Screening Assessment for the Challenge (2024)

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Bromic acid, potassium salt
(Potassium bromate)

Chemical Abstracts Service Registry Number
7758-01-2

Environment Canada
Health Canada

September 2010

(PDF Version - 445 KB)

• Synopsis
• Introduction
• Substance Identity
• Physical and Chemical Properties
• Sources
• Uses
• Releases to the Environment
• Environmental Fate
• Persistence and Bioaccumulation Potential
• Potential to Cause Ecological Harm
• Potential to Cause Harm to Human Health
• Conclusion
• References
• Appendix 1: Details of the modelling with WHAM VI and descriptions of water types used
• Appendix 2: Robust study summary
• Appendix 3: Summary of toxicological effects information for potassium bromate

Pursuant to section 74 of the Canadian Environmental Protection Act, 1999 (CEPA 1999), the Ministers of the Environment and of Health have conducted a screening assessment of potassium bromate, Chemical Abstracts Service Registry Number 7758-01-2. The substance potassium bromate was indentified in the categorization of the Domestic Substances List as a high priority for action under the Ministerial Challenge. Potassium bromate was identified as a high priority as it was considered to pose intermediate potential for exposure (IPE) of individuals in Canada and is classified by other agencies on the basis of carcinogenicity. This substance met the ecological categorization criteria for persistence and inherent toxicity to aquatic organisms, but not for bioaccumulation potential.

According to information submitted in response to a survey published under section 71 of CEPA 1999, less than 1000 kg of potassium bromate was imported into Canada in 2006. No Canadian companies reported manufacturing potassium bromate in 2006 and it was not reported to be released into the environment in 2006. In Canada, potassium bromate is used in primarily industrial and non consumer applications.

Based on available information from various sources and results from the aforementioned survey, exposure to the general population to potassium bromate in environmental media (e.g., drinking water) and in consumer products is considered to be negligible.

As potassium bromate was classified on the basis of carcinogenicity by international regulatory agencies, carcinogenicity was a key focus for this screening assessment. Kidney tumours, mesotheliomas (testes and peritoneal), and thyroid tumours were all observed after administration of potassium bromate in drinking water. No evidence was available to suggest a carcinogenic potential for potassium bromate via the inhalation or dermal routes. Data from a wide range of genotoxicity studies suggests that potassium bromate is genotoxic in vitro and in vivo. Although the mode of induction of tumours has not been fully elucidated, based on the genotoxicity of potassium bromate, it cannot be precluded that potassium bromate induces tumours via a mode of action involving direct interaction with genetic material.

Exposure to potassium bromate has also been associated with a variety of non-cancer effects in experimental animals. These include reproductive and immunological effects, as well as non -neoplastic effects in the kidney, thyroid, testes, and pituitary gland. Since exposure to potassium bromate is expected to be negligible and the most sensitive non-cancer effects occurred at a dose level at which pre-neoplastic lesions and tumours were also observed, margins of exposures were not calculated for non-cancer effects.

On the basis of the carcinogenic potential of potassium bromate, for which there may be a probability of harm at any exposure level, it is concluded that potassium bromate is a substance that may be entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

Based on the information available (relatively low quantity in commerce, moderate aquatic toxicity), it is concluded that potassium bromate is not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute or may constitute a danger to the environment on which life depends. Potassium bromate meets criteria for persistence in water but not the bioaccumulation criteria as set out in the Persistence and Bioaccumulation Regulations.

Where relevant, research and monitoring will support verification of assumptions used during the screening assessment.

Based on the information available, it is concluded that potassium bromate meets one or more of the criteria set out in section 64 of the Canadian Environmental Protection Act, 1999.

The Canadian Environmental Protection Act, 1999 (CEPA 1999) (Canada 1999) requires the Minister of the Environment and the Minister of Health to conduct screening assessments of substances that have met the categorization criteria set out in the Act to determine whether these substances present or may present a risk to the environment or human health.

Based on the information obtained through the categorization process, the Ministers identified a number of substances as high priorities for action. These include substances that

• met all of the ecological categorization criteria, including persistence (P), bioaccumulation potential (B) and inherent toxicity to aquatic organisms (iT), and were believed to be in commerce in Canada ; and/or
• met the categorization criteria for greatest potential for exposure (GPE) or presented an intermediate potential for exposure (IPE) and had been identified as posing a high hazard to human health based on classifications by other national or international agencies for carcinogenicity, genotoxicity, developmental toxicity or reproductive toxicity.

The Ministers therefore published a notice of intent in the Canada Gazette, Part I, on December 9, 2006 (Canada 2006), that challenged industry and other interested stakeholders to submit, within specified timelines, specific information that may be used to inform risk assessment and to develop and benchmark best practices for the risk management and product stewardship of those substances identified as high priorities.

The substance bromic acid, potassium salt (potassium bromate) was identified as a high priority for assessment of human health risk because it was considered to present IPE and had been classified by other agencies on the basis of carcinogenicity. The Challenge for this substance was published in the Canada Gazette on March 14, 2009 (Canada 2009). A substance profile was released at the same time. The substance profile presented the technical information available prior to December 2005 that formed the basis for categorization of this substance. As a result of the Challenge, submissions of information were received.

Although potassium bromate was determined to be a high priority for assessment with respect to human health it also met the ecological categorization criteria for persistence and inherent toxicity. This assessment therefore focuses on information relevant to both human health and the environment.

Screening assessments focus on information critical to determining whether a substance meets the criteria as set out in section 64 of CEPA 1999. Screening assessments examine scientific information and develop conclusions by incorporating a weight-of-evidence approach and precaution^Footnote1.

This final screening assessment includes consideration of information on substance properties, hazards, uses and exposure, including the additional information submitted under the Challenge. Data relevant to the screening assessment of this substance were identified in original literature, review and assessment documents and stakeholder research reports and from recent literature searches, up to October 2009 for the exposure and health effects sections and November 2009 for the ecological sections. Key studies were critically evaluated; modelling results may have been used to reach conclusions. Evaluation of risk to human health involves consideration of data relevant to estimation of (non-occupational) exposure of the general population, as well as information on health hazards (based principally on the weight of evidence assessments of other agencies that were used for prioritization of the substance). Decisions for human health are based on the nature of the critical effect and/or margins between conservative effect levels and estimates of exposure, taking into account confidence in the completeness of the identified databases on both exposure and effects, within a screening context. The final screening assessment does not represent an exhaustive or critical review of all available data. Rather, it presents a summary of the critical information upon which the proposed conclusion is based.

This final screening assessment was prepared by staff in the existing substances programs at Health Canada and Environment Canada and incorporates input from other programs within these departments. The ecological and human health portions of this assessment have undergone external written peer review/consultation. Comments on the technical portions relevant to human health were received from scientific experts selected and directed by Toxicology Excellence for Risk Assessment (TERA), including Dr. Bernard Gadagbui (TERA), Dr. Pam Williams (E Risk Sciences) and Dr. Harlee Strauss (Strauss Associates). Additionally, the draft of this screening assessment was subject to a 60-day public comment period. While external comments were taken into consideration, the final content and outcome of the screening assessment remain the responsibility of Health Canada and Environment Canada.

The critical information and considerations upon which the final assessment is based on are summarized below.

No natural sources of potassium bromate have been identified..

The Bromate (BrO₃^-) moiety also has not been reported to occur naturally in surface waters (Butler et al. 2005a). However, there is some evidence for the natural formation of bromate in certain environmental compartments. Hara et al. (2002), for example, detected the ion in bromine-rich particulate matter (sea salt sprays) in Arctic air and remote from anthropogenic sources of bromate. Hara et al. (2002) proposed that bromate is naturally synthesized via a gaseous production pathway involving oxy-brominated precursors and ozone, as per the following reactions:

Formation of bromate ion depends on oxidation of bromide present in some water sources when treated with ozone (a relatively uncommon method). Furthermore bromate contamination of hypochlorite stock solutions varies according to the source of the hypochlorite chemical feedstocks (Weinberg et al 2003)..

Based on information submitted in response to a notice published under section 71 of CEPA 1999, <1000 kg of potassium bromate was imported into Canada in 2006; no manufacturing or usage of potassium bromate was reported in that year (Environment Canada 2009a).

Two of three uses of potassium bromate reported under section 71 of CEPA 1999 have been requested to be treated as confidential business information; however, these uses have predominantly industrial and commercial applications (Environment Canada 2009a), and are addressed in this assessment.

Potassium bromate used to be a permitted food additive in Canada, but it was delisted in 1994 and therefore is no longer permitted to be used as a food additive in foods offered for sale in Canada (2009 and 2010 personal communications from Food Directorate, Health Canada; unreferenced). It is, however, present as an impurity in a processing aid for paper food packaging (2009 personal communication from Food Directorate, Health Canada ; unreferenced).

One company reported using potassium bromate as an oxidizer in flour milling; however, it also reported that all of the end product was exported to the United States (Environment Canada 2009a). The US Code of Federal Regulations permits potassium bromate to be used in various flours (US FDA 2009a, b) and in the malting of barley (US FDA 2009c).

Potassium bromate is not listed in the Drug Products Database, the Therapeutic Products Directorate's internal Non-Medicinal Ingredients Database, the Natural Health Products Ingredients Database or the Licensed Natural Health Products Database as a medicinal or non-medicinal ingredient present in pharmaceuticals and natural health products and it is not used in veterinary drugs (DPD 2010, NHPID 2010, LNHPD 2010, 2009 personal communications from Therapeutic Products Directorate and Veterinary Drugs Directorate, Health Canada; unreferenced).

Potassium bromate has been used as an oxidizing reagent in laboratories and in the dyeing of textiles (sulphur dyes). The cosmetics industry has also used it as an oxidizer or neutralizer in permanent wave neutralizing solutions (IARC 1999; WHO 2005; HSDB 2009).

No environmental releases of potassium bromate in 2006 were reported under section 71 of CEPA 1999 (Environment Canada 2009a). Environmental releases reported under the National Pollutant Release Inventory (NPRI) indicated that 21 kg of potassium bromate was released into air in 2007; however, no environmental releases were reported during the years 1994–2006 and for 2008 as well. In addition, the substance has not been reported to be released to water (NPRI 2009). In addition to environmental releases, information submitted under section 71 of CEPA 1999 revealed that less than 10 kg of potassium bromate was transferred to off-site waste management facilities (Environment Canada 2009a).

In 2006, the US Toxics Release Inventory (TRI) reported that 257 and 891 pounds of potassium bromate were released to air and transported to off-site disposal facilities, respectively. Additionally, between 1995 and 2005, 5 – 255 pounds of potassium bromate was released mainly to air, with the remainder being disposed of in landfills (TRI 2009).

Potassium bromate can be assumed to have a negligible vapour pressure, and it is therefore not expected to partition to air (Neely and Blau 1985). However, bromate may be associated with aerosols (Hara et al. 2002). Similar to many inorganic salts, potassium bromate is highly soluble in water and dissociates rapidly (primarily ionic bonds) to release the bromate ion, which is the moiety of interest in the ecological component of this assessment. As typified by many inorganic ions found primarily in anionic form in water (Garrett 2004), the bromate oxyanion is expected to have a high geochemical mobility in oxic waters (i.e., pH between 5 and 9; redox potential [E_h] between 0.5 and 1 V). As a possible consequence of this expected behaviour, there is a lack of impetus for researchers to study the speciation and bioavailability of bromate in solution. No studies have been found on interactions between bromate and colloidal organic matter, for example. However, available thermodynamic stability constants for bromate–inorganic ligand complexes suggest that this anion would be weakly complexed in natural waters (Smith and Martell 2004). The Windermere Humic Aqueous Model (WHAM 2001; Tipping 2002) was used to model the chemical speciation of bromate in 10% Lake Ontario water (diluted with deionized water), representing a very diluted Canadian surface water. The inorganic complexation of this ion was found to be negligible (<<1%). Appendix 1 provides the description of water type as well as details of the modelling with WHAM VI. Seawater and more mineralized waters are expected to also weakly complex bromate because of the tendency of chemical stability constants to decrease with increasing ionic strength (Smith and Martell 2004).

Considering its mobility in water, relatively little bromate is expected to partition to sediments and soils. Bromate ions found in sediments and soils are expected to be mobile in these compartments. For example, Butler et al. (2005a) reported a case in the United Kingdom of groundwater contamination by bromate in a chalk aquifer following an industrial spillage, indicating that bromate can, under some circ*mstances, pass through soil into groundwater.

Natural bromate reduction may occur in waters with low oxygen concentrations, according to the following reaction.

Butler et al. (2005a) indicated that bromate is persistent in water even if this ion is thermodynamically unstable (e.g., Takeno 2005) and subject to slow biological reduction under natural conditions. In aqueous solution, bromate is highly stable at room temperature, does not volatilize and is not removed by boiling (Butler et al. 2005a). Furthermore, Grguric et al. (1994) observed that concentrations of the ion in a sample of salt water left in total darkness did not show any statistically significant change (±2%) over a period of more than 2 years.

A number of studies have demonstrated that bromate can be reduced to bromide in soil, using enriched microbial communities and an appropriate carbon source (Rodgers 1980; Butler et al. 2005b). Furthermore, Rodgers (1980) observed 60% to nearly 100% conversion of BrO₃^- to Br^- following 14-day incubation, at 25°C, of aerobic and anaerobic soils, both amended and unamended with glucose. These results suggest that natural attenuation of bromate in soil is possible.

Anaerobic degradation of bromate in sediment at depths at which anoxic conditions persist is theoretically possible (see equation 6 above), but no data relating to the rate of bromate reduction in sediments have been identified. However, the presence of bromate in deep sediments is not expected to present a high degree of exposure potential to most aquatic organisms and therefore is not likely to present an ecological concern.

Based on the lines of evidence provided by the above-described literature, potassium bromate is considered to meet the persistence criterion in water (half-life in water ≥ 182 days) but does not meet the criteria for air, soil or sediment (half-life in air ≥ 2 days, half-life in soil ≥ 182 days and half-life in sediment ≥ 365 days) as set out in the Persistence and Bioaccumulation Regulations of CEPA 1999 (Canada 2000).

No studies were found with regards to the bioaccumulation potential (bioconcentration factor [BCF], bioaccumulation factor [BAF]) of bromate in plants and animals. However, toxico*kinetic studies conducted in the laboratory strongly suggest that sulphydryl-containing compounds such as glutathione (GSH) contribute to the reduction of bromate to bromide in body tissues of mammals. Bromide (along with residual bromate) is subsequently excreted via urine and feces (Kurokawa et al. 1990; IPCS 2000; US EPA 2001a). Because GSH is also part of the cellular defence mechanism in aquatic animals (Di Giulio et al. 1995), it is anticipated that the physiological pathway described for mammals also operates in aquatic animals. This GSH-based pathway should generally result in low net accumulation of bromate and its metabolite Br^- in animal tissues. This conclusion is consistent with that of Hutchinson et al. (1997), who concluded that it is unlikely that bromate has the potential to accumulate significantly in aquatic species. It is noted that, at present, the element bromine has no known essential function in animals or plants (Markert 1994) and that the bromide ion has a low to moderate potential for aquatic toxicity with short-term LC₅₀s greater than 30 mg/L (PAN Pesticide Database c2000-2010).

Considering published information and experimental evidence for metabolic transformation, potassium bromate does not meet the bioaccumulation criteria (BAF or BCF ≥ 5000) as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

The approach taken in this assessment was to examine the available scientific information and develop conclusions based on a weight of evidence approach and using precaution as required under CEPA 1999. Lines of evidence considered include results from a conservative risk quotient calculation, as well as information on the persistence, bioaccumulation, toxicity, sources and fate of the substance.

Since potassium bromate is expected to be mainly discharged to freshwater systems (see exposure scenario below), effects on sensitive freshwater organisms were considered the critical endpoints. Given its persistence in water, chronic effects were of particular interest.

Ecotoxicological data of bromate toxicity to aquatic biota are available for a range of aquatic organisms including freshwater algae, invertebrates, fish and estuarine and marine crustaceans and bivalves. Hutchinson et al. (1997) summarized the results from seven studies which indicate that the median effective(lethal) concentrations (E(L)C₅₀ values) spanned over 4 orders of magnitude. The lowest reported values, ranging from 0.05 to - 100 mg/L in a 48-hour EC₅₀ embryo study on the oyster, (Crassostrea gigas) were markedly lower than E(L)C₅₀ values obtained with the other species, which ranged from 31 to 100 mg/L bromate. In an attempt to reproduce the findings of the oyster study, Hutchinson et al. (1997) repeated twice the embryo development test using a similar protocol but was unable to reproduce the results and instead obtained a 24-hour EC₅₀ of 170 mg/L as bromate for this endpoint. Given the lack of reproducibility of the test, the next most sensitive results were considered.

The National Water Research Institute (NWRI) of Environment Canada in Burlington, Ontario, performed a suite of acute toxicity tests on metallic and non-metallic elements using Hyalella azteca (Environment Canada 2007). The objective of this experiment was to compare the relative toxicity of a number of inorganic ions in a reasonable worst-case situation using water chemistry representative of the diluted waters of the Canadian Shield (10% Lake Ontario water with low ionic strength and low dissolved organic carbon). Exposure lasted 7 days, and temperature was maintained between 24°C and 25ºC. A 7-day LC₅₀ of 1.093 mg/L was estimated for bromate based on nominal concentrations. Because bromate is stable in water, nominal concentrations can be considered a good estimate of exposure concentration. This study was determined to have a high degree of reliability (see robust study summary in Appendix 2) and is therefore considered a key line of evidence.

These toxicity data indicate that potassium bromate generally has only a low to moderate potential for toxicity to aquatic organisms; however, it may be highly hazardous to some sensitive organisms (e.g., Hyalella azteca).

Due to requests for confidentiality, the quantity used at specific sites cannot be revealed (Environment Canada 2009a). The upper limit of the range of the quantity of potassium bromate imported in Canada , 1000 kg or 770 kg of bromate ion (the entity of concern), is therefore conservatively assumed to be used entirely at one industrial site. A generic scenario was used to estimate a conservative concentration of bromate ion resulting from this industrial discharge of 770 kg of bromate ion using Environment Canada's Industrial Generic Exposure Tool – Aquatic (IGETA: Environment Canada 2009b). The scenario assumed that 5 % of the mass of bromate is lost to wastewater over the course of a year, that there was no removal in a wastewater treatment plant and that the effluent is discharged to a small river flowing at a rate of 0.36 m³/s. This yielded a predicted environmental concentration (PEC) of 4.5 × 10^-3 mg/L (Environment Canada 2009c)..

A predicted no-effect concentration (PNEC) was derived from the lowest acceptable toxicity value identified for a freshwater organism--an acute LC₅₀ for Hyalella azteca of 1.093 mg/L. This value was selected as the critical toxicity value (CTV) and divided by an assessment factor of 100 to account for uncertainties associated with extrapolation from a laboratory LC₅₀ to a chronic no-effect value in the field and for inter-species and intra-species variablity. This calculation resulted in a PNEC of 0.011 mg/L.

The resulting highly conservative risk quotient (PEC/PNEC) of 4.1 × 10^-1 indicates that exposure concentrations are unlikely to be high enough to cause harm to aquatic organisms. Significant exposure of organisms at other types of locations or in media other than water is considered to be unlikely. Soils and sediment would not be significant media of exposure based on uses and releases and the predicted partitioning behaviour of bromate.

Potassium bromate is thus unlikely to be causing ecological harm in Canada.

This conclusion was reached despite the conservative assumptions made in response to uncertainties encountered in the assessment. A key uncertainty relates to the lack of empirical data on environmental concentrations in Canada , which was addressed by predicting a conservative concentration in water using an industrial exposure scenario. There is also uncertainty associated with the PNEC, but there are a fair number of empirical data available (including algae, invertebrates and fish), and the Hyalella LC₅₀ value that was selected as the CTV, is about 30 times lower than the next lowest acute value reported by Hutchinson et al. (1997). Therefore, this uncertainty was addressed by dividing the CTV by an assessment factor of 100, to account for uncertainties associated with inter- and intra-species variability and extrapolation from a laboratory LC₅₀ to a chronic no-effect value in the field.

Environmental concentrations of potassium bromate and the bromate ion are limited in scope, as no empirical data on their presence in air or soil are available. As potassium bromate is a salt with a relatively high melting point and negligible volatility, it is expected that exposure to the substance through air will be negligible. Additionally, as a consequence of its strong oxidizing capabilities, potassium bromate is expected to be reduced to bromide if released to soil (Butler et al. 2005a; WHO 2005). Therefore, intake estimates from these two sources were not calculated. Finally, as a salt with the ability to dissolve in water (water solubility 1.33 10⁵ mg/L), potassium bromate is expected to dissociate readily into its component ions if released to water.

As stated in the section on sources, bromate ion may be present in drinking water treated with disinfection agents. However, the source of this bromate is naturally present bromide, not potassium bromate (see equations 3–5 in the sources section). Health Canada's Guidelines for Canadian Drinking Water Qualityset a maximum acceptable concentration of 10 µg/L for bromate in drinking water (Health Canada 1998), although bromate has been detected above this limit in bottled drinking waters (Dabeka et al. 2002). Since bromate is not expected to be naturally present in water (Butler et al. 2005a), its presence in untreated waters would likely come from the environmental release of bromate salts. The presence of bromate, presumably from industrial releases, has been reported in 4 of 36 river samples in the Netherlands (range: 4–8 µg/L; Versteegh et al. 1993) and in contaminated groundwater near a chemical production plant in the United Kingdom (>2 mg/L; Butler et al. 2005a).

As mentioned in the section on releases to the environment, small quantities of potassium bromate are being released to the environment in Canada (Environment Canada 2009a; NPRI 2009). Additionally, data from the US Toxics Release Inventory indicate that this substance is also being released in small quantities in the United States (TRI 2009).

Estimates of daily intake from drinking water were calculated using Health Canada 's maximum acceptable concentration (10 µg/L) for bromate. Maximum daily intake for all age groups including infants was estimated to be < 0.0011 mg/kg/day..

As of 1994, potassium bromate is no longer permitted to be used as a food additive in foods offered for sale in Canada (2009 and 2010 personal communications from Food Directorate, Health Canada ; unreferenced). One company reported using potassium bromate as an oxidizing agent in flour milling; however, it also indicated that the entire final product is exported to the United States (Environment Canada 2009a). Additionally, its possible presence in food packaging materials will not lead to exposure, as the food packaging is coated with either a plastic or wax, and so no contact with food would be expected (2009 personal communication from Food Directorate, Health Canada; unreferenced). As a result of the aforementioned considerations, the potential for exposure from food is expected to be negligible, and intake from this source was not calculated.

In light of its physical and chemical properties, the small quantities of environmental releases and the delisting of potassium bromate as a food additive, human exposure to potassium bromate from environmental media and food is expected to be negligible.

Two out of three uses for potassium bromate reported under section 71 of CEPA 1999 are confidential. However, the reported uses of these products are predominately industrial and commercial.

Potassium bromate has been used as an oxidizer or neutralizer in permanent wave neutralizing solutions (hair product) and is currently listed on the Cosmetic Ingredient Hotlist as a restricted ingredient (Health Canada 2007). No companies reporting under section 71 of CEPA 1999 reported manufacturing or importing potassium bromate in these products in Canada (Environment Canada 2009a). There were no reports of potassium bromate use in personal care products in Health Canada 's cosmetic notification system (CNS 2009). Furthermore, potassium bromate was not identified as an ingredient in products listed in the Household Products Database (HPD 2005).

Based upon information identified from various sources, there is high confidence that exposure to potassium bromate from use of consumer products is negligible.

Confidence in the exposure characterization for environmental media and food and consumer products is considered to be moderate. There is uncertainty due to limited information available with respect to the concentrations of potassium bromate in environmental media. However, based on the use patterns and limited amounts of releases, exposure to potassium bromate from environmental media and food would be expected to be negligible.

An overview of the toxicological database for potassium bromate is presented in Appendix 3. Since the toxicological effects are mediated primarily through the bromate ion, this assessment will incorporate data from the two major bromate salts (potassium bromate and sodium bromate).

On the basis of investigations in experimental animals, potassium bromate has been classified by the International Agency for Research on Cancer (IARC 1999) as “possibly carcinogenic to humans, based on inadequate evidence in humans and sufficient evidence in experimental animals” (Group 2B), while also being classified by the European Union (EU) as a Category 2 carcinogen, “May cause cancer” (ESIS 2008). Similarly, Health Canada classified the bromate moiety as “probably carcinogenic to humans, based on sufficient evidence in animals and no data in humans” (Health Canada 1999). The US Environmental Protection Agency (EPA) also classified the bromate moiety as a “probable human carcinogen based on no evidence in humans, but adequate evidence of carcinogenicity in male and female rats” (Group B2 carcinogen) under previous guidelines and as a “likely human carcinogen by the oral route of exposure, insufficient data for evaluation by the inhalation route” under current guidelines (US EPA 2001a, b). Recently, the World Health Organization (WHO) evaluated the bromate moiety under the WHO Guidelines for Drinking-water Quality and stated that “the weight of evidence from rat bioassays clearly indicates that bromate has the potential to be a human carcinogen” (WHO 2005). Recently, the California EPA published a draft Public Health Goal for Bromate in Drinking Water document (Cal-EPA 2009).

Multiple long-term bioassays have examined the effect of potassium bromate administered in drinking water on rodents. Administration of potassium bromate has induced renal cell tumours, thyroid follicular carcinomas and mesotheliomas, predominantly in rats. Renal cell tumours were observed in male mice and male Syrian hamsters; however, these effects were not as severe as those reported in rats.

Male and female F344 rats were administered potassium bromate at doses of 0, 250 or 500 mg/L in drinking water (equivalent to approximately 0, 9.6 and 21.2 mg kg-bw per day as bromate for males and 0, 9.6 and 19.5 mg/kg-bw per day as bromate for females) for 110 weeks. Percent survival and body weight gain were decreased in males, but not in females. Significantly increased incidences of renal cell tumours (adenomas and adenocarcinomas) were observed in all treated groups in both sexes. Male rats also showed significantly increased incidences of peritoneal mesotheliomas (Kurokawa et al. 1982, 1983a).

In a subsequent study, male F344 rats were administered potassium bromate at 0, 15, 30, 60, 125, 250 or 500 mg/L (equivalent to 0, 0.7, 1.3, 2.5, 5.6, 12.3 and 33 mg/kg-bw per day as bromate) in drinking water for 104 weeks. Dose-dependent increases in renal cell tumours (adenomas and adenocarcinomas) were observed starting at the 2.5 mg/kg-bw per day dose level, but significance was attained at 5.6 mg/kg-bw per day and higher. Preneoplastic lesions were also observed, with dose-dependent increases in frequency of dysplastic foci attaining significance at the 1.3 mg/kg-bw per day level and higher. Significant increases in incidences of peritoneal mesotheliomas and thyroid follicular adenomas and adenocarcinomas at the 33 mg/kg-bw per day level were also reported. At 33 mg/kg-bw per day, treated males showed decreased body weight gain and decreased survival (Kurokawa et al. 1986a).

Male F344 rats were administered potassium bromate doses of 0, 0.02, 0.1, 0.2 or 0.4 g/L in drinking water (corresponding to 0, 1.1, 6.1, 12.9 and 28.7 mg/kg-bw per day as bromate) for 100 weeks. The authors reported significant dose-dependent increased incidences of mesotheliomas, renal cell tumours (adenomas and carcinomas) and thyroid follicular tumours (adenomas and carcinomas). For mesotheliomas, significance was attained at 6.1 mg/kg-bw per day and greater (increased at 1.1 mg/kg-bw per day, p = 0.06). For renal and thyroid tumours, significance was attained only in the 28.7 and the 12.9 and 28.7 mg/kg-bw per day dose levels respectively. Furthermore, the high-dose group also had significantly depressed body weight gain and average body weight. Significantly increased kidney and thyroid weights and increased relative liver, kidney, thyroid and spleen weights were also observed in the high-dose group (DeAngelo et al. 1998).

Long-term cancer bioassays were also performed on female B6C3F1 mice. Potassium bromate was administered at doses of 0, 500 or 1000 mg/L (corresponding to 0, 43.5 and 92.2 mg/kg-bw per day as bromate) in drinking water for 78 weeks, followed by 26 weeks of water administration. No significant increases in incidences of tumours were observed, although the number of tumour-bearing mice was greater in the high-dose group (effect did not attain significance). Body weight gain was inhibited in the high-dose group, but survival was not affected (Kurokawa et al. 1986b).

Male B6C3F1 mice were also administered potassium bromate doses of 0, 0.08, 0.4 or 0.8 g/L (corresponding to 0, 7, 32.6 and 59.9 mg/kg-bw per day as bromate) in drinking water for 100 weeks. The authors reported statistically significant, but not dose-related, increases in incidence of renal tumours (adenomas and carcinomas) after 100 weeks of exposure. Specifically, significantly increased renal cell tumour incidence was reported in the 7 mg/kg-bw per day group. Although renal tumours were also observed in the 32.6 and 59.9 mg/kg-bw per day groups, these incidences did not attain statistical significance. The authors stated that the historical incidence of renal tumours for B6C3F1 mice was <0.5%, thus making potassium bromate–induced increases in renal tumours a biologically relevant finding. Body weight, organ weights and survival were not affected in this study (DeAngelo et al. 1998).

A long-term bioassay was performed using male Syrian hamsters that were administered potassium bromate at doses of 0, 125, 250, 500 or 2000 mg/L (equivalent to 0, 20.1, 40.2, 80.4 and 321.6 mg/kg-bw per day as bromate) in drinking water for 89 weeks. Incidences of renal cell tumours were increased in the 80.4 and 321.6 mg/kg-bw per day groups, but this effect was not dose dependent or significant. The authors stated that the spontaneous incidence of renal cell tumours in Syrian hamsters is very low (less than 1 in 1000); therefore, this finding may be biologically significant. No difference in mean survival times between treated groups and controls was observed, although the high-dose group had significantly lower mean body weights and significantly higher mean absolute and relative kidney weights (Takamura et al. 1985).

Potassium bromate has also been administered to rats and mice in their diet (bread made with added potassium bromate). No significant pathological findings were reported by the authors, although low levels of bromide were detected in adipose tissue (Fisher et al. 1979; Ginocchio et al. 1979). The absence of tumour induction through the dietary route may be explained by the reduction of potassium bromate to bromide in the baking process (Cunningham and Warner 2000).

The tumour-initiating and tumour-promoting potentials of potassium bromate have also been examined. No progression to renal cancer was observed with continuous treatment of sodium barbital after a single dose of potassium bromate, indicating that a single dose of potassium bromate does not initiate renal tumour growth (Kurata et al. 1992). Potassium bromate, on the other hand, has been shown to have promoting and enhancing activity in the induction of renal tumours in rats after being administered following N-ethyl-N-hydroxyethylnitrosamine (EHEN) dosing (Kurokawa et al. 1983b, 1985). It does not, however, show promoting or enhancing activity in liver and skin tumorigenesis when given after EHEN and 7,12-dimethylbenzanthracene (DMBA) administration, respectively (Kurokawa et al. 1983b, 1984).

The genotoxicity of potassium bromate has been well characterized both in vitro and in vivo. In vitro, potassium bromate has induced mixed results for mutagenicity in bacteria and silk worms (Kawachi et al. 1980; Ishidate et al 1981; Ishidate et al. 1984; Zeiger et al. 1992; Akintonwa et al. 2007). However, in mammalian cell lines, potassium bromate has increased mutation frequency (Speit et al. 1999; Harrington-Brock et al. 2003; Luan et al. 2007). Overall, while potassium bromate has induced mixed results in bacteria, it has produced predominantly positive mutagenic results in mammalian cell lines.

Potassium bromate induced deoxyribonucleic acid (DNA) damage in cultured mammalian cells and primary human thyroid, white blood and kidney cells as measured by the in vitro comet assay (Robbiano et al. 1999; Speit et al. 1999; Parsons and Chipman 2000; Plewa et al. 2002; Poul et al. 2004; Mattioli et al. 2006; Smith et al. 2006; Luan et al. 2007). Predominantly positive induction of micronuclei was also observed in cultured mammalian cells and primary human lymphocytes and kidney cells (Matsuoka et al. 1992; Robbiano et al. 1999; Speit et al. 1999; Poul et al. 2004; Ballmaier and Epe 2006; Kaya and Topaktas 2007; Luan et al. 2007; Fellows et al. 2008; Platel et al. 2009). Potassium bromate also induces chromosomal aberrations, DNA repair, Sister Chromatid Exchange, and DNA modifications (increased oxidation of DNA) in mammalian cell lines, primary human cultured cells and cell-free systems (Kawachi et al. 1980; Sasaki et al 1980; Ishidate et al 1981; Ishidate et al. 1984; Matsuoka et al. 1992; Sai et al. 1994; Ballmaier and Epe 1995; Chipman et al. 1998; Speit et al. 1999; Parsons and Chipman 2000; Murata et al. 2001; Ballmaier and Epe 2006; Mattioli et al. 2006; Kaya and Topaktas 2007). A weak chromosomal aberration induction was also observed in cultured mammalian cells (Speit et al. 1999).

No induction of oxidative DNA modifications in isolated perfused kidneys or calf thymus DNA was observed after potassium bromate administration (Sai et al. 1994; Chipman et al. 1998).

Potassium bromate and sodium bromate also induced micronuclei in vivo in multiple organs in rats and mice (Hayashi et al. 1982; CSGMT 1986; Nakajima et al. 1989; Awogi et al. 1992; Sai et al. 1992 a; Robbiano et al. 1999; Allen et al. 2000; Hamada et al. 2001; NTP 2007). In addition, potassium bromate induced DNA damage (as measured by the DNA comet assay) in the rat kidney, liver and thyroid (McLaren et al. 1994; Robbiano et al. 1999; Mattioli et al. 2006). DNA damage was also induced in the mouse kidney, liver, colon, stomach, bladder, lung, brain and bone marrow (Sasaki et al. 1997; Sekihashi et al. 2001). Potassium bromate has also been observed to induce chromosomal aberrations in rat bone marrow cells after oral administration (Kawachi et al. 1980; Fujie et al. 1988). Additionally, it induced in vivo mutagenicity in the kidneys of mice and rats (Arai et al 2002; Umemura et al. 2006; Yamaguchi et al. 2008). Increases in DNA oxidative modifications have also been observed in kidneys and livers of rats and mice treated with potassium bromate (Kasai et al. 1987; Sai et al. 1991, 1992 b; Cho et al. 1993; Umemura et al. 1995, 1998, 2004, 2006, 2009; Chipman et al. 1998; Cadenas and Barja 1999; Arai et al. 2002, 2003, 2006; McDorman et al. 2005; Yamaguchi et al. 2008).

Negative results in in vivo genotoxicity assays have also been reported for potassium bromate. No induction of micronuclei was observed in spermatids, and no induction of DNA damage was observed in the lung, spleen or bone marrow of mice treated with potassium bromate (Allen et al. 2000; Sasaki et al. 1997). Furthermore, inductions of oxidative and apurinic/apyrimidinic modifications were not observed in rat liver or kidney, respectively (Kasai et al. 1987; Umemura et al. 1995; McDorman et al. 2005). Results of a test for induction of DNA damage in rat kidneys were also inconclusive (Nesslany et al. 2007). Tests for in vivo mutagenicity in rat kidneys and mice livers, as measured by the gpt and red/gam mutation assays, were inconclusive and negative, respectively (Arai et al 2003; Umemura et al. 2006; Umemura et al 2009).

A fully elucidated mode of action for induction of tumours has not been developed. Oxidative stress may play a role in the formation of kidney tumours, as evidenced by the detection of 8 – hydroxydeoxyguanine in kidneys of rodents (US EPA 2001a). Evidence that cell proliferation also plays a role in bromate-mediated renal carcinogenicity also exists; however, this mechanism remains to be further elucidated (US EPA 2001a). The US EPA concluded that “observation of tumours at relatively early time points and the positive response of bromate in a variety of genotoxicity assays suggest that the predominant mode of action at low doses is DNA reactivity” (US EPA 2001a). Furthermore, WHO has stated that “bromate should be considered a mutagenic disinfection by-product” (WHO 2005).

Non-cancer effects have also been reported in numerous studies. Degenerative, necrotic, nephropathic and regenerative changes in kidneys were reported in F344 rats that were administered potassium bromate in drinking water (Kurokawa et al. 1983a, 1986a, b). However, information as to the incidence or statistical significance of these findings was not reported. Significant non-neoplastic observations were reported in the renal pelvis, where a dose-dependent increase in urothelial hyperplasia was observed, of F344 rats (DeAngelo et al. 1998). Based on these effects, a no-observed-adverse-effect level (NOAEL) of 1.1 mg/kg-bw per day as bromate and a lowest-observed-adverse-effect level (LOAEL) of 6.1 mg/kg-bw per day as bromate is derived. Additionally, hyaline degeneration of epithelial cells, dilatation of tubules, tubular regeneration, fibrosis and inflammatory cell infiltration were all observed in kidneys when potassium bromate was administered in drinking water to male Big Blue^® rats (five per group) for 16 weeks (Yamaguchi et al. 2008). Based on degeneration of epithelial cells, a LOAEL of 1.3 mg/kg-bw per day as bromate is derived, although the low number of rats reduces confidence in this determination.

Oral administration of sodium bromate in drinking water for 27 and 43 weeks to male and female Tg.AC hemizygous mice also induced significant non-neoplastic effects. Increased follicular cell hypertrophy, follicular depletion and lymphocyte infiltration were observed in the thyroid. Increased nephropathy, renal tubule degeneration and hypertrophy were also observed in the kidneys of treated mice. Hypertrophy of the pituitary gland and degeneration of the germinal epithelium in the testes were also observed. Based on significant increases in follicular cell hypertrophy in males, a LOAEL of 8.4 mg/kg-bw per day as bromate is derived. None of the aforementioned non-neoplastic lesions were reported in p53 haploinsufficient mice treated with sodium bromate in drinking water for 27 and 43 weeks (NTP 2007).

Significant non-cancer effects were observed after dermal application (26 and 39 weeks) of sodium bromate to Tg.AC hemizygous mice. Thyroid follicular cell hypertrophy (all dosage groups), secretory depletion and lymphocyte infiltration were observed. Non-neoplastic effects in the kidneys were also observed; specifically, relative kidney weights and nephropathy were increased (NTP 2007). Based on significant thyroid hypertrophic effects in males and females, a LOAEL of 54.2 mg/kg-bw per day as bromate is derived.

Non-cancer effects have also been reported in an immunotoxicity study in which drinking water containing sodium bromate was administered to mice for 28 days. Significantly increased spleen weights, increases in reticulocytes and decreased macrophage activities were observed (Guo et al. 2001). Although a lack of a clear dose–response relationship for the increase in absolute spleen weights was observed, a lowest-observed-effect level (LOEL) of 10.6 mg/kg-bw per day as bromate is derived.

Sodium bromate was also administered (via drinking water for 35 days) to male and female Sprague-Dawley rats in a short-term reproductive and developmental toxicity assay. Sodium bromate was deduced to be a selective male toxicant; specifically, males showed a significant decrease in epididymal sperm density (NTP 1996). Based on this effect, a LOAEL of 16.1 mg/kg-bw per day as bromate and a NOAEL of 5.5 mg/kg-bw per day as bromate are derived.

Potassium bromate, when injected subcutaneously for 2 weeks, can induce alterations in the auditory system (increased threshold of hearing) and vestibular system (reduced equilibrium performance and spontaneous locomotor activity) in guinea pigs (Chuu et al. 2000; Young et al. 2001). These findings are of importance, since ototoxicity has been observed after acute exposure in humans.

Data on bromate toxicity in humans are limited to acute toxicity case reports and one case–control study. Acute toxicity, through either voluntary or accidental ingestion of large quantities of bromate salt–containing home permanent wave solutions, involves reversible effects, such as gastrointestinal effects, central nervous system depression, hemolytic anemia and pulmonary edema. Irreversible effects include kidney failure and ototoxicity (summarized in Appendix 3). No robust epidemiological studies of human health effects associated with potassium bromate were found in the literature.

No data are available regarding the absorption of bromate from the respiratory tract. In the gastrointestinal tract, bromate is adequately absorbed (Fujii et al. 1984; Lichtenberg et al. 1989), and its detection in various organs indicates that ingestion of bromate may lead to widespread distribution (Fujii et al. 1984). Bromate may be reduced to bromide when ingested at low doses, as increased levels of bromide were detected in various organs (Fujii et al. 1984). The excretion of bromate occurs primarily through urine, although some bromate may also be excreted through feces (Fujii et al. 1984).

The confidence in the toxicity database is moderate to high, as data on acute and repeated-dose toxicity, carcinogenicity, genotoxicity, immunotoxicity and reproductive and developmental toxicity are available. There is some uncertainty associated with the lack of robust reproductive and multigenerational developmental toxicity studies. Additionally, toxicity data and data pertinent to the critical effect of cancer have been studied primarily through the oral route, as dermal and inhalation routes have not been fully characterized. Also, rat testicular mesotheliomas may have limited relevance to humans because of anatomical differences between rats and humans with respect to the scrotal cavity (Haber et al. 2009). However, both the US EPA and WHO used the incidence of these tumours to quantify cancer risk for humans. Finally, there is uncertainty associated with the lack of epidemiological studies specific to exposure of humans to potassium bromate.

As potassium bromate has been classified on the basis of carcinogenicity by other national and international agencies, carcinogenicity is the main focus of this assessment. Increased incidences of tumours were reported in the kidney, thyroid and mesothelium (testes and peritoneal cavity) of rats treated with potassium bromate in drinking water. Potassium bromate has also induced significant increased incidences of renal tumours in one mouse bioassay. Furthermore, it has been found to be genotoxic in vitro and in vivo. Although recent evidence links the genotoxicity of potassium bromate to oxidative stress, this potential mode of action has not been fully elucidated. Therefore, based on the genotoxicity of potassium bromate, it cannot be precluded that the tumours observed in experimental animals have resulted from direct interaction with genetic material.

Exposure to bromate salts has induced a range of non-cancer effects in experimental animals. Non–cancer effects after bromate salt administration include non-cancer effects in multiple organs, reproductive and developmental toxicity and immunotoxicity. The lowest effect level that has induced non-cancer effects has been in the induction of non-cancer effects in the kidney (LOAEL of 1.3 mg/kg-bw per day) in a subchronic study. At this dose level, preneoplastic lesions (dysplastic foci, kidney) and mesotheliomas (p = 0.06) were increased in long-term assays. A margin of exposure was not calculated for non-cancer effects, as exposure of the general population is considered to be negligible. Furthermore, preneoplastic lesions and tumours are observed at the same effect level as the non-cancer lesions.

There is some uncertainty with regard to exposure to potassium bromate from consumer products due to limited available information. However, the diminished use of potassium bromate in recent years suggests that exposure to products containing potassium bromate is unlikely. There is uncertainty due to limited information available with respect to the concentrations of potassium bromate in environmental media; however, based on limited use and releases of potassium bromate, exposure to potassium bromate from environmental media and food would be expected to be negligible.

There is some uncertainty associated with the limited characterization of human health effects through the dermal and inhalation routes. Also, since no epidemiological studies on the human health effects of exposure to bromate are available, there is uncertainty regarding its potential toxicity in humans. Finally, there is some uncertainty regarding the relevance of rat testicular mesotheliomas to humans; however, other organizations have used the incidence of these tumours in their cancer risk estimations for humans.

Based on the information presented in this screening assessment, it is concluded that potassium bromate is not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute or may constitute a danger to the environment on which life depends. Additionally, potassium bromate meets the persistence criterion in water but does not meet the criteria for air, soil or sediment, and it does not meet the bioaccumulation criteria as set out in the Persistence and Bioaccumulation Regulations (Canada 2000).

On the basis of the carcinogenicity of potassium bromate, for which there may be a probability of harm at any level of exposure, it is concluded that potassium bromate is a substance that may be entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

It is therefore concluded that potassium bromate meets one or more of the criteria set out in section 64 of CEPA 1999.

This substance will be considered for inclusion in the Domestic Substances List inventory update initiative. In addition and where relevant, research and monitoring will support verification of assumptions used during the screening assessmen.

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Speciation of bromate in the dissolved phase was determined with the help of the Windermere Humic Aqueous Model (WHAM 2001; Tipping 2002). The conditions for running the model are described below:

• Thermodynamic constants for metal–inorganic ligand interactions were obtained from the National Institute of Standards and Technology Standard Reference database 46 (Smith and Martell 2004).
• Constants were available for complexes with silver, iron, barium, lithium, sodium, potassium and calcium.
• The constants were corrected for an ionic strength of 0 using the Dubye–Huckel equation in order to produce a thermodynamic database usable by WHAM.
• All chemical concentrations were converted to moles per litre before entering them in the WHAM spreadsheet.
• Dissolved inorganic carbon concentrations were entered in the spreadsheet as CO₃^2- concentrations (Table A1.1).