S-EPA United States Environmental Protection Agency EPA/690/R-24/002F | August 2024 | FINAL Provisional Peer-Reviewed Toxicity Values for l-Phenyl-l-(4-methylphenyl)-ethane (PTE) (CASRN 3717-68-8) U.S. EPA Office of Research and Development Center for Public Health and Environmental Assessment ------- A mA United States Environmental Protection »»Agency EPA 690 R-24 002F August 2024 https://www.epa.gov/pprtv Provisional Peer-Reviewed Toxicity Values for 1 -Phenyl-1 -(4-methylphenyl)-ethane (PTE) (CASRN 3717-68-8) Center for Public Health and Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- AUTHORS, CONTRIBUTORS, AND REVIEWERS CHEMICAL MANAGER Kyoungju Choi, PhD Center for Public Health and Environmental Assessment, Cincinnati, OH SCIENTIFIC TECHNICAL LEAD Lucina E. Lizarraga, PhD Center for Public Health and Environmental Assessment, Cincinnati, OH CONTRIBUTOR Allison L. Phillips, PhD Center for Public Health and Environmental Assessment, Cincinnati, OH Lucina E. Lizarraga, PhD Center for Public Health and 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 Center for Public Health and Environmental Assessment, Cincinnati, OH M. Margaret Pratt, PhD Center for Public Health and Environmental Assessment, Washington, DC PRIMARY EXTERNAL REVIEWERS Organized by Eastern Research Group, Inc. 110 Hartwell Avenue Lexington, MA 02421-3136 PPRTV PROGRAM MANAGEMENT Teresa L. Shannon Center for Public Health and Environmental Assessment, Cincinnati, OH Allison Phillips, PhD Center for Public Health and Environmental Assessment, Cincinnati, OH J. Phillip Kaiser, PhD, DABT Center for Public Health and Environmental Assessment, Cincinnati, OH Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA Office of Research and Development (ORD) Center for Public Health and Environmental Assessment (CPHEA) website at https://ecomments.epa.gov/pprtv. ii 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS AND ACRONYMS iv BACKGROUND 1 QUALITY ASSURANCE 1 DISCLAIMERS 2 QUESTIONS REGARDING PPRTVs 2 1. INTRODUCTION 3 2. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 7 2.1. HUMAN STUDIES 10 2.2. ANIMAL STUDIES 10 2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 10 3. DERIVATION 01 PROVISIONAL VALUES 11 3.1. DERIVATION OF ORAL REFERENCE DOSES 11 3.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 11 3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES 11 3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 11 3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 12 APPENDIX A. SCREENING NONCANCER PROVISIONAL VALUES 13 APPENDIX B. PARAMETERS OF TOOLS USED FOR READ ACROSS 23 APPENDIX C. REFERENCES 24 in 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- COMMONLY USED ABBREVIATIONS AND ACRONYMS a2u-g alpha 2u-globulin IVF in vitro fertilization ACGIH American Conference of Governmental LC50 median lethal concentration Industrial Hygienists LD50 median lethal dose AIC Akaike's information criterion LOAEL lowest-observed-adverse-effect level ALD approximate lethal dosage MN micronuclei ALT alanine aminotransferase MNPCE micronucleated polychromatic AR androgen receptor erythrocyte AST aspartate aminotransferase MOA mode of action atm atmosphere MTD maximum tolerated dose ATSDR Agency for Toxic Substances and NAG 7V-acetyl-P-D-glucosaminidase Disease Registry NCI National Cancer Institute BMC benchmark concentration NO A F.I. no-observed-adverse-effect level BMCL benchmark concentration lower NTP National Toxicology Program confidence limit NZW New Zealand White (rabbit breed) BMD benchmark dose OCT ornithine carbamoyl transferase BMDL benchmark dose lower confidence limit ORD Office of Research and Development BMDS Benchmark Dose Software PBPK physiologically based pharmacokinetic BMR benchmark response PCNA proliferating cell nuclear antigen BUN blood urea nitrogen PND postnatal day BW body weight POD point of departure CA chromosomal aberration PODadj duration-adjusted POD CAS Chemical Abstracts Service QSAR quantitative structure-activity CASRN Chemical Abstracts Service registry relationship number RBC red blood cell CBI covalent binding index RDS replicative DNA synthesis CHO Chinese hamster ovary (cell line cells) RfC inhalation reference concentration CL confidence limit RfD oral reference dose CNS central nervous system RGDR regional gas dose ratio CPHEA Center for Public Health and RNA ribonucleic acid Environmental Assessment SAR structure-activity relationship CPN chronic progressive nephropathy SCE sister chromatid exchange CYP450 cytochrome P450 SD standard deviation DAF dosimetric adjustment factor SDH sorbitol dehydrogenase DEN diethylnitrosamine SE standard error DMSO dimethylsulfoxide SGOT serum glutamic oxaloacetic DNA deoxyribonucleic acid transaminase, also known as AST EPA Environmental Protection Agency SGPT serum glutamic pyruvic transaminase, ER estrogen receptor also known as ALT FDA Food and Drug Administration SSD systemic scleroderma FEVi forced expiratory volume of 1 second TCA trichloroacetic acid GD gestation day TCE trichloroethylene GDH glutamate dehydrogenase TWA time-weighted average GGT y-glutamyl transferase UF uncertainty factor GSH glutathione UFa interspecies uncertainty factor GST glutathione-S'-transfcrase UFC composite uncertainty factor Hb/g-A animal blood-gas partition coefficient UFd database uncertainty factor Hb/g-H human blood-gas partition coefficient UFh intraspecies uncertainty factor HEC human equivalent concentration UFl LOAEL-to-NOAEL uncertainty factor HED human equivalent dose UFS subchronic-to-chronic uncertainty factor i.p. intraperitoneal U.S. United States of America IRIS Integrated Risk Information System WBC white blood cell Abbreviations and acronyms not listed on this page are defined upon first use in the PPRTV assessment. iv 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F DRAFT PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR 1-IMIINYI-l-(4-MI TIIYI PIII NYI )-I TIIA\I (PTE; CASRN 3717-68-8) 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 U.S. Environmental Protection Agency (U.S. EPA) guidance on human health toxicity value derivations. 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. Currently available PPRTV assessments can be accessed on the U.S. EPA's PPRTV website at https://www.epa.gov/pprtv. PPRTV assessments are eligible to be updated on a 5-year cycle and revised as appropriate to incorporate new data or methodologies that might impact the toxicity values or affect the characterization of the chemical's potential for causing toxicologically relevant human-health effects. Questions regarding nomination of chemicals for update can be sent to the appropriate U.S. EPA eComments Chemical Safety website at https://ecomments.epa.gov/chemicalsafetv/. QUALITY ASSURANCE This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure data are of known and acceptable quality to support their intended use. Surveillance of the work by the assessment managers and programmatic scientific leads ensured adherence to QA processes and criteria, as well as quick and effective resolution of any problems. The QA manager, assessment managers, and programmatic scientific leads have determined under the QA program that this work meets all U.S. EPA quality requirements. This PPRTV assessment was written with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP), the QAPP titled Program Quality Assurance Project Plan (POAPP) for the Provisional Peer- Reviewed Toxicity Values (PPRTVs) and Related Assessments Documents (L-CPAD-0032718-OP), and the PPRTV assessment development contractor QAPP titled Quality Assurance Project Plan—Preparation of Provisional Toxicity Value (PIT) Documents (L-CPAD-0031971-OP). As part of the QA system, a quality product review is done prior to management clearance. A Technical Systems Audit may be performed at the discretion of the QA staff. All PPRTV assessments receive internal peer review by at least two CPHEA scientists and an independent external peer review by at least three scientific experts. The reviews focus on whether all studies have been correctly selected, interpreted, and adequately described for the purposes of deriving a provisional reference value. The reviews also cover quantitative and qualitative aspects of the provisional value development and address whether uncertainties associated with the assessment have been adequately characterized. 1 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F DISCLAIMERS The PPRTV document provides toxicity values and information about the toxicologically relevant 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 U.S. EPA ORD CPHEA website at https://ecomments.epa.gov/pprtv. 2 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F 1. INTRODUCTION 1-Phenyl-l-(4-methylphenyl)-ethane (PTE), CASRN 3717-68-8, is a discrete organic chemical; it is a hydrocarbon containing both aromatic and aliphatic moieties (see Figure 1). PTE is not listed with the U.S. EPA Substance Registry Services or the Toxic Substances Control Act (TSCA) public inventory (U.S. EPA 2022c. d). It is not listed on the European Chemicals (EC) inventory and is not preregistered within Europe's Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) program (ECHA 2022). There are no data available on the production of PTE in the United States or commercial uses reported for PTE (NLM. 2022b; U.S. EPA 2022d). Synonyms of PTE appearing in these databases and in other sources include l-methyl-4-(l-phenylethyl)benzene, 1-phenyl-l-(p-tolyl)-ethane, 4-(l-phenylethyl)toluene, and methylphenyl-p-tolylmethan. Figure 1. l-Phenyl-l-(4-methylphenyl)-ethane (PTE) (CASRN 3717-68-8) Structure The empirical formula for PTE is C15H16. Table 1 summarizes the physicochemical properties for PTE. There are no experimental physicochemical property data available for PTE; therefore, all property data presented are estimates from the U.S. EPA CompTox Chemicals Dashboard version 2.2.1 and the Estimation Programs Interface Suite (EPI Suite™). PTE has low water solubility and moderate vapor pressure. Its moderate vapor pressure indicates that it may volatilize from dry soil surfaces and will exist in the vapor phase in air. In the atmosphere, vapor-phase PTE has an estimated half-life of 0.8 days, based on the estimated rate of reaction with photochemically-produced hydroxyl radicals (U.S. EPA. 2012). At ambient temperatures, the potential for volatilization from water surfaces or moist soil surfaces is expected to be moderate, based on its estimated Henry's law constant. The estimated soil adsorption coefficient (K oc) values for PTE indicate that the potential for sorption to soil is high. Based on its log Koc value, PTE is classified to be hardly mobile in soils by the Food and Agriculture Organization of the United Nations (FAO) (U.S. EPA. 2012. 2009). Hydrolysis is not expected to be an important fate process due to the lack of hydrolysable functional groups in this chemical. 3 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F Table 1. Physicochemical Properties of PTE (CASRN 3717-68-8) Property (unit) Value3 Molecular formula C15H16 Physical state NA Boiling point (°C) 291b Melting point (°C) 21.0 (predicted) Density (g/cm3 at 25°C) NA Vapor pressure (mm Hg at 25°C) 2.0 x l(T3b Vapor density NA Acid dissociation constant (pKa) (unitless) NA Solubility in water (mol/L at 25°C) 4.5b Octanol-water partition coefficient (log Kow) 4.7b Henry's law constant (atm-m3/mol at 25°C) 5.25 x 10 4 (predicted) Soil adsorption coefficient (Koc) (L/kg) 1.15 x 103 (predicted) Atmospheric OH rate constant (cm3/molecule-sec at 25°C) 2.09 x 10 11 (predicted) Atmospheric half-life (d) 0.8 (calculated using a 12-hday; 1.5 x 106OH/cm3)b Molecular weight (g/mol) 196.29 Flash point (°C) 2.00 (predicted) aData were extracted from the U.S. EPA CompTox Chemicals Dashboard (l-phenyl-l-(4-methylphenyl)-ethane, CASRN 3717-68-8. https://comptox.epa.gov/dashboard/chemical/details/DTXSID101027177: accessed May 21, 2024). All values are experimental averages unless otherwise specified. bValues are from U.S. EPA (2012) EPI Suite™ estimates using SMILES CC(C1=CC=CC=C1)C1=CC=C(C)C=C1. EPI = Estimation Programs Interface; NA = not applicable; PTE = l-phenyl-l-(4-methylphenyl)-ethane; SMILES = Simplified Molecular Input Line Entry System; U.S. EPA = U.S. Enviromnental Protection Agency. A summary of available toxicity values for PTE from U.S. EPA and other agencies/ organizations is provided in Table 2. 4 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F Table 2. Summary of Available Toxicity Values and Qualitative Conclusions Regarding Carcinogenicity for PTE (CASRN 3717-68-8) Source (parameter)3 Value (applicability) Notes Referenceb Noncancer IRIS NV NA U.S. EPA (2024) HEAST NV NA U.S. EPA (2011c) DWSHA NV NA U.S. EPA (2018a) ATSDR NV NA ATSDR (2022) WHO NV NA WHO (2022); IPCS (2021) CalEPA NV NA CalEPA (2022. 2020) OSHA NV NA OSHA (2020. 2017a. 2017b) NIOSH NV NA NIOSH (2018) ACGIH NV NA ACGIH (2022) Cancer IRIS NV NA U.S. EPA (2024) HEAST NV NA U.S. EPA (2011c) DWSHA NV NA U.S. EPA (2018a) NTP NV NA NTP (2021) IARC NV NA IARC (2022) CalFPA NV NA CalEPA (2022. 2020) ACGIH NV NA ACGIH (2022) aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic Substances and Disease Registry; CalEPA = California Enviromnental Protection Agency; DWSHA = Drinking Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables; IARC = International Agency for Research on Cancer; IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; WHO = World Health Organization. bReference date is the publication date for the database and not the date the source was accessed. NA = not applicable; NY = not available; PTE = l-phenyl-l-(4-methylphenyl)-ethane. Literature searches were conducted in November 2018 and September 2020, and updated most recently in February 2024 for studies relevant to the derivation of provisional toxicity values for PTE. Search results were stored in the U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature (https://heronet.epa.gov/heronet/index.cfm/proiect/page/proiect id/2776). HERO was used to store results from the following databases: PubMed, Web of Science, Scopus and TOXLINE1 (including TSCATS1), Scopus, and Web of Science. The National Technical Reports Library 'Note that this version of TOXLINE is no longer updated (https://www.nlm.nih. gov/databases/download/toxlinesubset.html): therefore, it was not included in the literature search update from September 2020 or February 2024. 5 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA/690/R-24-002F (NTRL) was searched for government reports from 2018 through February 20242. The following resources were searched outside of HERO for health-related values: American Conference of Governmental Industrial Hygienists (ACGIH), U.S. Agency for Toxic Substances and Disease Registry (ATSDR), California Environmental Protection Agency (CalEPA), Defense Technical Information Center (DTIC), European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), European Chemicals Agency (ECHA), the U.S. EPA Chemical Data Access Tool (CDAT), the U.S. EPA ChemView, the U.S. EPA Health Effects Assessment Summary Tables (HEAST), the U.S. EPA Integrated Risk Information System (IRIS), the U.S. EPA Office of Water (OW) Drinking Water Standards and Health Advisories, the U.S. EPA TSCATS2/TSCATS8e, the U.S. EPA High Production Volume (HPV) Challenge database, International Agency for Research on Cancer (IARC), Chemicals via International Programme on Chemical Safety (IPCS) INCHEM, Japan Existing Chemical Data Base (JECDB), Organisation for Economic Co-operation and Development (OECD) Screening Information Data Sets (SIDS), OECD International Uniform Chemical Information Database (IUCLID), OECD HPV, U.S. National Institute for Occupational Safety and Health (NIOSH), U.S. National Toxicology Program (NTP), U.S. Occupational Safety and Health Administration (OSHA), and World Health Organization (WHO). 2NTRL was a subset of TOXLINE until December 2019 when TOXLINE was discontinued. Searches of NTRL were conducted starting in 2018 to ensure that references were not missed due to delays in importing items into the database. 6 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA/690/R-24-002F 2. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) As summarized in Tables 3A and 3B, no short-term, subchronic, chronic, or reproductive/developmental toxicity studies of PTE in humans or animals exposed by oral or inhalation routes adequate for deriving provisional toxicity values were identified. 7 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA/690/R-24-002F Table 3A. Summary of Potentially Relevant Noncancer Data for PTE (CASRN 3717-68-8) Category Number of Male/Female, Strain, Species, Study Type, Reported Doses, Study Duration Dosimetry Critical Effects NOAEL LOAEL Reference (comments) 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 LOAEL = lowest-observed-adverse-effect level; ND = no data; NOAEL = no-observed-adverse-effect level; PTE = l-phenyl-l-(4-methylphenyl)-ethane. 8 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA/690/R-24-002F Table 3B. Summary of Potentially Relevant Cancer Data for PTE (CASRN 3717-68-8) Category Number of Male/Female, Strain, Species, Study Type, Reported Doses, Duration Dosimetry Critical Effects Reference (comments) 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 ND = no data; PTE = l-phenyl-l-(4-methylphenyl)-ethane. 9 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F 2.1. HUMAN STUDIES No studies were located regarding the toxicity or carcinogenicity of PTE in humans after oral or inhalation exposure. 2.2. ANIMAL STUDIES No studies were located regarding the toxicity or carcinogenicity of PTE in animals after oral or inhalation exposure. 2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) No genotoxicity data or other supporting studies, including mode-of-action (MOA)/ mechanistic or metabolism/toxicokinetics studies, were identified for PTE. However, preliminary unpublished experiments suggest that exposure to sediments contaminated with PTE (and other chemicals) produced neurotoxic effects in zebrafish and mice (Hewett et al.. 2017). 10 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F 3. DERIVATION OF PROVISIONAL VALUES 3.1. DERIVATION OF ORAL REFERENCE DOSES No studies were located regarding toxicity of PTE to humans or animals via oral exposure. Due to the lack of oral toxicity data for PTE, subchronic and chronic provisional reference doses (p-RfDs) could not be derived directly. Instead, the derivation of oral toxicity values was attempted using an alternative analogue approach, but no suitable analogue with available toxicity values was identified (see Appendix A). 3.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS No studies were located regarding toxicity of PTE to humans or animals via inhalation exposure. Due to the lack of inhalation toxicity data for PTE, subchronic and chronic provisional reference concentrations (p-RfCs) could not be derived directly. Instead, the derivation of inhalation toxicity values was attempted using an alternative analogue approach, but no suitable analogue with available toxicity values was identified (see Appendix A). 3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES Table 4 presents a summary of noncancer provisional reference values. Table 4. Summary of Noncancer Reference Values for PTE (CASRN 3717-68-8) Toxicity Type (units) Species/ Critical p-Reference POD POD Principal Sex Effect Value Method (HED/HEC) UFc Study Subchronic p-RfD (mg/kg-d) NDr Chronic p-RfD (mg/kg-d) NDr Subchronic p-RfC (mg/m3) NDr Chronic p-RfC (mg/m3) NDr HEC = human equivalent concentration; HED = human equivalent dose; NDr = not determined; POD = point of departure; p-RfC = provisional reference concentration; p-RfD = provisional reference dose; PTE = l-phenyl-l-(4-methylphenyl)-ethane; UFC = composite uncertainty factor. 3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR No oral or inhalation studies have been conducted to assess the carcinogenicity of PTE. Under the U.S. EPA Cancer Guidelines (U.S. EPA. 2005). there is "Inadequate Information to Assess the Carcinogenic Potential" of PTE by oral or inhalation exposure (see Table 5). 11 1-Phenyl-l-(4-methylphenyl)-ethane ------- EPA/690/R-24-002F Table 5. Cancer WOE Descriptor for PTE (CASRN 3717-68-8) Possible WOE Descriptor Designation Route of Entry (oral, inhalation, or both) Comments "Carcinogenic to Humans" NS NA The available data do not support this descriptor. "Likely to be Carcinogenic to Humans " NS NA The available data do not support this descriptor. "Suggestive Evidence of Carcinogenic Potential" NS NA The available data do not support this descriptor. "Inadequate Information to Assess Carcinogenic Potential" Selected Both No adequate information is available to assess the carcinogenic potential of PTE by the inhalation or oral routes of exposure. "Not Likely to be Carcinogenic to Humans" NS NA The available data do not support this descriptor. NA = not applicable; NS = not selected; PTE = l-phenyl-l-(4-methylphenyl)-ethane; WOE = weight of evidence. 3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES Due to a lack of carcinogenicity data, derivation of cancer risk estimates is precluded (see Table 6). Table 6. Summary of Cancer Risk Estimates for PTE (CASRN 3717-68-8) Toxicity Type (units) Species/Sex Tumor Type Cancer Risk Estimate Principal Study p-OSF (mg/kg-d) 1 NDr p-IUR (lng/in3) 1 NDr NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor; PTE = l-phenyl-l-(4-methylphenyl)-ethane. 12 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F APPENDIX A. SCREENING NONCANCER PROVISIONAL VALUES Due to the lack of evidence described in the main Provisional Peer-Reviewed Toxicity Value (PPRTV) assessment, it is inappropriate to derive provisional toxicity values for 1 -phenyl-l-(4-methylphenyl)-ethane (PTE). However, some 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 Center for Public Health and Environmental Assessment (CPHEA) 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 provisional reference values 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 could be more uncertainty associated with deriving 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 CPHEA. APPLICATION OF AN ALTERNATIVE ANALOGUE APPROACH (METHODS) The analogue approach allows for the use of data from related compounds to calculate screening values when data for the target chemical are limited or unavailable. Details regarding searches and methods for analogue analysis are adapted from Wang et al. (2012) and Lizarraga et al. (2023) and chemical-specific parameters of read-across tools can be found in Appendix B. Candidate analogues are identified on the basis of three similarity categories (structure, toxicokinetics [metabolism], and toxicodynamics [toxicity and mode of action; MO A]) to facilitate the final source analogue selection. The analogue approach may or may not be route- specific or applicable to multiple routes of exposure. All information is considered together as part of the final weight-of-evidence (WOE) approach to select the most suitable source analogue. In this assessment, an expanded analogue identification approach was utilized to collect an augmented set of candidate analogues for the target chemical. As described below, this approach applies a variety of tools and methods for identifying candidate analogues that are similar to the target chemical based on structural features; metabolic relationships; or related toxic effects and mechanisms of action. The application of a variety of different tools and methods to identify candidate analogues minimizes the impact of limitations of any individual tool or method on the pool of chemicals included, chemical fragments considered, and methods for assessing similarity. Further, the inclusion of techniques to identify analogues based on metabolism and toxicity or bioactivity expands the pool of candidates beyond those based exclusively on structural similarity. The specific tools described below used for the expanded analogue searches were selected because they are publicly available, supported by U.S. and Organisation for Economic Co-operation and Development (OECD) agencies, updated regularly, and widely used. 13 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F To identify structurally-related compounds, an initial pool of analogues is identified using automated tools, including ChemlDplus3 (NLM. 2022a). the CompTox Chemicals Dashboard4 (U.S. EPA. 2022a). and the OECD Quantitative Structure-Activity Relationship (QSAR) Toolbox5 (OECD. 2021). Additional analogues identified as ChemlDplus-related substances, mixtures, and CompTox "related substances6" are also considered. CompTox General Read-Across (GenRA)7 analogues are collected using the methods deployed on the publicly available GenRA Beta version, which may include Morgan fingerprints, Torsion fingerprints, ToxPrints and the use of ToxCast, Tox21, and ToxRef data (Patlewicz and Shah. 2023). For compounds that have very few analogues identified by structure similarity using a similarity threshold of 0.8 or 80%, substructure searches may be performed in the QSAR Toolbox, or similarity searches may be rerun using a reduced similarity threshold (e.g., <80%). Structural analogues are clustered using the Chemical Assessment Clustering Engine (ChemACE)8 (U.S. EPA. 2011b) based on chemical fragments to support expert-driven refinement of the candidate pool. The ChemACE output is reviewed by an experienced chemist, who narrows the list of structural analogues based on expert judgment of multiple lines of evidence including known or expected structure-toxicity relationships, reactivity, and known or expected metabolic pathways. Initially, candidate analogues are screened for structural and chemical similarity to confirm that the analogues have the same reactive functional groups and similar overall size and structural features as the target chemical. Chemicals lacking key functionality or bearing additional functionality relative to the target are less desirable as analogues and are not selected as structural analogues. The selection may be expanded to include chemicals expected to be part of a metabolic series (either as metabolic precursors or as metabolites) of the target chemical. 3ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. The database contains over 350,000 chemical records, of which over 80,000 include chemical structures and allows users to draw a chemical structure to search for similar substances using PubChem Substructure fingerprints (NLM. 2009: Liwanag et al.. 2000). NLM retired ChemlDPlus in Dec. 2022. 4The U.S. EPA's CompTox Chemicals Dashboard provides publicly-accessible chemistry, toxicity, and exposure information for over one million chemicals (Williams et al„ 2017). Using ePam's Bingo fingerprints, the "Similar Compounds" tab provides a list of chemicals that are similar in structure to the selected chemical, based on the Tanimoto similarity search metric with a minimum similarity factor threshold of 0.8 (EPAM. 2024). 5The OECD QSAR Toolbox is a software application intended to be used by government, industry and other stakeholders to fill gaps in data needed for assessing the hazards of chemicals. The application allows users to search for analogues based on structure similarity criteria and input similarity thresholds (OECD. 2017). It also contains metabolism simulators which are simplified versions of the simulators in CATALOGIC and TIMES and consist of hierarchically ordered molecular transformations (Yordanova et al.. 2019). 6The CompTox Chemicals Dashboard "Related Substances" tab provides a chemical list of all chemicals related to the queried chemical through mapped relationships underlying the database. Relationships include: searched chemical (self-relationship), salt form, monomer, polymer, predecessor component, component, Markush parent, Markush child, transformation parent, and transformation product (Williams et al.. 2021). 7Operationalized within the CompTox Chemicals Dashboard, GenRA is an algorithmic approach that makes read-across predictions on the basis of a similarity weighted activity of source analogues (nearest neighbors). GenRA gives users the ability to identify candidate analogues based on structural and bioactivity information (U.S. EPA 2022b). 8ChemACE clusters chemicals into groups based on structural features and a reasonable presumption that toxicity may be influenced by such structural characteristics (e.g., structural alerts, toxicophores). ChemACE identifies structural diversity in a large chemical inventory and highlights analogous clusters for potential read across. In the expanded analogue approach, clustering with ChemACE supports expert refinement of the candidate analogue pool. The ChemACE methodology is based on logic implemented in the Analog Identification Methodology (AIM) tool (http://aim.epa. gov) that identifies analogues based on the presence of common fragments using a tiered approach (U.S. EPA 2011a). 14 1 -Phenyl-l-(4-methylphenyl)-ethane ------- EPA 690 R-24-002F Chemicals that produce metabolites in common with the target may also be selected if the metabolite is known or suspected to be part of the mechanism of action. All candidate analogues are then screened for structural features that can influence their activity relative to the target. Examples of such features include steric influences of bulky substituent groups, branching, rigidity, presence of blocking groups on a functional group and differing substitution patterns on aromatic rings. Finally, key physical and chemical properties of the candidate analogues are compared with the target to confirm that they can be expected to have similar bioavailability, similar transport, and similar abiotic transformation properties. Toxicokinetic studies tagged as potentially relevant supplemental material during screening are used to identify metabolic analogues (metabolites and metabolic precursors). Metabolites are also identified from two OECD QSAR Toolbox metabolism simulators (in vivo rat metabolism simulator and rat liver S9 metabolism simulator). Targeted PubMed searches are conducted to identify metabolic precursors and other compounds that share any of the observed or predicted metabolites identified for the target chemical. In vivo toxicity data for the target chemical (if available) are evaluated to determine whether characteristic effects associated with a particular mechanism of toxicity are observed (e.g., cholinesterase inhibition, inhibition of oxidative phosphorylation). In addition, in vitro mechanistic data tagged as potentially relevant supplemental material during screening or obtained from tools including GenRA, ToxCast/Tox219, and Comparative Toxicogenomics Database (CTD)10 (CTD. 2022) are also evaluated for this purpose. ToxCast/Tox 21 data available from the CompTox Chemicals Dashboard are collected for the target chemical to determine bioactivity in in vitro assays that may indicate potential mechanism(s) of action. The GenRA tool is used to search for analogues using Morgan, Torsion and ToxPrints fingerprint similarities and activity in ToxCast/Tox21 in vitro assays or ToxRef data (10 analogues collected from each neighbors dataset). Using the ToxCast/Tox21 bioactivity data, nearest neighbors identified may be considered potential candidate analogues. The CTD is searched to identify compounds with gene interactions similar to those induced by the target chemical; compounds with gene interactions similar to the target chemical (similarity index >0.5) may be considered potential candidate analogues. Candidate analogues identified on the basis of the structural, metabolic, and toxicodynamic similarity contexts are interrogated through the CompTox Chemicals Dashboard, where QSAR-ready simplified molecular-input line-entry system (SMILES) are collected and toxicity value availability is determined (e.g., from the Agency for Toxic Substances and Disease Registry [ATSDR], California Environmental Protection Agency [CalEPA] Office of Environmental Health Hazard Assessment [OEHHA], the U.S. EPA Integrated Risk Information System [IRIS], PPRTVs). Analogues that have subchronic or chronic toxicity data or toxicity values available from other public health agencies are flagged for potential consideration as supportive evidence. 9ToxCast and Tox21 are publicly available databases containing high-throughput assay endpoints covering a range of high-level cell responses (Thomas et al.. 2018: U.S. EPA. 2018b). u'The CTD is a publicly available database that provides manually curated information about chemical-gene/protein interactions, chemical-disease and gene-disease relationships. The CTD allows users to identify chemicals that induce gene interactions similar to those induced by the target chemical (Davis et al.. 2021). 15 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F Analogue Search Results for PTE Candidate analogues for PTE were identified based on structural, metabolic, and toxicity/mechanisms/MOA relationships. For candidates identified through these approaches, the U.S. EPA (IRIS and PPRTV), ATSDR, and CalEPA sources were searched for subchronic, intermediate, and chronic oral and inhalation toxicity values. Details are provided below. Identification of Structural Analogues with Established Toxicity Values Table A-l summarizes the candidate structural analogues for PTE. PTE is not a member of an existing OECD or New Chemical category. Candidate structural analogues for PTE were identified using the U.S. EPA CompTox Chemicals Dashboard and the OECD QSAR Toolbox. A total of 395 unique structural analogues were identified for PTE in the Dashboard version 2.2.1, GenRA version 3.2, and OECD QSAR Toolbox version 4.4. Table A-l. Candidate Structural Analogues Identified for PTE |1^ CH3 Tool (method)3 Analogue (CASRNs) Selected for Toxicity Value Searchesb Structure Dashboard (Tanimoto) and OECD QSAR Toolbox (Dice) 2-( 1 -Phenylethyl)-/?-xylene (6165-51 -1 )b h3cv HbC\^ ch3 Dashboard (Tanimoto) and OECD QSAR Toolbox (Dice) 1 -Methyl-2-( 1 -phenylethyl)benzene (40766-30-1) ch3 Dashboard (Tanimoto) 3 -Methyldiphenylmethane (620-47-3) 16 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F Table A-l. Candidate Structural Analogues Identified for PTE 0 ch3 /ks, J Tool (method)3 Analogue (CASRNs) Selected for Toxicity Value Searchesb Structure Dashboard (Tanimoto) 1,2-Dimethyl-4-( 1 -phenylethyl)benzene (6196-95-8) CH3 H3C y ch3 Dashboard (Tanimoto) l-Methyl-2-[l-(4-methylphenyl)ethyl]benzene (5080-10-4) Dashboard (Tanimoto) AND OECD QSAR Toolbox (Dice) 1,2-Dimethyl-3 -(1 -phenylethyl)benzene (40766-31 -2)b T3 H,C^ JL fl^l ^1^ ch3 Dashboard (Tanimoto) 1 -Methyl-4-(phenylmethyl)benzene (620-83 -7) CH, Dashboard (Tanimoto) l-Ethyl-4-(phenylmethyl)benzene (620-85-9) riSii 17 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F Table A-l. Candidate Structural Analogues Identified for PTE 11\ CH3 /ks, J Tool (method)3 Analogue (CASRNs) Selected for Toxicity Value Searchesb Structure Dashboard (Tanimoto) l-Methyl-4-[(4-methylphenyl)methyl]benzene (4957-14-6) XX"' ch3 Dashboard (Tanimoto) 1 -Methyl-3 -(1 -phenylethyl)benzene (32341-91-6) h,c\a\/ Dashboard (Tanimoto) 1,1 '-(Ethane-1,1 -diyl)bis(3 -methylbenzene) (89881-30-1) ^ CH3 Dashboard (Tanimoto) 1 -Ethyl-2-( 1 -phenylethyl)benzene (18908-70-8) Dashboard (Tanimoto) 1,2-Dimethyl-4-[ 1 -(3 -methylphenyl)ethyl]benzene (874811-05-9) H3C\ CH3 ch3 Dashboard (Tanimoto) l-Methyl-4-[l-(4-methylphenyl)ethyl]benzene (530-45-0) rvCH3 ch3 18 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F Table A-l. Candidate Structural Analogues Identified for PTE chj /-ks. J Tool (method)3 Analogue (CASRNs) Selected for Toxicity Value Searchesb Structure Dashboard (Tanimoto) 1 -Ethyl-3 -(1 -phenylethyl)benzene (18908-71 -9) h3c^jQi en. Dashboard (Tanimoto) l-Methyl-3-[(4-methylphenyl)methyl]benzene (21895-16-9) jCT™3 Dashboard (Tanimoto) l-Benzyl-3-ethylbenzene (28122-24-9) Dashboard (Tanimoto) AND OECD QSAR Toolbox (Dice) 1-Phenyl-l-(2,4-dimethylphenyl)-ethane (6165-52-2) ch3 ch3 aAll software tools set to 80% similarity threshold for analogue identification, unless otherwise noted. bOECD QSAR Toolbox reported that repeated-dose toxicity data are available in the Japanese NITE database. NITE = National Institute of Technology and Evaluation; OECD = Organisation for Economic Co-operation and Development; PTE = l-phenyl-l-(4-methylphenyl)-ethane; QSAR = quantitative structure-activity relationship. After eliminating analogues containing metals or deuterated compounds, the remaining list of analogues was reviewed by a chemist with expertise in read-across. The following criteria for determining PTE analogues were applied as part of the expert review: (1) the presence of a methylene or 1,1-ethylidene bridge connecting the two aromatic rings (compounds with other hydrocarbon moieties connecting the two aromatic rings were excluded because additional substitutions would impact the steric rotation of the molecule and would block the bridge atom from metabolism [or reactivity in general]); (2) compounds with any other atom (such as oxygen or sulfur) at the bridge or substituted on the structure were excluded because this could change the activation/reactivity of the aromatic rings; (3) consistent with the structure of PTE, methyl groups and/or an ethyl group on the rings were limited to no more than two per ring or one per 19 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA/690/R-24-002F ring, respectively, because more or larger substitutions would result in steric hinderance, decrease the solubility, and increase the log Kow of the compound; and (4) the presence of methyl or ethyl groups was required as they are potential sites for metabolism. Of the 395 unique structural analogues identified by similarity searches, only 18 met the criteria above and were carried forward as candidate structural analogues (see Table A-l). No toxicity values were identified for any of the 18 candidate structural analogues. Identification of Toxicokinetic Precursors or Metabolites with Established Toxicity Values PubMed searches (searching "1 -phenyl-l-(4-methylphenyl)-ethane" or "3717-68-8" and "metabolite") were conducted to identify metabolic precursors to PTE. No metabolic precursors were identified. No metabolites were identified for PTE in the scientific literature. Predicted metabolites were queried using the OECD QSAR Toolbox version 4.4 using the in vivo rat metabolism simulator and rat liver S9 metabolism simulator. PubMed was also searched to identify other compounds that are metabolized to one of the predicted metabolites of PTE (searching the metabolite name [none of the metabolites had CASRNs] and "metabolite"); no compounds that share at least one metabolite with PTE were identified. Table A-2 summarizes the 22 candidate metabolic analogues for PTE identified by the OECD QSAR Toolbox. Searches for relevant toxicity values available from the U.S. EPA, ATSDR, or CalEPA for the candidate metabolic analogues of PTE did not identify toxicity values for any of the predicted metabolites. 20 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA/690/R-24-002F Table A-2. Candidate Metabolic Analogues of PTE Relationship to PTE Compound3 Metabolic precursor None identified Predicted metabolites 4-[ 1-(4-Methylphenyl)ethyl]benzene-1,2-diol 4- [ 1 -(4-Methylphenyl)ethyl]phenol 3 - [ 1 -(4-Methylphenyl)ethyl]phenol 2- [ 1 -(4-Hydroxyphenyl)ethyl] -5-methylphenol 4- [ 1 -(4-Hydroxyphenyl)ethyl]benzaldehyde 4-[ 1 -(4-Hydroxyphenyl)ethyl]benzyl alcohol 2-Methyl-5-( 1 -phenylethyl)phenol 5-Methyl-2-( 1 -phenylethyl)phenol 4-( 1 -Phenylethyl)benzaldehyde [4-( 1 -Phenylethyl)phenyl] methanol 4-(l-Phenylethyl)benzoic acid 2-(4-Methylphenyl)-2-phenylacetic acid 2-(4-Hydroxyphenyl)-2-(4-methylphenyl)acetaldehyde 2-(4-Methylphenyl)-2-phenylacetaldehyde 2-(4-Hydroxyphenyl)-2-(4-methylphenyl) 2-(4-Methylphenyl)-2-phenylethan-1 -ol 4- [2-Hydroxy-1 - [4-(hydroxymethyl)phenyl]ethyl]phenol 4-( 1 -Phenyl-2-hydroxyethyl)benzaldehyde 2- [4-(Hydroxymethyl)phenyl] -2-phenylethan-1 -ol 4-( 1 -Phenyl-2-hydroxyethyl)benzoic acid 2- [4-(Hydroxymethyl)phenyl] -2-phenylacetic acid 2- [4-(Hydroxymethyl)phenyl] -2-phenylacetaldehyde Shares common metabolite(s) None identified aNo CASRNs are available for these metabolites. PTE = l-phenyl-l-(4-methylphenyl)-ethane. Identification of Analogues on the Basis of Toxicity/Mechanistic/MOA Information and Established Toxicity Values No toxicity or mechanistic/MOA data relevant for identifying candidate analogues for PTE were identified in the scientific literature. The GenRA option version 3.2 within the U.S. EPA CompTox Dashboard version 2.2.1 offers the ability to search for analogues based on similarities in activity in ToxCast/Tox21 in vitro assays; however, there were no bioactivity data for PTE, so this was not further investigated. The CTD did not have an entry for PTE. 21 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA/690/R-24-002F Candidate Analogues Moving Forward for Evaluation Searches for structural, metabolic, and toxicity/mechanistic analogues for PTE yielded a total of 40 unique candidate analogues: 18 structural analogues and 22 metabolism-related analogues. No candidate analogues were identified on the basis of having similar characteristic toxicity or mechanisms/MOAs. None of the candidate analogues have oral or inhalation toxicity values from the U.S. EPA, ATSDR, or CalEPA. Therefore, no suitable candidate analogues were identified to calculate screening oral or inhalation toxicity values. ORAL NONCANCER TOXICITY VALUES Derivation of Screening Subchronic and Chronic Provisional Reference Doses Screening subchronic and chronic provisional reference doses could not be derived due to the lack of an appropriate analogue having oral toxicity values. INHALATION NONCANCER TOXICITY VALUES Derivation of Screening Subchronic and Chronic Provisional Reference Concentrations Screening subchronic and chronic provisional reference concentrations could not be derived due to the lack of an appropriate analogue having inhalation toxicity values. 22 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA/690/R-24-002F APPENDIX B. PARAMETERS OF TOOLS USED FOR READ ACROSS Table B-l. Parameters of Tools Used for Read-Across Evaluation of PTE Similarity Context [417]a Tool Name [4] Settings/Parameters Searched by (date) Structural [395] The U.S. EPA CompTox Chemicals Dashboard [371] Tanimoto similarity threshold of 0.8 and related substances CASRN (April 2023) GenRA Beta version (in the U.S. EPA CompTox Chemicals Dashboard) [23] Collect 10 nearest neighbors by each similarity setting and combination available: • Morgan Fingerprints • Torsion Fingerprints • ToxPrints • Morg2TorlBiol • CTl:Bio3 Using each of the following data sources: ToxCast, Tox 21, and ToxRef OECD QSAR Toolbox [1] Similarity search with >80% similarity threshold using default settings: • Dice similarity • Atom centered fragments • Hologram calculation • All features combined • Atom characteristics: atom type, count H attached, and hybridization Metabolic [22] OECD QSAR Toolbox Metabolism Simulators [22] No settings or parameters; results obtained from: • Rat liver S9 metabolism simulator version 3.7 • in vivo rat metabolism simulator version 3.5 SMILESb (April 2023) T oxicity/mechanistic [0] GenRA Beta version (in the U.S. EPA CompTox Chemicals Dashboard) [0] Collected 10 nearest neighbors using the ToxCast similarity settings. • Nearest neighbors with a similarity index >0.5 considered for use as analogue. CASRN (April 2023) Comparative Toxicogenomics Database (CTD) [0] Identify compounds with gene interactions similar to those induced by PTE: • Used the interacting genes comparison search. • A similarity index of >0.5 is considered for use as a mechanistic analogue (April 2023) aUnique analogues identified using analogue identification search tools. bPhenyl-l-(4-methylphenyl)-ethane; SMILES: CC(C1=CC=CC=C1)C1=CC=C(C)C=C1) (CASRN 3717-68-8). GenRA = General Read-Across; NA = not applicable; OECD = Organisation for Economic Co-operation and Development; PTE = l-phenyl-l-(4-methylphenyl)-ethane; QSAR = quantitative structure-activity relationship; SMILES = Simplified Molecular Input Line Entry System; U.S. EPA = U.S. Environmental Protection Agency. 23 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F APPENDIX C. REFERENCES ACGIH. (2022). 2022 TLVs and BEIs: Based on the documentation of the threshold limit values for chemical substances and physical agents & biological exposure indices. In 2022 TLVs and BEIs: Based on the documentation of the threshold limit values for chemical substances and physical agents & biological exposure indices. Cincinnati, OH. ATSDR. (2022). Toxic substances portal: Toxicological profiles [Database], Atlanta, GA. Retrieved from https://www.atsdr.cdc.gov/toxprofiledocs/index.html CalEPA. (2020). Consolidated table of OEHHA/CARB approved risk assessment health values. Sacramento, California, https://ww2.arb.ca.gov/resources/documents/consolidated-table- oehha-carb-approved-risk-assessment-health-values CalEPA. (2022). OEHHA chemical database [Database], Sacramento, CA: Office of Environmental Health Hazard Assessment. Retrieved from https://oehha.ca.gov/chemicals CTD. (2022). 1-Phenyl-1-(2,4-dimethylphenyl)-ethane (PXE): Comparative toxicogenomics database [Database]: MDI Biological Laboratory. Retrieved from http://ctdbase.org/ Davis. AP; Grondin. CJ: Johnson. RJ; Sciaky. D; Wiegers. J: Wiegers. TC: Mattingly. CJ. (2021). The comparative toxicogenomics database (CTD): update 2021 [Database], Raleigh, NC: MDI Biological Laboratory. North Carolina State University. Retrieved from http://ctdbase.org/ ECHA. (2022). Registered substances: Helsinki, Finland. Retrieved from http://echa.europa.eu/web/guest/information-on-chemicals/registered-substances EPAM. (2024). Resources. Available online at https://lifescience.opensource.epam.com/resources.html Hewett, J; Lewis, K; Hassett, J; Middleton, F. (2017). Neurotoxicity of early life exposure to 1- phenyl-l-p-tolyl-ethane (PTE) isolated from Onondaga Lake sediment. Abstract presented at 9th Annual NYS Biotechnology Symposium, May 18 & 19, 2017, Syracuse, NY. IARC. (2022). Agents classified by the IARC monographs. Lyon, France. https://monographs.iarc.who.int/list-of-classifications/ IPCS. (2021). INCHEM: Chemical safety information from intergovernmental organizations [Database], Geneva, Switzerland. Retrieved from http://www.inchem.org/ Liwanag. PM; Hudson. VW; Hazard. GF. Jr. (2000). ChemlDplus: A web-based chemical search system. NLM Tech Bull March-April: e3. Lizarraga. LE; Suter. GW: Lambert. JC: Patlewicz. G: Zhao. JO: Dean. JL; Kaiser. P. (2023). Advancing the science of a read-across framework for evaluation of data-poor chemicals incorporating systematic and new approach methods. Regul Toxicol Pharmacol 137: 105293. http://dx.doi.org/10.1016/i.vrtph.2022.105293 NIOSH. (2018). NIOSH pocket guide to chemical hazards. Index of chemical abstracts service registry numbers (CAS No.). Atlanta, GA. http://www.cdc.gov/niosh/npg/npgdcas.html NLM. (2009). PubChem substructure fingerprint. https://ftp.ncbi.nlm.nih.gov/pubchem/specifications/pubchem fingerprints.pdf NLM. (2022a). ChemlDplus advanced [Database], Bethesda, MD: National Institutes of Health, National Library of Medicine. Retrieved from https://chem.nlm.nih. gov/chemidplus/ NLM. (2022b). PubChem: 4-(l-Phenylethyl)toluene. Available online at https://pubchem.ncbi.nlm.nih.gov/compound/10867260 (accessed August 15, 2022). 24 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F NTP. (2021). Report on carcinogens, fifteenth edition. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service. http://dx.doi.org/10.22427/NTP-QTHER-1003 OECD. (2017). Application manual of OECD QSAR toolbox v.4. https://www.oecd.org/chemicalsafetv/risk- assessment/TB4 Application manual Fl.compressed.pdf OECD. (2021). The OECD QSAR toolbox [version 4.4], Retrieved from http://www.oecd.org/chemicalsafetv/risk-assessment/oecd-qsar-toolbox.htm OSHA. (2017a). Table Z-l: Limits for air contaminants. Occupational safety and health standards, subpart Z, toxic and hazardous substances. (29 CFR 1910.1000). Washington, DC. https://www.govinfo.gov/content/pkg/CFR-2017-title29-vol6/pdf/CFR-2017-title29- vol6-secl910-1000.pdf OSHA. (2017b). Table Z: Shipyards. Occupational safety and health standards for shipyard employment. Subpart Z, toxic and hazardous substances. Air contaminants. (29 CFR 1915.1000). Washington, DC. https://www.govinfo.gov/content/pkg/CFR-2017-title29- vol7/pdf/CFR-2017-title29-vol7-sec 1915-1000.pdf OSHA. (2020). Table 1: Permissible exposure limits for airborne contaminants. Safety and health regulations for construction. Gases, vapors, fumes, dusts, and mists. (29 CFR 1926.55). Washington, DC. https://www.govinfo.gov/content/pkg/CFR-2020-title29- vol8/pdf/CFR-2020-ti tle29-vol8-secl926-55.pdf Patlewicz. G: Shah. I. (2023). Towards systematic read-across using Generalised Read-Across (GenRA). Computational Toxicology 25: 100258. http: //dx. doi. or g/10.1016/i. comtox .2022.100258 Thomas. RS: Paules. RS: Simeonov. A: Fitzpatrick. SC: Crofton. KM: Casey. WM; Mendrick. PL. (2018). The US Federal Tox21 Program: A strategic and operational plan for continued leadership. ALTEX 35: 163-168. http://dx.doi.org/10.14573/altex.1803011 U.S. EPA. (2005). Guidelines for carcinogen risk assessment [EPA Report], (EPA630P03001F). Washington, DC. https://www.epa.gov/sites/production/files/2013- 09/documents/cancer guidelines final 3-25-05.pdf U.S. EPA. (2009). Guidance for reporting on the environmental fate and transport of the stressors of concern in problem formulations for registration review, registration review risk assessments, listed species litigation assessments, new chemical risk assessments, and other relevant risk assessments, https://www.epa.gov/pesticide-science-and-assessing- pesticide-risks/guidance-reporting-environmental-fate-and-transport U.S. EPA. (2011a). ChemACE users manual [EPA Report], https://www.epa.gov/tsca-screening- tools/chemical-assessment-clustering-engine-chemace-user-tutorial U.S. EPA. (2011b). Chemical assessment clustering engine (ChemACE). Retrieved from https://www.epa.gov/tsca-screening-tools/chemical-assessment-clustering-engine- chemace U.S. EPA. (2011c). Health effects assessment summary tables (HEAST) for superfund [EPA Report], Washington, DC. https://epa-heast.ornl.gov/heast.php U.S. EPA. (2012). Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.11 [Computer Program], Washington, DC. Retrieved from https://www.epa.gov/tsca- screening-tools/epi-suitetm-estimation-program-interface U.S. EPA. (2018a). 2018 Edition of the drinking water standards and health advisories tables [EPA Report], (EPA822F18001). Washington, DC: U.S. Environmental Protection Agency, Office of Water, https://nepis.epa.gov/Exe/ZvPURL.cgi?Dockev=P100U7U8.txt 25 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- EPA 690 R-24-002F U.S. EPA. (2018b). ToxCast owner's manual- Guidance for exploring data. Available online at https://www.epa.gov/sites/default/files/2018- 04/documents/toxcastownermanual4252018.pdf U.S. EPA. (2022a). CompTox chemicals dashboard. Washington, DC. Retrieved from https://comptox.epa.gov/dashboard U.S. EPA. (2022b). Generalised read-across (GenRA) [Database], Retrieved from https://www.epa.gov/svstem/files/documents/2022-02/genra help 080222.pdf U.S. EPA. (2022c). Substance Registry Services (SRS). Available online at https://sor.epa.gov (accessed April 21, 2022). U.S. EPA. (2022d). The Toxic Substances Control Act's public inventory (TSCA inventory). Updated February 2022 [Database], Washington, DC: U.S. Environmental Protection Agency, Office of Chemical Safety and Pollution Prevention. Retrieved from https://www.epa.gOv/tsca-inventorv/how-access-tsca-inventory#download U.S. EPA. (2024). Integrated risk information system (IRIS) database. Available online at http://www.epa.gov/iris/ Wang. NC: Zhao. QJ: Wesselkamper. SC: Lambert. JC: Petersen. D; Hess-Wilson. JK. (2012). Application of computational toxicological approaches in human health risk assessment. I. A tiered surrogate approach. Regul Toxicol Pharmacol 63: 10-19. http://dx.doi.Org/10.1016/i.yrtph.2012.02.006 WHO. (2022). WHO institutional repository for information sharing (IRIS) [Database]: World Health Organization (WHO). Retrieved from https://apps.who.int/iris/ Williams. AJ; Grulke. CM: Edwards. J: Mceachran. AD: Mansouri. K; Baker. NC: Patlewicz. G: Shah. I: Wambaugh. JF; Judson. RS: Richard. AM. (2017). The CompTox chemistry dashboard: A community data resource for environmental chemistry. J Cheminform 9: 61. http://dx.doi.org/10.1186/sl3321-017-0247-6 Williams. AJ: Lambert. JC: Thayer. K; Dome. J. (2021). Sourcing data on chemical properties and hazard data from the US-EPA CompTox Chemicals Dashboard: A practical guide for human risk assessment [Review], Environ Int 154: 106566. http://dx.doi.Org/10.1016/i.envint.2021.106566 Yordanova. D; Kuseva. C: Tankova. K; Pavlov. T; Chankov. G: Chapkanov. A: Gissi. A: Sobanski. T; Schultz. TW: Mekenyan. OG. (2019). Using metabolic information for categorization and read-across in the OECD QSAR Toolbox. Computational Toxicology 12: 100102. http://dx.doi.Org/10.1016/i.comtox.2019.100102 26 1 -Phenyl-1 -(4-methylphenyl)-ethane ------- |