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    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 g 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 g/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). Dose-response studies on the carcinogenicity
    of potassium bromate in F344 rats after long-term oral
    administration.  J. Nat. Canc. Inst., 77, 977-982.

    Lee, C.C. & Tkachuk, R. (1960).  Cereal Chem., 37, 575.

    Menger, A. (1957).  Brot und Geback, 11, 167.

    Ministry of Agriculture, Fisheries & Food, U.K. (1974). Standards
    Committee Second Report on Bread and Flour. FSC/REP/61 H.M.S.O.

    Ministry of Health and Welfare, Japan (1979). The Japanese
    standards of food additives. 4th edition, p. 367.

    Niwa, T., Ho, T. & Matsui, E. (1979). Serial renal biopsy in
    potassium bromate intoxication.  Jap. Circ. J., 38, 387.

    Norris, J.A. (1965). Toxicity of home permanent waving and
    neutralizer solutions.  Fd. Cosmet. Toxicol., 3, 93-97.

    Osborne, B.G., Willis, K.H. & Barrett, G.M. (1988). Survival of
    bromate and bromide in bread baked from white flour containing
    potassium bromate.  J. Sci. Fd. Agric., 42, 255-260.

    Paul, A.H. (1966). Chemical food poisoning by potassium bromate.
     N. Z. Med. J., 65, 33.

    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)