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. Orotic acid salts as sources of orotic acid and various minerals added for nutritional purposes to food supplements 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.
Orotic acid salts as sources of orotic acid and various minerals added for nutritional purposes to food supplements
GRILLI, SANDRO;
2009
Abstract
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. Orotic acid salts as sources of orotic acid and various minerals added for nutritional purposes to food supplements 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
