SCIENTIFIC OPINION. Scientific Opinion on chromium(iii) lactate tri-hydrate as a source of chromium added for nutritional purposes to foodstuff 1

Transcription

1 EFSA Journal 2012;10(10):2881 SCIENTIFIC OPINION Scientific Opinion on chromium(iii) lactate tri-hydrate as a source of 1 ABSTRACT EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) 2, 3 European Food Safety Authority (EFSA), Parma, Italy The Panel on Food Additives and Nutrient Sources added to Food provides a scientific opinion on the safety and bioavailability of chromium(iii) lactate tri-hydrate as a source of chromium(iii) added for nutritional purposes to foodstuffs. The safety of chromium itself, in terms of the amounts that may be consumed, is outside the remit of this Panel. No new data have been provided as regards the safety and bioavailability of chromium from chromium(iii) lactate tri-hydrate. The Panel concurs with its earlier views stating that no evidence was provided supporting the bioavailability of chromium from chromium(iii) lactate tri-hydrate. Chromium(III) lactate tri-hydrate is claimed to be freely soluble in water, however, chromium(iii) lactate tri-hydrate exists as a weak complex that may influence the bioavailability of chromium(iii) in the gastrointestinal tract. The Panel re-iterates that because of the complex chemistry of chromium(iii) lactate tri-hydrate in aqueous solutions and its limited solubility at ph >5, the bioavailability of chromium(iii) from chromium(iii) lactate tri-hydrate is low. Based on a conservative exposure estimate, the Panel calculated the combined intake of chromium(iii) from supplements and from foods fortified with chromium(iii) lactate tri-hydrate, for both adults and children, to be approximately 240 μg chromium(iii)/day, which is below the value of 250 µg/day established by the WHO for supplemental intake of chromium that should not be exceeded. The Panel noted that the use of chromium(iii) lactate tri-hydrate in the form of a premix with lactose, added to foods, would result in an exposure at the mean for adults of approximately 7-37 mg lactose/day ( μg lactose/kg bw/day) and to μg lactate/day ( μg/kg bw/day). Given that subjects with lactose maldigestion will tolerate up to 12 g of lactose with no or minor symptoms, these levels are not of safety concern. European Food Safety Authority, 2012 KEY WORDS Food additive, chromium(iii) lactate tri-hydrate, CAS Registry Number On request from the European Commission, Question No EFSA-Q , adopted on 13 September Panel members: Fernando Aguilar, Riccardo Crebelli, Birgit Dusemund, Pierre Galtier, David Gott, Ursula Gundert- Remy, Jürgen König, Claude Lambré, Jean-Charles Leblanc, Alicja Mortensen, Pasquale Mosesso, Dominique Parent- Massin, Ivan Stankovic, Paul Tobback, Ine D.H. Waalkens-Berendsen, Rudolf Antonius Woutersen, Matthew Wright. Correspondence: ans@efsa.europa.eu 3 Acknowledgement: The Panel wishes to thank the members of the Working Group A on Food Additives and Nutrient Sources: P. Galtier, R. Guertler, U. Gundert-Remi, C. Lambré, J-C. Larsen, J-C. Leblanc, P. Mosesso, D. Parent-Massin, I. Stankovic, C. Tlustos, P. Tobback, and M. Wright for the preparatory work on this scientific opinion. Suggested citation: EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS); Scientific Opinion on chromium(iii) lactate tri-hydrate as a source of. EFSA Journal 2012;10(10):2881. [20 pp.] doi: /j.efsa Available online: European Food Safety Authority, 2012

2 SUMMARY Following a request from the European Commission, the Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver an opinion based on its consideration of the safety of chromium(iii) lactate tri-hydrate as a source of chromium(iii) added for nutritional purposes to foodstuffs and the bioavailability of chromium from this source. The Panel noted that no new data have been provided by the applicant as regards the safety and bioavailability of chromium from chromium(iii) lactate tri-hydrate and therefore concurs with its views expressed in 2009 stating that no evidence was provided by the applicant supporting the bioavailability of chromium from chromium(iii) lactate tri-hydrate. Although chromium(iii) lactate tri-hydrate is described by the applicant as freely soluble in water, chromium(iii) lactate tri-hydrate exists as a weak complex that may influence the bioavailability of chromium(iii) in the gastrointestinal tract. Therefore, the Panel re-iterates that because of the complex chemistry of chromium(iii) lactate tri-hydrate in aqueous solutions and its limited solubility at ph>5, the bioavailability of chromium(iii) from chromium(iii) lactate tri-hydrate is likely to be low. Although there are reports in the literature that chromium from organic sources such as chromiumenriched yeast is more bioavailable than chromium from inorganic chromium compounds such as chromium chloride, overall the available data do not permit a definite conclusion on this issue. The Panel also concurs with the view of the SCF (SCF, 2003) that, overall, the bioavailability of chromium is low and that therefore the bioavailability of chromium from chromium(iii) lactate trihydrate is likely to be similar to that of chromium from dietary sources (i.e %). The estimated chromium intake at the mean from the use of chromium(iii) lactate tri-hydrate as an added nutrient source of chromium from the new applications is in the range between 7-22 µg chromium/day for toddlers, µg chromium/day for children, 9-32 µg chromium/day for adolescents, 7-37 µg chromium/day for adults and 4-17 for elderly. The ranges for the percentile intakes are µg chromium/day for toddlers, µg chromium/day for children, µg/day for adolescents, µg/day for adults and µg/day for elderly. The major contributors to exposure for toddlers, children and elderly are fermented milk products providing about 26-81%, 12-48% and 14-64% of the chromium, respectively. For adolescents, the major contributor was found to be soft drinks, contributing between 15-49%, whereas for adults, beer and beer-like beverages were found to be the major contributor (11-46%), followed by soft drinks (12-38%). The maximum intake of chromium from food supplements containing chromium(iii) is estimated to be 200 µg chromium/day and would be of comparable magnitude to the intake from food sources. Based on a conservative exposure estimate, assuming a daily maximum intake of 200 µg chromium(iii) from supplements, in addition to an average daily intake of 37 and 43 µg/day in adults and children from food fortification, an intake of approximately 240 µg chromium(iii)/day for both adults and children can be calculated. This value is below the value of 250 µg/day, value established by the WHO for supplemental intake of chromium that should not be exceeded. The intake of lactate from the consumption of foods to which chromium(iii) lactate tri-hydrate has been added was estimated to be 5.2 g lactate per gram of chromium(iii), resulting in a maximum mean intake of lactate of µg lactate/day ( µg/kg bw/day) for children and µg lactate/day ( µg/kg bw/day) for adults. The Panel noted that lactic acid is a normal constituent of foods and is readily metabolised. Normal blood lactate levels range from 45 to 200 mg/l. Assuming a daily consumption of 100 g meat, adult exposure to lactic acid from this source will range from 100 to 400 mg lactic acid/day. EFSA Journal 2012;10(10):2881 2

3 The estimated intake of lactose from the use of chromium(iii) lactate tri-hydrate, in the form of the premix in the new applications, would be mg lactose/day ( µg lactose/kg bw/day) at the mean for children and 7-37 mg lactose/day ( µg lactose/kg bw/day) at the mean for adults. Given that subjects with lactose maldigestion will tolerate up to 12 g of lactose with no or minor symptoms, these levels are not of safety concern. Based on a conservative exposure estimate, the Panel calculated the combined intake of chromium(iii) from supplements and from food fortification, for both adults and children, to be approximately 240 µg chromium(iii)/day, which is below the value of 250 µg/day established by the WHO for supplemental intake of chromium that should not be exceeded. EFSA Journal 2012;10(10):2881 3

4 TABLE OF CONTENTS Abstract... 1 Summary... 2 Table of contents... 4 Background as provided by the European Commission... 5 Terms of reference as provided by the Commission... 5 Assessment Introduction Technical data Chemistry Specifications Manufacturing process Methods of analysis in food Reaction and fate in foods to which the source is added Case of need and proposed uses Information on existing authorisations and evaluations Food consumption data EFSA Comprehensive European Food Consumption Database Food consumption data for different age and consumer groups Exposure assessment Estimated exposure from new application (as added nutrient source) Estimated exposure from use in food supplements Total estimated intake of chromium(iii) from its use as added nutrient source and in food supplements Estimated intake of lactate and of lactose from the consumption of food to which chromium(iii) lactate tri-hydrate was added, as proposed by the applicant Biological and toxicological data Discussion Conclusions Documentation provided to EFSA References Appendix A Glossary and abbreviations EFSA Journal 2012;10(10):2881 4

5 BACKGROUND AS PROVIDED BY THE EUROPEAN COMMISSION The European Community legislation lists nutritional substances that may be used for nutritional purposes in certain categories of foods as sources of certain nutrients. The Commission has received a request for the evaluation of chromium(iii) lactate tri-hydrate as a source of chromium(iii) added for nutritional purposes to foodstuffs. The relevant Community legislative measure is: Regulation (EC) 1925/2006 of the European Parliament and of the Council on the addition of vitamins and minerals and of certain other substances to foods 42. TERMS OF REFERENCE AS PROVIDED BY THE COMMISSION In accordance with Article 29 (1) (a) of Regulation (EC) No 178/2002, the European Commission asks the European Food Safety Authority to provide a scientific opinion, based on its consideration of the safety of chromium(iii) lactate tri-hydrate as a source of chromium added for nutritional purposes to foodstuffs and the bioavailability of chromium from this source. 4 OJ L 404, , p.26 EFSA Journal 2012;10(10):2881 5

6 ASSESSMENT 1. Introduction The present opinion deals with the safety of chromium(iii) lactate tri-hydrate as a source of chromium, added for nutritional purposes to foodstuffs and foods for the general population, and with the bioavailability of the nutrient cation from this source. The safety of chromium itself, in terms of the amounts that may be consumed, is outside the remit of this Panel. The present application is a request for the extension of use of chromium(iii) lactate tri-hydrate in a wide range of food categories in addition to its permitted use in food supplements. The technical, biological and toxicological dataset provided by the applicant for the present application is identical to that available to the ANS Panel in 2009 for the evaluation of the safety in use of chromium(iii) lactate tri-hydrate in food supplements (EFSA, 2009). No additional data were provided. 2. Technical data 2.1. Chemistry Chromium(III) lactate tri-hydrate has as formula Cr(C 3 H 5 O 3 ) 3 3H 2 O, as molecular weight g/mol and the CAS Registry Number for the anhydrous form is No specific CAS Registry Number has been allocated to the tri-hydrate form. The formal name of the substance is propanoic acid, 2-hydroxy-, chromium(3+) salt (3:1). Chromium(III) lactate is freely soluble in water. Based on the Pearson acid base concept (Pearson, 1963), chromium(iii) readily forms complexes with oxygen-donor ligands such as lactate. Chromium(III) lactate has a pka of 3.66 and exists as a weak complex that precipitates in aqueous solutions at ph >5 (EFSA, 2009). Synonyms are: chromium(iii) lactate, chromium(iii) 2-hydroxypropionate Specifications The specifications as proposed by the applicant are given in Table 1. Table 1: Specifications as proposed by the applicant of chromium(iii) lactate tri-hydrate Assay Cr(III), min 136 g/kg (1) Lactate, g/kg (2) Description Green powder water: 67 g/100 ml, at 20 C Identification (solubility) in: ethanol: 0.2 g/100 ml, at 20 C ethanol: 6.5 g/100 ml, at 78 C acetone: insoluble at 20 C Purity 98 % Bulk density 0.83 g/cm³ Moisture content max 5 % Acidity (0.1% solution) ph 4.1 Sulphates max 1g/kg Heavy metals (as lead) < 10 mg/kg Bacterial counts: Total aerobic bacteria < 250 cfu E. coli (in 1 g) Negative Salmonella (in 25 g) Negative EFSA Journal 2012;10(10):2881 6

7 Moulds Chromium(III) lactate tri-hydrate as a source of < 100 cfu (1) Spectrophotometrically at 540 nm (reaction with diphenylcarbazide) (2) By capillary isotachophoresis 2.3. Manufacturing process The applicant described the process for the production of a 0.1% premix of chromium(iii) lactate trihydrate in lactose. A saturated solution of calcium lactate is mixed with a saturated solution of chromium(iii) sulphate at 60 ºC. In this reaction chromium(iii) lactate tri-hydrate and calcium sulphate are formed. Calcium sulphate is precipitated and separated by filtration. No secondary reactions occur. The solution of chromium(iii) lactate is put onto a food grade lactose support, dried (at 102 ºC) and milled Methods of analysis in food No method for the determination of chromium(iii) lactate tri-hydrate in foodstuffs was provided. The applicant only described a spectrophotometric method for the determination of chromium in chromium lactate and in the chromium lactate premix. In this method, chromium(iii) is oxidized with perchloric acid to form chromium(vi) which, in reaction with diphenylcarbazide, gives a chromophore complex that is quantified by UV-VIS absorption spectroscopy at 540 nm Reaction and fate in foods to which the source is added No information was provided by the applicant on the reaction and fate in foods to which the chromium(iii) lactate tri-hydrate is added. The applicant stated that chromium(iii) lactate is stable under the recommended (closed and dry) storage conditions Case of need and proposed uses The proposed use of chromium(iii) lactate tri-hydrate is as a source of chromium added for nutritional purposes to foods and will be provided as a 0.1% premix in a lactose vehicle. Table 2: Proposed application of chromium(iii) lactate tri-hydrate for food fortification submitted by the applicant, expressed as µg chromium(iii)/kg food. Non-alcoholic drinks µg/kg Water-based flavoured drinks, energy-reduced or with no added sugar 40 Milk and milk-derivative based preparations or fruit juice based drinks, energy-reduced or with no added sugar 40 Desserts and similar products Water based flavoured desserts, energy-reduced or with no added sugar 60 Milk and milk-derivate based preparations, energy-reduced or with no added sugar 60 Fruit and vegetable based desserts, energy-reduced or with no added sugar 60 Egg based desserts, energy-reduced or with no added sugar 60 Cereal based desserts, energy-reduced or with no added sugar 60 Fat based desserts, energy-reduced or with no added sugar 60 Snacks: certain flavours of ready-to-eat, pre-packed, dry, savoury starch products and coated nuts 30 Edible ices, energy-reduced or with no added sugar 50 Sugar and Confectionery Confectionery with no added sugar 60 Confectionery, alcohol free or with an alcohol content not exceeding 1.2%vol 40 Cocoa or dried fruit based confectionery, energy-reduced or with no added sugar 120 Starch based confectionery, energy reduced or with no added sugar 120 Cocoa, milk dried fruit or fat based sandwich spreads, energy-reduced or with not added sugar 60 Chewing gum with no added sugar 340 EFSA Journal 2012;10(10):2881 7

8 Table sweeteners (91 µg Cr 3+ /100 g of sweetener)* 910 Alcoholic drinks Cider and Perry 40 Bière de table/tafelbier/table beer (original wort content less than 6%) except for obergaeriges einfachbier 40 Beers with a minimum acidity of 30 milli-equivalent expressed as NaOH 40 Brown beers of oud bruin type 40 Fruit and Vegetable Preparations Canned or bottled fruit, energy reduced or with no added sugar 60 Energy reduced jams, jellies and marmalades 60 Energy reduced fruit and vegetable preparations 60 Fish products and condiments Sweet sour preserves and semi preserves of fish and marinades of fish, crustaceans and molluscs 20 Sauces 20 Mustard 20 PARNUTS Fine bakery products for special nutritional uses 100 Complete formulae for weight control intended to replace total daily food intake or an individual meal 50 Complete formulae and nutritional supplements for use under medical supervision 60 Liquid food supplement/dietary integrations 200** Solid food supplements/dietary integrations 200** Vitamins and dietary preparations 200** * Table sweeteners (91 µg Cr (III)/100 g of sweetener) not exceeding max daily intake of 200 µg Cr/day **max daily intake µg Cr In a previous application the applicant indicated that the source would be used in food supplements to provide a maximum daily intake of 1435 µg chromium(iii) lactate tri-hydrate, giving rise to a maximum daily intake of 200 µg chromium(iii) per person. The applicant further recommended a maximum single dose of chromium(iii) lactate tri-hydrate of 718 µg [to provide 100 µg chromium(iii)/person/day] Information on existing authorisations and evaluations Chromium(III) chloride and chromium(iii) sulphate are approved compounds listed in the Annex of Commission Regulation No 953/ as substances that may be added for specific nutritional purposes to Foods for Particular Nutritional Uses (PARNUTS). Chromium(III) lactate tri-hydrate, chromium(iii) chloride, chromium(iii) sulphate, chromium(iii) nitrate and chromium(iii) picolinate are included in Annex II of the Commission Regulation (EC) No 1170/ as regards the lists of minerals and their forms that may be used in the manufacture of food supplements. In 2009, the ANS Panel evaluated the safety of chromium(iii) lactate tri-hydrate as a source of chromium added for nutritional purposes to food supplements and on the bioavailability of chromium from this source. The Panel concluded that the use of chromium(iii) as a nutrient is not of safety concern, provided that the intake of chromium(iii) does not exceed 250 μg/day (EFSA, 2009). 5 Commission Regulation No 953/2009 of 13 October 2009 on substances that may be added for specific nutritional purposes in foods for particular nutritional uses. OJ L 269, , p Commission Regulation (EC) No 1170/2009 of 30 November 2009 amending Directive 2002/46/EC of the European Parliament and of the Council and Regulation (EC) No 1925/2006 of the European Parliament and of the Council as regards the lists of vitamins and minerals and their forms that can be added to foods, including food supplements. EFSA Journal 2012;10(10):2881 8

9 In 2010 the ANS Panel, re-evaluating the safety of chromium(iii) as a nutrient added to foods for particular nutritional uses (PARNUTS) and foods intended for the general population (including food supplements) re-iterated that chromium(iii) as a nutrient is not of safety concern, provided that the intake of chromium(iii) does not exceed 250 μg/day, a value for supplemental chromium set forward by the WHO (WHO, 1996; EFSA, 2010a). The UK Expert Group on Vitamins and Minerals (EVM) concluded that, overall, there were insufficient data from human and animal studies to derive a safe upper level for chromium. However, in the opinion of the EVM it is stated that a total daily intake of about 150 µg chromium(iii)/kg bw/day (approximately 10 mg chromium/person) would be expected to be without adverse health effects (EVM, 2003). The societies for Nutrition of Germany (DGE), Austria (ÖGE) and Switzerland (SGE) jointly established an Adequate Intake (AI) of μg chromium/day for adults (D-A-CH, 2000). The US Food and Nutrition Board (US FNB) also concluded that the data from animal and human studies were insufficient to establish an Upper Level for soluble chromium(iii) salts (FNB, 2001), while the WHO considered that supplementation of chromium should not exceed 250 μg Cr(III)/day (WHO, 1996). The ANS Panel also concluded that the exposure to lactate arising from the use of chromium(iii) lactate in food supplements, at the proposed use levels, is not of safety concern (EFSA, 2009). As regards lactose thresholds in lactose intolerance and galactosaemia, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) stated that the vast majority of subjects with lactose maldigestion will tolerate up to 12 g of lactose as a single dose with no or minor symptoms. Higher doses may be tolerated if distributed throughout the day (EFSA, 2010b). L-lactic acid (E 270) is a permitted food additive (quantum satis) (Commission Regulation 1129/2011) Food consumption data EFSA Comprehensive European Food Consumption Database In 2010, the EFSA Comprehensive European Food Consumption Database (Comprehensive Database) has been built from existing national information on food consumption at a detailed level (Merten et al., 2011; EFSA, 2011a). Competent authorities in the European countries provided EFSA with data from the most recent national dietary survey in their country at the level of consumption by the individual consumer. These included food consumption data concerning infants (2 surveys from 2 countries), toddlers (8 surveys from 8 countries), children (17 surveys from 14 countries), adolescents (14 surveys from 12 countries), adults (21 surveys from 20 countries), elderly (9 surveys from 9 countries) and very elderly (8 surveys from 8 countries), for a total of 32 different dietary surveys carried out in 22 different European countries. Surveys on children were mainly (for 13 different European countries) obtained through the Article 36 project Individual food consumption data and exposure assessment studies for children (acronym EXPOCHI) (De Neve et al., 2010). Overall, the food consumption data gathered at EFSA in the Comprehensive Database are the most complete and detailed data currently available in the EU. However, consumption data were collected using different methodologies and thus they are not suitable for direct country-to-country comparison. 7 Commission Regulation (EU) No 1129/2011 of 11 November 2011 amending Annex II to Regulation (EC) No 1333/2008 of the European Parliament and of the Council by establishing a Union list of food additives. OJ L 295, , p.1. EFSA Journal 2012;10(10):2881 9

10 Food consumption data for different age and consumer groups The ANS Panel considered that only chronic dietary exposure to chromium(iii) needed to be assessed. Therefore, as suggested by the EFSA Working Group on Food Consumption and Exposure (EFSA, 2011b), dietary surveys with only one day per subject were not considered for the calculation of chromium(iii) exposure, as they are not adequate to assess repeated dietary exposure. Similarly, subjects who participated only one day in the dietary studies where the protocol prescribed more reporting days per individual were excluded. The ANS Panel performed long-term (chronic) intake assessment for the following population groups: toddlers, children, adolescents, adults and the elderly. Thus, for the present assessment, food consumption data were available from 28 different dietary surveys carried out in 17 different European countries as mentioned in Table 3. Table 3: Population groups considered for the exposure estimates of chromium(iii) Population Age range Countries with chronic food consumption statistics Toddlers Children* Adolescents Adults Elderly** from 12 up to and including 35 months of age from 36 months up to and including 9 years of age from 10 up to and including 17 years of age from 18 up to and including 64 years of age From 65 up to and including 74 years of age Belgium, Bulgaria, Finland, Germany, Italy, Netherlands, Spain Belgium, Bulgaria, Czech Republic, Denmark, Finland, France, Germany, Greece, Italy, Latvia, Netherlands, Spain, Sweden Belgium, Cyprus, Czech Republic, Denmark, France, Germany, Italy, Latvia, Spain, Sweden Belgium, Czech Republic, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, Latvia, Netherlands, Spain, UK Belgium, Denmark, Finland, France, Germany, Hungary, Italy * denoted as other children in the Comprehensive Database, ** includes elderly and very elderly population groups in the Comprehensive Database. Further details on how the Comprehensive Database is used are published in the Guidance of EFSA Use of the EFSA Comprehensive European Food Consumption Database in Exposure Assessment (EFSA, 2011a) Exposure assessment To assess exposure to chromium(iii) lactate tri-hydrate from the proposed new application, the Panel agreed to perform a combined exposure to chromium(iii) lactate tri-hydrate from this new application and intake as food supplement, expressed as chromium(iii). For calculating exposure to chromium(iii) from the proposed new application, food consumption and body weight data at the individual level were accessed in the Comprehensive European Food Consumption Database Estimated exposure from new application (as added nutrient source) Exposure estimates have been performed by the Panel based on the EFSA Comprehensive European Food Consumption Database (see section 2.8). Proposed usage data provided by the applicant (Table 2) were matched as closely as possible with food intake information available from the Comprehensive Food Consumption Database. Table 4 EFSA Journal 2012;10(10):

11 provides an overview of the food categories taken from the Comprehensive Database which were included in the exposure assessment and the concentrations assigned based on the proposed use levels. Table 4: Concentration levels of chromium(iii) lactate tri-hydrate, expressed as µg chromium(iii)/kg food used in the exposure estimation Comprehensive Database Food Category Level 1 Comprehensive Database Food Category Level 2 µg Cr(III)/kg Grains and grain-based products Fine bakery wares 100 Vegetables and vegetable products (including fungi) Vegetable products 60 Fruit and fruit products Jam, marmalade and other fruit spreads 60 Fruit and fruit products Other fruit products (excluding beverages) 60 Fish and other seafood (including amphibians, reptiles, snails and Fish products 0 insects) Milk and dairy products Milk based beverages 60 Milk and dairy products Fermented milk products 60 Sugar and confectionary Sugar and confectionary (unspecified) 60 Sugar and confectionary Sugar substitutes 910 Sugar and confectionary Chocolate (Cocoa) products 120 Sugar and confectionary Confectionery (non-chocolate) 120 Sugar and confectionary Dessert sauces 20 Fruit and vegetable juices Concentrated fruit juice 40 Fruit and vegetable juices Fruit nectar 40 Non-alcoholic beverages Non-alcoholic beverages (excepting milk based (excepting milk based beverages) beverages) (unspecified) 40 Non-alcoholic beverages (excepting milk based beverages) Soft drinks 40 Alcoholic beverages Beer and beer-like beverage 40 Alcoholic beverages Wine-like drinks (e.g. cider, perry) 40 Herbs, spices and condiments Condiment 20 Herbs, spices and condiments Dressing 20 Herbs, spices and condiments Savoury sauces 20 Products for special nutritional use Products for special nutritional use (unspecified) 100 Products for special nutritional use Food for weight reduction 50 Products for special nutritional use Dietary supplements 0 Products for special nutritional use Dietetic food for diabetics (labelled as such) 50 Products for special nutritional use Medical food (are specially formulated and intended for the dietary management of a disease that has distinctive nutritional needs that cannot be met by normal diet 60 alone; intended to be used under medical supervision) Snacks, desserts, and other foods Snacks, desserts, and other foods (unspecified) 30 Snacks, desserts, and other foods Snack food 30 Snacks, desserts, and other foods Ices and desserts 50 Limitations in the dataset: The use of chromium(iii) lactate tri-hydrate as proposed in the application was made for a very broad category of foodstuffs and the specified categories could not always be completely harmonised with food consumption data. EFSA Journal 2012;10(10):

12 The Comprehensive Food Consumption Database does not distinguish between foods that are energy reduced or with no added sugar, or of reduced alcohol content, therefore exposure estimates are based on all foods contained within each category and will present an overestimate of intake. Table 5 provides the ranges for mean and percentile intake estimates, calculated for adults, adolescents, children, toddlers, and elderly, based on food consumption data contained in the Comprehensive Food Consumption Database. Country specific estimates are listed in Table 1 in Annex A. Table 5: Estimated exposure to chromium(iii) from use of chromium(iii) lactate tri-hydrate in the new applications µg Cr(III)/ day µg Cr(III)/kg bw/day Toddlers Children Adolescents Adults Elderly percentile percentile percentile percentile percentile The estimated chromium(iii) intake at the mean from the use of chromium(iii) lactate tri-hydrate as added nutrient source ranges from 7-22 µg chromium(iii)/day for toddlers, µg chromium(iii)/day for children, 9-32 µg chromium(iii)/day for adolescents, 7-37 µg chromium(iii)/day for adults and 4-17 µg chromium(iii)/day for the elderly. The ranges of high percentile intakes are µg chromium(iii)/day for toddlers, µg chromium(iii)/day for children, µg chromium(iii)/day for adolescents, µg chromium(iii)/day for adults and µg chromium(iii)/day for the elderly. Table 6 provides an overview of the major contributors to exposure and shows that for toddlers, children and the elderly, fermented milk products are the major contributor, providing %, 12-48% and 14-64% of chromium(iii), respectively. For adolescents, the major contributor was found to be soft drinks, contributing between 15-49%, whereas for adults, beer and beer-like beverages were found to be the major contributor (11-46%), followed by soft drinks (12-38%). However, since these estimates are based on all foods contained within each food-group and not only foods that are energy reduced or with no added sugar or of low alcohol content, actual major dietary contributors may vary. The latter observation may be particularly relevant for beers, as consumption of low alcohol/alcohol free/ light beers and also sugar reduced chocolates is assumed to be very low. Table 6: Percent contribution (>10%) of foodgroups to the total mean exposure to chromium(iii) from consumption of fortified foods Toddlers Children Adolescents Adults Elderly % contribution (>10 %) to total exposure (Number of surveys)* Fine bakery wares 14-36% (8) 12-53% (15) 17-44% (11) 11-38% (12) 13-48% (5) Vegetable products 16% (1) 18% (1) Milk based beverages 19% (1) 11-20% (3) 12-15% (2) 15 % (1) 23% (1) Fermented milk products 26-81% (all) 12-48% (all) 10-30% (9) 12-40% (10) 14-64% (all) EFSA Journal 2012;10(10):

13 Chocolate (Cocoa) products 13% (1) Concentrated fruit juice 10% (1) Fruit nectar 11% (1) Soft drinks 13-22% (3) 11-33% (14) 15-49% (all) 12-38% (all) 14% (1) Ices and desserts 13-14% (3) 10-11% (3) Beer and beer-like beverage 11-46% (13) 22-43% (3) * Total number of surveys may be greater than total number of countries as listed in Table 3, as some countries submitted more than one survey for a specific age range Estimated exposure from use in food supplements Currently, trivalent chromium [Cr(III)] is used in food supplements as a nutrient in a number of countries in the European Union. However, no data exist on intake of chromium(iii) from supplements in the EU. The applicant reported a maximum daily intake of 200 µg chromium(iii) per day from food supplements containing chromium(iii) lactate tri-hydrate (technical dossier, 2011) Total estimated intake of chromium(iii) from its use as added nutrient source and in food supplements Table 7 provides an overview of the data considered for the estimation of the total intake of chromium(iii) from chromium(iii) added as nutrient source and its use in supplements. It further provides an estimate of the combined exposure from these sources. Table 7: Total estimated intake of chromium(iii) from food supplements and fortified foods sources intake (µg/day) High intake (μg/day) Estimated daily intake from food (as added nutrient) for adults Estimated daily intake from food (as added nutrient) for children Food Supplements Not available 200 Total combined intake adults Total combined intake children The estimated mean chromium(iii) intake from the use of chromium(iii) lactate tri-hydrate as added nutrient source ranges from µg chromium(iii)/day for children and 7-37 µg chromium(iii)/day for adults. The ranges of high percentile intakes are µg chromium(iii)/day for children and µg chromium(iii)/day for adults. Intake of food supplements containing chromium(iii) was reported by the petitioner to amount to a maximum of 200 µg/day. No information on average daily intake is available. No information on total combined intake of chromium(iii) from both food supplements and fortified food is available; however, a highly conservative case estimate can be approximated by assuming a daily maximum intake of 200 µg chromium(iii) from supplements in addition to an average daily intake of 37 and 43 µg/day in adults and children from fortified foods, respectively. Such a consumption pattern would result in a daily intake of approximately 240 µg chromium(iii) per day for both adults and children. Assuming an even more conservative, worst case scenario, maximum intake of 200 µg chromium(iii) from supplements in addition to daily high percentile ( percentile) intake EFSA Journal 2012;10(10):

14 of chromium(iii) from fortified foods would indicate an intake of 286 µg chromium(iii)/day for both adults and children Estimated intake of lactate and of lactose from the consumption of food to which chromium(iii) lactate tri-hydrate was added, as proposed by the applicant The applicant reported the use of a premix of chromium(iii) lactate tri-hydrate and provided the following compositional data: 1 kg of premix with a content of 1 g chromium(iii) is composed of 7.3 g chromium(iii) lactate tri-hydrate and g lactose as support medium. Therefore, the estimated exposure to lactose can be calculated from the estimated intake of chromium(iii), at a rounded concentration of 1 mg lactose for each 1 µg chromium(iii): According to the specifications as proposed by the petitioner (Table 1), chromium(iii) lactate trihydrate contains a minimum of 136 g Cr(III)/kg and g lactate/kg. The intake of lactate from consumption of foods to which chromium(iii) lactate tri-hydrate has been added can therefore be estimated at 5.2 g lactate/g of chromium(iii). Table 8: Cr(III) µg/day Lactose mg/day Lactate µg/day Estimated exposure to lactose and lactate from use of chromium(iii) lactate tri-hydrate in the new applications Toddlers Children Adolescents Adults Elderly percentile percentile percentile percentile percentile No information on intake of lactose from the diet is available; however, compositional information is available for the majority of dairy products. On average, milk and milk products contain 5 g lactose/100g product, cheese approximately 2 g/100 g product and concentrated milk products (evaporated or condensed) from approximately 8 to 12g/100 g product (Holland et al., 1989). These data were used to roughly estimate the dietary intake of lactose, based on summary consumption statistics of dairy products as reported in the Comprehensive Food Consumption Database (Table 9). Table 9: Estimated exposure to lactose in g/day from consumption of dairy products Toddlers Children Adolescents Adults Elderly percentile percentile percentile percentile percentile Exposure estimates of lactose from the consumption of dairy products indicate a mean daily intake for all population groups ranging from 1.5 to 48 g per day. Exposure to lactose from the consumption of foodstuffs fortified with chromium(iii) tri-hydrate lactate in the form of the premix with lactose, ranges from 4-43 mg per day for all populations, and is therefore one order of magnitude lower. L-lactic acid (E 270) is a permitted food additive (quantum satis) (Commission Regulation 1129/2011). Lactic acid is also a normal constituent of foods and is readily metabolised. Normal blood lactate levels range from 45 to 200 mg/l. Assuming a daily consumption of 100 g meat, human exposure to lactic acid from this source will range from 100 to 400 mg/day (Choe et al., 2008). Exposure estimates of lactate from consumption of foodstuffs fortified with chromium(iii) tri-hydrate EFSA Journal 2012;10(10):

15 lactate, which ranges from µg per day for all populations, are therefore one order of magnitude lower. 3. Biological and toxicological data The Panel noted that the biological and toxicological database provided by the applicant for the present application is identical to that available for the evaluation by the Panel as regards the safety of chromium(iii) lactate tri-hydrate, as a source of chromium, added for nutritional purposes to food supplements and on the bioavailability of chromium from this source (EFSA, 2009). The Panel also noted that since then no additional data were provided. The Panel noted that reviews and evaluations of chromium(iii) (Eastmond et al., 2008; Levina and Lay, 2008) pointed at conflicting outcomes of genotoxicity assays and reported diverging views and conclusions on the consequences of this genotoxicity issue for the ultimate safety assessment of chromium(iii). The Panel also noted that additional relevant in vivo studies have shown that exposure to chromium(iii) chloride and chromium(iii) nitrate induced DNA deletions in mice and yeast respectively (Kirpnick-Sobol et al., 2006) and that it was recently reported that occupational exposure to chromium(iii) can lead to DNA damage to human peripheral lymphocytes, as evidenced by the Comet assay (Zhang et al., 2008). However, in 2010, re-evaluating the safety of chromium(iii), the Panel considered that based on the facts that (i) the maximum intake levels of up to 250 μg/day for supplemental intake as suggested by the WHO would be in the same order of magnitude as what would result from normal dietary intake, that (ii) in vitro, at high concentrations, chromium(iii) picolinate might cause DNA damage, and that this also applies to other sources of chromium(iii), but that this DNA damage is not reflected in in vivo genotoxicity assays, that (iii) chromium(iii) is not carcinogenic, and that (iv) there is a large margin of safety between a daily intake of 250 μg/day (amounting to 4.1 μg/kg bw/day for a 60 kg person) and the NOAEL from long-term studies (NTP, 2008) of 6100 mg/kg bw/day chromium(iii) picolinate monohydrate (equivalent to 727 mg chromium(iii)/kg bw/day) in mice and of 2400 mg/kg bw/day chromium(iii) picolinate monohydrate (equivalent to 300 mg chromium(iii)/kg bw/day) in rats (EFSA, 2010a). On these bases the Panel concluded that the safety of chromium(iii) as a nutrient is not of concern, provided that the intake of chromium(iii) from these sources does not exceed 250 μg/day, the value established by the WHO for supplemental intake of chromium that should not be exceeded' (EFSA, 2010a). 4. Discussion The Panel noted that no new data have been provided by the applicant as regards the safety and bioavailability of chromium from chromium(iii) lactate tri-hydrate and therefore concurs with its views expressed in 2009 stating that no evidence was provided by the applicant supporting the bioavailability of chromium from chromium(iii) lactate tri-hydrate. Although chromium(iii) lactate tri-hydrate is described by the applicant as freely soluble in water, chromium(iii) lactate tri-hydrate exists as a weak complex that may influence the bioavailability of chromium(iii) in the gastrointestinal tract. Therefore, the Panel re-iterates that because of the complex chemistry of chromium(iii) lactate tri-hydrate in aqueous solutions and its limited solubility at ph >5, the bioavailability of chromium(iii) from chromium(iii) lactate tri-hydrate is likely to be low. Although there are reports in the literature that chromium from organic sources, such as chromiumenriched yeast, is more bioavailable than chromium from inorganic chromium compounds, such as chromium chloride, overall the available data do not permit a definite conclusion on this issue. The Panel re-iterates its views expressed in the 2009 opinion (EFSA, 2009) that, overall, the bioavailability of chromium is low and that therefore the bioavailability of chromium from EFSA Journal 2012;10(10):

16 chromium(iii) lactate tri-hydrate is likely to be similar to that of chromium from dietary sources (i.e %). The estimated mean chromium intake from the use of chromium(iii) lactate tri-hydrate as an added nutrient source of chromium from the new applications is in the range between 7-22 µg chromium/day for toddlers, µg chromium/day for children, 9-32 µg chromium/day for adolescents, 7-37 µg chromium/day for adults and 4-17 for the elderly. The ranges for the percentile intakes are µg chromium/day for toddlers, µg chromium/day for children, µg/day for adolescents, µg/day for adults and µg/day for the elderly. The major contributors to exposure for toddlers, children and the elderly are fermented milk products, providing about 26-81%, 12-48% and 14-64% of the chromium, respectively. For adolescents, the major contributor was found to be soft drinks, contributing between 15-49%, whereas for adults, beer and beer-like beverages were found to be the major contributor (11-46%), followed by soft drinks (12-38%). The maximum intake of chromium from food supplements containing chromium(iii) is estimated to be 200 µg chromium/day and would be of comparable magnitude to the intake from food sources. Based on a conservative exposure estimate, assuming a daily maximum intake of 200 µg chromium(iii) from food supplements in addition to an average daily intake of 37 and 43 µg/day in adults and children from food fortification, an intake of approximately 240 µg chromium(iii)/day for both adults and children can be calculated. This is below the value of 250 µg/day, value established by the WHO for supplemental intake of chromium that should not be exceeded. The intake of lactate from the consumption of foods fortified with chromium(iii) lactate tri-hydrate was estimated. This intake was calculated to be 5.2 g lactate per gram of chromium(iii), resulting in a maximum mean intake of lactate of µg lactate/day for children and µg lactate/day for adults. The Panel noted that lactic acid is a normal constituent of foods and is readily metabolised. Normal blood lactate levels range from 45 to 200 mg/l. Assuming a daily consumption of 100 g meat, adult exposure to lactic acid from this source will range from 100 to 400 mg lactic acid/day ( mg lactic acid/kg bw/day). The estimated intake of lactose from the use of chromium(iii) lactate tri-hydrate, in the form of the premix, in the new applications would be mg lactose/day ( µg lactose/kg bw/day) at the mean for children and 7-37 mg lactose/day ( µg lactose/kg bw/day) at the mean for adults. Given that subjects with lactose maldigestion will tolerate up to 12 g of lactose with no or minor symptoms, these levels are not of safety concern. CONCLUSIONS The present opinion deals with the safety of chromium(iii) lactate tri-hydrate, as a source of chromium, added for nutritional purposes to foods for the general population and with the bioavailability of chromium(iii) from this source. The safety of chromium itself, in terms of the amounts that may be consumed, is outside the remit of this Panel. The Panel concurred with the view of the SCF that overall, the bioavailability of chromium is low and therefore the bioavailability of chromium from chromium(iii) lactate tri-hydrate is likely to be similar to that of chromium from dietary sources (0.5-2%). Based on a conservative exposure estimate, the Panel calculated the combined intake of chromium(iii) from supplements and from food fortification, for both adults and children, to be approximately 240 µg chromium(iii)/day, which is below the value of 250 µg/day established by the WHO for supplemental intake of chromium that should not be exceeded. EFSA Journal 2012;10(10):

17 The Panel considered that the intake levels of lactose from the chromium(iii) lactate tri-hydrate, in the form of the premix, are not of safety concern. DOCUMENTATION PROVIDED TO EFSA 1. Request for the Certification of Chromium(III) Lactate Tri-hydrate according to the Article 17(1)(b) of Regulation 1925/ November Submitted by Agrobac, Czech Republic. REFERENCES Choe JH, Choi YM, Lee SH, Shin HG, Ryu YC, Hong KC, Kim BC, The relation between glycogen, lactate content and muscle fiber type composition, and their influence on postmortem glycolytic rate and pork quality. Meat Science 80, D-A-CH Referenzwerte, Deutsche Gesellschaft für Ernährung, Österreichische Gesellschafter für Ernährung, Schweizerische Gesellschafter für Ernährungsforschung, Schweizerische Vereinigung für Ernährung: Referenzwerte für die Nährstoffzufuhr, Umschau/Braus Verlag. De Neve M, Sioen I, Boon PE, Arganini C, Moschandreas J, Ruprich J, Lafay L, Amiano P, Arcella D, Azpiri M, Busk L, Christensen T, D'Addezio L, Fabiansson S, Hilbig A, Hirvonen T, Kersting M, Koulouridaki S, Liukkonen K-H, Oltarzewski M, Papoutsou S, Rehurkova I, Ribas-Barba L, Serra-Majem L, Tornaritis M, Trolle E,Van Klaveren JD, Verger E, Walkiewicz A, Westerlund A, De Henauw S, Huybrechts I, Harmonisation of food categorisation systems for dietary exposure assessments among European children. Food Additives and Contaminants: Part A, 27, 12, EFSA (European Food Safety Authority), Scientific Opinion of the Panel on Food Additives and Nutrient Sources added to Food on chromium(iii) lactate tri-hydrate as a source of chromium added for nutritional purposes to food supplements. The EFSA Journal (2009), 1112, EFSA (European Food Safety Authority), 2010a. Scientific Opinion on the safety of trivalent chromium as a nutrient added for nutritional purposes to foodstuffs for particular nutritional uses and foods intended for the general population (including food supplements). EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS). The EFSA Journal (2010), 8(12):1882. EFSA (European Food Safety Authority), 2010b. Scientific Opinion on lactose thresholds in lactose intolerance and galactosaemia. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). EFSA Journal 2010;8(9):1777. EFSA (European Food Safety Authority), 2011a. Use of the EFSA Comprehensive European Food Consumption Database in Exposure Assessment. The EFSA Journal (2011), 9(3):2097, 34 pp. EFSA (European Food Safety Authority), 2011b. Evaluation of the FoodEx, the food classification system applied to the development of the EFSA Comprehensive European Food Consumption Database. The EFSA Journal (2011), 9(3):1970, 27 pp. Eastmond DA, MacGregor JT, Slesinski RS, Trivalent chromium: Assessing the genotoxic risk of an essential trace element and widely used human and animal nutritional supplement. Critical Reviews in Toxicology 38, EVM (Expert Group on Vitamins and Minerals), Part 3: trace elements - Chromium. In Safe Upper Levels for Vitamins and Minerals: Report of the Expert Group on Vitamins and Minerals Food Standards Agency (FSA), London, England. FNB (Food and Nutrition Board), Dietary Reference Intakes: Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc. Washington DC. EFSA Journal 2012;10(10):

18 Holland B, Unwin ID, Buss DH, McCance RA, Widdowson EM, McCance and Widdowson s The composition of foods. 4 th Supplement, Milk products and eggs. Royal Society of Chemistry and Ministry of Agriculture. Fisheries and Food. London: HMSO. Kirpnick-Sobol Z, Reliene R, Schiestl RH, Carcinogenic Cr(VI) and the nutritional supplement Cr(III) induce DNA deletions in yeast and mice. Cancer Res. 66, Levina A, Lay PA, Chemical properties and toxicity of chromium(iii) nutritional supplements. Chemical Research in Toxicology 21, Merten C, Ferrari P, Bakker M, Boss A, Hearty A, Leclercq C, Lindtner O, Tlustos C, Verger P, Volatier JL, Arcella D, Methodological characteristics of the national dietary surveys carried out in the European Union as included in the European Food Safety Authority (EFSA) Comprehensive European Food Consumption Database. Food Addit Contam, Part A, Chem Anal Control Expo Risk Assess. 28(8), NTP (US National Toxicology Programme), NTP Technical Report on the Toxicology and Carcinogenesis Studies of chromium(iii) picolinate monohydrate (CAS No ) in F344/N Rats and B6C3F1 Mice (Feed Studies): DRAFT. Department of Health and Human Services (DHHS). National Toxicology Program (NTP), Research Triangle Park, North Carolina. NTP Technical Report Series, No Abstract available from: Full draft available from: Pearson RG, Hard and Soft Acids and Bases. J. Am. Chem. Soc. 85, SCF (Scientific Committee on Food), Opinion of the Scientific Committee on Food on the tolerable upper intake level of trivalent chromium (expressed on 4 April 2003). Available at: WHO (World Health Organization), Trace elements in human nutrition and health, (A Report of a re-evaluation of the role of trace elements in human health and nutrition). Geneva. Zhang M, Chen Z, Chen Q, Zou H, Lou J and He J, Investigating DNA damage in tannery workers occupationally exposed to trivalent chromium using comet assay. Mutat. Res. 654, EFSA Journal 2012;10(10):