ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. These risk assessments will provide NFSA with the scientific basis for regulation of 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 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 Lactobacillus rhamnosus Rosell-11 ND, Lactobacillus rhamnosus W71, Lactobacillus rhamnosus GG and Lactobacillus rhamnosus Lr-329 based on previous risk assessments and also publications retrieved from literature search. The risk of the Lactobacillus strains listed above was assessed for the general population. However, in previous assessments of probiotics published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal microbiota (age group 0-36 months), population with mature gastro-intestinal microbiota (>3 years) and vulnerable groups with mature gastro-intestinal tract. VKM has also assessed the risk of L. rhamnosus Rosell-11 ND, L. rhamnosus W71, L. rhamnosus GG and L. rhamnosus Lr-329 in food supplements and other foods independent of the dose and have assessed exposure in general terms. VKM concludes that it is unlikely that L. rhamnosus Rosell-11 ND, L. rhamnosus W71, L. rhamnosus GG and L. rhamnosus Lr-329 would cause adverse health effects in the general healthy population with mature gastro-intestinal tract. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut microbiota and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. These risk assessments will provide NFSA with the scientific basis for regulation of 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 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 Lactobacillus acidophilus W37, Lactobacillus acidophilus DDS-1, Lactobacillus acidophilus La-5 and Lactobacillus acidophilus La-14 based on previous risk assessments and also publications retrieved from literature search. The risk of the Lactobacillus strains listed above was assessed for the general population. However, in previous assessments of probiotics published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal microbiota (age group 0-36 months), population with mature gastro-intestinal microbiota (>3 years) and vulnerable groups with mature gastro-intestinal tract. VKM has also assessed the risk of L. acidophilus W37, L. acidophilus DDS-1, L. acidophilus La-5 and L. acidophilus La-14 in food supplements and other foods independent of the dose and have assessed exposure in general terms. VKM concludes that it is unlikely that L. acidophilus W37, L. acidophilus DDS-1, L. acidophilus La-5 and L. acidophilus La-14 would cause adverse health effects in the general healthy population with mature gastro-intestinal tract. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut microbiota and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. These risk assessments will provide NFSA with the scientific basis for regulation of 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 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 Bifidobacterium lactis Bi-07, Bifidobacterium bifidum W23, Bifidobacterium longum Rosell-175, Bifidobacterium breve Rosell-70, and Bifidobacterium animalis sub. lactis Bb12 based on previous risk assessments and also publications retrieved from literature search. The risk of the Bifidobacterium strains listed above was assessed for the general population. However, in previous assessments of probiotics published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal microbiota (age group 0-36 months), population with mature gastro-intestinal microbiota (>3 years) and vulnerable groups with mature gastro-intestinal tract. VKM has also assessed the risk of Bifidobacterium spp. in food supplements and other foods independent of the dose and have assessed exposure in general terms. VKM concludes that it is unlikely that B. lactis Bi-07, B. bifidum W23, B. longum Rosell-175, B. breve Rosell-70, and B. animalis sub. lactis Bb12 would cause adverse health effects in the general healthy population with mature gastro-intestinal tract. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut microbiota and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses in food supplements and concentrations in energy drinks given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating the addition of "other substances" to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of specified doses of L-aspartic acid in food supplements, and it is based on previous risk assessments and articles retrieved from literature searches. According to information from NFSA, L-aspartic acid is an ingredient in food supplements sold in Norway. NFSA has requested a risk assessment of 3000, 3500, 4000, 4500, 5000 and 5700 mg/day of L-aspartic acid in food supplements. L-aspartic acid is a dispensable dicarboxylic amino acid that can be produced by the transamination of oxaloacetic acid, an intermediate in the metabolism of e.g. glucose and some amino acids. L-aspartic acid is present in frequently consumed foods of animal and plant origin and is also a component of the sweetener aspartame. Dietary intake of aspartic acid in Norway is not known, but data from NHANES III (USA) suggest a mean dietary intake of about 6.5 g/day in adults. The highest intake was seen in men 31 through 50 years of age at the 99th percentile of 15.4 g/day. In the literature review we did not identify any long-term studies in human individuals that could be used for risk assessment. Short-term human studies found no adverse health effect when L-aspartic acid was given in acute doses ranging from 1 to 10 g/day, for time periods between one single dose and four weeks. None of these studies were undertaken to assess the toxicity of L-aspartic acid. In the literature search, two animal studies were identified of which one was a 90-day subchronic toxicity study. In that study, a no observed adverse effect level (NOAEL) of 697 mg/kg bw per day in male rats and 715 mg/kg bw per day in female rats was established. No neurotoxicity was found, however a toxic effect on kidneys and possibly salivary glands was observed at 1400 mg/kg bw per day (lowest observed adverse effect level, LOAEL). For the risk characterisation, the NOAEL of 697 mg/kg bw per day derived from the abovementioned subchronic toxicity study in rats was used for comparison with the estimated exposures from food supplements. The calculated Margin of Exposure (MOE) values for this NOAEL ranged from 5 to 16 for a daily intake of 3000-5700 mg/day of Laspartic acid. These low MOE-values may not be regarded as acceptable since L-aspartic acid has caused toxic effects on the kidneys (regenerative renal tubules with tubular dilation) and acinar cell hypertrophy of salivary glands in rats. Further, direct information regarding potential adverse health effects in humans is not available due to absence of long-term studies. In adults (≥18 years), adolescents (14 to < 18 years) and children (10 to < 14 years), the specified doses 3000, 3500, 4000, 4500, 5000 and 5700 mg/day L-aspartic acid in food supplements may represent a risk of adverse health effects. Children younger than 10 years were not within the scope of the present risk assessment.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. The risk assessments are the scientific basis for NFSA in its efforts to regulate the use of "other substances". "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of the amino acid L-arginine and L-arginine alpha-ketoglutarate (AAKG), a salt of arginine. It is based on published articles retrieved from a literature search and previous risk assessments of L-arginine. According to information from NFSA, L-arginine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of L-arginine, which according to the information provided by NFSA is found in food supplements in the doses 3000, 3500, 4000, 4500, 5000, 5500, 6000 and 6800 mg/day. Arginine alpha-ketoglutarate is found in food supplements in doses of 1000 and 2000 mg/day. Arginine is a constituent of all food proteins. Dairy products, beef, pork, poultry, wild game and seafood, as well as plant sources such as wheat germ and flour, oatmeal and nuts are good sources of arginine. Arginine is a conditionally essential amino acid, meaning that under most circumstances endogenous synthesis by the human body is sufficient. However, the biosynthetic pathway may under certain conditions produce insufficient amounts. In such cases a dietary supply is needed. Individuals with poor nutrition or certain physical conditions are examples of vulnerable groups. Under normal conditions, endogenous production of arginine is 15-20 g/day. The requirements for L-arginine in adults are 117 mg/kg body weight (bw) per day (WHO, 2007), i.e. for a 70 kg adult person, the requirement is 8.2 g per day. The mean daily dietary intake for all life stage and gender groups of arginine is approximately 4.2 g/day (1988–1994 NHANES III, USA). Arginine is physiologically active in the L-form, which is synthesised by endothelial cells and excreted with urine. The major part of body L-arginine is found in proteins. However, L-arginine is also substrate of nitric-oxide, a potent vasodilator, which may play a major role in regulating blood pressure and improve vascular function. Arginine, supplied as alpha-ketoglutarate, has been observed to increase nitric-oxide production and is mostly studied in athletes because of its claimed enhancing effect on physical performance. Due to the lack of adequate scientific information, a no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL) of arginine has not been identified, thus a tolerable upper intake level for arginine has not been established. Most studies of arginine supplements have been of relatively short duration. The two most relevant randomised placebo-controlled trials for the current risk assessment are those published by Monti et al. (2012) and Lucotti et al. (2009). Both provided a daily dose of 6.4 g arginine, for a duration of 6 and 18 months, respectively. In both studies, adverse events did not differ between arginine and placebo groups. Thus, based on the studies reviewed as well as previous reports, VKM will use the value 6.4 g/day as value for comparison in the risk characterisation of L-arginine. The dose 6.4 g/day of arginine corresponds to 91 mg/kg bw per day in a 70 kg person. AAKG is one of several compounds that have been used as a source of arginine in food supplements. It has been studied in healthy athletic men without serious adverse side effects. However, studies of AAKG supplementation are too scarce to draw conclusions for this specific arginine compound. No data are available indicating whether children or adolescents have different tolerance levels than adults for L-arginine. No tolerance level is set for L-arginine specifically for children or adolescents. The conclusions are therefore based on the assumption of similar tolerance for children and adolescents, per kg body weight, as for adults. VKM concludes that: In adults (≥18 years), the specified doses of 3000, 3500, 4000, 4500, 5000, 5500 and 6000 mg/day of L-arginine in food supplement are considered unlikely to cause adverse health effects. The dose 6800 mg/day may represent a risk of adverse health effects. In adolescents (14 to <18 years), the specified doses 3000, 3500, 4000, 4500, 5000, 5500 mg/day L-arginine in food are considered unlikely to cause adverse health effects, whereas the doses 6000 and 6800 mg/day may represent a risk of adverse health effects. In children (10 to <14 years), the specified doses 3000 and 3500 mg/day L-arginine in food supplements are considered unlikely to cause adverse health effects, whereas the doses 4000, 4500, 5000, 5500, 6000 and 6800 mg/day may represent a risk of adverse health effects. Children below 10 years were not included in the terms of reference. No dosage of arginine alpha-ketoglutarate in food supplements can be evaluated, due to lack of data. In terms of the arginine content of AAKG, a dose of 1000 mg AAKG contains 544 mg arginine and 450 mg alpha-ketoglutarate (based on the molecular weight of 174.2 g/mol for arginine and 144.1 g/mol for alpha-ketoglutarate). A dose of 2000 mg AAKG, the highest dose found in food supplements sold in Norway, contains 1088 mg arginine and 900 mg alpha-ketoglutarate. This amount of arginine is well below the lowest specified dose of 3000 mg/day L-arginine found in food supplements.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating "other substances" in food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of specified doses of glycine in food supplements, and it is based on previous risk assessments and articles retrieved from two literature searches. Glycine is a non-essential amino acid which is synthesised from 3-phosphoglycerate via serine, or derived from threonine, choline and hydroxyproline via inter-organ metabolism involving primarily the liver and kidneys. Endogeneous synthesis is estimated to be in the magnitude of 8 g per day in adults. Glycine is a constituent of all proteins in the human body. It also functions as a neurotransmitter, and can play both stimulatory and depressant roles in the brain. Data on dietary intake of glycine in Norway are not available. Based on NHANES III (1988-1994), the overall mean intake of glycine from food and food supplements in the United States was 3.2 g per day. Thus, the combined dietary intake and endogenous synthesis is more than 11 g per day. Because glycine is not considered an essential amino acid, a dietary requirement in healthy humans has not been established. Foods rich in glycine are generally protein rich foods such as meat, fish, dairy products and legumes. According to information from NFSA, glycine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements. There is a lack of relevant supplementation studies with glycine in humans designed to address adverse effects and/or dose-response relationship, and none of the previous reports reviewed concluded with a no observed adverse effect level (NOAEL). For the current risk assessment, two literature searches were conducted, one for human studies and one for animal studies. No human studies were found that can be used for suggesting a "value for comparison", and there are no scientific data in the published literature suitable for assessing the specific doses in the terms of reference. The value for comparison used in this risk characterisation is 20 mg/kg per day. This value is derived from a study in rats in which the NOAEL was estimated at 2000 mg/kg per day. Using an uncertainty factor of 100, this corresponds to 20 mg/kg per day or 1.4 g per day for a person weighing 70 kg. This is more than twice as high as the highest dose for consideration in the present risk assessment, and it is far below the combined dietary intake and endogenous synthesis estimated at more than 11 g per day. No particular vulnerable groups for glycine supplements have been identified. VKM concludes that: In adults (≥18 years), the specified doses 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements are unlikely to cause adverse health effects. In adolescents (14 to <18 years), the specified doses 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements are unlikely to cause adverse health effects. In children (10 to <14 years), the specified doses 20, 50, 100, 300, 500 and 650 mg/day of glycine from food supplements are unlikely to cause adverse health effects. Children younger than 10 years were not within the scope of the present risk assessment.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. These risk assessments will provide NFSA with the scientific basis for regulation of 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 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 Lactobacillus plantarum W62, Lactobacillus plantarum 299v and Lactobacillus plantarum HEAL9 based on previous risk assessments and also publications retrieved from literature search. The risk of the Lactobacillus strains listed above was assessed for the general population. However, in previous assessments of probiotics published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal microbiota (age group 0-36 months), population with mature gastro-intestinal microbiota (>3 years) and vulnerable groups with mature gastro-intestinal tract. VKM has also assessed the risk of L. plantarum W62, L. plantarum 299v and L. plantarum HEAL9 in food supplements and other foods independent of the dose and have assessed exposure in general terms. VKM concludes that it is unlikely that L. plantarum W62, L. plantarum 299v and L. plantarum HEAL9 would cause adverse health effects in the general healthy population with mature gastro-intestinal tract. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut microbiota and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating "other substances" in food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of specified doses of L-proline in food supplements, and it is based on previous risk assessments and articles retrieved from literature searches. According to information from NFSA, L-proline is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of 50, 500, 1000, 1500 and 1800 mg/day of L-proline from food supplements. L-proline is considered a non-essential amino acid as it can be synthesised from arginine via the urea cycle in liver, and from glutamine/glutamic acid in the intestinal epithelium. In addition, L-proline is ingested through the diet. All protein rich foods provide L-proline, and animal proteins from milk and meat are particularly abundant sources. A dietary requirement for proline in healthy humans has not been estimated since proline is not considered an essential amino acid. Data on dietary intake of L-proline in Norway are not available. In the third US National Health and Nutrition Examination Survey (NHANES III; 1988-1994), overall mean intake of L-proline from food and supplements was 5.2 g/day. A previous report from the Institute of Medicine (2005) cited one small uncontrolled patient study (n=4) and two animal studies, none of which assessed the toxicity of L-proline in a dose-response manner. The report concluded that a tolerable upper intake level for L-proline could not be determined. In a risk grouping of amino acids from VKM (2011), proline was categorised as having potentially moderate risk, based on the scarce literature and the notion that amino acids are generally bioactive compounds. It was stated that "no conclusion can be drawn on a scientific basis due to lack of adequate scientific literature. Nor will it be possible to conduct a risk assessment until further studies are available". Three systematic literature searches without restriction on publication year were performed for the current risk assessment, aimed at identifying adverse effects of L-proline supplementation in human and animal studies. In humans, one uncontrolled experimental study was identified where a single oral dose of 500 mg/kg bw L-proline was administered as a growth hormone stimulatory agent to 20 children with hyposomatotropic dwarfism and 20 healthy children. No adverse effects were observed. In animals, one relevant subchronic (90 days) toxicological dose-response study in rats was included and forms the basis for the current risk assessment. In that study, performed in accordance with official guidelines from the Japanese Ministry of Health, Labour and Welfare, there were no indications of toxicity at the highest dose given through a powder diet (5.0% L-proline). This dose corresponded to 2773 mg L-proline/kg bw per day and was used as a no-observed-adverse-effect-level (NOAEL). Studies to set a tolerance level for L-proline for children or adolescents have not been found. Therefore, an assumption is made that these age groups have similar tolerance as adults relative to their body weight. To evaluate the safety of the specific doses given by NFSA, margin of exposure (MOE) was calculated with use of 2773 mg L-proline/kg bw per day as NOAEL. For the highest dose (1800 mg/day) MOE is 67 (= 2773* 43.3/1800) in children 10 to <14 years (default body weight 43.3 kg), and 94 (= 2773* 61.3/1800) in adolescents 14 to <18 years (default body weight 61.3 kg). For the dose of 1500 mg/day, the MOE in children is 80. MOE for all the other doses and age categories are above 100. Based on the magnitude of MOE, the lack of adverse effects at the highest dose tested (current NOAEL) and the notion that L-proline is a nutrient that is synthesised endogenously from other amino acids in addition to a dietary intake in the magnitude of 5 grams per day, VKM concludes that: In adults (≥18 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day Lproline in food supplements are unlikely to cause adverse health effects. In adolescents (14 to <18 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day L-proline in food supplements are unlikely to cause adverse health effects. In children (10 to <14 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day L-proline in food supplements are unlikely to cause adverse health effects. Children younger than 10 years were not within the scope of the present risk assessment.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of “other substances” in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating the addition of “other substances” to food supplements. “Other substances” are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of “other substances” evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of L-cysteine and L-cystine, and is based on previous risk assessments of these amino acids and articles retrieved from a comprehensive literature search. In this report L-cysteine and L-cystine are often termed merely cysteine and cystine, respectively. L-cysteine is a central compound in sulphur metabolism in the human body. L-cysteine is a conditionally essential sulphur-containing amino acid, obtained from L-methionine and from serine. Sulphur-containing amino acids are mainly found in cereal proteins and animal proteins, and less abundantly in pulses. Cysteine may occur in proteins either as cysteine itself or as cystine. Cystine is the disulphide dimer of cysteine, and is a more stable compound than cysteine. According to information from the Norwegian Food Safety Authority (NFSA), cysteine and cystine are ingredients in food supplements purchased in Norway and NFSA has requested a risk assessment of the following doses of cysteine and cystine in food supplements: L-cysteine 10 mg/day and L-cystine 250, 500, 750 and 1000 mg/day. The mean usual daily intake of cysteine in the USA for all life stage- and gender groups is 1.0 g/day (NHANES II, USA). Because there are few intervention studies with cysteine or cystine, studies with N-acetylcysteine (or N-acetyl-L-cysteine, NAC), which is readily converted to cysteine, is included in this risk assessment. NAC is used as a pharmaceutical drug for various conditions, mainly as mucolytic agent, as paracetamol antidote, and has been included in numerous clinical trials. Most of the cited studies have tested NAC in doses of about 600-1200 mg/day. The study groups have been various patient groups which included children, adolescents, adults and elderly, however relatively few studies have been conducted in children. In the randomised controlled trials there have been no differences in severe adverse events between the placebo and NAC-groups. The adverse effects reported are generally limited to mild gastrointestinal symptoms. The dose 1200 mg of NAC yields maximum 900 mg of L-cysteine or L-cystine. In adults, it is well documented that doses up to 900 mg per day for one year (corresponding to 13 mg/kg bw/day in a 70 kg adult) is without appreciable health risk. The data for doses above 900 mg/day are more scarce. There are no data indicating that children and adolescent are more vulnerable than adults for L-cysteine or L-cystine. No tolerance level is set for cysteine or cystine specifically for children or adolescents, but an assumption is made that these age groups have similar tolerance per kg body weight as adults. VKM concludes that: In adults (≥18 years), the specified doses 10 mg/day L-cysteine and 250, 500 and 750 mg/day L-cystine in food supplements are considered to be unlikely to cause adverse health effects, whereas the dose 1000 mg L-cystine per day may represent a risk of adverse health effects. In adolescents (14 to <18 years), the specified doses 10 mg/day L-cysteine and 250, 500 and 750 mg/day L-cystine in food supplements are considered to be unlikely to cause adverse health effects in adolescents, whereas the dose 1000 mg L-cystine per day may represent a risk of adverse health effects. In children (10 to <14 years), the specified doses 10 mg/day L-cysteine and 250 and 500 mg/day L-cystine in food supplements are considered to be unlikely to cause adverse health effects, whereas the doses 750 and 1000 mg L-cystine per day may represent a risk of adverse health effects. Children below 10 years were not included in the terms of reference.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of “other substances” in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating the addition of “other substances” to food supplements and other foods. “Other substances” are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. The substance is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of “other substances” evaluated any potential beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in food supplements, and is based on previous risk assessments and a literature search. It is emphasised that this risk assessment concerns the single fatty acids EPA, DPA or DHA separately and not mixtures of these as found in e.g. fish oil/cod liver oil. For risk assessment of combined mixtures of n-3 LCPUFAs in e.g. fish oil/cod liver oil, see the EFSA opinion from 2012 or the VKM assessment from 2011 (EFSA, 2012; VKM, 2011). In the reviewed literature of this risk assessment, no studies investigating ratios between EPA, DPA, DHA or other fatty acids in mixtures have been identified. EPA, DPA and DHA are long chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) and in food these fatty acids are incorporated in triacylglycerols (TAGs) and phospholipids (PLs). Dietary sources are fatty fish, cod liver-, seal-, whale-, fish- and krill oils and human milk, containing various ratios of these fatty acids in combination. EPA can be metabolised to eicosanoids such as prostaglandins, prostacyclins and leukotrienes, all groups are biologically active substances. The eicosanoids participate in the regulation of blood pressure, renal function, blood coagulation, inflammatory and immunological reactions. DHA is an essential structural component of the brain, skin, sperm, testicles and retina. DPA can be retro-converted to EPA or converted to DHA. Still little is known of the biological effects of DPA. Humans have a limited capacity to synthesise EPA, DPA and subsequently DHA from the precursor alpha-linolenic acid (ALA), and this endogenous production is negligible in comparison to the doses used in supplementation studies. According to information from the NFSA, EPA, DPA and DHA are food supplement ingredients in Norway, and NFSA has requested a risk assessment of these fatty acids in the following doses in food supplements: EPA: 1500, 1750 and 1825 mg/day DPA: 100, 125 and 150 mg/day DHA: 1050 and 1290 mg/day Children below 10 years were not included in the terms of reference. Information about intake of EPA, DPA and DHA from the diet is scarce, but calculations performed in the Norwegian Mother and Child Cohort Study indicate a mean total intake (SD) from food and supplements of EPA around 330 (340) mg/day, DPA 43 (30) mg/day and DHA 430 (380) mg/day among pregnant women (2002 to 2008). Mean combined intake of EPA, DPA and DHA from fish oil/ cod liver oil in adults participating in a nationally representative dietary survey was 735 mg/day (VKM, 2014). The major concerns with high intake of EPA and DHA have been increased bleeding time, adverse effects related to immune function, lipid peroxidation and glucose homeostasis. EFSA concluded in 2012 that long-term supplemental intakes of 5 g/day of the n-3 LCPUFA do not raise safety concerns for adults with regard to an increased risk of spontaneous bleeding episodes or bleeding complications, or affect glucose homeostasis, immune function or lipid peroxidation. In 2011, VKM concluded that an intake n-3 LCPUFA up to 6.9 g/day was not associated with increased risk of any serious adverse events. Some adverse health effects related to gastrointestinal function, including abdominal cramps, flatulence, eructation, vomiting and diarrhea have been reported, but seem to be associated with intake of an oily substance and not related specifically to EPA, DPA and/or DHA. EPA: In the report from 2012, EFSA concluded that 1.8 g/day of supplemental EPA does not raise safety concerns in adults. None of the included studies from our literature searches limited to 2012 and onwards have investigated bleeding complications. The dosages of EPA in the three included studies in this report range from 1.8 to 3.8 g/day for 12 weeks. The main endpoints in the studies included lipid peroxidation, inflammation biomarkers of cardiovascular diseases and no serious adverse events were found related to the main endpoints. In general, adverse events were described as gastrointestinal discomforts and not related to dosage. Studies of longer duration are necessary before an intake above 1.8 g of EPA can be considered safe. The Norwegian Scientific Committee for Food Safety (VKM) concludes that the specified doses of 1500, 1750, 1825 mg/day of EPA in food supplements are unlikely to cause adverse health effects in adults (≥18 years). In 2012, EFSA did not make conclusions for children or adolescents for EPA. No new studies with EPA supplementation have been identified in children or adolescents after 2012, and therefore no risk assessment can be made for children (≥10 years) or adolescents. DPA: No dosage of DPA in food supplements can be evaluated due to lack of data. DHA: EFSA concluded that 1 g/day of supplemental DHA does not raise safety concerns for the general population (including children and adolescents). The dosages of DHA in the included trials in this report range from 1.0 to 3.6 g/day and the duration from five weeks to four years. Six out of seven studies have used dosages from 1 to 2 g DHA/day. The last study included up to 3.6 g DHA/day for four years and the age spanned from 7 to 31 years. The main endpoints in all studies included lipid peroxidation, inflammation, cognitive performance, blood pressure and biomarkers of cardiovascular diseases and no serious adverse events were found related to the main endpoints. In general, adverse events were described as gastrointestinal discomforts and not related to dosage. VKM therefore considers that the specified daily doses of DHA that moderately exceed 1 g per day (1050 and 1290 mg/day) are unlikely to cause adverse health effects in the general population including children ≥10 years and adolescents. VKM concludes that the specified doses of 1050 and 1290 mg/day of DHA in food supplements are unlikely to cause adverse health effects in the general population including children (≥10 years), adolescents and adults (≥18 years).
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis for regulating the addition of "other substances" to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any potential beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of creatine as food supplement, and is based on previous risk assessments and articles retrieved in literature searches. According to information from the Norwegian Food Safety Authority (NFSA), creatine is an ingredient in food supplements sold in Norway, and NFSA has requested a risk assessment of the following doses of creatine in food supplements: 3.0, 5.0, 10.0 and 24.0 g/day. The average daily intake from the diet is about 1 g creatine, and the endogenous production also amounts to about 1 g/day. Most of the creatine supplements are in the form of creatine monohydrate. Creatine is an organic acid occurring in the body as either phosphocreatine (2/3) or as free creatine (1/3). Phosphocreatine provides phosphate groups for synthesis of adenosine triphosphate, the major energy-providing compound in the body. Previous risk assessments (AESAN, 2012; EFSA, 2004; SCF, 2000; VKM, 2010) all concluded that creatine supplementation with 3.0 g/day is unlikely to cause adverse health effects in adults. This is supported by human and animal data obtained in a literature search and assessed in the present report. Most of the studies with daily creatine intake above 3 g often (i) involved few and highly trained individuals of whom some took high daily loading doses of creatine for a short period, and (ii) were designed to test clinical benefit without emphasis on possible adverse effects. VKM therefore considers that there is insufficient evidence to conclude regarding possible adverse effects at doses of creatine above 3 g/day for the general population. VKM concludes that: In adults (≥ 18 years) the specified dose of 3.0 g/day creatine in food supplements is considered unlikely to cause adverse health effects. The documentation for absence of adverse health effects of doses 5.0, 10.0 and 24.0 g/day creatine in food supplements in the general population is limited. Hence, these doses may represent risk of adverse health effects in adults. In children (10-14 years) and adolescents (14-17 years), the specified doses of 3.0, 5.0, 10.0 and 24.0 g/day creatine in food supplements may represent a risk of adverse health effects. Children below 10 years were not included in the terms of reference.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. 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 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 Streptococcus thermopilus, and it is based on previous risk assessments and articles retrieved from a literature search. The risk of S. thermophilus was assessed for the general population. However, in previous assessments of “probiotics” published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal flora (age group 0-36 months), population with mature gastro-intestinal flora (>3 years) and vulnerable groups independent of age. VKM has also assessed the risk of S. thermophilus in food supplements independent of the dose and have assessed exposure in general terms. Other sources of S. thermophilus, such as foods, have not been included in the present risk assessment. VKM concludes that it is unlikely that S. thermophilus causes adverse health effects in the general healthy population with mature gastro-intestinal tract. Acquired resistance genes have been detected in this species and the assessment of susceptibility to antibiotics for each single strain is required. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut flora and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis for regulating the addition of "other substances" to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any potential beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of conjugated linoleic acids (CLAs), and is based on previous risk assessments of CLAs and articles retrieved from literature searches. According to information from the NFSA, CLAs are ingredients in food supplements sold in Norway, and NFSA has requested a risk assessment of the following doses of CLAs in food supplements: 3.0, 3.25 and 3.5 g/day. The daily intakes in Norway of CLAs range between 20 and 170 mg (MoBa 2008, version 4). The CLAs are mostly studied in overweight and obese subjects because of their claimed effects to reduce body weight. CLAs constitute a group of isomeric fatty acids mostly produced by bacterial fermentation in the gut. In the human diet, meat (mainly isomers c9,t11 and t10,c12) and dairy products (mainly isomer c9,t11) are main sources of CLAs. The various isomers may have different metabolic effects. In the food supplements evaluated by EFSA (EFSA, 2010 a; EFSA, 2010 b; EFSA, 2012), Clarinol® and Tonalin®, the t10,c12 and the c9,t11 isomers are present in about equal proportions. In research articles not all authors are consistent in reporting what they have studied, so in this report we sometimes do not distinguish between these isomers; hence they are referred collectively to as CLAs if it is not specified. Most of the cited studies have tested supplemental CLAs in doses of about 3.5 g/day, but ranging from 0.7 to 6.0 g/day. In most of the randomised controlled trials (RCTs) there have been no significant differences in adverse effects between the placebo and CLA-groups. Concerns about indications of an unfavourable effect on biomarkers of lipid- and carbohydrate metabolism in obese men with metabolic syndrome as well as unfavourable effect on antioxidant status; increased markers of oxidative stress after consumption of supplemental CLAs have been reported in previous studies. No clear dose-response effects have been found. It is concluded that supplemental CLAs may impair lipid- and carbohydrate metabolism in obese men with the metabolic syndrome. Intake of supplemental CLAs by lactating women may reduce fat content in breastmilk, and intake of supplemental CLAs by pregnant women may reduce birth weight and –length among their offsprings. Only one randomised controlled trial has included children (6-10 years). These children were all overweight or obese, subjects likely to have a different CLA-metabolism/-effect than normal-weight subjects. VKM considers that current data are too incomplete to evaluate any doses of CLAs for children and adolescents. There are few long-term studies, and adverse health effects were not primary outcomes in these studies. Based on available data no conclusions can be drawn for supplemental use of CLAs longer than six months. VKM concludes that: In adults (≥18 years), the specified doses 3.0, 3.25 and 3.5 g/day CLAs in food supplements are considered to be unlikely to cause adverse health effects if used for up to six months. CLA may cause lipid- and carbohydrate disturbances in obese men with metabolic syndrome as well as in overweight/obese subjects with type 2 diabetes. Use of CLA supplements in lactating and pregnant women may cause reduction in milk production and in the content on milk fat and cause decreased birth weight andlength in their off-springs. No conclusion can be made for children and adolescents. Data are insufficient to conclude regarding use of CLAs for more than six months.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. 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 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 Lactobacillus helveticus Rosell-52 ND, and it is based on previous risk assessments and articles retrieved from a literature search. The risk of L. helveticus Rosell-52 ND was assessed for the general population. However, in previous assessments of “probiotics” published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal microbiota (age group 0-36 months), population with mature gastro-intestinal microbiota (>3 years) and vulnerable groups independent of age. VKM has also assessed the risk of L. helveticus Rosell-52 ND in food supplements independent of the dose and have assessed exposure in general terms. Other sources of L. helveticus Rosell-52 ND, such as foods, have not been included in the present risk assessment. VKM concludes that it is unlikely that L. helveticus Rosell-52 ND causes adverse health effects in the general healthy population with mature gastro-intestinal tract. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut microbiota and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. 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 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 Lactobacillus delbrueckii subsp. bulgaricus, and it is based on previous risk assessments and articles retrieved from a literature search. The risk of L. delbrueckii subsp. bulgaricus was assessed for the general population. However, in previous assessments of “probiotics” published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal microbiota (age group 0-36 months), population with mature gastro-intestinal microbiota (>3 years) and vulnerable groups independent of age. VKM has also assessed the risk of L. delbrueckii subsp. bulgaricus in food supplements independent of the dose and have assessed exposure in general terms. Other sources of L. delbrueckii subsp. bulgaricus, such as foods, have not been included in the present risk assessment. VKM concludes that it is unlikely that L. delbrueckii subsp. bulgaricus causes adverse health effects in the general healthy population with mature gastro-intestinal tract. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut microbiota and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. 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 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 Lactobacillus casei W56, and it is based on previous risk assessments and articles retrieved from a literature search. The risk of L. casei W56 was assessed for the general population. However, in previous assessments of “probiotics” published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal microbiota (age group 0-36 months), population with mature gastro-intestinal microbiota (>3 years) and vulnerable groups independent of age. VKM has also assessed the risk of L. casei W56 in food supplements independent of the dose and have assessed exposure in general terms. Other sources of L. casei W56, such as foods, have not been included in the present risk assessment. VKM concludes that it is unlikely that L. casei W56 causes adverse health effects in the general healthy population with mature gastro-intestinal tract. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut microbiota and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating "other substances" in food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" the VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of specified doses of beta-alanine in food supplements, and it is based on previous risk assessments and articles retrieved from literature searches. According to information from NFSA, beta-alanine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of beta-alanine: 1000, 1500 and 2000 mg/day from food supplements. Beta-alanine is a non-essential, non-proteogenic naturally occurring beta amino acid. Beta-alanine is a component of the naturally occurring peptides carnosine, anserine and balenine. Supplementation with beta-alanine leads to an increased production of the peptide carnosine, which is found in high concentrations in the skeletal muscle of both vertebrates and non-vertebrates. Data suggest that beta-alanine functions as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. The only observed adverse effect from beta-alanin supplementation in humans is transient (1-2 hours) paraesthesia and flushing. Paraesthesia is characterised by a stinging or prickling sensation in the skin. There is no evidence that the paraesthesia in the skin is harmful in any way. Long-term studies in humans were not found. Four small human clinical studies have been included in this risk assessment. The occurrence of paraesthesia apparently is dependent on the magnitude of the individual doses that the daily dose is split into. Single doses of beta-alanine of 10 mg/kg bw (700 mg in a 70 kg person) or more provoked transient paraesthesia. Symptom occurrence and severity increased with the dose. Repeated intakes of 5 mg beta-alanine/kg bw or less taken with >2 hours intervals did not induce paraesthesia. Haematology and plasma clinical chemistry was found normal after daily doses of 2.8 g and 3.2 g for 4 weeks in healthy adults. Apart from occasional paraesthesia, a daily dose of 6.4 g for up to seven weeks did not induce any adverse clinical effects in healthy adults of 80 kg, corresponding to a dose of 5.6 g per day in a 70-kg person. We are not aware of any data indicating that children and adolescents are more vulnerable than adults for supplementation with beta-alanine on a per kg bw basis. No relevant animal studies were identified. VKM concludes that: In adults (≥18 years), the specified doses 1000, 1500 and 2000 mg/day of beta-alanine in food supplements are unlikely to cause adverse health effects provided that beta-alanine is consumed with maximum 5 mg/kg bw per intake and a minimum of 2 hours between the intakes. In adolescents (14 to <18 years) and children (10 to <14 years) the specified doses 1000, 1500 and 2000 mg/day of beta-alanine in food supplements are unlikely to cause adverse health effects provided that beta-alanine is consumed with maximum 5 mg/kg bw per intake and a minimum of 2 hours between the intakes. Children younger than 10 years were not within the scope of the present risk assessment.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. The risk assessments are the scientific basis for NFSA in its efforts to regulate the use of "other substances" to food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of L-leucine, L-isoleucine and L-valine and it is based on previous risk assessments and articles retrieved from a literature search. In this report Lleucine, L-isoleucine and L-valine may occasionally be termed merely leucine, isoleucine or valine. L-leucine, L-isoleucine and L-valine are essential amino acids. L-leucine, L-isoleucine and Lvaline are commonly known as Branched Chain Amino Acids (BCAAs), and are found in food items containing proteins and in particular, in protein-rich foods such as dairy products, meats, eggs, nuts, whole grains, seeds, avocadoes and edible seaweed. According to information from NFSA, L-leucine, L-isoleucine and L-valine are ingredients in food supplements sold in Norway. NFSA has requested a risk assessment of the following doses of L-leucine, L-isoleucine and L-valine in food supplements for adults, adolescents and children 10 years and above: L-leucine: 2500, 3000, 4000, 5000 and 5250 mg/day, Lisoleucine: 1500, 1750, 2000 and 2500 mg/day and L-valine: 1500, 1750, 2000, 2250 and 2500 mg/day. Usual dietary intakes of these amino acids in Norway are not known. Based on data from the 1988–1994 NHANES III, mean daily intakes in adults of leucine, isoleucine and valine from food and supplements are 6.1, 3.6 and 4.0 g/day, respectively (IOM, 2005). Most studies on BCAAs have focused on the three amino acids taken as single amino acids or together combined in food supplements. It has been shown that BCAAs are not metabolized in the liver as is common for most other amino acids but taken up by most peripheral tissues (in particular muscle) where they are either used in protein synthesis or as precursors for nitrogen and/or a number of carbon containing molecules. There is a lack of relevant well-designed supplementation studies with L-leucine, L-isoleucine and L-valine in humans designed to address adverse effects and dose-response relationships as primary outcome. However, daily doses of as much as 30 g BCAA per day given to athletes have been investigated and reported to improve performance. In these reports adverse effects were not addressed and not reported. L-leucine has been administered orally in single doses for one day of up to 50 g without showing any adverse effects. There are no published studies on the effects of longitudinal supplementation with either L-isoleucine or L-valine. Thus, there are no published studies that can be used for suggesting a "value for comparison", and there is no scientific data in the literature suitable for assessing the specific doses in the terms of reference. WHO (2007) recommendations for BCAAs are: Leucine 2730 mg/day, isoleucine 1400 mg/day and valine 1820 mg/day. For a 70 kg person, this corresponds to 39 mg leucine/kg body weight (bw) per day, 20 mg isoleucine/kg bw per day and 26 mg valine/kg bw per day. The acute upper tolerable metabolic limit of L-leucine for men between 20 and 35 years was determined by administration of single doses of 550-700 mg/kg bw over one day. This corresponded to 39 to 50 g/day for a person of 70 kg. Furthermore, based on several studies investigating L-leucine, L-isoleucine and L-valine supplemented as single doses ranging from 10 to 30 g/day without any reported adverse effects. The uncertainties for this consideration are described in chapter 5. VKM concludes that: Due to lack of studies addressing adverse effects for the specified doses 2500, 3000, 4000, 5000 and 5250 mg/day L-leucine, 1500, 1750, 2000 and 2500 mg/day L-isoleucine and 1500, 1750, 2000, 2250 and 2500 mg/day L-valine in food supplements, no conclusions can be made for adults (≥ 18 years), adolescents (≥ 10 and < 18 years) or children (< 10 years).
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating "other substances" in food supplements. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological e ffect . It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" the VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects. For the current report VKM has studied previous risk assessments and performed two systematic literature searches for any published studies assessing negative health effects of L-alanine in humans or animals. According to information from NFSA, L-alanine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of L-alanine: 3500, 3750, 4000, 4250 and 4500 mg/day. Foods rich in alanine are generally protein rich foods such as meat, dairy products, legumes, fish, nuts, seeds, eggs and whole grains. Based on NHANES III (19881994), the overall mean intake of L-alanine from food and food supplements in the United States was 3.6 g/day. L-alanine is a naturally occurring non-essential α-amino acid belonging to the group of the 20 amino acids that are normal components of food proteins. L-alanine acts as an intermediary between protein catabolism and carbohydrate synthesis. It can be easily synthesised from the alpha keto acid pyruvate and has close links to several metabolic pathways including glycolysis, gluconeogenesis, and the citric acid cycle. Together with lactate it is capable of generating glucose from muscle protein through gluconeogenesis in the liver. Alanine thus plays a central role in the metabolism of muscle protein and is a key factor in nitrogen metabolism. Previous reports from the US Institute of Medicine (IOM) 2005, the French Food Safety Agency (AFSSA) 2007 and the Spanish Agency for Food Safety and Nutrition (AESAN) 2012 did not conclude regarding safe doses of L-alanine, but stated that data on adverse effects of L-alanine intake from supplements were not sufficient for a dose-response assessment and establishment of a tolerable upper intake level. Few studies have assessed health effects of L-alanine supplementation in humans, and these were generally not designed to evaluate potential harmful effects of L-alanine. Most human experimental studies gave single doses (up to 50 g) or short-term loading doses (e.g. 25 to 45 g/hour during exercise) to study metabolic responses such as ergogenic effects during exercise or prevention of ketosis after fasting. Adverse health effects were not reported except for abdominal discomfort and stomach cramps, nausea and diarrhea after consuming high doses. No studies assessed long-term effects of L-alanine supplementation, and no studies gave doses comparable to the doses under consideration in the present report. Only one dose-reponse toxicity study in rodents has been found (Chow et al., 1976). In that study, growing Wistar rats were fed up to 20% DL-alanine (a racemic mixture of D- and Lalanine) in their basal diet for 26 weeks, with no effect on liver and kidney weight and no pathological changes in any organs. The study was taken into account due to the otherwise scarce literature on L-alanine toxicity, and could be used since there were no adverse effects at the highest dose tested. The no observed adverse effect level (NOAEL) in mg L-alanine per kg body weight per day was not stated. VKM has therefore estimated the NOAEL using information about average reported feed consumption and average body weights of the animals, and divided by 2 to obtain a NOAEL for L-alanine, arriving at approximately 6450 mg/kg bw/day in male rats and 9700 mg/kg bw/day in female rats. A standard toxicological approach dividing by an uncertainty factor (UF) of 10 for between-species variation and an additional UF of 10 for within-species variation gives the value of 64.5 mg/kg bw per day in females and 97.0 mg/kg bw per day in males, corresponding to approximately 4500 mg/day and 6800 mg/day for a 70 kg man and woman, respectively. VKM also calculated the margins of exposure (MOE) between the estimated NOAEL and the estimated daily exposures from the five supplement doses given by the NFSA (based on default average body weights for the age groups). MOE were 100 or higher for all five doses in adults. For adolescents 14 to <18 years, the MOE was 88 for the highest dose under consideration. For children 10 to <14 years, MOE ranged from 62 for the highest dose to 80 for the lowest dose. The VKM considers that these margins are relatively high and are acceptable based on the following considerations: The highest dose tested in growing rats did not cause adverse effects, implying that the “true” NOAEL is unknown and could be considerably higher. Furthermore, L-alanine is a nutrient participating in normal energy metabolism as a substrate for glucose. It is consumed in the magnitude of 3 to 4 g/day on average in the habitual diet, and it has not been associated with harmful effects in humans beyond gastrointestinal effects when consuming very high single doses (50 g, or at a consumption rate of 30 to 45 grams per hour during exercise). VKM concludes that: In adults (≥18 years), the specified doses 3500, 3750, 4000, 4250 and 4500 mg/day L-alanine in food supplements are unlikely to cause adverse health effects. In adolescents (14 to <18 years), the specified doses 3500, 3750, 4000, 4250 and 4500 mg/day L-alanine in food supplements are unlikely to cause adverse health effects. In children (10 to <14 years), the specified doses 3500, 3750, 4000, 4250 and 4500 mg/day L-alanine in food supplements are unlikely to cause adverse health effects. Children younger than 10 years were not within the scope of the present risk assessment.
ABSTRACT
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. 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 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 Lactococcus lactis W58, and it is based on previous risk assessments and articles retrieved from a literature search. The risk of L. lactis W58 was assessed for the general population. However, in previous assessments of “probiotics” published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal microbiota (age group 0-36 months), population with mature gastro-intestinal microbiota (>3 years) and vulnerable groups independent of age. VKM has also assessed the risk of L. lactis W58 in food supplements independent of the dose and have assessed exposure in general terms. Other sources of L. lactis W58, such as foods, have not been included in the present risk assessment. VKM concludes that it is unlikely that L. lactis W58 causes adverse health effects in the general healthy population with mature gastro-intestinal tract. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut microbiota and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.