Risk Assessment of "Other Substances" – Inulin

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 ph ysiological 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 inulin, and it is based on previous risk assessments and articles retrieved from a literature search. According to information from NFSA, inulin is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of the dose 3 g/day of inulin in food supplements. The total exposure to inulin from other sources than food supplements and cosmetics, such as foods, is not included in the risk assessment. Inulin is a naturally occurring carbohydrate found in a variety of vegetables and fruits such as onions, leeks, garlic, asparagus, artichokes, bananas and wheat. Chicory root is the most common source of industrially produced inulin. Inulin belongs to the nondigestible polysaccharides which are carbohydrates that resist digestion in the small intestine but are fermented by bacteria in the colon. No serious adverse health effects were identified in the human studies included in this opinion. The reported negative health effects of inulin-type fibres are generally mild gastrointestinal symptoms and include diarrhea, abdominal rumbling, bloating, cramping and excessive flatulence. Such effects occur over a wide range of doses and may also depend on the source of inulin. Chain length influences the negative gastrointestinal effects, which will be less with long-chained inulin molecules. As a pragmatic approach, the intake of 5 g/day of inulin from agave and Jerusalem artichoke and 10 g/day of inulin from chicory root and globe artichoke were chosen as the values for comparison with the exposure to inulin from food supplements in the risk characterization. These doses were without serious adverse health effects, even though mild gastrointestinal effects may occur in some/sensitive individuals. These doses are in the same range as the estimated average consumption of inulin from food in Europe (3 – 11 g/day). Data indicates that also doses up to 20 g/day may be well tolerated by most people. However, there is a wide interpersonal variability in the doses at which gastrointestinal effects associated with the colonic fermentation will appear. No studies on children (10 to <14 years) and adolescents (14 to <18 years) were identified. Based on the included literature there was no evidence indicating that age affects tolerance for inulin. Therefore, in this risk assessment the same tolerance as for adults was assumed for these age groups (adjusted for body weight). From a daily dose of 3 g inulin, the calculated intake levels are 69.1, 48.9 and 42.9 mg/kg bw per day for children (10 to <14 years), adolescents (14 to <18 years) and adults (³18 years), respectively. In the risk characterisation, the values used for comparisons with the exposure from food supplements is 5 g/day of inulin from agave and Jerusalem artichoke and 10 g/day of inulin from chicory root and globe artichoke (corresponding to 71 and 143 mg/kg bw per day, respectively, in a 70 kg adult). Comparing the exposure of a daily dose of 3 g/day of inulin from food supplements with the inulin doses of 5 g/day and 10 g/day considered to be without appreciable risk for most healthy adults, it is unlikely that this dose in food supplements causes any adverse health effects in children above 10 years, adolescents and adults. VKM concludes that it is unlikely that a daily dose of 3 g of inulin from food supplements causes adverse health effects in children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years).

Risk Assessment of "Other Substances" – D-Ribose

The Norwegian Scientific Committee for Food Safety (NFSA) [Vitenskapskomiteen (VKM) for mattrygghet] 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 D-ribose, and it is based on previous risk assessments and articles retrieved from a literature search. According to information from NFSA, D-ribose is an ingredient in food supplements sold in Norway. NFSA has requested a risk assessment of 3100 and 6200 mg/day of D-ribose in food supplements for the age groups children (10 to <14 years), adolescents (14 to <18 years) and adults (>18 years). Other sources of D-ribose, such as foods and cosmetics, have not been included in the present risk assessment. D-ribose is a component of the genetic material RNA and is synthesized in all living cells via the pentose phosphate pathway. D-ribose is also a structural component of adenosine triphosphate (ATP), the primary source of cellular energy and a key component of riboflavin (e.g. vitamin B2). The estimated endogen synthesis of D-ribose is referred to be from 2.7 g per day (women) to 16.5 g per day (men). D-ribose is available in small amounts in the diet via ripe fruits and vegetables. It is also an ingredient in food supplements, some so-called energy drinks and in cosmetics as skin conditioner and humectant. Orally administered D-ribose is absorbed in the small intestine by passive diffusion. Absorption rates after oral ingestion of doses up to 200 mg/kg bw per hour (administered for 5 hours) has been shown to range from 87.8 to 99.8% in humans. No serious adverse health effects were identified at doses up to 20 g per day as reported in the human studies included in this opinion. Based on a subchronic oral toxicity study in rats, no observed adverse effect levels (NOAELs) of 3.6 and 4.4 g/kg bw per day in males and females were derived. The NOAELs were based on a statistically significant decrease in body weight. In another study in rats, the NOAELs for embryo toxicity/teratogenicity of D-ribose were 3.6 and 4.6 g/kg bw per day based on individual females. This NOAELs were primarily based on a statistically significantly higher incidence of one or multiple wavy ribs in the mid- and high-dose groups compared to control animals. No studies on children (10 to <14 years) and adolescents (14 to <18 years) were identified. Based on the included literature there was no evidence indicating that age affects tolerance for D-ribose. Therefore, in this risk characterisation a tolerance as for adults, based on body weight, were assumed for these age groups. The values used for comparison with the estimated exposure in the risk characterization are 20 g per day (corresponding to 286 mg/kg bw per day in a 70 kg adult) considered to be without appreciable health risk for most healthy adults and the NOAEL of 3.6 g/kg bw per day from the subchronic toxicity and embryotoxicity/teratogenicity studies in rats. From a daily dose of 3100 mg or 6200 mg of D-ribose, the intake levels are 71.4, 50.6 and 44.3 mg/kg bw per day and 142.6, 101.1 and 88.6 mg/kg bw per day for for children (10 to <14 years), adolescents (14 to <18 years) and adults (³18 years), respectively. The calculated MOE values from the rat study for a daily intake of 3100 mg per day were 50.4, 71.1 and 81.3 for children (10 to <14 years), adolescents (14 to <18 years) and adults (³18 years), respectively. The calculated MOE values for a daily intake of 6200 mg per day were 25.2, 35.6 and 40.6 for children (10 to <14 years), adolescents (14 to <18 years) and adults (³18 years), respectively. In this case, MOE values below 100 are regarded as acceptable since D-ribose is present in all cells in the body and the daily doses from food supplements are in the same order as the endogenous production, which ranges from 2.7 g per day (women) to 16.5 g per day (men) (Bioenergy Life Science Inc., 2008). VKM concludes that it is unlikely that daily doses of 3100 mg or 6200 mg D-ribose in food supplements causes adverse effects in children (10 to <14 years), adolescents (14 to <18 years) and adults (above18 years).

Risk Assessment of "Other Substances" – Caffeine

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. 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 risk assessment of caffeine is based on previous risk assessments and articles retrieved from a literature search. According to information from NFSA, caffeine is an ingredient in food supplements and energy drinks sold in Norway. NFSA has requested a risk assessment of 100 and 300 mg/day of caffeine in food supplements, and of 32 mg/100 ml of caffeine in energy drinks. Drinking patterns reflecting a high acute intake, a mean chronic intake and a high chronic intake were assessed. The total exposure to caffeine from other sources than energy drinks, such as foods and cosmetic products, is not included in the risk assessment. The main sources of caffeine in the diet include coffee, tea, caffeinated soft drinks (including energy drinks) and chocolate. The means and 95th percentiles of daily caffeine intake from all sources for adults (from 16 EU Member States) calculated by the European Food Safety Authority (EFSA) ranged from 37 to 319 mg and from 109 to 742 mg, respectively. The median daily caffeine intake from different sources among pregnant Norwegian women, selfreported at gestational weeks 17 and 30, was 126 mg/day pre-pregnancy, 44 mg/day at gestational week 17, and 62 mg/day at gestational week 30. Caffeine is rapidly and completely absorbed after oral intake, and the peak plasma concentration can be reached within 30-120 minutes. Caffeine crosses the blood–brain barrier, the placental barrier and the blood–testicular barrier, and is excreted in breast milk. Several studies and assessments addressing safety or risk of caffeine have been performed. With regard to caffeine intake and adverse birth weight-related outcomes, these outcomes were observed at all levels of caffeine intake, with no threshold below which this relationship was not observed (EFSA, 2015). In the risk characterization, VKM has applied the intake levels considered unlikely to cause adverse health effects in the new and comprehensive risk assessment by EFSA (EFSA, 2015), also taking into account previous risk assessments and newer literature. The intake levels of caffeine for different population groups (children, adolescents, pregnant women and fetus, lactating women and the breastfed infant and adults) unlikely to cause adverse effects have been identified. For the general adult population (not including pregnant women), these levels are: • Single intake of caffeine up to 200 mg (about 3 mg/kg bw for a 70-kg adult) do not give rise to safety concerns. • Intakes up to 400 mg per day (about 5.7 mg/kg bw per day for a 70-kg adult) consumed throughout the day, do not give rise to safety concerns for adults in the general population, except for pregnant women (see below). • Caffeine intake of about 1.4 mg/kg bw may increase sleep latency and reduce sleep duration in adults. For children and adolescents, these levels are: • A daily intake of 3 mg/kg bw per day do not give rise to safety concerns. • Caffeine doses of about 1.4 mg/kg bw may increase sleep latency and reduce sleep duration in some children and adolescents. For pregnant women and the fetus, these levels are: • 200 mg per day (about 3 mg/kg bw for a 70-kg adult) consumed throughout the day do not give rise to safety concerns. • With regard to caffeine intake and adverse birth weight-related outcomes, it was concluded that these outcomes were observed at all levels of caffeine intake, with no threshold below which this relationship was not observed. It was considered that the risk becomes clinically relevant at total daily doses of about 200 mg of caffeine from all sources. Sengpiel et al. (2013) reported that caffeine intake from different sources was associated with lower birth weight, and that caffeine intake of 200 to 300 mg/day increased the odds for the baby being small for gestational age compared to 0 to 50 mg/day. For lactating women and the breastfed infant, these levels are: • Single doses of caffeine up to 200 mg (about 3 mg/kg bw) and habitual caffeine consumption at doses of 200 mg per day do not give rise to safety concerns. Food supplements: From a daily dose of 100 mg caffeine, the calculated intake levels are 2.3, 1.6 and 1.4 mg/kg bw per day for children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. From a daily dose of 300 mg caffeine, the calculated intake levels are 6.9, 4.9 and 4.3 mg/kg bw per day for the same age groups, respectively. VKM concludes that it is unlikely that a dose of 100 mg of caffeine per day from food supplements causes adverse health effects in children (10 years and above), adolescents (14 to <18 years), pregnant women and the fetus, lactating women and the breastfed infant and adults (≥18 years). However, for children and adolescents, a dose of 100 mg per day is above the intake that may increase sleep latency and reduce sleep duration. For adults, a dose of 100 mg per day is equal to the intake that may increase sleep latency and reduce sleep duration. VKM concludes that a dose of 300 mg of caffeine per day from food supplements may represent a risk of adverse health effects in children (10 years and above), adolescents (14 to <18 years), pregnant women and the fetus and lactating women and the breastfed infant. Consumed as a single dose, 300 mg of caffeine from food supplement may represent a risk of adverse health effects in adults (≥18 years). Consumed throughout the day, it is unlikely that a dose of 300 mg of caffeine per day from food supplements causes adverse health effects in adults. A dose of 300 mg per day is above the intake that may increase sleep latency and reduce sleep duration. Energy drinks: The estimated exposure to caffeine from a drinking pattern reflecting a high acute intake of caffeine from energy drinks (containing 32 mg caffeine/100 ml) is 13.9 mg/kg bw per day for children (3 to <10 years), 11.1 mg/kg bw per day for children (10 to <14 years), 10.4 mg/kg bw per day for adolescents (14 to <18 years) and 9.1 mg/kg bw per day for adults (≥18 years). VKM concludes that a drinking pattern reflecting a high acute intake of caffeine from energy drinks (containing 32 mg caffeine/100 ml) may represent a risk of adverse health effects in children (3 years and above), adolescents (14 to <18 years), pregnant women and the fetus, lactating women and the breastfed infant and adults (≥18 years). In addition, the intake is above the intake that may increase sleep latency and reduce sleep duration. The estimated exposure to caffeine from a drinking pattern reflecting a mean chronic intake of caffeine from energy drinks (containing 32 mg caffeine/100 ml) is 0.8 mg/kg bw per day for children (3 to <10 years), 0.5 mg/kg bw per day for children (10 to <14 years), 0.3 mg/kg bw per day for adolescents (14 to <18 years) and 0.3 mg/kg bw per day for adults (≥18 years). VKM concludes that it is unlikely that a drinking pattern reflecting a mean chronic intake of caffeine from energy drinks (containing 32 mg caffeine/100 ml) causes adverse health effects in children (3 years and above), adolescents (14 to <18 years), pregnant women and the fetus, lactating women and the breastfed infant and adults (≥18 years). In addition, the intake is below the intake that may increase sleep latency and reduce sleep duration. The estimated exposure to caffeine from a drinking pattern reflecting a high chronic intake of caffeine from energy drinks (containing 32 mg caffeine/100 ml) is 2.3 mg/kg bw per day for children (3 to <10 years), 1.3 mg/kg bw per day for children (10 to <14 years), 1.1 mg/kg bw per day for adolescents (14 to <18 years) and 1.5 mg/kg bw per day for adults (≥18 years). VKM concludes that it is unlikely that a drinking pattern reflecting a high chronic intake of caffeine from energy drinks (containing 32 mg caffeine/100 ml) causes adverse health effects in children (3 years and above), adolescents (14 to <18 years), pregnant women and the fetus, lactating women and the breastfed infant and adults (≥18 years). For children (3 to <10 years) and adults (≥18 years), the intake is above the intake that may increase sleep latency and reduce sleep duration. For children (10 to <14 years) and adolescents (14 to <18 years), the intake is below the intake that may increase sleep latency and reduce sleep duration.

Risk Assessment of "Other Substances" – Inositol

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 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 potential beneficial effects from these substances, only possible adverse effects. The present risk assessment is based on previous risk assessments of inositol and articles retrieved from a literature search. According to information from NFSA, inositol is an ingredient in energy drinks sold in Norway. NFSA has requested a risk assessment of 10 mg/100 ml inositol in energy drinks. Drinking patterns reflecting a high acute intake, a mean chronic intake and a high chronic intake were assessed. Inositol (CAS no. 6917-35-7) is a sugar alcohol. Among the nine possible stereoisomers, myo inositol (CAS no. 87-89-8) is the most abundant. The name inositol is frequently used as a synonym for myo -inositol. Inositol occurs naturally in all organisms including humans, and is an important component in all human cells. Inositol-containing lipids and phosphates are required for various structural and functional processes, including membrane formation, signalling, membrane trafficking and osmoregulation. Endogenous production of inositol in humans amounts to about 4 g/day (about 57 mg/kg bw per day in a 70 kg adult) (EFSA, 2014). The total dietary intake of inositol in adults is estimated to range between 500 to 1000 mg/day (about 7-14 mg/kg bw per day). Inositol added to energy drinks in Norway denotes the compound myo -inositol, according to information from NFSA. M yo -inositol is a water-soluble compound naturally occurring in the cells of all living organisms including humans, animals, plants and microorganisms. Certain plant (fruits and vegetables) and foods from animals contain inositol, and seeds of cereals and legumes show high levels of the inositol storage form, phytic acid (inositol hexaphosphate). With regard to hazard identification and characterisation of inositol, most of the adverse effects observed in several human studies were related to gastrointestinal symptoms such as nausea, flatulence, loose stools and diarrhoea. Drinking patterns reflecting a high acute intake, a mean chronic intake and a high chronic intake were assessed for energy drinks containing 10 mg inositol per 100 ml, for the age groups children (3 to <10 years and 10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years). For the high acute drinking pattern, the intake was estimated to be 1000, 1500, 2000 and 2000 ml/day for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (>18 years), respectively. For the mean chronic drinking pattern, the intake was estimated to be 58, 65, 64 and 71 ml/day for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. For the high chronic drinking pattern, the intake was estimated to be 163, 180, 210 and 320 ml/day for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. The data on toxicity of inositol was very limited. The human study with the longest exposure at highest doses (3 months treatment at maximum tolerated dose) that was available for risk assessment was a clinical study of 40-74 year old smokers with bronchial dysplasia, from which a NOAEL of 18 g/day of myo -inositol was established (Lam et al. 2006). VKM estimated the margins of exposure (MOE) based on the NOAEL established in this study. The MOE is the ratio of the NOAEL value to the exposure. An acceptable MOE value for a NOAEL-based assessment of inositol based on a human study is ≥10, taking into account a factor 10 for the interindividual variation between humans in toxicokinetics and toxicodynamics. Due to the uncertainty regarding the relevance of the study by Lam et al. (2006) for the general healthy population, an additional safety factor of 3 was used. Therefore, an acceptable MOE value was 30. For all age groups, the MOE values were in the range of 857 to 2570 for mean chronic intake and in the range of 367 to 857 for high chronic intake of energy drinks, respectively, i.e. far above the acceptable MOE value of 30. Since neither the sub-optimal human study by Lam et al. (2006) or the animal studies in rodent models of chronic diseases available were on healthy subjects, as a supplement to the MOE values calculated from the human study, comparisons with endogenous production and amounts in food of inositol were also performed. No studies specifically on children (3 to <10 years and 10 to <14 years) and adolescents (14 to <18 years) were identified. Based on the included literature there was no evidence indicating that age affects tolerance or endogenous production of inositol. Therefore, in this risk characterisation a tolerance and an endogenous production of inositol as for adults, based on body weight, was assumed for these age groups. For the high acute drinking pattern, and for the mean chronic and the high chronic drinking patterns all estimated intakes of inositol from energy drinks containing 10 mg/100 ml were far below the endogenous production (57 mg/kg bw per day), and also below the dietary intake (7-14 mg/kg bw per day). VKM concludes that it is unlikely that the exposure to inositol from the high acute, the mean chronic or the high chronic drinking patterns causes adverse health effects in children (3 to <10 years and 10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years).

Risk Assessment of "Other Substances" – L-Carnitine and L-Carnitine-L-tartrate

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 vitam ins 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 L-carnitine and L-carnitine-L-tartrate, and it is based on previous risk assessments and/or articles retrieved from a literature search. According to information from NFSA, L-carnitine and L-carnitine-L-tartrate are ingredients in food supplements sold in Norway. NFSA has requested a risk assessment of 1500 mg/day (21.4 mg/kg bw per day) of L-carnitine and 2250 mg/day (32.1 mg/kg bw per day) of Lcarnitine-L-tartrate in food supplements. Other sources of L-carnitine and L-carnitine-L-tartrate, such as e.g. cosmetics, have not been included in the present risk assessment. L-carnitine is a quaternary ammonium salt naturally occurring in all animals and bacteria. It is essential in the fatty acid metabolism. L-carnitine-L-tartrate is the salt of the L-carnitine base with tartaric acid, and is synthesised commercially. L-carnitine occurs naturally in foods, and the richest source is red meat. L-carnitine-L-tartrate does not occur naturally in foods. L-carnitine-L-tartrate dissociates into L-carnitine and Ltartaric acid in the gastrointestinal tract. L-carnitine is endogenously synthesised from lysine and methionine. L-carnitine is widely distributed in all mammalian tissues and is abundant in muscular tissue. After ingestion, L-carnitine is absorbed in the small intestine, and the bioavailability declines with increasing dose. L-carnitine is excreted mainly via the kidneys with a highly efficient tubular reabsorption; only 2% of the ingested L-carnitine is excreted in the faeces. The amount of L-carnitine absorbed into the systemic circulation is similar whether L-carnitine-Ltartrate or L-carnitine is administered. Neonates, infants and young children can be exposed to L-carnitine and L-carnitine-L-tartrate through foods for particular nutritional uses (including infant formulae and various baby foods). L-carnitine and L-carnitine-L-tartrate are used as supplements in animal food, and they are listed as ingredients in various cosmetic products. L-tartaric acid occurs naturally in fruits and wine, and L-tartaric acid and its salts are approved as food additives (E 334). Adverse effects of L-carnitine (-L-tartrate) are occasionally observed in vulnerable groups such as in patients with kidney disease and persons with high plasma values of trimethylamine (TMA) and trimethylamine-N-oxide (TMAO). High plasma L-carnitine levels in subjects with concurrently high TMAO levels have been associated with cardiovascular disease and adverse cardiac events in patients undergoing cardiac evaluation. Adverse effects are suspected in patients with inborn errors of metabolism. Further, interactions with certain types of drugs have been reported. One study of L-carnitine on children (6-13 year old boys diagnosed with attention deficit hyperactivity disorder (ADHD), but otherwise healthy) was identified, which did not indicate that children were more sensitive to L-carnitine than adults. No studies were found on adverse effects of L-carnitine-L-tartrate or tartaric acid specifically in children. No studies were found on adverse effects of L-carnitine, L-carnitine-L-tartrate or tartaric acid specifically in adolescents. Based on the included literature there was no evidence indicating that age affects sensitivity towards L-carnitine, L-carnitine-L-tartrate or tartaric acid. Therefore, in this risk characterisation the same tolerance level as for adults was assumed for children and adolescents (adjusted for body weight). EFSA established a human tolerance level of L-carnitine-L-tartrate up to 3 g/day (43 mg/kg bw per day), equivalent to 2 g/day (29 mg/kg bw per day) L-carnitine in healthy adults. A safety factor for interindividual variation was not included in the established value. Further, this value was based on few studies of which all but one was unavailable to VKM. Intake of 3 g of L-carnitine-L-tartrate would yield 1 g of tartaric acid (14 mg/kg bw per day) (values in parentheses apply to a 70 kg adult). An acceptable daily intake (ADI) based on animal studies is set for tartaric acid of 0-30 mg/kg bw per day. These values (29 mg/kg bw per day L-carnitine, 43 mg/kg bw per day L-carnitine-L-tartrate and 30 mg/kg bw per day tartaric acid) were compared with the estimated exposure in the risk characterisation. Based on the daily intake of 1500 mg L-carnitine (equivalent to 2250 mg L-carnitine-Ltartrate) and the default body weights determined by EFSA, the estimated exposure is 34.6, 24.5 and 21.4 mg/kg bw per day for the age groups children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. VKM concludes that a dose of 1500 mg of L-carnitine per day, which is equivalent to a dose of 2250 mg of L-carnitine-L-tartrate per day, is unlikely to cause adverse health effects in adolescents (14 to <18 years) and adults (≥18 years), whereas intake at this level in children (10 to <14 years) may represent a risk of adverse health effects. The tartaric acid exposure from this dose of L-carnitine-L-tartrate is unlikely to cause adverse health effects.

Risk Assessment of "Other Substances" – Taurine

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 s ubstances 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 taurine, and it is based on previous risk assessments and articles retrieved from a literature search. According to information from NFSA, taurine is an ingredient in food supplements and energy drinks sold in Norway. NFSA has requested a risk assessment of 750, 800, 900, 1000 and 2000 mg/day of taurine in food supplements, and of 300, 350 and 400 mg/100 ml of taurine in energy drinks. Drinking patterns reflecting a high acute intake, a mean chronic intake and a high chronic intake were assessed. For food supplements, the intake of taurine was estimated for the age groups children (10 to <14 years), adolescents (14 to <18 years) and adults (>18 years), whereas for energy drinks the age group children (3 to <10 years) was also included. Other sources of taurine, such as foods and cosmetics, have not been included in the present risk assessment. Taurine (CAS No. 107-35-7) is synthesised endogenously (average 50-125 mg per day), and participates in the formation of bile salts and is involved in a number of crucial physiological processes, including modulation of calcium flux and neuronal excitability, osmoregulation and membrane stabilisation. Taurine occurs naturally in food, especially in meat and seafood. The mean daily intake of taurine from the diet has been estimated to vary between 40 and 400 mg/day. There are indications that taurine may have cardiovascular and neurological effects in humans. However, based on the human studies, an intake of approximately 21 mg/kg bw per day is considered unlikely to cause adverse health effects. Based on a 13-week neurotoxicity study in rats, a no observed adverse effect level (NOAEL) of 1000 mg/kg bw per day for pathological changes was set in 2009 by the European Food Safety Authority (EFSA). In the present risk assessment, VKM has used this NOAEL of 1000 mg/kg bw per day from rats. The human studies available were not of sufficient quality (due to low number of participants, non-healthy populations, short duration) to be used as the sole basis for the risk characterisation. The risk characterisation is based on the margin of exposure (MOE) approach; the ratio of the NOAEL to the exposure. An acceptable MOE value for a NOAELbased assessment of taurine based on an animal study is ≥100, which includes a factor 10 for extrapolation from animals to humans and a factor 10 for interindividual human variation. However, since the NOAEL set by EFSA was based on the highest tested dose and there is a possibility that the actual NOAEL is higher than 1000 mg/kg bw per day, the intake that was considered unlikely to cause adverse health effects based on human studies (21 mg/kg bw per day) was also taken into consideration in the risk characterisation. Food supplements: For children (10 to <14 years), the estimated daily intakes of taurine were 17.3, 18.4, 20.7, 23.0 and 46.1 mg/kg bw per day from daily doses of 750, 800, 900, 1000 and 2000 mg taurine, respectively, from food supplements. The margin of exposure (MOE) values was in the range of 22-58 for the various taurine doses, i.e. all below 100. However, from a daily intake of 750, 800 or 900 mg taurine from food supplements, the estimated intakes were below 21 mg/kg bw per day (the intake considered unlikely to cause adverse health effects based on human studies). VKM therefore concludes that it is unlikely that a daily intake of 750, 800 or 900 mg taurine from food supplements causes adverse health effects in children (10 to <14 years). The estimated exposure from a daily intake of 1000 or 2000 mg taurine was above 21 mg/kg bw per day. Thus, VKM concludes that a daily intake of 1000 or 2000 mg taurine from food supplements may represent a health risk in children (10 to <14 years). For adolescents (14 to <18 years), the estimated daily intakes were 12.2, 13.1, 14.7, 16.3 and 32.6 mg/kg bw per day from daily doses of 750, 800, 900, 1000 and 2000 mg taurine, respectively, from food supplements. For adults (≥18 years), the estimated intakes were 10.7, 11.4, 12.9, 14.3 and 28.6 mg/kg bw per day from a daily intake of 750, 800, 900, 1000 and 2000 mg taurine, respectively, from food supplements. For adolescents (14 to <18 years) and adults (≥18 years), the MOE values were in the range of 31-82 and 35-93, respectively, i.e. all below 100. However, from a daily intake of 750, 800, 900 or 1000 mg taurine from food supplements the estimated intakes were below 21 mg/kg bw per day (the intake considered unlikely to cause adverse health effects based on human studies) for both age groups. Thus, VKM concludes that it is unlikely that a daily intake of 750, 800, 900 or 1000 mg of taurine causes adverse health effects in adolescents (14 to <18 years) and adults (≥18 years). For adolescents (14 to <18 years) and adults (≥18 years) the estimated MOE values were 31 and 35, respectively, i.e. below 100, after a daily intake of 2000 mg taurine from food supplements. In addition, the estimated intakes were above the intake level of 21 mg/kg bw per day (the intake considered unlikely to cause adverse health effects based on human studies) for both age groups. Thus, VKM concludes that a daily intake of 2000 mg of taurine may represent a risk of adverse health effects in adolescents (14 to <18 years) and adults (≥18 years). Energy drinks: High acute drinking pattern, all age groups: For the high acute drinking pattern, the estimated consumption of energy drinks was 1000, 1500, 2000 and 2000 ml/day for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. For the concentrations of 300, 350 and 400 mg taurine/100 ml energy drink, the intake levels of taurine after a high acute consumption of energy drinks (in mg/kg bw per day) were 130, 152 and 173; 104, 121 and 138; 97.9, 114 and 131; and 85.7, 100 and 114, for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. Due to lack of an acute reference dose or other data for acute toxicity of taurine, it was not possible to characterise the risk related to an acute intake of taurine for any of the age groups. Mean chronic drinking pattern, all age groups: For the mean chronic drinking pattern, the estimated consumption of energy drinks was 58, 65, 64 and 71 ml/day for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. For the concentrations of 300, 350 and 400 mg taurine/100 ml energy drink, the intake levels of taurine after a mean chronic drinking pattern (in mg/kg bw per day) were 7.5, 8.8 and 10.0; 4.5, 5.2 and 6.0; 3.1, 3.7 and 4.2; and 3.0, 3.6 and 4.1, for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. In all age groups, the estimated MOE values were 100-333, i.e. 100 or above, for all three taurine concentrations. In addition, the estimated intakes were all below 21 mg/kg bw per day (the intake considered unlikely to cause adverse health effects based on human studies) for all age groups. Thus, VKM concludes that it is unlikely that the mean chronic intake of all three concentrations of taurine causes adverse health effects in children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years). High chronic drinking pattern, all age groups: For the high chronic drinking pattern, the estimated consumption of energy drinks was 163, 180, 211 and 320 ml/day for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. For the concentrations of 300, 350 and 400 mg taurine/100 ml energy drink, the intake levels of taurine after a high chronic drinking pattern (in mg/kg bw per day) were 21.2, 24.7 and 28.2; 12.4, 14.5 and 16.6; 10.3, 12.0 and 13.8; and 13.7, 16.0 and 18.3 mg/kg bw per day for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. For children (3 to <10 years), the estimated MOE values were 47, 40 and 35, for the three taurine concentrations of 300, 350 and 400 mg/ml, respectively, i.e. all below 100. In addition, the estimated intakes were all above 21 mg/kg bw per day (the intake considered unlikely to cause adverse health effects based on human studies) for all three taurine concentrations. Thus, VKM concludes that a high chronic intake of all three concentrations of taurine from energy drinks may represent a health risk in children (3 to <10 years). For children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), the estimated MOE values were in the range of 55-97, i.e. all below 100 for all three taurine concentrations. However, the estimated intakes were all below the intake level of 21 mg/kg bw

Risk Assessment of "Other Substances" – Coenzyme Q10

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 t hat 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 potential beneficial effects from these substances, only possible adverse effects. The present risk assessment of coenzyme Q10 (CoQ10) is based on previous risk assessments and articles retrieved from a literature search. According to information from NFSA, CoQ10 is an ingredient in food supplements sold in Norway. NFSA has requested a risk assessment of intake of 100 mg/day of CoQ10 in food supplements. CoQ10 (CAS no. 303-98-0) is a naturally-occurring, lipid-soluble compound present in all tissues in humans. Ubiquinone is the totally oxidized form (CoQ10), whereas ubiquinol (CoQ10H2) is the totally reduced form. Meat and fish are the food sources richest in CoQ10. CoQ10 intake from the diet ranges between 3 and 6 mg/day in developed countries. The total body pool of CoQ10 is estimated to be approximately 0.5–1.5 g in an adult. Several studies of CoQ10 (both oxidized and reduced form) have been performed in healthy humans (adults) and animals, showing fairly similar results. The adverse effects reported in a small number of human subjects were generally limited to mild gastrointestinal symptoms such as nausea and stomach upset. In humans, orally ingested CoQ10 was well tolerated at doses up to 900 mg/day (corresponding to 12.9 mg/kg bw per day in a 70 kg adult) over periods up to one month. With regard to animal studies, the lack of adverse effects of CoQ10 doses up to 1200 mg/kg per day in long-term toxicity studies supported and extended the results from the human studies. No studies on children (10 to <14 years) and adolescents (14 to <18 years) were identified. Based on the included literature there was no evidence indicating that age affects tolerance for CoQ10. Therefore, in this risk characterisation the same tolerance as for adults was assumed for these age groups (adjusted for body weight). From a daily dose of 100 mg CoQ10, the daily exposure is 2.3 mg/kg bw for children (10 to <14 years), 1.6 mg/kg bw for adolescents (14 to <18 years), and 1.4 mg/kg bw for adults (≥18 years). For the risk characterization, the values used for comparison with the estimated exposure are 900 mg/day (corresponding to 12.9 mg/kg bw per day in a 70 kg adult) based on human studies (4 weeks) and the no observed adverse effect level (NOAEL) of 1200 mg/kg bw per day based on a long-term toxicity study in rats (52 weeks). The margin of exposure (MOE) approach is used for the rat study; that is the ratio of the NOAEL to the exposure. An acceptable MOE value for a NOAEL-based assessment of CoQ10 based on an animal study is ≥100, which includes a factor 10 for extrapolation from animals to humans, and a factor 10 for interindividual human variation. Comparing the NOAEL from a long-term toxicity study in rats with the estimated exposure for the different age groups, it is unlikely that a daily dose of 100 mg/day of CoQ10 causes adverse health effects in children above 10 years, adolescents and adults. Comparing the dose reported to be well tolerated for healthy adults directly with the estimated exposure, it is unlikely that a daily dose of 100 mg/day of CoQ10 causes adverse health effects in children above 10 years, adolescents and adults. VKM concludes that it is unlikely that a daily dose of 100 mg of CoQ10 from food supplements causes adverse health effects in children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years).

Risk Assessment of "Other Substances" – Piperine

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 . 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 piperine, and it is based on previous risk assessments and articles retrieved from a literature search. According to information from NFSA, piperine, derived from black pepper, is an ingredient in food supplements sold in Norway. NFSA has requested a risk assessment of the dose 1.5 mg/day of piperine in food supplements. The total exposure to piperine from other sources than food supplements, such as foods or cosmetics, is not included in the risk assessment. Piperine (( E , E )-piperine) is a naturally occurring alkaloid which is the major pungent compound found in spices like black pepper ( Piper nigrum L.) and long pepper ( Piper longum L.), but it also occurs in Grains of Paradise ( Aframomum melegueta K. Schum.). ( E,E ) piperine is the isomeric form which is used in food supplements. Several isomers structurally related to ( E,E )-piperine are found in pepper with less hot taste, including isopiperine, chavicine and isochavicine. In the European/Western cuisine, black pepper is the major source of piperine in the human diet. Other sources in the diet are piperine (pepper)flavoured finished food products, including beverages and spirits. Piperine is also used in cosmetics as a perfuming agent (CosIng, 2016). The range of doses reported to cause interactions with drugs and phytochemicals when studied in vivo , 5 to 20 mg/kg bw per day in humans and 10 to 50 mg/kg bw per day in animals (Chinta et al., 2015; Srinivasan, 2007; Srinivasan, 2013), exceeded estimated daily intake levels of piperine. Provided that the ingestion of piperine via pepper (food flavouring) or intake of dietary supplements containing P. nigrum or P. longum does not exceed common dietary levels, the risk of adverse piperine-drug and piperine-phytochemical interactions is minimal. Based on a 90-day toxicity study in rats, a no observed adverse effect level (NOAEL) of 5 mg/kg bw per day was set in 2015 by the European Food Safety Authority (EFSA). In the present risk assessment, VKM has used this NOAEL of 5 mg/kg bw per day for the risk characterisation. The risk characterisation is based on the margin of exposure (MOE) approach; the ratio of the NOAEL to the exposure. An acceptable MOE value for a NOAEL-based assessment of piperine based on an animal study is ≥100, which includes a factor 10 for extrapolation from animals to humans and a factor 10 for interindividual human variation. From a daily dose of 1.5 mg piperine, the calculated intake levels are 34.6, 24.5, and 21.4 µg/kg bw per day for children (10 to <14 years), adolescents (14 to <18 years) and adults (³18 years), respectively. Using the MOE approach, for a daily intake of 1.5 mg piperine from food supplements and a NOAEL of 5 mg/kg bw per day, the MOE values are 145, 204 and 234 for children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. Thus, for a daily intake of 1.5 mg piperine, the MOE values are above 100 for all age groups. VKM concludes that it is unlikely that a daily dose of 1.5 mg piperine from food supplements causes adverse health effects in children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years).

Risk Assessment of "Other Substances" – Lycopene

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 ph ysiological 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 lycopene, and it is based on previous risk assessments and articles retrieved from a literature search. According to information from NFSA, lycopene is an ingredient in food supplements sold in Norway. NFSA has requested a risk assessment of 10 mg/day of lycopene in food supplements. The intake of lycopene was estimated for the age groups children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years). Other sources of lycopene, such as foods and cosmetics, have not been included in the present risk assessment. Lycopene belongs to a large group of naturally-occurring pigments known as carotenoids, and is known to have antioxidant properties. Lycopene is a natural constituent of red fruits and vegetables and of certain algae and fungi. The major sources of natural lycopene in the human diet are tomatoes and tomato-based products. Fruits like pink grapefruit, water melon, rosehip, papaya and guava are also sources of lycopene. Lycopene can be obtained by solvent extraction of the natural strains of red tomatoes (Lycopersicon esculentum L.) with subsequent removal of the solvent. Synthetic lycopene can be produced by the Wittig condensation of synthetic intermediates commonly used in the production of other carotenoids used in food. Lycopene biosynthesis by the fungus B. trispora follows the same pathway as the synthesis of lycopene in tomatoes. There are case reports of yellow-orange skin discoloration and/or gastrointestinal discomfort after prolonged high intakes of lycopene-rich food and supplements, those effects being reversible upon cessation of lycopene ingestion. The results from one study indicated that lycopene increased the incidence of the preterm labor and low birthweight babies. However, due to weaknesses in the reporting, VKM cannot use the results from this study in the risk characterisation. An ADI of 0.5 mg/kg bw per day was established by EFSA in 2008. The ADI was derived from the NOAEL of 50 mg/kg bw per day from a 52-week toxicity study in rats, based on a partly reversible increased level of the liver enzyme alanine transaminase (ALT). An ADI is set to cover the general population, including children. This ADI-value was used for comparison with the estimated exposure in the risk characterization. From a daily dose of 10 mg lycopene, the daily exposure is 0.23 mg/kg bw for children (10 to <14 years), 0.16 mg/kg bw for adolescents (14 to <18 years), and 0.14 mg/kg bw for adults (Table 3.1-1). Thus, the intakes are below the ADI of 0.5 mg/bw per day for all age groups. VKM concludes that it is unlikely that a daily dose of 10 mg lycopene from food supplements causes adverse health effects in children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years).

Risk Assessment of "Other Substances" – Curcumin

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 purchased 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 ha ve 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 curcumin, and it is based on previous risk assessments and articles retrieved from literature searches. According to information from NFSA, curcumin is an ingredient in food supplements purchased in Norway. NFSA has requested a risk assessment of 300, 600 and 900 mg/day of curcumin in food supplements. The intake of curcumin was estimated for the age groups children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years). Other sources of curcumin, such as foods and cosmetics, have not been included in the present risk assessment. Curcumin is the main ingredient in the spice turmeric, which is derived from the ground rhizomes of the plant Curcuma longa Linn. Other curcuminoids in turmeric are demethoxycurcumin and bis -demethoxycurcumin (EFSA, 2010). Curcumin is used as a food additive (E100) and is a spice component, such as in turmeric and curry. The absorption of curcumin is low, and the absorbed curcumin is efficiently metabolised by the liver and excreted into the biliary system. The curcumin plasma levels peak within 2 hours of administration, and complete clearance occurs within a few hours thereafter (Heger et al., 2014). Maximum curcumin intake from food as food additive and spice combined has been reported to be 2.3 and 1.6-7.6 mg/kg bw per day for adults and children (1-10 years in the case of food additive; 5-12 years in the case of spices), respectively (EFSA, 2010). An acceptable daily intake (ADI) of 0-3 mg/kg bw per day was allocated by JECFA (2004), based on the NOAEL from a multigeneration reproductive toxicity study in rats (Ganiger, 2002; Ganiger et al., 2007). Based on the same study, EFSA established an ADI of 3 mg/kg bw per day (EFSA, 2010). For children (10 to <14 years), the estimated daily intakes of curcumin were 6.9, 13.8 and 20.7 mg/kg bw per day from daily doses of 300, 600 and 900 mg curcumin, respectively, from food supplements. For adolescents (14 to <18 years), the estimated daily intakes were 4.9, 9.8 and 14.7 mg/kg bw per day from daily doses of 300, 600 and 900 mg curcumin, respectively, from food supplements. For adults (≥18 years), the estimated intakes were 4.3, 8.6 and 12.9 mg/kg bw per day from a daily intake of 300, 600 and 900 mg curcumin, respectively, from food supplements. The intake from all three doses of curcumin exceeded the ADI value of 3 mg/kg bw per day for all age groups. VKM concludes that a daily intake of 300, 600 or 900 mg of curcumin in food supplements may represent a risk of adverse health effects in children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years).

Risk Assessment of "Other Substances" – L-Citrulline

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 L-citrulline, and it is based on a previous risk assessment and articles retrieved from a literature search. According to information from NFSA, L-citrulline is an ingredient in food supplements sold in Norway. NFSA has requested a risk assessment of 1000, 1500 and 2000 mg/day of L-citrulline in food supplements. The intake of L-citrulline was estimated for the age groups children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years). Other sources of L-citrulline, such as foods and cosmetics, have not been included in the present risk assessment. The natural isoform of citrulline is the L-form. In mammals, it is found in all organisms and tissues. L-Citrulline is not part of the amino acids that are incorporated into proteins by the standard genetic code; therefore it is classified as a non-protein amino acid. Thus, its presence in a protein always results from a post-translational modification of the protein. L-citrulline is found in high levels in certain Cucurbitacea, including watermelon, cucumber, pumpkin and courgette, and in certain algae such as Grateloupia vulgaris. It is also present in fish, meat, pulses and milk, and in vegetables such as onions and garlic. Following oral intake of L-citrulline, plasma L-citrulline concentration increases rapidly but returns to baseline values within 5-8 hours post-exposure. There are three interconnected metabolic pathways for L-citrulline: 1) arginine biosynthesis, 2) nitric oxide (NO) cycle, and 3) the complete urea cycle. Renal L-citrulline reabsorption appears very efficient because urinary loss is very low even at high (up to 15 g) L-citrulline intake. No adverse health effects of L-citrulline were observed in six human studies covering the ages 12 months to 56 years, with L-citrulline exposure lengths varying from less than one day (acute doses) to 2 years. The doses varied from 2.1-179 mg/kg bw per day for children. (<14 years), 1.5-175 mg/kg bw per day for adolescents (14 to <18 years) and 21-214 mg/kg bw per day in adults. The human studies available had low number of participants and, with exception of one study, included non-healthy populations. In a 2-year study by Rajantie et al. (1980), 19 patients with lysinuric protein intolerance, ages 1.9-32.7 years, were included. No adverse effects were reported from daily intakes of 65 mg/kg bw in children (10 to <14 years), 46 mg/kg bw in adolescents (14 to <18 years) and 40 mg/kg bw in adults (highest doses applied). These age-specific reference points were used for comparisons with the estimated exposures in the risk characterization. For children, from a daily intake of 1000, 1500 and 2000 mg the estimated exposures are 23.0, 34.6 and 46.1 mg/kg bw per day, respectively. These intake values are below 65 mg/kg bw per day. VKM therefore considers it unlikely that a daily intake of 1000, 1500 or 2000 mg L-citrullline from food supplements causes adverse health effects in children (10 to <14 years). For adolescents, from a daily intake of 1000, 1500 and 2000 mg the estimated exposures are 16.3, 24.5 and 32.6 mg/kg bw per day, respectively. These intake values are below 46 mg/kg bw per day. VKM therefore considers it unlikely that a daily intake of 1000, 1500 or 2000 mg L-citrullline from food supplements causes adverse health effects adolescents (14 to <18 years). For adults, from a daily intake of 1000, 1500 and 2000 mg the estimated exposures are 14.3, 21.4 and 28.6 mg/kg bw per day, respectively. These intake values are below 40 mg/kg bw per day. VKM therefore considers it unlikely that a daily intake of 1000, 1500 or 2000 mg L-citrullline from food supplements causes adverse health effects in adults (≥18 years). Since LPI patients have a different intestinal absorption, renal reabsorption and reduced intracellular efflux of cationic amino acids compared to healthy individuals, it is uncertain whether doses given to LPI patients can be directly extrapolated to healthy individuals. Persons with citrullinemia caused by mutations in enzymes involved in citrulline metabolism are potentially vulnerable to intake of additional L-citrulline from supplements. In addition, humans with chronic renal failure and/or mutations in renal citrulline transporters are potentially vulnerable to supplementation of L-citrulline.

Risk Assessment of "Other Substances" – Collagen from Fish Skin

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 risk assessment is based on a previous risk assessment of collagen from fish skin and articles retrieved from literature searches. According to information from NFSA, collagen from fish skin is an ingredient in food supplements sold in Norway. The food supplements on the Norwegian market may contain collagen hydrolysate. NFSA has requested a risk assessment of 750 mg/day of collagen from fish skin in food supplements. The intake of collagen from fish skin was estimated for the age groups children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years). Other sources of collagen from fish skin, such as foods and cosmetics, have not been included in the present risk assessment. Collagen is the major insoluble fibrous protein in the extracellular matrix and in connective tissue in vertebrates. The various collagens and the structures they form all serve the same purpose, to help tissues withstand stretching. All collagens contain an abundance of the amino acids glycine, proline and hydroxyproline. Fish gelatins are produced by extraction and hydrolysis of fibrous, insoluble collagen from skin or bones. Collagen and gelatin hydrolysate are processed forms, which are more water-soluble. No studies on metabolism of fish collagen, gelatin or collagen/gelatin hydrolysates in animals or humans have been found in the literature. However, as collagens or gelatins are proteins of variable solubility that will be partly absorbed from the gastrointestinal tract after digestion, it is anticipated that the absorbed parts will become building blocks of new proteins in the body. Hydroxyproline, which is a non-proteinogenic amino acid, will be metabolized to glycine and pyruvate and eventually oxidized. There were no toxicity studies found on fish collagen or gelatin or collagen/gelatin hydrolysates in the general human population. A 2-year oral toxicity study in rats on effects of marine collagen peptides prepared from chum salmon (Oncorhynchus keta) skin showed that there were no adverse effects of collagen up to 8.6 g/kg bw per day, which was the highest dose tested. One study on chromosomal aberrations and another study on allergic sensitization in Guinea pigs reported no effects of fish collagen. The value used for comparison with the estimated exposure in the risk characterisation is the NOAEL of 8.6 g/kg bw per day taken from the chronic oral toxicity study in rats. From a daily dose of 750 mg collagen from fish skin, the exposure is 17.3 mg/kg bw per day for children (10 to <14 years), 12.2 mg/kg bw per day for adolescents (14 to <18 years) and 10.7 mg/kg bw per day for adults (≥18 years). The margin of exposure (MOE), the ratio of the NOAEL value to the exposure, was calculated. An acceptable MOE value based on an animal study is ≥100. For a daily intake of 750 mg/day of collagen from fish skin, the MOE values were above 100 for all age groups. VKM concludes that it is unlikely that 750 mg/day of collagen from fish skin in food supplements causes adverse health effects in children (10 to <14 years), adolescents (14 to <18 years) or adults (≥18 years). Collagen from fish has been identified as a fish allergen. Persons allergic to fish are therefore vulnerable and might experience adverse effects from fish collagen. Two studies in humans indicate that individuals allergic to fish may also have allergic reactions to fish gelatin, which is processed fish collagen.

Risk Assessment of "Other Substances" – D-Glucurono-γ-lactone

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 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 D-glucurono-γ-lactone, and it is based on previous risk assessments. A literature search was performed, however, no articles fulfilled the inclusion criteria. According to information from NFSA, D-glucurono-γ-lactone is an ingredient in energy drinks sold in Norway. NFSA has requested a risk assessment of 24 mg/100 ml of D-glucurono-γ-lactone in energy drinks. Drinking patterns reflecting a high acute intake, a mean chronic intake and a high chronic intake were assessed. D-glucurono-γ-lactone (CAS no. 32449-92-6; EINECS no. 251-053-3) and its hydrolysis product glucuronic acid are endogenous metabolites in humans and other mammals, they occur naturally in several dietary sources and are readily metabolized to innocuous products and excreted. The estimated exposure to D-glucurono-γ-lactone from naturally occurring sources in the diet is 1-2 mg/day. No human toxicity data on D-glucurono-γ-lactone was available in the included literature. A no observed adverse effect level (NOAEL) of 1000 mg/kg bw per day, the highest dose tested, was set in 2009 by the European Food Safety Authority ( EFSA) (EFSA, 2009) based on a 13 week rat study of daily oral administration of D-glucurono-γ-lactone performed under good laboratory practice. VKM has used the NOAEL of 1000 mg/kg bw per day for the risk characterisation in the present risk assessment. The risk characterisation is based on the margin of exposure (MOE) approach; the ratio of the NOAEL to the exposure. An acceptable MOE value for a NOAEL-based assessment of D-glucurono-γ-lactone is ≥100, which includes a factor 10 for extrapolation from animals to humans, and a factor 10 for interindividual human variation. Due to lack of an acute reference dose or other data on acute toxicity for D-glucurono-γ-lactone, it is not possible to characterise the risk related to a high acute drinking pattern for any of the age groups. For the mean chronic drinking pattern, the intake was estimated to be 58, 65, 64 and 71 ml/day for 3 to <10 year old children, 10 to <14 year old children, 14 to <18 year old adolescents and adults, respectively. With regard to the mean chronic drinking pattern, the MOE values are 1667 for the age group 3 to <10 years, 2500 for the age group 10 to <14 years, 3333 for the age group 14 to <18 and 5000 for adults ≥18 years. VKM concludes that it is unlikely that a daily mean chronic intake of D-glucurono-γ-lactone from energy drinks (containing 24 mg/100 ml) causes adverse health effects to children (3 years and above), adolescents or adults. For the high chronic drinking pattern, the intake was estimated to be 163, 180, 211 and 320 ml/day for 3 to <10 year old children, 10 to <14 year old children, 14 to <18 year old adolescents and adults, respectively. With regard to the high chronic drinking pattern, the MOE values are 588 for the age group 3 to <10 years, 1000 for the age group 10 to <14 years, 1250 for the age group 14 to <18 and 909 for adults (≥18 years). VKM concludes that it is unlikely that a daily high chronic intake of D-glucurono-γ-lactone in energy drinks (containing 24 mg/100 ml) causes adverse health effects to children (3 years and above), adolescents or adults.