Evaluation of Tolerable Upper Intake Levels for Vitamin D in Children and Adolescents

In 2012, the European Food Safety Authority (EFSA) suggested a tolerable upper intake level (UL) for vitamin D at 100 µg/day for adults based on the risk of hypercalcaemia. EFSA concluded that consumption of up to 50 µg/day does not lead to hypercalcaemia in children and adolescents (10-17 years). Furthermore, EFSA stated that there is no reason to assume that children and adolescents in the phase of rapid bone formation and growth have a lower tolerance for vitamin D compared to adults, and a UL of 100 µg/day for adolescents aged 11-17 years and 50 µg/day in children 1-10 years, taking the smaller body size into account, was proposed. The Norwegian Food Safety Authority (NFSA) is currently revising the national regulation of maximum limits in food supplements (not yet harmonised in the European Economic Area (EEA)), including maximum limits for vitamin D. NFSA has therefore requested the Norwegian Scientific Committee for Food Safety (VKM) to evaluate the assumption in the EFSA opinion that children and adolescents can tolerate the same amount of vitamin D as adults due to rapid bone formation and growth. In children and adolescents with lower weight than adults, this assumption actually implies that adolescents can tolerate more vitamin D per kg body weight than adults. VKM is therefore requested to evaluate if there is scientific evidence that a UL at 50 µg/day for children (1-10 years) and 100 µg/day for adolescents (11-17 years) is safe. The present statement is prepared by members of the Panel on Nutrition, Dietetic Products and Novel Food and Allergy in VKM. Three literature searches were performed to find new relevant studies investigating high intakes of vitamin D in children and adolescents and the role of vitamin D in bone formation and growth. No studies supporting a higher tolerance to vitamin D in children and adolescents due to rapid bone formation and growth were retrieved in the literature search. Moreover, there is apparently no firm association between bone formation and vitamin D levels in children during their growth period into adolescence and adulthood. No studies investigating high intakes of vitamin D in children 1-10 years were found. Furthermore, no studies that have examined safety issues and/or adverse effects of vitamin D supplementation in doses above 50 µg/day in adolescents were identified. It can therefore not be concluded that the UL at 50 µg/day in children (1-10 years) and 100 µg/day in adolescents (11-17 years) is safe. In the 2002 report from European Scientific Committee on Food (SCF), a UL was set at 25 µg/day for children aged 2-10 years, and 50 µg/day for adolescents aged 11-17 years (corresponding to the UL for adults at that time). To the best of knowledge no serious, harmful effects have been reported for these doses of vitamin D.

Risk Assessment of "Other Substances" – L-aspartic Acid

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses in food supplements and concentrations in energy drinks given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating the addition of "other substances" to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of specified doses of L-aspartic acid in food supplements, and it is based on previous risk assessments and articles retrieved from literature searches. According to information from NFSA, L-aspartic acid is an ingredient in food supplements sold in Norway. NFSA has requested a risk assessment of 3000, 3500, 4000, 4500, 5000 and 5700 mg/day of L-aspartic acid in food supplements. L-aspartic acid is a dispensable dicarboxylic amino acid that can be produced by the transamination of oxaloacetic acid, an intermediate in the metabolism of e.g. glucose and some amino acids. L-aspartic acid is present in frequently consumed foods of animal and plant origin and is also a component of the sweetener aspartame. Dietary intake of aspartic acid in Norway is not known, but data from NHANES III (USA) suggest a mean dietary intake of about 6.5 g/day in adults. The highest intake was seen in men 31 through 50 years of age at the 99th percentile of 15.4 g/day. In the literature review we did not identify any long-term studies in human individuals that could be used for risk assessment. Short-term human studies found no adverse health effect when L-aspartic acid was given in acute doses ranging from 1 to 10 g/day, for time periods between one single dose and four weeks. None of these studies were undertaken to assess the toxicity of L-aspartic acid. In the literature search, two animal studies were identified of which one was a 90-day subchronic toxicity study. In that study, a no observed adverse effect level (NOAEL) of 697 mg/kg bw per day in male rats and 715 mg/kg bw per day in female rats was established. No neurotoxicity was found, however a toxic effect on kidneys and possibly salivary glands was observed at 1400 mg/kg bw per day (lowest observed adverse effect level, LOAEL). For the risk characterisation, the NOAEL of 697 mg/kg bw per day derived from the abovementioned subchronic toxicity study in rats was used for comparison with the estimated exposures from food supplements. The calculated Margin of Exposure (MOE) values for this NOAEL ranged from 5 to 16 for a daily intake of 3000-5700 mg/day of Laspartic acid. These low MOE-values may not be regarded as acceptable since L-aspartic acid has caused toxic effects on the kidneys (regenerative renal tubules with tubular dilation) and acinar cell hypertrophy of salivary glands in rats. Further, direct information regarding potential adverse health effects in humans is not available due to absence of long-term studies. In adults (≥18 years), adolescents (14 to < 18 years) and children (10 to < 14 years), the specified doses 3000, 3500, 4000, 4500, 5000 and 5700 mg/day L-aspartic acid in food supplements may represent a risk of adverse health effects. Children younger than 10 years were not within the scope of the present risk assessment.

Risk Assessment of "Other Substances" –L-arginine and Arginine Alpha-ketoglutarate

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. The risk assessments are the scientific basis for NFSA in its efforts to regulate the use of "other substances". "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of the amino acid L-arginine and L-arginine alpha-ketoglutarate (AAKG), a salt of arginine. It is based on published articles retrieved from a literature search and previous risk assessments of L-arginine. According to information from NFSA, L-arginine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of L-arginine, which according to the information provided by NFSA is found in food supplements in the doses 3000, 3500, 4000, 4500, 5000, 5500, 6000 and 6800 mg/day. Arginine alpha-ketoglutarate is found in food supplements in doses of 1000 and 2000 mg/day. Arginine is a constituent of all food proteins. Dairy products, beef, pork, poultry, wild game and seafood, as well as plant sources such as wheat germ and flour, oatmeal and nuts are good sources of arginine. Arginine is a conditionally essential amino acid, meaning that under most circumstances endogenous synthesis by the human body is sufficient. However, the biosynthetic pathway may under certain conditions produce insufficient amounts. In such cases a dietary supply is needed. Individuals with poor nutrition or certain physical conditions are examples of vulnerable groups. Under normal conditions, endogenous production of arginine is 15-20 g/day. The requirements for L-arginine in adults are 117 mg/kg body weight (bw) per day (WHO, 2007), i.e. for a 70 kg adult person, the requirement is 8.2 g per day. The mean daily dietary intake for all life stage and gender groups of arginine is approximately 4.2 g/day (1988–1994 NHANES III, USA). Arginine is physiologically active in the L-form, which is synthesised by endothelial cells and excreted with urine. The major part of body L-arginine is found in proteins. However, L-arginine is also substrate of nitric-oxide, a potent vasodilator, which may play a major role in regulating blood pressure and improve vascular function. Arginine, supplied as alpha-ketoglutarate, has been observed to increase nitric-oxide production and is mostly studied in athletes because of its claimed enhancing effect on physical performance. Due to the lack of adequate scientific information, a no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL) of arginine has not been identified, thus a tolerable upper intake level for arginine has not been established. Most studies of arginine supplements have been of relatively short duration. The two most relevant randomised placebo-controlled trials for the current risk assessment are those published by Monti et al. (2012) and Lucotti et al. (2009). Both provided a daily dose of 6.4 g arginine, for a duration of 6 and 18 months, respectively. In both studies, adverse events did not differ between arginine and placebo groups. Thus, based on the studies reviewed as well as previous reports, VKM will use the value 6.4 g/day as value for comparison in the risk characterisation of L-arginine. The dose 6.4 g/day of arginine corresponds to 91 mg/kg bw per day in a 70 kg person. AAKG is one of several compounds that have been used as a source of arginine in food supplements. It has been studied in healthy athletic men without serious adverse side effects. However, studies of AAKG supplementation are too scarce to draw conclusions for this specific arginine compound. No data are available indicating whether children or adolescents have different tolerance levels than adults for L-arginine. No tolerance level is set for L-arginine specifically for children or adolescents. The conclusions are therefore based on the assumption of similar tolerance for children and adolescents, per kg body weight, as for adults. VKM concludes that: In adults (≥18 years), the specified doses of 3000, 3500, 4000, 4500, 5000, 5500 and 6000 mg/day of L-arginine in food supplement are considered unlikely to cause adverse health effects. The dose 6800 mg/day may represent a risk of adverse health effects. In adolescents (14 to <18 years), the specified doses 3000, 3500, 4000, 4500, 5000, 5500 mg/day L-arginine in food are considered unlikely to cause adverse health effects, whereas the doses 6000 and 6800 mg/day may represent a risk of adverse health effects. In children (10 to <14 years), the specified doses 3000 and 3500 mg/day L-arginine in food supplements are considered unlikely to cause adverse health effects, whereas the doses 4000, 4500, 5000, 5500, 6000 and 6800 mg/day may represent a risk of adverse health effects. Children below 10 years were not included in the terms of reference. No dosage of arginine alpha-ketoglutarate in food supplements can be evaluated, due to lack of data. In terms of the arginine content of AAKG, a dose of 1000 mg AAKG contains 544 mg arginine and 450 mg alpha-ketoglutarate (based on the molecular weight of 174.2 g/mol for arginine and 144.1 g/mol for alpha-ketoglutarate). A dose of 2000 mg AAKG, the highest dose found in food supplements sold in Norway, contains 1088 mg arginine and 900 mg alpha-ketoglutarate. This amount of arginine is well below the lowest specified dose of 3000 mg/day L-arginine found in food supplements.

Risk Assessment of "Other Substances" – Glycine

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating "other substances" in food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of specified doses of glycine in food supplements, and it is based on previous risk assessments and articles retrieved from two literature searches. Glycine is a non-essential amino acid which is synthesised from 3-phosphoglycerate via serine, or derived from threonine, choline and hydroxyproline via inter-organ metabolism involving primarily the liver and kidneys. Endogeneous synthesis is estimated to be in the magnitude of 8 g per day in adults. Glycine is a constituent of all proteins in the human body. It also functions as a neurotransmitter, and can play both stimulatory and depressant roles in the brain. Data on dietary intake of glycine in Norway are not available. Based on NHANES III (1988-1994), the overall mean intake of glycine from food and food supplements in the United States was 3.2 g per day. Thus, the combined dietary intake and endogenous synthesis is more than 11 g per day. Because glycine is not considered an essential amino acid, a dietary requirement in healthy humans has not been established. Foods rich in glycine are generally protein rich foods such as meat, fish, dairy products and legumes. According to information from NFSA, glycine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements. There is a lack of relevant supplementation studies with glycine in humans designed to address adverse effects and/or dose-response relationship, and none of the previous reports reviewed concluded with a no observed adverse effect level (NOAEL). For the current risk assessment, two literature searches were conducted, one for human studies and one for animal studies. No human studies were found that can be used for suggesting a "value for comparison", and there are no scientific data in the published literature suitable for assessing the specific doses in the terms of reference. The value for comparison used in this risk characterisation is 20 mg/kg per day. This value is derived from a study in rats in which the NOAEL was estimated at 2000 mg/kg per day. Using an uncertainty factor of 100, this corresponds to 20 mg/kg per day or 1.4 g per day for a person weighing 70 kg. This is more than twice as high as the highest dose for consideration in the present risk assessment, and it is far below the combined dietary intake and endogenous synthesis estimated at more than 11 g per day. No particular vulnerable groups for glycine supplements have been identified. VKM concludes that: In adults (≥18 years), the specified doses 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements are unlikely to cause adverse health effects. In adolescents (14 to <18 years), the specified doses 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements are unlikely to cause adverse health effects. In children (10 to <14 years), the specified doses 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements are unlikely to cause adverse health effects. Children younger than 10 years were not within the scope of the present risk assessment.

Risk Assessment of "Other Substances" – L-proline

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating "other substances" in food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of specified doses of L-proline in food supplements, and it is based on previous risk assessments and articles retrieved from literature searches. According to information from NFSA, L-proline is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of 50, 500, 1000, 1500 and 1800 mg/day of L-proline from food supplements. L-proline is considered a non-essential amino acid as it can be synthesised from arginine via the urea cycle in liver, and from glutamine/glutamic acid in the intestinal epithelium. In addition, L-proline is ingested through the diet. All protein rich foods provide L-proline, and animal proteins from milk and meat are particularly abundant sources. A dietary requirement for proline in healthy humans has not been estimated since proline is not considered an essential amino acid. Data on dietary intake of L-proline in Norway are not available. In the third US National Health and Nutrition Examination Survey (NHANES III; 1988-1994), overall mean intake of L-proline from food and supplements was 5.2 g/day. A previous report from the Institute of Medicine (2005) cited one small uncontrolled patient study (n=4) and two animal studies, none of which assessed the toxicity of L-proline in a dose-response manner. The report concluded that a tolerable upper intake level for L-proline could not be determined. In a risk grouping of amino acids from VKM (2011), proline was categorised as having potentially moderate risk, based on the scarce literature and the notion that amino acids are generally bioactive compounds. It was stated that "no conclusion can be drawn on a scientific basis due to lack of adequate scientific literature. Nor will it be possible to conduct a risk assessment until further studies are available". Three systematic literature searches without restriction on publication year were performed for the current risk assessment, aimed at identifying adverse effects of L-proline supplementation in human and animal studies. In humans, one uncontrolled experimental study was identified where a single oral dose of 500 mg/kg bw L-proline was administered as a growth hormone stimulatory agent to 20 children with hyposomatotropic dwarfism and 20 healthy children. No adverse effects were observed. In animals, one relevant subchronic (90 days) toxicological dose-response study in rats was included and forms the basis for the current risk assessment. In that study, performed in accordance with official guidelines from the Japanese Ministry of Health, Labour and Welfare, there were no indications of toxicity at the highest dose given through a powder diet (5.0% L-proline). This dose corresponded to 2773 mg L-proline/kg bw per day and was used as a no-observed-adverse-effect-level (NOAEL). Studies to set a tolerance level for L-proline for children or adolescents have not been found. Therefore, an assumption is made that these age groups have similar tolerance as adults relative to their body weight. To evaluate the safety of the specific doses given by NFSA, margin of exposure (MOE) was calculated with use of 2773 mg L-proline/kg bw per day as NOAEL. For the highest dose (1800 mg/day) MOE is 67 (= 2773* 43.3/1800) in children 10 to <14 years (default body weight 43.3 kg), and 94 (= 2773* 61.3/1800) in adolescents 14 to <18 years (default body weight 61.3 kg). For the dose of 1500 mg/day, the MOE in children is 80. MOE for all the other doses and age categories are above 100. Based on the magnitude of MOE, the lack of adverse effects at the highest dose tested (current NOAEL) and the notion that L-proline is a nutrient that is synthesised endogenously from other amino acids in addition to a dietary intake in the magnitude of 5 grams per day, VKM concludes that: In adults (≥18 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day Lproline in food supplements are unlikely to cause adverse health effects. In adolescents (14 to <18 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day L-proline in food supplements are unlikely to cause adverse health effects. In children (10 to <14 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day L-proline in food supplements are unlikely to cause adverse health effects. Children younger than 10 years were not within the scope of the present risk assessment.

Risk Assessment of “Other Substances” - L-cysteine and L-cystine

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of “other substances” in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating the addition of “other substances” to food supplements. “Other substances” are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of “other substances” evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of L-cysteine and L-cystine, and is based on previous risk assessments of these amino acids and articles retrieved from a comprehensive literature search. In this report L-cysteine and L-cystine are often termed merely cysteine and cystine, respectively. L-cysteine is a central compound in sulphur metabolism in the human body. L-cysteine is a conditionally essential sulphur-containing amino acid, obtained from L-methionine and from serine. Sulphur-containing amino acids are mainly found in cereal proteins and animal proteins, and less abundantly in pulses. Cysteine may occur in proteins either as cysteine itself or as cystine. Cystine is the disulphide dimer of cysteine, and is a more stable compound than cysteine. According to information from the Norwegian Food Safety Authority (NFSA), cysteine and cystine are ingredients in food supplements purchased in Norway and NFSA has requested a risk assessment of the following doses of cysteine and cystine in food supplements: L-cysteine 10 mg/day and L-cystine 250, 500, 750 and 1000 mg/day. The mean usual daily intake of cysteine in the USA for all life stage- and gender groups is 1.0 g/day (NHANES II, USA). Because there are few intervention studies with cysteine or cystine, studies with N-acetylcysteine (or N-acetyl-L-cysteine, NAC), which is readily converted to cysteine, is included in this risk assessment. NAC is used as a pharmaceutical drug for various conditions, mainly as mucolytic agent, as paracetamol antidote, and has been included in numerous clinical trials. Most of the cited studies have tested NAC in doses of about 600-1200 mg/day. The study groups have been various patient groups which included children, adolescents, adults and elderly, however relatively few studies have been conducted in children. In the randomised controlled trials there have been no differences in severe adverse events between the placebo and NAC-groups. The adverse effects reported are generally limited to mild gastrointestinal symptoms. The dose 1200 mg of NAC yields maximum 900 mg of L-cysteine or L-cystine. In adults, it is well documented that doses up to 900 mg per day for one year (corresponding to 13 mg/kg bw/day in a 70 kg adult) is without appreciable health risk. The data for doses above 900 mg/day are more scarce. There are no data indicating that children and adolescent are more vulnerable than adults for L-cysteine or L-cystine. No tolerance level is set for cysteine or cystine specifically for children or adolescents, but an assumption is made that these age groups have similar tolerance per kg body weight as adults. VKM concludes that: In adults (≥18 years), the specified doses 10 mg/day L-cysteine and 250, 500 and 750 mg/day L-cystine in food supplements are considered to be unlikely to cause adverse health effects, whereas the dose 1000 mg L-cystine per day may represent a risk of adverse health effects. In adolescents (14 to <18 years), the specified doses 10 mg/day L-cysteine and 250, 500 and 750 mg/day L-cystine in food supplements are considered to be unlikely to cause adverse health effects in adolescents, whereas the dose 1000 mg L-cystine per day may represent a risk of adverse health effects. In children (10 to <14 years), the specified doses 10 mg/day L-cysteine and 250 and 500 mg/day L-cystine in food supplements are considered to be unlikely to cause adverse health effects, whereas the doses 750 and 1000 mg L-cystine per day may represent a risk of adverse health effects. Children below 10 years were not included in the terms of reference.

Risk Assessment of “Other Substances” –Eicosapentaenoic Acid, Docosapentaenoic Acid and Docosahexaenoic Acid

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of “other substances” in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating the addition of “other substances” to food supplements and other foods. “Other substances” are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. The substance is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of “other substances” evaluated any potential beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in food supplements, and is based on previous risk assessments and a literature search. It is emphasised that this risk assessment concerns the single fatty acids EPA, DPA or DHA separately and not mixtures of these as found in e.g. fish oil/cod liver oil. For risk assessment of combined mixtures of n-3 LCPUFAs in e.g. fish oil/cod liver oil, see the EFSA opinion from 2012 or the VKM assessment from 2011 (EFSA, 2012; VKM, 2011). In the reviewed literature of this risk assessment, no studies investigating ratios between EPA, DPA, DHA or other fatty acids in mixtures have been identified. EPA, DPA and DHA are long chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) and in food these fatty acids are incorporated in triacylglycerols (TAGs) and phospholipids (PLs). Dietary sources are fatty fish, cod liver-, seal-, whale-, fish- and krill oils and human milk, containing various ratios of these fatty acids in combination. EPA can be metabolised to eicosanoids such as prostaglandins, prostacyclins and leukotrienes, all groups are biologically active substances. The eicosanoids participate in the regulation of blood pressure, renal function, blood coagulation, inflammatory and immunological reactions. DHA is an essential structural component of the brain, skin, sperm, testicles and retina. DPA can be retro-converted to EPA or converted to DHA. Still little is known of the biological effects of DPA. Humans have a limited capacity to synthesise EPA, DPA and subsequently DHA from the precursor alpha-linolenic acid (ALA), and this endogenous production is negligible in comparison to the doses used in supplementation studies. According to information from the NFSA, EPA, DPA and DHA are food supplement ingredients in Norway, and NFSA has requested a risk assessment of these fatty acids in the following doses in food supplements: EPA: 1500, 1750 and 1825 mg/day DPA: 100, 125 and 150 mg/day DHA: 1050 and 1290 mg/day Children below 10 years were not included in the terms of reference. Information about intake of EPA, DPA and DHA from the diet is scarce, but calculations performed in the Norwegian Mother and Child Cohort Study indicate a mean total intake (SD) from food and supplements of EPA around 330 (340) mg/day, DPA 43 (30) mg/day and DHA 430 (380) mg/day among pregnant women (2002 to 2008). Mean combined intake of EPA, DPA and DHA from fish oil/ cod liver oil in adults participating in a nationally representative dietary survey was 735 mg/day (VKM, 2014). The major concerns with high intake of EPA and DHA have been increased bleeding time, adverse effects related to immune function, lipid peroxidation and glucose homeostasis. EFSA concluded in 2012 that long-term supplemental intakes of 5 g/day of the n-3 LCPUFA do not raise safety concerns for adults with regard to an increased risk of spontaneous bleeding episodes or bleeding complications, or affect glucose homeostasis, immune function or lipid peroxidation. In 2011, VKM concluded that an intake n-3 LCPUFA up to 6.9 g/day was not associated with increased risk of any serious adverse events. Some adverse health effects related to gastrointestinal function, including abdominal cramps, flatulence, eructation, vomiting and diarrhea have been reported, but seem to be associated with intake of an oily substance and not related specifically to EPA, DPA and/or DHA. EPA: In the report from 2012, EFSA concluded that 1.8 g/day of supplemental EPA does not raise safety concerns in adults. None of the included studies from our literature searches limited to 2012 and onwards have investigated bleeding complications. The dosages of EPA in the three included studies in this report range from 1.8 to 3.8 g/day for 12 weeks. The main endpoints in the studies included lipid peroxidation, inflammation biomarkers of cardiovascular diseases and no serious adverse events were found related to the main endpoints. In general, adverse events were described as gastrointestinal discomforts and not related to dosage. Studies of longer duration are necessary before an intake above 1.8 g of EPA can be considered safe. The Norwegian Scientific Committee for Food Safety (VKM) concludes that the specified doses of 1500, 1750, 1825 mg/day of EPA in food supplements are unlikely to cause adverse health effects in adults (≥18 years). In 2012, EFSA did not make conclusions for children or adolescents for EPA. No new studies with EPA supplementation have been identified in children or adolescents after 2012, and therefore no risk assessment can be made for children (≥10 years) or adolescents. DPA: No dosage of DPA in food supplements can be evaluated due to lack of data. DHA: EFSA concluded that 1 g/day of supplemental DHA does not raise safety concerns for the general population (including children and adolescents). The dosages of DHA in the included trials in this report range from 1.0 to 3.6 g/day and the duration from five weeks to four years. Six out of seven studies have used dosages from 1 to 2 g DHA/day. The last study included up to 3.6 g DHA/day for four years and the age spanned from 7 to 31 years. The main endpoints in all studies included lipid peroxidation, inflammation, cognitive performance, blood pressure and biomarkers of cardiovascular diseases and no serious adverse events were found related to the main endpoints. In general, adverse events were described as gastrointestinal discomforts and not related to dosage. VKM therefore considers that the specified daily doses of DHA that moderately exceed 1 g per day (1050 and 1290 mg/day) are unlikely to cause adverse health effects in the general population including children ≥10 years and adolescents. VKM concludes that the specified doses of 1050 and 1290 mg/day of DHA in food supplements are unlikely to cause adverse health effects in the general population including children (≥10 years), adolescents and adults (≥18 years).

Risk Assessment of "Other Substances" – Creatine

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis for regulating the addition of "other substances" to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any potential beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of creatine as food supplement, and is based on previous risk assessments and articles retrieved in literature searches. According to information from the Norwegian Food Safety Authority (NFSA), creatine is an ingredient in food supplements sold in Norway, and NFSA has requested a risk assessment of the following doses of creatine in food supplements: 3.0, 5.0, 10.0 and 24.0 g/day. The average daily intake from the diet is about 1 g creatine, and the endogenous production also amounts to about 1 g/day. Most of the creatine supplements are in the form of creatine monohydrate. Creatine is an organic acid occurring in the body as either phosphocreatine (2/3) or as free creatine (1/3). Phosphocreatine provides phosphate groups for synthesis of adenosine triphosphate, the major energy-providing compound in the body. Previous risk assessments (AESAN, 2012; EFSA, 2004; SCF, 2000; VKM, 2010) all concluded that creatine supplementation with 3.0 g/day is unlikely to cause adverse health effects in adults. This is supported by human and animal data obtained in a literature search and assessed in the present report. Most of the studies with daily creatine intake above 3 g often (i) involved few and highly trained individuals of whom some took high daily loading doses of creatine for a short period, and (ii) were designed to test clinical benefit without emphasis on possible adverse effects. VKM therefore considers that there is insufficient evidence to conclude regarding possible adverse effects at doses of creatine above 3 g/day for the general population. VKM concludes that: In adults (≥ 18 years) the specified dose of 3.0 g/day creatine in food supplements is considered unlikely to cause adverse health effects. The documentation for absence of adverse health effects of doses 5.0, 10.0 and 24.0 g/day creatine in food supplements in the general population is limited. Hence, these doses may represent risk of adverse health effects in adults. In children (10-14 years) and adolescents (14-17 years), the specified doses of 3.0, 5.0, 10.0 and 24.0 g/day creatine in food supplements may represent a risk of adverse health effects. Children below 10 years were not included in the terms of reference.

Risk Assessment of "Other Substances" – Conjugated Linoleic Acids

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis for regulating the addition of "other substances" to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any potential beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of conjugated linoleic acids (CLAs), and is based on previous risk assessments of CLAs and articles retrieved from literature searches. According to information from the NFSA, CLAs are ingredients in food supplements sold in Norway, and NFSA has requested a risk assessment of the following doses of CLAs in food supplements: 3.0, 3.25 and 3.5 g/day. The daily intakes in Norway of CLAs range between 20 and 170 mg (MoBa 2008, version 4). The CLAs are mostly studied in overweight and obese subjects because of their claimed effects to reduce body weight. CLAs constitute a group of isomeric fatty acids mostly produced by bacterial fermentation in the gut. In the human diet, meat (mainly isomers c9,t11 and t10,c12) and dairy products (mainly isomer c9,t11) are main sources of CLAs. The various isomers may have different metabolic effects. In the food supplements evaluated by EFSA (EFSA, 2010 a; EFSA, 2010 b; EFSA, 2012), Clarinol® and Tonalin®, the t10,c12 and the c9,t11 isomers are present in about equal proportions. In research articles not all authors are consistent in reporting what they have studied, so in this report we sometimes do not distinguish between these isomers; hence they are referred collectively to as CLAs if it is not specified. Most of the cited studies have tested supplemental CLAs in doses of about 3.5 g/day, but ranging from 0.7 to 6.0 g/day. In most of the randomised controlled trials (RCTs) there have been no significant differences in adverse effects between the placebo and CLA-groups. Concerns about indications of an unfavourable effect on biomarkers of lipid- and carbohydrate metabolism in obese men with metabolic syndrome as well as unfavourable effect on antioxidant status; increased markers of oxidative stress after consumption of supplemental CLAs have been reported in previous studies. No clear dose-response effects have been found. It is concluded that supplemental CLAs may impair lipid- and carbohydrate metabolism in obese men with the metabolic syndrome. Intake of supplemental CLAs by lactating women may reduce fat content in breastmilk, and intake of supplemental CLAs by pregnant women may reduce birth weight and –length among their offsprings. Only one randomised controlled trial has included children (6-10 years). These children were all overweight or obese, subjects likely to have a different CLA-metabolism/-effect than normal-weight subjects. VKM considers that current data are too incomplete to evaluate any doses of CLAs for children and adolescents. There are few long-term studies, and adverse health effects were not primary outcomes in these studies. Based on available data no conclusions can be drawn for supplemental use of CLAs longer than six months. VKM concludes that: In adults (≥18 years), the specified doses 3.0, 3.25 and 3.5 g/day CLAs in food supplements are considered to be unlikely to cause adverse health effects if used for up to six months. CLA may cause lipid- and carbohydrate disturbances in obese men with metabolic syndrome as well as in overweight/obese subjects with type 2 diabetes. Use of CLA supplements in lactating and pregnant women may cause reduction in milk production and in the content on milk fat and cause decreased birth weight andlength in their off-springs. No conclusion can be made for children and adolescents. Data are insufficient to conclude regarding use of CLAs for more than six months.

Risk Assessment of Magnesium in Food Supplements

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk associated with magnesium in food supplements. VKM is requested to evaluate upper tolerable intake levels for magnesium and high and low intakes in the Norwegian population. Pending establishment of common maximum limits in the EU, the NFSA is evaluating the national maximum limits for vitamins and minerals in food supplements. This risk assessment is the scientific basis for NFSA's evaluation of national limits for magnesium. Directive 2002/46/EC on food supplements was implemented in Norwegian law in 2004 in Regulation 20 May 2004 No. 755 on food supplements. Common maximum and minimum levels of vitamins and minerals in food supplements shall be set in the EU. Until common limits are established in the EU, the national limits apply. The present report is a risk assessment of magnesium in food supplements. It is based on published articles retrieved from literature searches and previous risk assessments of magnesium. Magnesium is an essential alkaline mineral and occurs as free cation Mg2+ in aqueous solution, or as the mineral part of a large variety of compounds such as chlorides, carbonates and hydroxides. Dietary sources of magnesium include green leafy vegetables, legumes, whole grain cereals, dark chocolate, nuts, fish and seafood, banana and coffee. NFSA has especially requested VKM to consider water as a source of magnesium. A few waterworks reported magnesium concentrations at 10 mg/L. Consumption of water from these waterworks may contribute up to 10% of recommended magnesium intake. However, most waterworks reported negligible magnesium concentrations. Magnesium has multiple functions in the body; it is a required cofactor for more than 300 enzyme systems in the body; for energy-dependent membrane transport, for gene regulation, and for sustained electrical potential in excitable cells. Magnesium also plays a major role in bone and mineral homeostasis. No tolerable upper intake level (UL) has been established for magnesium intake from food sources for the reason that no adverse effects have been recognised in healthy populations. Magnesium salts in food supplements may cause osmotic diarrhoea which is the most frequently reported adverse effect. However, these effects are considered relatively mild. Previous reports have arrived on UL or guidance levels (GLs) for supplemental magnesium ranging from 250 mg/day in the EU (Scientific Committee for Food (SCF, 2001)) through 350 mg/day in the USA (Institute of Medicine (IOM, 1997)) and up to 400 mg per day in the UK (Expert group on Vitamins and Minerals (EVM, 2003)). The UL from SCF (2001) is below the recommended daily dietary intakes for adults. Since the critical endpoint (gastrointestinal symptoms) is mild, rapidly reversible and no NOAEL could be identified, VKM finds it appropriate to base the UL for magnesium salts in food supplements on the LOAEL from IOM (1997). For the same reason, an uncertainty factor of 1 may be applicable for establishing a UL for magnesium salts in food supplements. VKM therefore proposes an amendment of the ULs suggested by SCF (2001) for magnesium in supplements. The IOM (1997) suggestion of a UL at 350 mg supplementary magnesium per day for adults was based on a LOAEL for mild diarrhea. VKM found no results to support an alteration of this UL. VKM therefore suggests a UL of 350 mg magnesium in food supplements per day in adults which is in accordance with the UL suggested by (IOM, 1997). This UL will also cover the recommended intakes for the adult population. VKM suggests that the ULs for children equal the recommended intakes for each age group: Age group ULs (mg/day) Children 1-3 years 85 Children 3-10 years 120-200 Children (10-<14 years) 280 Adolescents (14-<18 years) 280 Adults (≥18 years) 350 According to the habitual dietary intakes of magnesium estimated from nationwide dietary surveys in Norway, about 25% of adults have intakes of magnesium below the recommendations from food and supplements. Almost the same percentage was below the recommended intakes among 9-year-old children, while approximately 70% of 13-year-olds had an intake of magnesium below the recommendations. It should be noted that the intakes have been estimated with use of different dietary survey methods for the different age categories and a comparison of estimates across age groups can be misleading and has a high degree of uncertainty. Concentration of magnesium in water is low and about 60% of the waterworks reporting to the Norwegian Waterworks Registry had a magnesium concentration below 2 mg/L, indicating water as a negligible source of magnesium for the majority of the population.

Risk Assessment of "Other Substances" – L-leucine, L-isoleucine and L-valine, the Branched Chain Amino Acids (BCAA)

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. The risk assessments are the scientific basis for NFSA in its efforts to regulate the use of "other substances" to food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of L-leucine, L-isoleucine and L-valine and it is based on previous risk assessments and articles retrieved from a literature search. In this report Lleucine, L-isoleucine and L-valine may occasionally be termed merely leucine, isoleucine or valine. L-leucine, L-isoleucine and L-valine are essential amino acids. L-leucine, L-isoleucine and Lvaline are commonly known as Branched Chain Amino Acids (BCAAs), and are found in food items containing proteins and in particular, in protein-rich foods such as dairy products, meats, eggs, nuts, whole grains, seeds, avocadoes and edible seaweed. According to information from NFSA, L-leucine, L-isoleucine and L-valine are ingredients in food supplements sold in Norway. NFSA has requested a risk assessment of the following doses of L-leucine, L-isoleucine and L-valine in food supplements for adults, adolescents and children 10 years and above: L-leucine: 2500, 3000, 4000, 5000 and 5250 mg/day, Lisoleucine: 1500, 1750, 2000 and 2500 mg/day and L-valine: 1500, 1750, 2000, 2250 and 2500 mg/day. Usual dietary intakes of these amino acids in Norway are not known. Based on data from the 1988–1994 NHANES III, mean daily intakes in adults of leucine, isoleucine and valine from food and supplements are 6.1, 3.6 and 4.0 g/day, respectively (IOM, 2005). Most studies on BCAAs have focused on the three amino acids taken as single amino acids or together combined in food supplements. It has been shown that BCAAs are not metabolized in the liver as is common for most other amino acids but taken up by most peripheral tissues (in particular muscle) where they are either used in protein synthesis or as precursors for nitrogen and/or a number of carbon containing molecules. There is a lack of relevant well-designed supplementation studies with L-leucine, L-isoleucine and L-valine in humans designed to address adverse effects and dose-response relationships as primary outcome. However, daily doses of as much as 30 g BCAA per day given to athletes have been investigated and reported to improve performance. In these reports adverse effects were not addressed and not reported. L-leucine has been administered orally in single doses for one day of up to 50 g without showing any adverse effects. There are no published studies on the effects of longitudinal supplementation with either L-isoleucine or L-valine. Thus, there are no published studies that can be used for suggesting a "value for comparison", and there is no scientific data in the literature suitable for assessing the specific doses in the terms of reference. WHO (2007) recommendations for BCAAs are: Leucine 2730 mg/day, isoleucine 1400 mg/day and valine 1820 mg/day. For a 70 kg person, this corresponds to 39 mg leucine/kg body weight (bw) per day, 20 mg isoleucine/kg bw per day and 26 mg valine/kg bw per day. The acute upper tolerable metabolic limit of L-leucine for men between 20 and 35 years was determined by administration of single doses of 550-700 mg/kg bw over one day. This corresponded to 39 to 50 g/day for a person of 70 kg. Furthermore, based on several studies investigating L-leucine, L-isoleucine and L-valine supplemented as single doses ranging from 10 to 30 g/day without any reported adverse effects. The uncertainties for this consideration are described in chapter 5. VKM concludes that: Due to lack of studies addressing adverse effects for the specified doses 2500, 3000, 4000, 5000 and 5250 mg/day L-leucine, 1500, 1750, 2000 and 2500 mg/day L-isoleucine and 1500, 1750, 2000, 2250 and 2500 mg/day L-valine in food supplements, no conclusions can be made for adults (≥ 18 years), adolescents (≥ 10 and < 18 years) or children (< 10 years).

Assessment of Iron Intake in Relation to Tolerable Upper Intake Levels

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the intake of iron in the Norwegian population in relation to tolerable upper intake levels (ULs). The existing maximum limit for iron in food supplements is 27 mg/day. VKM has also conducted scenario calculations to illustrate the consequences of amending the maximum limit to 5, 10, 20, 30, 40 or 50 mg/day. Iron deficiency is one of the most common nutritional disorders in the world. Individuals with increased iron demand such as growing children and pregnant women, those who experience blood loss such as menstruating women are particularly at risk for the consequences or iron deficiency. Iron deficiency can lead to fatigue and anaemia. The most common adverse effects of iron supplementation are reversible gastrointestinal symptoms. Chronic iron excess can lead to iron overload which is associated with several irreversible severe health outcomes such as cancers and cardiovascular diseases. Up to 1% of the population have a genetic trait that leads to accumulation of iron and renders them more vulnerable to iron excess. An adult needs approximately 10 mg iron per day to overcome daily loss. The tolerable upper intake level (UL) for iron in adults range from 45 to 60 mg/day. However, all previous reports acknowledge the challenges in defining upper levels. The Expert Group on Vitamins and minerals (EVM), UK report provided a guidance level (GL) of 17 instead of a UL and the Nordic Nutrition Recommendations (NNR) (2012) suggested an UL of 60 mg/day, but did not suggest any clear upper levels for children. Institute of Medicine (IOM), US (2001) gives the most substantiated tolerable upper intake levels based on gastrointestinal effects, which is 40 mg/day for infants and children, regardless of age, and 45 mg/day for adolescents and adults. The Joint FAO/WHO Expert Committee on Food Additives 2003 (JECFA) also took the potential serious effects of iron overload into account and suggested a GL of 50 mg/day in adults or 0.8 mg/kg per day in children and adolescents. Because the risks and consequences from overload are significant and potentially serious, VKM suggests that the GL from JECFA (2003) is used. Using the GL from JECFA (2003), none of the suggested doses can be given to 2 or 4-yearold children, 9 year olds can add 5 mg iron from supplements, 13 year olds 20, and adults 30 mg without exceeding the guidance levels.

Assessment of Vitamin B6 Intake in Relation to Tolerable Upper Intake Levels

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the intake of vitamin B6 (pyridoxine) in the Norwegian population in relation to tolerable upper intake levels (ULs). The existing maximum limit for vitamin B6 in food supplements is 4.2 mg/day. VKM has also conducted scenario calculations to illustrate the consequences of amending the maximum limitto 2, 6, 8, 10, 20 or 25 mg/day. Vitamin B6 is water soluble and comprises six compounds with vitamin B6 activity; pyridoxine (PN, an alcohol), pyridoxal (PL, an aldehyde) and pyridoxamine (PM, the amine) and their corresponding phosphates; pyridoxine 5’-phosphate (PNP), pyridoxal 5’ -phosphate (PLP) and pyridoaxamin 5’ –phosphate (PMP). These six forms of vitamin B6 are all present in food in addition to the glycosylated form, pyridoxine-5’-β-δ-glucoside (PNG), in some plants. In food supplements the most common vitamin B6 form is pyridoxine hydrochloride. Eighty to ninety percent of vitamin B6 in the body is found in muscles and estimated body stores in adults amount to about 170 mg with a half-life of 25-33 days. Vitamin B6 deficiency is mostly seen in combination with deficiency of other B vitamins. Symptoms of vitamin B6 deficiency are anaemia and neurological abnormalities (EFSA, 2016). Intakes of vitamin B6 from the diet alone have not been reported to cause adverse effects. Sensory neuropathy has been reported to be the most sensitive adverse health effect of vitamin B6 supplementation. VKM proposes to adopt the tolerable upper intake level (UL) set by the Scientific Committee for Food (SCF) in 2000 at 25 mg/day for vitamin B6, which was based on a lowest observed adverse effect level (LOAEL) of 100 mg/day found in one randomised controlled trial. VKM recognises that there are no well-designed dose-response studies of long-term use available. However, for adults, no adverse effects have been reported at doses with vitamin B6 up to 25 mg/day. Dietary calculations have been performed for mean intakes and in various percentiles (P5, P25, P50, P75 and P95) in children (2-, 4- and 9-year-olds), adolescents (13-year-olds) and in adults. To illustrate the consequences of amending the maximum limit for vitamin B6 in food supplements to 2, 6, 8, 10, 20 or 25 mg/day in the different age groups, VKM has used the scenarios with P95 from food and added the alternative amounts of supplements. VKM has compared these scenarios with the tolerable upper intake levels set by the Scientific Committee for Food in 2000 for adults, adolescents and children. In these scenarios, the 2- and 4-year-old children will exceed the tolerable upper intake level with use of 6 mg/day or higher vitamin B6 in supplements. The 9-year-old children will exceed the tolerable upper intake level with supplemental use of 10 mg/day. The 13-year-old adolescents will exceed the tolerable upper intake level with 20 mg/day of vitamin B6 in supplements. Adults will exceed the tolerable upper intake level with use of 25 mg/day of vitamin B6/pyridoxine in supplements.

Assessment of Zinc Intake in Relation to Tolerable Upper Intake Levels

The Norwegian Food Safety Authority (NFSA, Mattilsynet) has requested the Norwegian Scientific Committee for Food Safety (VKM) to assess the intake of iron zinc in the Norwegian population in relation to tolerable upper intake levels (ULs). The existing maximum limit for zinc in food supplements is 25 mg/day. VKM has also conducted scenario calculations to illustrate the consequences of amending the maximum limit to 1, 2, 5, 10, 15 or 20 mg/day. Zinc is an essential trace element required for RNA, DNA and protein synthesis, cellular division, differentiation and growth (Mac Donald, 2000). Zinc is required for catalytic function in several enzymes and participates in all major biochemical pathways in the body. The function of the immune system depends on the ability of its cells to proliferate and differentiate, which is impaired in individuals with suboptimal zinc status (Barton et al. 2000). Due to its role in cell division and differentiation, adequate zinc nutrition is particularly important in children, and the requirements per kg body weight are highest in early life. The endogenous intestinal losses can vary from 7 mmol/day (0.5 mg/day) to more than 45 mmol/day (3 mg/day), depending on zinc intake (King and Turnlund, 1989). The requirements for zinc vary according to age and bioavailability. Several bioactive compounds in food such as tannins and phytic acids interact with zinc absorption and increase zinc requirements. The requirements vary twenty-fold according to life stage and diet. Zinc supplements, even at or slightly above the recommended intakes, can cause nausea and vomiting. The main concern with chronic zinc excess is, however, copper deficiency which is associated with several chronical illnesses. However, copper deficiency is uncommon due to the ubiquitous presence of copper in the diet. VKM proposes to use the ULs set by IOM (2001) as they provide values also for children and adolescents. The tolerable upper intake level set for adults is 40 mg zinc per day from food (and water) and supplements. Based on the scenario estimations, a dietary zinc intake at the 95th percentile and additionally 20 mg zinc from food supplements will lead to an intake close to the tolerable upper intake level established by IOM for adults. For adolescents and child populations the maximum amounts are 15 and 5 mg for 13- and 9-year-olds, respectively. For 2 and 4-yearolds, P95 from intake of zinc from food alone exceeds the UL.

Assessment of Dietary Intake of Vitamin C and Calcium in the Norwegian Population

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of vitamin C and calcium in the Norwegian population. VKM has also conducted scenario estimations to illustrate the consequences of amending maximum limits for vitamin C (to 100, 300, 500, 600, 800 or 1000 mg/day) and calcium (to 800, 1200 or 2000 mg/day) in food supplements. Vitamin C: Vitamin C refers to both ascorbic acid and dehydroascorbic acid. Scurvy is the manifestation of vitamin C deficiency which is preventable by a daily intake of 5-10 mg/day. Fruits, berries and vegetables are important food sources of vitamin C and especially citrus fruit are important contributors. The Norwegian recommendation for dietary intake of vitamin C is 75 mg/day for adults (Helsedirektoratet, 2014). Vitamin C is absorbed from the intestine by an active process that is dose dependent. The bioavailability is at least 80% for doses up to 100 mg, 70% for doses of 200-500 mg and less than 50% for doses exceeding 1000 mg. Intestinal discomfort and diarrhea have been reported by persons using large doses (>1000 mg/day) of vitamin C supplementation. In 2000 the Institute of Medicine (IOM) in the USA proposed a tolerable upper intake level (UL) for vitamin C intake from food and supplements of 2000 mg/day for adults. ULs for children and adolescents were extrapolated based on body weight; 400 mg for children 1-3 years, 650 mg/day for children 4-8 years, 1200 mg/day for 9-13 years old adolescents, 1800 mg/day for 14-18 years old (IOM, 2000). In the assessment of vitamin C, VKM uses the Norwegian recommendations for intakes (Helsedirektoratet, 2014), and the acceptable dose for supplemental vitamin C from EFSA (2004) for adults and the tolerable upper intake levels established by the IOM (2000) for children and adolescents. Daily intakes of vitamin C from diet and supplements are estimated from nationwide dietary surveys performed in selected age groups: Adults 18-70 years, adolescents aged 13 years, and children aged 2, 4, and 9 years. Not all age-groups in the Norwegian population reach the recommended intake of vitamin C. At the 5th percentile, only 13-year-olds have an intake of vitamin C from food alone above the recommendations. At the 25th percentile, all age groups except adults have a vitamin C intake from food alone at or above the recommendations. At the 40th percentile, adults reach the recommended intake of vitamin C. The whole population would reach the recommended dietary intake with supplementation of 100 mg vitamin C per day. All the alternative maximum limits for vitamin C in food supplements listed in the terms of reference from NFSA (100, 300, 500, 600, 800 or 1000 mg/day) will be within the acceptable dose for supplemental vitamin C suggested by EFSA (2004) for adults. None of the alternative maximum limits for vitamin C in food supplements listed in the terms of reference (100, 300, 500, 600, 800 or 1000 mg/day) leads to exceedance of the tolerable upper intake levels established by IOM in adults, 13- year-olds or 9-year-olds, even with intakes from food at the 95th percentile. However, the tolerable upper intake level proposed by the IOM will be exceeded for 4-year-old children at supplemental doses above 500 mg vitamin C per day, and for 2-year-old children at doses higher than 100 mg/day. Calcium: Calcium is the most abundant mineral in the body and constitutes approximately 1200 g and 1400 g in adult women and men, respectively. More than 99% of the calcium in the body is bound to hydroxyapatite in bone and tooth enamel. Calcium is crucial for many bodily functions such as cell signalling, coagulation, muscular contraction, and neural transmission as well as skeletal integrity. Milk and dairy products are the main dietary sources of calcium, but foods such as fish, pulses, nuts, seeds (especially millet) and green vegetables may contribute to the total intake. The Norwegian recommendation for dietary intake of calcium is 800 mg/day for adults. The bioavailability of calcium is dependent on the amount of calcium ingested as well as the individual’s vitamin D status and physiological needs, like e.g. growth and pregnancy. Adverse effects of excessive calcium intake include symptoms of hypercalcaemia such as e.g. anorexia, weight loss, polyuria, heart arrhythmias, fatigue and soft tissue calcification (Jones, 2008 in IOM, 2011), deterioration of kidney function, kidney stone formation, the milk-alkali syndrome and vascular calcification. In 2012 the European Food Safety Authority (EFSA) established a tolerable upper intake level (UL) for calcium at 2500 mg/day from food and supplements for adults. No UL was set for children and adolescents. In 2011, IOM established a UL for 1-8 years old children to 2500 mg/day and 3000 mg/day for 9-18 years old children and adolescents (IOM, 2011). VKM however suggests that the UL established for adults by EFSA (2012) is used for the purpose of this VKM opinion also for children and adolescents, as the ULs from IOM for children and adolescents are considered to be high. In the assessment of calcium, VKM uses the Norwegian recommendations for intakes (Helsedirektoratet, 2014) and the tolerable upper intake levels established by the European Food Safety Authority for adults (includes both foods and supplements) (EFSA, 2012). Daily intakes of calcium from diet and supplements are estimated from nationwide dietary surveys performed in selected age groups: Adults 18-70 years, adolescents aged 13 years, and children aged 2, 4, and 9 years. Not all age groups in the Norwegian population reach the recommended intake of calcium. At the 5th percentile, no age groups fulfil the recommended daily intakes of calcium from food alone, and in the 50th percentile the 13-year-olds did not reach the recommended intake for calcium from food alone. At approximately the 65th percentile, the 13-year-olds reach the recommended intake for calcium. The whole population would reach the recommended dietary intake with supplementation of 800 mg calcium per day. For calcium, three alternative maximum limits were listed in the terms of reference (800, 1200 and 2000 mg/day). In the scenarios for high intakes of calcium, a dietary calcium intake at the 95th percentile and additionally 800 mg calcium from food supplements, will lead to an intake close to the tolerable upper intake level established by EFSA for the adult population, and supplements with 1200 or 2000 mg calcium per day will lead to exceedance of the tolerable upper intake level in adults. Children and adolescents with a dietary intake at the 95th percentile and additionally 2000 mg calcium from food supplements, will all exceed the UL suggested for adults by EFSA in 2012. All age groups except 4-year-olds will also exceed the UL with 1200 mg supplemental calcium. With 800 mg supplemental calcium 13-year-old adolescents, 9-year-old, 4 year-old and 2-year-old children will not exceed the suggested UL.