INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY WORLD HEALTH ORGANIZATION TOXICOLOGICAL EVALUATION OF SOME FOOD COLOURS, ENZYMES, FLAVOUR ENHANCERS, THICKENING AGENTS, AND CERTAIN FOOD ADDITIVES WHO FOOD ADDITIVES SERIES 6 The evaluations contained in this publication were prepared by the Joint FAO/WHO Expert Committee on Food Additives which met in Rome, 4-13 June 19741 World Health Organization Geneva 1975 1 Eighteenth Report of the Joint FAO/WHO Expert Committee on Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 557. FAO Nutrition Meetings Report Series, 1974, No. 54. GLUCONO-DELTA-LACTONE Explanation This compound has been evaluated for acceptable daily intake by the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1, Ref. No. 13) in 1966. 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 Glucono-delta-lactone, in an aqueous medium, readily forms an equilibrium mixture of the lactone and gluconic acid. These are intermediates in the oxidation of glucose through the pentose phosphate cycle, which, while not the main pathway of glucose metabolism, is well recognized. When three men were given 10 g (167 mg/kg) of glucono-delta- lactone orally as a 10% solution, the amounts recovered in the urine in seven hours represented 7.7-15% of the dose. No pathological urine constituents were noted. When 5 g (84 mg/kg) was given orally none was recovered in the urine. The largest dose given to man was 30 g (500 mg/kg (Chenoweth et al., 1941). Groups of six rats each were fed a diet in which the limiting factor was inadequate caloric value. When the basal diet was supplemented with either glucose or d-glucono-delta-lactone, as a source of additional calories, an increased growth rate was observed. Glucose and d-glucono-delta-lactone were almost equally effective in the promotion of growth (Eyles & Lewis, 1943). Sodium gluconate uniformly labelled with C14 and D was administered (i.p.) to normal rats for three successive days. In the case of the normal rat, 57% of the administered C14 was excreted uncharged into the urine, and 14% of the C14 label appeared in expired CO2. Only a small fraction of gluconate carbon could be recovered as urinary saccharate. When labelled gluconate was administered to phlorizinized rat, about 10% of the total C14 label appeared in the expired CO2. Urinary glucose from the phlorizinized rat and liver glycogen from the normal rat were shown to be uniformly labelled with respect to C14 (Stetten & Stetten, 1950). TOXICOLOGICAL STUDIES Special studies on teratogenicity Mouse Six groups of 25 pregnant mice were given continuously from day 6-15 of gestation 0, 6.95 mg/kg bw, 32.5 mg/kg bw, 150 mg/kg bw, 695 mg/kg bw GDL by oral intubation. A positive control group of 150 mg/kg aspirin was included. No clearly discernible effects were seen on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls (Anonymous, 1974). Rat Six groups of 22 to 25 pregnant rats were given continuously from day 6-15 of gestation 0, 5.94, 27.6, 128 and 594 mg/kg bw GDL by oral intubation. A positive control group of 250 mg/kg aspirin was included. No clearly discernible effects were seen on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls (Anonymous, 1974). Hamster Six groups of approximately 25 pregnant hamsters were given continuously from day 6-10 of gestation 0, 5.6, 26, 121 or 560 mg/kg bw GDL by oral intubation. A positive control group of 250 mg/kg aspirin was included. No clearly discernible effects were seen on nidation or on maternal or fetal survival. The number of abnormalities seen on either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls (Anonymous, 1974). Rabbit Six groups of 10 pregnant rabbits were given continuously from day 6 to 18 of gestation 0, 7.8, 36.2, 168.5 or 780 mg/kg b w GDL by oral intubation. A positive control of 2.5 mg/kg bw 6-aminonicotinamide was included. No clearly discernible effects on nidation or on maternal or skeletal tissues of the test groups were seen. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls (Anonymous, 1974). Acute toxicity LD50 Animal Compound Route (mg/kg bw) Reference Rabbit Sodium gluconate i.v. 7 630 Gajatto, 1939 The administration for three to six days of large oral doses (5-10 g/day) of gluconic acid to five normal humans did not produce any renal changes, as shown by the absence of blood, protein, casts and sugar in the urine (Chenoweth et al., 1941). Short-term studies Rat Groups of 20 male and 20 female rats were fed gluconic acid (as glucono-delta-lactone) for 26 weeks at levels of 0 and 10 000 ppm in the diet without ill-effects or demonstrable changes in the main organs on microscopic examination (Harper & Gaunt, 1962). Long-term studies Rat As part of another experiment groups of 30 male and 30 female rats were fed diets containing meat treated with 1% glucono-delta- lactone (GDL) and untreated meat for 29 months. This was equivalent to feeding 0.4% GDL. Growth, food intake and mortality were not different from controls. Haematology, clinical biochemistry, liver function tests and histopathology revealed no differences from controls (Van Logten et al., 1972). OBSERVATIONS IN MAN Sixteen persons (seven with urologic conditions) were administered 5 g doses of glucono-delta-lactone at two-hour intervals, up to total doses of 15 to 25 g daily, and subsequently 10 g doses, up to total doses of from 20 to 50 mg daily. pH and specific gravity of the urine was determined on test and controls. In 8 of the 16 patients, the urine became more acid, and in the other half it became more alkaline during the period of treatment. Eleven of the 16 patients developed diarrhoea without nausea during the course of the study (Gold & Givin, 1939). Comments: Consideration of glucono-delta-lactone may be based on the metabolic evidence as intermediates of normal glucose metabolism in mammalian species. There is considerable experience with gluconates in man and animals. A single long-term test at one level showed no evidence of carcinogenicity. Teratogenic tests have shown no abnormalities in four species. EVALUATION Estimate of acceptable daily intake for man 0-50 mg/kg bw* REFERENCES Anonymous (1974) Unpublished report submitted by the United States Food and Drug Administration Chenoweth, M. B. et al. (1941) J. Lab. Clin. Med., 26, 1574 Eyles, R. & Lewis, H. B. (1943) J. Nutri. 26, 309 Gajatto, S. (1939) Arch. Farmacol. Sper., 68, 1 Gold H, & Givin, M. S. (1939) J. Lab. Clin. Chem., 24, 1139 Harper, K. H. & Gaunt, I. F. (1962) Unpublished report of Huntingdon Research Centre Stetten, M. R. & Stetten, D. jr (1950) J. Biol. Chem., 187, 241 Van Logten, M. J. et al. (1972) Food Cosmet. Toxicol., 10, 475 * Calculated as total gluconic acid from all sources.
See Also: Toxicological Abbreviations