Toxicological Review for 2-Methylnaphthalene (CAS No. 91-57-6 ...

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DISCLAIMER This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. 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. ii
CONTENTS — TOXICOLOGICAL REVIEW OF 2-METHYLNAPHTHALENE (CAS No. 91-57-6) LIST OF TABLES .............................................................v LIST OF FIGURES ............................................................v FOREWORD ................................................................ vi AUTHORS, CONTRIBUTORS, AND REVIEWERS ................................. vii 1. INTRODUCTION ...........................................................1 2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS .......3 3. TOXICOKINETICS RELEVANT TO ASSESSMENTS .............................5 3.1. ABSORPTION ......................................................5 3.2. DISTRIBUTION .....................................................6 3.3. METABOLISM .....................................................8 3.4. ELIMINATION AND EXCRETION ....................................14 3.5. PHYSIOLOGICALLY-BASED TOXICOKINETIC (PBTK) MODELING ......15 4. HAZARD IDENTIFICATION .................................................16 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY AND CASE REPORTS ..........16 4.2. PRECHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION ..............................16 4.2.1. Oral Exposure ...............................................16 4.2.1.1. Prechronic Toxicity ...................................16 4.2.1.2. Chronic Toxicity ......................................17 4.2.2. Inhalation Exposure ...........................................20 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION ...................................................20 4.4. OTHER STUDIES ..................................................20 4.4.1. Acute Toxicity Data ..........................................20 4.4.2. Studies with Methylnaphthalene Mixtures ...........................25 4.4.3. Other Cancer Studies .........................................28 4.4.4. Genotoxicity Studies ..........................................29 4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS AND MODE OF ACTION—ORAL AND INHALATION ......................30 4.5.1. Oral Exposure ...............................................30 4.5.2. Inhalation Exposure ...........................................42 4.5.3. Dermal Exposure ............................................42 4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER CHARACTERIZATION—SYNTHESIS OF HUMAN, ANIMAL, AND OTHER iii
Page 1: EPA 635/R-03/010 www.epa.gov/iris T
Page 5 and 6: LIST OF TABLES Table 1. Distributio
Page 7 and 8: AUTHORS, CONTRIBUTORS, AND REVIEWER
Page 9 and 10: EXTERNAL PEER REVIEWERS James Klaun
Page 11 and 12: Developmental Toxicity Risk Assessm
Page 13 and 14: 2-methylnaphthalene is a component
Page 15 and 16: Wistar rats, indicating that some a
Page 17 and 18: 24 hrs). Maximum irreversible bindi
Page 19 and 20: CYP enzymes catalyze the first comp
Page 21 and 22: atmosphere, piperonyl butoxide, and
Page 23 and 24: Important differences exist in the
Page 25 and 26: 4. HAZARD IDENTIFICATION 4.1. STUDI
Page 27 and 28: from the later study (Murata et al.
Page 29 and 30: significant increased incidence of
Page 31 and 32: hematotoxicity individually. Theref
Page 33 and 34: (score of 1+ on a 0, 1+, 2+, 3+, or
Page 35 and 36: Methylnaphthalene mixtures are used
Page 37 and 38: A subsequent study was performed to
Page 39 and 40: 1998). The inhibition of intracellu
Page 41 and 42: pulmonary alveolar proteinosis requ
Page 43 and 44: eported that 119 or 238 mg/kg of me
Page 45 and 46: alveolar proteinosis is diagnosed b
Page 47 and 48: 1992), compared with the incidence
Page 49 and 50: Table 5. Parenteral (single intrape
Page 51 and 52: 4.5.2. Inhalation Exposure availabl
Page 53 and 54:
In addition, in a skin painting stu
Page 55 and 56:
4.7.2. Possible Gender Differences
Page 57 and 58:
dermally exposed to 119 mg/kg methy
Page 59 and 60:
were similarly exposed, the concurr
Page 61 and 62:
mice. For the male mouse data, the
Page 63 and 64:
A 10-fold UF was used to account fo
Page 65 and 66:
mice for 6 minutes to evaluate sens
Page 67 and 68:
6. MAJOR CONCLUSIONS IN THE CHARACT
Page 69 and 70:
The principal study for the RfD (Mu
Page 71 and 72:
Emi, Y; Konishi, Y. (1985) Endogeno
Page 73 and 74:
Melancon, MJ; Rickert, DE; Lech, JJ
Page 75 and 76:
pharmacokinetic model for naphthale
Page 77 and 78:
Willems, BAT; Melnick, RL; Kohn, MC
Page 79 and 80:
APPENDIX A: SUMMARY OF EXTERNAL PEE
Page 81 and 82:
Comments: All reviewers agreed that
Page 83 and 84:
accumulation of lipid in the alveol
Page 85 and 86:
type II pneumocytes (Murata et al.,
Page 87 and 88:
APPENDIX B: BENCHMARK DOSE (BMD) AN
Page 89 and 90:
Table B3. Comparison of benchmark d
Page 91 and 92:
intercept = -4.52857 slope = 1 Asym
Page 93 and 94:
Output B2: Quantal-linear fit of lo
Page 95 and 96:
Output B2 (con’d): Quantal-linear
Page 97:
Asymptotic Correlation Matrix of Pa
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