Potassium Bromate

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Potassium Bromate
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Executive Summary Information

Compound Potassium Bromate (KBrO3)
Toxicities Nephrotoxicity and Ototoxicity
Mechanisms Oxidative damage.
Comments Potassium bromate is an MOA standard for strong oxidizing agents without the alkylating activity associated with some organic oxidants (e.g. quinones).
Feedback Contact Gold Compound Working Group (GCWG)
Potassium Bromate
Potassium Bromate.png


Identifiers
Leadscope Id LS-1721
CAS 7758-01-2
ChemSpider 22852
ChEBI 38211
Pathway DBs
KEGG C19295
Assay DBs
PubChem CID 23673461
Omics DBs
Properties
ToxCast Accepted no
ToxBank Accepted yes
Approved on 2012-10-23


In Vivo Data ? Compound Assessment
Adverse Events ? The oxidizing properties of potassium bromate are utilized in bread preparations and in hair straightening and permanent wave products. Acute high dose exposure is mainly via involuntary ingestion of hair products or accidental contamination of bread preparations. Chronic low dose exposure is most often due to trace levels in food and water; however, such exposure is difficult to assess and thus no epidemiological studies have been performed to evaluate the exposure levels and effects of KBrO3 in humans. Nevertheless, case studies of acute KBrO3 poisoning demonstrate severe nephrotoxicity (proximal tubule) and ototoxicity in children and adults.

References:

-Kathleen C.M. Campbell, “Bromate-induced ototoxicity”,Toxicology 221:205–211 (2006)
-Tom Parker, Patty Wong, Lindsey Roth, “Public Health Goal for Bromate in Drinking Water” (2009) report of the California EPA [oehha.ca.gov/water/phg/pdf/BromatePHG010110.pdf Link]
Toxicity Mechanisms ? Potassium bromate is a strong oxidizing agent. Extrapolated to pH 7, the redox potential for reduction to Br- is 1.0 V, which is intermediate between the oxidizing power of the acetaminophen/NAPQI couple (0.75 V) and cytochrome P450 (1.2 V).

References:

-John A. Dean, ed.,Lange’s Handbook of Chemistry, 13th edition, 1985, p. 6-7.
-Ali Özcan and Yücel Shin, “A novel approach for the determination of paracetamol based on the reduction of N-acetyl-p-benzoquinoneimine formed on the electrochemically treated pencil graphite electrode”, Analytica Chimica Acta 685 (2011) 9–14.
-Willem H. Koppenol, “Oxygen Activation by Cytochrome P450: A Thermodynamic Analysis”, J. Am. Chem. Soc. (2007) 129:9686-9690.

However, the reduction of bromate to bromide is a 6-electron transformation, while the oxidation of organic molecules will normally occur in 1- and 2-electron steps. Therefore, the mechanism of oxidation will be complex and will occur in multiple steps. Rates of reaction are often relatively slow.

References:

-Limonciel, A., Wilmes, A., Aschauer, L., Radford, R.,Bloch, K.M., McMorrow, T., Pfaller, W., van Delft, J.H., Slattery, C., Ryan, M.P., et al. (2012). Oxidative stress induced by potassium bromate exposure results in altered tight junction protein expression in renal proximal tubule cells. Archives of toxicology.
-S. B. Jonnalagadda and M. N. Shezi, “Kinetics and Mechanism of the Oxidation of Methylene Violet by Bromate at Acidic pH and the Dual Role of Bromide Ion”, J. Phys. Chem. A (2009) 113:5540–5549

Bromate oxidizes FeII and oxidizes haemoglobin to cause methemoglobinemia in animal models, where maximum effects are found at 48 h. Direct oxidation of cytochrome c would therefore be expected. The direct oxidation of GSH has been demonstrated, although the half-life at 1 mM KBrO3 is slow, 30 min, at pH 7. Therefore we can expect direct direct effects of bromate on oxidative phosphorylation and the cellular redox potential, although the rates of these reactions may be difficult to predict in cells because of the complexity of the mechanism and numerous reactive intermediates involved.

References:

-Kenneth Showalter, “Trigger Waves in the Acidic Bromate Oxidation of Ferroin”, J. Phys. Chem. 1901, 85, 440-447.
-Mir Kaisar Ahmad, Riaz Mahmood, “Oral administration of potassium bromate, a major water disinfection by-product, induces oxidative stress and impairs the antioxidant power of rat blood”, Chemosphere 87 (2012) 750–756.

A number of studies have shown the ability of KBrO3 to produce reactive oxygen species (ROS), which is generally reflective of expected effects on cellular reduction potential.

References:

-Ballmaier, D., and Epe, B. (1995). Oxidative DNA damage induced by potassium bromate under cell-free conditions and in mammalian cells. Carcinogenesis 16, 335-342.
-Sai, K., Uchiyama, S., Ohno, Y., Hasegawa, R., and Kurokawa, Y. (1992a). Generation of active oxygen species in vitro by the interaction of potassium bromate with rat kidney cell. Carcinogenesis 13, 333-339.
-Zhang, X., De Silva, D., Sun, B., Fisher, J., Bull, R.J., Cotruvo, J.A., and Cummings, B.S. (2010). Cellular and molecular mechanisms of bromate-induced cytotoxicity in human and rat kidney cells. Toxicology 269, 13-23.

Consistent with effects on cellular reduction potential and energy metabolism, recently it has been shown that KBrO3 potently activates the Nrf2 mediated oxidative response pathway and in addition causes claudin rearrangement in the proximal tubule tight junctions with a loss of claudin 2 and 10.

References:

-Limonciel, A., Wilmes, A., Aschauer, L., Radford, R., Bloch, K.M., McMorrow, T., Pfaller, W., van Delft, J.H., Slattery, C., Ryan, M.P., et al. (2012). Oxidative stress induced by potassium bromate exposure results in altered tight junction protein expression in renal proximal tubule cells. Archives of toxicology.

Potassium bromide is largely eliminated from plasma within 2 h after oral administration and not detected in any tissues at 24 h, whereas maximum physiological effects are observed later than this (48 h). Acute cytotoxicity in cell culture is similarly delayed: KBrO3-mediated necrosis is observed at 48 h but is not significant at 24 h. This pattern stands in stark contrast to alkylating toxicants which can induce cell death within minutes, immediately that ATP levels drop below a minimum threshold. This argues that KBrO3 cytotoxicity is not caused by depletion of cellular energy stores or reduction potential but rather is determined at the DNA level, which damage takes more time to manifest itself as cytotoxicity. In this regard, KBrO3 causes oxidative damage of DNA via 8-hydroxydeoxyguanosine (8-OHdG) formation, resulting in DNA fragmentation, which precedes and may be the cause of necrosis.

References:

-Fujii, M., Oikawa, K., Saito, H., Fukuhara, C., Onosaka, S. & Tanaka, K. (1984) Metabolism of potassium bromate in rats. I. In vivo studies. Chemosphere, 13, 1207–1212.
-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.
-Zhang, X., De Silva, D., Sun, B., Fisher, J., Bull, R.J., Cotruvo, J.A., and Cummings, B.S. (2010). Cellular and molecular mechanisms of bromate-induced cytotoxicity in human and rat kidney cells. Toxicology 269, 13-23.

The mechanism of carcinogenicity is also likely linked to oxidative damage of DNA and 8-OHdG formation, resulting in chromosomal aberration and the formation of micronuclei.

References:

-Murata, M., Bansho, Y., Inoue, S., Ito, K., Ohnishi, S., Midorikawa, K., and Kawanishi, S. (2001). Requirement of glutathione and cysteine in guanine-specific oxidation of DNA by carcinogenic potassium bromate. Chem Res Toxicol 14, 678-685.
-Cho, D.H., Hong, J.T., Chin, K., Cho, T.S., and Lee, B.M. (1993). Organotropic formation and disappearance of 8-hydroxydeoxyguanosine in the kidney of Sprague-Dawley rats exposed to adriamycin and KBrO3. Cancer Lett 74, 141-145.
-Kasai, H., Nishimura, S., Kurokawa, Y., and Hayashi, Y. (1987). Oral administration of the renal carcinogen, potassium bromate, specifically produces 8-hydroxydeoxyguanosine in rat target organ DNA. Carcinogenesis 8, 1959-1961.
-Sai, K., Tyson, C.A., Thomas, D.W., Dabbs, J.E., Hasegawa, R., and Kurokawa, Y. (1994). Oxidative DNA damage induced by potassium bromate in isolated rat renal proximal tubules and renal nuclei. Cancer Lett 87, 1-7.
-Sai, K., Umemura, T., Takagi, A., Hasegawa, R., and Kurokawa, Y. (1992b). The protective role of glutathione, cysteine and vitamin C against oxidative DNA damage induced in rat kidney by potassium bromate. Jpn J Cancer Res 83, 45-51.
-Hayashi, M., Kishi, M., Sofuni, T., and Ishidate, M., Jr. (1988). Micronucleus tests 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., and Matsuoka, A. (1984). Primary mutagenicity screening of food additives currently used in Japan. Food Chem Toxicol 22, 623-636.
-Fujie, K., Shimazu, H., Matsuda, M., and Sugiyama, T. (1988). Acute cytogenetic effects of potassium bromate on rat bone marrow cells in vivo. Mutat Res 206, 455-458.

However, due to inadequate evidence in humans, the International Agency for Research on Cancer (IARC) classified this compound as a possible carcinogen to humans (Group 2B)

References:

-IARC (1999). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, pp. 481-496.
Therapeutic Target ? Potassium bromate is not used therapeutically.

PK-ADME ? Compound Assessment
PK parameters ? Rats treated with KBrO3 by gavage exhibited rapid bromate absorption and elimination (or degradation). 2 h after administration, bromate was no longer detected in plasma, and 4 h after treatment, bromate was no longer detected in bladder urine or small intestine. No bromate was detected in any tissues at 24 h, but maximum physiological effects are observed later than this – at 48 h.

References:

-Fujii, M., Oikawa, K., Saito, H., Fukuhara, C., Onosaka, S. & Tanaka, K. (1984) Metabolism of potassium bromate in rats. I. In vivo studies. Chemosphere, 13, 1207–1212.
-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.
Therapeutic window ? Not applicable
Metabolically activated ? Not applicable

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ?

References:

-Limonciel, A., Wilmes, A., Aschauer, L., Radford, R., Bloch, K.M., McMorrow, T., Pfaller, W., van Delft, J.H., Slattery, C., Ryan, M.P., et al. (2012). “Oxidative stress induced by potassium bromate exposure results in altered tight junction protein expression in renal proximal tubule cells. Archives of toxicology”
-Mir Kaisar Ahmad, Riaz Mahmood, “Oral administration of potassium bromate, a major water disinfection by-product, induces oxidative stress and impairs the antioxidant power of rat blood”, Chemosphere 87 (2012) 750–756.
-Zhang, X., De Silva, D., Sun, B., Fisher, J., Bull, R.J., Cotruvo, J.A., and Cummings, B.S. (2010). “Cellular and molecular mechanisms of bromate-induced cytotoxicity in human and rat kidney cells”. Toxicology 269, 13-23.
-David R. Geter, William O. Ward, Geremy W. Knapp, Anthony B. DeAngelo, Jessica A. Rubis, Russell D. Owen, James W. Allen and Don A. Delker, “Kidney Toxicogenomics of Chronic Potassium Bromate Exposure in F344 Male Rats”, Translational Oncogenomics 2006:33–52.
Proteomics profiles known. ? None Found
Metabonomics profiles known. ?

References:

-Ellis JK, Athersuch TJ, Cavill R, Radford R, Slattery C, Jennings P, McMorrow T, Ryan MP, Ebbels TM, Keun HC. Metabolic response to low-level toxicant exposure in a novel renal tubule epithelial cell system. Mol Biosyst.

2011 Jan;7(1):247-57. Epub 2010 Nov 19. PubMed pmid:21103459

.
-Mir Kaisar Ahmad, Riaz Mahmood, “Oral administration of potassium bromate, a major water disinfection by-product, induces oxidative stress and impairs the antioxidant power of rat blood”, Chemosphere 87 (2012) 750–756.
Fluxomics profiles known. ?
Epigenomics profiles known. ? None found.
Observed IC50 for in vitro cellular efficacy. ? Not Applicable
Observed IC50 for in vitro cellular toxicity studies. ? 5 mM in RPTEC/TERT1 cells at 72 h and 1.8 mM in NRK-52E also at 72 h. The dose response curve for cell death is extremely steep, indicating that there is a threshold effect for toxicity. The threshold may reflect reaction of bromate with species in the medium rather than in the cell, although we are not aware of direct evidence that this is true.

References:

-Limonciel, A., Wilmes, A., Aschauer, L., Radford, R., Bloch, K.M., McMorrow, T., Pfaller, W., van Delft, J.H., Slattery, C., Ryan, M.P., et al. (2012). “Oxidative stress induced by potassium bromate exposure results in altered tight junction protein expression in renal proximal tubule cells. Archives of toxicology”.

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? No - Not included in ToxCast Phase I and II Chemicals List
Substance stability. ? Highly stable in water at room temperature. It is more reactive (less stable) in acidic solutions. Because it is a strong oxidant, it reacts with organic matter, which ultimately leads to the formation of bromide ion. Incompatible with strong oxidizing/reducing agents, strong acids, heavy metal salts.

Chemical Book

Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? Soluble in water up to 0.4 M. Temperature dependence of solubility (g/100 g water): 3.1 at 0 deg C; 6.9 at 20 deg C; 13.1 at 40 deg C; 22.2 at 60 deg C; 33.9 at 80 deg C; 49.7 at 100 deg C.

Hazardous Substances Data Bank

Solubility in DMSO 100 times buffer solubility. ? 6.5 g/100ml at 25°C

Gaylord Chemical

Vessel binding properties. ? Unlikely
Vapor pressure. (Non-volatile) ? Non-volatile


Authors of this ToxBank wiki page

David Bower
Retrieved from "http://wiki.toxbank.net/wiki/Potassium_Bromate"
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