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. XANTHAM GUM BIOLOGICAL DATA BIOCHEMICAL ASPECTS The caloric availability and digestibility indicated that xantham gum is not utilized by the body and the conclusion was substantiated by finding that practically all of the gum fed during a seven-day period could be accounted for in the faeces (Booth et al., 1963). When 14C-labelled xantham gum prepared by fermentation of uniformly labelled glucose with xanthomonas campestris was fed to rats at a level of 2% (50 mg in total) in the diet a maximum of 15% of the label was metabolized to carbon dioxide in 100 hours. In vitro tests showed that the acetate content was labile at gastric pH. Acetate and pyruvate accounted for only 9.8% of the label in the gum used. The finding that 15% of the label was metabolized to carbon dioxide indicated that the hexoses were used to a certain extent also. No accumulation in tissues were found and the observed metabolism of labelled material and distribution of 14C in tissues was that expected from feeding a simple 14C-labelled molecule such as acetate or a hexose. Analysis of faecal material showed no accumulation of the five polysaccharide constituents, except acetate. Some 98% of the radioactivity in the faeces could be attributed to unchanged or only slightly modified polysaccharide. In vitro tests indicated that nonenzymatic hydrolysis and the action of faecal-microorganisms is responsible for the initial breakdown of polysaccharide in vivo (Gumbmann, sine data). TOXICOLOGICAL STUDIES Special studies on reproduction Rat A three-generation reproduction study was carried out using groups of 10 male and 20 female rats in the first generation and 20 male and 20 female rats in subsequent generations. Dosage levels of 0, 0.25 and 0.5 g/kg/day were administered in the diet. Criteria evaluated were survival, body weights, general appearance, behaviour, the number of litters produced, numbers of live births and stillbirths, physical condition of young, weight of young at birth and weaning and the survival of young. Females that had fewer than two litters were examined to determine whether there was foetal resorption. Malformations in offspring were recorded and gross and micropathological examinations made on the offspring of the second and third generations. No adverse effects attributable to xantham gum were found in this study (Woodard et al., 1973). Acute toxicity Animal Route LD50 References (mg/kg bw) Mouse oral > 1 000 Booth et al., 1963 i.p. > 50 Booth et al., 1963 i.v. 100-250 Hendrickson & Booth (sine data) Rat oral >45 000 Jackson et al., (sine data I) Dog oral >20 000 Jackson et al., (sine data II) Daily application of a 1% solution for 15 days to rat skin produced no signs of irritation. Daily application of a 1% solution for five days to rabbit conjunctiva produced no signs of irritation. Intradermal challenge tests in guinea-pigs did not produce evidence of sensitization (Hendrickson & Booth (sine data)). Short-term studies Rat A study was carried out on an unspecified number of rats fed on diets containing 7.5% or 10% xantha gum for 99-110 days. No untoward effects were observed in extensive investigations on these animals (Booth et al., 1963). In a 91-day feeding study a reduced rate of weight gain was found in groups of rats receiving 7.5% or 15% of xantham gum in the diet. Diets containing 3% or 6% gum did not reduce weight gain. No significant alterations in haemoglobin, red and white cell counts, and organ weights were observed in these rats. Histological examination of tissues from rats at the 15% level showed no pathological effects. At the highest dosage level the animals produced abnormally large faecal pellets but diarrhoea did not occur. A paired-feeding test was used to compare the growth of rats ingesting a diet containing 7.5% xantham gum and comparable rats restricted to the same intake of control diet. No difference in weight gains was found at the end of 18 days, indicating the absence of a growth-inhibiting factor (Booth et al., 1963). Dog Four groups of two male and two female young adult beagle dogs were fed for two weeks on diets providing 0, 1 or 2 g/kg bw/day of xantham gum or 2 g/kg/day of cellulose powder. Persistent diarrhoea occurred in dogs receiving the 2 g/kg/day xantham gum and occasional diarrhoea in those receiving 1 g/kg/day. All dogs, including controls, lost weight but the weight loss was most marked in animals receiving xantham gum. The red blood cell count, haemoglobin concentration and serum cholesterol were lowered and the relative adrenal weight increased in dogs receiving 2 g/kg/day xantham gum. These effects were considered to be due to the persistent diarrhoea in this group. Liver and kidney function tests indicated no disturbance in the function of these organs. Extensive gross and histopathological examination failed to detect lesions which could be attributed to ingestion of the gum (Robbins et al., 1964). Groups of three male and three female beagle dogs were fed on diets supplying 0, 0.25 and 0.5 g/kg bw/day of xantham gum for 12 weeks. Animals receiving the 0.5 g/kg level had softer stools than normal but no diarrhoea. Growth was slightly retarded in the males and the serum cholesterol level was lowered in both sexes of the group receiving 0.5 g/kg/day. No other untoward effects were seen. The no- untoward-effect-level in this test was considered to be 0.25 g/kg/day (Research report, 1964). Xantham gum was administered in the diet at levels supplying 0, 0.25, 0.37 and 1.0 g/kg bw/day to groups of four male and four female beagle dogs for 107 weeks. No effects attributable to administration of gum were seen in the treated animals with regard to survival, food intake, body weight gain, ECG, blood pressure, heart rate, body temperature, and ophthalmic and neurological examinations. The haemoglobin, total and differential white cell counts, coagulation and prothrombin times, thrombocyte counts, serum alkaline phosphates, blood urea nitrogen, blood glucose, SGOT and SPGT were the same in control and treated animals. Urine pH, glucose and sediment contents were comparable with controls but there was a dose related increase in urine SG and a more frequent appearance of urinary albumin in dogs consuming 1.0 g/kg/day of gum. Stool consistency was normal at the 0.37 g/kg level but loose at the top dosage level. The weight of faeces showed a dose-related increase, as would be expected from feeding a non-absorbed hydrophilic gum at high dosage levels. The increased urinary SG is consistent with physiological adjustment for the extra water excreted in the faeces. Examination of the appearance and weights of organs and histopathological examinations failed to detect any untoward effects of treatment with xantham gum at any dosage level (Woodard et al., 1973). Long-term studies Rat Groups of 30 male and 30 female rats were fed on diets for 104 weeks supplying 0, 0.25, 0.5 or 1.0 g/kg bw/day of xantham gum. No abnormalities which could be attributed to ingestion of these experimental diets were found with regard to survival, body weight gain, food consumption, behaviour and appearance. Ophthalmic and haematologic examination yielded normal results. Analysis of blood for glucose, SGOT and prothrombin time showed no abnormalities in test groups. Organ weights were within normal limits and no lesions attributable to xantham gum were found on gross and histopathological examination (Woodard, 1973). Comments: Studies indicate that this polymeric material is poorly absorbed. It is partially degraded at gastric pH and probably also by intestinal organisms in the rat. Molecules, or parts of the molecule which are absorbed, are metabolized by normal energy-forming pathways. There is no evidence of accumulation of the substance in tissues. At high dosage levels it causes diarrhoea in dogs which was considered not unusual for a hydrophilic gum. The possibility of this effect occurring in man has been considered but use as food additive according to general principles should preclude this. An adequate two- year test in rats failed to show any carcinogenicity attributable to the material. The reproduction study on rats revealed no untoward effects. EVALUATION Level causing no toxicological effect Rat: 1000 mg/kg bw Estimate of acceptable daily intake for man 0-10 mg/kg bw REFERENCES Booth, A. N., Hendrickson, A. P. & DeEds, F. (1963) Toxicol. appl. Pharmacol., 5, 478 Gumbmann, M. R., Research Report "Metabolism of 14C Polysaccharide B-1459 by the Rat", Western Regional Research Laboratory, Albany, California Hendrickson, A. P. & Booth, A. N., Research Report "Supplementary acute toxicological studies of polysaccharide B-1459", Western Regional Research Laboratory, Albany, California Jackson, N. N., Woodard, M. W. & Woodard, G., Research Report "Xantham gum, acute oral toxicity to rats", Woodard Research Corporation Jackson, N. N., Woodard, M. W. & Woodard, G., Research Report "Xanthan gum, acute oral toxicity to dogs", Woodard Research Corporation Research Report (1964) "Safety evaluation of polysaccharide B-1459 (xanthan gum) in laboratory animals - effects of feeding to dogs" Western Regional Research Laboratory, Albany, California Robbins, D. J., Moulton, J. E. & Booth, A. N. (1964) Food. Cosmet. Toxicol., 2, 545 Technical bulletin on Keltral, Kelco Co., San Diego, California, United States of America Woodard, G. et al. (1973) Toxicol. appl., Pharmacol., 24, 30
See Also: Toxicological Abbreviations