EFSA Completes First Supplement Assessment, Disputes Orotate Safety

186 applications were withdrawn at various stages during the evaluation process, and EFSA received insufficient scientific evidence to be able to assess around half of the remaining applications. Possible safety concerns were identified in relation to 39 applications.

29 Jul 2009 The European Food Safety Authority (EFSA) has completed the first comprehensive assessment of substances used as sources of vitamins and minerals in food supplements which are currently sold in the European Union. EFSA has examined 533 applications since 2005, relating to 344 different substances. The assessments were based on scientific evidence provided by food supplement manufacturers to demonstrate the safety of these nutrient sources and the extent to which they are absorbed in the body (i.e. their bioavailability).

186 applications were withdrawn at various stages during the evaluation process, and EFSA received insufficient scientific evidence to be able to assess around half of the remaining applications. Possible safety concerns were identified in relation to 39 applications.

John-Christian Larsen, the Chair of EFSA’s Panel on additives and nutrient sources added to food (the ANS Panel), said: “Millions of people across Europe regularly take food supplements in addition to their normal diet. The work of the Panel will help to ensure that the sources of vitamins and minerals used in food supplements which are sold in the EU are safe and can effectively provide these nutrients to the body.”

“Completing this huge task in line with the challenging deadline agreed with the European Commission is an important milestone in EFSA’s work in the area of consumer protection, and represents a significant achievement for the ANS Panel in particular. I would like to thank all of the scientists involved for their hard work.”

Food supplements are concentrated sources of nutrients or other substances with a nutritional or physiological effect, whose purpose is to supplement the normal diet. Examples of the substances assessed by EFSA included chromium nitrate used in food supplements as a source of chromium, and vitamin B12-enriched yeast used in supplements as a source of vitamin B12.

EU Directive 2002/46/EC specifies that only nutrient sources whose safety and bioavailability have been assessed by EFSA and listed in the relevant Annex of the Directive can continue to be used in food supplements from 1 January 2010.

EFSA reported that following a request from the European Commission, the Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to provide a scientific opinion on the safety of magnesium orotate, zinc orotate, calcium orotate, chromium orotate, copper orotate, iron orotate, manganese orotate, potassium orotate, sodium orotate and choline orotate added for nutritional purposes as a source of magnesium, zinc, calcium, chromium, copper, iron, manganese, potassium, sodium and choline in food supplements and on the bioavailability of these cations from these sources.

The present opinion deals only with the safety of orotate sources of the ten cations mentioned above and the bioavailability of the nutrient cations from these sources, intended for use in food supplements. The safety of the nutrient cations themselves, in terms of amounts that may be consumed, is outside the remit of this Panel.

Orotic acid is an intermediate in the pyrimidine biosynthesis, which is required for DNA and RNA synthesis. It was originally introduced as a vitamin, called vitamin B13, but essentiality has not been demonstrated.

Orotic acid occurs mainly in milk from ruminants, with highest amounts being found in animals which are deficient in arginine and uridine-5’-monophosphate activity. In cows’ milk amounts of 20-100 mg/L are found and somewhat higher amounts in goat’s and sheep’s milk. Orotic acid has also been detected in infant formula in amounts of 15-118 mg/L, which is reflecting the range of cow’s milk.

No use levels are provided for sodium or choline orotate. For the other orotate sources, there is a large difference concerning the daily doses proposed by the petitioners: 1.8 - 6206 mg/day. Largest exposures to orotate from an orotate source would result from the proposed uses for calcium and magnesium orotate, providing the amount of 800 mg calcium/day (equivalent to 6.2 g orotate or about 100 mg/kg bw/day), and magnesium of 250 mg/day (equivalent to 3.2 g orotate/day or 53 mg/kg bw/day). For consumers who would consume several nutrients with orotates as source, the total anticipated combined exposure would amount over 11 g/day.

Orotic acid is synthesised in situ from carbamoyl phosphate and aspartic acid through dihydroorotic acid. Orotic acid is then transformed to orotidin-5’-phosphate and further to uridine-5’-monophosphate. When there is insufficient capacity for detoxifying the load of ammonia presented for urea synthesis, carbamoyl phosphate leaves the mitochondria and enters the pyrimidine pathway, where orotic acid biosynthesis is stimulated; orotic acid excretion in urine then increases. Orotic acid synthesis is abnormally high in hereditary deficiencies of urea-cycle enzymes or uridine monophosphate synthase.

Little documentation on the bioavailability of the mineral salts of orotic acid has been submitted, but one study reveals that the bioavailability of zinc from zinc orotate is comparable to that of zinc from another organic source, as well as an inorganic salt. The Panel concludes that this will probably also be the case for the bioavailability of the cations from the other orotate salts, for which no documentation has been supplied.

The petitioners have submitted only few data concerning the toxicity of orotic acid and none on the salts. Orotic acid has a low acute toxicity. In repeated doses orotic acid induces fatty livers in the rat, but not in other species tested. No data were submitted on reproductive and developmental toxicity and only irrelevant data on genotoxicity.

Several studies have shown that repeated dosing of orotic acid to rats and some other species promotes the formation of tumours initiated by various known carcinogenic substances. The usual concentration to promote tumours has been 1 % in the diet, but also 0.5 and 0.2 % in the diet has been shown to have promoting effect, while 0.1 % in the diet did not have effect within the time span tested (up to 20 weeks). A No Observed Adverse Effect Level for this effect can thus be determined to be 50 mg/kg bw/day, while the Lowest Observed Effect Level is 100 mg/kg bw/day.

In a long-term feeding study in rats, 1 % orotic acid in the diet without any initiation, increased the frequency of tumours likely due to a promoting effect of orotic acid on spontaneously arising and/or diet induced altered cells.

The Panel considers that it is not appropriate to conclude on the safety for a combination between chromium and a tumour promoter as long as it is not clear whether chromium is genotoxic or not.

The Panel concludes that in the light of the tumour-promoting effect of orotic acid in animal experimentation, the small margin of safety to this effect from foreseeable exposure, and the absence of any relevant studies on genotoxicity and of any developmental studies, the use of orotate as a source of the eight other minerals and choline at the proposed levels of use is of safety concern.