United States kS^laMIjk Environmental Protection ^J^iniiil m11 Agency EPA/690/R-17/001F Final 1-13-2017 Provisional Peer-Reviewed Toxicity Values for />-Chlorobenzenesulfonic Acid (CASRN 98-66-8) Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- AUTHORS, CONTRIBUTORS, AND REVIEWERS CHEMICAL MANAGER Jason C. Lambert, PhD, DABT National Center for Environmental Assessment, Cincinnati, OH DRAFT DOCUMENT PREPARED BY SRC, Inc. 7502 Round Pond Road North Syracuse, NY 13212 PRIMARY INTERNAL REVIEWERS J. Phillip Kaiser, PhD, DABT National Center for Environmental Assessment, Cincinnati, OH Jeff Swartout, MS National Center for Environmental Assessment, Cincinnati, OH This document was externally peer reviewed under contract to: Eastern Research Group, Inc. 110 Hartwell Avenue Lexington, MA 02421-3136 Questions regarding the content of this PPRTV assessment should be directed to the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300). li /;-Chlorobenzenesulfonic acid ------- TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS AND ACRONYMS iv BACKGROUND 1 DISCLAIMERS 1 QUESTIONS REGARDING PPRTVs 1 INTRODUCTION 2 REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 6 HUMAN STUDIES 10 ANIMAL STUDIES 10 Oral Exposures 10 Inhalation Exposures 13 OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 13 Supporting Animal Studies 13 Genotoxicity 13 Mode-of-Action/Mechanistic Studies 15 DERIVATION 01 PROVISIONAL VALUES 15 DERIVATION OF ORAL REFERENCE DOSES 16 DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 16 CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 16 DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 17 APPENDIX A. SCREENING PROVISIONAL VALUES 18 APPENDIX B. DATA TABLES 22 APPENDIX C. REFERENCES 26 in /;-Chlorobenzenesulfonic acid ------- COMMONLY USED ABBREVIATIONS AND ACRONYMS a2u-g alpha 2u-globulin MN micronuclei ACGIH American Conference of Governmental MNPCE micronucleated polychromatic Industrial Hygienists erythrocyte AIC Akaike's information criterion MOA mode of action ALD approximate lethal dosage MTD maximum tolerated dose ALT alanine aminotransferase NAG N-acetyl-P-D-glucosaminidase AST aspartate aminotransferase NCEA National Center for Environmental atm atmosphere Assessment ATSDR Agency for Toxic Substances and NCI National Cancer Institute Disease Registry NOAEL no-observed-adverse-effect level BMD benchmark dose NTP National Toxicology Program BMDL benchmark dose lower confidence limit NZW New Zealand White (rabbit breed) BMDS Benchmark Dose Software OCT ornithine carbamoyl transferase BMR benchmark response ORD Office of Research and Development BUN blood urea nitrogen PBPK physiologically based pharmacokinetic BW body weight PCNA proliferating cell nuclear antigen CA chromosomal aberration PND postnatal day CAS Chemical Abstracts Service POD point of departure CASRN Chemical Abstracts Service Registry PODadj duration-adjusted POD Number QSAR quantitative structure-activity CBI covalent binding index relationship CHO Chinese hamster ovary (cell line cells) RBC red blood cell CL confidence limit RDS replicative DNA synthesis CNS central nervous system RfC inhalation reference concentration CPN chronic progressive nephropathy RfD oral reference dose CYP450 cytochrome P450 RGDR regional gas dose ratio DAF dosimetric adjustment factor RNA ribonucleic acid DEN diethylnitrosamine SAR structure activity relationship DMSO dimethylsulfoxide SCE sister chromatid exchange DNA deoxyribonucleic acid SD standard deviation EPA Environmental Protection Agency SDH sorbitol dehydrogenase FDA Food and Drug Administration SE standard error FEVi forced expiratory volume of 1 second SGOT glutamic oxaloacetic transaminase, also GD gestation day known as AST GDH glutamate dehydrogenase SGPT glutamic pyruvic transaminase, also GGT y-glutamyl transferase known as ALT GSH glutathione SSD systemic scleroderma GST glutathione-S-transferase TCA trichloroacetic acid Hb/g-A animal blood-gas partition coefficient TCE trichloroethylene Hb/g-H human blood-gas partition coefficient TWA time-weighted average HEC human equivalent concentration UF uncertainty factor HED human equivalent dose UFa interspecies uncertainty factor i.p. intraperitoneal UFh intraspecies uncertainty factor IRIS Integrated Risk Information System UFS subchronic-to-chronic uncertainty factor IVF in vitro fertilization UFd database uncertainty factor LC50 median lethal concentration U.S. United States of America LD50 median lethal dose WBC white blood cell LOAEL lowest-observed-adverse-effect level iv /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR /j-CHLOROBENZENESULFONIC ACID (CASRN 98-66-8) BACKGROUND A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant scientific literature using established Agency guidance on human health toxicity value derivations. All PPRTV assessments receive internal review by a standing panel of National Center for Environment Assessment (NCEA) scientists and an independent external peer review by three scientific experts. The purpose of this document is to provide support for the hazard and dose-response assessment pertaining to chronic and subchronic exposures to substances of concern, to present the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to characterize the overall confidence in these conclusions and toxicity values. It is not intended to be a comprehensive treatise on the chemical or toxicological nature of this substance. PPRTV assessments are eligible to be updated on a 5-year cycle to incorporate new data or methodologies that might impact the toxicity values or characterization of potential for adverse human-health effects and are revised as appropriate. Questions regarding nomination of chemicals for update can be sent to the appropriate U.S. Environmental Protection Agency (EPA) Superfund and Technology Liaison (https://www.epa.gov/research/fact-sheets-regional- science). DISCLAIMERS The PPRTV document provides toxicity values and information about the adverse effects of the chemical and the evidence on which the value is based, including the strengths and limitations of the data. All users are advised to review the information provided in this document to ensure that the PPRTV used is appropriate for the types of exposures and circumstances at the site in question and the risk management decision that would be supported by the risk assessment. Other U.S. EPA programs or external parties who may choose to use PPRTVs are advised that Superfund resources will not generally be used to respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program. This document has been reviewed in accordance with U.S. EPA policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. QUESTIONS REGARDING PPRTVs Questions regarding the content of this PPRTV assessment should be directed to the EPA Office of Research and Development's (ORD's) NCEA, Superfund Health Risk Technical Support Center (513-569-7300). 1 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 INTRODUCTION ^-Chlorobenzenesulfonic acid (p-CBSA), CASRN 98-66-8, belongs to the class of compounds known as benzenesulfonic acids. p-CBSA is produced by the sulfonation of chlorobenzene with sulfuric acid and involves the continuous removal of water during the reaction and is used as an intermediate in the manufacture of 4-chloro-3-nitrobenzenesulfonic acid (Linder and Rodefeld. 2012). /?-CBSA is listed on the public inventory of the U.S. EPA's Toxic Substances Control Act (U.S. EPA 2015); it is not, however, registered with Europe's Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) program (ECHA. 2016). The empirical formula for/?-CBSA is C6H5CIO3S. The chemical structure is shown in Figure 1. Table 1 summarizes the physicochemical properties of/?-CBSA. /?-CBSA exists as deliquescent needles at room temperature (Linder and Rodefeld, 2012). /;-CBSA's low estimated vapor pressure and low estimated Henry's law constant indicate that it is not expected to volatilize from either dry or moist surfaces. /?-CBSA's vapor pressure indicates that it will exist in both the vapor and particulate phases in the atmosphere. The estimated half-life of vapor-phase p-CBSA in air by reaction with photochemically produced hydroxyl radicals is 25 days. The estimated high water solubility and low soil adsorption coefficient for /;-CBSA indicate that it may leach to groundwater or undergo runoff after a rain event. o ci o H Figure l./7-Chlorobenzenesulfonic Acid Structure 2 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table 1. Physicochemical Properties of/7-Chlorobenzenesulfonic Acid (CASRN 98-66-8) Property (unit) Value Physical state Solid Boiling point (°C at 25 mm Hg) UT Melting point (°C) 67b Density (g/cm3 at 20°C) ND Vapor pressure (mm Hg at 25 °C) 4.3 x 10 6 (estimated)13 pH (unitless) ND pKa (unitless) ND Solubility in water (mg/L at 25 °C) 3.1 x io5 (estimated)13 Octanol-water partition coefficient (log Kow) -0.52 (estimated)13 Henry's law constant (atm-m3/mol at 25°C) 1.9 x 10 9 (estimated)13 Soil adsorption coefficient Koc (L/kg) 16 (estimated)13 Atmospheric OH rate constant (cm3/molecule-sec at 25°C) 4.3 x 10 13 (estimated)13 Atmospheric half-life (d) 25 (estimated)13 Relative vapor density (air = 1) NA Molecular weight (g/mol) 193b Flash point (closed cup in °C) ND "Havnes (2014). bU.S. EPA (2012b). NA = not applicable; ND = no data. A summary of available toxicity values for /;-CBSA from U.S. EPA and other agencies/organizations is provided in Table 2. 3 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table 2. Summary of Available Toxicity Values for />-Chlorobenzenesulfonic Acid and Its Sodium Salt (CASRNs 98-66-8 and 5138-90-9) Source (parameter)ab Value (applicability) Notes Reference Noncancer IRIS NV NA U.S. EPA (2016) HEAST NV NA U.S. EPA (2011a) DWSHA NV NA U.S. EPA (2012a) ATSDR NV NA ATSDR (2016) IPCS NV NA IPCS (2016); WHO (2016) IARC NV NA IARC (2016) Cal/EPA Acute Acceptable Daily Dose = 0.80 mg/kg-d; Chronic Acceptable Daily Dose = 0.27 mg/kg-d Based on BMDLisd of 797 mg/kg-d for reduced body-weight gain in a 32-d rat studv bv American Biogenics CorDOration (1985) and total UF of 1,000 for the acute acceptable daily dose and 3,000 for the chronic acceptable daily dose Cal/EPA (2015) MiDEQ Chronic RfD = 1 mg/kg-d Based on a NOAEL of 1,000 mg/kg-d in a 32-d rat studv bv American Biogenics Corporation (1985) and total Michigan DEO (2006) UF of 1,000 OSHA NV NA OSHA (2006): OSHA (2011) NIOSH NV NA NIOSH (2016) ACGIH NV NA ACGIH (2015) DOE (PAC) PAC-3: 99 mg/m3; PAC-2: 17 mg/m3; PAC-1: 1.5 mg/m3 (for p-CBSA) PAC-1 and PAC-2 based on adjustments to 1-hr TEEL-1 and TEEL-2; PAC-3 based on rat oral LD5o DOE (2016) USAPHC (air-MEG) 1-hr critical: 200 mg/m3; 1-hr marginal: 40 mg/m3; 1-hr negligible: 6 mg/m3 (for />-CBSA) Based on 1-hr TEELs. Documentation of the TEEL derivations was not located U.S. APHC (2013) 4 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table 2. Summary of Available Toxicity Values for />-Chlorobenzenesulfonic Acid and Its Sodium Salt (CASRNs 98-66-8 and 5138-90-9) Source (parameter)ab Value (applicability) Notes Reference Cancer IRIS NV NA U.S. EPA (2016) HEAST NV NA U.S. EPA (201 la) DWSHA NV NA U.S. EPA (2012a) NTP NV NA NTP (2014) IARC NV NA IARC (2015) Cal/EPA NV NA Cal/EPA (2011); Cal/EPA (2016a): Cal/EPA (2016b) ACGIH NV NA ACGIH (2015) aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency; DOE = Department of Energy; DWSHA = Drinking Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables; IARC = International Agency for Research on Cancer; IPCS = International Programme on Chemical Safety; IRIS = Integrated Risk Information System; MiDEQ = Michigan Department of Environmental Quality; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; USAPHC = U.S. Army Public Health Center. Parameters: MEG = military exposure guideline; PAC = protective action criteria. BMDL = benchmark dose lower confidence limit; /?-CBS A = /j-chlorobcnzcncsulfonic acid; LD50 = median lethal dose; NA = not applicable; NOAEL = no-observed-adverse-effect level; NV = not available; RfD = reference dose; SD = standard deviation; TEEL = temporary emergency exposure limit; UF = uncertainty factor. Non-date-limited literature searches were conducted in May 2015 and updated in June 2016 for studies relevant to the derivation of provisional toxicity values for /;-CBSA (CASRN 98-66-8) and its sodium salt (CASRN 5138-90-9). Searches were conducted using the U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature. HERO searches the following databases: PubMed, ToxLine (including TSCATS1), and Web of Science. The following databases were searched outside of HERO for health-related data: ACGIH, ATSDR, Cal/EPA, EPA IRIS, EPA HEAST, EPA Office of Water (OW), EPA TSCATS2/TSCATS8e, EPA High Production Volume (HPV), ECETOC, Japan Existing Chemical Data Base (JECDB), European Chemicals Agency (ECHA), Organisation for Economic Cooperation and Development (OECD) Screening Information Data Sets (SIDS), OECD International Uniform Chemical Information Database (IUCLID), OECD HPV, NIOSH, NTP, OSHA, and Defense Technical Information Center (DTIC). 5 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) Tables 3A and 3B provide overviews of the relevant noncancer and cancer databases, respectively, for /;-CBSA and include all potentially relevant repeated-dose short-term-, subchronic-, and chronic-duration studies, as well as reproductive and developmental toxicity studies. Principal studies are identified in bold. The phrase "statistical significance," used throughout the document, indicates ap-walue of < 0.05 unless otherwise specified. 6 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table 3A. Summary of Potentially Relevant Noncancer Data for />-Chlorobenzenesulfonic Acid (CASRN 98-66-8) Category3 Number of Male/Female, Strain Species, Study Type, Reported Doses, Study Duration Dosimetryb Critical Effects NOAEL BMDL/ BMCL LOAEL Reference (comments) Notes0 Human 1. Oral (mg/kg-d) ND 2. Inhalation (mg/m3) ND Animal 1. Oral (mg/kg-d) Subchronic 10 M/10 F, S-D rat, gavage administration of 0,10,50,500,1,000, or 2,000 /7-CBSA sodium salt for 31-32 consecutive d 0,9.0,45, 449,898, 1,800 as /7-CBSA No effects clearly related to /j-CBSA exposure were observed. 1,800 NDr NDr American Biogenics NPR, Corporation (1985) PS Observations in rats included: Increased (8.5-11% compared to control) group mean relative kidney weight, clinical signs of toxicity (salivation, gasping, irregular breathing), and decreased body-weight gain in two males, as well as ileal enteritis in one male. These effects may have all been confounded by issues unrelated to /j-CBSA exposure. 7 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table 3A. Summary of Potentially Relevant Noncancer Data for />-Chlorobenzenesulfonic Acid (CASRN 98-66-8) Category3 Number of Male/Female, Strain Species, Study Type, Reported Doses, Study Duration Dosimetryb Critical Effects NOAEL BMDL/ BMCL LOAEL Reference (comments) Notes0 Chronic Rabbit; number, sex, strain, frequency and mode of administration, and formulation not reported; 0, 0.1, 1, 10 mg/kg for 7 mo ND Authors reported significant changes in hematology, clinical chemistry, and liver and kidney function tests; however, study design details and quantitative data were lacking. NDr NDr NDr Krvatov (1970) (Lack of study design details and quantitative data preclude affirmation of actual dosimetry [e.g., ADD] or effect level identification) PR Developmental 25 F, CD rat, gavage administration of 0, 1,000, or 2,000/?-CBSA sodium salt on GDs 7-16 0, 898, 1,800 as p-CBS A No effects on maternal weight gain, average litter size, or pup weight on PNDs 1 or 3. 1,800 (based on very limited evaluations) NDr NDr Chernoff and Rosen (1985) as cited in U.S. EPA (1986) NPR 2. Inhalation (mg/m3) ND aTreatment/exposure duration (unless otherwise noted): Short-term = repeated exposure for 24 hours to <30 days; long-term (subchronic) = repeated exposure for >30 days and <10% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure for >10% lifespan for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002). bDosimetry values are presented as ADDs (mg/kg-day) for oral noncancer studies. In contrast to other repeated dose studies, dosimetry values from gestational exposure studies are not adjusted for duration in the calculation of an ADD. Where applicable, the dose of /?-CBSA was calculated from the dose of /?-CBSA sodium salt by multiplying the ratio of the molecular weights of the two compounds (192.6 g/mol /?-CBSA:214.6 g/mol /j-CBSA sodium salt). °Notes: NPR = not peer reviewed; PR = peer reviewed; PS = principal study. ADD = adjusted daily dose; BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit; /?-CBS A = /j-chlorobenzenesulfonic acid; F = female(s); GD = gestation day; LOAEL = lowest-observed-adverse-effect level; M = male(s); ND = no data; NDr = not determined; NOAEL = no-observed-adverse-effect level; PND = postnatal day; S-D = Sprague-Dawley. 8 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table 3B. Summary of Potentially Relevant Cancer Data for />-Chlorobenzenesulfonic Acid (CASRN 98-66-8) Category Number of Male/Female, Strain, Species, Study Type and Duration Dosimetry Critical Effects NOAEL BMDL/BMCL LOAEL Reference Notes Human 1. Oral (mg/kg-d) ND 2. Inhalation (mg/m3) ND Animal 1. Oral (mg/kg-d) ND 2. Inhalation (mg/m3) ND BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit; LOAEL = lowest-observed-adverse-effect level; ND = no data; NOAEL = no-observed-adverse-effect level. 9 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 HUMAN STUDIES No relevant data have been located regarding the toxicity of p-CBSA to humans following oral or inhalation exposure. ANIMAL STUDIES Oral Exposures Subchronic-Duration Studies American Biogenics Corporation (1985) In an unpublished, good laboratory practice (GLP)-compliant study, American Biogenics Corporation (1985) examined the effects of/>-CBSA sodium salt (purity not reported) administered by gavage in distilled water to Sprague-Dawley (S-D) rats. Groups of 10 rats/sex/dose were given doses of 0, 10, 50, 500, 1,000, or 2,000 mg/kg-day for 31 or 32 consecutive days (beginning at 45 days of age). Equivalent doses of/?-CBSA are 0, 9.0, 45, 449, 898, or 1,800 mg/kg-day1. In-life evaluations included twice-daily observations and weekly detailed examinations for clinical signs and weekly body-weight and food-consumption measurements. On study Day 28, all rats were given ophthalmologic examinations. At the end of exposure, blood samples were collected for evaluation of hematology (red blood cell [RBC] count, hemoglobin [Hb], hematocrit [Hct], mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin count [MCHC], platelet count, and total and differential leukocyte counts) and serum chemistry (electrolytes, glucose, blood urea nitrogen [BUN], creatinine, aspartate aminotransaminase [AST], alanine aminotransaminase [ALT], y-glutamyl transferase [GGT], total protein, albumin, globulin, and total bilirubin). At sacrifice on study Days 32 or 33, gross necropsies were performed on all animals, and the following organs were weighed: adrenals, testes with epididymides, ovaries, kidneys, and liver. Microscopic examination of the following organs was performed in control and animals in the highest-dose group: adrenals, bone and marrow, brain, gonads, heart, small and large intestines, kidneys, liver, pancreas, spleen, stomach, thyroid and parathyroid, urinary bladder, uterus, and cervix, and any other tissue exhibiting grossly observed changes. Statistical analyses consisted of analysis of variance (ANOVA) with the Tukey or Scheffe's test of multiple comparisons for parametric data and the Kruskal-Wallis test with the Kruskal-Wallis multiple comparison test for nonparametric data; these tests are considered to be appropriate for the nature of the data. No rats in any exposure group died prior to study termination ( American Biogenics Corporation. 1985). Clinical signs possibly related to/>-CBSA exposure were salivation, gasping, and irregular breathing observed in one highest-dose male rat on Day 8 (only), and irregular breathing observed in a second male from the highest-dose group, along with crusty nose and eye, on Day 33 (the day of sacrifice for this rat). Necropsy findings in the latter rat (a fractured snout and black crusted material around nose and mouth) suggest that the animal may have experienced trauma, which may have been responsible for, or contributed to, the irregular breathing in this animal. Due to the low incidence of affected animals, the transitory occurrence of signs in one animal, and possible confounding cause of signs (potentially related to physical trauma) in the other, these clinical signs are not considered to be related top-CBSA exposure. Further, crusty nose or eye and misaligned or missing incisor(s) were also noted in two male rats exposed to 898 mg/kg-day, one male rat exposed to 449 mg/kg-day, and one 'The dose of p-CBS A sodium salt was multiplied by the ratio of molecular weights (192.6 g/mol /?-CBSA:214.6 g/mol /j-CBSA sodium salt) to yield an equivalent dose of p-CBSA. 10 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 female rat exposed to 45 mg/kg-day, and were considered by the study authors to be unrelated to exposure. The same two male rats from the highest-dose group that showed clinical signs of toxicity (and trauma in one) also exhibited lower body-weight gain than others in their group (90 and 117 g total weight change compared with 141-194 g in the remaining rats), as well as markedly lower total food consumption (572 and 650 g total food consumed vs. 725-839 g for the remaining rats). Thus, while the lower body-weight gain was likely attributable to lower food intake, it is unclear whether the reduction in food intake reflected generalized diminished health in one of these animals, and a more traumatic physical condition (e.g., fractured snout) in the other. There were no statistically significant differences among the groups in mean body weight or food consumption at any time point. Although the American Biogenics Corporation (1985) ANOVA analysis of total body-weight change in males indicated a statistically significant difference among the mean values for all of the groups, there were no biologically significant (difference >10% compared with control) changes in body weight in any group. Mean Week 4 and terminal (fasted) body weights were within 5% of control means in all exposure groups (see Tables B-l and B-2). Hematology and clinical chemistry results did not reveal any treatment-related changes; a significant increase in white blood cell (WBC) count was seen in females exposed to 449 mg/kg-day, but not at higher doses or in males (see Tables B-l and B-2) (American Biogenics Corporation. 1985). Ophthalmology examinations were unremarkable. At gross necropsy, one of the two males from the highest-dose group, exhibiting clinical signs and body-weight decrements, was observed to have dark contents in the stomach, ileum, and cecum, as well as a discolored testis, enlarged lymph node, fractured snout, and black crusted material about the nose and mouth. The only statistically significant organ-weight changes were decreases in the absolute and relative weights of the left adrenal gland in males exposed to 449 mg/kg-day; these effects were not seen at higher doses, in the right adrenal weights, or in female rats (see Tables B-l and B-2). An increase of 11% (compared with controls; not statistically significant) in mean relative left kidney weight was observed in male rats of the highest dose; mean relative right kidney weight was increased by 8.5% at the same dose. Absolute left and right kidney weights were increased by 5 and 3%, respectively, in highest dose males. In contrast, absolute and relative kidney weights were decreased at lower doses in males and at all doses in females. Fluctuations in relative and absolute ovary weights as high as 31% difference from control were also observed; these changes did not exhibit a dose-response relationship and were not statistically significant (/>values > 0.05 for Jonckheere-Terpstra tests and linear regression analyses performed for this review) ( American Biogenics Corporation. 1985). Further, the biological significance of ovarian-weight changes can be difficult to interpret because ovarian weights are highly variable in control populations and are influenced by both reproductive cycling and stress (Sellers et al.. 2007). One male rat from the highest-dose group exhibited slight bilateral testicular tubular degeneration and epididymal aspermia. Another male rat from the highest-dose group exhibited slight ileal enteritis. The study authors considered these and other observed changes to be common in rats and unrelated to exposure. 11 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 In summary, observations at the highest dose included clinical signs of toxicity and decreased body-weight gain in 2/10 males, a marginally biologically significant increase in group mean relative kidney weight in males, testicular tubular degeneration (1/10 males vs. 0/10 male controls), and enteritis of the ileum (1/10 males vs. 0/10 male controls). As described above, the relationship between clinical signs potentially indicative of an effect (salivation, gasping, and irregular breathing) and exposure to />CBSA is uncertain due to the low incidence of affected animals, transitory occurrence of signs in one animal, and possible confounding signs of physical trauma in the other. Decreased body-weight gain was seen only in the two males exhibiting clinical signs of toxicity, and there were no statistically or biologically significant differences among treatment groups in mean body weight at any time during the study. The increase in relative kidney weight was observed only in males, was not statistically significant, was only marginally biologically significant (11% increase in the left kidney and 8.5% increase in the right kidney), and reflects, in part, 4% decreased body weight in males from the highest-dose group (increases in absolute kidney weight were only 3-5% in males from the highest-dose group). It should be noted that the increases in kidney weight in males from the highest-dose group stand in contrast to decreases in kidney weight in lower dose males and in females. However, histopathology findings in individual male rats from the highest-dose group were not correlated with organ-weight changes; the study authors characterized the findings as common and unrelated to treatment. Based on the lack of a clear (nonconfounded) relationship between potential toxic effects and/>CBSA exposure, a no-observed-adverse-effect level (NOAEL) of 1,800 mg/kg-day is identified for this study. Chronic-Duration Studies Kryotov (1970) In a chronic-duration toxicity study, originally published in Russian but with an available English translation, Krvatov (1970) administered 0, 0.1, 1.0, or 10 mg/kg of/>-CBSA (purity and formulation not reported) orally (presumably by gavage based on the description of the short-term-duration experiment described elsewhere in the report) to rabbits for 7 months. The strain, sex, number of rabbits per group, vehicle, and frequency of administration were not reported. Parameters measured include body weight, behavior, conditioned reflexes, hematology (RBC, WBC, Hb, phagocytic activity) and clinical chemistry (AST, ALT, serum cholesterol), liver and kidney function tests (bromosulfophthalein [BSP] in the liver and phenol red [phenolsulfonphthalein] in the kidney), organ weight, and vitamin C content of organs. Histopathology was not conducted. No mortality data were presented, and no quantitative values were presented for any of the results. Statistical analyses were limited to Student's t-tests. Apart from graphical reporting of BSP retention data, no quantitative results were provided. The study author reported that exposure to 10 mg/kg-day p-CBSA significantly decreased erythrocyte counts and hemoglobin, and increased reticulocyte counts, plasma transaminase activities, serum urea, and serum cholesterol (Krvatov. 1970). The text of the translation reported that treatment with the high dose also decreased BSP retention in the liver; however, data shown graphically indicate that BSP retention was increased. Krvatov (1970) also reported decreased phenol red in the kidneys and decreased vitamin C content in the adrenal glands at this dose. Observations at the mid dose of 1 mg/kg-day included nonsignificant increases in the activity of plasma transaminases and a significant increase in 12 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 BSP retention in the liver in the third and sixth months on study. The study author considered 1 mg/kg-day to be a "threshold" dose for/?-CBSA in rabbits and 0.1 mg/kg-day to be a "subliminal" (i.e., ineffective) dose. The methods and results were not presented with enough detail to allow for a full evaluation of this study; in addition, quantitative results were presented graphically (and without any measure of variability) and only for BSP retention, not for other endpoints. Therefore, effect levels cannot be identified for this study. Developmental Studies Chernoff and Rosen (1985) as cited in U.S. EPA (1986) C hern off and Rosen (1985) as cited in U.S. EPA (1986) conducted a screening-level teratology study of />CBSA sodium salt in rats. Mated female CD rats were given gavage doses of 0, 1,000, or 2,000 mg/kg-day/?-CBSA sodium salt on Gestation Days (GDs) 7-16. Equivalent doses of />CBSA are 0, 898, and 1,800 mg/kg-day1. Maternal-weight gain during pregnancy was recorded, as were average litter sizes and average pup weights on Postnatal Days (PNDs) 1 and 3; no other endpoints were evaluated. No differences in maternal-weight gain, average litter size, or pup weights were observed among the exposed and control groups. While a NOAEL of 1,800 mg/kg-day is identified for the study, the lack of detailed maternal and offspring evaluations limits the confidence in this effect level determination. Inhalation Exposures No relevant data have been located regarding the toxicity of p-CBSA to animals following inhalation exposure. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) Other supporting studies on /;-CBSA include an acute lethality study in multiple species, two poorly reported acute or short-term-duration oral toxicity studies, and genotoxicity data; these are described below. Table 4 provides an overview of genotoxicity studies of />CBSA, Supporting Animal Studies Kryatov (1970) reported oral median lethal dose (LD50) values of 8,350 (white mice), 11,100 (albino rats), 7,100 (rabbits), and 16,000 mg/kg (guinea pigs) for/>-CBSA; no details of the study design were reported. Mortalities occurred within 2 days of administration. The author also briefly reported repeated-dose experiments in rats and rabbits (numbers of animals not reported) exposed to/?-CBSA by gavage to doses of l/5th and 1/10th the animals' LD50 values (equivalent to -2,220 and 1,110 mg/kg-day, respectively, in rats and -1,400 and 710 mg/kg-day, respectively, in rabbits) for 20 days (Kryatov, 1970). No "marked cumulative properties" were observed, although at necropsy the author did indicate evidence of hemorrhage in the gastrointestinal tract and visceral hyperemia; however, it is unclear in the original report whether this was in reference to/>CBSA exposure or another chemical (chloral) evaluated in the study. One animal in the highest-dose group died (species not reported). No additional information on this experiment was provided in the report. In addition, Krvatov (1970) briefly noted an experiment in rats exposed to 0.1 or 1 mg/kg/;-CBSA and tested for effects on conditioned reflexes; the results of this experiment were either not reported or of unclear biological relevance (e.g., 'slower fixation of differentiation reaction'). Genotoxicity /?-CBSA has been tested for genotoxicity in Ames assays, in a mammalian cell mutagenicity assay, and in rats exposed in vivo [all tests conducted by Pharmakon Research 13 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 International (1985) as cited in U.S. EPA (1986)1. with uniformly negative results (see Table 4). /;-CBSA did not increase the frequency of mutations in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 or in L5178Y mouse lymphoma cells when tested with or without metabolic activation, or the frequency of chromosomal aberrations (CAs) in bone marrow in male rats given a single oral gavage dose of 2,000 mg/kg/>CBSA. Table 4. Summary of/7-Chlorobenzenesulfonic Acid (CASRN 98-66-8) Genotoxicity Endpoint Test System Doses/ Concentrations Tested Results Without Activation3 Results With Activation3 Comments Reference Genotoxicity studies in prokaryotic organisms Mutation Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, TA1538 50, 167, 500, 1,667, 5,000 mg/plate Positive and solvent controls gave expected responses. Pharmakon Research International (1985) as cited in U.S. EPA (1986) Genotoxicity studies in mammalian cells—in vitro Mutation L5178Y mouse lymphoma 50, 125, 250, 500, 1,000 mg/mL Positive and solvent controls gave expected responses. Pharmakon Research International (1985) as cited in U.S. EPA (1986) Genotoxicity studies—in vivo CAs Male rats given single dose by gavage and sacrificed 6, 12, and 24 hr after dosing for scoring of CAs in bone marrow smears 2,000 mg/kg Positive and solvent controls gave expected responses. Pharmakon Research International (1985) as cited in U.S. EPA (1986) a- = negative. CA = chromosomal aberration. 14 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Mode-of-Action/Mechanistic Studies /;-CBSA gave uniformly negative results in a large number of high-throughput screening assays under the National Toxicology Program's (NTP's) Tox21 program2: 21 cell cycle assays, 86 nuclear receptor assays, 2 cell morphology assays, 78 deoxyribonucleic acid (DNA) binding assays, 2 growth factor assays, 3 cytochrome assays, and 1 hydrolase assay. These high-throughput assays are designed to survey the potential for a given xenobiotic to be bioactive across a broad array of modes of action (MO As) known to be associated with altering the structure and/or function of mammalian cells. The negative results for p-CBSA across the specific assays listed here suggest a low potential for bioactivity in MO As involving direct/indirect interaction with DNA, cell cycle activation/deactivation, or nuclear or growth factor-dependent cell signaling. DERIVATION OF PROVISIONAL VALUES Tables 5 and 6 present summaries of noncancer and cancer references values, respectively. Table 5. Summary of Noncancer Reference Values for />-Chlorobenzenesulfonic Acid (CASRN 98-66-8) Toxicity Type (units) Species/Sex Critical Effect p-Reference Value POD Method POD (HED) UFc Principal Study Screening subchronic p-RfD (mg/kg-d) S-D rat/M No effects clearly related to p-CBSA exposure were observed. 1 NOAEL 432 300 American Biogenics Corporation (1985) Screening chronic p-RfD (mg/kg-d) S-D rat/M No effects clearly related to p-CBSA exposure were observed. 1 x KT1 NOAEL 432 3,000 American Biogenics Corporation (1985) Subchronic p-RfC (mg/m3) NDr Chronic p-RfC (mg/m3) NDr HED = human equivalent dose; M = male(s); NDr = not determined; NOAEL = no-observed-adverse-effect level; /?-CBS A = /j-chlorobcnzcncsulfonic acid; POD = point of departure; p-RfC = provisional reference concentration; p-RfD = provisional reference dose; S-D = Sprague-Dawley; UFC = composite uncertainty factor. 2Data are available online at http://actor.epa.gOv/dashboard/#chemical/98-66-8. 15 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table 6. Summary of Cancer Reference Values for />-Chlorobenzenesulfonic Acid (CASRN 98-66-8) Toxicity Type (units) Species/Sex Tumor Type Cancer Value Principal Study p-OSF (mg/kg-d) 1 NDr p-IUR (mg/m3) 1 NDr NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor. DERIVATION OF ORAL REFERENCE DOSES No data have been located on the effects of oral exposure to />CBSA in humans. Information on the toxicity of repeated oral exposure to />CBSA is limited to an unpublished 32-day gavage study (although referred to in various literature as a "28-day" study, the actual length of gavage exposure was 31-32 days) in rats (American Biogenics Corporation. 1985). an unpublished screening-level developmental toxicity study in rats exposed by gavage [Chernoff and Rosen (1985) as cited in U.S. EPA (1986)1. and the translated version of a paper published in Russian describing a 7-month study in rabbits (Krvatov. 1970). Kryatov (1970) did not report the sex or strain of rabbit exposed, nor the frequency or mode of p-CBSA administration. In addition, Krvatov (1970) reported data on BSP retention graphically and without any measure of variability, while quantitative results for other endpoints were not reported. Thus, effect levels could not be determined. The available studies were unpublished and/or not peer reviewed and thus were determined to be unsuitable for use in deriving provisional toxicity values. However, the unpublished study by American Biogenics Corporation (1985) was well conducted and reported adequate information with which to derive screening subchronic and chronic provisional reference doses (p-RfDs) for /;-CBSA (see Appendix A). DERIVATION OF INHALATION REFERENCE CONCENTRATIONS There are no studies of p-CBSA toxicity in humans or animals exposed by inhalation, thus precluding derivation of provisional reference concentrations (p-RfCs). CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR No studies were located examining possible associations between exposure to />CBSA and cancer in humans or animals. Studies in animals (one 32-day study in rats, a poorly reported 7-month study in rabbits, and a developmental toxicity screening study in rats) are inadequate to assess the carcinogenicity of/?-CBSA. In vitro bacterial and mammalian mutagenicity assays and an in vivo CA assay were uniformly negative. The cancer weight-of-evidence (WOE) descriptor forp-CBSA is provided in Table 7. 16 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table 7. Cancer WOE Descriptor for/7-Chlorobenzenesulfonic Acid (CASRN 98-66-8) Possible WOE Descriptor Designation Route of Entry (oral, inhalation, or both) Comments "Carcinogenic to Humans " NS NA There are no human data to support this. "Likely to Be Carcinogenic to Humans " NS NA There are no sufficient animal studies to support this. "Suggestive Evidence of Carcinogenic Potential" NS NA There are no sufficient animal studies to support this. "Inadequate Information to Assess Carcinogenic Potential" Selected Both No carcinogenicity studies of />-CBSA are available. "Not Likely to Be Carcinogenic to Humans " NS NA No evidence of noncarcinogenicity is available. NA = not applicable; NS = not selected; /?-CBSA = /j-chlorobcnzcnesulfonic acid; WOE = weight of evidence. DERIVATION OF PROVISIONAL CANCER POTENCY VALUES The lack of data on the carcinogenicity of p-CBSA following oral or inhalation exposure precludes the derivation of quantitative estimates of carcinogenic potency. 17 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 APPENDIX A. SCREENING PROVISIONAL VALUES For reasons noted in the main provisional peer-reviewed toxicity value (PPRTV) document, it is inappropriate to derive provisional toxicity values for /;-chlorobenzenesulfonic acid (p-CBSA). However, information is available for this chemical which, although insufficient to support derivation of a provisional toxicity value under current guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk Technical Support Center summarizes available information in an appendix and develops a "screening value." Appendices receive the same level of internal and external scientific peer review as the PPRTV documents to ensure their appropriateness within the limitations detailed in the document. Users of screening toxicity values in an appendix to a PPRTV assessment should understand that there is considerably more uncertainty associated with the derivation of an appendix screening toxicity value than for a value presented in the body of the assessment. Questions or concerns about the appropriate use of screening values should be directed to the Superfund Health Risk Technical Support Center. DERIVATION OF A SCREENING SUBCHRONIC PROVISIONAL REFERENCE DOSE Information on the toxicity of repeated oral exposure to />CBSA is limited to a 32-day gavage study in rats (American Biogenics Corporation, 1985), a screening-level developmental toxicity study in rats exposed by gavage [Chernoff and Rosen (1985) as cited in U.S. EPA (1986)1, and a 7-month study in rabbits (Krvatov. 1970) with significant deficiencies in reporting. In the study by Krvatov (1970). the methods and results were not presented with enough detail to allow for a full evaluation of the findings; quantitative results were presented graphically (and without any measure of variability) and only for bromosulfophthalein (BSP) retention, not for other endpoints. Thus, effect levels could not be determined from this study. The developmental toxicity study in rats [Chernoff and Rosen (1985) as cited in U.S. EPA (1986)1 identified a no-observed-adverse-effect level (NOAEL) of 1,800 mg/kg-day (as />CBSA) based on limited toxicological evaluations. The unpublished 32-day rat study by American Biogenics Corporation (1985) provided repeat-dose information on the potential effects of/>CBSA on body weight, clinical toxicity (e.g., salivation, gasping, and irregular breathing), and changes in organ weight (e.g., adrenals, ovaries, and kidneys). However, none of these effects could be attributed solely to/>CBSA exposure. For example, decreased body-weight gain was associated primarily with two males in the highest-dose group that consumed significantly less food than control rats and were reported to be in poor physical condition (e.g., fractured snout). Further, total body weights were not significantly different between treatment groups in general. Similarly, clinical signs of toxicity were observed in the same two male rats that suffered apparent trauma, which confounds interpretation of potential exposure-related effects. Lastly, adrenal-weight changes occurred only in the left adrenal, only in males, and did not exhibit a dose-response relationship. Similarly, while ovary weights were increased in treated females, this effect did not have a dose-response relationship and was not statistically significant compared to control females. Increased relative kidney weight occurred only in male rats, did not exhibit a dose-response relationship, was not statistically significant, and may be more an artifact of decreased body weight than an increase in actual kidney weight (e.g., absolute kidney weights increased by 3-5% and were not biologically significant). As such, a NOAEL of 1,800 mg/kg-day (as />CBSA) was identified for the 32-day gavage study ( American Biogenics Corporation. 1985) based on the lack of effects clearly related to exposure; 18 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 this study was selected as the principal study for the screening subchronic provisional reference dose (p-RfD). The NOAEL of 1,800 mg/kg-day for lack of effects following 32 days of oral gavage exposure was used to derive the screening subchronic p-RfD for p-CBSA, The NOAEL was converted to a human equivalent dose (HED) according to current U.S. EPA (2011b) guidance. In Recommended Use of Body Weight4 as the Default Method in Derivation of the Oral Reference Dose (U.S. EPA. 2011b). the Agency endorses body-weight scaling to the 3/4 power (i.e., BW3/4) as a default to extrapolate toxicologically equivalent doses of orally administered agents from all laboratory animals to humans for the purpose of deriving an RfD from effects that are not portal-of-entry. Following U.S. EPA (2011b) guidance, the point of departure (POD) is converted to an HED through the application of a dosimetric adjustment factor (DAF) derived as follows: DAF = (BWa1/4 - BWh1/4) where DAF = dosimetric adjustment factor BWa = animal body weight BWh = human body weight Using a reference BWa of 0.25 kg for rats and a reference BWh of 70 kg for humans, the resulting DAF is 0.24 (U.S. EPA. 201 lb). Applying this DAF to the NOAEL of 1,800 mg/kg-day yields a POD (HED) as follows: POD (HED) = NOAEL (mg/kg-day) x DAF = 1,800 mg/kg-day x 0.24 = 432 mg/kg-day The screening subchronic p-RfD for /;-CBSA was derived using the POD (HED) and a composite uncertainty factor (UFc) of 300 (reflecting an interspecies uncertainty factor [UFa] of 3, an intraspecies uncertainty factor [UFh] of 10, and a database uncertainty factor [UFd] of 10): Screening Subchronic p-RfD = POD (HED) UFc = 432 mg/kg-day -^300 = 1 mg/kg-day Table A-l summarizes the uncertainty factors for the screening subchronic p-RfD for p-CBSA. 19 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table A-l. Uncertainty Factors for the Screening Subchronic p-RfD for /J-Chlorobenzenesulfonic Acid (CASRN 98-66-8) UF Value Justification UFa 3 A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or toxicodynamic differences between rats and humans following /j-CBSA exposure. The toxicokinetic uncertainty has been accounted for by calculation of a human equivalent dose (HED) through application of a dosimetric adjustment factor (DAF) as outlined in the EPA's Recommended Use of Bodv Weight3/4 as the Default Method in Derivation of the Oral Reference Dose ('U.S. EPA. 2011b). UFh 10 A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in susceptibility in the absence of quantitative information to assess the toxicokinetics and toxicodynamics of /?-CBSA in humans. UFd 10 A UFd of 10 is applied to account for the limited toxicity database for /j-CBSA. which consists of an unpublished 32-d rat study, an unpublished screening-level teratogenicity study in rats (which does not suffice for evaluating the potential developmental effects of /?-CBSA exposure), and a poorly reported chronic-duration toxicity study in rabbits from the Russian literature. UFl 1 A UFl of 1 is applied because the POD is a NOAEL. UFS 1 A UFS of 1 is applied because a subchronic-duration study was selected as the principal study. UFC 300 Composite Uncertainty Factor = UFA x UFH x UFD x UFL x UFS. HED = human equivalent dose; NOAEL = no-observed-adverse-effect level; /?-CBSA = /j-chlorobcnzcncsulfonic acid; POD = point of departure; p-RfD = provisional reference dose; UF = uncertainty factor. DERIVATION OF A SCREENING CHRONIC PROVISIONAL REFERENCE DOSE The screening chronic p-RfD for />CBSA was derived using the same POD (HED) as the screening subchronic p-RfD (432 mg/kg-day) and a UFc of 3,000 (reflecting a UFa of 3, a UFh of 10, a UFd of 10, and a UFs of 10 for extrapolation from a subchronic to a chronic duration): Screening Chronic p-RfD = POD (HED) UFc = 432 mg/kg-day ^ 3,000 = 1 x 10"1 mg/kg-day Table A-2 summarizes the uncertainty factors for the screening chronic p-RfD for /?-CBSA. 20 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table A-2. Uncertainty Factors for the Screening Chronic p-RfD for /J-Chlorobenzenesulfonic Acid (CASRN 98-66-8) UF Value Justification UFa 3 A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or toxicodynamic differences between rats and humans following /j-CBSA exposure. The toxicokinetic uncertainty has been accounted for by calculation of a human equivalent dose (HED) through application of a dosimetric adjustment factor (DAF) as outlined in the EPA's Recommended Use of Bodv Weight3/4 as the Default Method in Derivation of the Oral Reference Dose (U.S. EPA. 2011b). UFh 10 A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in susceptibility in the absence of quantitative information to assess the toxicokinetics and toxicodynamics of /?-CBSA in humans. UFd 10 A UFd of 10 is applied to account for the limited toxicity database for /j-CBSA. which consists of an unpublished 32-d rat study, an unpublished screening-level teratogenicity study in rats (which does not suffice for evaluating the potential developmental effects of /?-CBSA exposure), and a poorly reported chronic-duration toxicity study in rabbits from the Russian literature. UFl 1 A UFl of 1 is applied because the POD is a NOAEL. UFS 10 A UFS of 10 is applied because a subchronic-duration study was selected as the principal study. UFC 3,000 Composite Uncertainty Factor = UFA x UFH x UFD x UFL x UFS HED = human equivalent dose; NOAEL = no-observed-adverse-effect level; /?-CBSA = /j-chlorobcnzcncsulfonic acid; POD = point of departure; p-RfD = provisional reference dose; UF = uncertainty factor. 21 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 APPENDIX B. DATA TABLES Table B-l. Selected Results in Male S-D Rats Administered p-CBSA Sodium Salt by Gavage for 31-32 Days" Endpoint Dose in mg/kg-d as />-CBSA Sodium Salt (mg/kg-d as />-CBSA)b 0 10 (9.0) 50 (45) 500 (449) 1,000 (898) 2,000 (1,800) Total body-weight change (g) 165 ±20.9 170 ±21.3 (+3.0%) 176 ±9.8 (+6.7%) 160 ± 14.9 (-3.0%) 153 ± 19.6 (-7.3%) 150 + 29.2 (-9.1%) Wk 4 body weight (g) 379 ± 26 378 ±30.4 (-0.3%) 392 ± 18.5 (+3.4%) 365 ±31.3 (-3.7%) 364 ±35.5 (-4.0%) 365 + 36.1 (-3.7%) Terminal (fasted) body weight (g) 360.5 ±25.98 357.4 ±29.08 (-0.9%) 374.9 ±20.19 (+4.0%) 349.9 ±29.58 (-2.9%) 349.2 ±34.29 (-3.1%) 344.7 + 34.65 (-4.4%) WBC count (thousand/mm3) 13.43 ±3.14 12.46 ±2.16 (-7.2%) 12.48 ±4.07 (-7.1%) 14.01 ±3.81 (+4.3%) 13.57 ±4.88 (+1.0%) 14.15 + 2.53 (+5.4%) Adrenal weight Right absolute (g) 0.0308 ±0.0109 0.0302 ± 0.0062 (-1.9%) 0.0316 ±0.0081 (+2.6%) 0.0314 + 0.0098 (+1.9%) 0.0312 + 0.0077 (+1.3%) 0.0301 +0.0064 (-2.3%) Right relative (% body weight) 0.0086 ±0.0033 0.0084 ±0.0015 (-2.3%) 0.0085 ± 0.0023 (-1.2%) 0.0090 ± 0.0029 (+4.7%) 0.0089 + 0.002 (+3.5%) 0.0089 + 0.0026 (+3.5%) Left absolute (g) 0.0375 ± 0.0042 0.0313 ±0.0062 (-17%) 0.0336 ±0.0048 (-10%) 0.0252 + 0.003** (-33%) 0.0323 + 0.0086 (-14%) 0.0320 + 0.0044 (-15%) Left relative (% body weight) 0.0105 ±0.0014 0.0088 ± 0.002 (-16%) 0.0090 ±0.0016 (-14%) 0.0072 ±0.0009** (-31%) 0.0092 + 0.0022 (-12%) 0.0093 + 0.0014 ("11%) 22 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table B-l. Selected Results in Male S-D Rats Administered p-CBSA Sodium Salt by Gavage for 31-32 Days3 Endpoint Dose in mg/kg-d as />-CBSA Sodium Salt (mg/kg-d as />-CBSA)b 0 10 (9.0) 50 (45) 500 (449) 1,000 (898) 2,000 (1,800) Kidney weight Right absolute (g) 1.6435 ±0.199 1.6129 ±0.2155 (-1.9%) 1.6685 + 0.1918 (+1.5%) 1.5122 + 0.159 (-8%) 1.5799 + 0.1807 (-3.9%) 1.6979 + 0.1974 (+3.3%) Right relative (% body weight) 0.4557 ±0.0408 0.4503 ±0.0389 (-1.2%) 0.4455 + 0.0504 (-2.2%) 0.4326 + 0.0343 (-5.1%) 0.4528 + 0.0319 (-0.6%) 0.4945 + 0.0579 (+8.5%) Left absolute (g) 1.6012 ±0.1813 1.6132 ±0.1784 (+0.7%) 1.6327 + 0.1769 (+2%) 1.5026 + 0.1415 (-6.2%) 1.5482 + 0.1827 (-3.3%) 1.6835 + 0.1332 (+5.1%) Left relative (% body weight) 0.4441 ±0.0362 0.4518 ±0.0429 (+1.7%) 0.4362 + 0.0497 (-1.8%) 0.4295 + 0.0184 (-3.3%) 0.4443 + 0.0424 (+0.0%) 0.4913 + 0.0483 (+11%) "American Biogenics Corporation (1985). bData reported as mean ± standard deviation (percent change compared with control); % change control = ([treatment mean - control mean] + control mean) x 100. **Statistically significantly different from control (p < 0.01), as reported by the study authors. /?-CBSA =/?-chlorobenzenesulfonic acid; S-D = Sprague-Dawley; WBC = white blood cell. 23 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table B-2. Selected Results in Female S-D Rats Administered p-CBSA by Gavage for 31-32 Days3 Endpoint Dose in mg/kg-d as />-CBSA Sodium Salt (mg/kg-d as />-CBSA)b 0 10 (9.0) 50 (45) 500 (449) 1,000 (898) 2,000 (1,800) Total body-weight change (g) 66 ±9.6 63 ± 10 (-4.5%) 69 + 20.5 (+4.5%) 68+12 (+3%) 66 + 8.1 (0) 61 + 12.4 (-7.6%) Wk 4 body weight (g) 223 ± 16.6 217 ±11 (-2.7%) 225 + 26.9 (+0.9%) 220 + 16.6 (-1.3%) 222+ 16.8 (-0.4%) 216 + 21.2 (-3.1%) Final (fasted) body weight (g) 208.252 ± 14.0241 201.105 ± 11.6435 (-3.4%) 209.344 + 25.2218 (0.5%) 206.477+ 16.1061 (-0.9%) 209.687 + 14.9094 (+0.7%) 202.877 + 20.4691 (-2.6%) WBC count (thousand/mm3) 7.35 ± 1.5204 7.57 ± 1.82 (+3%) 9.21 + 2.61 (+25%) 11.15 + 4.78* (+52%) 8.70 + 2.60 (+18%) 9.85 + 2.12 (+34%) Adrenal weight Right absolute (g) 0.0352 ±0.0077 0.0417 ±0.0082 (+18%) 0.0414 + 0.0089 (+18%) 0.0364 + 0.0066 (+3.4%) 0.0405 + 0.0086 (+15%) 0.0357 + 0.0068 (+1.4%) Right relative (% body weight) 0.0169 ±0.0035 0.0208 ±0.0041 (+23%) 0.0200 + 0.0047 (+18%) 0.0176 + 0.0029 (+4.1%) 0.0193 + 0.0039 (+14%) 0.0178 + 0.0041 (+5.3%) Left absolute (g) 0.0372 ±0.0083 0.0407 ±0.0081 (+9.4%) 0.0383 + 0.0077 (+3%) 0.0372 + 0.0084 (0) 0.0432 + 0.008 (+16%) 0.0373 + 0.0057 (+0.3%) Left relative (% body weight) 0.0178 ±0.0037 0.0203 ± 0.0044 (+14%) 0.0185 + 0.004 (+3.9%) 0.0180 + 0.0035 (+1.1%) 0.0206 + 0.0038 (+16%) 0.0186 + 0.0035 (+4.5%) Kidney weight Right absolute (g) 0.9644 ±0.1053 0.9648 + 0.0818 (0) 0.9563 +0.1316 (-0.84%) 0.9404 + 0.1107 (-2.5%) 0.959 + 0.0782 (-0.56%) 0.901 + 0.1082 (-6.5%) Right relative (% body weight) 0.4631 ±0.0383 0.48 ±0.0332 (+3.6%) 0.4566 + 0.0294 (-1.4%) 0.4548 + 0.029 (-1.8%) 0.4577 + 0.0255 (-1.2%) 0.45 + 0.0584 (-3.5%) Left absolute (g) 0.9527 ± 0.0906 0.9689 + 0.812 (+1.7%) 0.9298 + 0.1361 (-2.4%) 0.9149 + 0.01333 ("4%) 0.9522 + 0.0586 (-0.1%) 0.9006 + 0.0948 (-5.5%) Left relative (% body weight) 0.4574 ± 0.0286 0.4819 + 0.0306 (+5.4%) 0.4436 + 0.0355 (-3%) 0.4417 + 0.0411 (-3.4%) 0.4561 +0.0411 (-0.3%) 0.45 + 0.0471 (-2.5%) 24 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 Table B-2. Selected Results in Female S-D Rats Administered p-CBSA by Gavage for 31-32 Days3 Endpoint Dose in mg/kg-d as />-CBSA Sodium Salt (mg/kg-d as />-CBSA)b 0 10 (9.0) 50 (45) 500 (449) 1,000 (898) 2,000 (1,800) Ovary weight Right absolute (g) 0.0459 ±0.012 0.0479 ±0.0104 (+4.4%) 0.056 ± 0.0084 (+22%) 0.0554 + 0.0198 (+21%) 0.0434 + 0.0093 (-5.4%) 0.0534 + 0.0125 (+16%) Right relative (% body weight) 0.022 ± 0.0055 0.0238 ± 0.0046 (+8.2%) 0.0271 +0.0052 (+23%) 0.0265 + 0.0076 (+20.5%) 0.0207 + 0.0035 (-5.9%) 0.0264 + 0.0058 (+20%) Left absolute (g) 0.0436 ±0.0115 0.0508 ±0.0177 (+17%) 0.0494 + 0.0123 (+13%) 0.0536 + 0.0141 (+23%) 0.04 + 0.0091 (-8.3%) 0.0557 + 0.0119 (+28%) Left relative (% body weight) 0.0209 ± 0.0052 0.0252 ± 0.0086 (+21%) 0.024 + 0.0071 (+15%) 0.0258 + 0.0053 (+23%) 0.0191 + 0.0042 (-8.6%) 0.0274 + 0.005 (+31%) "American Biogenics Corporation (1985). bData reported as mean ± standard deviation (percent change compared with control); % change control = ([treatment mean - control mean] + control mean) x 100. * Statistically significantly different from control (p < 0.05), as reported by the study authors. /?-CBSA =/?-chlorobenzenesulfonic acid; S-D = Sprague-Dawley; WBC = white blood cell. 25 /;-Chlorobenzenesulfonic acid ------- FINAL 01-13-2017 APPENDIX C. 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