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" – 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" – 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).