels of 50, 100 and 150

mg copper from copper sulphate or from chelated amino acid hydrate, did the highest element dose

result in significantly higher copper liver deposition independent of source. However, this level of

29 Supplementary Information/March 2012.


13 EFSA Journal 2013;11(2):3107

copper feed supplementation (150 mg/kg) exceeds by six times the maximum EU authorised total

copper level in complete feed.

For kidney, data from only one study on pigs were submitted. No differences in kidney copper levels

depending on the source of copper used were observed at the feed supplementation levels tested (0, 10,

30 and 50 mg Cu/kg feed) (Hernandez et al., 2009).

For muscle copper deposition two studies in broiler chickens were cited. Petrovič et al. (2010)

supplemented the diet with 0, 2.5 or 5 mg Cu/kg feed while Jegede et al. (2011) supplied chickens for

fattening with supranutritional copper levels (50, 100 and 150 mg Cu/kg) from copper sulphate and

chelated amino acid hydrate. Neither study found any differences in tissue deposition between the

sources. Similarly, no difference in muscle copper concentrations in ewes was found when copper was

given in the form of sulphate or chelated amino acid hydrate (Pal et al., 2010). The overall equivalent

bioavailability of copper from both sources in terms of copper deposition is also supported by data

from the tibia in chickens for fattening (Bao et al., 2007; Jegede et al., 2011).

Regarding animal products, no difference in copper levels in eggs were observed between hens fed

diets supplemented with copper sulphate or chelated amino acid hydrate at levels that did not exceed

the maximum authorised total element level (Mabe et al., 2003) or with levels highly exceeding it

(Idowu et al., 2006). Data from one study carried out with dairy cows (total dietary copper 13.8

mg/kg) did not show any difference in milk copper levels depending on copper source (Kinal et al.,

2007).

Based on the review of scientific literature dealing with use of cupric chelate of amino acid hydrate,

the FEEDAP Panel does not consider the tissue/product deposition of copper from the additive under

assessment to be any different from that of copper sulphate, which is a standard inorganic copper

compound widely used in animal nutrition. Consequently, the use of the additive cupric chelate of

amino acid hydrate in feed is not expected to modify the current consumer exposure to copper.

The amino acids from the additive will be absorbed, enter the amino acid pool of protein and be

metabolised accordingly.

3.2.2. Assessment of consumer safety

A tolerable upper intake level (UL) for copper of 5 mg/day for adults and 1 mg/day for toddlers (one

to three years) was defined by the SCF (EC, 2003b). This figure was derived from an overall no

observed adverse effect level of 10 mg Cu/day identified in the study by Pratt et al. (1985) (daily

single dose levels administered only to seven male adult volunteers for 12 weeks, and serum liver

markers as endpoints), applying an uncertainty factor of 2 for potential variability in the normal

population. This UL value has been consistently used in the assessments of copper in different forms

by the following EFSA scientific panels: the NDA Panel (EFSA, 2006), the AFC Panel (EFSA,

2008b), the FEEDAP Panel (EFSA, 2008a, 2009a, 2012), the ANS Panel (EFSA, 2009b) and the CEF

Panel (EFSA, 2010).

Studies on copper dietary intakes in industrialised countries did provide comparable results. Mean

dietary copper intakes by adults in different European countries have been estimated to be within a

range of about 1.0 2.0 mg/day (Van Dokkum, 1995; EC, 2003b; Sadhra et al., 2007; Rubio et al.,

2009; Turconi et al., 2009). Based on 11 independent, peer-reviewed surveys considering only

analytically confirmed copper (n = 849) in Belgium, Canada, the UK and the USA, the mean copper

intakes for men and women were estimated to be 1.48 (95th percentile 2.87) and 0.92 (95th percentile

2.18) mg/day, respectively (Klevay, 2011). A recent analytical study of Catalonian diets showed a

copper intake of 1.2 mg/day (Domingo et al., 2012). It has been suggested that calculated copper

intakes are overestimated when only food composition tables are used in nutrition surveys (Klevay,

2012).


14 EFSA Journal 2013;11(2):3107

Among edible tissues of animal origin, the highest concentration of copper is found in liver (the main

deposition organ), followed by kidney and muscle. Among products of animal origin, milk shows the

lowest values (for quantitative figures, see EFSA, 2012).

Since the supplementation of animal feed with copper-containing compounds has not essentially

changed over the last decade, it is reasonable to assume that food of animal origin recorded in the

above-mentioned consumption surveys originated from animals fed copper-supplemented diets and

showing copper concentrations of tissues and products in the range mentioned above. The continued

use of cupric chelate of amino acids hydrate in animal nutrition would not modify consumer exposure

to copper.

3.2.3. Conclusions on the safety for the consumer

Consumption surveys indicate that the mean dietary copper intake by adults in Europe is between 1.0

and 2.0 mg/day. These data include copper from foodstuffs of animal origin. Since the

supplementation of animal feed with copper-containing compounds has not essentially changed over

the last decade, no change in the contribution of foodstuffs originating from supplemented animals to

the overall copper intake of consumers is expected.

The use of the cupric chelate of amino acids hydrate in animal nutrition would not lead to different

copper concentrations in food of animal origin compared with the standard authorised copper sulphate

and would, therefore, not modify the exposure of consumers to dietary copper. The FEEDAP Panel

concludes that the cupric chelate of amino acids hydrate additive is safe for consumers when used as a

supplemental source of copper up to the maximum authorised levels for total copper in feedingstuffs.

3.3. Safety for the users/workers

No specific studies have been provided by the applicant. Some copper compounds are recognised as

skin and eye irritants. The additive should be considered as a skin and eye irritant and, owing to its

amino acid/peptide component, as a skin/respiratory sensitiser.

3.4. Safety for the environment

During the use of copper-containing feed additives, copper is unavoidably released into the

environment. When used in livestock feed, copper excreted in the faeces will enter the soil

environment when the faeces are applied as fertiliser to the land in the form of manure, slurry or litter.

This may present two main potential risks:

copper accumulation within the topsoil to concentrations posing potential toxic risk to soil

organisms;

leaching of copper from the soil to surface waters in concentrations posing potential toxic risk

to organisms resident in the water column and bottom sediments.

When used in aquaculture, trace elements such as copper may be released directly to the broader

aquatic environment around an aquaculture facility or be taken up by fish and then excreted into the

environment. As stated in the EFSA technical guidance for assessing the safety of feed additives for

the environment (EFSA, 2008c), the compartment of concern for fish farmed in cages is assumed to be

the sediment, whereas for fish farmed in land-based systems the effluent flowing to surface water is

considered to pose the main environmental risk.

EFSA commissioned a study on the environmental impact of zinc and copper used in animal nutrition

(Monteiro et al., 2010). The results of this study were used as the basis for the present opinion.

To assess the potential risks from copper used as additive in feed for terrestrial animals, a model that

integrates the physicochemical and hydrological processes that determine the accumulation and

leaching of metals in soil was used. Input rates of metals resulting from the use of feed additives and

the spreading of animal manure on the land were based on the maximum allowable metal contents of


15 EFSA Journal 2013;11(2):3107

feed additives for different livestock types and the maximum allowable rates of nitrogen input of

170 kg/ha per annum. The assessment is based on the worst case assumption that the total amount of

additive consumed will be excreted.

Concentrations in surface water (as dissolved metal) and sediment (as total sediment metal) were

calculated based upon the Forum for the Coordination of Pesticide Fate Models and their Use

(FOCUS) scenario methodology and taking into consideration the speciation in the environment. More

specific information on the parameterisation and assumptions made is given in the report.

The predicted no-effect concentrations (PNECs) for the different compartments were calculated

following the same methodologies as those presented in the EU risk assessment report for copper by

correcting for bioavailability based on the assumed soil and water chemistry of the different scenarios.

Likewise, it was decided to use the added PNEC approach for copper.

The environmental risks of copper arising from aquaculture were assessed using the exposure models

recommended in the technical guidance (EFSA, 2008d). The estimated concentrations in surface water

resulting from the use of copper as feed additive for different fish species farmed in raceways, ponds,

tanks and recirculation systems and the estimated concentration in sediment arising from the use of

feed additives in sea cages were all below the PNEC and therefore do not give rise to concern.

Concerning the terrestrial environment, potential risks to soil organisms have been identified as a

result of application of piglet manure. However, of the nine scenarios in which a potential risk was

identified, only two have local significance for pig production. Levels of copper in other types of

manure are too low to create a potential risk within the timescale considered.

For the water compartment, none of the scenarios resulted in the PNEC being exceeded when

corrected for bioavailability. However, predicted concentrations of metals in the sediments of

receiving waters, derived from the erosion of metal-enriched particles and transport in drainage and

runoff, responded significantly to increases in metal inputs resulting from manure application.

Potential risks were predicted within 50 years for several scenarios (i.e. R3, R1, D6, D5, D2 and D1).

In two scenarios (D2 and R3) ), all manure types were predicted to result in exceedances. The

predictions of the D2 scenario are of particular note as it is a cracking clay soil of the type vulnerable

to bypass flow during events and thus potentially to extensive transport of particles to drainage as is

simulated in that scenario.

In the view of the FEEDAP Panel, these findings should be treated with caution as further model

validation is needed and refinements are feasible, e.g. by taking into account the surface water

chemistry of the locations of the FOCUS scenarios, more updated bioavailability models, re-

suspension and washout of deposited sediment and chemical transformation of trace elements in the

sediment following deposition (i.e. formation of acid-volatile sulphide and metal sulphides).

The extent to which copper-resistant bacteria contribute to the overall antibiotic resistance situation

cannot be quantified at present (EFSA, 2012).

3.4.1. Conclusions on safety for the environment




sediment owing to drainage and the run-off of copper to surface water. In order to draw a final



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.


16 EFSA Journal 2013;11(2):3107

4. Efficacy

The use of cupric chelate of amino acids hydrate in animal nutrition is well documented in scientific

literature. It is recognised as an efficacious source of copper to meet animal requirements (Baker and

Ammerman, 1995). The efficacy of the cupric chelate of amino acids hydrate was further

demonstrated in two studies provided by the applicant one in dairy cows (Ballantine et al., 2002) and

one in laying hens (Mabe et al., 2003).

5. Post-market monitoring

The FEEDAP Panel considers that there is no need for specific requirements for a post-market

monitoring plan other than those established in the Feed Hygiene Regulation30

and Good

Manufacturing Practice.

CONCLUSIONS AND RECOMMENDATIONS

CONCLUSIONS

Cupric chelate of amino acids hydrate is safe for all animal species/categories up to the authorised

maximum of total copper content in complete feed.

Consumption surveys include copper from foodstuffs of animal origin. Since the supplementation of

animal feed with copper-containing compounds has not essentially changed over the last decade, no

change in the contribution of foodstuffs originating from supplemented animals to the overall copper

intake of consumers is expected. No concerns for consumer safety are expected from the use of cupric

chelate of amino acids hydrate in animal nutrition, which would substitute for other copper sources.

The additive should be considered as a skin and eye irritant and, owing to its amino acid/peptide

component, as a skin/respiratory sensitiser.




sediment owing to drainage and the run-off of copper to surface water. In order to draw a final



required. The use of copper-containing additives in aquaculture up to the authorised maximum of total

copper content in complete 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.

Cupric chelate of amino acids hydrate is recognised as an efficacious source of copper to meet animal

requirements.

RECOMMENDATIONS

The description of the product proposed by the applicant should be amended as follows: Cu(x)1–3·

nH2O (x= anion of any amino acids derived from acid hydrolysed soya protein). At least 90 % of the

molecules should have a molecular weight not exceeding 1500 Dalton.

Since the copper compounds are not available for control, and valuable information to the user of the

product can only be given for the final product, the FEEDAP Panel proposes to evaluate the possibility

of introducing the formulated product in the register of feed additives.

30 Regulation (EC) No 183/2005 of the European Parliament and of the Council of 12 January 2005 laying down

requirements for feed hygiene. OJ L 35, 8.2.2005, p. 1.


17 EFSA Journal 2013;11(2):3107

GENERAL REMARK

More recent findings on the copper requirements of animals indicate the potential to considerably

reduce the current maximum content for dietary copper without affecting animal health and welfare

and the productivity of animal husbandry. A reduction in the maximum content of copper would

decrease the copper load in the environment.

The FEEDAP Panel stresses the need for analytical methods to detect the organic compounds of trace

elements in feed, independent from the trace element background.

DOCUMENTATION PROVIDED TO EFSA

1. Dossier Copper Amino Acid Chelate, Hydrate (Availa® Cu) for all animal species. July 2010.

Submitted by Zinpro Animal Nutrition Inc.

2. Dossier Copper Amino Acid Chelate, Hydrate (Availa® Cu) for all animal species..

Supplementary information. March 2012. Submitted by Zinpro Animal Nutrition Inc.


Supplementary information. June 2012. Submitted by Zinpro Animal Nutrition Inc.


Supplementary information. January 2013. Submitted by Zinpro Animal Nutrition Inc.

5. Evaluation report of the European Union Reference Laboratory for Feed Additives on the

methods(s) of analysis for Copper (E4).

6. Comments from Member States received through the ScienceNet.

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21 EFSA Journal 2013;11(2):3107

APPENDICES

APPENDIX A

Executive Summary of the Evaluation Report of the European Union Reference Laboratory for

Feed Additives on the Method(s) of Analysis for Copper31

In the current application authorisation is sought under articles 4(1) and 10(2) for 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 & liquid) under the category/functional group 3(b) "nutritional additives"/"compounds

of trace elements", according to the classification system of Annex I of Regulation (EC) No

1831/2003. Specifically, authorisation is sought for the use of the feed additives for all categories and

species.

Applicants stated minimum total copper content of: 31% in Cupric acetate monohydrate; 55% in

Basic cupric carbonate monohydrate; 37% in Cupric chloride dihydrate; 77% in Cupric oxide; 24%

in Cupric sulphate pentahydrate; 10% in Cupric chelate of amino-acids hydrate; and 23% and 6% in

solid and liquid Cupric chelate of glycine hydrate, respectively.

The feed additives are intended to be incorporated into premixtures, feedingstuffs and water. All

Applicants suggested maximum levels of total copper in the feedingstuffs complying to the limits set

in Regulations (EC) No 1334/2003 and 479/2006 and ranging from 15 to 170 mg/kg, depending of the

animal species/category.

The EURL recommends three European Pharmocopoeia methods: - Ph. Eur. monograph 01/2008:2146

for the identification of Copper acetate monohydrate; - Ph. Eur. monograph 01/2008:0894, for the

identification of Copper sulphate pentahydrate; and - the generic Ph. Eur. monograph 01/2008:20301

for the "identification reactions of ions and functional groups", such as acetates, carbonates, chlorides

and sulfates. Additionally crystallographic techniques such as X-Ray diffraction could be used for the

characterisation of crystalline structure of Cupric acetate monohydrate, Cupric chloride dehydrate,

Copper oxide and Cupric sulphate pentahydrate.

For the quantification of "amino" content in the amino copper chelates (i.e. Copper chelate of glycine

hydrate and Copper chelate amino acids hydrate), the Applicant proposed - upon request from the

EURL - the Community method based on High Performance Liquid Chromatography (HPLC)

combined with post-column derivatisation using ninhydrin as derivatisation agent and photometric

detection at 570 nm. The EURL considers the Community method suitable for the characterisation of

the amino compounds in the frame of official control.

For the determination of total copper in the feed additive, premixtures and feedingstuffs the Applicants

submitted internationally recognised ring trial validated methods EN 15510 and CEN/TS 15621. Both

methods are based on inductively coupled plasma atomic emission spectroscopy, with or without

pressure digestion. The following performance characteristics were reported for EN 15510:

- a relative standard deviation of repeatability (RSDr) ranging from 2.9 to 12 %;

- a relative standard deviation for reproducibility (RSDR) ranging from 8 to 22 %; and

- a limit of quantification (LOQ) of 3 mg/kg.

A variety of matrices (i.e. feed for pigs and for sheep, rock phosphate, a mineral premix and a mineral

mix) with a total copper content ranging from 7.3 to 470 mg/kg was used in the frame of the CEN/TS

31 The full report is available on the EURL website: http://irmm.jrc.ec.europa.eu/SiteCollectionDocuments/FinRep-

CopperGroup.pdf

http://irmm.jrc.ec.europa.eu/SiteCollectionDocuments/FinRep-CopperGroup.pdf

http://irmm.jrc.ec.europa.eu/SiteCollectionDocuments/FinRep-CopperGroup.pdf


22 EFSA Journal 2013;11(2):3107

15621 ring-trial. The following performance characteristics were reported: - RSDr ranging from 2.6 to

6.8 %; - RSDR ranging from 3.8 to 12 %; and - LOQ = 1 mg/kg feedingstuffs.

Furthermore, a Community method is available for the determination of total copper in feedingstuffs,

but no performance characteristics for the method were provided. The UK Food Standards Agency

recently reported results of a ring-trial based on the above mentioned Community method, and

reported precisions (RSDr and RSDR) for feedingstuffs ranging from 2.4 to 9.2 %.

Based on these performance characteristics the EURL recommends for official control the CEN

methods EN 15510 or CEN/TS 15621 to determine total copper content by ICP-AES in the feed

additive and premixtures. As for the determination of total copper content in feedingstuffs, the EURL

recommends for official control the Community method based on AAS and the above mentioned CEN

methods (EN 15510 or CEN/TS 15621).

Similarly to the "SANCO Zinc group", the EURL recommends the ring-trial validated CEN method

EN ISO 11885, based on inductively coupled plasma optical emission spectroscopy (ICP-AES) for the

quantification of total copper in water.

Further testing or validation of the methods to be performed through the consortium of National

Reference Laboratories as specified by Article 10 (Commission Regulation (EC) No 378/2005) is not

considered necessary.


23 EFSA Journal 2013;11(2):3107

APPENDIX B

List of Risk Assessment Reports on copper and copper compounds

In addition to the reports cited in the Background section, risk assessments have been carried out

by other EU bodies, Institutions and Industry (see list below). Stern (2010) reviewed the

essentiality and toxicity in copper health risk assessment.

1. EU Risk Assessment Reports (RARs)

The Voluntary Risk Assessment Reports (VRAR) submitted to ECHA for Cu

(http://echa.europa.eu/chem_data/transit_measures/vrar_en.asp)

2. EC Health and Consumers Scientific Committees Opinions

The Scientific Committee on Health and Environmental Risk (SCHER) opinion on the VRAR on

Copper, Copper II sulphate pentahydrate, Copper(I)oxide, Copper(II)oxide, Dicopper chloride

trihydroxide (Human health part)

(http://echa.europa.eu/doc/trd_substances/VRAR/Copper/scher_opinion/scher_opinion_hh.pdf)

The Scientific Committee on Health and Environmental Risk (SCHER) opinion on the VRAR on

Cu and its compounds (Environmental part)

(http://echa.europa.eu/doc/trd_substances/VRAR/Copper/scher_opinion/scher_opinion_env.pdf)

3. EU Member States. Risk Assessment Reports

Risk Assessment Copper. Expert Group on Vitamins and Minerals 2003.

(http://www.food.gov.uk/multimedia/pdfs/evm_copper.pdf)

Prediction of the long term accumulation and leaching of copper in Dutch agricultural soils: a risk

assessment study. Published on 20 April 2006. (report n° 1278,

http://www.alterra.wur.nl/NL/publicaties+Alterra/Alterra+rapporten/)

4. EFSA-ANS Panel Opinions

Copper(II) oxide as a source of copper added for nutritional purposes to food supplements

(http://www.efsa.europa.eu/en/efsajournal/pub/1089.htm)

Magnesium aspartate, potassium aspartate, magnesium potassium aspartate, calcium aspartate,

zinc aspartate, and copper aspartate as sources for magnesium, potassium, calcium, zinc, and

copper added for nutritional purposes to food supplements - Scientific Panel on Food Additives

and Nutrient Sources added to food (http://www.efsa.europa.eu/en/efsajournal/pub/883.htm)

Orotic acid salts as sources of orotic acid and various minerals added for nutritional purposes to

food supplements (http://www.efsa.europa.eu/en/efsajournal/pub/1187.htm)

5. EFSA-CEF Panel Opinions

Scientific Report of EFSA on the risk assessment of salts of authorised acids, phenols or alcohols

for use in food contact materials (http://www.efsa.europa.eu/en/efsajournal/pub/1364.htm)

Scientific Opinion on the safety evaluation of the substance, copper hydroxide phosphate, CAS

No. 12158-74-6, for use in food contact materials


6. EFSA-AFC Panel Opinions

Opinion on certain bisglycinates as sources of copper, zinc, calcium, magnesium and glycinate

nicotinate as source of chromium in foods intended for the general population (including food

http://echa.europa.eu/chem_data/transit_measures/vrar_en.asp

http://echa.europa.eu/doc/trd_substances/VRAR/Copper/scher_opinion/scher_opinion_hh.pdf

http://echa.europa.eu/doc/trd_substances/VRAR/Copper/scher_opinion/scher_opinion_env.pdf

http://www.food.gov.uk/multimedia/pdfs/evm_copper.pdf

http://www.alterra.wur.nl/NL/publicaties+Alterra/Alterra+rapporten/







24 EFSA Journal 2013;11(2):3107

supplements) and foods for particular nutritional uses[1] - Scientific Opinion of the Scientific

Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food


7. EFSA-NDA Panel Opinions

Scientific Opinion on the substantiation of health claims related to copper and protection of DNA,

proteins and lipids from oxidative damage (ID 263, 1726), function of the immune system (ID

264), maintenance of connective tissues (ID 265, 271, 1722), energy-yielding metabolism (ID

266), function of the nervous system (ID 267), maintenance of skin and hair pigmentation (ID 268,

1724), iron transport (ID 269, 270, 1727), cholesterol metabolism (ID 369), and glucose

metabolism (ID 369) pursuant to Article 13(1) of Regulation (EC) No 1924/2006


Scientific Opinion on the substantiation of health claims related to copper and reduction of

tiredness and fatigue (ID 272), maintenance of the normal function of the nervous system (ID

1723), maintenance of the normal function of the immune system (ID 1725) and contribution to

normal energy-yielding metabolism (ID 1729) pursuant to Article 13(1) of Regulation (EC) No

1924/2006 (http://www.efsa.europa.eu/en/efsajournal/pub/2079.htm)

References

Stern BR, 2010. Essentiality and Toxicity in Copper Health Risk Assessment: Overview, Update

and Regulatory Considerations. Journal of Toxicology and Environmental Health Part A,

73,114–127.





25 EFSA Journal 2013;11(2):3107

APPENDIX C

List of authorisations for copper other than as a feed additive

The following copper compounds are authorised for use in food (Regulation (EC) No 1170/2009):1

copper L-aspartate, copper bisglycinate, copper lysine complex, copper (II) oxide (which may be

used in the manufacture of food supplements); copper lysine complex which may be added to

foods.

The following copper compounds can be used for the manufacturing of dietetic foods

(Commission Regulation (EC) No 953/2009):2 cupric carbonate, cupric citrate, cupric gluconate,

cupric sulphate and copper lysine complex.

The following copper compounds can be used for the manufacturing of processed cereal-based

foods and baby foods for infants and young children (Commission Directive 2006/125/EC):3

Copper-lysine complex, Cupric carbonate, Cupric citrate, Cupric gluconate, Cupric sulphate.

Regarding pharmacologically active substances and their classification regarding maximum

residue limits in foodstuffs of animal origin, the following copper compounds are listed in Table 1

of the Annex of Regulation 37/20104 as Allowed substances, no MRL required: Copper chloride,

Copper gluconate, Copper heptanoate, Copper methionate, Copper oxide, Copper sulphate and

Dicopper oxide.

The following copper compounds are listed in Annex of Commission Implementing Regulation

(EU) No 540/20115 as ―Active substances approved for use in plant protection products‖: Copper

(II) hydroxide (Copper hydroxide), Dicopper chloride trihydroxide (Copper oxychloride) and

Copper oxide.

The following type of fertilisers for copper as fertilisers containing only one micro-nutrient are

listed in Annex I of Regulation (EC) No 2003/20036 of the European Parliament and of the

Council: (a) Copper salt (chemically obtained product containing a mineral salt of copper as its

essential ingredient), (b) Copper oxide (chemically obtained product containing copper oxide as its

essential ingredient), (c) Copper hydroxide (chemically obtained product containing copper

hydroxide as its essential ingredient), (d) Copper chelate (water-soluble product obtained by

combining copper chemically with a chelating agent), (e) Copper-based fertiliser (product obtained

by mixing types ―a‖ and/or ―b‖ and/or ―c‖ and/or a single one of type ―d‖ and, if required, filler

that is neither nutrient nor toxic), (f) Copper fertiliser solution (product obtained by dissolving

types ―a‖ and/or one of the type ―d‖ in water), (g) Copper oxychloride (chemically obtained

product containing copper oxychloride [Cu2Cl(OH)3] as an essential ingredient), (h) Copper

oxychloride suspension (product obtained by suspension of type ―g‖).

1 Commission Regulation (EC) No 1170/2009 of 30 November 2009 amending Directive 2002/46/EC of the European

Parliament and of Council and Regulation (EC) No 1925/2006 of the European Parliament and of the Council as

regards the lists of vitamin and minerals and their forms that can be added to foods, including food supplements. OJ L

314, 1.12.2009, p. 36. 2 Commission Regulation (EC) No 953/2009 of 13 October 2009 on substances that may be added for specific

nutritional purposes in foods for particular nutritional uses. OJ L 269, 14.10.2009, p. 9. 3 Commission Directive 2006/125/EC of 5 December 2006 on processed cereal-based foods and baby foods for infants

and young children. OJ L 339, 6.12.2006, p. 16. 4 Commission Regulation (EU) No 37/2010 of 22 December 2009 on pharmacologically active substances and their

classification regarding maximum residue limits in foodstuffs of animal origin. OJ L 15, 20.1.2010, p. 1. 5 Commission Implementing Regulation (EU) No 540/2011 of 25 May 2011 implementing Regulation (EC) No

1107/2009 of the European Parliament and of the Council as regards the list of approved active substances. OJ L 153,

11.6.2011, p. 1. 6 Regulation (EC) No 2003/2003 of the European Parliament and of the Council of 13 October 2003 relating to

fertilisers. OJ L 304, 21.11.2003, p. 1.


26 EFSA Journal 2013;11(2):3107

The following copper compounds can be used for cosmetic purposes (Regulation (EC) No

1223/2009 of the European Parliament and of the Council):7 74160 (29H,31H-Phthalocyaninato

(2-)-N29,N30, N31, N32 copper), 74260 (Polychloro copper phthalocyanine), 77400 (Copper).

According to the Annex to Regulation (EC) No 432/20128 the following health claims can be

made only for food which is at least a source of copper as referred to in the claim SOURCE OF

[NAME OF VITAMIN/S] AND/OR [NAME OF MINERAL/S] as listed in the Annex to Regulation

(EC) No 1924/20069: ―Copper contributes to maintenance of normal connective tissues‖, ―Copper

contributes to normal energy-yielding metabolism‖, ―Copper contributes to normal functioning of

the nervous system‖, ―Copper contributes to normal hair pigmentation‖, ―Copper contributes to

normal iron transport in the body‖, ―Copper contributes to normal skin pigmentation‖, ―Copper

contributes to the normal function of the immune system‖ and ―Copper contributes to the

protection of cells from oxidative stress‖.

7 Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic

products. OJ L 342, 22.12.2009, p. 59. 8 Commission Regulation (EC) No 432/2012 of 16 May 2012 establishing a list of permitted health claims made on

foods, other than those referring to the reduction of disease risk and to children‘s development and health. OJ L 136,

25.05.2012, p.1. 9 Regulation (EC) No 1924/2006 of the European Parliament and of the council of 20 December 2006 on nutrition and

health claims made for food. OJ L 404, 30.12.2006, p.9.

efsa reglementation

Documents

use of copper

runoff of copper

assessment of copper

levels of copper

copper sources

amino acids hydrate

animal feed feedap2

supplementation of animal