Vitamin and mineral supplements: a risk management model Directive 2002/46/EU harmonizes vitamins and their chemical forms allowed for food supplements without setting maximum supplement levels (MSLs). For most of these nutrients Upper Tolerable Intake Levels (Uls) for intake from all sources (ordinary foods, fortified foods, and food supplements) have been set by the Scientific Committee for Food (SCF) or the European Food Safety Agency (EFSA). It will be absolutely key for the successful implementation of the new directive to develop a harmonized and transparent risk management model for setting MSLs. Nutrient characterisation according to their risk Nutrients can be categorised in three risk groups following the assessment of the SCF: Group 1: No UL set, because no data available so far could demonstrate any side effect Group 2: UL set, mild and reversible side effects, large gap between nutritional need (RDA) and UL. Group 3: UL set, potentially serious and irreversible side effects, small gap between RDA and UL. The Risk Management Model Group 1For Group 1 no risk exists. Risk management is not necessary or MSLs can be set according to existing market experience of manufacturers. Group 3 nutrients should be regulated on a case by case basis taking into consideration the respective risk as well as the nutritional need (risk – benefit balance). MSLs for group 2 nutrients can be calculated with a model equation taking into consideration all other nutritional sources plus an additional margin for potential long-term changes of dietary habits. Member States may use this model for updating their national nutritional surveys to improve the respective data base needed for the calculation. Group 3 Group 2 MSL = UL – (MHI x factor); MHI = mean highest intake from all sources Factor = margin for potential long term changes of dietary habits

Vitamin and mineral supplements: a risk management model Stage 1: Characterising the Safety of Vitamins and Minerals Nutrients with established UL: Upper level derived from LOAEL or NOAEL by applying uncertainty factors ARE NOT thresholds for adverse effects. RLV : UPPER LEVELS (UL): (= upper tolerable levels of intake) (As set by SCF / EFSA) Quantitative Safety Characterisation INTAKE RISK LOAELNOAELULRLV SAFE RANGE INTAKE INTAKE FROM FOOD AND WATER MSL ARE intake levels that can be consumed daily over a lifetime without being likely to pose any risk to health according to available evidence. MSL: Represent total figure for intake from all sources UL derived from scientific risk assessment by independent scientists Lowest dose that shows observed adverse effects UL Recommended daily intake level in the population as published by the Scientific Committee on Food Maximum level for long-term daily supplement consumption Highest dose that will not give undesirable effects NOAEL LOAEL:

Vitamin and mineral supplements: a risk management model Stage 1: Characterising the Safety of Vitamins and Minerals INTAKE RISK ULRLV MHI + IW = INTAKE FOOD AND WATER PSI = RLV UL- (MHI + IW) Classification of minerals and vitamins into risk categories IW: Intake from water (only relevant for minerals) MHI: (Mean Highest Intake): Highest intake from dietary sources (97.5th percentile intake) Adult male intake data from available studies (Ire, It, Nl and UK) PSI (Population Safety Index):Measure for the relative potential of higher intake groups exceeding UL The most comprehensive data on nutrient intake patterns from supplements (UK and D) indicate on average, that supplements contribute a maximum of 141% of the RLV (in the case of Vitamin C) to total nutrient intake. Chances of exceeding UL through supplementation is extremely low at PSI higher than 1.5 (I.e. where the difference between current highest intake from food and UL is more than 150% of RLV) Potential risk of exceeding the UL (based on calculated PSI) Iron Iodine Copper Calcium Zinc Vitamin A (preformed retinol) Low risk of exceeding the UL (based on calculated PSI) Nicotinamide Vitamin E Vitamin C Vitamin B Vitamin D Molybdenum Selenium Phosphorus Remark: For Magnesium and Folic Acid the UL established by the SCF are UL for supplementation and do not include intake from normal foods and beverages. RLV: Reference Labelling Values (SCF 2003; cfr. RDA, PRI, …)

Vitamin and mineral supplements: a risk management model Stage 1: Characterising the Safety of Vitamins and Minerals If UL is not established, qualitative risk characterisation is required on the basis of available risk assessment. Extensive reviews by the Scientific Committee on Food and EFSA give indications of the nature of adverse effects associated with each nutrient and potential risks in relation to existing patterns of intake. Nutrients without a UL:Qualitative Safety Characterisation Qualitative assessment of the SCF opinions (and other authoritative reports) show no adverse effects in healthy individuals associated with high intakes of Conclusions:Three categories of Vitamins and Minerals A: No evidence of risk within ranges currently consumed; Does not represent a risk to human health Vitamin B1, Vitamin B2, Biotin, Vitamin B12, Pantothenic acid, Vitamin K, Chromium B: Low risk of exceeding the UL Vitamin B6, Vitamin C, Vitamin D, Vitamin E, Nicotinamide, Molybdenum, Phosphorus, Selenium C: Potential risk of exceeding the UL Vitamin A, Beta-carotene (smokers), Calcium, Copper, Fluoride, Iodine, Iron, Manganese, Zinc Magnesium, Folic acid: UL for supplementation set by SCF Biotin / Chromium / Pantothenic acid / Vitamin B2 / Vitamin B1 / Vitamin B12 / Vitamin K.

For vitamins Vitamin and mineral supplements: a risk management model Stage 2: Setting of Maximum Supplement Levels (MSL) A: No evidence of risk: B: Low risk of exceeding UL:MSL to take into account changing dietary patterns Scale of potential changes from UK surveys (1986/ /1): Increase of intake more than 20 % only for Vitamin B6 and C. intake from foods and fortified foods (in a liberal market place) C: Potential risk of exceeding UL:MSL to take into account RLV, risk of deficiency and risk of excessive intake INTAKE RISK ULRLV MHI + IW = INTAKE FOOD + WATER INTAKE FROM FOOD SUPPLEMENTS ? ? Potential increase in nutrient intake Risk Management Factor Required No setting of MSL required Precautionary risk management factor of 50% to take into account potential changes in dietary pattern. MSL = UL – (MHI x 150%) MSL for Magnesium and Folic acid have been set by SCF For minerals For technical and taste reasons, mineral fortification is self-limiting. Therefore a factor of 10% could be set. MSL = UL –[(MHI x 110%) + IW]

Categorisation Vitamin B1 Vitamin B2 Biotin Vitamin B12 Pantothenic acid Vitamin K Chromium Vitamin and mineral supplements: a risk management model Vitamin B6 Vitamin C Vitamin D Vitamin E Folic acid Nicotinamide Phosphorus Magnesium Molybdenum Selenium Qualitative Risk CharacterisationQuantitative Risk Characterisation Intake through water Mean Highest Intake (97.5th percentile) Data indicate that MHI is max 141% Beta-carotene (smokers) Vitamin A Calcium Copper Fluoride Iodine Iron Manganese Zinc PSI Higher than 1.5PSI Lower than 1.5 No evidence of risk within ranges currently consumed; Does not represent a risk to human health Low risk of exceeding the ULPotential risk at excessive intakes Nutrients without established UL Nutrients with UL established by the SCF Based on extensive reviews by SCF Based on Population Safety Index (PSI) Stage 1: Characterising the Safety of Vitamins and Minerals

Vitamin and mineral supplements: a risk management model No evidence of risk within ranges currently consumed; Does not represent a risk to human health Low risk of exceeding the ULPotential risk at excessive intakes Stage 2: Setting of Maximum Supplement Levels (MSL) MSL to take into account RLV, risk of deficiency and risk of excessive intake No setting of MSL required MSL to take into account changing dietary patterns Data indicate that impact of changes in dietary pattern are seldom higher than 20% Ranges reflect widely divergent ULs from international risk assessments. † No UL set by SCF 10–15 mgZinc 2 mgManganese † 14–20 mgIron 150–200 µgIodine 3.5 mgFluoride 1–2 mgCopper 1000–1500 mgCalcium 4.8–7 mgBeta-carotene † 800–1000 µgVitamin A Proposed MSLNutrient † No UL set ; †† ULs set for supplementation by SCF. ††† Ranges reflect widely divergent ULs from international risk assessments 600 µg †† Folic acid 250 mg †† Magnesium 200 µgSelenium 1250 mgPhosphorus 350 µgMolybdenum 820 mgNicotinamide 270 / 970 mg ††† Vitamin E 35 µgVitamin D 1750 mgVitamin C † 18 / 93 mg ††† Vitamin B 6 Proposed MSLNutrient † Classification based on those sources currently approved in Annex II of Directive 2002/46/EC and 2001/15/EC -Chromium † -Vitamin K -Pantothenic acid -Vitamin B 12 -Biotin -Vitamin B 2 -Vitamin B 1 Proposed MSLNutrient