1 2 Output metadata Output category Scientific opinion Date adopted [Panel/SC] / Date approved [non-Panel/SC] / Author list [names or ORCID in EFSA Panel on Contaminants in the Food Chain (CONTAM), order of authorship WIN, beginning Dieter Schrenk, Margherita Bignami, Laurent Bodin, James with EFSA Panel] Kevin Chipman, Jesús del Mazo, Bettina Grasl-Kraupp, Christer Hogstrand, Laurentius (Ron) Hoogenboom, Jean- Charles Leblanc, Carlo Stefano Nebbia, Evangelia Ntzani, Annette Petersen, Salomon Sand, Tanja Schwerdtle, Christiane Vleminckx, Heather Wallace, Thierry Guérin, Peter Massanyi, Henk Van Loveren, Katleen Baert, Petra Gergelova and Elsa Nielsen DOI 10.2903/j.efsa.2020.xxxx Requestor European Commission Output number ONXXX Question number(s) [separate EFSA-Q-2019-00214 multiple entries with commas] Correspondence [email protected] Short title [header] Nickel in food and drinking water Panel members Margherita Bignami, Laurent Bodin, James Kevin Chipman, Jesús del Mazo, Bettina Grasl-Kraupp, Christer Hogstrand, Laurentius (Ron) Hoogenboom, Jean-Charles Leblanc, Carlo Stefano Nebbia, Elsa Nielsen, Evangelia Ntzani, Annette Petersen, Salomon Sand, Dieter Schrenk, Tanja Schwerdtle, Christiane Vleminckx, Heather Wallace Copyright for non-EFSA content [Example: Reproduction of the images listed below is prohibited and permission must be sought directly from the copyright holder: Figure 1: © ECDC] Acknowledgements The Panel wishes to thank the following for the support provided to this scientific output: Elena Rovesti. The Panel wishes to DRAFTacknowledge all European competent institutions, Member State bodies and other organisations that provided data for this scientific output. Minority opinion / Competing interests / Note Legal notice Disclaimer Example data are in square brackets and need to be updated or deleted before dispatch to Wiley 3 4 Update of the risk assessment of 5 nickel in food and drinking water 6 7 EFSA Panel on Contaminants in the Food Chain (CONTAM), Dieter Schrenk, Margherita 8 Bignami, Laurent Bodin, James Kevin Chipman, Jesús del Mazo, Bettina Grasl-Kraupp, 9 Christer Hogstrand, Laurentius (Ron) Hoogenboom, Jean-Charles Leblanc, Carlo Stefano 10 Nebbia, Evangelia Ntzani, Annette Petersen, Salomon Sand, Tanja Schwerdtle, Christiane 11 Vleminckx, Heather Wallace, Thierry Guérin, Peter Massanyi, Henk Van Loveren, Katleen 12 Baert, Petra Gergelova and Elsa Nielsen 13 14 Abstract 15 The European Commission asked EFSA to update its previous Opinion on nickel in food and 16 drinking water, taking into account new occurrence data, the updated benchmark dose (BMD) 17 Guidance and newly available scientific information. More than 47,000 analytical results on 18 the occurrence of nickel were used for calculating chronic and acute dietary exposure. An 19 increased incidence of post-implantation loss in rats was identified as the critical effect for the 20 risk characterisation of chronic oral exposure and a BMDL10 of 1.3 mg Ni/kg bw per day was 21 selected as the reference point for the establishment of a tolerable daily intake (TDI) of 22 13 µg/kg bw. Eczematous flare-up reactions in the skin elicited in nickel-sensitised humans, a 23 condition known as systemic contact dermatitis (SCD), was identified as the critical effect for 24 the risk characterisation of acute oral exposure. A BMDL could not be derived and therefore, 25 the lowest-observed-adverse-effect-level of 4.3 µg Ni/kg bw was selected as the reference 26 point. The margin of exposure (MOE) approach was applied and an MOE of 30 or higher was 27 considered as being indicative of a low health concern. The mean chronic dietary exposure 28 was below or at the level of the TDI. The 95th percentile chronic dietary exposure was below 29 the TDI in adolescents and in all adult age groups, but generally exceeded the TDI in toddlers 30 and in other children, as well as in infants in some surveys. This may raise a health concern 31 in these young age groups. The MOE values for the mean acute dietary exposure and for the 32 95th percentile raises a healthDRAFT concern for nickel-sensitised individuals. The MOE values for 33 an acute scenario regarding consumption of a glass of water on an empty stomach do not 34 raise a health concern. 35 36 Keywords 37 Nickel, tolerable daily intake (TDI), margin of exposure (MOE), food, dietary exposure, 38 sensitisation, toxicity 1 39 Summary 40 The European Commission asked the European Food Safety Authority (EFSA) to update the previous 41 EFSA Scientific Opinion on the risks to public health related to the presence of nickel in food and drinking 42 water (EFSA CONTAM Panel, 2015), taking into account the new occurrence data, the updated BMD 43 Guidance and any newly available scientific information. 44 Nickel is a widespread component of Earth’s crust and is ubiquitous in the biosphere. Its presence in 45 food and drinking water can arise from both natural and anthropogenic sources. Nickel occurs in 46 different oxidation states. In food and drinking water, nickel generally occurs in the divalent form, which 47 is the most stable oxidation state. 48 Nickel is usually measured in food as total nickel and there are only few studies of nickel speciation in 49 food. It is generally assumed that nickel occurs in food in the form of complex bound organic nickel, 50 which has different physico-chemical and possibly also different biological properties than inorganic 51 nickel. 52 Hazard identficaction and characterisation 53 Nickel absorption from the gastrointestinal tract is dependent on the chemical form and thus, the 54 solubility of the nickel compound. Absorption may be decreased by binding or chelating substances, 55 competitive inhibitors, or redox reagents. On the other hand, absorption is often enhanced by 56 substances that increase pH, solubility, or oxidation, or by chelating agents that are actively absorbed. 57 In humans, the bioavailability of nickel following ingestion also depends on the solubility of the 58 administered nickel compound, the dosing vehicle and the fasting state of the subject. A low absorption 59 (0.7-2.5%) was reported when nickel was ingested in the presence of food or under a non-fasted state, 60 whereas a higher absorption (25-27%) was reported when nickel was ingested via drinking water in 61 the absence of food, or under a fasted state. The number of individuals examined in the relevant human 62 studies was low. There was also a considerable inter-individual variability in these studies. Thus, a 63 precise estimate of the oral bioavailability of nickel in humans under different conditions cannot be 64 established for the acute risk characterisation. 65 A study in rats showed an absorption of around 10% when soluble nickel compounds were administered 66 in a 5% starch saline solution as vehicle. Such a condition is considered as being representative for 67 dietary exposure via food and beverages for the chronic risk characterisation. 68 After absorption, nickel is widely distributed in the organism. Nickel was shown to cross the placenta in 69 mice. Nickel can also be transported across the blood brain barrier. Absorbed nickel is excreted mainly 70 via the urine. During lactation nickel can also be excreted in the breast milk. An elimination half-life of 71 28 ± 9 hours was estimated in human volunteers. 72 The divalent metal transporter 1 (DMT1) mediates the transport of nickel and other divalent metal ions 73 such as iron from the lumen of the intestine into the enterocyte and also mediates apical uptake of 74 divalent cations in the kidney. DMT1 is known to be involved in the transport of divalent iron into the 75 cytosol of endosomal cells priorDRAFT to transport across the blood brain barrier by ferroportin. Since nickel 76 is also a substrate for DMT1, this transporter is likely to also be involved in nickel uptake into the brain. 77 The major effects observed in the short-term repeated dose toxicity studies in rodents and dogs 78 following oral administration were decreased body weight and effects in the liver and kidney (changes 79 in organ weights and histopathological changes). Effects on bone and on gut microbiota have also been 80 reported in a few recent studies. 81 A few studies indicate that nickel can disturb neurobehavioural functions in mice and rats as indicated 82 by impaired spatial memory performance and effects on locomotor activity. Neurodegeneration in adult 83 rats has also been reported. 84 In mice, different reproductive effects such as decreased male sex organ weights and histopathological 85 changes in these organs, disturbed spermatogenesis, decreased sperm motility and sperm damages 86 have been reported after oral exposure to soluble nickel compounds. The reproductive effects were 87 responsible for a decreased fertility in mice. A recent short-term toxicity study (28 days) with limited 2 88 reporting suggested that nickel may also cause testicular degeneration in rats. Mice appear to be more 89 sensitive than rats regarding reproductive effects. 90 There is consistent evidence of developmental toxicity in rats in the form of increased pup mortality 91 (stillbirth or post implantation loss/perinatal lethality) and decreased pup weight after oral exposure to 92 soluble nickel compounds. Developmental toxicity was also observed in mice (decreased fetal weight, 93 malformations) but at higher doses than for rats suggesting that rats appear to be more sensitive than 94 mice regarding developmental toxicity. Based on the available data, the CONTAM Panel considers that 95 the increased incidence of post-implantation loss in rats is the critical effect for the risk characterisation 96 of chronic oral exposure to nickel. This is in agreement with the previous Opinion. 97 Nickel compounds are inactive in almost all bacterial mutagenicity tests and are weakly mutagenic in 98 cultured mammalian cells. Nickel ions may be co-mutagenic, which is likely due to interference with 99 DNA repair processes.