United States Environmental Protection 1=1 m m Agency EPA/690/R-11/029F Final 3-24-2011 Provisional Peer-Reviewed Toxicity Values for Fluorobenzene (CASRN 462-06-6) 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 Harlal Choudhury, DVM, PhD, DABT National Center for Environmental Assessment, Cincinnati, OH DRAFT DOCUMENT PREPARED BY ICF International 9300 Lee Highway Fairfax, VA 22031 PRIMARY INTERNAL REVIEWERS Anuradha Mudipalli, MSc, PhD National Center for Environmental Assessment, Research Triangle Park, NC Geniece M. Lehmann, PhD National Center for Environmental Assessment, Research Triangle Park, NC This document was externally peer reviewed under contract to Eastern Research Group, Inc. 110 Hartwell Avenue Lexington, MA 02421-3136 Questions regarding the contents of this document may be directed to the U.S. EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300). ------- TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS ii BACKGROUND 1 HISTORY 1 DISCLAIMERS 1 QUESTIONS REGARDING PPRTVS 2 INTRODUCTION 2 REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 4 HUMAN STUDIES 6 Oral Exposures 6 Inhalation Exposures 6 Other Exposures 6 ANIMAL STUDIES 6 Oral Exposures 6 Inhalation Exposures 6 Subacute Studies 6 OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 10 DERIVATION 01 PROVISIONAL VALUES 10 DERIVATION 01 ORAL REFERENCE DOSES 11 Derivation of Subchronic Provisional RfD (Subchronic p-RfD) 11 Derivation of Chronic Provisional RfD (Chronic p-RfD) 11 DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 12 Derivation of Subchronic Provisional RfC (Subchronic p-RfC) 12 Derivation of Chronic Provisional RfC (Chronic p-RfC) 12 CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 13 DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 13 Derivation of Provisional Oral Slope Factor (p-OSF) 13 Derivation of Provisional Inhalation Unit Risk (p-IUR) 13 APPENDIX A. PROVISIONAL SCREENING VALUES 14 APPENDIX B. DATA TABLES 18 APPENDIX C. BMD OUTPUTS 22 APPENDIX D. REFERENCES 26 l Fluorobenzene ------- COMMONLY USED ABBREVIATIONS BMC benchmark concentration BMD benchmark dose BMCL benchmark concentration lower bound 95% confidence interval BMDL benchmark dose lower bound 95% confidence interval HEC human equivalent concentration HED human equivalent dose IUR inhalation unit risk LOAEL lowest-observed-adverse-effect level LOAELadj LOAEL adjusted to continuous exposure duration LOAELhec LOAEL adjusted for dosimetric differences across species to a human NOAEL no-ob served-adverse-effect level NOAELadj NOAEL adjusted to continuous exposure duration NOAELrec NOAEL adjusted for dosimetric differences across species to a human NOEL no-ob served-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional reference concentration (inhalation) p-RfD provisional reference dose (oral) POD point of departure RfC reference concentration (inhalation) RfD reference dose (oral) UF uncertainty factor UFa animal-to-human uncertainty factor UFC composite uncertainty factor UFd incomplete-to-complete database uncertainty factor UFh interhuman uncertainty factor UFl LOAEL-to-NOAEL uncertainty factor UFS subchronic-to-chronic uncertainty factor WOE weight of evidence 11 Fluorobenzene ------- FINAL 3-24-2011 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR FLUOROBENZENE (CASRN 462-06-6) BACKGROUND HISTORY On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) Office of Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human health toxicity values for Superfund risk assessments, establishing the following three tiers as the new hierarchy: 1) EPA's Integrated Risk Information System (IRIS) 2) Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in EPA's Superfund Program 3) Other (peer-reviewed) toxicity values, including ~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease Registry (ATSDR); ~ California Environmental Protection Agency (CalEPA) values; and ~ EPA Health Effects Assessment Summary Table (HEAST) values. A PPRTV is defined as a toxicity value derived for use in the Superfund Program when such a value is not available in EPA's IRIS. PPRTVs are developed according to a Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific literature using the same methods, sources of data, and Agency guidance for value derivation generally used by the EPA IRIS Program. All provisional toxicity values receive internal review by a panel of six EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram consensus review provided for IRIS values. This is because IRIS values are generally intended to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund Program. Because new information becomes available and scientific methods improve over time, PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS value for a specific chemical becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It should also be noted that some PPRTV documents conclude that a PPRTV cannot be derived based on inadequate data. DISCLAIMERS Users of this document should first check to see if any IRIS values exist for the chemical of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to carefully review the information provided in this document to ensure that the PPRTVs used are appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically updated; therefore, users should ensure that the values contained in the PPRTV are current at the time of use. 1 Fluorobenzene ------- FINAL 3-24-2011 It is important to remember that a provisional value alone tells very little about the adverse effects of a chemical or the quality of evidence on which the value is based. Therefore, users are strongly encouraged to read the entire PPRTV document and understand the strengths and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may choose of their own initiative to use these PPRTVs are advised that Superfund resources will not generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund Program. QUESTIONS REGARDING PPRTVS Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on chemicals not covered, or whether chemicals have pending IRIS toxicity values) may 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), or OSRTI. Fluorobenzene is an intermediate in the production of pharmaceuticals, pesticides, and other organic compounds. The empirical formula for fluorobenzene is CeHsF (see Figure 1). A table of chemicophysical properties is provided below (see Table 1). In this document, "statistically significant" denotes a Rvalue of <0.05. INTRODUCTION F Figure 1. Fluorobenzene Structure 2 Fluorobenzene ------- FINAL 3-24-2011 Table 1. Chemico-physical Properties Table (Fluorobenzene)3 Property (unit) Value Boiling point (°C at 760 mm Hg) 84.73 Melting point (°C) -40 Density (g/cm3) 1.024 Vapor pressure (Pa at 20°C) 8000 pH (unitless) Not available Solubility in water (g/100 mL at 20°C) 0.15 Relative vapor density (air = 1) Not available Molecular weight (g/mol) 96.10 Flash point (°C) -15 Octanol/water partition coefficient (unitless) 2.27 aValues from DuPont Co. (2003). No reference dose (RfD), reference concentration (RfC), or cancer assessment for fluorobenzene is included in the EPA IRIS database (U.S. EPA, 2010b) or on the Drinking Water Standards and Health Advisories List (U.S. EPA, 2006). No RfD or RfC values are reported in HEAST (U.S. EPA, 2010a). The CARA list (U.S. EPA, 1994) does not include a Health and Environmental Effects Profile (HEEP) for fluorobenzene. The toxicity of fluorobenzene has not been reviewed by ATSDR (2008) or the World Health Organization (WHO, 2010). CalEPA (2008, 2009a) has not derived toxicity values for exposure to fluorobenzene. The American Conference of Governmental Industrial Hygienists (ACGIH, 2010), the National Institute of Occupational Safety and Health (NIOSH, 2005), and the Occupational Safety and Health Administration (OSHA, 2010) have not derived exposure limits. The HEAST (U.S. EPA, 2010a) has not reported an EPA (1986) cancer weight-of-evidence (WOE) classification for fluorobenzene. Fluorobenzene has not been evaluated under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005). The International Agency for Research on Cancer (IARC, 2010) has not reviewed the carcinogenic potential of fluorobenzene. Fluorobenzene is not included in the 11th Report on Carcinogens (NTP, 2005). CalEPA (2008, 2009a,b,c) has not prepared a quantitative estimate of carcinogenic potential for fluorobenzene. Literature searches were conducted on sources published from 1900 through March 1, 2010, for studies relevant to the derivation of provisional toxicity values for fluorobenzene, CAS No. 462-06-6. Searches were conducted using EPA's Health and Environmental Research Online (HERO) evergreen database of scientific literature. HERO searches the following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library; DOE: Energy Information Administration, Information Bridge, and Energy Citations Database; EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing Office; Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National Service Center for Environmental Publications [NSCEP] and National Environmental Publications Internet Site [NEPIS] database); PubMed: MEDLINE and CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET 3 Fluorobenzene ------- FINAL 3-24-2011 (Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI, and TSCATS; Virtual Health Library; Web of Science (searches Current Content database among others); WHO; and Worldwide Science. The following databases outside of HERO were searched for risk assessment values: ACGIH, ATSDR, CalEPA, EPA IRIS, EPA HEAST, EPA HEEP, EPA OW, EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS. REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) Table 2 provides an overview of the relevant database for fluorobenzene and includes all potentially relevant repeated short-term, subchronic-duration, and chronic-duration studies. NOAELs, LOAELs, and BMDL/BMCLs are provided in HED/HEC units for comparison except that oral noncancer values are not converted to HEDs and are identified in parentheses as (Adjusted) rather than HED/HECs. Principal studies (PS) are identified in bold. 4 Fluorobenzene ------- FINAL 3-24-2011 Table 2. Summary of Potentially Relevant Data for Fluorobenzene (CASRN 462-06-6) Notes3 Category Number of Male/Female, Species, Study Type, Study Duration Dosimetryb Critical Effects NOAELb'c BMDL/ BMCLb LOAELbc Reference (Comments) Human None Animal 1. Oral (mg/kg-day)b Subchronic None Chronic None Developmental None Reproductive None Carcinogenic None 2. Inhalation (mg/m3)b PS, NPR Subacute 5/5 Sprague-Dawley rat, inhalation (nose only), 6 hours/day, 7 days a week, 28 days 92.5,375, and 1560 Clinical signs: hunched posture and piloerection in medium- and high-dose groups that increased over time. Medium- and high-dose group males showed increased relative liver weight, which was also seen in the high-dose females; relative kidney weights were increased in high-dose males; histopathological effects were observed in the liver and kidneys of high dose males. 92.5 8.9 375 Safepharm Labs, Ltd. (1993) Subchronic None Chronic None Developmental None Reproductive None Carcinogenic None aNotes: IRIS = Utilized by IRIS, date of last update; PS = principal study; NPR = not peer reviewed. bDosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to human equivalent doses (HEDs in mg/kg-day) or human equivalent concentrations (HECs in mg/m3) units. Noncancer oral data are only adjusted for continuous exposure. following EPA guidance for Category 3 gases (U.S. EPA, 2009), concentrations were converted to adjust for continuous exposure by using the following equation: ConcADj = Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days). Concentrations were calculated for an extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default value of 1.0 is used for this ratio. ConcHEc = ConcADj x Blood Air Partition Coefficient of 1. 5 Fluorobenzene ------- FINAL 3-24-2011 HUMAN STUDIES Oral Exposures No studies investigating the effects of subchronic- or chronic-duration oral exposure to fluorobenzene in humans were identified. Inhalation Exposures No quantitative data were located regarding the toxicity of fluorobenzene to humans following subchronic- or chronic-duration inhalation exposure. Other Exposures No subchronic or long-term studies investigating the effects of occupational exposure to fluorobenzene in humans were identified. ANIMAL STUDIES Oral Exposures No subchronic-duration, chronic-duration, reproduction, or developmental studies regarding the effects of oral exposure to fluorobenzene could be located. Inhalation Exposures The effects of inhalation exposure of animals to fluorobenzene have been evaluated in a subacute (Safepharm Labs, Ltd., 1993) toxicity study. No subchronic-duration, chronic-duration, reproductive, or developmental inhalation studies could be identified. Subacute Studies The study by Safepharm Labs, Ltd. (1993) is selected as the principal study for deriving the screening subchronic p-RfC. In an unpublished, Good Laboratory Practice (GLP)-certified, subacute inhalation toxicity study, Safepharm Labs, Ltd. (1993) exposed groups of 10 Sprague-Dawley rats (5 per gender) per dose to concentrations of 0.4, 1.5, and 6.0 mg/L fluorobenzene (purity not reported) for 6 hours/day, 7 days a week, for 28 days. The study authors exposed a control group of five animals per sex to air only. The test substance was kept in glass flasks that were held in water baths at 20°C. Compressed air was passed through a water trap and respiratory quality filters before entering the system. The main air supply went through a tangential channel at the top of each exposure chamber. Some of this air was bubbled through the test substance before reaching the exposure chamber, which had a volume of approximately 30 L. Temperature and relative humidity were measured daily, and oxygen levels were measured weekly. Concentration of the test substance was measured daily. Mean atmospheric concentrations of fluorobenzene were calculated as 0, 0.37, 1.50, and 6.24 mg/L for the 0-, 0.4-, 1.5-, and 6.0-mg/L-dose groups, respectively. The corresponding exposure concentrations adjusted for continuous exposure in Sprague-Dawley rats are 0, 92.5, 375, and 1560 mg/m3. During exposure, rats were individually restrained by a polycarbonate tube, and only the nose was exposed to the test atmosphere. Animals were gradually acclimatized to the restraint procedure, and during the study period, they were rotated to account for any variation within the chambers. Rats were monitored throughout each exposure period for changes in appearance, respiration, and behavior. Clinical observations were noted before each exposure period and after removal from the test chambers. Body weight was measured at Days 0, 7, 14, 21, and 28; food consumption was measured weekly; and water consumption was initially inspected and then measured daily from 6 Fluorobenzene ------- FINAL 3-24-2011 Day 15 onward. Home cage, open field, and neurotoxicity functional observations were completed the day before initial dosing and then on Days 13 and 14 for females and Days 27 and 28 for males. Hematology and blood chemistry were analyzed prior to necropsy on Day 29; no fasting occurred before samples were taken. Urine samples following 2 weeks postdosing were also collected over a period of approximately 16 hours while rats were kept in metabolism cages. Animals were fasted, with water provided. Hematology measurements and calculations were performed, including hematocrit, hemoglobin, erythrocyte count, total leukocyte count, differential leukocyte count, platelet count, mean corpuscular hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin concentration. Blood chemistry calculations or measurements were done for blood urea, total protein, albumin, albumin/globulin ratio, sodium, potassium, chloride, calcium, inorganic phosphorus, creatinine, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, glucose, and total bilirubin. In urine, researchers measured volume, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, reducing substances, and blood, as well as microscopic examination of sediment. At the study's end, all animals were necropsied; organ weights and relative organ weights were calculated for adrenals, brain, heart, kidneys, liver, lungs, ovaries, pituitary, spleen, and testes (including epididymides). Samples of approximately 35 tissues were collected, including adrenals, aorta, bone and bone marrow, brain, cecum, kidneys, larynx, liver, lungs, lymph nodes, mammary gland, muscle, nasal cavity, esophagus, ovaries, pancreas, pituitary, prostate, rectum, salivary glands, sciatic nerve, seminal vesicles, skin, spinal cord, spleen, stomach, testes with epididymides, thymus, thyroid/parathyroid, trachea, urinary bladder, and uterus. All preserved tissues from control and high-dose groups were stained and prepared for microscopic examinations. Lungs, gross lesions, liver, and kidneys from the other dose groups were examined as well. Samples of the sternum bone and the teeth were taken from each rat and pooled to analyze for fluoride. Data were analyzed to yield group means and standard deviations, where necessary. Absolute and relative organ weights and hematological and blood chemistry parameters were analyzed using one-way analysis of variance incorporating the F-max test for homogeneity variance. Data with heterogeneous variance were tested using the Kruskal-Wallis analysis of variance and Mann-Whitney I /-test. There was no mortality during the study. Red/brown staining of the exterior body and wetness of the fur were seen in all groups. The study authors concluded that these observations were a result of restraint. Hunched posture and piloerection were seen at the 375- and 1560-mg/m3 doses. Incidence increased with progression of the study, and by Day 24, all animals exposed to a concentration of 1560 mg/m3 showed these behaviors. Animals exposed to 375 mg/m3 showed these signs from Day 21 and continuing through the study. Rats did not show any significant signs of neurotoxicity. There were no significant adverse effects indicated by body weight, food or water consumption, hematology, blood chemistry, or urine composition. Necropsies revealed no treatment-related macroscopic abnormalities. The males exposed to 375 and 1560 mg/m3 (medium and high exposures) experienced significant (p < 0.01) increases in absolute (126-129%) and relative (115-125%) liver weights; relative liver weight was also elevated (113%) in the high-dose female group (see Tables B. 1 and B.2). Relative kidney weight was also significantly increased in the high-dose male group. There were no effects detected in the low-dose group. The results of the histopathology examination of tissues from the control and high-dose animals showed irregularities in the high-dose males consisting of hepatocyte enlargement in the centrilobular liver and abnormal quantities of eosinophilic material in the 7 Fluorobenzene ------- FINAL 3-24-2011 renal proximal tubular epithelium as well as groups of basophilic/dilated tubules (see Table B.3). Other adaptive kidney changes were reported, including hydrocarbon nephropathy in males in all dose groups. Eosinophilic droplets were seen in the tubular epithelium of the kidneys of male rats at the medium and high doses. This was noted as a treatment-related effect, typical of hydrocarbon administration. There were no treatment-related respiratory effects found. Additionally, a substantial increase in fluoride was measured in teeth and sternum samples from all groups (see Table B.4). Authors established a NOAEL of 0.37-mg/L (NOAELadj of 92.5-mg/m3) fluorobenzene, based on the lack of treatment-related adverse effects at this dose level. A LOAELadj of 375 mg/m3 is identified based on increased liver weight (absolute and relative) in male rats, which is supported by an increase in incidence of centrilobular hepatocyte enlargement at the higher dose. Although an increase in relative kidney weight, supported by histopathology changes, was observed in treated animals, the effects were only significant in the high-dose group (1560 mg/m3), making the liver a more sensitive indicator of exposure. This study is GLP certified, and the procedures were based on guideline recommendations Method B8, Annex V of the European Economic Community (EEC) Commission Directive 84/449/EEC, and Organisation for European Economic Co-operation (OECD) Guideline 412 (OECD, 1997). Despite the lack of peer review and the shortness in exposure duration, the quality of the study supports its use in the derivation of a screening subchronic p-RfC. 8 Fluorobenzene ------- FINAL 3-24-2011 Table 3. Other Studies Test Materials and Methods Results Conclusions References Genotoxicity Conducted Ames test on Salmonella typhimurium strains TA98, TA1538, TA1537, TA100, and TA1535 with and without rat liver metabolic activation. Authors reported no positive results in any strain with or without metabolic activation. Negative for mutagenicity. Shimizu et al. (1983) Genotoxicity Conducted preincubationally modified Ames test using S. typhimurium strains TA97, TA98, TA100, and TA1535 with and without rat and hamster liver metabolic activation. Test results indicated a positive response. Activation and strain unknown. Positive for mutagenicity. Zeiger and Margolin (2000) Genotoxicity Performed in vivo micronucleus assay in mice. Procedure was based on the recommendations for OECD Guideline 474 (OECD, 1997), but precise study methods were unavailable. Results were negative. OECD Guideline 474 (OECD, 1997) defines negative as meaning there was no significant increase in the ratio of normochromatic to polychromatic erythrocytes. These results suggest no genotoxicity of fluorobenzene. DuPont Co. (2003) 9 Fluorobenzene ------- FINAL 3-24-2011 OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) Table 3 presents summary of short-term studies. The genotoxicity of fluorobenzene has been tested in multiple studies. In a published study, Shimizu et al. (1983) investigated the mutagenic effects of fluorobenzene on Salmonella typhimurium. The study authors conducted an Ames test using S9 rat liver fraction in strains TA98, TA1538, and TA1537 to evaluate potential frameshift mutations, and in strains TA100 and TA1535 to evaluate potential mutation by base-pair substitution and incubation for 3 days. The authors observed no change in the number of revertant colonies and concluded that fluorobenzene is not genotoxic with or without metabolic activation. In a National Toxicology Program-sponsored, published study, Zeiger and Margolin (2000) performed an in vitro bacterial reverse mutation assay investigating the genetic toxicity of fluorobenzene on S. typhimurium strains. The authors conducted a modified Ames test, using a preincubation procedure with and without rat and hamster liver metabolic activation in strains TA97 and TA98 to evaluate potential frameshift mutations and in strains TA100 and TA1535 to evaluate potential mutation by base-pair substitution and incubation for 3 days. The authors reported that fluorobenzene was mutagenic; however, the strains and activation resulting in the positive response were not specified. Cytotest Cell Research Gmbh & Co. (1991) conducted a micronucleus assay investigating the genotoxicity of fluorobenzene in mice. Though the original report and data of Cytotest Cell Research Gmbh & Co. (1991) is reported in German, an acceptable review of the study has been conducted by DuPont Co. (2003), and information from DuPont Co. (2003) is presented for the purposes of this review. The authors conducted an OECD (1997) 474 mouse micronucleus assay by dosing NMRI male and female mice with fluorobenzene (99.7% pure) in corn oil (unreported dose and method of administration) and measuring the ratio of normochromatic to polychromatic erythrocytes (NCEs and PCEs, respectively). The results were reported to be negative, indicating no significant increase in the number of micronucleated PCEs was found in test subjects as compared to controls. The genotoxicity of fluorobenzene has been tested using in vitro test systems (Cytotest Cell Research Gmbh & Co., 1991; Zeiger and Margolin, 2000; Shimizu et al., 1983). With these few reported studies, the literature on the mutagenicity of fluorobenzene is equivocal. Further investigations are needed before a conclusive understanding of the mutagenic potential of fluorobenzene can be reached. DERIVATION OF PROVISIONAL VALUES Table 4 below presents a summary of noncancer reference values. Table 5 presents a summary of cancer values. The toxicity values are converted to HEC/HED units, with the exception of noncancer oral values, which are converted to adjusted daily doses (ADJ). The conversion process is described in the footnotes. IRIS data are indicated in the tables, if applicable. 10 Fluorobenzene ------- FINAL 3-24-2011 Table 4. Summary of Reference Values for Fluorobenzene (CASRN 462-06-6)a Toxicity Type (Units) Species/Sex Critical Effect p-Reference Value POD Method POD UF Principal Study Subchronic p-RfD (mg/kg-day) None None None None None None None Chronic p-RfD (mg/kg-day) None None None None None None None Screening Subchronic p-RfC (mg/m3) Sprague-Dawley rat/male Centrilobular hepatocyte enlargement 3.0 x 10"2 BMC 8.9 300 Safepharm Labs, Ltd. (1993) Screening Chronic p-RfC (mg/m3) Sprague-Dawley rat/male None None None None None None following the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009) concentrations were converted to adjust for continuous exposure and HEC by using the following equations: ConcADi= Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days); ConcnEc = ConcADj x Blood Air Partition Coefficient of 1; concentrations were calculated for an extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default value of 1.0 is used for this ratio. Table 5. Summary of Cancer Values for Fluorobenzene (CASRN 462-06-6)a Toxicity Type Species/Sex Tumor Type Cancer Value Principal Study p-OSF None None None None p-IUR None None None None ""Following the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009) concentrations were converted to adjust for continuous exposure and HEC by using the following equations: ConcADj= Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days); ConcHEc = ConcADj x Blood Air Partition Coefficient of 1; concentrations were calculated for an extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default value of 1.0 is used for this ratio. DERIVATION OF ORAL REFERENCE DOSES Derivation of Subchronic Provisional RfD (Subchronic p-RfD) No appropriate human or animal studies examining the effects of oral sub chronic-duration exposure could be located. Therefore, derivation of a subchronic p-RfD is precluded. Derivation of Chronic Provisional RfD (Chronic p-RfD) No human or animal studies examining the effects of oral chronic-duration exposure could be located. Therefore, derivation of a chronic p-RfD is precluded. 11 Fluorobenzene ------- FINAL 3-24-2011 DERIVATION OF INHALATION REFERENCE CONCENTRATIONS Table 6 presents a summary of inhalation studies identified. Derivation of Subchronic Provisional RfC (Subchronic p-RfC) No subchronic p-RfC can be derived for the following reason: A nonpeer-reviewed study is selected as the principal study. However, a screening value is provided in Appendix A. Derivation of Chronic Provisional RfC (Chronic p-RfC) No human or animal inhalation studies examining the effects of chronic exposure could be located. Because the study used to derive the subchronic p-RfC is a subacute study, it cannot be used to derive a chronic provisional value. Therefore, derivation of a chronic p-RfC is precluded. Table 6. Summary of Relevant Inhalation Toxicity Studies for Fluorobenzene Reference Number of Male/Female, Species Exposure (mg/m3) Frequency/ Duration NOAELW (mg/m3) loaelAI)I (mg/m3) Critical Endpoint Safepharm Labs, Ltd. (1993) 5/5 Sprague-Dawley rats 92.5, 375, and 1560 6 hours/day, 7 days a week, 28 days (nose only) 92.5a 375a Centrilobular hepatocyte enlargement ""Following the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009) concentrations were converted to adjust for continuous exposure and HEC by using the following equations: ConcADi= Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed/Total Days); ConcnEc = ConcADj x Blood Air Partition Coefficient of 1; concentrations were calculated for an extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default value of 1.0 is used for this ratio. 12 Fluorobenzene ------- FINAL 3-24-2011 CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR Table 7 identifies the cancer WOE descriptor for fluorobenzene. Table 7. Cancer WOE Descriptor for Fluorobenzene Possible WOE Descriptor Designation Route of Entry (Oral, Inhalation, or Both) Comments "Carcinogenic to humans " N/A N/A No human cancer studies are available. "Likely to be carcinogenic to humans " N/A N/A No strong animal cancer data are available. "Suggestive evidence of carcinogenic potential" N/A N/A The evidence from human and animal studies is not sufficient to be suggestive of carcinogenicity. "Inadequate information to assess carcinogenic potential" X Both Inadequate information is available to assess carcinogenic potential. The mutagenicity studies are equivocal, and in vivo studies have not been of sufficient duration to evaluate carcinogenicity. "Not likely to be carcinogenic to humans " N/A N/A No strong evidence of noncarcinogenicity in humans is available. DERIVATION OF PROVISIONAL CANCER POTENCY VALUES Derivation of Provisional Oral Slope Factor (p-OSF) No human or animal studies examining the carcinogenicity of fluorobenzene following oral exposure have been located. Therefore, derivation of a p-OSF is precluded. Derivation of Provisional Inhalation Unit Risk (p-IUR) No human or animal studies examining the carcinogenicity of fluorobenzene following inhalation exposure have been located. Therefore, derivation of a p-IUR is precluded. 13 Fluorobenzene ------- FINAL 3-24-2011 APPENDIX A. PROVISIONAL SCREENING VALUES DERIVATION OF SCREENING PROVISIONAL INHALATION REFERENCE CONCENTRATIONS Derivation of Screening Subchronic Provisional RfC (Subchronic p-RfC) For the reasons noted in the main document, it is inappropriate to derive a provisional subchronic p-RfC for fluorobenzene. However, information is available that, 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 a supplement and develops a screening value. Appendices receive the same level of internal and external scientific peer review as the main document to ensure their appropriateness within the limitations detailed in the main document. Users of the screening toxicity values in a supplement to a PPRTV assessment should understand that there is considerably more uncertainty associated with the derivation of a supplemental 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. The study by Safepharm Labs, Ltd. (1993) is selected as the principal study for the derivation of a screening subchronic p-RfC. The study is unpublished but is reviewed in DuPont's (2003) Robust Summary for Fluorobenzene, which is publicly available as part of EPA's Chemical Right-to-Know Program. The study is GLP compliant, but does not reach the exposure duration that current EPA and OECD guidelines recommend for an inhalation study. The critical endpoint, resulting in the benchmark concentration lower bound 95% confidence interval (BMCL), is centrilobular hepatocyte enlargement in male Sprague-Dawley rats. Other endpoints considered for modeling include an increase in kidney weight, eosinophilic droplets in the tubular epithelium of the kidney, and by the enlargement in the liver of male rats exposed to 375 mg/m3 or more of fluorobenzene, and is specifically mentioned by the study authors as being an "observed effect of concern." There are no other studies of an appropriate duration to support the findings of the Safepharm Labs, Ltd. (1993) study. Chlorobenzene, a similar but more studied chemical than fluorobenzene, has been shown in subchronic- and chronic-duration inhalation rodent studies to cause an increase in liver and kidney weights (ASTDR, 1990). Available data from chlorobenzene support identifying the liver and kidneys as target organs for toxicity in rodents. The significant liver and kidney changes observed in the study by Safepharm Labs, Ltd. (1993) (centrilobular hepatocyte enlargement, relative liver weight, eosinophilic droplets in the kidney, and relative kidney weight) were considered as candidates for determination of a point of departure (POD) and were modeled using EPA's BMDS (version 2.1) (2008). The summary of the modeling results for all endpoints considered is presented in Table C. 1. The results from the modeling of the centrilobular hepatocyte enlargement data represent the lowest and most appropriate BMCL, and, thus, POD for developing a screening p-RfC. The characteristics of fluorobenzene indicate that it is a Category 3 gas and, thus, has effects peripheral to the respiratory system (U.S. EPA, 2009). Because Category 3 gases cause extrarespiratory effects, the concentrations in the study were converted to adjusted doses (to 14 Fluorobenzene ------- FINAL 3-24-2011 account for continuous exposure) and then to HEC concentrations utilizing a default blood:air partition coefficient of 1 because the actual value is unknown. To determine the POD for derivation of the screening subchronic p-RfC, benchmark dose (BMD) modeling of the centrilobular hepatocyte enlargement data has been conducted using EPA's BMDS (version 2.1) (2008). As recommended by EPA (2008), a 10% risk above the control mean has been used as the benchmark response (BMR) level. The following dosimetric adjustments were made for inhalation exposure in adjusting for continuous exposure and then human equivalent concentrations: Continuous exposure conversion: Coiicadj = Concentration x (Hours per Day x Days Dosed + Total Days) = 0.37 mg/L x 1000 L/m3 x (6 h 24 h in a day) x (28 Days Dosed ^ 28 Total Days) = 370 mg/m3 x 0.25 = 92.5 mg/m3 HEC conversion: ConcHEc ConcADj x Blood Air Partition Coefficient = 92.5 mg/m x 1 = 92.5 mg/m3 Table A.l presents the model input data for the incidence of hepatocyte enlargement in male rats exposed to fluorobenzene by inhalation for 28 days. Table A.l. Concentration-Response Data for Fluorobenzene-Induced Hepatocyte Enlargement in Male Rats Exposed by Inhalation for 28 Days3 Cone (mg/L) Coiicadj (mg/m3)b Coiichec (mg/m3)b Subjects in Dose Group Incidence 0 0 0 5 0 0.37 92.5 92.5 5 2 1.50 375 375 5 3 6.25 1560 1560 5 4 aSafepharm Labs, Ltd. (1993). bFollowing the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009) concentrations were converted to adjust for continuous exposure and HEC by using the following equations: ConcADj = Concentrations in mg/L x 1000 L/m3 x (Hours per Day ^ 24 hours) x (Days Dosed ^ Total Days); ConcHEc = ConcADj x Blood Air Partition Coefficient of 1; concentrations were calculated for an extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default value of 1.0 is used for this ratio. 15 Fluorobenzene ------- FINAL 3-24-2011 Table A.2 shows the modeling results. Adequate model fit is obtained for hepatocyte enlargement incidence data using the Log-Logistic model. The modeling results for hepatocyte enlargement yield a BMCio of 24.6 mg/m3 and a BMCLio of 8.9 mg/m3. Table A.2. Model Predictions for Hepatocyte Enlargement in Male Rats Exposed by Inhalation for 28 Days" Model Goodness-of-Fit /?-Valueb AICb for Fitted Model BMC10 (mg/m3) BMCL10 (mg/m3) Conclusions Gamma 0.29 25.229 74.177 33.904 Hit bound (power =1) Weibull 0.29 25.229 74.173 33.904 Hit bound (power =1) Log-Probit 0.21 25.855 117.737 40.369 Hit bound (slope = 1) Log-Logistic 0.91 20.962 24.563 8.871 Lowest AIC Lowest BMCL Hit bound (slope = 1) Multistage 0.29 25.229 74.173 33.904 Maximum order beta = 0 P2 = 0 03 = 0 Logistic 0.23 26.580 198.917 100.387 Probit 0.23 26.588 201.270 113.902 Quantal Linear 0.29 25.229 74.173 33.904 "Safepharm Labs Ltd., 1993. bValues <0.10 fail to meet conventional goodness-of-fit criteria. AIC = Akaike's Information Criteria; BMC = benchmark concentration; BMCL = lower confidence limit (95%) on the benchmark concentration. -3 The screening subchronic p-RfC is based on the BMCLio of 8.9 mg/m (lowest BMCLio for a range of 9-114) derived from male rats exposed to fluorobenzene for 28 days (Safepharm Labs Ltd., 1993). The screening subchronic p-RfC for fluorobenzene, based on the BMCLio, is derived as follows: Screening Subchronic p-RfC = BMCLisd + UFC = 8.9 mg/m3 ^ 300 = 0.03 mg/m3 or 3 x 10~2 mg/m3 Table A.3 summarizes the uncertainty factors (UFs) for the screening subchronic p-RfC for fluorobenzene. 16 Fluorobenzene ------- FINAL 3-24-2011 Table A.3. Uncertainty Factors for Screening Subchronic p-RfC for Fluorobenzene UF Value Justification Notes UFa 3 A UFa of 3 is applied for animal-to-human extrapolation to account for the toxicodynamic portion of a UFA, because the toxicokinetic portion (10°5) has been addressed in dosimetric conversions. ufd 10 A UFd of 10 is selected because there are no acceptable two-generation reproduction studies or developmental studies, and there are no indications of any other studies that may be relevant for the database UF. UFh 10 A UFh of 10 is applied for intraspecies differences to account for potentially susceptible individuals in the absence of information on the variability of response in humans. ufl 1 A UFl of 1 is applied because the POD was developed using a BMCL. UFS 1 A UFS of 1 is applied because a subchronic-duration study was utilized as the critical study. A UFS greater than 1 is not necessary when using subacute study to support a subchronic value. UFC 300 17 Fluorobenzene ------- FINAL 3-24-2011 APPENDIX B. DATA TABLES Table B.l. Body and Organ Weights in Sprague-Dawley Rats Exposed to Inhaled Fluorobenzene for 28 Days3 Exposure Group (Human Equivalent Concentration, mg/m3) 0 mg/L 0.37 mg/L 1.50 mg/L 6.25 mg/L Parameter (0)b (92.5)b (375)b (1560)b Male Sample size 5 5 5 5 Final body weight0 312± 17 333 ±26 339 ±32 320 ±36 Adrenal gland0 0.0334 ±0.0080 0.0404 ±0.0128 0.0419 ±0.0073 0.0403 ±0.0114 Brain0 1.9417 ±0.0698 1.9462 ±0.0771 1.9964 ±0.0517 1.8847 ±0.1086 Heart0 1.2317 ±0.1486 1.3466 ±0.1667 1.3366 ±0.1477 1.2651 ±0.1712 Kidneys0 2.1192 ±0.1284 2.3213 ±0.2689 2.4787 ±0.2937 2.4747 ± 0.3402 Liver0 11.2929 ± 1.1165 12.5349 ± 1.3711 14.263 ± 1.8717d 14.5066 ± 1.3553d Lungs0 1.5063 ±0.0570 1.5511 ±0.0848 1.5056 ±0.1607 1.4079 ±0.1811 Pituitary0 0.0090 ±0.0015 0.0133 ±0.0015d 0.0137 ±0.0026d 0.0092 ±0.0017 Spleen0 0.6470 ± 0.0766 0.6445 ±0.1095 0.7208 ± 0.0796 0.6687 ±0.1256 Gonads0 4.0022 ±0.2316 4.1775 ±0.2197 4.1332 ±0.2833 4.1712 ±0.2978 Female Sample size 5 5 5 5 Final body weight0 226 ± 16 237 ±28 225 ± 23 229 ±9 Adrenal gland0 0.0444 ±0.0041 0.0609 ±0.0053° 0.0495 ±0.0123 0.0500 ±0.0115 Brain0 1.7808 ±0.0678 1.9142 ±0.0760° 1.8002 ±0.1076 1.8139 ±00.413 Heart0 0.9744 ±0.0939 0.9638 ±0.1150 0.8672 ±0.1020 0.9125 ±0.0684 Kidneys0 1.6653 ±0.0930 1.7663 ±0.1963 1.7167 ±0.1970 1.7858 ±0.2181 Liver0 8.5148 ±0.6904 8.7789 ± 1.0033 8.5537 ±0.9723 9.3969 ±0.3052 Lungs0 1.3077 ±0.1136 1.2636 ±0.1375 1.2444 ±0.1017 1.2238 ±0.0702 Pituitary0 0.0144 ±0.0040 0.0122 ±0.0034 0.0118 ±0.0032 0.0123 ±0.0029 Gonads0 0.3413 ±0.0798 0.3618 ± 0.1134 0.5902 ±0.0399 0.5237 ±0.0494 aSafepharm Labs, Ltd. (1993). bFollowing the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009) concentrations were converted to adjust for continuous exposure and HEC by using the following equations: ConcADi = Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days); ConcnEc = ConcADi x Blood Air Partition Coefficient of 1; concentrations were calculated for an extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default value of 1.0 is used for this ratio. °Mean ± SD. Significantly different from control group at the p < 0,01 level by one-way analysis of variance performed by the researchers. "Significantly different from control group at the p < 0.05 level by one-way analysis of variance performed by the researchers. 18 Fluorobenzene ------- FINAL 3-24-2011 Table B.2. Relative Organ Weights (Percentage of Body Weight) in Sprague-Dawley Rats Exposed to Inhaled Fluorobenzene for 28 Days3 Exposure Group (Human Equivalent Concentration, mg/m3) Parameter 0 mg/L (0)b 0.37 mg/L (92.5)b 1.50 mg/L (375)b 6.25 mg/L (1560)b Male Sample size 5 5 5 5 Adrenal gland0 0.0109 ±0.0027 0.0121 ±0.0031 0.0127 ±0.0027 0.0127 ±0.0029 Brain0 0.6374 ±0.0534 0.5984 ±0.0282 0.6035 ± 0.0466 0.6021 ±0.0556 Heart0 0.4058 ±0.0712 0.4113 ±0.0656 0.4133 ±0.0789 0.4026 ± 0.0454 Kidneys0 0.6994 ± 0.0493 0.7032 ±0.0306 0.7446 ± 0.0458 0.7842 ± 0.0494d Liver0 3.6883 ±0.1919 3.7994 ±0.1782 4.2361 ±0.1889° 4.6111 ±0.1877° Lungs0 0.4934 ±0.0235 0.4721 ±0.0295 0.4532 ±0.0373f 0.4462 ± 0.023 lf Pituitary0 0.0029 ± 0.0005 0.0040 ± 0.0004d 0.0041 ±0.0004° 0.0029 ± 0.0005 Spleen0 0.2112 ±0.0175 0.1955 ±0.0287 0.2169 ±0.0170 0.2109 ±0.0196 Gonads0 1.3114 ±0.0932 1.2719 ±0.0852 1.2469 ±0.0737 1.3447 ±0.2584 Female Sample size 5 5 5 5 Adrenal gland0 0.0206 ±0.0016 0.0257 ± 0.0026f 0.0218 ±0.0031 0.0220 ± 0.0043 Brain0 0.7899 ±0.0374 0.8299 ±0.0868 0.8073 ± 0.0769 0.8061 ±0.0392 Heart0 0.4308 ± 0.0222 0.4153 ±0.0394 0.3867 ±0.0281f 0.4048 ±0.0312 Kidneys0 0.7385 ±0.0425 0.7603 ± 0.0446 0.7663 ± 0.0669 0.7932 ±0.1066 Liver0 3.7672 ±0.1119 3.7745 ±0.1368 3.8111 ±0.2072 4.2625 ±0.3416d Lungs0 0.5784 ±0.0213 0.5473 ± 0.0473 0.5576 ± 0.0420 0.5434 ±0.0464 Pituitary0 0.0066 ± 0.0020 0.0053 ±0.0013 0.0054 ±0.0018 0.0054 ±0.0012 Spleen0 0.2398 ±0.0324 0.2401 ±0.0329 0.2643 ± 0.0243 0.2318 ±0.0149 Gonads0 0.0322 ±0.0054 0.0469 ± 0.0058 0.0565 ±0.0052 0.0567 ± 0.0080 aSafepharm Labs, Ltd. (1993). bFollowing the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009) concentrations were converted to adjust for continuous exposure and HEC by using the following equations: ConcADi = Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days); ConcnEc = ConcADi x Blood Air Partition Coefficient of 1; Concentrations were calculated for an extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default value of 1.0 is used for this ratio. °Mean ± SD. Significantly different from control group at the p < 0.01 level by one-way analysis of variance performed by the researchers. "Significantly different from control group at the p < 0.001 level by one-way analysis of variance performed by the researchers. Significantly different from control group at the p < 0.05 level by one-way analysis of variance performed by the researchers. 19 Fluorobenzene ------- FINAL 3-24-2011 Table B.3. Incidences of Histopathological Findings in Kidneys and Livers of Sprague-Dawley Rats Exposed to Inhaled Fluorobenzene for 28 Days3 Exposure Group (Human Equivalent Concentration, mg/m3) Parameter 0 mg/L (0)b 0.37 mg/L (92.5)b 1.50 mg/L (375)b 6.25 mg/L (1560)b Male Rats Kidney Groups of basophilic/dilated tubules0 0/5 0/5 2/5 2/5 Eosinophilic droplets proximal tubular epithelium0 0/5 0/5 3/5 4/5 d Liver Scattered mononuclear cell foci0 5/5 5/5 5/5 5/5 Focal hepatocyte necrosis0 0/5 0/5 0/5 1/5 Centrilobular hepatocyte enlargement0 0/5 2/5 3/5 4/5 d Female Rats Kidney Groups of basophilic/dilated tubules0 2/5 0/5 0/5 0/5 Liver Scattered mononuclear cell foci0 5/5 4/5 5/5 5/5 Focal hepatocyte necrosis0 0/5 0/5 1/5 0/5 aSafepharm Labs, Ltd. (1993). ''Following the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009) concentrations were converted to adjust for continuous exposure and HEC by using the following equations: ConcADi = Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed ^ Total Days); ConcnEc = ConcADi x Blood Air Partition Coefficient of 1; concentrations were calculated for an extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default value of 1.0 is used for this ratio. °Number of animals with endpoint/number of animals examined. Significantly different from control (p < 0.05) by Fisher's exact test (two-tailed) performed for this review. 20 Fluorobenzene ------- FINAL 3-24-2011 Table B.4. Fluoride Concentration in Sternum and Teeth3 Exposure Group (Human Equivalent Concentration, mg/m3) 0 mg/L 0.37 mg/L 1.50 mg/L 6.25 mg/L Parameter (0)b (92.5)b (375)b (1560)b Fluoride concentration (ppm) Male Sample size 5 5 5 5 Sternum0 100 339 [+239] 344 [+244] 556 [+456] Teeth0 138 92 [-33] 273 [+98] 396 [186] Female Sample size 5 5 5 5 Sternum0 149 277 [+86] 427 [+187] 534 [+258] Teeth0 60 213 [+255] 292 [+387] 436 [+627] aSafepharm Labs, Ltd. (1993). ''Following the methods in the Risk Assessment Guidance for Superfund Volume I (U.S. EPA, 2009) concentrations were converted to adjust for continuous exposure and HEC by using the following equations: ConcADi = Concentrations in mg/L x 1000 L/m3 x (Hours per Day x Days Dosed + Total Days); ConcnEc = ConcADj x Blood Air Partition Coefficient of 1; concentrations were calculated for an extrarespiratory effect for a Category 3 gas. Because the Blood Air Partition Coefficient lambda for humans is unknown, a default value of 1.0 is used for this ratio. °Mean [change compared to control]. 21 Fluorobenzene ------- FINAL 3-24-2011 APPENDIX C. BMD OUTPUTS Table C.l. Summary of BMDS Results for Fluorobenzene3 Endpoint Gender Species Model Type £ s OS u S as -J U S as BMC/BMCL % H 2 13 > i a. H 2 cS > i % 0 H ,2 sS > 1 a. /j-Valuc Test 4 U — < Scaled Residual of Interest Model Selection Notes Bound Flags? Parameter Notes Liver Centrilobular hepatocyte enlargement13 Male Rat Dichotomous -Log-Logistic 0.1 2.5 x lo1 8.9 x 10° 2.8 N/A N/A N/A 0.908 20.9618 0 Lowest AIC Lowest BMCL hit bound (slope =1) Flag Hit bound (slope = 1) Relative Liver Weight0 Male Rat Continuous- Hill 1 1.2 x 102 4.7 x 101 2.6 <0001 0.999 0.985 NA -39.5839 0.00037 Lowest BMCL p-score p < 0.1 Wrong variance model No Flag Kidney Eosinophilic droplets proximal tubular epithelium Male Rat Dichotomous -Log-Probit 0.1 1.3 x 102 6.6 x 101 1.9 N/A N/A N/A 0.715 15.2874 -0.538 Lowest AIC hit bound (slope =1) Flag Hit bound (slope = 1) Relative Kidney Weight Male Rat Continuous- Linear 1 2.4 x 102 1.4 x 102 1.7 <0001 <0001 0.332 0.332 -74.9061 -0.0961 Lowest AIC Lowest BMCL No Flag Relative Liver Weight Female Rat Continuous- Linear 1 4.0 x 102 2.4 x 102 1.7 1 X 10"3 0.06 0.521 0.922 -43.2711 -0.677 Lowest AIC Lowest BMCL No Flag Relative Lung Weight Male Rat Continuous- Linear 1 1.2 x 103 7.0 x 102 1.8 0.135 0.655 0.655 0.164 -116.618 0.322 Lowest AIC Lowest BMCL No Flag aSafepharm Labs, Ltd. (1993). bEndpoint used for POD. °No models for this endpoint passed the selection criteria for an appropriate fit. 22 Fluorobenzene ------- FINAL 3-24-2011 SafePharml993_Liver_ CentrilMLogLogisticl Log-Logistic Model with 0.95 Confidence Level Log-Logistic 1 0.8 0.6 0.4 0.2 0 B BMD 0 200 400 600 800 1000 1200 1400 1600 dose 15:20 04/28 2010 Logistic Model. (Version: 2.12; Date: 05/16/2008) Input Data File: C:\l\SafePharm 1993 Liver Centril M LogLogistic 1. (d) Gnuplot Plotting File: C:\l\SafePharm 1993 Liver Centril M LogLogistic l.plt Wed Apr 28 15:20:01 2010 [add notes here] The form of the probability function is: P[response] = background+(1-background)/[1+EXP(-intercept- slope*Log(dose) ) ] Dependent variable = DichEff 23 Fluorobenzene ------- FINAL 3-24-2011 Independent variable = Dose Slope parameter is restricted as slope >= 1 Total number of observations = 4 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: le-008 Parameter Convergence has been set to: le-008 User has chosen the log transformed model Default Initial background = intercept = slope = Parameter Values 0 -5.73806 1 Asymptotic Correlation Matrix of Parameter Estimates ( *** The model parameter(s) -background -slope have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix ) intercept intercept 1 Parameter Estimates Confidence Interval Variable Estimate Upper Conf. Limit background 0 ~k intercept -5.39846 ~k slope 1 Std. Err. 95.0% Wald Lower Conf. Limit * - Indicates that this value is not calculated. Analysis of Deviance Table Model Log(likelihood) # Param's Deviance Test d.f. P-value Full model -9.23213 4 Fitted model -9.48092 1 0.497573 3 0.9194 Reduced model -13.7628 1 9.06129 3 0.02849 24 Fluorobenzene ------- FINAL 3-24-2011 AIC: 20.9618 Goodness of Fit Scaled Dose Est. Prob. Expected Observed Size Residual 0.0000 0.0000 0.000 0.000 5 0.000 92.5000 0.2950 1.475 2.000 5 0.515 375.0000 0.6291 3.146 3.000 5 -0.135 1560.0000 0.8759 4.379 4.000 5 -0.515 ChiA2 = 0.55 d.f. = 3 P-value = 0.9082 Benchmark Dose Computation Specified effect = 0.1 Risk Type = Extra risk Confidence level = 0.95 BMC = 2 4.5628 BMCL = 8 . 8712 8 25 Fluorobenzene ------- FINAL 3-24-2011 APPENDIX D. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 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CalEPA (California Environmental Protection Agency). (2009a) OEHHA/ARB approved chronic reference exposure levels and target organs. Sacramento: Office of Environmental Health Hazard Assessment. Available online at http://www.arb.ca.gov/toxics/healthval/chronic.pdf. CalEPA (California Environmental Protection Agency). (2009b) Hot spots unit risk and cancer potency values. Sacramento, CA: Office of Environmental Health Hazard Assessment. Available online at http://www.oehha.ca.gov/air/hot_spots/pdf/TSDlookup2002.pdf CalEPA (California Environmental Protection Agency). (2009c) Technical support document for describing available cancer potency factors. Appendix I. Sacramento, CA: Office of Environmental Health Hazard Assessment. Available online at http://www.oehha.ca.gov/air/hot_spots/pdf/Appendix%20I2002.pdf. Dupont Co. (2003) Robust summary for fluorobenzene. 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(2000) The proportion of mutagens among chemicals in commerce. Regul Toxicol Pharmacol 32(2):219-225. 596362 28 Fluorobenzene ------- |