Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents WHO FOOD ADDITIVES SERIES NO. 5 The evaluations contained in this publication were prepared by the Joint FAO/WHO Expert Committee on Food Additives which met in Geneva, 25 June - 4 July 19731 World Health Organization Geneva 1974 1 Seventeenth Report of the Joint FAO/WHO Expert Committee on Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 539; FAO Nutrition Meetings Report Series, 1974, No. 53. ASCORBIC ACID AND ITS POTASSIUM AND SODIUM SALTS Explanation Ascorbic acid and sodium ascorbate were evaluated for acceptable daily intake by the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1, Ref. No. 6) in 1961. Since the previous evaluation, additional data have become available and are summarized and discussed in the following monograph. The previously published monograph has been expanded and is reproduced in its entirety below. BIOLOGICAL DATA BIOCHEMICAL ASPECTS Ascorbic acid is readily absorbed and metabolized. However, after oral administration of large quantities only small amounts are excreted in the urine, while there is a steady rise in the level of ascorbic acid in the plasma. If the oral ingestion is continued for a sufficient period, the plasma concentration rises to a maximum, after which a rapid urinary excretion of a large part of the ingested ascorbic acid occurs (Abt & Farmer, 1938). Using 14C-labelled ascorbic acid, it was found that in the rat after intraperitoneal injection of 1.5-5.9 mg approximately 19 to 29% was converted to CO2 and only 0.4% was excreted as oxalate within 24 hours (Curtin & King, 1955). TOXICOLOGICAL STUDIES Acute toxicity LD50 Animal Route (mg/kg bw) Reference Mouse oral > 5 000 Demole, 1934 i.v. > 1 000 Rat oral > 5 000 Demole, 1934 i.v. > 1 000 Guinea-pig oral > 5 000 Demole, 1934 i.v. > 500 Short-term studies Mouse Mice given ascorbic acid orally, subcutaneously and intravenously in daily doses of 500-1000 mg/kg bw for seven days, showed no difference in appetite, weight gain and general behaviour from controls receiving the same amount of the biologically inactive galacturonic acid. Histological examination of various organs showed no definite changes (Demole, 1934). Guinea-pig Guinea-pigs given ascorbic acid orally, subcutaneously and intravenously in daily doses of 400-2500 mg/kg bw for six days, showed no difference in appetite, weight gain and general behaviour from controls receiving the same amounts of the biologically inactive galacturonic acid. Histological examination of various organs showed no definite changes (Demole, 1934). Long-term studies Rat Four groups of 26 male and 26 female rats were given in their diet for two years daily doses of 0, 1000, 1500 or 2000 mg/kg bw of L-ascorbic acid. Haematological examinations, urine analyses, blood enzyme activity, liver and renal function tests yielded results within the normal range of values observed in the control group. No macro- or micropathologically detectable toxic organic lesions were observed which could be attributed to the daily ingestion of large doses of L-ascorbic acid. Age-dependent degenerative processes in organs, increasing predisposition of aging animals to intercurrent diseases and the appearance of spontaneous tumours occurred at the same rate in control animals and in those treated (Surber & Cerioli, 1971). OBSERVATIONS IN MAN One woman and three men were each given 1000 mg of ascorbic acid a day for three months. The ascorbic acid levels in the serum and in the white blood cells and the urinary excretion of this acid did not shown any progressive changes. Further, no harmful effects were observed in these four subjects during the three months (Lowry et al., 1952). After a daily dose of 5 mg/kg for three days a significant increase in urinary volume was observed in 30 children (10 active rheumatic, 10 convalescent rheumatic patients and 10 controls) (Abbasy, 1937). This diuretic effect was confirmed in another study on nine patients with heart failure, given 300 mg of ascorbic acid daily (Evans, 1938). Doses up to 6000 mg of ascorbic acid were given to 29 infants, 93 children of preschool and school age, and 20 adults for more than 1400 days. With the higher doses, toxic manifestations were observed in five adults and four infants. The signs and symptoms in adults were nausea, vomiting, diarrhoea, flushing of the face, headache, fatigue and disturbed sleep. The main toxic reactions in the infants were skin rashes (Widenbauer, 1936). Comments: Animal studies reveal that ascorbic acid is not toxic after a single or repeated administrations of relatively large doses. Studies in man indicate that ascorbic acid has a diuretic effect at 5 mg/kg bw in children and adults and glycosuria was observed with doses of 30-100 mg/kg. Daily doses, of the order of 200 mg/kg, have been taken over periods of time for a therapeutic effect which has not been unequivocably demonstrated. The recommended dietary allowances range from 30-75 mg with a minimum of 5-10 mg/day. It is estimated that the daily intake of ascorbic acid is between 30-100 mg from natural sources. EVALUATION Estimate of acceptable daily intake for man 0-15 mg/kg bw REFERENCES Abbasy, M. A. (1937) Biochem. J., 31, 339 Abt, A. F. & Farmer, C. J. (1938) J. Amer. med. Ass., 111, 1555 Curtin, C. O' H. & King, C. G. (1955) J. biol. Chem., 216, 539 Demole, V. (1934) Biochem. J., 28, 770 Evans, W. (1938) Lancet, 1, 308 Lowry, O. H., Bessy, O. A. & Bunch, H. B. (1952) Proc. Soc. exp. Biol., 80, 361 Surber, W. & Cerioli, A. (1971) A two-year toxicity study with L-ascorbic acid on the rats. Unpublished report of the Battelle Laboratories submitted by Hoffman-La Roche AG Widenbauer, F. (1936) Klin. Wschr., 33, 1157
See Also: Toxicological Abbreviations