Risk Assessment of Furan Exposure in the Norwegian Population

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has on request of The Norwegian Food Safety Authority performed a risk assessment of furan intake in the Norwegian population based on the most recent national food consumption surveys. National occurrence data of furan concentrations in food were preferentially used in the risk assessment. When national data were lacking, VKM has used occurrence data of furan from other countries. The assessment has been performed by the VKM Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics and the VKM Panel on Contaminants. Furan is a volatile and lipophilic compound formed in a variety of heat-treated commercial foods and contributes to the sensory properties of the product. The substance has been found in a number of foods such as coffee, canned and jarred foods including baby food containing meat and various vegetables. High concentrations of furan have been found in coffee and the presence of furan in jarred baby food and infant formulae has received much attention since such products may be the sole diet for many infants. The occurrence of furan in a variety of foods suggests that there are multiple routes of furan formation rather than a single mechanism. The Norwegian Food Safety Authority has in 2008 and 2009 collected data on furan concentrations in different food products sold on the Norwegian market (Norwegian Food Safety Authority, 2008). In 2011, the Norwegian Food Safety Authority also decided to analyse commercial porridges for infants and children sold on the Norwegian market, to see if furan could be detected in such products. The calculated furan exposures from food and beverages are based on data from the nationally representative food consumption surveys; Spedkost, Småbarnskost, Ungkost and Norkost. The consumption for each relevant food or food category in the dietary surveys were multiplied with the corresponding mean furan concentrations and totalled for each individual. The liver is the main target organ for furan toxicity both in mice and rats, but the rat is the most sensitive species. A dose-dependent increase in hepatocellular adenomas and carcinomas was observed in mice and rats, and an increase in the incidence of cholangiocarcinomas was observed in rat liver. Cholangiocarcinomas in male and female rats were the most sensitive toxicological end point observed in rodents. On the basis of the available data, VKM considers that rat cholangiocarcinomas may be relevant for assessing human risk from furan. Available in vivo data with furan indicate that a reactive metabolite, most likely cis-2-butene1,4-dial (BDA), is formed and that this metabolite can react with DNA and induce mutations. To VKM’s knowledge, no in vivo studies on genotoxicity of BDA have been performed, but BDA was found to be genotoxic in several in vitro tests. VKM therefore considers that a genotoxic mechanism in furan-induced carcinogenesis cannot be excluded and the substance was assessed as a genotoxic carcinogen. VKM used the Margin of Exposure (MOE) approach in this risk assessment. The suitability of different studies on cholangiocarcinomas for dose-response modelling was considered. The 9-month interim evaluation of a 2-year study from NTP (1993) was chosen because it demonstrates a dose-response relationship. From this study, a point of departure of 0.02 mg/kg bw/day was chosen, based on a benchmark dose lower bound (BMDL10) of 0.14 mg furan/kg bw/day and a correction factor of 7 for shorter than full life-time (2 years) study duration. For 6-, 12- and 24-month-old children, the main source of furan exposure is jarred baby food. For 4-, 9- and 13-year-old children, the major food source to the furan exposure is breakfast cereals. In adults, the major contribution to the furan exposure is coffee. The highest furan exposure was calculated for 12-month-old infants and ranged from 0.62-1.51 µg/kg bw/day. In adults the furan exposure ranged from 0.27-0.82 µg/kg bw/day. For mean exposure among infants, children and adolescents, the MOE-values ranged from 29 in 12-month-infants to 2000 in the 13-year-old adolescents. Among high consumers in these groups, the MOE-values ranged from 13 to 400. In adults, the corresponding MOE-values ranged from 59 to 74 for mean furan exposure and from 24 to 26 for high exposure. It should be noted that this risk assessment of furan contains notable uncertainties and limitations. The use of the 9-month interim study in rats including a correction factor of 7 to derive a point of departure, instead of a full life-time study (2-year) study, likely overestimates the hazard of furan. A possible over-diagnosis of the cholangiocarcinomas, due to the similarities in histopathology between cholangiofibrosis and cholangiocarcinomas in rats, may overestimate the hazard. There are also limitations in assessing food consumption and furan content in foods, leading to uncertainties in estimation of furan exposure. VKM considers that the current exposure to furan in all age groups, particularly among infants and children, is of health concern.

Risk Assessment of Coumarin Intake 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) conducted a risk assessment of the coumarin intake in the Norwegian population. VKM was asked to assess if any part of the population has a total intake of coumarin that will exceed the tolerable daily intake (TDI). It should further be considered whether an intake of coumarin exceeding TDI 1-2 times a week for several years would represent a risk to the health of the consumer. The assessment has been performed by the VKM Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics (Panel 4). Coumarin is a naturally flavouring substance in cinnamon and occurs in many plants. The substance can be found in different types of cinnamon to a varying degree. The two main types are Ceylon (Cinnamomum zeylandicum) and Cassia cinnamon (Cinnamomum aromaticum). Cassia cinnamon, which currently is most frequently used in food products on the Norwegian market, contains more coumarin than the lesser used Ceylon cinnamon. Oral intake of coumarin is mostly related to consumption of cinnamon-containing foods or cinnamon as a spice. This includes both direct addition of cinnamon to foods as well as the use of cinnamon oils and other cinnamon extracts by the food industry. Other important sources of exposure could be food supplements based on cinnamon or the use of cosmetic products through dermal exposure, as synthetic coumarin is added as a fragrance ingredient to perfumes, skin gels, lotions and deodorants. It is known from animal experiments that coumarin can cause liver toxicity. It is considered as a non-genotoxic carcinogen in mice and rats. In 2004, the European Food Safety Authority (EFSA) established a TDI of 0.1 mg coumarin/kg body weight (bw), based on a no observed adverse effect level (NOAEL) for liver toxicity in a 2-year dog study. This TDI was maintained when the substance was re-evaluated in 2008. EFSA further concluded that exposure to coumarin resulting in an intake 3 times higher than the TDI for 1-2 weeks was not of safety concern. In order to answer the second question as stated in the terms of reference, the VKM Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics found it necessary to further examine the data on toxicity of coumarin, which were the basis for the TDI established by EFSA. The most significant hazards of coumarin appears to be liver toxicity, which is well documented, and demonstrated in mice, rats, dogs, baboons and humans, and kidney adenomas in male rats. In a review of human case reports, a small subgroup of the human population appears for unknown reasons to be more susceptible to medical treatment with coumarin. The lowest reported dose of coumarin associated with liver toxicity in humans is around 0.4 mg/kg bw/day. It should be noted that the liver toxicity of coumarin in humans usually is reversible. Since there were no dose-response data for humans, animal data were used in the hazard characterisation. The VKM Panel decided to use the benchmark dose (BMD) approach to determine a point of departure for adverse effects of coumarin. The 2-year chronic toxicity/carcinogenicity study in rats by the US National Toxicology Program (NTP) was chosen for model simulation and BMD/BMDL (benchmark dose lower confidence limit) calculations. The best model fit of the dose-response data combined with the lowest BMDL05 (dose where the response is likely to be smaller than 5%) was seen for increased relative liver weight in female rats, which gave a BMDL05 of 7 mg/kg bw/day (converted from 10 mg/kg bw, 5 times per week). The VKM Panel used the BMDL05 for relative increase in liver weight in female rats to establish a TDI of 0.07 mg/kg bw/day using an uncertainty factor of 100 to account for interand intraspecies variation. The intake calculations for coumarin from food and drinks in this opinion are based on both data from the nationally representative food consumption surveys Norkost, Ungkost, Småbarnskost and Spedkost, as well as on assumed worst intake scenarios of different cinnamon-containing food products. The average coumarin levels found in cinnamoncontaining food categories such as ginger bread, cinnamon buns and similar bakery products, cinnamon-containing cakes, thin pastry with cinnamon and cinnamon-based tea sold on the Norwegian market, were used to calculate the total coumarin intake in different age groups in the population. For the calculation of the coumarin intake from cinnamon powder sprinkled on oatmeal porridge and rice porridge, a coumarin level of 3000 mg/kg in cinnamon powder was used. The frequency of consumption and the amount of cinnamon powder (from ¼ - 1 teaspoon) sprinkled on the porridge were taken into account in the calculations. To assess if any part of the Norwegian population has an intake of coumarin that will exceed the TDI, the different intake scenarios presented in the opinion have been compared with the TDI of 0.07 mg/kg bw/day established by VKM. The main conclusions from the VKM Panel were: The total estimated intake of coumarin for mean and high consumers of cinnamon-containing foods are below the TDI for all age groups when consumption of cinnamon-based tea and porridge with cinnamon was excluded. Children and adults who regularly consume oatmeal porridge sprinkled with cinnamon may exceed the TDI by several folds depending on the frequency of consumption and the amount of cinnamon used. Small children (1- and 2-years old) who have a mean or high consumption of oatmeal porridge may exceed the TDI even if they use moderate amounts of cinnamon powder on the porridge. In a worst case scenario with high consumption of porridge and use of high amounts of cinnamon powder, the estimated coumarin intake could exceed the TDI by about 20-fold. This intake is similar to dose levels of coumarin used in medical treatment of adults and where cases of liver toxicity have been reported. Drinking of cinnamon-based tea, which may have a high content of coumarin, can also result in a total intake of coumarin that exceeds the TDI both for children and adults. Other relevant sources of coumarin are cosmetics and food supplements with cinnamon. The recommended dose of two cinnamon supplements sold on the Norwegian market can lead to an exceedance of TDI in adults. It is not anticipated that children will consume supplements with cinnamon. Cosmetic products (shower gels, body lotions, deodorants and oils) are important sources of coumarin exposure both for children and adults, but quantification of the coumarin exposure from cosmetics was not possible due to lack of data. The VKM Panel concludes that based on the available data, the possibility of an adverse health effect by exceeding the TDI 3-fold for 1-2 times per week for several years cannot be assessed. Generally, a minor or an occasional exceedance of TDI is not considered to increase the risk of adverse health effects. The coumarin intake could exceed the TDI by 7-20 fold in some instances. Liver toxicity may occur shortly after the start of coumarin exposure. Such large daily exceedances of TDI, even for a limited time period of 1-2 weeks, cause concern of adverse health effects.

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" – 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.

Risk Assessments of Cyclamate, Saccharin, Neohesperidine DC, Steviol Glycosides and Neotamefrom Soft Drinks, “Saft” and Nectar.

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM), Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics, has at the request of the Norwegian Food Safety Authority (Mattilsynet) conducted a risk assessment of the intense sweeteners cyclamate, saccharin, neohesperidine DC, steviol glycosides and neotame in soft drinks, “saft” and nectar. The risk assessment includes exposure assessments and the calculated exposures are compared to the acceptable daily intake (ADI) for the respective sweeteners. VKM was also requested to compare the current calculated intake of saccharin and cyclamate to the calculated intake reported by VKM in 2007 (the VKM report «Impact on health when sugar is replaced with intense sweeteners in soft drinks, “saft” and nectar») when possible (VKM, 2007). Six different intake scenarios with varying concentrations of added sweeteners (either the average concentration or the highest reported concentration for the respective sweetener) and varying consumption of beverages with sweeteners (either the actual reported consumption of beverages added sweetener or the assumption that all reported beverages were added sweeteners) were used for the exposure calculations. • Scenario 1 gives the best estimate of the current situation in the population (average content of sweeteners, actual reported consumption). • Scenario 2 is based on the average content of sweeteners and that all consumed beverages contain sweeteners. • Scenario 3 is based on the highest reported content of sweeteners and the actual reported consumption. • Scenario 4 is based on the highest reported content of sweeteners and that all consumed beverages contain sweeteners. Scenarios 5 and 6 are based on the maximum allowed amounts of sweeteners within a category in accordance with the Regulation on food additives, within the categories soft drinks, “saft” and nectar in Norway (Regulation No 668 of 6 June 2011 on food additives, 2011). • In scenario 5 the consumption of beverages with added sweeteners or sugar reported in dietary surveys were used for the calculations. • In scenario 6 it was assumed that all consumed soft drinks, “saft” and nectar contained sweeteners (no sugar). In the current risk assessment, the intake of the sweeteners was calculated for 2-year-old children and 18-70 year old men and women. Due to lack of new dietary surveys, the other age groups of children and adolescents were not included. For all age groups in all scenarios, the intake of the sweeteners cyclamate, saccharin, neohesperidine DC, steviol glycosides and neotame was below their respective established ADI values. Due to possible differences in the calculation, it was not possible to compare the current calculated intake of saccharin and cyclamate to the calculated intake reported by VKM in 2007. VKM concludes that there is no major health concern related to the intake of the sweeteners cyclamate, saccharin, neohesperidine DC, steviol glycosides and neotame from the beverage categories included in this risk assessment per today. VKM further concludes that among young women who are high consumers of beverages with cyclamate, and 2-year-old children who are high consumers of beverages with steviol glycosides, the estimated intake approaches the ADI values. The high intakes approaching ADI are considered conservative estimates, as the highest reported content of sweetener or the maximum allowed amounts is used. Thus, these estimates are only relevant for the part of the population that are both loyal to beverages with sweeteners and a particular brand of sweetened beverage. It should be noted that intake of sweeteners from other foods or from tabletop sweeteners is not included in the intake estimates, and that a considerable contribution from these sources cannot be excluded.