Outcome of the public consultation on the draft guidance on the assessment of the safety of feed additives for the target species

Transcription

1 TECHNICAL REPORT APPROVED: 9 October 2017 doi: /sp.efsa.2017.en-1304 Outcome of the public consultation on the draft guidance on the assessment of the safety of feed additives for the target species European Food Safety Authority (EFSA) Abstract The European Food Safety Authority (EFSA) carried out a public consultation to receive input from the scientific community and all interested parties on the draft guidance on the assessment of the safety of feed additives for the target species prepared by the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) and endorsed by the Panel for public consultation at its Plenary meeting on 22 March The written public consultation for this document was open from 06 April to 31 May EFSA received a total of 135 comments from eleven interested parties. EFSA and its FEEDAP Panel wish to thank all stakeholders for their contributions. The current report summarises the outcome of the public consultation, and includes the comments received and how the comments were addressed. The FEEDAP Panel prepared an updated version of the guidance on the assessment of the safety of feed additives for the target species taking into account the questions/comments received. This guidance was discussed and adopted at the FEEDAP Plenary meeting on 26 September 2017, and is published in the EFSA Journal. European Food Safety Authority, 2017 Key words: Guidance, assessment of the safety of feed additives for the target species Requestor: European Food Safety Authority Question number: EFSA-Q Correspondence: feedap@efsa.europa.eu EFSA Supporting publication 2017:EN-1304

2 Acknowledgements: EFSA wishes to thank the members of the Working Group on Guidance update Andrew Chesson, Jürgen Gropp, Secundino López Puente, Guido Rychen and John Wallace and the EFSA staff members Montserrat Anguita, Jaume Galobart and Matteo Lorenzo Innocenti for the support provided to this scientific output. Suggested citation: EFSA (European Food Safety Authority), Outcome of the public consultation on the draft guidance on the assessment of the safety of feed additives for the target species. EFSA supporting publication 2017:EN pp. doi: /sp.efsa.2017.en-1304 ISSN: European Food Safety Authority, 2017 Reproduction is authorised provided the source is acknowledged. 2 EFSA Supporting publication 2017:EN-1304

3 Table of contents Abstract Introduction Background and Terms of Reference as provided by EFSA Methodologies Assessment... 4 References EFSA Supporting publication 2017:EN-1304

4 1. Introduction 1.1. Background and Terms of Reference as provided by EFSA The European Food Safety Authority (EFSA) asked the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) to produce a guidance document on the assessment of the safety of feed additives for the target species. The draft guidance was endorsed by the FEEDAP Panel on 16 March In line with EFSA s policy on openness and transparency and in order for EFSA to receive comments from the scientific community and stakeholders on its work, EFSA engages in public consultations on key issues. The FEED Unit is requested to produce a Technical report summarising the outcome of the public consultation on the draft guidance on the assessment of the safety of feed additives for the target species. 2. Methodologies The draft guidance on the assessment of the safety of feed additives for the target species, which was endorsed by the FEEDAP Panel on 16 March 2017, was released for public consultation from 6 April to 31 May Stakeholders were informed and invited to submit comments. All comments were subject to evaluation and assessment. Where considered appropriate, the guidance document has been modified to take account of the comments (EFSA FEEDAP Panel, 2017). 3. Assessment EFSA received 135 comments from eleven interested parties: three public organisations, three industry associations, three private companies and two consultant organisations. The comments received (after removal of duplicates) are listed in Table 1, together with answers or comments from EFSA. All comments were subject to evaluation and assessment. EFSA and its FEEDAP Panel wish to thank all stakeholders for their contributions. 4 EFSA Supporting publication 2017:EN-1304

5 Table 1: Comments received during the public consultation on the draft guidance on the assessment of the safety of feed additives for the target species. # Organization Chapter Comment Comment by EFSA General comments, part 1 In general, this document does not provide requirements for feed additives intended for use in water. The present draft guidance includes the requirement that the additive should be assessed under the proposed conditions of use. For example, in the Extensive literature search it is specified that Extensive literature searches should be used as a first step to provide information on the safety of the feed additive under the proposed conditions of use. Similarly, under Tolerance in target animals, the following requirements consider use in water The additive could be administered via feed or water for drinking depending on the conditions of use. The concentration of the active substance(s) or agent(s) in the feedingstuffs/water should be confirmed by analysis. 1. Federal Institute for Risk Assessment (BfR) General comments Tables about the duration of the tolerance study: - Details of the weights for the animal categories were no longer listed. - Listed categories have been roughly summarized. Pigs, line In the guidance of 2011 animals were defined as porcine animals, further specification seems to be appropriate also for the present guidance. Suckling piglets are not listed separately, although a suckling period is seen as a very sensitive development phase for the pigs. The BfR recommend to re-add the category suckling piglets. Also, against the background of the potential risk of nosocomial infections as well as the development of resistance by feeding e.g. microorganisms or copper, it is recommended for the applicant to perform tolerance with suckling piglets using a study design as required in the Regulation (EC) 429/2008 or the last EFSA Technical Guidance on tolerance and efficacy in target animals ( If suckling and weaned piglets are applied for, a combined study (14 days suckling piglets and 28 days weaned piglets) would be considered sufficient. (EFSA Journal 2011;9(5):2175, page 3) Text modified in Section 4 to cover the use in water when calculating maximum safe concentration in feed. The tables in the current guidance are not intended to substitute for the legal definition of the animal categories in Annex IV of Regulation (EC) No 429/2008 but are intended to be used as a guide for the demonstration of safety for the target animals. They have been simplified indicating the age groups/physiological stage of the animals for which should be performed. The feed intake in suckling piglets is very low and difficult to measure, which makes in such category impractical. Therefore, for piglets, suckling and weaned, the Panel considers that in weaned piglets would suffice to assess the safety for both categories. Poultry, line No distinction is made between the poultry (chicken/turkey) reared for reproduction and poultry reared for fattening. In general, the feeding requirements for livestock depend on their specific use (reproduction, fattening). In contrast to fattened animals, animals for rearing often need another feeding regime to ensure a high lifetime production. A wrong feeding regime (not in accordance with its condition of use) can result in nutritionally induced deficiencies. This cannot be sufficiently considered by tolerance with adult animals. Thus, there different requirements for tolerance with animals reared for reproduction or fattening, and should be listed specifically. Tolerance are not intended to assess the nutritional requirements of the animals, but to test the safety of feed additives. The Panel considers that chickens/turkeys for fattening with a higher feed intake/growing rate are more sensitive to the potential adverse effects of the additive than the slower growing animals reared for reproduction. 5 EFSA Supporting publication 2017:EN-1304

6 Cows, line No distinction is made between the calves reared for reproduction and calves reared for fattening. In general, the feeding requirements for livestock depend on their specific use (reproduction, fattening, dairy). Animals for rearing often need another feeding regime to ensure a high lifetime production. A wrong feeding regime (not in accordance with its condition of use) can result in nutritionally induced deficiencies. This cannot be sufficiently considered by tolerance with adult animals. Thus, there different requirements for tolerance with animals reared for reproduction or fattening, and should be listed specifically. Tolerance for lactating ruminants are proposed to start 4 weeks after beginning of lactation. The defined starting point seems to be unsuitable for feed additives intended for use between the time of calving to four weeks post partum. The same principle as described above applies. 2. Federal Institute for Risk Assessment (BfR) General comments General remarks, part 2 Sheep/goats, line No distinction is made between lambs/kids reared for reproduction and lambs/kids reared for fattening as well as among sheep/goats for lactation and fattening. In gen-eral, the feeding requirements for livestock depend on their specific use (reproduction, fattening, dairy). Animals for rearing often need another feeding regime to ensure a high lifetime production. A wrong feeding regime (not in accordance with its condition of use) can result in nutritionally induced deficiencies. This cannot be sufficiently considered by tolerance with adult animals. Thus, there different requirements for tolerance with animals reared for reproduction or fattening, and should be listed specifically. Tolerance for lactating ruminants are proposed to start 4 weeks after beginning of lactation. The defined starting point seems to be unsuitable for feed additives intended for use between the time of lambing to four weeks post partum. The same principle as described above applies. Rabbits, line The duration of the tolerance study has been reduced from 49 to 42 days. What are the reasons for the reduction of about one week. The Panel considers that, in general, a duration of 42 days is sufficient for the assessment of the short-term toxicity of the additive for growing animals. 3. MANGHEBATI SAS General comments Page 22, line 686 (proposal for aquatic animals) The general health status does not need to be certified by a veterinarian anymore. We have no remarks on the form of the document, it is clearly written and the approach seems reasonable. But as we work on plant tinctures, which can be considered as complex chemical mixtures highly diluted in aqueous solvent, we have some questions at our level. We noticed that all the advice given in the Guidance refers to a single molecule, so we don t understand how we can apply it to our mixtures. It has been clarified in the text that general health should be checked by a veterinarian or under veterinary supervision The guidance applies to all types of additives, not only to single compounds. The text has been modified to include consideration of mixtures (see for example, section 3). 4. EFFSACO General comments Page 5 line 137 Based on the list of exemptions for "2. additives for which safety can be presumed without additional ", EFFSACO proposes to add: - Botanical products from the EFSA QPS list of botanicals As specified in the Scientific Opinion on a Qualified Presumption of Safety (QPS) approach for the safety assessment of botanicals and botanical preparations : The use of botanicals and botanical preparations in animal feed is excluded 6 EFSA Supporting publication 2017:EN-1304

7 - Other products produced by or from QPS microorganisms (not limited to nutritional additives). from consideration at this stage. The lack of category-specific data and the potential differences in pharmacokinetics found amongst livestock including fish makes it unlikely that a composite conclusion necessary for a QPS approach could be achieved. For other products derived from QPS microorganisms, the tolerance are intended to assess the safety of the chemical product itself, not only the potential production of toxic metabolites by the production strain. 5. Federal Institute for Risk Assessment (BfR) Scope of the guidance line 95, Scope of the guidance In the technical guidance from 2011 concerning safety and efficacy are specified. In contrast to the guidance from 2011, efficacy are no longer considered, but they are an important subject for the risk assessment according to the Regulation (EC) 429/2008, Section 4. Where are the requirements for the efficacy mentioned, when the new guidance on the safety for the target species comes into force? For the current guidance, it is recommended to give a short explanation of how to con-duct and report efficacy or to indicate that efficacy is no longer the object of the guidance. This guidance covers only the requirements for the assessment of safety for the target animals. The FEEDAP Panel is working on a specific guidance for the assessment of efficacy. 6. Pen & Tec Consulting SLU General comments 7. EFFSACO General comments Pen & Tec Consulting SLU (PenTec) welcomes this update of EFSA s guidance document on safety of feed additives for target species. Via the REFIT procedure, the EU Commission (EC) may review Regulation (EC) Nº 429/2008, which sets out the legal guidelines in force. A possible change of the current Regulation would be to shorten and harmonise the duration of tolerance across species. PenTec understands that EFSA accepts the iterative nature of the review processes (e.g. Lines of Background and Terms of reference). Hence, PenTec proposes that EFSA allows for adapting and finalising the draft guidance documents to relevant provisions published subsequent to any REFIT changes in Regulation (EC) Nº 429/2008. In other words, since Regulation 429/2008 is the legal document that sets guidelines, we recommend that EFSA guidance documents are updated after any amendments to Regulation 429/2008. The reason for this proposal is that PenTec s technical team has experienced several cases where the applicant has followed the provisions of Regulation (EC) Nº 429/2008, notably the flexibility to propose the use of feed additives in feeds administered for short periods (e.g. for 2-3 days during the piglet suckling period, or for the first 4-5 weeks post-weaning), only to have efficacy rejected by EFSA due to the short study duration. Innovation is driving new uses of feeds and feed additives (e.g. the use of feed additives in nutrients delivered from 18 days in ovo and in the period through hatching, delivery of chicks to farms, and acclimatisation of chicks at farms). EFSA TAS (and efficacy) guidance documents may therefore need to be adapted further as these innovations are taken into account during REFIT programmes, or become common industry practices. Comments to "Guidance on the assessment of the safety of feed additives for the target species" Endorsed for public consultation on 22 March 2017 Comments from EFFSACO (European Federation of Food Safety Consultants). EFFSACO is a federation of consultants providing regulatory advice and services to the EU feed industry and its EU-based and global suppliers. Since 2003, EFFSACO members have participated in several hundreds of feed additive applications, The guidance documents will be revised, if needed, to consider any changes that may be introduced in Regulation (EC) No 429/2008 that may impact the assessment of the safety of the feed additives. EFSA notes that the flexibility that the commenter refers to in Regulation (EC) No 429/2008 is already considered in the different FEEDAP guidance documents (for example see page 3 of the guidance on Tolerance and efficacy in target animals). This flexibility is still present in the updated draft guidance. Repeated comment #6 7 EFSA Supporting publication 2017:EN-1304

8 representing more than 100 applicants and manufacturers from both EU and non- EU countries. General remarks EFFSACO proposes that EFSA guidance takes into account current EU legislation, i.e. Reg (EC) Nº 429/2008 and its future amendments, and should not go beyond the legislation in force. For example, current EU law allows applicants to determine that feed additives may be used for shorter periods than life-long administration, and for shorter periods than the study durations proposed by EFSA for TAS (target animal safety ), or indeed existing EFSA efficacy guidance. The flexibility allowed in EU guidelines should be reflected and maintained in EFSA guidances to allow for innovation in the use of feeds and feed additives. For example, in ovo feeding and nutrition from 18 days incubation to hatch is a fast-developing field yielding promising zootechnical improvements in poultry post-hatch. 8. Association of Veterinary Consultants 1. Introduction AVC (Association of Veterinary Consultants) members are 50 international veterinary practitioners, providing regulatory services to EU and global food, pharmaceutical and feed industries. AVC members have been involved in many EU feed additive applications, supporting manufacturers based in the EU and elsewhere. AVC proposes that EFSA takes into account current EU legislation, i.e. Regulation (EC) Nº 429/2008 and future amendments. AVC proposes that, for maximum flexibility, coupled with creativity and innovation, EFSA s recommendations should not be more restrictive than existing EU guidelines, which allow applicants to propose use of feed additives for shorter periods than life-long, and for shorter periods than proposed by EFSA for TAS (target animal safety ), or current EFSA efficacy guidance. The flexibility in EU guidelines should be maintained in EFSA guidance to allow for innovation in the use of feeds and feed additives. For example, in ovo feeding and nutrition from 18 days incubation to hatch is a fast-developing field yielding promising zootechnical improvements in poultry post-hatch. AVC proposes, therefore, that EFSA TAS guidance allows for short-term TAS to cover short-term use of feed additives. In the case of in ovo feeding, the AVC is in a unique position to support EFSA in formulating appropriate safety and efficacy guidance, since AVC members have accumulated decades of experience in the development and use of in ovo application techniques, e.g. for veterinary vaccines. Such expertise can also be applied to the use of innovative feeds and feed additives via spray and gel presentations in the period through hatch until delivery of day-old chicks to farms. AVC is also in a unique position to advice on the case of coccidiostat feed additives which are essentially veterinary in nature, preventing coccidiosis, but legally classed as feed additives. Repeated comment #6 9. FEFANA 1. Introduction It is understood when going throughout the guidance that a stepwise approach is taken for the assessment of feed additives: 1st check whether the additive falls under the scope of section 2. Additives for which safety can be presumed without additional 2nd a literature search in case the additive does not fall in scope of section 2 3rd deriving safe concentrations from in laboratory animals, The text has been modified to make clear that the safety for target species can be derived by any of the different methodologies described. There is not the need to follow a strict step-wise approach. 8 EFSA Supporting publication 2017:EN-1304

9 4th if the derived values in step 2 are too low, a tolerance test shall be performed Proposal for amendment of the text: Please include a paragraph in the introduction section in order to provide clear guidance to users on how the document shall be used based on this stepwise approach Association of Veterinary Consultants Pen & Tec Consulting SLU 1. Introduction 1. Introduction Lines : AVC proposes that, in the interests of animal welfare and the 3 Rs (reduce, refine, replace experimental animals), good quality TAS (Target Animal Safety) carried out in compliance with, as examples, Chinese or US FDA requirements, using different study designs, are accepted by EFSA. AVC encourages EFSA to continue to work globally with other regulating and evaluating agencies to achieve enhanced global harmonisation of TAS study designs, and the development of alternative testing methods that do not require the use of experimental animals. Lines : PenTec proposes that, in the interests of animal welfare and the 3 Rs (reduce, refine, replace experimental animals), good quality TAS (Target Animal Safety) carried out in compliance with, as examples, Chinese or US FDA requirements, using different study designs, are accepted by EFSA. PenTec encourages EFSA to continue to work globally with other regulating and evaluating agencies to achieve enhanced global harmonisation of TAS study designs, and the development of alternative testing methods that do not require the use of experimental animals. 1. Introduction, lines Noted, thank you Repeated comment # FEFANA 1. Introduction Comment: The non-repetition of animal trials is a very valuable objective, however, we need to ensure that data protection measures in article 20 of Regulation (EC) No 1831/2003 shall be respected. Proposal for amendment of the text: Studies involving animals should respect the rules on animal welfare laid down by European Union legislation, particularly those listed in Directive 63/2010/EU, and they should not be repeated if available elsewhere, taking into account the requirements of the Article 20 of Regulation (EC) No 1831/2003 with regards to data protection. Footnote added to clarify the text. 13. Association of Veterinary Consultants 2. Additives for which safety can be presumed without additional Lines : AVC suggests to add that no safety are required for live (non-gmm) bacterial feed additives, whose taxonomy is established as per current EFSA requirements; where the full bacterial genome is supplied to EFSA; where genomic analysis and phenotypic testing demonstrate the absence of transferrable antimicrobial resistance (AMR) to key antibiotics defined by EFSA; and where genomic analysis and relevant in vitro testing demonstrate the absence of toxins and virulence factors. Effectively, an extension of the QPS status to all live (non- GMM) bacteria used in animal nutrition can be applied. In the case of live GMM bacteria and GMM producer strains (e.g. of vitamins, amino acids and enzymes) the above approach can be used with the addition of the safe strain lineage concept, particularly useful for GMM yeasts and fungi, in those cases where the genetic modifications do not give rise to safety concerns. For microorganisms not listed in the QPS list (or for those which biology is not sufficiently well known to allow pathogenic/toxigenic strains to be excluded by direct testing) the Panel considers that, at present it is not possible to accurately predict the potential for toxic metabolites or virulence factors based on the basis of whole genome sequence. This may be revised in the future as annotation becomes complete. 9 EFSA Supporting publication 2017:EN-1304

10 AVC proposes to add that no safety are required for botanical products from the EFSA QPS list of botanicals As specified in the Scientific Opinion on a Qualified Presumption of Safety (QPS) approach for the safety assessment of botanicals and botanical preparations : The use of botanicals and botanical preparations in animal feed is excluded from consideration at this stage. The lack of category-specific data and the potential differences in pharmacokinetics found amongst livestock including fish makes it unlikely that a composite conclusion necessary for a QPS approach could be achieved. Lines : According to the guidance on technological additives no safety are required for substances or microbiological agents which are already approved as additives for the same target species/categories at a comparable use level. Suggest adding this information and make it clear this is only applicable for technological additives. This provision has been deleted since so far this case has not been encountered. PenTec suggests to add that no safety are required for live (non-gmm) bacterial feed additives, whose taxonomy is established as per current EFSA requirements; where the full bacterial genome is supplied to EFSA; where genomic analysis and phenotypic testing demonstrate the absence of transferrable antimicrobial resistance (AMR) to key antibiotics defined by EFSA; and where genomic analysis and relevant in vitro testing demonstrate the absence of toxins and virulence factors. Effectively, an extension of the QPS status to all live (non- GMM) bacteria used in animal nutrition can be applied. Repeated comment # Pen & Tec Consulting SLU 2. Additives for which safety can be presumed without additional In the case of live GMM bacteria and GMM producer strains (e.g. of vitamins, amino acids and enzymes) the above approach can be used with the addition of the safe strain lineage concept, particularly useful for GMM yeasts and fungi, in those cases where the genetic modifications do not give rise to safety concerns. Moreover, according to current EFSA guidance on nutritional additives toxicological are not required for: - Urea - Amino acids naturally occurring in proteins of plants and animals (and their salts) - Amino acids analogues already authorised as feed additives - Compounds of trace elements already authorised as feed additives - Vitamins, pro-vitamins and chemically well-defined substances having similar effect which do not have a potential to accumulate - Vitamins, pro-vitamins and chemically well-defined substances having a similar effect which do have a potential to accumulate if their potency is not higher than that of the corresponding vitamin(s) Repeated comment #13 The FEEDAP Panel considers that only those nutritional additives already assessed and authorised under the provisions of Regulation (EC) No 1831/2003 should be excluded from the need of specific. (see lines ). According to current EFSA guidance on technological additives no safety are required for substances or microbiological agents which are already approved as additives for the same target species/categories at a comparable use level but this information is not included in the draft guidance. The same applies for additives already authorised in food (according to the current EFSA guidance on additives already authorised in food) since a tolerance study is not required if the use level of the feed additives is less than or similar to that used in food. The Panel already expressed in its Statement on Analysis of the need for an update of the guidance Documents that The appropriateness of using a comparison of human exposure and animal exposure in the assessment of safety for target species given additives already authorised in food should be reconsidered. The Panel considers that this inter-species extrapolation without any uncertainty factor is not justified EFSA Supporting publication 2017:EN-1304

11 For clarity, PenTec suggests to add the above points. 15. DGCCRF 2. Additives for which safety can be presumed without additional Line : this does not rule out potential contaminations/residues (other than the active substance or agent) that may remain in the feed. Their possible presence and the risk they may pose must be assessed as well. Text modified to consider the comment Line Further clarification for no significant amounts of the active substance is needed. Text modified to not detectable amounts 16. Federal Institute for Risk Assessment (BfR) 2. Additives for which safety can be presumed without additional Line Recent scientific should be taken into consideration for all new applications. Line % of a substance means 10 mg of this substance in 1 kg feed which could exceed the maximum acceptable concentration for substances in Cramer class I in complete feed, mentioned page 7, line Line ; Line The QPS-status of a substance is insufficient for a risk assessment of the whole product. Applicants should demonstrate that the other ingredients of the additive are of no concern for the target species. The Panel does not see the need to change the approach regarding the safety for the target species for additives already assessed and authorised. However, if new information is available, the applicant should submit it to EFSA Taking into consideration that this provision applies only to nutritional additives, that the production process will be fully described, the Panel considers that this 1% provides enough reassurance of the safety of the additive. However, if based on the information provided, the Panel has reservations, additional may be requested. Text modified to consider the other substances used to prepare the feed additive Pen & Tec Consulting SLU Pen & Tec Consulting SLU 2. Additives for which safety can be presumed without additional 2. Additives for which safety can be presumed without additional Lines : PenTec recommend adding the purity level, i.e. A product will be considered as sufficiently purified if the concentration of the active substance is > 95% and the unidentified material is <1%, on a dry matter basis. EFSA should also clarify whether or not the levels are expressed on dry matter basis. Lines : no TAS are required for nutritional additives not already authorised when the additive is produced by fermentation using a production organism that (i) satisfies the requirements of the QPS approach to safety assessment, or (ii) is a genetically modified microorganism (GMM) for which the recipient strain is considered by EFSA to qualify for the QPS approach to safety assessment and for which the molecular/genetic characterisation does not give rise to concern. Pen & Tec believe a similar approach can be used for enzymes (zootechnical additives) especially since this approach is already permitted for enzymes to justify the omission of toxicological. Hence, the following sentence can be added: The safety for the target species for these products is not necessarily linked only to the active substance. Of particular concern are those substances not identified. For example, an additive can have a content of the active substance of 75% and 25 % of substances identified and without any toxicological concerns. Text modified to clarify that the value is in % dry matter. For enzymes, the tolerance study is intended also to assess the potential adverse effects of the enzyme per se on the animals. - Enzymes (zootechnical additives) produced by micro-organisms (i) considered by EFSA to qualify for the QPS approach to safety assessment, or (ii) produced by GMMs for which the recipient strain is considered by EFSA to qualify for the QPS approach to safety assessment, and for which the molecular characterisation of the event does not give rise to concern EFSA Supporting publication 2017:EN-1304

12 19. FEDIAF 20. MANGHEBATI SAS 21. FEFAC 2. Additives for which safety can be presumed without additional 2. Additives for which safety can be presumed without additional 2. Additives for which safety can be presumed without additional The concept of No significant amounts should be clarified and detailed as to give more legal certainty to stakeholders. we suggest to add tinctures (water/ethanol 75:25) - in the paragraph N 2 Additives for which safety can be presumed without additional. Indeed, we already know that our tinctures are composed of 98 % moisture in average, that is to say around 2 % of dry extract. This dry extract contains mainly carbohydrates, minerals, and polyphenols (highly water-soluble components), and there is no substance of concern in most of our additives. Even if a substance of concern is present, it is in trace levels in the tincture (of ppm level). What is more, the additive is used as an aroma in the feed, which means that it will be incorporated in very low doses (for information purposes, the maximal rate admitted in human food is 2 %, but generally a sensory additive is used in lower doses in feed). Considering these elements, we estimate that a substance of concern will be at best found at trace levels in the final product : we can reasonably consider that no significant amounts of the active substances will be remaining in the feed, so tinctures are a part of the first point of the paragraph from our point of view. Consequently, we would like to see it clearly written in the Guidance in order to avoid any confusion for this kind of products. We also would like to highlight the fact that some of our tinctures are made from plants intended for food : in this case, it should be possible to consider this as a valuable argument for safety, as the plant equivalent brought by the additive will always be lower than the quantities of plant commonly consumed as food. In any case, the guidance should be more explicit concerning flavouring additives of botanically defined origin, in order to become a more exhaustive tool for the preparation of technical dossiers. other additives that should be mentioned are the food additives with a long history of use in human that are not yet authorized for animals. Text modified to no detectable amounts The Panel does not agree with this interpretation. Tinctures, even if very diluted, can contain active compounds of concerns. The Panel already expressed in its Statement on Analysis of the need for an update of the guidance Documents that The appropriateness of using a comparison of human exposure and animal exposure in the assessment of safety for target species given additives already authorised in food should be reconsidered. The Panel considers that this inter-species extrapolation without any uncertainty factor is not justified. 22. FEFANA 2. Additives for which safety can be presumed without additional There seems to be no scientific basis for referring exclusively to nutritional additives in lines Please also consider specifying the level of purification in line 130. The following additives should also be eligible for the presumption of safety for the target animals: - additives that have been already authorised with similar use levels (e.g. for a different function) according to Reg. (EC) 1831/ additives already authorised for use in food (and with similar use level as in feed) - additives for which a long history of safe use is worldwide recognized (e.g. over 10 years of use) - microorganisms satisfying the requirements of Safe Strain Lineage Concept Proposal for amendment of the text: - The level of purity is already defined in line 130 in terms of unidentified substances. - This provision has been deleted since so far this case has not been encountered. - The Panel already expressed in its Statement on Analysis of the need for an update of the guidance Documents that The appropriateness of using a comparison of human exposure and animal exposure in the assessment of safety for target species given additives already authorised in food should be reconsidered. The Panel considers that this inter-species extrapolation without any uncertainty factor is not 12 EFSA Supporting publication 2017:EN-1304

13 23. FEFANA 2. Additives for which safety can be presumed without additional (please add the following to the list of additives for which safety for the target animals can be presumed) - Additives already authorised for use in food, when the level of use in animal feed is similar - Additives scientifically assessed and authorised by international competent authorities -Additives produced by microorganisms satisfying the requirements of Safe Strain Lineage Concept - Nutritional additives assessed and authorised with similar conditions of use) following the provisions of Regulation (EC) No 1831/ Nutritional additives not already authorised, for which the active substance is the same as one already authorised: o When the active substance is sufficiently purified. A product will be considered as sufficiently purified, if the concentration of active substance is above 95 % and the unidentified fractions would not. o When the additive is produced by fermentation. (iii) satisfies the requirements of the Safe Strain Lineage Concept. lines : Please clarify whether unidentified fraction 1% is expressed on dry matter or on the additive/active substance as such. lines : A literature search will not be possible for many additives: Microorganisms (=> strain specific), Enzymes (=> Production host specific), Innovative additives It will make little to no sense to put reasonable efforts (quote line 142) into a literature search of at least the last 20 years (quote line 174) where chances of finding anything pertaining to very specific substances/organisms are negligible. justified. - The extensive literature search can be used to support the safety of products. - The Panel recognises the concept of safe strain lineage and it has been applied in EFSA. However, the criteria to be applied for its implementation across EFSA are still under discussion. If a consensus is reached this may result in a modification of the approach currently proposed. - Assessments or authorisations by international competent authorities should be provided in the dossier. They can suffice for the demonstration of safety for the target animals if they satisfy the requirements of the current guidance document. Text modified to clarify that the value is in % dry matter. In the spirit of reducing the use of animals, the FEEDAP Panel encourages the use of extensive literature searches to support the safety of the additive for the target species. However, if the applicant considers that this is not practical/useful, it can be omitted. The text has been modified to clarify it is not a mandatory requirement. Is it still required to conduct and document extensive literature searches (quote line 140) in such cases? 24. Biomin Holding GmbH 3. Extensive literature search for with target animals It would seem that literature searches will only make sense (or even only work) if the application concerns a very generic kind of additive. Would it be it possible to omit a literature search when an appropriate justification is provided (e.g. innovative product, for which no publications are available yet; additive, for which a tolerance trial is already available)? lines : Providing copies of the relevant papers to a literature study could be legally questionable. Many papers are not free to download, also, standardized methods the applicant may refer to are usually bought as user-licenses, which are not intended to be shared. EFSA is not in a position to assume the responsibility for intellectual property compliance for acts performed by legal or natural persons other than itself. Therefore, the applicants are responsible to provide the necessary evidence for EFSA to perform an assessment. Furthermore, this potentially concerns dozens of papers within 1 literature study, 13 EFSA Supporting publication 2017:EN-1304

14 which may cause red tape and license fees to explode. This makes the demand for all relevant papers highly disproportionate, especially with the requirement that the applicant be the sole responsible and liable for sharing the publications with EFSA. Is EFSA working on a strategy to solve this legal issue? 25. FEFANA 3. Extensive literature search for with target animals lines : A literature search will not be possible for many additives: Microorganisms (=> strain specific), Enzymes (=> Production host specific), Innovative additives It will make little to no sense to put reasonable efforts (quote line 142) into a literature search of at least the last 20 years (quote line 174) where chances of finding anything pertaining to very specific substances/organisms are negligible. Repeated comment # FEFANA 3. Extensive literature search for with target animals Proposal for amendment of the text: Please describe cases in which extensive literature searches can be waived. lines Providing copies of the relevant papers to a literature study could be legally questionable. Many papers are not free to download, and standardised methods to which the applicant may refer are usually bought as user-licences, which are not intended to be shared. Also, this potentially concerns dozens of papers within 1 literature study, which may cause red tape and licence fees to explode. This makes the demand for all relevant papers highly disproportionate, especially with the requirement that the applicant be the sole responsible and liable for sharing the publications with EFSA. Would the applicant need to justify the copyright status of all the. Repeated comment #24 Please amend as follows: Copies of the relevant papers should be provided where a licence for sharing is available. 27. FEFANA 3. Extensive literature search for with target animals lines : The requirement for referring to performed with an identical active substance should be replaced by similar or comparable (e.g. salt of an acid). How should the applicant consider the impurities (e.g. as the quoted 1% in line 130) that are not identified or not described in the publication? The last sentence most probably belongs to section 4. This section is about target animals, not laboratory animals. Proposal for text amendment: The analysis of these data must establish that the active substance/agent in literature is comparable to that under application or, if not, would still allow conclusions on the additive under application to be made; for additives produced by fermentation identity includes the production strain. This is already considered in the current draft The analysis of these data must establish that the active substance/agent in literature is identical to that under application or, if not, would still allow conclusions on the additive under application to be made. Genotoxicity is an important end-point relevant for the safety of target species EFSA Supporting publication 2017:EN-1304

15 28. FEFAC 29. FEFAC 30. Pen & Tec Consulting SLU 3. Extensive literature search for with target animals 3. Extensive literature search for with target animals 3. Extensive literature search for with target animals 159: some terms used might include IP from the company and this should be protected 175: The license for a reference management software is a cost that not all companies can afford just for the purpose of a dossier. Lines : With respect to copyright, PenTec proposes that the summary or abstract of relevant published papers may be used, since these are often in the public domain and may provide adequate safety conclusions. This will reduce the administrative burden on applicants, and does not prevent EFSA requesting the full publication, if deemed necessary. The applicant can claim confidentiality according to the provisions of Article 18 of Regulation (EC) No 1831/2003. There are free reference manager tools available. The Panel does not consider the abstracts and/or summary as sufficient to allow conducting an assessment. 31. FEFAC 32. Federal Institute for Risk Assessment (BfR) 33. FEFAC Association of Veterinary Consultants Pen & Tec Consulting SLU 3. Extensive literature search for with target animals 3. Extensive literature search for with target animals 3. Extensive literature search for with target animals 4. Toxicity data from repeated dose in laboratory animals 4. Toxicity data from repeated dose in laboratory animals : regarding copyright, EFSA should be the one satisfying the terms and conditions, since they are a scientific organization and have more power to reach agreements than the companies individually. Literature can be a big investment and companies should not face copyright problems to provide EFSA with articles, reviews, etc. Line or, if not... identity includes the production strain.. With regard to Regulation (EC) 429/2008 literature with similar substances or the use of almost the same production strain is inappropriate for risk assessment. Hence, differences and Similarities should be described in detail. Line 192 It should be mentioned that applicants have to give a résumé of the submitted and why they suppose that these will support their application. The submitted should respect the requirements of Regulation (EC) 429/ : line 190, it is said that genotoxicity should be covered in the literature search, but then in Chapter 6, lines it is said that genotoxicity may be required for long-living animals. So then should be the literature search for genotoxicity be only relevant for long-living animals and consumer? Lines : AVC concurs with EFSA that in the case of micro-organisms, safety data must include correct taxonomy, genomic analysis, and appropriate in vitro/phenotypic assays (e.g. AMR, toxins/virulence factors). However, where good quality toxicological data are available for micro-organisms, for example, OECD/GLP 90-day oral toxicity in rats, these data can be used to justify omission of TAS in target animals. Such an approach can also be used for GMMproducer strains, with the addition of the safe strain lineage concept, and where the active substances produced (e.g. amino acids vitamins, enzymes) are highly purified (e.g. amino acids and vitamins), well-characterised, and not novel (e.g. glucanases, phytases, xylanases). Lines : PenTec agrees with EFSA that in the case of micro-organisms, safety data must include correct taxonomy, genomic analysis, and appropriate in vitro/phenotypic assays (e.g. AMR, toxins/virulence factors). However, where good quality toxicological data are available for micro-organisms, for example, Repeated comment #24 The production strain for those additives produced by fermentation should be the same as indicated in line 184. This is not considered necessary. When safety is demonstrated using extensive literature searches, these should cover all the relevant toxicological endpoints including genotoxicity. Specific testing of genotoxicity may be required for additives intended to be used in long living animals or reproductive animals based on structural alerts or other toxicological considerations. Studies like 90-day oral toxicity are not considered relevant to assess the safety of the microorganism in animals species different from those tested, because of the possible different pathogenicity between species. Repeated comment # EFSA Supporting publication 2017:EN-1304

16 OECD/GLP 90-day oral toxicity in rats, these data can be used to justify omission of safety in target animals. Such an approach can also be used for GMM-producer strains, with the addition of the safe strain lineage concept, and where the active substances produced (e.g. amino acids vitamins, enzymes) are highly purified (e.g. amino acids and vitamins), well-characterised, and not novel (e.g. glucanases, phytases, xylanases). Moreover, EFSA should clarify if all additives with the exception of microorganisms include additives produced by microorganisms or only additives that include microorganisms as active substances. The exclusion is only for microorganisms, not for fermentation products. Text has been clarified. Lines Table 1: information of certain animal categories is missing (e.g. horses, rabbits, lambs/kids, sheep/goat). If it is not possible for EFSA to provide this information we suggest adding a sentence allowing the applicant to estimate values for daily feed intake scaled to body weight. Default values have been included for horses, sheep/goats and rabbits. Moreover, the text has been modified to account for those species for which values are not provided. Line In this part, a definition for the used uncertainty factor of 100 is missing. A certainty factor of 100 is normally used to extrapolate toxicity between laboratory animals and humans. Overall, an additional uncertainty factor has to be considered for the extrapolation to animals with different physiology or high sensitivity. For example, copper is well tolerated by rats, but not by the most sensitive species sheep. The text has been modified to include information on the default value. 36. Federal Institute for Risk Assessment (BfR) 4. Toxicity data from repeated dose in laboratory animals Line 204, 206 The use of factor 0.88 is suitable to express the feed concentration in complete feed, but not for feedstuff with high water content e.g. silage. Table 1 The category ornamental fish does not match with the category salmon and trout as specified in the Regulation (EC) 429/2008, and should be adjusted. The use of the 0.88 is considered as the standard for the authorisation of feed additives (88% dry matter). Concentrations in feedingstuffs with different dry matter content should be converted in the standard complete feed dry matter. The default values for salmon/trout are different to those for ornamental fish. 37. FEFAC 38. FEFANA 39. FEFANA 4. Toxicity data from repeated dose in laboratory animals 4. Toxicity data from repeated dose in laboratory animals 4. Toxicity data from repeated dose in Line An overlap occurred by the classification of the Cramer class I ( mg/kg) and II ( mg/kg), so that an accurate classification of the additive is not possible. 213:it should be possible to apply TTC to other additives, not only flavourings, when properly justified. table 1: Info on horses is missing in the list: 400kg BW (medium size sport horses); 8kg DM/day (i.e. 2% of BW) Table1: As the table 1 does not cover all animal species, a sentence should be added to apply the same approach on the proposal of the applicant. The ranges for each Cramer class represent the concentrations for the different target species, and for that reason some overlap exists. The TTC approach is not intended to be used of substances intentionally added to feed with the exception of food flavours. In the case of feed flavourings, the Panel follows the approach used in food flavourings. Default value added for horses The text has been modified to account for those species for which values are not provided EFSA Supporting publication 2017:EN-1304