The EFSA Journal (2007) 456, 1-6

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1 The EFSA Journal (2007) 456, 1-6 Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to a notification from Finnsugar Ltd on glucose syrups produced from barley starch pursuant to Article 6, paragraph 11 of Directive 2000/13/EC (Request Nº EFSA-Q ) (adopted on 15 February 2007) SUMMARY Information is provided by the applicant on barley starch hydrolysates concerning their preparation, analysis and potential effects in coeliac disease and cereal allergy. It is stated that glucose syrups based on barley do not contain gluten and that they are not likely to trigger adverse reactions. This statement is based on the description of the manufacturing process which includes nearly 100% removal of nitrogen compounds. The evidence of nonallergenicity of barley starch hydrolysates provided includes a review of the scientific literature which did not find any reports on adverse reactions in patients with coeliac disease or cereal allergic individuals linked to barley starch hydrolysates. No amino acids were found in samples of barley starch hydrolysates (detection limit 5-23 mg/kg). ELISA and Western blot immunochemical testing showed values below detection limit (2.4 mg/kg) for nine out of ten samples. In one sample low levels of gluten (up to 50 mg/kg) were detected. Immuno-spot and RAST inhibition using a pool of sera from patients positive for IgE antibodies against cereals including barley did not reveal substantial allergen binding, although some low-level inhibition in several samples was observed. A new clinical study on the allergenicity of barley starch hydrolysate in cereal allergic patients is reported. 15 cereal allergic subjects did not show an allergic reaction during daily consumption of 30 g barley starch hydrolysate for five days. However, the study did not specify clinical reactivity of patients to barley. No further studies have been reported with regard to coeliac disease. Glucose syrups produced from barley may contain low levels of proteins, peptides or fragments thereof. It is not known at which levels of intake glucose syrups derived from barley would cause allergic reactions in barley and cereal allergic individuals. Based on the data provided by the applicant, a review of the scientific literature and clinical information, the Panel considers that it is not very likely that barley hydrolysates will cause a severe allergic reaction in the majority of cereal allergic individuals. However, the probability of allergic reactions to barley hydrolysates in barley mono-allergic individuals is unknown. For coeliac disease, in the absence of direct clinical data using barley hydrolysates, assessment of the data submitted indicates that glucose syrups produced from barley starch are unlikely to cause an adverse reaction in individuals with coeliac disease provided that the (provisional) value of gluten considered by Codex Alimentarius for foods rendered gluten-free is not exceeded. Page 1 of 6

2 The EFSA Journal (2007) 456, 1-6 KEY WORDS Barley, starch hydrolysates, glucose, isoglucose and maltose syrups, coeliac disease, food (cereal) allergy. BACKGROUND In November 2003, the European Parliament and the Council adopted Directive 2003/89/EC 1 amending Directive 2000/13/EC, as regards indication of the ingredients present in foodstuffs. Annex IIIa of the Directive specifies a list of food ingredients or substances that are known to trigger allergic reactions or intolerances in sensitive individuals for which no labelling exemptions are allowed. Whenever the listed ingredients/substances or their derivatives are used in the production of foodstuffs, they must be labelled. Article 1, paragraph 11, subparagraph 2 of the Directive establishes a procedure allowing for temporary labelling exemption of derivatives from ingredients listed in Annex IIIa for which it has been scientifically established that it is not possible for them to cause adverse reactions. In accordance with this provision, submissions of request for temporary labelling exemption were notified to the Commission before 25 August The Commission, after consultation with the European Food Safety Authority, adopted a list (Directive 2005/26/EC 2 ) of those ingredients which are temporarily excluded from Annex IIIa until 25 November 2007, pending the final results of the notified studies. Consequently, applicants who submitted a dossier in 2004 on the basis of subparagraph 2, resulting in the inclusion of a product in the list of Directive 2005/26/EC, and who are seeking exclusion of that product from Annex IIIa beyond 25 November 2007 will have to submit a request enclosing the final results of the notified scientific studies. Therefore in the context of the permanent labelling exemption procedure, the European Food Safety Authority is asked to provide scientific opinions on the submissions in accordance with the present terms of reference. TERMS OF REFERENCE In accordance with Article 29 (1) (a) of Regulation (EC) N 178/2002, the European Commission requests the European Food Safety Authority to evaluate the scientific data submitted by Finnsugar Ltd. in the framework of the procedure laid down in Article 6, paragraph 11 of Directive 2000/13/EC. On the basis of that evaluation, EFSA is requested to issue an opinion on the information provided, and particularly to consider the likelihood of adverse reactions triggered in susceptible individuals by the consumption of the following ingredients/substances used under the conditions specified by the applicant: glucose syrups based on barley. 1 Directive 2003/89/EC of the European Parliament and of the Council amending Directive 2000/13/EC as regards indication of the ingredients present in foodstuffs. OJ L , p Commission Directive 2005/26/EC of 21 March 2005 establishing a list of food ingredients or substances provisionally excluded from Annex IIIa of Directive 2000/13/EC of the European Parliament and of the Council. OJ L 75, , p Page 2 of 6

3 ASSESSMENT Since barley is relevant both as a source of epitopes known to elicit coeliac disease and as an allergen eliciting non-coeliac food allergy (NDA, 2004a), it is appropriate to assess barley products, namely barley starch hydrolysates for their potential to induce coeliac disease or food allergy. In 2004, the Panel issued an Opinion on a notification submitted by Finnsugar Ltd. to the European Commission pursuant to Article 6, paragraph 11 of Directive 2000/13/EC as amended by Directive 2003/89/EC, for temporary exemption from labelling (NDA, 2004b). Under the framework of permanent exemption from labelling, the present Opinion is based on assessment of an updated dossier from Finnsugar Ltd., which contains additional information or data mainly with regard to a new clinical study conducted in15 cereal allergic patients to investigate allergenicity of barley starch hydrolysates. The applicant states that glucose syrups based on barley are highly purified products of barley starch and do not contain gluten. The applicant states that barley starch hydrolysates are not likely, under specific circumstances, to trigger adverse reactions. The following information is presented by the applicant in support of the statements given above. 1. Manufacturing process: preparation of barley starch hydrolysates The data provided show that in the preparation process of barley starch hydrolysates (isolation of starch, hydrolysis, purification), good manufacturing practice is observed as well as ISO 9001:2000 and Hygiene Directive 93/43/EEC including Codex Alimentarius HACCP Principles. Using nitrogen measurements it was shown that 97.7% of the protein was removed during starch manufacturing and 2.3% were removed during membrane filtration. It is rightly stated that a substantial part of the nitrogen measured is non-protein nitrogen (e.g., phospholipids). Therefore, it is justified to assume that the real protein content of starch hydrolysates is overestimated by using nitrogen measurements. In the final product nitrogen levels were between 1-30 mg/kg. From these data and from the production process the applicant concludes that the barley starch hydrolysates described were free of protein. 2. Characterisation of the product Barley starch hydrolysates include isoglucose and maltose syrups (as defined by Directive 2001/111/EC and the Codex Standard for Sugars). Isoglucose syrups are mostly used for beverages, maltose syrups are mostly used for confectionery products. In an exposure study it has been shown that the maximum nitrogen intake in adult individuals was mg nitrogen per day concerning the isoglucose product NESTE 70 FSS. With maltose syrup nitrogen intake was considerably lower. The relevance of these findings with regard to coeliac disease and food allergy cannot be ascertained. Page 3 of 6

4 3. Evidence of non-allergenicity 3.1 History of non-allergenicity of the product There are no reports on coeliac or cereal allergic reactions linked to barley starch hydrolysates. Therefore a history of non-allergenicity of barley starch hydrolysates is assumed by the applicant. 3.2 Laboratory-based tests Ten samples of barley starch hydrolysates were selected by the applicant and subjected to further analysis. No further information as to the source material or specific batches was given. Using amino acid analysis after hydrolysis, no amino acids were detected up to 5-23 mg/kg detection limit in ten samples (technique was not given in detail). Using six samples of maltose syrup, isoglucose and a blend of isoglucose and sucrose there were only very weakly staining bands or smear strikes on SDS-PAGE. It was concluded that the syrup samples studied contained negligible amounts of proteinaceous compounds (molecular weight over 6.5 kda). Further data is produced using R5 ELISA and Western blot methodology for gluten analysis. Nine out of ten samples of maltose syrup, isoglucose and a blend of isoglucose and sucrose did not give any signal for gluten or its hydrolysates with a limit of detection of gluten at 2.4 mg/kg and 3.1 mg/kg, respectively. The same was observed using Western blot analysis on those nine samples. However, one maltose syrup sample, out of three maltose samples, contained 26.5 mg gluten/kg shown by the sandwich R5 ELISA and 50.1 mg gluten/kg using the competitive R5 ELISA specific for partially hydrolysed gluten. This positive finding was confirmed by Western blot. The clinical significance of this finding with regard to coeliac disease or cereal allergy cannot be defined. However, it has been shown that the samples provided for analysis were heterogeneous and that in one out of ten there was detectable material at the level given, below the provisional value suggested by Codex Alimentarius for food rendered gluten-free. The data submitted show negative results with regard to allergen activity with ten samples of maltose/isoglucose/isoglucose and sucrose using immuno-spot and RAST inhibition based on a pool of sera from patients positive for IgE antibodies against cereals including barley. No IgE binding was detected, and no significant inhibition was demonstrated. Further information on the quality of the serum pool used was not made available. There was some low-level inhibition of samples 3-7 and 9. However, this did not reach the level of the positive control. According to the applicant, the clinical significance of the findings cannot be ruled out. 3.3 Clinical study One new clinical study by Nermes et al. (2006) is presented by the applicant. This study was based on the double-blind placebo-controlled food challenge (DBPFC) using barley starch hydrolysate for challenge in individuals with allergic reactions to a mixture of wheat, oats, rye and barley for challenge. The study did not specify clinical reactivity to barley alone and was not designed to address how many barley-allergic individuals were likely to react to barley starch hydrolysates. Subjects with three or more food allergies were excluded from the study. It included 15 children (age range years) with clinical allergic reactions at skin, intestinal and also respiratory level. Skin prick test results were positive to barley in 5/15 patients, and negative to barley starch hydrolysate in all patients. The 15 patients were challenged with 30 g Page 4 of 6

5 of barley starch hydrolysate per day over a period of five days. No allergic reaction was observed. There is very little information as to the dose of cereals triggering allergic reactions. The French study by Moneret-Vautrin et al. (2003) indicated that 80% of allergic children reacted to less than 2 g, and 40% to less than 1 g of wheat protein. However, 6% (2 out of 32) of the children reacted to less than 10 mg of protein. The relevance of these findings with regard to triggering allergic reactions to glucose syrups based on barley is unknown. CONCLUSIONS AND RECOMMENDATIONS 1. Glucose syrups produced from barley may contain low levels of proteins, peptides or fragments thereof. It is not known at which levels of intake glucose syrups derived from barley would cause allergic reactions in barley and cereal allergic individuals. Based on the data provided by the applicant, a review of the scientific literature and clinical information, the Panel considers that it is not very likely that barley hydrolysates will cause a severe allergic reaction in the majority of cereal allergic individuals. However, the probability of allergic reactions to barley hydrolysates in barley mono-allergic individuals is unknown. 2. For coeliac disease, in the absence of direct clinical data using barley hydrolysates, assessment of the data submitted indicates that glucose syrups produced from barley starch are unlikely to cause an adverse reaction in individuals with coeliac disease provided that the (provisional) value of gluten considered by Codex Alimentarius for foods rendered gluten-free is not exceeded. DOCUMENTATION PROVIDED TO EFSA Dossier submitted by Finnsugar Ltd. to the European Commission pursuant to Article 6 paragraph 11 of Directive 2000/13/EC as amended by Directive 2003/89/EC, 13 June Nermes M, Karvonen H, Sarkkinen E, Isolauri E (2006). The allergenicity of barley starch hydrolysate in cereal allergic patients. Oy Foodfiles Ltd., Kuopio, Finland. REFERENCES Council Directive 2001/111/EC relating to certain sugars intended for human consumption. Official Journal L 010, , p. 53. Codex standard for sugars. Codex Standard (Amd ), p.1-5. NDA (Scientific Panel on Dietetic Products, Nutrition and Allergies) (2004a). Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission relating to the evaluation of allergenic foods for labelling purposes. The EFSA Journal 32, Page 5 of 6

6 NDA (Scientific Panel on Dietetic Products, Nutrition and Allergies) (2004b). Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to a notification from Finnsugar on glucose syrups produced from barley starch pursuant to Article 6 paragraph 11 of Directive 2000/13/EC. The EFSA Journal 128, Moneret-Vautrin DA, Kanny G, Perrier P, Denery-Papini S, Morisset M, Leduc V, Parisot L, Beaudouin E, Croizier A, Guenard L, Sergeant P, Guérin L, Frémont S, Commun N, Battaus F (2003) prospective study of wheat flour allergy in children and adults, with reference to celiac disease. Relationship of DR1 allele to allergy in children [in French]. Alim Inter 8: 2-8. PANEL MEMBERS Jean-Louis Bresson, Albert Flynn, Marina Heinonen, Karin Hulshof, Pagona Lagiou, Martinus Løvik, Rosangela Marchelli, Ambroise Martin, Bevan Moseley, Andreu Palou, Hildegard Przyrembel, Seppo Salminen, John John (Sean) Strain, Stephan Strobel, Henk van den Berg, Hendrik van Loveren, and Hans Verhagen. ACKNOWLEDGEMENT The Scientific Panel on Dietetic Products, Nutrition and Allergies wishes to thank Taraneh Dean, Martin Stern, and Jean-Michel Wal for their contributions to the draft opinion. Page 6 of 6