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 µg/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)