Registration Dossier

Administrative data

Description of key information

The European Food Safety Authority (EFSA) Scientific Committee on Food - Scientific Panel on Dietetic Products, Nutrition and Allergies (2006) set a tolerable upper intake level for Nicotinamide. Based on a number of human trials, the upper level for Nicotinamide is established at 12.5 mg/kg bw/day or approximately 900 mg/day for adults.

Additional information

Human data on Nicotinamide is presented in a weight of evidence approach. Available human data was previously reviewed by the European Commission Scientific Committee on Food, the EFSA Panel on Additives and Products or Substances used in Animal Feed, the US FDA and the UK Food Standards Agency Expert Group on Vitamins and Minerals. An OECD SIDS review concluded that Nicotinamide is essential for human and animal health. Based on all available human information the substance does not present a hazard to human health.

The European Food Safety Authority (EFSA) compiled relevant human data (2006):

HUMAN DATA

The principal identification of hazards associated with excessive intakes of niacin have arisen from studies in which high doses of nicotinic acid have been used for its therapeutic effects in lowering blood cholesterol and blood hyperlipidaemias. The most comprehensive study was that conducted by the Coronary Drug Project Research Group (1975). A number of hazards have been reported to be associated with high doses of nicotinic acid. These have been summarised by the US National Academy of Sciences Institute of Medicine in their evaluation of dietary reference intakes.

In addition, Nicotinamide has been investigated as a method for reducing the risk of the development of diabetes (Knip et al, 2000). Studies have shown that Nicotinamide can afford protection in an animal model of immune mediated insulin-dependent diabetes (Reddy et al, 1990), and it has been investigated in a number of clinical trials, some of which are still ongoing.

Vasodilatory effects (flushing)

Vasodilation is commonly seen in patients given high doses of nicotinic acid for the treatment of hyperlipidaemias. Very large single doses cause hypotension, although tolerance develops to this effect after several days of continued high dose intake. In general, flushing is a mild and transient effect although in many clinical trials it has resulted in patients withdrawing from treatment. The flushing activity appears to be related to the presence of a carboxyl group on the pyridine nucleus since compounds lacking this function, including Nicotinamide, are not associated with facial flushing (Bean and Spies,1940). Flushing is associated with periods of rapid rises in blood concentrations, and sustained-release formulations were developed for the use of nicotinic acid in the treatment of hypercholesterolaemia, in order to minimise this side-effect. Flushing is produced via prostaglandin D2 release (Morrow et al, 1989 and 1992) and a “niacin flush-test” has been used as a method of investigating essential fatty

acid metabolism (Glen et al, 1996). Tolerance develops due to decreased formation of prostaglandin D2 on repeated dosage (Stern et al, 1991). Although flushing is not a clearly adverse effect and single oral doses of 100 mg do not alter heart rate or blood pressure, some patients in the study of Spies et al(1938) reported dizziness after oral nicotinic acid (doses not defined). Theoretically if flushing occurred in the elderly, it could exacerbate mild postural hypotension, and could increase the risk of falls, which are a common cause of morbidity in the elderly. This risk relates to taking supplements containing nicotinic acid (not Nicotinamide), especially if taken on an empty stomach.

Gastrointestinal effects

Gastrointestinal effects such as dyspepsia, diarrhoea and constipation are common in patients with hypercholesterolaemia given high doses of nicotinic acid (3 g/day - especially as the sustained-release formulation; Knopp et al, 1985).

Hepatotoxicity

Severe and potentially life-threatening hepatotoxicity has been associated with treatment of patients with 3-9 g nicotinic acid per day for periods of months or years for the treatment of hypercholesterolaemia. Severe cases show liver dysfunction and fulminant hepatitis and may even proceed to encephalopathy requiring liver transplantation. Many of the patients showing hepatotoxicity were taking the slow release formulation of the compound, so that in contrast to the flushing discussed above, the development of hepatic toxicity is a function of long-term chronic exposure to relatively constant levels rather than the fluctuating levels and rapid rises which produce flushing.

Glucose intolerance

Nicotinic acid (3 g/day) has been reported to impair glucose tolerance in otherwise healthy individuals treated for hypercholesterolaemia.

Other effects

There have been rare reported cases of a range of effects including blurred vision, macular oedema and increased plasma homocysteine concentrations in patients given high doses of nicotinic acid. These effects were reported at doses similar to those producing hepatic dysfunction, and were reversible upon cessation of high dose treatment. There has been a single report of a possible association with congenital malformation in women taking Nicotinamide during early pregnancy (Nelson and Forfar, 1971). On the basis of their retrospective survey of drug and vitamin prescriptions during pregnancy in 1369 mothers, the authors reported that a significantly (P<0.05) higher proportion of women with infants showing abnormalities took Nicotinamide in the first 56 days (5/458), compared with mothers of normal babies (1/911). In contrast no such relationship was found during later phases of pregnancy or over the whole of the pregnancy. The paper did not report the doses of Nicotinamide taken. This finding is in contrast to the results of the large multicentre study on vitamins and the prevention of neural tube defect (MRC Vitamin Study Research Group, 1991). In that study 1817 women with high risk for producing a baby with neural tube defect were randomised into 4 groups; one group received folic acid, one group a multivitamin preparation (that did not include folate but contained 15 mg/day of Nicotinamide), one group was given both preparations and one group received neither preparation. Although the study focused on neural tube defects, any foetal malformation was recorded together with other pregnancy outcomes, and there was no difference in incidence between the multivitamin preparation and placebo.

DOSE-RESPONSE ASSESSMENT

Vasodilatory effects (flushing)

The flushing reported with nicotinic acid does not occur following Nicotinamide, either given as an intravenous injection (Bean and Spies, 1940) or when it is given orally at high-doses to patients with diabetes (Knip et al., 2000).

Gastrointestinal effects

Gastrointestinal effects are rare following high-dose treatment with Nicotinamide (Knip et al., 2000). Nausea was reported in a single subject who had taken Nicotinamide 3 g daily followed by 9 g per day for several days (Winter and Boyer, 1973).

Hepatotoxicity

Only one patient has been reported to have developed hepatitis after Nicotinamide alone, and this subject had been given 3 g daily followed by 9 g per day for several days (Winter and Boyer, 1973); other subjects who developed liver disease after Nicotinamide had also received prolonged treatment with nicotinic acid (see Rader et al., 1992).

Increased serum transaminase levels were reported for 17 out of 41 children with attention deficit disorders treated for 12 weeks with daily doses of 3 g Nicotinamide, in combination with 1.2 g pantothenic acid, 3 g ascorbic acid and 0.6 g pyridoxine (Haslam et al., 1984). Whether this hepatotoxic effect was related to the high dose of Nicotinamide, or to the combination with the high doses of pantothenic acid, vitamin C and pyridoxine, cannot be concluded from this study, and therefore, this study cannot be used in risk assessment of Nicotinamide.

The supplementation trials on the use of Nicotinamide to prevent or delay the development of diabetes mellitus have not reported hepatitis as an adverse effect (Knip et al., 2000); however these have involved smaller number of subjects, have been of shorter duration and at lower doses than the trials on the use of nicotinic acid for the treatment of hypercholesterolaemia. Ten newly diagnosed Type 1 diabetic patients were given 1 g/day for 45 days (Mendola et al., 1989), and compared over the following year with a group who were treated with placebo; the authors reported that no adverse effects were observed when physical, biochemical and haematological parameters were considered (no details of the tests were given and the main aim of the paper was to study efficacy). A group of 35 patients, aged 6 to 18 years, were given either placebo (n=17), or up to 1.5 g/day of slow-release Nicotinamide (n=18) for 12 months (Chase et al., 1990); various tests, including measurement of serum transaminases, alkaline phosphatase and bilirubin, were performed after 4 and 12 months, and remained normal in all subjects. No adverse effects were reported in a group of nine Type 1 diabetic patients with ketosis given 3 g of Nicotinamide per day, three of whom were treated for up to 12 months, compared to 7 similar patients given placebo (Vague et al., 1987).

Major long-term studies in patients with Type 1 diabetes mellitus, at dosages of 2-3 g of Nicotinamide per day, have been undertaken recently (ENDIT - see Pociot et al., 1993; IMDIAB III - see Pozzilli et al., 1995; DENIS - see Lampeter et al., 1998). The ENDIT (European Nicotinamide Diabetes Intervention Trial) has reviewed the safety data on Nicotinamide before starting the clinical phase, but no results of the trial have yet been published (Pociot et al., 1993; Knip et al., 2000). The IMDIAB III study involved a doubleblind trial in which 28 newly diagnosed patients with Type 1 diabetes mellitus were given 25 mg/kg bw of Nicotinamide daily for 12 months, and a similar number treated with placebo; no adverse effects were reported and biochemical parameters including liver and kidney function were normal during follow-up (the publication describes the measurement of bilirubin). The

DENIS trial (Deutsche Nicotinamide Intervention Study) was a study in young children (average age 3 years) at high risk of developing Type 1 diabetes mellitus in which 25 subjects were randomised to receive Nicotinamide (1.2 g per m2 per day), and 30 to receive placebo; the trial continued for 3 years and during this period all biochemical markers (including alanine aminotransferase, aspartate aminotransferase and bilirubin) were in the normal range.

Glucose intolerance

Nicotinamide has been studied in relation to reducing the risk of the development of diabetes mellitus; none of the studies (see above) has reported a worsening of symptoms in the treated groups.

Other effects and overall dose-response relationships

There have been no other adverse effects reported following the administration of Nicotinamide in trials in patients with diabetes. Determination of the NOAEL from the intervention trials is difficult, because of the different dosage regimens employed. Studies have used fixed doses of 1 g/day (Mendola et al., 1989), 1.5 g/day (Chase et al., 1990), 3 g/day (Vague et al., 1987), 25 mg/kg bw/day (IMDIAB III trial) and 1.2 g/m2/day (DENIS trial). These different doses can be calculated on a body weight basis using the data on body weights or ages in the different publications; the doses approximate to 17 mg/kg bw/day 13 (Mendola et al., 1989; average age 18.3 years), 37 mg/kg bw/day (Chase et al., 1990; average age 12.5 years), 43 mg/kg bw/day (Vague et al., 1987; adults), 25 mg/kg bw/day (IMDIAB III trial; ages in the range 5-35 years) and 50-40 mg/kg bw/day (DENIS trial; ages 3-12 years). The lowest of these values (25 mg/kg bw/day) was from one of the largest published studies, and this has been used as the NOAEL for Nicotinamide.

DERIVATION OF A TOLERABLE UPPER INTAKE LEVEL

Nicotinamide does not produce the flushing response that has been used as the basis for the upper level for nicotinic acid. There has been only one reported case of hepatotoxicity in a patient receiving high-dose Nicotinamide (however, Nicotinamide has not been subject to extensive clinical trials [at 3 g per day or more] for use as a hypolipidaemic agent). No significant adverse effects have been reported in trials on the possible benefits of Nicotinamide in patients with or at risk of diabetes, which have used doses up to the equivalent of 3 g per day, for periods up to 3 years. The NOAEL from these studies is approximately 25 mg/kg bw/day. This value represents the lowest reported dose in a number of recent trials of high quality, many of which used sensitive markers of hepatic function and glucose homeostasis, and included a range of age groups, with some subjects treated with up to 50 mg/kg bw/day. An uncertainty factor of 2 has been used to allow for the fact that adults may eliminate Nicotinamide more slowly than the study groups, many of which were children, and that data for children would not reflect the full extent of intersubject variability that could occur in an older population. The upper level for Nicotinamide is established at 12.5 mg/kg bw/day or approximately 900 mg/day for adults.

Reference: EFSA Scientific Committee on Food - Scientific Panel on Dietetic Products, Nutrition and Allergies (2006) Tolerable Upper Intake Levels for Vitamins and Minerals.