Safety and efficacy of a feed additive consisting of copper(II)‐betaine complex for all animal species (Biochem Zusatzstoffe Handels‐ und Produktionsges. mbH)

Abstract

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 efficacy of copper(II)‐betaine as a nutritional additive for all animal species and on the safety for the marine sediment when the additive is used in sea cages. The FEEDAP Panel concluded that the risk to the marine sediment is acceptable when the additive is used in sea cages. The additional statistical analysis of the results of the efficacy study already assessed in the previous opinion did not allow the Panel to conclude on the efficacy of the additive.

1. INTRODUCTION

1.1. Background and terms of reference as provided by the requestor

Regulation (EC) No 1831/2003 ¹ establishes the rules governing the Community authorisation of additives for use in animal nutrition and in particular, Article 9 defines the terms of the authorisation by the Commission.

The European Commission received a request from Biochem Zusatzstoffe Handels‐ und Produktionsges. mbH for the authorisation of the additive consisting of copper(II)‐betaine complex, when used as a feed additive for all animal species (category: nutritional additive; functional group: compound of trace elements) (Table 1).

TABLE 1.

Description of the substances.

Category of additive	Nutritional
Functional group of additive	Compounds of trace elements
Description	Copper(II)‐betaine complex
Target animal category	All animal species
Applicant	Biochem Zusatzstoffe Handels‐ und Produktionsges. mbH
Type of request	New opinion

On 11 January 2023, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP Panel) of the European Food Safety Authority (EFSA), in its opinion on the safety and efficacy of the feed additive consisting of copper(II)‐betaine complex for all animal species, could not conclude on the safety of the additive for marine sediment when it is used in sea cages nor on the efficacy of the additive.

During the discussions with the Member States at a meeting of the Standing Committee on Plants, Animals, Food and Feed (Animal Nutrition section), it was suggested to check for the possibility to demonstrate the safety for the marine sediment and the efficacy of the additive.

The Commission gave the possibility to the applicant to submit supplementary information and data in order to complete the assessment and to allow a revision of the EFSA's opinion. The new data have been received on 23 May 2023 and the applicant has been requested to transmit them to the European Commission by using the e‐submission food chain platform (ESFC) system.

In view of the above, the Commission asks EFSA to deliver a new opinion on copper(II)‐betaine based on the supplementary information submitted by the applicant, in accordance with Article 29(1)(a) of Regulation (EC) No 178/2002.

1.2. Additional information

The additive is copper(II)‐betaine complex. The FEEDAP Panel already assessed safety and efficacy of this additive in a previous opinion (EFSA FEEDAP, 2023); however, the efficacy and safety for the marine sediment remained inconclusive.

The additive has not been previously authorised as a feed additive in the European Union.

2. DATA AND METHODOLOGIES

2.1. Data

The present assessment is based on data submitted by the applicant in the form of supplementary information ² to a previous application ³ on the same product, for the authorisation of copper(II)‐betaine complex as a feed additive. The dossier was received on 8 June 2023 and the general information and supporting documentation are available on Open.EFSA at https://open.efsa.europa.eu/questions/EFSA‐Q‐2023‐00401

In accordance with Article 38 of the Regulation (EC) No 178/2002 ⁴ and taking into account the protection of confidential information and of personal data in accordance with Articles 39 to 39e of the same Regulation, and of the Decision of EFSA's Executive Director laying down practical arrangements concerning transparency and confidentiality, ⁵ a non‐confidential version of the supplementary information has been published on Open.EFSA.

The FEEDAP Panel used the data provided by the applicant together with data from other sources, such as previous risk assessments by EFSA or other expert bodies, peer‐reviewed scientific papers, other scientific reports and experts' knowledge, to deliver the present output.

2.2. Methodologies

The approach followed by the FEEDAP Panel to assess the safety for the environment and the efficacy of copper(II)‐betaine is in line with the principles laid down in Regulation (EC) No 429/2008 ⁶ and the relevant guidance documents: Guidance on the assessment of the efficacy of feed additives (EFSA FEEDAP Panel, 2018), Guidance on the assessment of the safety of feed additives for the environment (EFSA FEEDAP Panel, 2019).

3. ASSESSMENT

The additive under assessment is copper(II)‐betaine complex. The additive corresponds to the active compound. It is intended for use in feed as a nutritional additive (functional group: compounds of trace elements) for all animal species and categories.

The additive has been previously characterised (EFSA FEEDAP Panel, 2023). It is a complex defined by the applicant with a chemical formula [Cu(H₂O)₂((CH₃)₃NCH₂COO)(SO₄)]n. Based on manufacturer's specification, copper(II)‐betaine complex contains minimum 19% of copper, minimum 36% of betaine, sulfur content 9%–12% (equivalent to 27%–36% of sulfate, calculated from reported sulfur) and a maximum 5% of moisture.

The additive is intended for use in all types of feed and for all animal species up to the maximum authorised total copper content in complete feeds: ⁷ 15 mg/kg (bovines before the start of rumination), 30 mg/kg (other bovines), 15 mg/kg (ovines), 35 mg/kg (caprines), 150 mg/kg (piglets: suckling and weaned up to 4 weeks after weaning), 100 mg/kg (piglets from 5 to 8 weeks after weaning), 50 mg/kg (crustaceans) and 25 mg/kg (other animals).

In the previous opinion, the FEEDAP Panel concluded that the additive is safe for the target species and the consumers when used up to the maximum authorised levels of copper in the EU (EFSA FEEDAP Panel, 2023). In the same opinion, it was concluded that the additive is not a skin irritant but is an eye irritant and should be considered a skin and respiratory sensitiser. The use of copper(II)‐betaine complex in animal nutrition at the proposed use levels for the terrestrial species and land‐based aquaculture systems was considered safe for the environment. However, the data available did not allow a conclusion to be made on the safety of the additive for marine sediment when it is used in sea cages. Based on the data available, the efficacy of the additive could not be demonstrated.

The applicant has provided new data to support the safety for the marine sediment and the efficacy, which are assessed below.

3.1. Safety for the environment

In the previous opinion (EFSA FEEDAP Panel, 2023), to assess the environmental risk of copper from the additive, the Panel compared the worst‐case predicted environmental concentrations (PECs) ⁸ calculated at the maximum authorised level of copper, with the natural background concentration considered as 90th percentile value from FOREGS Geochemical Baseline Database. ⁹

Since the calculated PEC_soil and PEC_swaq were below 10% off the background concentrations, the FEEDAP Panel concluded that the use of the additive for terrestrial species and land‐based aquaculture systems is safe. On the contrary, the copper concentration in marine sediment (PEC_sed) (calculated to be 55 mg Cu/kg dw, at use level 25 mg Cu/kg feed) was not below the 10% of the background concentration (median copper concentration 20 mg/kg in the marine sediment, data from the OSPAR Commission, 2014). The available data did not allow to conclude on the safety of the additive when used in sea cages.

In the additional information provided by the applicant, ¹⁰ reference is made to the copper predicted no effect concentration in sediment (PNEC_sed) of 338 mg Cu/kg dw (Monteiro et al., 2010), derived using the equilibrium partitioning approach. The FEEDAP Panel noted that, although the calculated PEC_sed exceeds the reported median copper level in marine sediment (OSPAR Commission, 2014) (EFSA FEEDAP Panel, 2023), the ratio PEC/PNEC resulted to < 1, indicating no risk for marine sediment.

The FEEDAP Panel concludes that, based on the new information submitted, the use of the additive at the proposed conditions of use in marine aquaculture does not a pose a risk to the marine sediment compartment.

3.2. Efficacy

In the original application, the applicant provided a combined tolerance/efficacy study in chickens for fattening (EFSA FEEDAP Panel, 2023). The raw data on the copper deposition in edible tissues (kidney, liver, muscle, skin and fat) were analysed with ANOVA, and the means of the different groups were compared using the Tukey test. The results did not indicate any clear trend in relation to the level of copper in the diets and/or the source of copper. The Panel considered that the level of copper in the control (unsupplemented) diet may have been sufficient to cover the requirement of the animal and acknowledged that only at high dietary levels, copper concentration in liver or tissues shows a marked increase (see also EFSA FEEDAP Panel, 2016). In the absence of evidence of the copper bioavailability, the FEEDAP Panel was not in the position to conclude on the efficacy.

In the current submission, the applicant provided a statistical re‐analysis of the same raw copper deposition data (in kidney, liver, muscle, skin and fat) by using a different post hoc analysis (Dunnett's test). ¹¹ Regardless of the results of the statistical re‐analysis, the Panel is not in a position to change its previous decision and reiterates that the copper deposition did not indicate any consistent dose–response trend, in particular in the main target organ (liver), for any of the copper sources (including the positive control as a recognised source of copper). The copper deposition values in skin and fat are not considered reliable due to the high variability observed in the raw data.

The applicant also provided a statistical re‐analysis of the zootechnical performance data of the chickens in the same trial to support the efficacy of the additive. ¹² However, the Panel considers that the efficacy of compounds of trace elements should rely on the demonstration of the bioavailability of the trace element, and not on the effects on the performance.

Therefore, based on the submitted supplementary information, the FEEDAP Panel is not in a position to conclude on the efficacy of the additive.

3.3. 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 Regulation ¹³ and good manufacturing practice.

4. CONCLUSIONS

The FEEDAP Panel concludes that the use of the additive at the proposed conditions of use in marine aquaculture does not a pose a risk to the marine sediment compartment.

The Panel reiterates its previous conclusion that, based on the data available, the efficacy of the additive cannot be demonstrated.

ABBREVIATIONS

CAS

Chemical Abstracts Service

DM

dry matter

EINECS

European Inventory of Existing Chemical Substances

EMA

European Medicines Agency

EURL

European Union Reference Laboratory

FCR

feed conversion ratio

FEEDAP

EFSA Scientific Panel on Additives and Products or Substances used in Animal Feed

IUPAC

International Union of Pure and Applied Chemistry

CONFLICT OF INTEREST

If you wish to access the declaration of interests of any expert contributing to an EFSA scientific assessment, please contact interestmanagement@efsa.europa.eu.

REQUESTOR

European Commission

QUESTION NUMBER

EFSA‐Q‐2023‐00401

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PANEL MEMBERS

Vasileios Bampidis, Giovanna Azimonti, Maria de Lourdes Bastos, Henrik Christensen, Mojca Durjava, Birgit Dusemund, Maryline Kouba, Marta López‐Alonso, Secundino López Puente, Francesca Marcon, Baltasar Mayo, Alena Pechová, Mariana Petkova, Fernando Ramos, Roberto Edoardo Villa, and Ruud Woutersen.

EFSA FEEDAP Panel (EFSA Panel on Additives and Products or Substances used in Animal Feed) , Bampidis, V. , Azimonti, G. , Bastos, M. L. , Christensen, H. , Durjava, M. , Dusemund, B. , Kouba, M. , López‐Alonso, M. , López Puente, S. , Marcon, F. , Mayo, B. , Pechová, A. , Petkova, M. , Ramos, F. , Villa, R. E. , Woutersen, R. , Galobart, J. , Innocenti, M. L. , … Radovnikovic, A. (2023). Safety and efficacy of a feed additive consisting of copper(II)‐betaine complex for all animal species (Biochem Zusatzstoffe Handels‐ und Produktionsges. mbH). EFSA Journal, 21(11), e8460. 10.2903/j.efsa.2023.8460