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    POTASSIUM BROMATE

    First draft prepared by
    Dr G.J.A. Speijers and Mrs M.E. van Apeldoorn
    National Institute of Public Health and Environmental Protection
    Laboratory for Toxicology
    Bilthoven, The Netherlands

    1.  EXPLANATION

         Potassium bromate was evaluated as a flour treatment agent at
    the seventh, twenth-seventh, and thirty-third meetings of the
    Committee (Annex 1, references 7, 62, and 83), when the general
    principle was reiterated that bromate should not be present in foods
    as consumed, and that the use of potassium bromate could only be
    approved in such circumstances. At the thirty-third meeting the
    Committee reduced the acceptable level of potassium bromate
    treatment of flour for bread making to 60 mg/kg on grounds that:

    a)   bromide arising from flour treatment with potassium bromate at
         levels < 60 mg/kg did not present a toxicological hazard,
         and

    b)   residue data indicated that no detectable levels of bromate
         were found in bread baked from flour treated with bromate
         levels up to 62.5 mg/kg.

         No acceptable levels of treatment could be established for food
    other than flour intended for baking due to the absence of residue
    data. Since the previous evaluation some additional information has
    become available which is summarized in the following monograph
    addendum.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

         No new information available.

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

        Table 1. Acute toxicity
                                                                                               

    Species     Strain              Sex       Route       LD50           Reference
                                                          (mg/kg bw)
                                                                                               

    Mouse       B6C3F1              M         Oral        280            Kurokawa et al., (1990)

    Mouse       B6C3F1              F         Oral        355            Kurokawa et al., (1990)

    Rat         F344                M         Oral        400            Kurokawa et al., (1990)

    Rat         F344                M         Oral        495            Kurokawa et al., (1990)

    Rat         Wistar              M&F       Oral        160-190        Kurokawa et al., (1990)

    Hamster     Syrian Golden       M         Oral        388            Kurokawa et al., (1990)

    Hamster     Syrian Golden       F         Oral        460            Kurokawa et al., (1990)
                                                                                               
    
    2.2.2  Short-term toxicity studies

    2.2.2.1  Mice

         Groups of 10 male and 10 female B6C3F1 mice received for
    10 weeks 250, 500, 1000, 2000 or 4000 mg potassium bromate/l in
    drinking water. Doses > 2000 mg/l were not palatable. No mortality
    nor particular histopathological changes due to potassium bromate
    were observed (Kurokawa  et al., 1990).

    2.2.2.2  Rats

         Groups of 10 male and 10 female F344 rats received for 13 weeks
    150, 300, 600, 1250, 2500, 5000 and 10 000 mg potassium bromate/l of
    drinking water. Doses > 2500 mg/l were not palatable. All animals
    given doses greater than 1250 mg/l died within 7 weeks, whereas all

    animals given doses < 600 mg/l survived. Growth was decreased
    significantly in males on 1250 and 600 mg/l. Significantly increased
    levels of ASAT, ALAT, LDH, SAP, BUN, serum Na and ChE were seen in
    males and females on 600 mg/l. Serum K levels were decreased
    significantly at the 600 mg/l level. Many various-sized droplets
    stained strongly with eosin were seen in the cytoplasm of the
    proximal tubular epithelium of kidneys in treated males. Extensive
    regenerative changes in the renal tubules were observed (dose-levels
    were not mentioned) (Kurokawa  et al., 1990).

         Male F344 rats received 600 mg potassium bromate/l of drinking
    water for 12 weeks. The rats were killed after a treatment period of
    4, 8 or 12 weeks and at 16 weeks after a treatment period of 12
    weeks followed by a recovery period of 4 weeks. Various-sized
    droplets stained by eosin were observed in the proximal renal
    tubules after 4 weeks of treatment. The droplets were also seen in
    control rats, but to a lesser degree. The incidence of the droplets
    returned to control levels 4 weeks after a 12-week treatment period.
    Morphological characteristics of the droplets indicated that they
    are so-called eosinophilic bodies rather than hyaline droplets
    (Summary only available) (Onodera  et al., 1986).

    2.2.3  Long-term/carcinogenicity studies

    2.2.3.1  Mice

         Groups of 27 male B6C3F1, BDF1 or CDF1 mice received
    750 mg potassium bromate/l of drinking water (approx. 60-90 mg/kg
    bw) for 88 weeks. A control group of 15 male/strain was used. One
    renal adenocarcinoma was found in a B6C3F1 treated mouse and a
    renal adenoma was found in 2, 1 and 0 treated mice of the
    B6C3F1, BDF1 and CDF1 strain, respectively. No renal
    adenocarcinomas or adenomas were found in the control group. Renal
    dysplastic foci were seen in 2, 4 and 0 treated mice of
    B6C3F1, DBF1 and CDF1 strain, respectively (in control
    groups 1, 1 and 0, respectively). In addition, significant increased
    incidences of liver adenomas in B6C3F1 mice and adenomas of
    the small intestine in CDF1 mice were observed (Kurokawa  et al.,
    1990).

         A group of 20 female Sencar mice received twice weekly for 51
    weeks topical applications on the shaven dorsal skin with 0.2 ml of
    a potassium bromate solution in acetone (40 mg/ml). A control group
    of 15 mice received applications with acetone only. No skin tumours
    were seen in the test group or control group (Kurokawa  et al.,
    1984).

         Newborn ICR mice received s.c injections with 12.5, 25, 50, 100
    or 200 mg/kg bw either as a single dose (24 h after birth) or as
    4 weekly injections until weaning. Surviving mice were killed at
    week 78. No neoplastic or non-neoplastic lesions were seen at the
    injection site. No renal cell tumours were observed. Numbers of
    dysplastic foci in the kidneys was high in both control and treated
    groups (Matsushima  et al., 1986).

    2.2.3.2  Rats

         Male Slc:Wistar rats received 0.04% potassium bromate in their
    drinking water (equal to 400 mg/l). Markedly decreased growth was
    seen after one month. After 7-11 weeks karyopicnotic foci of tubules
    in the inner stripe of the medulla were seen. Markedly increased BUN
    levels were observed after 1 year and 3 months accompanied by marked
    structural abnormalities of the cortical tubules. Degeneration,
    regeneration atypism and cystic changes of the renal cortex were
    seen. Renal adenocarcinoma were seen in 2 out of 9 rats (only
    English summary of Japanese publication available) (Nakano  et al.,
    1989).

         Potassium bromate was administered to groups of 8-20 male F344
    rats at a dose-level of 500 mg/l of drinking water for periods of
    13, 26, 39, 52 or 104 weeks. The animals were sacrificed immediately
    or were given drinking water up to 104 weeks. In the kidneys the
    number of dysplastic foci, adenomas and adenocarcinomas in all
    discontinued treatment groups were approximately equal to or even
    higher than those in the group given potassium bromate continuously
    for 104 weeks. The minimum induction time for the development of
    renal adenomas was 26 weeks and the minimum treatment period and
    minimum total dose for the induction of renal adenomas and
    adenocarcinomas were 13 weeks and 4 g/kg bw, respectively, when the
    rats were maintained thereafter on drinking water for 2 years. In
    this study, also, induction of mesothelioma of the peritoneum was
    observed (Kurokawa  et al., 1987a).

         Newborn F344 rats received s.c injections with 12.5, 25, 50, or
    100 mg potassium bromate/kg bw either as a single dose (24 h after
    birth) or as 4 weekly injections until weaning. Surviving rats were
    killed at week 82. No neoplastic or non-neoplastic lesions were seen
    at the injection site. Only a few tumorous lesions in the kidney
    (no further details available) were observed (Kurokawa  et al.,
    1990).

    2.2.3.3  Hamsters

         Groups of 20 male Syrian golden hamsters received 0, 125, 250,
    500 or 2000 mg potassium bromate/l of drinking water for 89 weeks.
    Survival times did not show differences. Mean final body weights in
    the 2000 mg/l group were significantly reduced. Mean absolute and

    relative kidney weights were significantly increased at the 2000 and
    250 mg/l levels. One, two and four hamsters in 250, 500 and
    2000 mg/l group developed a renal adenoma. No renal tumours were
    seen in the control group. Structural and cellular morphological
    characteristics of the renal tumours as well as the dysplastic foci
    found in the treated groups, were similar to those induced in rats
    (Takamura  et al., 1985).

    2.2.4  Reproduction studies

         No information available.


    
    2.2.5  Special studies in genotoxicity

    Table 2. Special studies in genotoxicity
                                                                                                                     

    Test system       Test object                    Dose-levels          Results           References
                                                     used
                                                                                                                     

    Ames test         Salmonella typhimurium         up to 3.0 mg/        weakly            Ishidate et al., 1984
                      TA100                          late                 positive1

    Ames test         Salmonella typhimurium         not given            negative2         as cited in Kurokawa
                      TA98, TA1535, TA1537,                                                 et al., 1990
                      TA1538

    Ames test         Salmonella typhimurium         2-4 mg/plate         positive2         as cited in Kurokawa
                      TA100, TA102, TA104                                                   et al., 1990

    Gene-mutations    Escherichia coli               not given            negative2         as cited in Kurokawa
                                                                                            et al., 1990

    Rec-assay         Bacillus subtilis              not given            negative2         Kawachi et al., 1980

    Rec-assay         Bacillus subtilis              not given            positive3         Nonaka, 1989

    Chromosomal       Chinese hamster lung           0.0625-0.25          positive4         Ishidate et al., 1984
    aberrations       cells                          mg/ml

    Chromosomal       Chinese hamster                0.0835 mg/ml         positive3         Sasaki et al., 1989
    aberrations       DON-6 cells

    Chromosomal       Male rats, Long-Evans          oral and i.p.        positive at       Fujie et al., 1988
    aberrations       in vivo                        167-501 mg/kg        both routes
                                                     bw

                                                                                                                     

                                                                                                                     

    Test system       Test object                    Dose-levels          Results           References
                                                     used
                                                                                                                     

    Micronuclei       Male mice, ddY, MS/Ae,         ddY strain oral      positive          Hayashi et al., 1988
                      and CD-1 strain                25-400 mg/kg         at both           Nakajima et al., 1989
                                                     bw                   routes in
                                                     ddY strain ip        all strains
                                                     25-200 mg/kg 
                                                     bw
                                                     MS/Ae + CD-1
                                                     strains
                                                     both oral and ip
                                                     18.8-300 mg/kg
                                                     bw

                      Silk worms                     not given            negative          Kawachi et al., 1980

                                                                                                                     

    1   with metabolic activation
    2   with and without metabolic activation
    3   no data on metabolic activation
    4   without metabolic activation

    

         The Collaborative Study Group for the Micronuleus Test did not
    observe a sex difference for inducing micronuclei in CD-1 mice for
    potassium bromate (CSG, 1986).

    2.2.6  Special studies for initiating and promoting activity of
           potassium bromate

         In a two-stage forestomach carcinogenesis assay male C57BL mice
    received a single oral dose of 25 or 50 mg/kg bw
    dimethylbenzanthracene followed by 500 mg potassium bromate/l of
    drinking water for 26 weeks. No increased incidences of papillomas,
    nor of hyperplasia in the forestomach epithelium were seen in the
    potassium bromate group (Kurokawa  et al., 1990).

         Groups of 15-20 female Sencar mice received a single dermal
    application with 0.2 ml of a solution of dimethylbenzanthracene in
    acetone on the shaven skin followed one week later by dermal
    applications with potassium bromate in acetone (40 mg/ml),
    12-O-tetradecanoylphorbol-13-acetate in acetone (10 g/ml) or
    acetone only twice weekly for 51 weeks. No promoting activity of
    potassium bromate on the development of skin tumours was observed
    (Kurokawa  et al., 1984).

         The promoting activity of potassium bromate was tested in
    6-week old male F344 rats. The animals received 500 mg
    N-ethyl-N-hydroxyethyl-nitrosamine (EHEN)/l of drinking water for 2
    weeks for initiation of carcinogenesis. Thereafter the animals were
    divided in groups of 15 and were treated for 24 weeks with 0, 15,
    30, 60, 125, 250 or 500 mg potassium bromate/l of drinking water. In
    rats treated with dose-levels > 30 mg/l a dose-related increase
    in the number of dysplastic foci in the kidneys was seen. At
    500 mg/l the number of renal cell tumours was increased
    significantly (Kurokawa  et al., 1985).

         In a two-stage carcinogenesis model potassium bromate did not
    show a promoting activity on the development of tumours of the
    nervous, haematopoietic nor GI tract systems, nor on thyroid, liver
    nor urinary bladder in male F344 rats. Methylnitrosourea was used as
    initiating agent (Kurokawa  et al., 1990).

         Male F344 rats received 500 mg dibutylnitrosamine/l of drinking
    water for 4 weeks followed by 500 mg potassium bromate/l for 32
    weeks. No increased incidences of neoplasms in oesophagus nor other
    G.I. tract organs were seen (Kurokawa  et al., 1990).

    2.2.7  Special studies on the mechanism of carcinogenicity

         Levels of kidney lipid peroxidation (LPO) were determined in
    male F344 rats, BDF1, CDF1 and B6C3F1 mice, and Syrian
    Golden hamsters after a single i.v. injection of potassium bromate
    at various doses. Significant increases in kidney LPO levels in a

    dose-dependent and time-dependent manner in rats, but not in mice or
    hamsters, were seen. Pretreatment with cysteine or glutathione had a
    protective effect on the increases in LPO levels and also on the
    formation of eosinophilic bodies in renal tubular cells.
    Pretreatment with diethyl maleate (DEM) resulted in exacerbation of
    the effects. These data indicate a possible relationship between LPO
    formation in the kidney and the species difference in renal toxicity
    and carcinogenicity of potassium bromate (Kurokawa  et al., 1987b).

         Increased levels of 8-hydroxydeoxyguanosine (8-OH-dG) in kidney
    DNA were found in male F344 rats after oral and i.p. treatment with
    potassium bromate. In liver DNA no increased levels of 8-OH-dG were
    observed. In a dose-response study i.p. doses from 40 mg/kg bw and
    higher caused significantly increased levels of LPO and 8-OH-dG. The
    results suggest that increased levels of 8-OH-dG in kidney-DNA are
    related to increased LPO levels (Kasai  et al., 1987; Sai  et al.,
    1991).

    2.2.8  Special studies on ototoxicity

    2.2.8.1  Guinea-pigs

         Because deafness had been reported as symptom in several case
    studies in man, ototoxicity of potassium bromate and sodium bromate
    was studied in guinea-pigs. The animals received i.p. injections
    daily for 10-20 days of 10-20 mg/kg bw of the compound.
    Histopathology showed degeneration of the cochlear sensory cells,
    particularly of the outer hair cells of the inner ear. At the same
    time nephrotoxic effects were seen (Mizushima, 1978).

    2.3  Observations in man

         Many cases of poisoning in humans have been reported. In
    Western countries most poisoning cases are by accidental ingestion
    mainly by children, while in Japan more cases are suicide by young
    women. Lethal doses for humans varied from 5 to 500 mg/kg bw. In the
    case reports the amounts ingested ranged from 12 to 50 g, and 9 out
    of 24 adults died within 3 to 5 days. Acute symptoms of poisoning
    are vomiting and diarrhoea with abdominal pain. Further symptoms are
    oliguria, anuria, deafness, vertigo, hypotension, depression of the
    central nervous system and thrombocytopenia. Acute renal failure was
    observed. Biopsy showed kidney atrophy, necrosis, degeneration and
    regeneration of the proximal tubular epithelium. In later stages
    sclerosis of the glomeruli and interstitial fibrosis were seen;
    cardiotoxicity and hepatotoxicity have also been reported (as cited
    in Kurokawa  et al., 1990).

    3.  COMMENTS

         Recent oral long-term toxicity/ carcinogenicity studies of
    potassium bromate have revealed renal-cell tumours, peritoneal
    mesotheliomas, and thyroid follicular-cell tumours in rats and a
    slightly increased incidence of renal-cell tumours in hamsters. In
    view of these findings and the results obtained  in vivo as well as
     in vitro mutagenicity studies, it was concluded that potassium
    bromate is a genotoxic carcinogen. Experiments using new sensitive
    methods have also demonstrated that, when it is used for
    flour-treatment at what were regrded as acceptable levels, bromate
    is nevertheless present in bread.

    4.  EVALUATION

         On the basis of the new safety data and the new data on
    residual bromate in bread, the Committee concluded that the use of
    postassium bromate as a flour-treatment agent was not appropriate.
    The previous acceptable level of treatment of flours for
    bread-making was therefore withdrawn. The Committee was aware that
    alternatives were available. It was unable to address the use of
    potassium bromate in beer-making owing to the lack of data on its
    levels in beer.

    5.  REFERENCES

    CSG (1986) Sex difference and the micronucleus test. The
    collaborative study group for the micronucleus test.  Mutat. Res.,
    172: 151-163.

    FUJIE, K., SHIMAZU, H., MATSUKA, M. & SUGIYAMA, T. (1988) Acute
    cytogenetic effects of potassium bromate on rat bone marrow cells
     in vivo. Mutat. Res., 206: 455-458.

    HAYASHI, M., KISHI, M., SOFUNI, T. & ISHIDATE, M., Jr. (1988)
    Micronucleus test in mice on 39 food additives and eight
    miscellaneous chemicals.  Food Chem. Toxicol., 26: 487-500.

    ISHIDATE, M., Jr., SOFUNI, T., YOSHIKAWA, K., HAYASHI, M., NOHMI,
    T., SAWADA, M. & MATSUOKA, A. (1984) Primary mutagenicity screening
    of food additives currently used in Japan.  Food Chem. Toxicol.,
    22: 623-636.

    KASAI, H., NISHIMURA, S., KUROKAWA, Y. & HAYASHI, Y. (1987) Oral
    administration of the renal carcinogen, potassium bromate,
    specifically produces 8-hydroxydeoxyguanosine in rat target organ
    DNA.  Carcinogenesis, 8, 1959-1961.

    KAWACHI, T., KOMATSU, T., KADA, T., ISHIDATE, M., SASAKI, M.,
    SUGIYAMI, 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. As cited in Kurokawa
     et al., 1990

    KUROKAWA, Y., TAKAMURA, N., MATSUSHIMA, Y., IMAZAWA, T. & HAYASHI,
    Y. (1984) Studies on the promoting and complete carcinogenic
    activities of some oxidizing chemicals in skin carcinogenesis.
     Cancer Lett., 24: 299-304.

    KUROKAWA, Y., AOKI, S., IMAZAWA, T., HAYASHI, Y., MATSUSHIMA, Y. &
    TAKAMURA, N. (1985) Dose-related enhancing effect of potassium
    bromate on renal tumorigenesis in rats initiated with
    N-ethyl-N-hydroxyethylnitrosamine.  Jpn. J. Cancer Res. (Gann).,
    76: 583-589.

    KUROKAWA, Y., MATSUSHIMA, Y., TAKAMURA, N., IMAZAWA, T. & HAYASHI,
    Y. (1987a) Relationship between the duration of treatment and the
    incidence of renal cell tumors in male F344 rats administered
    potassium bromate.  Jpn. J. Cancer Res. (Gann), 78: 358-364.

    KUROKAWA, Y., TAKAMURA, N., MATSUOKA, C., IMAZAWA, T., MATSUSHIMA,
    Y., ONODERA, H. & HAYASHI, Y. (1987b) Comparative studies on lipid
    peroxidation in the kidney of rats, mice and hamsters and on the
    effect of cysteine, glutathione, and diethyl maleate treatment on
    mortality and nephrotoxicity after administration of potassium
    bromate.  J. Am. Coll. Toxicol., 6: 489-501.

    KUROKAWA, Y., MAEKAWA, A., TAKAHASHI, M. & HAYASHI, Y. (1990)
    Toxicity and carcinogenicity of potassium bromate - A new renal
    carcinogen.  Environ. Health Perspect., 87: 309-335.

    MATSUSHIMA, Y., TAKAMURA, N., IMAZAWA, T., KUROKAWA, Y. & HAYASHI,
    Y. (1986) Lack of carcinogenicity of potassium bromate after
    subcutaneous injection to newborn mice and newborn rats.  Sci. Rep.
     Tokohu Univ., Ser.-C., 33: 22-26. As cited in: Kurokawa  et al.,
    (1990)

    MIZUSHIMA, N. (1978) Experimental study on the ototoxicity of the
    bromate (in Japanese).  Nichidaiishi, 37: 1057-1082. As cited in:
    Kurokawa  et al. (1990).

    NAKAJIMA, M., KITAZAWA, M., OBA, K., KITAGAWA, Y. & TOYODA, Y.
    (1989) Effect of route of administration in the micronucleus test
    with potassium bromate.  Mutat. Res., 223: 399-402.

    NAKANO, K., OKADA, S., TOYOKUNI, S. & MIDORIKAWA, O. (1989) Renal
    changes induced by chronic oral administration of potassium bromate
    or ferric nitrilotriacetate in Wistar rats.  Naikan Hokan. Jap.
     Arch. Int. Med., 36: 41-47.

    NONAKA, M. (1989) DNA repair tests on food additives.  Environ. Mol.
     Mutagen., 14: 143.

    ONODERA, H., TANIGAWA, H., MATSUSHIMA, Y., MAEKAWA, A., KUROKAWA, Y.
    & HAYASHI, Y. (1986) Eosinophilic bodies in the proximal renal
    tubules of rats given potassium bromate.  Bull. Natl. Inst. Hyg.
     Sci., 103: 15-20.

    SAI, K., TAGAKI, A., UMEMURA, T., HASEGAWA, R. & KUROKAWA, Y. (1991)
    Relation of 8-hydroxydeoxyguanosine formation in rat kidney to lipid
    peroxidation, glutathione level and relative organ weight after a
    single administration of potassium bromate.  Jpn. J. Cancer Res.
     (Gann), 82: 165-169.

    SASAKI, M., SUGIMURA, K., YOSHIDA, M.A. & ABE, S. (1980) Cytogenetic
    effects of 60 chemicals on cultured human and Chinese hamster cells.
     Kromosomo II, 20: 574-584. As cited in: Kurokawa  et al. (1990)

    TAKAMURA, H., KUROKAWA, Y., MATSUSHIMA, Y., IMAZAWA, T., ONODERA, H.
    & HAYASHI, Y. (1985) Long-term oral administration of potassium
    bromate in male Syrian golden hamsters.  Sci. Rep. Res. Inst. Tokohu
     Univ., Ser.-C., 32: 43-46. As cited in: Kurokawa  et al., (1990).


    See Also:
       Toxicological Abbreviations
       Potassium bromate (ICSC)
       Potassium bromate (WHO Food Additives Series 18)
       Potassium bromate (WHO Food Additives Series 24)
       POTASSIUM BROMATE (JECFA Evaluation)
       Potassium Bromate  (IARC Summary & Evaluation, Volume 40, 1986)