Abstract
Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of copper lysinate sulfate as nutritional feed additive for all animal species. The additive has not yet been authorised in the EU. The FEEDAP Panel concluded that the additive copper lysinate sulfate is safe for all animal species and categories at the respective maximum authorised total copper levels in feed. In the absence of reliable deposition data, the FEEDAP Panel could not conclude on the safety of the additive for the consumer. In the absence of data, the FEEDAP Panel could not conclude on the eye irritation potential of the additive. The Panel concluded that the additive is not a skin irritant and thus it should be considered a skin and respiratory sensitiser; inhalation and dermal exposure are considered a risk. The FEEDAP Panel concluded that the use of the additive under the proposed conditions of use is safe for the environment. The Panel was not in the position to conclude on the efficacy of the additive at the maximum authorised inclusion level.
Keywords: copper, copper lysinate sulfate, efficacy, nutritional additive, Plexomin L‐Cu, safety
1. INTRODUCTION
1.1. Background and Terms of Reference
Regulation (EC) No 1831/2003 1 establishes the rules governing the Community authorisation of additives for use in animal nutrition. In particular, Article 4(1) of that Regulation lays down that any person seeking authorisation for a feed additive or for a new use of feed additive shall submit an application in accordance with Article 7.
The European Commission received a request from Phytobiotics Futterzusatzstoffe GmbH 2 for the authorisation of the additive consisting of copper lysinate sulfate, 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) as an application under Article 4(1) (authorisation of a feed additive or new use of a feed additive). The dossier was received on 3 January 2024 and the general information and supporting documentation are available at https://open.efsa.europa.eu/questions/EFSA‐Q‐2024‐00001. The particulars and documents in support of the application were considered valid by EFSA as of 10 April 2024.
According to Article 8 of Regulation (EC) No 1831/2003, 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. EFSA shall deliver an opinion on the safety for the target animals, consumer, user and the environment and on the efficacy of the feed additive consisting of copper lysinate sulfate, when used under the proposed conditions of use (see Section 3.1.3 ).
1.2. Additional information
The additive copper lysinate sulfate 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 a technical dossier 3 in support of the authorisation request for the use of copper lysinate sulfate as a feed additive.
The confidential version of the technical dossier was subject to a target consultation of the interested Member States from 12 April 2024 to 12 July 2024; the comments received were considered for the assessment.
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 dossier has been published on Open.EFSA.
According to Article 32c(2) of Regulation (EC) No 178/2002 and to the Decision of EFSA's Executive Director laying down the practical arrangements on pre‐submission phase and public consultations, EFSA carried out a public consultation on the non‐confidential version of the technical dossier from 28 August to 18 September 2024 for which no comments were received.
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.
EFSA has verified the European Union Reference Laboratory (EURL) report as it relates to the methods used for the control of the active substance in animal feed. 6
2.2. Methodologies
The approach followed by the FEEDAP Panel to assess the safety and the efficacy of copper lysinate sulfate is in line with the principles laid down in Regulation (EC) No 429/2008 7 and the relevant guidance documents: Guidance on the assessment of the safety of feed additives for the consumer (EFSA FEEDAP Panel, 2017a), Guidance on the identity, characterisation and conditions of use of feed additives (EFSA FEEDAP Panel, 2017b), Guidance on the assessment of the safety of feed additives for the target species (EFSA FEEDAP Panel, 2017c), Guidance on the assessment of the safety of feed additives for the environment (EFSA FEEDAP Panel, 2019), Guidance on studies concerning the safety of use of the additive for users/workers (EFSA FEEDAP Panel, 2023) and Guidance on the assessment of the efficacy of feed additives (EFSA FEEDAP Panel, 2024).
3. ASSESSMENT
The additive copper lysinate sulfate (Cu‐Lys) is intended to be used as a nutritional additive (functional group: compounds of trace elements) as a source of copper in feed for all animal species.
3.1. Characterisation
3.1.1. Characterisation of the additive
The additive is copper lysinate sulfate (Cu‐Lys). 8 Copper lysinate sulfate is described as a 1:1 complex (copper: L‐lysine) with a chemical formula C6H14CuN2O6S·2H2O and structural formula [Cu(Lys)(H2O)2]SO4. 9 The International Union of Pure and Applied Chemistry (IUPAC) name is diaquamonolysinatocopper(II) sulfate; the molecular weight is 341.82 g/mol.
Infrared (IR) spectroscopic data supported the formation of a complex. 10
The additive is specified to contain a minimum of 18% copper, 40% lysine and less than 10% moisture. Data on the batch‐to‐batch variation 11 and impurities 12 are presented in Table 1 and on the physical and physico‐chemical properties 13 of the additive are shown in Table 2.
TABLE 1.
Data on the batch‐to‐batch variation and impurities of copper lysinate sulfate.
| Parameter | Specification | Analysis | ||
|---|---|---|---|---|
| Average | Range | # batches | ||
| Batch‐to‐batch variation | ||||
| Copper (%, as is) | ≥ 18 | 18.2 | 17.5–18.6 | 5 |
| Lysine (%, as is) | ≥ 40 | 41.6 | 40.8–42.2 | 5 |
| Moisture (%, as is) | ≤ 10 | 5.9 | 5.4–6.8 | 5 |
| Sulfate (%, as is, calculated value) | 29.7 | 28.7–30.6 | 5 | |
| Impurities | ||||
| Lead (mg/kg) | 10.3–10.8 | 3 | ||
| Mercury (mg/kg) | < 0.03 | 3 | ||
| Cadmium (mg/kg) | 0.31–0.42 | 3 | ||
| Arsenic (mg/kg) | < 0.5 | 3 | ||
| Fluorine (mg/kg) | < 40 | 3 | ||
| Nickel (mg/kg) | 5.4–6.4 | 3 | ||
| Dioxins and furans (upper bound) (1) | ||||
| PCDD/Fs (ng WHO2005‐TEQ/kg) | 0.9 | 3 | ||
| PCDD/Fs + PCBs (ng WHO2005‐TEQ/kg) | 0.12 | 3 | ||
| Non DL‐PCBs (μg/kg) | 1.7 | 3 | ||
| Mycotoxins | ||||
| Aflatoxin B1 (μg/kg) | < 0.3 | 3 | ||
| Microbial contamination | ||||
| Salmonella spp. (per 25 g) | Not detected | 3 | ||
| Escherichia coli (per 1g) | Not detected | 3 | ||
| Aerobic mesophilic bacteria (CFU/g) | ■■■■■ | ■■■■■ | ||
| Moulds (CFU/g) | ■■■■■ | ■■■■■ | ||
| Yeasts (CFU/g) | ■■■■■ | ■■■■■ | ||
| Enterobacteriaceae (CFU/g) | ■■■■■ | ■■■■■ | ||
Abbreviations: CFU, colony forming units; MPN, most probable number; PCBs, polychlorinated biphenyls; PCDDs, polychlorinated dibenzo‐p‐dioxins; PCDFs, polychlorinated dibenzofurans; TEQ, toxic equivalency factors for dioxins, furans and dioxin‐like PCBs established by WHO in 2005 (Van den Berg et al., 2006); WHO, World Health Organization.
Upper bound concentrations are calculated on the assumption that all values of the different congeners below the limit of quantification are equal to the limit of quantification. Values are expressed per kg of additive with 88% dry matter content.
<: means below the limit of quantification (LOQ).
TABLE 2.
Physical properties of copper lysinate sulfate.
| Parameter | Analysis | |
|---|---|---|
| Range | # batches | |
| Physical properties | ||
| Physical form | Solid/granules | |
| Solubility in water (g/L; 20°C) | 2050 | 1 |
| Dusting potential (Stauber‐Heubach) (mg/m3) | 90–125 | 3 |
| Cu content in dust (mg/kg) | 125,756–159,500 | 3 |
| Particle size of the dust (laser diffraction) (% of particles below, v/v) | ||
| 50 μm | 100–100 | 2 |
| 10 μm | 32–37 | 2 |
| Particle size distribution (laser diffraction) (% of particles below, v/v) | ||
| 100 μm | 0.95–1.64 | 3 |
| 50 μm | 0.42–0.58 | 3 |
| 10 μm | 0.25–0.29 | 3 |
| Homogeneity (coefficient of variation, %) | ||
| Complete feed starter (average of 10 subsamples) | 27 | |
| Complete feed grower (average of 10 subsamples) | 39 | |
The data provided showed compliance with the proposed specifications for copper lysinate sulfate, except from one batch in which the copper values were slightly below the specification.
The FEEDAP Panel considers that the microbial contamination and the amounts of the detected impurities do not raise safety concerns, except nickel which is further addressed in the user safety section.
3.1.2. Manufacturing process
The additive is produced by mixing the raw ingredients ■■■■■ ■■■■■ ■■■■■ ■■■■■ ■■■■■ ■■■■■ ■■■■■ ■■■■■ ■■■■■ ■■■■■ ■■■■■
3.1.3. Conditions of use
The additive is intended for use in feed for all animal species up to the maximum authorised total copper content in complete feeds, as reported in Table 3:
TABLE 3.
Maximum authorised total copper content.
| Animal species/categories | Maximum authorised total copper content (mg/kg complete feed) |
|---|---|
| Bovines before the start of rumination | 15 |
| Other bovines | 30 |
| Ovines | 15 |
| Caprines | 35 |
| Suckling and weaned piglets up to 4 weeks after weaning | 150 |
| Piglets from 5th week after weaning up to 8 weeks after weaning | 100 |
| Crustaceans | 50 |
| Other animals | 25 |
3.2. Safety
3.2.1. Safety for the target species
The applicant provided a combined tolerance and efficacy study in chickens for fattening to support the safety for the target species. 19
■■■■■ The intended and analysed dietary copper levels are provided in Table 4. ■■■■■.
TABLE 4.
Selection of experimental groups to illustrate the effects of copper lysinate sulfate on zootechnical performance, blood chemistry and gross pathology parameters of chickens for fattening (■■■■■).
| Parameters | Treatment groups | ||
|---|---|---|---|
| Control | Cu‐Lys 1× | Cu‐Lys 11× | |
| Copper (mg/kg) | |||
| Intended | ■■■■■ | ■■■■■ | ■■■■■ |
| Analysed (■■■■■) | ■■■■■ | ■■■■■ | ■■■■■ |
| Mortality, (1) % – (n) | 1.67 (4) | 1.25 (3) | 1.67 (4) |
| Performance parameters | |||
| Final body weight (g) | 2264 | 2239 | 2241 |
| Feed intake (g/day) | 93.3 | 92.6 | 91.6 |
| Daily weight gain (g/day) | 63.2 | 62.6 | 62.5 |
| Feed to gain ratio | 1.48 | 1.48 | 1.47 |
| Blood parameters (2) | |||
| Haematocrit (%) | ■■■■■ | ■■■■■ | ■■■■■ |
| Glucose (mg/dL) | ■■■■■ | ■■■■■ | ■■■■■ |
| Magnesium (mg/dL) | ■■■■■ | ■■■■■ | ■■■■■ |
| Uric acid (mg/dL) | ■■■■■ | ■■■■■ | ■■■■■ |
| C‐reactive protein (ng/mL) | ■■■■■ | ■■■■■ | ■■■■■ |
■■■■■
Mortality includes culled birds.
Blood samples obtained from ■■■■■.
■■■■■. Blood samples were obtained ■■■■■ on day 35 for haematology 20 and biochemical 21 analysis. Additionally, at 35 days, ■■■■■ ■■■■■ were killed for superoxide dismutase (SOD) analysis in blood and the copper content determination in breast, liver, bone (tibia) tissues, kidneys and feathers.
■■■■■
The main results of the study are presented in Table 4. No differences were observed in mortality or any of the performance parameters due to the supplementation with Cu‐Lys at any of the levels tested.
For the blood biochemical parameters, no statistically significant differences were found between the groups that received the additive and the control group, except for a decrease in the concentration of uric acid (■■■■■) and C‐reactive protein (■■■■■) in the 11× group. In both cases, the variations are within physiological ranges and do not present safety concerns.
The results of the tolerance study indicate that the additive is safe for chickens for fattening at the currently authorised maximum level of copper in feed.
3.2.1.1. Conclusions on safety for the target species
The FEEDAP Panel concludes that the additive is safe for chickens for fattening at the maximum authorised levels of copper in feed. This conclusion is extrapolated to all animal species and categories at the respective maximum authorised levels in the EU for total copper in feed.
3.2.2. Safety for the consumer
Copper lysinate sulfate likely dissociates under physiological conditions into its three main components: lysine, sulfate and copper. Therefore, the FEEDAP Panel considers that only potential exposure to copper is of interest concerning the consumer safety.
The toxicology of copper compounds has been reviewed by the FEEDAP Panel, the Panel on Nutrition, Novel Foods and Food Allergens (NDA) and the Scientific Committee of EFSA (SC) (EFSA FEEDAP Panel, 2016; EFSA NDA Panel, 2015; EFSA SC, 2023). Under normal circumstances, copper homoeostasis ensures that copper overload in humans does not occur. An excess of copper has been recorded and shown to cause problems only under certain specific conditions, notably genetic disorders such as Wilson disease (EFSA NDA Panel, 2015). The primary target of copper toxicity is the hepatocyte and copper excess impair liver function (European Commission, 2003).
Dietary upper levels (ULs) for copper have already been established by the Scientific Committee on Food (SCF) for different population classes (European Commission, 2003). The SCF derived a tolerable upper intake level (UL) of 5 mg Cu/day for adults and extrapolated UL for toddlers, children and adolescents (e.g. UL of 1 mg/day for toddlers). More recently, the EFSA SC re‐evaluated the existing health‐based guidance values for copper and exposure assessment from all sources and established an acceptable daily intake (ADI) for copper (EFSA SC, 2023). In establishing this ADI, EFSA SC placed emphasis on hepatic copper retention as an early marker of potential adverse effects. The relationships between (a) chronic copper exposure and its retention in the body, particularly the liver and (b) hepatic copper concentrations and evidence of toxicity were examined. The SC concluded that no hepatic retention of copper is expected to occur with intake of 5 mg/day and established an ADI of 0.07 mg/kg bw, equivalent to 5 mg Cu/day for adults. The FEEDAP Panel notes that this ADI is established for the general population and that ULs for all age groups are established by the NDA Panel in line with the NDA Panel Guidance on establishing and applying tolerable upper intake levels for vitamins and essential minerals (EFSA NDA Panel, 2022).
Data on copper deposition following the use of the additive under assessment were available from the study on tolerance/bioavailability in chickens for fattening (see Section 3.2.1). In this study animals were supplemented with ■■■■■ from either ■■■■■ or Cu‐Lys, and samples of kidney, liver, muscle, tibia and feathers were taken on ■■■■■.
The main results are reported in the efficacy section (see Table 5, Section 3.3). All the results of copper deposition in liver, kidney and muscle were below the limit of quantification (LOQ) (5 mg/kg).
TABLE 5.
Selection of experimental groups to illustrate the effects of copper supplementation from either source (■■■■■) on copper deposition in tissues and relevant blood parameters in chickens for fattening (■■■■■).
| Parameters | Treatment groups | ||
|---|---|---|---|
| Control | Cu‐Lys 1× | ■■■■■ 1× | |
| Copper in feed (mg/kg) | |||
| Intended | ■■■■■ | ■■■■■ | ■■■■■ |
| Analysed (starter/grower) | ■■■■■ | ■■■■■ | ■■■■■ |
| Copper deposition in tissues (mg/kg DM) (1) | |||
| Liver | ■■■■■ | ■■■■■ | ■■■■■ |
| Tibia (2) | ■■■■■ | ■■■■■ | ■■■■■ |
| Breast muscle | ■■■■■ | ■■■■■ | ■■■■■ |
| Kidneys | ■■■■■ | ■■■■■ | ■■■■■ |
| Feathers (3) | ■■■■■ | ■■■■■ | ■■■■■ |
| Blood markers | |||
| Cu (mg/L) | ■■■■■ | ■■■■■ | ■■■■■ |
| Superoxide dismutase (SOD) (IU/mL) | ■■■■■ | ■■■■■ | ■■■■■ |
Limit of quantification (LOQ) of the method used (■■■■■) was 5 mg/kg DM.
■■■■■.
■■■■■.
The FEDAP Panel notes that the LOQ of the method of analysis 22 used (5 mg/kg) is very high and did not allow to identify possible differences in tissue deposition either among the copper lysinate sulfate and the control group or among copper supplementation from either source (copper lysinate sulfate vs. ■■■■■) (Section 3.2.1). Therefore, a consumer exposure estimate that would allow to quantify the contribution of the additive to the total exposure of the consumer to copper cannot be calculated. In addition, the FEEDAP Panel notes that no data on deposition of copper in skin and fat were submitted.
Due to these limitations and in the absence of reliable deposition data, the FEEDAP Panel cannot perform an exposure assessment of consumers to copper derived from food animal origin and therefore, cannot conclude on the safety of the additive for the consumer.
3.2.3. Safety for the user
Based on the highest dusting potential measured (see Table 2), the FEEDAP Panel considers that the exposure of users through inhalation is likely.
The additive contains copper, for which an occupational exposure limit (OEL) of 0.01 mg/m3 is set for the respirable fraction (European Commission, 2014).
The FEEDAP Panel notes that the additive contains nickel (see Table 1). The European Directive 2022/431 23 set an OEL of 0.01 and 0.05 mg/m3 for both respirable and inhalable fraction, respectively as nickel meets the criteria for classification as carcinogenic (category 1A). Therefore, to reduce the risk, the FEEDAP Panel considers that the exposure of the users should be minimised. Additionally, due to the presence of nickel the additive should be considered as a skin and respiratory sensitiser.
The skin irritation potential of the additive was tested in a study performed according to the Organisation for Economic Co‐operation and Development (OECD) Guidelines for the Testing of Chemicals (TG) 439, 24 which showed that the additive is not a skin irritant (UN GHS No Category).
The eye irritation potential of the additive was tested in a study performed according to OECD TG 437. 25 Based on the results obtained, a prediction could not be made (No standalone prediction can be made).
3.2.3.1. Conclusions on safety for the user
The FEEDAP Panel cannot conclude on the eye irritation potential. The additive is not a skin irritant but should be considered a skin and respiratory sensitiser. Inhalation and dermal exposure are considered a risk.
3.2.4. Safety for the environment
The additive under assessment contains copper, l‐lysine and sulfate. The environmental risk assessment is made assuming that the whole amount of the additive ingested by the animals is excreted.
Sulfates are naturally abundant in the environment and the use of the additive will not result in a substantial increase above its background concentration under the current conditions of use. 26
The amino acid l‐lysine is a physiological and natural component in animals and plants. When supplemented to feed, as component of the additive under assessment, it will be incorporated into animal proteins and any potential excess will be catabolised and excreted.
To assess the environmental risk of copper from the additive, the Panel compared the worst‐case predicted environmental concentrations (PECs) 27 calculated at the maximum authorised level of copper with the natural background concentration considered as 90th percentile value from FOREGS database. If the predicted concentrations (PECs) fall below 10% of this value, no further risk assessment is needed. Determination of the natural background concentration for metals in water is described in the Guidance for implementing environmental quality standards (EQSs) for metals, by the Water Framework Directive implementation strategy. 28
The 90th percentile concentration of copper in soil based on 840 topsoil samples collected throughout Europe for the FOREGS survey was 34 mg Cu/kg. The 90th percentile concentration of copper in freshwater obtained from occurrence data from 808 water samples collected throughout Europe for the FOREGS survey was 2.45 μg Cu/L.
As regards the use of the additive in terrestrial farm animals, piglets were considered as the worst‐case scenario. The worst‐case PECsoi l– after 1 year application 29 at the maximum authorised level (150 mg Cu/kg), is 2.5 mg Cu/kg soil dw for piglets. Compared with the 10% of the natural background concentration of copper in soil, corresponding to 3.4 mg Cu/kg soil dry weight (FOREGS, 2005) 30 , the calculated PECsoil is below this value. Therefore, no concerns are expected for the terrestrial compartment at the authorised conditions of use.
Considering the use of the additive in aquaculture, the highest PEC in surface water (land‐based aquaculture) for sea bass/sea bream is of 0.063 μg Cu/L, which is below 0.24 μg/L (10% of the natural background concentration in surface waters reported by FOREGS, see above). No safety concerns are expected from the use of the additive in land‐based aquaculture at the authorised conditions of use.
When the additive is used in marine aquaculture (sea cages), the PEC for marine sediment (PECsed) is 55 mg Cu/kg sediment dry weight. The applicant provided information from the Oslo and Paris Conventions (OSPAR) commission (2014) indicating that copper has a background concentration in marine sediment of 20 mg/kg sediment dry weight, which is lower than the estimated concentration in marine sediments. The applicant, in addition, referred to the copper predicted no effect concentration in sediment (PNECsed) of 338 mg Cu/kg dw (Monteiro et al., 2010), derived using the equilibrium partitioning approach. The FEEDAP Panel notes that, although the calculated PECsed exceeds the reported median copper level in marine sediment (OSPAR Commission, 2014), the ratio PEC/PNEC is lower than 1, indicating no safety concerns for marine sediment.
Considering the above, the FEEDAP Panel concludes that the use of the additive under the proposed conditions of use is safe for the environment.
3.3. Efficacy
The applicant provided a combined tolerance/efficacy study in chickens for fattening (see Section 3.2.1) 31 in which copper deposition in liver, muscle, kidney, tibia and feathers as well as the copper content in blood were measured (Table 5). Additionally, the applicant provided the serum levels of SOD and supportive evidence of its reliability as a copper marker in blood.
All determinations of copper in liver, kidney and muscle were reported as below the LOQ of the analytical method employed (5 mg/kg DM). The FEEDAP Panel notes that this LOQ is markedly higher than the physiological concentrations normally found in these tissues (≤ 3 mg/kg DM for liver in chickens for fattening). Consequently, the method lacked the sensitivity needed to detect potential differences between treatments, and no information on hepatic copper deposition – the primary biomarker of copper status – could be generated.
Serum copper concentrations and SOD activity in blood did not differ between the control group and the groups receiving ■■■■■ from either copper lysinate sulfate or ■■■■■. The analysed copper content of the control diet (■■■■■) already met the nutritional requirements for chickens for fattening; therefore, any additional copper supplied by the test products was unlikely to translate into measurable changes in systemic biomarkers.
The FEEDAP Panel considers the main limitations of the study, and namely (i) the insufficient analytical sensitivity for tissue copper measurement and (ii) the adequate copper supply in the control diet likely preventing the study from demonstrating any bioavailability or biological response attributable to copper lysinate sulfate. Therefore, the FEEDAP Panel is not in the position to conclude on the efficacy of the additive.
3.4. 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 32 and Good Manufacturing Practice.
4. CONCLUSIONS
The FEEDAP Panel concludes that the additive copper lysinate sulfate is safe for all animal species and categories at the respective maximum authorised total copper levels in feed.
In the absence of adequate deposition data, the FEEDAP Panel cannot conclude on the safety of the additive for the consumer.
The additive is not a skin irritant. The FEEDAP Panel cannot conclude on the eye irritation potential due to the lack of data. The additive should be considered a skin and respiratory sensitiser. Inhalation and dermal exposure are considered a risk.
The FEEDAP Panel concludes that the use of the additive under the proposed conditions of use is safe for the environment.
The Panel is not in the position to conclude on the efficacy of the additive at the maximum authorised inclusion level.
ABBREVIATIONS
- ADI
acceptable daily intake
- ANS
EFSA Scientific Panel on Additives and Nutrient Sources added to Food
- BW
body weight
- CAS
Chemical Abstracts Service
- CFU
colony forming unit
- DM
dry matter
- ECHA
European Chemicals Agency
- EINECS
European Inventory of Existing Chemical Substances
- EMA
European Medicines Agency
- EQS
environmental quality standards
- EURL
European Union Reference Laboratory
- FEEDAP
EFSA Scientific Panel on Additives and Products or Substances used in Animal Feed
- GLM
general linear model
- IR
infrared
- IUPAC
International Union of Pure and Applied Chemistry
- LOQ
limit of quantification
- NDA
Panel on Nutrition, Novel Foods and Food Allergens
- OECD
Organisation for Economic Co‐operation and Development
- OEL
occupational exposure limit
- OSPAR
Oslo and Paris Conventions
- PECs
predicted environmental concentrations
- PECsed
PEC for marine sediment
- PNECsed
predicted no effect concentration in sediment
- RH
relative humidity
- SCF
Scientific Committee on Food
- SOD
superoxide dismutase
- ULs
upper levels
- WHO
World Health Organization
REQUESTOR
European Commission
QUESTION NUMBER
EFSA‐Q‐2024‐00001
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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
The scientific output published implements EFSA's decision on the confidentiality requests submitted on specific items. As certain items have been awarded confidential status by EFSA, they are consequently withheld from public disclosure by redaction.
EFSA FEEDAP Panel (EFSA Panel on Additives and Products or Substances used in Animal Feed) , Villa, R. E. , Azimonti, G. , Bonos, E. , Christensen, H. , Durjava, M. , Dusemund, B. , Gehring, R. , Glandorf, B. , Kouba, M. , López‐Alonso, M. , Marcon, F. , Nebbia, C. , Pechová, A. , Prieto‐Maradona, M. , Röhe, I. , Theodoridou, K. , Bories, G. , Gropp, J. , … Navarro‐Villa, A. (2025). Safety and efficacy of a feed additive consisting of copper lysinate sulfate for all animal species (Phytobiotics Futterzusatzstoffe GmbH). EFSA Journal, 23(7), e9555. 10.2903/j.efsa.2025.9555
Adopted: 26 June 2025
The declarations of interest of all scientific experts active in EFSA's work are available at https://open.efsa.europa.eu/experts
Notes
Regulation (EC) No 1831/2003 of the European Parliament and of the council of 22 September 2003 on the additives for use in animal nutrition. OJ L 268, 18.10.2003, p. 29.
Phytobiotics Futterzusatzstoffe GmbH, Wallufer Str. 10a Eltville – Germany.
Dossier reference: FEED‐2023‐19411.
Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety. OJ L 31, 1.2.2002, pp. 1–48.
Decision available at: https://www.efsa.europa.eu/en/corporate‐pubs/transparency‐regulation‐practical‐arrangements.
Evaluation report received on 12/8/2024 and available on the EU Science Hub https://joint‐research‐centre.ec.europa.eu/reports‐and‐technical‐documentation/feed‐2023‐19411_en.
Commission Regulation (EC) No 429/2008 of 25 April 2008 on detailed rules for the implementation of Regulation (EC) No 1831/2003 of the European Parliament and of the Council as regards the preparation and the presentation of applications and the assessment and the authorisation of feed additives. OJ L 133, 22.5.2008, p. 1.
Section_II_Identity_2.1_2.2 and Annex II.2.1_11.
Annex II.2.1_24.
Annex II.2.1_24.
ADR July 2024: Annex_II.2.1_1_Phytobiotics_Product_Spec_Plex_L_Cu_2022; Annex II.2.1_5; ADR July 2024: PB Declaration Batch‐to‐batch.
Annex II.2.1_9; Annex_II.2.1_10; ADR July 2024: Microbial_CoAs Cu‐Lys and Annex_II.2.1_1_Phytobiotics_Product_Spec_Plex_L_Cu_2022.
Annex_II.2.5_2_Phytobiotics_SDS_L‐Cu_2022; Annex II.2.4_1; Annex II.2.1_24; ADR July 2025: Water solubility CuLys_Plexomin‐L Cu_2022‐06‐13‐sol; Annex II.2.1_23; Annex II.2.4_2; Annex_II.2.4_3.
Annex II.2.3_1 and Annex_II.2.3_2.
Annex II.2.3_3 and Annex_II.2.3_4.
Annex II.2.1_13 and Annex II.2.1_14.
Annex II.2.1_15.
Annex II.2.1_16 and Annex_II.2.1_17.
Annex II 3.1_1; ADR reply November 2024: ADR_CuLys_Safety_Target_Species; ADR reply March 2025: Answers_EFSA_Mgblood.
Haematology parameter: Total red blood cell count, packed cell volume, haemoglobin, mean, corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, total & differential counts for leukocytes, platelet counts, prothrombin time and fibrinogen.
Biochemical parameters: Sodium, potassium, chloride, calcium, phosphate, magnesium, total protein, albumin, globulin, glucose, urea/uric acid, cholesterol, creatinine, bilirubin, acute phase proteins ovotransferrin and C‐reactive protein, amylase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, gamma‐glutamyltransferase, alkaline phosphatase and creatine kinase.
Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP‐AES).
Directive (EU) 2022/431 of the European Parliament and of the Council of 9 March 2022 amending Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work. OJ L 88, 16.3.2022, p. 1–14. https://data.europa.eu/eli/dir/2022/431/oj
Annex III.3.3_15.
Annex III.3.3_12.
Based on the data available in FORGES database http://weppi.gtk.fi/publ/foregsatlas/ForegsData.php. Geochemical Atlas of Europe; copyright © 2005 the Association of the Geological Surveys of The European Union (EuroGeoSurveys)/ the Geological Survey of Finland.
Calculated by Feed additives environmental risk assessment (FERA) tool, available online: https://www.efsa.europa.eu/en/applications/feedadditives/tools.
Guidance document N38. Technical Guidance for implementing Environmental Quality Standards (EQS) for metals. Consideration of metal bioavailability and natural background concentrations in assessing compliance (2019). Common Implementation Strategy for the Water Framework Directive (2000/60/EC). Available online: https://metals‐toolbox.com/uploads/pdf/environment/Guidance%2520No%252038%2520‐%2520Technical%2520guidance%2520for%2520EQS%2520for%2520metals%2520(2).pdf.
Section_III_Safety_3.4.
Based on the data available in FORGES database http://weppi.gtk.fi/publ/foregsatlas/ForegsData.php. Geochemical Atlas of Europe; copyright © 2005 the Association ofthe Geological Surveys of The European Union (EuroGeoSurveys)/the Geological Survey of Finland.
Annex II 3.1_1 and ADR reply in November 2024: ADR_CuLys_Efficacy.
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.
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