INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY WORLD HEALTH ORGANIZATION SAFETY EVALUATION OF CERTAIN FOOD ADDITIVES WHO FOOD ADDITIVES SERIES: 42 Prepared by the Fifty-first meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA) World Health Organization, Geneva, 1999 IPCS - International Programme on Chemical Safety GLUCONO-delta-LACTONE AND THE CALCIUM, MAGNESIUM, POTASSIUM, AND SODIUM SALTS OF GLUCONIC ACID First draft prepared by Dr C. Whiteside and Dr M. Bonner Division of Health Effects Evaluation Office of Premarket Approval Center for Food Safety and Applied Nutrition Food and Drug Administration Washington DC, USA Explanation Biological data Biochemical aspects Absorption, distribution, and excretion Toxicological studies Acute toxicity Short-term studies of toxicity Long-term studies of toxicity Reproductive and developmental toxicity Genotoxicity Observations in humans Comments Evaluation References 1. EXPLANATION Glucono-delta-lactone was previously evaluated by the Committee at its tenth, eighteenth, and thirtieth meetings (Annex 1, references 13, 35, and 73). At the tenth meeting, the Committee established an ADI of 0-50 mg/kg bw for glucono-delta-lactone. At its thirtieth meeting, the Committee changed the ADI for glucono-delta-lactone to an ADI 'not specified' on the basis of biochemical and metabolic data on glucono-delta-lactone and gluconic acid, noting that in an aqueous medium glucono-delta-lactone exists in equilibrium with D-gluconic acid. These compounds are intermediates in the oxidation of glucose through the pentose phosphate cycle. Data from studies that were evaluated previously by the Committee showed no evidence for the carcinogenicity, teratogenicity, or genotoxicity of glucono-delta-lactone. Since the last toxicological evaluation of glucono-delta-lactone, a new study of acute toxicity and two new 28-day studies of the oral toxicity of sodium gluconate in rats have become available. These studies are evaluated in order to determine whether the ADI 'not specified' for glucono-delta-lactone could be extended to a group ADI 'not specified' for glucono-delta-lactone and the calcium, magnesium, potassium, and sodium salts of gluconic acid. The calcium, magnesium, potassium, and sodium gluconates were previously evaluated by the Committee as individual compounds or in other group categories as inorganic salts and salts of organic acids. The Committee concluded that they are freely ionizable and that it was appropriate to allocate ADIs on the basis of data on their corresponding anion (gluconic acid). 2. BIOLOGICAL DATA 2.1 Biochemical aspects In studies previously evaluated by the Committee, glucono-delta-lactone was reported to readily form an equilibrium mixture of 55-60% D-gluconic acid and 40-45% delta- and gamma-D-lactones. The rate of hydrolysis is accelerated by heat and high pH (Pocker & Green, 1973). These breakdown products are intermediates in the normal pathway of glucose metabolism through the pentose phosphate cycle in mammalian species. Groups of six rats receiving a low-calorie basal diet had an increased growth rate when the diet was supplemented with either glucose or glucono-delta-lactone. The two compounds were of almost equal effectiveness in promoting growth (Eyles & Lewis, 1943; Annex 1, references 36 and 74). 2.1.1 Absorption, distribution, and excretion Intraperitoneal administration of calcium gluconate resulted in excretion of primarily unchanged gluconate anion in the urine; the remainder was metabolized. Twenty percent of a dose of calcium gluconate was absorbed from the intestine (AkzoChemie, Inc., undated). When uniformly labelled 14C, 3H-sodium gluconate was administered intraperitoneally to normal rats for three successive days, 37% of the administered 14C was excreted unchanged in the urine, 14% appeared in expired carbon dioxide, and a fraction (gluconate carbon) was recovered as urinary saccharate. When labelled gluconate was administered to phlorizinized rats, about 10% of the total 14C label appeared in expired carbon dioxide. Urinary glucose from the phlorizinized rats and liver glycogen from the normal rats was uniformly labelled with 14C (Annex 1, references 36 and 74). Radiolabel was measured in the blood, intestinal content, and faeces of normal and alloxan-diabetic Wistar rats 5 h after oral administration of 14C-glucono-delta-lactone (0.8 g/kg) or 14C-sodium gluconate. The authors concluded that glucono-delta-lactone is absorbed more rapidly from the intestine than sodium gluconate; initial oxidation occurred after 7 h with the gluconate and 4 h for the lactone. The oxidative turnover of lactone and gluconate was significantly enhanced in diabetic animals (Tharandt et al., 1979). When three men were given an oral dose of 10 g (equivalent to 167 mg/kg bw) of a 10% solution of glucono-delta-lactone, 7.7-15% of the dose was recovered over the succeeding 24 h, most excretion occurring within 7 h. No toxic urinary metabolites were observed. When 5 g (84 mg/kg bw) were given orally, none was recovered in the urine. The largest dose given was 30 g, equivalent to 500 mg/kg bw (Chenoweth et al., 1941). 2.2 Toxicological studies 2.2.1 Acute toxicity Studies of the acute toxicity of glucono-delta-lactone and other salts of gluconic acid in several species are summarized in Table 1. Table 1. Acute toxicity of derivatives of gluconic acid Species Compound Route LD50 Reference (mg/kg bw) Rat Sodium gluconate Oral, gavage > 2000 Mochizuki (1995a) Rat Glucono-delta-lactone Oral 5940 Food & Drug Research Laboratories (1973a) Mouse Calcium gluconate Intravenous 950 Coulston et al. (1962) Mouse Glucono-delta-lactone Oral 6800 FOod & Drug Research Laboratories (1973a) Rabbit Sodium gluconate Intravenous 7630 Gajatto (1939) Rabbit Glucono-delta-lactone Oral 7850 Food & Drug Research Laboratories (1973a) Hamster Glucono-delta-lactone Oral 5600 Food & Drug Research Laboratories (1973a) Groups of five Sprague-Dawley rats of each sex were given sodium gluconate orally by gavage as single doses of 500, 1000, or 2000 mg/kg bw after an overnight fast. The rats were then observed for 14 days for mortality, abnormal clinical signs, body-weight changes (on days 1, 2, 3, 7, 10, and 14), and gross pathological changes in brain, pituitary, thyroid, salivary gland, thymus, heart, lung, liver, spleen, kidney, adrenals, stomach, small and large intestine, pancreas, gonads, urinary bladder, and lymph nodes. None of the rats died during the study. Soft faeces and diarrhoea, seen in one male and three females at 2000 mg/kg bw, were the only clinical effects observed 2-3 h after treatment. The body weights of treated rats were comparable to those of controls. No gross abnormalities were observed at necropsy. The minimum lethal dose was > 2000 mg/kg bw, although a transient, initial laxative effect was observed in rats at doses > 1000 mg/kg bw (Mochizuki, 1995a). 2.2.2 Short-term studies of toxicity Rats Groups of 12 male and 12 female Sprague-Dawley rats were given sodium gluconate by gavage at doses of 0, 500, 1000, or 2000 mg/kg bw per day in water at a volume of 1 ml/100 g bw for four weeks. The doses were selected on the basis of the results of the study of acute toxicity described above (Mochizuki, 1995a). Satellite groups of four rats of each sex were included to determine the plasma concentrations of sodium gluconate. Body weight and food consumption were measured on day 1 and every third or fourth day of the study. Ophthalmological examinations were performed on all of the animals at the start of the study and on six animals of each sex per group at week 4. Haematological and clinical chemical parameters were measured at the end of treatment on blood collected from fasted surviving rats and on all animals at necropsy. Qualitative and quantitative urinalyses were performed on six rats of each sex from each group at the end of treatment (week 4), with a one-day water intake measurement. The weights of the brain, pituitary, thyroids, salivary glands, thymus, heart, lungs, liver, spleen, kidneys, adrenals, testes, prostate, seminal vesicle, ovaries, and uterus were recorded. Detailed histopathological examinations were performed on representative tissues from all control animals and those receiving 2000 mg/kg bw per day and on all gross lesions. No deaths or signs of clinical abnormality were observed in any of the groups. Body weights, food consumption, and water intake were comparable in the treated and control animals. The ophthalmological examinations revealed a persistent hyaloid artery (bilateral) in the transparent body in all rats in the control and treated groups, which was considered to be an incidental physiological change during development of the eyeball. The quantitative urinary analyses showed a significant increase (p < 0.01) in urinary sodium excretion in males and females at 2000 mg/kg bw per day. Although the urine volume was increased in treated males and in females at the high dose, the increases were not statistically significant. Specific gravity and potassium and chloride excretion were not affected by sodium gluconate. The qualitative urinary analyses showed increased prevalences of urinary ketone bodies (ranging from - to +/- to + to ++), urobilogen (ranging from +/- to +), and phosphate sedimentation (ranging from - to +/- to +) and increased urinary protein concentrations in all treated animals. The author reported that the increased urinary protein concentrations were due to interference in the assay. Urinary pH and triglyceride and glucose concentrations were comparable to those in the control group. Bilirubin, blood urea nitrogen, and creatinine concentrations were not affected by treatment. None of the haematological parameters measured in this study were affected by sodium gluconate. The only statistically significant effect on blood chemistry was a decrease in serum sodium concentration in males at 500 mg/kg bw per day and in males and females at 2000 mg/kg bw per day. Statistically significant increases were noted in the relative weights of the kidneys of males at 1000 and 2000 mg/kg bw per day and in the absolute weights of the adrenal glands of males at 1000 mg/kg bw per day, but these differences were not dose-related. The only treatment-related histopathological effect reported was an increased incidence of thickening of the limiting ridge of the stomach in 5/12 males at 2000 mg/kg bw per day. As the limiting ridge is a tissue specific to rodents, this lesion is not toxicologically significant for humans. Other lesions occurred incidentally and were not related to treatment. The author concluded that the NOEL was 1000 mg/kg bw per day; however, because of the small group sizes and the positive findings in the qualitative analyses, the Committee concluded that this study was not suitable for identifying a NOEL (Mochizuki, 1995b). Groups of 10 male and 10 female Crj:CD(SD) Sprague-Dawley SPF rats were fed basal diet containing sodium gluconate at concentrations of 0, 1.25, 2.5, or 5% w/w for 28 days, equal to 0, 1000, 2000, and 4100 mg/kg bw per day for males and 0, 1000, 2000, and 4400 mg/kg bw per day for females. A control group was fed basal diet containing 1.35% w/w NaCl, equivalent to the sodium concentration of the group receiving 5% sodium gluconate (equal to 1100 mg/kg bw per day in males and 1200 mg/kg bw per day in females). The doses were selected on the basis of the results of the four-week study of toxicity described above (Mochizuki, 1995b). Body weights and food consumption were measured on day 1 and every third or fourth day of the study. Food efficiency was calculated from the body-weight gain and food consumption. Ophthalmological examinations were performed on all animals at the start of the study and on six rats of each sex per group at week 4. Haematological and clinical chemical examinations were performed on all animals at necropsy. Qualitative and quantitative urinary examinations were performed at the end of treatment (week 4), and water intake was measured over 24 h. The weights of the brain, pituitary, thyroids, salivary glands, thymus, heart, lungs, liver, spleen, kidneys, adrenals, testes, prostate, seminal vesicles, ovaries, and uterus were recorded. Detailed histopathological examinations were performed on representative tissues from all animals at 0 and 5% sodium gluconate and the NaCl control group and on all gross lesions. No deaths or clinical abnormalities were observed in any group. The body weights and food consumption of treated animals were comparable to those of controls on the basal diet. While there was a significant decrease (82% of the basal diet control, p < 0.05) in the mean feed efficiency of males at 5% sodium gluconate at week 4, the overall mean feed efficiency for the entire treatment period was comparable to that of control males. The mean feed efficiencies of females treated with sodium gluconate were comparable to that of females on the basal control diet. Water intake was significantly increased (by 26%) in males at 5% sodium gluconate relative to that in the basal diet control group. There was also an insignificant increase in water intake (by 20%) in the group receiving 1.35% NaCl. The water intake of treated females was comparable to that of females given basal diet. Statistically significant differences in some urinary parameters were reported in animals receiving 2.5 or 5% sodium gluconate when compared with those on basal diet; however, these differences were comparable to those observed in the NaCl control group and appeared to be related to the high sodium concentration of the sodium gluconate. Sodium excretion was significantly (p < 0.05) increased in both males and females at 2.5 and 5% sodium gluconate relative to that in the basal diet control group; however, the sodium concentrations were not significantly different from that in the group given 1.35% NaCl. Urine volumes were not significantly affected by sodium gluconate. Qualitative measurements of urinary protein showed significantly increased concentrations in females at 2.5 and 5% sodium gluconate when compared with those on basal diet. Males at 5% showed a tendency for increased urinary protein concentrations, while the concentrations in males at 2.5% were not affected. The author reported that the increases in urinary protein were due to assay interference. Qualitative measurements of urinary ketone bodies also showed increases in males at 2.5% sodium gluconate. Prothrombin times were significantly decreased (8%) in males at 2.5 and 5% in comparison with the basal diet controls. There were no other significant haematological effects. Statistically significant alterations in blood chemistry were increased blood urea nitrogen in males at 2.5%, decreased serum chloride in females at 1.25 or 2.5% and in rats given 1.35% NaCl, and decreased total protein in males at 1.25% and males and females at 2.5%. None of these differences was related to dose or treatment. Gross histopathological examination revealed only incidental, insignificant findings. Significant increases were seen in the relative weights of the kidneys of males at 5% and of females at 2.5% when compared with those of rats on the basal diet. There was no dose-response relationship. The authors concluded that the NOEL was 5% (equal to 4100 mg/kg bw per day); however, because of the small group sizes and the positive findings in the qualitative analyses, the Committee concluded that this study was not suitable for identifying a NOEL (Mochizuki, 1997). The findings from a short-term study on calcium gluconate and calcium chloride that were initially published by Smith (1940) were summarized in a report on calcium salts by the Select Committee on GRAS Substances (1975). In this study, groups of 10 rats weighing 200 g were given a suspension of calcium gluconate (0.4 g/kg calcium) or calcium chloride by gavage for 70 days. Two of the rats treated with calcium gluconate died before sacrifice. None of the treated rats showed histopathological alterations of the heart, kidney, or liver. The authors concluded that calcium chloride was more toxic to rats than calcium gluconate. Cats and dogs In a study previously reviewed by the Committee, five cats and three dogs received a daily dose of 1 g gluconic acid (10% solution) by stomach intubation for 14 days. No changes were observed in general appearance or in the urine of either species. Several incidences of vomiting and diarrhoea were reported in three of the cats. Gross examination of the lungs, heart, liver, kidneys, gastrointestinal tract, urinary bladder, ureter, and spleen of treated animals showed that they were normal. No histological abnormalities were observed in the livers, lungs, or kidneys. The blood pressure of cats given intravenous injections of gluconic acid and ammonium gluconate (500 mg/kg) fell temporarily but returned to normal within 5 min (Chenoweth et al., 1941). 2.2.3 Long-term studies of toxicity Rats In a study previously evaluated by the Committee, groups of 20 rats of each sex were fed diets containing 40% meat treated with 1% glucono-delta-lactone (equivalent to 0.4% glucono-delta-lactone) or untreated meat for 29 months. Neither growth, survival, nor food intake was affected. Haematological, clinical biochemical, liver function, and histopathological examinations revealed no differences between treated animals and controls (van Logten et al., 1972). 2.2.4 Reproductive and developmental toxicity In a study previously evaluated by the Committee, glucono-delta-lactone was administered to pregnant mice, rats, hamsters, and rabbits by oral intubation on days 6-15 of gestation (days 6-18 for rabbits). Six groups of 25 CD-1 mice received doses of 0, 7, 32, 150, or 700 mg/kg bw; groups of 22-25 Wistar rats received doses of 0, 5.9, 28, 130, or 590 mg/kg bw; groups of 25 hamsters received doses of 0, 5.6, 120, or 560 mg/kg bw; and groups of 10 Dutch belted rabbits received doses of 0, 7.8, 36, 170, or 780 mg/kg bw. No skeletal or developmental abnormalities (nidation, maternal, or fetal survival) were seen (Food & Drug Research Laboratories, 1973b). 2.2.5 Genotoxicity The results of tests for the genotoxicity of glucono-delta-lactone and gluconic acid and some of its salts are summarized in Table 2. Glucono-delta-lactone was not mutagenic in either Saccharomyces cerevisiae or Salmonella typhimurium strains when tested at doses of 0.25 or 0.5% with and without metabolic activation (Litton Bionetics, Inc., 1974). Table 2. Results of assays for the genotoxicity of gluconic acid Substance and end-point Test object Concentration Result Reference Glucono-delta-lactone Reverse mutation S. cerevisiae D4 0.25 and 0.5% Negativea Litton Bionetics, S. typhimurium Inc. (1974) TA 1535, TA 1537, TA 1538 Manganese gluconate Reverse mutation S. typhimurium 0.033, 0.1, Negativea Prival et al. TA 98, TA 100, 0.33, 1, 3.3, (1991) TA 1535, TA 1537, 10 mg/plate TA 1538 Tryptophan reversion E. coli WP2 0.033, 0.1, Negative Prival et al. 0.33, 1, 3.3, (1991) 10 mg/plate a With and without metabolic activation Manganese gluconate was not mutagenic in S. typhimurium strains or Escherichia coli (Prival et al., 1991). 2.3 Observations in humans Single doses of > 20 g glucono-delta-lactone have a laxative effect in humans (Annex 1, references 36 and 74). Sixteen persons, seven of whom had urological conditions, were given 5 g glucono-delta-lactone at 2-h intervals up to total doses of 20-50 g daily. The pH and specific gravity of the urine were monitored in the treated group and in an untreated group. Acidic urine was observed in eight of the treated subjects, and alkaline urine was observed in the others. Diarrhoea without nausea occurred in 11 of the 16 subjects during the study (Gold & Civin, 1939). Oral administration of gluconic acid at doses of 5-10 g/day to five volunteers induced no renal changes; i.e. no blood, protein casts, or sugar was observed in the urine (Chenoweth et al., 1941). Four of 45 premature infants developed localized necrosis of the scalp after receiving a 5% solution of calcium gluconate intravenously into the scalp for 15 days, at a rate of 5 mg calcium per kg bw per hour, as therapy for hypocalcaemia. The necrosis was observed within 48 h after the end of the 15-day infusion (Weiss et al., 1975). The toxic effects of glucono-delta-lactone, gluconic acid, and its magnesium, sodium, potassium, and ferrous salts were compared by Prescott et al. (1953) on the basis of data reported by Nugent (1940), Bernhard (1951), Parker (1940), and Teeter (1945). Prescott concluded that gluconic acid and its derivatives are nontoxic and well tolerated in humans, since there had been no evidence of gastric or renal irritation in patients treated with these compounds. Potassium gluconate induced less gastric irritation than potassium chloride when administered orally as a 3-g dose (Parker, 1940). Bernhard (1951) stated that gluconic acid is well tolerated by the digestive system, is of relatively low toxicity when injected parenterally, and has no obvious physiological action. Unlike mandelic acid, gluconic acid induced no gastric irritation when used to treat pyelonephritis (Nugent, 1940). A dose of 2 g ferrous gluconate did not cause gastrointestinal upset in anaemic patients (Teeter, 1945). 3. COMMENTS The results of the new study of acute toxicity provided no evidence of toxicity in rats given single doses of 500, 1000, or 2000 mg/kg bw sodium gluconate. In two new four-week studies in rats, sodium gluconate was administered orally either by gavage at doses of 0, 500, 1000, or 2000 mg/kg bw per day or by feeding at doses of 0, 1, 1.25, 2.5, or 5% w/w (equal to 1000, 2000, and 4100 mg/kg bw per day). A further group received 1.35% w/w sodium chloride (equal to 1100 mg/kg bw per day), equivalent to the concentration of sodium in 5% sodium gluconate. After gavage, a significant increase in the relative weight of the kidneys (unilateral) was seen in males at 1000 or 2000 mg/kg bw per day. No treatment-related or dose-related effect was observed on any of the other parameters examined in this study. The effects observed in the feeding study, i.e. increased water intake, increased prothrombin time, and increased relative kidney weights, were not dose-related. Qualitative urine analyses revealed effects in both four-week studies that were considered by the Committee to be related to the high sodium intake arising from the sodium gluconate. 4. EVALUATION On the basis of a re-evaluation of data previously considered by the Committee and new data on the short-term toxicity of sodium gluconate, the Committee extended the previous ADI 'not specified' for glucono-delta-lactone to a group ADI for glucono-delta-lactone and the calcium, magnesium, potassium, and sodium salts of gluconic acid. 5. REFERENCES AkzoChemie, Inc. (undated) Gluconates. Unpublished data sheet. Submitted to WHO by the US Food and Drug Administration (GRP 6T0151, pp. 000130-143). Bernhard, A. (1951) The use of potassium glucose in hypopotassemia. Science, 113, 751. Chenoweth, M.D., Civin, H., Salzman, C., Cohn, M. & Gold, H. (1941) Further studies on the behaviour of gluconic acid and ammonium gluconate in animals and man. J. Lab. Clin. Med., 26, 1574-1582. Coulston, F., Hulmue, N.A., Milens, L.E. & Minatoya, H. (1962) Comparison of parenterally administered calcium kinate gluconate with calcium gluconate and calcium chloride. Toxicol. Appl. Pharmacol., 4, 492-503. Eyles, R. & Lewis, H.B. (1943) The utilization of d-glucono-delta-lactone by the organism of the young white rats. J. Nutr., 26, 309-317. Food & Drug Research Laboratories (1973a) Acute LD50 data in mice, rats, hamsters and rabbits. Unpublished data, report No. FDA 71-260 FDRL, Maspeth, New York, USA. Submitted to WHO by the US Food and Drug Administration GRM 000069. Food & Drug Research Laboratories (1973b) Teratologic evaluation of FDA 71-72 (glucono-delta-lactone). Unpublished data, contract No. FDA71-260, FDRL, Maspeth, New York, USA. Available from National Technical Information Service, Springfield, Virginia, USA, No. PB-223, 830. Gajatto, S. (1939) [Pharmacological research on sodium gluconate.] Arch. Farmacol. Sper., 68, 1-13 (in Italian). Gold, H. & Civin, H. (1939) Gluconic acid as a urinary acidifying agent in man. J. Lab. Clin. Chem., 24, 1139-1146. Litton Bionetics, Inc. (1974) Mutagenic evaluation of compound 71-72 glucono-delta-lactone. Unpublished report No. PB-245,498 from National Technical Information Service, Springfield, VA, USA. Submitted to WHO by the US Food and Drug Administration GRP 9T0242, volume 1, pp. 000292-000334. van Logten, M.J., den Tonkelaar, E.M., Kroes, R., Berkvens, J. M. & van Esch, G.J. (1972) Long-term experiment with canned meat treated with sodium nitrite and glucono-delta-lactone in rats. Food Cosmet. Toxicol., 10, 475-488. Mochizuki, M. (1995a) A toxicity study of sodium gluconate (FR2531) by single oral administration in rats. Final report No. BOZO/B-2965 from Gotemba Laboratory, Bozo Research Center, Inc., Setagaya-Ku, Tokyo 156, Japan. Mochizuki, M. (1995b) A 4-week oral toxicity study of sodium gluconate (FR2531) in rats. Final report No. BOZO/B-2966 from Gotemba Laboratory, Bozo Research Center, Inc., Setagaya-Ku, Tokyo 156, Japan. Mochizuki, M. (1997) A 28-day toxicity study in rats fed diet containing sodium gluconate (FR2531). Final report No. BOZO/B-3731 from Gotemba Laboratory, Bozo Research Center, Inc., Setagaya-Ku, Tokyo 156, Japan. Nugent, J.J. (1940) Pyelonephritis. J. Florida Med. Assoc., 27, 18-23. Parker, F.P. (1940) Blood potassium studies in allergic states. South. Med. J., 33, 1301-1309. Prescott, F.J., Shaw, J.K., Bilello, J.P. & Cragwall, G.O. (1953) Gluconic acid and its derivatives. Ind. Eng. Chem., 45, 338-342. Pocker, Y. & Green, E. (1973) Hydrolysis of D-glucono-delta-lactone. I. General acid-base catalysis, solvent deuterium isotope effects and transition state characterization. J. Am. Chem. Soc., 95, 113-119. Prival, M.J., Simmon, V.F. & Mortelmans, K. (1991) Bacterial mutagenicity testing of 49 food ingredients gives very few positive results. Mutat. Res., 260, 321-329. Select Committee on GRAS Substances (1975) Tentative evaluation of the health aspects of certain calcium salts as food ingredients. FASEB-SCOGS Report No. 6T3135. Life Science Research Office. Federation of American Societies for Experimental Biology, Bethesda, Maryland, USA. Smith, E.R.B. (1940) A comparison of the effects of large doses of calcium gluconate-iodonate, calcium gluconate, and calcium chloride. J. Lab. Clin. Med., 25, 1018-1021. Teeter, E.J. (1945) Anemia therapy. J. Am. Med. Assoc., 127, 973-976. Tharandt, L., Hubner, W. & Hollman, S. (1979) [Investigation of the metabolic conversion of D-gluconate and D-glucono-delta-lactone in normal and alloxan-diabetic rats.] J. Clin. Chem. Clin. Biochem., 17, 257-267 (in German). Weiss, Y., Ackerman, C. & Shmilovitz, L. (1975) Localized necrosis of scalp in neonates due to calcium gluconate infusions: A cautionary note. Pediatrics, 56, 1084-1086.
See Also: Toxicological Abbreviations