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

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 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.