POTASSIUM BROMATE EXPLANATION Potassium bromate is used in treating barley in beer making in addition to its use in the treatment of flour, and it has been used for the improvement of the quality of fish paste products in Japan (Ministry of Health and Welfare, Japan, 1979). Potassium bromate has been evaluated for acceptable level of treatment for flour to be consumed by man by the Joint FAO/WHO Committee on Food Additives in 1963 and 1983 (Annex 1, references 1 and 62). At the last review the Committee reiterated that, as a general principle, bromate should not be present in food as consumed. The previous acceptable level of treatment of flour used for baking products was made temporary with a maximum treatment level of 75 mg KBrO3 per kg flour pending further work to establish the residual levels of potassium bromate in foods treated with it. No acceptable level of treatment was established for other foods. Bromate is extensively reduced to bromide for which an ADI of 0-1 mg/kg bw has been established by the FAO Working party on Pesticide Residues and the WHO Expert Committee on Pesticide Residues (Annex 1, reference 62). Since the previous evaluation, additional data have become available. The previously published monograph (Annex 1, reference 63) is reproduced in its entirety below and has been expanded to include a summary and discussion of the new data. BIOLOGICAL DATA Biochemical aspects Metabolism In a preliminary study, male Wistar rats were given an aqueous solution of potassium bromate by gavage; urine and faeces were collected for 24 hrs and the content of bromate and bromide determined. After this period, the animals were sacrificed and the bromate and bromide content was determined in the following tissues/organs: plasma, RBC, spleen, kidney, pancreas, stomach and small intestine. No bromate was detectable in any tissue after this time although substantial amounts were found in urine (detection limits 2.5 µg BrO3-/ml urine & plasma, 5.0 g/g tissue). Conversely, bromide was widely distributed in tissues and urine (Fujii et al., 1984). Groups of four small Wistar rats were given a single oral dose of 100 mg KBrO3 and sacrificed after 15 min, 30 min, 1, 2, 4 or 8 hrs. Bromate was then measured in stomach, small intestine, plasma and urine in the bladder. Bromate disappeared slowly from the stomach; in the small intestine the levels peaked after 30 min and fell to undetectable levels by 4 hrs. The plasma concentration of bromate was maximal (4 µg/ml) at the first sampling at 15 min and fell rapidly, being undetectable after 2 hrs. Urinary levels reached a peak after 1 hr and decreased rapidly so that no further urinary excretion was detectable after 4 hrs (Fujii et al., 1984). Groups of four male Wistar rats were given potassium bromate by oral gavage at doses of 0, 0.625, 1.25, 2.5, 5, 10, 20, 40, 60, 80, or 100 mg/kg bw and bromate and bromide were determined in the subsequent 24 hr urine. No bromate was detectable at doses of 2.5 mg/kg or less; at higher doses bromate concentration increased in a dose related manner. Nonsignificant differences from controls were seen in the bromide concentration of the urine at dose levels up to 5 mg/kg but at higher doses the bromide concentration increased with increasing dose (Fujii et al., 1984). Bromate is therefore rapidly absorbed from the gastrointestinal tract, partially converted to bromide in the tissues, and rapidly excreted. Since unchanged bromate could be detected in urine at doses of 5 mg/kg and above, it must come into contact with renal tissues, at least at this dose level (Fujii et al., 1984). Effects of baking on potassium bromate-treated flour When potassium bromate was present in flour at levels of 5 to 80 mg/kg, no residual bromate was detected in bread prepared from the flour by a bulk fermentation process after 20-25 minutes baking (Bushuk & Hlynka, 1960). Potassium bromate present in flour at 30 mg/kg was quantitatively converted to bromide in breed prepared from the flour by a bulk-fermentation process (Lee & Tkachuk, 1960). Breed was made by bulk fermentation and also by mechanical development from flour doughs containing 0 to 200 mg/kg potassium bromate and the amount of residual bromate in the bread was determined. When the added potassium bromate was 50 mg/kg or less, no residual potassium bromate could be detected; at higher levels of addition, increasing amounts of residual potassium bromate were detected, bulk fermentation giving higher residual levels than mechanical development (Thewlis, 1974). In a similar experiment but using a more sensitive analytical procedure with a detection limit of 0.06 mg bromate/kg in bread, no residual bromate could be detected at flour treatment levels of 25, 50, or 62.5 mg/kg. Residual levels of bromate in bread made from flour treated at levels of 75 and 100 mg/kg were 0.14 and 0.22 mg/kg, respectively (expressed on a 40% moisture basis). Within the limits of experimental error, all of the added bromate not detected unchanged was accounted for as bromide (Osborne et al., 1988). Effects on nutritional value Treatment of flour with potassium bromate at a concentration of 45 mg/kg did not cause any decrease in its content of thiamine, riboflavin or nicotinic acid (Ford et al., 1959). Wheat flours treated with potassium bromate at a concentration of 25 mg/kg and stored for 12 months did not show any greater decrease in tocopherol content than flour, either untreated or treated with ascorbic acid, stored under the same conditions (i.e., not more than 35-50% decrease) (Menger, 1957). At high levels of use, about 200 mg/kg bromate has no significant effect on the thiamine, riboflavin or nicotinic acid content of flour, or bread made from it. No statistically significant differences have been found in essential fatty acid content in flour treated with 200 mg/kg potassium bromate or in bread made from such flour (Ministry of Agriculture, Fisheries and Food, U.K., 1974). Potassium bromate completely destroys folic acid in solution in 10 days (British Food Manufacturing Industries Research Association, 1980). Toxicological studies Studies on bromate-treated flour and bread Short-term studies Rats Bread made from flour treated with 14 mg/kg and with 100 mg/kg of potassium bromate was fed to two groups of 6 male and 20 female rats each and these diets continued over three generations, the entire experiment lasting 10 months. The health, behavior, weight gain and reproductive performance remained normal throughout. Histological study of the tissues showed no abnormalities and analyses of brain and liver showed no accumulation of bromine (Ford et al., 1959). Eighteen rats were fed a diet containing 84% of flour treated with potassium bromate at a level of about 75 mg/kg for a period of 4 weeks. Growth and reproductive performance were normal (Ford et al., 1959). Bread made from flour treated with 200 mg/kg of potassium bromate was fed to 12 rats for 16 days and the flour itself to 16 rats for 10 weeks without adverse effects (Ford et al., 1959). Dogs Three dogs were fed for 12 weeks a diet containing 84% of bread made from flour treated with 75 mg/kg potassium bromate. No ill-effects were observed. Five dogs were fed for 6-14 weeks flour treated at a level of 75 mg/kg potassium bromate. Two dogs were fed for 16 days with bread made from flour treated at a level of 200 mg/kg with potassium bromate. No ill-effects were observed (Ford et al., 1959). Three dogs were fed for 6 weeks on diets containing flour treated with 70 mg/kg potassium bromate showed no ill-effects or 'running fits'. Four dogs fed for 17 months on bread made from flour containing 200 mg/kg potassium bromate showed no adverse effects attributable to the diet (Impey et al., 1961). Monkeys Three monkeys fed for 8 weeks on a diet containing 84% of bread made from flour treated with 75 mg/kg potassium bromate showed no adverse effect (Ford et al., 1959). Long-term studies Mice Groups of mice fed flour treated with 15 mg/kg potassium bromate showed no ill-effects over 8 generations (Ford et al., 1959). Groups of 60 male and 60 female mice were fed for 80 weeks on five diets containing 79% breadcrumbs; the bread used was prepared from untreated flour (control), from flour treated with 50 mg/kg or 75 mg/kg potassium bromate, or from flour treated with 50 mg/kg bromate plus one of two mixtures of other commonly used flour additives (escorbic acid, benzoyl peroxide and chlorine dioxide). Appearance, behavior, health and survival were similar in test and control groups and there was no evidence that any of the treatments affected the incidence of neoplasms, the incidence of malignant tumours being similar in control and test groups. Anaemia was observed in males of all groups (including controls) and in females at 18 months. No dose-related differences in blood chemistry were found in male mice; in the females, dose-related increases in blood-glucose levels were observed at 1 and 12 months but not at 18 months. Renal concentration and dilution tests, and urine analysis were indicative of normal renal function. Some dose-related differences in the weights of heart, pituitary and uterus were found but when expressed relative to body weight, the values for heart and uterus were not dose-related. The relative weights of pituitary, brain, kidneys and thyroid showed dose-related changes in males only, with relative weights of heart and pituitary being lowered and kidneys and thyroid elevated. These changes were not associated with any histopathological abnormalities. No significant dose-related accumulation of covalently bound bromine was observed in adipose tissue (Ginocchio et al., 1979). Rats Twenty rats were fed 2 years with flour treated at a level of 627 mg/kg potassium bromate. Weight gain, general health and survival rate were not significantly different than those of controls (Ford et al., 1959). Five generations of rats were fed bread made from flour treated with potassium bromate at a level of 15 mg/kg. No effects on weight gain, reproductive performance or survival were observed (Ford et al., 1959). Five groups of 60 male and 60 female rats were fed for 104 weeks on five diets containing 79% breadcrumbs; the bread was prepared from untreated flour (control), from flour treated with 50 mg/kg or 75 mg/kg potassium bromate, or from flour treated with 50 mg/kg bromate plus one of two mixtures of other flour additives. Appearance, behavior and health were similar in test and control groups. The death rate was lower in the test groups than in controls in the females and the males of the high dose group had fewer deaths than the other groups taken together. No evidence of carcinogenicity nor of chronic toxicity was attributable to the compounds under test at the dose levels used. There was no evidence of accumulation of covalently-bound bromine in the adipose tissue (Fisher et al., 1979). Studies on potassium bromate Studies on mutagenicity Potassium bromate was reported to give positive results for mutagenicity in the Ames test, chromosome aberration test and micronucleus test but gave negative results in the Rec-assay and in a silk-worm assay (Kawachi et al., 1980; Ishidate et al., 1981). Studies on carcinogenicity Mice A 78 week carcinogenicity study was performed on female B6C3F1 mice given potassium bromate at concentrations of 500 or 1000 mg/l in drinking water. No carcinogenic effect was detected (Kurokawa et al., 1982a). Rats Groups of 53 male and 53 female F-344 rats were given potassium bromate in drinking water at concentrations of 0, 250, and 500 mg/l for 110 weeks, except that the high concentration was reduced to 400 mg/l for male rats in week 60 due to severe inhibition of body weight gain. Animals dying or moribund in the course of the study were autopsied immediately; survivors were killed and autopsied at week 111 and a detailed histopathological examination was carried out, including 10-15 serial step sections on the kidneys. The mean survival time was shortest in males given 500 mg/l potassium bromate (88.1 ± 18.1 w), the mean survival times of the other groups were between 101 and 104 weeks. Renal tubules in potassium bromate-treated rats showed various pathological changes; degenerative, necrotic and regenerative changes were very common. All the male animals bore tumours (including controls) and tumour incidence was very high in females (85%, 92% and 83% in females receiving 0, 250 and 500 mg/l potassium bromate, respectively). However, the incidence of tumours of the kidney, peritoneum and thyroid was statistically significantly higher in treated animals than in controls. Tumours (adenocarcinomas and adenomas) of the kidney developed in 6%, 50% and 85% of males and 0%, 40% and 63% of the females receiving 0, 250 and 500 mg/l respectively. The incidence of mesotheliomas of the peritoneum was 11%, 32% and 54% in male rats given 0, 250 and 500 mg/l respectively but there was zero incidence of this type of tumour in females, either treated or controls. Induction times for renal cell tumours were relatively long, the shortest being 14 w (male, 500 mg/l). It was concluded by the authors that potassium bromate was carcinogenic in Fischer 344 rats by oral administration (Kurokawa et al., 1982a, b; Kurokawa, 1982). Dose-response studies on the carcinogenicity of potassium bromate were carried out to examine its effects at low doses. Seven groups of 20-24 male F344 rats were given potassium bromate in the drinking water at concentrations of 0, 15, 30, 60, 125, 250 or 500 mg/ml for 104 weeks; the mean respective intakes of potassium bromate over the test period were 0, 0.9, 1.7, 3.3, 7.3, 16.0 and 43.4 mg/kg bw. Animals dying on test or in a moribund condition were immediately autopsied; at termination the remaining animals were given a complete autopsy. At autopsy, the weights of brain, sub-mandibular gland, lung, heart, liver, spleen, adrenals, kidneys and testes and of any tumours were recorded. These and other organs were examined histologically. Marked decrease in body weight gain and in survival times were observed in the group given potassium bromate at a concentration of 500 mg/ml. The combined incidences of renal adenomas and adenocarcinomas were significantly increased in rats receiving bromate at concentrations of 125 mg/ml and above in a dose related manner. Significant increases in the number of dysplastic foci in the kidney were seen at the dose level of 30 mg/ml and above, the incidence varying in a dose related manner. In addition to the renal lesions, a group treated with drinking water containing 500 mg/ml displayed increased incidence of combined follicular adenomas and adenocarcinomas of the thyroid and of peritoneal mesotheliomas (Kurokawa, 1986). Observations in Man A number of case studies of acute human intoxication with potassium bromate have been reported following accidental ingestion or attempted suicide. In autopsy cases, degeneration of kidney tubules and liver parenchymal cells, and acute myocarditis were the principal pathological changes observed (Paul, 1966; Stewart et al., 1969; Niwa et al., 1979; Norris, 1965; Quick et al., 1975). COMMENTS The Committee reiterated the recommendation made in the previous reports that, as a general principle, bromate should not be present in foods as consumed, and the use of potassium bromate could only be approved in such circumstances. Evidence was considered that, at levels of flour treatment up to 62.5 mg/kg, no bromate residues were detected in the bread with the principle breakdown product being bromide; at levels of treatment of 75 mg/kg or higher, detectable residues of bromate were found in bread. In the light of the previously established ADI for bromide, the Committee was of the opinion that the bromide arising from flour- treatment with bromate within the acceptable levels of treatment did not present a toxicological hazard. However, as levels of treatment of 75 mg/kg resulted in detectable residues of bromate in bread, the Committee reduced the previous acceptable level of treatment for flour for bread-making to 0-60 mg potassium bromate/kg flour. In arriving at this conclusion, the Committee took cognizance of earlier long-term studies in mice and rats which showed that products made from flour treated with bromate produced no adverse effects. The Committee had no toxicological data on other food products treated with bromate and were aware that some applications could give rise to significant residues. Accordingly, no acceptable level of treatment could be established for foods other than flour intended for baking. EVALUATION Level resulting in no detectable residues of bromate For flour used in bread making 0 - 62.5 mg/kg. Estimate of acceptable level of treatment of food to be consumed by man For flour: 0 - 60 mg/kg flour (providing that bakery products prepared from such treated flour contains negligible residues of potassium bromate) For other foods: No acceptable level of treatment allocated. REFERENCES British Food Manufacturing Industries Research Association (1980). Annual Report, p. 29. Bushuk, W. & Hlynka, I. (1960). Cereal Chem., 37, 573. Fisher, N., Hutchinson, J.B., Berry, R., Hardy, J., Ginocchio, A.V. & Waite, V. (1979). Long-term toxicity and carcinogenicity studies of the bread improver potassium bromate 1. Studies in rats. Fd. Cosmet. Toxicol., 17, 33-39. Ford, W.P., Kent-Jones, D.W. & Frazer, A.C. (1959). Unpublished submission, dated 8th December, 1959, to the Preservatives Sub-Committee of the United Kingdom Food Standards Committee, Appendices I-IV. Fujii, M., Oikawa, K., Saito, H., Fukuhara, K.C., Ouosaka, S. & Tanaka, K. (1984). Metabolism of potassium bromate in rats 1. In vivo studies. Chemosphere, 13, 1207-1212. Ginocchio, A.V., White, V., Hardy, J., Fisher, N., Hutchinson, J.B. & Berry, R. (1979). Long-term toxicity and carcinogenicity studies of the bread improver potassium bromate 2. Studies in mice. Fd. Cosmet. Toxicol., 17, 41. Impey, S.G., Moore, T. & Sharman, I.M. (1961). J. Sci. Fd, Agric., 11, 729. Ishidate, M., Sofuni, J. & Yoshikawa, K. (1981). Chromosomal aberration tests in vitro as a primary screening tool for environmental mutagens and/or carcinogens. Gann Monograph on Cancer Research, 27, 95. Kawachi, T., Komatsu, T., Kada, T., Ishidate, M., Sasaki, M., Sugiyama, T., Tazima, Y. & Williams, G.M. (ed) (1980). In: The predictive value of short-term screening tests in carcinogenicity evaluation, Elsevier, Amsterdam, pp. 253-267. Kurokawa, Y. (1982). Communication submitted to WHO. Kurokawa, Y., Hayashi, Y., Maekawa, Y., Takahashi, M. & Kokubo, T. (1982a). Induction of renal cell tumors in F-344 rats by oral administration of potassium bromate, a food additive. Gann, 73, 335. Kurokawa, Y., Hayashi, Y., Maekawa, Y., Takahashi, M., Kokubo, T. & Odashima, S. (1982b). Carcinogenicity of potassium bromate by oral administration to F-344 rats. Report submitted to WHO by Y. Kurokawa. Kurokawa, Y., Aoki, S., Matsushima, Y., Takamura, N., Imazawa, T. & Hayashi, Y. (1986). 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Quick, C.A., Chole, R.A. & Mauer, S.M. (1975). Deafness and renal failure due to potassium bromate poisoning. Arch. Otolaryngol., 101, 494. Stewart, T.H., Sherman, Y. & Politzer, W.M. (1969). An outbreak of food poisoning due to a flour improver, potassium bromate. S. A. Med. J., 43, 200. Thewlis, B.H. (1974). The fate of potassium bromate when used as a breadmaking improver. J. Sci. Fd. Agric., 25, 1471. Viggiano, J. & Turk, E.F.H. (1937). Analyst, 62, 559.
See Also: Toxicological Abbreviations Potassium bromate (ICSC) Potassium bromate (WHO Food Additives Series 18) Potassium bromate (WHO Food Additives Series 30) POTASSIUM BROMATE (JECFA Evaluation) Potassium Bromate (IARC Summary & Evaluation, Volume 40, 1986)