Outcome of a public consultation on the draft Statement on Exposure Assessment of Food Enzymes

TECHNICAL REPORT ADOPTED: 19 October 2016 doi:10.2903/sp.efsa.2016.en-1106 Outcome of a public consultation on the draft Statement on Exposure Assessment of Food Enzymes Abstract European Food Safety Authority (EFSA), Yi Liu, Magdalena Andryszkiewicz, Claudia Roncancio Peña A public consultation was conducted on the draft Statement of the EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF Panel) on Exposure assessment of food enzymes from 16 February 2016 to 31 March 2016. During the consultation period, EFSA received comments and proposals from nine organisations. All comments were found to be within EFSA s remit. Based on these comments, the CEF Panel revised the document, and adopted a Statement on Exposure Assessment of Food Enzymes on 14 September 2016. This document reports the outcome of the public consultation. It lists comments received, summarises the issues pertinent to the approach and methodology for assessing food enzyme exposure, and outlines how those comments were taken into account in the adopted statement. European Food Safety Authority, 2016 Key words: food enzyme, exposure assessment, public consultation Requestor: EFSA Question number: EFSA-Q-2015-00515 Correspondence: FIP@efsa.europa.eu www.efsa.europa.eu/publications EFSA Supporting publication 2016:EN-1106

Acknowledgements: EFSA wishes to thank the following for the support provided to this scientific output: Christina Tlustos, Davide Arcella, Karl-Heinz Engel, André Penninks, Annamaria Rossi, Andrew Smith, Holger Zorn. Suggested citation: EFSA (European Food Safety Authority), Liu Y, Andryszkiewicz M, Roncancio Peña C, 2016. Outcome of a public consultation on the CEF Panel s draft Statement on Exposure Assessment of Food Enzymes. EFSA supporting publication 2016:EN-1106. 23 pp. doi:10.2903/sp.efsa.2016.en-1106 ISSN: 2397-8325 European Food Safety Authority, 2016 Reproduction is authorised provided the source is acknowledged. www.efsa.europa.eu/publications 2 EFSA Supporting publication 2016:EN-1106

Table of contents Abstract... 1 1. Introduction... 4 2. Data and Methodologies... 4 2.1. Comments received... 4 2.2. Methodology of analysis... 4 3. Evaluation and response to comments received... 4 3.1. Overall feedback... 5 3.2. Approach and tiers... 6 3.3. Input parameter... 7 3.4. Margin of exposure... 7 4. Conclusions and Recommendations... 8 References... 9 Abbreviations... 10 Appendix A Instruction on how to submit a comment through the public consultation... 11 Appendix B Organisations that submitted comments during the public consultation... 12 Appendix C Comments received during the public consultation... 13 www.efsa.europa.eu/publications 3 EFSA Supporting publication 2016:EN-1106

1. Introduction In September 2015, the EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF Panel) endorsed a Draft statement on exposure assessment of food enzymes during its 57th meeting 1, which was presented and discussed on 3 February 2016 at a technical meeting with stakeholders/applicants 2. In accordance with EFSA s policy on openness and transparency when a statement concerns a guidance document, the CEF Panel undertook a public consultation in order to receive comments from the scientific community and stakeholders. This consultation was held from 16 February to 31 March 2016 through a web form 3. On the basis of stakeholder s feedback, the CEF Panel revised the draft statement. The final Statement (EFSA CEF Panel, 2016) was adopted by the Panel on 14 September 2016 4. EFSA is committed to publishing technical reports 5 on the outcome of its public consultation. This technical report compiled and analysed all comments received through the consultation, and explains how relevant issues are taken into account by the CEF Panel in revising the statement. This report was approved by the Head of the Scientific Evaluation of Regulated Products Department of EFSA. 2. Data and Methodologies 2.1. Comments received Through the web form (see Appendix A), EFSA received comments from nine organisations. The interested organisations comprise European national risk assessment bodies, as well as European and international industrial sectors (see Appendix B). All sections in the draft statement were commented on. All comments received were compiled with reference to the contributor and the section of the draft statement to which they referred (see Appendix C). One stakeholder also submitted an extended comment to EFSA by email (see Appendix D). 2.2. Methodology of analysis The CEF Panel s Working Group on Food Enzymes screened the comments received for their relevance with regard to the risk assessment of food enzymes. All comments were found to be within EFSA s remit under Regulation (EC) 1332/2008 6 and its Implementing Regulation (EU) 234/2011 7. Consequently, all comments were analysed in details. Comments were grouped into four areas. For each area, comments and proposal from stakeholders were summarised, followed by Panel s response (see Section 3). The Panel s recommendation about the way forward can be found in Section 4. 3. Evaluation and response to comments received As shown in Table 1, comments and proposals were grouped into four areas: (1) overall feedback; (2) approach and tiers; (3) input parameters; and (4) margin of exposure (MoE). The corresponding section in the adopted Statement in which the comments were addressed is also indicated in Table 1. 1 Further information is available online: http://www.efsa.europa.eu/sites/default/files/event/150908b-m.pdf 2 Further information is available online: http://www.efsa.europa.eu/en/events/event/160203 3 The consultation was made through the website: http://www.efsa.europa.eu/en/press/news/160216a 4 Plenary meeting minutes is available at http://www.efsa.europa.eu/en/events/event/160913 5 Definition of a technical report can be found at: http://www.efsa.europa.eu/en/efsajournal/scdocdefinitions 6 OJ L 354, 31.12.2008, p. 7; available online: http://eurlex.europa.eu/lexuriserv/lexuriserv.do?uri=oj:l:2008:354:0007:0015:en:pdf 7 OJ L 64, 10.03.2011, p. 15; available online: http://eurlex.europa.eu/lexuriserv/lexuriserv.do?uri=oj:l:2011:064:0015:0024:en:pdf www.efsa.europa.eu/publications 4 EFSA Supporting publication 2016:EN-1106

Table 1: Overview of comments and proposals received from stakeholders. Respondent* Area of comments Overall Approach and feedback tiers (T) (O) Input parameters (I) MoE (M) Amfep T, I, M ABIAM ETA M Food Drink Europe GMA Intertek T JEA NFID M RIVM Corresponding section in the adopted Statement Section 2.2.1 Sections 2.2.1, 2.2.5 and 2.3 Sections 2.2.2, 2.2.3 and 2.2.4 Section 2.1.2 Proposal for modification * Amfep, European Association of Manufacturers and Formulators of Enzyme Products; ABIAM, Brazilian Association of Additive Manufacturers; ETA, Enzyme Technical Association (Trade Association in North, Central and South America); GMA, Grocery Manufacturers Association; Intertek, Intertek Scientific and Regulatory Consultancy; JEA, Japan Enzyme Association; NFID, National Food Institute, Technical University of Denmark; RIVM, Netherlands National Institute for Public Health and the Environment. 3.1. Overall feedback Comments received Eight of the nine stakeholders provided overall feedback. Nearly all of them expressed appreciation of the opportunity to providing comments via the public consultation platform. Concerning the actual need for such a statement, two opposing views were expressed. One stakeholder welcomed EFSA s efforts in harmonising dietary exposure methodology by using actual consumption data in food safety assessment across scientific panels (Appendix C comment No 2). Food industry representatives were generally positive about conducting more realistic exposure scenarios (Appendix C comment No 7b); whereas food enzyme manufacturer associations from Europe and outside of Europe were opposed to the proposal. The opposing view was based on the argument of proportionality, stressing the adequacy of the Budget method in relation to the recognised low level of safety concerns related to the use of enzymes in food process (Appendix C comments No 3a, 8). Respondents with opposing views stressed the importance of a smooth switchover to a Community list of food enzymes (Appendix C comments No 3a, 4, 7a,b). The main concerns referred to potential delay in the safety assessment process by the introduction of a new methodology and potential negative evaluation. In particular, concerns referred to (i) the timing of this statement publication about 1 year after the submission of enzyme dossiers to the European Commission, and the Budget method was used in the submitted dossiers; (ii) the proposed method potentially could overestimate the exposure to food enzymes, when compared to the Budget method. One stakeholder explicably questioned the need for the draft statement (Appendix C comment No 3a). Proposals received None Consideration of the comments received EFSA understands the concerns raised by stakeholders. The drive for revisiting the methodology came from experience gained during the evaluation of submitted dossiers. The Budget method was found not adequate, which identified a clear need for a uniform approach to assess all the dossiers in the same way. To this end, it is important to use the same source of consumption data for estimating dietary exposure to food enzymes, and to follow the best practice in science. These considerations all together necessitated the consideration of an appropriate methodology. www.efsa.europa.eu/publications 5 EFSA Supporting publication 2016:EN-1106

Consideration of these comments resulted in Section 2.2.1 in the adopted Statement (EFSA CEF Panel, 2016). 3.2. Approach and tiers Comments received Several organisations expressed concerns about the three tiers proposed in the flow chart, and argued for retaining the Budget method as the screening method (instead of the Tier 1 as proposed in the draft statement). Respondents were of the opinion that the removal of default factors would result in an excessive conservative estimation of food enzyme intake (Appendix C comments No 5, 8). Several stakeholders also expressed the view that, based on the nature and fate of food enzymes in the food as consumed, the Budget method was still valid (i.e. conservative enough and simple to use) to serve as the screening method. Tier 2a was generally welcomed by the stakeholders. In terms of its implementation, concerns were expressed regarding the accessibility of individual food consumption data and the challenge in proper assignment of food categories related to the intended conditions of use of the food enzymes. Tier 2b was of concern to many stakeholders. One stakeholder questioned the method of deriving factors from dietary survey-based consumption data. Some stakeholders perceived it as a modified Budget method with factors specific to the enzyme in question. How to derive these enzyme-specific factors remained to be a challenge. Proposals received Two proposals were received: To add the original Budget method as an additional step between Tier 1 and Tier 2a or 2b (Appendix D). To add (back) ad hoc consideration of exposure to young children and infants (Appendix C comment No 9). Consideration of the comments received Following the extensive comments received on the Budget method, the Panel provided clarification about why this method was no longer appropriate, also explained why to advocate an actual food consumption data-based assessment methodology, as the following in the adopted Statement. The following issues were considered in reaching this conclusion: Availability of more refined and accurate food consumption information in EFSA, which is representative for the European population. Harmonisation of exposure methodology used across EFSA Panels. Difficulty in identifying the proportion of solid foods and liquids potentially containing the food enzymes under investigation when these are mainly used as ingredients at industrial level. Application of technical conversion factors specific to each food production process. Necessity to consider the child population, and in particular toddlers, since they are often at the high end when calculating exposure, as recommended by EFSA (EFSA, 2011). Having considered multiple comments received on the (removal of) factors used in the previous Tier 1 and the availability of actual consumption data, the CEF Panel, in its adopted Statement, affirmed its view that dietary exposure to food enzymes should be based on consumption data collected from dietary surveys. This view is in line with EFSA s recommendation across different Panels (EFSA, 2011). Depending on the availability and quality of consumption data, exposure estimates aggregated at different levels can be calculated using the EFSA Comprehensive European Food Consumption Database (Comprehensive Database) 8. Hence, the adopted Statement reflects these considerations, 8 http://www.efsa.europa.eu/en/food-consumption/comprehensive-database www.efsa.europa.eu/publications 6 EFSA Supporting publication 2016:EN-1106

and presents an exposure assessment method that is based solely on the use of actual food consumption data (i.e., the Tier 2a proposed in the draft statement). Consequently, the previously proposed Tier 1 and Tier 2b were no longer considered in the adopted Statement. Consideration of these comments resulted in Sections 2.2.1, 2.2.5, 2.3 in the adopted Statement, as well as a modified flow chart in the Annex (EFSA CEF Panel, 2016). 3.3. Input parameter Comments received Several stakeholders called for the retaining of default factors typically used in the Budget method to avoid unrealistically high exposure estimates (Appendix C comment No 14, 15, 16). Specific factors used in the exposure assessment as proposed by EFSA should be derived in cooperation with enzyme manufacturers and the food industry (Appendix C comment No 17). Proposals received One stakeholder proposed using five factors according to the tier (see Appendix D): 1) enzyme use level (expressed as TOS) factor 2) processing factor 3) ratio raw material to final food factor 4) occurrence factor 5) brand loyalty factor Consideration of the comments received Proposal of more factors made by stakeholders showed the need for more detailed information than those provided in the dossiers. Such information concerns both the enzyme usage levels and the description of the intended conditions of use specified in the submitted dossiers. In the adopted Statement, the new methodology will translate the intended conditions of use into a list of food process-specific FoodEx categories, will also make use of technical factors in order to synchronise the enzyme usage levels and the consumption data to the same food levels (food as consumed, or food ingredient, or raw agriculture commodity). The implementation of technical conversion and processing factors is complex and will require stakeholder input. Consideration of these comments resulted in Sections 2.2.2, 2.2.3 and 2.2.4 in the adopted Statement (EFSA CEF Panel, 2016). 3.4. Margin of exposure Comments received A number of concerns have been expressed by the stakeholders regarding the use of 300 as a possible default value for the Margin of Exposure MoE (Annex C comments No 1, 2, 5, 7e and 9). They consider that this value may be unnecessarily high and in contrast to current practice in industry (use of 100) and EFSA Scientific Committee s suggestion for use of an uncertainty factor (UF) of 2 (further than the 100) to extrapolate from the effects of subchronic to chronic exposure. Proposals received The values of 100 and 200 are proposed as default values. Consideration of the comments received The MoE of 300 has been given as a first indication. However, each safety assessment is performed on a case-by-case basis requiring expert judgement of the entire toxicological dataset and information related to the intrinsic properties of specific food enzymes. Therefore, no generally acceptable threshold value can be established for MoE. www.efsa.europa.eu/publications 7 EFSA Supporting publication 2016:EN-1106

The calculated indicative value of 300 consists of different uncertainty factors (UFs) as described below. A factor of 10 has been considered to account for inter-species variation (EFSA Scientific Committee, 2012). A factor of 10 to account for human inter-individual variation (EFSA Scientific Committee, 2012). An additional factor of 3 for the extrapolation from short-term studies to chronic studies (EFSA Scientific Committee, 2012) and for further uncertainties such as those related to the limited statistical power of the testing procedure employed (EFSA CEF Panel, 2010). The use of these UFs is based on the following arguments: For the hazard identification and characterisation of food enzymes, a toxicological dataset consisting of at least two in vitro genotoxicity tests and a subchronic 90-day oral toxicity study is requested. However, it should be emphasised that, although the current Organization for Economic Co-operation and Development (OECD) guidance on repeated dose 90-day oral toxicity study in rodents (OECD 408, 1998) gives additional emphasis on neurological endpoints and provides an indication of immunological and reproductive effects, it is recognised that the potential effects observed may be predictive of some aspects but are not sufficient to cover all aspects of these toxicities. For some applications, additional uncertainties arise from the use of dated or testing protocols that miss important endpoints (e.g. the OECD 408 of 1981 that misses neurological, immunological and reproductive observations) or that deviate from the internationally accepted protocols (e.g. nonadequate dosing ranges). Based on all the above, the CEF Panel decided not to provide a single default threshold value for MoE but, instead, to perform the safety assessment case-by-case based on the entire toxicological database and the information related to the intrinsic properties of specific food enzymes. 4. Conclusions and Recommendations All comments received through the public consultation were taken into account by the CEF Panel to revise the draft Statement Exposure Assessment of Food Enzymes. In the adopted Statement, the CEF Panel recommended that exposure estimates to food enzymes should be based on actual food consumption data. The move to an actual-food-consumptiondata-based assessment methodology approach necessitates the implementation of technical factors. The CEF Panel also recommended collecting information and data through engagement with relevant stakeholders, ranging from universities and research institutes to applicants and food producers associations. The adopted Statement indicated that A publicly available process-based tool will be developed. It is likely to be based on summary statistics, similar to the Food Additive Intake Model (FAIM) template used for food additives. As each process will require specific information on several input parameters, input from industrial associations and/or applicants for more technical data and factors will be sought as appropriate. It is foreseen that the tool will be rolled out process-by-process over a period of time. During the development and validation of the tool, EFSA will use individual data reported in the Comprehensive Database to estimate dietary exposure of food enzymes for applications submitted within the legal deadline 9. By doing so, the CEF Panel endeavours to ensure the continuity of the risk assessment process. 9 OJ L 313, 12.11.2012, p. 9. Available online: http://eurlex.europa.eu/lexuriserv/lexuriserv.do?uri=oj:l:2012:313:0009:0010:en:pdf www.efsa.europa.eu/publications 8 EFSA Supporting publication 2016:EN-1106

References EFSA (European Food Safety Authority), 2011a. Overview of the procedures currently used at EFSA for the assessment of dietary exposure to different chemical substances. EFSA Journal 2011;9(12):2490. 33 pp. doi:10.2903/j.efsa.2011.2490 EFSA CEF Panel (EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids), 2010. Statement on the safety evaluation of smoke flavourings primary products: Interpretation of the Margin of Safety. EFSA Journal 2010;8(1): 1325. 7 pp. doi:10.2903/j.efsa.2009.1325 EFSA CEF Panel (EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids); Silano V, Bolognesi C, Castle L, Cravedi JP, Fowler P, Franz R, Grob K, Gürtler R, Husøy T, Kärenlampi S, Mennes W, Milana MR, Penninks A, Smith A, Tavares Poças MF, Tlustos C, Wölfle D, Zorn H, Zugravu CA, Arcella D, Liu Y, and Engel KH, 2016. Panel statement on the exposure assessment of food enzymes. EFSA Journal 2016;14(11):4581, 11 pp. doi:10.2903/j.efsa.2016.4581 EFSA Scientific Committee, 2012. Guidance on selected default values to be used by the EFSA Scientific Committee, Scientific Panels and Units in the absence of actual measured data. EFSA Journal 2012;10(3):2579. 32 pp. doi:10.2903/j.efsa.2012.2579 OECD (Organisation for Economic Co-operation and Development), 1998. Guideline for the Testing of Chemicals Test No. 408: Repeated Dose 90-day Oral Toxicity Study in Rodents. Available online: http://www.oecd-ilibrary.org/environment/test-no-408-repeated-dose-90-day-oral-toxicity-study-inrodents_9789264070707-en www.efsa.europa.eu/publications 9 EFSA Supporting publication 2016:EN-1106

Abbreviations CEF EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids FIP Food Ingredients and Packaging MoE margin of exposure OECD Organization for Economic Co-operation and Development UF uncertainty factor www.efsa.europa.eu/publications 10 EFSA Supporting publication 2016:EN-1106

Appendix A Instruction on how to submit a comment through the public consultation All stakeholders and interested parties are invited to submit written comments by 31/03/2016. Please use the electronic template provided (http://registerofquestions.efsa.europa.eu/roqfrontend/consultation/doc/61) to submit comments and refer to the line and page numbers. Kindly note that, after 2 hours of non-activity, your working session will expire and comments submitted after that time will not be recorded and transmitted. Therefore, if the page is left inactive for more than 2 hours, please re-open it from the link before restarting to comment. If you would like to submit additional data to support your comments or file, send an email to: [fip.publicconsult.61@efsa.europa.eu]. Please note that comments will not be considered if they: - are submitted after the closing date of the public consultation - are presented in any form other than what is provided for in the instructions and template - are not related to the contents of the document - contain complaints against institutions, personal accusations, irrelevant or offensive statements or material - are related to policy or risk management aspects, which is out of the scope of EFSA's activity. EFSA will assess all comments from interested parties which are submitted in line with the criteria above. The comments will be further considered by the relevant EFSA Panel and taken into consideration. All comments submitted will be published. Comments submitted by individuals in a personal capacity will be presented anonymously. Comments submitted formally on behalf of an organisation will appear with the name of the organisation. www.efsa.europa.eu/publications 11 EFSA Supporting publication 2016:EN-1106

Appendix B Organisations that submitted comments during the public consultation Contributing organisation Country Comment No in Appendix C EU national risk assessment body National Food Institute Technical University of Denmark DK 1 RIVM (Netherlands National Institute for Public Health and the Environment) Enzyme manufacturer association AMFEP (European Association of Manufacturers and Formulators of Enzyme Products) NL BE 2 3a, b, c, d JEA (Japan Enzyme Association) JP 4 Enzyme Technical Association (Trade Association in North, Central and South America) ABIAM (Brazilian Association of Additive Manufacturers) BR 6 Food industry association FoodDrink Europe BE 7a, b, c, d, e GMA (Grocery Manufacturers Association) US 8 Consulting company Intertek (Intertek Scientific and Regulatory Consultancy) GB 9 US 5 www.efsa.europa.eu/publications 12 EFSA Supporting publication 2016:EN-1106

Appendix C Comments received during the public consultation *O, overall feedback; T, approach and tiers; I, input parameters; M, margin of exposure. Underlined text indicates the area with respect to which a proposal was made by the stakeholder. No Area* Contributor Country Section Comments and proposals received 1 O, T, M National Food Institute, Technical University of Denmark DK General comment: We do acknowledge the efforts made by EFSA in order to refine the exposure estimates for food enzymes and find that the present scientific statement provides a good background for further discussions. 3. Assessment Denmark has had many years of evaluating enzyme preparations notified to the authorities before being taken into use. We have all the time used the Budget method as a model for screening potential intake to compare with the toxicological data. Experience has shown, that the method is easy to use and a reasonable conservative model. Except in a few cases, where the enzyme is foreseen to be used in a large varieties of foods, including staple foods, the basic assumption of the Budget method has been used (i.e. a factor 160 x ADI for solid foods and a factor of 40 x ADI for beverages have been applied). We therefore see no reason to use lower levels of the tiered system suggested. If a given enzyme preparation is only foreseen to be used in a small number of foods, the use of the Budget method could on the other hand be too restrictive, and in those cases the use of the EFSA Comprehensive Food Consumption Database is a useful tool to obtain a more precise estimate of the actual exposure. However, this is very much dependent on how the EFSA Comprehensive Food Consumption Database is used. Adding high exposure scenarios from a multiple number of food categories could give an unrealistic estimate. Despite this the Budget method has proven very useful to estimate the exposure in where a specific food enzyme is used in multiple food categories. The use of the tiered approach seems a bit superfluous, especially Tier 1. Why don t from the beginning decide on whether the EFSA Comprehensive Food Consumption Database can be used or whether the exposure should be estimated using the Budget method using the appropriate described standard factors. The decision on which method to use should depend on the number of food categories in which the food enzyme is intended to being used. The use of a default margin of exposure (MoE) of 300 is proposed. This includes a factor 100 of inter- and intra-species differences and a factor of 3 for the extrapolation from short-term studies to chronic studies. We would like to question whether a this factor of 3 is necessary for food enzymes. For food enzymes a predefined number of specific safety studies are required. This covers two in vitro studies and one 90-day study in rodents. This set of studies has been considered as sufficient to identify potential hazards arising from the intake of food enzymes. Applying a factor of 3 seems to make the risk assessment unnecessary conservative, also taking into account the already applied conservatism in using the Budget method for the exposure assessment. Considering also the facts that 1) enzymes are not typically added to the final food, 2) the enzyme itself is not typically active in the final food product and 3) many of the production organisms have a www.efsa.europa.eu/publications 13 EFSA Supporting publication 2016:EN-1106

*O, overall feedback; T, approach and tiers; I, input parameters; M, margin of exposure. Underlined text indicates the area with respect to which a proposal was made by the stakeholder. No Area* Contributor Country Section Comments and proposals received long history of safe use for enzyme production including numbers of 90 days studies from almost identical production conditions, the use of the default MOE of 300 seems in many cases not to be scientific grounded and therefore unnecessary. A chapter that could include this discussion would be highly appreciated. This should also include consideration how to deal with the situations where it can be documented that the active enzyme itself is responsible for an observed adverse effect in the animal test but the active enzyme is not exposed to the consumer. 2 O, T RIVM NL 3. Assessment The approach as proposed fits in the aim of EFSA to harmonise the exposure assessment procedures over the different panels as much as possible and to use the individual food consumption data available in the Comprehensive Database to refine assessments. At the moment, especially the ANS and CONTAM panel regularly use the individual food consumption data of the Comprehensive Database in their risk assessments of food additives and contaminants, respectively. With the use of individual food consumption data more refined exposure estimates can be obtained. This will minimize the application of unnecessary mitigation measures and the removal of compounds like additives from the European market that are not harmful in the amounts to which the European population is exposed via food. Also new applications of existing compounds, or introduction of new compounds, will be optimised by the use of more refined exposure assessment procedures. We support the proposed stepwise approach for use in the evaluation of food enzymes, which aims to refine the exposure assessment only when needed. We also recognise that various difficult issues still need to be addressed in practice when using this approach, mostly on a case by case basis, dependent on the data available. These issues include the used Margin of Exposure as cut-off point for refinement, and the specific conversion factors per food enzyme as needed in Tier 2B. 3a O, T, I, M Amfep BE Abstract General comment: Amfep is the European Association of the Manufacturers and Formulators of enzyme Products. Amfep is grateful for the opportunity to comment on EFSA s Draft statement on exposure assessment of food enzymes. The below Amfep input to EFSA s public consultation on its Draft Statement on Exposure Assessment of Food Enzymes has been compiled with the help and support of an independent scientific adviser. This independent scientific adviser provides scientific regulatory support on the application of dietary risk assessment techniques in Europe. A key activity is the provision of consumer exposure analyses www.efsa.europa.eu/publications 14 EFSA Supporting publication 2016:EN-1106

*O, overall feedback; T, approach and tiers; I, input parameters; M, margin of exposure. Underlined text indicates the area with respect to which a proposal was made by the stakeholder. No Area* Contributor Country Section Comments and proposals received and risk assessments for pesticide residues, food additives, nutrients, novel ingredients and other food and feed components using deterministic, distributional and probabilistic models. Consumer exposure to food enzymes has been assessed for decades with well-established methods, in several countries globally. Such methods are proportionate to the recognized very low level of safety concern related to the use of enzymes in food processing. One of the primary rationales for the establishment of a Food Enzyme Regulation (EC 1332/2008) by the European Parliament and the Council was the harmonization of rules across the internal market, and the free movement of safe and wholesome food (Recitals 1-4 of Regulation 1332/2008). It is also stated (Recital 13) that provision should be made to ensure that the switchover to a Community list of food enzymes takes place smoothly and does not disturb the existing food enzyme market. Therefore, and while Amfep acknowledges EFSA s desire of clarifying and refining the established methods, we strongly question the actual need and urgency of doing this. Over 300 food enzyme dossiers were submitted by the enzyme industry by the deadline of 11 March 2015, built in accordance with the EFSA guidelines on food enzymes (2009), as last updated in November 2014. The updated guidelines clearly describe the exposure assessment process as it has so far been conducted by enzyme manufacturers and reviewed by authorities globally. The corresponding food enzymes have for the most part been on the market (and often evaluated by other authorities in Europe or globally) for many years. We therefore face a situation where the whole industry has been working according to the existing EFSA guidelines (and to commonly accepted scientific practice globally), and now sees its dossiers and their conclusions questioned by a new approach that emerges more than a year after the submission deadline. Amfep is also very much concerned with the consequences of this new approach in terms of the resources spent by all parties which is in contrast with Recital 13 as cited before. Since all dossiers have been submitted with the existing exposure assessment methods, this means that EFSA and applicants will have to re-do this work according to the new method. All in all, Amfep calls for a thorough scientific dialogue between EFSA, the enzyme industry and the food industry, in order to ensure transparency as to how and when the new approach is implemented, by which data and assumptions it is supported, and how expert judgment will be applied by EFSA in its evaluations. 3b Amfep BE 1. Introduction General comment: Food enzymes are substances renowned for low safety concern. This is acknowledged by authorities www.efsa.europa.eu/publications 15 EFSA Supporting publication 2016:EN-1106

*O, overall feedback; T, approach and tiers; I, input parameters; M, margin of exposure. Underlined text indicates the area with respect to which a proposal was made by the stakeholder. No Area* Contributor Country Section Comments and proposals received globally and reflected in regulatory guidelines, that do not require extensive toxicological data nor refined exposure assessment methods except in very specific cases. Indeed, oral 90-day toxicological studies on food enzymes typically exhibit No Observed Adverse Effect levels (NOAELs) of several hundred to thousand mg per kg body weight and per day. This often corresponds to the maximal amount of food enzyme concentrate that can be ingested by test animals without severely unbalancing their diet, and create side effects without any relation to the nature of the test substance. Even so, many of these toxicological studies do not exhibit a NOAEL per se because the highest dose does not cause adverse effects. A NOAEL of 1000 mg TOS/kg bw/day is equivalent to an ingestion of 60 g TOS per 60 kg person per day. Many food ingredients cannot be ingested to this level without severe health effects. The above explains why Amfep is concerned that many resources are currently being spent by EFSA and the enzyme industry, on addressing a safety concern that does not seem to be significant. 3c Amfep BE 2. Data and Methodologies General comment: Overall, the enzyme industry has submitted data and used methodologies according to globally recognized approaches which are also recommended by the CEF panel in their technical reports (including the Budget method and its standard assumptions and factors). It is not clear why these methods and data would suddenly no longer be sufficient to assess the safety in use of food enzymes while they have been validated by the European Commission and EFSA as late as November 2014 after discussion with industry. 3d Amfep BE 3. Assessment General comment: Although we tend to disagree with the perceived need to establish a new assessment method, Amfep finds that the tiered approach proposed in the draft guidance could be acceptable in its principles providing it is made predictable and transparent. It however seems in its present form more adapted to food additives (which are added to final foods) rather than to food enzymes (which are used during food processing). Since enzymes are used as processing aids in the production of food and food ingredients, residues might end up at low concentrations in a large variety of food products. Additional factors can affect the presence of residues in finished foods. These factors have a considerable effect on the variability of amounts of Total Organic Solids (TOS) present in foods as eaten, so that actual concentrations of TOS in foods can vary by orders of magnitude from the maximum added amounts as specified in dossiers. This means that for the majority of consumers, for the majority of the time, they will be exposed to a very wide range of possible TOS concentrations. For chronic consumer exposure assessments it is necessary to incorporate these additional factors into the exposure algorithms in order to generate realistic estimates of true longterm exposures, in contrast to acute exposures where it would be more appropriate to consider maximum amounts. www.efsa.europa.eu/publications 16 EFSA Supporting publication 2016:EN-1106

*O, overall feedback; T, approach and tiers; I, input parameters; M, margin of exposure. Underlined text indicates the area with respect to which a proposal was made by the stakeholder. No Area* Contributor Country Section Comments and proposals received This means that the presented method tends to greatly overestimate food intake when used for enzymes. It also means that a number of uncertainties remain, which may prove of crucial importance when the proposed method is applied to real cases in food enzyme dossiers. Amfep therefore respectfully re-iterates its request from the 03 February stakeholders meeting, that EFSA, the enzyme industry and the food industry establish a scientific cooperation to clarify and resolve the following issues, before the method is put to actual use in dossier evaluation: - How can this evaluation process be made transparent, reasonable and predictable? - How can applicants get access to the data used by EFSA to assess exposure? - Is it realistic to assume that the whole daily food intake for a given consumer is made of processed foods and processed drinks as prescribed in Tier 1? - Re-introduce the Budget method standard factor daily processed food intake (as this is applicable to food enzymes being used only during processing of food) in Tier 2, thereby ensuring that resources are focused on a limited number of dossiers. - When should Tier 2a be used, rather than Tier 2b? - What are reasonable assumptions on diet balance (when assessing the intake of high consumers )? - Since the proposed method is prone to large overestimation of food intake (calculations made by industry on real dossier cases), how to use the EFSA daily energy requirements as a first sanity check of the exposure assessment? - Since the proposed method is prone to large overestimation of food intake when used for enzymes as processing aid (calculations made by industry on real dossier cases), additional factors should be considered for a sanity check of the exposure assessment. The calculated food enzyme intake should not be higher than what is needed to process the annual raw material consumption in the EU. - Which factors can be used to calculate and refine the level of carry-over of Total Organic Solids (TOS) from the food enzyme into final foods? Will EFSA accept that certain food processes eliminate a significant part of the TOS? - How can it be assured in the decision tree that there remains room for expert judgment and refinement factors (lines 157-159)? Amfep s views and suggestions, incl. possible refinement factors are further detailed in a document that is provided to EFSA simultaneously to the present input. 4 O, T Japan Enzyme Association (JEA) JP General comment: JEA, Japan Enzyme Association, is the association which is comprised of enzyme manufacturers and distributors in Japan. JEA is grateful for the opportunity to comment on EFSA s Draft statement on exposure assessment of food enzymes. www.efsa.europa.eu/publications 17 EFSA Supporting publication 2016:EN-1106

*O, overall feedback; T, approach and tiers; I, input parameters; M, margin of exposure. Underlined text indicates the area with respect to which a proposal was made by the stakeholder. No Area* Contributor Country Section Comments and proposals received 1. Introduction We understand that one of the primary rationales for the establishment of a Food Enzyme Regulation (EC 1332/2008) by the European Parliament and the Council was the harmonization of rules across the internal market, and the free movement of safe and wholesome food (Recitals 1-4 of Regulation 1332/2008). It is also stated (Recital 13) that provision should be made to ensure that the switchover to a Community list of food enzymes takes place smoothly and does not disturb the existing food enzyme market. The enzyme industry in Japan also submitted data and used methodologies according to globally recognized approaches which are also recommended by the CEF panel in their technical reports (including the Budget method and its standard assumptions and factors). It is not clear why these methods and data would suddenly no longer be sufficient to assess the safety in use of food enzymes while they were validated by the European Commission and EFSA as late as November 2014 after the discussion with the industry. JEA and the Japanese food industry who exports processed foods to Europe are therefore very much concerned that the new approach, that is the calculation method using the database which is to be applied to the safety assessment, may cause confusion. It is also hard to understand the details due to not being well-explained even after the stakeholders meeting on 3rd February. JEA, therefore, respectfully requests EFSA to give us clear explanation of its necessity and further instruction in order to apply the method. Overall, since JEA works closely with other enzyme associations such as Amfep, JEA fully supports their position and their inputs with regards to this matter. 5 O, T, I, M Enzyme Technical Association US 3. Assessment General comment: The Enzyme Technical Association ( ETA ) is a trade association that represents manufacturers and marketers of enzyme products in North, Central, and South America. It has been in existence since 1970 and maintains an active role in assisting in the development of regulations and policies that affect the enzyme industry. Its membership represents the majority of the enzyme product industry in the Americas. ETA appreciates the opportunity to submit comments to the European Food Safety Authority ( EFSA or Agency ) concerning the Agency s Draft Statement on Exposure Assessment of Food Enzymes ( Draft Statement ). In short, ETA supports the position of the Association of Manufacturers and Formulators of Enzyme Products ( AMFEP ) and shares its concern as it relates to the need and urgency of modifying the proposed consumer exposure methods. In addition to incorporating the full comments of AMFEP, ETA provides additional supportive evidence that it hopes will further encourage EFSA to reevaluate its exposure assessment approach. Lines 157-163 and 191: I. Margin of Exposure The Draft Statement recommends a margin of exposure ( MoE ) of 300 as sufficient provided that data are complete and the quality of the data is acceptable. However, a MoE of 300 runs counter to what has been customarily used by the industry, and except in limited circumstances, is unlikely to www.efsa.europa.eu/publications 18 EFSA Supporting publication 2016:EN-1106

*O, overall feedback; T, approach and tiers; I, input parameters; M, margin of exposure. Underlined text indicates the area with respect to which a proposal was made by the stakeholder. No Area* Contributor Country Section Comments and proposals received provide additional safety benefit. The US, as well as other international regulatory bodies, have always used a MoE of 100 unless evidence is submitted which justifies a different MoE. If implemented, ETA believes that a MoE of 300 will have a negative impact on manufacturers given its deviation from other regulatory bodies and be inconsistent with recognized standards established to assure safe exposure levels. 6 O, T, I, M Brazilian Association of Additive Manufacturers (ABIAM) Lines 133-134: II. Exposure Assessments The Draft Statement indicates that it will not use the standard factors normally applied in the assessment of additives when using the Budget method for enzymes. ETA is concerned that this will result in an extremely conservative and unrealistic assumption: that all food and beverages consumed contain the same enzyme at the maximum theoretical concentration. Further, this proposed method does not take into account the loss of the enzyme during the production process. Food processing enzymes are generally consumed during processing and then inactivated and removed at the end of the production process. Thus, ETA hopes that EFSA will reconsider its approach as it relates to exposure assessments. In closing, ETA believes it is important that regulations applying to enzymes do not create unnecessary regulatory barriers for the use of enzymes in food production. The use of enzymes is ubiquitous and the safety concern of these processing aids has been recognized by many other regulatory bodies as low. We thank you for your time and consideration. Please do not hesitate to contact us if you have any questions. BR 1. Introduction General comment: ABIAM has discussed the draft EFSA guidance document with Amfep and fully shares Amfep s concerns and proposals. 7a O, T, M FoodDrinkEurope BE Abstract Lines 5-15: The systematic and harmonised approach for the safety evaluation of food enzymes in Europe by EFSA is new territory for all stakeholders involved. The use of enzymes is important for the food industry to deliver standardised high quality foods to consumers and allow access to a diversity of foods. Furthermore the use of food enzymes is also fundamental for innovation in the food industry. Hence a smooth safety evaluation is very important. 7b FoodDrinkEurope BE 1. Introduction Lines: 58-62: Tiered refined approaches that intend to help to come to more realistic exposure scenarios are welcome. Lines: 67-71: Questions and concerns raised by stakeholders during the Info Session organised by EFSA on 3 February and during the consultation should be analysed by EFSA prior to the finalisation of the process in order to ensure a smooth evaluation of the enzymes. FoodDrinkEurope is of the opinion that the concerns expressed by Stakeholders are substantiated and require due consideration by EFSA. www.efsa.europa.eu/publications 19 EFSA Supporting publication 2016:EN-1106

*O, overall feedback; T, approach and tiers; I, input parameters; M, margin of exposure. Underlined text indicates the area with respect to which a proposal was made by the stakeholder. No Area* Contributor Country Section Comments and proposals received 7c FoodDrinkEurope BE 2. Data and Methodologies Lines: 75-82: More than 300 food enzyme dossiers were submitted by the enzyme industry by the deadline of 11 March 2015. These dossiers were built in accordance with the EFSA guidelines on food enzymes (2009), as last updated in November 2014, after discussions involving industry and EFSA. The guidelines clearly describe the exposure assessment process as it has so far been conducted by enzyme manufacturers and reviewed by authorities globally. The corresponding food enzymes have for the most part been on the market (and often evaluated by other authorities in Europe or globally) for many years. We therefore face a situation where the whole industry has been working according to the existing EFSA guidelines (and to commonly accepted scientific practice globally), and now sees its dossiers and their conclusions questioned by a new approach that emerges more than a year after the submission deadline. Therefore we are concerned that the new proposed exposure assessment method may disrupt the ongoing evaluation process and threaten the availability of food enzymes to the food industry. Moreover, FoodDrinkEurope is concerned by the challenges raised by EFSA experts during the Info Session on 3 February (http://www.efsa.europa.eu/sites/default/files/160203-p6.pdf). It remains unclear how the new approach will work out in reality. FoodDrinkEurope is in particular concerned about the nonpredictability of the described evaluation process, access to data used by EFSA to assess exposure is important. 7d FoodDrinkEurope BE 3. Assessment Line 157: Whilst the use of a factor of 3 to extrapolate from short term studies to chronic chronic may be appropriate depending on the nature of the studies, this is not mentioned in the referenced EFSA 2012 document which specifically states that extrapolation from a 90 days tox study to chronic exposure requires a factor of 2. pg 21 The EFSA Scientific Committee concludes that the extrapolation from subchronic to chronic study duration can be performed as proposed by ECHA (UF of 2) and supported by Zarn et al. (2010, 2011), provided the 90-day study used to extrapolate is of adequate quality (e.g. similar parameters investigated as usually done in chronic studies). EFSA guidance (2012) : Guidance on selected default values to be used by the EFSA Scientific Committee, Scientific Panels and Units in the absence of actual measured data : http://www.efsa.europa.eu/en/efsajournal/pub/2579 7e FoodDrinkEurope BE Appendix A - Flowchart Line 189: We fear that the majority of the enzyme dossiers will not be approved after assessment in Tier 1 and that the overestimation resulting from the other tiers will lead to inconclusive or negative opinions of EFSA with the consequence of unavailability of enzymes on the market in future. The possible negative opinions will not only be the result of an increased estimated exposure level, but might also result from an increased scrutiny of the results of the toxicity studies as well as from an increase of the Margin of Exposure from the typical value of 100 to 300. All three aspects form a threat to the availability of food enzymes for future use in food processing in Europe. www.efsa.europa.eu/publications 20 EFSA Supporting publication 2016:EN-1106