TOXICOLOGICAL REVIEW OF CHLORINE DIOXIDE AND CHLORITE

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

2004

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CONTENTS

FOREWORD . v

AUTHORS, CONTRIBUTORS, AND REVIEWERS .. vi

1. INTRODUCTION..1

2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS 2

3. TOXICOKINETICS RELEVANT TO ASSESSMENTS .3

3.1. ABSORPTION 3

3.1.1. Gastrointestinal Absorption 3

3.1.2. Respiratory Tract Absorption..4

3.1.3. Dermal Absorption.4

3.2. DISTRIBUTION..4

3.2.1. Chlorine Dioxide ..4

3.2.2. Chlorite 4

3.3. METABOLISM . 5

3.3.1. Chlorine Dioxide ..5

3.3.2. Chlorite 5

3.4. ELIMINATION ..5

3.4.1. Chlorine Dioxide ..5

3.4.2. Chlorite 5

4. HAZARD IDENTIFICATION .6

4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS .6

4.1.1. Oral Exposure .6

4.1.2. Inhalation Exposure ..9

4.2. PRECHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL

AND INHALATION .10

4.2.1. Oral Exposure 10

4.2.2. Inhalation Exposure .16

4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION 18

4.3.1. Chlorine Dioxide .18

4.3.2. Chlorite ..20

4.4. OTHER STUDIES ..26

4.4.1. Other Carcinogenicity Studies 26

4.4.2. Genotoxicity Studies .27

4.4.3. Mechanistic Studies ..28

4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS AND MODE OF

ACTION (IF KNOWN)—ORAL AND INHALATION . 28

4.5.1. Oral Exposure 28

4.5.2. Inhalation Exposure ..30

4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER CHARACTERIZATION—SYNTHESIS

OF HUMAN, ANIMAL, AND OTHER SUPPORTING EVIDENCE, CONCLUSIONS ABOUT HUMAN

CARCINOGENICITY, AND LIKELY MODE OF ACTION ..31

4.6.1. Chlorine Dioxide .31

4.6.2. Chlorite ..31

4.7. SUSCEPTIBLE POPULATIONS 32

4.7.1. Possible Childhood Susceptibility 32

4.7.2. Possible Gender Differences .32

5. DOSE-RESPONSE ASSESSMENTS.33

5.1. ORAL REFERENCE DOSE (RfD)..33

5.1.1. Choice of Principal Study and Critical Effect—With Rationale and Justification ..33

5.1.2. Methods of Analysis—Including Models (PBPK, BMD, etc.) .. 34

5.1.3. RfD Derivation—Including Application of Uncertainty Factors and Modifying Factors 35

5.2. INHALATION REFERENCE CONCENTRATION (RfC) .35

5.2.1. Choice of Principal Study and Critical Effect—With Rationale and Justification ..35

5.2.2. Methods of Analysis—NOAEL/LOAEL .36

5.2.3. RfC Derivation—Including Application of Uncertainty Factors and Modifying Factors 37

5.3. CANCER ASSESSMENT ..38

5.3.1. Chlorine Dioxide .38

5.3.2. Chlorite ..38

6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE

.38

6.1. HUMAN HAZARD POTENTIAL ..38

6.2. DOSE RESPONSE ..40

7. REFERENCES 40

APPENDIX A. EXTERNAL PEER REVIEW—SUMMARY OF COMMENTS AND DISPOSITION .46