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

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.