Statement on the preparation of guidance for the assessment of plant/herbal products and their constituents used as feed additives 1

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1 SCIENTIFIC OPINION Statement on the preparation of guidance for the assessment of plant/herbal products and their constituents used as feed additives 1 EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) 2 European Food Safety Authority (EFSA), Parma, Italy SUMMARY The European Food Safety Authority (EFSA) asked the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) to prepare a background paper on the biological effects of botanical products and their constituents on livestock (including horses, companion animals and game birds), highlighting the issues of likely importance in risk assessment. The FEEDAP Panel was also asked to undertake further work including the development of guidance for applicants seeking authorisation for feed additives based on botanical extracts or their constituent phytochemicals. The FEEDAP Panel tendered for the preparation of the background paper. The tender was awarded to a Consortium led by the University of Veterinary Medicine, Vienna, and a report Study on the assessment of plants/herbs, plant/herb extracts and their naturally or synthetically produced components as additives for use in animal production was produced. On the basis of this document and protocols developed elsewhere in EFSA for the assessment of botanicals extracts/components used as food/food supplements, the FEEDAP Panel was able to propose the approach to botanicals eventually incorporated into Commission Regulation (EC) No 429/2008 (the detailed rules for the implementation of Regulation (EC) No 1831/2003). In addition, the FEEDAP Panel also developed a series of detailed guidance documents intended to further support applicants in the preparation of dossiers. Botanical extracts and the components of botanical extracts are primarily dealt with in the guidance document on the category of sensory additives flavouring compounds. However, since some applications have been made under the technological and zootechnical categories, the relevant guidance documents for those categories of feed additives also make provision for botanically-derived products. KEY WORDS Guidance, botanicals, plant/herbal products, safety 1 On request of EFSA, Question No EFSA-Q , adopted on 13 July Panel members: Gabriele Aquilina, Georges Bories, Paul Brantom, Andrew Chesson, Pier Sandro Cocconcelli, Joop de Knecht, Noël Albert Dierick, Mikolaj Antoni Gralak, Jürgen Gropp, Ingrid Halle, Reinhard Kroker, Lubomir Leng, Sven Lindgren, Anne-Katrine Lundebye Haldorsen, Alberto Mantovani, Miklós Mézes, Derek Renshaw and Maria Saarela. Correspondence: feedap@efsa.europa.eu Suggested citation: EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) Statement on the preparation of guidance for the assessment of plant/herbal products and their constituents used as feed additives. EFSA Journal 2010; 8(7):1694. [7 pp.]. doi: /j.efsa Available online: European Food Safety Authority,

2 TABLE OF CONTENTS Summary... 1 Key words... 1 Table of contents... 2 Background as provided by EFSA... 3 Terms of reference as provided by EFSA Introduction Preparation of the background paper Recommendation for further work EFSA guidance documents Outcome

3 BACKGROUND AS PROVIDED BY EFSA 3 The legal frame One of the principles of Regulation (EC) No 1831/2003 of the European Parliament and of the Council (of 22 September 2003) on additives for use in animal nutrition is laid down in Article 3: No person shall place on the market, process or use a feed additive unless it is covered by an authorisation granted in accordance with this Regulation. For existing products (according to Directive 70/524/EEC or 82/741/EEC) transitional measures are foreseen. Article 10(2) specifies that: an application shall be submitted within a maximum of seven years after the entry into force of Regulation 1831/2003 for additives authorised without a time limit. The regulation also make provision for a detailed calendar listing in order of priority for the different classes of additives to be re-evaluated and consultation with EFSA in drawing up such a list. One class of feed additives listed in Directive 70/524 EEC and now in the Regulation under Article 6 (1) has never been subject of any evaluation. These are the so called sensory additives defined as any substance, the addition of which to feed improves or changes the organoleptic (sensory) properties of the feed. Annex I describes this class more precisely as flavouring compound: substances the inclusion of which in feeding stuffs increases smell or palatability. The labelling and packaging instructions (Article 16 (2)) for sensory additives make an exception since for flavouring compounds, the list of additives may be replaced by the words mixture of flavouring compounds. According to Directive 70/524/EEC flavouring compounds (to improve smell or to stimulate appetite) are generally plant extracts and their naturally or synthetically produced components. No positive list for such extracts or compounds exists although the European Federation of Animal Feed Additive Manufacturers (FEFANA) notes that some 250 plant extracts and a further 1700 chemically defined compound have been used within Member States as sensory additives in animal feeds. Scientific issues relating to efficacy and safety Most herbal extracts and plant-derived compounds of varying degrees of purity do not in fact influence feed intake. Instead they are increasingly being used (and informally marketed) for other purposes not covered by a Directive or the Regulation (notably better growth or feed conversion, improved meat quality, and for prophylactic purposes). There are strong indications that such use will further increase as replacement additives for the antibiotic growth promoters whose use will be prohibited by the end of Few plant extracts are standardised and, consequently, may be inconsistent in their effects and, in the majority of cases, routine methods for their detection in feeds for control purposes are not available. This is further complicated by the tendency to market plant extracts and individual compounds in admixtures rather than as individual agents. Assessing safety requires the full range of possible biological activities to be considered. Plant/herb extracts can, and usually do, show a multiple pattern of activity. Some compounds in the extract or admixture may be bacteriocidal, others may show anti-viral or anti-protozoal effects. Many extracts function as potent antioxidants acting both in the feed to reduce lipid oxidation and as radical scavenger after ingestion and absorption. Metabolic process may be influenced either directly at a biochemical level (enzyme inhibition) or indirectly via modulation of gene expression. Whether such effects are beneficial or harmful (toxic) is often dependent on dose. A few plant/herb-derived compounds may be carcinogenic. In addition, nothing is known on the carry over from feeding stuffs to animal products. 3 Background and Terms of Reference provided by EFSA in April

4 TERMS OF REFERENCE AS PROVIDED BY EFSA Statement on plants/herbal feed additives The existing guidelines such as the Annex for additives other than micro-organisms and enzymes of Council Directive 87/153/EEC amended by Commission Directive 2001/79EC, and the drafts of the DG SANCO s former Scientific Committee on Animal Nutrition (SCAN) for other additives (microorganisms and enzymes) do not offer a sound scientific basis for assessing the risk of plants/herbs and plant/herb extracts and their naturally or synthetically produced components used in feed. Although the concern with respect to the safe use of plant/herb products and their components as additives is similar both for their use in food and in feed, the approaches to address the concern may well be different. Nonetheless, the responses to the questionnaire on plant/herb products as food supplements may possibly provide useful information also for their use as feed additives. Therefore, such information may well assist in determining the best possible approach for addressing the risks of plants/herbs, plant/herb extracts and their naturally or synthetically produced components as additives for use in animal nutrition. Considering the background and taking into account the scientific issues addressed above, EFSA requests the FEEDAP Panel to: Prepare a background paper, based on the FEFANA list, on the known biological effects of plant/herbal products and their constituents on livestock (including horses, companion animals and game birds), highlighting those issues of likely importance in risk assessment. Recommend further work taking into account both the background paper and the results of EFSA s call for information from Member States on their concerns with respect to the use of plants/herbs, plant/herb extracts and their naturally or synthetically produced components as food supplements. This follow-up work may include: o o The preparation of guidance for companies seeking authorisation for plant/herbal products and their constituents under the present regulation indicating the nature of the data likely to be required to assess safety and efficacy; and Ascertaining whether plant/herbal products and their constituents used as a feed additive can have benefits not foreseen in the present legislation. It would be greatly appreciated if the work could start early in 2005 and if the tasks described in the first two bullets above could be completed within 6 months following the start of the work. 4

5 1. Introduction In 2004, the Scientific Committee of EFSA (SC) adopted a discussion paper on botanicals and botanical preparations used as food supplements and related products. 4 In this paper the Committee expressed concerns about quality and safety issues and argued for the need for a better characterisation of botanicals entering the European market and for harmonising the risk assessment approaches. A subsequent survey of competent authorities showed that the concerns outlined in the SC paper were widely shared by Member States. As a result, the SC developed a general framework for the safety assessment of botanicals and, in parallel, began to compile a compendium of relevant plants reported to contain toxic, addictive, psychotropic or other substances to help establish priorities for safety assessment. 5 This work is now being continued and further developed by an EFSA Scientific Cooperation (ESCO) Working Group on Botanicals created to enlarge the Compendium and to test the safety assessment of botanicals proposed by the SC. The emphasis of the work of the SC was on the use of botanicals in human food and the comparable use in animal feed was not directly considered. Botanical extracts and components of such extracts are widely used in animal nutrition, typically as flavouring agents but increasingly for other purposes. Although the approach taken by the SC for the assessment in food has relevance for the assessment of consumer safety following the use of such products in animal feed, it does not address other important issues such as target animal safety. Regulation (EC) No 1831/2003 covering the authorisation of additives used in animal nutrition includes reference to a number of groups of additives which have never been subject to an evaluation at Community level. Sensory additives, defined as products which increase the smell or palatability of feed, fall into this category. For such additives, the Regulation specifies an interim period of seven years after which a formal assessment is required to allow the additive to remain on the market. Surveys by an industry association and notifications to the Commission have shown that some 600 botanical extracts and some 1800 individual compounds naturally occurring as components of extract are, or have been, used for sensory purposes in feedstuffs. In addition, there is an increasing use of botanical extracts for other purposes, notably as alternative growth promoters encouraged by the withdrawal of authorisations for antibiotics used for such purposes. In anticipation of a need to develop guidance for applicants seeking authorisation of botanical extracts and/or components of extracts as feed additives for a variety of purposes and recognising that the assessment methodology developed for their use in food use was insufficient, EFSA agreed a self-task to be undertaken by the FEEDAP Panel with the terms of reference given in the Background (q.v). 2. Preparation of the background paper As a first step in meeting the terms of reference, the FEEDAP Panel decided to tender for the preparation of the background paper. The call for tender requested data on the known biological effects of plant/herbal products and their constituents on livestock with emphasis on the issues likely to be important in any risk assessment. It was recognised that such a call could not be comprehensive and so was restricted to plant species already identified by FEFANA as those commonly used in animal feed which also presented a range of toxicological/pharmacological profiles likely to influence a safety assessment. The tender was awarded to a Consortium led by the University of Veterinary Medicine, Vienna, and a final report Study on the assessment of plants/herbs, plant/herb extracts and their naturally or synthetically produced components as additives for use in animal production

6 (cft/efsa/feedap/2005/01) was produced. 6 The report consisted of a brief overview of the use of botanical products in animal nutrition, followed by 26 structured monographs covering a total of 42 plant species. Each monograph included sections dealing with the historical uses of the plant, particularly in livestock, its description and taxonomy, its phytochemistry, and pharmacology, any antimicrobial properties, its effects on animals and animal products and specific considerations of safety. The authors in their conclusions listed a number of issues to be considered in any assessment of safety. Those included a need for the unambiguous identification of the starting material, factors influencing composition and the need to ensure consistency, and the risks of contamination and product quality. Those conclusions matched closely the issues also identified and incorporated into the safety assessment protocol proposed by the SC for botanicals used in food. However, the authors highlighted the added difficulty of hazard identification and characterisation when botanical preparations are used in feed for livestock. Identification of the inherent biological activity of the preparation and the assessment of relevance to animals (and humans) are necessary before the exposure-dependent risk can be characterised. For the majority of species considered in the various monographs in the background document at least some data relevant to human safety is available. Much less is known about the parallel activities and metabolism in target animals and absorption, distribution, metabolism and excretion (ADME) data is virtually non-existent. The authors recognised that this absence of data could make the assessment of safety for target species and the possible carryover of individual components of botanical preparations into the food chain a demanding process. Nonetheless, in their final conclusion, the authors stressed a need for specific guidance on the assessment of botanical products used as additives in animal nutrition. 3. Recommendation for further work As anticipated in the terms of reference, with the introduction of Regulation (EC) No 1831/2003 the then existing guidelines (the Annex for additives other than micro-organisms and enzymes of Council Directive 87/153/EEC amended by Commission Directive 2001/79/EC, and the drafts of the DG SANCO s former Scientific Committee on Animal Nutrition (SCAN) for other additives (microorganisms and enzymes)) lost any legal status and relevance. Subsequently, new guidelines were developed by the Commission in conjunction with EFSA and others. The FEEDAP Panel s suggestions for both Annex II and Annex III of the resulting Commission Regulation (EC) No 429/2008 on the detailed rules for the implementation of Regulation (EC) No 1831/2003 were largely incorporated unchanged. In particular, the rules for applicants wishing to obtain authorisation for sensory additives were based on the work done for comparable food use and on the conclusions arising from the background document described above. For example, the FEEDAP Panel took note of the use of the principle of threshold of toxicological concern used in the assessment of consumer safety for individual components of botanical extracts and proposed that the same principle could be equally applied to target animal safety. In this way some of the difficulties raised for the assessment of target animal safety in the background document could be overcome. 4. EFSA guidance documents The FEEDAP Panel also developed a series of detailed guidance documents intended to further support applicants in the preparation of dossiers. 7 Each of the five basic guidance documents (technological, sensory, nutritional, zootechnical and coccidiostats and histomonostats) follow the structure of Regulation (EC) No 429/2008 and cover one of the five categories recognised in Regulation (EC) No 1831/2003. These five basic documents are supported by other guidance documents dealing with specific topics and generally applicable to all five of the basic guidance documents

7 Botanical extracts and the components of botanical extracts are primarily dealt with in Part 2 of the basic guidance document dealing with the category of sensory additives flavouring compounds. 8 The approach to the assessment of such additives and the detailed requirements for data are similarly based on the approaches developed within EFSA for the assessment of food flavours, the protocol proposed by the SC and the conclusions arising from the background document. The number of applications for the use of botanical extracts and/or the components of such extracts for purposes other than sensory have proved to be less than initially anticipated following the withdrawal of antibiotics used for growth promotion. However, some applications have been made both under the technological and the zootechnical categories. Consequently, both of the relevant basic guidance documents make provision for such botanically-derived products. 5. Outcome As a conclusion of the self-task, the FEEDAP Panel has been able to develop and document its approach to the assessment of botanical extracts and constituent phytochemicals. In addition, the Panel now has access to the monographs contained within the background document, to the compendia developed by the SC/ESCO working groups and to the various databases of phytochemicals supported by EFSA and others which provide specific data on botanical extracts and component compounds to aid in future assessments