TECHNICAL REPORT. European Food Safety Authority 2,3. European Food Safety Authority (EFSA), Parma, Italy

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1 EFSA supporting publication 2014:EN-633 TECHNICAL REPORT Outcome of a public consultation on the draft Scientific Opinion of the EFSA Panel on Dietetic Products, and Allergies (NDA) on the essential composition of infant and follow-on formulae 1 ABSTRACT European Food Safety Authority 2,3 European Food Safety Authority (EFSA), Parma, Italy 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 scientific opinion on the essential composition of infant and follow-on formulae, prepared by the EFSA Panel on Dietetic Products, and Allergies (NDA Panel) and endorsed by the Panel for public consultation at its Plenary meeting on 11 April The written public consultation for this document was open from 24 April 2014 to 29 May EFSA received comments from 31 interested parties. EFSA and its NDA Panel wish to thank all stakeholders for their contributions. The current report summarises the outcome of the public consultation, and includes a brief summary of the comments received and how the comments were addressed. The NDA Panel prepared an updated version of the scientific opinion on essential composition of infant and follow-on formulae taking into account the questions/comments received. The opinion was discussed and adopted at the NDA Plenary meeting on 26 June 2014, and is published in the EFSA Journal. European Food Safety Authority, 2014 KEY WORDS infant formula, follow-on formula, composition, public consultation, outcome 1 On request from EFSA, Question No EFSA-Q , approved on 17 July Correspondence: nda@efsa.europa.eu 3 Acknowledgement: EFSA wishes to thank the members of the Working Group on Dietetic Products: Carlo Agostoni, Roberto Berni Canani, Tamás Decsi, Mary Fewtrell, Lotte Lauritzen, Hildegard Przyrembel, Yolanda Sanz, Inga Thorsdottir, Daniel Tomé and Dominique Turck and the members of the Panel on Dietetic Products, and Allergies (NDA) for their contribution to this output. Suggested citation: European Food Safety Authority, 2014; Outcome of a public consultation on the draft Scientific Opinion of the EFSA Panel on Dietetic Products, and Allergies (NDA) on the essential composition of infant and follow-on formulae. EFSA supporting publication 2014:EN pp. Available online: European Food Safety Authority, 2014

2 TABLE OF CONTENTS Abstract... 1 Table of contents... 2 Background... 3 Terms of reference... 3 Consideration Introduction Screening and evaluation of comments received Comments received Nature of specific comments General comments Summary Introduction Methodological considerations Protein Formulae containing protein hydrolysates Formulae containing isolated soy protein (ISP) Fat Arachidonic acid (ARA) Linoleic acid (LA) and alpha-linolenic acid (ALA) Docosahexaenoic acid (DHA) Triacylglycerol (TAG) with palmitic acid predominantly in the sn-2 position Digestible (glycaemic) carbohydrates Non-digestible (non-glycaemic) carbohydrates Fluoride Iodine Molybdenum Manganese Copper Vitamin D Vitamin E Vitamin K Vitamin C Choline Maximum content of micronutrients Nucleotides Probiotics and synbiotics Use of formulae by young children Conclusions Comments related to risk management References Appendices Appendix A. Explanatory text published in relation to the public consultation on the draft scientific opinion on the essential composition of infant and follow-on formulae Appendix B. Comments received Abbreviations EFSA supporting publication 2014:EN-633 2

3 BACKGROUND Regulation (EU) No 609/2013 of the European Parliament and the Council on food intended for infants and young children, food for special medical purposes, and total diet replacement for weight control ( Food for Specific Groups ) was adopted on 12 June 2013 and will apply from 20 July The Regulation requires the Commission to adopt through delegated acts specific compositional rules for infant and follow-on formulae. In the light of this, the European Commission has asked the European Food Safety Authority (EFSA) to provide advice on the essential composition requirements of infant formulae and follow-on formulae by updating the relevant opinions of the Scientific Committee on food (SCF) on the matter. TERMS OF REFERENCE In line with EFSA s policy on openness and transparency, and in order for EFSA to receive comments from the scientific community and stakeholders, EFSA shall release the draft Scientific Opinion on the essential composition of infant and follow-on formulae for public consultation. The comments resulting from the public consultation shall be published in a technical report. Before its adoption by the EFSA Panel on Dietetic Products, and Allergies (NDA Panel), the draft Scientific Opinion on the essential composition of infant and follow-on formulae may need to be revised, taking into account the comments received during the public consultation. EFSA supporting publication 2014:EN-633 3

4 CONSIDERATION 1. Introduction Following a request from the European Commission, the EFSA Panel on Dietetic Products, and Allergies (NDA) drafted a scientific opinion on the essential composition of infant and follow-on formulae. In line with EFSA s policy on openness and transparency, and in order for EFSA to receive comments on its work from the scientific community and stakeholders, EFSA engages in public consultations on key issues. Accordingly, the draft scientific opinion was published on EFSA s website for comments (24 April 2014 to 29 May 2014) (see Appendix A). The NDA Panel prepared an updated version of the scientific opinion, taking into account the comments received. The updated scientific opinion was discussed and adopted at the NDA Plenary meeting on 26 June 2014, and is published in the EFSA Journal (EFSA NDA Panel, 2014a). EFSA is committed to publishing the comments received during the public consultation, as well as a short report on the outcome of the consultation. 2. Screening and evaluation of comments received 2.1. Comments received EFSA received 377 comments from 31 interested parties: two universities, five governmental organisations, eight non-governmental organisations, one medical society and 15 food industry, food industry associations or organisations representing the food industry. Table 1: List of organisations submitting comments Organisation Abbott (Asociación Nacional de Fabricantes de Productos Dietetica Infantil) Balchem Corporation Comité Société Française de Pédiatrie Croatian Food Agency Danone Nutricia Early Life DSM al Products Early Academy ELC (Federation of European Specialty Food Ingredients Industries) ENSA (European Natural Soy and Plant Based Manufacturers Organisation) First Steps Trust Food Safety Authority of Ireland Belgian FPS (Federal Public Service) Public Health, Food Safety and Environment GOED (Global Organization for EPA and DHA Omega-3s) Healthy eating from the start! IBFAN Baby Feeding Law Group Initiativ Liewensufank Intertek Scientific & Regulatory Consultancy Lactalis LIFIB (The Lancashire Infant Feeding Information Board) Mead Johnson New Zealand Ministry for Primary Industries Country US ES US FR HR NL US DE BE BE UK IE BE US AT UK LU UK FR + ES UK NL NZ EFSA supporting publication 2014:EN-633 4

5 Organisation Swedish National Food Agency NCT (National Childbirth Trust) Nestlé SA NutriKids Sedan SFAE (Syndicat Français des Aliments de l Enfance) SNE (Specialised Europe) Université Paris Sud University of Illinois Country SE UK CH IE DK FR BE FR US AT, Austria; BE, Belgium; CH, Switzerland; DE, Germany; DK, Denmark; ES, Spain; FR, France; HR, Croatia; IE, Ireland; LU, Luxembourg; NL, the Netherlands; NZ, New Zealand; SE, Sweden; US, the United States of America; UK, the United Kingdom. A summary of the comments is given below, and all written comments received are listed in Appendix B. Several parties submitted identical comments. The comments related to policy or risk management aspects are briefly summarised in section As policy or risk management aspects (i.e. which are under the responsibility of the European Commission and Member States) are outside the remit of EFSA and thus outside the scope of the consultation, they are not addressed in this report. Also, comments related to the Panel s previous opinion on dietary requirements and nutrient intakes of infants and young children (EFSA NDA Panel, 2013a) are outside the scope of the present consultation and are therefore not covered in this report Nature of specific comments The main issues raised in the comments received are summarised below, together with the way in which the Panel addressed the comments. The NDA Panel has reviewed all comments carefully and has updated the scientific opinion on the essential composition of infant and follow-on formulae accordingly. The updated scientific opinion is published in the EFSA Journal (EFSA NDA Panel, 2014a) General comments Comments received 1. It was suggested to include a chapter on aluminium in the opinion as it was indicated that some formulae are high in aluminium. 2. Comments were made that the recommendations of the Panel for a number of micronutrients are not in line with recommendations of other scientific bodies, especially considering that data available for deriving dietary requirements for infants are weak. 3. Several comments were received for minor amendments to the text in various sections of the opinion. 4. There was a request to add information on opinions of the Panel related to the evaluation of health claims relevant to infants and young children. 5. A request was made to maintain the general principles set out in the opinion of the SCF (2003) with respect to the modification of the composition of formulae beyond established standards (i.e. guidance on the presentation of dossiers for authorisations to modify formulae beyond established standards). EFSA supporting publication 2014:EN-633 5

6 6. It was questioned why Tolerable Upper Intake Levels (ULs) were not clearly mentioned in the opinion. Panel consideration of comments received Ad 1. Aluminium is not considered a nutrient and is therefore outside the scope of the opinion. The safety of aluminium from dietary intake was assessed by the EFSA Panel on Food Additives, Flavourings, Processing Aids and Food Contact Materials (AFC) (EFSA, 2008) and risk management measures exist to reduce the exposure to aluminium. In addition, European Union legislation on contaminants 4 foresees that food containing a contaminant in an amount which is unacceptable from the public health viewpoint and, in particular, at a toxicological level shall not be placed on the market. It also requires that contaminant levels shall be kept as low as can reasonably be achieved by following good practice. No changes to the opinion were considered necessary. Ad 2. Ad 3. Ad 4. Ad 5. Ad 6. For the majority of nutrients, the proposed minimum content in infant formula (IF) and follow-on formula (FOF) was derived based on nutrient intakes the Panel had considered adequate for the majority of infants in its previous opinion (EFSA NDA Panel, 2013a), in which also the methodology used is outlined. Dietary Reference Values (DRVs), upon which the conclusions of the Panel in its previous opinion were based, evolve with new evidence becoming available and/or with differing appreciation of existing data. No changes to the opinion were considered necessary. The comments relating to minor amendments of the text have been taken into account when they were deemed to increase clarity of the text. These comments are not listed separately in the following sections of this report. Health claims for IF and FOF are outside the scope of the opinion. A general description of the role of each nutrient in human physiology is included in the opinion. References to previous assessments made by the Panel related to health claims referring to children s health and development are therefore not considered to add additional information to the opinion. No changes to the opinion were considered necessary. The opinion of the SCF (2003) is not retracted by the opinion of the Panel and the general principles laid down therein with respect to the modification of formulae beyond established standards are still applicable. No changes to the opinion were considered necessary. Information on the UL was consistently available in the draft opinion for each micronutrient and, therefore, no changes to the opinion were considered necessary Summary Comments received 7. It was suggested that a statement be included in the summary that IF cannot imitate breast milk with respect to its composition, in line with the main text of the opinion. Panel consideration of comments received Ad 7. A sentence in line with the comment received has been added to the summary of the opinion. 4 Council Regulation (EEC) No 315/93 of 8 February 1993 laying down Community procedures for contaminants in food. OJ L 37, , p EFSA supporting publication 2014:EN-633 6

7 Introduction Comments received Outcome of a public consultation essential composition of infant and follow-on formulae 8. It was noted that the original Terms of Reference had been slightly reformulated with respect to the advice to be provided in relation to the essential composition of IF and FOF, by stating that the Panel will advise on whether it is considered necessary to revise the essential composition of IF and FOF as laid down by Directive 2006/141/EC. 5 It was also noted that this revised version of the Terms of Reference has not been answered in the opinion and it was asked whether the Panel considered that there would be a need to amend Directive 2006/141/EC in the event that the changes proposed by the Panel are minimal. 9. It was suggested that the following statement be modified: The general considerations and the specifications with respect to nutrients or other ingredients proposed in the Opinion may serve as a basis for defining compositional requirements for foods for special medical purposes for infants, unless the disease conditions for which such foods are to be used necessitate other compositional aspects. In this respect, it was requested that the statement reflect the fact that other considerations, such as the diverse nature of the product category, may also need to be taken into account when defining compositional requirements for foods for special medical purposes for infants. Panel consideration of comments received Ad 8. It is acknowledged that the rewording of the sentence of the original Terms of Reference resulted in a different meaning; however, this was not the intention of the Panel and the sentence has been amended to reflect the original Terms of Reference. Providing recommendations with respect to the need for a revision of Directive 2006/141/EC would be outside the remit of the Panel. Ad 9. It is believed that the statement related to the applicability of the opinion to foods for special medical purposes for infants as included in the opinion already accounts for the fact that the composition of foods for special medical purposes for infants may necessitate a different composition if the disease condition so requires. No changes to the opinion were considered necessary Methodological considerations Comments received 10. A question on whether the variable sodium and bicarbonate content of certain local water supplies and bottled water was considered by the Panel when proposing specifications for nutrients in IF and FOF was received. 11. A suggestion was made to clarify on which level of evidence recommendations were made. 12. Comments were made that certain substances are added to formulae for technological reasons (e.g. as antioxidant) or in order to guarantee that the minimum content as declared in the labelling is still present in the product at the end of shelf life (i.e. stability) and that the statement by the Panel that nutrients and substances should be added to formulae for infants only in amounts that serve a nutritional or other health benefit did not reflect this technological need. 13. It was also asked how differences in absorption efficiency had been taken into account when proposing minimum contents of micronutrients in IF and FOF. 5 Commission Directive 2006/141/EC of 22 December 2006 on infant formulae and follow-on formulae and amending Directive 1999/21/EC, OJ L 401, , p EFSA supporting publication 2014:EN-633 7

8 14. Clarification of how to measure that a substance or amounts of nutrients may put a burden on the infant s metabolism or on other physiological functions was requested and EFSA was asked to provide scientific evidence for this. 15. A general comment was made that the Panel had not considered the totality of the evidence as it had not considered dossiers that had been submitted to the Member States for evaluation. 16. Use of the term adequate content instead of minimum content of nutrients in IF and FOF is proposed as this would better reflect the considerations of the Panel. 17. It was questioned why there was a need to demonstrate that a substance should be used in IF or FOF rather than to demonstrate that is should not be used because of safety concerns. 18. A comment was made that for some micronutrients, such as folate, minimum contents of that nutrient have been derived based on a very limited number of studies and that that these studies may not be representative of the European population. 19. It was questioned how the minimum content of micronutrients in formulae proposed by the Panel based on an average energy requirement of 500 kcal during the first six months of life can be reconciled with the manufacturer s instruction to consume 700 kcal of formula during the last two months of this period. 20. It was suggested that the lack of systematic reporting mechanisms for any short- or longterm health consequences of consumption of formulae with certain ingredients be stressed. 21. The Panel was asked to define what it meant by saying that there is no necessity to add certain substances to formulae and why it did not choose to say that these substances were optional ingredients in formulae. 22. Definitions of the terms suitability and health benefit were requested. 23. It was contested that complementary foods would compensate for the higher requirements of infants and for the potentially lower feeding volume of formulae in infants receiving complementary foods, as was indicated by the Panel. 24. The Panel was requested to consider not only a benefit of a substance as an appropriate determinant for the composition of formulae but also the similarity to human milk, as it was assumed that formulae which are compositionally dissimilar to human milk could have some potential detrimental effects. 25. The approach taken by the Panel to derive minimum contents of nutrients in IF and FOF based on dietary requirements, which were derived from average contents of nutrients in breast milk, was questioned. It was considered that the breast milk content of nutrients may not reflect optimal levels owing to insufficient nutrient intakes by the mother and that nutrients consumed in amounts higher than requirements may potentially serve a special benefit. Panel consideration of comments received Ad 10. The Panel recognises the importance of the quality of water used to reconstitute powdered formulae. Water can be the source of several nutrients that should be taken into account to ensure that the final content of nutrients in the reconstituted formula will not exceed the maximum content as laid down in current or any potential future legislation. As no maximum content of nutrients has been proposed by the Panel (which may be proposed in any future legislation), no changes to the opinion were considered necessary. EFSA supporting publication 2014:EN-633 8

9 Ad 11. Ad 12. Ad 13. Ad 14. Ad 15. Ad 16. Ad 17. Ad 18. Ad 19. Ad 20. An explanatory paragraph was added in section 4 on methodological considerations with respect to the strengths of the estimates used as a basis to define the minimum content of nutrients and other substances in IF and FOF. It is recognised that the addition of nutrients or other substances for technological reasons may have an impact on the final content of these nutrients in IF and FOF and this has to be considered by operators to ensure that the nutrient content will not exceed the maximum content or not be below the minimum content that may be set in future legislation by risk managers, if deemed appropriate. The sentence has been amended and refers now to other benefits and not only to health benefits in the strict sense. For most micronutrients, the minimum content in IF and FOF was based on the average content in breast milk. Whenever there was indication that the absorption efficiency from formula was different from breast milk, this has been described in the appropriate section and considered when setting minimum contents of these nutrients. No changes to the opinion were considered necessary. All substances which are ingested and absorbed but are not necessary have to be metabolised and/or excreted. However, infants in the first months of life have limited metabolic capacities, particularly in the kidneys, the liver and the gastro-intestinal tract (WHO, 2005; EFSA NDA Panel, 2010a). Therefore, as stated in the opinion, providing substances or amounts of nutrients which are not needed by the developing infant should be avoided. No changes to the opinion were considered necessary. The Panel had considered all published (and in a few cases, where available, also unpublished) data which had become available after the opinion of the SCF (2003). A reevaluation of dossiers submitted so far to Member States for evaluation was not part of the Terms of Reference. The term minimum content, as used in the opinion, can indeed be considered in the sense of being an adequate content. The Panel, however, decided not to change the terminology owing to the potential to confuse the meaning with the meaning of an Adequate Intake (AI). As outlined in the opinion and explained above, unnecessary substances in formulae may put a burden on the infant s metabolism or on other physiological functions, as substances which are not used or stored have to be excreted. Therefore, safety considerations in the toxicological sense alone are not an appropriate basis to determine the suitability of a formula. No changes to the opinion were considered necessary. The proposed minimum contents of nutrients were based on the intakes the Panel had considered adequate for the majority of infants in its previous opinion (EFSA NDA Panel, 2013a), mainly based on average intakes from breast milk. Generally, the Panel had endeavoured to use reliable European data on the average content of nutrients in breast milk. If these were not available, it relied on adequate data from other regions, preferentially those comparable to European populations. No changes to the opinion were considered necessary. The reasons why an average formula consumption of 500 kcal per day has been assumed by the Panel are outlined in the opinion. A discussion on the conditions of use of formulae currently available in the European market is outside the remit of this opinion. No changes to the opinion were considered necessary. Existing guidelines (Aggett et al., 2001) for studies on the nutritional and safety assessments of breast milk substitutes recommend long-term follow-up. This also entails that potential adverse effects are reported. Therefore, a broad statement on the general lack of reporting EFSA supporting publication 2014:EN-633 9

10 mechanisms does not seem appropriate to the Panel. No changes to the opinion were considered necessary. Ad 21. Ad 22. Ad 23. Ad 24. Ad 25. The Panel meant by no necessity for the addition of a substance that the absence of the substance in IF or FOF will not put the infant at risk of inadequate growth or development. Whether these substances should be considered to be optional ingredients is a risk management decision (i.e. a decision which has to be taken by the European Commission and Member States) and outside the remit of the Panel. With respect to the meaning of suitability the Panel would like to refer the requestor to Articles 5 and 6 of Directive 2006/141/EC, in which it is laid down that suitability refers to the expected benefits (in relation to growth and development) and to safety. The Panel did not consider it necessary to redefine this term in the opinion. With respect to the use of the term health benefit, the reader is referred to the answer to comment 12 (above). That complementary foods compensate for the higher requirements of infants and for the potentially lower feeding volume of formulae in infants receiving complementary foods was an assumption made by the Panel. This is in line with using the breast-fed infant as a model. There is no evidence that breast milk (and hence also formula with a similar average nutrient composition) would not be adequate to fulfil the dietary requirements of infants receiving complementary foods. No changes to the opinion were considered necessary. Compositional similarity to human milk is not the only appropriate determinant or indicator of safety and nutritional suitability of formulae. Human milk changes from one feed to the next, from the beginning to the end of a feed, over lactation and also with the diet of the mother and the gestational age of the breast-fed infant. The presence of a substance in human milk does not necessarily reflect a requirement for that substance. This is already outlined in the opinion. No changes to the opinion were considered necessary. The Panel acknowledges that the diet of the mother will influence the content of some nutrients in breast milk (e.g. water-soluble vitamins, vitamin A, iodine, long-chain polyunsaturated fatty acids (LCPUFAs)). Whenever the average content of a nutrient in breast milk has been used to propose a minimum content of that nutrient in IF and FOF, data from healthy, well-nourished mothers (i.e. mothers without apparent underlying deficiencies) formed the basis. Even if extreme values had occurred in the underlying cohort(s), these would have been compensated for by using the average and not the extremes of the range. However, for some nutrients the content in breast milk does not reflect the infant s requirement. In those cases, other data were used to estimate requirements and to propose minimum contents in IF and FOF. The Panel is not aware of any data that would establish that nutrient intakes above requirements would convey any additional benefit to the infant. No changes to the opinion were considered necessary Protein Comments received 26. A comment was received that a protein content of FOF could be proposed which is lower than the one proposed for IF, as this would be more in line with the lower protein requirements from six months of age onwards. 27. In relation to section on the calculation of protein content, a question was received on whether the ratio of protein energy to total energy is a contributing factor and why this has not been considered important. EFSA supporting publication 2014:EN

11 Panel consideration of comments received Ad 26. It is assumed that the comment relates to the recommendations for the composition of FOF made by the Early Academy (Koletzko et al., 2013). In these recommendations, a protein content of FOF of g/100 kcal is proposed. While the proposed maximum content is in line with the recommendations made by the Panel, the minimum content is slightly lower (1.7 vs. 1.8 g/100 kcal). This lower protein content proposed by the Early Academy has been derived from DRVs for protein of 6- to 12 month-old infants. However, there are no randomised control trials (RCTs) which have studied the safety and suitability of a formula with a protein content of 1.7 g/100 kcal. The Panel, therefore, considered that the available evidence was insufficient to change the conclusions of the Panel. No changes to the opinion were considered necessary. Ad 27. The Panel has proposed ranges of protein content and energy content in the opinion which yield a protein energy ratio between 10 and 17 E %, and is higher than that of human milk (5-10 E %). However, this higher ratio was considered to be justified by the assumed lower nutritional quality of the protein sources compared with human milk protein. The purpose of section on the calculation of protein content was to propose a conversion factor to calculate the protein content from the total nitrogen content of a sample and not as a measure of dietary quality, for which the amino acid score could be used Formulae containing protein hydrolysates Comments received 28. It was asked why formulae containing hydrolysed protein are included in the opinion if the purpose of the opinion is not to address infants with particular nutritional requirements. 29. It was questioned why the Panel considered the need for clinical studies to prove the safety and suitability of formulae containing protein hydrolysates with a minimum protein content of 2.25 g/100 kcal, given the history of safe use of such formulae. 30. It was also stated that the amino acid contribution of the hydrolysed protein would be identical to that of the unhydrolysed protein, and that hydrolysing the protein would enhance the delivery of amino acids to the infant. 31. The need for an appropriate characterisation of formulae containing hydrolysed protein when evaluating their safety and potential effects on the reduction of the risk of developing allergy (to milk protein) was emphasised. It was also indicated that a characterisation by the product name alone would not be sufficient as products changed composition over time. 32. It has also been stated that clinical trials to study the potential of a formula to reduce the risk of developing an allergy to milk proteins are difficult to implement. Another comment in this relation indicated that the reduction in allergen content of formulae containing protein hydrolysates is generally evaluated in vitro before such a formula is marketed. Panel consideration of comments received Ad 28. Protein hydrolysates are a permitted source of protein for IF and FOF for healthy infants as per Directive 2006/141/EC and are therefore considered by the Panel in the opinion. The opinion does not refer to formulae for special medical purposes containing extensively hydrolysed protein. No changes to the opinion were considered necessary. Ad 29. As outlined in the opinion, formulae containing protein hydrolysates are insufficiently characterised by the declared protein content even if they fulfil regulatory criteria concerning amino acid patterns and contents and even if they contain a minimum of 2.25 g/100 kcal protein. Therefore, the safety and suitability of each specific IF or FOF containing protein EFSA supporting publication 2014:EN

12 hydrolysates should be established by clinical studies. As this was already explained in the opinion, no changes to the opinion were considered necessary. Ad 30. Ad 31. Ad 32. The assumption that the amino acid contribution of the hydrolysed protein would be identical to that of the unhydrolysed protein and that the amino acid availability is modified is speculative as this assumption has not been investigated in infants. No changes to the opinion were considered necessary. The Panel fully agrees that there is a need for an appropriate characterisation of formulae containing protein hydrolysates when evaluating their safety and potential benefits. Such characterisation has to be sufficient to ensure that the formulae used in the studies are the same as the formulae under evaluation. As this will have to be dealt with in the framework of individual evaluations, no changes to the opinion were considered necessary. In vitro studies cannot predict the occurrence of effects in vivo and therefore cannot substitute for human studies. Advice on what type of evidence would be needed to substantiate that a formula would reduce the risk of developing allergy to milk protein is outside the scope of this opinion. No changes to the opinion were considered necessary Formulae containing isolated soy protein (ISP) Comments received 33. It was highlighted that one of the indications of use of formulae containing ISP is the choice of caregivers to provide a vegan diet to the infant and not a vegetarian diet, as indicated in the opinion. 34. Some comments argued that the statement by the Panel that concentrations of isoflavones, trypsin inhibitors, lectins and phytic acid in IF and FOF should be kept as low as is feasible is not sufficiently precise, while other comments argued that such a statement by the Panel is not needed as there was no indication of inadequate growth of infants having been fed formulae containing ISP. 35. There were some general statements on the safety of formulae containing ISP and on the quality of soy protein. 36. It was requested that the opinion include a statement to the effect that formulae containing ISP are also indicated in infants allergic to cow s milk. Panel consideration of comments received Ad 33. The opinion has been amended and vegetarian diet has been replaced by vegan diet as indication for use of formulae containing ISP. Ad 34. Ad 35. Ad 36. There are no studies which would allow the establishment of safe concentrations of isoflavones, trypsin inhibitors, lectins and phytic acid which should not be exceeded in IF and FOF. Taking into account the considerations made in the opinion related to these substances, the Panel considered it justified to underline the need for careful quality control of ISP used in the manufacture of IF. No changes to the opinion were considered necessary. As no contradiction between the opinion and the statements made in the comments with respect to soy protein could be identified, no amendments to the opinion were deemed necessary. As adverse reactions to soy have been reported in milk protein-allergic patients fed with formulae containing ISP (EFSA NDA Panel, 2014b), the Panel does not consider it EFSA supporting publication 2014:EN

13 Fat Outcome of a public consultation essential composition of infant and follow-on formulae appropriate, in line with paediatric nutrition societies (ESPGHAN Committee on et al., 2006), to include a statement that formulae containing ISP are indicated also in cow s milk-allergic infants. Moreover, the management of an allergy to cow s milk is outside the scope of the opinion. No changes to the opinion were considered necessary. Comments received 37. It has been highlighted that cow s milk and goat s milk are hardly used as fat sources for IF and FOF and that mainly vegetable oils are used. It was suggested that coprah oil be included in Table 8, as it is more frequently used than palm oil. 38. It was commented that vegetable oils are supposed to be safe from a toxicological point of view and therefore the Panel seemed to have stated the obvious in its opinion. In this respect, a concern was expressed over the use of vegetable oils instead of dairy fats owing to the absence in vegetable oils of certain fatty acids found in milk fat. 39. It was stated that low fat intakes in early life have been associated with a risk of developing obesity later in life and it was suggested that this should be reflected in the opinion. 40. It was suggested that a minimum content of cholesterol in IF and FOF be proposed and to include a statement that it is not desirable to manufacture IF and FOF devoid of cholesterol, as the presence of cholesterol in the diet in early life could be linked with a reduced risk of cardiovascular diseases. 41. It was suggested that the effects of the addition of bovine milk fat globule membrane to IF and FOF be addressed. Panel consideration of comments received Ad 37. Table 8 was not intended to be comprehensive and provides only examples of fatty acid composition of fat sources, which could be used, amongst other fat sources, in the manufacture of IF and FOF. Therefore, no changes to the opinion were considered necessary. Ad 38. Ad 39. Ad 40. The Panel did not prescribe a specific fat source in IF and FOF and gave an adequate range of fat content in IF and FOF. The choice of fat source will be up to the manufacturer. No changes to the opinion were considered necessary. A negative association between fat intake in early life and body fat has been reported in one cohort study (Rolland-Cachera et al., 2013), but most epidemiological studies, performed so far, did not find any association between the level of dietary fat intake of infants and children and body weight and/or fatness (Macé et al., 2006). No causal relationship has been established between either high or low fat intakes during infancy and adiposity later in life. In addition, the Panel does not propose a low-fat formula. For completeness, the reference to the study by Rolland-Cachera et al. (2013) has been added to the opinion. The presence of cholesterol in breast milk may play a role in the lower cholesterol plasma level observed in adults who were breast fed during infancy. It has, however, not been shown that higher cholesterol intakes during infancy could play a role in a reduced risk of cardiovascular diseases later in life. Also, it has not been shown that formulae devoid of cholesterol would have a negative impact on later health outcomes. No changes to the opinion were considered necessary. EFSA supporting publication 2014:EN

14 Ad 41. EFSA provided advice on the essential composition requirements of IF and FOF by revising and updating the opinion of the SCF (2003) in the light of new evidence as requested in the Terms of Reference for the opinion. This review did not include an evaluation of all substances which could potentially be added to IF and/or FOF. No changes to the opinion were considered necessary Arachidonic acid (ARA) Comments received 42. It was suggested that the Panel also proposes a minimum amount of ARA to be contained in IF in the presence of docosahexaenoic acid (DHA), as data indicate that high intakes of DHA in the absence of adequate intakes of ARA may have a negative effect on ARA status and adverse effects on growth in pre-term infants have been observed. 43. It was also suggested that a statement that the ARA and the eicosapentaenoic acid (EPA) content should not exceed the DHA content be included. 44. It was suggested that information on ARA intakes be added to the opinion. 45. It was indicated that the most widely used form of DHA in IF and FOF is DHA-rich single cell oil and therefore the statement made by the Panel that ARA and EPA will be introduced via sources of LCPUFAs is not correct. This will also be the case if fish oil is used as a source of DHA, which does not provide ARA. Panel consideration of comments received Ad 42. The Panel is aware of the studies reporting adverse growth effects from high intakes of DHA in the absence of ARA in pre-term infants. The support for the concept of the essentiality of ARA in infant nutrition was provided by the observation of potentially adverse effects of a relatively high dose of n-3 LCPUFAs in pre-term formulae in a small RCT in pre-term infants (Carlson et al., 1993). In this study, plasma phosphatidylcholine ARA concentration was found to correlate with measures of normalised growth, which led the authors to hypothesise that ARA deficiency may contribute to decreased growth in pre-term infants over the first year of life. Earlier observational data had also shown a positive correlation between body weight and post-natal plasma triglyceride ARA (and total n-6 PUFA) content and an inverse correlation with ALA (Koletzko and Braun, 1991). These data have, however, not been replicated in RCTs and, furthermore, do not prove an essential role of dietary ARA. Carlson et al. (1993) used marine oil, including both EPA and DHA, and subjects were very pre-term. The evidence that similar effects would occur in term infants is weak. Thus, it was considered that any recommendations to propose a minimum content of ARA in IF for term infants would have been made on weak grounds. A discussion of the available evidence for ARA has been included in the opinion for transparency reasons, but the recommendations of the Panel with respect to ARA remain unchanged. Ad 43. Ad 44. Some recommendations suggest that ARA should exceed DHA. The ratio of ARA to DHA in human milk is variable and there is no adequate basis on which to claim that one ratio would be preferable over another. In contrast, DHA always exceeds EPA in breast milk, which would not be the case if standard fish oil was used in the manufacture of formulae. The evidence that adverse effects would occur in a term infant if EPA exceeds DHA in IF and FOF is weak and therefore not an appropriate basis for determining a desirable EPA:DHA ratio. A generic recommendation that EPA should not exceed DHA could be proposed based on breast milk contents and has been added to the opinion. The addition of information on ARA intakes in the opinion has not been considered necessary as no minimum content of ARA is proposed. EFSA supporting publication 2014:EN

15 Ad 45. The sentence on the introduction of ARA and EPA via sources of LCPUFAs to IF and FOF has been deleted Linoleic acid (LA) and alpha-linolenic acid (ALA) Comments received 46. The exemplary range of LA content of human milk as given in Table 8 was questioned. 47. It was indicated that the discussion on the effect of ALA is incomplete as the effects of ALA addition to formulae on a decrease in plasma phospholipid ARA were not addressed. 48. The decisions of the Panel not to propose a LA:ALA ratio and not to propose a EPA:DHA ratio were questioned. Panel consideration of comments received Ad 46. It is acknowledged that the LA content of human milk has decreased over the past decades owing to changes in the habitual diets. The LA concentrations reported by the Panel reflect concentrations measured in recent years in Europe. It is not considered necessary to add any information to the opinion if historic values are also reported. No changes to the opinion were considered necessary. Ad 47. Ad 48. In the absence of recommendations of the Panel to add ALA in isolation to IF and/or FOF, no in-depth discussion on the effects of the addition of ALA to IF and FOF on plasma levels of polyunsaturated fatty acid (PUFAs) was considered necessary. The meta-analysis to which the comment referred was used to illustrate that in infancy a conversion of ALA to DHA takes place and that there are no adverse effects of ALA on growth and development. No changes to the opinion were considered necessary. A response to the question on the need for a DHA:EPA ratio was commented on in the answer to question 43. As outlined in the opinion, there is limited evidence for a need of an LA:ALA ratio in the presence of DHA and therefore such a ratio was not considered necessary and no changes were made to the opinion Docosahexaenoic acid (DHA) Comments received 49. It was requested that information on the fatty acid composition of fungal oils be added to Table 8, in addition to add a statement that DHA-rich algal oils from Crypthecodinium cohnii and Schizochytrium sp. can be used as sources of DHA in IF. 50. A question was asked on how the recommendation for a minimum content of DHA in IF and FOF is compatible with the general principle that any substance added to IF or FOF should have a demonstrated nutritional or other health benefit. 51. The recommendation to propose a minimum content of DHA in IF and FOF was questioned as it was indicated that DHA accretion in the brain of animals is similar when animals are fed fodder supplemented with ALA or DHA. 52. The statement that there is no convincing evidence of DHA benefits beyond infancy on any functional outcomes was deemed unnecessary as it was considered that the evaluation of effects of formula consumption should be limited to infancy. All effects later in life were considered irrelevant as long as adequate growth and development during infancy and the compositional similarity to breast milk were ensured. EFSA supporting publication 2014:EN

16 53. A comment was received that DHA intakes in infancy considered by the Panel to be adequate deviate from the recommendations of other expert bodies and that the minimum content indicated is higher than that indicated in the conditions of use of an authorised health claim for DHA for FOF. 54. It was also stated that the minimum content of DHA proposed by the Panel would cause organoleptic and stability problems. 55. It was suggested that the minimum content of DHA be expressed as % of total fatty acids (FA %) rather than per 100 kcal. 56. It was suggested that information on the dietary requirements of DHA for young children also be included. 57. It was indicated that the meta-analyses by Schulzke et al. (2011) reviewed LCPUFA supplementation in pre-term infants and should therefore be removed from the opinion. It was also stated that the meta-analysis by Delgado-Noguera et al. (2010) evaluated the effect of n-3 LCPUFA supplementation during pregnancy and lactation and therefore cannot be used to evaluate the effect of n-3 LCPUFAs in IF and FOF. It was also commented that the total scores of the Bayley Scales of Infant Development (BSID), as used in the meta-analysis by Qawasmi et al. (2012), are not validated and, furthermore, were calculated by the authors of the analysis using data in the original publications, which did not provide this information. It was emphasised that these meta-analyses do not invalidate the results of the original studies, especially done on particular products. 58. Some additional studies were considered necessary to be added to the evaluation of the effect of DHA. 59. It was stated that the Panel did not sufficiently consider that the meta-analyses by Makrides et al. (2005) (which concluded that LCPUFAs in general have no negative impact on the growth of infants) included studies in which both DHA and ARA were given to infants. It was indicated that there was a need to investigate the effect on growth of DHA alone. Panel consideration of comments received Ad 49. Algal oil from Crypthecodinium cohnii has been added in the opinion as a source of DHA. Algal oil from Schizochytrium sp. is considered to be a novel food and has not yet been authorised for addition to IF and FOF in the EU. Therefore, this source of DHA has not been added in the opinion. The title of Table 8 was amended to indicate that it does not cover sources of LCPUFAs. Ad 50. Ad 51. There is currently no convincing evidence on any functional effects of DHA remaining beyond infancy. There is also a lack of long-term follow-up data on specific aspects of cognitive and behavioural function from adequately powered RCTs of DHA addition to IF and FOF to demonstrate any purported biologically plausible effect of DHA on these aspects. However, as outlined in the opinion, DHA is involved in normal brain and visual development. Therefore, the Panel considered it prudent to recommend a minimum content of DHA in formula. As is also true for other substances, recommendations may need to be revised when new evidence becomes available. No changes to the opinion were considered necessary. As outlined in the opinion, studies in humans have shown that the intake of pre-formed DHA generally results in an erythrocyte DHA status more closely resembling that of a breast-fed infant than is achieved with ALA alone, which was an additional reason to recommend a minimum content of pre-formed DHA in IF and FOF. No changes to the opinion were considered necessary. EFSA supporting publication 2014:EN

17 Ad 52. Ad 53. Ad 54. As stated above, long-term follow-up of infants included in RCTs investigating the safety, suitability and efficacy of IF and/or FOF is the general standard. Neglecting any long-term adverse or beneficial effects of formula consumption during infancy would be negligent. No changes to the opinion were considered necessary. The minimum content of DHA proposed by the Panel is based on the AI for DHA for infants in the second half of the first year of life of 100 mg/day established in its opinion on DRV for fat (EFSA NDA Panel, 2010b) and on the assumption that the dietary requirement for DHA of infants in the first half-year of life would not be very different from that of older infants. The present opinion is fully consistent with the Panel s previous opinion and the opinion on DRVs for fat (EFSA NDA Panel, 2010b, 2013a). As a general rule, health claim authorisations are not an appropriate basis for defining dietary requirements. Nonetheless, it should be noted that the conditions of use of the health claim to which the comment referred require information to be given to the consumer that the beneficial effect could be expected at daily intakes of 100 mg DHA, which is consistent with the AI used as a basis to derive recommendations for the minimum content of DHA in IF and FOF. No changes to the opinion were considered necessary. The Panel is not aware of any studies that indicate that formulae with the proposed content of DHA would not be palatable to infants. A study in which DHA doses up to 0.96 FA % were investigated did not report any differences in losses to follow-up among groups and also the occurrence of adverse events was not statistically significantly different between groups (Drover et al., 2011). In addition, the proposed DHA content is within what is usually found in breast milk. The question on stability is considered a technological issue which may impact shelf life rather than a scientific issue which could be answered by the Panel. No changes to the opinion were considered necessary. Ad 55. The proposal for the DHA content in IF and FOF has now also been given as FA %. Ad 56. Ad 57. Ad 58. Ad 59. Dietary requirements of young children for all nutrients have been addressed in the Panel s previous opinion (EFSA NDA Panel, 2013a) and its opinions on DRVs and are outside the scope of the present opinion. No changes to the opinion were considered necessary. The Panel fully agrees that meta-analyses do not invalidate the results of well-powered and well-designed human intervention studies. The meta-analyses were used to summarise the evidence as the evaluation of the individual studies does not lead to a different conclusion. For the sake of clarity, the individual studies have now been briefly described in the opinion. The evaluation of potential effects of particular products is not the purpose of this opinion. The conclusions of the opinion remain unchanged. The additional studies cited which investigated the impact of DHA supplementation on blood DHA concentrations did not provide evidence on the role of DHA on functional outcomes. It is established that the intake of pre-formed DHA generally results in an erythrocyte DHA status more closely resembling that of a breast-fed infant than is achieved with ALA alone. The Panel did not consider it necessary to exhaustively cite all studies dealing with this fact. The additional studies provided which investigated the effect of DHA on functional outcomes are now included in the description of the available evidence which had been previously summarised by using meta-analyses. The conclusions of the opinion remain unchanged. Indeed, the number of studies available which investigated an effect of ARA and DHA in combination on infant growth is higher than for DHA alone. However, there is no indication that DHA alone would have a differential effect to the combination of ARA and DHA (see also answer to comment 42). As the Panel has now addressed the effect of DHA on growth EFSA supporting publication 2014:EN