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

TL;DR

This study confirms that a copper(II)-betaine complex is an effective and safe source of copper in animal feed for all species.

Contribution

The study provides new evidence of the bioavailability and efficacy of copper(II)-betaine complex in chickens for fattening.

Findings

The additive is a bioavailable source of copper for all animal species.

The FEEDAP Panel confirms the efficacy of the additive as a copper source in feed.

The additive was previously found safe for animals, consumers, and the environment.

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 complex as a nutritional feed additive for all species and categories. In a previous opinion, the FEEDAP Panel characterised the feed additive and concluded that it is safe for the target animals, consumers, and the environment when used up to the maximum authorised levels of copper in the diets. With regard to the safety of users, the additive is considered irritant to the eyes and a skin and respiratory sensitiser. In the current submission, the applicant provided a new efficacy study in chickens for fattening to support the efficacy of the additive. The data submitted provided evidence that the additive is a bioavailable source of copper and thus, the FEEDAP Panel concludes that the additive is efficacious as a source of copper for all animal species.

Tables

TABLE 1. Description of the substances.

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

TABLE 2. Intended and analysed content of copper in the experimental diets.

Treatment	Copper source	Total intended copper content (mg Cu/kg)	Analysed Cu in experimental feeds (mg Cu/kg)
			Starter	Grower	Finisher
Control	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
CuSO4‐■■■■■	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
CuSO4‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■
CuSO4‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■
BetaTrace‐Cu‐■■■■■	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
BetaTrace‐Cu‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■
BetaTrace‐Cu‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■

TABLE 3. Effect of copper supplementation from two different sources of copper (copper sulfate pentahydrate and copper(II) betaine complex) on zootechnical performance in chicken for fattening after 35 days.

Treatment	Copper source	Intended Cu (1) (mg/kg feed)	Feed intake (2) (g)	Body weight gain (2) (g)	Feed to gain ratio	Mortality (3) (%)
Control	Native	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
CuSO4‐■■■■■	CuSO4	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
CuSO4‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
CuSO4‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
BetaTrace‐Cu‐■■■■■	BetaTrace	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
BetaTrace‐Cu‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
BetaTrace‐Cu‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■	■■■■■

TABLE 4. Effect of copper supplementation from two different sources of copper (copper sulfate pentahydrate and copper(II) betaine complex) on copper tissue deposition in chicken for fattening after 35 days.

Treatment	Copper source	Total intended copper content (1) (mg/kg feed)	Copper deposition (mg/kg tissue ‐ fresh matter)
			Kidneys	Liver	Skin+fat	Muscle
Control	Native	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
CuSO4‐■■■■■	CuSO4	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
CuSO4‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
CuSO4‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
BetaTrace‐Cu‐■■■■■	BetaTrace	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
BetaTrace‐Cu‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
BetaTrace‐Cu‐■■■■■		■■■■■	■■■■■	■■■■■	■■■■■	■■■■■

Full text

INTRODUCTION

1

Background and Terms of Reference as provided by the requestor

1.1

Regulation (EC) No 1831/200311 establishes the rules governing the Community authorisation of additives for use in animal nutrition. In particular, Article 9 defines the terms of the authorisation by the Commission.

The applicant, Biochem Zusatztoffe Handels und Produktionsges mbH, is seeking a Community authorisation of copper(II)‐betaine complex as a feed additive to be used as a compound of trace elements for all animal species and categories (Table 1).

On 15 of November 2023, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) of the European Food Safety Authority (EFSA), in its opinion on the safety and efficacy of the product, could not conclude on 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 supplementary information and data have been transmitted by the applicant received on 06.10.2023 on the e‐submission food chain platform (application number FEED‐2024‐31691).

In view of the above and in accordance with Article 29(1)(a) of Regulation (EC) No178/2002, The European Commission requests EFSA to deliver a new scientific opinion on the efficacy of the feed additive consisting of copper (II)‐betaine complex under the conditions of Regulation (EC) No 1831/2003, based on the supplementary information and data submitted by the applicant.

Additional information

1.2

The additive copper(II)‐betaine complex has not been previously authorised as a feed additive in the European Union (EU). The FEEDAP Panel adopted two opinions on the safety and efficacy of this compound (EFSA FEEDAP Panel, 2023a, 2023b).

DATA AND METHODOLOGIES

2

Data

2.1

The present assessment is based on data submitted by the applicant in the form of supplementary information2 to a previous application on the same product.3 The dossier was received on 27/11/2024 and the general information and supporting documentation are available on Open EFSA at https://open.efsa.europa.eu/questions/EFSA‐Q‐2024‐00682.

In accordance with Article 38 of the Regulation (EC) No 178/20024 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 dossier has been published on Open.EFSA.

Methodologies

2.2

The approach followed by the FEEDAP Panel to assess the efficacy of copper(II)‐betaine complex is in line with the principles laid down in Regulation (EC) No 429/20086 and the relevant guidance documents: Guidance on the assessment of the efficacy of feed additives (EFSA FEEDAP Panel, 2024).

ASSESSMENT

3

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

In the previous opinions, the FEEDAP Panel characterised the feed additive and concluded that it is safe for the target animals, consumers, and the environment when used up to the maximum authorised levels of copper in the diets. With regard to the safety of users, the additive is considered irritant to the eyes and a skin and respiratory sensitiser. However, the Panel could not conclude on the efficacy of additive (EFSA FEEDAP Panel, 2023a, 2023b). The applicant has provided new data on the characterisation of the additive and additional evidence to support the efficacy, which are assessed below.

Copper(II)‐betaine complex is intended to be used in feed for all animal species and categories 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).

Characterisation

3.1

Characterisation of the additive

3.1.1

The additive was fully characterised in two previous opinions (EFSA FEEDAP Panel, 2023a, 2023b). Per specifications, the additive contains a minimum of 19% of copper, minimum 36% of betaine, 9%–12% of sulfur (equivalent to 27%–36% of sulfate, calculated from reported sulfur) and a maximum 5% of moisture.

In the original application, the applicant set specifications for nickel in the additive of maximum 100 mg/kg. In the previous opinion (EFSA FEEDAP Panel, 2023a), the Panel reported the content of nickel of the additive based on the analysis of three batches, which ranged between 10.5 and 15.8 mg/kg. In the current application, the applicant has provided data on three additional batches, which showed concentrations of nickel of 67.6, 73.4 and 76.8 mg/kg, confirming the possibility of higher nickel concentrations in the additive, due to the great variations of nickel content in the raw materials used for the manufacturing of the additive.

Efficacy

3.2

In a previous assessment (EFSA FEEDAP Panel, 2023a), a tolerance‐efficacy trial in chickens for fattening was reviewed. Diets were either non‐supplemented with copper (control group, background content of 7.5 mg Cu/kg feed) or supplemented with copper (15, 25, or 200 mg/kg complete feed) from either copper sulfate or copper(II)‐betaine complex. Data indicated no clear trend in copper deposition in tissues and organs. The Panel concluded that the level of copper in the unsupplemented diet might have been sufficient for the animals, and only high dietary levels would markedly increase copper concentration in tissues.

In a follow‐up opinion (EFSA FEEDAP Panel, 2023b), no new experimental data was submitted, but a new statistical analysis of the previous study was provided. Despite this, the Panel could not alter its previous decision, reiterating that copper deposition did not show a consistent dose–response trend. In particular, data on copper deposition in the liver, the main target organ, and skin/fat were unreliable due to high variability. Thus, the FEEDAP Panel maintained it could not conclude on the efficacy of copper(II)‐betaine complex for all animal species.

In the current application, a new study in chickens for fattening was submitted to support the efficacy of the additive as a source of copper.8 A total of 560 male Ross 308 chickens were randomly allocated into seven groups (8 replicates/group; 10 birds/replicate). Birds were distributed in pens and each pen randomly assigned to an experimental group. The basal diet was based on maize, wheat and soybean meal, and birds were fed a three‐phase feeding program (starter 1‐11 days, grower 12–24 days and finisher 25–35 days) for a total duration of 35 days. Diets were either non‐supplemented with copper (control group) or supplemented with either copper sulfate pentahydrate or copper(II)‐betaine complex (BetaTrace‐Cu) to reach an intended total dietary copper content of ■■■■■, ■■■■■ or ■■■■■ mg/kg complete feed. The content of copper in the diets was analytically confirmed (see Table 2).

Mortality and health status of the birds was daily checked. Birds were weighed on days 11, 24 and 35 and feed consumption at the end of each feeding phase. Average body weight gain, average feed consumption and feed to gain ratio were calculated. At 35 days, tissues samples of muscle, liver, kidney and skin+fat were collected from 8 random birds per treatment (1 bird/pen) for determination of copper deposition in these tissues.

The pen was considered the experimental unit. Data were analysed by an analysis of variance using the general linear model's procedure. Significance was set at p < 0.05 (Table 3).

Overall mortality in the study was ■■■■■ No significant differences between groups were observed in mortality during the experimental period. Relative to control, a lower feed consumption was observed in birds receiving copper betaine at ■■■■■ mg/kg feed but this observation was not found in any other copper supplemented group (either sulfate or copper(II) betaine). No differences in body weight gain were observed but feed to gain ratio was lower in all copper betaine supplemented groups relative to control (Table 4).

No differences were observed between treatments at the end of the experimental period in the total copper in kidneys and muscle. However, the copper(II) betaine complex group supplemented with ■■■■■ mg Cu/kg feed resulted in significantly higher copper depositions in liver and skin+fat compared to the control group.

The Panel notes that (1) liver is the main target organ for copper deposition and (2) that significant increases in copper deposition in liver and other tissues might become only evident at high copper dietary levels specially if the background copper levels cover the requirements of the animal.

The new data submitted provides evidence of higher copper deposition in liver and skin+fat in the copper(II) betaine complex supplemented birds, relative to the unsupplemented group. The FEEDAP Panel concludes that the additive is a bioavailable source of copper and therefore the additive is efficacious in meeting the birds copper requirements. This conclusion can be extrapolated to all animal species and categories.

Post‐market monitoring

3.3

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 Regulation9 and Good Manufacturing Practice.

CONCLUSIONS

4

The FEEDAP Panel concludes that the additive is efficacious as a source of copper for all animal species.

RECOMMENDATIONS AND/OR REMARKS

5

The Panel notes that some breeds of dog are particularly sensitive to copper toxicity (EFSA FEEDAP Panel, 2016). It is recommended that this is indicated in the label of the feed supplemented with copper.ABBREVIATIONSFEEDAPEFSA Scientific Panel on Additives and Products or Substances used in Animal Feed

REQUESTOR

European Commission

QUESTION NUMBER

EFSA‐Q‐2024‐00682

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PANEL MEMBERS

Roberto Edoardo Villa, Giovanna Azimonti, Eleftherios Bonos, Henrik Christensen, Mojca Durjava, Birgit Dusemund, Ronette Gehring, Boet Glandorf, Maryline Kouba, Marta López‐Alonso, Francesca Marcon, Carlo Nebbia, Alena Pechová, Miguel Prieto‐Maradona, Ilen Röhe, and Katerina Theodoridou.

LEGAL NOTICE

Relevant information or parts of this scientific output have been blackened in accordance with the confidentiality requests formulated by the applicant pending a decision thereon by EFSA. The full output has been shared with the European Commission, EU Member States (if applicable) and the applicant. The blackening may be subject to review once the decision on the confidentiality requests is adopted by EFSA and in case it rejects some of the confidentiality requests.