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.

Assessment of Dietary Intake of Vitamin K and Maximum Limits for Vitamin K in Food Supplements

The Norwegian Scientific Committee for Food and Environment (Vitenskapskomiteen for mat og miljø, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of vitamin K in the diet. VKM has also assessed the consequences of establishing maximum limits for vitamin K in food supplements at 100, 200, 300, 600 or 800 µg/day. The former maximum limit for vitamin K of 200 µg/day in food supplements was repealed 30 May 2017. Vitamin K is a fat-soluble vitamin required for the carboxylation of glutamic acid residues in proteins that regulate blood coagulation and bone metabolism. The naturally occurring forms of vitamin K present in food and supplements are phylloquinone (vitamin K1) mainly produced by plants, and a range of menaquinones (vitamin K2) mainly produced by bacteria. The chemical structure of vitamin K is characterised by a methylated naphtoquinone ring structure assumed to be responsible for its function, in addition to a side chain which differs in length and degree of saturation. Due to the varying side chains, the different forms of vitamin K are thought to behave differently with regard to absorption, metabolism, bioavailability and thereby also toxic potential. Dark green leafy vegetables are rich sources of phylloquinone. Meat and liver products provide menaquinone-4, the most common menaquinone in Western diets, while other menaquinones are found in fermented foods and cheese. An Adequate Intake (AI) of phylloquinone of 1 µg/kg body weight per day was set by the Scientific Committee on Food (SCF) in 1993 and maintained by the European Food Safety Authority (EFSA) in 2017. No dietary reference values (DRVs) have been established for menaquinones due to insufficient evidence. Furthermore, no tolerable upper intake levels (ULs) have been established for any form of vitamin K due to insufficient evidence, but previous reports stated that no adverse effects associated with vitamin K consumption from food or supplements had been reported in humans or animals. In 2003, the UK Expert Group on Vitamins and Minerals (EVM) proposed a guidance level (GL) for safe upper intake of supplemental phylloquinone of 1 mg/day in adults. The GL was set by applying an uncertainty factor of 10 for inter-individual variation to the supplemental dose of 10 mg/day that had been consumed by eight female athletes (age 20-44) for 30 days with no reported adverse effects. The UK expert group emphasised that GLs had been derived from limited data and were less secure than safe upper levels. This GL was supported by a double-blind randomised study cited in the Nordic Nutrition Recommendations (2012), in which 440 postmenopausal women with osteopenia received a daily supplement of 5 mg phylloquinone or placebo for up to four years with no difference in adverse events between the randomised groups. Corresponding GLs for children and adolescents have been derived by adjusting for reference body weights0.75 by Rasmussen et al. (2006). The distribution of intakes of vitamin K across age groups in Norway is not known, since food composition data is not available. However, habitual intakes in a representative sample of middle-aged and older adults in Western Norway were assessed in the population-based Hordaland Health Study 1997-2000, and revealed higher intakes than those estimated from dietary surveys in the other Nordic countries. Due to lack of representative estimates of vitamin K intakes in the Norwegian population, information on vitamin K intakes from other Nordic countries is included in the current opinion. This includes the distribution of vitamin K intakes in Sweden and Finland reported by EFSA, and the distribution of vitamin K intakes in Denmark, assessed by the Technical University of Denmark (DTU). In middle-aged and older Western Norwegians participating in the Hordaland Health Study 1997-2000, estimated mean intakes of total vitamin K (denoting the sum of K1+K2) ranged from 109 to 148 µg/day in four groups based on age and gender, while the 95-percentiles ranged from 261 to 329 µg/day. Average intakes of total vitamin K in the other Nordic countries are in the magnitude of 100 µg/day in adults, while 95-percentiles in adults are in the magnitude of 200 µg/day. To illustrate the consequences of establishing maximum limits for vitamin K at 100, 200, 300, 600 or 800 µg/day in food supplements, VKM has compared these levels to the age-specific GLs for supplemental phylloquinone proposed by EVM (2003). The GLs are: 1000 µg/day for adults, 870 µg/day at age 15-17 years, 670 µg/day at age 11-14 years, 500 µg/day at age 710 years, 370 µg/day at age 4-6 years and 270 µg/day at age 1-3 years. VKM concludes that: In adults and adolescents 15-17 years old, maximum limits of 100, 200, 300, 600 and 800 µg/day are below GL. In adolescents 11-14 years old, maximum limits of 100, 200, 300 and 600 µg/day are below GL while the maximum limit of 800 µg exceeds GL. In children 4-10 years old, maximum limits of 100, 200 and 300 µg/day are below GL while maximum limits of 600 µg/day and 800 µg/day exceeds GL. In children 1-3 years old, maximum limits of 100 µg/day and 200 µg/day are below GL while maximum limits of 300, 600 and 800 µg/day exceeds GL. VKM notes that the current conclusions apply to phylloquinone (vitamin K1) only, while there is insufficient evidence to appraise potential health consequences of maximum limits of menaquinones (vitamin K2). VKM emphasises that the current assessment of maximum limits for vitamin K in food supplements is merely based on published reports concerning upper levels from the IOM (2001, USA), SCF (2003, EU), EVM (2003, UK) and NNR (2012, Nordic countries). VKM has not conducted any systematic review of the literature for the current opinion, as this was outside the scope of the terms of reference from NFSA.

Assessment of Dietary Intake of Molybdenum in Relation to Tolerable Upper Intake Level

The Norwegian Scientific Committee for Food and Environment (Vitenskapskomiteen for mat og miljø, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of molybdenum. VKM has also conducted scenario calculations to illustrate the consequences of amending maximum limits for molybdenum to 100, 250, 500 or 1000 µg/day in food supplements. The previous maximum limit was 250 µg/day. Molybdenum is as a cofactor for some important enzymes in humans. These enzymes are involved in the catabolism of sulfur amino acids and heterocyclic compounds, including purines and pyridines. A distinct molybdenum deficiency has not been described in animals when subjected to molybdenum restriction, despite considerable reduction in the activity of molybdoenzymes. Molybdenum deficiency is not observed in healthy humans. The estimated Adequate Intake (AI) proposed by the European Food Safety Authority (EFSA) is 65 µg per day for men and women. Legumes, grains, and nuts are major contributors of molybdenum in the diet. Molybdenum is a potential antagonist to copper absorption, but symptoms of copper deficiencies due to excess molybdenum intake have only been observed in ruminants. Based on the effect on reproduction and growth in animals, tolerable upper intake levels (ULs) have been estimated to be 2 mg/day by the U.S. Institute of Medicine (IOM) in 2001 and 0.6 mg/day by the Scientific Committee on Food (SCF) in 2000. These ULs were based on the same scientific evidence, but IOM used an uncertainty factor (UF) of 30 and SCF used a UF of 100 because the evidence base was considered to be weak. Because of the limited safety data on molybdenum, VKM support the use of the default uncertainty factors at 100 for extrapolation of data from animal studies to humans. Additionally, molybdenum deficiency is very rare and no studies have indicated a nutritional need for additional molybdenum from dietary supplements. The ULs for children were derived by adjusting the adult UL according to default body weights. According to the scenario estimations, only the highest suggested maximum limit of 1000 µg molybdenum from food supplements will lead to exceedance of the UL for adults. For 1-3 year old children, all the suggested maximum limits for molybdenum will lead to exceedance of the UL. In children 4-10 years, supplements with 250, 500 or 1000 µg molybdenum will lead to exceedance of the ULs, whereas for adolescents 11-17 years, the UL will be exceeded with supplemental doses at 500 or 1000 µg per day. VKM emphasises that the current assessment of maximum limits for molybdenum in food supplements is merely based on published reports concerning upper levels from the SCF (2000, EU), IOM (2001, USA), EVM (2003, UK) and NNR (2012, Nordic countries). VKM has not conducted any systematic review of the literature for the current opinion, as this was outside the scope of the terms of reference from NFSA.

Assessment of Dietary Intake of Manganese in Relation to Tolerable Upper Intake Level

The Norwegian Scientific Committee for Food and Environment (Vitenskapskomiteen for mat og miljø, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of manganese from the diet and 1, 5 or 10 mg manganese per day in food supplements. The former maximum limit for manganese in food supplements was 5 mg per daily dose. Manganese (Mn) is an essential dietary mineral for mammals, and is a component of metalloenzymes such as superoxide dismutase, arginase and pyruvate carboxylase. Manganese is involved in amino acid-, lipid- and carbohydrate metabolism and in proteoglycan synthesis in bone formation. In 2013, the European Food Safety Authority (EFSA) suggested 3 mg/day to represent an adequate intake (AI) of manganese because data was considered insufficient to set an average requirement (AR). Reports of adverse effects resulting from manganese exposure in humans are associated primarily with inhalation in occupational settings. Excess oral exposure to manganese, especially from contaminated water sources, has been shown to cause permanent neurological disorder known as “manganism” which can be irreversible. The amount of manganese absorbed is inversely related to the concentration of manganese in the diet. This regulation seems to be part of the adaptive changes to the amount of dietary manganese intake, which allow the maintenance of manganese homeostasis over a wide range of intakes. Manganese is mainly absorbed as Mn(II), and absorption is reported to be below 10% of ingested manganese. The main route of elimination of manganese from the body is via bile to the small intestine, while very little is excreted in the urine. Half-life for manganese can vary from 13 to 37 days, with a longer half-life in women than in men, but large inter-individual variation exists. In Norway, manganese content in drinking water is low, and does not contribute to any magnitude of manganese intake. Daily dietary intake of manganese in Norway is not known, but it is proposed that manganese intake is adequate in the Scandinavian countries (NNR Project Group, 2012). Results from the Swedish Market Basket study, 2015, indicate an average daily manganese intake of 4.2 mg per person and day. Calculations based on data from Denmark, 2013 and 2015, evaluate mean dietary intake of manganese to 3.9 mg/day for adults and up to 6.9 mg/day in the higher intake groups. EFSA report on an observed mean intake in EU around 3 mg/day for adults. Main contributor to dietary manganese intake is cereals (57%) followed by fruit, vegetables, nuts and coffee/tea. Irreversible neurotoxic adverse effects from intakes of manganese close to adequate intakes have been reported in humans (SCF, 2000). The Scientific Committee on Food (SCF) could not set a no observed adverse effect level (NOAEL), because no relevant dose-response animal studies were found. Consequently SCF did not set a tolerable upper intake level (UL) for manganese. VKM considers that any dose of manganese as an ingredient in food supplements may be associated with increased risk of negative health effects. VKM emphasises that the current assessment of maximum limits for manganese in food supplements is merely based on published reports concerning upper levels from the IOM (2001, USA), SCF (2003, EU), EVM (2003, UK) and NNR (2012, Nordic countries). VKM has not conducted any systematic review of the literature for the current opinion, as this was outside the scope of the terms of reference from NFSA.

Comparison of Organic and Conventional Food and Food Production Part V: Human Health – Pesticide Residues

The present report is based on data from the 2010 EFSA Report on pesticide residues in food, the Norwegian monitoring programmes 2007-2012 and data from peer reviewed literature and governmental agencies. It is a challenge to perform quantitative estimates and comparative studies of residue levels due to large variation in the measured levels, and the large number of different pesticides present in the samples. Thus, the focus is on the frequency of observed contaminations in relation to regulatory limits and to present examples to illustrate the variation in residue values and number of detected substances. Pesticide residues in conventional and organic products: Of the 12,168 samples (plant- and animal products) in the 2010 EU-coordinated programme, 1.6% exceeded the respective maximum residue level (MRL) values, and 47.7% had measurable residues above the limit of quantification (LOQ), but below or at the MRL. Of the 1168 samples analysed in Norway in 2012 (from both imported and domestic products), 1.9% exceeded MRL and 53% contained measurable pesticide residues. Direct comparison of these values is however not possible, since they contain different types of food samples, and are analysed for a different number of pesticides. When organic and conventional samples from fruit, vegetables and other plant products in the 2010 EU-coordinated programme were compared, 4.2% of the conventional and 1.0% of the organic samples exceeded the MRL values, while 43.2% of the conventional and 10.8% of the organic samples had measurable residues below or at the MRL value. Most of the pesticide residues detected in organic samples are not permitted for use in organic farming. Of the 624 organic samples analysed in Norway 2007 - 2012, 0.2% (one sample) had residues exceeding MRL, while measurable residues were detected in 1.8% of the samples (11 samples). Conventional products were often found to contain different pesticides while most organic samples were found to contain few or only one type of pesticide. Lack of data on pesticide residue levels of organic samples in the EU-coordinated programme, and few Norwegian samples do not allow for a quantitative comparison of pesticide residue levels in organic and conventional samples. Comparative estimation of pesticide residues faces a number of challenges and uncertainties. However, it seems unquestionable based on available data that organic plant products contain fewer and substantially lower amounts of pesticide residues than conventional products. Health risk associated with pesticide residues: The general level of pesticide residues in both conventional and organic food is low, and well below what is likely to result in adverse health effects. This conclusion is based on the comparison of estimated dietary exposure with toxicological reference values i.e. acceptable daily intake (ADI) for chronic effects, and acute reference dose (ARfD) for acute effects. The finding of pesticide residues that exceeds established regulatory limits in a minority of tested samples is not considered to represent a health risk. When dietary exposure that was estimated in six different food commodities in the 2010 EUcoordinated programme was compared with their relevant reference values, EFSA concluded that for 79 of 18243 conventionally grown fruit and vegetable samples, a short-term acute consumer health risk could not be excluded. The conclusion was based on the exceeding of ARfD. None of these 79 samples were organic. It is important to also consider that the exceeding of the acute reference value only occurred in 0.4% of the samples and that the scenario used for acute intake assessment is conservative, suggesting that the toxicological implications are limited. This is also reflected in the chronic exposure assessment, where none of the samples were found to exceed the toxicological reference value ADI. Dietary exposure assessments on the basis of Norwegian samples of apples, tomatoes, carrots, strawberries and lettuce did not show an exceeding of any toxicological reference value. Combined exposure and cumulative risk assessment of pesticide residues: No generally accepted methodology is at present established for cumulative risk assessment of combined exposure to pesticide residues. Available data suggest however that combined exposure is not likely to result in increased human health risk.

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” - 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"-Beta-Alanine

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" the 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 beta-alanine in food supplements, and it is based on previous risk assessments and articles retrieved from literature searches. According to information from NFSA, beta-alanine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of beta-alanine: 1000, 1500 and 2000 mg/day from food supplements. Beta-alanine is a non-essential, non-proteogenic naturally occurring beta amino acid. Beta-alanine is a component of the naturally occurring peptides carnosine, anserine and balenine. Supplementation with beta-alanine leads to an increased production of the peptide carnosine, which is found in high concentrations in the skeletal muscle of both vertebrates and non-vertebrates. Data suggest that beta-alanine functions as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. The only observed adverse effect from beta-alanin supplementation in humans is transient (1-2 hours) paraesthesia and flushing. Paraesthesia is characterised by a stinging or prickling sensation in the skin. There is no evidence that the paraesthesia in the skin is harmful in any way. Long-term studies in humans were not found. Four small human clinical studies have been included in this risk assessment. The occurrence of paraesthesia apparently is dependent on the magnitude of the individual doses that the daily dose is split into. Single doses of beta-alanine of 10 mg/kg bw (700 mg in a 70 kg person) or more provoked transient paraesthesia. Symptom occurrence and severity increased with the dose. Repeated intakes of 5 mg beta-alanine/kg bw or less taken with >2 hours intervals did not induce paraesthesia. Haematology and plasma clinical chemistry was found normal after daily doses of 2.8 g and 3.2 g for 4 weeks in healthy adults. Apart from occasional paraesthesia, a daily dose of 6.4 g for up to seven weeks did not induce any adverse clinical effects in healthy adults of 80 kg, corresponding to a dose of 5.6 g per day in a 70-kg person. We are not aware of any data indicating that children and adolescents are more vulnerable than adults for supplementation with beta-alanine on a per kg bw basis. No relevant animal studies were identified. VKM concludes that: In adults (≥18 years), the specified doses 1000, 1500 and 2000 mg/day of beta-alanine in food supplements are unlikely to cause adverse health effects provided that beta-alanine is consumed with maximum 5 mg/kg bw per intake and a minimum of 2 hours between the intakes. In adolescents (14 to <18 years) and children (10 to <14 years) the specified doses 1000, 1500 and 2000 mg/day of beta-alanine in food supplements are unlikely to cause adverse health effects provided that beta-alanine is consumed with maximum 5 mg/kg bw per intake and a minimum of 2 hours between the intakes. Children younger than 10 years were not within the scope of the present risk assessment.

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).

Risk Assessment of "Other Substances" – L-alanine

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 e ffect . It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" the VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects. For the current report VKM has studied previous risk assessments and performed two systematic literature searches for any published studies assessing negative health effects of L-alanine in humans or animals. According to information from NFSA, L-alanine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of L-alanine: 3500, 3750, 4000, 4250 and 4500 mg/day. Foods rich in alanine are generally protein rich foods such as meat, dairy products, legumes, fish, nuts, seeds, eggs and whole grains. Based on NHANES III (19881994), the overall mean intake of L-alanine from food and food supplements in the United States was 3.6 g/day. L-alanine is a naturally occurring non-essential α-amino acid belonging to the group of the 20 amino acids that are normal components of food proteins. L-alanine acts as an intermediary between protein catabolism and carbohydrate synthesis. It can be easily synthesised from the alpha keto acid pyruvate and has close links to several metabolic pathways including glycolysis, gluconeogenesis, and the citric acid cycle. Together with lactate it is capable of generating glucose from muscle protein through gluconeogenesis in the liver. Alanine thus plays a central role in the metabolism of muscle protein and is a key factor in nitrogen metabolism. Previous reports from the US Institute of Medicine (IOM) 2005, the French Food Safety Agency (AFSSA) 2007 and the Spanish Agency for Food Safety and Nutrition (AESAN) 2012 did not conclude regarding safe doses of L-alanine, but stated that data on adverse effects of L-alanine intake from supplements were not sufficient for a dose-response assessment and establishment of a tolerable upper intake level. Few studies have assessed health effects of L-alanine supplementation in humans, and these were generally not designed to evaluate potential harmful effects of L-alanine. Most human experimental studies gave single doses (up to 50 g) or short-term loading doses (e.g. 25 to 45 g/hour during exercise) to study metabolic responses such as ergogenic effects during exercise or prevention of ketosis after fasting. Adverse health effects were not reported except for abdominal discomfort and stomach cramps, nausea and diarrhea after consuming high doses. No studies assessed long-term effects of L-alanine supplementation, and no studies gave doses comparable to the doses under consideration in the present report. Only one dose-reponse toxicity study in rodents has been found (Chow et al., 1976). In that study, growing Wistar rats were fed up to 20% DL-alanine (a racemic mixture of D- and Lalanine) in their basal diet for 26 weeks, with no effect on liver and kidney weight and no pathological changes in any organs. The study was taken into account due to the otherwise scarce literature on L-alanine toxicity, and could be used since there were no adverse effects at the highest dose tested. The no observed adverse effect level (NOAEL) in mg L-alanine per kg body weight per day was not stated. VKM has therefore estimated the NOAEL using information about average reported feed consumption and average body weights of the animals, and divided by 2 to obtain a NOAEL for L-alanine, arriving at approximately 6450 mg/kg bw/day in male rats and 9700 mg/kg bw/day in female rats. A standard toxicological approach dividing by an uncertainty factor (UF) of 10 for between-species variation and an additional UF of 10 for within-species variation gives the value of 64.5 mg/kg bw per day in females and 97.0 mg/kg bw per day in males, corresponding to approximately 4500 mg/day and 6800 mg/day for a 70 kg man and woman, respectively. VKM also calculated the margins of exposure (MOE) between the estimated NOAEL and the estimated daily exposures from the five supplement doses given by the NFSA (based on default average body weights for the age groups). MOE were 100 or higher for all five doses in adults. For adolescents 14 to <18 years, the MOE was 88 for the highest dose under consideration. For children 10 to <14 years, MOE ranged from 62 for the highest dose to 80 for the lowest dose. The VKM considers that these margins are relatively high and are acceptable based on the following considerations: The highest dose tested in growing rats did not cause adverse effects, implying that the “true” NOAEL is unknown and could be considerably higher. Furthermore, L-alanine is a nutrient participating in normal energy metabolism as a substrate for glucose. It is consumed in the magnitude of 3 to 4 g/day on average in the habitual diet, and it has not been associated with harmful effects in humans beyond gastrointestinal effects when consuming very high single doses (50 g, or at a consumption rate of 30 to 45 grams per hour during exercise). VKM concludes that: In adults (≥18 years), the specified doses 3500, 3750, 4000, 4250 and 4500 mg/day L-alanine in food supplements are unlikely to cause adverse health effects. In adolescents (14 to <18 years), the specified doses 3500, 3750, 4000, 4250 and 4500 mg/day L-alanine in food supplements are unlikely to cause adverse health effects. In children (10 to <14 years), the specified doses 3500, 3750, 4000, 4250 and 4500 mg/day L-alanine 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.

Assessment of Vitamin E 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 E (alpha-tocopherol) in the Norwegian population in relation to tolerable upper intake levels (ULs). The existing maximum limit for vitamin E in food supplements is 30 mg/day. VKM was also requested to conduct scenario calculations to illustrate the consequences of amending the maximum limit for alpha-tocopherol to 15, 50, 100, 150, 200 and 300 mg/day. Naturally vitamin E is a fat soluble compound synthesised by plants and consists of eight different tocopherols (α-, β-, γ- and δ- tocopherols and α-, β-, γ- and δ- tocotrienols) with varying vitamin E antioxidant activity. α-Tocopherol is recognised to meet human vitamin E requirements and accounts for 90% of the activity in human tissue. Vitamin E activity in food is expressed as α-tocopherol equivalents (α-TE) and 1 α-TE is defined as 1 mg d-αtocopherol. The physiological role of vitamin E is to react with free radicals in cell membranes and other lipid milieu, thereby preventing polyunsaturated fatty acids (PUFA) from being damaged by lipid peroxidation. This antioxidant activity is important to maintain membrane integrity and takes place in all cells in the body. Vitamin E deficiency symptoms include peripheral neuropathy, ataxia, myopathy and retinopathy. Vitamin E is dependent on lipid and lipoprotein metabolism and it takes decades for body depletion. The Norwegian recommended intakes for vitamin E for adults are 10 αTE/day for men and 8 α-TE/day for women. There is no evidence of adverse effects from the consumption of vitamin E naturally occurring in foods. Animal studies have shown that α-tocopherol is not mutagenic, carcinogenic or teratogenic. However, high doses of α-tocopherol supplements can cause haemorrhage and interrupt blood coagulation. VKM propose to adopt the tolerable upper intake level set by the Scientific Committee for Food Safety (SCF) which is based on one human dose-response study. Hence, the upper level for supplemental vitamin E is suggested to 300 mg/day for adults. The upper level for children and adolescents is derived from scaling the adult upper level based on body surface area (body weight 0.75). The tolerable upper intake levels set for vitamin E concern only intake from supplements, since intake of vitamin E from the diet is considered safe. VKM has therefore not conducted or evaluated scenarios with intake from both diet and supplements. Dietary calculations have, however, been performed for intake in various percentiles (P) P5, P25, mean, P50, P75 and P95 in children (2- 4- and 9-year-olds), adolescents (13-year-olds) and in adult men and women as background information. Mean and median intakes of vitamin E are above the recommended intakes for all age groups. No age group reaches the recommended intake at P5, and 9- and 13-year-old boys and 9-year-old girls do not reach the recommended intake at P25 from diet alone. Because the tolerable upper intake level for supplemental vitamin E for adults is 300 mg/day, none of the suggested amendments of the maximum limit in food supplements (to 15, 50, 100, 150, 200 and 300 mg/day) will lead to exceedance of this upper level in adults. In 13year-olds supplements with 300 mg/day vitamin E will lead to exceedance of the upper level. In 9-year-olds supplements with 200 mg/day vitamin E will lead to exceedance of the upper level. In 4- and 2-year-olds supplements with 150 mg/day vitamin E will lead to exceedance of the upper level. Vitamin E intake from fortified products is not included in the calculations, but are however, evaluated to be very low.

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.

Assessment of Dietary Intake of Potassium in Relation to Upper Guidance Level

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 potassium in the Norwegian population. VKM has also evaluated the consequences of amending the existing maximum limit for potassium at 1000 mg/day to 300, 2000 or 3000 mg/day in food supplements. Potassium is an essential mineral to humans and is important as the osmotically active element inside the cells, whereas sodium and chloride are the main elements outside the cells. The enzyme Na+/K+ -ATPase pumps potassium ions into the cells and sodium ions out of the cells and helps keep the intracellular potassium concentration about 30 times higher than that of plasma and interstitial fluids. The plasma potassium concentration is maintained within narrow limits (3.5 to 5.0 mmol/L) by multiple mechanisms making up the potassium homeostasis. The strict regulation is essential for a broad array of important physiological processes, like the resting cellular membrane potential and the transmission action in neuronal, muscular and cardiac tissue. Potassium is also important for hormone secretion, vascular tone, systemic blood pressure control, gastrointestinal motility, acid-base balance, glucose and insulin metabolism, mineralocorticoid action, renal concentration ability and fluid and electrolyte balance. Both hypo- and hyperkalaemia result in increased mortality. The EFSA recommendations (2016) for adequate intake (AI) of potassium is 3500 mg/day for adults, both sexes, whereas the recommended intake (RI) in the Nordic Nutrition recommendations (2012) is 3500 mg/day for men and 3100 mg/day for women. Tolerable upper intake levels have not been established for potassium from food, because intake from food has not caused adverse health effects in the healthy population. In children the renal function rapidly reaches the normal adult level in early childhood and no concern about high intake of potassium from food has been put forward. Potassium chloride supplement has, however, resulted in hyperkalaemia and case reports have described heart failure and cardiac arrest at plasma concentrations above 5.5 mmol/L and doses over 6.5 - 6.8 g supplementary potassium per day. VKM proposes to use 3000 mg/day of potassium as an upper guidance level for daily dose of supplemental potassium in adults since this dose has not been shown to cause hyperkalaemia or heart failure, and has not resulted in gastrointestinal lesions. The proposed upper guidance level for adults extrapolated for body weights corresponds to 2630 mg/day for adolescents 14 to <18 years, 1860 mg/day for children 10 to < 14 years and 990 mg/day for children 3 to 10 years. For vulnerable groups all doses of potassium supplementation could lead to hyperkalaemia. Vulnerable groups such as persons with impaired kidney function and elderly have been estimated to comprise 15-20% of the population of Norway. However, most of the vulnerable individuals will be aware of the condition and be under medical supervision. Accordingly, all the evaluated doses from NFSA (300, 1000, 2000 and 3000 mg/day of potassium in food supplements are at or below the suggested upper guidance level for supplemental potassium for adults (>18 years). In adolescents 14 to <18 years, the supplemental doses of 300, 1000 and 2000 mg/day are below the suggested upper guidance level. For the younger age groups, only 300 mg/day is below the suggested upper guidance level for supplemental potassium.

Assessment of Dietary Intake of Phosphorus 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), evaluated the intake of phosphorus in the Norwegian population. VKM has also conducted scenario calculations to illustrate the consequences of amending maximum limits for phosphorus (to 1000, 2000 or 2500 mg/day) in food supplements. Phosphorus is an essential nutrient and is involved in many physiological processes, such as in the cell’s energy cycle, in regulation of the body’s acid-base balance, as a component of the cell structure, in cell regulation and signalling, and in the mineralisation of bones and teeth. In the human body, phosphorus is present in different forms. Serum contains mainly inorganic phosphates (Pi) (dihydrogen and monohydrogen phosphate), bone contains phosphorus largely in the form of hydroxyapatite, whereas the soft tissues and extracellular fluids contain organic phosphates in complex with carbohydrates, lipids and proteins. Phosphorus is the main mineral constituent of bones. About 85% of the body’s phosphorus is in bones and teeth, and together with calcium account for around 80-90% of bone composition. The remaining 15% of the body’s phosphorus is essential in functions ranging from the transfer of genetic information to energy utilisation. Phosphorus is a structural component of the nucleic acids DNA and RNA and thus involved in the storage and transmission of genetic material. It is an essential component of phospholipids (e.g. phosphatidylcholine) that form all membrane bilayers throughout the body. Phosphorus is also an essential component of adenosine triphosphate (ATP), the body’s key energy source. Currently there is no reliable biomarker of phosphorus status, and serum phosphorus increases for a short period after ingestion of a meal and then decreases and remains within a relatively narrow range as a result of homeostatic mechanisms. The EFSA recommendations (2015) for adequate intake (AI) of phosphorus is 550 mg/day for adults, both sexes, whereas the recommended intake (RI) in the Nordic Nutrition Recommendations (2012) is 600 mg/day. Adolescents have a higher requirement of phosphorous because of bone accretion (640 mg/day EFSA and 700 mg/day NNR). EFSA (2005) concluded that the available data were not sufficient to establish a tolerable upper level for phosphorus, however, data indicate that normal healthy individuals can tolerate phosphorus intakes up to 3000 mg/day. EFSA advised supplemental intake not to exceed 750 mg/day, because mild gastrointestinal symptoms have been reported when this dose was increased. EFSA gave no UL suggestions for children, lactating or pregnant women, while Institute of Medicine set a UL for total intake of phosphorous for children at 3000 mg/day and 4000 mg/day for adolescents and adults and 3500 mg/day for lactating women. In accordance with EFSA (2005), VKM suggests to use 3000 mg/day as a provisional UL for total intake of phosphorous for adults, and suggests 750 mg/day as an upper level for supplements. Because of lack of data no provisional ULs are set for adolescents or children. Accordingly, all the suggested doses from NFSA (1000, 2000 and 2500 mg/day) in supplements exceed 750 mg/day, the suggested UL for supplemental phosphorus for adults.

Assessment of Dietary Intake of Chromium (III) in Relation to Tolerable Upper Intake Level

The Norwegian Scientific Committee for Food and Environment (Vitenskapskomiteen for mat og miljø, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of chromium. VKM has also conducted scenario calculations to illustrate the consequences of establishing maximum limit for chromium at 50, 125, 200 or 300 μg/day in food supplements. The former maximum limit for chromium of 125 μg/day in food supplements was revoked 30 May 2017. Chromium is present in food and supplements mainly as trivalent chromium, Cr(III), whereas in drinking water, chromium is present mainly as Cr(VI). Trivalent chromium has been reported to be an essential trace element in that it has been postulated to be necessary for the efficacy of insulin in regulation of the metabolism of carbohydrates, lipids and proteins. However, no mechanisms for these roles have been identified. Absorption of Cr(III) from food has been estimated to range from 0.4 to 2.5%, depending among other factors on the chemical properties of the ingested source and the presence of other dietary components. Absorption efficiency of supplemental Cr(III) has been reported to be between 0.1 and 5.2%, and to vary between the chromium complex ingested. In general, Cr(III) has very low toxicity by the oral route (ATSDR, 2012), and there are hardly any well-documented observations of toxicity after peroral intake in humans. In a series of animal repeat dose toxicity studies, the no observed adverse effect level (NOAEL) for general toxicity was consistently the highest dose tested (EFSA, 2014b). Chromium is ubiquitous in foods, and rich sources include meat and meat products, oils and fats, breads and cereals, fish, pulses and spices. There are no Norwegian recommendations for intake of chromium. The Nordic Nutrition Recommendations and the European Food Safety Authority (EFSA) concluded that no recommendations could be given for chromium due to lack of sufficient evidence (EFSA, 2014a; NNR Project Group, 2012). Furthermore, no tolerable upper intake levels (UL) have been established for chromium. However, the EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) suggested a tolerable daily intake (TDI) at 300 μg trivalent chromium per kg bodyweight per day based on a NOAEL in a rat study and an uncertainty factor at 1000. Due to uncertainty in the available data on developmental and reproduction toxicity, the EFSA Panel applied an uncertainty factor of 10 in addition to the default uncertainty factor of 100 for the extrapolations from rodents to humans and for human variability. The chromium intake in Norway is not known, since Norwegian food composition data are not available. VKM has therefore based this evaluation upon intake data from EFSA. Values from EFSA are likely to be valid also for Norway. Median dietary chromium intakes were 28.6 -44.0 μg/day (medians of lower and upper bound) in the category toddlers (1 to < 3 years), 55.4-76.2 μg/day in other children (3 to < 10 years), 52.1-69.4 μg/day in adolescents (≥10 to <14 years), 73.6-98.1 in adolescents (≥14 to <18 years) and 63.0-84.0 μg/day in adults (18-65 years) (EFSA, 2014b). These values are 80-300 times lower than the suggested tolerable daily intake (TDI). To illustrate the consequences of amending maximum limits for chromium to 50, 125, 200 or 300 μg per daily dose in food supplements, VKM has compared these levels and various intakes from food to the TDI at 300 μg/kg bw per day. Even with the highest level of supplemental intake and additional median levels as well as the 95 percentile intakes from food, the estimated exposure will be 16-48 times lower than the TDI of 300 μg/kg bw per day in all age groups except for the 95 th percentile intake in toddlers, where it will be about nine times lower. VKM emphasises that the current assessment of maximum limits for Cr(III) in food supplements is merely based on published reports concerning upper levels from the WHO (1996), IOM (2001, USA), SCF (2003, EU), EVM (2003, UK) , NNR (2012, Nordic countries), and EFSA (2014b). VKM has not conducted any systematic review of the literature for the current opinion, as this was outside the scope of the terms of reference from NFSA.