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 assessment of the application for renewal of authorisation of 6‐phytase produced by Trichoderma reesei CBS 122001 (brand name: Finase® EC). The applicant has provided evidence that the additive currently in the market complies with the existing conditions of authorisation. The Panel concludes that the additive remains safe for poultry for fattening, breeding and laying, and all pigs, the consumer and the environment under the authorised conditions of use. Regarding user safety, the Panel reiterates that the additive is not a skin or eye irritant or sensitiser but should be considered a potential respiratory sensitiser. There is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation. These conclusions also apply to the new proposed liquid formulation Finase® EC 5 L.
Keywords: zootechnical additives, digestibility enhancers, 6‐phytase, Finase®EC, swine, poultry, renewal
1. Introduction
1.1. Background and Terms of Reference as provided by the requestor
Regulation (EC) No 1831/20031 establishes the rules governing the Community authorisation of additives for use in animal nutrition. In particular, Article 14(1) of that Regulation lays down that an application for renewal shall be sent to the Commission at the latest one year before the expiry date of the authorisation.
The European Commission received a request from Roal Oy2 for renewal of the authorisation of 6‐phytase produced by Trichoderma reesei CBS 122001, when used as a feed additive for pigs other than sows, sows, poultry for fattening and breeding other than turkeys for fattening, poultry for laying and turkeys (category: zootechnical additives; functional group: digestibility enhancers).
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 14(1) (renewal of the authorisation). The particulars and documents in support of the application were considered valid by EFSA as of 2 August 2019.
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 6‐phytase produced by Trichoderma reesei CBS 122001, when used under the proposed conditions of use, (see Section 3.1.4).
1.2. Additional information
The additive is a preparation of 6‐phytase produced by a genetically modified strain of Trichoderma reesei CBS 122001; its brand name is Finase®EC.
The EFSA Panel on Additives and Products or Substances used in Animal feed (FEEDAP) issued one opinion on the safety and efficacy of 6‐phytase produced by T. reesei CBS 122001 when used in chickens for fattening and reared for laying, laying hens, turkeys for fattening and reared for laying, ducks and other minor poultry species, piglets (weaned), pigs for fattening and sows, which included the safety aspects of the genetic modification (EFSA FEEDAP Panel and EFSA GMO Panel, 2009; EFSA FEEDAP Panel, 2010). Other two opinions were adopted on the use of the additive in turkeys (EFSA FEEDAP Panel 2010) and sows (EFSA FEEDAP Panel, 2011).
The additive 6‐phytase (4a12)3 is currently authorised as a feed additive for poultry species for fattening and breeding (other than turkeys for fattening), for poultry for laying and for pigs (other than sows),4 for turkeys5 and for sows.6 The applicant is now seeking the renewal of those authorisations.
2. Data and methodologies
2.1. Data
The present assessment is based on data submitted by the applicant in the form of a technical dossier7 in support of the authorisation request for the use of 6‐phytase produced by a genetically modified strain of T. reesei CBS 122001 as a feed additive.
The FEEDAP Panel used the data provided by the applicant together with data from other sources, such as previous risk assessments by EFSA, to deliver the present output.
The European Union Reference Laboratory (EURL) considered that the conclusions and recommendations reached in the previous assessment are valid and applicable for the current application.8
2.2. Methodologies
The approach followed by the FEEDAP Panel to assess the safety and the efficacy of 6‐phytase produced by a genetically modified strain of T. reesei CBS 122001 is in line with the principles laid down in Regulation (EC) No 429/20089 and the relevant guidance documents: Guidance on the renewal of the authorisation of feed additives (EFSA FEEDAP Panel, 2013) and the Guidance on the characterisation of microorganisms used as feed additives or as production organisms (EFSA FEEDAP Panel, 2018).
3. Assessment
The additive is a preparation of 6‐phytase produced by a genetically modified strain of Trichoderma reesei CBS 122001. It will be hereafter referred as Finase®EC.
Finase®EC is currently authorised as a feed additive for all poultry for fattening, breeding and laying, and for all pigs. This assessment regards the renewal of the authorisation of Finase®EC for the above‐mentioned species.
3.1. Characterisation
3.1.1. Characterisation of the additive
The additive is currently authorised and marketed as:
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a solid form (Finase®EC 40 P) with a minimum activity of 40,000 PPU10 /g, that contains the enzyme preparation (16–24%), water as moisture (5%) and wheat flour (up to 100%).
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a liquid form (Finase®EC 10 L) with a minimum activity of 10,000 PPU/g, that contains the enzyme preparation (4–6%), sorbitol (20%), sodium benzoate (0.35%) and water (up to 100%).
The applicant is also requesting the authorisation of a new liquid form (Finase®EC 5 L) with a minimum activity of 5,000 PPU/g that contains the enzyme preparation (2–3%), sorbitol (20%), sodium chloride (4%), sodium benzoate (0.35%), and water (up to 100%).
The applicant stated that minor changes have been applied to the manufacturing ■■■■■ during the last years to improve the fermentation process.11 The Panel considers that these modifications do not have an impact on the final product and the data provided support this conclusion.
Compliance with specifications was confirmed by analysis of three batches of Finase®EC 10 L12 and five batches for Finase®EC 40 P13 and Finase®EC 5 L14 (all recent batches). The mean enzyme activity in Finase®EC 40 P was 46,580 PPU/g (range 44,400–49,000), in Finase®EC 10 L was 12,700 PPU/g (range 12,000–14,000) and in the Finase®EC 5 L was 6,016 PPU/g (range 5,620–6,280).
The same batches were tested for microbiological contamination: Escherichia coli and Salmonella spp. (absence in 25 g), coliforms at 37°C (< 1 colony forming unit (CFU)/g in the Finase®EC 10 L and 5L formulations, but < 10 CFU/g in the Finase®EC 40 P), yeasts and filamentous fungi (< 1,000 CFU/g) and total viable cells (< 1,000 CFU/g) in four batches, but 1,500 CFU/g in one batch of the Finase®EC 40 P formulation).
Chemical contamination was measured in the same batches. Data were provided for heavy metals (cadmium, < 0.05 mg/kg; mercury, < 0.05 mg/kg; lead, < 0.05 mg/kg), and arsenic (< 0.50 mg/kg).15 Mycotoxins were also analysed in the same batches (aflatoxin (B1, B2 and G1, G2) < 0.1 μg/kg in Finase®EC 10 L and 5 L formulations and from < 0.1 to < 0.01 μg/kg in the Finase®EC 40 P formulation; fumonisins (B1, B2 and B3) < 20 μg/kg; ochratoxin A < 2 μg/kg; deoxynivalenol < 20 μg/kg in Finase®EC 10 L and 5L formulations, but from < 20 μg/kg to 180 μg/kg in the Finase®EC 40 P formulation; T2 toxin, HT‐2 toxin, zearalenone and sterimagocystin were all < 10 μg/kg. Based on these results, no concerns were identified.
No antimicrobial activity was detected in five batches of the liquid diluted (Finase®EC 5 L)16 and three batches of the liquid concentrated (Finase®EC 10 L)17 forms of the additive, following the provisions of the Guidance on the characterisation of microorganisms used as feed additives or as production organisms (EFSA FEEDAP Panel, 2018). The strains tested were Staphylococcus aureus ATCC 6538, Streptococcus pyogenes ATCC 12344, E. coli ATCC 11229, Serratia marcescens ATCC 14041, Bacillus cereus ATCC 2 and Bacillus circulans ATCC 4516. The only known secondary metabolites naturally produced by T. reesei are peptaibols, e.g. paracelsin A, C, and D (Frisvad et al., 2018),18 which are peptides that show antimicrobial activity. The genome of T. reesei contains genes for two peptaibol synthases (Kubicek et al., 2011).19 The peptides are produced under stress conditions only, not under conventional fermentation conditions (Frisvad et al., 2018). T. reesei seems to be unable to produce mycotoxins (EFSA, 2007; Frisvad et al., 2018; EFSA BIOHAZ Panel, 2020). Analysis of three recent batches of the common dry concentrate show that the trichothecene trichodermin is not detected in the product.20
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3.1.2. Characterisation of the production organism
The 6‐phytase present in the additive is obtained by fermentation with a genetically modified strain of T. reesei which is deposited at the Central Bureau of Fungal Cultures (Centraal Bureau voor Schimmelcultures, CBS), with the deposition number CBS 122001.22
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The identification of the strain and its taxonomic identification were confirmed.■■■■■■■■■■■■■■■
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The assessment of the genetic modification was performed in a previous opinion (EFSA FEEDAP Panel and EFSA GMO Panel, 2009) and the Panel concluded that the genetic modification did not raise any safety concern. The production strain has not been subject to any further genetic modification. Nevertheless, in the current application the applicant provided further data on the genetic modification. In particular, these data concern ■■■■■■■■■■■■■■■■■■■■ These data confirmed the previous conclusion of the Panel on the safety of the genetic modification of the production strain in accordance with the guidance on the characterisation of microorganisms used as feed additives or as production organisms (EFSA FEEDAP Panel, 2018).
The presence of viable cells of the production strain was investigated in the formulations of Finase®EC 5L (four batches),27 Finase®EC 40P (five batches),13 Finase®EC 10L (two batches)28 and the liquid intermediate concentrate (three batches).29 However, the analyses of two of the batches of the Finase®EC 5L30 and of both batches of the Finase®EC 10L formulation were not further considered in the assessment since they were dated 2009 and 2008, respectively. ■■■■■ No cells were detected in any of the batches tested.32
3.1.3. Stability and homogeneity
The stability of the additive was already assessed in the previous opinion (EFSA FEEDAP Panel and EFSA GMO Panel, 2009). The changes in the manufacturing do not imply changes in the physical chemical properties that would modify the stability. The applicant provided new stability studies for Finase® EC 40 P and on the stability to pelleting of Finase® EC 5 L, which are described below.
A study on Finase® EC 40 P was performed in three batches when stored at 6°C in closed transparent PET bottles; or at 20–23°C, at 25°C/60% relative humidity (RH) or at 30°C/65% RH in sealed mini bags for up to 24 months. After 24 months, the recovery of the samples stored at 6°C averaged 91% and at 20–23°C averaged 87%. After 12 months, the recovery of the samples kept at 25°C/60% RH averaged 75% and at 30°C/65% RH averaged 51%.36
The stability to pelleting Finase® EC 40 P was re‐measured in three batches at temperatures starting from 70 up to 95°C.37 The recovery declined at the increase of the temperature (the recovery after pelleting at 70°C averaged 79% (range 72–85%) and at 95°C averaged 0.5% (range 0.4–0.7%).
The stability of Finase® EC 5 L in three batches was studied when stored in polyethylene terephthalate (PET) transparent bottles at 20–23°C or in polypropylene transparent test tubes at 6 or 37°C. After 24 months, the recovery ranged from 89% to 90% when kept at 6°C, and 68% to 69% at 20–23°C. Recovery ranged from 18% to 20% at 37°C after 12 months depending on the batch considered.38
3.1.4. Conditions of use
The additive is currently authorised for use in all pigs and poultry for fattening and breeding at a minimum recommended dose of 250 PPU39 /kg complete feed and for use in poultry for laying at a minimum recommended dose of 125 PPU/kg of complete feed. The maximum recommended level in all species/categories is 1,000 PPU/kg complete feed.
Under the other provisions of the authorisations, it is specified that:
in the directions for use of the additive and premixture, indicate the storage temperature, storage life, and stability to pelleting.
maximum recommended dose per kilogram of complete feed for all authorised species: 1,000 PPU.
for use in feed containing more than 0.23% phytin‐bound phosphorus.
for safety: breathing protection, glasses and gloves shall be used during handling.
The applicant has not requested to modify these conditions of use.
3.2. Safety
In its previous opinions (EFSA FEEDAP Panel and EFSA GMO Panel, 2009; EFSA FEEDAP Panel, 2010, 2011), the FEEDAP Panel concluded that the additive is safe for poultry for fattening and breeding, including turkeys, for poultry for laying and for pigs, including sows at the maximum recommended level of 1,000 PPU/kg as well as for the consumers and the environment. Concerning user safety, the Panel concluded that the additive was not a skin or eye irritant or sensitiser but should be considered a potential respiratory sensitiser.
The applicant stated that no adverse effects on target animals, consumer, user or the environment have been reported as part of its quality control system.40
Two literature searches were conducted in PubMed and Web of Science and included the search terms ‘Finase®EC’, ‘safety’, ‘toxicity’ in the first and ‘Finase®EC’, ‘safety’, ‘toxicity’ and ‘phytase’ in the second; A third search in PubMed, AGRIS and Scifinder, contained the search terms ‘phytase’, ‘safe’, ‘toxic’, ‘adverse’ and ‘incompatibilities’. The searches covered the period 2010–2020. The number of hits identified after duplicates removal was 402. Titles and abstracts were further screened against the inclusion criteria information concerning potentially harmful effects of phytases on humans or production animals, resulting in 32 hits, from which 19 were EFSA scientific opinions of phytase additives. The 13 remaining publications were full‐text screened and 11 were considered for this assessment. Only one publication referred to sensitising effects of several enzymes (including phytases) on manufacturer workers, while the remaining publications did not mention safety concerns.41
None of the scientific publications finally considered reported safety concerns with the additive under assessment.
The new formulation does not introduce any hazards for the target animals, consumers, users and environment not already considered in the previous assessments.
3.2.1. Conclusions on the safety
Considering the previous conclusions on the safety, the information provided and the fact that the changes in the manufacturing and the new liquid form did not introduce any causes of concern, the FEEDAP Panel considers that there is no evidence to reconsider the conclusions reached in the previous opinions (EFSA FEEDAP Panel and EFSA GMO Panel, 2009; EFSA FEEDAP Panel, 2010, 2011). Therefore, the Panel concludes that the additive remains safe for poultry for fattening, breeding and laying, and all pigs, the consumer and the environment under the authorised conditions of use. Regarding user safety, the Panel reiterates that the additive is not a skin or eye irritant or sensitiser, but should be considered a potential respiratory sensitiser.
3.3. Efficacy
The present application for renewal of the authorisation does not include a proposal for amending or supplementing the conditions of the original authorisation that would have an impact on the efficacy of the additive. Therefore, there is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation, including the introduction of the new additive formulation.
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 Regulation42 and Good Manufacturing Practice.
4. Conclusions
The applicant has provided evidence that the additive currently in the market complies with the existing conditions of authorisation.
The Panel concludes that the additive remains safe for poultry for fattening, breeding and laying, and all pigs, the consumer and the environment under the authorised conditions of use. Regarding user safety, the Panel reiterates that the additive is not a skin or eye irritant or sensitiser but should be considered a potential respiratory sensitiser
There is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.
These conclusions also apply to the new proposed liquid formulation Finase®EC 5 L.
5. Documentation as provided to EFSA/Chronology
| Date | Event |
|---|---|
| 15/04/2019 | Dossier received by EFSA. 6‐phytase. Submitted by Roal Oy |
| 20/05/2019 | Reception mandate from the European Commission |
| 02/08/2019 | Application validated by EFSA – Start of the scientific assessment |
| 18/09/2019 | Request of supplementary information to the applicant in line with Article 8(1)(2) of Regulation (EC) No 1831/2003 – Scientific assessment suspended. Issues: 1. Characterisation of the additive: a) Characterisation of the production strain, b) Genetic modifications of the production strain, c) Purity, d) Manufacturing. 2) Safety |
| 16/06/2020 | Reception of supplementary information from the applicant ‐ Scientific assessment re‐started |
| 02/09/2020 | Request of supplementary information to the applicant in line with Article 8(1)(2) of Regulation (EC) No 1831/2003 – Scientific assessment suspended. Issues: 1. Characterisation of the additive: a) Characterisation of the production strain, b) Genetic modifications of the production strain, c) Purity, d) Manufacturing. 2) Safety |
| 14/10/2020 | Reception of supplementary information from the applicant ‐ Scientific assessment re‐started |
| 18/11/2020 | Opinion adopted by the FEEDAP Panel. End of the Scientific assessment |
Abbreviations
- CBS
Centraal Bureau voor Schimmelcultures
- CFU
colony forming unit
- EURL
European Union Reference Laboratory
- FEEDAP
EFSA Panel on Additives and Products or Substances used in Animal Feed
- PET
polyethylene terephthalate
Suggested citation: EFSA FEEDAP Panel (EFSA Panel on Additives and Products or Substances used in Animal Feed) , Bampidis V, Azimonti G, Bastos ML, Christensen H, Dusemund B, Fašmon Durjava M, Kouba M, López‐Alonso M, López Puente S, Marcon F, Pechová A, Petkova M, Ramos F, Sanz Y, Villa RE, Woutersen R, Cocconcelli R, Glandorf B, Herman L, Prieto MM, Saarela M, Brozzi R, Galobart J, Innocenti M, López‐Gálvez G, Pettenati E, Revez J, Sofianidis K, Vettori MV, Gregoretti L and Mayo B, 2020. Scientific Opinion on the assessment of the application for renewal of authorisation of 6‐phytase produced by Trichoderma reesei CBS 122001 as a feed additive for pigs and poultry, from Roal Oy. EFSA Journal 2020;18(12):6336, 10 pp. 10.2903/j.efsa.2020.6336
Requestor: European Commission
Question number: EFSA‐Q‐2019‐00333
Panel members: Vasileios Bampidis, Giovanna Azimonti, Maria de Lourdes Bastos, Henrik Christensen, Birgit Dusemund, Mojca Fašmon Durjava, Maryline Kouba, Marta López‐Alonso, Secundino López Puente, Francesca Marcon, Baltasar Mayo, Alena Pechová, Mariana Petkova, Fernando Ramos, Yolanda Sanz, Roberto Edoardo Villa and Ruud Woutersen.
Acknowledgments: The Panel wishes to acknowledge the contribution of Yolanda Garcia Cazorla to this opinion.
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 the European Commission. The full output has been shared with the European Commission, EU Member States and the applicant. The blackening will be subject to review once the decision on the confidentiality requests is adopted by the European Commission.
Adopted: 18 November 2020
Notes
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.
Roal Oy, Tykkimäentie 15b, 05200, Rajamäki, Finland.
Identification number of the additive.
Commission Regulation (EU) No 277/2010 of 31 March 2010 concerning the authorisation of 6‐phytase as a feed additive for poultry for fattening and breeding other than turkeys for fattening, for poultry for laying and for pigs other than sows (holder of authorisation Roal Oy) (Text with EEA relevance). OJ L 86, 1.4.2010, p. 13–14.
Commission Regulation (EU) No 891/2010 of 8 October 2010 concerning the authorisation of a new use of 6‐phytase as a feed additive for turkeys (holder of authorisation Roal Oy) Text with EEA relevance. OJ L 266, 9.10.2010, p. 4–5.
Commission Implementing Regulation (EU) No 886/2011 of 5 September 2011 concerning the authorisation of 6‐phytase (EC 3.1.3.26) produced by Trichoderma reesei (CBS 122001) as a feed additive for sows (holder of authorisation Roal Oy) Text with EEA relevance. OJ L 229, 6.9.2011, p. 5–6.
FEED dossier reference: FAD‐2019‐0027.
The full report is available on the EURL website: https://ec.europa.eu/jrc/sites/jrcsh/files/FinRep-FAD-2008-0040.pdf
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.
1 PPU is the amount of enzyme which liberates 1 µmol of inorganic phosphate from sodium phytate per minute at pH 5.0 and 37°C.
Technical dossier/Section II and Supplementary Information May 2020 answer.
Technical dossier/Section II/Supplementary Information June 2020/Annex 6 (10L).
Technical dossier/Section II/Annex II‐006_Composition & purity_FEC 40 P.pdf
Technical dossier/Section II/Supplementary Information June 2020/Annex 5 (5L).
No indication of the Limit of detection or Limit of quantification of the method.
Technical dossier/Section II/Supplementary Information June 2020/Annex 05_Composition & purity_FEC 5 L.pdf
Technical dossier/Section II/Supplementary Information June 2020/Annex 06_Composition & purity_Finase EC 10 L.pdf
Technical dossier/Section II/Annexes/References/Frisvad, Møller et al. 2018 ‐ Safety of the fungal workhorses.pdf
Technical dossier/Section II/Annexes/References/Kubicek_et_al_2011_Genome_Biology_12_R40.pdf
Technical dossier/Section II/Supplementary Information October 2020/Annex 5a and 5b; the limit of detection (LOD) of the method is 1.2 μg/kg.
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Technical dossier/Section II/Annex II‐004b_Composition & purity of FEC 5 L.pdf and Annex II‐004a_Composition & purity of FEC 5 L.pdf
Technical dossier/Section II/Annex II‐005_Composition & purity_FEC 10L.pdf
Technical dossier/Section II/Annex II‐021.
Technical dossier/Section II/Annex II‐004a_Composition & purity of FEC 5 L.pdf.
Technical dossier/Section II/Annex II.26.
Technical dossier/Section II/Annex II.20.
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Technical dossier/Section II/Annex II‐029_Storage stability of Finase EC 40 P.pdf
Technical dossier/Section II/Annexes II‐030 a, b, c.
Technical dossier/Section II/Annex II‐27a.
1 PPU is the amount of enzyme which liberates 1 μmol of inorganic phosphate from sodium phytate per minute at pH = 5.0 and 37C°.
Technical dossier/Section II/Supplementary Information June 2020/FEC_renewal_Supplementary information.pdf.
Technical dossier/Section III/Supplementary Information June 2020/FEC_renewal_Supplementary information.pdf and Annex 13_Budnik_et_al_2017_Occup_Environ_Med_74_39‐45.pdf.
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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