Chlorine Dioxide Toxicology Disciplinary Chapter Case 4023 Timothy McMahon, Ph. D. Office of Pesticide Programs Antimicrobials Division U. S. Environmental Protection Agency 1200 Pennsylvania Avenue, NW Washington, DC 20460 April 5, 2006 Page 2 of 32 1.0 HAZARD CHARACTERIZATION Chlorine dioxide ( ClO2; CASRN 10049 04 4) is a yellow to reddish yellow gas at room temperature that is stable in the dark but is unstable in light. It is a strong oxidizing agent that under oxidant demand conditions is readily reduced to chlorite ( ClO2; CASRN 7758 19 2), another strong oxidizing agent, and to a lesser extent, chlorate. These substances are water soluble. Therefore, what exists in water or the stomach is a mixture of these chemical species ( i. e., chlorine dioxide, chlorite, and chlorate) and possibly their reaction products with the gastrointestinal contents. As a result, chlorine dioxide and chlorite are characterized together in this report because studies conducted with chlorite are relevant to characterizing the toxicity of chlorine dioxide.

Chlorine dioxide is used as an alternative to chlorine for disinfection of municipal drinking water. It is also registered for use on a variety of sites, including swimming pool water systems, fruits and vegetables, wood protection, household uses, and metalworking cutting fluids. The Antimicrobials Division has previously supported a Section 18 use of chlorine dioxide on stored potatoes for control of late blight and silver scurf. However, a formal risk assessment is necessary to support renewal of the Section 18 as well as existing and potential new use patterns. The ADTC evaluated the existing database and selected toxicity endpoints for dietary and non dietary exposures to chlorine dioxide. For this evaluation, one human study is included, the dermal sensitization study.

Other uses of chlorine dioxide include bleaching textiles and wood pulp for paper manufacturing, antimicrobial applications, and reducing loads of adsorbable organic halogenated compounds in industrial effluents. Chlorite is also used for etching printed circuit boards.

The acute toxicity of chlorine dioxide ( 79% ai.) is moderate by the oral route ( LD50 = 292 mg/ kg [ males]; 340 mg/ kg [ females]; Toxicity Category II). The acute toxicity of chlorine dioxide using sodium chlorite as the test material ( 80% ai.) is considered minimal by the dermal route ( LD50 > 2000 mg/ kg; Toxicity Category III). By the inhalation route using sodium chlorite as the test material ( 80.6%), chlorine dioxide was moderately toxic ( LC50 = 0.29 mg/ L). For primary eye irritation, chlorine dioxide ( 2% a. i.) was a mild irritant ( Toxicity Category III), but the technical test material was not used. For primary dermal irritation, sodium chlorite ( 80% a. i.) was a primary irritant ( Toxicity Category II). For dermal sensitization, there are no acceptable animal studies for chlorine dioxide or sodium chlorite.

The subchronic toxicity database is considered adequate for characterizing the subchronic oral and inhalation toxicity of chlorine dioxide/ chlorite. Daniel et al. ( 1990) exposed groups of 10 male and 10 female Sprague Dawley rats to chlorine dioxide in drinking water for 90 days at concentrations of 0, 25, 50, 100, or 200 mg/ L ( 0, 2, 4, 6, or 12 mg/ kg day chlorine dioxide for males and 0, 2, 5, 8, or 15 mg/ kg day chlorine dioxide for females). The LOAEL for this study is 25 mg/ L ( 2 mg/ kg day) based on a significant increase in incidence of nasal lesions. In a study by Harrington, et al. ( 1995a), Crl: CD ( SD) BR rats ( 15/ sex/ group) were administered doses of 0, 10, 25, or 80 mg/ kg day sodium chlorite ( equivalent to 0, 7.4, 19, or 60 mg chlorite/ kg day, respectively) via gavage for 13 weeks. The NOAEL for this study is 7.4 mg/ kg day, and the Page 3 of 32 LOAEL is 19 mg/ kg day, based on stomach lesions and increases in spleen and adrenal weights. Dalhamn ( 1957) and Paulet and Desbrousses ( 1970, 1972, and 1974) are co critical inhalation toxicity studies included in the subchronic toxicity database for chlorine dioxide/ chlorite. A NOAEL of 0.1 ppm (~ 0.28 mg/ m3) was selected from Dalhamn ( 1957) and a LOAEL of 1.0 ppm (~ 2.8 mg/ m3) was selected from Paulet and Desbrousses ( 1970, 1972, and 1974), based on respiratory distress and decreased body weights observed in exposed animals.

One developmental toxicity study conducted using rats ( Orme et al., 1985) is included in the developmental toxicity database for chlorine dioxide and chlorite. In Orme et al. ( 1985), a NOAEL of 20 mg/ L ( 3 mg/ kg/ day) was established based on neurodevelopment effects in the offspring of rats exposed to chlorine dioxide in drinking water.

A two generational reproductive toxicity study ( CMA, 1996) was conducted with sufficient numbers of animals of both sexes and examined numerous endpoints. The study is acceptable and consistent with EPA testing guidelines that were in effect at the time of the study. The NOAEL for this study is 35 ppm ( 2.9 mg/ kg day chlorite) and the LOAEL is 70 ppm ( 5.9 mg/ kg day chlorite) based on lowered auditory startle amplitude and altered liver weights in two generations.

Chlorine dioxide has not been formally assessed for carcinogenic potential. The following studies do not definitively characterize the carcinogenicity of chlorine dioxide, and additional studies may be required.

One subchronic study ( Daniel et al., 1990) examined the effects of administration of chlorine dioxide to groups of male and female Sprague Dawley rats ( 10/ sex/ dose) at dose levels of 0, 25, 50, 100, or 200 mg/ L for 90 days in drinking water. A significant increase in the incidence of nasal lesions ( goblet cell hyperplasia and inflammation of nasal turbinates) was found at all dose levels tested. The significance of these findings is uncertain as they have not been observed in other long term studies of chlorine dioxide.

The potential for chlorine dioxide to induce proliferative epidermal hyperplasia was examined by Robinson et al. ( 1986). Groups of five dorsally shaved female SENCAR mice were placed in chambers filled with 0, 1, 10, 100, 300, or 1,000 ppm liquid chlorine dioxide. The animals were exposed 10 minutes/ day for 4 days. A significant increase in interfollicular epidermal thickness was observed in the 1,000 ppm group, but not at the lower concentrations. Increases in total cell numbers and basal cell numbers in skin sections were observed in both the 300 and 1,000 ppm groups. In a follow up study, groups of 40 mice were immersed in 0 or 1,000 ppm chlorine dioxide for 10 minutes; animals ( 5/ group) were killed 1, 2, 3, 4, 5, 8, 10, or 12 days postexposure A significant increase in interfollicular epidermis thickness was observed at all time periods, with the highest values at 10 and 12 days post exposure. The authors concluded that even short term dermal exposure to high concentrations of chlorine dioxide is capable of inducing hyperplastic responses in the mouse skin.

In a carcinogenicity study by Kurokawa et al. ( 1984), chlorite did not show increases in tumor incidences in rats and mice; this study is considered inadequate for assessing human carcinogenicity because the exposure was for less than a lifetime, a high incidence of Sendai virus Page 4 of 32 was found in the rats, and mortality was high in the mouse control group because of excessive fighting.

Data on the mutagenicity of chlorine dioxide exist in the open scientific literature as well as within the Agency's database of submitted studies. In Miller et al. ( 1986) negative effects were reported in Salmonella strains TA98 and TA100 from a 400 fold drinking water concentrate of chlorine dioxide, whereas a 4000 fold concentrate was mutagenic to strain TA98 only in the absence of metabolic activation. In Accession No. 265867, chlorine dioxide was positive for forward mutations under non activated conditions ( dose related from 3.2 24.3 µ g/ ml) and activated conditions ( 48.3 µ g/ mL) in L5178Y/ TK cells, positive for structural chromosome aberrations under non activated and activated conditions ( 10, 15, and 50 µ g/ ml), and negative for increased transformed foci up to cytotoxic levels. In vivo micronucleus and bone marrow chromosomal aberration assays in Swiss CD 1 mice administered 0.1  0.4 mg chlorine dioxide via gavage for 5 consecutive days were negative, as was a sperm head abnormality assay in B6C3F1 mice administered 0.1  0.4 mg via gavage for 5 consecutive days ( 0, 3.2, 8, and 16 mg/ kg day) ( Meier et al., 1985).

Neurotoxicity of chlorine dioxide has been observed. In the two generation reproduction toxicity study ( CMA 1996), significant changes were observed in maximum response in startle amplitude and absolute brain weight in F1 rat pups at a dose of 3 mg/ kg/ day. In the Orme et al. ( 1985) developmental toxicity study, neurobehavioral deficits in offspring were observed also at a dose of 14 mg/ kg/ day administered to maternal rats.

Information regarding the pharmacokinetics of chlorine dioxide and chlorite is predominantly derived from oral studies in laboratory animals. Chlorite ( ClO2) does not persist in the atmosphere either in ionic form or as chlorite salt. The rapid appearance of 36Cl in plasma following oral administration of chlorine dioxide ( 36ClO2) or chlorite ( 36ClO2) has been shown in laboratory animals ( Abdel Rahman et al., 1984). In rats, absorbed 36Cl ( from 36ClO2 or 36ClO2 sources) is slowly cleared from the blood and is widely distributed throughout the body ( Abdel Rahman et al., 1984). Chlorine dioxide rapidly dissociates, predominantly into chlorite ( which itself is highly reactive) and chloride ion ( Cl), ultimately the major metabolite of both chlorine dioxide and chlorite in biological systems ( Abdel Rahman et al., 1984). Urine is the primary route of elimination, predominantly in the form of chloride ion ( Abdel Rahman et al., 1984). Additional pharmacokinetic studies of chlorine dioxide and chlorite should be designed to examine mechanisms of absorption and metabolic changes that might account for observed neurodevelopment effects.

2.0 TOXICOLOGY DATA REQUIREMENTS With the exception of the acute toxicity studies and the reproductive toxicity study ( CMA, 1996), the Antimicrobials Division has relied upon available published scientific data to characterize the hazard of chlorine dioxide, as the data are from peer reviewed journals and also are consistent with regard to the type of toxicity and effect levels observed. These same data are also found in the recently published Toxicological review for chlorine dioxide and chlorite in the EPA's IRIS database ( USEPA, 2002) and in the Agency for Toxic Substances and Disease Registry's Page 5 of 32 Toxicological Profile for chlorine dioxide ( ATSDR, 2004). The Agency considers these hazard data adequate to support reregistration eligibility of chlorine dioxide unless otherwise noted.

3.0 DATA GAPS For chlorine dioxide/ chlorite, carcinogenicity data are lacking . As noted in the recent IRIS toxicological review, no studies have examined the carcinogenic potential of chlorine dioxide. Based on the registered uses of chlorine dioxide in swimming pool water systems and as a metalworking fluid, additional data addressing the carcinogenic potential of chlorine dioxide are required.

4.0 HAZARD ASSESSMENT 4.1 Acute Toxicity Adequacy of database for Acute Toxicity: The acute toxicity of chlorine dioxide ( 79% ai.) is considered severe by the oral route ( LD50 = 292 mg/ kg [ males]; 340 mg/ kg [ females]; Toxicity Category II). The acute toxicity of sodium chloride ( 80% ai.) is considered moderate by the dermal route ( LD50 > 2000 mg/ kg; Toxicity Category III). For primary eye irritation, chlorine dioxide ( 2% a. i.) was a mild irritant ( Toxicity Category III). For primary dermal irritation, sodium chloride ( 80% a. i.) was a primary irritant ( Toxicity Category II). For dermal sensitization, there are no acceptable animal studies for chlorine dioxide or sodium chlorite. The acute toxicity data for chlorine dioxide and sodium chlorite are summarized below in Table 1.

Table 1. Acute Toxicity Profile for Chlorine Dioxide/ Sodium chlorite Guideline Number Study Typea / Test substance (% a. i.) MRID Number/ Citation Results Toxicity Category 870.1100 ( § 81 1) Acute oral ( 79% chlorine dioxide) 43558601 LD50 = 292 mg/ kg ( males) LD50 = 340 mg/ kg ( females) II 870.1200 ( § 81 2) Acute dermal ( 80% sodium chlorite) 40168704 LD50 > 2000 mg/ kg III 870.1300 ( § 81 3) Acute inhalation ( 80.6% sodium chlorite) 42484101 LC50 = 0.29 mg/ L II 870.2400 ( § 81 4) Primary eye irritation ( 2% chlorine dioxide) 43441903 Mild irritant III 870.2500 ( § 81 5) Primary dermal irritation ( 80% sodium chlorite) 40168704 Primary irritant II 870.2600 ( § 81 6) Dermal sensitization No acceptable sensitization study available.

a The available acute studies are all graded as acceptable. An acceptable dermal sensitization study is not available in Page 6 of 32 the database.

4.2 Subchronic Toxicity Adequacy of database for Subchronic Toxicity: The subchronic toxicity database includes oral toxicity studies conducted by Daniel et al. ( 1990) and Harrington et al. ( 1995a) as well as inhalation toxicity studies conducted by Dalhamn ( 1957) and Paulet and Desbrousses ( 1970, 9172, and 1974). These data are considered adequate for characterizing the subchronic toxicity of chlorine dioxide/ chlorite.

870.3100 Subchronic ( Oral) Toxicity  Chlorine dioxide   Rat Daniel et al. ( 1990) exposed groups Sprague Dawley rats ( 10/ sex/ dose) to chlorine dioxide in drinking water for 90 days at concentrations of 0, 25, 50, 100, or 200 mg/ L ( equivalent to 0, 2, 4, 6, or 12 mg/ kg day chlorine dioxide for males and 0, 2, 5, 8, or 15 mg/ kg day chlorine dioxide for females, respectively). No exposure related deaths were reported. Exposure to 200 mg/ L resulted in significant reductions in terminal body weights and body weight gain ( 26%  29% lower than controls). Significant reductions in water consumption were observed in the males exposed to   50 mg/ L and in females exposed to   25 mg/ L; decreases in food consumption were also observed in the 200 mg/ L males. Absolute liver weights were decreased in males at   50 mg/ L, and absolute spleen weights were decreased in females at   25 mg/ L. No consistent alterations in hematology were observed. Serum lactate dehydrogenase and aspartate aminotransferase levels were decreased and serum creatinine levels were increased in the males exposed to 100 or 200 mg/ L; no other alterations in serum chemistry parameters were consistently found. A significant increase in incidence of nasal lesions ( goblet cell hyperplasia and inflammation of nasal turbinates) was found in males exposed to   25 mg/ L and in females at   100 mg/ L. The study authors postulated that these lesions were likely caused by inhalation of chlorine dioxide vapors at the drinking water sipper tube or from off gassing of the vapors after drinking rather than ingestion of the drinking water. Thus, 25 mg/ L ( 2 mg/ kg day) can be described as a lowest observed adverseeffect level ( LOAEL), but the toxicological significance of the nasal lesions is not known. Respiratory tract pathologies have not been reported in other oral studies and the effect may possibly be an artifact of treatment.

870.3100 Subchronic ( Oral) Toxicity  Sodium chlorite   Rat In a 14 day range finding study ( Harrington, et al., 1995), rats were administered gavage doses of sodium chlorite in the range of 25 to 200 mg/ kg/ day ( equivalent to 18.6 to 149.2 mg chlorite/ kg/ day). One exposure related death was observed in each sex in the 200 mg/ kg/ day group on treatment days 2 and 3. No treatment related deaths occurred in the groups receiving chlorite doses   56 mg/ kg/ day.

In the main study performed by Harrington et al. ( 1995a) Crl: CD ( SD) BR rats ( 15/ sex/ group) were administered doses of 0, 10, 25, or 80 mg/ kg day sodium chlorite ( equivalent to 0, 7.4, 19, or 60 mg chlorite/ kg day, respectively) via gavage for 13 weeks. In the 60 mg/ kg day group, four animals died during treatment and both sexes exhibited salivation, significantly decreased Page 7 of 32 erythrocyte counts, and decreased total serum protein levels. The males receiving 60 mg/ kg day exhibited significantly decreased hematocrit and hemoglobin levels and increased methemoglobin and neutrophil levels, whereas in the females, methemoglobin levels were significantly decreased. Possible reasons for the decrease in methemoglobin in females, which is unexpected considering the known oxidative effects of sodium chlorite, were not discussed by the study authors. The following observations were also noted in the 60 mg/ kg day group: morphological changes in erythrocytes in some animals of both sexes, significant increases in relative adrenal and spleen weights in the males, increases in absolute and relative spleen and adrenal weight in females, and increases in relative liver and kidney weights in the females. Body weight and food consumption were not affected by treatment. Histopathologic alterations in the 60 mg/ kg day group included squamous epithelial hyperplasia, hyperkeratosis, ulceration, chronic inflammation, and edema in the stomachs of seven males and eight females. At 19 mg/ kg day, the following alterations were reported: occasional salivation in two males, hematologic alterations in males ( increased methemoglobin levels and neutrophil count, decreased lymphocyte count), increases in absolute and relative spleen and adrenal weights in females, and histologic alterations in the stomach of two males, similar to those seen in the high dose group. The increase in absolute spleen weight was attributed to morphological alterations in erythrocytes, but no explanation was provided for alterations in absolute adrenal weight. The NOAEL in this study is determined to be 7.4 mg/ kgday and the LOAEL is 19 mg/ kg day for stomach lesions and increases in spleen and adrenal weights in rats subchronically treated with sodium chlorite.

870.3465 Subchronic ( Inhalation) Toxicity  Chlorine dioxide   Rat Dalhamn ( 1957) reported the results of several inhalation studies in laboratory animals. In one study, a single 2 hour inhalation exposure of four rats to a chlorine dioxide concentration of 260 ppm ( 728 mg/ m3) resulted in pulmonary edema and nasal bleeding. In another study, rats were subject to 3 minute exposures to decreasing concentrations of airborne chlorine dioxide from 3,400 to 800 ppm ( from 9,520 to 2,240 mg/ m3) once a week for 3 consecutive weeks. Respiratory distress was reported in three rats subjected and bronchopneumonia was observed in two of these rats. In a third rat study, repeated exposure to approximately 10 ppm ( 28 mg/ m3) of chlorine dioxide ( 4 hours/ day for 9 days in a 13 day period) resulted in rhinorrhea, altered respiration, and respiratory infection. No indications of adverse effects were seen in rats exposed to approximately 0.1 ppm ( 0.28 mg/ m3) of chlorine dioxide 5 hours / day for 10 weeks.

870.3465 Subchronic ( Inhalation) Toxicity  Chlorine dioxide   Rat Paulet and Desbrousses ( 1970, 1972, and 1974) conducted a series of studies in which laboratory animals were exposed to atmospheres of chlorine dioxide. Nasal discharge and localized bronchopneumonia ( with desquamation of alveolar epithelium) were noted in rats exposed to an airborne concentration of 10 ppm ( 28 mg/ m3), 2 hours/ day for 30 days. Another group of rats exposed to a concentration of 5 ppm ( 14 mg/ m3) exhibited similar, but less severe, respiratory tract effects. Bronchial inflammation and alveolar congestion and hemorrhage were observed in Page 8 of 32 rats exposed to 2.5 ppm ( 7 mg/ m3), 7 hours/ day for 30 days. Alveolar congestion and hemorrhage were also seen in rabbits following inhalation exposure to 2.5 ppm ( 7 mg/ m3), 4 hours/ day for 45 days. In a group of rats and rabbits sacrificed 15 days after exposure termination, recovery from the pulmonary lesions was apparent ( Paulet and Desbrousses 1970). Vascular congestion and peribronchiolar edema were noted in the lungs of rats exposed to a concentration of 1 ppm ( 2.8 mg/ m3), 5 hours/ day, and 5 days/ week for 2 months ( Paulet and Desbrousses 1972). A LOAEL of 1 ppm for respiratory effects was identified in this study.

4.3 Prenatal Developmental Toxicity Adequacy of database for Prenatal Developmental Toxicity: Two developmental toxicity drinking water studies are included in the toxicity database for chlorine dioxide/ sodium chlorite. In one, chlorine dioxide was administered to ( Orme et al., 1985) while in the other study, rabbits were administered sodium chlorite. The studies are acceptable and consistent with EPA testing guidelines.

870.3700 Prenatal Developmental Toxicity ( Oral) Study   Rat In a study conducted by Orme et al. ( 1985) designed to assess toxicity of chlorine dioxide, female Sprague Dawley rats ( 13 16/ dose) were administered drinking water containing 0, 2, 20, or 100 mg/ L ( 0, 1, 3, and 14 mg/ kg/ day estimated doses) chlorine dioxide from 2 weeks prior to mating until day 21 post partum, and the effects on brain development in pups examined. There were no significant effects of chlorine dioxide on body weight of dams or pups at any dose level tested. Depression of serum thyroxin ( T4) and increased serum triiodothyronine ( T3) were observed in pups at weaning at the 100 mg/ L ( 14 mg/ kg/ day) dose level. Neurobehavioral exploratory and locomotor activities were decreased in pups at the 14 mg/ kg/ day dose ( p = 0.08). These effects were not observed in pups at the 20 mg/ L dose level ( 3 mg/ kg). Pups administered chlorine dioxide by gavage at 14 mg/ kg/ day on post natal days 5 20 showed a larger depression of serum T4 levels and greater delays in development of exploratory and locomotor behavior activity. There were no apparent effects in maternal animals up to the 14 mg/ kg/ day dose level. The developmental toxicity NOAEL of 3 mg/ kg/ day was selected based on depression of serum T4 levels in pups from dosed maternal rats and delays in development of locomotor and exploratory behavior activity.

870.3700 Prenatal Developmental Toxicity ( Oral) Study   Rabbit In a developmental drinking water study ( MRID 41715701), time mated female New Zealand White rabbits ( 16 17/ dose) were administered sodium chlorite ( purity 80.58%) from gestation days 7 through 19 at 0, 200, 600, or 1200 ppm ( calculated intake 0, 12.2 13.8, 30.1 38.3, or 32.0 60.1 mg/ kg/ day). Mean intake of the test compound via the drinking water was consistent throughout the dosing period only at the lowest level, but was suppressed in a dose related fashion at the highest levels, especially over the first few days of dosing. These variations in Page 9 of 32 compound intake were considered to reflect problems in palatability of the preparations at high concentrations. There was no compound related mortality, but two doses had to be sacrificed in extremis for other ( incidental) reasons. The sole treatment related clinical effect was a doserelated increase in incidence of does with reduced fecal output during the dosing period, days 7 to 19, which was considered consistent with decreased food consumption. At necropsy, there were no abnormalities considered treatment related in survivors. Among gross findings in scheduled sacrifices were: pitted kidneys in two mid dose and one high dose animal; alopecia in two lowdose three mid dose, and two high dose does; and thoracic fluid in one low dose animal. No significant differences from control were observed in pregnancy rate, mean gavid uterine weight, or reproductive indices. Mean fetal weights were comparable in all groups. External, visceral, and skeletal examinations of all live fetuses revealed no major abnormalities which could be considered related to sodium chlorite treatment. An increased incidence of minor skeletal variants was observed among 600 and 1200 ppm fetuses, which was considered generally related to retardation and/ or delayed ossification, rather than structural abnormalities. No evidence of embryolethality, fetotoxicity, or teratogenicity was found. There was a slight effect on embryonic growth of mid and high dose levels, but no clear dose response was evident. The maternal toxicity NOAEL of 200 ppm ( 12 14 mg/ kg/ day) and LOAEL of 600 ppm ( 36 42 ppm) were selected based on decreases in feces, food consumption, and water intake. The developmental toxicity NOAEL of 200 ppm ( 12 14 mg/ kg/ day) and LOAEL of 600 ppm ( 36 42 mg/ kg/ day) were selected based on decreased fetal weight and skeletal retardation.

4.4 Reproductive Toxicity Adequacy of database for Reproductive: A two generation reproduction toxicity study was conducted by the Chlorine Dioxide Panel of the Chemical Manufacturers Association ( now called the American Chemistry Council) in 1996 and reviewed by the Agency's Office of Water. The CMA ( 1996) study was conducted with sufficient numbers of animals of both sexes and examined numerous endpoints. The study is acceptable and consistent with EPA testing guidelines that were in effect at the time of the study.

870.3800 Reproduction and Fertility Effects   Rat The Chemical Manufacturers Association ( CMA) conducted a two generation study to examine reproductive, developmental neurotoxicity, and hematologic endpoints in rats exposed to sodium chlorite ( CMA, 1996). Thirty male and 30 female Sprague Dawley rats of the OFA( SD) IOPSCaw strain ( F0) generation received drinking water containing 35, 70, or 300 ppm sodium chlorite for 10 weeks and were then paired ( 1M: 1F) for mating. A similar group received purified water and served as controls. Males were exposed throughout mating and then were sacrificed. Exposure for the females continued through mating, pregnancy, and lactation until necropsy following weaning of their litters. Sodium chlorite concentrations were adjusted downward during lactation to offset increases in the volume of water consumed so that a constant intake ( mg/ kg day) could be maintained. Twenty five males and females from each of the first 25 litters to be weaned in a treatment group were chosen to produce the F1 generation. The F1 pups were continued on the same treatment regimen as their parents. At approximately 14 weeks of age, they were mated to produce the F2a generation. Because of a reduced number of litters in the 70 Page 10 of 32 ppm F1 F2a generation, the F1 animals were re mated following weaning of the F2a to produce the F2b generation. Pregnant F1 females were allowed to litter and rear the F2a and F2b generations until weaning at postnatal day 21. Doses for the F0 animals were 0, 3, 5.6, and 20 and 0, 3.8, 7.5, and 28.6 mg/ kg day chlorite for males and females, respectively. For the F1 animals, doses were 0, 2.9, 5.9, and 22.7 mg/ kg day chlorite for the males and 0, 3.8, 7.9, and 28.6 mg/ kg day chlorite for the females. Body weight, food and water consumption, estrus cycle in the F0 and F1 rats, and hematology and T3 and T4 levels in the F1 rats ( blood samples collected from 1 male and 1 female from the first 20 F1 litters at age 25 days and another group at 13 weeks), gestation duration, litter size, pup sex, pup body weight, pup developmental landmarks, number alive/ dead pups in the F1 and F2 generations, total caudal sperm number and percent motile, morphology by computer assisted sperm motility analysis in the F0 and F1 rats, and organ weight and histopathology examination of the brain, pituitary gland, liver, adrenal gland, spleen, thymus, kidneys, and reproductive organs of all F0 and F1 controls and high dose animals were measured. An additional group of F1 pups was chosen for neurohistopathology on postnatal day 11 ( examination of the brain and spinal cord) or postnatal day 60 ( sensory ganglia, dorsal and ventral nerve roots, and several peripheral nerves and muscles). Another group of F1 rats was examined for neurotoxicological endpoints ( motor activity in a  Figure 8" Activity System and neuropathology on postnatal day 60, auditory startle in the SR Screening System, learning and memory retention in a water E maze). A functional observational battery ( FOB) was also conducted on the pups undergoing auditory and learning assessments. This group was composed of 2 males and 2 females from 20 litters, and exposure was discontinued after weaning. Reevaluation of the auditory startle response was conducted in 20 males and 20 females in the F2a and F2b generations.

There were reductions in water consumption, food consumption, and body weight gain in both sexes in all generations at various times throughout the experiment ( e. g., during pre mating, pregnancy, gestation, post weaning), primarily in the 70 and 300 ppm groups. The authors attributed these reductions to lack of palatability of the drinking water solution, but did not show data to support this contention. Significant alterations related to treatment at 300 ppm include reduced absolute and relative liver weight in F0 females and F1 males and females, reduced pup survival, and reduced body weight at birth and throughout lactation in F1 and F2 rats, lower thymus and spleen weight in both generations, lowered incidence of pups exhibiting normal righting reflex and with eyes open on postnatal day 15, alteration in clinical condition in F2 animals chosen for neurotoxicity, decrease in absolute brain weight for F1 males and F2 females, delay in sexual development in males ( preputial separation) and females ( vaginal opening) in F1 and F2 rats, and lower red blood cell parameters in F1 rats. The reported alterations in pup sexual maturation measures might be due to reduced pup body weight, but a definitive conclusion cannot be drawn. In the 70 ppm groups, reduced absolute and relative liver weight in F0 females and F1 males was observed. A significant decrease in maximum response to an auditory startle stimulus was noted in the 70 and 300 ppm groups on postnatal day 24, but not on postnatal day 60. Analysis of the 21E maze data by EPA personnel indicated possible alterations in learning behavior in the 70 ppm group, but the differences from the conclusions of the report could not be resolved.

The NOAEL for this study is 35 ppm ( 2.9 mg/ kg day chlorite) and the LOAEL is 70 ppm ( 5.9 Page 11 of 32 mg/ kg day chlorite) based on lowered auditory startle amplitude and altered liver weights in two generations.

4.5 Chronic Toxicity Adequacy of database for Chronic Toxicity: One chronic toxicity study, Haag ( 1949) is included in the toxicity database for chlorine dioxide. The study was limited because an insufficient number of animals were tested per group, pathology was conducted on a small number of animals, and it did not provide adequate evaluations of more sensitive parameters, which would have been more useful in the overall assessment of chronic toxicity.

870.4100 Chronic Toxicity ( Oral)   Rat In a chronic study by Haag ( 1949), groups of rats ( 7/ sex/ group) were exposed to 0, 1, 2, 4, 8, 100, or 1,000 mg/ L chlorite in the drinking water ( 0, 0.09, 0.18, 0.35, 0.7, 9.3, or 81 mg/ kg day) for 2 years. Animals exposed to chlorite concentrations of 100 or 1,000 mg/ L exhibited treatment related renal pathology, characterized by distention of the glomerular capsule and appearance of a pale pinkish staining material in the renal tubules. These effects were also observed in a group of animals administered sodium chloride at a concentration equimolar to 1,000 mg sodium chlorite/ L. The study author concluded that the renal pathology was a nonspecific salt effect, but this observation does not alter the observation that concentrations of 100 mg/ L or higher led to adverse effects. Based on renal effects, this study identifies a NOAEL of 8 mg/ L ( 0.7 mg/ kg day) and a LOAEL of 100 mg/ L ( 9.3 mg/ kg day).

4.6 Carcinogenicity Adequacy of database for Carcinogenicity: Robinson et al. ( 1986) assessed the potential for chlorine dioxide to induce proliferative epidermal hyperplasia, but these data are considered inadequate for characterizing the carcinogenicity of chlorine dioxide/ chlorite. A dermal carcinogenicity study ( Kurokawa et al., 1984), conducted to assess the ability of chlorite to act as a complete carcinogen, was considered inadequate because the exposure was for less than a lifetime, a high incidence of Sendai virus was found in the rats, and mortality was high in the mouse control group because of excessive fighting. These data are considered inadequate to assess the carcinogenicity of chlorine dioxide / chlorite in humans and additional studies may be required.

870.4200 Carcinogenicity ( Dermal)   Mouse The potential for chlorine dioxide to induce proliferative epidermal hyperplasia was examined by Robinson et al. ( 1986). Groups of five dorsally shaved female SENCAR mice were placed in chambers filled with 0, 1, 10, 100, 300, or 1,000 ppm liquid chlorine dioxide. The animals were exposed 10 minutes/ day for 4 days. A significant increase in interfollicular epidermal thickness was observed in the 1,000 ppm group, but not at the lower concentrations. Increases in total cell numbers and basal cell numbers in skin sections were observed in both the 300 and 1,000 ppm groups. Page 12 of 32 In a follow up study, groups of 40 mice were immersed in 0 or 1,000 ppm chlorine dioxide for 10 minutes; animals ( 5/ group) were killed 1, 2, 3, 4, 5, 8, 10, or 12 days post exposure. A significant increase in interfollicular epidermis thickness was observed at all time periods, with the highest values at 10 and 12 days post exposure. The authors concluded that even short term dermal exposure to high concentrations of chlorine dioxide is capable of inducing hyperplastic responses in the mouse skin.

870.4200 Carcinogenicity   Rat and Mouse Kurokawa et al. ( 1984) conducted a dermal carcinogenicity study to assess the ability of chlorite to act as a complete carcinogen. Groups of 20 female SENCAR mice were exposed twice weekly for 51 weeks to 20 mg/ mL sodium chlorite in acetone. The solution ( 0.2 mL; 100 mg/ kg sodium chlorite per application) was applied to the shaved backs of the mice. The sodium chlorite exposure did not result in increased tumor incidence.

To test the ability of chlorite to act as a tumor promoter, a single initiating dose of 20

mol of dimethylbenzanthracene ( DMBA) was applied to the skin of 20 SENCAR mice. The DMBA application was followed by a 51 week exposure to sodium chlorite ( as described for the complete carcinogen study). Tumor incidence was 6/ 20 ( 30%) compared with 0/ 20 in mice that received DMBA followed by acetone treatments for 51 weeks. Squamous cell carcinomas were observed in 5/ 20 animals in the chlorite group. However, the results were not statistically significant.

4.7 Mutagenicity Data on the mutagenicity of chlorine dioxide exist in the open scientific literature as well as within the Agency's database of submitted studies. The following studies have been reviewed by the Agency and are considered acceptable:

1) Miller et al. ( 1986) reported negative effects in Salmonella strains TA98 and TA100 from a 400 fold drinking water concentrate of chlorine dioxide and positive effects in a 4000 fold concentrate to strain TA98 only in the absence of metabolic activation.

2) In L5178Y/ TK cells, chlorine dioxide was positive for forward mutations under nonactivated conditions ( dose related from 3.2 24.3 µ g/ ml) and activation conditions ( 48.3 µ g/ mL) [ Accession no. 265867].

3) Chlorine dioxide was positive for structural chromosome aberrations under nonactivated and activated conditions ( 10, 15, and 50 µ g/ ml) [ Accession no. 265867].

4) Chlorine dioxide was negative for increased transformed foci up to cytotoxic levels [ Accession no. 265867].

5) In vivo micronucleus and bone marrow chromosomal aberration assays in Swiss CD 1 Page 13 of 32 mice administered 0.1  0.4 mg chlorine dioxide via gavage for 5 consecutive days were negative, as was a sperm head abnormality assay in B6C3F1 mice administered 0.1  0.4 mg via gavage for 5 consecutive days ( 0, 3.2, 8, and 16 mg/ kg day) ( Meier et al., 1985).

4.8 Neurotoxicity Adequacy of database for Neurotoxicity: Neurotoxicity of chlorine dioxide has been observed. In the two generation reproduction toxicity study ( CMA 1996), significant changes were observed in maximum response in startle amplitude and absolute brain weight in F1 rat pups at a dose of 3 mg/ kg/ day. In the Orme et al. ( 1985) developmental toxicity study, neurobehavioral deficits in offspring were observed also at a dose of 14 mg/ kg/ day administered to maternal rats.

4.9 Metabolism and Pharmacokinetics Adequacy of database for Metabolism and Pharmacokinetics: Information regarding the pharmacokinetics of chlorine dioxide and chlorite is predominantly derived from oral studies in laboratory animals. Chlorite ( ClO2) does not persist in the atmosphere either in ionic form or as chlorite salt. The rapid appearance of 36Cl in plasma following oral administration of chlorine dioxide ( 36ClO2) or chlorite ( 36ClO2) has been shown in laboratory animals ( Abdel Rahman et al., 1984). In rats, absorbed 36Cl ( from 36ClO2 or 36ClO2 sources) is slowly cleared from the blood and is widely distributed throughout the body ( Abdel Rahman et al., 1984). Chlorine dioxide rapidly dissociates, predominantly into chlorite ( which itself is highly reactive) and chloride ion ( Cl), ultimately the major metabolite of both chlorine dioxide and chlorite in biological systems ( Abdel Rahman et al., 1984). Urine is the primary route of elimination, predominantly in the form of chloride ion ( Abdel Rahman et al., 1984). Additional pharmacokinetic studies of chlorine dioxide and chlorite should be designed to examine mechanisms of absorption and metabolic changes that might account for observed neurodevelopment effects.

4.10 Inhalation Exposure An inhalation risk assessment is required for chlorine dioxide for three scenarios involving antimicrobial uses of chlorine dioxide. Occupational exposures to chlorine dioxide gas are expected to cover a typical work day/ work week ( 8 hours/ day, 5 days/ week) over several years of exposure. There are also two homeowner exposure scenarios for chlorine dioxide. One scenario involves one time exposures through use of chlorine dioxide in homes involving the cleaning of HVAC systems, floors, carpets, etc., and is considered short term exposure, while the other exposure scenario involves a long term exposure from the proposed use of chlorine dioxide in continuous release products. There is no exposure scenario considered as intermediate term in the current inhalation assessment.

For these assessments, the following inhalation toxicity data on chlorine dioxide is cited:

Dalhamn, T. ( 1957): Chlorine Dioxide: Toxicity in Animal Experiments and Industrial Risks. Arch. Page 14 of 32 Ind. Health 15: 101 107.

Paulet G, Desbrousses S. 1970. On the action of ClO2 at low concentrations on laboratory animals. Arch Mal Prof 31: 97 106.

Paulet G, Desbrousses S. 1972. On the toxicology of chlorine dioxide. Arch Mal Prof 33: 59 61.

Paulet G, Desbrousses S. 1974. Action of a discontinuous exposure to chlorine dioxide ( ClO2) on the rat. Arch Mal Prof 35: 797 804.

Dalhamn ( 1957) reported the results of several inhalation studies in laboratory animals. In one study, a single 2 hour inhalation exposure of four rats to a chlorine dioxide concentration of 260 ppm ( 728 mg/ m3) resulted in pulmonary edema and nasal bleeding. In a second study, respiratory distress was reported in three other rats subjected to 3 weekly 3 minute exposures to decreasing concentrations of airborne chlorine dioxide from 3,400 to 800 ppm ( from 9,520 to 2,240 mg/ m3); bronchopneumonia was observed in two of these rats. In a third rat study, repeated exposure to approximately 10 ppm ( 28 mg/ m3) of chlorine dioxide ( 4 hours/ day for 9 days in a 13 day period) resulted in rhinorrhea, altered respiration, and respiratory infection. In a fourth study, no indications of adverse effects were seen in rats exposed to the NOAEL of approximately 0.1 ppm ( 0.28 mg/ m3) of chlorine dioxide 5 hours / day for 10 weeks.

Paulet and Desbrousses ( 1970, 1972,1974) conducted a series of studies in which laboratory animals were exposed to atmospheres of chlorine dioxide. Nasal discharge and localized bronchopneumonia ( with desquamation of alveolar epithelium) were noted in rats exposed to an airborne concentration of 10 ppm ( 28 mg/ m3), 2 hours/ day for 30 days. Another group of rats exposed to a concentration of 5 ppm ( 14 mg/ m3) exhibited similar, but less severe, respiratory tract effects. Bronchial inflammation and alveolar congestion and hemorrhage were observed in rats exposed to 2.5 ppm ( 7 mg/ m3), 7 hours/ day for 30 days. Alveolar congestion and hemorrhage were also seen in rabbits following inhalation exposure to 2.5 ppm ( 7 mg/ m3), 4 hours/ day for 45 days. In a group of rats and rabbits sacrificed 15 days after exposure termination, recovery from the pulmonary lesions was apparent ( Paulet and Desbrousses 1970). Vascular congestion and peribronchiolar edema were noted in the lungs of rats exposed to a concentration of 1 ppm ( 2.8 mg/ m3), 5 hours/ day, 5 days/ week for 2 months ( Paulet and Desbrousses 1972). A LOAEL of 1 ppm ( 2.8 mg/ m3) for respiratory effects was identified in this study.

LOAEL and NOAEL values were not always available from the above studies for each experimental duration studied. Ideally, each inhalation exposure scenario of concern ( i. e., shortterm intermediate term, and long term) for chlorine dioxide would be represented in the database, or, a single value of sufficient duration would cover short term and longer term inhalation exposures. However, the inhalation data for chlorine dioxide does not contain all of this information. Therefore, the HIARC and ADTC selected values felt to best represent the exposure scenarios of interest.

The scenarios of interest include occupational exposure ( typical 8 hour workday five days per Page 15 of 32 week), short term homeowner exposure ( essentially a single exposure in this case), and long term homeowner exposure. From the available data, a LOAEL value of 10 ppm ( 28 mg/ m3) was chosen from the Dalhamn study for short term homeowner exposures; for occupational exposures, a LOAEL of 1.0 ppm ( 2.8 mg/ m3) is identified from the Paulet and Desbrousses study and a NOAEL of 0.1 ppm ( 0.28 mg/ m3) is identified from the Dalhamn study. The unit conversion for chlorine dioxide is: 1 ppm ClO2 x 67.46/ 24.45 = 2.8 mg/ m3 As shown below for each exposure scenario of interest, the NOAEL and LOAEL values from the available animal data are used to derive human equivalent concentrations using the Agency's RfC guidance ( USEPA, 1994: Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry. Office of Research and Development, publication # EPA/ 600/ 8 90/ 066F) and the Agency's updated Toxicological Profile for Chlorine Dioxide and Chlorite ( USEPA, 2000; available at www. epa. gov/ iris/ toxreviews/ 0496 tr. pdf ). Derivation of human equivalent concentrations reduces the magnitude of uncertainty and also provides a more direct comparison with estimated human exposures for calculation of inhalation risk. The steps taken in this process are detailed within the report of the HIARC and ADTC committees, dated April 20, 2005.

5.0 Toxicity Endpoint Selection 5.1 See Section 7.1, Summary of Toxicological Doses and Endpoint Selection, Table 2.

5.2 Dermal Absorption Dermal Absorption Factor: 100%

Based on the lack of dermal absorption data, a default value of 100% will be used for dermal risk assessments for those applications involving use of aqueous solution of chlorine dioxide/ chlorite.

5.3 Classification of Carcinogenic Potential Chlorine dioxide has not been formally assessed for carcinogenic potential. One subchronic study ( Daniel et al., 1990) examined the effects of administration of chlorine dioxide to groups of male and female Sprague Dawley rats ( 10/ sex/ dose) at dose levels of 0, 25, 50, 100, or 200 mg/ L for 90 days in drinking water. A significant increase in the incidence of nasal lesions ( goblet cell hyperplasia and inflammation of nasal turbinates) was found at all dose levels tested. The significance of these findings is uncertain as they have not been observed in other long term studies of chlorine dioxide.

The potential for chlorine dioxide to induce proliferative epidermal hyperplasia was examined by Robinson et al. ( 1986). Groups of five dorsally shaved female SENCAR mice were placed in chambers filled with 0, 1, 10, 100, 300, or 1,000 ppm liquid chlorine dioxide; the chambers were designed to prevent the head from getting wet and to prevent inhalation of vapors. The animals were exposed 10 minutes/ day for 4 days. A significant increase in interfollicular epidermal Page 16 of 32 thickness was observed in the 1,000 ppm group, but not at the lower concentrations. Increases in total cell numbers and basal cell numbers in skin sections were observed in both the 300 and 1,000 ppm groups. In a second study, dermal immersion of 40 dorsally shaved female SENCAR mice in an aqueous solution of chlorine dioxide at a concentration of 1000 mg/ L for a 10 minute period, with subsequent sacrifice of 5 mice per day on days 1, 2, 3, 4, 5, 8, 10, or 12 showed an increase in the thickness of the interfollicular epidermis. This increase was apparent within 24 hours and persisted over the 12 day period. Highest values for the increase in skin thickness were observed on days 10 and 12. The authors concluded that even short term dermal exposure to high concentrations of chlorine dioxide is capable of inducing hyperplastic responses in the mouse skin.

Miller et al. ( 1986) tested the carcinogenic potential of drinking water disinfected with chlorine dioxide using three short term assays. Following disinfection with chlorine dioxide, the water samples ( containing 0.5 mg/ L chlorine dioxide residue) were concentrated 2,000H or 4,000H using a macroreticular resin process. In a mouse initiation promotion assay, groups of 14  34 SENCAR mice ( sex not specified) were orally administered 0.5 mL of the 4000H concentrate in 2% emulphor 3 times/ week for 2 weeks followed by topical exposure to 1.0 : g 12 tetradecanylphorbal 13 acetate ( TPA) in acetone applied to the dorsal skin 3 times/ week for 20 weeks and then sacrificed. No significant increases, compared with vehicle controls, in the number of skin tumors or the number of tumors per animal were observed.

In a lung adenoma assay ( Miller et al., 1986), groups of 20 male and 20 female Strain A mice received 0.25 mL gavage doses of 2000H or 4000H concentrates in 2% emulphor 3 times/ week for 8 weeks followed by a 16 week observation period. The number of animals with lung adenomas and the number of adenomas per animal were not significantly altered compared with vehicle controls.

Miller et al. ( 1986) also examined the development of liver foci in rats in a short term assay. In this study, groups of partially hepatectomized rats received a single dose of concentrated water ( chlorine dioxide concentration not reported) in 2% emulphor followed 1 week later by administration of 500 ppm sodium phenobarbital in drinking water for 56 days; animals were sacrificed on day 70. A control group received nondisinfected water. No significant increases in incidence of gamma glutamyltranspeptidase foci were observed.

In Kurokawa et al. ( 1984) chlorite was not shown to increase tumor incidences in rats and mice; these studies are considered inadequate for assessing human carcinogenicity because the exposure was for less than a lifetime, a high incidence of Sendai virus was found in the rats, and mortality was high in the mouse control group because of excessive fighting.

These data do not definitively characterize the carcinogenicity of chlorine dioxide or chlorite, and additional studies may be required.

6.0 FQPA Considerations 6.1 Developmental Toxicity Study Conclusions Page 17 of 32 Increased susceptibility to effects of chlorine dioxide have been observed in the two generation reproduction toxicity study in rats ( CMA, 1996) as well as from the Orme et al. ( 1985) study. In the two generation reproduction toxicity study, significant changes were observed in maximum response in startle amplitude and absolute brain weight in F1 rat pups at a dose of 3 mg/ kg/ day. In the Orme et al. developmental toxicity study, neurobehavioral deficits in offspring were observed also at a dose of 14 mg/ kg/ day administered to maternal rats. These deficits in pups were observed in the absence of significant maternal toxicity.

A developmental toxicity study in rabbits ( Harrington et al., 1995) showed no evidence of increased susceptibility when chlorite was administered to mated female New Zealand White rabbits at dose levels of 0, 200, 600, or 1200 ppm in drinking water.

6.2 Reproductive Toxicity Study Conclusions There was no evidence of a primary effect of reproduction based on the available data for chlorine dioxide.

6.3 Information from Literature Sources The Office of Pesticide Programs has also decided to rely upon available published data to characterize the hazard of chlorine dioxide, as the data are from peer reviewed journals and also are consistent with regard to the effect levels observed and the type( s) of toxicity observed. These data include the IRIS Toxicological Review of Chlorine dioxide and Chlorite ( EPA, 2002), Toxicological Profile for Chlorine dioxide ( ATSDR, 2004), The US EPA National Primary Drinking Water Regulations ( EPA, 1998), and the US EPA Office of Water drinking Water Health Advisory for Chlorine dioxide, Chlorite, and Chlorate ( EPA 1996).

6.4 Pre and/ or Postnatal Toxicity A. Determination of Susceptibility Developmental delays have been observed in animal studies following in utero and postnatal exposure to ingested chlorine dioxide or chlorite, suggesting that infants and children may be more likely than adults to experience adverse effects following exposure to these chemicals, although the reasons for this increased sensitivity are not fully understood. It is well recognized that neurological development continues after birth and that gastrointestinal uptake of many nutrients and chemicals is greater in the neonate than the adult.

B. Degree of Concern Analysis and Residual Uncertainties At the time of the original toxicity endpoint assessment, the HIARC concluded that an extra 10x uncertainty factor under the Food Quality Protection Act should be considered in risk assessments conducted for chlorine dioxide. This recommendation was based upon evidence of susceptibility in a two generation reproduction toxicity study in rats and evidence of susceptibility from Page 18 of 32 scientific literature reports.

Since the time of this 1999 recommendation, policy guidance was issued in September of 2001 through the Health Effects Division, Office of Pesticide Programs regarding the determination of the appropriate FQPA safety factor in tolerance assessment. This guidance states that whereas in the past "... OPP has routinely applied an additional FQPA safety factor where data on a pesticide shows increased susceptibility or sensitivity ( either qualitative or quantitative) in the developing organism," It is now the intent that "... OPP will now put greater emphasis on analyzing the degree of concern and, rather than apply an additional safety factor based solely on the identification of heightened sensitivity or susceptibility, will conduct a case by case weight of evidence approach that qualitatively examines the level of concern for sensitivity / susceptibility and assess whether traditional uncertainty factors already incorporated into the risk assessment are adequate to protect the safety of infants and children. Using this approach, in many cases the concerns regarding pre and postnatal toxicity can be addressed when a Reference Dose ( RfD) or Margin of Exposure ( MOE) is based on the pre or postnatal endpoints in the offspring."

C. Proposed Hazard based Special FQPA Safety Factor( s):

In the case of chlorine dioxide, the endpoint selected for both dietary and non dietary exposures was based upon adverse effects observed in offspring from developmental and reproductive toxicity data. Consistent with the approach used by the EPA's Office of Water for use of chlorine dioxide as a drinking water disinfectant ( Federal Register Vol. 63, No. 61, pages 15673 15692, March 31, 1998) and the updated guidance on selection of a safety factor under FQPA, the endpoint selected for assessment of risk from dietary and non dietary exposure to chlorine dioxide is felt to be protective of potentially susceptible populations including children, based upon the selection of an endpoint and effects observed in offspring and the use of an NOAEL value based on those effects. Therefore it can be concluded that an additional safety factor under FQPA is not necessary in this case and that the traditional uncertainty factor ( MOE) of 100 for intraspecies and interspecies variation will support the safety standard of ` reasonable certainty of no harm' as required by the FQPA statute for food use pesticides.

6.5 Recommendation for a Developmental Neurotoxicity Study A developmental neurotoxicity study is not recommended, based upon the examination of these endpoints in the two generation reproduction toxicity study submitted by the Chemical Manufacturers Association ( 1996) and the use of these data in support of the toxicity endpoints selected for chlorine dioxide.

7.0 Summary of Toxicological Doses and Endpoints for Chlorine dioxide/ sodium chlorite for Use in Human Risk Assessment 7.1 Summary Table of Toxicological Dose and Endpoint Selection ( Table 2) Page 19 of 32 Table 2: Summary of Toxicological Doses and Endpoint Selection for Chlorine dioxide/ sodium chlorite Exposure Scenario Dose Used in Risk Assessment ( mg/ kg/ day) UF/ MOE for Risk Assessment Study and Toxicological Effects Acute Dietary An acute dietary endpoint was not identified in the database for chlorine dioxide. This risk assessment is not required.

Chronic Dietary NOAEL = 3 mg/ kg/ day UF = 100 ( 10x interspecies extrapolation, 10x intra species variation)

Chronic PAD = 0.03 mg/ kg/ day Two generation reproduction toxicity study ( CMA, 1996)  decreases in absolute brain and liver weight, and lowered auditory startle amplitude at LOAEL of 6 mg/ kg/ day Developmental Toxicity  Rat ( Orme et al., 1985) neurobehavioral and exploratory deficits in rat pups at LOAEL of 14 mg/ kg/ day Incidental Oral ( short and intermediate term) NOAEL = 3 mg/ kg/ day MOE = 100 See summary for dietary assessment Short Term Dermala ( 1 30 days) NOAEL = 3 mg/ kg/ day MOE = 100 See summary for dietary assessment Intermediate Term Dermala ( 30 days 6 months) NOAEL = 3 mg/ kg/ day MOE = 100 See summary for dietary assessment Long Term Dermala ( > 6 months) NOAEL = 3 mg/ kg/ day MOE = 100 See summary for dietary assessment Inhalation ( occupational and homeowner shortterm See text for explanation of NOAEL/ LOAEL values chosen Occupational ` RfC' = 0.009 mg/ m3 ( 0.003 ppm) b Homeowner short term ` RfC' = 0.14 mg/ m3 ( 0.05 ppm) b Inhalation toxicity studies Rat homeowner short term: Dalhamn, 1957 [ LOAEL of 28 mg/ m3 ( 10 ppm)]

occupational exposure: Paulet and Debrousses, 1970, 1972 using LOAEL of 1.0 ppm ( 2.8 mg/ m3); Dalhamn, 1957 using NOAEL of 0.1 ppm ( 0.28 mg/ m3). Inhalation ( homeowner longterm Agency RfC methodology used to derive an RfC value of 2 x 10 4 mg/ m3 ( USEPA, 2000) ( Paulet and Desbrousses, 1970, 1972) selected as cocritical studies ( USEPA, 2000)

a Based on the use of an oral endpoint for dermal risk assessments and the lack of a dermal absorption study, a dermal absorption value of 100% as a default will be used. b unit conversion: 1 ppm ClO2 x 67.46/ 24.45 = 2.8 mg/ m3 8.0 Toxicity Profile Tables 8.1 Acute Toxicity Profile Table ( Table 3). Page 20 of 32 Table 3. Acute Toxicity Profile for Chlorine Dioxide/ Sodium Chlorite. Guideline No./ Study Type/ Test Substance (% a. i.) MRID No. ( Year)/ Citation/ Classification/ Doses Results 870.1100 ( § 81 1) Acute Oral Toxicity   Rats Chlorine dioxide  Oxine ( purity not reported) MRID 41919701 Unacceptable 0, 2720, 3340, 4110, or 5050 mL/ kg ( assume 100%, thus 0, 2720, 3340, 4110, or 5050 mg/ kg) administered via intubation Rats ( 5/ sex/ dose) Toxicity Category III LD50 = 4560 mg/ kg ( males) = 4150 mg/ kg ( females)

There were no deaths in males or females at the two lowest doses ( 2720 and 3340 mg/ kg). At 4110 mg/ kg, there were three female deaths during the first day and one male death on day 2. At the high dose ( 5050 mg/ kg), there were 4 male deaths and 3 female deaths.

Effects observed include GI distress, nosebleed, dark urine, polyuria, or cyanosis. 870.1100 ( § 81 1) Acute Oral Toxicity   Rats Chlorine dioxide purity   79% a. i. MRID 43558601 Acceptable 0, 18.0, 40.9, 149.4, 180.0, or 225.0 mg/ kg ( males) and 0, 25.0, 56.8, 207.5, 250.0, or 312.5 mg/ kg ( females) administered via gavage Rats ( 6/ sex/ dose) Toxicity Category II LD50 = 292 mg/ kg ( males) = 340 mg/ kg ( females)

Toxic signs first appeared 2 4 hours after dosing in Dose Group 3 females ( 207.5 mg/ kg) and Group 4 males ( 180 mg/ kg), as decreased activity, with increasing severity at higher doses. These signs were accompanied by rapid/ labored breathing, abdominal respiration, depilation, and weight loss, leading to death at the highest dosages in both sexes. Post mortem examination of animals revealed hyperemic internal organs ( liver, spleen, kidney, lung). 870.1100 ( § 81 1) Acute Oral Toxicity   Rats Chlorine dioxide purity   2% a. i. MRID 43441901 Acceptable 0, 2000, 4000, 5050, or 5500 administered via intubation Rats ( 5/ sex/ dose) Toxicity Category III LD50 = 3455 mg/ kg ( males) = 2773 mg/ kg ( females) = 3084 mg/ kg ( combined)

Clinical signs of toxicity preceding death included piloerection, diarrhea, polyuria, ptosis, lacrimation, decreased activity, nasal and ocular discharge, salivation, whole body tremors, emaciation, blanching, corneal opacity, dehydration, prolapsed penis, crusted eyes/ nose/ mouth, discolored fur, pale mucous membranes, necrotic tails, and general cachexia. Body weight in survivors appeared unaffected, but those that died lost between 25 and 35 g prior to death. Gross necropsy examinations revealed signs of chromodacryorrhea; discolorations of thymus, lungs, pancreas, lymph nodes, fatty tissues, mesentery, kidneys, and urine; discoloration of the contents of the stomach, bladder, small intestine, and pleural cavity; GI tract distended with " gas;" swollen/ undersized lungs; discolored/ enlarged heart; and constricted blood vessels. 870.1100 ( § 81 1) Acute Oral Toxicity   Rats Chlorine dioxide purity   5% a. i. Accession 40168701 MRID Supplemental Doses not reported. Toxicity Category III LD50 = 1550 mg/ kg 870.1200 ( § 81 2) Acute Dermal Toxicity   Rabbits Chlorine dioxide  Oxine ( purity not reported) MRID 41919702 Unacceptable 0 or 1.91 mL/ kg ( assume 100%, thus 0 or 2020 mg/ kg)

Rabbits ( 5/ sex/ dose) Toxicity Category III LD50> 2020 mg/ kg No animals died, and all survived to termination in apparently normal health. Page 21 of 32 Table 3. Acute Toxicity Profile for Chlorine Dioxide/ Sodium Chlorite. Guideline No./ Study Type/ Test Substance (% a. i.) MRID No. ( Year)/ Citation/ Classification/ Doses Results 870.1200 ( § 81 2) Acute Dermal Toxicity   Rabbits Sodium chlorite   80% a. i., Lot # 220984 15 Accession 40168704 MRID Core minimum Aqueous paste containing 2 g/ kg sodium chlorite Rabbits ( 5/ sex) Toxicity Category III LD50> 2000 mg/ kg No animals died, and no adverse clinical effects were noted during the observation period. Body weight gain was normal for both sexes ( 6.7% for males, 5.9% for females), and no pathological changes were attributed to the test compound. 870.1200 ( § 81 2) Acute Dermal Toxicity   Rabbits Chlorine dioxide   Oxine ( 2% a. i.) MRID 43441902 Acceptable 0 or 2020 mg/ kg, applied to at least 10% of body surface Rabbits ( 5/ sex) Toxicity Category III LD50> 2020 mg/ kg No animals died. Occasional evidence of decreased defacation and/ or diarrhea, or nasal discharge in one or two animals, was manifest during the 14 day study period. One male displayed discolored stomach contents, with the stomach, cecum, and rectum distended with gas; two females showed discolored ( gray) edges of several lung lobes.

Dermal irritation was minimal, and included Grades 1 to 2 erythema and/ or edema or desquamation, but no undue thickening or fissuring. None of these skin effects persisted to Day 14. 870.1300 ( § 81 3) Acute Inhalation Toxicity   Rats Chlorine dioxide  Oxine ( purity not reported) MRID 41919703 Unacceptable Rats were exposed to 0, 4.54, or 5.75 mg/ L for 4 hours.

Rats ( 5/ sex/ dose) Toxicity Category IV LC50 > 5.75 mg/ L ( highest dose tested)

There were no deaths. Gross necropsy revealed no observable abnormalities at either concentration.

870.1300 ( § 81 3) Acute Inhalation Toxicity   Rats Chlorine dioxide  purity not reported Accession 40168707 MRID Core supplemental Rats were exposed to 0, 1.51 or 2.80 mg/ L for 1 hour.

Rats ( 5/ sex/ dose) Toxicity Category III LC50 > 2.8 mg/ L ( 1 hour)

No animals died and no clinical signs of irritation were evident in either test group. Body organs appeared to be grossly normal, and weights of heart, liver, and kidneys were within normal ranges for this strain.

Testing guideline criteria not met include: 1. Only 1 hour exposure; 4 hours required. 2. Exposure chamber inadequately described. Particle sizing is not reported. 4. Concentrations too low to determine LC50. 5. Only nominal concentrations were reported. 870.1300 ( § 81 3) Acute Inhalation Toxicity   Rats Chlorine dioxide   100% a. i. MRID 43558602 Unacceptable Rats were exposed to 260 ppm ( 0.72 mg/ L) for 4 hours.

4 rats One of the four treated rats died during the first hour of exposure, and all four rats displayed ocular discharges and epistaxis ( nosebleed). The three survivors were sacrificed immediately after termination of the two hour exposure, and presented evidence of pulmonary edema, and " circulatory engorgement." Page 22 of 32 Table 3. Acute Toxicity Profile for Chlorine Dioxide/ Sodium Chlorite. Guideline No./ Study Type/ Test Substance (% a. i.) MRID No. ( Year)/ Citation/ Classification/ Doses Results 870.1300 ( § 81 3) Acute Inhalation Toxicity   Rats Sodium chlorite   80.6% a. i. MRID 42484101 Core Minimum Rats were exposed to 0, 0.29, 0.30, 0.35, 0.7, or 1.6 mg/ L for 4 hours.

Rats ( 5/ sex/ dose) Toxicity Category II LC50 = 0.29 mg/ L ( 4 hour)

Death before termination of the study occurred in all groups except in the 0.3 mg/ L group, usually within 2 to 6 days of exposure, preceded by labored respiration and lethargy and/ or ataxia. Survivors to 14 days lost weight during the first post exposure week, but partially regained it during the second week ( although mean weights remained markedly depressed).

In contrast to grossly normal internal organs in the 0.3 mg/ L animals, a number of rats in the other test groups exhibited either congestion or discoloration of the lungs. 870.2400 ( § 81 4) Primary eye irritation   Rabbits Chlorine dioxide  Oxine ( purity not reported) MRID 41919704 Unacceptable Rabbits were exposed to 0.1 mL of undiluted test article instilled directly into conjunctival sac of left eye ( right as control). Eyes in 3/ 9 animals were washed with water.

Rabbits ( 3/ sex/ dose) Toxicity Category III The maximum average irritation score ( PIS) 24 hours after treatment was 4.3 for non washed eyes and 5.3 for washed eyes. These scores correspond to " minimally irritating" and " mildly irritating."

Since conjunctival irritation was cleared by Day 7, oxine is assigned a Tox III.

870.2400 ( § 81 4) Primary eye irritation   Rabbits Chlorine dioxide  Oxine ( 2% a. i.) MRID 43441903 Acceptable Rabbits were exposed to 0.1 mL of undiluted test article instilled directly into conjunctival sac of left eye ( right as control). Eyes in 3 males were washed with water.

Rabbits ( 6 males, 3 females) Toxicity Category III PIS = 7.0 ( unwashed at 24 hours) = 4.0 ( unwashed at 1 hour)

Neither the washed nor the unwashed eyes stained positive for fluorescein. All effects cleared by Day 4. Test substance is considered " mildly irritating."

870.2400 ( § 81 4) Primary eye irritation   Rabbits Chlorine dioxide   5% a. i. Accession 40168705 MRID Supplemental Unspecified amount of test substance instilled into the eye.

2 rabbits Toxicity Category III Test substance is a mild ocular irritant, producing mild conjunctivitis lasting for 2 days ( completely resolved by Day 3).

870.2500 ( § 81 5) Primary dermal irritation   Rabbits Chlorine dioxide   Oxine ( purity not reported) MRID 41919705 Unacceptable 0.5 mL undiluted test material; wrappings were removed and test sites were washed with tap water after 4 hours.

Rabbits ( 3/ sex) Toxicity Category IV Irritation scores ranged from 0.3 observed 90 minutes after washing) to 0.2 at 24 hours. No irritation ( 0.0) was encountered at 48 and 72 hours. The test article is classified as " practically not an irritant."

870.2500 ( § 81 5) Primary dermal irritation   Rabbits Sodium chlorite   80% a. i., Lot # 220984 15 Accession 40168704 MRID Core minimum Aqueous paste containing 2 g/ kg sodium chlorite Rabbits ( 5/ sex) Toxicity Category II Draize primary irritation score ( PIS)   7.3, thus sodium chlorite is considered a primary skin irritant. Page 23 of 32 Table 3. Acute Toxicity Profile for Chlorine Dioxide/ Sodium Chlorite. Guideline No./ Study Type/ Test Substance (% a. i.) MRID No. ( Year)/ Citation/ Classification/ Doses Results 870.2500 ( § 81 5) Primary dermal irritation   Rabbits Chlorine dioxide   5% Accession 40168706 MRID Core minimum Unspecified amount of test material applied to four areas of skin in 2 animals.

Rabbits ( 2 animals, sex not specified) Toxicity Category IV No dermal irritation reported.

870.2500 ( § 81 5) Primary dermal irritation   Rabbits Chlorine dioxide   Duozon 100 L ( 0.3 ppm a. i.) MRID 43503201 Acceptable 0.5 mL of 0.3 ppm, covered. After 4 hours, dressing and residual material removed.

3 Rabbits Toxicity Category IV All indices of irritation were zero; PII score was 0.0 for all time periods up to 7 days. This formulation is considered non irritating.

8.2 Subchronic, Chronic and Other Toxicity Profiles Table ( Table 4)

Table 4: Subchronic, Chronic and Other Toxicity Profiles for Chlorine Dioxide/ Sodium Chlorite. Guideline Number/ Study Type/ Test Substance (% a. i.) MRID Number ( Year)/ Citation/ Classification/ Doses Results 870.3100 ( § 82 1) 90 Day Oral ( Drinking water)   Rat Chlorine Dioxide purity not reported Daniel, et al. 1990 0, 25, 50, 100, or 200, mg/ L ( Male: 0, 2, 4, 6, or 12 mg/ kg/ day) ( Female: 0, 2, 5, 8, or 15 mg/ kg/ day) NOAEL < 2 mg/ kg/ day ( lowest dose tested) LOAEL = 2 mg/ kg/ day, based on nasal lesions, and organ weight decrease ( spleen and liver)

No exposure related deaths were reported. Exposure to 200 mg/ L resulted in significant reductions in terminal body weights and body weight gain. Significant reductions in water consumption were observed in the males and females exposed to   50 mg/ L and   25 mg/ L, respectively. Absolute liver weights were decreased in males at   50 mg/ L. Absolute spleen weights were decreased in females at   25 mg/ L. Serum lactate dehydrogenase and aspartate aminotransferase levels were decreased and serum creatinine levels were increased in the males exposed to   100 mg/ L. A significant increase in incidence of nasal lesions was found in males exposed to   25 mg/ L and in females at   100 mg/ L. These lesions may be a result of rats inhaling chlorine dioxide vapors at the drinking water sipper tube or from vapors off gassing after drinking the water. Page 24 of 32 Table 4: Subchronic, Chronic and Other Toxicity Profiles for Chlorine Dioxide/ Sodium Chlorite. Guideline Number/ Study Type/ Test Substance (% a. i.) MRID Number ( Year)/ Citation/ Classification/ Doses Results 870.3100 ( § 82 1) 90 Day Oral ( Gavage)   Rat Sodium Chlorite purity not reported Harrington, et al. ( 1995a) 0, 10, 25, or 80 mg/ L ( 0, 7.4, 19, or 60 mg/ kg/ day) NOAEL = 7.4 mg/ kg/ day LOAEL = 19 mg/ kg/ day, based on stomach lesions and increases in spleen and adrenal weights Body weight and food consumption were not affected by treatment. The following was noted in the high dose group: ( 1) four animals died during treatment; ( 2) both sexes exhibited salivation, significantly decreased erythrocyte counts and morphologic changes in erythrocytes, and decreased total serum protein levels; ( 3) males exhibited significantly decreased hematocrit and hemoglobin levels and increased met hemoglobin and neutrophil levels, whereas female met hemoglobin levels were significantly decreased; ( 5) relative adrenal and spleen weights increased in both sexes and absolute adrenal and spleen weights and relative liver and kidney weights were increased in females; and ( 6) both sexes displayed squamous epithelial hyperplasia, hyperkeratosis, ulceration, chronic inflammation, and edema in the stomachs.

In the 19 mg/ kg day dose group, the following observations were made: ( 1) in males, occasional salivation, increased met hemoglobin levels and neutrophil counts, decreased lymphocyte counts, and histologic alterations in the stomach of two males; and ( 2) in females, increased relative and absolute spleen and adrenal weights.

Non guideline Subchronic Inhalation Toxicity Rat and Rabbit Chlorine Dioxide purity not reported Dalhamn ( 1957)

Study 1: Decreasing concentrations for 3 minutes, once a week. 3400 ppm ( Week 1), 1100 ppm ( Week 2), and 800 ppm ( Week 3) ( 9500, 3000, and 2200 mg/ m3).

Study 2: 0 or 260 ppm ( 0 or 720 mg/ m3) for 2 hours.

Study 3: 0 or 10 ppm ( 0 or 28 mg/ m3), 4 hours/ day for 9 days in 13 day period.

Study 4: 0 or 0.1 ppm ( 0 or 0.28 mg/ m3), 5 hours/ day for 10 weeks. NOAEL = 0.1 ppm ( 0.28 mg/ m3), rats exposed 5 hours/ day for 10 weeks LOAEL = 10 ppm ( 28 mg/ m3), rats exposed 4 hours/ day for 2 weeks, based on respiratory tract irritation.

Study 1: Respiratory distress and decreased body weight were observed. Bronchopneumonia and hyperemia of the renal corticomedullary junction were observed in exposed rats ( 2/ 3); renal hyperemia was also observed in the control group ( 2/ 3).

Study 2: Ocular discharge, epistaxis, death ( 1/ 4 rats), pulmonary edema, and circulatory engorgement were observed.

Study 3: Death ( 3/ 5 rats), rhinorrhea, " embarrassed respiration," weight loss, and respiratory infection with acute renal and hepatic congestion were observed in the exposed rats.

Study 4: No effects on body weight gain were observed and no histologic alterations were observed in the lungs, kidneys, or liver. Page 25 of 32 Table 4: Subchronic, Chronic and Other Toxicity Profiles for Chlorine Dioxide/ Sodium Chlorite. Guideline Number/ Study Type/ Test Substance (% a. i.) MRID Number ( Year)/ Citation/ Classification/ Doses Results Non guideline Subchronic Inhalation  Rat and Rabbit Chlorine Dioxide purity not reported Paulet and Desbrousses ( 1970)

Group 1: 5 male and 5 female rats exposed to 10 ppm ( 28 mg/ m3), 2 hours/ day for 30 days.

Group 2: 10 male rats, 10 female rats, and 4 rabbits exposed to 5 ppm ( 14 mg/ m3), 2 hours/ day for 30 days.

Group 3: 10 male and 10 female rats exposed to 2.5 ppm ( 6.9 mg/ m3), 7 hours/ day for 30 days.

Group 4: 8 rabbits exposed to 2.5 ppm ( 6.9 mg/ m3), 4 hours/ day for 45 days. LOAEL = 2.5 ppm ( 6.9 mg/ m3) based on thoracic effects in rats ( 7 hours/ day for 30 days) and pulmonary effects in rabbits ( 4 hours/ day for 45 days).

Group 1: Adverse effects observed in exposed rats include: nasal discharge and red eyes, localized bronchopneumonia with desquamation of the alveolar epithelium, and significantly increased blood erythrocyte and leukocyte levels.

Group 2: Similar effects to those observed in Group 1 rats were noted in this study. There were no alterations in erythrocyte or leukocyte levels at this concentration.

Group 3: Lymphocyte infiltration of the alveolar spaces, alveolar vascular congestion, hemorrhagic alveoli, epithelial erosions, and inflammatory infiltrations of the bronchi were observed in exposed rats. Body weight gain was " slightly slowed" ( data not presented) and the erythrocyte and leukocyte levels were 85% and 116% of controls, respectively ( statistical analysis not reported), in exposed rats.

Group 4: In exposed rabbits, hemorrhagic alveoli and congested capillaries were observed in the lungs. Body weight gain was not adversely affected, and erythrocyte and leukocyte levels were 80% and 116% of controls ( statistical analysis not reported).

Non guideline Subchronic Inhalation   Rat Chlorine Dioxide purity not reported Paulet and Desbrousses ( 1972) 1 ppm ( 2.8 mg/ m3), 5 hours/ day, 5 days/ week for 2 months LOAEL = 1 ppm ( 2.8 mg/ m3), based on respiratory effects.

Weight gain and erythrocyte and leukocyte levels were not affected, but concurrent control data was not presented. Vascular congestion and peribronchiolar edema were observed in the lungs of exposed rats; no alterations in the epithelium or parenchyma were observed.

Non guideline Subchronic Inhalation  Rat and Rabbit Chlorine Dioxide purity not reported Paulet and Desbrousses ( 1974) 5, 10, or 15 ppm ( 14, 28, or 41 mg/ m3), for 15 minutes, 2 or 4 times/ day for 1month NOAEL = 5 ppm ( 14 mg/ m3) LOAEL = 10 ppm ( 28 mg/ m3), based on lung damage.

At 15 ppm, 1/ 10 and 1/ 15 rats exposed two or four times/ day, respectively, died; body weight loss was observed in both groups. Histologic alterations observed in the high dose groups included nasal and ocular inflammation and discharge, bronchitis, and catarrhous lesions of the alveoli with peribronchiolar infiltrations ( more pronounced in the 4 times/ day group). The alveolar lesions were reversible; 15 days after exposure termination, the lung histology was similar to that of controls. No histologic alterations were observed in the liver. At 10 ppm, alveolar irritation and decreases in body weight gain were observed. No adverse effects on clinical signs, body weight gain, or histopathology of the lungs were observed at 5 ppm. Exposure to chlorine dioxide did not adversely affect hematologic parameters. Page 26 of 32 Table 4: Subchronic, Chronic and Other Toxicity Profiles for Chlorine Dioxide/ Sodium Chlorite. Guideline Number/ Study Type/ Test Substance (% a. i.) MRID Number ( Year)/ Citation/ Classification/ Doses Results Developmental Rabbit Sodium chlorite purity 80.58% Acceptable   Guideline MRID 41715701 Females ( 16 17/ dose) exposed in drinking water 0, 200, 600, or 1200 ppm ( 0, 12 14, 36 42, or 76 84 mg/ kg/ day) from GD 7 19 Maternal Toxicity NOAEL = 200 ppm ( 12 14 mg/ kg/ day) LOAEL = 600 ppm ( 36 42 mg/ kg/ day) Developmental Toxicity NOAEL = 200 ppm ( 12 14 mg/ kg/ day) LOAEL = 600 ppm ( 36 42 mg/ kg/ day), based on decreased fecal output, food consumption, and water intake.

Drinking water administration of sodium chlorite to pregnant NZW does during the dosing period of major organogenesis caused dose related reductions in water consumption ( due to decreased palatability at 600 and 1200 ppm) as well as consequential decreases in food consumption and body weight gain, especially early in treatment. Despite these maternal effects, no evidence of embryolethality, fetotoxicity, or teratogenicity was found. There was a slight effect on embryonic growth of mid and high dose levels, but no clear dose response was evident, hence any association between treatment at 600 or 1200 ppm and retardation was considered inconclusive.

Non Guideline Developmental Rat Chlorine dioxide purity not reported Orme et al. ( 1985)

Group 1: Females exposed in drinking water 0, 1, 20, or 100 mg/ L ( 0, 1, 3, or 14 mg/ kg/ day) 2 weeks prior to mating and throughout gestation and lactation.

Group 2: 5 day old pups exposed via gavage 0 or 14 mg/ kg/ day, postnatal days 5 20. Developmental Toxicity NOAEL = 20 mg/ L ( 3 mg/ kg/ day) LOAEL = 100 mg/ L ( 14 mg/ kg/ day) for neurobehavioral effects in offspring of rats exposed in drinking water.

No significant alterations in pup weight were observed in the pups exposed in utero; the postnatally exposed pups weighed significantly less than controls on postnatal days 14  21. Age of eye opening was not affected by chlorine dioxide exposure. There was a significant correlation between T4 levels and locomotor activity.

Group 1: Locomotor activity was consistently decreased in the 100 mg/ L group, but the decrease was not statistically significant. There was a significant decrease in T3 and T4 levels In all groups. T4 levels were not significantly altered in exposed dams.

Group2: Activity was significantly decreased in exposed rats on postnatal days 18  19; on days 15  17 and 20, activity levels were similar to controls. T4 levels were also significantly decreased in exposed rats.

Non Guideline Reproduction ( Drinking water)   Rat Sodium chlorite purity 81.4% CMA ( 1996) F0: 0, 3, 5.7, or 21 mg/ kg/ day ( males) 0, 3.9, 7.6, or 29 mg/ kg/ day ( females) F1: 0, 2.9, or 23 mg/ kg/ day ( males) 0, 3.9, 8, or 29 mg/ kg/ day ( females) NOAEL = 2.9 mg/ kg/ day LOAEL = 5.7 mg/ kg/ day, based on low auditory startle response amplitude and hematotoxicity on postnatal day 24.

Significant alterations related to treatment at high dose included reduced absolute and relative liver weight in F1 males and females, reduced pup survival, and reduced body weight at birth and throughout lactation in F1 and F2 rats, lower thymus and spleen weight in both generations, decreased absolute brain weight for F1 and F2 females, delayed sexual development in F1 and F2 males and females, and lowered red blood cell parameters and white blood cell counts in F1 rats. In the mid dosed groups, reduced absolute and relative liver weight in F1 males was observed. In addition, a significant decrease in maximum response to an auditory startle stimulus was noted in mid and high dose groups on postnatal day 24, but not on postnatal day 60. Page 27 of 32 Table 4: Subchronic, Chronic and Other Toxicity Profiles for Chlorine Dioxide/ Sodium Chlorite. Guideline Number/ Study Type/ Test Substance (% a. i.) MRID Number ( Year)/ Citation/ Classification/ Doses Results 870.4100 ( § 83 1) Chronic Toxicity Rat Chlorite purity not reported Haag ( 1949) 0, 1, 2, 4, 8, 100, or 1000 mg/ L chlorite for 2 years ( 0, 0.09, 0.18, 0.35, 0.7, 9.3, or 81 mg/ kg/ day) NOAEL = 8 mg/ L ( 0.7 mg/ kg/ day) LOAEL = 100 mg/ L ( 9.3 mg/ kg/ day), based on renal effects. Animals exposed to chlorite concentrations   100 mg/ L exhibited treatment related renal pathology, characterized by distention of the glomerular capsule and appearance of a pale pinkish staining material in the renal tubules.

Non Guideline Carcinogenicity Mouse Chlorite purity not reported Robinson et al. ( 1986)

Study 1: 5 dorsally shaved females in chambers filled with 0, 1, 10, 100, 300, or 1000 ppm liquid chlorine dioxide, 10 min/ day for 4 days.

Study 2: 40 mice immersed in 0 or 1000 ppm chlorine dioxide for 10 minutes. Study 1: A significant increase in interfollicular epidermal thickness was observed in the 1,000 ppm group, but not at the lower concentrations. Increases in total cell numbers and basal cell numbers in skin sections were observed in both the 300 and 1,000 ppm groups.

Study 2: A significant increase in interfollicular epidermis thickness was observed at all time periods, with the highest values at 10 and 12 days postexposure.

The authors concluded that even short term dermal exposure to high concentrations of chlorine dioxide is capable of inducing hyperplastic responses in the mouse skin.

Non Guideline Carcinogenicity Mouse and Rat Chlorite purity not reported Kurokawa et al. ( 1984)

Study 1: 20 dorsally shaved females exposed to 20 mg/ mL sodium chlorite in acetone ( 100 mg/ kg sodium chlorite per application) twice a week for 51 weeks.

Study 2: 20 mice exposed to 20 µ mol DMBA followed by 51 week exposure to sodium chlorite. Study 1: Sodium chlorite did not result in increased tumor incidence.

Study 2: Tumor incidence was 6/ 20 ( 30%) compared with 0/ 20 in mice that received DMBA followed by acetone treatments for 51 weeks. Squamous cell carcinomas were observed in 5/ 20 animals in the chlorite group. Results were not statistically significant.

870.5100 ( § 84 2) Bacterial reverse Chlorine dioxide purity not reported Miller et al. ( 1986)

TA98 and TA100, 400 fold drinking water concentration chlorine dioxide ( with and without metabolic activation)

TA98, 4000 fold drinking water concentration chlorine dioxide ( with and without metabolic activation) 400 fold: Negative ( with or without metabolic activation)

4000 fold: Positive ( without metabolic activation)

870.5300 ( § 84 2) Acceptable   Guideline In Vivo Mouse cell gene mutation test Chlorine dioxide purity not reported Accession No. 265867 4 hours to a range of 7 concentrations ( 1.32 to 36.9 µ g/ mL) in the absence of metabolic activation and ( 6.73 to 65.2 µ g/ mL) in the presence of metabolic activation Positive ( in the absence and presence of metabolic activation)

870.5300 ( § 84 2) In Vivo Mouse cell gene mutation test Chlorine dioxide purity not reported Meier et al. ( 1985) 0.1 0.4 mg via gavage for 5 consecutive days Negative 870.5375 ( § 84 2) In Vivo mammalian chromosome aberration test  Mouse Chlorine dioxide purity not reported Accession No. 265867 10, 15, or 50 µ g/ mL ( in the presence and absence of metabolic activation) Positive ( in the absence and presence of metabolic activation)

870.5380 ( § 84 2) Mammalian spermatogonial chromosomal aberration test  Rat Chlorine dioxide purity not reported Meier et al. ( 1985) 0.1 0.4 mg via gavage for 5 consecutive days ( 0, 3.2, 8, or 16 mg/ kg/ day) Negative 870.5385 ( § 84 2) In Vivo bone marrow chromosome aberration test  Mouse Chlorine dioxide purity not reported Meier et al. ( 1985) 0.1 0.4 mg via gavage for 5 consecutive days Negative Page 28 of 32 Table 4: Subchronic, Chronic and Other Toxicity Profiles for Chlorine Dioxide/ Sodium Chlorite. Guideline Number/ Study Type/ Test Substance (% a. i.) MRID Number ( Year)/ Citation/ Classification/ Doses Results 870.8800 Morphologic transformations of cells in culture Chlorine dioxide purity not reported Accession No. 265867 to cytotoxic levels Negative for increased transform foci.

a Converted from ppm to mg/ kg/ day using a reference body weight of 0.0316 kg and water intake of 0.0078 L/ day. Page 29 of 32 9.0 REFERENCES 265867 ( Accession #): Mutagenicity Evaluation of Chlorine Dioxide in the Mouse Lymphoma Foreword Mutation Assay. Litton Bionetics, Kensington, MD, LBI Project No. 20989, March 1984.

40129404 ( MRID #): Inaba, Masumi. " Can Human Hair grow Again?" Azabu Shokan, Inc., 23 3, Higashi Azabu 1 Chrome, Minatio Ku Tokyo, Japan. May 1985. pp. 71 75.

40168701 ( Accession #): Acute Oral Toxicity   Rat [ EPA " Report of Analysis" of D67/ 5H28, Anthium Dioxcide ( EC), Stabilized Chlorine Dioxide, 5%]. Air and Hazardous Materials Division, EPA, Region 1 ( Boston, MA), International Dioxcide, Inc. Study Number NA, February 13, 1976.

40168704 ( Accession #): Acute Dermal LD50 on Rabbit   Sodium Chlorite Powder, Lot # 110984 15. Gibraltar Biological Lab, Inc. ( Fairfield, NJ), Internaltional Dioxcide, Inc. Study Number GBL 024065, April 23, 1985.

40168705 ( Accession #): Primary Eye Irritation   Rabbit [ EPA " Report of Analysis" of P67/ 5H28, Anthium Dioxcide ( EC), Stabilized Chlorine Dioxide, 5%]. Air and Hazardous Materials Division, EPA, Region 1 ( Boston, MA), International Dioxcide, Inc. Study Number NA, February 13, 1976.

40168707 ( Accession #): Acute Inhalation Toxicity, Rats. Woodard Research Corporation ( Herndon, VA), International Dioxcide, Inc. Study Number NA, August 8, 1968.

41715701 ( MRID #): Irvine, Lorraine F. Sodium Chlorite: Rabbit Teratology Study ( Drinking Water Administration). Toxicol. Labs, Ltd., Ledbury, UK, Study Number CMA/ 3/ R, September 21, 1990.

41919701 ( MRID#): Rat Acute Oral Toxicity: Oxine   New Powerful Bacteriostat and Sanitizer. Stillmeadow, Inc., Houston, TX, Lab. Project No. 3347 84, August 3, 1984.

41919702 ( MRID #): Rat Acute Dermal Toxicity: Oxine   New Powerful Bacteriostat and Sanitizer. Stillmeadow, Inc., Houston, TX, Lab. Project No. 3348 84, July 11, 1984.

41919703 ( MRID #): Rat Acute Inhalation Toxicity: Oxine   Bacteriostat/ Deodorizer ( AKA Purogene). Stillmeadow, Inc., Houston, TX, Lab. Project No. 4777 87, June 10, 1987.

41919704 ( MRID #): Rabbit Eye Acute Irritation: Oxine New Powerful Bacteriostat and Sanitizer. Stillmeadow, Inc., Houston, TX, Lab. Project No. 3349 84, June 26, 1984.

41919705 ( MRID #): Rabbit Skin Irritation: Oxine   New Powerful Bacteriostat and Sanitizer. Stillmeadow, Inc., Houston, TX, Lab. Project No. 3350 84, June 26, 1984. Page 30 of 32 42484101 ( MRID #): Acute Inhalation Toxicity Evaluation in Rats. International Research and Development Corporation ( IRDC), Mattawan, MI. Lab. Project No. 632 001, August 14, 1992.

43441901 ( MRID #): Acute Oral Toxicity Study in Rats. Stillmeadow, Inc., Sugar Land, TX, Lab. Project No. 1439 94, October 26, 1994.

43441902 ( MRID #): Acute Dermal Toxicity Study in Rabbits. Stillmeadow, Inc., Sugar Land, TX, Lab. Project No. 1440 94, October 10, 1994.

43441903 ( MRID #): Primary Eye Irritation Study in Rabbits. Stillmeadow, Inc., Sugar Land, TX, Lab. Project No. 1441 94, October 11, 1994.

43503201 ( MRID #): Irritant Effects of Duozon 100 1 As a concentration of 0.3 ppm relating to chlorine dioxide ( CLO2) on rabbit skin. Pharmatox, Landkreis, Hannover, Germany, Lab. Project No. Not Available, July, 1994.

43558601 ( MRID #): Abdel Rahman, et al., " Toxicity of Alcide," published in J. Appl. Toxicol. 2( 3): 160 164, 1982.

43558602 ( MRID #): Dalhamn, T., " Chlorine Dioxide: Toxicity in Animal Experiments and Industrial Risks," published in A. M. A. Arch. Indust. Hlth. 15( 2): 101 107, 1957.

Abdel Rahman, et al. ( 1984): The kinetics of chlorite and chlorate in the rat. J Am Coll Toxicol 3: 261 267.

ATSDR ( 2004): Toxicological Profile for Chlorine dioxide. U. S. Health and Human Services, Public Health Service.

CMA ( 1997): Sodium Chlorite: Drinking Water Rat Two Generation Reproductive Toxicity Study. Chemical Manufacturers Association. Quintiles Report Ref. CMA/ 17/ 96.

Dalhamn, T. ( 1957): Chlorine Dioxide: Toxicity in Animal Experiments and Industrial Risks. Arch. Ind. Health 15: 101 107.

Daniel, F. B., et al. ( 1990): Comparative subchronic toxicity studies of three disinfectants. J Am Water Works Assoc 82: 61 69.

Haag, H. B. ( 1949): The effect on rats of chronic administration of sodium chlorite and chlorine dioxide in the drinking water. Report to the Mathieson Alkali Works from H. B. Haag of the Medical College of Virginia. February 7, 1949.

Harrington, R. M., et al. ( 1995a): Subchronic toxicity of sodium chlorite in the rat. J Am Coll Toxicol 14: 21 33.

Harrington, R. M., et al. ( 1995b) Developmental toxicity of sodium chlorite in the rabbit. J Am Page 31 of 32 Coll Toxicol 14: 109 118.

Kurokawa, Y., et al. ( 1984): Studies on the promoting and complete carcinogenic activities of some oxidizing chemicals in skin carcinogenesis. Cancer Lett 24: 299 304.

Meier, J. R., et al. ( 1985): Evaluation of chemicals used for drinking water disinfection for production of chromosomal damage and sperm head abnormalities in mice. Environ Mutagen 7: 201 211.

Miller, R. G., et al. ( 1986): Results of toxicological testing of Jefferson Parish pilot plant samples. Environ Health Perspect 69: 129 139.

Mobley, S. A., et al. ( 1990): Chlorine dioxide depresses T3 uptake and delays development of locomotor activity in young rats. In: Jolley, RL, et al., eds. Water chlorination: chemistry, environmental impact and health effects, vol. 6. Chelsea, MI: Lewis Publications, pp. 347 358.

Moore, G. S. and E. J. Calabrese ( 1982): Toxicological effects of chlorite in the mouse. Environ Health Perspect 46: 31 37.

Orme, J., et al. ( 1985): Effects of chlorine dioxide on thyroid function in neonatal rats. J Toxicol Environ Health 15: 315 322.

Paulet G and S. Desbrousses ( 1970): On the action of ClO2 at low concentrations on laboratory animals. Arch Mal Prof 31: 97 106.

Paulet G and S. Desbrousses ( 1972): On the toxicology of chlorine dioxide. Arch Mal Prof 33: 59 61.

Paulet G and S. Desbrousses ( 1974): Action of a discontinuous exposure to chlorine dioxide ( ClO2) on the rat. Arch Mal Prof 35: 797 804.

Robinson, M; Bull, RJ; Schmaer, M; Long, RF. ( 1986) Epidermal hyperplasia in the mouse skin following treatment with alternate drinking water disinfectants. Environ Health Perspect 69: 293 300.

USEPA ( 1996): Chlorine dioxide, Chlorite, and Chlorate. Drinking Water Health Advisory, Office of Water.

USEPA ( 1998): National Primary Drinking Water Regulations: Disinfectants and Disinfection Byproducts Notice of Data Availability; Proposed Rule, Code of Federal Regulations 40 CFR 141 and 142.

USEPA ( 2000): Toxicological Review of Chlorine Dioxide and Chlorite, Integrated Risk Information System ( IRIS). Page 32 of 32 USEPA ( 2005): Chlorine Dioxide/ Sodium Chlorite  Report of the Hazard Identification Assessment Review Committee ( HIARC) and the Antimicrobials Division Toxicity Endpoint Selection Committee ( ADTC).


[Federal Register Volume 77, Number 130 (Friday, July 6, 2012)]
[Notices]
[Page 40125]
[FR Doc No: 2012-16541]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-67327; File No. 4-443]

Joint Industry Plan; Notice of Filing and Immediate Effectiveness
of Amendment to the Plan for the Purpose of Developing and Implementing
Procedures To Facilitate the Listing and Trading of Standardized
Options To Add NASDAQ OMX BX, Inc. as a Sponsor

June 29, 2012.
    Pursuant to Section 11A(a)(3) of the Securities Exchange Act of
1934 (``Act'') \1\ and Rule 608 thereunder,\2\ notice is hereby given
that on June 27, 2012, NASDAQ OMX BX, Inc. (``BX'' or ``Exchange'')
filed with the Securities and Exchange Commission (``Commission'') an
amendment to the Plan for the Purpose of Developing and Implementing
Procedures to Facilitate the Listing and Trading of Standardized
Options (``OLPP'').\3\ The amendment proposes to add BX as a Sponsor of
the OLPP. The Commission is publishing this notice to solicit comments
on the proposed rule change from interested persons.
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    \1\ 15 U.S.C. 78k-1(a)(3).
    \2\ 17 CFR 242.608.
    \3\ On July 6, 2001, the Commission approved the OLPP, which was
proposed by the American Stock Exchange LLC (``Amex''), Chicago
Board Options Exchange, Incorporated (``CBOE''), International
Securities Exchange LLC (``ISE''), Options Clearing Corporation
(``OCC''), Philadelphia Stock Exchange, Inc. (``Phlx''), and Pacific
Exchange, Inc. (``PCX'') (n/k/a NYSE Arca). See Securities Exchange
Act Release No. 44521, 66 FR 36809 (July 13, 2001). On February 5,
2004, Boston Stock Exchange, Inc. (``BSE'') was added as a Sponsor
to OLPP. See Securities Exchange Act Release No. 49199, 69 FR 7030
(February 12, 2004). On March 21, 2008, the Nasdaq Stock Market, LLC
(``Nasdaq'') was added as a Sponsor to the OLPP. See Securities
Exchange Act Release No. 57546, 73 FR 16393 (March 27, 2008). On
February 17, 2010, BATS Exchange, Inc. (``BATS'') was added as a
Sponsor to the OLPP. See Securities Exchange Act Release No. 61528,
75 FR 8415 (February 24, 2010). On October 22, 2010, C2 Options
Exchange Incorporated (``C2'') was added as a Sponsor to the OLPP.
See Securities Exchange Act Release No. 63162, 75 FR 66401 (October
28, 2010). On May 9, 2012, BOX Options Exchange LLC (``BOX'') was
added as a Sponsor to the OLPP. See Securities Exchange Act Release
No. 66952, 77 FR 28641 (May 15, 2012).
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I. Description and Purpose of the Amendment

    The current Sponsors of the OLPP are BATS, BOX, BSE., CBOE, C2,
ISE., NYSE Amex, NYSE Arca, OCC, Phlx and Nasdaq. The proposed
amendment to the OLPP would add BX as a Sponsor of the OLPP. A national
securities exchange may become a Sponsor if it satisfies the
requirement of Section 7 of the OLPP. Specifically an Eligible Exchange
\4\ may become a Sponsor of the OLPP by: (i) Executing a copy of the
OLPP, as then in effect; (ii) providing each current Plan Sponsor with
a copy of such executed Plan; and (iii) effecting an amendment to the
OLPP, as specified in Section 7(ii) of the OLPP.
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    \4\ The OLPP defines an ``Eligible Exchange'' as a national
securities exchange registered with the Commission pursuant to
Section 6(a) of the Exchange Act, 15 U.S.C. 78f(a), that (1) has
effective rules for the trading of options contracts issued and
cleared by the OCC approved in accordance with the provisions of the
Exchange Act and the rules and regulations thereunder and (2) is a
party to the Plan for Reporting Consolidated Options Last Sale
Reports and Quotation Information (the ``OPRA Plan''). BX has
represented that it has met both the requirements for being
considered an Eligible Exchange.
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    Section 7(ii) of the OLPP sets forth the process by which an
Eligible Exchange may effect an amendment to the OLPP. Specifically, an
Eligible Exchange must: (a) execute a copy of the OLPP with the only
change being the addition of the new sponsor's name in Section 8 of the
OLPP; \5\ and (b) submit the executed OLPP to the Commission. The OLPP
then provides that such an amendment will be effective at the later of
either the amendment being approved by the Commission or otherwise
becoming effective pursuant to Section 11A of the Act. BX has submitted
a signed copy of the OLPP to the Commission and to each Plan Sponsor in
accordance with the procedures set forth in the OLPP regarding new Plan
Sponsors.
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    \5\ The Commission notes that the list of plan sponsors is set
forth in Section 9 of the OLPP.
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II. Effectiveness of the Proposed Linkage Plan Amendment

    The foregoing proposed OLPP amendment has become effective pursuant
to Rule 608(b)(3)(iii) \6\ because it involves solely technical or
ministerial matters. At any time within sixty days of the filing of
this amendment, the Commission may summarily abrogate the amendment and
require that it be refiled pursuant to paragraphs (a)(1) of Rule
608,\7\ if it appears to the Commission that such action is necessary
or appropriate in the public interest, for the protection of investors
or the maintenance of fair and orderly markets, to remove impediments
to, and perfect the mechanisms of, a national market system or
otherwise in furtherance of the purposes of the Act.
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    \6\ 17 CFR 242.608(b)(3)(iii).
    \7\ 17 CFR 242.608(a)(1).
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III. Solicitation of Comments

    Interested persons are invited to submit written data, views, and
arguments concerning the foregoing, including whether the proposed
amendment is consistent with the Act. Comments may be submitted by any
of the following methods:

Electronic Comments

     Use the Commission's Internet comment form (http://www.sec.gov/rules/sro.shtml); or
     Send an email to<EMAIL_ADDRESS>Please include
File Number 4-443 on the subject line.

Paper Comments

     Send paper comments in triplicate to Elizabeth M. Murphy,
Secretary, Securities and Exchange Commission, 100 F Street NE.,
Washington DC 20549-1090.

All submissions should refer to File Number 4-443. This file number
should be included on the subject line if email is used. To help the
Commission process and review your comments more efficiently, please
use only one method. The Commission will post all comments on the
Commission's Internet Web site (http://www.sec.gov/rules/sro.shtml).
Copies of the submission, all subsequent amendments, all written
statements with respect to the proposed rule change that are filed with
the Commission, and all written communications relating to the proposed
rule change between the Commission and any person, other than those
that may be withheld from the public in accordance with the provisions
of 5 U.S.C. 552, will be available for Web site viewing and printing in
the Commission's Public Reference Room, 100 F Street NE., Washington,
DC 20549, on official business days between the hours of 10:00 a.m. and
3:00 p.m. Copies of such filing also will be available for inspection
and copying at BX's principal office. All comments received will be
posted without change; the Commission does not edit personal
identifying information from submissions. You should submit only
information that you wish to make available publicly. All submissions
should refer to File No. 4-443 and should be submitted on or before
July 27, 2012.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\8\
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    \8\ 17 CFR 200.30-3(a)(29).
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Elizabeth M. Murphy,
Secretary.
[FR Doc. 2012-16541 Filed 7-5-12; 8:45 am]
BILLING CODE 8011-01-P