EPA/635/R-02/006 TOXICOLOGICAL REVIEW OF Phenol (CAS No. 108-95-2) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2002 U.S. Environmental Protection Agency Washington D.C. DISCLAIMER Mention of trade names or commercial products does not constitute endorsement or recommendation for use. Note: This document may undergo revisions in the future. The most up-to-date version will be made available electronically via the IRIS Home Page at http://www.epa.gov/iris. CONTENTS - TOXICOLOGICAL REVIEW FOR PHENOL (CAS No. 108-95-2) Foreword................................................................... vi Authors, Contributors and Reviewers.......................................... vii 1. INTRODUCTION ......................................................1 2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS........................................................2 3. TOXICOKINETICS RELEVANT TO ASSESSMENTS ......................5 3.1 Absorption ......................................................5 3.2 Distribution.....................................................10 3.3 Metabolism.....................................................12 3.4 Excretion .......................................................23 4. HAZARD IDENTIFICATION ...........................................24 4.1 Studies in Humans - Epidemiology, Case Reports, Clinical Controls .....25 4.1.1 Oral .....................................................25 4.1.2 Inhalation ................................................27 4.2 Pre-chronic, Chronic Studies and Cancer Bioassays in Laboratory Animals ...............................................................32 4.2.1 Oral .....................................................32 4.2.2 Inhalation ................................................52 4.2.3 Dermal ...................................................60 4.3 Reproductive/Developmental Studies ...............................61 4.4 Other Studies ...................................................72 4.4.1 Initiation/Promotion Studies, Other Short-term Tumorigenicity Assays, and Cancer Mechanism Studies .......................72 4.4.2 Genotoxicity ..............................................75 4.4.3 Neurological Effects ........................................83 4.4.4 Immunotoxicity ...........................................84 4.4.5 Other Studies .............................................85 4.5 Synthesis and Evaluation of Major Noncancer Effects and Mode of Action ...............................................................86 4.6 Weight of Evidence Evaluation and Cancer Characterization - Synthesis of Human, Laboratory Animal and Other Supporting Evidence, Conclusions about Human Carcinogenicity, and Likely Mode of Action .............92 4.7 Susceptible Populations...........................................95 4.7.1 Possible Childhood Susceptibility .............................95 iii 4.7.2 Possible Gender Differences .................................96 5. DOSE RESPONSE ASSESSMENTS......................................96 5.1 Oral Reference Dose (RfD) .......................................97 5.1.1 Choice of Principal Study and Critical Effect ..................97 5.1.2 Method of Analysis - Benchmark dose .......................100 5.1.3 RfD Derivation ...........................................100 5.2 Inhalation Reference Concentration (RfC) .........................102 5.2.1 Choice of Principal Study and Critical Effect .................102 5.2.2 Methods of Analysis ......................................103 5.3 Cancer Assessment ............................................103 6. MAJOR CONCLUSIONS IN CHARACTERIZATION OF HAZARD AND DOSE- RESPONSE .........................................................104 6.1 Human Hazard Potential ........................................104 6.1.1 Oral Noncancer ..........................................104 6.1.2 Inhalation Noncancer .....................................106 6.1.3 Cancer ..................................................107 6.2 Dose-response..................................................107 7.0 REFERENCES.......................................................111 Appendix A. Summary of External Peer Review Comments and Disposition. 124 Appendix B. Benchmark Dose Modeling Results. 129 Appendix C. Benchmark Dose Modeling Output. 133 iv List of Tables and Figures Table 1. Physical Properties and Chemical Identity of Phenol .......................4 Table 2. Summary of Oral Toxicity Studies......................................34 Table 3. Total Activity Counts in Rats Provided Phenol in Drinking Water (ClinTrials BioResearch, 1998) ...........................................41 Table 4. Individual Data on Dehydration and Week 4 Motor Activity in Rats Provided Phenol in Drinking Water (ClinTrials BioResearch, 1998) ..........................................43 Table 5. Effects of Phenol Exposure on Spleen Cellularity and Selected Blood Parameters in Mice and Rats ...........................47 Table 6. Effects of Phenol Exposure on Spleen Cellularity and Selected Blood Parameters in Mice and Rats ......................................................49 Table 7. Summary of Inhalation Toxicity Studies.................................54 Table 8. Selected Results of Two-Generation Drinking Water Study (Ryan et al., 2001; IIT Research Institute, 1999) ............................63 Table 9. Key Results in Argus Research Laboratories, (1997) Rat Developmental Toxicity Study................................................................67 Table 10. Key Results from Developmental Toxicity Study in Rats Administered Phenol by Gavage (NTP, 1983a) ..............................69 Table 11. Summary of Genotoxicity Studies .....................................77 Figure 1. Metabolism of Phenol................................................13 Figure 2. Plot of severity with dose for drinking water or gavage ....................90 v FOREWORD The purpose of this Toxicological Review is to provide scientific support and rationale for the hazard identification and dose-response assessment in IRIS pertaining to chronic exposure to phenol. It is not intended to be a comprehensive treatise on the chemical or toxicological nature of phenol. In Section 6, EPA has characterized its overall confidence in the quantitative and qualitative aspects of hazard and dose-response. Matters considered in this characterization include knowledge gaps, uncertainties, quality of data, and scientific controversies. This characterization is presented in an effort to make apparent the limitations of the assessment and to aid and guide the risk assessor in the ensuing steps of the risk assessment process. For other general information about this assessment or other questions relating to IRIS, the reader is referred to EPA’s IRIS Hotline at 301-345-2870. vi AUTHORS, CONTRIBUTORS, AND REVIEWERS Chemical Manager/Author Monica A. Barron Office of Solid Waste U.S. Environmental Protection Agency Washington, DC Contract Authors Lynne Haber Toxicology Excellence for Risk Assessment Cincinnati, OH Andrew Maier Toxicology Excellence for Risk Assessment Cincinnati, OH Jay Zhao Toxicology Excellence for Risk Assessment Cincinnati, OH Michael Dourson Toxicology Excellence for Risk Assessment Cincinnati, OH Reviewers This document and summary information on IRIS have received peer review by both EPA scientists and independent scientists external to EPA. Subsequent to external review and incorporation of comments, this assessment underwent an Agency-wide review process whereby the IRIS Program Manager achieved a consensus approval among the Office of Research and Development; Office of Air and Radiation; Office of Prevention, Pesticides, and Toxic Substances; Office of Solid Waste and Emergency Response (OSWER) of Water; Office of Policy, Economics, and Innovation; Office of Children’s Health Protection; Office of Environmental Information; and the Regional Offices. Internal EPA Reviewers Dorothy Canter OSWER vii Nancy Chiu Office of Water, Health and Ecological Criteria Division (HECD) Annie Jarabek National Center for Environmental Assessment Edward Ohanian Office of Water/HECD Diana Wong Office of Water/HECD Robert MacPhail (reviewed portions) National Health and Environmental Effects Research Laboratory Selene Chou Agency for Toxic Substances Disease Registry External Peer Reviewers Rolf Hartung University of Michigan Michele Medinsky ToxCon Anthony Scialli Department of Obstetrics and Gynecology Georgetown University Medical Center Summaries of the external peer reviewers’ comments and the disposition of their recommendations are presented in Appendix A. viii 1. INTRODUCTION This document presents background and justification for the hazard and dose-response assessment summaries in U.S. Environmental Protection Agency’s (EPA’s) Integrated Risk Information System (IRIS). IRIS summaries may include an oral reference dose (RfD), an inhalation reference concentration (RfC), and a carcinogenicity assessment. The RfD and RfC provide quantitative information for noncancer dose-response assessments. The RfD is based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis but may not exist for other toxic effects such as some carcinogenic responses. It is expressed in units of milligrams per kilogram per day (mg/kg-day). In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups)