The analytical method used to support the established exemptions from the requirement of a tolerance is a non specific colorimetric method ( Branderis, J. Sci. Food Agric., 16, 558 ( 1965)), deemed acceptable for data collection. The method was originally developed to estimate residual chlorate concentrations in soil and as a rapid diagnostic test for chlorate toxicity in plants. Briefly, the method involves acid extraction, clean up by shaking with activated charcoal, and filtration. A solution of ortho toluidine in HCl is then added to the concentrated extract and the resulting color is measured at 448 nm for low concentrations and at 490 nm for higher concentrations of dye. The method is not specific for chlorate since it measures any oxidizing agent capable of oxidizing chloride ion to free chlorine. A standard curve is prepared with sodium chlorate for comparison. The lowest sensitivity of the method is estimated at 1 ppm based on available fortification data from field trials. Chloride does not interfere with the method but residues of chlorite, which might be present, may also be detected with this method. This method is hereby deemed adequate for enforcement of sodium chlorate exemptions from the requirement of a tolerance. [ Note: If needed, a more selective HPLC method (" Determination of Residues of Sodium Chlorate in Potatoes", Method # S57023, 4/ 2/ 91) is available for the detection of sodium chlorate residues in or on raw agricultural commodities ( RACs).]

New reference standards must be supplied to the EPA National Pesticide Standards Repository.

Only crop field trial data have been submitted to support the reregistration of sodium chlorate. No storage stability or processing data are available. The available crop field trial data have been re evaluated herein. No additional plant magnitude of the residue or storage stability data are required to support the reregistration of sodium chlorate. Available crop field trial data deemed the primary sources of information to support the reregistration of sodium chlorate are briefly discussed below and summarized in Table C. 5. All other available crop field trial data are considered supplemental and will not be discussed further.

The subject data, except the potato tuber data, were all collected using the colorimetric method ( Branderis, J. Sci. Food Agric., 16, 558 ( 1965)), deemed acceptable for data collection and enforcement of the established sodium chlorate exemptions from the requirement of a tolerance. The potato tuber data were collected with a more selective HPLC method (" Determination of Residues of Sodium Chlorate in Potatoes", Method # S57023, 4/ 2/ 91) deemed adequate for data collection. The lowest limits of quantitation ( LOQs) of these methods is estimated at 1 ppm. Page 45 of 141 Based on the available flax, guar, southern pea, soybean, and sunflower field trial data no detectable residues of sodium chlorate (< 1 ppm) are expected in/ on dry beans, guar beans, southern peas, soybeans, flaxseed, safflower seed, and sunflower seed at the point of harvest from the maximum use rate of sodium chlorate on dry beans, guar, southern peas, soybeans, flax, safflower, and sunflower ( 1 application; 7.5 lbs ai/ A; 7 day PHI). Furthermore, no detectable residues of sodium chlorate (< 1 ppm) are expected in/ on cottonseed at the point of harvest from the maximum use rate of sodium chlorate on cotton ( 2 applications, 7.5 lbs ai/ A/ application; 7 day PHI). Any residues which might be detected at the point of harvest are expected to be primarily surface residues which would be substantially removed prior to the point of consumption.

Based on the available chili pepper field trial data, it is possible that detectable residues of sodium chlorate ( ca. 13 ppm) might be found on the surface of unwashed chili peppers treated with sodium chlorate at the maximum use rate of sodium chlorate on chili peppers ( 1 application; 12.5 lbs ai/ A/ application; 10 day PHI). However, these residues are primarily surface residues present at the point of harvest which would be substantially removed by washing (< 1 ppm) prior to the point of consumption.

Based on the available potato field trial data, no detectable residue of sodium chlorate (< 1 ppm) are expected in/ on potato tubers at the point of harvest from the maximum use rate of sodium chlorate on potatoes ( 1 application; 12.5 lbs ai/ A; 7 day PHI). As demonstrated by the chili pepper field trial data, any residues present at harvest are expected to be primarily surface residues which would be substantially removed by washing prior to the point of consumption.

Based on the available oat, rice, sorghum, and wheat field trial data, it is possible that detectable residues of sodium chlorate ( ca. 70 ppm ( maximum) as demonstrated by sorghum grain) might be found on the surface of cereal grains retaining their outer hulls at harvest ( such as oats and sorghum) from the maximum use rate of sodium chlorate on rice and sorghum ( 1 application; 7.5 lbs ai/ A; 7 day PHI) and wheat ( 1 application; 6 lbs ai/ A; 3 day PHI). However, once the outer hulls are removed ( either at harvest or during processing), no detectable residues of sodium chlorate (< 1 ppm) are expected in/ on cereal grains such as rice and wheat ( as demonstrated by rice w/ out hulls and wheat grain data).

Based on the available sorghum field trial data alone, maximum residues in/ on sorghum grain harvested 7 14 days after treatment with sodium chlorate at the maximum use rate for sorghum ( 1 application; 7.5 lbs ai/ A; 7 day PHI) are not expected to exceed 70 ppm. On average, residues in/ on sorghum grain harvested 7 14 days after treatment with sodium chlorate at the maximum use rate on sorghum ( 1 application; 7.5 lbs ai/ A; 7 day PHI) are not expected to exceed 40 ppm.

Translating the available sorghum field trial data to corn, residues of sodium chlorate are not expected to exceed 20 ppm ( ca. 10 ppm on average) in/ on corn grain at the point of harvest from the maximum use rate of sodium chlorate on corn ( 1 application, 7.5 lbs ai/ A; 14 day PHI). As demonstrated by the chili pepper field trial data, any residues present at harvest are expected to be primarily surface residues which would be substantially removed by washing prior to the point of Page 46 of 141 consumption. Hence, residues of sodium chlorate in/ on sweet corn after washing and prior to consumption would not be expected to exceed 1 ppm.

Based on the available straw ( flax, oat, wheat, rice) and forage ( guar plants, sorghum stalks, soybean forage) data, maximum residues of sodium chlorate in/ on straw and forage livestock feedstuffs harvested 3 7 days after treatment with sodium chlorate at the maximum use rate permitted on forage crops ( 1 or 2 applications; 7.5 lbs ai/ A/ application) are not expected to exceed 300 ppm at the point of harvest. On average, residues in/ on straw and forage livestock feedstuffs should not exceed 100 ppm when harvested 7 14 days after foliar treatment with sodium chlorate at the maximum use rate permitted on forage crops ( 1 or 2 applications; 7.5 lbs ai/ A/ application).

The highest average residues of chlorate ( excluding percent crop treated data) in meat, poultry, and eggs are expected to be < 4 ppm and in milk are expected to be < 0.5 ppm based on the following information and assumptions:

° The highest average theoretical dietary burden for livestock is 175 ppm for cattle feed on a dry wt. basis ° Cattle eat a maximum of 9.1 kg of feed per day on a dry wt. basis ( Update of Livestock Feed Consumption, 1993); hence, the highest average theoretical dietary exposure for sodium chlorate to livestock is 1600 mg per day ° Based on the available rat metabolism data, < 1% of the initial dose of chlorate is expected to be incurred in animal tissues 72 hours after exposure ( Abdel Rahman et al, 1982, 1984b and 1985); hence < 16 mg is expected to be incurred in any livestock tissue of interest ° Assuming that kidneys have the lowest weight of the organs/ tissues of interest ( other than milk) in livestock ( i. e., compared to meat, liver, fat, and eggs) ° Assuming that the average weight of cattle kidneys is about 4 kg ( Update of Livestock Feed Consumption, 1993; cattle kidneys weigh 3.6 4.5 kg) ° Assuming that the average milk production per day is about 30 kg ( Frank, 2002; milk production is 50 90 lb milk/ cow/ day)

Calculations:

( Highest Average Theoretical Dietary Exposure ( 1600 mg) x Percent of Dietary Exposure Expected in Organs (< 1%) Average Weight of the Organ/ Tissue of Interest ( Kidney at 4 Kg or Milk at 30 Kg)

Highest Average Residue Estimate in Meat, Poultry, and Eggs = < 4 ppm Highest Average Residue Estimate in Milk = < 0.5 ppm The maximum residues of chlorate ( excluding percent crop treated data) in meat, poultry, and eggs are expected to be < 12 ppm and in milk are expected to be < 2 ppm based on the following information and assumptions: Page 47 of 141 ° The maximum theoretical dietary burden for livestock is 500 ppm for cattle feed on a dry wt. basis ° Cattle eat a maximum of 9.1 kg of feed per day on a dry wt. basis ( Update of Livestock Feed Consumption, 1993); hence, the highest average theoretical dietary exposure for sodium chlorate to livestock is 4600 mg per day ° Based on the available rat metabolism data, < 1% of the initial dose of chlorate is expected to be incurred in animal tissues 72 hours after exposure ( Abdel Rahman et al, 1982, 1984b and 1985); hence < 46 mg is expected to be incurred in any livestock tissue of interest ° Assuming that kidneys have the lowest weight of the organs/ tissues of interest ( other than milk) in livestock ( i. e., compared to meat, liver, fat, and eggs) ° Assuming that the average weight of cattle kidneys is about 4 kg ( Update of Livestock Feed Consumption, 1993; cattle kidneys weigh 3.6 4.5 kg) ° Assuming that the average milk production per day is about 30 kg ( Frank, 2002; milk production is 50 90 lb milk/ cow/ day)

Calculations:

( Maximum Theoretical Dietary Exposure ( 4600 mg) x Percent of Dietary Exposure Expected in Organs (< 1%) Average Weight of the Organ/ Tissue of Interest ( Kidney at 4 Kg or Milk at 30 Kg)

Maximum Residue Estimate in Meat, Poultry, and Eggs = < 12 ppm Maximum Residue Estimate in Milk = < 2 ppm Page 48 of 141 6.1.2 Chronic ( non cancer) Dietary ( food only) Exposure and Risk A chronic ( non cancer) dietary risk assessment was conducted for all potential chlorate dietary exposure routes, using the Dietary Exposure Evaluation Model FCID   software with the Food Commodity Intake Database ( DEEM FCID   Version 2.03) and food consumption data from the United States Department of Agriculture's ( USDA's) Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998. In this analysis the chronic dietary exposure and risk estimates resulting from food intake were determined for the general U. S. population and various population subgroups.

No food monitoring data are available for this risk assessment; only limited, chemical specific field trial data are available. Exposure estimates in food were based on field trial data or, in the case of fruit/ vegetable/ other washes, was derived from a film thickness model. No chemical specific livestock metabolism or feeding data are available; exposure estimates in meat, milk, poultry, and eggs were derived from rat metabolism data, field trial data, and livestock reference information concerning feed consumption, tissue weights, and milk production. In some cases, due to raw data limitations, food exposure estimates are calculated as sodium chlorate. Default concentration factors ( no chemical specific processing data are available) and the effects of washing after foliar treatments were also incorporated into the risk assessment. Percent crop treated data were used in this analysis. Exposures were single point estimates.

The chronic ( non cancer) dietary ( food only) risk assessment is below the Agency's level of concern for the General U. S. Population and all subgroups. The highest exposed population subgroup, Children 1 2 years of age, was 28% of the chronic Population Adjusted Dose ( cPAD). See Table 6.1.2 below for details.

Table 6.1.2. Summary of Chronic ( non cancer) Dietary ( food only) Exposure and Risk for Inorganic Chlorates Population Subgroup cPAD a mg/ kg/ day % cPAD General U. S. Population 0.03 9 All Infants (< 1 yr) 15 Children 1 2 yrs 28 Children 3 5 yrs 23 Children 6 12 yrs 14 Youth 13 19 yrs 8 Adults 20 49 yrs 7 Adults 50+ yrs 6 Females 13 49 yrs 7 a The BMDL is 0.9 mg chlorate/ kg/ day. The level of concern for the Margin of Exposure ( MOE) is 30. Page 49 of 141 6.1.3 Cancer Dietary ( food only) Exposure and Risk A cancer dietary risk assessment was conducted for all potential chlorate dietary exposure routes, using the same dietary ( food only) exposure estimates used in the chronic ( non cancer) dietary risk assessment for the U. S. Population, with a 9% cPAD.

Note: Sodium chlorate is a thyroid toxicant producing thyroid gland follicular cell hypertrophy in rats and mice following chronic exposures and some evidence of follicular cell tumors in rats. The lack of mutagenicity indicates that the thyroid tumors are induced by a non mutagenic mechanism. Therefore, for the purposes of this risk assessment, the Margin of Exposure ( MOE) approach is used to estimate inorganic chlorate cancer risk. Children are not expected to be more susceptible to chlorate induced thyroid effects than adults and the endpoint selected for the thyroid effects is protective for all populations, including children.

6.2 Water Exposure/ Risk Pathway 6.2.1 Environmental Fate Sodium chlorate is used as a desiccant/ defoliant because it is a strong oxidizer. As a strong oxidizing agent, chlorate ( ClO 3 b , oxidation state V) gets reduced to chlorine species in lower oxidation states, such as the oxyanions chlorite ( ClO 2 b , oxidation state III) and hypochlorite ( ClO b , oxidation state I), chlorine dioxide ( oxidation state IV), and chloride ( oxidation state  I). Thus, at least some and possibly substantial reduction of the applied chlorate is likely to occur in the field prior to any runoff to surface water. Under environmental ( terrestrial field) redox conditions and based on chemical equilibria alone, the thermodynamically favored, end reduction product of chlorate in soil and in water is the chloride anion. Any intermediate chlorine dioxide that may form under environmental conditions will undergo photochemical reactions when exposed to sunlight. The chlorine oxyanions chlorite and hypochlorite ( other possible more reduced intermediates in the ultimate reduction of chlorate to chloride) are strong oxidizers in themselves and thus, they are also reduced and/ or undergo disproportionation reactions. Although reduction reactions of chlorate, chlorite, and hypochlorite are said to occur " very fast", how fast they occur is not known ( i. e., the actual rate constants in the environment are not known). Therefore, at any given time the distribution of reduced species ( type and concentration) cannot be estimated. However, it is unlikely that a single reduced species would be present.

6.2.2 Drinking Water Page 50 of 141 <IP_ADDRESS> Sources and Control of Chlorate Ion Chlorate ion ( ClO 3 b ) is primarily present in drinking water as a result of the use of chlorine dioxide or hypochlorite solutions for oxidation/ disinfection in the treatment process. It may also be present in the untreated source water, but the ClO 3 b concentrations contributed to drinking water by ambient water are generally much lower than those resulting from the treatment process.

The American Water Works Association ( AWWA) Disinfection Systems Committee tracks disinfection practices in US community water systems. Their most recent comprehensive survey ( completed in 1998) estimated that approximately 20% of the systems serving populations greater than 10,000 use sodium hypochlorite ( 2% generated it on site), 8% use chlorine dioxide, and < 1% use calcium hypochlorite. ( AWWA, 2000a) For systems serving populations less than 10,000, the survey estimated that approximately 34% use sodium hypochlorite, none use chlorine dioxide, and at least 4.5% use calcium hypochlorite. ( AWWA, 2000b)

Chlorine Dioxide: The use of chlorine dioxide can introduce ClO 3 b into the finished water by several routes. Drinking water plants generally use sodium chlorite as a starting material in the production of chlorine dioxide. Chlorate ion may be present as a contaminant in the feedstock material ( usually less than four percent of the active chlorite is chlorate). A typical range of ClO 3 b carryover to the finished water from chlorite feedstock contamination is about 50 µ g/ L for a 1 mg/ L dose of chlorine dioxide. ( Gates, 1998) Technology to generate chlorine dioxide using sodium chlorate is now available to the drinking water industry, which introduces the possibility of ClO 3 b carryover to the finished water from the chlorate feedstock.

Chlorate ion may also be produced due to inefficient generation of chlorine dioxide. Excess chlorine will favor the production of ClO 3 b over chlorine dioxide, as will keeping the generator mixtures at highly alkaline ( pH > 11) or acidic ( pH < 3) conditions. If the concentrations of feedstock reactants are too low or too much dilution water is added during the reaction, ClO 3 b formation is also favored.

Chlorite ion ( ClO 2 b ) is a major degradation product resulting from the reaction of chlorine dioxide with inorganic and organic constituents in the water. When free chlorine is used after the application of chlorine dioxide in the treatment process, ClO 2 b is oxidized to ClO 3 b . This conversion will continue over time as the water travels through the distribution system. Chlorate ion is also formed by photodecomposition of chlorine dioxide when treated water is exposed to bright sunlight in open basins.

The primary ways in which water systems can control the levels of ClO 3 b in the finished water is through high efficiency operation of their chlorine dioxide generators and by reducing ClO 2 b concentrations prior to the addition of free chlorine. Careful control of the generation process minimizes ClO 3  formation. Ferrous ion, which is a coagulant aid, can be used to convert ClO 2 b to chloride ion and thus prevent it from reacting with free chlorine to form ClO 3 b . Page 51 of 141 Hypochlorite: Some water systems use sodium hypochlorite or calcium hypochlorite as their source of free chlorine. Chlorate ion can be formed in these products during the manufacturing process, but the decomposition of hypochlorite solutions during storage is the more significant source of ClO 3 b in systems using hypochlorite. Sodium hypochlorite is usually purchased as a solution, and ClO 3 b concentrations increase between the time of manufacture and delivery to the water plant. Calcium hypochlorite is a solid, and thus ClO 3 b concentrations don't increase until calcium hypochlorite solutions are prepared for use at the water treatment plant.

The rate at which hypochlorite ion ( OCl b ) disproportionates to ClO 3 b is influenced by concentration of OCl b , pH, and temperature. The rate of decomposition increases as the concentration of OCl b increases, so water systems can use dilution as one control strategy. The pH should be in the 12 to 13 range to minimize decomposition; a pH below 11 greatly increases the rate of decomposition. Hypochlorite solutions should be protected from high temperatures and sunlight. Storage time should be minimized; both from the time of manufacture to delivery and from the time of delivery to use.

<IP_ADDRESS> Chlorate Ion Occurrence Data Data on the occurrence of ClO 3 b in drinking water are available from two primary sources: the Information Collection Rule ( ICR) Auxiliary 1 Database, Version 5.0 ( USEPA, 2000) and the AwwaRF research study on the control of ClO 3 b in hypochlorite solutions ( Gordon et al, 1995).

Information Collection Rule: The most extensive data on the occurrence of ClO 3 b in drinking water is from the ICR ( USEPA, 1996). Source water and drinking water were monitored for ClO 3 b between July 1997 and December 1998. Water systems serving a population of at least 100,000 were required to monitor for ClO 3 b at treatment plants using chlorine dioxide or hypochlorite solutions in the treatment process. Plants using chlorine dioxide collected monthly samples of the source water entering the plant, the finished water leaving the plant, and at three sample points in the distribution system ( near the first customer, an average residence time and a maximum residence time). Plants using hypochlorite solutions were only required to collect quarterly samples of the water entering and leaving the plant. If chlorine dioxide or hypochlorite solutions were used intermittently at a plant, ClO 3 b samples were only required in sample periods in which they were in use.

Chlorine dioxide was used by 22 water systems ( 29 treatment plants) during at least one of the 18 monthly ICR sampling periods. Data from 413 samples collected at the entry point to the distribution system showed ClO 3 b concentrations ranging from < 20 µ g/ L to 1,600 µ g/ L. The ClO 3 b concentrations ranged from < 20 µ g/ L to 2,200 µ g/ L in the 1084 samples collected in the distribution system. The distribution of average ClO 3 b concentrations calculated for each treatment plant and sample point are summarized in Table <IP_ADDRESS>.1. The distribution system average concentrations determined for each water plant by averaging the data from the three distribution system sample points are summarized in the last column of Table <IP_ADDRESS>.1. The median distribution system average concentration is 129 µ g/ L with a range from < 20 µ g/ L to 691 µ g/ L. Page 52 of 141 Sodium hypochlorite solutions were in use in 44 water systems ( 61 treatment plants) during the six quarterly ICR sampling periods. ( None of the systems reported using calcium hypochlorite as the source of their chlorine solutions.) Data from 312 samples were reported with concentrations ranging from < 20 µ g/ L to a maximum of 1,400 µ g/ L. The average ClO 3 b concentration in the finished drinking water for each treatment plant ranged from < 20 µ g/ L to 502 µ g/ L with a median concentration of 99 µ g/ L. The table below summarizes the distribution of average ClO 3 b concentrations calculated for each plant.

Table <IP_ADDRESS>.1. Chlorate Concentrations1 ( µ g/ L)  ICR Data Hypochlorite Plants Chlorine Dioxide Plants Combined Hypochlorite and Chlorine Dioxide Plants 10th Percentile 23 56 24 20th Percentile 37 77 53 50th Percentile 99 119 108 80th Percentile 155 195 179 90th Percentile 239 226 242 Maximum 502 687 691 # WTPs 61 29 90 # PWSs 44 22 66 1The average chlorate concentration was calculated for each sample point at each water treatment plant ( WTP) over the entire ICR monitoring program. The distribution of these averages is presented in this table. 2The distribution system average chlorate concentration was calculated for each WTP using the three distribution system sample points. The distribution of these averages is presented in this column.

AwwaRF Hypochlorite Project: The American Water Works Association Research Foundation sponsored a project to study how water systems could minimize ClO 3 b formation in the hypochlorite solutions they use for disinfection. As part of the data gathering effort, they obtained information from 185 water systems concerning their use of hypochlorite solutions. Samples of source water, hypochlorite solution, and finished drinking water from 111 of the water systems were analyzed for ClO 3 b . Only one set of samples was collected for each system.

Background information on the subset of 111 water systems that provided samples was not reported separately from the 185 systems who answered the questionnaire. Therefore, the ClO 3 b Page 53 of 141 concentrations cannot be directly related to the size of the water system or type of hypochlorite solution in use. However, 73.5 % of the systems who responded to the questionnaire served populations less than 100,000 with a subset of 66% serving populations less than 10,000. There is a possibility that a few systems using calcium hypochlorite were sampled in the AwwaRF project, since 13% of the 185 systems reported using calcium hypochlorite and 85% reported using sodium hypochlorite.

The ClO 3 b concentrations reported in the finished water are summarized in Table 2. The median concentration in the finished water is 161 µ g/ L. The distribution of ClO 3 b is shown below in Table <IP_ADDRESS>.2. The ClO 3 b concentrations in the hypochlorite solutions used to treat the water ranged from 0.03 to 113 g/ L.

Table <IP_ADDRESS>.2. Chlorate Concentrations  AwwaRF Project ( PWSs using Hypochlorite Solutions) 1 Finished Water Chlorate Concentration ( µ g/ L)

Minimum < 10 10th Percentile 15 20th Percentile 41 50th Percentile 161 80th Percentile 611 90th Percentile 1,160 Max 9,180 # PWSs 111 # States 13 1 A single sample was collected from each of the public water systems ( PWSs) in the survey.

<IP_ADDRESS> Chronic Exposure to Chlorate Ion The ICR data were collected from systems suspected of having ClO 3 b contamination due to the treatment process in use. It is reasonable to assume that there were not significant ClO 3 b levels in the systems in the same size category that were not sampled. This is based on earlier drinking water studies that found ClO 3 b concentrations in source water were too low to impact the levels in drinking water on the same scale as treating the water with either chlorine dioxide or hypochlorite ( Bolyard et al, 1993). Page 54 of 141 The ICR data confirm the presence of ClO 3 b in source water ( 75 of 744 samples of water entering the treatment plants contained measurable ClO 3 b ), but also demonstrate that the concentrations are generally very low, can vary considerably over time at the same sample site, and are minor compared to those observed from chlorine dioxide or hypochlorite use. Data were reported from 105 treatment plant influent sample points in the ICR and samples from 33 of those sites contained ClO 3 b concentrations of 20 µ g/ L or greater. Chlorate concentrations were reported in influent samples from both surface and ground water sources. Samples from fifteen of the 33 sites contained measurable ClO 3 b in more than one sampling period, but with one exception, the concentrations were all # 120 µ g/ L; 70% were between 20 and 50 µ g/ L. One influent water had a ClO 3 b concentration of 944 µ g/ L in one sample period, but the concentrations were # 100 µ g/ L in the other sample periods. Three influent waters contained a high ClO 3 b concentration ( 1,300 to 1,600 µ g/ L) in one sample period and none in the other sample periods. The ICR data indicate that the influence of source water ClO 3 b ( as reflected by the influent samples) on the concentrations in finished drinking water is minimal compared to the contribution from using chlorine dioxide or hypochlorite solutions in the treatment process.

The ICR data set provides the best available estimate of long term exposure to ClO 3 b from drinking water, because multiple samples were collected over an 18 month period. Only systems serving populations of at least 100,000 were sampled during the ICR. Even though this size category includes roughly one percent of the total number of drinking water systems in the United States, it serves almost 60 percent of the population. During the ICR, there were 296 water systems in this size category; 7% used chlorine dioxide and 15% used hypochlorite solutions.

When chlorine dioxide is the source of ClO 3 b in drinking water, it is appropriate to use the average concentration in the distribution system to estimate exposure. This is because the concentration is expected to change within the system due to the conversion of ClO 2 b to ClO 3 b in the presence of chlorine. Fifty percent of the chlorine dioxide plants had average distribution system ClO 3 b concentrations of # 129 µ g/ L. Ninety percent had concentrations # 264 µ g/ L.

The average ClO 3 b concentration at the entry point to the distribution system can be used to estimate exposure when hypochlorite solutions are the source of the ClO 3 b contamination. No additional ClO 3 b is expected to be formed in the distribution system. Fifty percent of the plants using hypochlorite solutions had finished water ClO 3 b concentrations of # 99 µ g/ L. Ninety percent had concentrations # 239 µ g/ L.

The AwwaRF data set is much smaller than the ICR data set, because the 111 systems from 13 states were only sampled once. Low levels of ClO 3 b were measured in almost 20% of the source waters with 90 percent of the samples having concentrations less than 35 µ g/ L. ( Over 30% of the source waters sampled during the ICR contained measurable concentrations of ClO 3 b with 90 percent having concentrations less than 23 µ g/ L.) The finished water ClO 3 b concentrations measured in the AwwaRF study are generally higher than those observed in the ICR. This difference could be the result of a number of factors such as: 1) The AwwaRF data represents a single point in time while the ICR data reflects an average over 18 months; 2) Most of the Page 55 of 141 AwwaRF samples were collected from utilities that served population of less than 100,000, while all of the ICR samples were from utilities serving at least 100,000; and 3) Hypochlorite treatment practices may have changed between when the AwwaRF samples were collected ( 1993) and the ICR samples were collected ( 1997 98).

Section <IP_ADDRESS> explains the mode of conversion of hypochlorite ion ( OCl) to ClO 3  for systems using hypochlorite as their source of free chlorine. The conversion is influenced by the solution concentration, pH, and ambient temperature. For systems using chlorine dioxide, ClO 3  level in the finished water depends on concentration of chlorate ion in the feedstock, the efficiency of chlorine dioxide generation, and subsequent disinfection techniques. Awareness of these factors is critical in controlling chlorate concentrations in finished water. Smaller systems using chlorine dioxide or hypochlorite, those serving fewer than 100,000, may be more likely to have finished water with higher levels of chlorate due to smaller budgets and, consequently, fewer resources to devote to running their systems or training their staff. An untrained staff may not know, for example, that when free chlorine is used after the application of chlorine dioxide, that ClO 2  is oxidized to ClO 3 .

Both the AwwaRF study and the ICR data reveal high concentrations of chlorate ion to be a local problem affecting a relatively small number of systems. Section <IP_ADDRESS> outlines simple measures that systems of any size can use to maintain low levels of chlorate ion in finished drinking water.

<IP_ADDRESS>. Estimated Concentrations of Chlorate Ion Deemed Appropriate for Inclusion in the Dietary Risk Assessment( s)

Based on the available occurrence data ( essentially at the tap) from the ICR AUX1 Database ( USEPA, 2000d) and the AwwaRF ( 1995) survey study, which are discussed above, the following estimated concentrations of chlorate ion ( ClO 3 b ) in drinking water are deemed appropriate for inclusion in the dietary risk assessment for inorganic chlorates:

° The highest annual average concentration of chlorate ion ( ClO 3 b ) in drinking water is estimated at 0.69 mg/ L and is based on the ICR AUX1 Database ( USEPA, 2000d). ° The 90th percentile average concentration of chlorate ion ( ClO 3 b ) in drinking water is estimated at 0.24 mg/ L and is based on the ICR AUX1 Database ( USEPA, 2000d). ° The treatment system median average concentration of chlorate ion ( ClO 3 b ) in drinking water in tested large treatment systems is estimated at 0.11 mg/ L and is based on the ICR AUX1 Database ( USEPA, 2000d).

Use of the ICR AUX1 database could underestimate concentrations in drinking water since higher levels of chlorate ion ( ClO 3 b ) in drinking water were found at the small water treatment utilities sampled in the AwwaRF ( 1995) project than at the large water treatment plants included in the ICR AUX1 Database ( USEPA, 2000d). However, the AwwaRF ( 1995) survey study is a less robust data set consisting of only one sample per utility and, therefore, the ICR AUX1 Database Page 56 of 141 ( USEPA, 2000d) was considered the more appropriate source for estimating averages from individual water treatment plants.

Chronic ( non cancer) dietary and cancer dietary risk assessments for water only were conducted using the Dietary Exposure Evaluation Model FCID   software with the Food Commodity Intake Database ( DEEM FCID   Version 2.03) and food and water consumption data from the United States Department of Agriculture's ( USDA's) Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998. Available ICR and AwwaRF monitoring data were used to estimate chlorate concentrations in drinking water. Exposures were single point estimates.

The chronic ( non cancer) dietary risk assessment for chlorate in drinking water ( highest annual average concentration estimated at 0.69 mg/ L) is below the Agency's level of concern for the General U. S. Population and all subgroups, except all infants (< 1 year of age). The highest exposed population subgroup, all infants < 1 year of age, was 159% of the chronic Population Adjusted Dose ( cPAD). See Table <IP_ADDRESS> below for details.

Table <IP_ADDRESS>. Summary of Estimated Chronic ( non cancer and cancer) Dietary ( water only) Exposure and Risk for Inorganic Chlorates by Average Annual Concentration in Large Drinking Water Systemsa Population Subgroup b cPAD mg/ kg/ dayc % cPAD Water Estimated at the Highest Annual Average ( 0.69 mg/ L) Water Estimated at the 90th Percentile Annual Average ( 0.24 mg/ L) Water Estimated at the Median Annual Average ( 0.11 mg/ L)

General U. S. Population 0.03 49 17 8 All Infants (< 1 yr) 159 55 25 Children 1 2 yrs 72 25 12 Children 3 5 yrs 67 23 11 Children 6 12 yrs 47 16 7 Youth 13 19 yrs 35 12 6 Adults 20 49 yrs 45 16 7 Adults 50+ yrs 48 17 8 Females 13 49 yrs 45 16 7 a The estimated exposures and risks are based on the ICR data ( multiple data points per water system). Higher concentrations of chlorate ion ( ClO3 ) in drinking water were reported in the AwwaRF data set ( only a single data point per water system), which sampled smaller water systems. b The values for the population with the highest risk for each type of risk assessment are bolded. C The BMDL is 0.9 mg chlorate/ kg/ day. The level of concern for the Margin of Exposure ( MOE) is 30.

The Office of Water characterizes the population included in the ICR data as follows: Page 57 of 141 o " EPA collected data required by the Information Collection Rule ( ICR) to support future regulation of microbial contaminants, disinfectants, and disinfection byproducts. The systems represented in the ICR database serve 60% of the US population. o " Included in the ICR are levels of chlorate ion concentrations in the finished water of these systems. The agency's level of concern for chlorate ion is 370 ppb. During the ICR, four water treatment plants had average chlorate ion levels above the agency's level of concern and represented 0.5% of the ICR population ( 621,000 persons). o " One treatment plant serving 218,000 persons had average chlorate ion concentrations of 0.69 mg/ L. This corresponds to 0.17% of the ICR population; 98 percent of this ICR population received finished water with average chlorate ion concentrations at or below 0.2 mg/ L; 93 percent received finished water with average chlorate ion concentration at or below 0.1 mg/ L; and over 99 percent receives finished water below the Agency's level of concern of 0.37 mg/ L. o " 1 percent of the ICR population ( 1,260,000 persons) is exposed to chlorate concentrations at or greater than the 90th percentile concentration of 0.24 mg/ L, while, 6.5 percent ( 8,490,000 persons) is exposed to chlorate concentrations at or greater than the median concentration of 0.11 mg/ L. o " The best way for these systems to lower the level of chlorate ion in their finished water is to implement the simple measures explained above."

No separate cancer dietary risk assessment for chlorate in drinking water ( lifetime average concentration estimated at 0.1 mg/ L) was conducted. The cancer dietary risk assessment is based on the chronic ( non cancer) dietary risk assessment for the General U. S. Population The cancer dietary risk assessment for chlorate in drinking water is below the Agency's level of concern ( i. e., % cPAD less than 100). Page 58 of 141 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway  Conventional Pesticides All residential ( non occupational) risk estimates for inorganic chlorates, as active or inert ingredients in conventional pesticide products used in residential environments, are below the Agency's level of concern ( i. e., Margin of Exposures ( MOEs) are greater than the Level of Concern ( LOC) of 100). These uses are considered to be short term only due to the episodic uses associated with homeowner products. Since the episodic nature of residential exposure is inconsistent with the mechanism of chlorate carcinogenicity, a residential cancer risk assessment was not conducted.

6.3.1 Home Uses <IP_ADDRESS> Sodium Chlorate ( 073301) as an active ingredient in conventional pesticide products  Short Term Residential Handler Exposure via Inhalation Route only There is the potential for exposure to sodium chlorate by residential handlers in outdoor residential settings during the application of conventional pesticide products containing sodium chlorate ( 073301) as the active ingredient. Sodium chlorate ( 073301) can be used as a non selective herbicide in outdoor residential environments as a spot treatment or edging treatment around patios, along fence lines, lawn edges, around foundations, underneath or around wood decks, and in cracks and crevices of driveways. Residential handler exposure scenarios are considered to be short term only due to the episodic uses associated with homeowner products. Although there is the potential for dermal exposure by residential handlers, sodium chlorate is an inorganic salt, therefore, significant absorption of sodium chlorate through intact skin is not expected. Hence, a short term risk assessment for residential handlers via the inhalation exposure route was conducted for sodium chlorate as the active ingredient in conventional pesticide products.

Although there is the potential for exposure to sodium chlorate in outdoor residential settings from entering areas previously treated with sodium chlorate ( 073301), as the active ingredient in conventional pesticide products, a residential postapplication exposure risk assessment for sodium chlorate was not conducted because:

° Although there is the potential for postapplication dermal exposure in residential settings, sodium chlorate is an inorganic salt, therefore, significant dermal absorption of sodium chlorate through intact skin is not expected. ° Postapplication inhalation exposure for sodium chlorate is not expected due to negligible vapor pressure. ° Postapplication exposure assessments for residential settings are not typically performed for spot treatments.

A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessment. Each assumption and factor is detailed below. In addition to these factors, Page 59 of 141 unit exposures were used to calculate risk estimates. Unit exposures were taken from PHED, ORETF studies, and one proprietary study. [ Note: Several of the assumptions and factors used for the assessment are similar to those used in the occupational assessment presented under Section 9.1. As such, only factors that are unique to the residential scenarios are presented here.] The assumptions and factors used in the risk calculations include:

C Due to the lack of chemical specific data, exposures from a scenario deemed similar might be used. As an example, mixer/ loader/ applicator data for hose end sprayers were used to assess sprinkler can applications. These application methods are believed to be similar enough to bridge the data.

C HED always considers the maximum application rates allowed by labels in its risk assessments. If additional information such as average or typical rates are available, these values also may be used to allow risk managers to make a more informed risk management decision.

C Residential risk assessments are based on estimates of what homeowners would typically treat, such as the size of a lawn, or the size of a garden. The factors used for the sodium chlorate assessment were from the Health Effects Division Science Advisory Council for Exposure Policy 12: Recommended Revisions To The Standard Operating Procedures For Residential Exposure Assessment which was completed on February 22, 2001 and on professional judgement. The daily volumes handled and area treated, used in each residential scenario, include:

° 1000 square feet when mixing/ loading/ applying liquids as a spot treatment with a lowpressure handwand and sprinkler cans; ° 1 gallon when applying with a RTU sprinkler can and trigger pump sprayer; and, ° 1000 square feet for granular formulation spot treatments.

Short term risks for residential handlers via the inhalation exposure route are presented below in Table <IP_ADDRESS>. All risks are below the Agency's level of concern ( i. e, Margin of Exposures ( MOEs) are greater than the Level of Concern ( LOC) of 100). The scenarios assessed represent worse case exposures and risks. It should also be noted that there were many other scenarios where medium to low PHED quality data were used to complete the assessment. Data quality should be considered in the interpretation of the uncertainties associated with each risk value presented. Page 60 of 141 Table <IP_ADDRESS>. Sodium Chlorate ( 073301)  Short Term Residential Inhalation Exposure1 Exposure Scenario ( Scenario #) Daily Area Treated2 Crop/ Target3 Application Rate4 Inhalation MOE5 Mixer/ Loader/ Applicators, Loader/ Applicators, & Applicators M/ L/ A liquids with a Low Pressure Handwand Sprayer ( 1) 1000 Spot/ edging treatment 23.7 3000 L/ A RTU liquid with a Trigger Pump Sprayer ( 2) 1 Spot/ edging treatment 0.196 87000 M/ L/ A liquids with a Sprinkler Can ( 3) 1000 Spot/ edging treatment 23.7 5200 Applying liquid with a RTU Sprinkler Can ( 4) 1 Spot/ edging treatment 0.27 710000 Applying granules by Hand ( 5) 1000 Spot/ edging treatment 12 370 L/ A granules with a Belly Grinder ( 6) 1000 Spot/ edging treatment 12 2800 L/ A granules with a Push type Spreader ( 7) 1000 Spot/ edging treatment 12 200000 1 Residential exposures assessments do not include PPE.

2 Amount treated is presented in ft2/ day, except for Scenario # s 2 and 4 which are presented in gallons/ day. ( Standard EPA/ OPP/ HED values).

3 Crops and use patterns are from label extractions ( Appendix 1), BEAD's LUIS reports, and the Sodium Chlorate Use Closure Memo ( J. Guerry, 8/ 5/ 04; 10/ 13/ 04; 11/ 15/ 04).

4 Ranges of application rates are based on values from label extractions ( Appendix 1), BEAD's LUIS reports, and the Sodium Chlorate Use Closure Memo ( J. Guerry, 8/ 5/ 04;

10/ 13/ 04; 11/ 15/ 04). Application rates upon which the analysis is based are presented as lb ai/ 1000 ft2, except for Scenario # s 2 and 4 which are presented in lb ai/ gallon.

5 Inhalation MOE = Oral NOAEL ( 30 mg/ kg/ day) / Daily Inhalation Dose. HED LOC for MOE is 100. Page 61 of 141 <IP_ADDRESS> Sodium Chlorate ( 873301) as an inert ingredient in conventional pesticide products  Short Term Residential Postapplication Exposure via Incidental Oral Route only There is the potential for postapplication exposure in outdoor residential settings from entering areas previously treated with conventional pesticide products containing sodium chlorate ( 873301) as an inert ingredient. Hence, a residential postapplication risk assessment was conducted. However, since these products are professionally applied, residential handler exposure is not of concern.

Sodium chlorate ( 873301) as an inert ingredient in herbicide formulation products can be applied professionally to residential sites. These conventional pesticide products contain < 1 % sodium chlorate and can be applied at rates no greater than 0.07 lb ( as sodium chlorate) per acre.

As an inert ingredient in herbicide formulations broadcast on residential sites, there is potential for children to have incidental oral exposures ( hand to mouth ( HTM), object to mouth( OTM), and soil ingestion ( SI)); however, residential postapplication exposures via dermal and inhalation routes are not of concern because:

° Although there is the potential for postapplication dermal exposure in residential settings, sodium chlorate is an inorganic salt, therefore, significant dermal absorption of sodium chlorate through intact skin is not expected.

° Postapplication inhalation exposure for sodium chlorate is not expected due to negligible vapor pressure.

A series of assumptions and exposure factors served as the basis for completing the residential postapplication risk assessments. Each assumption and factor is detailed below.

° Residential exposure and risk estimates are conducted assuming no personal protective equipment ( i. e., short sleeved shirt, shorts, shoes/ socks, and no respirator). ° Residential postapplication exposures are assessed on the day of pesticide application. ° 15 kg represents the body weight of a toddler ( 3 year old). ° 5% of the application rate has been used to calculate the day zero residue levels used for assessing risks from HTM behaviors. ° 20% of the application rate has been used to calculate the day zero residue levels used for assessing risks from OTM behaviors. ° 100% of the application rate has been used to calculate the day zero soil residue levels used for assessing risks from SI. ° Hand to mouth exposures are based on a frequency of 20 events/ hour and a surface area per event of 20 cm2 representing the palmar surfaces of three fingers; ° 50% saliva extraction factor for HTM exposures. ° OTM exposures are based on a 25 cm2 surface area. ° Exposure durations are expected to be 2 hours. Page 62 of 141 ° Soil residues are contained in the top 1 centimeter and soil density is 0.67 cm3/ gram.

Table <IP_ADDRESS> below shows the risk estimates for incidental oral exposures to sodium chlorate ( 877301) for children playing in treated areas following its application.

Table <IP_ADDRESS>. Short term Residential Postapplication Risk Estimates for Sodium Chlorate ( 873301)

Population Subgroup Scenario Route MOE Combined MOE Child Hand to Mouth Oral 29000 23000 Object to Mouth Oral 110000 Soil Ingestion Oral 8600000 6.3.2 Recreational Uses Recreational exposures are expected to be similar to, or in many cases, less than, those evaluated in Section 6.3.1 Home Uses; therefore, a separate recreational exposure assessment was not conducted.

6.3.3 Other ( Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for sodium chlorate. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift with specific products with significant risks associated with drift. Page 63 of 141 7.0 Aggregate Risk Assessments and Risk Characterization Evaluation of the hazard and exposure ( food, water, and residential) components for inorganic chlorates indicates the need to estimate potential risks for the following scenarios: Short term inhalation, screening level acute dietary ( food + water), chronic ( non cancer) dietary ( food + water), and cancer dietary ( food + water).

7.1 Short Term Aggregate Risk  Residential Handler Inhalation plus background ( chronic dietary ( food + water))

Table 7.1. Short Term Aggregate Risk Calculations Population Target Aggregate MOE 1 MOE food+ water 2 MOE inhalation 3 Aggregate MOE ( food+ water and residential) 4 Adult 100 1715 400 324 1 Inhalation MOE = Oral NOAEL ( 30 mg/ kg/ day) / Daily Inhalation Dose. HED LOC for MOE is 100. 2 MOE food+ water = [( Short Term oral NOAEL = 30 mg/ kg/ day)/( chronic dietary exposure food + water) Chronic dietary exposure food + water = 0.002730mg/ kg/ day( food) + 0.01476mg/ kg/ day( water) = 0.01749mg/ kg/ day 3 MOE inhalation = [( Short Term inhalation NOAEL = 30 mg/ kg/ day)/( high end inhalation residential exposure)] 4 Aggregate MOE ( food+ water and residential) = 1 ÷ [ [( 1 ÷ MOE food+ water) + ( 1 ÷ MOE inhalation)]]

7.2 Chronic ( non cancer) Dietary Risk  Food + Water Table 7.2. Summary of Chronic ( non cancer) Dietary ( food + water) Exposure and Risk for Inorganic Chlorates Population Subgroup a cPAD mg/ kg/ day % cPAD Food + Water Estimated at the Highest Annual Average ( 0.69 mg/ L) Food + Water Estimated at the 90th Percentile Annual Average ( 0.24 mg/ L) Food+ Water Estimated at the Median Annual Average ( 0.11 mg/ L)

General U. S. Population 0.03 58 26 17 All Infants (< 1 yr) 174 70 40 Children 1 2 yrs 100 53 39 Children 3 5 yrs 90 47 34 Children 6 12 yrs 60 30 21 Youth 13 19 yrs 43 20 14 Adults 20 49 yrs 52 23 14 Adults 50+ yrs 54 23 14 Females 13 49 yrs 52 23 14 a The values for the population with the highest risk for each type of risk assessment are bolded. Page 64 of 141 b The BMDL is 0.9 mg chlorate/ kg/ day. The level of concern for the Margin of Exposure ( MOE) is 30.

7.3 Cancer Dietary Risk  Food + Water No separate cancer dietary ( food + water) risk assessment was conducted. The chronic ( food + water) dietary risk assessment is protective for cancer for the General U. S. Population. ( See Table 7.2.) The estimated risk does not exceed our level of concern ( less than 100% cPAD).

Note: Sodium chlorate is a thyroid toxicant producing thyroid gland follicular cell hypertrophy in rats and mice following chronic exposures and some evidence of follicular cell tumors in rats. The lack of mutagenicity indicates that the thyroid tumors are induced by a non mutagenic mechanism. Therefore, for the purposes of this risk assessment, the Margin of Exposure ( MOE) approach is used to estimate inorganic chlorate cancer risk. Children are not expected to be more susceptible to chlorate induced thyroid effects than adults and the endpoint selected for the thyroid effects is protective for all populations, including children. Page 65 of 141 8.0 Cumulative Risk Characterization/ Assessment Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to inorganic chlorates and any other substances. However, available data indicate that there may be some interconversion between chlorate and chlorite in water, in the environment, and in the gut.

For the purposes of this tolerance action, EPA has not assumed that inorganic chlorates have a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ pesticides/ cumulative/. Page 66 of 141 9.0 Occupational Exposure/ Risk Pathway  Conventional Pesticide Products Only 9.1 Short/ Intermediate/ Long Term Handler Risk There is potential for occupational handler exposure to inorganic chlorates from: ( 1) the application of sodium chlorate ( 073301) as the active ingredient in conventional pesticide products used on both agricultural and commercial ( non agricultural) sites ( i. e., mixer/ loaders, applicators, flaggers, and mixer/ loader/ applicators); ( 2) the application of sodium chlorate ( 873301) as an inert ingredient in conventional pesticide products used on both agricultural and commercial ( nonagricultural sites ( i. e., mixer/ loaders, applicators, flaggers, and mixer/ loader/ applicators); and ( 3) the application of potassium chlorate ( 900583) as an inert ingredient in conventional pesticide products used in poultry premises.

With the addition of PPE ( dust/ mist respirator) or engineering controls ( enclosed cockpits or cabs), all occupational handler scenarios for the use of inorganic chlorates as an active or inert ingredient in conventional pesticides are below the Agency's level of concern ( i. e., Margin of Exposures ( MOEs) are greater than the Level of Concern ( LOC) of 100). Exposure durations are short and intermediate term only. Since the exposure durations for occupational handlers are inconsistent with the mechanism of chlorate carcinogenicity, an occupational cancer risk assessment was not conducted.

9.1.1 Sodium chlorate ( 073301) as the active ingredient in conventional pesticide products  Short/ Intermediate Term Occupational Handler Exposure via Inhalation Route only There is potential for occupational handler exposure to sodium chlorate from the application of sodium chlorate ( 073301) as the active ingredient in conventional pesticide products used on both agricultural and commercial ( non agricultural) sites ( i. e., mixer/ loaders, applicators, flaggers, and mixer/ loader/ applicators). Occupational handler scenarios were identified for which exposure to sodium chlorate is expected ( see Table 9.1.1).

Sodium chlorate is an agricultural defoliant/ desiccant and a commercial herbicide. Use patterns vary from short to intermediate term exposure durations. Occupational handlers may be exposed dermal and inhalation routes; however, sodium chlorate is an inorganic salt, therefore, significant absorption of sodium chlorate through intact skin is not expected. Hence, only short and intermediate term sodium chlorate risk assessment for occupational handlers via the inhalation exposure route was conducted.

Risk for most occupational handler baseline ( without a respirator) inhalation exposure scenarios do not exceed the Agency's level of concern ( i. e., Margin of Exposures ( MOEs) are greater than the Level of Concern ( LOC) of 100). However, occupational handler risks for some of the high end application rates ( 1032 and 523 lb ai/ A) did exceed the Agency's level of concern at baseline. Risk mitigation for these scenarios was accomplished with the addition of a dust/ mist respirator ( with an Page 67 of 141 80% reduction factor), or, for certain scenarios, with engineering controls ( enclosed cabs or cockpits).

No chemical specific handler exposure data are available and, therefore, the following data and assumptions were used to assess the subject handler exposures and risks:

C Occupational handler exposure estimates were based on surrogate data from: ( 1) the Pesticide Handlers Exposure Database ( PHED), and ( 2) Outdoor Residential Exposure Task Force ( ORETF).

C Average body weight of an adult handler is 70 kg because the toxicity endpoint values used for the assessments are appropriate for average adult body weight representing the general population. This is the case because none of the effects identified in the selected toxicity studies were sex specific.

C Exposure factors used to calculate daily exposures to handlers are based on applicable data if available. For lack of appropriate data, values from a scenario deemed similar enough by the assessor might be used. As an example, for sodium chlorate handler exposures, ORETF data for hose end sprayer equipment were used to assess sprinkling can applications. The nature of these application methods are believed to be similar enough to bridge the data.

C HED always considers the maximum application rates allowed by labels in its risk assessments. If additional information such as a different range of rates are available, these values also may be used to allow risk managers to make a more informed risk management decision.

C The typical occupational workday is assumed to be 8 hours.

C The daily area treated was defined for each handler scenario ( in appropriate units) by determining the amount that can be reasonably treated in a single day ( e. g. acres, square feet, or gallons per day). When possible, the assumptions for daily areas treated is taken from ExpoSAC SOP # 9: Standard Values for Daily Acres Treated in Agriculture which was completed on July 5, 2000. Assumptions for these scenarios, including further refinements based on HED estimates, are listed below.

Agricultural Scenarios S Aerial applications: 350 acres ( typical field crop assumption) for guar beans, southern peas, chili peppers ( for processing only), potatoes, ornamental gourds, and cucurbits ( grown for seed); 1200 acres ( high acreage crop assumption) for cotton, corn, rice, dry beans, sorghum, flax, safflower, sunflower, soybeans, wheat, and fallow land.

S Groundboom: 80 acres ( typical field crop assumption) for guar beans, southern peas, chili peppers ( for processing only), potatoes, ornamental gourds, and cucurbits ( grown for seeds); 200 acres ( high acreage crop assumption) for cotton, corn, rice, dry beans, sorghum, flax, safflower, sunflower, soybeans, wheat and fallow land. Page 68 of 141 S Flaggers: 350 acres.

Refinements into " typical field" and " high acreage" crops was performed with help from HED crop expert Bernard Schneider ( email from B. Schneider, 5/ 24/ 04).

Industrial/ Non Crop Sites S Rights of Way Sprayer and Handgun Sprayer: 5 acres per day;

S Low Pressure Handwand Sprayer: 2 acres per day;

Note: Although assessments for applications involving rights of way sprayers and low pressure handwands typically use a volume based approach for amount handled/ treated per day ( 1000 gallons and 40 gallons, respectively, from ExpoSAC Policy # 9), label specific application rates and their respective dilution factors for larger application settings are better represented by a daily unit area treated than a volume based approach. For example, the label specific application of 8 pints per 100 square feet [ EPA Reg. No. 7701 34] yields the application rate of 1032 lb ai in 2196 gallons of solution per acre. At this rate, the volumebased approach of 1000 gallons per day would have a worker treating approximately ½ acres per day. Because a rights of way sprayer would likely treat more than ½ acre per day, a daily unit area of 5 acres was used as more appropriate estimate.

S Belly grinder: 1 acre per day.

S Push type spreader: 5 acres per day S Groundboom and Tractor drawn Spreader: 40 acres per day. Page 69 of 141 Table 9.1.1. Sodium Chlorate ( 073301): Short and Intermediate Term Occupational Inhalation Exposure Exposure Scenario ( Scenario #) Daily Area Treated1 Crop/ Target2 Application Rate3 Inhalation MOE4 Mitigation Level5 Mixer/ Loader Mixing/ Loading liquids for Aerial application ( 1a) 1200 Cotton, Corn, Rice, Dry Beans, Grain Sorghum, Flax,

Safflower, Sunflower, Soybeans 7.5 190 Baseline Fallow Land, Wheat 6 240 Baseline 350 Chili Peppers ( for processing only), Potatoes 12.5 400 Baseline Ornamental Gourds, Cucurbits ( grown for seed) 6 830 Baseline Guar Beans, Southern Peas 7.5 670 Baseline Mixing/ Loading liquids for Groundboom application ( 1b) 200 Cotton, Corn, Rice, Dry Beans, Grain Sorghum, Flax,

Safflower, Sunflower, Soybeans 7.5 1200 Baseline Fallow Land, Wheat 6 1500 Baseline 80 Chili Peppers ( for processing only), Potatoes 12.5 1800 Baseline Ornamental Gourds, Cucurbits ( grown for seed) 6 3600 Baseline Guar Beans, Southern Peas 7.5 2900 Baseline 40 Industrial/ Non Crop Sites 1032 210 PPE  80% R 523 420 PPE  80% R 132 330 Baseline Mixing/ Loading liquids for Rights of

Way Sprayer application ( 1c) 5 Rights of Way & Industrial/ Non Crop Sites 1032 340 Baseline 523 670 Baseline 132 2700 Baseline Loading granules for Tractor drawn Spreader application ( 2) 40 Industrial/ Non Crop Sites 523 300 PPE  80% R 240 130 Baseline 161 190 Baseline Applicator Table 9.1.1. Sodium Chlorate ( 073301): Short and Intermediate Term Occupational Inhalation Exposure Exposure Scenario ( Scenario #) Daily Area Treated1 Crop/ Target2 Application Rate3 Inhalation MOE4 Mitigation Level5 Page 70 of 141 Aerial spray applications ( 3a) 1200 Cotton, Corn, Rice, Dry Beans, Grain Sorghum, Flax,

Safflower, Sunflower, Soybeans 7.50 3400 Engineering Control Fallow Land, Wheat 6 4300 Engineering Control 350 Guar Beans, Southern Peas 7.5 12000 Engineering Control Chili Peppers ( for processing only), Potatoes 12.5 7100 Engineering Control Ornamental Gourds, Cucurbits ( grown for seed) 6 15000 Engineering Control Groundboom spray applications ( 3b) 1200 Cotton, Corn, Rice, Dry Beans, Grain Sorghum, Flax,

Safflower, Sunflower, Soybeans 7.5 1900 Baseline Fallow Land, Wheat 6 2400 Baseline 350 Guar Beans, Southern Peas 7.5 4700 Baseline Chili Peppers ( for processing only), Potatoes 12.5 2800 Baseline Ornamental Gourds, Cucurbits ( grown for seed) 6 5900 Baseline 40 Industrial/ Non Crop Sites 1032 350 PPE  80% R 1200 Engineering Control 523 140 Baseline 2300 Engineering Control 132 540 Baseline 9200 Engineering Control Rights of Way Sprayer Applications ( 3c) 5 Rights of Way & Industrial/ Non Crop Sites 1032 110 Baseline 523 210 Baseline 132 820 Baseline Tractor drawn Spreader Applications ( 4) 40 Industrial/ Non Crop Sites 523 420 PPE  80% R 460 Engineering Control 240 180 Baseline Table 9.1.1. Sodium Chlorate ( 073301): Short and Intermediate Term Occupational Inhalation Exposure Exposure Scenario ( Scenario #) Daily Area Treated1 Crop/ Target2 Application Rate3 Inhalation MOE4 Mitigation Level5 Page 71 of 141 990 Engineering Control 161 270 Baseline 1500 Engineering Control Table 9.1.1. Sodium Chlorate ( 073301): Short and Intermediate Term Occupational Inhalation Exposure Exposure Scenario ( Scenario #) Daily Area Treated1 Crop/ Target2 Application Rate3 Inhalation MOE4 Mitigation Level5 Page 72 of 141 Flagger Flagging for Aerial Spray applications ( 5) 350 Various Agricultural Crops 12.5 1400 Baseline Mixer/ Loader/ Applicators & Loader/ Applicators M/ L/ A liquids with a Low Pressure Handwand Sprayer ( 6) 2 Industrial/ Non Crop Sites 1032 170 PPE  80% R 523 330 PPE  80% R 132 270 Baseline M/ L/ A liquids with a Handgun Sprayer ( 7) 5 Industrial/ Non Crop Sites 1032 230 Baseline 523 450 Baseline 132 1800 Baseline L/ A granules with a Belly Grinder ( 8) 1 Industrial/ Non Crop Sites 523 320 PPE  80% R 240 140 Baseline 161 210 Baseline L/ A granules with a Push type Spreader ( 9) 5 Industrial/ Non Crop Sites 523 110 Baseline 240 240 Baseline 161 360 Baseline 1 Amount treated is presented in acres/ day. ( Standard EPA/ OPP/ HED values).

2 Crops and use patterns are from label extractions ( Appendix 1), BEAD's LUIS reports, and the Sodium Chlorate Use Closure Memo ( J. Guerry, 8/ 5/ 04; 10/ 13/ 04; 11/ 15/ 04).

3 Ranges of application rates are based on values from label extractions ( Appendix 1), BEAD's LUIS reports, and the Sodium Chlorate Use Closure Memo ( J. Guerry, 8/ 5/ 04; 10/ 13/ 04;

11/ 15/ 04). Application rates upon which the analysis is based are presented as lb ai/ acre.

4 Inhalation MOE = Oral NOAEL ( 30 mg/ kg/ day) / Daily Inhalation Dose. HED LOC for MOE is 100.

5 Mitigation Levels Baseline: No respirator PPE  80% R: Dust/ mist respirator with an 80% reduction factor Engineering Control: Closed cockpit or cab Page 73 of 141 9.1.2 Sodium chlorate ( 873301) as an inert ingredient in conventional pesticide products  Short/ Intermediate Term Occupational Handler Exposure via Inhalation Route only There is potential for occupational handler exposure to chlorate from the application of sodium chlorate ( 873301) as an inert ingredient in conventional pesticide products used on both agricultural and commercial ( non agricultural) sites ( i. e., mixer/ loaders, applicators, flaggers, and mixer/ loader/ applicators). Occupational handler scenarios were identified for which exposure to sodium chlorate is expected ( see Table 9.1.2).

Herbicide formulations containing < 1% sodium chlorate ( 873301) as an inert ingredient may be professionally applied to agricultural and commercial ( non agricultural) sites at the maximum use rate of 0.07 lb ( as sodium chlorate) per acre. Use patterns vary from short to intermediate term exposure durations. Occupational handlers may be exposed dermal and inhalation routes; however, sodium chlorate is an inorganic salt, therefore, significant absorption of sodium chlorate through intact skin is not expected. Hence, only short and intermediate term sodium chlorate risk assessment for occupational handlers via the inhalation exposure route was conducted.

No chemical specific handler exposure data are available and, therefore, the following data and assumptions were used to assess the subject handler exposures and risks:

C Assumptions for daily area treated are taken from ExpoSAC SOP # 9: Standard Values for Daily Acres Treated in Agriculture ( July 5, 2000) or from professional judgement.

C Unit exposures are from the PHED Surrogate Exposure Guide ( August, 1998) or data from the Outdoor Residential Exposure Task Force ( ORETF).

C Baseline personal protective equipment ( PPE) represents ( in terms of inhalation exposure and risk) a worker without a respirator.

C Average body weight of an adult handler is 70 kg because the toxicity endpoint values used for the assessments are appropriate for average adult body weight representing the general population. This is the case because none of the effects identified in the selected toxicity studies were sex specific. Page 74 of 141 Table 9.1.2. Short/ Intermediate Term Occupational Inhalation Exposure Risk Estimates for Sodium Chlorate ( 873301) as an Inert Ingredient in Herbicide Formulations Exposure Scenario Unit Exposure Daily Area Treated Crop/ Target Application Rate Non Cancer MOE Mitigation Level Mixer/ Loader Mixing/ Loading liquids for Aerial application 0.0012 1200 Agricultural crops 0.07 21000 Baseline Mixing/ Loading liquids for Groundboom application 0.0012 350 Agricultural crops 0.07 71000 Baseline Mixing/ Loading liquids for Rights of Way Sprayer application 0.0012 5 Non agricultural sites 0.07 5000000 Baseline Mixing/ Loading liquids for Handgun Sprayer application 0.0012 100 Residential sites 0.07 250000 Baseline Applicator Aerial spray applications 0.000068 1200 Agricultural crops 0.07 370000 Engineering Control Groundboom spray applications ( open cab) 0.00074 350 Agricultural crops 0.07 120000 Baseline Rights of Way Sprayer Applications 0.0039 5 Non agricultural sites 0.07 1500000 Baseline Flagger Flagging for Aerial Spray applications 0.00035 350 Agricultural Crops 0.07 240000 Baseline Mixer/ Loader/ Applicators M/ L/ A liquids with a Low Pressure Handwand Sprayer 0.03 1 Residential sites 0.07 1000000 Baseline M/ L/ A liquids with a Handgun Sprayer 0.0018 5 Residential sites 0.07 3300000 Baseline M/ L/ A liquids with a Backpack Sprayer 0.03 1 Residential sites 0.07 1000000 Baseline Page 75 of 141 9.1.3 Potassium chlorate ( 900583) as an inert ingredient in conventional pesticide products  Short/ Intermediate Term Occupational Handler Exposure via Inhalation Route only There is potential for occupational handler exposure to potassium chlorate from the application of potassium chlorate ( 900583) as an inert ingredient in conventional pesticide products used in poultry premises. Occupational handler scenarios were identified for which exposure to potassium chlorate is expected ( see Table 9.1.3).

Potassium chlorate ( 900583) as an inert ingredient in airborne fungicide products can be applied in poultry premises. These conventional pesticide products contain < 20% potassium chlorate and can be applied at rates not greater than 0.01 lb ( as potassium chlorate) per 500 ft3.

Use patterns vary from short to intermediate term exposure durations. Occupational handlers may be exposed dermal and inhalation routes; however, potassium chlorate is an inorganic salt, therefore, significant absorption of potassium chlorate through intact skin is not expected. Hence, only short and intermediate term potassium chlorate risk assessment for occupational handlers via the inhalation exposure route was conducted.

No chemical specific handler exposure data are available and, therefore, the following data and assumptions were used to assess the subject handler exposures and risks:

C This risk calculation is assumed to be a very conservative estimate. It assumes that all the potassium chlorate ( no greater than 0.01 lb) is present in the air, and available for inhalation, following application of the airborne fungicide.

C Baseline PPE represents ( in terms of inhalation exposure and risk) a worker without a respirator.

C Exposure duration is estimated to be 1 minute per day.

C Adult inhalation rate for light activity is 16.6 l/ min.

C Average body weight of an adult handler is 70 kg because the toxicity endpoint values used for the assessments are appropriate for average adult body weight representing the general population. This is the case because none of the effects identified in the selected toxicity studies were sex specific.

Table 9.1.3. Short/ Intermediate Term Occupational Inhalation Exposure Risk Estimates for Potassium Chlorate ( 900583) as an Inert Ingredient Used in Airbourne Fungicides Exposure Scenario Application Rate Maximum Potential Airborne Concentration ( mg KClO3/ l) Non Cancer MOE Mitigation Level Airborne Application of Fungicide 0.01 lb/ 500 ft3 0.32 400 Baseline Page 76 of 141 9.2 Short/ Intermediate/ Long Term Postapplication Risk Postapplication exposures do not need to be included in the occupational risk assessment for inorganic chlorates. Although dermal and inhalation exposures are possible, these exposures are expected to be negligible due to the physical and chemical characteristics of inorganic chlorates.

10.0 Data Needs and Label Requirements 10.1 Toxicology 870.3465 28 Day Inhalation Study These data are needed to refine the need for additional PPE ( dust/ mist respirator) or engineering controls ( enclosed cockpit or cabs) to protect occupational handlers from potential inhalation exposure resulting from conventional agricultural use of sodium chlorate.

10.2 Residue Chemistry 860.1480 Magnitude of the Residue  Meat, Milk, Poultry, Eggs New ruminant and poultry feeding studies are required. 860.1650 Submittal of Analytical Reference Standards Submission of a reasonable amount of the analytical reference standards for sodium chlorate to the Pesticide Repository is required and replenishment of standards as requested by the repository.

10.3 Occupational and Residential Exposure Sodium chlorate ( 073301) end use product labels should be amended, as necessary, to include application rates in terms of lbs/ acre treated for clarification.

Unpublished References:

Benchmark Dose Analysis of Sodium Chlorate FCH Response in Rats: No DP Barcode, B. Daiss, 01/ 26/ 2005.

Chlorate Ion in Drinking Water, memo from Patricia Fair ( Office of Ground Water and Drinking Water Technical Support Center) to Jacqueline Guerry ( OPPTS/ OPP/ SRRD/ RB3), dated 08/ 10/ 2005.

Drinking Water Assessment of Sodium Chlorate as a Desiccant/ Defoliant on Food/ Feed Terrestrial Uses: D303556, S. Termes, 01/ 05/ 2005. Page 77 of 141 Incident Report: D310573, J. Blondell, 03/ 31/ 2005.

Inorganic Chlorates Dietary Exposure Assessment for the Reregistration Eligibility Decision: D303555. T. Morton, 01/ 26/ 2006.

Occupational and Residential Exposure Assessment for Sodium Chlorate ( 073301) as an Active Ingredient in Conventional Pesticides: D307365, M. Crowley, 06/ 13/ 2005.

Occupational and Residential Exposure Assessment for Inorganic Chlorates in Antimicrobial Pesticides: D312200, T. Leighton, 01/ 24/ 2005.

Occupational and Residential Exposure Assessment for Inorganic Chlorates as Inert Ingredients in Conventional Pesticides: D318045, M. Crowley, 06/ 13/ 2005.

Response to Sodium Chlorate Preliminary Risk Assessment, memo of OW to Jacqueline Guerry, SRRD, 10/ 20/ 2005.

Note: Residue Chemistry Considerations are addressed under Appendix C.

Published References:

AWWA Water Quality Division Disinfection Systems Committee, Committee Report: Disinfection at Large and Medium Size Systems, May 2000a, p 32 43.

AWWA Water Quality Division Disinfection Systems Committee, Committee Report: Disinfection at Small Systems, May 2000b, p 24 31.

Bolyard, M., Fair, P. S., and Hautman, D. P. " Sources of Chlorate Ion in US Drinking Water," Journal AWWA Vol 85( 9) 81 88, 1993.

Dohler, K. D., Wong, C. C., Von Zur Muhlen, A. ( 1979) The rat as a model for the study of drug effects on thyroid function: Consideration of methodological problems. Pharmacol. Ther. 5, 305 318 Gates, D. J. The Chlorine Dioxide Handbook. American Water Works Association, Denver, CO, 1998.

Gordon, G. G., Adam, L., and Bubnis, B. Minimizing Chlorate Ion Formation in Drinking Water When Hypochlorite Ion is the Chlorinating Agent. American Water Works Association Research Foundation, Denver, CO, 1995. Page 78 of 141 McClain, R. M. ( 1992). Thyroid gland neoplasia: non genotoxic mechanisms. Toxicol. Lett. 64/ 65, 397 408.

USEPA, 1996. National Primary Drinking Water Regulation: Monitoring Requirements for Public Drinking Water Supplies: Cryptosporidium, Giardia, Viruses, Disinfection Byproducts, Water Treatment Plant Data and Other Information Requirements. Final Rule. FR 61: 94: 24354 24388 ( May 14, 1996).

USEPA, 2000. ICR Auxiliary 1 Database. EPA 815 C 00 002. Office of Water, Cincinnati, OH, April 2000. Page 79 of 141 APPENDIX A TOXICOLOGY DATA REQUIREMENTS Test Technical Required Satisfied 870.1100 Acute Oral Toxicity . . . . . . . . . . . . . . . . . . . . . . 870.1200 Acute Dermal Toxicity . . . . . . . . . . . . . . . . . . . . 870.1300 Acute Inhalation Toxicity . . . . . . . . . . . . . . . . . . 870.2400 Primary Eye Irritation . . . . . . . . . . . . . . . . . . . . 870.2500 Primary Dermal Irritation . . . . . . . . . . . . . . . . . . 870.2600 Dermal Sensitization . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 Oral Subchronic ( Rodent) . . . . . . . . . . . . . . . . . . . . 870.3150 Oral Subchronic ( Non Rodent) . . . . . . . . . . . . . . . . 870.3200 21 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.3250 90 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.3465 28 Day Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . yes yes no no yes yes yes

no 870.3700a Developmental Toxicity ( Rodent) . . . . . . . . . . . . . 870.3700b Developmental Toxicity( Non rodent) . . . . . . . . . . . 870.3800 Reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes* yes**

870.4100a Chronic Toxicity ( Rodent) . . . . . . . . . . . . . . . . . 870.4100b Chronic Toxicity ( Non rodent) . . . . . . . . . . . . . . 870.4200a Oncogenicity ( Rat) . . . . . . . . . . . . . . . . . . . . . . 870.4200b Oncogenicity ( Mouse) . . . . . . . . . . . . . . . . . . . . 870.4300 Chronic/ Oncogenicity . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes* yes*** yes* yes* yes*

870.5100 Mutagenicity  Gene Mutation  bacterial . . . . . . . . 870.5300 Mutagenicity  Gene Mutation  mammalian . . . . . 870.5395 Mutagenicity  Erythrocyte Micronucleus . . . . . . . 870.5385 Mutagenicity  Bone Marrow Cytogenetics . . . . . . 870.5550 Mutagenicity  Unscheduled DNA Synthesis . . . . . 870.5275 Mutagenicity  Recessive lethal in Drosophila . . . . yes yes yes yes yes yes yes yes yes* yes* yes yes*

870.6100a Acute Delayed Neurotox. ( Hen) . . . . . . . . . . . . . . 870.6100b 90 Day Neurotoxicity Hen) . . . . . . . . . . . . . . . . . 870.6200a Acute Neurotoxicity. Screening Battery ( Rat) . . . . . 870.6200b 90 Day Neurotoxicity Screening Battery ( Rat) . . . . . 870.6300 Develop. Neurotoxicity . . . . . . . . . . . . . . . . . . . no no no no no

870.7485 General Metabolism . . . . . . . . . . . . . . . . . . . . . 870.7600 Dermal Penetration . . . . . . . . . . . . . . . . . . . . . . yes no yes*

Special Studies for Ocular Effects . . . . . . . . . . . . . . . . . . . . . . . Acute Oral ( Rat) . . . . . . . . . . . . . . . . . . . . . . . . . . . Subchronic Oral ( Rat) . . . . . . . . . . . . . . . . . . . . . . . Six month Oral ( Dog) . . . . . . . . . . . . . . . . . . . . . . . no no no

 Not Applicable * Chlorate published study ** Chlorite published study *** The 2 year NTP ( DRAFT NTP Report 2004) study in the rat satisfies this requirement. No toxicity was seen in the subchronic study in dogs administered sodium chlorate by oral gavage except for emesis at the highest dose of 360 mg/ kg/ day.

APPENDIX B TOXICOLOGY STUDIES The executive summaries of tox studies presented in the sodium chlorate toxicology profile are provided below. Page 80 of 141 Acute Toxicity The acute oral LD50 of potassium chlorate has been reported to be 1870 mg/ kg in rats and the lowest oral lethal dose in rats was 7000 mg/ kg, in rabbits 2000 mg/ kg and in dogs 1200 mg/ kg ( Cosmetic Ingredient Review Panel, 1995)

The published literature provides numerous references to sodium chlorate poisoning. In one report ( Helliwell & Nunn, 1979), 14 cases of deliberate and accidental sodium chlorate poisonings in individuals ( males and females) ranging in age from 3 55 years old are described. In one case a 48 year old female died after 20 hours of accidentally ingesting 15 g of sodium chlorate. Death is described occurring from massive intra vascular hemolysis and acute renal failure. Recovery from sodium chlorate poisoning was low even with medical intervention. The clinical features of sodium chlorate poisonings in these cases were nausea and vomiting, cyanosis, abdominal pain, diarrhea, dyspnea. In the patients who died, a " constant necropsy finding was a chocolate discoloration of the blood and viscera due to staining by bilirubin and methemoglobin".

The acute toxic effects of potassium chlorate are summarized in the 1995 Cosmetic Ingredient Review Panel, 1995. The toxic dose of potassium chlorate is often reported to be 5 g with the lethal adult dose being 15 35 g. Mortality of a child has been reported after ingestion of 1 g of potassium chlorate. Human chlorate ingestion can produce gastritis, a late toxic nephritis, hemolysis, methemoglobinemia, hemoglobinuria and acute renal failure. The toxic effects of potassium chlorate appear cumulative because of the slow excretion of the chlorate ion; repeated 1 g ingestions have been fatal. Dermal irritation and burns have been reported in industrial uses. Use of potassium chlorate in toothpastes may have caused inflammation and bleeding of the gums.

In a case of severe chlorate poisoning of a 26 year old female who ingested 150 200 grams of sodium chlorate, methemoglobinaemia was described as the early symptom of intoxication ( Steffen and Seitz, 1981). Methemoglobin was converted to hematin. The patient was deeply cyanotic when admitted to hospital approximately 5 hours after ingesting the material. After extensive gastric lavage and administration of methylene blue and ascorbic acid intravenously, 7.4 grams of sodium chlorate were excreted in the urine. The patient voided clear urine initially, turning dark brown becoming muddy before it completely subsided, the result of renal failure. After the renal failure, the patient required several weeks of hemodialysis. Renal function was absent for 10 days and recovered slowly and the patient was discharged after 3 months. Liver function was only moderately disturbed. Serum tranasaminases were elevated during the first 10 days. Bilirubin was only slightly elevated for 3 weeks.

Subchronic Toxicity 870.3100 90 Day Oral Toxicity  Rat In a subchronic oral toxicity study ( MRID 40444801), Sprague Dawley CD rats ( 15/ sex/ group) were dosed with technical grade sodium chlorate ( 100% a. i., white granular solid) gavage at 0 Page 81 of 141 ( distilled water), 10, 40, 100, or 1000 mg/ kg/ day for 90 consecutive days. Body weight gain was lower in females of all dosed groups compared to controls which had abnormal body weight gain. The body weights of males were minimally lower ( not statistically significant) in the two highest dose groups. The most notable effects of sodium chlorate dosing were on the hematological parameters. At the 1000 mg/ kg/ dose, hemoglobin concentration, hematocrit, red blood cell counts were statistically significantly decreased, and reticulocyte count was statistically significantly increased in females. In males, only the hematocrit was statistically significantly decreased at the highest dose tested ( HDT). The adrenal weight was depressed in both males and females at the HDT. Histological lesions were detected in all groups but with no apparent dose relationship. The LOAEL derived from this study was 1000 mg/ kg/ day based on the hematological effects and the NOAEL was 100 mg/ kg/ day. This study is considered Acceptable/ guideline.

In a published study ( Kurokawa et al, 1985) it was reported that administration of 1% sodium or potassium chlorate in the drinking water ( 654 686 mg/ kg/ day) to male F344 rats for 25 weeks produced significant decrease in mean body weights compared to the controls. This dose was the maximum tolerated dose based on a 6 week screening study at 0.25, 0.5, 1 and 2% doses in drinking water. Relative kidney weights of the potassium chlorate treated rats were significantly increased over the control group, suggesting renal toxicity.

Studies were conducted to determine the toxicity of chlorine dioxide ( 0, 1, 10, 100, 1000 mg/ L) and its conversion products chlorite and chlorate ( 10, 100 mg/ L) in drinking water in rats. After 9 month treatment the osmotic fragility of the red blood cells ( RBC) was decreased in all treatment groups, while a decreased blood glutathione was only observed in the chlorite/ chlorate groups. At 2, 4 and 6 months, no significant hematologic changes were noted in treated rats compared to control. After 9 month RBC counts, hematocrit and Hb were decreased in all treatment groups. Chlorine dioxide, chlorite and chlorate administered chronically in drinking water for 3 months inhibited the incorporation of 3H thymidine into nuclei of rat testes. This inhibition was observed in the liver of the chlorite groups and in the kidney of 100 mg/ L chlorine dioxide treatment. The incorporation in small intestinal nuclei was increased in 10 and 100 mg/ L chlorine dioxide and in 10 mg/ L chlorite groups. Rat body weight was decreased in all groups after 10 and 11 months ( Abdel Rahman et al. 1984) Page 82 of 141 EPA/ PATHOLOGY ASSOCIATES Study In a published study conducted by USEPA Risk Reduction Engineering Laboratory/ Environmental Monitoring Systems Laboratory in Cincinnati, Ohio and by Pathology Associates in Ohio ( McCauley et al, 1995), Sprague Dawley rats ( 10/ sex/ group) were exposed to sodium chlorate in the drinking water at concentrations of 0 ( distilled water control), 48 mM saline ( sodium chloride) control, 3.0 mM sodium chlorate, 12 mM sodium chlorate or 48 mM sodium chlorate for 90 days. The final sodium concentration was 48.0 mM for each group except for the distilled water control. At the end of 90 day exposure animals were sacrificed and organs were collected for gross pathological and histopathological examination. Blood was collected for clinical and hematological evaluation.

During the course of chlorate exposure, no behavioral or clinical abnormalities were noted and there were no compound related deaths. The water consumption was 100 g/ kg/ day for the distilled water control group males and the mid dose group males. The other male groups consumed 20 to 30% more. The water consumption for the females was 133, 167, 172, 163, and 200 g/ kg/ day for the distilled water control, saline control, low, mid and high dose groups, respectively. Based on the water consumption, the mean delivered doses were calculated to be 0.36 mM ( 30 mg), 1.2 mM ( 100 mg), and 6.14 mM ( 510 mg) chlorate/ kg/ day for the low, midand high dose males and 0.5 ( 42 mg), 1.9 ( 158 mg), and 9.6 mM ( 797 mg) chlorate/ kg/ day for the low, mid and high dose females, respectively. Treatment related effects were conspicuous in the high dose group. These included significant body weight reduction throughout the exposure group in both sexes, significant decreases in male relative organ weights of the heart, kidneys and liver with relative brain and testes weights increased, significant declines in female relative weights of adrenals, thymus and spleen with significant brain weight increased, significant decreases in clinical chemistry parameters: ALT, AST, calcium, creatine, and phosphorus and an increase in the serum cholesterol. Calcium and creatinine also declined in the mid dose group, serum BUN levels were decreased in the low dose females. The biological relevance of the clinical chemistry changes in all chlorate groups was considered doubtful, since most of the values were within the normal reference ranges. There was a significant decrease in hematocrit concentration and red and white blood cell counts in the high dose animals while females of this group exhibited a trend towards decreased erythrocyte and hematocrit values. Histopathologically, thyroid colloid depletion was noted in both control and treated animals in a dose related manner and was characterized by an increased number of smaller follicles which were lined by a prominent cuboidal epithelium but devoid of colloid. The control group had an incidence of 30% with a minimal to mild severity while those in the mid and high dose groups exhibited a 100% incidence level with a moderate to marked severity. The authors cite a published study ( Harrington and Shertzer, 1985) which demonstrates the effects of chlorine dioxide on the bioavailability of iodide in drinking water and diet. In that paper, it was concluded that chlorine dioxide in drinking water oxidizes iodide to a reactive form which binds to tissues of the digestive tract while with dietary chow it converts iodide to a less easily absorbed by organification to dietary constituents. According to current study authors " these findings suggest a possible mechanism by which chlorate, a by product of chloride dioxide degradation, may Page 83 of 141 accentuate colloid depletion due to this anti thyroid effect of reducing iodide availability". The study authors concluded that based on the biologically significant changes noted in the mid and high dose groups of both sexes ( thyroid colloid depletion) and hematological effects at the high dose, the LOAEL is 1.20 mM ( 100 mg chlorate)/ kg bw/ day in males and 1.9 mM ( 158 mg chlorate)/ kg bw/ day for females and the NOAEL is 0.36 mM ( 30 mg chlorate/ kg bw/ day in males) and 0.50 mM ( 42 mg chlorate/ kg bw/ day for females).

EPA/ NTP Studies In a 21 day oral toxicity study ( NTP 1999a and 1999b), B6C3F1 mice and Fisher 344 rats ( 10/ sex/ dose) were exposed to sodium chlorate in the drinking water at 0, 125, 500, 1000 or 2000 mg/ L . Measured consumption was 0, 22, 43, 173 or 348 mg/ kg/ day for male mice, 0, 20, 44, 94, 192 or 363 mg/ kg/ day for female mice; 0, 20, 36, 77 or 170 mg/ kg/ day for male rats and 0, 21, 38, 73, 152 or 338 mg/ kg/ day for female rats. In mice, sodium chlorate had no effect on survival, body weights, clinical signs, water consumption, hematology parameters, methemoglobin concentration, or organ weights of either sex. There were no gross or microscopic lesions that were considered to be due to sodium chlorate treatment. In rats, sodium chlorate had no effect on survival, body weights, clinical signs or water consumption. A moderate to severe neutropenia was observed in both sexes on day 4 and 22. Very mild decreases in erythrocyte counts, hemoglobin, and hematocrit were considered not to be biologically significant. The only gross or microscopic lesion that was considered to be treatment related was a minimal to mild follicular cell hyperplasia of the thyroid gland seen in males at 500 mg/ L or greater and in females at 250 mg/ L or greater. The thyroid gland was considered to be a target organ for sodium chlorate toxicity in the rat.

In a published study conducted by USEPA National Health and Environmental Effects Research Laboratory and the NTP National Institute of Environmental Health Sciences in North Carolina ( Hooth et al, 2001), to evaluate development of thyroid lesions in rodents exposed to sodium chlorate in the drinking water, male and female F344 rats and B6C3F 1 mice ( 10/ group) were exposed to sodium chlorate in drinking water at 0, 0.125, 0.25, 1 or 2 g/ L for 21 days ( NTP study) . In another test, male and female rats ( 10/ group) were exposed at 0, 0.125, 1 or 2 g/ L for 4, 21 or 90 days ( NTP study). Additional male rats ( 10/ group) were exposed to 0, 0.001, 0.01, 0.1, 1 or 2 g/ L for 90 days ( EPA study). Mean compound consumption at these water concentrations was estimated by the reviewer to be 0.112, 1.12, 11.2, 112, and 225 mg/ kg/ day for the males and 0.16, 1.6, 16.0, 160, 320 mg/ kg/ day for the females based on water consumption values reported in the McCauley et al, 1995 article. Additional female rats and female mice ( 6/ group) were exposed to 0, 0.500, 1, 2, 4, or 6 g/ L for 105 days ( EPA study) ( 82, 165, 330, 660, 990 estimated mg/ kg/ day). Animals were observed daily and moribund animals were necropsied. Prior to necropsy, a blood sample was collected from animals treated for 4, 21 or 90 days and the serum was separated and frozen ( NTP study). Complete necropsies were performed on all animals and tissues of interest were removed, examined macroscopically, and fixed in 10% neutral buffered formalin. Fixed thyroid tissues were processed by routine methods to 5 um paraffin sections and stained with hematoxylin and eosin for histological examination by light Page 84 of 141 microscopy. The thyroids were examined for the presence of colloid depletion, follicular cell hypertrophy, and follicular cell hyperplasia.

Total serum triiodothyronine ( T 3 ) and thyroxine ( T 4 ) concentrations were determined as well as the thyroid stimulating hormone ( TSH) concentrations. Serum T 3 and T 4 levels were decreased significantly and TSH levels increased significantly in male and female rats after 4 days of treatment with 1.0 or 2.0 g/ L sodium chlorate and after 21 days of treatment with 2.0 g/ L. TSH levels also increased significantly in male rats after 21 days of treatment with 1.0 g/ L. Serum T 3 and T 4 levels were comparable to controls in male and female rats after 90 days of treatment, but TSH levels were increased in both sexes.

Thyroid alterations were initially diagnosed using standard published methods. According to this method, follicular cell hyperplasia and severe colloid depletion were present in all male and female F344 rats following 21 days of treatment with 1.0 g/ L treatment of sodium chlorate or greater. The severity of the lesions was the same in all animals. The present study utilized a " novel" method of diagnosis detailed in the article. According to this diagnosis colloid depletion and hypertrophy were present in male and female rats treated with 0.125 g/ L or greater, but were statistically significant ( p< 0.05) at 0.5 g/ L treatments. In males, the incidence and severity of thyroid alterations was greater at 1.0 g/ L Sodium chlorate than 2.0 g/ L, but in females, it was the opposite. After 90 days of treatment, significant colloid depletion was diagnosed in most treated male F344 rats but the incidences were similar in all groups. Colloid depletion was more significant in female rats treated with 1.0 or 2.0 g/ L sodium chlorate for 21 days than for 105 days. Significant colloid depletion was diagnosed in female F344 rats treated for 105 days at sodium chlorate concentrations of 2.0 g/ L or greater.

Follicular cell hypertrophy was present in most male and female rats after 21 or 90 days of sodium chlorate treatment, but the incidence did not increase in a concentration dependent manner. The incidence of follicular cell hypertrophy was higher in female rats treated with 1.0 or 2.0 g/ L sodium chlorate for 21 days than for 105 days. At 105 days, 6.0 g/ L of sodium chlorate caused a significant increase in the incidence of follicular cell hypertrophy. Complex papillary infolding or branching was more frequent in thyroid tissue from male rats at the 1.0 and 2.0 g/ L concentrations. The area of the thyroid tissue affected in male rats increased in a concentration dependent manner following 90 days of treatment. Thyroid alterations were not present in male or female mice.

It was concluded by the study authors that sodium chlorate treatment induced a concentration dependent increase in the incidence and severity of thyroid follicular cell hyperplasia. Colloid depletion and hypertrophy were the most sensitive histopathological indicators of sodium chlorate exposure in male F344 rats at 21 and 90 days, although the hypertrophy response was variable when concentration dependency was evaluated. Male rats were more sensitive to the effects of sodium chlorate treatment than female rats. Decreases in serum hormone levels observed in the present study may suggest that sodium chlorate has the potential to induce acute detrimental neurodevelopmental effects. Hormone and histological alterations may reflect a transient Page 85 of 141 physiologic response of the thyroid to sodium chlorate exposure. It is not known whether the histological effects of sodium chlorate are reversible following cessation of chemical exposure. Alternatively, the concentration dependent increase in incidence and severity of thyroid follicular cell hyperplasia may indicate an increased likelihood of the lesions progressing to cancer. The study authors did not provide a NOAEL for the effects of sodium chlorate treatment in rats, but based on the article, a NOAEL may be derived at 0.5 g/ L ( 28 mg/ kg/ day in males and 40 mg/ kg/ day in females) based on colloid depletion and follicular cell hyperplasia at a LOAEL of 1.0 g/ L ( 112 mg/ kg day for males and 160 mg/ kg/ day for females) sodium chlorate after 90 days of exposure. Chlorate is related in structure to bromate and perchlorate, both are thyroid toxicants and chemical oxidants.

870.3150 90 Day Oral Toxicity  Dog In a subchronic oral toxicity study ( MRID 40460402), beagle dogs ( 4/ sex/ group) were dosed with technical grade sodium chlorate ( 100% a. i., white granular solid) by oral gavage at dose levels of 0 ( distilled water), 30, 60, or 360 mg/ kg/ day for 90 consecutive days. All dogs survived the treatment. Clinical signs were sporadic, one female in the high dose group exhibited emesis during the first three weeks of dosing and two other females developed yellow/ brown watery stool. There were no effects on hematological parameters, clinical chemistry ( including methemoglobin), opthalmology or histopathology. Urinalysis was not conducted. The adrenal, and spleen weights, and organ/ body weight ratios in males were increased at the HDT. Only the spleen weights in females were increased at the HDT. Hypercellularality of the bone marrow of males appeared to increase in severity and number of animals responding as the dose was increased. The effect was less pronounced in females. None of these effects are sufficiently adverse to establish an effect level. The dose levels used in this study were too low to detect unequivocal toxicity. At higher dose levels in a range finding study, emesis occurred, and it was stated that emesis would have precluded a study at higher dose levels. The LOAEL derived from this study is > 360 mg/ kg/ day and the NOAEL is 360 mg/ kg/ day ( the HDT). This study is considered Acceptable/ guideline ( The study was originally classified supplementary because of missing data regarding incomplete histopathological examination of mammary tissues, and number of animals examined opthalmologicaly was not stated. These do not impact the acceptability of the study).

In a sub acute exposure study in dogs, doses of 200 to 326 mg/ kg/ day of sodium chlorate administered daily by intubation as 50 ml of 6% solution to 8 dogs for 5 days caused reduction of packed cell volume, hemoglobin and red blood cells ( Heywood et al, 1972 cited in the Final Draft Drinking Water Criteria, Clement International Corp., 1994). A consistent increase in plasma urea concentration was also observed, suggesting some compromise of renal function. Two animals that received 308 or 326 mg/ kg/ day suffered appetite loss, body weight decline and appearance of blood in their urine or feces. One of the animals ( not specified) died after 4 days of exposure. Postmortem examination of both animals revealed typical signs of chlorate poisoning, including cyanotic kidney surface and evidence of necrosis and hemolysis in the kidney. Five of the 8 animals displayed tissue pathology indicative of hemolysis such as Kupffer cells containing Page 86 of 141 brown pigment. Hematological values of red blood cells were reduced in all animals. The highest methemoglobin concentrations was seen in the animal that died. Methemoglobinemia was not correlated with changes in the other hematological parameters.

870.4100a Chronic Toxicity  Mouse In the NTP ( DRAFT NTP Report 2004) study presented in a draft form, Groups of 50 male and 50 female B6C3F 1 mice were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/ L sodium chlorate for 2 years ( equivalent to average daily doses of approximately 40, 80, and 160 mg/ kg per day to male mice and 30, 60, and 120 mg/ kg per day to female mice). Survival of exposed mice was similar to that of the control groups. Mean body weights of exposed females were generally less ( 88 90% of controls in all treated females at week 104) than those of the control groups after week 84 of the study. Water consumption by exposed mice was generally similar to that by controls throughout the study ( 3.4 4.2 g/ male/ day; 2.5 3.6 g/ female/ day). There was a positive trend in the incidences of pancreatic islet cell adenoma or carcinoma ( combined) in female mice ( 0/ 46, 2/ 47, 2/ 49, 4/ 49). Thyroid gland follicular cell hypertrophy was significantly increased in 2,000 mg/ L females ( 3/ 48, 2/ 50, 5/ 49, 14/ 50). The incidences of bone marrow hyperplasia were significantly increased in all exposed groups of females ( 14/ 50, 28/ 50, 29/ 50, 31/ 50).

Carcinogenicity 870.4200a Carcinogenicity Study  rat A 2 year bioassay to determine the potential of sodium chlorate to induce thyroid tumors in laboratory animals ( rats and mice) has been recently reported in a draft form. A final report of this study is expected during 2005. In the NTP ( 2004) study summarized in Section 4.4.3 of the main body of this memo, there was some evidence of thyroid gland follicular cell carcinogenicity in male rats which may be attributed to the imbalance of thyroid hormones ( reduced T 3 and T 4 and elevated TSH) seen in these studies as a result of exposure to high doses of sodium chlorate. Current EPA HED policy considers nonmutagenic pesticides that induce elevated levels of TSH and thyroid follicular cell tumors in the rat as not likely to be cargencogenic to humans at doses that do not alter rat thyroid hormone homeostasis.

In a published study, sodium chlorate and potassium chlorate were tested for potential promoting effect in a two stage rat renal carcinogenesis assay ( Kurokawa et al, 1985). In this assay three groups of 15 male F344 rats were given N ethyl N hydroxyethylnitrosamine ( EHEN) at 0.05% concentration in the drinking water for the first 2 weeks during the initiation phase. Subsequently, one group of the initiated rats was treated with 1% sodium chlorate, second group with 1% potassium chlorate and the third group with distilled water for 25 weeks. Three other groups ( controls) were treated similarly, except that distilled water was given in the initiation phase. Page 87 of 141 These doses were selected on the basis of 6 week study where male F344 rats were administered the test compounds in the drinking water at 0, 0.25%, 1% or 2% concentrations and found that 1% concentration was the maximum tolerated concentration for both test compounds. All animals survived the treatment in the main study. The mean final body weight in the sodium chlorate and potassium chlorate groups with or without initiation were significantly lower ( p < 0.05 0.01) than the controls. The mean intake of drinking water ( water consumption) in rats treated with sodium chlorate or potassium chlorate was slightly lower than the controls and it ranged from 19.2  22.1 ml/ day/ rat. The mean consumption of sodium chlorate was 654 686 mg/ kg/ day for sodium chlorate and 667 to 675 mg/ kg/ day for the potassium chlorate. At the end of promotion phase, rats were sacrificed and kidneys examined histopathologically for renal neoplastic lesions which were classified as dysplastic foci and renal cell tumors. The mean absolute kidney weights were comparable in all groups, but the mean relative kidney weights given the sodium chlorate or potassium chlorate with or without initiation were significantly ( p< 0.01 0.05) lower than the control group. There were no statistically significant differences in the incidences in the mean number of the types of the kidney lesions between the test compounds and the distilled water treated rats initiated with EHEN, it was concluded that sodium chlorate and potassium chlorate did not have a promoting effect in rat renal carcinogenesis assay ( Kurokawa et al, 1985).

870.4200b Carcinogenicity ( feeding)  Mouse A 2 year bioassay to determine the potential of sodium chlorate to induce thyroid tumors in laboratory animals ( rats and mice) has been recently reported in a draft form ( DRAFT NTP Report 2004). A final report of this study is expected during 2005. As summarized above, there was a positive trend in the incidences of pancreatic islet cell adenoma or carcinoma ( combined) in female mice ( 0/ 46, 2/ 47, 2/ 49, 4/ 49). This finding was considered to be equivocal evidence.

870.7485 Metabolism  Rat The pharmacokinetics of chlorite ion and chlorate ion was studied in rats ( Abdel Rahman et al, 1982, 1984b and 1985). Two groups of male Sprague Dawley rats ( 4/ group) were administered orally 36Cl labeled potassium chlorate or potassium chlorite at concentrations of 10 mg/ L. In one group, blood samples were collected at selected times between 5 minutes and 48 hours after dosing and assayed for 36Cl activity and at 72 hours, the rats were killed and the tissue distribution of 36Cl activity was determined. In the other group, expired air, urine, and fecal samples were obtained for up to 72 hours and assayed for 36Cl activity. Maximum blood 36Clconcentrations occurred 2 hours after dosing with potassium chlorite and 1 hour after treatment with potassium chlorate. Potassium chlorate elimination from the blood was biphasic, with half lives of 6 hours for the first phase and 36.7 hours for the second phase. Potassium chlorite elimination was monophasic with a half life of 35 hours. After 72 hours, 36Cl activity was highest in whole blood following potassium chlorite administration and highest in plasma following potassium chlorate administration. The highest measured radioactivity after the plasma in the chlorate treated rats was in the whole blood followed by stomach, testes, lungs, kidneys, Page 88 of 141 skin, duodenum, spleen, brain, packed cells, ileum, carcass, liver, and bone marrow. 36Clconcentration in the plasma was 2 ng/ g, and in bone marrow was less than 0.5 ng/ g. Significantly high levels of 36Cl activity after dosing with both compounds were found in the testes. Seventy two hours after dosing with potassium chlorite, 35 percent of the dose was eliminated in the urine and 5% in the feces. Approximately 43% of the potassium chlorate dose was eliminated by the urinary and feces routes. 36Cl was not detected in exhaled air after dosing with either compound. The administered chlorate was eliminated as chlorate ( ca. 13% of the administered dose), chlorite ( ca. 4% of the administered dose) and chloride ( ca. 20% of the administered dose). The authors suggest that the high levels of 36Cl activity in the testes after 72 hours suggest possible pharmacological action at this site.

870.7485 Metabolism  Dog A metabolism study in dogs is reported in the National Research Council 1980 report on Drinking Water and Health and is summarized in California EPA/ OEHHA 2002 Report ( OEHHA, 2002). In this study, when seven female dogs were given 500 mg/ kg doses of chlorate in 500 mL water, 55 70 % of the dose was excreted in the urine in the first 6 hours. By 24 to 48 hours, 76 99% of the dose had been excreted unchanged in urine. The chlorate concentration in the blood peaked at 2 hours and decreased to little or none by 24 hours. Page 89 of 141 Special/ Other Studies Sodium Chlorate as an Inhibitor of Protein Sulfation Sodium chlorate has been described as a non toxic inhibitor of tyrosine sulfation ( Beinfeld, 1994). This property is utilized by biochemists to study peptide and protein synthesis, regulation of protein secretion and function ( Beinfeld, 1994; Mintz et al, 1994). Sodium chlorate is an in vitro inhibitor of ATP sulfurylase, the first enzyme in the biosynthesis of 3' phosphoadenosine 5' phosphosulfate which is the ubiquitous co substrate for sulfation ( Baeuerle and Huttner, 1986). Treatment of hybridoma derived cells and rat pheochromocytoma cell cultures with 1 mM sodium chlorate in a medium low in sulfate and sulfur containing amino acids resulted in more than 95% inhibition of protein sulfation as well as tyrosine and carbohydrate sulfation, but did not inhibit protein synthesis even after prolonged incubation. The authors concluded from this study that sodium chlorate " provides powerful tool for studying the biological significance of protein sulfation" ( Baeuerle and Huttner, 1986). The sulfation of polyethylene glycol 200 by the isolated perfused guinea pig liver was inhibited to about 60% by 10 mM of sodium chlorate in the plasma of the perfusate when the concentration of the sulfate ion was 1.18 mM, but in a low sulfate medium ( 0.1mM), the inhibition was almost complete ( 94%) ( Roy et al, 1988). Bile production from isolated perfused livers was not affected by the presence of sodium chlorate in this test, suggesting that chlorate is not a general liver poison according to the authors of this article ( Roy et al, 1988). When bovine aorta endothelial cells were cultured in a medium containing 3Hglucosamine 35S sulfate and various concentrations of sodium chlorate, cell growth and viability was not affected by 10mM chlorate and slight inhibition at 30 mM ( Humphries and Silbert, 1988). Chlorate concentrations of 10 mM and greater resulted in significant inhibition of sulfation of chondroitin. With 30 mM chlorate the inhibition was 90% for chondroitin and 65% for heparin, but 3H glucosamine incorporation was not inhibited. Removal of chlorate from the cell culture medium restored the rapid resumption of sulfation.

Chlorate Toxicity in Humans In a series of studies by Lubbers et al ( 1984a, 1984b), investigating the physiological impact of human ingestion of chlorine dioxide and its water breakdown byproducts ( chlorite and chlorate), reported no effects attributable to the daily consumption of water treated with these products for periods extending to 12 weeks. In these studies normal healthy adult male volunteers ( 21 35 years of age) divided into groups ( 10/ group) drank daily 500 mL of water containing 5 ppm of chlorite, or chlorate or distilled water ( control) for 12 weeks. Subjects were monitored weekly during the 12 week treatment and for 8 additional weeks by conducting physical medical examination, checking vital signs. Special chemical tests for thyroid function, antibody formation, hepatoglobin and methemoglobin concentrations, and blood morphology were repeated regularly to assess physiological functions in areas " suspected to be most sensitive to oxidative challenge". Subjective evaluations of the palatability of the water disinfectant solutions were recorded at regular intervals. A total of 47 quantitative chemical parameters derived from an extensive battery of blood and urine testing were recorded regularly. Abnormalities in the qualitative blood and urine analysis were few and appeared to be randomly distributed. In several cases, Page 90 of 141 statistically significant trends ( mean corpuscular hemoglobin levels) were associated with treatment, but " none of these were judged to have physiological consequence". The authors concluded that the possibility that these trends might achieve proportions of clinical importance cannot be ruled out, but " within the limits of the study, the relative safety of oral ingestion of chlorine dioxide, and its metabolites, chlorite and chlorate, was demonstrated". In their second study ( Lubbers et al, 1984b), 3 male healthy adult volunteers deficient in glucos 6 phosphate dehydrogenase and receiving 500 mL of water containing 500 ppm of sodium chlorite did not experience any adverse effects demonstrating the safety of this chemical to a susceptible group of the human population.

These data were not deemed useful for dose response evaluation and were not relied upon in the risk assessment.

Chlorates Mechanism of Toxicity The mode of action in sodium chlorate poisoning in humans is summarized by Smith and Oehme ( 1991) in their review article. The chlorate ion initially reacts with thiol groups on the red blood cells and may cause it to lyse, similar to nitrite ions, converting the hemoglobin to methemoglobin. The chlorate ion is a strong oxidizer, and it oxidizes the ferrous ion of the hemoglobin molecule to ferric ion to result in methemoglobin formation. With chlorate, in contrast to nitrite, a concentration dependent lag phase was seen before methemoglobin was formed ( Singelmann et al, 1984). Sodium chlorate ranked the least potent among six direct acting methemoglobin agents ( French et al, 1995). These were ( most to least) p dinitrobenzene > o dinitrobenzene > copper = nitrite > chlorite > chlorate. The ranking was based on linear regression analysis of dose response data, the calculated dose expected to induce a given amount of methemoglobin formation and the calculated percentage methemoglobin response induced by mmole/ L of the agent in Dorset sheep erythrocytes. Calbarese et al, 1995 also investigated the potency of sodium chlorate to produce methemoglobin in mink erythrocytes and it was the least potent among six other chemicals ( anaphthol nitrite> copper> p dinitrobenzene> chlorite> o dinitrobenzene> chlorate).

Potassium chlorate incubated with washed erythrocytes from human venous blood ( 0.1 to 6.0 mmol/ L) caused a dose related increase in glutathione activity and mechanical fragility with a parallel increase in Heinz body formation ( Hopkins and Tudhope, 1974). There was also a close relationship between increased mechanical fragility and increased inhibition of glutathione peroxidase. Spontaneous hemolysis in this test was less than 10%.

The mechanism of chlorate poisoning was explored in a set of in vitro and in vivo experiments by Steffen and Wetzel ( 1993). They found that incubation of human erythrocytes with 5 mM sodium chlorate oxidized hemoglobin to methemoglobin after a lag period of approximately 60 minutes. When after different periods of contact with the 30 mM chlorate, samples of erythrocytes were washed free of the chlorate and incubated with methylene blue, reduction of methemoglobin was only partial during the first hour of incubation ( 8%) but became nil after 2 hours of incubation. Page 91 of 141 The catalytic reduction of methemoglobin by methylene blue was found to be dependent on the availability of NADPH formed in the pentose phosphate cycle. Therefore, an intact enzyme system in erythrocytes is required. Incubation of homeliest erythrocytes with 5 mM sodium chlorate showed that glucose 6 phosphate dehydrogenase and glyceraldehyde  3 phosphate dehydrogenase were most sensitive, whereas glutathione reductase was very stable. When human erythrocyte membranes ( devoid of hemoglobin) were incubated with 5 mM sodium chlorate, there was a rapid inactivation of glyceraldehyde  3 phosphate dehydrogenase when hemoglobin was added, but not in its absence. This suggests that sodium chlorate does not inactivate the membane bound glyceraldehyde  3 phosphate dehydrogenase, the key enzyme in the NADPHdependent methemoglobin reduction. Nearly all membrane proteins were affected by the hemoglobin catalyzed oxidation. Earlier work by Heubner and Jung, 1941 ( cited by Steffen and Wetzel, 1993) demonstrated that methemoglobin formation by chlorate was an autocatalytic reaction. Both the lag period and the rate were dependent on the actual methemoglobin concentration.

Steffen and Wetzel ( 1993) also explored the in vitro effects of chlorate on rabbit erythrocytes and compared them to the in vivo effects on methemoglobin formation in rabbits. It was discovered in 1888 by Cahn ( cited by Steffen and Wetzel, 1993) that rabbits do not develop methemoglobine anemia after chlorate administration. When rabbit erythrocytes were incubated with sodium chlorate at concentrations ranging from 7.5 to 75 mM, methemoglobin was formed in a dose dependent manner. Higher concentrations of the chlorate were needed for rabbit erythrocytes than for the human erythrocytes. No methemoglobin was formed after the oral administration of sodium chlorate ( 1000 mg/ kg body weight) in 50 mL water. The serum concentration of the chlorate was 10  20 mM for at least 12 hours. The highest concentration of the chlorate in the serum was reached after 90 minutes ( 16 ± 4.3 mM) and in the urine after 6 hours ( 246 ± 99 mM). The elimination half life was 20 hours. During 7 days of observation period there were no changes in serum values of urea, creatinine, aspartate and alanine aminotransferases. When the animals were killed at the end of the 7 day observation period and kidneys examined histologically, there were no pathologic findings detected, indicating lack of nephrotoxicity in the treated rabbits. Page 92 of 141 TOXICOLOGY REFERENCES UNPUBLISHED MRID: 40444801 Barrett, D. ( 1987) A Subchronic ( 3 Month) Oral Toxicity Study of Sodium Chlorate in the Rat Gavage: Final Report: Project No. 86 3112. Unpublished study prepared by Bio/ dynamics, Inc. 464 p.

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