Statement on the safety of iodized ethyl esters of poppy seed oil as a source of iodine added for nutritional purposes to foodstuffs 1

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1 EFSA Journal 2013;11(3):3120 SCIENTIFIC OPINION Statement on the safety of iodized ethyl esters of poppy seed oil as a source of iodine added for nutritional purposes to 1 ABSTRACT EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) 2, 3 European Food Safety Authority (EFSA), Parma, Italy 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 on the safety of iodized ethyl esters of poppy seed oil (ethyl esters of iodinated fatty acids of poppy seed oil, EEIFA PSO ) and the bioavailability of the iodine from this source when used for the fortification of vegetable oils with iodine. The safety of iodine itself, in terms of amounts that may be consumed, is outside the remit of this Panel. EEIFA PSO are described as a mixture of ethyl palmitate, ethyl stearate, ethyl monoiodostearates, ethyl diiodostearates and ethyl triiodostearates. The iodine content of EEIFA PSO is % (w/w) and the source is intended to be added at the concentration of mg of EEIFA PSO per kg of vegetable oil. The Panel noted that kinetic data referring to exposure conditions of fortification are limited and that available results are indicating that a possible bioaccumulation of EEIFA PSO and/or their metabolites may occur. Furthermore the available data did not allow a quantitative assessment of the bioavailability of iodine from EEIFA PSO. No data are available on short-term, subchronic and chronic toxicity, carcinogenicity and reproductive toxicity of EEIFA PSO. Overall the Panel could not conclude on the safety of EEIFA PSO as a source of iodine in food fortification and on the bioavailability of iodine from this source due to data gaps in the kinetic and the dynamic properties of the different iodinated compounds in EEIFA PSO. European Food Safety Authority, 2013 KEY WORDS Iodized ethyl esters of poppy seed oil, ethyl esters of iodinated fatty acids of poppy seed oil. 1 On request from the European Commission, Question No EFSA-Q , adopted on 19 February 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, Agneta Oskarsson, Dominique Parent-Massin, Martin Rose, Ivan Stankovic, Paul Tobback, Ine Waalkens-Berendsen, Rudolf Antonius Woutersen and Matthew Wright. Correspondence: ans@efsa.europa.eu 3 Acknowledgement: The Panel wishes to thank the members of the Working Group B on Food Additives and Nutrient Sources added to Food: Fernando Aguilar, Martine Bakker (until February 2013), Riccardo Crebelli, Birgit Dusemund, David Gott, Torben Hallas-Møller, Jürgen König, Oliver Lindtner, Daniel Marzin, Inge Meyland, Alicja Mortensen, Iona Pratt, Paul Tobback, Ine Waalkens-Berendsen and Rudolf Antonius Woutersen for the preparatory work on this scientific opinion. Suggested citation: EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS); Statement on the safety of iodized ethyl esters of poppy seed oil as a source of iodine added for nutritional purposes to. EFSA Journal 2013;11(3):3120. [10 pp.] doi: /j.efsa Available online: European Food Safety Authority, 2013

2 SUMMARY Following a request from the European Commission to the European Food Safety Authority (EFSA), the Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver an opinion on the safety of iodized ethyl esters of poppy seed oil (ethyl esters of iodinated fatty acids of poppy seed oil, EEIFA PSO ) and the bioavailability of the iodine from this source when used for the fortification of vegetable oils with iodine. The safety of iodine itself, in terms of amounts that may be consumed, is outside the remit of this Panel. EEIFA PSO are described as a mixture of ethyl palmitate, ethyl stearate, ethyl monoiodostearates, ethyl diiodostearates and ethyl triiodostearates. The source is intended to be added at the concentration of mg of EEIFA PSO per kg of vegetable oil. The iodine content of EEIFA PSO is % (w/w) and the resulting final iodine content in the iodine-enriched vegetable oils amounts to to mg/kg. The Panel considered that EEIFA PSO are a mixture containing potentially a variety of 14 positional isomers of the ethyl esters of mono-, di-, or triiodostearic acid, each existing in the form of two to eight stereoisomers. The relative proportions of the isomers present in EEIFA PSO were not indicated by the applicant. Kinetic studies in humans with oral administration of EEIFA PSO in a single high dose followed by observations for up to one year showed that iodine was retained in the body and progressively released over a long time period. The Panel noted that this was indicative of a long half life of EEIFA PSO or their metabolites. The Panel also noted that kinetic data referring to exposure conditions of fortification are limited and that available results indicate that a possible bioaccumulation of EEIFA PSO and/or their metabolites may occur. Furthermore the available data did not allow a quantitative assessment of the bioavailability of iodine from EEIFA PSO. The Panel was aware of results showing that monoiodostearic acid esters or their metabolites have a higher retention in the organism than diiodostearic acid esters or their metabolites and will therefore release iodide for longer periods. Thus the Panel presumed that different iodinated components in EEIFA PSO such as ethyl mono-, di- and triiodostearates may persist for different times in the body and the Panel further noted that corresponding data were missing. It had to be considered that variations in composition of EEIFA PSO, which may be due to the use of poppy seed oils of different origin in the manufacturing process, could lead to differences in the rate of release of iodine. No data were available on short-term, subchronic and chronic toxicity, carcinogenicity and reproductive toxicity of EEIFA PSO. Overall the Panel could not conclude on the safety of EEIFA PSO as a source of iodine for the fortification of food and on the bioavailability of iodine from this source due to data gaps in the kinetic and the dynamic properties of the different iodinated compounds in EEIFA PSO. EFSA Journal 2013;11(3):3120 2

3 TABLE OF CONTENTS Abstract... 1 Summary... 2 Table of contents... 3 Background as provided by the European Commission... 4 Terms of reference as provided by the European Commission... 4 Evaluation Introduction Assessment... 5 Conclusions... 8 Documentation provided to EFSA... 8 References... 9 Glossary and abbreviations EFSA Journal 2013;11(3):3120 3

4 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 iodized ethyl esters of poppy seed oil as a source of iodine added for nutritional purposes to. The relevant Community legislative measures are: 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 4. TERMS OF REFERENCE AS PROVIDED BY THE EUROPEAN COMMISSION In accordance with Article 29 (1) (a) of Regulation (EC) No 178/2002 5, the European Commission asks the European Food Safety Authority to: provide a scientific opinion, based on its consideration of the safety and bioavailability of iodized ethyl esters of poppy seed oil as a source of iodine added for nutritional purposes to. 4 Regulation (EC) No 1925/2006 of the European Parliament and of the Council of 20 December 2006 on the addition of vitamins and minerals and of certain other substances to foods. OJ L 404, , p Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety. OJ L31, , p.1. EFSA Journal 2013;11(3):3120 4

5 EVALUATION 1. Introduction Following a request from the European Commission to the European Food Safety Authority (EFSA), the Panel on Food Additives and Nutrient Sources added to Food (ANS), was asked to deliver a scientific opinion on the safety of iodized ethyl esters of poppy seed oil (ethyl esters of iodinated fatty acids of poppy seed oil, EEIFA PSO ) and on the bioavailability of the iodine from this source when used for the fortification of vegetable oils with iodine. The safety of iodine itself, in terms of amounts that may be consumed, is outside the remit of this Panel. 2. Assessment EEIFA PSO are described as a mixture of ethyl palmitate ( %), ethyl stearate ( %), ethyl monoiodostearates ( %), ethyl diiodostearates ( %), ethyl triiodostearates (< 0.6 %) and as stabiliser poppy seed oil (1 %). The source is intended to be added at the concentration of mg of EEIFA PSO per kg of vegetable oil. The iodine content of EEIFA PSO is % (w/w). The final iodine content in the iodine-enriched vegetable oils ranges from to mg /kg. According to the applicant the aim is to use EEIFA PSO as a source of iodine to fortify vegetable oils. An oil, containing 1 mg iodine/kg oil, was introduced on the market in Romania in 2006 where it is used in addition to iodized salt. The Panel noted that oils fortified with EEIFA PSO are intended for long term regular consumption by the general population. EEIFA PSO have also been used as slow release preparations, orally administered once per year in prophylactic campaigns for the prevention and control of iodine deficiency disorders (IDD), especially in developing countries. Claude (1997) calculated the recommended oral single dosage to be equivalent to mg iodine (approximately 2-5 capsules, 1 capsule containing 190 mg iodine in the form of 500 mg EEIFA PSO ) in adults for 12 months of efficacy. According to the applicant EEIFA PSO are obtained from poppy seed oil by complete iodination under conditions, in which one iodine atom is added per double bond of the unsaturated fatty acid chains (Wolff, 2001). The Panel noted that EEIFA PSO are a mixture containing a variety of up to 14 positional isomers of the ethyl esters of mono-, di-, or triiodostearic acid, differing in the number of iodine atoms and/or in the position of the iodine atom(s) in the fatty acid chain. In addition, due to the introduction of one to three chiral centres by iodination, each of the 14 individual positional isomers exists in the form of one to eight stereoisomers. The Panel noted that the use of poppy seed oils of other botanical origins and/or geographical origins as indicated by the applicant in the manufacturing procedure could result in different proportions of ethyl monoiodostearates, ethyl diiodostearates and ethyl triiodostearates as described above due to variation in the pattern of individual unsaturated fatty acids in the oils. An altered composition of the iodinated components of EEIFA PSO might influence the persistence of iodine in the body, since available data show that monoiodostearate esters or their metabolites have a higher retention in the rat than diiodostearate esters or their metabolites (van der Heide et al., 1989). Poppy seeds may be contaminated with alkaloids such as morphine, codeine, thebaine, noscapine, papaverine and oripavine which could also contaminate poppy seed oil (EFSA Panel on Contaminants in the Food Chain (CONTAM), 2011). Corresponding results of analysis for EEIFA PSO were made available by the applicant upon request of the Panel. None of the aforementioned alkaloids could be detected in EEIFA PSO. The limits of detection were 0.04, 0.02, 0.02, 0.75, 0.11 or 0.05 μg/g, respectively. The analytical procedure was based on RP-HPLC (reversed phase High-performance liquid chromatography) separation and subsequent ESI-MS (electrospray ionisation mass spectrometry) detection (morphine, codeine, thebaine, noscapine and papaverine) or HPLC EFSA Journal 2013;11(3):3120 5

6 (oripavine). The Panel concluded that none of the alkaloids mentioned is considered to be associated with a health risk for consumers with respect to the maximum levels given for EEIFA PSO taking into consideration that the concentrations of EEIFA PSO in the fortified vegetable oils is limited to 2.76 to 3.05 mg/kg. The Panel noted the absence of adequate data on the stability of EEIFA PSO and on the fate of EEIFA PSO in vegetable oil during storage and processing of food. Kinetic studies in humans with oral administration of EEIFA PSO in a single high dose followed by observations for up to one year showed that iodine was retained in the body and progressively released over a long time period (Ingenbleek et al., 2000; Leverge et al., 2003; Untoro et al., 2006). The Panel noted that this was indicative of a long half life of EEIFA PSO or their metabolites. The Panel noted that a new study investigating the kinetics in rat after a single dose of 125 I labelled EEIFA pso and after a single dose of 125 I labelled EEIFA pso preceeded by 28 days dosing with unlabelled EEIFA pso resulted in greater absorption and altered kinetics of 125 I labelled material after repeated administration (TNO Triskelion, 2012). The Panel also noted that rat data can only be used with caution in assessing the safety and kinetics of EEIFA PSO due to species differences in iodine metabolism and the absence of thyroxine binding globulin in adult rats (Hetzel and Maberly, 1986; IOM, 2001; Savu et al., 1992; SCF, 2002). In a study in Romanian school children, who for a one-month-period received daily doses of oil fortified with EEIFA PSO, elevated median urinary iodine excretion persisted in the 1 st month following the fortification period and returned to baseline values during the 3 rd to 6 th month (de Benoist et al., 2009; Simescu et al., 2008). The Panel concluded that the slow clearance and altered kinetics after repeated administration raises the question of potential bioaccumulation which cannot be ruled out based on the current data. The Panel noted that no data are available on short-term, sub-chronic and chronic toxicity, carcinogenicity and reproductive toxicity of EEIFA PSO. Mutagenicity testing with different strains of Salmonella typhimurium and Escherichia coli with and without metabolic activation gave negative responses (Claude, 1997). In an in vitro chromosomal aberration test with and without metabolic activation in human lymphocytes, negative results were also obtained (Claude, 1997), but because of insufficient reporting, the Panel noted that the validity of this assay could not be determined. Pregnant rats (n=25 per group) received EEIFA PSO by gavage from day 6 to day 17 of gestation in doses corresponding to 0, 50, 110 and 250 mg iodine/kg bw/day. The authors identified NOAELs for EEIFA PSO corresponding to 110 mg iodine/kg bw/day (mid dose equivalent to mg EEIFA PSO /kg bw/day) for maternal toxicity and to 250 mg iodine/kg bw/day (highest dose equivalent to mg EEIFA PSO /kg bw/day) for developmental toxicity (Claude, 1997). Furthermore EEIFA PSO were tested in two studies with continuous or intermittent administration by gavage in pregnant rabbits (Claude, 1997). In the first study with continuous application from day 6 to day 18 of gestation at levels of 12.5, 25 and 50 mg iodine in EEIFA PSO /kg bw/day, the maternal tolerance of the treatment was poor. The number of early resorptions increased in all treatment groups. Malformations in the fetuses were observed in the low and high dose groups. The Panel noted that under these conditions of continuous treatment, the NOAEL has to be expected to be below the lowest dose of EEIFA PSO tested, corresponding to 12.5 mg iodine/kg bw/day (equivalent to mg EEIFA PSO /kg bw/day). In the second study with intermittent application of EEIFA PSO corresponding to 12.5 mg iodine/kg bw/day (Group 1: dosing on gestation days 6, 9, 12, 15 and 18; Group 2: dosing on gestation days 7, 10, 13 and 16; Group 3: dosing on gestation days 8, 11, 14 and 17), no maternal toxicity was observed and no abnormalities were seen in the offspring. The Panel noted that the only EFSA Journal 2013;11(3):3120 6

7 dose of EEIFA PSO which has been tested, corresponding to 12.5 mg iodine/kg bw/day (equivalent to mg EEIFA PSO /kg bw/day), did not induce any adverse effect after intermittent treatment. Overall the Panel noted the following: EEIFA PSO are a mixture containing potentially a variety of 14 positional isomers of the ethyl esters of mono-, di-, or triiodostearic acid, differing in their degree of iodine content and/or in the position of the iodine atom(s) in the fatty acid chain. Each of the 14 individual positional isomers exists in the form of two to eight stereoisomers. No data were provided on which of the positional isomers (and stereoisomers) occur in EEIFA PSO. The concentrations of the individual positional isomers (and stereoisomers) in EEIFA PSO are not known. There are no data on the stability of EEIFA PSO and on the fate of EEIFA PSO in vegetable oil during storage and/or processing of food. Kinetic data referring to conditions of fortification (low, repeated, oral, long-term exposure) are limited and available results indicate that a bioaccumulation of EEIFA PSO and/or their metabolites may occur. Data are inadequate for the quantitative assessment of the bioavailability of iodine from EEIFA PSO. On the basis of the available data, an adequate comparison of the bioavailability of iodine from EEIFA pso to that from iodized salt (which is common for fortification purposes in food), or to that from other sources is not possible. The mechanism by which the different iodinated components of EEIFA PSO release iodine is not known. The break-down products or metabolites of EEIFA PSO have not been identified and it is also uncertain where deiodination of the components of EEIFA PSO occurs in the body. Monoiodostearic acid esters or their metabolites have a higher retention in the body than diiodostearic acid esters or their metabolites (no further characterisation of esters given) and will, thus, release iodide for longer periods (van der Heide et al, 1989). Thus the Panel presumed that different iodinated components in EEIFA PSO such as ethyl esters of mono-, diand triiodostearic acid in the form of their various isomers may have different retention times in the body. Therefore a variation in composition of EEIFA PSO may lead to differences in the rate of release of iodine. It has to be taken into account that different manufacturers may produce EEIFA PSO from poppy seed oil of different botanical and/or geographical origins. Such oils may have different proportions of unsaturated fatty acids influencing the final proportions of ethyl esters of mono-, di-, or triiodostearic acid in EEIFA PSO. No adequate data on the residence time of iodine (retention time) in the body from ethyl monoiodostearate esters, ethyl diiodostearate esters and ethyl triiodostearate esters are available. There is a lack of data on possible differences in the kinetic and the dynamic properties of individual positional isomers (and stereoisomers) having the same molecular formula. EFSA Journal 2013;11(3):3120 7

8 No data are available on short-term, sub-chronic and chronic toxicity, carcinogenicity and reproductive toxicity of EEIFA PSO. Negative results were obtained in mutagenicity tests with and without metabolic activation with Salmonella typhimurium strains and Escherichia coli and in human lymphocytes, but the validity of the latter assay could not be determined because the reporting of test conditions was inadequate. In developmental studies by gavage, in rats NOAELs for EEIFA PSO corresponding to 110 mg iodine/kg bw/day or 250 mg iodine/kg bw/day were identified for maternal toxicity or developmental toxicity, respectively. In rabbits receiving a daily administration of EEIFA PSO corresponding to 12.5 mg iodine/kg bw/day from day 6 to day 18 of gestation, maternal tolerance was poor and an increase in the numbers of early resorptions and malformations was induced. As a whole the Panel considered the database to be inadequate for the evaluation of a mixture of substances to be used for the fortification of food and therefore it could neither conclude on the safety of EEIFA PSO as a source of iodine added for nutritional purposes to, nor on the bioavailability of iodine from this source. This was due to gaps in knowledge on the composition of EEIFA PSO and in the kinetic and dynamic properties of the different iodinated compounds being present in EEIFA PSO. CONCLUSIONS The present opinion deals with the safety of EEIFA PSO as a source of iodine added for nutritional purposes to and on the bioavailability of iodine from this source. The safety of iodine itself, in terms of amounts that may be consumed, is outside the remit of this Panel. In view of the inadequate data base the Panel cannot conclude on the safety of EEIFA PSO as a source of iodine added for fortification purposes to, and on the bioavailability of iodine from this source due to data gaps concerning the composition of EEIFA PSO and in the kinetic and the dynamic properties of the different iodinated compounds being present in EEIFA PSO. DOCUMENTATION PROVIDED TO EFSA 1. Additional information related to a bioavailability and kinetics study on iodized ethyl esters of poppy seed oil. January Submitted by Bunge Europe, Switzerland. 2. Additional reference, December Submitted by Bunge Europe, Switzerland. 3. Updated authorisation dossier submitted for the safety evaluation of a source of iodine proposed for the addition to vegetable oil (Article 17 of Regulation (EC) N 1925/2006 of the European Parliament and of the Council on the addition of vitamins and minerals and of certain substances to foods. September Submitted by Bunge Europe, Switzerland. 4. Additional technical and exposure data. March Submitted by Bunge Europe, Switzerland. 5. Additional data on occurrence of oripavine in ethyl esters of iodized fatty acids. June Submitted by Bunge Europe, Switzerland. 6. Additional data on impurities, exposure data and references. April Submitted by Bunge Europe, Switzerland. 7. Authorisation dossier submitted for the safety evaluation of a source of iodine proposed for the addition to vegetable oil (Article 17 of Regulation (EC) N 1925/2006 of the European Parliament EFSA Journal 2013;11(3):3120 8

9 and of the Council on the addition of vitamins and minerals and of certain substances to foods. January Submitted by Bunge Europe, Switzerland. REFERENCES Claude JR, Expert Report on the toxicological documentation. Laboratoire Guerbet, Paris, Unpublished Report. De Benoist B, Simescu M, Podia-Igna CC, Sava M, Delange F, Correction of iodine deficiency by iodine fortified sunflower oil. 34th Annual European Meeting of the European Thyroid Association, 5-9 September 2009, p: 260. Lisbon, Portugal (abstract only). EFSA Panel on Contaminants in the Food Chain (CONTAM), Scientific Opinion on the risks for public health related to the presence of opium alkaloids in poppy seeds. EFSA Journal 2011;9(11):2405. [150 pp.] doi: /j.efsa Available online: Hetzel BS and Maberly GF Iodine. In: Mertz W, ed. Trace Elements in Human and Animal Nutrition, Vol. 2. Orlando: Academic Press. Pp as reported in IOM, Ingenbleek Y, Jung L, Férard G, Brassiodol. A new iodised oil for eradicating endemic goitre. The Journal of Trace Elements in Experimental Medicine 13 (1), IOM (Institute of Medicine), Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Food and Nutrition Board 2001: , National Academy, Washington DC. Leverge R, Bergmann JF, Simoneau G, Tillet Y, Bonnemain B, Bioavailability of oral vs. intramuscular iodinated oil (Lipiodol UF) in healthy subjects. Journal of Endocrinology and Investigation 26, Savu L, Vranckx R, Rouaze-Romet M, Nunez EA, The pituitary control of rat thyroxine binding globulin. Acta Medica Austriaca 19(1): SCF (Scientific Committee on Food), Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Iodine 26 September Health and Consumer Protection Directorate-General. SCF/CS/NUT/UPPLEV/26 Final. European Commission. Brussels. Simescu M, de Benoist B, Sava M, Podia-Igna C, Delange F. Correction of iodine deficiency by an iodized vegetable oil Floriol Iodine product (partial results). In: Metal Elements in Environment, Medicine and Biology. Publishing House Eurobit Timişoara, Tome VIIII; pp.: TNO Triskelion, Kinetics and ADME of Ethyl esters of [ 125 I] labeled iodized fatty acids of poppy seed oil (EEIFApso). Unpublished study report. Untoro J, Schultink W, West CE, Gross R, Hautvast GAJ, Efficacy of oral iodized peanut oil is greater than that of iodized poppy seed oil among Indonesian schoolchildren. The American Journal of Clinical Nutrition 84, Van der Heide D, de Goeje MJ, van der Bent C, 1989.The effectiveness of iodized oil in rats and man. Ann Endocrinol 50, Abstract 63. Wolff J, Physiology and pharmacology of iodized oil in goitre prophylaxis. Medicine 80, EFSA Journal 2013;11(3):3120 9

10 GLOSSARY AND ABBREVIATIONS ANS Scientific Panel on Food Additives and Nutrient Sources added to Food EC European Commission EEIFA Ethyl esters of iodized fatty acids EEIFA PSO Ethyl esters of iodized fatty acids of poppy seed oil EFSA European Food Safety Authority IDD Iodine deficiency disorders SCF Scientific Committee on Food EFSA Journal 2013;11(3):