regulat.pro.kid IMMUN and immune system of children Adopted on 11 July 2008

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1 The EFSA Journal (2008) 782, 1-9 regulat.pro.kid IMMUN and immune system of children Scientific substantiation of a health claim related to regulat.pro.kid IMMUN and immune system of children during growth pursuant to Article 14 of Regulation (EC) No 1924/ Scientific Opinion of the Panel on Dietetic Products, Nutrition and Allergies (Question No EFSA-Q ) Adopted on 11 July 2008 PANEL MEMBERS Jean-Louis Bresson, Albert Flynn, Marina Heinonen, Karin Hulshof, Hannu Korhonen, Pagona Lagiou, Martinus Løvik, Rosangela Marchelli, Ambroise Martin, Bevan Moseley, Andreu Palou, Hildegard Przyrembel, Seppo Salminen, Sean (J.J.) Strain, Stephan Strobel, Inge Tetens, Henk van den Berg, Hendrik van Loveren, and Hans Verhagen. SUMMARY Following an application from enzyme.pro.ag, submitted pursuant to Article 14 of Regulation (EC) No 1924/2006 via the Competent Authority of Germany, the Panel on Dietetic Products, Nutrition and Allergies was asked to deliver an opinion on the scientific substantiation of a health claim related to regulat.pro.kid IMMUN and the immune system of children during growth. The scope of the application was proposed to fall under a health claim referring to children s development and health. regulat.pro.kid IMMUN is a food supplement targeted at children aged 3-16 years. It contains different fruits and vegetables, nuts and spices, which are blended together and fermented stepwise by the addition of five different strains of lactobacilli that are filtered away after fermentation. Two strains of specific freeze-dried lactic acid bacteria are added via a cap that releases them into the fermented liquid when the container is opened. The bacteria used in the fermentation process are not adequately characterised and there are no studies on the impact of the food matrix on the viability and activity of the lactic acid bacteria added after the so called cascade fermentation. The combinations of lactic acid bacteria used in the fermentation and the specific bacteria added through the product cap when opened have not been assessed in combination or within the fermented vegetable and fruit containing food base. 1 For citation purposes: Scientific Opinion of the Panel on Dietetic Products, Nutrition and Allergies on a request from enzyme.pro.ag on the scientific substantiation of a health claim related to regulat.pro.kid IMMUN and the immune system of children during growth. The EFSA Journal (2008) 782, 1-9 European Food Safety Authority, 2008

2 A well functioning immune system is important for maintaining physiological integrity and thus of health and growth. The claimed effect is to support, stimulate and modulate the immune system of children during growth. However no definition is provided of what constitutes a healthy immune system or how the support, stimulation or modulation of the immune system can be assessed. There are no intervention studies conducted with the final product, regulat.pro.kid IMMUN, in the target population concerning the proposed health claim. Existing studies on different probiotics and the reviews supplied do not verify the health claim on regulat.pro.kid IMMUN. On the basis of the data presented, the Panel concludes the following: The food for which the claim is made, regulat.pro.kid IMMUN, has not been sufficiently characterised, e.g. sufficient information has not been provided on the lactic acid bacteria strains used for the fermentation of the fruit and vegetable base. While a well functioning immune system is important for maintaining physiological integrity and thus health and growth, the claimed effect (support/modulate/improve the immune system in children) is not sufficiently defined and can not be verified from the data provided. A cause and effect relationship has not been established between the consumption of regulat.pro.kid IMMUN and the claimed effect. Key words: regulat.pro.kid IMMUN, food supplement, probiotic, fermented vegetables, fruits, immune modulation and stimulation, children, growth The EFSA Journal (2008) 782, 2-9

3 TABLE OF CONTENTS Panel Members...1 Summary...1 Table of Contents...3 Background...4 Terms of reference...4 EFSA Disclaimer...4 Acknowledgements Information provided by the applicant Food/constituent as stated by the applicant Health relationship as claimed by the applicant Wording of the health claim as proposed by the applicant Specific conditions of use as proposed by the applicant Assessment Characterisation of the food/constituent Relevance of the claimed effect to human health Scientific substantiation of the claimed effect...7 Conclusions...8 Documentation provided to EFSA...8 References...8 The EFSA Journal (2008) 782, 3-9

4 BACKGROUND Regulation (EC) No 1924/ harmonises the provisions that relate to nutrition and health claims and establishes rules governing the Community authorisation of health claims made on foods. As a rule, health claims are prohibited unless they comply with the general and specific requirements of that Regulation, are authorised in accordance with this Regulation and included in the lists of authorised claims provided for in Articles 13 and 14 thereof. In particular, Articles 14 to 17 of that Regulation lay down provisions for the authorisation and subsequent inclusion of reduction of disease risk claims and claims referring to children s development and health in a Community list of permitted claims. According to Article 15 of that Regulation, an application for authorisation shall be submitted by the applicant to the national competent authority of a Member State, who will make the application and any supplementary information supplied by the applicant available to the European Food Safety Authority (EFSA). Steps taken by EFSA: The application was received on 08/08/2007. The scope of the application was proposed to fall under a health claim referring to children s development and health. During the check for completeness 3 of the application, the applicant was requested to provide missing information on 02/10/2007, and subsequently on 13/05/2008. The applicant provided the missing information on 01/04/2008 and subsequently on 09/06/2008. The scientific evaluation procedure started on 15/06/2008. During the meeting on 11/07/2008, the NDA Panel, after having evaluated the overall data submitted, adopted an opinion on the scientific substantiation of a health claim related to regulat.pro.kid IMMUN and the immune system of children during growth. TERMS OF REFERENCE EFSA is requested to evaluate the scientific data submitted by the applicant in accordance with Article 16 of Regulation (EC) No 1924/2006. On the basis of that evaluation, EFSA will issue an opinion on the scientific substantiation of a health claim related to: regulat.pro.kid IMMUN and immune system of children during growth. EFSA DISCLAIMER The present opinion does not constitute, and cannot be construed as, an authorisation to the marketing of regulat.pro.kid IMMUN, a positive assessment of its safety, nor a decision on whether regulat.pro.kid IMMUN is, or is not, classified as a foodstuff. It should be noted that such an assessment is not foreseen in the framework of Regulation (EC) No 1924/ European Parliament and Council (2006). Regulation (EC) No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods. Official Journal of the European Union OJ L 404, Corrigendum OJ L 12, , p In accordance with EFSA Scientific and Technical guidance for the Preparation and Presentation of the Application for Authorisation of a Health Claim The EFSA Journal (2008) 782, 4-9

5 It should also be highlighted that the scope, the proposed wording of the claim and the conditions of use as proposed by the applicant may be subject to changes, pending the outcome of the authorisation procedure foreseen in Article 17 of Regulation (EC) No 1924/2006. ACKNOWLEDGEMENTS The European Food Safety Authority wishes to thank the members of the Working Group for the preparation of this opinion: Jean-Louis Bresson, Albert Flynn, Marina Heinonen, Hannu Korhonen, Ambroise Martin, Andreu Palou, Hildegard Przyrembel, Seppo Salminen, Sean (J.J.) Strain, Inge Tetens, Henk van den Berg, Hendrik van Loveren and Hans Verhagen. The EFSA Journal (2008) 782, 5-9

6 1. Information provided by the applicant Applicant s name and address: enzyme.pro.ag, Böhleli 7, CH-9050 Appenzell, Switzerland Food/constituent as stated by the applicant regulat.pro.kid IMMUN is a food supplement with probiotics and fermented vegetables and fruits Health relationship as claimed by the applicant Probiotics and fermented vegetables and fruits support general health and show a specific immune modulating activity, which improves the immune system of children during growth Wording of the health claim as proposed by the applicant regulat.pro.kid IMMUN supports, stimulates and modulates the immune system of children during growth. 1.4 Specific conditions of use as proposed by the applicant 20 ml regulat.pro.kid IMMUN is the recommended daily dose, which should be consumed in two parts per day (10 ml in the morning and 10 ml in evening). 2. Assessment 2.1. Characterisation of the food/constituent The constituents of regulat.pro.kid IMMUN have been described through the process of manufacturing regulat.pro.kid IMMUN and the patent related to the regulat.pro.kid IMMUN cascade fermentation process. In short, different fruits, vegetables, nuts and spices are blended together and fermented stepwise by the addition of five different strains of lactobacilli ( cascade fermentation ). After filtration the resultant liquid is filled into flasks that are fitted with special caps. These caps contain freeze-dried live Lactobacillus rhamnosus GG and Lactobacillus reuteri (10 9 cfu each), that are released into the fermented liquid when the container is opened prior to consumption. The quantity and pattern of consumption of the food required to obtain the claimed effect has been estimated based on the dose of lactic acid bacteria in the final product. The recommended dose is 20 ml daily in two parts, 10 ml in the morning and 10 ml in the evening. The bacteria used in the fermentation process are not adequately characterised. No data are provided for the stability and viability of the added lactic acid bacteria stored in the cap, in the final product after opening the cap and for at least one day after opening. No studies were provided on the impact of mixing the lactic acid bacteria in the regulat.pro.kid IMMUN and leaving one portion to be taken within half a day after the opening of the flask. No studies verifying the survival and the activity of the lactic acid bacteria in the product food matrix have been provided. The Panel considers that the food for which the health claim is made, regulat.pro.kid IMMUN, has not been sufficiently characterised. The EFSA Journal (2008) 782, 6-9

7 2.2. Relevance of the claimed effect to human health The target population is children aged 3-16 years. The claimed effect is to support, stimulate and modulate the immune system of children during growth. No definition is provided of what constitutes a healthy immune system or how the support, stimulation or modulation of the immune system can be assessed. A well functioning immune system is important for maintaining physiological integrity and thus health and growth. Even if it is possible to upregulate certain aspects of immune function, not every manipulation of a food/constituent that leads to an enhancement of immune responses may be considered beneficial. The Panel considers that the claimed effect is not sufficiently defined Scientific substantiation of the claimed effect The systematic review conducted by the applicant identified 17 human studies involving children of various ages and considered by the applicant as pertinent to the claimed effect. One study assessed a combination of Bifidobacterium lactis and Lactobacillus reuteri in infant formula on infections in 4-10 month old infants (Weizman et al., 2005). A second study assessed the impact of a Lactobacillus rhamnosus GG containing probiotic milk product on infections in day-care centre children from 1-6 years (Hatakka et al., 2001). Both studies did not address the bacterial combination in the regulat matrix. The other studies provided in the application included both human intervention studies with specific probiotics or probiotic combinations and reviews of probiotic studies (Casas and Dobrogosz, 2006; Isolauri et al., 1995; Kaila et al., 1992; Majamaa and Isolauri, 1997; Majamaa et al., 1995; Malin et al., 1996 and 1997; Pohjavuori et al., 2004; Shornikova et al., 1997a and b; Viljanen et al., 2005a and b; Ruiz-Palacios et al., 1992, 1996 and 1999). No study specifically addressed the proposed health claim under consideration with respect to consumption of 20 ml of the product regulat.pro.kid IMMUN in two portions daily. Instead the studies presented consider more general associations between the consumption of specific lactic acid bacteria or probiotic products and the impact on health in various populations, such as infants, children and adolescents of different ages. Such effects concern rotavirus diarrhea, acute gastroenteritis, reduction of the risk of infections in specific target groups or improvement of the rotavirus vaccine immunogenicity and they are strain-specific and combination-specific. The results of the reviewed studies cannot be transferred to other products and target populations. In these studies on different individual lactic acid bacteria and bifidobacteria and their health benefits, the doses varied and in some cases differed significantly from the proposed 10 9 cfu of Lactobacillus rhamnosus GG and Lactobacillus reuteri, which are provided by regulat.pro.kid IMMUN. No interactions between the two strains have been assessed and thus the combined impact with the food constituent (fermented vegetables and fruits) is not known. The evidence provided by the applicant cannot serve as evidence for a beneficial effect on the immune system of the target group as a consequence of consumption of the product regulat.pro.kid IMMUN. Some of the individual constituents of the product have been assessed for their health effects in specific target groups. However, combining such ingredients can result in either beneficial, detrimental or no effects on the host. No human intervention studies have been performed with the final product (i.e. regulat.pro.kid IMMUN) and specifically in the intended target population. The EFSA Journal (2008) 782, 7-9

8 The Panel considers that a cause and effect relationship has not been established between the consumption of regulat.pro.kid IMMUN and the claimed effect. CONCLUSIONS On the basis of the data presented, the Panel concludes that: The food for which the claim is made, regulat.pro.kid IMMUN, has not been sufficiently characterised, e.g. sufficient information has not been provided on the lactic acid bacteria strains used for the fermentation of the fruit and vegetable base. While a well functioning immune system is important for maintaining physiological integrity and thus health and growth, the claimed effect (support/modulate/improve the immune system in children) is not sufficiently defined and can not be verified from the data provided. A cause and effect relationship has not been established between the consumption of regulat.pro.kid IMMUN and the claimed effect. DOCUMENTATION PROVIDED TO EFSA Health claim application on regulat.pro.kid IMMUN and immune system of children during growth pursuant to Article 14 of the Regulation (EC) No 1924/2006 (Claim serial No: DE). April and June Submitted by enzyme.pro.ag. REFERENCES Casas IA and Dobrogosz WJ, Validation of the probiotic concept: Lactobacillus reuteri confers broadspectrum protection against disease in humans and animals. Microbial. Ecology in Health and Disease. 12, Hatakka K, Savilahti E, Pönkä A, Meurman JH, Poussa T, Näse L, Saxelin M, Korpela R, Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial. B.M.J. 322, Isolauri E, Joensuu J, Suomalainen H, Luomala M, Vesikari T, Improved immunogenicity of oral D x RRV reassortant rotavirus vaccine by Lactobacillus casei GG. Vaccine. 13, Kaila M, Isolauri E, Soppi E, Virtanen E, Laime S, Arvilommi H, Enhancement of the circulating antibody secreting cell response in human diarrhea by a human Lactobacillus strain. Pediatr. Res. 32, Majamaa H, Isolauri E, Saxelin M, Vesikari T, Lactic acid bacteria in the treatment of acute rotavirus gastroenteritis. J. Pediatr. Gastroent. Nutr. 20, Majamaa H and Isolauri E, Probiotics: a novel approach in the management of food allergy. J. Allergy Clin. Immunol. 99, Malin M, Suomalainen H, Saxelin M, Isolauri E, Promotion of IgA immune response in patients with Crohn's disease by oral bacteriotherapy with Lactobacillus GG. Ann. Nutr. Metabolism. 40, Malin M, Verronen P, Korhonen H, Syväoja E-L, Salminen S, Mykkänen H, Arvilommi H, Eerola E, Isolauri E, Dietary therapy with Lactobacillus GG, bovine colostrum or bovine immune colostrum in patients with juvenile chronic arthritis: evaluation of effect on gut defence mechanisms. Inflammopharmacol. 5, The EFSA Journal (2008) 782, 8-9

9 Pohjavuori E, Viljanen M, Korpela R, Kuitunen M, Tiittanen M, Vaarala O, Savilahti E, Lactobacillus GG effect in increasing IFN-gamma production in infants with cow's milk allergy. J. Allergy Clin. Immunol. 114, Ruiz-Palacios G, Tuz F, Arteaga F, Guerrero ML, Dohnalek M, Hilty M, Tolerance and fecal colonization with Lactobacillus reuteri in children fed a beverage with a mixture of Lactobacillus spp. Pediatr. Res. 39, 1090 (Abst., included in the review by Casas and Dobrogosz, 2006). Ruiz Palacios G, Guerrero ML, Hilty M, et al., Feeding of a probiotic for the prevention of community-acquired diarrhea in young Mexican children. Pediatr. Res. 39, 104 (Abst., included in the review by Casas and Dobrogosz, 2006). Ruiz Palacios G, Guerrero ML, Tuz-Dzib F, Feeding a Lactobacillus reuteri- containing probiotic drink for prevention of infantile diarrhea. Microbial. Ecol. Health Dis. 11, 189 (Abst., included in the review by Casas and Dobrogosz, 2006). Shornikova AV, Casas IA, Isolauri E, Mykkanen H, Vesikari T, 1997a. Lactobacillus reuteri as a therapeutic agent in acute diarrhea in young children. J. Pediatr. Gastroenterol. Nutr. 24, Shornikova AV, Casas IA, Mykkanen H, Salo E, Vesikari T, 1997b. Bacteriotherapy with Lactobacillus reuteri in rotavirus gastroenteritis. Pediatr. Infect. Dis. J. 16, Viljanen M, Kuitunen M, Haahtela T, Juntunen-Backman K, Korpela R, Savilahti E, 2005a. Probiotic effects on faecal inflammatory markers and on faecal IgA in food allergic atopic eczema/dermatitis syndrome infants. Pediatr. Allergy Immunol. 16, Viljanen M, Pohjavuori E, Haahtela T, Korpela R, Kuitunen M, Sarnesto A, Vaarala O, Savilahti E, 2005b. Induction of inflammation as a possible mechanism of probiotic effect in atopic eczemadermatitis syndrome. J. Allergy Clin. Immunol. 115, Weizman Z, Asli G, Alsheikh A, Effect of a probiotic infant formula on infections in child care centers: comparison of two probiotic agents. Pediatrics. 115, 5-9. The EFSA Journal (2008) 782, 9-9