INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY WORLD HEALTH ORGANIZATION SUMMARY OF TOXICOLOGICAL DATA OF CERTAIN FOOD ADDITIVES AND CONTAMINANTS WHO FOOD ADDITIVES SERIES NO. 13 The data contained in this document were examined by the Joint FAO/WHO Expert Committee on Food Additives* Rome, 3-12 April 1978 Food and Agriculture Organization of the United Nations World Health Organization * Twenty-second Report of the Joint FAO/WHO Expert Committee on Food Additives, Geneva, 1978, WHO Technical Report Series No. 631 MALTOL Explanation This compound has been evaluated for acceptable daily intake by the Joint FAO/WHO Expert Committee on Food Additives in 1967. Since the previous evaluation additional data have become available and are summarized below. BIOLOGICAL DATA BIOCHEMICAL ASPECTS No data available. Acute toxicity LD50 Animal Route mg/kg bw References Mouse Oral 550 Dow Chemical Company, 1967 Rat Oral 1 410 Dow Chemical Company, 1967 Guinea-pig (male) Oral 1 410 Dow Chemical Company, 1967 Rabbit Oral 1 620 Dow Chemical Company, 1967 (male) Short-term studies Rat Groups of 15 males and 15 females were fed 0 and 1.0% maltol for six months without adverse effect on growth, survival, organ weights, haematology and microscopic appearance of major organs (Dow Chemical Company, 1967). Dog Groups of four dogs, not necessarily distributed according to sex, were given maltol by capsule at levels of 0, 125, 250 and 500 mg/kg/day, for 90 days. By day 41 all dogs at the 500 mg/kg level had died. Signs of death suggested liver damage and red cell destruction, in addition to which emesis, ataxia and finally prostration were noted. Histological examination revealed pulmonary oedema, pericentral and mid-zonal hepatic necrosis, fatty degeneration of the myocardium, adrenal cortical and medullary necrosis and testicular degeneration. Elevated serum bilirubin was seen in the 500 mg/kg and at 30 days in the 250 mg/kg. Histologically the 250 mg/kg showed a moderate number of Kupffer cells containing haemosiderin and small amounts of intracellular bilirubin. At the 125 mg/kg level only a moderate number of haemosiderin-laden Kupffer cells were observed. As effects at the lowest level appeared to be marginal, a conservative no-effect level could be estimated at 100 mg/kg (Gralla et al., 1969). Long-term studies Mouse Groups each of 100 mice (Charles River CDI) equally divided by sex were maintained on diets containing maltol at levels of 0, 100, 200 or 400 ppm for a period of 18 months. There were no significant differences in survival between test and control groups. The mean body weights of male mice in the 400 ppm group were significantly lower than controls. Blood chemistry at sacrifice was within normal limits with the exception of plasma urea which was significantly elevated in males in the 400 ppm maltol group, and a dose-related increase in serum alkaline phosphatase in all female test groups. No dose-related haematological changes were observed. Ophthalmic observations at 6, 12 and 18 months showed no compound-related ocular lesions. At autopsy, the relative organ/body weight ratio was similar for test and control animals with the exception of the kidney and testes weights of males in the 400 mg/kg group, which were significantly lower than controls. Histological examination of tissues and organs did not show any compound-related lesions except for the testes. Focal testicular atrophy was observed in both control and test males, but was most severe in the 400 mg/kg group (King et al., 1978a). Rat A two-year study was carried out in the F1 generation of rats (Crl:CD-COB 5 (SD)), derived from parents exposed to diets containing maltol at 0, 100, 200 or 400 mg/kg of diet. After weaning the rats (groups of 100 equally divided by sex) were maintained on the appropriate diets containing maltol. The rats were mated on days 189 and 245 respectively of the study to provide the F2a and F2b generations of a three-generation reproduction study. During the course of the study on days 134 and 418 respectively all animals showed signs of sialodacryodenitis, a contagious disease of viral origin. No deaths occurred from this disease and signs regressed within 10 days. There were no significant differences in survival between test and control animals. Ophthalmic examinations of the high and control groups performed at months 12, 18 and 24 showed no compound-related eye lesions. Blood chemistry and haematology at sacrifice showed that test and control animals were similar and within normal limits with the exception of significant increases in K+, Cl-, urea and bilirubin in the 400 mg/kg male and female groups, and urea and K+ in the 200 mg/kg male group. The gross and microscopic examination of tissues and organs showed no compound-related lesions, nor was there any indication that maltol had an effect upon tumour incidence (King et al., 1978b). Special studies on reproduction Rat A three-generation reproduction study was carried out on rats (Crl:CD-COB 5 (SD)) using groups of 20 male and 20 female rats for the production of each generation. Dosage levels of 0, 100, 200 or 400 mg/kg of maltol was administered in the diet. During the course of the study on day 134 (F1 generation) all animals showed signs of sialodacryodenitis, a contagious disease of viral origin. No deaths occurred from this disease and signs regressed within 10 days. Criteria evaluated were body weight and food consumption of parents, fertility index, mating index, gestation index, survival index and sex ratio of each generation. At birth all offspring were examined for gross morphological abnormalities. Maltol had no effect on copulation rate, mating index, fertility index, gestation index and length of gestation. The viability index, lactation index, 21-day survival index and sex ratios were within normal limits. Differences in growth rate of the pups appears to be related to the outbreak of sialodacryodenitis in the colony. No specific compound-related abnormalities or lesions were reported in the pups (King et al. 1978b). REFERENCES Dow Chemical Co. (1967) Unpublished report Gralla, E. J., Stebbins, R. B., Coleman, G. L. and Delahunt, C. S. (1969) Toxicity studies with ethyl maltol, Toxicol. appl. Pharmacol., 15, 604-613 King, T. O., Reinert, H., Pelé, M. F., Chvedoff, M., Taradach, C., Nachbaur, J., Faccini, J. M., Irisarri, E., Clarke, M. R. and Monro, A.M. (1978a) Unpublished data. Research Center, Pfizer, France Protocol 75-009. 18-month mouse study with maltol King, T. O., Perraud, J., Faccini, J. M., Nachbaur, J. and Monro, A.M. (1978b) Unpublished data. Research Center, Pfizer, France Protocol 74107-Maltol. 3 generation and carcinogenicity study in rats
See Also: Toxicological Abbreviations Maltol (FAO Nutrition Meetings Report Series 44a) Maltol (WHO Food Additives Series 16) MALTOL (JECFA Evaluation)