The EFSA Journal (2004) 158, 1-6

Transcription

1 The EFSA Journal (2004) 158, 1-6 Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to a notification from EPA on lactitol pursuant to Article 6 paragraph 11 of Directive 2000/13/EC (Request N EFSA-Q ) (adopted on 2 December 2004) SUMMARY Milk is a major allergenic food especially in infancy. Data on prevalence of milk allergy vary according to the different countries and studies but about 1% of the general population of adults and 2-3% of children can be considered approximate figures. Cows milk allergy is an adverse reaction which is mediated by immunological mechanisms and may be triggered by minute amount of milk proteins. Lactose intolerance results from a reduced capacity to digest lactose in lactase deficient adults. Doses less than 10 g per day are likely to be tolerated by most of the population of lactase deficient adults. Residual proteins present in lactose, however, may be an issue for milk Lactitol is a sweet tasting polyol used as sugar replacer. It is prepared from lactose by reduction at high temperature and under pressure. Only a schematic procedure of the purification process of the lactitol solution is described in the application. The applicant based their evidence that lactitol preparations are unlikely to trigger neither lactose intolerance nor cows milk allergic reactions on analytical data related to the residual content of lactose and of two major milk proteins in lactitol preparations. No relevant clinical data is provided. Based on the data submitted, assuming a lactose content in lactitol of less than 0.2% and a normal daily intake of lactitol of g, intolerance reactions due to lactose are unlikely since the intake of lactose would be ca 0.04 g which is much lower than the dose of 10 g generally recognized as tolerated in lactose mal-digesters. Based on the data submitted by the applicant, it is unlikely that lactitol will cause adverse reactions in lactose intolerant individuals, under the conditions of use specified by the applicant. The scientific data submitted by the applicant are insufficient to predict the likelihood of adverse reactions in cows milk Nevertheless, taking all the information into account, the Panel considers that it is not very likely that lactitol, under the conditions of use specified by the applicant, could cause a severe allergic reaction in the majority of milk However, this needs to be confirmed by appropriate analytical and clinical studies in milk Page 1 of 6

2 KEY WORDS Cows milk allergy, lactose, intolerance, lactitol. 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 ingredients that are known to trigger allergic reactions or intolerances for which no labelling exemptions are allowed. Whenever the listed ingredients or their derivatives are used in the production of foodstuffs, they must be labelled. Article 1, paragraph 11 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 shall, not later than 25 November 2004, and after consultation with the European Food Safety Authority, adopt a list of those ingredients which shall be temporarily excluded from Annex IIIa, pending the final results of the notified studies, or at the latest until 25 November Therefore, 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 European Association of Polyol Producers (EPA) in the framework of the procedure laid down for temporary labelling exemptions 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, pending the final results of the studies undertaken, 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: Lactitol. ASSESSMENT Milk is a major allergenic food especially in infancy. Data on prevalence of milk allergy vary according to the different countries and studies but about 1% of the general population of adults and 2-3% of children can be considered approximate figures (NDA, 2004). Cows milk allergy is an adverse reaction which is mediated by immunological mechanisms and may be triggered by minute amount of milk proteins. 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 Page 2 of 6

3 1. Manufacturing process Lactitol is prepared from lactose by reduction at high temperature and under pressure. Detailed conditions are not provided by the applicant nor are the nature of the metal catalyst. Yield of the conversion of lactose to lactitol is said to be nearly 100%. An schematic procedure of the purification process of the lactitol solution was provided, e.g. sedimentation of the catalyst then filtration and purification on activated carbon and on ion exchange resins. After concentration of the solution, the lactitol is crystallised and used either anyhydrous or as lactitol monohydrate. No reference is made to GMP or to quality controls made during the manufacturing process. 2. Characterisation of the product and its use Lactitol is a sweet tasting polyol. It is used as sugar replacer (food additive E966). It has also pharmaceutical uses (e.g. laxative). The information provided by the applicant includes i) theoretical specifications of the starting material, i.e. lactose; ii) a few data on protein and peptide content in lactose and in lactitol, obtained from industrial batches analysis; and iii) general considerations on the effects that the heat treatment applied during the process may have on lactose, on protein-lactose interactions and on their impact on allergenicity. The last point will be discussed in section 3 of this Opinion. Lactose used for lactitol preparation is of pharmaceutical grade or a recrystallized, refined or purified food grade because otherwise it would inactivate the catalyst. The lactose concentration of lactitol is reported to be less than 0.2%. A maximum content of 40 mg/kg organic nitrogen is required for its use, which corresponds to ca. 250 mg protein per kg lactose. Analysis of protein content suggests that batches mainly contain (51-100, and ) mg proteins per kg lactose. However some batches contained up to 500 mg/kg. No detailed information on the procedure and conditions for sampling and for determinations are provided. Molecular weight distribution of peptide fragments present in one lactose sample was determined by MALDI TOF mass spectrometry analysis. All the detected peptides had a molecular weight below 2600 Da and most of them were below 1500 Da. Presence of residual cows milk proteins in lactose and in lactitol was analysed using ELISA test. From the general description given in the application, the Panel assumes it is a classical competitive inhibition ELISA using animal antisera. The determination of two major milk allergens, i.e. whole casein fraction and β-lactoglobulin (BLG), were performed using ELISA tests in lactose. Concentrations ranging from 1.4 to 9.7 mg/kg and 11.8 to 118 mg/kg were found for casein and BLG, respectively. Determinations were also performed in 8 lactitol samples. Casein concentration was below 1.4 mg/kg in 7 samples and below 1.9 mg/kg in one sample. BLG concentration was below 1 Page 3 of 6

4 mg/kg in all the samples. Casein and BLG represent the major milk allergens, although other allergens can also be clinically relevant. The methodology used may not allow detecting altered proteins and peptide fragments derived from milk proteins that could be formed during the process and remained in the finished products. 2.1 Conditions of use Polyols are contained in beverages and milk products. 2.2 Exposure estimation The applicant does not provide likely exposure estimations. Clinical challenge studies cited use 10 g/day as the highest exposure level per adult. 3. Lack of adverse effects in lactose intolerance and evidence of non-allergenicity Two kind of adverse reactions can be triggered: lactose intolerance and allergy to cows milk proteins. Evidence by the applicant stating that lactitol is very unlikely to trigger any reaction of intolerance or allergy in predisposed individuals is essentially based on threshold assumptions. The applicant suggests that given the purity of the starting material and the expected effects of the processing, the residual amounts of lactose and of residual proteins in the finished product are too low to trigger any reactions in i) lactose intolerance and ii) in cows milk protein allergy. 3.1 Evidence that lactitol can be consumed safely by lactose intolerant persons The applicant states i) that doses up to 10 g lactose per day may be tolerated by lactose maldigesters which indeed corresponds to the literature and particularly to the Opinion of the Panel (NDA, 2004); ii) that lactitol contains less than 0.2% lactose; and iii) that normal intake of lactitol is 10 g per day via food products. Consequently the amount of lactose that may be ingested with a normal daily intake of lactitol is far lower than the dose that might provoke clinical manifestations of intolerance. The Panel considers this as an acceptable conclusion. As far as intolerance to lactitol itself is concerned, e.g. through its osmotic activity, it is a general problem experienced with polyols which is beyond the scope of this Opinion. In conclusion it is unlikely that lactitol, as it is prepared and used in the context of this application, triggers a reaction of lactose intolerance in a population of lactose mal-digesters. 3.2 Evidence of non allergenicity of lactitol All the argumentation of the applicant is based on the assertion that i) residual amount of cows milk proteins is unlikely to elicit an allergic reaction in a large majority of sensitive patients; and ii) that peptides fragments that were detected in the final products using mass spectrometry are too small to elicit an allergic reaction. These issues have been extensively discussed in the Opinion of the Panel (NDA, 2004) and the application does not provide any new information. Page 4 of 6

5 The applicant mentions an estimated daily intake of lactitol of 10 g and, assuming a protein content of 1 mg/kg, calculates a total daily intake of 10 µg of allergen. 3.3 Historical evidence of non-allergenicity The applicant also provides some historical evidence based on literature search using the Chemical Abstract Service, on its 20-year long-experience of the use of lactitol in food products and as a medicine and also on the clinical studies performed for the registration of lactitol as drugs. The applicant mentions that no case of allergic reaction has been recorded. It should be noted that other more comprehensive search strategies are available. Searches that only relate to allergic reactions may lead to underreporting due to lack of awareness of the presence of cows milk protein in lactitol. 3.4 Laboratory-based tests Apart of the analytical studies, the application does not contain experimental laboratory based tests including in vitro test using allergic patients sera, animal studies nor human clinical studies. 4 Clinical studies Not performed nor proposed. CONCLUSIONS AND RECOMMENDATIONS Based on the data submitted by the applicant, it is unlikely that lactitol will cause adverse reactions in lactose intolerance individuals, under the conditions of use specified by the applicant. The scientific data submitted by the applicant are insufficient to predict the likelihood of adverse reactions in cows milk Nevertheless, taking all the information into account, the Panel considers that it is not very likely that lactitol, under the conditions of use specified by the applicant, could cause a severe allergic reaction in the majority of milk However, this needs to be confirmed by appropriate analytical and clinical studies in milk DOCUMENTATION PROVIDED TO EFSA Data submitted by European Association of Polyol Producers (EPA) to the European Commission pursuant to Article 6 paragraph 11 of Directive 2000/13/EC, 30 July Page 5 of 6

6 REFERENCES NDA (2004). 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, PANEL MEMBERS Wulf Becker, Francesco Branca, Daniel Brasseur, Jean-Louis Bresson, Albert Flynn, Alan A. Jackson, Pagona Lagiou, Martinus Løvik, Geltrude Mingrone, Bevan Moseley, Andreu Palou, Hildegard Przyrembel, Seppo Salminen, Stephan Strobel, Henk van den Berg, and Hendrik van Loveren. ACKNOWLEDGEMENT The Scientific Panel on Dietetic Products, Nutrition and Allergies wishes to thank Elide Pastorello, Martin Stern, and Jean-Michel Wal for their contributions to the draft opinion. Page 6 of 6