TOXICOLOGICAL PROFILE FOR 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 

2-METHYLNAPHTHALENE 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

Agency for Toxic Substances and Disease Registry 

August 2005 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and does not imply endorsement by the 

Agency for Toxic Substances and Disease Registry. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE iii 

UPDATE STATEMENT 
 

A Toxicological Profile for Naphthalene, 1-Methylnaphthalene, and 2-Methylnaphthalene, Draft for 

Public Comment was released in September 2003. This edition supersedes any previously released draft 

or final profile. 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology/Toxicology Information Branch 

1600 Clifton Road NE 

Mailstop F-32 

Atlanta, Georgia 30333 



NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children? 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)? 

Section 3.7 Children’s Susceptibility 

Section 6.6 Exposures of Children 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-888-42-ATSDR or (404) 498-0110 Fax: (770) 488-4178 

E-mail: atsdric@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE viii 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

Other Agencies and Organizations 

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, 

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 

• Phone: 800-35-NIOSH. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212. 

Referrals 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, 

Elk Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Hisham El-Masri, Ph.D. 

Moiz Mumtaz, Ph.D. 

G. Daniel Todd, Ph.D. 
 

ATSDR, Division of Toxicology, Atlanta, GA 
 

Peter McClure, Ph.D., DABT 
 

Brian R. Marable, Ph.D., DABT 
 

Syracuse Research Corporation, Syracuse, NY 
 

Mona Singh, Ph.D. 
 

Syracuse Research Corporation, Arlington, VA 
 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1. 	 Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2.	 Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3. 	 Data Needs Review. The Research Implementation Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

4. 	 Green Border Review. Green Border review assures the consistency with ATSDR policy. 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE	 xi 

PEER REVIEW 
 

A peer review panel was assembled for naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. 

The panel consisted of the following members: 

1. 	 Martin Alexander, Ph.D., Cornell University, Ithaca, New York; 

2. 	 Susan Borghoff, Ph.D., DABT, CIIT Centers for Health Research, Research Triangle Park, North 

Carolina; and 

3. 	 G.A. Shakeel Ansari, Ph.D., The University of Texas Medical Branch, Galveston, Texas. 

These experts collectively have knowledge of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene's physical and chemical properties, toxicokinetics, key health end points, mechanisms of 

action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in 

conformity with the conditions for peer review specified in Section 104(I)(13) of the Comprehensive 

Environmental Response, Compensation, and Liability Act, as amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE xiii 

CONTENTS 
 

DISCLAIMER ..............................................................................................................................................ii 
 

UPDATE STATEMENT .............................................................................................................................iii 
 

FOREWORD ................................................................................................................................................ v 
 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS....................................................................vii 
 

CONTRIBUTORS ....................................................................................................................................... ix 
 

PEER REVIEW ........................................................................................................................................... xi 
 

CONTENTS...............................................................................................................................................xiii 
 

LIST OF FIGURES ..................................................................................................................................xvii 
 

LIST OF TABLES ..................................................................................................................................... xix 
 

1. PUBLIC HEALTH STATEMENT.......................................................................................................... 1 
 

1.1 	 WHAT ARE NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 

 2-METHYLNAPHTHALENE? .................................................................................................. 1 
 

1.2 	 WHAT HAPPENS TO NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 
 

2-METHYLNAPHTHALENE WHEN THEY ENTER THE ENVIRONMENT?..................... 2 
 

1.3 	 HOW MIGHT I BE EXPOSED TO NAPHTHALENE, 1-METHYLNAPHTHALENE, 

 AND 2-METHYLNAPHTHALENE? ........................................................................................ 4 
 

1.4 	 HOW CAN NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 
 

2-METHYLNAPHTHALENE ENTER AND LEAVE MY BODY? ......................................... 5 
 

1.5 	 HOW CAN NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 
 

2-METHYLNAPHTHALENE AFFECT MY HEALTH? .......................................................... 6 
 

1.6 	 HOW CAN NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 
 

2-METHYLNAPHTHALENE AFFECT CHILDREN? ............................................................. 8 
 

1.7 	 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO NAPHTHALENE, 
 

1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE? ..................................... 9 
 

1.8 	 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
 

EXPOSED TO NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 

 2-METHYLNAPHTHALENE? .................................................................................................. 9 
 

1.9 	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE 
 

TO PROTECT HUMAN HEALTH? ........................................................................................ 10 
 

1.10 	 WHERE CAN I GET MORE INFORMATION? ..................................................................... 11 
 

2. RELEVANCE TO PUBLIC HEALTH ................................................................................................. 13 
 

2.1 	 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO NAPHTHALENE, 
 

1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE IN THE 

 UNITED STATES..................................................................................................................... 13 
 

2.2 	 SUMMARY OF HEALTH EFFECTS...................................................................................... 14 
 

2.3 	 MINIMAL RISK LEVELS (MRLs) ......................................................................................... 21 
 

3. HEALTH EFFECTS .............................................................................................................................. 27 
 

3.1 	 INTRODUCTION ..................................................................................................................... 27 
 

3.2 	 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE .................................. 27 
 

3.2.1 	 Inhalation Exposure .............................................................................................................. 28 
 

3.2.1.1 Death ............................................................................................................................ 28 
 

3.2.1.2 Systemic Effects ........................................................................................................... 29 
 

3.2.1.3 Immunological and Lymphoreticular Effects ............................................................... 43 
 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE	 xiv 

3.2.1.4 Neurological Effects ..................................................................................................... 43 
 

3.2.1.5 Reproductive Effects .................................................................................................... 44 
 

3.2.1.6 Developmental Effects ................................................................................................. 44 
 

3.2.1.7 Cancer........................................................................................................................... 44 
 

3.2.2 Oral Exposure........................................................................................................................ 46 
 

3.2.2.1 Death ............................................................................................................................ 46 
 

3.2.2.2 Systemic Effects ........................................................................................................... 47 
 

3.2.2.3 Immunological and Lymphoreticular Effects ............................................................... 72 
 

3.2.2.4 Neurological Effects ..................................................................................................... 74 
 

3.2.2.5 Reproductive Effects .................................................................................................... 75 
 

3.2.2.6 Developmental Effects ................................................................................................. 76 
 

3.2.2.7 Cancer........................................................................................................................... 77 
 

3.2.3 Dermal Exposure................................................................................................................... 78 
 

3.2.3.1 Death ............................................................................................................................ 78 
 

3.2.3.2 Systemic Effects ........................................................................................................... 78 
 

3.2.3.3 Immunological and Lymphoreticular Effects ............................................................... 84 
 

3.2.3.4 Neurological Effects ..................................................................................................... 85 
 

3.2.3.5 Reproductive Effects .................................................................................................... 85 
 

3.2.3.6 Developmental Effects ................................................................................................. 85 
 

3.2.3.7 Cancer........................................................................................................................... 85 
 

3.3 GENOTOXICITY ..................................................................................................................... 85 
 

3.4 TOXICOKINETICS.................................................................................................................. 91 
 

3.4.1 Absorption............................................................................................................................. 93 
 

3.4.1.1 Inhalation Exposure...................................................................................................... 93 
 

3.4.1.2 Oral Exposure ............................................................................................................... 93 
 

3.4.1.3 Dermal Exposure .......................................................................................................... 94 
 

3.4.2 Distribution ........................................................................................................................... 95 
 

3.4.2.1 Inhalation Exposure...................................................................................................... 95 
 

3.4.2.2 Oral Exposure............................................................................................................... 96 
 

3.4.2.3 Dermal Exposure .......................................................................................................... 97 
 

3.4.2.4 Other Routes of Exposure ............................................................................................ 97 
 

3.4.3 Metabolism............................................................................................................................ 98 
 

3.4.4 Elimination and Excretion................................................................................................... 105 
 

3.4.4.1 Inhalation Exposure.................................................................................................... 105 
 

3.4.4.2 Oral Exposure............................................................................................................. 105 
 

3.4.4.3 Dermal Exposure ........................................................................................................ 107 
 

3.4.4.4 Other Routes of Exposure .......................................................................................... 107
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 108 
 

3.5 MECHANISMS OF ACTION ................................................................................................ 112 
 

3.5.1 Pharmacokinetic Mechanisms............................................................................................. 112 
 

3.5.2 Mechanisms of Toxicity...................................................................................................... 114 
 

3.5.3 Animal-to-Human Extrapolations ....................................................................................... 123 
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ........................ 124 
 

3.7 CHILDREN’S SUSCEPTIBILITY ......................................................................................... 125 
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT .................................................................. 129 
 

3.8.1	 Biomarkers Used to Identify or Quantify Exposure to Naphthalene, 

 1-Methylnaphthalene, and 2-Methylnaphthalene................................................................ 130 
 

3.8.2 	 Biomarkers Used to Characterize Effects Caused by Naphthalene, 

 1-Methylnaphthalene, and 2-Methylnaphthalene................................................................ 132 
 

3.9 INTERACTIONS WITH OTHER CHEMICALS .................................................................. 132 
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ............................................. 133 
 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE	 xv 

3.11 METHODS FOR REDUCING TOXIC EFFECTS................................................................. 135 
 

3.11.1 Reducing Peak Absorption Following Exposure ............................................................ 135 
 

3.11.2 Reducing Body Burden................................................................................................... 136 
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects ......................................... 136 
 

3.12 ADEQUACY OF THE DATABASE...................................................................................... 137 
 

3.12.1 	 Existing Information on Health Effects of Naphthalene, 1-Methylnaphthalene, 

 and 2-Methylnaphthalene ............................................................................................... 137 
 

3.12.2 	 Identification of Data Needs ........................................................................................... 141 
 

3.12.3 	 Ongoing Studies.............................................................................................................. 156 
 

4. CHEMICAL AND PHYSICAL INFORMATION.............................................................................. 159 
 

4.1 CHEMICAL IDENTITY......................................................................................................... 159 
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES...................................................................... 159 
 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL .......................................................... 163 
 

5.1 PRODUCTION ....................................................................................................................... 163 
 

5.2 IMPORT/EXPORT ................................................................................................................. 166 
 

5.3 USE.......................................................................................................................................... 166 
 

5.4 DISPOSAL .............................................................................................................................. 167 
 

6. POTENTIAL FOR HUMAN EXPOSURE ......................................................................................... 169 
 

6.1 OVERVIEW............................................................................................................................ 169 
 

6.2 RELEASES TO THE ENVIRONMENT ................................................................................ 173 
 

6.2.1 Air ....................................................................................................................................... 174 
 

6.2.2 Water ................................................................................................................................... 177 
 

6.2.3 Soil ...................................................................................................................................... 178 
 

6.3 ENVIRONMENTAL FATE.................................................................................................... 179
 

6.3.1 Transport and Partitioning................................................................................................... 179 
 

6.3.2 Transformation and Degradation ........................................................................................ 180 
 

6.3.2.1 	 Air............................................................................................................................... 180 
 

6.3.2.2 	 Water .......................................................................................................................... 181 
 

6.3.2.3 	 Sediment and Soil....................................................................................................... 182 
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ............................... 183 
 

6.4.1 Air ....................................................................................................................................... 184 
 

6.4.2 Water ................................................................................................................................... 186 
 

6.4.3 Sediment and Soil ............................................................................................................... 187 
 

6.4.4 Other Environmental Media................................................................................................ 188 
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ..................................... 190 
 

6.6 EXPOSURES OF CHILDREN ............................................................................................... 193 
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ........................................... 195 
 

6.8 ADEQUACY OF THE DATABASE...................................................................................... 195 
 

6.8.1 Identification of Data Needs ............................................................................................... 195 
 

6.8.2 Ongoing Studies .................................................................................................................. 199 
 

7. ANALYTICAL METHODS ............................................................................................................... 203 
 

7.1 BIOLOGICAL MATERIALS ................................................................................................. 203 
 

7.2 ENVIRONMENTAL SAMPLES............................................................................................ 204 
 

7.3 ADEQUACY OF THE DATABASE...................................................................................... 209 
 

7.3.1 Identification of Data Needs ............................................................................................... 210 
 

7.3.2 Ongoing Studies .................................................................................................................. 211 
 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE xvi 

8. REGULATIONS AND ADVISORIES ............................................................................................... 213 
 

9. REFERENCES .................................................................................................................................... 219 
 

10. GLOSSARY ...................................................................................................................................... 285 
 

APPENDICES 
 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1 
 

B. USER'S GUIDE .................................................................................................................................. B-1 
 

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS...................................................................... C-1 
 

D. INDEX ................................................................................................................................................D-1 
 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE xvii 

LIST OF FIGURES 

3-1. Levels of Significant Exposure to Naphthalene (Nap) or Methylnaphthalene (1-Mn or 2-Mn)— 

Inhalation............................................................................................................................................ 37 
 

3-2. Levels of Significant Exposure to Naphthalene (Nap) or Methylnaphthalene (1-Mn or 2-Mn)— 
 

Oral..................................................................................................................................................... 61 
 

3-3. Scheme for Naphthalene Metabolism and Formation of Multiple Reactive Metabolites, That 
 

May Be Involved in Naphthalene Toxicity ......................................................................................... 99 
 

3-4. Metabolism of 2-Methylnaphthalene................................................................................................ 103
 

3-5. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a 
 

Hypothetical Chemical Substance .................................................................................................... 110
 

3-6. Existing Information on Health Effects of Naphthalene .................................................................. 138
 

3-7. Existing Information on Health Effects of 1-Methylnaphthalene.....................................................139
 

3-8. Existing Information on Health Effects of 2-Methylnaphthalene.....................................................140
 

6-1. Frequency of NPL Sites with Naphthalene Contamination.............................................................. 170
 

6-2. Frequency of NPL Sites with 1-Methylnaphthalene Contamination ................................................ 171
 

6-3. Frequency of NPL Sites with 2-Methylnaphthalene Contamination ................................................ 172
 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE xix 

LIST OF TABLES 
 

3-1. Levels of Significant Exposure to Naphthalene (Nap) or Methylnaphthalene (1-Mn or 2-Mn)—
 

Inhalation............................................................................................................................................ 30 
 

3-2. Levels of Significant Exposure to Naphthalene (Nap) or Methylnaphthalene (1-Mn or 2-Mn)— 
 

Oral..................................................................................................................................................... 48 
 

3-3. Levels of Significant Exposure to Naphthalene (Nap) or Methylnaphthalene (1-Mn or 2-Mn)—
 

Dermal................................................................................................................................................ 79 
 

3-4. Results of Genotoxicity Testing of Naphthalene or Metabolites........................................................ 86
 

3-5. Genotoxicity of 1-Methylnaphthalene and 2-Methylnaphthalene In Vitro......................................... 92
 

4-1. Chemical Identity of Naphthalene, 1-Methylnaphthalene, and 2-Methylnaphthalene ..................... 160
 

4-2. Physical and Chemical Properties of Naphthalene, 1-Methylnaphthalene, and 

 2-Methylnaphthalene ........................................................................................................................ 161
 

5-1. Facilities that Produce, Process, or Use Naphthalene....................................................................... 164
 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Naphthalene ............... 175
 

6-2. Ongoing Studies on the Potential for Human Exposure to Naphthalene.......................................... 200
 

7-1. Analytical Methods for Determining Naphthalene, 1-Methylnaphthalene, and 2-Methylnaphthalene 
 

in Biological Samples ....................................................................................................................... 205
 

7-2. Analytical Methods for Determining Naphthalene in Environmental Samples ............................... 206
 

7-3. Analytical Methods for Determining 2-Methylnaphthalene in Environmental Samples ................. 208
 

8-1. Regulations and Guidelines Applicable to Naphthalene, 1-Methylnaphthalene, and 2-Methyl-
 

naphthalene ....................................................................................................................................... 215
 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 1 

1. PUBLIC HEALTH STATEMENT 
 

This public health statement tells you about naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene and the effects of exposure to these chemicals. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in 

the nation. These sites are then placed on the National Priorities List (NPL) and are targeted for 

long-term federal clean-up activities. Naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene have been found in at least 654, 36, and 412, respectively, of the 1,662 current or 

former NPL sites. Although the total number of NPL sites evaluated for these substances is not 

known, the possibility exists that the number of sites at which naphthalene, 1-methylnaphthalene, 

and 2-methylnaphthalene are found may increase in the future as more sites are evaluated. This 

information is important because these sites may be sources of exposure and exposure to these 

substances may harm you. 

When a substance is released either from a large area, such as an industrial plant, or from a 

container, such as a drum or bottle, it enters the environment. Such a release does not always 

lead to exposure. You can be exposed to a substance only when you come in contact with it. 

You may be exposed by breathing, eating, or drinking the substance, or by skin contact. 

If you are exposed to naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene, many factors 

will determine whether you will be harmed. These factors include the dose (how much), the 

duration (how long), and how you come in contact with them. You must also consider any other 

chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, and state of health. 

1.1 	 WHAT ARE NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE? 

Naphthalene is a white solid that evaporates easily. It is also called mothballs, moth flakes, 

white tar, and tar camphor. When mixed with air, naphthalene vapors easily burn. Fossil fuels, 

such as petroleum and coal, naturally contain naphthalene. Burning tobacco or wood produces 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 2 

1. PUBLIC HEALTH STATEMENT 

naphthalene. The major commercial use of naphthalene is to make other chemicals used in 

making polyvinyl chloride (PVC) plastics. The major consumer products made from 

naphthalene are moth repellents, in the form of mothballs or crystals, and toilet deodorant blocks. 

It is also used for making dyes, resins, leather tanning agents, and the insecticide carbaryl. 

Naphthalene has a strong but not unpleasant smell. Its taste is unknown, but it must not be 

unpleasant since children have eaten mothballs and deodorant blocks. You can smell 

naphthalene in the air at a concentration of 84 parts naphthalene per one billion parts (ppb) of air. 

You can smell it in water when 21 ppb are present. 

1-Methylnaphthalene is a naphthalene-related compound that is also called alpha methylnaphthalene. It is a clear liquid. Its taste and odor have not been described, but you can smell it 

in water when only 7.5 ppb are present. 

Another naphthalene-related compound, 2-methylnaphthalene, is also called beta methylnaphthalene. It is a solid like naphthalene. The taste and odor of 2-methylnaphthalene have not 

been described. Its presence can be detected at a concentration of 10 ppb in air and 10 ppb in 

water. 

1-Methylnaphthalene and 2-methylnaphthalene are used to make other chemicals such as dyes, 

and resins. 2-Methylnaphthalene is also used to make vitamin K. All three chemicals are 

present in cigarette smoke, wood smoke, tar, asphalt, and at some hazardous waste sites. 

See Chapters 4, 5, and 6 for more information on the properties and uses of naphthalene, 

1-methylnaphthalene, and 2-methylnaphthalene. 

1.2 	 WHAT HAPPENS TO NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 

2-METHYLNAPHTHALENE WHEN THEY ENTER THE ENVIRONMENT? 

Naphthalene enters the environment from industrial uses, from its use as a moth repellent, from 

the burning of wood or tobacco, and from accidental spills. Naphthalene at hazardous waste 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 3 

1. PUBLIC HEALTH STATEMENT 

sites and landfills can dissolve in water and be present in drinking water. Naphthalene can 

become weakly attached to soil or pass through the soil particles into underground water. 

Most of the naphthalene entering the environment is from the burning of woods and fossil fuels 

in the home. The second greatest release of naphthalene is through the use of moth repellents. 

Only about 10% of the naphthalene entering the environment is from coal production and 

distillation. Less than 1% of the naphthalene released to the atmosphere can be attributed to the 

losses from naphthalene production. Cigarette smoking also releases small amounts of 

naphthalene into the air. 

Naphthalene evaporates easily. That is why you can smell mothballs. In the air, moisture and 

sunlight make it break down, often within 1 day. Naphthalene can change to 1-naphthol or 

2-naphthol. These chemicals have some of the toxic properties of naphthalene. Some 

naphthalene will dissolve in water in rivers, lakes, or wells. Naphthalene in water is destroyed 

by bacteria or evaporates into the air. Most naphthalene will be gone from water in rivers or 

lakes within 2 weeks. 

Naphthalene binds weakly to soils and sediments. It easily passes through sandy soils to reach 

underground water. In soil, some microorganisms break down naphthalene. When near the 

surface of the soil, naphthalene will evaporate into air. Microorganisms present in the soil will 

break down most of the naphthalene in 1–3 months. 

Naphthalene does not accumulate in the flesh of animals and fish that you might eat. If dairy 

cows are exposed to naphthalene, some naphthalene will be in their milk; if laying hens are 

exposed, some naphthalene will be in their eggs. Naphthalene and the methylnaphthalenes have 

been found in very small amounts in some samples of fish and shellfish from polluted waters. 

Scientists know very little about what happens to 1-methylnaphthalene and 2-methylnaphthalene 

in the environment. These compounds are similar to naphthalene and should act like it in air, 

water, or soil. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 4 

1. PUBLIC HEALTH STATEMENT 

See Chapters 5 and 6 for more information on what happens to naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene in the environment. 

1.3 	 HOW MIGHT I BE EXPOSED TO NAPHTHALENE, 1-METHYLNAPHTHALENE, 

AND 2-METHYLNAPHTHALENE? 

You are most likely to be exposed to naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene 

from the air. Outdoor air contains low amounts of these chemicals. Burning of wood or fossil 

fuels and industrial discharges adds these chemicals to the environment. Automobile exhaust 

contributes naphthalene among other chemicals to air pollution in the cities. Typical air 

concentrations for naphthalene are low, 0.2 ppb or less. Studies of outdoor air reported 

concentrations of 0.09 ppb 1-methylnaphthalene and 0.011 ppb 2-methylnaphthalene. In homes 

or businesses where cigarettes are smoked, wood is burned, or moth repellents are used, the 

levels of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene in the air are higher. 

Studies of indoor air typically report that average indoor air concentrations of these contaminants 

are less than 1 ppb. 

You are not likely to be exposed to naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene 

by eating foods or drinking beverages. These materials are unlikely to come in contact with 

naphthalene or methylnaphthalenes during production or processing. Naphthalene and the 

methylnaphthalenes are also unlikely to be present in tap water. 

If you live near a hazardous waste site and have a well used for drinking water, you might be 

exposed to naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. For this to happen, the 

chemicals must pass through the soil and dissolve in the underground water that supplies your 

well. Children might also contact these chemicals by playing in or eating the dirt near a waste 

site. 

Work using or making moth repellents, coal tar products, dyes, or inks could expose you to 

naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene in the air. Working in the woodpreserving, leather tanning, or asphalt industries could expose you to naphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 5 

1. PUBLIC HEALTH STATEMENT 

Using moth repellents containing naphthalene in your home will expose you to naphthalene 

vapors. Your skin can come in contact with naphthalene via the use of naphthalene-treated 

clothing, blankets, or coverlets. You can breathe in the naphthalene vapors that are present in 

clothes and linen stored with moth-balls. Smoke from cigarettes can also expose you to 

naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. The highest airborne naphthalene 

concentrations in indoor air occur in the homes of cigarette smokers. 

See Chapter 6 for more information on how you might be exposed to naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. 

1.4 	 HOW CAN NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE ENTER AND LEAVE MY BODY? 

Naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene can enter your body if you breathe 

air that contains these chemicals, if you smoke, if you eat mothballs, if you drink water that 

contains these chemicals, or if they touch your skin. These chemicals are most likely to enter 

your body through the air you breath into your lungs. Naphthalene can also enter your body 

through your skin when you handle mothballs, particularly if you have used an oil-based skin 

lotion. You can also breathe in naphthalene vapors from clothes that have been stored in 

mothballs. 

Once naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene enter your body, small 

amounts will dissolve in your blood. Your blood carries them to your liver and other organs. 

These organs change them so that they pass through your body, mainly into your urine. Some 

naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene, and their breakdown products can 

be present in your stool. Naphthalene also has been found in some samples of fatty tissue and 

breast milk taken from the general U.S. population, but the concentrations of naphthalene were 

low. Most naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene that enters your body is 

expected to leave quickly within 1–3 days. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 6 

1. PUBLIC HEALTH STATEMENT 

See Chapter 3 for more information on how naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene enter and leave your body. 

1.5 	 HOW CAN NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE AFFECT MY HEALTH? 

Scientists use many tests to protect the public from harmful effects of toxic chemicals and to find 

ways for treating persons who have been harmed. 

One way to learn whether a chemical will harm people is to determine how the body absorbs, 

uses, and releases the chemical. For some chemicals, animal testing may be necessary. Animal 

testing may also help identify health effects such as cancer or birth defects. Without laboratory 

animals, scientists would lose a basic method for getting information needed to make wise 

decisions that protect public health. Scientists have the responsibility to treat research animals 

with care and compassion. Scientists must comply with strict animal care guidelines because 

laws today protect the welfare of research animals. 

Exposure to a large amount of naphthalene may damage or destroy some of your red blood cells. 

This could cause you to have too few red blood cells until your body replaces the destroyed cells. 

This problem is called hemolytic anemia. People, particularly children, have developed this 

problem after eating naphthalene-containing mothballs or deodorant blocks. Anemia has also 

occurred in infants wearing diapers that have been stored in mothballs. If your ancestors were 

from Africa or Mediterranean countries, naphthalene may be more dangerous to you than to 

people of other origins. These populations have a higher incidence of problems with an enzyme 

that usually protects red blood cells from damage created by oxygen in the air. 

Some of the symptoms that occur with hemolytic anemia are fatigue, lack of appetite, 

restlessness, and a pale appearance to your skin. Exposure to a large amount of naphthalene, 

such as by eating mothballs, may cause nausea, vomiting, diarrhea, blood in the urine, and a 

yellow color to the skin. If you have these symptoms, you should see a doctor quickly. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 7 

1. PUBLIC HEALTH STATEMENT 

Anemia is a common condition in pregnancy that can be due to causes other than naphthalene 

exposure. However, if you are a pregnant woman and are anemic due to naphthalene exposure, 

then it is possible that your unborn child may be anemic as well. Naphthalene can move from 

your blood to your baby's blood. Once your baby is born, naphthalene may also be carried from 

your body to your baby's body through your milk. It is not completely clear if naphthalene 

causes reproductive effects in animals; most evidence says that it does not. 

Laboratory rabbits, guinea pigs, mice, and rats sometimes develop cataracts (cloudiness) in their 

eyes after swallowing naphthalene at high dose levels. It is not certain whether cataracts also 

develop in humans exposed to naphthalene, but the possibility exists. 

When mice or rats breathed in naphthalene vapors daily throughout their lives (2 years), cells in 

the lining of their noses or lungs were damaged. Some exposed female mice also developed lung 

tumors. Some exposed male and female rats developed nose tumors. When mice or rats were 

fed naphthalene in their food for 13 weeks, no tumors or other tissue changes were found. The 

only effect found was decreased body weight in rats that were fed naphthalene. 

Based on these results from animal studies, the U.S. Department of Health and Human Services 

concluded that naphthalene is reasonably anticipated to be a human carcinogen. The 

International Agency for Research on Cancer (IARC) concluded that naphthalene is possibly 

carcinogenic to humans, because there is enough evidence that naphthalene causes cancer in 

animals, but not enough evidence about such an effect in humans. Under the EPA 1986 cancer 

guidelines, naphthalene was assigned to Group C – possible human carcinogen. 

When mice were fed food containing 1-methylnaphthalene or 2-methylnaphthalene for most of 

their lives (81 weeks), the gas-exchange part of the lungs of some mice became filled with an 

abnormal material. This type of lung injury is called pulmonary alveolar proteinosis. A few 

mice also had lung tumors, but the numbers of mice with lung tumors were not enough to 

conclude that 1-methylnaphthalene or 2-methylnaphthalene caused the tumors. Pulmonary 

alveolar proteinosis has been seen in some people, but the cause of this uncommon lung disease 

in humans is unknown. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 8 

1. PUBLIC HEALTH STATEMENT 

See Chapter 3 for more information on the effects of naphthalene, 1-methylnaphthalene, or 

2-methylnaphthalene on your health. 

1.6 	 HOW CAN NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE AFFECT CHILDREN? 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 

Hospitals have reported many cases of hemolytic anemia in children, including newborns and 

infants, who either ate naphthalene mothballs or deodorant cakes or who were in close contact 

with clothing or blankets stored in naphthalene mothballs. Newborns or infants are thought to be 

especially susceptible to this effect on the blood, because their bodies are less able to get rid of 

naphthalene than adults. 

Newborn mice appear to be more susceptible to lung injury than adult mice, when they are 

injected with naphthalene. These results suggest that children may be more susceptible to lung 

injury from naphthalene than adults. Scientists do not know if lung injury from breathing in 

naphthalene in childhood may lead to lung disease later in life. 

There are no reports that prenatal or postnatal exposure to naphthalene has caused developmental 

problems in human offspring. When pregnant mice, rats, or rabbits were fed naphthalene during 

their pregnancy, the development of their offspring was normal. Normal offspring development 

occurred even when the amounts of naphthalene given were large enough to prevent the pregnant 

animals from gaining their normal amount of weight. 

There are no studies in humans or animals indicating whether or not children are more 

susceptible to health effects from 1-methylnaphthalene or 2-methylnaphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 9 

1. PUBLIC HEALTH STATEMENT 

1.7 	 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO NAPHTHALENE, 

1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE? 

If your doctor finds that you have been exposed to substantial amounts of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene, ask whether your children might also have been exposed. 

Your doctor might need to ask your state health department to investigate. 

The most important way that families can reduce the risk of exposure to naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene is to avoid smoking tobacco, generating smoke during 

cooking, or using fireplaces or heating appliances in their homes. If families use naphthalenecontaining moth repellants, the material should be enclosed in containers that prevent vapors 

from escaping. The containers should not be accessible to young children. Blankets and 

clothing stored with naphthalene moth repellents should be aired outdoors to remove naphthalene 

odors and washed before they are used. To further minimize the risk of exposure to naphthalene, 

families should inform themselves of the contents of air deodorizers that are used in their homes, 

and refrain from using deodorizers with naphthalene. 

1.8 	 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN 

EXPOSED TO NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE?

 Several tests determine whether you have been exposed to naphthalene, 1-methylnaphthalene, or 

2-methylnaphthalene. These tests include measuring naphthalene, 1-methylnaphthalene, 

2-methylnaphthalene, or their breakdown products in samples of urine, stool, blood, maternal 

milk, or body fat. These tests require special equipment, which is not routinely available in a 

doctor's office. Body fluids, urine, stool samples, or tissue samples can be sent to a special 

laboratory for the tests. These tests cannot determine exactly how much naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene you were exposed to or predict whether harmful effects 

will occur. If the samples are collected within a day or two of exposure, then the tests can show 

if you were exposed to a large or small amount of naphthalene, 1-methylnaphthalene, or 

2-methylnaphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 10 

1. PUBLIC HEALTH STATEMENT 

See Chapters 3 and 7 for more information on tests for exposure to naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. 

1.9 	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. 

Regulations can be enforced by law. The EPA, the Occupational Safety and Health 

Administration (OSHA), and the Food and Drug Administration (FDA) are some federal 

agencies that develop regulations for toxic substances. Recommendations provide valuable 

guidelines to protect public health, but cannot be enforced by law. The Agency for Toxic 

Substances and Disease Registry (ATSDR) and the National Institute for Occupational Safety 

and Health (NIOSH) are two federal organizations that develop recommendations for toxic 

substances. 

Regulations and recommendations can be expressed as “not-to-exceed” levels, that is, levels of a 

toxic substance in air, water, soil, or food that do not exceed a critical value that is usually based 

on levels that affect animals; they are then adjusted to levels that will help protect humans. 

Sometimes these not-to-exceed levels differ among federal organizations because they used 

different exposure times (an 8-hour workday or a 24-hour day), different animal studies, or other 

factors. 

Recommendations and regulations are also updated periodically as more information becomes 

available. For the most current information, check with the federal agency or organization that 

provides it. Some regulations and recommendations for naphthalene, 1-methylnaphthalene, and 

2-methylnaphthalene include the following: 

The federal government has developed regulations and advisories to protect individuals from the 

possible health effects of naphthalene in the environment. OSHA set a limit of 10 parts per 

million (ppm) for the level of naphthalene in workplace air over an 8-hour workday. NIOSH set 

a limit of 500 ppm for the level of naphthalene in workplace air expected to be immediately 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 11 

1. PUBLIC HEALTH STATEMENT 

dangerous to life or health. Exposure to workplace air concentrations above this limit for more 

than 30 minutes would be expected to impair a worker’s ability to escape the contaminated 

workplace. 

EPA recommends that children not drink water with over 0.5 ppm naphthalene for more than 

10 days or over 0.4 ppm for any longer than 7 years. Adults should not drink water with more 

than 1 ppm for more than 7 years. For water consumed over a lifetime (70 years), EPA suggests 

that it contain no more than 0.1 ppm naphthalene. 

Industrial releases of naphthalene into the environment of more than 100 pounds must be 

reported to EPA. 

There are no regulations or advisories for 1-methylnaphthalene or 2-methylnaphthalene. 

See Chapter 8 for more information on government regulations for naphthalene. 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These 

clinics specialize in recognizing, evaluating, and treating illnesses that result from exposure to 

hazardous substances. 

Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You 

may request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information 

and technical assistance number at 1-888-42ATSDR (1-888-422-8737), by e-mail at 

atsdric@cdc.gov, or by writing to: 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 12 

1. PUBLIC HEALTH STATEMENT 

Agency for Toxic Substances and Disease Registry 

 Division of Toxicology 

1600 Clifton Road NE 

 Mailstop F-32 

 Atlanta, GA 30333 

 Fax: 1-770-488-4178 

Organizations for-profit may request copies of final Toxicological Profiles from the following: 

National Technical Information Service (NTIS) 
 

5285 Port Royal Road 

 Springfield, VA 22161 

 Phone: 1-800-553-6847 or 1-703-605-6000 

 Web site: http://www.ntis.gov/ 
 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 13 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 	 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO NAPHTHALENE, 

1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE IN THE UNITED STATES 

Naphthalene and methylnaphthalenes occur naturally in fossil fuels such as petroleum and coal, and are 

produced when organic materials (e.g., fossil fuels, wood, tobacco) are burned. Naphthalene is also 

produced commercially from either coal tar or petroleum. In 2000, estimates of commercial production 

of naphthalene in Japan, Western Europe, and the United States were 179, 205, and 107 thousand tonnes. 

Commercially-produced naphthalene is predominately used in the production of phthalic anhydride, 

which is used as an intermediate for polyvinyl chloride plasticizers such as di(2-ethylhexyl) phthalate. In 

1999, this use of naphthalene accounted for 73 and 60% of commercial demand for naphthalene in Japan 

and the United States, respectively. Other uses of naphthalene include production of naphthalene 

sulfonates (used in concrete additives and synthetic tanning agents), pesticides (e.g., carbaryl insecticides 

and moth repellents), and dye intermediates. 

Naphthalene is frequently present in industrial and automobile emissions and effluents and in various 

media in the general environment due to its natural occurrence in coal and petroleum products and 

emissions, its use as an intermediate in the production of plasticizers, resins, and insecticides, and its use 

in a variety of consumer products such as moth repellants. In 2002, environmental releases of 

naphthalene reported under the EPA Toxics Release Inventory (TRI) program were about 2.07 million 

pounds in air emissions, 0.03 million pounds in surface water discharges, 0.23 million pounds in 

underground injection discharges, and 0.37 million pounds in releases to land. These figures reflect 

estimates that most naphthalene entering the environment is discharged to the air, with the largest releases 

associated with the combustion of plant material and fossil fuels and volatilization from naphthalenecontaining consumer products. 

Monitoring studies of outdoor ambient air levels of naphthalene have reported concentrations in the range 

of about 0.4–170 μg/m3

, with a median naphthalene concentration of 0.94 μg/m3 (0.0002 ppm) reported 

for urban/suburban air samples collected from 11 U.S. cities. The highest outdoor air concentrations have 

been found in the immediate vicinity of certain industrial sources and hazardous waste sites. For 

example, average concentrations of naphthalene in ambient air at five hazardous waste sites and one 

landfill in New Jersey ranged from 0.42 to 4.6 μg/m3

 (0.00008–0.0009 ppm). In indoor air, emissions 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 14 

2. RELEVANCE TO PUBLIC HEALTH 

from cooking, tobacco smoking, or moth repellants are expected to be the predominant sources of 

naphthalene. Indoor air concentrations of naphthalene in homes with smoking residents and homes 

without smoking residents were reported to be 2.2 μg/m3 (0.0004 ppm) and 1.0 μg/m3 (0.0002 ppm), 

respectively. A study of indoor and outdoor air in 24 low-income homes in North Carolina found 

naphthalene levels ranging from 0.33–9.7 μg/m3 and 0.57–1.82 μg/m3 respectively. Methylnaphthalenes 

have also been detected in ambient outdoor and indoor air. For example, average concentrations of 

1-methylnaphthalene and 2-methylnaphthalene in ambient outdoor air samples were reported to be 

0.51 and 0.065 μg/m3

, respectively, whereas 2-methylnaphthalene in indoor air samples showed an 

average concentration of 1.5 μg/m3 (0.0003 ppm). Based on a median concentration of 0.95 μg/m3 

(0.0002 ppm) naphthalene in urban and suburban air samples and an inhalation rate of 20 m3

/day, the 

average daily intake of naphthalene from ambient air is estimated at 19 μg/day, or 0.3 μg/kg/day 

assuming 70-kg body weight. 

Levels of naphthalene (and methylnaphthalenes), when detected in water, sediments, and soil tend to be 

low: usually <10 μg/L in surface water or groundwater, <500 μg/kg in sediments, and 0–3 μg/kg in 

untreated agricultural soils. However, in the immediate vicinity of point sources of release, such as 

chemical waste sites, concentrations can be higher. For example, concentrations of 6.1 and 2.9 mg/kg 

were reported for naphthalene and methylnaphthalene, respectively, in soil samples contaminated with 

coal tar. 

2.2 SUMMARY OF HEALTH EFFECTS 

Reports that establish associations between naphthalene exposure and health effects in humans are 

restricted to numerous reports of hemolytic anemia or cataracts following acute exposure or occupational 

exposure to naphthalene, either by ingestion or by inhalation of naphthalene vapors, but these reports 

have not identified exposure levels associated with these effects. A relationship appears to exist between 

an inherited deficiency in the enzyme, glucose 6-phosphate dehydrogenase (G6PD), and susceptibility to 

naphthalene-induced hemolysis. Newborn infants also appear to be susceptible to naphthalene-induced 

hemolysis presumably due to a decreased ability to conjugate and excrete naphthalene metabolites. The 

only studies of cancer in humans exposed to naphthalene are two case series reports of cancer; one report 

of four laryngeal cancer cases (all of whom were smokers) among workers in a naphthalene purification 

plant in East Germany, and another report of 23 cases of colorectal carcinoma admitted to a hospital in 

Nigeria. NTP, EPA, and IARC concur that these studies provide inadequate evidence of naphthalene 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 15 

2. RELEVANCE TO PUBLIC HEALTH 

carcinogenicity in humans. No cohort mortality or morbidity studies or case-control studies examining 

possible associations between naphthalene exposure and increased risk of cancer (or other health effects) 

are available. 

Epidemiology studies, case reports, or controlled-exposure studies examining the potential health effects 

of human exposure to 1-methylnaphthalene or 2-methylnaphthalene by any route of exposure are not 

available. 

Results from animal studies exposed to naphthalene by oral administration, by inhalation exposure, or by 

parenteral administration identify several health effects of potential concern for humans, including 

maternal toxicity during pregnancy with acute oral exposure, decreased body weight (without lesions 

developing in any tissues or organs) with intermediate oral exposure, and increased incidence of 

nonneoplastic and neoplastic lesions in the nose (in rats and mice) and the lung (in mice only) with 

chronic inhalation exposure. 

Hemolytic and Ocular Effects of Naphthalene in Animals. Rats and mice do not appear to be 

susceptible to the hemolytic effects of naphthalene as hematological end points have not been affected in 

acute or intermediate duration oral studies or in acute 14-day inhalation studies. There is one report of 

hemolytic anemia in a few dogs orally exposed to naphthalene, but the data are inadequate to describe 

dose-response relationships that can be reliably extrapolated to human exposure scenarios. Naphthaleneinduced cataracts or lens opacities are well studied in rats and rabbits and appear to occur at acute- or 

intermediate-duration oral exposure levels >500 mg/kg/day. Naphthalene-induced cataracts were not 

found with intermediate-duration (i.e., 13 weeks) oral exposure at lower dose levels up to 200 mg/kg/day 

in mice or 400 mg/kg/day in rats. 

Maternal and Developmental Toxicity of Naphthalene in Animals. Acute oral exposure of pregnant rats 

to naphthalene doses of 150 or 450 mg/kg/day (but not 50 mg/kg/day) during gestation has produced 

maternal toxicity including clinical signs (lethargy and prone position) and severe decreases in body 

weight gain, but clear effects on the developing fetus have not been found at maternal oral doses as high 

as 450 mg/kg/day in rats, 300 mg/kg/day in mice, or 120 or 400 mg/kg/day in rabbits. Reduced numbers 

of mouse pups per litter were observed when naphthalene (300 mg/kg/day) in corn oil was orally 

administered to pregnant mice; however, no fetotoxic effects were seen when pregnant rabbits were orally 

administered naphthalene at even higher doses (400 mg/kg/day) but delivered in methylcellulose rather 

than in an oil vehicle. It is unclear if these differences are due to species differences in sensitivity or to 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 16 

2. RELEVANCE TO PUBLIC HEALTH 

the vehicle used to deliver naphthalene. The finding of maternal toxicity in orally exposed pregnant rats 

serves as the basis of the acute oral MRL for naphthalene (see Section 2.3). Dermal or inhalation 

developmental toxicity studies in animals are not available. 

Body Weight Effects of Naphthalene in Animals. Comprehensive intermediate-duration (13 weeks) oral 

toxicity studies found no evidence for naphthalene-induced lesions in any tissue or organs in male or 

female Fischer 344 rats exposed to doses as high as 400 mg/kg/day or in male or female B6C3F1 mice 

exposed to doses as high as 200 mg/kg/day. The only biologically significant effects found in these 

studies were decreases in rat terminal body weights compared with controls at dose levels of 

200 mg/kg/day (12% decrease in male rats) and 400 mg/kg/day (28 and 23% decreases in male and 

female rats, respectively). No effect on food consumption was observed in exposed rats. Exposed male 

mice had higher body weights than controls, and exposed female mice had lower body weights than 

controls, but mean body weights were not decreased by more than 5%. In another intermediate-duration 

oral study with CD-1 mice that focused on a battery of immunologic tests (but did not include 

comprehensive histopathologic examination of tissues), no biologically significant effects were found 

except for decreases in weights of several organs (brain, liver, and spleen) in mice exposed to 

133 mg/kg/day, but not to 53 or 5.3 mg/kg/day. The lack of naphthalene-induced lesions in these organs 

in the NTP studies suggests that the brain, liver, and spleen are not sensitive targets of naphthalene 

following intermediate oral exposure. Body weight changes in rats were the most sensitive, biologically 

relevant effects observed in the available toxicity studies in animals orally exposed for intermediate 

durations. These effects were considered in deriving the intermediate-duration oral MRL for naphthalene 

(see Section 2.3). Chronic-duration oral toxicity studies with naphthalene in animals are not available. 

Cancer and Respiratory Effects of Naphthalene in Animals. Chronic inhalation studies found increased 

incidences of nonneoplastic and neoplastic lesions in the nose of rats, nonneoplastic lesions in the nose of 

mice, and neoplastic and nonneoplastic lesions in the lungs of mice. In mice of both sexes, chronic 

inhalation of 10 or 30 ppm naphthalene induced inflammation of the nose and lung, metaplasia of the 

olfactory epithelium, and hyperplasia of the nasal respiratory epithelium. In female mice (but not male 

mice), exposure to 30 ppm (but not 10 ppm) increased the incidence of benign lung tumors (alveolar/ 

bronchiolar adenomas) compared with controls. One other female mouse exposed to 30 ppm showed a 

malignant lung tumor (alveolar/bronchiolar carcinoma). In rats of both sexes, inhalation of 10, 30, or 

60 ppm naphthalene induced nonneoplastic and neoplastic lesions only in the nasal cavity. Nonneoplastic 

nasal lesions included (1) hyperplasia, atrophy, chronic inflammation, and hyaline degeneration of the 

olfactory epithelium and (2) hyperplasia, metaplasia or degeneration of the respiratory epithelium or 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 17 

2. RELEVANCE TO PUBLIC HEALTH 

glands. Neoplastic lesions associated with naphthalene exposure in rats were olfactory epithelial neuroblastoma (a rare malignant tumor) and respiratory epithelial adenoma. The chronic inhalation MRL for 

naphthalene is based on the LOAEL of 10 ppm for nonneoplastic lesions in the olfactory epithelium and 

respiratory epithelium of the nose of rats (see Section 2.3). 

The mechanisms by which naphthalene causes nonneoplastic or neoplastic lesions in the respiratory tract 

of rodents are incompletely understood, but are thought to involve reactive metabolites of naphthalene, 

including 1,2-naphthalene oxide, 1,2-naphthoquinone, 1,4-naphthoquinone, and possibly 

1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydronaphthalene(see Sections 3.4.3. and 3.5). 

Comparison of species susceptibility to naphthalene-induced nonneoplastic lung damage suggests that 

mice are much more sensitive than rats (e.g., nonneoplastic or neoplastic lung lesions were not found in 

chronically exposed rats in the NTP study) and that differences in rates and stereoselectivity of 

naphthalene metabolism to epoxide intermediates may be involved in this species difference. Acute 

(4-hour) inhalation exposure of mice to naphthalene concentrations as low as 2–10 ppm induced lung 

injury, whereas rats exposed to naphthalene concentrations as high as 110 ppm showed no signs of lung 

injury. Some evidence has been reported that rates and stereoselectivity of naphthalene metabolism in 

primate lung tissue may be more like rats than mice. In in vitro studies with microsomes from 

lymphoblastoid cells, which expressed recombinant human CYP2F1, metabolism of naphthalene to 

epoxide intermediates was demonstrated, but the predominant enantiomeric form produced (1S,2R-oxide) 

was different from the form (1R,2S-oxide) produced by mouse CYP2F2. Although these observations on 

epoxide formation may suggest that mice may be more sensitive than humans to acute naphthalene lung 

toxicity from epoxide intermediates, the possible role of other potentially reactive metabolites of 

naphthalene (e.g., the naphthoquinone metabolites) is unknown with chronic exposure scenarios. To date, 

mechanistic understanding of species differences in naphthalene bioactivation in the lung is too 

incomplete to definitively rule out the possible human relevance of naphthalene-induced lung lesions in 

mice (see Section 3.5). 

In contrast, the olfactory epithelium and respiratory epithelium of the nose of rats and mice do not appear 

to differ in sensitivity to naphthalene nonneoplastic toxicity from chronic inhalation exposure. 

Nonneoplastic nasal lesions were found in nearly all exposed animals of both species at the lowest 

exposure level, 10 ppm, in both chronic studies. CYP monooxygenases, which might be involved in 

naphthalene metabolism and bioactivation, have been demonstrated to exist in nasal respiratory epithelial 

and olfactory epithelial tissue from rodents and humans. Studies designed to specifically characterize 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 18 

2. RELEVANCE TO PUBLIC HEALTH 

metabolism of naphthalene in nasal tissue, however, have not been conducted, with the exception of a 

single study, which examined in vitro rates of metabolism of naphthalene to naphthalene oxides in 

postmitochondrial supernatants from mouse, rat, and hamster olfactory tissue. Metabolic rates (units of 

nmol/min/mg protein) showed the following order: mouse (87.1) > rat (43.5) > hamster (3.9). This order 

did not correspond with species differences in sensitivity to single intraperitoneal injections of 

naphthalene in a companion study. The lowest dose levels producing substantial necrosis and exfoliation 

in olfactory epithelium were 200 mg/kg in rats and 400 mg/kg in mice and hamsters. To date, 

mechanistic understanding of species differences in naphthalene bioactivation in the respiratory tissues is 

too incomplete to definitively rule out the possible human relevance of naphthalene-induced nasal lesions 

in rodents (nonneoplastic lesions in rats and mice and neoplastic lesions in rats; see Section 3.5). 

It is unknown whether the naphthalene-induced neoplastic lesions found in mice (lung adenomas) and rats 

(nose respiratory epithelial adenomas and olfactory epithelial neuroblastomas) are produced via a 

genotoxic mode of action or a nongenotoxic mode requiring tissue damage and regenerative responses as 

precursor events. Results from genotoxicity tests for naphthalene have been predominately (but not 

completely) negative (see Section 3.3), and the general sites of neoplastic lesions, the nose in rats and the 

lungs in mice, show some correspondence (but not complete) with the general sites of nonneoplastic 

lesions. However, mechanistic understanding of naphthalene’s carcinogenic mode of action is too 

incomplete to rule out the possibility of a genotoxic mode of action. Key issues that remain unexplained 

or unstudied include: 

(1) the possible significance of the few positive genotoxicity results that have been obtained, 

including: reverse mutations in Salmonella typhimurium by 1,2-naphthoquinone; in vitro 

formation of N-7 guanine adducts of DNA by 1,2-naphtoquinone; reverse mutations for 

luminescence in the marine bacteria, Vibrio fischeri, by naphthalene; induction of sister 

chromatid exchanges in Chinese hamster ovary cells by naphthalene and in human mononuclear 

leukocytes by 1,2- or 1,4-naphthoquinone; induction of chromosomal aberrations in Chinese 

hamster ovaries and preimplantation mouse embryos by naphthalene; induction of somatic 

mutations and recombination in Drosophila melanogaster by naphthalene; and weak (about 

2-fold) induction of micronuclei in red blood cells from Pleurodeles waltl larvae by naphthalene. 

(2) the lack of a mechanistic explanation of why nearly all rats and mice develop nasal 

nonneoplastic lesions following chronic exposure to naphthalene at concentrations ≥10 ppm, but 

only some rats develop nasal tumors; 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 19 

2. RELEVANCE TO PUBLIC HEALTH 

(3) the lack of a mechanistic explanation of why both male and female mice exposed to 

naphthalene show similar incidences of chronic lung inflammation following chronic exposure to 

10 or 30 ppm, but only female mice showed statistically significant increased incidence of lung 

tumors; 

(4) the lack of in vivo genotoxicity assays involving target tissues of naphthalene carcinogenicity 

(nose and lung); and 

(5) the lack of information on the possible threshold exposure levels for nonneoplastic nasal 

lesions in rats and mice at air concentrations <10 ppm. 

The National Toxicology Program 11th Report on Carcinogens includes naphthalene in its list of 

chemicals reasonably anticipated to be human carcinogen. 

International Agency for Research on Cancer concluded that naphthalene is possibly carcinogenic to 

humans (Group 2B) based on specific evaluations that there is inadequate evidence in humans and 

sufficient evidence in animals for the carcinogenicity of naphthalene. IARC considered the findings for 

nasal tumors in male and female rats and lung tumors in female mice in the NTP bioassays as sufficient 

evidence, noting that both nasal tumor types (olfactory epithelial neuroblastomas and respiratory 

epithelial adenomas) are rare in untreated rats. 

EPA last assessed the carcinogenicity of naphthalene before the availability of the results from the 

chronic rat bioassay. In the EPA (1998c) Toxicological Review on Naphthalene, it was concluded that 

there was inadequate evidence in humans and limited evidence in animals of naphthalene carcinogenicity 

(increased incidence of lung tumors in female mice). Under the EPA 1986e cancer guidelines, 

naphthalene was assigned to Group C—possible human carcinogen. Under the EPA 1996a proposed 

cancer guidelines, it was judged that the human carcinogenic potential of naphthalene via the oral or 

inhalation routes “cannot be determined”, but it was noted that there was suggestive evidence of potential 

human carcinogenicity based on increased lung tumors in female mice. Currently, the EPA Integrated 

Risk Information System (IRIS) Office is reassessing the inhalation carcinogenicity of naphthalene. 

Cancer and Respiratory Effects of 1- and 2-Methylaphthalene in Animals. Increased incidences of 

pulmonary alveolar proteinosis have been observed in mice of both sexes exposed to 1-methyl-
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 20 

2. RELEVANCE TO PUBLIC HEALTH 

naphthalene in the diet for 81 weeks at approximate dose levels of 72–75 and 140–144 mg/kg/day and 

2-methylnaphthalene in the diet at doses of 50–54 and 108–114 mg/kg/day. Histologic examination of 

major tissues and organs in these studies showed no other exposure-related nonneoplastic or neoplastic 

lesions at other sites (including the bronchiolar regions of the lung). Mice dermally exposed to 30 or 

119 mg/kg of methylnaphthalene (a mixture of 1- and 2-methylnaphthalene) for 30–61 weeks also 

showed increased incidence of pulmonary alveolar proteinosis. The chronic studies with mice exposed to 

1- or 2-methylnaphthalene in the diet provide the basis for the chronic oral minimal risk levels (MRLs) 

for these substances (see Section 2.3). 

Pulmonary alveolar proteinosis is characterized by an accumulation in the alveolar lumen of foamy cells, 

cholesterol crystals, and proteinaceous materials rich in lipids. The condition is rare in humans and has 

not been associated with human exposure to 2-methylnaphthalene or 1-methylnaphthalene. Human 

subjects with this condition can display pulmonary function deficits. The absence of pulmonary alveolar 

proteinosis in a 13-week range-finding study that exposed B6C3F1 mice to dietary doses as high as 

2,500 mg/kg/day suggests that the development of this lesion requires chronic-duration exposure. 

The mechanisms by which 1- or 2-methylnaphthalene may cause pulmonary alveolar proteinosis are 

poorly understood, but light and electron microscopic observations of lung tissues from mice repeatedly 

exposed to dermal doses of methylnaphthalene indicate that type II pneumocytes are a specific cellular 

target. It has been hypothesized that, in response to 1- or 2-methylnaphthalene, type II pneumocytes 

produce increased amounts of lamellar bodies due to hyperplasia and hypertrophy, and eventually 

transform into balloon cells. The rupture of balloon cells is hypothesized to lead to the accumulation of 

proteinaceous materials rich in lipids in the alveolar lumen. It is unknown whether the methylnaphthalenes themselves or their metabolites are responsible for the development of pulmonary alveolar 

proteinosis. 

The chronic dietary studies with 1- or 2-methylnaphthalene provide limited evidence for the 

carcinogenicity of these chemicals. In the 1-methylnaphthalene study, respective incidences of mice with 

lung adenomas or carcinomas were 5/50, 2/50, and 5/50 for control through high-dose females, and 2/49, 

13/50, and 15/50 for males. With 2-methylnaphthalene, incidences for lung adenomas or carcinomas 

were 5/50, 4/49, and 6/48 for females and 2/49, 10/49, and 6/49 for males. The tumorigenic response was 

predominantly benign and was only consistently seen in male mice exposed to 1-methylnaphthalene. The 

available data on the methylnaphthalenes appear inadequate to determine their carcinogenicity potential in 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 21 

2. RELEVANCE TO PUBLIC HEALTH 

humans, given the lack of any human studies on the potential carcinogenicity of the methylnaphthalenes 

and the limited evidence of carcinogenicity in animals. 

The NTP 11th Report on Carcinogens does not include 1-methylnaphthalene or 2-methylnaphthalene on 

its list of chemicals known to be human carcinogens or reasonably anticipated to be human carcinogens. 

IARC has not assessed the carcinogenicity potential of the methylnaphthalenes. The EPA concluded that 

the available data for 2-methylnaphthalene are inadequate to assess human carcinogenic potential, noting 

that there are no human data and the available evidence of 2-methylnaphthalene in animals is limited and 

insufficient to determine that 2-methylnaphthalene is carcinogenic to humans. 

2.3 MINIMAL RISK LEVELS (MRLs) 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for naphthalene, 

1-methylnaphthalene, and 2-methylnaphthalene. An MRL is defined as an estimate of daily human 

exposure to a substance that is likely to be without an appreciable risk of adverse effects 

(noncarcinogenic) over a specified duration of exposure. MRLs are derived when reliable and sufficient 

data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific 

duration within a given route of exposure. MRLs are based on noncancerous health effects only and do 

not consider carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration 

exposures for inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for 

dermal exposure. 

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), 

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional 

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an 

example, acute inhalation MRLs may not be protective for health effects that are delayed in development 

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic 

bronchitis. As these kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

Inhalation MRLs 

• An MRL of 0.0007 ppm was derived for chronic inhalation exposure to naphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 22 

2. RELEVANCE TO PUBLIC HEALTH 

The MRL was derived from two chronic inhalation toxicity and carcinogenicity studies with mice (NTP 

1992a) and rats (Abdo et al. 2001; NTP 2000). In one study, groups of 75 B6C3F1 mice of each sex were 

exposed by inhalation at concentrations of 0, 10, or 30 ppm, 6 hours/day, 5 days/week for 104 weeks. In 

the other study, groups of 49 male and 49 female F344/N rats were exposed to naphthalene at 

concentrations of 0, 10, 30, or 60 ppm, 6 hours/day, 5 days/week for 105 weeks. The lowest exposure 

level in both studies, 10 ppm, was a lowest-observed-adverse-effect level (LOAEL) in both sexes of both 

species for nonneoplastic lesions in nasal olfactory epithelium (metaplasia in mice, and hyperplasia, 

atrophy, and chronic inflammation in rats) and respiratory epithelium (hyperplasia in mice, and 

hyperplasia, metaplasia, hyaline degeneration, or gland hyperplasia in rats). At 10 ppm, nearly all of the 

animals showed nasal lesions. Exposed rats also showed increased incidences of nasal tumors 

(respiratory epithelial adenomas and olfactory epithelial neuroblastomas), but mice did not develop nose 

tumors. Exposed mice also showed an increased incidence of chronic lung inflammation at both exposure 

levels and an increased incidence of lung tumors in females exposed to 30 ppm. Lung lesions did not 

occur in exposed rats. 

Following EPA (1994b) Methods for Derivation of Inhalation Reference Concentrations and Application 

of Inhalation Dosimetry, equations for a category 1 gas producing nasal effects were used to derive 

human equivalent concentrations of 0.2 ppm based on the rat data and 0.3 ppm based on the mouse data 

(see Appendix B). Using public health protection reasoning, the LOAELHEC based on the rat data, 

0.2 ppm, was selected as the point of departure for the chronic inhalation MRL, which was divided by a 

total uncertainty factor of 300 (10 for the use of a LOAEL, 3 for extrapolation from animals to humans 

using dosimetric adjustment, and 10 for human variability) to derive the MRL of 0.0007 ppm 

(3x10-3 mg/m3

). 

No appropriate data were located on effects of acute- and intermediate-duration inhalation exposure in 

humans or animals that could be used to derive acute and intermediate MRLs for inhalation exposure to 

naphthalene. 

No appropriate data were located for deriving inhalation MRLs for 1-methylnaphthalene or 2-methylnaphthalene. 

Oral MRLs 

• An MRL of 0.6 mg/kg/day was derived for acute oral exposure to naphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 23 

2. RELEVANCE TO PUBLIC HEALTH 

A rat developmental toxicity study involving exposure of Sprague-Dawley rats to gavage doses of 50, 

150, or 450 mg/kg/day naphthalene on gestation days 6-15 was selected as the basis of the acute oral 

MRL (NTP 1991a). The only maternal or fetal effects observed at the lowest dose level were slow 

respiration, lethargy, or prone body posture in most dams following dose administration on the first and 

second day of dosing. These effects did not occur on subsequent days of dosing at this dose level. 

Because of the transient nature of these observations and the lack of any other effect, 50 mg/kg/day was 

judged to be a minimal lowest-observed-adverse-effect level (LOAEL) for clinical signs of toxicity. At 

150 and 450 mg/kg/day, clinical signs of toxicity were more persistent and were accompanied with severe 

decreases in body weight gain during the exposure period (31 and 53%, respectively, compared with 

controls). No exposure-related fetal effects were found in any of the exposure groups compared with the 

controls in this study. 

The MRL was calculated from the minimal LOAEL of 50 mg/kg/day using an uncertainty factor of 

90 (3 for the use of a minimal LOAEL, 10 for extrapolation from animals to humans, and 3 for human 

variability) to derive the MRL of 0.6 mg/kg/day (see Appendix A). An uncertainty factor of 3 was used 

for human variability because the critical effect is based on effects in a sensitive animal subpopulation. 

Pregnant rats appear to be more sensitive for the effects observed (clinical signs of toxicity in response to 

gavage exposure and decreased body weight gain) than nonpregnant rats. In 13-week gavage studies with 

nonpregnant rats (NTP 1980b), similar persistent clinical signs were not observed following 

administration of doses as high as 200 mg/kg/day, but were observed at 400 mg/kg/day. In nonpregnant 

rats exposed for 13 weeks, significant body weight decreases occurred at 200 mg/kg/day throughout 

exposure, but not at 100 mg/kg/day (NTP 1980b) or in nonpregnant mice exposed for 13 weeks to 

133 mg/kg/day (Shopp et al. 1984) or 200 mg/kg/day (NTP 1980a). Mice in the NTP (1980a) study 

showed transient signs of toxicity (lethargy, rough hair coats, and decreased food consumption), but these 

only occurred between weeks 3 and 5 in the 200-mg/kg/day group. 

•	 The acute-duration oral MRL of 0.6 mg/kg/day is adopted as the intermediate-duration oral MRL 

for naphthalene. 

There are three intermediate-duration oral toxicity studies in laboratory animals that were considered for 

deriving the intermediate-duration oral MRL for naphthalene. A 13-week comprehensive oral toxicity 

study in Fischer 344 rats found no adverse exposure-related effects other than decreased body weight 

(NTP 1980b). This study identified 100 mg/kg/day as a no-observed-adverse-effect level (NOAEL) and 

200 mg/kg/day as a LOAEL for decreased body weight in male and female rats. Another 13-week 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 24 

2. RELEVANCE TO PUBLIC HEALTH 

comprehensive oral toxicity study in B6C3F1 mice found no adverse effects in mice exposed to doses as 

high as 200 mg/kg/day (NTP 1980a). Another 90-day gavage study in CD-1 mice focused on immune 

system variables and other toxicity variables (e.g., body weight, organ weight, haematological 

parameters) and identified 133 mg/kg/day as a LOAEL and 53 mg/kg/day as a NOAEL for weight 

decreases in several organs (brain, liver, and spleen), but found no biologically significant exposurerelated changes in other end points evaluated (Shopp et al. 1984). This study, however, did not include 

histopathological examination of tissues. 

The findings from the three intermediate-duration oral toxicity studies do not collectively identify a clear, 

biologically significant target of toxicity other than body weight changes in rats (see Appendix A for 

comprehensive descriptions of the design and results of these studies). Consideration was given to basing 

the MRL on the NOAEL of 53 mg/kg/day and LOAEL of 133 mg/kg/day for decreases in absolute weight 

of brain, liver, and spleen, and in relative weight of spleen, in female mice (Shopp et al. 1984). However, 

the biological significance of these effects is uncertain because (1) the effects were only observed in 

females, and (2) histological effects in the affected organs were not observed in the other 13-week oral 

studies with rats and mice. 

As discussed in Appendix A, a potential intermediate-duration MRL of 0.7 mg/kg/day was derived based 

on the duration-adjusted NOAEL of 71 mg/kg/day for decreased body weight in male and female rats 

exposed by gavage to naphthalene 5 days/week for 13 weeks (NTP 1980b) and a total uncertainty factor 

of 100 (10 for extrapolating from rats to humans and 10 for human variability). Because the value of 

0.7 mg/kg/day is slightly larger than the acute-duration oral MRL of 0.6 mg/kg/day, the acute MRL is 

expected to be protective for intermediate-duration exposure scenarios and was adopted as the 

intermediate-duration oral MRL. 

No appropriate studies were located for deriving an MRL for chronic oral exposure to naphthalene. One 

chronic study was located that examined the toxicity of naphthalene in rats (Schmahl 1955). No 

treatment-related effects were reported at a dose level of 41 mg/kg/day for 700 days. The study was not 

suitable as the basis for deriving a chronic MRL because only one dose level was evaluated, 

histopathological examination was limited, and dosing was not precisely controlled. 

• An MRL of 0.07 mg/kg/day was derived for chronic oral exposure to 1-methylnaphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 25 

2. RELEVANCE TO PUBLIC HEALTH 

The MRL for 1-methylnaphthalene was derived from an 81-week study in groups of 50 male and 

50 female mice using diets containing 0, 71.6 (males), 75.1 (females), 140.2 (males), or 143.7 (females) 

mg/kg/day (Murata et al. 1993). Food intake, clinical signs, and body weight were determined throughout 

the study. At the end of 81 weeks, peripheral blood samples were collected and the animals were 

sacrificed. Organ weights were determined and the tissues examined histologically; tumors were 

identified and characterized. Hematological parameters and biochemical indices were evaluated in the 

blood samples. 

Male and female mice in both exposure groups showed increased incidences of pulmonary alveolar 

proteinosis. In males, there was also a significant increase in pulmonary adenomas. The alveolar nodules 

were filled with an amorphous acidophilic material, cholesterol crystals, and foamy cells. They were not 

accompanied by inflammation, edema, or fibrosis. The LOAEL of 71.6 mg/kg/day for pulmonary 

alveolar proteinosis in female mice was used for the derivation of the MRL (see Appendix A), employing 

an uncertainty factor of 1,000 (10 for using a LOAEL, 10 for extrapolating from animals to humans, and 

10 for human variability). 

• An MRL of 0.04 mg/kg/day was derived for chronic oral exposure to 2-methylnaphthalene. 

The chronic MRL is based on a study in which groups of 50 male and 50 female B6C3F1 mice were 

exposed to dietary levels of 0, 0.075, or 0.15% 2-methylnaphthalene (Murata et al. 1997). Average 

intakes were reported as 0, 54.3, or 113.8 mg/kg/day for males and 0, 50.3, or 107.6 mg/kg/day for 

females. Survival and food consumption were not affected by exposure. Mean final body weights were 

decreased by 7.5 and 4.5% in high-dose males and females, respectively; these changes are not considered 

to be biologically significant. Histopathology only found exposure-related changes in the lung. Tissues 

examined were brain, heart, kidney, liver, lung, pancreas, salivary glands, spleen, testis, adrenals, bone, 

eye, Harderian glands, mammary gland, ovary, seminal vesicle, skeletal muscle, skin, small and large 

intestine, spinal cord, stomach, trachea, uterus, and vagina. No evidence of bronchiolar Clara cell 

necrosis or sloughing was found. Females showed statistically significantly decreased differential counts 

of stab and segmented form neutrophils and increased lymphocytes compared to controls, but the 

biological significance of these changes is not clear due to a lack of reporting of the data (i.e., the report 

did not specify the response magnitudes or the dose levels at which they occurred). Incidences for mice 

with pulmonary alveolar proteinosis were (control through high-dose groups): 5/50, 27/49, and 22/49 for 

females, and 4/49, 21/49, and 23/49 for males. Incidences for mice with lung adenomas were: 4/50, 4/49, 

and 5/48 in females, and 2/49, 9/49, and 5/49 in males. Only the lung adenoma incidence in the male 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 26 

2. RELEVANCE TO PUBLIC HEALTH 

54.3-mg/kg/day groups was significantly different from the control incidence. Combined incidences for 

lung adenomas or adenocarcinomas were: 5/50, 4/49, and 6/48 for females, and 2/49, 10/49, and 6/49 for 

males. 

Support for pulmonary alveolar proteinosis as the critical effect for the chronic oral MRL for 2-methylnaphthalene comes from chronic duration studies with the isomer, 1-methylnaphthalene, and methylnaphthalene (a mixture of 1- and 2-methylnaphthalene). Increased incidence of pulmonary alveolar 

proteinosis was reported in B6C3F1 mice exposed to 1-methylnaphthalene in the diet for 81 weeks at 

dose levels as low as 71.6 mg/kg/day (Murata et al. 1993), and in mice dermally exposed to 30 or 

119 mg/kg of methylnaphthalene for 30–61 weeks (a mixture of 1- and 2-methylnaphthalene) (Emi and 

Konishi 1985; Murata et al. 1992). 

The lower 95% confidence limit on a benchmark dose associated with 5% extra risk for pulmonary 

alveolar proteinosis in male mice (4 mg/kg/day) was selected as the point of departure for deriving the 

chronic-duration oral MRL for 2-methylnaphthalene (see Appendix A). A benchmark response of 5% 

extra risk was selected over a default value of 10% extra risk in order to provide protection for children 

who may develop pulmonary alveolar proteinosis. This selection is supported by reports that children 

with pulmonary alveolar proteinosis (albeit of unknown etiology) experience more severe symptoms of 

respiratory dysfunction than do adults (EPA 2003r; Mazzone et al. 2001). The point of departure was 

divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human 

variability) to derive the chronic oral MRL of 0.04 mg/kg/day for 2-methylnaphthalene. 

No appropriate studies were located for deriving acute or intermediate-duration oral MRLs for 1-methylnaphthalene or 2-methylnaphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 27 

3. HEALTH EFFECTS 

3.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of naphthalene, 

1-methylnaphthalene, and 2-methylnaphthalene. It contains descriptions and evaluations of toxicological 

studies and epidemiological investigations and provides conclusions, where possible, on the relevance of 

toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an end point should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 28 

3. HEALTH EFFECTS 

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 

considered to be important because it helps the users of the profiles to identify levels of exposure at which 

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not 

the effects vary with dose and/or duration, and place into perspective the possible significance of these 

effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user's perspective. Public health officials and others concerned with 

appropriate actions to take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no 

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans 

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. 

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of naphthalene, are 

indicated in Tables 3-1 and 3-2 and Figures 3-1 and 3-2. 

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in 

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

3.2.1 Inhalation Exposure 

3.2.1.1 Death 

Two Greek infants died as a consequence of acute hemolysis that resulted from exposure to 

naphthalene-treated materials (clothing, diapers, blankets, rugs, etc.). Both infants exhibited a severe 

form of jaundice (kernicterus), which often causes brain damage (Valaes et al. 1963). Exposure levels 

experienced by these children are unknown. One infant suffered from a glucose-6-phosphate 

dehydrogenase (G6PD) deficiency. The other infant was apparently heterozygous for this trait. 

Individuals with a G6PD genetic defect are prone to hemolysis after exposure to a variety of chemical 

oxidizing agents including nitrates, nitrites, aniline, phenols (Dean et al. 1992), and naphthalene. 

No studies were located that documented lethal effects in humans after inhalation exposure to 1-methylnaphthalene or 2-methylnaphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 29 

3. HEALTH EFFECTS 

Exposure to 78 ppm naphthalene for 4 hours did not cause any deaths in rats. In addition, no definitive 

adverse clinical signs were observed during the 14 days after exposure, and no gross pathologic lesions 

were observed at necropsy (Fait and Nachreiner 1985). A high background mortality in the male control 

group precluded drawing conclusions regarding the effects of lifetime exposures to 10 and 30 ppm 

naphthalene (6 hours/day, 5 days/week) on lifetime mortality; no apparent effects on mortality occurred in 

the females (NTP 1992a). Similarly, exposure of male and female rats to 10, 30, or 60 ppm naphthalene 

(6 hours/day, 5 days/week) for 2 years did not affect survival, compared to controls (Abdo et al. 2001; 

NTP 2000). 

No studies were located that documented lethal effects in animals after inhalation exposure to 1-methylnaphthalene or 2-methylnaphthalene. 

3.2.1.2 Systemic Effects 

No studies were located that documented dermal effects in humans or animals after inhalation exposure to 

naphthalene. Most of the human data come from occupational and domestic settings where mothballs 

were the source of the naphthalene vapors. The highest NOAEL values and all LOAEL values from each 

reliable study for systemic effects in each species and duration category are recorded in Table 3-1 and 

plotted in Figure 3-1. No studies were located that documented systemic effects in humans after 

inhalation exposure to 1-methylnaphthalene or 2-methylnaphthalene. In animals, one study evaluated 

hematological end points in dogs following acute inhalation exposure to undetermined air concentrations 

of 1-methylnaphthalene or 2-methylnaphthalene (Lorber 1972). This study, however, did not identify 

reliable NOAEL or LOAEL values, and the results are not included in Table 3-1 or Figure 3-1. 

Respiratory Effects. No studies were located that documented respiratory effects in humans after 

inhalation exposure to naphthalene. 

The nose is the most sensitive toxicity target in rats and mice following chronic inhalation exposure to 

naphthalene. Chronic inhalation exposure resulted in increased incidences of nonneoplastic and 

neoplastic lesions in the nose of rats (Abdo et al. 2001; Long et al. 2003; NTP 2000), nonneoplastic 

lesions in the nose of mice (NTP 1992a), and neoplastic and nonneoplastic lesions in the lungs of mice 

(NTP 1992a). No exposure-related lesions were found in other tissues or organs in these studies, which 

included comprehensive histopathological examinations of major tissues and organs. Nearly all mice of 
Table 3-1 Levels of Significant Exposure to Naphthalene (Nap) Or Methylnaphthalene (1-Mn Or 2-Mn) - Inhalation 

Exposure/ LOAEL 

Duration/ a Frequency 

Key to Species NOAEL Less Serious Serious (Specific Route) figure (Strain) System (ppm) (ppm) (ppm) 

ACUTE EXPOSURE Systemic 

1 Rat 4 h 

Resp 100 (Sprague- 

Dawley) 

2 Mouse 14 d 

5 d/wk Hemato 30 B6C3F1 

6 hr/d 
Table 3-1 Levels of Significant Exposure to Naphthalene (Nap) Or Methylnaphthalene (1-Mn Or 2-Mn) - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ a Frequency 

Key to Species NOAEL Less Serious Serious (Specific Route) figure (Strain) System (ppm) (ppm) (ppm) 

3 Mouse 4 h 

Resp 2 10 (Clara cell necrosis and 75 (Proximal and terminal (Swiss- 

decreased Clara cell mass epithelium devoid of Clara cells) Webster) [volume/surface area] in proximal airways) 

Neurological 

4 Rat 4 h 

26 44 (increased latency of paw lick (Wistar) 

response to being placed on a hot surface [decreased pain sensitivity]; no change in rotarod performance) 

5 Rat 4 h 

39 61 (increased latency of paw lick (Wistar) 

response to being placed on a hot surface [decreased pain sensitivity]; no change in rotarod performance) 
Table 3-1 Levels of Significant Exposure to Naphthalene (Nap) Or Methylnaphthalene (1-Mn Or 2-Mn) - Inhalation 

(continued) 

Exposure/ LOAEL 

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious 

figure (Strain) (Specific Route) System (ppm) (ppm) (ppm) 

CHRONIC EXPOSURE Systemic 

6 Rat 105 wk 

(Fischer- 344) 5 d/wk 6 hr/d Resp 

b 

10 (inflammation of the nose; 

olfactory epithelium: atypical 

hyperplasia, atrophy, 

vapor degeneration; nasal respiratory 

epithelium: hyperplasia, squamous metaplasia, degeneration; Bowman's glands: hyperplasia) 

Cardio 10 Gastro 10 Musc/skel 10 Hepatic 10 Renal 10 Endocr 10 Ocular 10 Bd Wt 10 
Table 3-1 Levels of Significant Exposure to Naphthalene (Nap) Or Methylnaphthalene (1-Mn Or 2-Mn) - Inhalation 

(continued) 

Exposure/ LOAEL 

Duration/ 

a

Key to Species Frequency NOAEL Less Serious Serious 

figure (Strain) (Specific Route) System (ppm) (ppm) (ppm) 

7 Mouse 

B6C3F1 

104 wk 5 d/wk 6 hr/d 

Resp 10 (inflammation of the nose and 

lung, metaplasia of the olfactory epithelium, and hyperplasia of the respiratory epithelium) 
Table 3-1 Levels of Significant Exposure to Naphthalene (Nap) Or Methylnaphthalene (1-Mn Or 2-Mn) - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ a Frequency 

Key to Species NOAEL Less Serious Serious (Specific Route) figure (Strain) System (ppm) (ppm) (ppm) 

8 Mouse 104 wk 

5 d/wk Cardio 30 B6C3F1 

6 hr/d 

Gastro 30 Hepatic 30 Renal 30 Dermal 30 

Neurological 

9 Rat 105 wk 

5 d/wk 60 (Fischer- 344) 

6 hr/dvapor 
Table 3-1 Levels of Significant Exposure to Naphthalene (Nap) Or Methylnaphthalene (1-Mn Or 2-Mn) - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ a Frequency 

Key to Species NOAEL Less Serious Serious (Specific Route) figure (Strain) System (ppm) (ppm) (ppm) 

10 Mouse 104 wk 

5 d/wk 30 B6C3F1 

6 hr/d 

Reproductive 

11 Rat 105 wk 

5 d/wk 60 (Fischer- 344) 

6 hr/dvapor 
Table 3-1 Levels of Significant Exposure to Naphthalene (Nap) Or Methylnaphthalene (1-Mn Or 2-Mn) - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ a Frequency 

Key to Species NOAEL Less Serious Serious (Specific Route) figure (Strain) System (ppm) (ppm) (ppm) 

12 Mouse 104 wk 

5d/wk 30 B6C3F1 

6 hr/d 

Cancer 

13 Rat 105 wk 

10 (CEL: nasal respiratory 5d/wk (Fischer- 344) epithelial adenomas in males & 

6hr/d 

in females at higher 

vapor concentrations; olfactory 

epithelial neuroblastomas in both sexes at higher concentrations) 

14 Mouse 104 wk 

30 (CEL: pulmonary alveolar 5 d/wk B6C3F1 adenomas in females) 

6 hr/d 

a The number corresponds to the entries in Figure 3-1. b Used to derive a chronic-duration Minimal Risk Level (MRL) of 0.0007 ppm; based on a human equivalent concentration LOAEL of 0.2 ppm which was dividefactor of 300 (10 for the use of LOAEL, 3 for extrapolating from rodents to humans with interspecies dosimetric adjustment, and 10 for human variability). Cardio = cardiovascular; d = day(s); Gastro = gastrointestinal; Hemato = hematological; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s) 
Respiratory Hematological Neurological 

Figure 3-1. Levels of Significant Exposure to Naphthalene (NAP) Or Methylnaphthalene (1-MN 

Systemic Acute (≤14 days) 

ppm 

1000 

100 1r 

3m 

5r 4r5r 

2m 

4r 

10 3m 

3m 

1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Cardiovascular Gastrointestinal Musculoskeletal Hepatic Renal Endocrine Dermal Ocular Body Weight Neurolo

Figure 3-1. Levels of Significant Exposure to Naphthalene (NAP) Or Methylnaphthalene (1-MN Or 2-M

Chronic (≥365 days) 

Systemic 

ppm Respiratory 

100 

8r 

7m 7m 7m 7m 7m 9m 

10 7m 6r 6r 6r 6r 6r 6r 6r 6r 6r 

1 

0.1 

0.01 

0.001 NAP 

*Doses represent the lowest dose tested per study that produced a tumorigenic 

0.0001 response and do not imply the existence of a threshold for the cancer end point. 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 39 

3. HEALTH EFFECTS 

both sexes (>95%) exposed to naphthalene vapors for 2 years (10 or 30 ppm) showed chronic 

inflammation and metaplasia of the olfactory epithelium and hyperplasia of the nasal respiratory 

epithelium (NTP 1992a). Chronic lung inflammation was also observed in exposed mice, but at lower 

incidences than incidences for nasal lesions. Incidences for chronic lung inflammation were 0/70, 21/69, 

and 56/135 for male mice and 3/69, 13/65, and 52/135 for female mice exposed to 0, 10, or 30 ppm. In 

addition, exposure to 30 ppm (but not 10 ppm) increased the incidence of benign lung tumors 

(alveolar/bronchiolar adenomas) in female mice, compared with controls. One other female mouse 

exposed to 30 ppm showed a malignant lung tumor (alveolar/bronchiolar carcinoma). In rats of both 

sexes, inhalation of 10, 30, or 60 ppm naphthalene induced nonneoplastic and neoplastic lesions only in 

the nasal cavity (Abdo et al. 2001; NTP 2000). Nearly all rats in each exposure group (>95%) showed 

nonneoplastic nasal lesions. Nonneoplastic nasal lesions in exposed rats included (1) hyperplasia, 

atrophy, chronic inflammation, and hyaline degeneration of the olfactory epithelium and (2) hyperplasia, 

metaplasia, or degeneration of the respiratory epithelium or glands. Neoplastic lesions associated with 

naphthalene exposure in rats were olfactory epithelial neuroblastoma (a rare malignant tumor) and 

respiratory epithelial adenoma. 

The chronic inhalation MRL for naphthalene is based on the LOAEL of 10 ppm for nonneoplastic lesions 

in the olfactory epithelium and respiratory epithelium of the nose of rats (NTP 2000; see Table 3-1, 

Figure 3-1, Appendix A, and Section 2.3). To derive the chronic MRL, the rat LOAEL was converted to 

a human equivalent concentration of 0.2 ppm for continuous exposure using EPA (1994b) equations for a 

category 1 gas producing nasal effects and divided by an uncertainty factor of 300 (10 for the use of a 

LOAEL, 3 for extrapolation from animals to humans using dosimetric adjustment, and 10 for human 

variability). Naphthalene-induced damage to the nasal tissue is thought to be due to reactive metabolites 

formed in the nasal tissues (Buckpitt et al. 2002). Sections 3.4.3 and 3.5 discuss current mechanistic 

hypotheses in more detail. 

Acute (4-hour) inhalation exposure to naphthalene induced necrosis of Clara cells in the epithelium of the 

proximal airways of the lungs of mice at exposure levels as low as 10 ppm, but did not affect lung tissue 

in rats at concentrations as high as 100 ppm (West et al. 2001). These results, and those from the chronic 

inhalation studies, show that mice are more susceptible than rats to lung damage from inhaled 

naphthalene. However, there are no studies that have examined nasal tissues for the development of 

lesions following acute inhalation exposure. No acute inhalation MRL was derived for naphthalene, due 

to the lack of such data and the results of the chronic studies indicating that nasal tissues are the critical 

toxicity targets of inhaled naphthalene in both rats and mice. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 40 

3. HEALTH EFFECTS 

A change to mouth breathing occurred in rats during exposure to 78 ppm naphthalene, but no other effects 

on respiration were noted (Fait and Nachreiner 1985). 

Cardiovascular Effects. No studies were located that documented cardiovascular effects in humans 

after inhalation exposure to naphthalene. 

No histological changes were seen in the hearts of mice (30 ppm) or rats (60 ppm) that were exposed to 

naphthalene for 2 years (Abdo et al. 2001; NTP 1992a, 2000). 

Gastrointestinal Effects. Nausea, vomiting, and abdominal pain were reported in eight adults and 

one child exposed to naphthalene vapors from large numbers of mothballs (300–500) scattered throughout 

their homes for odor and pest control (Linick 1983). Air samples collected in one home contained 

naphthalene at 20 ppb; concentrations could have been higher when the mothballs were fresh. 

Gastrointestinal symptoms disappeared after the mothballs were removed. Few location-specific 

background data to support this air concentration were reported. 

There were no histopathological changes in the stomach or intestines of mice (30 ppm) or rats (60 ppm) 

exposed to naphthalene for 2 years (Abdo et al. 2001; NTP 1992a, 2000). 

Hematological Effects. Hemolytic anemia is the most frequently reported manifestation of 

naphthalene exposure in humans. Acute hemolytic anemia was observed in 21 infants exposed to 

naphthalene via mothball-treated blankets, woolen clothes, or materials in the infants' rooms (Valaes et al. 

1963). Ten of these children had a G6PD genetic defect that increased their sensitivity to hemolysis from 

a variety of chemicals, including naphthalene. Clinical observations included high serum bilirubin values, 

methemoglobin, Heinz bodies, and fragmented red blood cells. Inhalation appeared to be the primary 

route of exposure because in all children but two, the naphthalene-treated material was not worn next to 

the skin. One of the exceptions was an infant who wore diapers that had been stored in naphthalene. 

Anemia was reported in nine individuals exposed to large numbers of mothballs distributed throughout 

their homes (Linick 1983). The nature of the anemia and specific levels of naphthalene exposure were 

not identified. In one home, the naphthalene concentration was determined to be 20 ppb at the time of 

testing, but could have been higher when the mothballs were first distributed. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 41 

3. HEALTH EFFECTS 

In another study, a woman who was exposed to reportedly high (but unmeasured) concentrations of a 

combination of naphthalene and paradichlorobenzene for several weeks in a hot, poorly ventilated work 

area developed aplastic anemia (Harden and Baetjer 1978). It is difficult to determine the contribution of 

naphthalene to the aplastic anemia since there was simultaneous exposure to paradichlorobenzene. 

In animals, no treatment-related effects on hematologic parameters (hematocrit, hemoglobin 

concentration, erythrocyte counts, mean cell volume, reticulocytes, and leucocytes) were observed among 

mice exposed to 10 and 30 ppm naphthalene for 14 days (NTP 1992a). Due to high mortality in the 

control males, hematology measurements were not continued beyond 14 days. 

The effects of 1-methylnaphthalene (pure and practical grade) and 2-methylnaphthalene (pure and 

practical grade) on the hematocrit values, total and differential white blood cell counts, and reticulocyte 

counts were determined in intact and splenectomized dogs. Each compound was dispersed in the 

atmosphere in a refined kerosene base using a fogger. Exposures occurred on four consecutive mornings 

(Lorber 1972). Based on the information presented, it was not possible to determine the exposure 

concentration. 

Pure 1-methylnaphthalene increased the reticulocyte counts in the splenectomized dogs but not the intact 

dogs. Reticulocyte values remained elevated for 10 days after the fogging ceased. Practical grade 

1-methylnaphthalene increased leukocyte counts in intact and splenectomized dogs and neutrophil counts 

in intact dogs, but pure 1-methylnaphthalene had no effect on these parameters. 2-Methylnaphthalene had 

no effect on any of the parameters monitored (Lorber 1972). 

Neither 1-methylnaphthalene nor 2-methylnaphthalene had an effect on hematocrit values, suggesting that 

these compounds do not cause hemolysis under the conditions of the study. Since the increased 

reticulocyte counts were seen only in splenectomized dogs, it is difficult to interpret whether or not this 

change signifies increased hematopoiesis in response to 1-methylnaphthalene exposure (Lorber 1972). 

Musculoskeletal Effects. No studies were located that documented musculoskeletal effects in 

humans after inhalation exposure to naphthalene. 

Histological examination of the femur did not reveal compound-related effects in mice (NTP 1992a) or 

rats (Abdo et al. 2001; NTP 2000) exposed for 2 years to naphthalene concentrations as high as 30 or 

60 ppm, respectively. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 42 

3. HEALTH EFFECTS 

Hepatic Effects. Jaundice has been reported in infants and adults after exposure to naphthalene 

(Linick 1983; Valaes et al. 1963). However, the jaundice is a consequence of hemolysis rather than a 

direct effect of naphthalene on the liver. Infant exposures lasted 1–7 days (Valaes et al. 1963); adult 

exposure durations were not provided (Linick 1983). Dose was not determined in either instance, 

although a concentration of 20 ppb was measured in the home of one affected individual (Linick 1983). 

In animals, no treatment-related gross or histopathological lesions of the liver were reported in mice (NTP 

1992a) or rats (Abdo et al. 2001; NTP 2000) exposed for 2 years to naphthalene concentrations as high as 

30 or 60 ppm, respectively. 

Renal Effects. Renal disease was reported in nine individuals (details not specified) exposed to large 

numbers of mothballs in their homes, but symptoms were not described and dose could not be determined 

(Linick 1983). 

In animals, no treatment-related gross or histopathological lesions of the kidneys were observed in mice 

(NTP 1992a) or rats (Abdo et al. 2001; NTP 2000) exposed for 2 years to naphthalene concentrations as 

high as 30 or 60 ppm, respectively. 

Ocular Effects. Twenty-one workers exposed to naphthalene for up to 5 years in a plant that 

manufactured dye intermediates were examined for eye problems (Ghetti and Mariani 1956). During the 

period of exposure, plant conditions were primitive, involving heating of naphthalene in open vats and 

considerable worker contact with the naphthalene. Eight of the 21 workers developed multiple pin-point 

lens opacities that had no correlation with the age of the workers. These effects were not overtly 

noticeable and apparently had no effect on vision. They were judged to be a consequence of naphthalene 

exposure on the basis of their location in the crystalline lens and the fact that occurrence did not correlate 

with age. Exposure involved long-term inhalation of vapors and direct contact of vapors with the eyes 

and skin. 

Retinal bleeding and the beginnings of a cataract were identified in a worker from a naphthalene storage 

area who was most likely exposed to naphthalene through inhalation and dermal/ocular contact (van der 

Hoeve 1906). The duration of exposure prior to seeking medical attention for eye irritation and problems 

with vision was not identified. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 43 

3. HEALTH EFFECTS 

In animals, no treatment-related gross or histopathological lesions of the eyes were observed in mice 

(NTP 1992a) or rats (Abdo et al. 2001; NTP 2000) exposed for 2 years to naphthalene concentrations as 

high as 30 or 60 ppm, respectively. However, during a 4-hour exposure of rats to a concentration of 

78 ppm, irritation to the eyes was evidenced through lacrimation (Fait and Nachreiner 1985). 

3.2.1.3 Immunological and Lymphoreticular Effects 

No studies were located that examined immunological or lymphoreticular end points in humans or 

animals after inhalation exposure to naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. 

3.2.1.4 Neurological Effects 

Infants are prone to permanent neurological damage (kernicterus) as a consequence of the jaundice that 

results from naphthalene-induced hemolysis. Bilirubin is absorbed by vulnerable brain cells and this 

leads to convulsions and sometimes death. Survivors often suffer from motor disturbances and mental 

retardation (McMurray 1977). Kernicterus was diagnosed in 8 of 21 Greek infants that experienced 

hemolysis as a result of naphthalene exposure (Valaes et al. 1963). Two of the eight died. One of the 

infants that died had no G6PD enzyme activity and the other had intermediate activity. Two of the infants 

were normal with regard to the G6PD trait. Of the remaining infants, three had no G6PD activity and the 

fourth had intermediate activity. Brain damage seldom occurs in adults as a consequence of jaundice 

(McMurray 1977). 

Nausea, headache, malaise, and confusion were reported in several individuals (children and adults) 

exposed to large numbers of mothballs in their homes (Linick 1983). Actual levels and duration of 

exposure were unknown, although a concentration of 20 ppb was measured in one of the affected 

residences. 

In animals, no treatment-related gross or histopathological lesions of the brain were observed in mice 

(NTP 1992a) or rats (Abdo et al. 2001; NTP 2000) exposed for 2 years to naphthalene concentrations as 

high as 30 or 60 ppm, respectively. Clinical observations (made twice daily in these studies) revealed no 

gross behavioral changes except that exposed mice tended to huddle together in cage corners during 

exposure periods. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 44 

3. HEALTH EFFECTS 

No studies were located that documented neurological effects in humans after inhalation exposure to 

1-methylnaphthalene or 2-methylnaphthalene. 

In male Wistar rats, decreased sensitivity to pain occurred after 4-hour inhalation exposures to 253 or 

407 mg/m3 1-methylnaphthalene (44 or 70 ppm), or 352 or 525 mg/m3 2-methylnaphthalene (61 or 

90 ppm), but not after exposure to 152 mg/m3 (26 ppm) 1-methylnaphthalene or 229 mg/m3

 (39 ppm) 

2-methylnaphthalene (Korsak et al. 1998). Decreased sensitivity to pain was measured as a decreased 

time to begin licking of the paws after being placed on a hot plate at 54.5 °C. The ability of exposed rats 

to balance on a rotating rod (rotarod performance), however, was not affected by any of these exposure 

conditions (Korsak et al. 1998). NOAEL and LOAEL values for decreased pain sensitivity from this 

study are included in Table 3-1 and Figure 3-1. 

3.2.1.5 Reproductive Effects 

No studies were located that documented reproductive effects in humans after inhalation exposure to 

naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. 

In animals, histological examination did not reveal damage to male or female reproductive organs in mice 

(NTP 1992a) or rats (Abdo et al. 2001; NTP 2000) exposed for 2 years to 30 or 60 ppm, respectively. 

No studies were located that documented reproductive effects in animals after inhalation exposure to 

1-methylnaphthalene or 2-methylnaphthalene. 

3.2.1.6 Developmental Effects 

No studies were located that examined developmental end points in humans or animals after inhalation 

exposure to naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. 

3.2.1.7 Cancer 

No studies were located that documented carcinogenic effects in humans after inhalation exposure to 

naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 45 

3. HEALTH EFFECTS 

In animals, inhalation exposure to naphthalene (6 hours/day) has been associated with: (1) increased 

incidences of F344/N rats of both sexes with nasal tumors following 2 years of exposure (Abdo et al. 

2001; NTP 2000); (2) increased incidences of female B6C3F1 mice, but not male mice, with lung tumors 

following 2 years of exposure (NTP 1992a); and (3) increased number of tumors per tumor-bearing 

A/J strain mice following 6 months of exposure (Adkins et al. 1986). 

In F344/N rats, incidences of nasal respiratory epithelial adenomas were statistically significantly 

elevated, compared with controls, in males exposed to 0, 10, 30, or 60 ppm naphthalene (0/49, 6/49, 8/48, 

or 15/48), but not in females (0/49, 0/49, 4/49, 2/49) (Abdo et al. 2001; NTP 2000). Incidences for 

olfactory epithelial neuroblastoma were 0/49, 0/49, 4/48, and 3/48 in male rats, and 0/49, 2/49, 4/48, and 

12/49 in female rats. Both tumor types are rare in NTP control F344/N rats (NTP 2000). For example, 

neither tumor type was observed in 299 control male rats given NTP-2000 feed or 1,048 control male rats 

given NIH-07 feed. NTP (2000) concluded that there was clear evidence of carcinogenic activity of 

naphthalene in male and female F344/N rats based on increased incidences of respiratory epithelial 

adenoma and olfactory epithelial neuroblastoma of the nose. Nearly all rats in all exposure groups 

showed nonneoplastic nasal lesions in both olfactory and respiratory epithelia, including atypical 

hyperplasia in olfactory epithelium, hyaline degeneration in olfactory and respiratory epithelia, and 

Bowman’s gland hyperplasia. 

In B6C3F1 mice, statistically significant increased incidence of alveolar/bronchiolar adenomas and 

carcinoma was found in 30-ppm females, but not in 10-ppm females or in males (females: 5/69, 2/65, 

29/135; males: 7/70, 17/69, and 31/135) (NTP 1992a). Although Fisher Exact tests indicated that 

incidences in both exposed male groups and the high-dose female group were significantly increased 

compared with control groups, logistic regression analysis, which modeled tumor incidence as a function 

of dose and exposure time, indicated that only the incidence in the 30-ppm female group was elevated 

compared with controls. The response was predominantly benign; only one female mouse in the 30-ppm 

group developed a carcinoma. Exposed mice of both sexes also showed increased incidences of chronic 

lung inflammation (males: 0/70, 21/69, 56/135; females: 3/69, 13/65, 52/135). Nonneoplastic nasal 

lesions were found in nearly all exposed mice, but no nasal tumors developed. On the basis of this 

analysis, NTP (1992a) determined that there was some evidence of naphthalene carcinogenicity in female 

mice, but no evidence of carcinogenicity in male mice in this study. 

In a 6-month study, there was a statistically significant increase in the number of tumors per tumorbearing mouse, but not in the number of mice with pulmonary adenomas after exposure to 10 or 30 ppm 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 46 

3. HEALTH EFFECTS 

naphthalene vapors (Adkins et al. 1986). However, the incidence of adenomas in the control group for 

this experiment was significantly lower than the pooled incidence observed in the control groups of eight 

concurrently conducted 6-month studies, and the difference in tumor incidence was not significantly 

greater than that of the historic controls. 

No studies were located that documented carcinogenic effects in animals after inhalation exposure to 

1-methylnaphthalene or 2-methylnaphthalene. 

3.2.2 Oral Exposure 

3.2.2.1 Death 

Death has been documented in humans who intentionally ingested naphthalene. A 17-year-old male died 

5 days after the ingestion of an unknown quantity of naphthalene mothballs. Death was preceded by 

vomiting, evidence of gastrointestinal bleeding, blood-tinged urine, and coma (Gupta et al. 1979). A 

30-year-old female died following similar sequelae 5 days after reportedly swallowing 40 mothballs 

(25 were recovered intact from the stomach upon autopsy) (Kurz 1987). No studies were located that 

documented lethal effects in humans after oral exposure to 1-methylnaphthalene or 2-methylnaphthalene. 

Several animal studies have been conducted to estimate lethal doses of naphthalene. Mice appear to be 

more sensitive than rats or rabbits. The LD50 values in male and female mice were 533 and 710 mg/kg, 

respectively (Shopp et al. 1984). An LD50 of 354 mg/kg was estimated in female mice treated with 

naphthalene once daily by gavage for 8 consecutive days (Plasterer et al. 1985). The dose response curve 

appeared to be very steep because no deaths occurred at 250 mg/kg/day, but all animals died with a dose 

of 500 mg/kg/day. At the 300 mg/kg/day dose, mortality was approximately 15%. In a different study 

with a 14-day dosing period, 10% of the males and 5% of the females died at a dose of 267 mg/kg/day, 

but none were affected by doses of 27 and 53 mg/kg/day (Shopp et al. 1984). 

The oral LD50 values in male and female rats were 2,200 and 2,400 mg/kg, respectively, in one study 

(Gaines 1969), and 2,600 in a second study that did not differentiate by sex (Papciak and Mallory 1990). 

Male rats tolerated daily doses of 1,000 mg/kg without lethality, even after 18 days of administration 

(Yamauchi et al. 1986). In an increasing dose study, Germansky and Jamall (1988) treated male rats with 

naphthalene at doses beginning at 100 mg/kg/day and raised the dose weekly to a final level of 

750 mg/kg/day over 6 weeks. Doses were then kept constant for an additional 3 weeks. The animals 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 47 

3. HEALTH EFFECTS 

tolerated 750 mg/kg/day with no mortalities. No increase in mortality was observed in rats administered 

naphthalene at 41 mg/kg/day in a 2-year feeding study (Schmahl 1955). 

Although few data are available, rabbits appear to tolerate naphthalene in doses similar to those 

administered to rats. Two different rabbit strains were administered 1,000 mg/kg twice per week for 

12 weeks without lethality (Rossa and Pau 1988). 

Male and female mice survived oral exposure to doses of 71.6–143.7 mg/kg/day 1-methylnaphthalene for 

81 weeks (Murata et al. 1993). No studies were located that documented lethal effects in animals after 

ingestion of 1-methylnaphthalene. 

All LOAEL values for lethality in each species after acute exposure to naphthalene are recorded in 

Table 3-2 and plotted in Figure 3-2. 

3.2.2.2 Systemic Effects 

No studies were located that documented musculoskeletal or dermal effects in humans or animals after 

oral exposure to naphthalene; data were available for all other systems. The highest NOAEL values and 

all LOAEL values from each reliable study for systemic effects in each species and duration category are 

recorded in Table 3-2 and plotted in Figure 3-2. 

No studies were located that documented systemic effects in humans after oral exposure to 1-methylnaphthalene or 2-methylnaphthalene. In animals, data are restricted to two studies with B6C3F1 mice 

exposed to 1-methylnaphthalene (Murata et al. 1993) or 2-methylnaphthalene (Murata et al. 1997) in the 

diet for 81 weeks. The highest chronic NOAEL values and the lowest LOAEL value for systemic effects 

in mice are recorded in Table 3-2 and plotted in Figure 3-2. 

Respiratory Effects. No reports have been located to indicate that there are direct effects of oral 

exposure to naphthalene on the respiratory system in humans. In situations where respiratory effects such 

as hypoxia or pulmonary edema were noted, the respiratory effects appear to be secondary to hemolysis 

and the events leading to general multiple organ failure (Gupta et al. 1979; Kurz 1987). On hospital 

admission, one male infant was described as experiencing labored breathing after presumably chewing a 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) -

Exposure/ LOAEL 

Oral 

a

Key to Species 

Figure (Strain) 

ACUTE EXPO

Duration/ 

Frequency 

(Route)

SURE 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious

(mg/kg/day) 

Reference Chemical Form 

Death 

1 Rat once 

Sherman (GO) 2200 (LD50 - male) 

Gaines 1969 NAP 

2400 (LD50 - female) 

2 Rat once 

Sprague- (GO) Dawley 

2600 LD50 

Papciak and Mallory 19NAP 

3 Mouse 8 d 

CD-1 1x/d 

(GO) 

300 (5/33 died) 

Plasterer et al. 1985 NAP 

4 Mouse once 

CD-1 (GO) 710 (LD50) 

Shopp et al. 1984 NAP 

533 (LD50) 

5 Mouse 14 d 

CD-1 1x/d 

(GO) 

267 (10/96 male, 3/60 

female) 

Shopp et al. 1984 NAP 

Systemic 

6 Human once Gastro 109 (adbominal pain) Gidron and Leurer 1956 

NAP 

Hemato 109 (hemolytic anemia) 

Other 109 (106 degree F fever) 

7 Rat 9 d 

Sprague- Gd 6-15Dawley (GO) 

Bd Wt 50 150 (31% decrease in 

maternal body weight 

gain) 

NTP 1991a

NAP
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg) 

Reference Chemical Form Less Serious (mg/kg) Serious (mg/kg) 

8 Rat 

SpragueDawley 

once (GO) Resp 1000 lung lesions 

Papciak and Mallory 19NAP 

9 Rat 

SpragueDawley 

once (GO) Gastro 1000 stomach lesions 

Papciak and Mallory 19NAP 

10 Rat 

NS 

10 d 1x/d (G) 

Hepatic 1000 (39% increase in liver 

weight; increased lipid peroxidation, aniline 

Rao and Pandya 1981 NAP hydroxylase activity) 

Renal 1000 Ocular 1000 

11 Mouse 

CD-1 

14 d 1x/d (GO) 

Resp 267 M 

53 F 

267 F (increase in lung weight) 

Shopp et al. 1984 NAP 

Hemato 267 

Hepatic 267 Renal 267 Bd Wt 53 267 (6% (female) or 13% 

(male) decreased final body weight) 

12 Dog 

NS 

once (F) Hemato 1525 (hemolysis) 

Zuelzer and Apt 1949

NAP 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

13 Rabbit 

NS 

5 d (F) Hepatic 2000 

Srivastava and Nath 19NAP 

Ocular 2000 (cataracts) 

14 Rabbit 

NS 

10 d 1x/d (GO) 

Ocular 1000 (lens opacities, 

decreased ascorbic acid in aqueous humor) 

van Heyningen and PiriNAP 

Immuno/ Lymphoret 

15 Mouse 

CD-1 

14 d 1x/d (GO) 

53 267 (30% decrease in thymus 

weight in males; 18% decrease in spleen weight in females) 

Shopp et al. 1984 NAP Neurological 

16 Rat 

SpragueDawley 

9d Gd 6-15 (GO) 

b 

50 (transient clinical signs of 

toxicity in dams; at higher exposure levels, signs were more persistent and accompanied by decreases in body weight gain) 

NTP 1991a NAP 

17 Mouse 

CD-1 

14 d (GO) 267 Shopp et al. 1984 NAP 

Reproductive 

18 Rat 

SpragueDawley 

9 d Gd 6-19 (GO) 

450 

NTP 1991a NAP 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

Exposure/ LOAEL 

a

Key to 

Figure 

Species 

(Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

19 Mouse 

CD-1 

8d Gd 7-14 (GO) 

300 (>10% maternal 

mortality) 

Plasterer et al. 1985 NAP 

20 Rabbit 

New Zealand white 

14 d Gd 6-19 (GO) 

120 

NTP 1992b NAP 

Developmental 

21 Rat 

SpragueDawley 

9 d Gd 6-15 (GO) 

150 (decreased maternal 

weight gain >20%; no fetotoxic or teratogenic effects at 150 or 450 mg/kg/day) 

NTP 1991a NAP 50 22 Mouse 

CD-1 

8d Gd 7-14 (GO) 

300 

Plasterer et al. 1985 NAP 

23 Rabbit 

New Zealand white 

14 d Gd 6-19 (GO) 

120 NTP 1992b 

NAP 

24 Rabbit 

New Zealand white 

13 d 1x/d Gd 6-18 (G) 

40 200 (maternal dyspnea, 

cyanosis, body drop, hypoactivity with no pathological aberrations) 

PRI 1985, 1986 NAP 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

Exposure/ LOAEL 

Duration/ a

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) 

INTERMEDIATE EXPOSURE Systemic 

25 Rat 

blue spruce 

9 wk 3.5d/wk (GO) 

System 

Resp 

NOAEL 

(mg/kg/day) 

169 

Less Serious 

(mg/kg/day) 

Hepatic 169 (elevated lipid peroxides) Bd Wt 

26 Rat 

BrownNorway 

4 wk 3.5d/wk (GO) 

Ocular 

27 Rat 

SpragueDawley BrownNorway 

6 wk Ocular 

Reference 

(mg/kg/day) Chemical Form 

Serious 

Germansky and Jamall NAP 

169 (20% decreased body 

weight gain) 

500 (lens opacity) Kojima 1992 

NAP 

500 (cataract formation) Murano et al. 1993 

NAP 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

Exposure/ LOAEL 

Duration/ a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

28 Rat 

Fischer 344 

29 Rat 

black-hooded 

30 Rat 

BrownNorway 

31 Rat 

5 strains 

13 wk 5x/wk (GO) 79 d (GO) 102 d NS (GO) 4-6 wk (GO) 

Resp Cardio Gastro Hemato Hepatic Renal Ocular Bd Wt 

400 400 400 400 200 M 

400 F 

400 

100 

400 (intermittent diarrhea) 

400 M (10% had cortical tubular 

degeneration) 

200 (decreased terminal body 

weight: 12% male & 6% female) 

400 

NTP 1980b NAP 

Ocular Ocular 

5000 

700 

(lens opacity) 

(lens opacity) 

Rathbun et al. 1990 NAP Tao et al. 1991 NAP 

Ocular 1000 (lens opacity) Xu et al. 1992b 

NAP 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

32 Rat 

Wistar 

18 d 1x/d (G) 

Hepatic 1000 (elevated lipid peroxides) 

Yamauchi et al. 1986 NAP 

Ocular 1000 (cataracts) 

33 Mouse 

B6C3F1 

13 wk 5x/wk 1x/d 

Resp 200 

NTP 1980a NAP 

(GO) 

Cardio 200 Gastro 200 Hemato 200 Hepatic 200 Renal 200 Ocular 200 Bd Wt 200 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

Exposure/ 

Duration/ a Frequency Key to Species (Route) Figure (Strain) 

34 Mouse 90 d 

CD-1 7d/wk

1x/d (GO) 

35 Rabbit 5 wk 

NS 

36 Rabbit 12 wk 

Chinchilla 2d/wkBastard New 1x/dZealand white (GO) 

37 Rabbit 4 wk 1x/d 

NS (GO) 

System 

Resp Hemato Hepatic Renal Bd Wt Other Ocular Ocular Ocular 

NOAEL 

(mg/kg/day) 

133 133 133 133 

133 

53 

LOAEL

Less Serious Serious 

(mg/kg/day) (mg/kg/day) 

133 (decreases in absolute 

weights of brain (9%), liver (18%), and spleen (28%) and relative weight of spleen (24%) in females only) 

500 (destruction of retinal 

photoreceptors and vascularization of the retinal area) 

1000 (cataracts) 

1000 (increased ascorbic acid 

in lens) 

Reference Chemical Form 

Shopp et al. 1984 NAP Orzalesi et al. 1994 NAP Rossa and Pau 1988 NAP van Heyningen 1970 NAP 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

a

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

38 Rabbit 

NS 

4 wk 1x/d (GO) 

Ocular 1000 (lens opacities, retinal 

damage) 

van Heyningen and PiriNAP 

Immuno/ Lymphoret 

39 Rat 

Fischer 344 

13 wk 5d/wk 1x/d (GO) 

400 (lymphoid depletion of 

thymus in 2/10 females) 

NTP 1980b NAP 

200 

40 Mouse 

CD-1 

90 d (GO) 

Neurological 

41 Rat 

Fischer 344 

13 wk 5x/wk (GO) 

133 

400 (hunched posture and 

lethargy) 

Shopp et al. 1984 NAP NTP 1980b NAP 

42 Mouse 

B6C3F1 

13 wk 5d/wk 1x/d (GO) 

200 NTP 1980a 

NAP 

43 Mouse 

CD-1 

90 d (GO) 

Reproductive 

44 Rat 

Fischer 344 

13 wk 5x/wk (GO) 

133 400 

Shopp et al. 1984 NAP NTP 1980b NAP 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

Exposure/ LOAEL 

Duration/ a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

45 Mouse 13 wk 

B6C3F1 5d/wk

1x/d (GO) 

CHRONIC EXPOSURE Systemic 

46 Mouse 81 wk 

B6C3F1 (F) 

200 

Resp 

c 

71.6 

Cardio 143.7 Gastro 143.7 Hemato 143.7 Hepatic 143.7 Renal 143.7 Endocr 143.7 Bd Wt 143.7 

NTP 1980a NAP 

(increased incidence of Murata et al. 1993 

pulmonary alveolar 1-MN proteinosis in males and females) 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

Exposure/

Duration/ a Frequency Key to Species (Route) Figure (Strain) 

47 Mouse 81 wk 

(B6C3F1) (F) 

Immuno/ Lymphoret 

48 Mouse 81 wk 

B6C3F1 1x/d

(F) 

49 Mouse 81 wk 

(B6C3F1) (F) 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Dermal Ocular Bd Wt 

NOAEL 

(mg/kg/day) 

113.8 

113.8 

113.8 113.8 113.8 113.8 113.8 113.8 

113.8 143.7113.8 

LOAEL 

Less Serious Serious 

(mg/kg/day) (mg/kg/day) 

d 

50.3 (increased incidence of 

pulmonary alveolar proteinosis in males andfemales)

Reference Chemical Form 

Murata et al. 1997 2-MN Murata et al. 1993 1-MN Murata et al. 1997 2-MN 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

a

Key to Species 

Figure (Strain) 

Neurological 

50 Mouse 

B6C3F1 

51 Mouse 

(B6C3F1) 

Reproductive 

52 Mouse 

B6C3F1 

53 Mouse 

(B6C3F1) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Less Serious

(mg/kg/day)

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

81 wk 1x/d 143.7 Murata et al. 1993 

1-MN 

(F) 81 wk (F) 81 wk 1x/d 

113.8143.7 F 

Murata et al. 1997 2-MN Murata et al. 1993 1-MN 

(F) 81 wk (F) 113.8 Murata et al. 1997 2-MN 
Table 3-2 Levels of Significant Exposure to Naphthalene (nap) Or Methylnaphthalene (1-mn Or 2-mn) - Oral (continued) 

Exposure/ LOAEL 

Duration/ a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Cancer 

54 Mouse 

B6C3F1 

81 wk 1x/d 71.6 (CEL: increased incidence of lung 

adenomas in males only) 

Murata et al. 1993 1-MN 

(F) 

55 Mouse 

(B6C3F1) 

81 wk (F) 54.3 (CEL: increased incidence of lung 

adenomas in males only; not at higher exposure level in males or in females at either exposure level) 

Murata et al. 1997 2-MN 

a The number corresponds to the entries in Figure 3-2 b Used to derive an acute-duration Minimal Risk Level (MRL) of 0.6mg/kg/day; based on a minimal LOAEL of 50 mg/kg/day for transient clinical signs of toxicity in pwhich was divided by an uncertainty factor of 90 (3 for the use of a minimal LOAEL, 10 for extrapolation from animals to humans, and 3 for human variability). Baseof results from the three available intermediate-duration oral toxicity studies in animals (NTP 1980a,b; Shopp et al. 1984), the acute-duration MRL is expected to be protective for intermediate-duration exposure scenarios (see Section 2.3 and Appendix A). c Used to derive a chronic-duration Minimal Risk Level (MRL) of 0.07 mg/kg/day for 1-MN; based on a LOAEL of 71.6 mg/kg/day which was divided by an uncertain(10 for use the use of a LOAEL, 10 for extrapolation from animals to humans; and 10 for human variability) d Used to derive a chronic-duration Minimal Risk Level (MRL) of 0.04 mg/kg/day for 2-MN; based on a BMDL (LED05) of 4 mg/kg/day which was divided by an unc100 (10 for extrapolation from animals to humans, and 10 for human variability). Bd Wt = body weight; BMDL (LED05) = lower 95% confidence limit on a dose associated with 5% extra risk; BUN = blood urea nitrogen; Cardio = cardiovascular; d = endocrine; F = females; (F) = feed; (G) = gavage; Gastro = gastrointestinal; Gd = gestation day(s); (G) = gavage in oil; Hemato = hematological; hr = hour(s); Immimmunological; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = males; NOAEL = no-observed-adverse-effect level; NS = not specrespiratory; wk = week(s); x = time(s); 1-Mn = 1-methylnaphthalene; 2-Mn = 2-methylnaphthalene. 
Death Respiratory Gastrointestinal Hematological Hepatic Renal Ocular Body Weight Other 

Figure 3-2. Levels of Significant Exposure to Naphthalene (NAP) or Methylnaphthalene (1-M

Acute (≤14 days) 

Systemic 

mg/kg/day Immuno/Lymphor Neurolog

10000 

2r 1r 1r 13h 13h 

12d 

1000 8r 9r 10r 10r 10r 14h 

4m4m 

3m 

5m 11m 11m 11m 11m 11m 11m 15m 17m 

7r 

6 6 6 100 

11m 11m 7r 15m 16r 

10 

1 

N

0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Respiratory Cardiovascular Gastrointestinal Hematological Hepatic Renal Ocular Body Weight Other 

Figure 3-2. Levels of Significant Exposure to Naphthalene (NAP) or Methylnaphthalene (1-MN or 2

Intermediate (15-364 days) 

Systemic 

mg/kg/day 

10000 

29r 

1000 32r 31r 32r 36h 37h 38h 

30r 27r 35h 26r 

28r 28r 28r 28r 28r 28r 28r 28r 28r 

33m 33m 33m 33m 33m 33m 28r 33m 33m 28r 25r 25r 25r 34m 34m 34m 34m 34m 34m 

100 28r 

34m 

10 

1 

0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
1000 

Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Ocular Body Weight Immuno/Lym

Figure 3-2. Levels of Significant Exposure to Naphthalene (NAP) or Methylnaphthalene (1-MN or 2

Chronic (≥365 days) 

Systemic 

mg/kg/day Respiratory 

46m 46m 46m 46m 46m 46m 46m 48m 

47m 47m 47m 47m 47m 47m 47m 47m 47m 49m 

100 

46m 

47m 

10 

1 

0.1 

1-MN 

2-MN 

*Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer endpoint. 0.01 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 64 

3. HEALTH EFFECTS 

naphthalene-containing diaper pail deodorant block (Haggerty 1956). This may have been a reflection of 

the reduced oxygen carrying capacity of the blood due to hemolysis. 

Lesions of the lungs were seen in rats that died after being given a single large dose of naphthalene 

(1,000–4,000 mg/kg) during an LD50 study (Papciak and Mallory 1990). On the other hand, no significant 

respiratory toxicity was seen in rats following oral administration of naphthalene at time-weighted 

average doses of 169 mg/kg/day for 9 weeks (Germansky and Jamall 1988). Dosages were increased 

from 100 to 750 mg/kg/day over a 6-week period and held constant at 750 mg/kg/day for the last 3 weeks 

of the 9-week exposure period. 

Lung weights were increased in female mice administered naphthalene at 267 mg/kg/day for 14 days; 

however, these effects were not seen in either sex at 133 mg/kg/day for 90 days (Shopp et al. 1984). No 

gross or histopathological lesions of the lungs were noted in mice at doses up to 200 mg/kg/day (NTP 

1980a) or in rats at doses of 400 mg/kg/day (NTP 1980b) after 13 weeks of exposure. 

There was a significantly increased incidence of pulmonary alveolar proteinosis in male and female 

B6C3F1 mice fed diets containing 1-methylnaphthalene for 81 weeks (Murata et al. 1993). The lesions 

contained acidophilic amorphous material, foam cells, and cholesterol crystals. There was no apparent 

inflammation, edema, or fibrosis of the tissues. Average administered doses were 0, 71.6, or 

140.2 mg/kg/day for males and 0, 75.1, or 143.7 mg/kg/day for females. Respective incidences for 

pulmonary alveolar proteinosis in the control, low-, and high-dose groups were 4/49, 23/50, and 19/49 for 

males and 5/50, 23/50, and 17/49 for females. Histopathological examination of major organs and tissues 

only found exposure-related lesions in the lung. This effect was used as the basis of the chronic-duration 

oral MRL for 1-methylnaphthalene. 

Pulmonary alveolar proteinosis is characterized by the accumulation of surfactant material in the alveolar 

lumen, and has been hypothesized to be caused by either excessive secretion of surfactant by type II 

pneumocytes, or disruption of surfactant clearance by macrophages (Lee et al. 1997; Mazzone et al. 2001; 

Wang et al. 1997). Electron microscopic examination of lungs of mice exposed dermally to a mixture of 

1-methylnaphthalene and 2-methylnaphthalene showed that alveolar spaces were filled with numerous 

myelinoid structures resembling lamellar bodies of type II pneumocytes (Murata et al. 1992). 

In a companion study, pulmonary alveolar proteinosis was the only exposure-related lesion found in 

B6C3F1 mice of both sexes exposed to 2-methylnaphthalene in the diet at doses as low as 50.3 mg/kg/day 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 65 

3. HEALTH EFFECTS 

(Murata et al. 1997). Average administered doses were 0, 54.3, or 113.8 mg/kg/day for males and 0, 50.3, 

or 107.6 mg/kg/day for females. Respective incidences for pulmonary alveolar proteinosis in the control, 

low-, and high-dose groups were 4/49, 21/49, and 23/49 for males and 5/50, 27/49, and 22/49 for females. 

This effect was used as the basis of the chronic-duration oral MRL for 2-methylnaphthalene. 

Cardiovascular Effects. No studies were located that demonstrate any direct effects of naphthalene 

ingestion on the cardiovascular system. In those reports where cardiovascular effects such as increased 

heart rate and decreased blood pressure were noted in humans, the cardiovascular effects appeared to be 

secondary to the hemolytic effects and the events leading to general multiple organ failure (Gupta et al. 

1979; Kurz 1987). 

No gross or histopathological lesions of the heart were noted in mice at doses up to 200 mg/kg/day (NTP 

1980a) or in rats at doses of 400 mg/kg/day (NTP 1980b) after 13 weeks of exposure. 

Heart weights were significantly decreased (6–7%) in male and female mice that were fed 1-methylnaphthalene for 81 weeks in their diet. However, the changes in heart weight were not dose-related and 

there were no accompanying tissue abnormalities (Murata et al. 1993). Histopathological examination 

revealed no lesions in the hearts of mice fed 1-methylnaphthalene at doses as high as 143.7 mg/kg/day 

(Murata et al. 1993) or 2-methylnaphthalene at doses as high as 113.8 mg/kg/day (Murata et al. 1997). 

Gastrointestinal Effects. Gastrointestinal disorders are common following naphthalene ingestion by 

humans. These effects have been attributed to the irritant properties of naphthalene (Kurz 1987). Nausea, 

vomiting, abdominal pain, and diarrhea (occasionally containing blood) have been reported (Bregman 

1954; Gidron and Leurer 1956; Gupta et al. 1979; Haggerty 1956; Kurz 1987; MacGregor 1954; Ojwang 

et al. 1985). While the presence of blood in the stool is indicative of intestinal bleeding, only a few areas 

of mucosal hemorrhage were noted in postmortem examination of the intestines (Kurz 1987). These areas 

were restricted to the small bowel and colon. No frank erosions or perforations were noted anywhere in 

the gastrointestinal tract. 

A single dose of 1,000–4,000 mg/kg was associated with stomach lesions and discoloration of the 

intestines in rats that died during an LD50 study. The survivors were not affected (Papciak and Mallory 

1990). No gross or histopathological lesions of the stomach, small intestine, and colon were noted in 

mice at doses of up to 200 mg/kg/day (NTP 1980a) or in rats at doses of up to 400 mg/kg/day after 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 66 

3. HEALTH EFFECTS 

13 weeks of exposure (NTP 1980b). There was some intermittent diarrhea in the rats, but this may not 

have been treatment related. 

No histopathological lesions were seen in the stomach or intestines of mice fed 71.6–143.7 mg/kg/day 

1-methylnaphthalene for 81 weeks (Murata et al. 1993) or 50.3–113.8 mg/kg/day 2-methylnaphthalene 

for 81 weeks (Murata et al. 1997). 

Hematological Effects. The most commonly reported hematologic effect in humans following the 

ingestion of naphthalene is hemolytic anemia (Dawson et al. 1958; Gidron and Leurer 1956; Gupta et al. 

1979; Haggerty 1956; Kurz 1987; MacGregor 1954; Mackell et al. 1951; Melzer-Lange and Walsh-Kelly 

1989; Ojwang et al. 1985; Shannon and Buchanan 1982). Changes observed in hematology and blood 

chemistry are consistent with this effect: hemolysis, decreased hemoglobin and hematocrit values, 

increased reticulocyte counts, serum bilirubin levels, and Heinz bodies. This was caused by hemolysis. 

Most of the reported case studies provide no information on dose. However, in one case report, a 

16-year-old girl swallowed 6 g of naphthalene before exhibiting hemolytic anemia (Gidron and Leurer 

1956). This is a dose of 109 mg/kg (assuming a 55-kg body weight). The hematological condition of this 

individual, who was an immigrant from Kurdistan, was not provided. 

As mentioned previously, there is an association between G6PD deficiency and the hemolytic effects of 

naphthalene (Dawson et al. 1958; Melzer-Lange and Walsh-Kelly 1989; Shannon and Buchanan 1982). 

Individuals with a genetic defect for this enzyme show an increased susceptibility to hemolysis from 

naphthalene exposure. 

Few hematologic changes have been reported in animals. Standard laboratory animals do not appear to 

be sensitive to the hemolytic effects of naphthalene. In CD-1 mice, naphthalene at doses up to 

267 mg/kg/day for 14 days or up to 133 mg/kg/day for 90 days did not result in hemolytic anemia (Shopp 

et al. 1984). However there was an increase in eosinophils in the 14- and 90-day studies. There was an 

increase in prothrombin time at 14 days. The clinical significance of these observations is not clear; the 

effects are not considered to be adverse. 

There were no pronounced changes in red cell related hematological parameters in mice following 

13-week exposures to doses of up to 200 mg/kg/day (NTP 1980a) and up to 400 mg/kg/day in rats (NTP 

1980b). In male mice exposed to 200 mg/kg/day for 13 weeks, there was a decrease in segmented 

neutrophils and an increase in lymphocytes, but in male rats given 400 mg/kg/day, there were increased 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 67 

3. HEALTH EFFECTS 

neutrophils and decreased lymphocytes. These effects are not considered to be biologically significant or 

adverse. 

Hemolytic anemia was reported by Zuelzer and Apt (1949) in a dog receiving a single 1,525 mg/kg dose 

of naphthalene in food and in another dog receiving approximately 263 mg/kg/day for 7 days in food. 

Dogs are more susceptible to chemically induced hemolysis than are rats and mice. 

Exposure to 75.1 or 143.7 mg/kg/day 1-methylnaphthalene for 81 weeks was associated with a slight but 

statistically significant increase in the hemoglobin concentration, mean corpuscular hemoglobin, and 

mean corpuscular hemoglobin concentration in female mice (Murata et al. 1993). Corresponding changes 

were not observed in male mice given comparable doses of 1-methylnaphthalene, or in male or female 

mice exposed to 2-methylnaphthalene doses as high as 113.8 mg/kg/day (Murata et al. 1997). Consistent 

exposure-related changes were not found in differential white blood cell counts or several serum 

biochemical parameters in male and female mice exposed to 1-methylnaphthalene or 2-methylnaphthalene in these studies. The results from these studies do not provide consistent evidence that 

hematological parameters are consistent toxicity targets of chronic oral exposure to 1-methylnaphthalene 

or 2-methylnaphthalene. 

Hepatic Effects. Evidence of hepatotoxicity following oral exposure to naphthalene has been 

reported in humans, based on elevated plasma levels of hepatic enzymes (such as aspartate 

aminotransferase and lactic acid dehydrogenase) (Kurz 1987; Ojwang et al. 1985) and liver enlargement 

(Gupta et al. 1979; MacGregor 1954). The relationship between liver enlargement and potential 

naphthalene-induced hemolysis is unknown. 

There is limited evidence of hepatic effects in laboratory animals, but the liver does not appear to be a 

critical toxicity target of orally administered naphthalene. A 39% increase in liver weight, a modest 

elevation in activity of aniline hydroxylase, and evidence of lipid peroxidation were observed in male rats 

treated with naphthalene at 1,000 mg/kg/day for 10 days (Rao and Pandya 1981). Male rats demonstrated 

an elevation in hepatic lipid peroxides at naphthalene doses of 1,000 mg/kg/day for 18 days (Yamauchi et 

al. 1986). In rats administered increasing doses of naphthalene up to 750 mg/kg/day (time-weighted 

average of 169 mg/kg/day), hepatic lipid peroxides were doubled at the end of 9 weeks of treatment 

(Germansky and Jamall 1988). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 68 

3. HEALTH EFFECTS 

No effects on liver weight were observed in male or female mice receiving naphthalene at doses up to 

267 mg/kg/day for 14 days or male mice receiving 133 mg/kg/day for 90 days (Shopp et al. 1984). 

Absolute liver weight was statistically significantly decreased, compared with the control value (by about 

18%), in female mice receiving 133 mg/kg/day naphthalene for 90 days, but the biological significance of 

this change is unclear. Relative liver weight in exposed females was not changed to a statistically 

significant degree, and several serum biochemical end points indicative of liver damage (e.g., lactate 

dehydrogenase, SGPT, SGOT, and alkaline phosphatase) were unaffected in male and female mice 

exposed to doses up to 133 mg/kg/day for 90 days (Shopp et al. 1984). No other consistent biologically 

relevant exposure-related changes in serum chemistry end points were found. Activities of two hepatic 

microsomal mixed function oxidases (aniline hydroxylase, aminopyrine N-demethylase) were unchanged 

in exposed mice, although hepatic activities of benzo[a]pyrene hydroxylase were statistically significantly 

decreased in exposed mice (Shopp et al. 1984). The biological significance of this change is unclear. 

Supporting the concept that the liver is not a critical toxicity target of oral exposure to naphthalene, no 

gross or histopathological lesions of the liver were noted in mice at doses of up to 200 mg/kg/day (NTP 

1980a) or in rats at doses of up to 400 mg/kg/day after 13 weeks of exposure (NTP 1980b). 

There were no changes in liver weights or tissue histopathology in male or female mice that consumed 

71.6–143.7 mg/kg/day 1-methylnaphthalene in the diet for 81 weeks (Murata et al. 1993) or 50.3– 

113.8 mg/kg/day 2-methylnaphthalene in the diet for 81 weeks (Murata et al. 1997). 

Renal Effects. Renal toxicity has been reported in case studies of humans who ingested naphthalene. 

Frequent findings include the elevation of creatinine and blood urea nitrogen and the presence of 

proteinuria and hemoglobinuria (Gupta et al. 1979; Haggerty 1956; Kurz 1987; MacGregor 1954; Ojwang 

et al. 1985; Zuelzer and Apt 1949). The presence of blood in the urine and increased concentrations of 

urobilinogen are a consequence of acute hemolysis and do not reflect any direct action of naphthalene on 

the kidney. Oliguria (Kurz 1987) and anuria (Gupta et al. 1979) were noted in two case reports, although 

urine output was normal in a third (Ojwang et al. 1985). Painful urination with swelling of the urethral 

orifice was also associated with medicinal naphthalene ingestion (Lezenius 1902). Proximal tubule 

damage and general tubular necrosis were found in postmortem examinations of two individuals who died 

following naphthalene ingestion (Gupta et al. 1979; Kurz 1987). 

Renal effects were not consistently observed in animals exposed orally to naphthalene. Following 

10 days of exposure of rats to naphthalene at 1,000 mg/kg/day, no changes were noted in kidney weight, 

lipid peroxidation, or in the activity of alkaline phosphatase and aniline hydroxylase (Rao and Pandya 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 69 

3. HEALTH EFFECTS 

1981). No changes were observed in the kidney weights of mice administered naphthalene at doses up to 

267 mg/kg/day for 14 days or 133 mg/kg/day for 90 days (Shopp et al. 1984). No gross or histopathological lesions of the kidney were noted in mice at doses of up to 200 mg/kg/day (NTP 1980a) or in 

rats at doses of up to 200 mg/kg/day after 13 weeks of exposure (NTP 1980b). In the male rats, 10% 

showed cortical tubular degeneration that may have been compound-related at a dose of 400 mg/kg/day 

(NTP 1980b). 

Relative kidney weights were increased slightly in male mice fed diets containing 71.6 or 

140.2 mg/kg/day 1-methylnaphthalene for 81 weeks (Murata et al. 1993). The females were not affected, 

and there were no histopathological lesions in the males or females. There were no changes in kidney 

weights or tissue histopathology in male or female mice consuming 50.3–113.8 mg/kg/day 2-methylnaphthalene in the diet for 81 weeks (Murata et al. 1997). 

Ocular Effects. In an early report of naphthalene toxicity, a 36-year-old pharmacist who ingested an 

unspecified amount of unpurified naphthalene in a castor oil emulsion over a 13-hour period as treatment 

of an intestinal disorder became nearly blind 8 or 9 hours later (Lezenius 1902). A medical examination 

the following month revealed constricted visual fields associated with optic atrophy and bilateral zonular 

cataracts. At 1.5 meters, the patient's vision was limited to finger counting. 

Several animal studies have demonstrated ocular changes following oral naphthalene exposure. Within 

1 week following exposure to naphthalene (500 or 1,000 mg/kg/day), lens densities were increased in rats 

and cataracts developed within 4 weeks (Kojima 1992; Murano et al. 1993; Yamauchi et al. 1986). Eight 

rabbits (strain not identified) developed cataracts during oral administration of naphthalene at 

2,000 mg/kg/day for 5 days (Srivastava and Nath 1969). Cataracts began to develop by the first day after 

a single 1,000 mg/kg naphthalene dose in three Chinchilla Bastard rabbits (Rossa and Pau 1988). In the 

solitary New Zealand white rabbit tested, cataracts began to develop after administration of four 

1,000 mg/kg doses (dosing 2 times/week) and maximized after 12 weeks (Rossa and Pau 1988). 

When naphthalene was administered orally at 1,000 mg/kg/day for up to 28 days, cataracts developed in 

10 of 16 Dutch (pigmented) rabbits and in 11 of 12 albino rabbits (Van Heyningen and Pirie 1976). Lens 

changes were seen as early as day 2 of exposure. The authors noted that albino strains were more likely 

to develop cataracts over a 4-week course of treatment at 1,000 mg/kg/day than pigmented strains such as 

the Dutch rabbit. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 70 

3. HEALTH EFFECTS 

In contrast, administration of a time-weighted-average 500-mg/kg/day dose of naphthalene in corn oil by 

gavage for 6 weeks resulted in more rapid development of cataracts in pigmented Brown-Norway rats 

than in nonpigmented Sprague-Dawley rats (Murano et al. 1993). Cataracts developed in three distinct 

phases. In the first phase, water clefts formed in the anterior subcapsular region of the eye. The second 

stage was the development of a semicircular opaque area in the lens, and the last stage was the appearance 

of a wedge-shaped opacity that could be seen with retroillumination and a wide, zonular-ring opacity that 

was seen with slit imaging. Each stage occurred about 1 week earlier in the Brown-Norway rats than in 

the Sprague Dawley rats. The first stage began 1 week after treatment was initiated in the Brown-Norway 

rats, and stage three cataracts were seen in all animals by the end of the 6 weeks. Progressive 

development of lens opacities was also reported in rats that were exposed to 700 or 5,000 mg/kg/day 

naphthalene by gavage for 79–102 days (Rathburn et al. 1990; Tao et al. 1991). 

Damage to the eyes with continued exposure to naphthalene is not limited to lens opacification (Orzalesi 

et al. 1994). Retinal damage was noted in pigmented rabbits given time-weighted-average doses of 

500 mg/kg/day naphthalene in corn oil by gavage for 5 weeks. The first changes to the retina occurred at 

about 3 weeks with degeneration of the photoreceptors. There was a subsequent increase in the retinal 

pigment epithelium as these cells phagocytized the debris from the photoreceptors. By the end of 

6 weeks, the photoreceptor layer had almost entirely disappeared and was replaced with fibroglial tissue. 

As damage progressed, there was dense subretinal neovascularization of the area. 

A number of biochemical changes were seen in the eyes after acute- and intermediate-duration 

naphthalene exposures. After 1 week of treatment with 1,000 mg/kg/day, glutathione levels in the lens 

were decreased in rats (Xu et al. 1992b; Yamauchi et al. 1986). After 30 days of treatment with doses of 

5,000 mg/kg/day, total glutathione levels were reduced by 20% (Rathbun et al. 1990), and there was a 

22% reduction at 60 days with a dose of 700 mg/kg/day (Tao et al. 1991). At 60 days, glutathione 

peroxidase activity in the lens was decreased by up to 45% and there was a 20–30% decrease in 

glutathione reductase activity (Rathbun et al. 1990). Comparable decreases in the activities of both 

enzymes were seen at 102 days with lower naphthalene doses (Tao et al. 1991). No changes were 

observed in the activity of glutathione synthetase or gamma-glutamyl cysteine synthetase (Rathbun et al. 

1990). After 4 weeks of compound treatment (500 mg/kg/day), the activities of aldose reductase, sorbitol 

dehydrogenase, lactic dehydrogenase, and glutathione reductase were lower than in controls (Kojima 

1992). No changes in ocular lipid peroxides were reported when male Blue Spruce pigmented rats were 

administered incremental doses of naphthalene that peaked at 750 mg/kg/day for 9 weeks (Germansky 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 71 

3. HEALTH EFFECTS 

and Jamall 1988). Lens and capsule LDH activities were greatly reduced in rabbits while o-diphenyl 

oxidase activity was elevated with a dose of 2,000 mg/kg/day for 5 days (Srivastava and Nath 1969). 

In 13-week studies, histopathologic examination revealed no ocular lesions in F344/N rats or B6C3F1 

mice exposed to doses as high as 400 or 200 mg/kg/day, respectively (NTP 1980a, 1980b). In a 2-year rat 

feeding study, no eye damage was seen at a naphthalene dosage of 41 mg/kg/day (Schmahl 1955). The 

details of the eye examination were not provided. 

There were no changes in eye tissue histopathology in male or female mice that consumed 71.6– 

143.7 mg/kg/day 1-methylnaphthalene in the diet for 81 weeks (Murata et al. 1993) or 50.3– 

113.8 mg/kg/day 2-methylnaphthalene in the diet for 81 weeks (Murata et al. 1997). 

Body Weight Effects. No studies were located that documented effects on body weight in humans 

after oral exposure to naphthalene. 

In pregnant Sprague-Dawley rats exposed to 50, 150, or 450 mg/kg/day on gestation days 6–15, body 

weight gains were depressed by 31 and 53% at 150 and 450 mg/kg/day, respectively, but were unaffected 

at 50 mg/kg/day. The decreased body weight gains were accompanied by persistent clinical signs of 

toxicity (slow respiration, lethargy, or prone position) at the 150 and 450 mg/kg/day dose levels, but these 

signs were only apparent at the 50-mg/kg/day level during the first 2 days of dosing. The minimal 

LOAEL of 50 mg/kg/day for transient clinical signs and the LOAEL of 150 mg/kg/day for clinical signs 

associated with decreased body weight gains in pregnant rats are the basis of the acute oral MRL for 

naphthalene (see Section 2.3 and Appendix A). 

In animals, body weight effects appear to be the critical effect associated with intermediate-duration oral 

exposure to naphthalene. After 13 weeks of exposure to naphthalene, mean terminal body weights in 

F344/N rats exposed to gavage doses ≥200 mg/kg/day were decreased by more than 10% relative to 

control values (NTP 1980b). Body weights were decreased by 12 and 28% in 200- and 400-mg/kg/day 

male rats, and by 23% in 400-mg/kg/day female rats. Food consumption was not affected by exposure. 

In B6C3F1 mice exposed to naphthalene doses up to 200 mg/kg/day for 13 weeks, exposed males gained 

more weight than controls during exposure, whereas exposed females gained less weight than controls 

(NTP 1980a). However, terminal body weights in exposed female mice were within 95% of control 

values, indicating that the naphthalene-induced changes were not biologically significant. In male and 

female CD-1 mice exposed to doses as high as 133 mg/kg/day for 90 days, average terminal body weight 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 72 

3. HEALTH EFFECTS 

in exposed groups were within 90% of control values (Shopp et al. 1984). Mice exposed to 

267 mg/kg/day naphthalene for 14 days showed a decreased body weight gain; terminal body weights 

were decreased by 6% in females and 13% in males compared with control values (Shopp et al. 1984). 

As discussed in Section 2.3 and Appendix A, the NOAEL of 100 mg/kg/day and the LOAEL of 

200 mg/kg/day for decreased body weights in rats exposed by gavage to naphthalene 5 days/week for 

13 weeks (NTP 1980b) provide the best available basis for MRL derivation among the findings from the 

studies in animals orally exposed to naphthalene for intermediate-durations. However, because an 

intermediate-duration oral MRL based on these data is slightly larger than the acute-duration oral MRL 

for naphthalene, the acute MRL was adopted as the intermediate-duration oral MRL for naphthalene (as 

indicated in Figure 3-2 and discussed in Section 2.3). 

There was no significant difference between body weights of mice that were given up to 143.7 mg/kg/day 

1-methylnaphthalene in their diets and those of the control animals throughout an 81-week exposure 

period (Murata et al. 1993). In mice exposed to 2-methylnaphthalene doses as high as 113.8 mg/kg/day in 

the diet for up to 81 weeks, average body weights were within 10% of control values (Murata et al. 1997). 

Other Systemic Effects. Several humans who consumed naphthalene experienced elevated body 

temperatures which may have been related to their hemolytic crisis (Chusid and Fried 1955; Gidron and 

Leurer 1956; Haggerty 1956; Kurz 1987; MacGregor 1954; Ojwang et al. 1985). However, in some 

situations, bacterial infections rather than hemolysis may have been the cause of the fever (Kurz 1987; 

Melzer-Lange and Walsh-Kelly 1989; Ojwang et al. 1985; Zuelzer and Apt 1949). 

No studies were located that documented other systemic effects in animals after oral exposure to 

naphthalene. 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located that documented immunological or lymphoreticular effects in humans after oral 

exposure to naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. However, an enlarged spleen is 

a frequent consequence of hemolysis and was noted in the postmortem examination of one human subject 

who died after ingesting a large quantity of naphthalene (Kurz 1987). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 73 

3. HEALTH EFFECTS 

Mice treated with naphthalene at oral doses as high as 267 mg/kg/day for 14 days showed no effects on 

humoral immune responses, delayed hypersensitivity responses, bone marrow stem cell number, or bone 

marrow DNA synthesis (Shopp et al. 1984). Mitogenic responses to concanavalin A (but not to 

lipopolysaccharide) were reduced in high dose females only. None of these effects were noted at doses of 

27 or 53 mg/kg/day. At naphthalene doses of 133 mg/kg/day for 13 weeks, naphthalene had no effect on 

immune function (Shopp et al. 1984). After 14 days, thymus weights were reduced approximately 30% in 

male mice, but no differences were seen with a dose of 133 mg/kg/day at 13 weeks (Shopp et al. 1984). 

There was lymphoid depletion of the thymus in 2 of 10 female rats exposed to 400 mg/kg/day 

naphthalene for 13 weeks (NTP 1980b). 

Spleen weights were reduced approximately 20% in female mice exposed to 267 mg/kg/day naphthalene 

for 14 days and 25% in females exposed to 133 mg/kg/day for 13 weeks (Shopp et al. 1984). 

Monocyte concentrations were significantly elevated in male and female mice exposed to 71.6– 

143.7 mg/kg/day 1-methylnaphthalene for 81 weeks (Murata et al. 1993). The increase in monocyte 

counts appeared to be dose related. The authors hypothesized that these changes may have been a 

physiological response to the pulmonary alveolar proteinosis seen in the exposed animals. There were no 

changes in spleen or thymus weights and the histopathology of these tissues was normal. With 81 weeks 

of exposure of male and female B6C3F1 mice to 2-methylnaphthalene, neutrophils were reported to be 

decreased, and lymphocytes increased, compared with control values, but neither the magnitude of these 

changes, or the dose groups in which they occurred, were specified in the study report (Murata et al. 

1997). As with 1-methylnaphthalene, histologic examination revealed no exposure-related lesions in the 

spleen or thymus. 

The highest NOAEL values and all LOAEL values from each reliable naphthalene study for 

immunological/lymphoreticular effects in each species and duration category are recorded in Table 3-2 

and plotted in Figure 3-2. The highest NOAEL values from the 1-methylnaphthalene and 2-methylnaphthalene studies for immunological/lymphoreticular effects are also recorded in Table 3-2 and plotted 

in Figure 3-2. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 74 

3. HEALTH EFFECTS 

3.2.2.4 Neurological Effects 

The neurologic symptoms of naphthalene ingestion reported in human case studies include confusion 

(Ojwang et al. 1985), altered sensorium (Gupta et al. 1979), listlessness and lethargy (Bregman 1954; 

Chusid and Fried 1955; Kurz 1987; MacGregor 1954; Zuelzer and Apt 1949), and vertigo (Gidron and 

Leurer 1956). Muscle twitching, convulsions (Kurz 1987; Zuelzer and Apt 1949), decreased responses to 

painful stimuli, and coma occurred prior to death in individuals who ingested naphthalene (Gupta et al. 

1979; Kurz 1987). At autopsy, the brain has appeared edematous (Gupta et al. 1979; Kurz 1987), with 

separation of neural fibers and swelling of myelin sheaths being noted histologically (Gupta et al. 1979). 

The neurologic symptomatology could result from the cerebral edema, which was probably secondary to 

acute hemolysis. 

No studies were located that documented neurological effects in humans after oral exposure to 1-methylnaphthalene or 2-methylnaphthalene. 

Dose-related clinical signs of toxicity were apparent in female Sprague-Dawley rats exposed to doses of 

50, 150, or 450 mg/kg/day naphthalene for 10 days during organogenesis. Slow respiration and lethargy 

were observed in a large percentage of the exposed animals. Some rats were dazed, had periods of apnea, 

or were unable to move after exposure. In the lowest dose group, 73% of the animals were affected on 

the first day of dosing. In the two higher dose groups, over 90% of the rats were affected (NTP 1991a). 

The animals in the 50-mg/kg/day group acclimatized quickly. Symptoms were only apparent during the 

first 2 days of dosing. Clinical signs of toxicity persisted for longer periods in the higher dose groups, 

and were accompanied by decreased body weight gains (31 and 53% decreased at 150 and 

450 mg/kg/day, respectively compared with control). It is not known if the observed clinical signs were 

due to treatment-related effects on the nervous system or were the indirect consequence of severe 

systemic toxicity, as indicated by the dramatic decreases in body weight gain. Comparable effects were 

not observed in F344/N rats exposed to doses of up to 400 mg/kg/day for 13 weeks or in B6C3F1 mice at 

doses of up to 200 mg/kg/day (NTP 1980a, 1980b). These results suggest that pregnant animals may be 

more susceptible to the effects of naphthalene than non-pregnant animals. The minimal LOAEL of 

50 mg/kg/day for transient clinical signs of toxicity and the LOAEL of 150 mg/kg/day for more persistent 

signs of toxicity accompanied with depressed weight gain in pregnant rats exposed on gestation days 6– 

15 are the basis of the acute oral MRL for naphthalene (see Section 2.3 and Appendix A). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 75 

3. HEALTH EFFECTS 

There were no changes in the brain weights in mice exposed to naphthalene at doses up to 267 mg/kg/day 

for 14 days or 133 mg/kg/day for 90 days (Shopp et al. 1984). No gross or histopathological lesions of 

the brain were noted in mice at doses of up to 200 mg/kg/day (NTP 1980a) or in rats at doses of up to 

400 mg/kg/day after 13 weeks of exposure (NTP 1980b). Transient clinical signs of neurotoxicity were 

observed in rats following daily gavage administration of 400 mg/kg, but not 200 mg/kg, doses (NTP 

1980b). In mice, transient lethargy was observed following dose administration only between weeks 3 

and 5 in the highest dose group, 200 mg/kg/day (NTP 1980a). 

Absolute brain weight was significantly increased in male mice fed diets containing 71.6 or 

140.2 mg/kg/day 1-methylnaphthalene for 81 weeks (Murata et al. 1993), or 54.3 or 113.8 mg/kg/day 

2-methylnaphthalene for 81 weeks (Murata et al. 1997). The increases in brain weights were not dose 

related and there were no histopathological abnormalities of the brain. There were no differences in brain 

weights or histopathology in the female mice given comparable doses (Murata et al. 1993, 1997). 

No studies were located that documented neurological effects in animals after oral exposure to 2-methylnaphthalene. 

The highest NOAEL values and all LOAEL values from each reliable study for neurological effects for 

naphthalene exposure in each species and duration category are recorded in Table 3-2 and plotted in 

Figure 3-2. The highest NOAEL values for neurological effects in the intermediate-duration 1-methylnaphthalene and 2-methylnaphthalene mouse studies are also recorded in Table 3-2 and plotted in 

Figure 3-2. 

3.2.2.5 Reproductive Effects 

No studies were located that documented reproductive effects in humans after oral exposure to 

naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. 

Oral exposures of pregnant rabbits to naphthalene at dosages up to 400 mg/kg/day (gestational days 6– 

18), using methylcellulose as the vehicle, resulted in no apparent adverse reproductive effects (PRI 1986). 

When administered in corn oil to pregnant mice, however, a dosage of 300 mg/kg/day (gestational 

days 7–14) resulted in a decrease in the number of live pups per litter (Plasterer et al. 1985). It is not clear 

whether the observed differences in response are attributable to species differences or a possible increase 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 76 

3. HEALTH EFFECTS 

in the absorption of naphthalene when it is administered in corn oil compared with administration as a 

suspension in methyl cellulose. 

Transient signs of toxicity were present in female rats exposed to doses of 50, 150, or 450 mg/kg/day on 

gestational days 6–15 (NTP 1991a). Effects on maternal weight gain were noted in the mid- and 

high-dose groups but not in the lowest dose group. The mid-dose group had a 31% decrease in weight 

gain while the high-dose group had a 53% weight gain decrease. 

No treatment-related effects were reported on testicular weights of mice administered naphthalene at 

doses up to 267 mg/kg/day for 14 days or 133 mg/kg/day for 90 days (Shopp et al. 1984). No gross or 

histopathological lesions of the testes were noted in mice at doses of up to 200 mg/kg/day (NTP 1980a) or 

in rats at doses of up to 400 mg/kg/day after 13 weeks of exposure (NTP 1980b). 

No gross or histopathological lesions of the testis, seminal vesicles, ovaries, uterus, or vagina were 

observed in mice exposed to 1-methylnaphthalene doses as high as 143.7 mg/kg/day (Murata et al. 1993) 

or 2-methylnaphthalene doses as high as 113.8 mg/kg/day (Murata et al. 1997). 

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects in 

each species and duration category are recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.6 Developmental Effects 

In humans, transplacental exposure of the fetus to naphthalene that had been ingested by the mother 

resulted in neonatal (and presumably fetal) hemolytic anemia (Anziulewicz et al. 1959; Zinkham and 

Childs 1957, 1958). No estimates of dose or duration were available, although in one case naphthalene 

consumption was described as being most pronounced during the last trimester (Zinkham and Childs 

1958). 

No studies were located that documented developmental effects in humans after oral exposure to 

1-methylnaphthalene or 2-methylnaphthalene. 

No congenital abnormalities were observed after oral administration of naphthalene at 300 mg/kg/day to 

pregnant mice on days 7–14 of gestation (Plasterer et al. 1985), or at doses up to 400 mg/kg/day to 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 77 

3. HEALTH EFFECTS 

pregnant rabbits on days 6–18 of gestation (PRI 1986). Similarly, naphthalene was not teratogenic in rats 

at doses up to 450 mg/kg/day during gestation days 6–15 (NTP 1991a). However, there was a slight, but 

dose-related, increase in fused sternebrae in female pups of rabbits administered doses of 20– 

120 mg/kg/day on days 6–19 of gestation (NTP 1992b). These effects were seen in 2 of 21 litters at 

80 mg/kg/day and 3 of 20 litters at 120 mg/kg/day. No other developmental effects were noted in this 

study. 

No studies were located that evaluated developmental end points in animals after oral exposure to 

1-methylnaphthalene or 2-methylnaphthalene. 

The highest NOAEL values and all LOAEL values from each reliable study for developmental effects in 

each species and duration category are recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.7 Cancer 

No studies were located that documented carcinogenic effects in humans after oral exposure to 

naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. 

In a 2-year feeding study of rats receiving naphthalene at about 41 mg/kg/day, no tumors were reported 

(Schmahl 1955). Specific details pertaining to the tissues examined were not provided. 

The chronic dietary studies with 1-methylnaphthalene or 2-methylnaphthalene provide limited evidence 

for the carcinogenicity of these chemicals. Long-term exposure (81 weeks) of mice to 71.6 or 

140.2 mg/kg/day 1-methylnaphthalene in the diet was associated with statistically significant increases in 

bronchiolar/alveolar adenomas in males, but not in females (Murata et al. 1993). Incidences for mice 

with lung adenomas were 2/49, 13/50, and 12/50 for control through high-dose male mice, and 4/50, 2/50, 

and 4/49 for female mice. Combined incidence for mice with lung adenomas or adenocarcinomas were 

2/49, 13/50, and 15/50 for male mice, and 5/50, 2/50, and 5/50 for female mice. In mice exposed to 

2-methylnaphthalene in the diet for 81 weeks, incidences for mice with lung adenomas were 2/49, 9/49, 

and 5/49 in males groups that received 0, 54.3, or 113.8 mg/kg/day, and 4/50, 4/49, and 5/48 in female 

groups that received comparable doses (Murata et al. 1997). Only the incidence in the 54.3-mg/kg/day 

group was elevated to a statistically significant degree. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 78 

3. HEALTH EFFECTS 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

Two cases of hemolytic anemia were observed in infants exposed to naphthalene-treated diapers (Schafer 

1951; Valaes et al. 1963). One case was fatal. Jaundice, methemoglobinemia, hemolysis, and cyanosis 

were noted. In the fatal case the symptoms persisted, even after the naphthalene-containing diapers were 

no longer used (Schafer 1951). The author suggested that use of baby oil on the infant's skin might have 

facilitated the naphthalene absorption. 

No treatment-related deaths occurred within the 14-day observation period when naphthalene was applied 

at 2,500 mg/kg to the skin of male and female rats or when doses of up to 1,000 mg/kg/day were applied 

to the skin for 6 hours/day, 5 days/week for 13 weeks (Frantz et al. 1986; Gaines 1969). There were also 

no deaths in New Zealand White rabbits after application of 2,000 mg/kg naphthalene to intact and 

abraded shaved areas of skin in an LD50 study (Papciak and Mallory 1990). 

No studies were located that documented lethal effects in humans or animals after dermal exposure to 

1-methylnaphthalene or 2-methylnaphthalene. 

3.2.3.2 Systemic Effects 

No studies were located that documented musculoskeletal effects in humans or animals after dermal 

exposure to naphthalene. The highest NOAEL and all LOAEL values for dermal exposure to naphthalene 

are recorded in Table 3-3. Data for systemic effects in humans or animals from dermal exposure to 

1-methylnaphthalene or 2-methylnaphthlene are restricted to two studies that only examined the lung for 

lesions following repeated dermal exposure to methylnaphthalene, a mixture of 1-methylnaphthalene and 

2-methylnaphthalene (Emi and Konishi 1985; Murata et al. 1992). 

Respiratory Effects. No studies were located that documented respiratory effects in humans after 

dermal exposure to naphthalene. 

No histological changes of the lungs were noted in rats dermally treated with doses of up to 

1,000 mg/kg/day naphthalene (6 hours/day, 5 days/week) for 13 weeks (Frantz et al. 1986). 
Species 

Table 3-3 Levels of S

Exposure/

Duration/

Frequency 

ignificant Exposure to Naphthalene (Nap) Or Methylnaphthalene (1-Mn Or 2-Mn) 

LOAEL 

- Dermal 

(Strain) (Specific Route)

ACUTE EXPOSURE 

System NOAEL Less Serious Serious 

Systemic 

Rabbit once 

24hr contact New Zealand 

White 

Dermal 2000 

mg/kg (skin irritation, edema, fissuring) 

PaNA

Rabbit once Dermal 125 

mg/kg (reversible erythema) 

PRNA

Immuno/ Lymphoret 

Gn Pig 3 wk 1000 

PR

1x/wk mg/kg 

NA
Table 3-3 Levels of Significant Exposure to Naphthalene (Nap) Or Methylnaphthalene (1-Mn Or 2-Mn) - Dermal 

(continued) 

Species 

Exposure/

Duration/

Frequency 

LOAEL 

(Strain) (Specific Route) System NOAEL Less Serious Serious 

INTERMEDIATE EXPOSURE 

Systemic 

Rat 90 d Resp 1000 

Fr

5d/wk 6 hr/d mg/kg/day 

NA

Cardio 1000 

mg/kg/day 

Gastro 1000 

mg/kg/day 

Hemato 1000 

mg/kg/day 

Hepatic 1000 

mg/kg/day 

Renal 1000 

mg/kg/day 

Dermal 300 

mg/kg/day 

1000 

mg/kg/day (increased incidence of excoriated skin and 

papules) 

Mouse 30 wk 

2x/wk (B6C3F1) 

Resp 119 

mg/kg (100% incidence of mice with pulmonary alveolar 

proteinosis) 

M1-
Species 

Table 3-3 Levels of Si

Exposure/

Duration/

Frequency 

gnificant Exposure to Naphthalene (Nap) Or Methylnaphthalene (1-Mn Or 2-Mn) 

LOAEL 

- Dermal 

(continued) 

(Strain) (Specific Route)

CHRONIC EXPOSURE 

System NOAEL Less Serious 

Serious 

Systemic 

Mouse 61 wk 

2x/wk (B6C3F1) 

Cardio = cardiovascular; d = day(s); 

Resp 

Gastro = gastroi

30 

mg/kg 

ntestinal; Gn Pig = Guinea pig; Hemato

119 

mg/kg 

 = hematological; hr = hour(s)

(31/32 mice had pulmonary alveolar proteinosis; an unspecified number died) 

; LOAEL = lowest-observed-ad

Em1-

verse

no-observed-adverse-effect level; Resp = respiratory; wk = week(s); x = time(s). 1-Mn = 1-methylnaphthalene; 2-Mn = 2-methylnaphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 82 

3. HEALTH EFFECTS 

Pulmonary alveolar proteinosis was noted in nearly all female B6C3F1 mice given dermal doses of 

methylnaphthalene (a mixture of 1-methylnaphthalene and 2-methylnaphthalene) twice a week at a dose 

level of 119 mg/kg for 30 weeks (Murata et al. 1992) or 61 weeks (Emi and Konishi 1985). Endogenous 

lipid pneumonia was the term used to describe this lesion in the earlier study. With the longer-duration 

exposure to 119 mg/kg methylnaphthalene, an unspecified number of mice died early. Pulmonary 

alveolar proteinosis developed in 3/11 female mice treated twice weekly with dermal doses of 30 mg/kg 

for 61 weeks, compared with 0/4 controls (Emi and Konishi 1985). 

Cardiovascular Effects. No studies were located that documented cardiovascular effects in humans 

after dermal exposure to naphthalene. 

No differences in organ weight or histological changes of the heart were noted in rats dermally treated 

with 1,000 mg/kg/day naphthalene (6 hours/day, 5 days/week) for 13 weeks (Frantz et al. 1986). 

Gastrointestinal Effects. No studies were located that documented gastrointestinal effects in 

humans after dermal exposure to naphthalene. 

No histological changes of the esophagus, stomach, or intestines were noted in rats dermally treated with 

1,000 mg/kg/day naphthalene (6 hours/day, 5 days/week) for 13 weeks (Frantz et al. 1986). 

Hematological Effects. Hemolytic anemia was reported in infants dermally exposed to diapers or 

other clothing treated with naphthalene mothballs (Dawson et al. 1958; Schafer 1951; Valaes et al. 1963). 

Jaundice, fragmentation of erythrocytes, Heinz bodies, methemoglobinemia, and reticulocytosis were 

observed. Several of the infants had G6PD deficiencies. Individuals with this genetic disorder are 

particularly susceptible to hemolysis from chemical agents. The application of oil to the skin may have 

aided absorption of naphthalene, as shown by the increasing severity of symptoms (jaundice and 

cyanosis) even after the use of the naphthalene-containing diapers ceased (Schafer 1951). 

There were no changes in hemoglobin, hematocrit, red blood cell count, leukocyte count, or platelet count 

at 4 and 13 weeks in rats treated with doses of up to 1,000 mg/kg/day applied to the skin (6 hours/day, 

5 days/week) for 13 weeks (Frantz et al. 1986). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 83 

3. HEALTH EFFECTS 

Hepatic Effects. The liver was enlarged in two infants who experienced acute hemolysis after dermal 

exposure to naphthalene (Dawson et al. 1958; Schafer 1951). The relationship between liver enlargement 

and potential naphthalene-induced hemolysis is unknown. 

There were no differences in liver weights or histological damage to the liver in rats dermally treated with 

doses of up to 1,000 mg/kg/day naphthalene (6 hours/day, 5 days/week) for 13 weeks (Frantz et al. 1986). 

In addition, the levels of aspartate amino transferase, alanine amino transferase, urea nitrogen, and 

bilirubin were not elevated in the exposed rats as compared to the controls. 

Renal Effects. No studies were located that documented renal effects in humans after dermal 

exposure to naphthalene. 

There were no differences in kidney weights or histological damage to the liver in rats dermally treated 

with doses of up to 1,000 mg/kg/day naphthalene (6 hours/day, 5 days/week) for 13 weeks (Frantz et al. 

1986). In addition, the results of urinalysis conducted at 4 and 13 weeks on the treated rats were not 

different from the control results, indicating that there was no impairment of kidney function. 

Dermal Effects. No studies were located that documented dermal effects in humans after dermal 

exposure to naphthalene. 

A study in rabbits has shown that naphthalene is a mild dermal irritant, causing erythema and fissuring, 

when directly applied to the shaved, abraded, or nonabraded skin under a dressing; healing occurred 

within 6–7 days (Papciak and Mallory 1990; PRI 1985a). In rats that were dermally treated for 

6 hours/day, 5 days/week, for 13 weeks with 1,000 mg/kg/day naphthalene, there was an increased 

incidence of excoriated skin lesions and papules (Frantz et al. 1986). However, similar lesions were seen 

in the controls and lower dose group animals. At the high dose, naphthalene appeared to exacerbate the 

severity of the lesions. Acute and chronic exposures of animal skin to naphthalene appear to cause 

dermal irritation. 

Ocular Effects. Two case studies were reported in which humans experienced eye irritation and 

conjunctivitis as a result of naphthalene exposure (van der Hoeve 1906). In one case, a worker 

accidentally got naphthalene powder in his left eye. The exact amount was unknown, but was described 

by the worker as large. Despite immediate cleansing of the eye, the subject experienced conjunctivitis 

and pain shortly after exposure. Symptoms of irritation subsided, but then reappeared 6 weeks later. At 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 84 

3. HEALTH EFFECTS 

that time, the subject noticed decreased vision in his left eye. When examined by a doctor, the eye had 

retinal lesions (one fresh and others seemingly older); the entire retina appeared clouded. The subject's 

vision in the left eye was poorer than in the right. Five years earlier, vision was the same in both eyes. 

In the second case study, an adult male who worked in a storage area where naphthalene was used as a 

pesticide complained of ocular pain, conjunctivitis, and impaired vision (van der Hoeve 1906). Neither 

the duration nor the mode of exposure was described. The subject most likely was exposed to 

naphthalene vapors. When examined by a doctor, the subject was found to have retinal bleeding and the 

beginning of a cataract. 

Dermal and ocular contact with naphthalene vapors accompanied by inhalation may have contributed to 

the development of multiple lens opacities in 8 of 21 workers involved with a dye manufacturing process 

that used naphthalene as a raw material (Ghetti and Mariani 1956). Workers, who were employed at the 

plant for up to 5 years, melted naphthalene in open vats, resulting in high atmospheric vapor 

concentrations. 

Mild ocular irritation was observed in the nonrinsed eyes of rabbits after instillation of naphthalene at 

0.1 mg/eye (Papciak and Mallory 1990; PRI 1985b). Observed effects were reversible within 7 days after 

exposure. When the eyes were rinsed with water immediately after exposure, there were no signs of 

irritation (Papciak and Mallory 1990). Oral administration of naphthalene in rats resulted in cataract 

formation beginning at the posterior outer cortex, suggesting that this region is the most sensitive part of 

the lens (Kojima 1992). The lenses of pigmented Brown-Norway rats had changes, such as water cleft 

formation, during the first week that 10 mg/kg/day naphthalene was orally administered every other day 

(Murano et al. 1993). These rats were more sensitive to cataract formation than albino Sprague-Dawley 

rats, presumably because they more effectively metabolized naphthalene to the toxic compound 

naphthoquinone (Murano et al. 1993). 

3.2.3.3 Immunological and Lymphoreticular Effects 

No studies were located that documented immunological or lymphoreticular effects in humans after 

dermal exposure to naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. An enlarged spleen was 

noted in two human subjects dermally exposed to unspecified doses of naphthalene (Dawson et al. 1958; 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 85 

3. HEALTH EFFECTS 

Schafer 1951). However, spleen enlargement is a result of hemolysis rather than a direct effect of 

naphthalene on the spleen. 

In animals, dermal application of pure naphthalene (1,000 mg/kg) 1 time/week for 3 weeks did not result 

in delayed hypersensitivity reactions in guinea pigs (Papciak and Mallory 1990; PRI 1985c). 

No studies were located that documented immunological or lymphoreticular effects in animals after 

dermal exposure to 1-methylnaphthalene or 2-methylnaphthalene. 

A NOAEL for immunological/lymphoreticular effects following dermal exposure to naphthalene is 

recorded in Table 3-3. 

No studies were located that documented the following health effects in humans or animals after dermal 

exposure to naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene: 

3.2.3.4 Neurological Effects 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 

3.3 GENOTOXICITY 

No studies of genotoxic effects in humans exposed to naphthalene were located. 

Table 3-4 summarizes results for naphthalene and its metabolites in bacterial mutation assays; in vitro 

eukaryotic gene mutation, cytogenetic, or DNA damage assays; and in vivo eukaryotic gene mutation, 

cytogenetic, or DNA damage assays. 

Bacterial Gene Mutation Assays for Naphthalene. Naphthalene was not mutagenic in Salmonella 

typhimurium assays in the presence or absence of rat liver metabolic preparations (Bos et al. 1988; 

Connor et al. 1985; Florin et al. 1980; Gatehouse 1980; Godek et al. 1985; Kaden et al. 1979; McCann et 

al. 1975; Mortelmans et al. 1986; Nakamura et al. 1987; Narbonne et al. 1987; NTP 1992a; Sakai et al. 

1985). The metabolites, 1-naphthol and 1,4-naphthoquine, were not mutagenic in several S. typhimurium 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 86 

3. HEALTH EFFECTS 

a Table 3-4. Results of Genotoxicity Testing of Naphthalene or Metabolites

Dose/ HID or 

Assay Test system concentration LED Result Reference 

Bacterial gene mutation assays 

Reverse Salmonella 100 μg/plate 100 Negative McCann et al. 

mutation typhimurium ±S9 activation 1975 

TA1535, TA1537, 

TA98, TA100 

S. typhimurium 0.3–100 μg/plate 100 Negative Mortelmans et 

TA1535, TA1537, ±S9 activation al. 1986 

TA98, TA100 

S. typhimurium 0.3–100 μg/plate 100 Negative NTP 1992a 

TA1535, TA1537, ±S9 activation 

TA98, TA100 

S. typhimurium 10–200 μg/plate 100 Negative, toxic above Gatehouse 

TA1537, TA1538 ±S9 activation 100 μg/plate 1980 

S. typhimurium 10–50 μg/plate 50 Negative Bos et al. 1988 

TA98, TA100 ±S9 activation 

S. typhimurium 0.03– 3 Negative, toxic above Florin et al. 

TA1535, TA1537, 30 μmol/plate 3 μmol/plate 1980 

TA98, TA100 ±S9 activation 

S. typhimurium 250 μg/plate 250 Negative Sakai et al. 

TA1535, TA1537, ±S9 activation 1995 

TA98, TA100 

S. typhimurium 3–300 μg/plate 300 Negative, toxic above Godek 1985 

TA1535, TA1537, ±S9 activation 300 μg/plate 

TA1538, TA98, 

TA100 

S. typhimurium 1–2 mM 2 Negative Kaden et al. 

TM677 ±S9 activation 1979 

S. typhimurium 5–1,000 μg/plate 1,000 Negative Narbonne et al. 

TA98, TA1535 ±S9 activation 1987 

S. typhimurium 100– 2,000 Negative Conner et al. 

UTH8413, 2,000 μg/plate 1985 

UTH8414, TA98, ±S9 activation 

TA100 

S. typhimurium 1,000 μg/plate 1,000 Negative (1-naphthol) McCann et al. 

TA1535, TA1537, ±S9 activation 1975 

TA98, TA100 

S. typhimurium 5–1,000 μg/plate 1,000 Negative (1-naphthol) Narbonne et al. 

TA98, TA1535 ±S9 activation 1987 

S. typhimurium 250 μg/plate 250 Negative Sakai et al. 

TA1535, TA1537, ±S9 activation (1,4-naphthoquinone) 1995 

TA98, TA100 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 87 

3. HEALTH EFFECTS 

a Table 3-4. Results of Genotoxicity Testing of Naphthalene or Metabolites

Dose/ HID or 

Assay Test system concentration LED Result Reference 

Bacterial gene mutation assays (continued) 

S. typhimurium 0–100 nmol/plate 17.5 Positive (1,2-naphtho- Flowers-Geary 

TA97a, TA98, ±S9 activation quinone), et al. 1996 

TA100, TA104 1.8- to 3.4-fold 

increase without S9; 

+S9 results similar to 

-S9 results 

SOS response 	 S. typhimurium 83 μg/mL 83 Negative Nakamura et 

TA1535/p5K1002 ±S9 activation al. 1987 

(uMuC-lacZ) 

Escherichia coli 2,000 μg/plate 2,000 Negative Mamber et al. 
 

K12 inductest (λ ±S9 activation 1984 
 

lysogen GY5027; 
 

uvrB-, envA-) 
 

SOS E. coli 0.156– 10 Negative 	 Merschchromotest PQ37 (sfiA::lacZ 10.0 μg/assay Sundermann et 

fusion) ±S9 activation al. 1993 

Pol A- or Rec E. coli WP2/WP10 2,000 μg/mL 2,000 Negative Mamber et al. 

assay (uvrA-, recA-) ±S9 activation 1983 

E. coli WP2/WP67 	 Dose not NS Negative Mamber et al. 

(uvrA-, pol A-) 	 specified 1983 

±S9 activation 

Pol A- or Rec E. coli Dose not NS Negative Mamber et al. 

assay WP2/WP3478 specified 1983 

(pol A-) ±S9 activation 

Mutatox Vibrio fischeri Up to 0.203 Negative without S9 Arfsten et al. 

(reversion to M169 5,000 μg/tube 0.625 activation 1994 

luminescence) ±S9 activation Positive with S9 

activation 

In vitro eukaryotic gene mutation, cytogenetic, or DNA damage assays 

Mutation at Human B- 40 μg/mL 40 Negative Sasaki et al. 

hprt and tk loci lymphoblastoid cell 1997 

line MCL-5 

Human B- 40 μg/mL 40 Negative Sasaki et al. 

lymphoblastoid cell (1,4-naphthoquinone) 1997 

line MCL-5 

Chromosomal 	 Chinese hamster 15–75 μg/mL 30 Positive with NTP 1992a 

aberrations ovary cells ±S9 activation 75 	 S9 activation 

Negative without 

S9 activation 

Chromosomal Preimplantation 0.16 mM 0.16 Positive, more Gollahon et al. 

aberrations whole mouse ±S9 activation pronounced with 1990 [abstract 

embryos S9 activation only] 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 88 

3. HEALTH EFFECTS 

a Table 3-4. Results of Genotoxicity Testing of Naphthalene or Metabolites

Dose/ HID or 

Assay Test system concentration LED Result Reference 

In vitro eukaryotic gene mutation, cytogenetic, or DNA damage assays (continued) 

Sister Human 100 μM 100 Negative 	 Tingle et al. 

chromatid mononuclear ± human liver 1993; Wilson et 

exchange leukocytes microsomes al. 1995 

Sister Human 0–100 μM 10 Positive (1,2- and Wilson et al. 

chromatid mononuclear ± human liver 1,4-naphthoquinone) 1996 

exchange leukocytes microsomes Negative 

(naphthalene 

1,2-epoxide) 

Sister Chinese hamster 9–90 μg/mL 27 Positive with S9 in the NTP 1992a 

chromatid ovary cells ±S9 activation second of two trials 

exchange and without S9 in both 

trials 

Alkaline elution Rat hepatocytes 3 mM, 3-hour 3 mM 	 Negative for Sina et al. 1983 

(in vitro) exposure 	 increased incidence 

of DNA single-strand 

breaks 

Unscheduled Rat primary 0.16– 16 Negative, toxic above Barfknecht et 

DNA synthesis hepatocytes 5,000 μg/mL 16 μg/mL al. 1985 

(in vitro) 	 Rat primary 0.5–1,000 nM/mL 1,000 Negative (1-naphthol, Probst et al. 

hepatocytes 2-naphthol) 1981 

Cell Fischer rat embryo 0.1, 0.5 μg/mL 0.5 Negative Freeman et al. 

transformation cells (F1706P96) 1973 

Syrian baby 0.08–250 μg/mL 250 Negative Purchase et al. 
 

hamster kidney +S9 1978 
 

cells (BHK-21C13) 
 

Mouse (BALB/c) 0.001– 0.1 Negative, cytotoxic Tonelli et al. 
 

whole mammary 1.0 μg/gland above 0.1 μg/gland 1979 
 

gland cultures
 

Mouse BALB/c 3T3 15–150 μg/mL 150 Negative, toxic at Rundell et al. 
 

cell culture highest dose 1983 
 

Human diploid 0.08–250 μg/mL 250 Negative Purchase et al. 
 

fibroblasts +S9 1978 
 

(WI-38)
 

In vivo eukaryotic gene mutation, cytogenetic, or DNA damage assays 

Somatic Drosophila 1, 5, 10 mM 5 Positive, loss of Delgadomutation, melanogaster (feeding larvae) heterozygosity of two Rodriguez et al. 

recombination recessive wing genes 1995 

(about 2-fold increase 

in number of wing 

spots) 

Micronuclei Male ICR Swiss 50, 250, and 500 Negative Harper et al. 

induction mice: 500 mg/kg 1984 

bone marrow cells gavage 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 89 

3. HEALTH EFFECTS 

a Table 3-4. Results of Genotoxicity Testing of Naphthalene or Metabolites

Dose/ HID or 

Assay Test system concentration LED Result Reference

In vivo eukaryotic gene mutation, cytogenetic, or DNA damage assays (continued) 

Male and female 250 mg/kg 250 Negative Sorg 1985 

CD-1 mice: intraperitoneal 

bone marrow cells 

Micronuclei Salamander larvae 0.125–0.5 ppm in 0.25 Positive at 0.5 ppm, Djomo et al. 

induction (Pleurodeles waltl): the tank water weakly positive at 1995 

erythrocytes 0.25 ppm 

Alkaline elution DNA from 359 mg/kg oral 359 Negative for DNA Kitchin et al. 

(in vivo) hepatocytes of single-strand breaks 1992, 1994 

female rats given 

single oral doses 

Unscheduled Hepatocytes from 600, 1,000, and 1,600 Negative RTC 1999 

DNA synthesis rats given single 1,600 mg/kg 

(in vivo) oral doses gavage 

DNA DNA fragmentation 0, 3, 32, and 32 Positive (1.0- to Bagchi et al. 

fragmentation in liver or brain 158 mg/kg 1.5-fold and 1.8- to 2002 

tissue from mice (0.01, 0.1, 0.5 of 2.2-fold increase in 

given single doses LD50=316 mg/kg) DNA fragmentation at 

32 and 158 mg/kg, 

respectively) 

DNA DNA fragmentation 0, and 110 mg/kg 110 Positive (1.9- to Bagchi et al. 

fragmentation in liver or brain in corn oil 2.5-fold maximal 1998a 

tissue from rats increases in DNA 

given daily doses fragmentation in brain 

for up to 120 days and liver tissue) 

DNA DNA fragmentation 0, 3, 32, and 158 Positive (1.8- to Bagchi et al. 

fragmentation in liver or brain 158 mg/kg (0.01, (std) 3.9-fold increases in 2000 

tissue from p53- 0.1, and 0.5 of 3 DNA fragmentation in 

deficient and LD50=316 mg/kg) (-p53) brain and liver tissue; 

standard mice p53-deficient (tumor 

given single oral suppressor gene) 

doses strain was more 

sensitive 

Neoplastic F344 partially 100 mg/kg 100 Negative for gamma- Tsuda et al. 

transformation hepatectomized gavage (in corn glutamyl trans­ 1980 

(in vivo) rats (sex not oil) peptidase foci 

specified) 

a

Metabolites are noted in result column. 

DNA = dioxyribonucleic acid; HID = highest ineffective dose for negative tests; LED = lowest effective dose for 

positive tests; NS = not specified; SOS = an emergency system to repair single strand DNA breaks; std = standard 

deviation 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 90 

3. HEALTH EFFECTS 

strains in the presence or absence of metabolic activation (McCann et al. 1975; Narbonne et al. 1987; 

Sakai et al. 1985). Naphthalene was not mutagenic, with or without metabolic activation, in the Pol A- or 

Rec assays in several Escherichia coli strains (Mamber et al. 1983). Naphthalene did not damage DNA 

(as assayed by the induction of the SOS-repair system) in E. coli PQ37 (Mersch-Sundermann et al. 1993), 

in E. coli K12 (Mamber et al. 1984), or in S. typhimurium TA1535/p5K1002 (Nakamura et al. 1987). 

1,2-Naphthoquinone induced reverse mutations in several S. typhimurium strains without a metabolic 

activation system (Flowers-Geary et al. 1996), and naphthalene, in the presence of rat liver metabolic 

activation, induced reverse mutations in the marine bacterium Vibrio fischeri (Arfsten et al. 1994). 

In Vitro Eukaryotic Gene Mutation, Cytogenetic, or DNA Damage Assays for Naphthalene. In vitro 

eukaryotic gene mutation assays are restricted to a single report that naphthalene and 1,4-naphthoquinone 

(1,2-naphthoquinone was not tested) did not induce mutations at the hprt and tk loci in human 

lymphoblastoid cells (Sasaki et al. 1997). However, naphthalene (in the presence of rat liver metabolic 

activation) induced chromosomal aberrations in Chinese hamster ovary cells (NTP 1992a) and 

preimplantation whole mouse embryos (Gollahon et al. 1990). Naphthalene also induced sister chromatid 

exchanges (in the presence or absence of rat liver metabolic activation) in Chinese hamster ovary cells 

(NTP 1992a), but did not do so in human mononuclear leukocytes in the presence or absence of human 

liver microsomes (Tingle et al. 1993; Wilson et al. 1995). In contrast, 1,2-naphthoquinone and 

1,4-naphthoquinone (but not 1,2-naphthalene oxide), in the absence of metabolic activation, induced sister 

chromatid exchanges in human leukocytes at concentrations (10 and about 50 μM) that depleted cellular 

glutathione levels and induced about 35-45% cell death (Wilson et al. 1996). Naphthalene did not induce 

cell transformations in several mammalian cell types (see Table 3-4) or DNA single-strand breaks (Sina et 

al. 1983) or unscheduled DNA synthesis (Barfknecht et al. 1985; Probst et al. 1981) in rat hepatocytes. 

In cell-free test systems (not included in Table 3-4), 1,2-naphthoquinone formed N7 adducts with 

deoxyguanosine (McCoull et al. 1999) and caused DNA strand scission in the presence of NADPH and 

copper via reactive oxygen species from a Cu(II)/Cu(I) oxidation/reduction cycle (Flowers et al. 1997). 

In Vivo Eukaryotic Gene Mutation, Cytogenetic, or DNA Damage Assays for Naphthalene. 

Naphthalene was mutagenic in Drosophila melanogaster (Delgado-Rodriquez et al. 1995), but no in vivo 

mutagenicity tests of naphthalene or its metabolites are available in mammalian systems (Table 3-4). 

Naphthalene induced micronuclei in erythrocytes of salamander (Pleurodeles waltl) larvae exposed to 

concentrations of 0.5 mM, but did not induce micronuclei in bone marrow of mice given single oral doses 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 91 

3. HEALTH EFFECTS 

(50, 250, or 500 mg/kg) or intraperitoneal doses (250 mg/kg) (Harper et al. 1984; Sorg 1985). 

Naphthalene did not cause increased single-stranded DNA breaks in hepatocytes of rats given single oral 

doses of 359 mg/kg (Kitchin et al. 1992, 1994), unscheduled DNA synthesis in hepatocytes from rats 

given single doses as high as 1,600 mg/kg (RTC 1999), or transformation foci (γ-glutamyl transpeptidasepositive) in livers of F344 partially hepatectomized rats given single 100 mg/kg doses, but did cause DNA 

fragmentation in brain and liver tissue from mice given single doses of 32 or 158 mg/kg (Bagchi et al. 

2000, 2002) and rats exposed to 110 mg/kg/day for up to 120 days (Bagchi et al. 1998a). In the DNA 

fragmentation assays, the effect was accompanied by increased lipid peroxidation in the same tissues. It 

is unclear whether the apparent DNA damage in these assays was due to direct effects of naphthalene 

metabolites or reactive oxygen species or was secondary to cell death induced at an extranuclear site. 

No studies were located that examined possible genotoxic effects of naphthalene or its metabolites in 

sensitive target tissues of naphthalene in rodents (lung and nasal epithelial tissue). 

Genotoxicity Assays for 1-Methylnaphthalene and 2-Methylnaphthalene. No studies were located that 

documented genotoxic effects of 1-methylnaphthalene or 2-methylnaphthalene in humans or animals by 

any route of exposure. Data are limited to one in vitro study where 1-methylnaphthalene and 2-methylnaphthalene failed to induce chromosomal aberrations or sister chromatid exchanges in human peripheral 

lymphocytes (Kulka et al. 1988). In an in vitro microbial assay employing S. typhimurium, mutagenic 

activity was not detected with either compound, with either the presence or absence of microsomal 

activation (Florin et al. 1980). These studies are presented in Table 3-5. 

3.4 TOXICOKINETICS 

Little information is available that documented the toxicokinetics of naphthalene in humans by any route 

of exposure. No information on the toxicokinetics of 1-methylnaphthalene or 2-methylnaphthalene in 

humans was located. The available animal data pertaining to naphthalene are described in the following 

sections. The relevance of this information to the toxicokinetics of naphthalene in exposed humans, 

however, is not known. 

No toxicokinetic data on 1-methylnaphthalene-exposed animals were located. Animal data pertaining to 

2-methylnaphthalene were limited. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 92 

3. HEALTH EFFECTS 

Table 3-5. Genotoxicity of 1-Methylnaphthalene and 

2-Methylnaphthalene In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

1-Methylnaphthalene 

 Prokaryotic organisms:

 Salmonella typhimurium 

(TA98, TA100, TA1535, 

TA1537) 

Gene mutation – – Florin et al. 1980 

 Mammalian cells: 

Human lymphocytes Chromosomal aberration, 

sister chromatid exchange 

– – Kulka et al. 1988 

2-Methylnaphthalene 

 Prokaryotic organisms: 

S. typhimurium (TA98, Gene mutation 

TA100, TA1535, TA1537) 

– – Florin et al. 1980 

 Mammalian cells: 

Human lymphocytes Chromosomal aberration, 

sister chromatid exchange 

– – Kulka et al. 1988 

– = negative result 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 93 

3. HEALTH EFFECTS 

3.4.1 Absorption 

Based on the presence of adverse effects following exposure, humans and animals can absorb naphthalene 

by pulmonary, gastrointestinal, and cutaneous routes. However, the rate and extent of naphthalene 

absorption are unknown in many instances. 

3.4.1.1 Inhalation Exposure 

Clinical reports suggest that prolonged exposure to naphthalene vapors can cause adverse health effects in 

humans (Harden and Baetjer 1978; Linick 1983; Valaes et al. 1963). Unfortunately, the rate and extent of 

naphthalene absorption were not determined in these studies. Presumably naphthalene moves across the 

alveolar membrane by passive diffusion through the lipophilic matrix. 

No animal data that documented the absorption of naphthalene after inhalation were located. The only 

data observed in animal studies involved localized effects in the lungs and nasal passages. Thus, it is not 

possible to conclude that they were the consequence of absorbed naphthalene. However, absorption can 

be presumed to occur based on the human data. 

No information has been located that documented the absorption of 1-methylnaphthalene or 2-methylnaphthalene in humans or animals after inhalation exposure. 

3.4.1.2 Oral Exposure 

Several case reports indicate that naphthalene ingested by humans can be absorbed in quantities sufficient 

to elicit toxicity (Bregman 1954; Chusid and Fried 1955; Gidron and Leurer 1956; Gupta et al. 1979; 

Haggerty 1956; Kurz 1987; MacGregor 1954; Mackell et al. 1951; Ojwang et al. 1985; Santhanakrishnan 

et al. 1973; Shannon and Buchanan 1982; Zuelzer and Apt 1949). However, no studies have been located 

that report the rate or extent of absorption. Absorption of naphthalene presumably occurs by passive 

diffusion through the lipophilic matrix of the intestinal membrane. 

In one patient who died as a result of naphthalene ingestion, 25 mothballs were found in the stomach 

5 days after her death (Kurz 1987). A single naphthalene mothball reportedly weighs between 0.5 and 5 g 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 94 

3. HEALTH EFFECTS 

depending on its size (Ambre et al. 1986; Siegel and Wason 1986). The gastric contents of a person who 

mistakenly ingested naphthalene flakes still smelled strongly of naphthalene at least 2 days following 

ingestion (Ojwang et al. 1985). These findings suggest that dissolved naphthalene is transported slowly 

into the intestines. Uptake from the intestines is governed by the partition coefficient between the 

materials in the intestinal lumen and the membrane lipids. Ingestion of mothballs or other forms of 

particulate naphthalene will lead to continued absorption over a period of several days as the solid 

dissolves. Unfortunately, none of the human data permit a quantitative evaluation of absorption 

coefficients or rates. 

No information that documented the absorption of naphthalene after oral administration to animals has 

been located. The occurrence of ocular effects in rats and rabbits indicates that gastrointestinal absorption 

does occur (Kojima 1992; Murano et al. 1993; Srivastava and Nath 1969). 

No information was located that documented the absorption of 1-methylnaphthalene in humans or 

animals after oral administration. Systemic effects observed after the ingestion of 1-methylnaphthalene 

demonstrate that intestinal absorption does occur in rats (Murano et al. 1993). 

No information has been located that documented absorption in humans after oral exposure to 2-methylnaphthalene. Small doses of 2-methylnaphthalene appear to be rapidly absorbed from the gastrointestinal 

tract in guinea pigs. At least 80% of a 10 mg/kg oral dose of 2-methylnaphthalene was absorbed within 

24 hours based on recovery of the radiolabel in the urine (Teshima et al. 1983). 

3.4.1.3 Dermal Exposure 

Several cases of naphthalene toxicity in neonates have been reported in which the proposed route of 

exposure was dermal (Dawson et al. 1958; Schafer 1951). Each case involved the use of diapers which 

had been stored in contact with naphthalene (mothballs or naphthalene flakes). The authors proposed that 

the naphthalene was absorbed through the skin, causing hemolytic anemia. It was suggested that this 

absorption may have been enhanced by the presence of oils which had been applied to the babies' skin 

(Schafer 1951). Inhalation of vapors from the treated diapers probably contributed to the total exposure. 

14C-Naphthalene was rapidly absorbed when the neat material (43 μg) was applied for a 48-hour period 

under a sealed glass cap to shaved 13-cm2

 areas of rat skin. Half of the sample (3.3 μg/cm3) was absorbed 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 95 

3. HEALTH EFFECTS 

in 2.1 hours (Turkall et al. 1994). When the naphthalene was mixed with either a sandy soil or a clay soil 

prior to contact with the skin, the presence of the soil slowed the absorption (Turkall et al. 1994). The 

absorption half-time from the clay and sandy soil samples were 2.8 and 4.6 hours, respectively. The rate 

of absorption did not influence the total amount of naphthalene absorbed in 48 hours since the areas under 

the plasma concentration curve did not differ significantly with any of the three exposure scenarios (0.42– 

0.63%/mL hour). The authors proposed that naphthalene was absorbed more slowly from the sandy soil 

than the clay soil because the sandy soil had a higher organic carbon content (Turkall et al. 1994). The 

sandy soil contained 4.4% organic matter and the clay soil 1.6% organic matter. 

No studies were located that examined the absorption of 1-methylnaphthalene or 2-methylnaphthalene in 

humans or animals after dermal administration. 

3.4.2 Distribution 

There are limited data concerning the distribution of naphthalene in human tissues. Naphthalene was 

present in 40% of the adipose tissue samples that were analyzed as part of the National Human Adipose 

Tissue Survey (EPA 1986g). The maximum concentration observed was 63 ng/g. Naphthalene was also 

detected in human milk samples (concentration not reported) (Pellizzari et al. 1982). The sources of 

naphthalene in these milk and body fat samples are not known. 

Information is available for the distribution of naphthalene in swine after oral exposure, the distribution of 

naphthalene in rats after dermal exposure, and the distribution of 2-methylnaphthalene in guinea pigs after 

oral exposure. No data were located for the inhalation exposure routes and no data were identified on the 

distribution of 1-methylnaphthalene by any route of exposure. 

3.4.2.1 Inhalation Exposure 

No studies were located that examined the distribution of naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene in humans or animals after inhalation exposure. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 96 

3. HEALTH EFFECTS 

3.4.2.2 Oral Exposure 

Naphthalene can cross the human placenta in concentrations high enough to cause red cell hemolysis and 

lead to anemia in newborn infants of mothers who consumed naphthalene during pregnancy (Anziulewicz 

et al. 1959; Zinkham and Childs 1957, 1958). 

The distribution of naphthalene and its metabolites in young pigs given a single dose of 0.123 mg/kg 

(4.8 Ci/kg) 14C-labeled naphthalene was monitored at 24 and 72 hours (Eisele 1985). At 24 hours, the 

highest percentage of the label (3.48"2.16% dose/mg tissue) was in the adipose tissue. The kidneys had 

the next highest concentration of label (0.96% dose/mg tissue), followed by the liver (0.26"0.06% 

dose/mg tissue) and lungs (0.16% dose/mg tissue). The heart contained 0.09"0.04% dose/mg tissue and 

the spleen contained 0.07"0.01% dose/mg tissue. At 72 hours, the amount of label in the fat had fallen to 

2.18"1.16% dose/mg tissue, that in the liver to 0.34"0.24% dose/mg tissue, and the kidneys and lungs 

contained the same concentration (0.26% dose/mg tissue). 

Pigs were also given oral doses of 0.006 mg/kg/day (0.22 Ci/kg/day) 14C-labeled naphthalene for 31 days 

(Eisele 1985). With repeated administration of the radiolabel, the tissue distribution differed considerably 

from that observed with a single dose of the compound. The highest concentration of label was in the 

lungs (0.15% dose/mg tissue), followed by the liver and heart (0.11% dose/mg tissue). There was very 

little label in the fat tissue (0.03% dose/mg tissue). The spleen had 0.09"0.05% dose/mg tissue and the 

kidney had 0.09% dose/mg tissue. 

In one dairy cow, naphthalene distributed to milk with both single and repeated doses of 14C-labeled 

naphthalene. The label was distributed between the milk and the milk fat (Eisele 1985). When the cow 

was given naphthalene for a 31-day period, the amount of label found in the milk remained relatively 

constant throughout the exposure period. The amount in the milk fat was lower for the first 7 days than it 

was for the remainder of the exposure. 

The tissue distribution of 2-methylnaphthalene was measured in guinea pigs 3, 6, 24, and 48 hours after 

oral administration of tritium-labeled 2-methylnaphthalene (10 mg/kg; 59 μCi/kg) (Teshima et al. 1983). 

The highest concentration of label was present in the gallbladder with 20.17 μg at 3 hours and 15.72 μg at 

6 hours. (All concentrations are expressed in μg equivalents of 3

H/g wet tissue.) At 24 hours, the value 

fell to 0.43 μg and at 48 hours, to 0.04 μg. The presence of label in the gallbladder presumably reflects 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 97 

3. HEALTH EFFECTS 

the excretion of hepatic metabolites in the bile. The values for the kidney were 5.64 μg at 3 hours, 

7.62 μg at 6 hours, 0.29 μg at 24 hours, and 0.09 μg at 48 hours. 

Radiolabelled compound was detected in the liver immediately after exposure (Teshima et al. 1983). 

When converted to units of mass, hepatic concentrations were 1.71 μg at 3 hours and 2.66 μg at 6 hours, 

falling to 0.18 μg at 24 hours. Lung concentrations were similar to those for blood at all time points. The 

amount in blood at 3 hours was 0.75 μg and that for the lungs was 0.69 μg; at 6 hours, the blood had a 

concentration of 0.71 μg and the lung had 0.76 μg. The half-life of 2-methylnaphthalene in the blood was 

10.4 hours. The decay of naphthalene in the other tissues examined was described as biphasic. 

3.4.2.3 Dermal Exposure 

No information was located that documented the distribution of naphthalene, 1-methylnaphthalene, or 

2-methylnaphthalene in humans after dermal exposure. 

In rats, radiolabel from naphthalene distributed to the ileum, duodenum, and kidney (0.01–0.02% of 

initial dose) when tissues were analyzed 48 hours after naphthalene contact with the skin (Turkall et al. 

1994). The largest concentration was found at the site of application (0.56% of initial dose). A total of 

20 tissues were evaluated; the percentage of label in all other tissues was minimal. 

No information that documented the distribution of 1-methylnaphthalene or 2-methylnaphthalene in 

dermally exposed animals was located. 

3.4.2.4 Other Routes of Exposure 

After intraperitoneal administration in mice, 14C-labeled 2-methylnaphthalene distribution was measured 

in the fat, kidney, liver, and lung for 24 hours (Griffin et al. 1982). The amount of label in the fat peaked 

3 hours after exposure and remained higher than the amount of label in other tissues at 8 hours. The liver, 

kidney, and lung followed the fat in order of decreasing concentration. The maximum concentration in 

the fat was 13 nmol equivalents/mg wet weight. The maximum value for the liver was 3.5 nmol 

equivalents/mg wet weight at 1 hour. Maximum values were about 1.75 nmol equivalents/mg wet weight 

for the kidneys at 2 hours and 0.8 nmol equivalents/mg wet weight for the lungs at 4 hours. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 98 

3. HEALTH EFFECTS 

3.4.3 Metabolism 

The metabolism of naphthalene in mammalian systems has been studied extensively and is depicted in 

Figure 3-3. The metabolic scheme in Figure 3-3 illustrates that there are multiple reactive metabolites 

formed from naphthalene: 1,2-naphthalene oxide, 1,2-naphthoquinone, 1,4-naphthoquinone, and 

1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydronaphthalene. This section presents an overview of the 

metabolic scheme and the evidence for the involvement of the 1,2-epoxide and the naphthoquinones in 

naphthalene toxicity. The fourth metabolite listed above is expected to be reactive, but its potential role 

in naphthalene toxicity has not been investigated. A recent review of the metabolism and bioactivation of 

naphthalene has been published by Buckpitt et al. (2002). 

The first step in naphthalene metabolism is catalyzed by cytochrome P-450 (CYP) oxygenases and 

produces a reactive electrophilic arene epoxide intermediate, 1,2-naphthalene oxide. In mammalian 

systems, several CYP isozymes have been demonstrated to metabolize naphthalene, including 1A1, 1A2, 

1B1, 3A7, 3A5 (Juchau et al. 1998), 2E1 (Wilson et al. 1996), 2F2 (Buckpitt et al. 1995; Shultz et al. 

1999), and 2B4 (Van Winkle et al. 1996). The epoxide can spontaneously rearrange to form naphthols 

(predominantly 1-naphthol) and subsequently conjugate with glucuronic acid or sulfate to form 

conjugates, which are excreted in urine. 

Alternatively, the 1,2-epoxide can react with tissue macromolecules. This reaction is thought to be 

involved in several aspects of naphthalene toxicity, especially injury to Clara cells (ciliated cells in the 

epithelium of proximal and distal airways of the lung) from acute exposure to naphthalene (Buckpitt et al. 

2002; Zheng et al. 1997). In pH 7.4 buffer, the epoxide has been shown to have a half-life of 

approximately 2–3 minutes, which is extended by the presence of albumins to about 11 minutes (Buckpitt 

et al. 2002; Kanekal et al. 1991). Mice are markedly more susceptible than rats to acute naphthaleneinduced Clara cell injury (Buckpitt et al. 1992; West et al. 2001). The susceptibility difference apparently 

extends to chronic exposure scenarios. Mice exposed by inhalation to 10 or 30 ppm naphthalene for 

2 years showed lung inflammation, but rats exposed to concentrations up to 60 ppm showed no lung 

inflammation (Abdo et al. 2001; NTP 1992a, 2000). The species difference in lung susceptibility has 

been correlated with higher rates of formation of a specific enantiomeric epoxide (1R,2S-naphthalene 

oxide) in lung microsomes and isolated dissected airways of mice compared with rats (Buckpitt et al. 

1992, 1995). Rat, hamster, and monkey lung microsomes preferentially formed the 1S,2R-naphthalene 

oxide enantiomer and showed lower rates of formation of epoxides than mouse lung microsomes 

(Buckpitt et al. 1992). Microsomes from human lymphoblastoid cells expressing recombinant human 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 99 

3. HEALTH EFFECTS 

Figure 3-3. Scheme for Naphthalene Metabolism and Formation of Multiple 

Reactive Metabolites, That May Be Involved in Naphthalene Toxicity* 

glucuronides and sulfates 

(eliminated in the urine) 

OH 

OH 

O 

? 

CYP 

2-naphthol 1-naphthol O 

1,4-naphthoquinone 

toxicity 

? 

O 

spontaneous 

OH 

epoxide 

OH
 

CYP
 

hydrolase 

napthalene naphthalene 1,2-oxide 1,2-dihydroxy-1,2-dihydronaphthalene 

dihydrodiol glutathione GSH dehydrogenase S-transferase 

OH O 

SG O 

1-hydroxy-2-glutathionyl­ 1,2-naphthoquinone 

1,2-dihydronaphthalene ? 

toxicity 

OH 

OH 

mercapturic acids 

(eliminated in the urine) 

O 

1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydronaphthalene 

dihydroxydimethylthio and ? trihydroxymethylthio metabolites,
 

trihydroxymercapturic acid
 

(eliminated in the urine)
 

toxicity 

CYP 

toxicity
 

CYP = cytochrome P450 enzyme(s); GSH = reduced glutathione; SG = glutathione 

*Adapted from Buckpitt et al. (2002) and Waidyanatha et al. (2002) 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 100 

3. HEALTH EFFECTS 

CYP2F1 also showed preferential formation of the 1S,2R-naphthalene oxide enantiomer, providing some 

evidence that human transformation of naphthalene to reactive epoxides in lung tissue may be more like 

rats than mice (Lanza et al. 1999). 

In contrast to the lung, species differences in susceptibility at another sensitive target of naphthalene, the 

olfactory and respiratory epithelia of the nose, do not correlate with differences in rates of transformation 

to 1,2-epoxide derivatives in extracts of olfactory tissue (Buckpitt et al. 1992; Plopper et al. 1992a). 

Metabolic rates (units of nmol naphthalene converted to epoxide derivatives/minute/mg protein) in 

olfactory tissue extracts showed the following order: mouse (87.1) > rat (43.5) > hamster (3.9). However, 

rats were more susceptible to naphthalene-induced cell injury than mice or hamsters. The lowest single 

intraperitoneal doses producing necrosis and exfoliation in olfactory epithelium were 200 mg/kg in rats 

and 400 mg/kg in mice and hamsters. These observations suggest that the reasons for species differences 

in susceptibility to naphthalene toxicity are complex and do not solely involve the formation of the 

1,2-epoxide metabolites. Although CYP monooxygenases, which might be involved in naphthalene 

metabolism and bioactivation, have been demonstrated to exist in nasal respiratory epithelial and 

olfactory epithelial tissue from rodents and humans (Thornton-Manning and Dahl 1997), studies designed 

to specifically characterize metabolism of naphthalene in nasal tissue are restricted to those by Buckpitt et 

al. (1992) and Plopper et al. (1992a). 

In addition to being converted to the naphthols, the 1,2-epoxide can be conjugated with glutathione via 

glutathione-S-transferase catalysis. Figure 3-3 shows one such conjugate, 1-hydroxy-2-glutathionyl-1,2-dihydronaphthalene. The glutathionyl conjugates are converted in several steps to mercapturic 

acids, which are excreted in the urine. The conjugation of the epoxide is thought of as a detoxication 

mechanism, as evidenced by studies showing that glutathione depletion increased the degree of acute 

naphthalene-induced Clara cell injury in mice (Warren et al. 1982; West et al. 2000a). In addition, 

elevated activities of γ-glutamylcysteine synthetase, the enzyme catalyzing the rate limiting step in 

glutathione synthesis, were observed in dissected airways from mice that developed tolerance to acute 

naphthalene Clara cell cytotoxicity (West et al. 2000a). 

The 1,2-epoxide can also be enzymatically hydrated by epoxide hydrolase to form 1,2-dihydroxy-1,2-dihydronaphthalene (Figure 3-3). This 1,2-dihydrodiol derivative was the major stable metabolite of 

naphthalene produced by human liver microsomes, whereas the major stable metabolite formed by mouse 

liver microsomes was 1-naphthol (Tingle et al. 1993). In the presence of an inhibitor of epoxide 

hydrolase (trichloropropene oxide), the major stable metabolite with human liver microsomes was 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 101 

3. HEALTH EFFECTS 

1-naphthol. How this species difference in liver metabolism may relate to the human relevance of 

toxicity of inhaled naphthalene in sensitive target tissues in the nose and lung of mice is unknown. 

The 1,2-dihydrodiol can be catalytically transformed by dihydrodiol dehydrogenase to 1,2-naphthoquinone (also known as naphthalene-1,2-dione). 1,2-Naphthoquinone is both reactive itself and capable 

of producing reactive oxygen species through redox cycling (Flowers et al. 1997) and has been shown to 

be mutagenic in several strains of S. typhimurium (Flowers-Geary et al. 1996). In isolated Clara cells 

incubated with 0.5 mM naphthalene, 1,2-naphthoquinone was the major naphthalene derivative covalently 

bound to proteins, although covalent binding with the 1,2-epoxide was also observed (Zheng et al. 1997). 

The formation of the other naphthoquinone, 1,4-naphthoquinone, from 1-naphthol, presumably via a CYP 

monooxygenase, has been proposed based on the finding that, following incubations of liver microsomes 

with 1-naphthol, ethylene diamine, a compound that reacts readily with 1,2-naphthoquinone, did not trap 

reactive metabolites (D’Arcy Doherty et al. 1984). Cysteinyl adducts of both 1,2-naphthoquinone and 

1,4-naphthoquinone (and of 1,2-naphthalene oxide) with hemoglobin and albumin have been detected in 

blood of rats given single oral doses of naphthalene ranging from 100 to 800 mg/kg (Troester et al. 2002; 

Waidyanatha et al. 2002). Levels of 1,2-naphthalene oxide adducts were greater than levels of 

1,2-naphthoquinone adducts, which were greater than levels of 1,4-naphthoquinone adducts (Troester et 

al. 2002; Waidyanatha et al. 2002). In in vitro studies with whole human blood samples, 1,2- or 

1,4-naphthoquinone induced increased frequencies of sister chromatid exchanges at concentrations 

≥10 μM, whereas naphthalene 1,2-epoxide did not at concentrations up to 100 μM (Wilson et al. 1996). 

Similarly, incubation of human mononuclear leukocytes with 1,2-naphthoquinone or 1,4-naphthoquinone 

caused significant depletion of cellular glutathione levels and significant cytotoxicity at concentrations 

between 1 and 100 μM, whereas naphthalene 1,2-epoxide did not display these toxic actions in this 

concentration range (Wilson et al. 1996). 

1,2-Naphthoquinone formed in lens tissue is thought to be involved in naphthalene-induced cataracts in 

rats and rabbits. The enzyme involved in the transformation of the 1,2-dihydrodiol to 1,2-naphthoquinone 

in lens tissue is thought to be aldose reductase (this enzyme is not specified in Figure 3-3). Support for 

this hypothesis includes findings that aldose reductase inhibitors prevent cataract formation in 

naphthalene-fed rats (Tao et al. 1991; Xu et al. 1992a), dihydrodiol dehydrogenase is apparently absent in 

rat lens (Greene et al. 2000), and aldose reductase appears to be the only enzyme in rat lens that can 

transform 1,2-dihydroxy-1,2-dihydronaphthalene to 1,2-naphthoquinone (Sugiyama et al. 1999). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 102 

3. HEALTH EFFECTS 

Support for the in vivo formation of another potentially reactive metabolite, 1,2-dihydroxy-3,4-epoxy1,2,3,4-tetrahydronaphthalene, comes from the identification of several urinary metabolites, including a 

number of trihydroxytetrahydromethylthio derivatives (Horning et al. 1980) and a trihydroxytetrahydromercapturic acid (Pakenham et al. 2002). These urinary metabolites, however, are minor, and the 

importance of their common proposed precursor in naphthalene toxicity is unstudied to date. Figure 3-3 

proposes an oxidative transformation of dihydrodiol derivative to the tetrahydrodiol epoxide derivative 

via CYP catalysis. 

The methyl substituent of 1-methylnaphthalene and 2-methylnaphthalene presents the opportunity for side 

chain oxidation reactions in addition to the ring oxidation, which is the sole initial step in naphthalene 

metabolism. A proposed metabolic scheme for 2-methylnaphthalene is shown in Figure 3-4. Oxidation 

at the methyl group (the predominant path), or at several competitive positions on the rings, is catalyzed 

by CYP monooxygenases (Figure 3-4). No information was located that documented the metabolism of 

1-methylnaphthalene. It may be similar to that for 2-methylnaphthalene with oxidation of the side chain 

and the ring. 

In rats and mice, about 50–80% of 2-methylnaphthalene is oxidized at the 2-methyl group to produce 

2-hydroxymethylnaphthalene (Breger et al. 1983; Teshima et al. 1983). This 2-hydroxymethylnaphthalene metabolite is further oxidized to 2-naphthoic acid (Grimes and Young 1956; Melancon et al. 

1982; Teshima et al. 1983), and this step proceeds either directly or through the intermediate, 

2-naphthaldehyde (Figure 3-4). Detection of 2-naphthaldehyde has only been reported following in vitro 

incubation of 2-methylnaphthalene with recombinant mouse CYP2F2 (Shultz et al. 2001). 2-Naphthoic 

acid may be conjugated with either glycine or glucuronic acid (Figure 3-4). The glycine conjugate of 

2-naphthoic acid forms 2-naphthuric acid, which is the most prevalent urinary metabolite of 2-methylnaphthalene detected in exposed animals (Grimes and Young 1956; Melancon et al. 1982; Teshima et al. 

1983). 

Ring epoxidation at the 7,8-, 3,4-, or 5,6- positions occurs in approximately 15–20% of 2-methylnaphthalene (Breger et al. 1983; Melancon et al. 1985). These epoxidation reactions are catalyzed by 

CYP isozymes that include CYP1A and CYP1B. These epoxides are proposed intermediates based on 

experimentally-observed metabolites, but have not been individually isolated (Figure 3-4). These 

epoxides may be further oxidized by epoxide hydrolase to produce dihydrodiols (the 7,8-dihydrodiol, 

3,4-dihydrodiol, or 5,6-dihydrodiol of 2-methylnaphthalene) or may be conjugated with glutathione 

(Griffin et al. 1982; Melancon et al. 1985) by glutathione S-transferase catalysis or can proceed 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 103 

3. HEALTH EFFECTS 

Figure 3-4. Metabolism of 2-Methylnaphthalene* 

HO 

HO 

CH3 

O 

OH 

2-naphthaldehyde** 

CYP 

O 

OH 

N 

H 

O 

OH 

O 

2-naphthuric acid 

CH3 glucuronidation 

2-hydroxymethylnapthalene 2-naphthoic acid 

OH 

i 

EH 

3,4-d hydrodiol 

CH3 

OH
 

5,6-dihydrodiol
 CYP OH 

CH3 CH CH3 3 CYP 

CYP 

EH 

O 2-methylnaphthalene O 5,6-epoxide 3,4-epoxide 

CH CH3 CH3 3 CH3 

GS SG OH

SG OH OH SG 

hydroxy glutathionyl dihydro-2-methylnaphthalenes** hydroxy glutathionyl dihydro-2-methylnaphthalenes** 

CYP 

OH SG

O 

OH CH3 CH3 CH3

EH 

7,8-dihydrodiol 7,8-epoxide 1-glutathionyl-7-methylnaphthalene OH O 

OH CH3

7-methyl-2-naphthol 

CH3 

OH 

SG 

CH3 CH3 

OH 

GS 

S NH2 

l 

l l 

OH 

7-methy -1-naphthylcysteine 

7-methy -1-naphtho 

hydroxy glutathionyl dihydro-2-methylnaphthalenes** 

[ ] = putative metabolite; CYP = cytochrome P450 enzyme(s); EH = epoxide hydrolase; GS = glutathione 

*Adapted from Buckpitt and Franklin (1989), EPA (2003r); Shultz et al. (2001), and Teshima et al. (1983) 

**Metabolites identified in vitro only 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 104 

3. HEALTH EFFECTS 

spontaneously. The hydroxy glutathionyl dihydro-2-methylnaphthalenes (Figure 3-4) have been detected 

after incubation of 2-methylnaphthalene with hepatic microsomes from Swiss-Webster mice or with 

isolated recombinant mouse CYP2F2 enzyme and glutathione S-transferase (Shultz et al. 2001). 

Figure 3-4 indicates six hydroxy glutathionyl 2-methylnaphthalenes; two are formed for each of the 

epoxide intermediates (3,4-, 5,6-, and 7,8-epoxides), and each can exist in two enantiomeric forms not 

shown in Figure 3-4 (Shultz et al. 2001). 

Three other minor metabolites formed via the 7,8-epoxide pathway are shown in Figure 3-4. Urinary 

1-glutathionyl-7-methylnaphthalene was identified in guinea pigs and by in vitro experiments with guinea 

pig microsomes (Teshima et al. 1983). 7-Methyl-1-naphthol and 7-methyl-2-naphthol were identified in 

the urine of rats, mice, guinea pigs, and rabbits following oral exposure (Grimes and Young 1956). 

In rats administered subcutaneous injections of 2-methylnaphthalene (0.3 mg/kg 2-methyl-[8-14C]-

naphthalene), 2-naphthoic acid, and naphthoic acid conjugates were identified in the urine (Melancon et 

al. 1982). The naphthoic acid and various conjugates of the acid were estimated to account for 36–43% 

of the radiolabel in collected urine. Most of this (30–35% of radiolabel in urine) was found as a glycine 

conjugate. The urine contained 3–5% unreacted 2-methylnaphthalene; free dihydrodiols accounted for 6– 

8% of the label. Unidentified highly polar metabolites comprised another 36–45% of the excreted label. 

At least three diol derivatives of 2-methylnaphthalene were produced by hepatic microsomes from mice 

(Griffin et al. 1982) suggesting that the ring oxidation reactions of 2-methylnaphthalene are similar to 

those for naphthalene. Rat liver microsomes also produced 2-hydroxymethylnaphthalene and three diols 

from 2-methylnaphthalene (Breger et al. 1981, 1983; Melancon et al. 1985). The three diols were 

identified as 3,4-dihydrodiol, 5,6-dihydrodiol, and 7,8-dihydrodiol (Breger et al. 1983). 

Metabolites isolated in the urine of guinea pigs after oral dosing with tritium labeled 2-methylnaphthalene 

(10 mg/kg) were 2-naphthoic acid and its glycine and glucuronic acid conjugates (Teshima et al. 1983). 

These metabolites accounted for 76% of the label in collected urine. Glucuronic acid and sulfate 

conjugates of 7-methyl-1-naphthol along with S-(7-methyl-1-naphthyl)cysteine accounted for 18% of the 

excreted label. No diol metabolites were identified. 

Glutathione conjugation appears to be an important detoxication pathway for 2-methylnaphthalene. 

Pretreatment of male C57BL/6J mice with 625 mg/kg of diethylmaleate (a depletor of glutathione) 1 hour 

prior to intraperitoneal administration of 400 mg/kg of 2-methylnaphthalene resulted in mortality in 

4/5 mice, whereas treatment without glutathione depletion was not fatal (Griffin et al. 1982). Bronchiolar 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 105 

3. HEALTH EFFECTS 

necrosis was not observed in male ddY mice given single intraperitoneal injections of 200 mg/kg of 

2-methylnaphthalene; pretreatment with the glutathione depletor diethylmaleate (600 μL/kg) 1 hour prior 

to injections caused “extensive sloughing and exfoliation of bronchiolar epithelial cells” in all animals 

(5/5) (Honda et al. 1990). In contrast, pretreatment of male DBA/2J mice (5/group) with 625 mg/kg of 

diethylmaleate did not increase the severity of pulmonary necrosis induced by 400 mg/kg of 2-methylnaphthalene (Griffin et al. 1983). The observed differences among mouse strains in response to depletion 

of glutathione remain unexplained. Other experiments (without pretreatment) observed decreased tissue 

or intracellular levels of glutathione in response to exposure to high acute doses of 2-methylnaphthalene, 

demonstrative of glutathione conjugation (Griffin et al. 1982, 1983; Honda et al. 1990). Similarly, 

depletion of glutathione (by 35% compared to controls) was detected in primary cultures of female 

Sprague-Dawley rat hepatocytes treated with 1,000 μM of 2-methylnaphthalene (Zhao and Ramos 1998). 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

Little information is available pertaining to the excretion of naphthalene in humans after inhalation 

exposure to naphthalene. Workers employed in the distillation of naphthalene oil and at a coke plant had 

peak levels of urinary 1-naphthol 1 hour after finishing a shift. Of three workers and a nonoccupationally 

exposed group, naphthalene oil distribution plant workers had the highest concentrations of urinary 

1-naphthol, with a mean excretion rate of 0.57% mg/hour. Investigators calculated the half-life for the 

urinary excretion of 1-naphthol as approximately 4 hours (Bieniek 1994). This urinary metabolite may 

indicate both exposure to naphthalene and low concentrations of 1-naphthol during naphthalene oil 

distillation (Bieniek 1994). No studies were located that documented excretion in humans after inhalation 

exposure to 1-methylnaphthalene or 2-methylnaphthalene. 

No studies were located that documented excretion in animals after inhalation exposure to naphthalene, 

1-methylnaphthalene, or 2-methylnaphthalene. 

3.4.4.2 Oral Exposure 

Little information is available pertaining to the excretion of orally ingested naphthalene by humans. The 

urine of one patient was tested for naphthalene and its derivatives. Naphthol was found at the time of 

hospital admission (4 days post-ingestion). Smaller quantities were present 1 day later, but naphthalene 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 106 

3. HEALTH EFFECTS 

was not detected in later specimens (Zuelzer and Apt 1949). In another instance, the urine of an 

18-month-old child was found to contain 1-naphthol, 2-naphthol, 1,2-naphthoquinone, and 1,4-naphthoquinone (but no naphthalene) 9 days after exposure (Mackell et al. 1951). With the exception of the 

1,4-naphthoquinone, these metabolites were still detectable on day 13, but not on day 17. These data 

indicate that urinary excretion of metabolites may be prolonged following exposure. It is important to 

note, however, that delayed dissolution and absorption from the gastrointestinal tract may also be a 

contributing factor. Unabsorbed naphthalene was visible in the fecal matter after ingestion of naphthalene 

flakes or mothballs in several individuals (Zuelzer and Apt 1949). 

In nonhuman primate studies, Rhesus monkeys given naphthalene at oral doses up to 200 mg/kg did not 

excrete naphthalene as thioethers in urine or feces (Rozman et al. 1982). In a similar study, chimpanzees 

orally administered naphthalene at 200 mg/kg did not excrete naphthalene as thioethers in urine (Summer 

et al. 1979). These data suggest that glutathione conjugation of naphthalene may not occur to any great 

extent in nonhuman primates. Data from two chimpanzees indicate that most of the naphthalene excreted 

in this species is excreted as glucuronic acid and sulfate conjugates (Summer et al. 1979). 

In rats administered radiolabelled naphthalene, the amount of label recovered in 24 hours was 77–93% in 

urine and 6–7% in feces (Bakke et al. 1985). There was a dose-dependent increase in urinary thioether 

excretion following gavage doses of naphthalene at 30, 75, and 200 mg/kg within 24 hours (Summer et al. 

1979). The levels of thioethers excreted accounted for approximately 39, 32, and 26% of the three dose 

levels tested. 

No information was located that documented excretion in humans after oral exposure to 2-methylnaphthalene. In guinea pigs, 80% of a 10 mg/kg tritium-labeled dose was excreted in the urine within 

24 hours and about 10% was recovered in the feces (Teshima et al. 1983). Most of the excreted material 

(76%) was found as 2-naphthoic acid or its conjugates. About 18% of the recovered label was found as 

conjugates of 7-methyl-1-naphthol. 

No studies were located that examined excretion in humans or animals after oral exposure to 1-methylnaphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 107 

3. HEALTH EFFECTS 

3.4.4.3 Dermal Exposure 

No reports have been located which discuss the excretion of naphthalene, 1-methylnaphthalene, or 

2-methylnaphthalene in humans following dermal exposure. 

The dermal exposure of rats to 14C-labeled naphthalene was evaluated over a 48-hour period (Turkall et 

al. 1994). Naphthalene (43 μg) samples were applied to shaved 13-cm2

 areas on the skin under a sealed 

plastic cap. Neat naphthalene or naphthalene adsorbed to the surface of sandy soil or clay soil was tested. 

In all three cases, excretion of the label was primarily through the urine (70–87%). With the pure 

naphthalene and naphthalene adsorbed to clay soil, the exhaled air accounted for 6–14% of the 

administered label. Exhaled air contained only 0.9% of the label in the sandy soil group. This finding 

was presumably related to the slower adsorption of naphthalene from the sandy soil and its more rapid 

metabolism to nonvolatile metabolites. Less than 0.02% of the label was exhaled as carbon dioxide in all 

groups. The feces contained 2–4% of the label. 

The primary metabolites in the urine after dermal application of naphthalene were 2,7-dihydroxynaphthalene, 1,2-dihydroxynaphthalene, and 1,2-naphthoquinone (Turkall et al. 1994). The ratio of these 

metabolites for pure naphthalene and naphthalene adsorbed to clay soil were roughly 3:2:1. For the sandy 

soil, the corresponding ratio was 3:2:1.5. Small amounts of 1-naphthol and 2-naphthol were also 

excreted. In all cases, the amount of urinary free naphthalene was less than 0.4% of the administered 

label. 

No studies were located that documented excretion in animals after dermal exposure to 1-methylnaphthalene or 2-methylnaphthalene. 

3.4.4.4 Other Routes of Exposure 

In mouse studies using the intraperitoneal or subcutaneous exposure routes, several naphthalene 

metabolites were excreted in the urine. After intraperitoneal administration of 100 mg/kg naphthalene, 

conjugates accounted for 80–95% of the urinary metabolites (Horning et al. 1980; Stillwell et al. 1982). 

Much of the conjugated material was present as thioethers (glutathione conjugates and their derivatives). 

The major oxidation products of naphthalene metabolism were 1-naphthol and trans-1,2-dihydro-1,2-naphthalenediol. 
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3. HEALTH EFFECTS 

Following subcutaneous administration of 0.3 mg/kg 14C-labeled 2-methylnaphthalene, 55% was found in 

the urine of rats (Melancon et al. 1982). Naphthoic acid and its glycine conjugate were identified. Three 

other metabolites were tentatively identified as isomeric diols. 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 109 

3. HEALTH EFFECTS 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-5 shows a conceptualized representation of a PBPK model. 

If PBPK models for naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene exist, the overall results 

and individual models are discussed in this section in terms of their use in risk assessment, tissue 

dosimetry, and dose, route, and species extrapolations. 

This section will discuss the structure and application of the most recent PBPK models for naphthalene 

that were developed with in vivo data for the time-course of naphthalene in blood in rats and mice 

following inhalation exposure or intravenous administration (Willems et al. 2001). The inhalation data 

were used to select best-fitting models with the fewest assumptions possible and to optimize model 

parameters. The intravenous data were used to examine the validity of the final models. These models 

are refinements of earlier PBPK models for naphthalene in rats and mice, which were developed using 

parameters estimated from in vitro data (Ghanem and Shuler 2000; Quick and Shuler 1999; Sweeney et 

al. 1996). The most recent models have been used to attempt to explain why naphthalene-induced lung 

tumors in female B6C3F1 mice, but did not induce lung tumors in F344/N rats in chronic inhalation 

studies (Abdo et al. 2001; NTP 1992a, 2000). The use of these models to extrapolate dosimetry from 

rodents to humans is not possible until appropriate validated human physiologically based toxicokinetic 

(PBTK) models for naphthalene are developed. 
Inhaled chemical Exhaled chemical 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

Lungs 

Liver 

Slowly 

ti 

Richly 

ti 

Kidney 

Skin 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

V Km 

Ingestion 

GI 

Tract 

Feces 

Urine

Fat 

perfused 

ssues 

perfused 

ssues 

max 

Chemicals in air 

contacting skin 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 110 

3. HEALTH EFFECTS 

Figure 3-5. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance 

Source: adapted from Krishnan et al. 1994 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 111 

3. HEALTH EFFECTS 

The models do not include nasal compartments that metabolize naphthalene, because no data were 

available on nasal deposition and epithelial absorption of naphthalene (Willems et al. 2001). Without 

such data, reliable models for nasal deposition, tissue dosimetry, and nasal-tissue metabolism cannot be 

developed for naphthalene (models similar to those developed for other nasal toxicants such as acrylic 

acid [Frederick et al. 2001]). The existence of validated PBTK models with metabolizing nasal 

compartments would be useful to help to explain why male and female rats develop nasal tumors with 

chronic inhalation exposure to naphthalene, but mice do not, even though both species develop 

nonneoplastic lesions in the nasal tissues in which tumors developed in rats (Abdo et al. 2001; NTP 

1992a, 2000). In addition, development of human models incorporating anatomical and physiological 

characteristics of nasal tissue will be useful to decrease uncertainty in extrapolating dose-response 

relationships for nasal effects in rodents to humans. 

The final best-fitting models for rats and mice are comprised of two parts: (1) a diffusion-limited 

naphthalene submodel with compartments for arterial and venous blood, alveolar space, and tissue and 

capillary spaces for the lung, liver, kidney, fat, and other organs (with naphthalene metabolism occurring 

in the liver and lung by the same CYP isozyme with one set of Michaelis-Menten metabolic rate 

constants); and (2) a flow-limited 1,2- naphthalene oxide submodel describing metabolism and 

distribution of naphthalene oxide in the same compartments as in the naphthalene submodel (but without 

tissue capillary spaces) (Willems et al. 2001). Physiological parameters in both submodels (e.g., cardiac 

output, ventilation rates, tissue volumes, tissue capillary volumes, tissue blood flows) were taken from the 

literature and scaled to body weights of rats in the NTP (2000) bioassay and reference values for mice. 

Partition coefficients between the various compartments were calculated from octanol-water partition 

coefficients. Metabolic rate constants (Vmax and Km) and permeability constants (blood:fat and 

blood:other tissues) for naphthalene were estimated by fitting the models to naphthalene blood timecourse data from the inhalation studies. The naphthalene oxide submodel was essentially the same as that 

developed by Quick and Shuler (1999) with in vitro data, with the exception that it contained a subroutine 

for reduced glutathione synthesis involving γ-glutamylcysteine synthetase modeled with MichaelisMenten rate constants and noncompetitive inhibition by reduced glutathione. The metabolic fate of 

naphthalene oxide in the lung and liver was restricted to dihydrodiol formation via epoxide hydrolase and 

conjugation to glutathione via glutathione-S-transferase. The model did not include spontaneous 

conversion of naphthalene oxide to 1-naphthol or metabolic transformations to the naphthoquinones. 

Because no in vivo data were available on naphthalene oxide distribution or metabolism, the model 

predictions for naphthalene oxide tissue dosimetry could not be verified. 
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3. HEALTH EFFECTS 

Under exposure conditions used in the rat (0, 10, 30, or 60 ppm) and mouse (0, 10, or 30 ppm) NTP 

(1992a, 2000) chronic inhalation bioassays with naphthalene (6 hours/day), the models predicted that: 

(1) steady-state lung concentrations of the parent compound, naphthalene, were not very different in rats 

and mice at equivalent exposure concentrations; (2) cumulative daily naphthalene metabolism in the lung 

was greater in the mouse than in the rat (by about 1.5- to 2.5-fold) at equivalent exposure concentrations; 

(3) cumulative daily naphthalene metabolism in the lung (64.9 mg/kg) and estimated maximal lung 

concentrations of naphthalene oxide (about 12 nmol/mL) for 30-ppm female mice, some of which 

developed lung tumors, were greater than respective values of 45.9 mg/kg and about 8 nmol/mL in 

60-ppm female rats, which did not develop lung tumors; and (4) cumulative daily naphthalene 

metabolism in the lung was only slightly greater in 30-ppm female mice (64.9 mg/kg) than in the 30-ppm 

male mice (60.7 mg/kg), which did show statistically significant increased incidence of lung tumors 

(comparisons of lung concentrations of naphthalene oxide in female and male mice were not reported). 

The model simulations are consistent with the hypothesis that the difference in lung tumor response 

between mice and rats may be due to a combination of greater maximal levels of naphthalene oxide or 

other metabolites in the mouse lung and, perhaps, a greater susceptibility of the mouse lung to epoxideinduced carcinogenesis. Results with other chemicals, such as ethylene oxide, suggest that the mouse 

lung may be more susceptible to epoxides than the rat lung (Willems et al. 2001). Differences in 

predicted cumulative lung metabolism of naphthalene in 30-ppm female mice and 30-ppm male mice 

were smaller than the difference noted between 30-ppm female mice and 60-ppm female rats; thus the 

model simulations do not explain the apparent gender difference in tumor response of the mouse lung. 

The formation of naphthoquinone metabolites was not included in the model. Thus, the model 

simulations do not provide a basis for identifying which metabolite is responsible for the nonneoplastic 

and neoplastic responses to naphthalene in the female mouse lung. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Absorption. No studies were located regarding the mechanisms by which naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene are absorbed from the guts, lungs, or skin. Although absorption of 

these compounds at these sites has been demonstrated, it is unknown if the transport is passive, active, or 

carried out by a facilitated diffusion mechanism. The relatively small molecular weights and lipophilicity 

of these compounds indicate that passive diffusion across cell membranes is a possible mechanistic path. 
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3. HEALTH EFFECTS 

There is some evidence that different vehicles may influence the rate and extent of gastrointestinal or 

dermal absorption. Naphthalene adsorbed to organic-rich soils was absorbed across the skin more slowly 

than naphthalene from organic-poor soils (Turkall et al. 1994). 

Distribution. As discussed in more detail in Section 3.4.2, there are limited data on the distribution of 

naphthalene and 2-methylnaphthalene in animals following oral or parenteral administration, but there are 

no data for these compounds following inhalation exposure or for 1-methylnaphthalene by any exposure 

route. The available data are inadequate to characterize the mechanisms by which 2-methylnaphthalene 

may be transported following oral exposure to the lung, the site of toxic action with acute or chronic 

exposure. No data are available on differences in deposition and absorption of inhaled naphthalene in 

nasal epithelial tissue, two of which (olfactory epithelium and respiratory epithelium) are key toxicity 

targets in rats and mice following chronic inhalation exposure to naphthalene. 

Metabolism. As discussed in more detail in Section 3.4.3, results from in vitro and in vivo metabolic 

studies in mammalian systems indicate that naphthalene metabolism is complex, with multiple competing 

pathways leading to the formation of several reactive metabolites (e.g., 1,2-naphthalene oxide, 

1,2-naphthoquinone, and 1,4-naphthoquinone) and an array of conjugated and nonconjugated metabolites 

that are excreted predominantly in the urine. Conjugation of the reactive metabolites is viewed as a 

detoxifying mechanism for the reactive metabolites. With oral exposure, the liver is expected to be the 

principal site of metabolism, but metabolism of naphthalene at other tissue sites, including the nasal 

olfactory epithelium, Clara cells in pulmonary epithelial tissue, and eye tissue, has been demonstrated. A 

first-pass metabolic effect due to liver metabolism is expected with oral exposure, but the degree to which 

a first-pass effect due to respiratory tissue metabolism occurs with inhalation exposure to naphthalene has 

not been studied quantitatively. 

Section 3.4.3 also discusses in more detail the complexity of 2-methylnaphthalene metabolism, which, in 

contrast to naphthalene, involves several competing initial steps: oxidation of the methyl side group and 

oxidation at several positions on the rings. Oxidation of the methyl side group is the principal metabolic 

pathway, representing about 50–80% of administered doses in animal studies. An array of conjugated 

and nonconjugated metabolites that are principally excreted in the urine have been identified in animal 

studies. Although conjugation of metabolites (principally with glutathione) appears to be a detoxication 

mechanism with acute exposure in animal studies, the involvement of reactive metabolites in the 

development of pulmonary alveolar proteinosis from chronic exposure to 2-methylnaphthalene is 
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3. HEALTH EFFECTS 

uncertain (see Section 3.5.2). No studies were located on the metabolism of 1-methylnaphthalene in 

humans or animals, but it is expected to be similar to 2-methylnaphthalene metabolism based on its 

similar chemical, physical, and toxicological properties. 

Excretion. As discussed in more detail in Section 3.4.4, results from animal studies involving oral or 

parenteral exposure indicate that naphthalene and 2-methylnaphthalene are principally excreted as 

metabolites in urine. Excretion in the feces represents a minor excretion pathway for these chemicals, and 

the possibility of excretion via exhalation of unmetabolized parent compounds has not been examined in 

available studies. Data for 1-methylnaphthalene were not located, but excretion is likely to be similar to 

2-methylnaphthalene given the similarity in chemical and physical properties of these chemicals. 

3.5.2 Mechanisms of Toxicity 

Some information on the mechanism of toxicity is available for three of the health effects associated with 

naphthalene exposure: hemolysis, the development of lens opacities (cataracts), and nonneoplastic and 

neoplastic respiratory tract lesions. Mechanistic hypotheses for these naphthalene-induced effects are 

discussed below, followed by a discussion of the limited mechanistic information on 1-methylnaphthalene- and 2-methylnaphthalene-induced pulmonary alveolar proteinosis. 

Naphthalene-induced Hemolysis. Humans experience red-cell hemolysis after naphthalene exposure by 

the inhalation, oral, and dermal routes. In general, animal species are less susceptible than humans. 

There are no reports of naphthalene-induced hemolysis in either rats or mice; however, hemolysis has 

been observed in dogs. 

Chemically induced red blood cell hemolysis is caused by a breakdown of the system that protects the 

erythrocyte biomolecules from oxidation. In the erythrocyte, glutathione peroxidase rather than catalase 

is the major antioxidant enzyme. Glutathione peroxidase (Gpx) is a selenium containing metalloprotein 

that utilizes reduced glutathione as a cofactor. Oxidized glutathione is reduced by glutathione reductase, 

a nicotinamide adenine dinucleotide phosphate (NADPH)-requiring enzyme. 

The primary source of erythrocyte NADPH is glucose-6-phosphate oxidation by the enzyme G6PD. 

Individuals who suffer from a genetic defect resulting in a modified enzyme structure (a recessive trait) 

have a reduced capacity to produce NADPH. Accordingly, they are more susceptible to red cell 
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3. HEALTH EFFECTS 

hemolysis than individuals without this defect (Gosselin et al. 1984). There is some evidence that 

heterozygotes may also have an increased susceptibility to red cell hemolysis (Dawson et al. 1958). 

When the red blood cell is exposed to oxidizing agents, heme iron is oxidized to the ferric state, 

producing methemoglobin. This in turn leads to Heinz body formation. It is believed that free radical 

oxygen modifies membrane lipids leading to increased membrane fragility and lysis. Destruction of the 

red blood cells decreases erythrocyte counts and stimulates hematopoiesis (leading to increased numbers 

of reticulocytes). The oxygen carrying capacity of the blood is reduced. Cell lysis releases heme and 

protein into the blood. Heme breakdown produces bilirubin and biliverdin, causing jaundice. Both 

erythrocytes and heme breakdown products (urobilinogen) spill into the urine. 

Several suggestions can be made regarding the impact of naphthalene on this sequence of events. Since 

naphthalene is conjugated with glutathione for excretion, it can reduce the supplies of glutathione 

available for glutathione peroxidase and increase the vulnerability of the cell to oxidation. It is also 

possible that a naphthalene metabolite may act as an inhibitor for either glutathione peroxidase or 

glutathione reductase. Glutathione reductase activity was reduced in children who experienced hemolysis 

following dermal exposure to naphthalene and in related family members (Dawson et al. 1958). Both 

glutathione peroxidase and glutathione reductase activity were decreased in the lens of rats orally exposed 

to naphthalene (Rathbun et al. 1990; Tao et al. 1991). 

Each of the hypotheses discussed above would serve to increase the sensitivity of any naphthaleneexposed subject to an external oxidizing agent. However, given the severity of the hemolysis that follows 

naphthalene exposure, it is probable that naphthalene or a naphthalene metabolite also acts as an oxidizing 

agent in the erythrocyte. Unfortunately, data could not be identified which would correlate the production 

of any particular metabolite with initiation of red cell peroxidation. 

Naphthalene-induced Cataracts. Although there are reports that inhalation, oral, and dermal naphthalene 

exposure in humans can lead to lens opacities (Grant 1986), the case studies or industrial exposure reports 

that link naphthalene to cataracts in humans have not been verified by well-conducted epidemiological 

studies of individuals exposed to naphthalene vapors on a chronic basis. In addition, impurities present in 

the naphthalene may have contributed to the cataract development in all recorded human cases. 

Conversely, there are data from a number of well-conducted studies which demonstrate that naphthalene 

can induce cataracts in animals. 
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3. HEALTH EFFECTS 

Much of the animal data regarding ocular effects suggest that the toxicity of naphthalene is mediated by 

the in situ formation of 1,2-naphthalenediol in the lens. It has been proposed that metabolism of 

naphthalene starts in the liver, yielding epoxide metabolites that are subsequently converted to stable 

hydroxy compounds that circulate to the lens (Van Heyningen and Pirie 1967). The 1,2-naphthalenediol 

metabolite is subsequently oxidized to 1,2-naphthaquinone and hydrogen peroxide. The quinone 

metabolite binds to constituents of the lens (protein, amino acids, and glutathione), disrupting its integrity 

and transparency (Rees and Pirie 1967; Uyama et al. 1955; Van Heyningen and Pirie 1967; Van 

Heyningen 1976, 1979; Wells et al. 1989). 

Intraperitoneal administration of naphthalene (125–1,000 mg/kg), 1-naphthol (56–562 mg/kg), 

1,2-naphthoquinone (5–250 mg/kg), and 1,4-naphthoquinone (5–250 mg/kg) caused a dose-related 

increase in cataracts in C57BL/6 mice, but administration of 2-naphthol (56–456 mg/kg) did not (Wells 

et al. 1989). The cataractogenic potency of the naphthoquinones was about 10 times that of naphthalene. 

The cataractogenic potency of 1-naphthol was intermediate to that of naphthalene and the 

naphthoquinones. The potency of naphthalene was increased by pretreatment with cytochrome 

P-450 inducers and a glutathione-depleting agent. It was inhibited by pretreatment with a cytochrome 

P-450 inhibitor. This suggests that the unconjugated oxidized naphthoquinone metabolites are a 

necessary prerequisite for cataract formation. There are differences in species and strain susceptibility to 

cataract formation that theoretically relate to the animals' ability to form these metabolites. Naphthalene, 

1-naphthol, 1,2-naphthoquinone, and 1,4-naphthoquinone did not form cataracts in DBA/2 mice 

suggesting the difference between strains is not simply due to metabolite exposure (Wells et al. 1989). 

Because hydrogen peroxide is also formed following the oxidation of 1,2-dihyroxynaphthalene, peroxides 

may play a role in naphthalene-induced ocular damage. Increased levels of ocular lipid peroxides were 

noted in rats given incremental doses of naphthalene which increased from 100 to 750 mg/kg/day during a 

9 week period (Germansky and Jamall 1988). The antioxidants caffeic acid (527 mg/kg) and vitamin E 

(250 mg/kg), which have free radical protection properties, and the free radical spin trapping agent 

α-phenyl-N-t-butylnitrone (PBN) (518 mg/kg) diminished the incidence of cataracts in animals given 

750 mg/kg naphthalene (Wells et al. 1989). There were no cataracts in the rats given only PBN. 

Support for this mechanism of cataract formation was provided by a gavage study in which five rat strains 

(pigmented and albino) were given 500 mg/kg/day naphthalene for 3 days and 1,000 mg/kg/day for the 

remainder of the 28-day treatment period (Xu et al. 1992b). After 3 weeks, there was a decrease in 

reduced glutathione (GSH) in the lens, an increase in protein-glutathione mixed disulfides, and an 
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3. HEALTH EFFECTS 

increase in high molecular weight insoluble proteins (Xu et al. 1992a, 1992b). The only metabolite 

detected in the aqueous humor of the lens was 1,2-dihydro-1,2-naphthalenediol. The authors 

hypothesized that 1,2-dihydro-1,2-naphthalenediol was oxidized to 1,2-naphthalenediol and then to 

1,2-naphthoquinone. The 1,2-naphthoquinone is believed to be responsible for the chemical changes in 

the eyes either through crosslinking reactions or by generating free radicals (Xu et al. 1992a). All of the 

rats developed cataracts. 

The complete mechanism for this sequence of reactions is not clear. In in vitro studies of cataract 

formation, 1,2-dihydro-1,2,naphthalenediol was the only metabolite that resulted in cataracts that were 

morphologically the same as those generated in vivo (Xu et al. 1992a). Although 1,2-naphthalenediol and 

naphthoquinone also formed cataracts in lens culture studies, the opacities were located in the outer layer 

of the cortex rather than inside the lens. Also, the permeability of the cultured lens to the metabolites in 

the media may have contributed to the differences in lesion location. 

When the aldose reductase inhibitor, AL01576, was given to rats along with the same naphthalene doses, 

no cataracts developed (Xu et al. 1992a, 1992b). Aldose reductase is an enzyme found in the lens, liver, 

and peripheral neurons that reduces aldehyde sugars such as glucose to their corresponding alcohols 

(McGilvery 1983). It is believed to oxidize 1,2-naphthalenediol to 1,2-naphthoquinone; therefore, when 

this reaction is inhibited, the quinone hypothetically does not form and there is no eye damage (Xu et al. 

1992a). Support for this hypothesis includes observations that aldose reductase inhibitors inhibit cataract 

formation in naphthalene-exposed rats (Tao et al. 1991; Xu et al. 1992a), dihydrodiol dehydrogenase is 

apparently absent in rat lens (Greene et al. 2000), and aldose reductase appears to be the only enzyme in 

rat lens that can transform 1,2-dihydroxy-1,2-dihydronaphthalene to 1,2-naphthoquinone (Sugiyama et al. 

1999). 

Naphthalene-induced Nonneoplastic and Neoplastic Respiratory Tract Lesions. The mechanisms by 

which naphthalene affects mouse lung epithelial tissue and mouse and rat nasal epithelial tissue are 

thought to involve metabolic intermediates that can react with tissue macromolecules: 1,2-naphthalene 

oxide, 1,2-naphthoquinone, and 1,4-naphthoquinone (Buckpitt et al. 2002). The innate reactivity of 

1,2-naphthalene oxide is demonstrated by a half-life of approximately 2–3 minutes in buffer at pH 7.4; the 

half-life is extended by the presence of albumins to about 11 minutes (Buckpitt et al. 2002; Kanekal et al. 

1991). The reactivity of 1,2-naphthoquinone has been demonstrated by its ability to form N7-adducts 

with deoxyguanosine under acidic conditions (McCoull et al. 1999). A second mode by which 

1,2-naphthoquinone may damage tissue macromolecules involves redox cycling of the ortho-quinone 
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3. HEALTH EFFECTS 

moiety and the subsequent generation of reactive oxygen species, which can lead to lipid peroxidation, 

consumption of reducing equivalents, oxidation of DNA, or DNA strand breaks (Bolton et al. 2000). 

1,2-Naphthoquinone caused hydroxyl radical formation and DNA strand scission in buffered solutions in 

the presence of NADPH and CuCl2 (Flowers et al. 1997), was directly mutagenic in S. typhimurium 

(Flowers-Geary et al. 1996), and directly induced sister chromatid exchanges in human mononuclear 

leukocytes (Wilson et al. 1996). The comparative importance of these reactive metabolic intermediates of 

naphthalene in producing nonneoplastic and neoplastic lesions in lung or nasal epithelial tissue is 

unknown, although the difference between mice and rats in susceptibility to naphthalene-induced lung 

damage has been associated with greater rates of naphthalene transformation to epoxides and the 

formation of a different enantiomeric form of 1,2-naphthalene oxide in mice compared with rats. 

A fourth reactive metabolic intermediate, 1,2-dihyroxy-3,4-epoxy-1,2,3,4-tetrahydronaphthalene, has 

been proposed based on molecular structure characterizations of some urinary metabolites (Horning et al. 

1980; Pakenham et al. 2002), but these metabolites represent minor metabolic fates of naphthalene and 

the potential importance of their proposed precursor in naphthalene toxicity is unstudied to date. 

Mice are markedly more susceptible than rats to acute naphthalene-induced Clara cell injury (Buckpitt et 

al. 1992; West et al. 2001), as well as to lung inflammation and tumor development from chronic 

inhalation exposure (Abdo et al. 2001; NTP 1992a, 2000). The species difference in lung susceptibility 

has been correlated with higher rates of formation of a specific enantiomeric epoxide (1R,2S-naphthalene 

oxide) in lung microsomes and isolated dissected airways of mice compared with rats (Buckpitt et al. 

1992, 1995). Rat, hamster, and monkey lung microsomes preferentially formed the 1S,2R-naphthalene 

oxide enantiomer and showed lower rates of formation of epoxides than mouse lung microsomes 

(Buckpitt et al. 1992). Microsomes from human lymphoblastoid cells expressing recombinant human 

CYP2F1 also showed preferential formation of the 1S,2R-naphthalene oxide enantiomer, providing some 

evidence that human transformation of naphthalene to reactive epoxides in lung tissue may be more like 

rats than mice (Lanza et al. 1999). 

Although these observations on epoxide formation suggest that naphthalene may be metabolized to 

epoxide intermediates at faster rates and with different stereoselectivity in the mouse lung than in the 

human lung, the toxicologic significance of this species difference is uncertain. The uncertainty arises 

due to the possibility (and potential toxicological importance) of species differences in several steps in 

downstream metabolism including glutathione conjugation of the epoxide, transformation to the 

dihydrodiol via epoxide hydrolase, and transformations to 1,2- or 1,4-naphthoquinone. For example, 
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human liver microsomes have been reported to be more proficient at converting naphthalene to the 

dihydrodiol metabolite than rat and mouse liver microsomes (Kitteringham et al. 1996). These results 

suggest that epoxide hydrolase activities may be higher in humans than mice (although they do not 

necessarily reflect activities in the pertinent naphthalene target tissues) and that this may decrease the 

potential for epoxide-induced tissue damage in humans relative to mice (see Figure 3-3). However, this 

difference may cause relatively greater formation of 1,2-naphthoquinone (from the dihydrodiol via 

dihydrodiol dehydrogenase) in human tissue than in mouse tissue. While the toxicologic significance of 

such a difference is uncertain, it is possible that humans may be more susceptible than mice, due to the 

possible involvement of 1,2-naphthoquinone in naphthalene-induced lung injury as suggested by a report 

that 1,2-naphthoquinone was the predominant naphthalene metabolite covalently bound to proteins 

obtained from freshly isolated mouse Clara cells incubated for 1 hour with 0.5 mM naphthalene (Zheng et 

al. 1997). To date, mechanistic understanding of species differences in naphthalene bioactivation in the 

lung is too incomplete to definitively identify which naphthalene metabolite is responsible for the 

development of nonneoplastic or neoplastic lung lesions, or to rule out the possible human relevance of 

naphthalene-induced lung lesions in mice. 

Species differences in susceptibility to naphthalene-induced nonneoplastic and neoplastic lesions in the 

olfactory and respiratory epithelia of the nose have not been correlated with differences in rates of 

transformation to 1,2-epoxide derivatives in extracts of olfactory tissue (Buckpitt et al. 1992; Plopper et 

al. 1992a). Rates of epoxide formation showed the order, mouse > rat > hamster, but rats were the most 

susceptible to acute nasal injury from naphthalene, showing olfactory epithelial necrosis and exfoliation 

following single intraperitoneal doses as low as 200 mg/kg naphthalene, compared with 400 mg/kg in 

mice and hamsters (Plopper et al. 1992a). These observations suggest that the reasons for species 

differences in susceptibility to naphthalene nasal toxicity are complex and do not solely involve 

differences in the formation of the 1,2-epoxide metabolic intermediates. 

Involvement of the naphthoquinone metabolites is possible, but studies comparing species in their ability 

to form or accumulate reacted derivatives of naphthoquinones (or 1,2-naphthalene oxide) in nasal tissues 

(i.e., protein adducts) are not available. In blood of rats following gavage administration of single oral 

doses of naphthalene (100–800 mg/kg), levels of hemoglobin and albumin adducts with 1,2-naphthalene 

oxide were greater than levels of adducts of 1,2- and 1,4-naphthoquinone (Troester et al. 2002; 

Waidyanatha et al. 2002). These findings suggest that levels of the epoxide in the rats’ blood were greater 

than levels of the naphthoquinones, but do not provide information on the relative amounts of these 

reactive metabolites in the target tissue, the nose. 
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Current information is inadequate to (1) identify which metabolite(s) are responsible for nonneoplastic or 

neoplastic nasal lesions that develop in rodents following chronic inhalation exposure, (2) explain why 

nasal tumors develop in rats but not in mice, or (3) rule out the possible human relevance of naphthaleneinduced nasal lesions in rats or mice. 

Evidence to support a nongenotoxic mode of action in naphthalene carcinogenicity involving sustained 

cell proliferation following repeated naphthalene-induced tissue damage includes the negative results in 

the genotoxicity database (see Section 3.3) suggesting that naphthalene and its metabolites (with the 

likely exception of 1,2-naphthoquinone) are not mutagens, and the findings that naphthalene-induced 

tumors in mice and rats occur in the same general tissues as those displaying nonneoplastic lesions. 

Evidence to support a genotoxic mode of action includes the consistently positive results for genotoxic 

action by 1,2-naphthoquinone and the limited and scattered positive results for genotoxic action by 

naphthalene in the presence of metabolic activation. Current evidence is not adequate to rule out the 

possibility of naphthalene genotoxic action or to determine pertinent threshold levels for genotoxic action, 

due to the absence of studies examining genotoxic end points in naphthalene target tissues, the nose and 

lung. As suggested by Moore and Harrington-Brock (2000), answering critical questions in human cancer 

risk assessment involves an understanding of the mode(s) of action of tumor induction in the target 

tissue(s) at environmentally-relevant concentrations. Such understanding can come from experiments 

examining genotoxic endpoints in target tissues. These data are not available for naphthalene. 

In summary, the available evidence regarding the mechanism(s) by which naphthalene produces 

neoplastic and nonneoplastic lesions in the respiratory tract of rodents suggests the involvement of 

reactive metabolites. The identity of this metabolite(s), and evidence of its presence in known target 

tissues, remains unknown. The finding that mice are more susceptible than rats to naphthalene-induced 

lung toxicity may correlate with the in vivo generation of this reactive intermediate in target tissues. 

Whether the mechanism by which naphthalene produces neoplastic and nonneoplastic changes in the 

respiratory tract of rodents involves genotoxicity remains unknown. 

1-Methylnaphthalene or 2-Methylnaphthalene-induced Pulmonary Alveolar Proteinosis. Exposure of 

mice to 1-methylnaphthalene or 2-methylnaphthalene in the diet for 81 weeks induced increased 

incidences of pulmonary alveolar proteinosis (Murata et al. 1993, 1997). The absence of nonneoplastic 

lesions in other lung regions or in other tissues indicates that the alveolar region of the lung is a critical 

and specific toxicity target of chronic oral exposure to 1-methylnaphthalene or 2-methylnaphthalene. 
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Increased incidences of pulmonary alveolar proteinosis have also been observed in mice exposed to 

dermal doses of methylnaphthalene (a 2:1 mixture of 2-methylnaphthalene and 1-methylnaphthalene) 

applied twice weekly for 20–61 weeks (Emi and Konishi 1985; Murata et al. 1992). 

There is evidence to suggest that type II pneumocytes are specific cellular targets of the methylnaphthalenes. Pulmonary hyperplasia and hypertrophy of type II pneumocytes in alveolar regions with 

proteinosis was observed by light microscopy in mice that were repeatedly exposed to dermal doses of 

methylnaphthalene (119 mg/kg methylnaphthalene twice a week for 30 weeks [Murata et al. 1992]). In 

this same study, electron microscopic examination showed that alveolar spaces were filled with numerous 

myelinoid structures that resembled lamellar bodies of type II pneumocytes. This extracellular material 

was associated with mononucleated giant cells (called balloon cells) containing numerous myelinoid 

structures, lipid droplets, and electron dense ascicular crystals. The authors hypothesized that, in response 

to 1-methylnaphthalene or 2-methylnaphthalene, type II pneumocytes produce increased amounts of 

lamellar bodies due to hyperplasia and hypertrophy, and eventually transform into balloon cells. Balloon 

cell rupture has been hypothesized to lead to the accumulation of the myelinoid structures in the alveolar 

lumen. Ultrastructural studies of the pathogenesis of pulmonary alveolar proteinosis from chronic 

exposure to 2-methylnaphthalene or 1-methylnaphthalene alone were not available. However, the lesions 

detected by light microscopy following chronic oral exposure to 2-methylnaphthalene or 1-methylnaphthalene alone were very similar to the lesions detected following chronic dermal exposure to the 

mixture. These similarities suggest that the mechanistic hypotheses prompted by observations for the 

mixture are relevant to the individual methylnaphthalenes. 

The mechanism of targeting type II pneumocytes is consistent with what is generally known regarding the 

etiology of pulmonary alveolar proteinosis in humans. The disease in humans, characterized by the 

accumulation of surfactant material in the alveolar lumen, has been hypothesized to be caused by either 

excessive secretion of surfactant by type II pneumocytes, or disruption of surfactant clearance by 

macrophages (Lee et al. 1997; Mazzone et al. 2001; Wang et al. 1997). The condition in humans has 

been associated with pulmonary dysfunction, characterized by decreased functional lung volume, reduced 

diffusing capacity, and symptoms such as dyspnea and cough. Pulmonary alveolar proteinosis has not 

been associated with airflow obstruction (EPA 2003; Lee et al. 1997; Mazzone et al. 2001; Wang et al. 

1997). 

The development of pulmonary alveolar proteinosis in mice appears to require prolonged oral exposure to 

2-methylnaphthalene (or 1-methylnaphthalene). Exposure to a dietary concentration of 0.075% 2-methyl-
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naphthalene for 81 weeks induced increased incidences of the lesion, but 13-week exposure to 

concentrations as high as 1.33% 2-methylnaphthalene did not (Murata et al. 1997). No further studies of 

the temporal development of methylnaphthalene-induced pulmonary alveolar proteinosis are available. 

It is unknown whether the parent compounds or metabolites are responsible for the development of 

methylnaphthalene-induced pulmonary alveolar proteinosis. Type II pneumocytes are enriched in CYP 

monooxygenases (Castranova et al. 1988), which are involved in metabolizing 2-methylnaphthalene, and 

it is possible that metabolites may play a role in the pathogenesis of pulmonary alveolar proteinosis. 

Studies designed to test this hypothesis, however, have not been conducted. 

In contrast to chronic oral exposure, which targets alveolar type II pneumocytes, acute intraperitoneal 

injection of 2-methylnaphthalene into mice targets bronchiolar Clara cells, inducing Clara cell 

abnormalities, focal or complete sloughing of Clara cells, or complete sloughing of the entire bronchiolar 

lining (Buckpitt et al. 1986; Griffin et al. 1981, 1982, 1983; Honda et al. 1990; Rasmussen et al. 1986). 

Mechanistic studies have not provided clear evidence that metabolites are involved in this response to 

acute exposure to 2-methylnaphthalene. For example, pretreatment of male C57BL/6J mice with 

phenobarbital (an inducer of CYP2B; 75 mg/kg, 4 days prior) or 3-methylcholanthrene (an inducer of 

CYP1A; 80 mg/kg, 2 days prior) prior to injection with 400 mg/kg 2-methylnaphthalene reduced the 

severity of bronchiolar necrosis in all mice compared to those injected without pretreatment (Griffin et al. 

1982). However, CYP inhibitors, such as piperonyl butoxide (a mixed monooxygenase inhibitor; 

1,000 mg/kg, 30 minutes prior) and SKF 525-A (an inhibitor of CYP1B; 25 mg/kg, 30 minutes prior), had 

no effect on the severity of the lung lesions. The mechanism of acute Clara cell toxicity of 2-methylnaphthalene may be similar to that of naphthalene, which involves CYP-mediated metabolism via ring 

epoxidation to reactive species such as the 1,2-naphthalene oxide and 1,2-naphthoquinone (Cho et al. 

1995; Greene et al. 2000; Lakritz et al. 1996; Van Winkle et al. 1999). This hypothesis is supported by 

the finding that 2-methylnaphthalene is less acutely toxic than naphthalene (Buckpitt and Franklin 1989; 

Cho et al. 1995) and that only a small fraction of 2-methylnaphthalene (15-20%) undergoes metabolic 

ring epoxidation (Breger et al. 1983; Melancon et al. 1985). Information on the mechanism of the acute 

response of Clara cells is not expected to be directly related to the pathogenesis of pulmonary alveolar 

proteinosis from chronic oral or dermal exposure to 2-methylnaphthalene, because in mice chronically 

exposed to 2-methylnaphthalene or 1-methylnaphthalene for 81 weeks, no evidence for exposure-related 

bronchiolar Clara cell lesions was found (Murata et al. 1993, 1997). This finding is not surprising, as 

Clara cells have been shown to develop resistance to the acute toxicity of naphthalene (Lakritz et al. 
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3. HEALTH EFFECTS 

1996). The possible development of Clara cell resistance to the acute toxicity of 2-methylnaphthalene, 

however, has not been studied. 

Data are limited to support the hypothesis that rats are less sensitive than mice to the lung damage caused 

by acute exposure to 2-methylnaphthalene. Wistar rats given intraperitoneal doses of 142 mg/kg 

2-methylnaphthalene did not develop lung lesions (Dinsdale and Verschoyle 1987). However, 

bronchiolar necrosis was induced in Swiss-Webster mice injected with the same dose (Rasmussen et al. 

1986) and in C57BL/6J and DBA/2J mice injected with 100 mg/kg 2-methylnaphthalene (Griffin et al. 

1981, 1982, 1983). No data are available for interspecies comparisons of the chronic toxicity of 

1-methynaphthalene or 2-methylnaphthalene. 

3.5.3 Animal-to-Human Extrapolations 

Naphthalene-induced lesions in nasal epithelia of mice and rats appear to be the critical nonneoplastic 

effect (i.e., the effect occurring at the lowest exposure level) associated with inhalation exposure to 

naphthalene. As discussed in Section 3.5.2, studies with microsomes from human and animal cells 

indicate that there are species differences in specific steps of naphthalene metabolism (Buckpitt et al. 

1992; Kitteringham et al. 1996; Lanza et al. 1999), but mechanistic understanding of these differences is 

too incomplete to effectively argue that they rule out the possible human relevance of naphthaleneinduced lung lesions in mice or nasal lesions in rats or mice. Rodents and humans also display distinct 

differences in nasal anatomy and respiratory physiology that may cause different deposited doses, and 

subsequently different responses, in human nasal tissue relative to rats or mice. However, the anatomical 

and physiological differences alone are insufficient to rule out the possible human relevance of 

naphthalene-induced nasal lesions in rats or mice. For example, rat and human hybrid computational 

fluid dynamics and PBPK models, developed for acrylic acid, another rodent nasal toxicant, predicted that 

tissue concentrations of acrylic acid in human and rat nasal tissues would be similar when exposure 

conditions were the same (Frederick et al. 2001). Current PBPK models for naphthalene do not include 

nasal compartments that metabolize naphthalene, because no data were available on nasal deposition and 

epithelial absorption of naphthalene (Willems et al. 2001). In the absence of this type of data or a 

pertinent validated human PBPK model, it is reasonable to assume that naphthalene-induced 

nonneoplastic and neoplastic lesions observed in nasal tissues of rats and mice are relevant to humans. 

Development of rat, mouse, and human hybrid computational fluid dynamics and PBPK models that 

include metabolizing nasal compartments and the application of the models to extrapolating rat or mouse 
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nasal doses to humans will likely decrease uncertainty in extrapolating naphthalene health hazards from 

rodents to humans. 

In animals orally exposed to naphthalene, the critical effects appear to be decreased weight gain and 

clinical signs of toxicity in pregnant rats with acute exposure and decreased body weight in rats with 

intermediate-duration exposure. Mechanisms associated with these effects are unstudied. Reliable data 

to preclude the relevance of these effects to humans were not located. 

Pulmonary alveolar proteinosis induced in mice following chronic oral exposure to 1-methylnaphthalene 

or 2-methylnaphthalene is assumed to be relevant to humans, in the absence of data to indicate otherwise. 

Pulmonary alveolar proteinosis is a condition that has been described in humans, although reports noting 

associations with human exposure to 1-methylnaphthalene or 2-methylnaphthalene were not located. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Colborn and Clement (1992), was also used in 1996 when Congress mandated the EPA 

to develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 
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descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 

No studies were located regarding endocrine disruption in human or animals after exposure to 

naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene. 

No in vitro studies were located regarding endocrine disruption of naphthalene, 1-methylnaphthalene, or 

2-methylnaphthalene. 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 
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3. HEALTH EFFECTS 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

Newborns and infants are thought to be more susceptible to adverse health effects from naphthalene (e.g., 

hemolytic anemia from acute exposure) because hepatic enzyme systems involved in conjugation and 

excretion of naphthalene metabolites are not well developed shortly after birth (EPA 1987a). No studies 

were located, however, that specifically examined the influence of age on naphthalene toxicokinetic 

capabilities in humans. 
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Although the occurrence of hemolytic anemia in neonates of anemic, naphthalene-exposed mothers 

demonstrates that naphthalene and/or its metabolites can cross the placental barrier (Anziulewicz et al. 

1959; Zinkham and Childs 1957, 1958), oral-exposure developmental toxicity studies in animals do not 

provide evidence that naphthalene was fetotoxic or impaired fetal development, even at maternally toxic 

dose levels as high as 450 mg/kg/day (NTP 1991a; Plasterer et al. 1985; PRI 1986). 

Naphthalene has been detected in human milk samples (concentration not reported) (Pellizzari et al. 

1982), but no studies were located that have specifically examined the rate or extent of naphthalene 

distribution to breast milk in exposed humans or animals. 

Children with genetically determined glucose-6-phosphate dehydrogenase (G6PD) deficiency are 

expected to be especially susceptible to the hemolytic action of naphthalene (Owa 1989; Owa et al. 1993; 

Santucci and Shah 2000; Valaes et al. 1963). In support of this hypothesis, in 21 cases of hemolytic 

anemia in Greek infants exposed to naphthalene, 10 of the children had a genetically determined 

deficiency in G6PD (Valaes et al. 1963). In a 10-year chart review of 24 African-American children 

hospitalized with acute hemolytic anemia, 14 were noted to have been exposed to naphthalene-containing 

moth repellants (Santucci and Shah 2000). Deficiency in G6PD makes red blood cells more susceptible 

to oxidative damage from a wide range of causes including naphthalene exposure. Relatively high rates 

of genetically determined G6PD deficiency have been reported in males of certain subpopulations of 

Asian, Arabic, Caucasian, African, and African-American ancestry (EPA 1987a). 

The limited mobility of infants when they are wearing naphthalene-treated clothing or when they are near 

other naphthalene-treated articles (e.g., blankets treated with naphthalene-containing moth repellants) 

may maximize exposure due to the development of a microenvironment with a high level of naphthalene 

vapor in the space around the infant. The tendency for infants and small children to place small objects, 

such as mothballs, in their mouths also increases their risk. 

An association between elevated maternal exposure to naphthalene and increased maternal cord-blood 

levels of one of four T cell types, IL-4, has recently been reported (Lehmann et al. 2002). The study 

looked for possible associations between maternal indoor exposure to 28 volatile organic chemicals 

(including naphthalene) and putative immune status at birth assessed by cord-blood levels of cytokineproducing T cells [interleukin-4 (IL-4), interleukin-2 (IL-2), interferon-γ (IFN-γ), and tumor necrosis 

factor-α (TNF-α)]. Levels of 28 volatile organic chemicals in air samples, collected during a 4-week 

postnatal period in bedrooms of 85 newborn children, were measured as surrogate indices of maternal 
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3. HEALTH EFFECTS 

indoor exposure. A logistic regression analysis found an elevated odds ratio (OR=2.9; 95% CI 1.0–8.2) 

for elevated naphthalene air concentrations (>75th percentile) and elevated percentage of IL-4-producing 

T cells in cord blood. The analysis adjusted for possible confounding factors of family allergic (i.e., 

atopic) history and maternal smoking during pregnancy. Several other statistically significant 

associations were found for changes in levels of different types of T cells and air levels of other 

chemicals, including methylcyclopentane, trichloroethylene, and tetrachloroethylene. The significance of 

the observed variations in cord blood T cell levels to the immune status of the newborn children is 

unknown. The findings from this study are inadequate to determine if maternal exposure to naphthalene 

may influence the immune status of newborn children. 

Studies that have examined age-related effects of toxicokinetic variables specifically related to 

naphthalene are restricted to a study with results indicating that neonatal mice may be more susceptible 

than adult mice to lung injury from single intraperitoneal doses of 25, 50, or 100 mg/kg naphthalene 

(Fanucchi et al. 1997). Epithelial damage in terminal bronchioles (principally in the Clara cells) was 

observed in 7-day-old mice exposed to 25 mg/kg, but was absent in adult mice at the same dose level. In 

adult mice exposed to 50 mg/kg, injury was only mild and variable (from mouse to mouse) and only 

became consistent with exposure to 100 mg/kg. Epithelial damage in 14-day-old mice was less severe 

than the damage in 7-day-old mice. Activities of CYP-mediated naphthalene metabolism in bronchiolar 

tissues were 2.5 times lower in neonatal mice than in adult mice, suggesting that the difference in 

susceptibility is not explained by differences in ability to form reactive metabolites alone (e.g., 

1,2-naphthalene oxide). Differences between neonates and adults in the balance between formation of 

reactive naphthalene metabolites and downstream transformations could potentially explain the difference 

in susceptibility to naphthalene toxicity, but the possibilities for specific, age-related differences in 

downstream enzyme activities for naphthalene (e.g., epoxide hydrolase, dihydrodiol dehydrogenase) have 

not been studied to date. Alternatively, toxicodynamic differences may exist between neonatal and adult 

mice (e.g., different target macromolecules). Based on findings that in utero exposure to other chemicals, 

which are bioactivated by CYP, caused Clara cell tumors in adult offspring, Fanucchi et al. (1997) 

postulated that naphthalene exposure during the neonatal period, when increased susceptibility to 

naphthalene-induced cytotoxicity occurs, may lead to loss of regulatory mechanisms resulting in Clara 

cell proliferation and tumor formation in adult animals, but direct evidence for naphthalene in support of 

this hypothesis is not available (e.g., demonstration that in utero or neonatal naphthalene exposure will 

cause increased incidence of lung tumors in adult mice). 
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No direct information was located on the relative susceptibility of children or young animals to 1-methylnaphthalene or 2-methylnaphthalene toxicity, compared with adults. However, clinical experience with 

humans displaying pulmonary alveolar proteinosis of unknown etiology has indicated that children with 

this condition experience more severe symptoms and a poor prognosis for survival than do adults (EPA 

2003r; Mazzone et al. 2001). 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic 

substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target 

molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The 

preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in 

readily obtainable body fluid(s) or excreta. However, several factors can confound the use and 

interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures 

from more than one source. The substance being measured may be a metabolite of another xenobiotic 

substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic 

compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental 

conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the 

body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous 

substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as 

copper, zinc, and selenium). Biomarkers of exposure to naphthalene, 1-methylnaphthalene, and 

2-methylnaphthalene are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 
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capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene are discussed in Section 3.8.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10, Populations That Are Unusually Susceptible. 

Additional information concerning biomarkers for effects on the immune, renal, and hepatic systems can 

be found in the CDC/ATSDR Subcommittee Report on Biological Indicators of Organ Damage 

(CDC/ATSDR 1990), and on the neurological system in the Office of Technology Assessment Report on 

Identifying and Controlling Poisons of the Nervous System (OTA 1990). Additional details concerning 

the health effects caused by naphthalene can be found in Section 3.2. 

3.8.1 	 Biomarkers Used to Identify or Quantify Exposure to Naphthalene, 1-Methylnaphthalene, and 2-Methylnaphthalene 

In cases where humans have swallowed one or more mothballs, it is possible to identify the undissolved 

naphthalene in the stomach or duodenum by radioluminescence (Woolf et al. 1993). Thus, radiography of 

the abdominal area is of value in determining if exposure has occurred, especially in children who are 

often unreliable sources of exposure information. Of the 2,400 cases on naphthalene ingestion reported to 

72 Poison Control Centers in the United States, 2,100 involve children less than 6 years old. Radioluminescence has the advantage of differentiating naphthalene-containing solids in the gastrointestinal 

tract from paradichlorobenzene or other materials used in moth repellants and deodorizers. 

Methods are available for the determination of naphthalene in human adipose tissue (EPA 1986g; Liao et 

al. 1988). In the National Human Adipose Tissue Survey, 40% of the subjects surveyed had measurable 

levels of naphthalene with concentrations of up to 63 ng/g. Naphthalene and its metabolites can be 

detected in human and animal urine (Horning et al. 1980; Mackell et al. 1951; Stillwell et al. 1982). 

Investigators have reported strong correlations between 1-naphthol concentrations in the urine of exposed 

workers and naphthalene concentrations in the breathing zone air (Bieniek 1994). Peak naphthalene 

concentrations in the urine occurred immediately after the end of the exposure period and declined 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 131 

3. HEALTH EFFECTS 

thereafter. In some instances, 1-naphthol concentrations had returned to baseline 8 hours later. Few 

current data are available relating naphthalene levels in adipose tissue or urine with the human exposure 

concentrations. 

In swine, a good correlation existed between 1-naphthol levels in hydrolyzed urine samples collected in 

the first and second 24 hours after dosing with as little as 7 μg/kg/day naphthalene (Keimig and Morgan 

1986). Thus, 1-naphthol may be an appropriate biomarker for monitoring naphthalene exposures in the 

occupational setting. Some caution must be exercised in using 1-naphthol as a biomarker of naphthalene 

exposure in the general population since this metabolite is also excreted after exposure to the common 

insecticide, carbaryl (Benson and Dorough 1984). 

Early work to develop biomarkers of exposure, such as naphthalene mercapturic acid derivatives in urine 

(Marco et al. 1993) and naphthalene hemoglobin adducts in blood (Cho et al. 1994b), has been extended 

to develop techniques to measure cysteinyl adducts formed from reactions of hemoglobin and albumin 

with reactive metabolites of naphthalene (Troester et al. 2002; Waidyanatha et al. 2002). One of the 

reasons for developing these techniques is that it is difficult to measure reactive metabolites of 

naphthalene in vivo. Using these techniques, hemoglobin and albumin adducts of 1,2-naphthalene oxide, 

1,2-naphthoquinone, and 1,4-naphthoquinone were shown to increase with increasing dose in F344 rats 

given single oral doses of 0, 100, 200, 400, or 800 mg/kg naphthalene (Waidyanatha et al. 2002). The 

stabilities of the adducts were measured in rats following exposure to naphthalene (Troester et al. 2002). 

Some were found to be stable and others unstable, although they all were more stable than the reactive 

metabolites themselves. As such, the adducts are expected to be useful in estimating internal doses of 

these metabolites. 

An analytical method is available to determine levels of 2-methylnaphthalene and its derivatives in rat 

urine (Melancon et al. 1982). This method would probably also be useful in measuring 2-methylnaphthalene levels in human urine. Because of the lack of information for 1-methylnaphthalene, it is not 

possible to identify a biomarker of exposure for this substance. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 132 

3. HEALTH EFFECTS 

3.8.2 	 Biomarkers Used to Characterize Effects Caused by Naphthalene, 1-Methylnaphthalene, and 2-Methylnaphthalene 

Hemolytic anemia has been frequently reported to be a consequence of exposure to naphthalene. 

However, this effect can also occur without exposure to naphthalene, and may not be useful as a specific 

biomarker of effect. 

Clara cell damage may be identified by the presence of naphthalene/protein adducts in lung lavage fluids 

(Cho et al. 1994a). Additional research is needed to improve the specificity of this technique as a 

biomarker of effect. 

Because of the lack of information for 1-methylnaphthalene or 2-methylnaphthalene, it is not possible to 

identify a biomarker of effects for these chemicals. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

When either naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene was applied dermally in 

combination with benzo[a]pyrene (BaP), there was an inhibitory effect on the induction of skin tumors in 

female mice (Schmeltz et al. 1978). These investigators also reported that a mixture containing 

naphthalene (0.02%), 2-methylnaphthalene (0.02%) and 10 other methylated and ethylated naphthalenes 

(each at 0.02%) also appeared to inhibit the development of BaP-induced skin tumors. The authors 

suggested that it is likely that certain naphthalenes compete with BaP for the same enzyme sites, resulting 

in alteration of the BaP metabolic pathway and decreased production of the active BaP metabolite. This 

hypothesis is consistent with the observation that benzo(a)pyrene hydroxylase is inhibited by naphthalene 

(Shopp et al. 1984). Dermal application of the naphthalene mixture did not induce tumors in the absence 

of BaP. The results of these studies were not analyzed statistically. 

Several studies have been conducted to assess factors that influence the toxicity of naphthalene. For the 

most part, these studies have evaluated the effects of mixed function oxidase activity (MFO) and 

alterations in glutathione levels on pulmonary and ocular toxicities. The effects of cyclooxygenase 

activity, antioxidants, and epoxide hydrolase inhibitors on the cataractogenic effect of naphthalene have 

also been evaluated. The administration of MFO inhibitors (SKF-525A, metyrapone) and antioxidants 

(caffeic acid and vitamin E) decreased ocular toxicity in mice (Wells et al. 1989). Use of ALO1576, an 

inhibitor of the enzyme aldose reductase, prevented cataract formation in both in vivo and in vitro studies 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 133 

3. HEALTH EFFECTS 

(Xu et al. 1992a, 1992b). On the other hand, naphthalene-induced cataracts were enhanced by 

pretreatment with a MFO inducer (phenobarbital) and a glutathione depletor (diethyl maleate) (Wells 

et al. 1989). Pulmonary damage was decreased by prior treatment with a MFO inhibitor (piperonyl 

butoxide), but enhanced by prior treatment with a glutathione depletor (diethyl maleate) (Warren et al. 

1982). For the most part, these studies support the role for mixed function oxidase activity and 

glutathione conjugation in naphthalene-induced pulmonary and ocular lesions. 

Mixed function oxidase inducers also affect the metabolism of 2-methylnaphthalene. Inducers that 

influence cytochrome P-450 increase the oxidation of the side chain and the concentration of one 

dihydrodiol. Induction of cytochrome P-450 increased the production of two other dihydrodiols 

(Melancon et al. 1985). The production of naphthoic acid in preference to the diols may explain why 

acute exposure to 2-methylnaphthalene is less toxic to Clara cells than acute exposure to naphthalene. 

In general, interactions with environmental contaminants, such as polycyclic aromatic hydrocarbons, 

should be expected at hazardous waste sites. Most hazardous waste sites (with the notable exception of 

certain pharmaceutical sites) would not be expected to contain substantial volumes of certain types of 

contaminants, such as antioxidants or cytochrome P-450 inhibitors. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene than will most persons exposed to the same level of naphthalene, 

1-methylnaphthalene, and 2-methylnaphthalene in the environment. Reasons may include genetic 

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters result in reduced detoxification or excretion of naphthalene, 1-methylnaphthalene, or 

2-methylnaphthalene, or compromised function of organs affected by naphthalene, 1-methylnaphthalene, 

or 2-methylnaphthalene. Populations who are at greater risk due to their unusually high exposure to 

naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene are discussed in Section 6.7, Populations 

with Potentially High Exposures. 

The hemolytic response to naphthalene is enhanced by the presence of inherited erythrocyte G6PD 

deficiency. Although any human may experience acute hemolysis if exposed to a sufficiently high dose 

of naphthalene, this enzyme deficiency may cause some persons to be unusually sensitive. The incidence 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 134 

3. HEALTH EFFECTS 

of the deficiency among Caucasians of European origin is relatively low, while there is a higher incidence 

among certain groups of Asians and Middle Eastern populations. A study of hemolytic anemia in 

African-American children with G6PD deficiency by Shannon and Buchanan (1982) suggests that this is 

a population that may be susceptible to the hemolytic effects of naphthalene exposure. It was also 

reported that 16% of African-American males are G6PD-deficient (Calabrese 1986). According to 

Shannon and Buchanan (1982), a syndrome of acute severe hemolysis following exposure to oxidative 

stress is associated with the Mediterranean variant of the deficiency, whereas the hemolytic anemia seen 

in African-Americans is generally mild. 

Results from a recent study indicate that female mice are more susceptible than male mice to lung injury 

from acute parenteral exposure to naphthalene (Van Winkle et al. 2002). Male and female Swiss-Webster 

mice were given intraperitoneal injections of 0 or 200 mg/kg naphthalene in corn oil, and lungs were 

removed at 1, 2, 3, 6, and 24 hours after treatment. Acute lung injury was determined by (1) highresolution microscopic assessment of differential permeability to fluorescent nuclear dyes in cells along 

the long axis of conducting airway trees of microdissected right middle lung lobes and (2) high-resolution 

histopathology of sections of Karnovsky-fixed left lung lobes. Clara cell injury occurred in the terminal 

bronchioles of both male and female mice. Clara cell injury in terminal bronchioles, however, occurred 

earlier, affected cells farther up the airway tree, and showed a different temporal pattern of changes in 

female mice compared with male mice. Twenty-four hours after injection, Clara cell injury in the lobar 

bronchus of female mice was evidenced by numerous vacuolated cells, whereas normal bronchiolar 

epithelium containing Clara and ciliated cells was found in vehicle-control males and females, as well as 

in exposed male mice. Assessment of in vitro naphthalene metabolism in microdissected regions of 

airways from male and female mice by high performance liquid chromatography (HPLC) analysis 

indicated that the rate of formation of a dihydrodiol metabolite (1,2-dihydroxy-1,2-dihydronaphthalene) 

was greater in female tissue than in male tissue. This metabolic difference may be related to the apparent 

gender difference in susceptibility to acute lung injury from naphthalene. It is unknown whether or not 

the gender difference in susceptibility to acute lung injury is relevant to nasal or lung lesions formed with 

chronic-duration exposure to naphthalene. 

There are no data that indicate whether there are populations that are unusually susceptible to the toxic 

effects of 1-methylnaphthalene or 2-methylnaphthalene. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 135 

3. HEALTH EFFECTS 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. However, because some of the 

treatments discussed may be experimental and unproven, this section should not be used as a guide for 

treatment of exposures to naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. When specific 

exposures have occurred, poison control centers and medical toxicologists should be consulted for 

medical advice. The following texts provide specific information about treatment following exposures to 

naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene: 

Kurz JM. 1987. Naphthalene poisoning: Critical care nursing techniques. Dimens Crit Care Nurs 

6:264-270. 

Melzer-Lange M, Walsh-Kelly C. 1989. Naphthalene-induced hemolysis in a black female toddler 

deficient in glucose-6-phosphate dehydrogenase. Pediatr Emerg Care 5:24-26. 

Siegel E, Wason S. 1986. Mothball toxicity. Pediatr Clin North Am 33:369-374. 

Stutz DR, Janusz SJ. 1988. Hazardous materials injuries: A handbook for pre-hospital care. Second 

edition. Beltsville, MD: Bradford Communications Corporation. 

3.11.1 Reducing Peak Absorption Following Exposure 

If inhalation of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene has occurred, movement to 

fresh air is recommended. In cases where a small amount (e.g., one mothball, 0.5–3.6 g) of naphthalene 

has been ingested, measures are implemented to empty the stomach contents. Syrup of Ipecac, which 

may be used for this purpose, is administered after ingestion to induce vomiting and is most effective if 

initiated within a 2-hour period after exposure (Siegel and Wason 1986). If large quantities of 

naphthalene have been ingested, syrup-of-ipecac-induced vomiting is usually followed by gastric 

aspiration using a large gauge lavaculator (to remove mothballs) (Kurz 1987). This will only be of value 

if the naphthalene particles are small enough to be aspirated. Measures are usually taken to protect the 

respiratory tract from aspiration of gastric contents. Activated charcoal can be given to bind dissolved 

naphthalene in the gastrointestinal tract. Further treatment with a cathartic (e.g., magnesium sulfate) to 

speed fecal excretion is recommended (Melzer-Lange and Walsh-Kelly 1989). Milk or fatty meals 

ingested within 2–3 hours after exposure may increase absorption (Siegel and Wason 1986). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 136 

3. HEALTH EFFECTS 

In order to reduce absorption of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene through the 

skin, areas of skin that have come in contact with the compound should be washed with soap and water. 

Application of oil based lotions should be avoided. If these compounds are splashed into the eyes, 

irrigation with large amounts of water for 15–30 minutes may be useful to wash away unabsorbed 

material (Stutz and Janusz 1988). 

3.11.2 Reducing Body Burden 

Some evidence exists that naphthalene metabolites may be retained in the body in adipose tissue (EPA 

1986g). Naphthalene was identified in 40% of the samples evaluated for the Human Adipose Tissue 

Survey (EPA 1986g). Naphthalene metabolites were detected in urine up to 13 days following exposure 

(Mackell et al. 1951). 

The most frequently documented acute toxic effect of naphthalene in humans is red cell hemolysis. In 

cases of clinically significant hemolysis, accelerated urinary excretion of naphthol metabolites is 

recommended to protect the kidney from products of hemolysis (EPA 1989d). In cases of renal failure, 

hemodialysis may be effective in controlling extracellular fluid (plasma) composition (EPA 1989d). It 

should be noted that this method is not very effective in removing lipophilic compounds from blood. 

Ocular effects have also been reported in humans; however, there are no specific treatments for reducing 

the toxic effects on the eyes. Respiratory effects have been observed in animals but these effects have not 

been reported in humans. Due to lack of data, it is difficult to speculate regarding the benefits of 

treatments that enhance elimination of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene and 

their metabolites as a basis for reducing toxic effects. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

Existing data indicate that lung, nose, and eye toxicity may be mediated by reactive metabolites for 

naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene, although the evidence for the involvement 

of reactive metabolites is greater than the evidence for methylnaphthalenes. More information is needed 

on the bioactivation of naphthalene and transport mechanisms before methods for blocking those 

mechanisms can be developed. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 137 

3. HEALTH EFFECTS 

Many of the symptoms of acute naphthalene poisoning in humans are a direct consequence of red blood 

cell hemolysis. Blood transfusions, packed red blood cell transfusions, and exchange transfusions 

(particularly in infants) can be used to replenish the concentration of red blood cells and diminish the 

risks of cellular anoxia (Bregman 1954; Chusid and Fried 1955; MacGregor 1954; Mackell et al. 1951). 

Bicarbonate is also administered to hemolysis patients to increase the alkalinity of the urine and thereby 

minimize deposition of hemoglobin in the kidney tubules (Chusid and Fried 1955; Gidron and Leurer 

1956). 

3.12 ADEQUACY OF THE DATABASE 

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene is available. Where adequate information is not available, ATSDR, in conjunction with the 

National Toxicology Program (NTP), is required to assure the initiation of a program of research designed 

to determine the health effects (and techniques for developing methods to determine such health effects) 

of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.12.1 	 Existing Information on Health Effects of Naphthalene, 1-Methylnaphthalene, and 

2-Methylnaphthalene 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene are summarized in Figures 3-6, 3-7, and 3-8, 

respectively. The purpose of this figure is to illustrate the existing information concerning the health 

effects of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. Each dot in the figure indicates 

that one or more studies provide information associated with that particular effect. The dot does not 

necessarily imply anything about the quality of the study or studies, nor should missing information in 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 138 

3. HEALTH EFFECTS 

Figure 3-6. Existing Information on Health Effects of Naphthalene 

Death

Acute 

Intermediate 

Chronic 

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Reproductive 

Developmental 

Genotoxic 

Cancer 

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NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 139 

3. HEALTH EFFECTS 

Figure 3-7. Existing Information on Health Effects of 1-Methylnaphthalene 

Death

Acute 

Intermediate 

Chronic 

mmunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

ic System

I 

Inhalation 

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NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 140 

3. HEALTH EFFECTS 

Figure 3-8. Existing Information on Health Effects of 2-Methylnaphthalene 

Death

Acute 

Intermediate 

Chronic 

mmunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

ic System

I 

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NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 141 

3. HEALTH EFFECTS 

this figure be interpreted as a “data need”. A data need, as defined in ATSDR’s Decision Guide for 

Identifying Substance-Specific Data Needs Related to Toxicological Profiles (Agency for Toxic 

Substances and Disease Registry 1989), is substance-specific information necessary to conduct 

comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any 

substance-specific information missing from the scientific literature. 

Figure 3-6 shows that the database on naphthalene toxicity in humans is not extensive. There are case 

reports and case series of deaths, acute hemolytic anemia, and ocular effects in humans, but these reports 

lack quantitative information on exposure levels. Epidemiologic studies designed to examine possible 

associations between intermediate- or chronic-duration human exposure to naphthalene by any route of 

exposure and neoplastic or nonneoplastic health effects are not available. Animal data on naphthalene 

exist in several areas. Oral toxicity data are adequate for deriving acute- and intermediate-duration oral 

MRLs, but adequate chronic-duration oral toxicity studies in animals are not available. Available 

toxicology and carcinogenesis studies of chronic inhalation exposure to naphthalene in rats and mice are 

adequate for deriving a chronic-duration inhalation MRL for naphthalene and assessing the potential 

carcinogenicity of naphthalene, but available acute- and intermediate-duration inhalation toxicity studies 

are not adequate for deriving MRLs. 

Figures 3-7 and 3-8 show that no information was located on the health effects of 1-methylnaphthalene or 

2-methylnaphthalene in humans via inhalation, oral, or dermal exposure. These figures also reflect that 

data in animals are limited to cancer and toxicity studies of intermediate- and chronic-duration oral 

exposure of mice to 1-methylnaphthalene or 2-methylnaphthalene, a single poorly reported acute 

inhalation exposure study of hematologic end points in dogs exposed by inhalation to 1-methylnaphthalene or 2-methylnaphthalene, a study that reported decreased pain sensitivity, but no effects on the 

ability to balance on a rotating rod, in rats exposed for 4 hours by inhalation to 1-methylnaphthalene or 

2-methylnaphthalene, and cancer and toxicity studies of intermediate- and chronic-duration dermal 

exposure of mice to a mixture of 1-methylnaphthalene and 2-methylnaphthalene. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. A number of reports of human exposure to acute inhalation, oral, or 

dermal doses of naphthalene have established the erythrocyte as a toxicity target (Dawson et al. 1958; 

Haggerty 1956; Kurz 1987; Linick 1983; MacGregor 1954; Mackell et al. 1951; Melzer-Lange and 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 142 

3. HEALTH EFFECTS 

Walsh-Kelly 1989; Ojwang et al. 1985; Schafer 1951; Shannon and Buchanan 1982; Valaes et al. 1963). 

However, the data from these reports were not useful in predicting toxic or lethal dose levels by any of 

these routes because the exposure levels were not defined. 

The acute oral toxicity of naphthalene has been studied in animals but there are limited data for acute 

inhalation and dermal exposures. 

The most frequently reported adverse effects associated with acute oral exposure are ocular lesions 

(primarily cataracts). These have been observed in rabbits (Srivastava and Nath 1969; Van Heyningen 

and Pirie 1967) and rats (Kojima 1992; Murano et al. 1993; Rathburn et al. 1990; Tao et al. 1991; 

Yamauchi et al. 1986) and occur following exposure to high (>500 mg/kg) doses. Acute oral exposure of 

pregnant rats to naphthalene doses of 150 or 450 mg/kg/day (but not 50 mg/kg/day) during gestation 

produced maternal toxicity including clinical signs (lethargy and prone position) and marked decreases in 

body weight gain (NTP 1991a), but clear effects on the developing fetus have not been found at maternal 

oral doses as high as 450 mg/kg/day in rats (NTP 1991a), 300 mg/kg/day in mice (Plasterer et al. 1985), 

or 120 (NTP 1992b) or 400 mg/kg/day (PRI 1985i,1986) in rabbits. Slightly reduced numbers of mouse 

pups per litter were observed when naphthalene in corn oil was orally administered to pregnant mice 

(Plasterer et al. 1985); however, no effects were seen when pregnant rabbits were orally administered 

naphthalene at even higher doses but delivered in methylcellulose rather than in an oil vehicle (PRI 1986). 

It is unclear if these differences are due to species differences in sensitivity or to possible differences in 

the effects of the two vehicles on naphthalene absorption. Effects on liver (Rao and Pandya 1981) and 

lung (Shopp et al. 1984) weights have been reported, but no treatment-related histopathological lesions 

were observed in these acute oral exposure studies. Lethal doses have been identified in mice (Plasterer 

et al. 1985; Shopp et al. 1984) and rats (Gaines 1969). 

The finding of transient clinical signs of toxicity in orally-exposed pregnant rats (NTP 1991a) serves as 

the basis of the acute-duration oral MRL for naphthalene. The MRL was calculated from a minimal 

LOAEL of 50 mg/kg/day using an uncertainty factor of 90 (3 for the use of a minimal LOAEL, 10 for 

extrapolation from animals to humans, and 3 for human variability). An uncertainty factor of 3 was used 

for human variability because the critical effect is based on effects in a sensitive animal subpopulation. 

Dermal or inhalation developmental toxicity studies in animals are not available. Pregnant rats appear to 

be more sensitive for the effects observed (clinical signs in response to gavage exposure and decreased 

body weight gain) than nonpregnant rats. In 13-week gavage studies with nonpregnant rats (NTP 1980b), 

similar persistent clinical signs were not observed following administration of doses as high as 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 143 

3. HEALTH EFFECTS 

200 mg/kg/day, but were observed at 400 mg/kg/day. In nonpregnant rats exposed for 13 weeks, 

significant body weight decreases occurred at 200 mg/kg/day throughout exposure, but not at 

100 mg/kg/day (NTP 1980b) or in nonpregnant mice exposed for 13 weeks to 133 mg/kg/day (Shopp et 

al. 1984) or 200 mg/kg/day (NTP 1980a). Mice in the NTP (1980a) study showed transient signs of 

toxicity (lethargy, rough hair coats, and decreased food consumption), but these only occurred between 

weeks 3 and 5 in the 200-mg/kg/day group. 

Data are inadequate for deriving an acute-duration inhalation MRL for naphthalene. Data are restricted to 

a 14-day (6 hours/day, 5 days/week) range-finding study in B6C3F1 mice (NTP 1992a), which only 

examined hematologic end points and did not histologically examine expected critical toxicity targets 

(lung and nasal cavity epithelial tissue) (NTP 1992a), and a study (West et al. 2001) with Swiss Webster 

mice and Sprague-Dawley rats, which involved single 4-hour exposure periods. The more recent study, 

however, only histologically examined the lung and did not examine nasal tissue. A comprehensive 

inhalation study involving an acute repeated exposure scenario and examining the other critical target (the 

nose, based on the findings from chronic mouse and rat bioassays) is not currently available. Results 

from such a study may be useful for deriving an acute-duration inhalation MRL for naphthalene. 

Hemolysis is the best documented effect of acute naphthalene exposures in humans, but it has not been 

observed in studied strains of rats (F344) or mice (CD-1, B6C3F1). Dose-response data for hemolysis 

from a susceptible animal species (such as dogs or the Jackson Laboratory hemolytic anemia mouse) may 

be useful to obtain data that could be used for considering changes to the acute-duration oral MRL. Data 

from both inhalation and oral exposure protocols would be useful. 

No acute-duration studies are available on 1-methylnaphthalene or 2-methylnaphthalene exposure in 

humans using the inhalation, oral, or dermal routes. Two acute inhalation studies in animals were 

identified. The first study reported that 1-methylnaphthalene (pure) administered in a kerosene aerosol 

was associated with increased reticulocyte and lymphocyte counts in splenectomized dogs and practical 

grade 1-methylnaphthalene was associated with increased leucocyte and neutrophil counts (Lorber 1972). 

Neither grade of 1-methylnaphthalene had any effect on hematocrit values. None of these parameters 

were affected when 2-methylnaphthalene aerosols were used. The physiological significance of these 

findings is not apparent and the exposure levels in the study were not clearly specified. As such, the data 

are not suitable for use in deriving an MRL for 1-methylnaphthalene or 2-methylnaphthalene. The second 

study measured decreased sensitivity to pain in rats exposed by inhalation for 4 hours to 1-methylnaphthalene (44 ppm) or 2-methylnaphthalene (61 ppm), but found no effects on the ability to balance on 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 144 

3. HEALTH EFFECTS 

a rotating rod at exposure levels as high as 70 ppm 1-methylnaphthalene or 90 ppm 2-methylnaphthalene 

(Korsak et al. 1998). The biological significance of these findings is uncertain, and, in the absence of 

corroborative evidence of acute neurotoxicity, the findings are not suitable for deriving acute inhalation 

MRLs for 1-methylnaphthalene or 2-methylnaphthalene. 

Parenteral studies in animals revealed that a single intraperitoneal injection of 2-methylnaphthalene 

(1,000 mg/kg) was lethal in mice (Griffin et al. 1981). When a glutathione-depleting agent (diethyl 

maleate) was administered prior to administration of 2-methylnaphthalene, a lower dose of 2-methylnaphthalene (400 mg/kg) was also lethal. A single intraperitoneal injection of 1-methylnaphthalene 

(426 mg/kg) was not lethal in mice (Griffin et al. 1982). Systemic effects have been reported and were 

limited to effects on the respiratory system (Rasmussen et al. 1986). Exfoliation of the bronchiolar 

epithelium in mice was reported following a single intraperitoneal injection of 2-methylnaphthalene 

(Buckpitt et al. 1986; Griffin et al. 1981, 1983). A single intraperitoneal injection of 2-methylnaphthalene 

(1,000 mg/kg) did not cause liver or kidney lesions (Griffin et al. 1981, 1983). 

Because populations living near hazardous waste sites might be exposed to 1-methylnaphthalene or 

2-methylnaphthalene for short periods, comprehensive toxicity studies of acute exposure in animals by 

the inhalation and oral routes to determine potential target tissues and dose-related effects would be useful 

in assessing possible health hazards to humans. The studies would be most useful if they included a 

battery of neurological end points and comprehensive histological examination of nasal and lung tissue. 

Intermediate-Duration Exposure. Quantitative data were not provided in any intermediateduration inhalation case studies of human naphthalene exposure and, in one case, there was simultaneous 

exposure to paradichlorobenzene (Harden and Baetjer 1978; Linick 1983). 

The results from three intermediate-duration oral toxicity studies in animals (two in mice and one in rats) 

identified body weight changes as the most sensitive biologically significant effect on which to base the 

intermediate-duration oral MRL for naphthalene. Comprehensive intermediate-duration oral toxicity 

studies found no evidence for naphthalene-induced lesions in any tissue or organs in male or female 

Fischer 344 rats exposed to doses up to 400 mg/kg/day (NTP 1980b) or in male or female B6C3F1 mice 

exposed to doses up to 200 mg/kg/day (NTP 1980a). The only biologically significant effect found in 

these studies was decreased body weight (>10% decreased compared with control values) in rats at doses 

of 200 and 400 mg/kg/day. The other intermediate-duration oral study (with CD-1 mice) focused on a 

battery of immunologic tests, but did not include comprehensive histopathologic examination of tissues 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 145 

3. HEALTH EFFECTS 

(Shopp et al. 1984). No biologically significant effects were found except for decreases in weights of 

several organs (brain, liver, and spleen) in mice exposed to 133 mg/kg/day, but not to 53 or 

5.3 mg/kg/day. The lack of naphthalene-induced lesions in these organs in the NTP (1980a, 1980b) 

studies suggests that the brain, liver, and spleen are not sensitive targets of naphthalene following 

intermediate-duration oral exposure. Statistically significant changes were reported in several 

hematological parameters, hepatic enzyme activities, and serum chemical parameters (Shopp et al. 1984), 

but these changes are not considered to be biologically significant or adverse. The acute-duration oral 

MRL was adopted as the intermediate-duration oral MRL for naphthalene, because a potential 

intermediate-duration oral MRL (see Section 2.3 and Appendix A) based on the NOAEL for decreased 

body weight changes in rats exposed by gavage 5 days/week for 13 weeks (NTP 1980b) was slightly 

larger than the acute MRL value. 

No data were suitable for the development on an intermediate-duration inhalation MRL for naphthalene. 

Intermediate-duration dermal toxicity data are restricted to an report that dermal exposure of male and 

female Sprague-Dawley rats (occluded exposure 6 hours/day, 5 days/week) to technical-grade 

naphthalene at doses up to 1,000 mg/kg/day for 13 weeks did not affect comprehensive ophthalmologic, 

hematologic, serum chemistry, or urinalysis parameters (Frantz et al. 1986). In addition, exposure did not 

produce increased incidences of histological lesions in 34 tissues that were examined (however, the nasal 

cavity was not included). The only exposure-related effect found was an increased incidence of 

excoriated skin and papules at the site of exposure at the highest dose level (1,000 mg/kg/day). 

Intermediate-duration studies on 1-methylnaphthalene or 2-methylnaphthalene exposure in humans or 

animals using the inhalation, oral, or dermal routes are restricted to a study that found no pulmonary 

alveolar proteinosis in male or female mice exposed to diets containing up to 1.33% 2-methylnaphthalene 

for 13 weeks (Murata et al. 1997). The reporting of the experimental protocol and results from this study, 

however, is too limited to reliably use the results as a basis for an intermediate-duration oral MRL for 

2-methylnaphthalene. New intermediate-duration toxicity studies using the inhalation route of exposure 

may be the most useful to better assess the health hazard of intermediate-duration exposure to 

naphthalene, based on the findings that the alveolar region of the lung is the most sensitive tissue in mice 

chronically exposed to 1-methylnaphthalene or 2-methylnaphthalene in the diet (Murata et al. 1993, 

1997). 
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3. HEALTH EFFECTS 

Chronic-Duration Exposure and Cancer. There is one report of cataracts occurring in humans 

following chronic-duration inhalation exposure to naphthalene (Ghetti and Mariani 1956) but no 

information on effects from exposures by the oral or dermal routes. The only studies of cancer in humans 

exposed to naphthalene are two case series reports of cancer; one report of four laryngeal cancer cases (all 

of whom were smokers) among workers in a naphthalene purification plant in East Germany (Wolf 1976, 

1978), and another report of 23 cases of colorectal carcinoma admitted to a hospital in Nigeria (Ajao et al. 

1988). NTP (2002b), EPA (2002b), and IARC (2002) concurred that these studies provide inadequate 

evidence of naphthalene carcinogenicity in humans. No cohort mortality or morbidity studies or casecontrol studies examining possible associations between naphthalene exposure and increased risk of 

cancer (or other health effects) are available. 

There are two comprehensive chronic-duration inhalation toxicology and carcinogenicity studies of 

naphthalene in animals, one in rats (Abdo et al. 2001; NTP 2000) and one in mice (NTP 1992a). These 

studies identify respiratory tissues as the most sensitive toxicity targets of chronic-duration exposure to 

inhaled naphthalene in animals: nonneoplastic and neoplastic lesions in the nose of rats, nonneoplastic 

lesions in the nose of mice, and nonneoplastic and neoplastic lesions in the lungs of mice. Exposurerelated lesions in other tissues were not found in these studies. NTP (2002b) and IARC (2002) concurred 

that these studies provide sufficient evidence of naphthalene carcinogenicity in animals. The chronicduration inhalation MRL for naphthalene is based on the LOAEL of 10 ppm for nonneoplastic lesions in 

the olfactory epithelium and respiratory epithelium of the nose of rats. 

No appropriate studies were located for deriving an MRL for chronic-duration oral exposure to 

naphthalene. One chronic study was located that examined the toxicity of naphthalene in rats (Schmahl 

1955). No treatment-related effects were reported at a dose level of 41 mg/kg/day for 700 days. The 

study was not suitable as the basis for deriving a chronic MRL or for assessing carcinogenicity because 

only one dose level was evaluated (apparently below the maximum tolerated dose), histopathological 

examination was limited, and dosing was not precisely controlled. 

New chronic oral or dermal toxicity studies would be useful to better determine the possible 

carcinogenicity and noncancer toxicity of naphthalene via these routes of exposure. 

Epidemiology studies, case reports, or controlled-exposure studies examining the potential health effects 

of human chronic exposure to 1-methylnaphthalene or 2-methylnaphthalene by any route of exposure are 

not available. 
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3. HEALTH EFFECTS 

No chronic-duration studies are available on 1-methylnaphthalene or 2-methylnaphthalene exposure in 

animals using the inhalation routes. 

A chronic-duration study of 1-methylnaphthalene in the diet that identified a LOAEL of 71.6 mg/kg/day 

for the occurrence of pulmonary alveolar proteinosis in mice (Murata et al. 1993) was used as the basis of 

the oral MRL for 1-methylnaphthalene. A chronic-duration oral study of 2-methylnaphthalene in the diet 

(Murata et al. 1997) that identified a LOAEL of 50.3 mg/kg/day for pulmonary alveolar proteinosis in 

mice was the basis of the chronic oral MRL for 2-methylnaphthalene. Support for pulmonary alveolar 

proteinosis as the critical effect for the chronic oral MRLs for 1-methylnaphthalene and 2-methylnaphthalene comes from dermal chronic-duration studies with methylnaphthalene (a mixture of 1- and 

2-methylnaphthalene), which reported increased incidences of this lesion in mice dermally exposed to 

30 or 119 mg/kg of methylnaphthalene for 30–61 weeks (Emi and Konishi 1985; Murata et al. 1992). 

Increased incidences of lung adenomas were found in several exposed groups in the oral chronic-duration 

studies, but the evidence for carcinogenicity is considered to be limited. The tumorigenic response was 

predominantly benign and was only consistently seen in male mice exposed to 1-methylnaphthalene. The 

available data on the methylnaphthalenes appear inadequate to determine the potential carcinogenicity in 

humans. 

A new chronic-duration oral study in rats or another animal species may help to better assess the potential 

carcinogenicity and noncancer toxicity of the methylnaphthalenes. Because the lung is the most sensitive 

toxicity target of the methylnaphthalenes in mice exposed orally or dermally, it is plausible that chronic 

inhalation exposure may also target the lung. The availability of repeated-exposure inhalation 

carcinogenicity and toxicity studies would help to better determine this possibility. 

Genotoxicity. As discussed in Section 3.3, results in bacterial mutation assays were predominantly 

negative (see Table 3-4 for citations) with the exceptions that the metabolite, 1,2-naphthoquinone, was 

mutagenic in S. typhimurium without metabolic activation (Flowers-Geary 1996), and naphthalene was 

mutagenic in V. fischeri with metabolic activation (Arfsten et al. 1994). 

Results from a limited number of in vitro eukaryotic genotoxicity assays are mixed. Negative results 

were obtained for mutations and sister chromatid exchanges in cultured human cells exposed to 

naphthalene, for DNA single strand breaks and unscheduled DNA synthesis in rat hepatocytes, and for 

cell transformation in several types of mammalian cells (see Table 3-3 for citations). Positive results 
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3. HEALTH EFFECTS 

included increased chromosomal aberrations in Chinese hamster ovary cells and preimplantation whole 

mouse embryos exposed to naphthalene, and increased sister chromatid exchanges in human mononuclear 

leukocytes exposed to 1,2- or 1,4-naphthoquinone and in Chinese hamster ovary cells exposed to 

naphthalene (see Table 3-3 for citations). Other studies in cell-free systems reported that 

1,2-naphthoquinone formed N7 adducts with deoxyguanosine (McCoull et al. 1999) and caused DNA 

strand scission in the presence of NADPH and copper via reactive oxygen species from an 

oxidation/reduction cycle (Flowers et al. 1997). 

In vivo genotoxicity assays with naphthalene are also limited and do not provide consistently negative or 

positive results for naphthalene genotoxicity. Positive results were obtained for somatic mutations in 

D. melanogaster, micronuclei in salamander larvae erythrocytes, and DNA fragmentation in liver and 

brain tissue from mice and rats orally exposed to naphthalene (see Table 3-3 for citations). Negative 

results were obtained for micronuclei formation in bone marrow of mice given oral or intraperitoneal 

injections of naphthalene, DNA single strand breaks and unscheduled DNA synthesis in hepatocytes of 

rats given oral doses of naphthalene, and neoplastic transformations in liver cells of partially 

hepatectomized rats given oral doses of naphthalene (see Table 3-3 for citations). 

The available data suggest that genotoxic action by the naphthalene metabolite, 1,2-naphthoquinone, is 

plausible and that the mutagenic/genotoxic potential of naphthalene and its metabolites may be weak. 

Assays of possible genotoxic action in sensitive target tissues of naphthalene in rodents (lung and nasal 

epithelial tissue), however, are not available. New studies examining genotoxic end points in lung and 

nasal epithelial tissue following inhalation exposure to naphthalene would help to better determine the 

potential genotoxicity of naphthalene and it metabolites. 

For the methylnaphthalenes, data in humans are limited to one study that reported no effects on human 

chromosomes in tests evaluating the effects of 1-methylnaphthalene or 2-methylnaphthalene on human 

peripheral lymphocytes in vitro (Kulka et al. 1988). 1-Methylnaphthalene and 2-methylnaphthalene were 

also determined to be nonmutagenic in four strains of S. typhimurium (Florin et al. 1980). Additional 

mutagenicity studies using an in vivo approach would be useful to better assess the genotoxicity potentials 

of 1-methylnaphthalene and 2-methylnaphthalene. 

Reproductive Toxicity. No information is available on the reproductive effects of naphthalene in 

humans, although the occurrence of hemolytic anemia in the neonates of anemic, naphthalene-exposed 

mothers demonstrates that naphthalene and/or its metabolites can cross the placental barrier (Anziulewicz 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 149 

3. HEALTH EFFECTS 

et al. 1959; Zinkham and Childs 1957, 1958). Animal studies involving naphthalene exposure during 

gestation reported no reproductive effects in rabbits administered doses of up to 120 mg/kg/day by gavage 

or in rats given doses of up to 450 mg/kg/day, although doses of 150 mg/kg/day and greater were 

maternally toxic to rats. There was a decrease in the number of live mouse pups per litter with a dose of 

300 mg/kg/day given during gestation (Plasterer et al. 1985) and in vitro studies of naphthalene 

embryotoxicity in the presence of liver microsomes support the concept that naphthalene metabolites may 

be harmful to the developing embryo (Iyer et al. 1991). No exposure-related lesions in reproductive 

tissues were found in intermediate-duration oral exposure studies in rats (NTP 1980b) and mice (NTP 

1980a) or in chronic inhalation studies in rats (Abdo et al. 2001; NTP 2000) or mice (NTP 1992a). Oneor two-generation reproductive toxicity studies evaluating reproductive performance variables in male 

and female animals exposed to naphthalene are not available. Results from such studies may help to 

better determine the potential reproductive toxicity of naphthalene. 

No studies are available on the reproductive toxicity of 1-methylnaphthalene or 2-methylnaphthalene in 

humans or animals following inhalation, oral, or dermal exposure, with the exceptions of the reports that 

81-week oral exposure to 1-methylnaphthalene or 2-methylnaphthalene did not induce lesions in 

reproductive tissues of male or female mice (Murata et al. 1993; 1997). One- or two-generation 

reproductive toxicity studies evaluating reproductive performance variables in male and female animals 

exposed to 1-methylnaphthalene or 2-methylnaphthalene are not available. Results from such studies 

may help to better determine the potential reproductive toxicity of the methylnaphthalenes. 

Developmental Toxicity. There is no information on the potential developmental effects of 

naphthalene in humans, although, as mentioned previously, naphthalene and/or its metabolites can cross 

the placental barrier and cause hemolytic anemia in newborns (Anziulewicz et al. 1959; Zinkham and 

Childs 1957, 1958). Studies of the developmental effects of orally administered naphthalene in rats (NTP 

1991a), mice (Plasterer et al. 1985), and rabbits (NTP 1992b; PRI 1985i, 1986) have been negative, 

except for a slight nonsignificant increase in fused sternebrae in female rabbit pups from a small number 

of litters at doses of 80 and 120 mg/kg/day (NTP 1992b). No developmental toxicity studies involving 

inhalation or dermal exposure to naphthalene are available. The availability of such studies would help to 

better determine the developmental toxicity potential of naphthalene. 

No studies are available on the developmental toxicity of 1-methylnaphthalene or 2-methylnaphthalene in 

humans or animals following inhalation, oral, or dermal exposure. 
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3. HEALTH EFFECTS 

Immunotoxicity. There have been no comprehensive studies of the immunotoxicity of naphthalene in 

humans exposed by the inhalation, oral, or dermal routes. The animal oral exposure data indicate that 

naphthalene did not affect humoral or cell-mediated immunity in mice (Shopp et al. 1984). Minor effects 

on the thymus and spleen were noted in mice and rats (NTP 1980b; Shopp et al. 1984), but in no case 

were animals of both sexes affected. Because there are few data pertaining to the immunotoxicity of 

naphthalene, a battery of in vitro/in vivo screening assays of immune function may be useful to determine 

whether more detailed and longer-term studies are needed. 

No studies are available on the immunotoxicity of 1-methylnaphthalene or 2-methylnaphthalene in 

humans or animals following inhalation, oral, or dermal exposure. However, the reported increase in the 

level of monocytes in mice following long-term oral exposure to 1-methylnaphthalene (Murata et al. 

1993) may deserve additional study. As with naphthalene, a battery of in vitro/in vivo screening assays of 

immune function may be useful to determine whether more detailed and longer-term studies are needed. 

Neurotoxicity. The direct effects of naphthalene on the central nervous system have not been 

investigated in either humans or animals. Neurotoxic effects seen in humans exposed to naphthalene via 

inhalation or oral exposure may be a consequence of the diminished oxygen-carrying capacity of the 

blood which results from red cell hemolysis (Bregman 1954; Gupta et al. 1979; Kurz 1987; Linick 1983; 

MacGregor 1954; Ojwang et al. 1985; Zuelzer and Apt 1949). Persistent clinical signs of toxicity 

(lethargy and prone position) were seen in pregnant rats following gavage administration of naphthalene 

at dose levels of 150 or 450 mg/kg/day; at 50 mg/kg/day, the signs were only observed during the first 

2 days of dose administration (NTP 1991a). Comparable effects were not observed in F344/N rats 

exposed to doses of up to 400 mg/kg/day for 13 weeks or in B6C3F1 mice at doses of up to 

200 mg/kg/day (NTP 1980a, 1980b). With inhalation exposure, no treatment-related gross or 

histopathological lesions of the brain were observed in mice (NTP 1992a) or rats (Abdo et al. 2001; NTP 

2000) exposed for 2 years to naphthalene concentrations as high as 30 or 60 ppm, respectively. Clinical 

observations revealed no gross behavioral changes indicative of neurological impairment. Additional 

studies involving batteries of neurological end points following oral and/or inhalation exposure may help 

to better determine the potential neurotoxicity of naphthalene and explain why pregnant rats appear to be 

more susceptible to the behavioral effects of acute-duration exposures to naphthalene. 

No studies on the neurotoxicity of 1-methylnaphthalene or 2-methylnaphthalene in humans following 

inhalation, oral, or dermal exposure were located with the exception of a single study that found 

decreased sensitivity to pain in rats exposed by inhalation for 4 hours to 1-methylnaphthalene (44 ppm) or 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 151 

3. HEALTH EFFECTS 

2-methylnaphthalene (61 ppm), but no effects on rotarod performance at exposure levels as high as 

70 ppm 1-methylnaphthalene or 90 ppm 2-methylnaphthalene (Korsak et al. 1998). The biological 

significance of these findings is uncertain. Additional studies involving batteries of neurological end 

points may help to better determine the potential neurotoxicity of the methylnaphthalenes. 

Epidemiological and Human Dosimetry Studies. A small number of reports have equivocally 

suggested that workers exposed to naphthalene for long periods of time may have an elevated risk of 

cataract development (Ghetti and Mariani 1956; Lezenius 1902). This information, coupled with the 

cataractogenic effects of naphthalene in orally exposed rats (Kojima 1992; Xu et al. 1992b; Yamauchi 

et al. 1986) and rabbits (Rossa and Pau 1988; Srivastava and Nath 1969; Van Heyningen and Pirie 1967) 

in acute- and intermediate-duration studies, suggests that studies of occupationally-exposed workers 

would help to determine its potential to produce ocular toxicity in humans. The incidence of tumors, 

anemia, and reproductive problems in this population could be determined at the same time. Available 

case reports of cancer in naphthalene-exposed humans provide inadequate evidence of naphthalene 

carcinogenicity. Currently, no cohort mortality or morbidity studies or case-control studies examining 

possible associations between naphthalene exposure and increased risk of cancer (or other health effects) 

are available. If human populations that are specifically and repeatedly exposed to naphthalene can be 

identified, epidemiological studies of these populations may help to better assess the potential chronicduration toxicity and carcinogenicity of naphthalene. 

No epidemiological or human dosimetry studies on the effects of 1-methylnaphthalene or 2-methylnaphthalene were located. Exposure to these compounds, particularly through dermal contact or 

inhalation, can occur in workplaces where the compounds are produced or used. Populations living near 

hazardous waste sites can potentially be exposed by the oral, inhalation, and dermal routes. If an 

appropriate population can be identified, it may be helpful to conduct epidemiological studies to 

determine if there are toxic effects (particularly on the lungs) resulting from exposure to these substances. 

Biomarkers of Exposure and Effect. 

Exposure. There are methods to determine the presence of naphthalene in adipose tissue and these 

methods have been used in a national monitoring program for the analysis of naphthalene in the adipose 

tissue of the general population (EPA 1986g). Metabolites of naphthalene, such as naphthols and 

naphthoquinones, have been detected in the urine of a patient 4 days after ingestion of naphthalene 

(Zuelzer and Apt 1949), but not in another patient at 17 days after ingestion (Mackell et al. 1951). 
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3. HEALTH EFFECTS 

1-Naphthol is present in the urine of workers occupationally exposed to naphthalene. Maximum 

1-naphthol levels occurred immediately after the end of the work period and in some cases had returned 

to baseline levels 8 hours later (Bieniek 1994). New techniques have been developed to measure 

cysteinyl adducts formed from reactions of hemoglobin and albumin with reactive metabolites of 

naphthalene (Troester et al. 2002; Waidyanatha et al. 2002). The adducts are expected to be useful in 

estimating internal doses of these metabolites, and with further development, they may become useful 

biomarkers of exposure. 

Effect. There are no known specific biomarkers of effects for naphthalene, 1-methylnaphthalene, or 

2-methylnaphthalene. Hemolytic anemia has been frequently associated with human exposure to 

naphthalene, but may also be the result of exposure to other chemicals. Pulmonary alveolar proteinosis in 

mice has been associated with chronic oral exposure to 1-methylnaphthalene and 2-methylnaphthalene. 

The condition has been described in humans, but has not been associated with human exposure to 

1-methylnaphthalene or 2-methylnaphthalene. Currently, these effects (hemolytic anemia or pulmonary 

alveolar proteinosis) do not hold promise as specific biomarkers of effect for naphthalene or methylnaphthalenes. Identification of specific biomarkers of effect such as particular protein adducts in 

naphthalene-affected target tissues in animals (e.g., nasal epithelium tissue) may be useful to test whether 

similar biomarkers of effect may exist in naphthalene-exposed human populations. 

Absorption, Distribution, Metabolism, and Excretion. Although human absorption of 

naphthalene has not been quantitatively characterized, case reports indicate that humans can absorb 

toxicologically significant amounts of this compound by the oral, inhalation, or dermal routes (Bregman 

1954; Chusid and Fried 1955; Dawson et al. 1958; Gidron and Leurer 1956; Gupta et al. 1979; Haggerty 

1956; Kurz 1987; Linick 1983; MacGregor 1954; Mackell et al. 1951; Ojwang et al. 1985; 

Santhanakrishnan et al. 1973; Schafer 1951; Shannon and Buchanan 1982; Valaes et al. 1963; Zuelzer 

and Apt 1949). Laboratory animals such as rats, mice, and rabbits also absorb the chemical via their skin 

and gastrointestinal and respiratory tracts (NTP 1992a; Rao and Pandya 1981; Shopp et al. 1984; 

Srivastava and Nath 1969; Turkall et al. 1994; van Heyningen and Pirie 1967). Naphthalene adsorbed to 

organic-rich soils is absorbed across the skin more slowly than naphthalene from organic-poor soils 

(Turkall et al. 1994). The compound apparently partitions between the soil organic carbon and the 

hydrophobic components of the epidermis and dermis. More information concerning the mechanism of 

absorption (facilitated versus passive transport) across nasal and pulmonary epithelial membranes, the 

gastrointestinal tract, and the skin may be helpful in estimating the effect of dose on absorption 

coefficients and in better determining the effect of the medium of exposure (water, oil, food, etc.) on oral 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 153 

3. HEALTH EFFECTS 

or dermal absorption. Empirical measurements of permeability coefficients for naphthalene in blood or 

air with various tissues from various species may be useful to further develop PBPK models for 

naphthalene. 

As discussed in Sections 3.4.3 and 3.5.2, extensive research on the bioactivation and metabolic 

transformations of naphthalene in mammalian systems has identified several reactive metabolites that are 

potentially responsible for the nasal, pulmonary, and ocular toxicity of naphthalene (1,2-naphthalene 

oxide, 1,2-naphthoquinone, and 1,4-naphthoquinone), but the relative importance of these metabolites in 

affecting these toxicity targets remains uncertain. Because nasal respiratory and olfactory epithelia are 

the most sensitive targets in rodents following acute or chronic inhalation exposure, better understanding 

of the deposition, absorption, and metabolism of inhaled naphthalene in different regions of nasal 

epithelia, and the degree to which species (particularly rodents and primates) differ in these processes, 

may be useful for decreasing uncertainty in extrapolating human health hazards from data for rodents 

exposed to naphthalene. In vivo, in vitro, and modeling research approaches are likely to create better 

understanding of these processes, which may also provide explanations for observed species differences 

in response to naphthalene. For example, both rats and mice developed nonneoplastic nasal lesions 

following chronic inhalation exposure to naphthalene concentrations as low as 10 ppm, but only rats 

developed nasal tumors (Abdo et al. 2001; NTP 1992a, 2000). Other examples are the findings that in 

vitro rates of epoxide formation from naphthalene in extracts of nasal olfactory tissue showed the order, 

mouse>rat>hamster, but rats were more susceptible to acute nasal injury from naphthalene than mice or 

hamsters (Buckpitt et al. 1992; Plopper et al. 1992a). Mechanistic explanations for these differences are 

not currently available. 

The most recently developed PBPK models for naphthalene in mice and rats (Willems et al. 2001) do not 

include nasal compartments that metabolize naphthalene and do not include the spontaneous conversion 

of 1,2-naphthalene oxide to 1-naphthol or metabolic transformations to the naphthoquinones. Additional 

toxicokinetic data are needed to further refine these models to include these potentially important 

processes. Application of such further refined models, and the development of comparable models for 

humans, may be useful to decrease uncertainty in extrapolating dose-response relationships for nasal 

effect in rodents to humans. 

No studies were located on the absorption, metabolism, and excretion of 1-methylnaphthalene in humans 

or animals following inhalation, oral, or dermal exposure. There was one study of 2-methylnaphthalene 

in guinea pigs (Teshima et al. 1983). Parenteral studies in animals show that 2-methylnaphthalene is 
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3. HEALTH EFFECTS 

converted to both monohydrated compounds and dihydrodiols (Breger et al. 1981, 1983; Melancon et al. 

1982). In addition, 2-naphthoic acid and the glycine or the cysteine conjugates were identified in rats 

(Melancon et al. 1982) and guinea pigs (Teshima et al. 1983). Studies by relevant exposure routes would 

further characterize the toxicokinetics of these compounds and may enhance the understanding of the 

potential risk associated with exposure to these compounds. 

Comparative Toxicokinetics. Data suggest that there are strain- and species-specific effects 

associated with naphthalene toxicity. Laboratory animals, such as rats and mice, do not exhibit red cell 

hemolysis after exposure to naphthalene, while humans and dogs do (NTP 1980a, 1980b, 1992a; Shopp et 

al. 1984; Zuelzer and Apt 1949). Mice and rats both develop nonneoplastic nasal lesions after chronic 

inhalation exposure to naphthalene, but only rats develop nasal tumors, and only mice develop 

nonneoplastic lung lesions or lung tumors (Abdo et al. 2001; NTP 1992a; 2000). There are differences in 

susceptibility to the acute pulmonary toxicity of naphthalene among mice, rats, hamsters, and guinea pigs 

(Buckpitt et al. 2002; Plopper et al. 1992a, 1992b). Differences in the susceptibility of rats and mice, and 

of different mouse strains, to the cataractogenic properties of naphthalene have also been reported (Wells 

et al. 1989). These differences may relate to differences in tissue distribution of specific CYP isoenzymes, rates of formation of reactive metabolites, rates of transformation of reactive metabolites to 

nonreactive metabolites, or partitioning of the parent compound or metabolites within and between 

tissues. For example, the difference in susceptibility to the acute pulmonary toxicity of naphthalene 

between mice and rats has been correlated with higher rates of metabolic formation and different 

stereoselectivity of epoxide metabolites in mice compared with rats (Buckpitt et al. 1992; 1995; 2002). In 

contrast, differences among rat, mice and hamsters in susceptibility to naphthalene-induced nasal lesions 

were not correlated with species differences in rates of epoxide formation from naphthalene in extracts of 

olfactory epithelial tissue (Plopper et al. 1992; see Section 3.5.2). Further evaluation of these differences 

and comparative studies of distribution and metabolic patterns among species may help to decrease 

uncertainty in extrapolating estimates of human health hazards from data for animals exposed to 

naphthalene. 

There are no data available concerning the toxicokinetics of 1-methylnaphthalene or 2-methylnaphthalene 

in humans following inhalation, oral, or dermal exposure. There are no data from studies of 1-methylnaphthalene in animals, but there are limited data for 2-methylnaphthalene (Breger et al. 1983; Griffin et 

al. 1982; Melancon et al. 1982, 1985; Teshima et al. 1983). New studies that evaluate toxicokinetic 

parameters in several animal species may be useful to decrease uncertainty in the chronic oral MRLs for 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 155 

3. HEALTH EFFECTS 

1-methylnaphthalene and 2-methylnaphthalene, which are based on the occurrence of pulmonary alveolar 

proteinosis in mice. 

Methods for Reducing Toxic Effects. Available methods are sufficient for reducing peak 

absorption of naphthalene following ingestion (Melzer-Lange and Walsh-Kelly 1989; Siegel and Wason 

1986; Stutz and Janusz 1988). No antidotal methods are available that would be useful for treatment of 

naphthalene exposure based on any proposed hypothesis pertaining to the mechanism of action. 

Additional studies to characterize the metabolic activation of naphthalene and the role of circulating 

reactive metabolites from nontarget tissues may be useful in developing methods for interfering with the 

mechanism of action. Further studies to identify ways to reduce or prevent accumulation of toxic 

metabolites in target tissues may be warranted when mechanisms of naphthalene toxic action are better 

understood. 

There are no compound-specific methods for reducing the toxic effects of 1-methylnaphthalene and 

2-methylnaphthalene. Additional information on the toxicokinetics and mechanism of action for these 

compounds may be beneficial in identifying possible approaches for reducing compound toxicity. 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 

As discussed in Section 3.7, cases of naphthalene-induced hemolytic anemia in children have been 

frequently reported (Owa 1989; Owa et al. 1993; Santucci and Shah 2000; Valaes et al. 1963). Newborns 

and infants are thought to be more susceptible than older people because hepatic enzymes involved in 

conjugation and excretion of naphthalene metabolites are not well developed after birth, and children with 

genetically determined G6PD deficiency are thought to be especially susceptible to chemically-induced 

hemolytic anemia (EPA 1987a). There are no studies that have specifically examined the influence of age 

on naphthalene toxicokinetic capabilities in humans. Although the availability of such studies may 

increase the understanding of the specific physiological basis for the apparent susceptibility of newborns, 

they are unlikely to be conducted. Experiments examining the most sensitive targets in animals (see 

below) are likely surrogates. 

Although naphthalene and/or its metabolites can cross the placental barrier (Anziulewicz et al. 1959; 

Zinkham and Childs 1957, 1958), oral-exposure developmental toxicity studies in animals do not provide 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 156 

3. HEALTH EFFECTS 

evidence that naphthalene was fetotoxic or impaired fetal development, even at maternally toxic dose 

levels as high as 450 mg/kg/day (NTP 1991a; Plasterer et al. 1985; PRI 1986). Additional developmental 

toxicity studies in animals with inhalation or dermal exposure would determine if naphthalene exposure 

by these routes represents a greater developmental hazard than oral exposure. 

Neonatal mice (7 days old) appear to be more susceptible than adult mice to lung injury induced by acute 

intraperitoneal injection of naphthalene (Fanucchi et al. 1997). The mechanistic basis of this difference is 

currently unknown, but does not appear to be explained by differences in CYP catalytic capabilities to 

produce epoxide metabolites, since CYP activities were 2.5 time lower in neonates than in adults. 

Downstream metabolic capabilities, however, were not examined in this study. Comparison of neonatal 

and adult tissues in these metabolic steps may help to explain this apparent susceptibility of neonatal 

mice. Based on findings that in utero exposure to other CYP-bioactivated chemicals caused Clara cell 

tumors in adult offspring, Fanucchi et al. (1997) postulated that naphthalene exposure during the neonatal 

period may lead to loss of regulatory mechanisms resulting in Clara cell proliferation and tumor 

formation in adult animals. Direct evidence for naphthalene in support of this hypothesis, however, is not 

available. Additional research may help to determine whether or not in utero or neonatal naphthalene 

exposure will cause increased incidence of lung tumors in adult mice. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

3.12.3 Ongoing Studies 

Dr. Alan Buckpitt and colleagues at the University of California, Davis have been conducting studies in 

several areas related to naphthalene toxicology including (1) identifying specific naphthalene-protein 

adducts in lungs of mice, rats, and Rhesus macaques and characterizing the time course of their 

generation and disappearance; (2) identifying cellular and molecular events involved in the development 

of naphthalene-induced acute lung injury by comparing lung tissue from rodents, Rhesus macaques, and 

humans; and (3) comparing the cellular distribution and catalytic activities of CYP monooxygenases in 

lung tissues from various species. 

Dr. Charles Plopper and colleagues at the University of California, Davis have been conducting studies 

comparing acute naphthalene-induced lung injury in neonatal mice and adult mice and the biochemical 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 157 

3. HEALTH EFFECTS 

effects of in utero or neonatal exposure to lung toxicants on the development of bronchiolar repair 

capabilities. This work is part of an effort to increase understanding of molecular mechanisms involved 

in lung diseases that may originate in childhood exposures. 

Dr. Leena Nylander French and colleagues at the University of North Carolina, Chapel Hill have been 

conducting studies to test the hypothesis that low levels of exposure to benzene or naphthalene can be 

detected using samples of keratinized epidermis removed by tape stripping. 

Dr. Y. Awasthi and colleagues at the University of Texas, Galveston are studying the roles of glutathione 

S-transferases in protecting against ocular cytotoxicity and apoptosis caused by several oxidants, 

including naphthalene. Studies include the use of genetically altered knock-out mice strains, which are 

deficient in specific types of glutathione-S-transferases. 

Dr. Barry Stripp and colleagues at the University of Pittsburgh are studying the role of proliferative cells 

originating from the neuroepithelial body in repair of airway epithelial cell damage in mice exposed to 

ozone or naphthalene. 

Dr. John Markley and colleagues at the University of Wisconsin, Madison are studying the 1-, 2-, and 

3-dimensional molecular structures of toluene 4-monooxygenase, an enzyme that catalyzes NADH- and 

O2-dependent conversion of toluene to p-cresol, as well as the oxidation of numerous hydrocarbons, 

including naphthalene. 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 159 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Information regarding the chemical identity of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene is located in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Information regarding the physical and chemical properties of naphthalene, 1-methylnaphthalene, and 

2-methylnaphthalene is located in Table 4-2. 
Characteristic Naphthalene 

Synonyms Tar camphor; 

albocarbon; 

naphthene; 

mothballs; mothflakes; white tar; 

and others 

Trade name Caswell No. 

5877® 

Chemical formula C10H8 

Chemical structure 

1-Methylnaphthalene 2-Methylnaphthalene Reference 

Alpha-methyl- Beta-methyl- HSDB 2004 
 

naphthalene; naphthalene; 
 

naphthalene, 1-methyl; naphthalene, 2-methyl; 
 

naphthalene, alpha- naphthalene, beta-
 

methyl methyl 
 

No data No data 	 HSDB 2004 
 

C11H10 C11H10 HSDB 2004

CH3 CH HSDB 2004 3 

Identification numbers: 

CAS registry 

 NIOSH RTECS 

91-20-3 

QJ0525000 

90-12-0 

QJ9630000 

91-57-6 

QJ9635000 

HSDB 2004 

NIOSH 1987

 EPA hazardous U165 No data No data HSDB 2004 

waste 

OHM/TADS 

 DOT/UN/NA/IMCO 

shipping 

7216808 

UN1334, 

UN2304, IMCO 

4.1 

No data 

No data 

No data 

No data 

Agency for 

Toxic 

Substances 

and Disease 

Registry 1995

HSDB 2004 

HSDB 184 5268 5274 HSDB 2004 

NCI C52904 No data No data HSDB 2004 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North 
 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency;
 

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for 
 

Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; 
 

RTECS = Registry of Toxic Effects of Chemical Substances
 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 160 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Naphthalene, 1-Methylnaphthalene, and 

2-Methylnaphthalene 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 161 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Naphthalene, 

1-Methylnaphthalene, and 2-Methylnaphthalene 

1-Methyl- 2-MethylProperty Naphthalene naphthalene naphthalene

Molecular weight 128.19 142.20 142.20 

Color White Colorless No data 

Physical state Solid Liquid Solid 

Melting point 80.5 °C -22 °C 34.6 °C 

Boiling point 218 °C 244.6 °C 241 °C 

Density at 20 °C 1.145 g/mL 1.0202 g/mL 1.0058 g/mL 

Odor Strong (tar or No data No data 

mothballs) 

Odor threshold: 

Water 0.021 mg/L 0.0075 mg/L 0.01 mg/L 

Air 0.44 mg/m3

 No data 0.0581– 

0.2905 mg/m3 

Solubility: 

Water at 25 °C 31.7 mg/L 25.8 mg/L 24.6 mg/L 

 Organic Soluble in benzene, Soluble in alcohol, Soluble in alcohol, 

solvents alcohol, ether, ether, benzene ether, benzene 

acetone 

Partition coefficients: 

 Log Kow 3.29 3.87 3.86 

 Log Koc 2.97 No data 3.39 

Vapor pressure 0.087 mmHg 0.054 mmHg 0.068 mmHg 

Henry’s law 4.6x10-4 atm-m3

/mol 3.6x10-4 atm- 4.99x10-4 atm3 constant m /mol m3

/mol 

Autoignition 567 °C 529 °C No data 

temperature 

Flashpoint 79 EC (open cup) No data No data 

Flammability 0.9–5.9% No data No data 

limits 

Conversion 1 ppm=5.24 mg/m3 1 ppm=5.91 mg/m3 1 ppm=5.91 mg/m3 

factors 1 mg/m3

=0.191 ppm 1 mg/m3=0.17 ppm 1 mg/m3=0.17 ppm 

Explosive limits No data No data No data 

 Reference 

Weast et al. 1985 

Verschueren 1983 

Verschueren 1983 

Weast et al. 1985 

Sax and Lewis 1989; 

Weast et al. 1985 

Weast et al. 1985 

HSDB 2004 

Amoore and Hautala 

1983; HSDB 2004; 

Verschueren 1983 

Amoore and Hautala 

1983; Ruth 1986 

EPA 1982e; HSDB 2004

Sax and Lewis 1989; 

Weast et al. 1985 

EPA 1982e; HSDB 1995

EPA 1982e; GDCH 

1992; Kenaga 1980 

EPA 1982e; HSDB 1995 

EPA 1982e; Yaws et al.

1991 

Sax and Lewis 1989 

Sax and Lewis 1989 

HSDB 2004 

Verschueren 1983 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 163 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 PRODUCTION 

Naphthalene may be produced from either coal tar or petroleum. Distillation and fractionation of coal tar 

is the most common production process. The middle fraction (containing most of the naphthalene) is 

cooled, crystallizing the naphthalene. The crude naphthalene may be refined by distillation, washing, and 

sublimation (EPA 1982d; Hughes et al. 1985). 1-Methylnaphthalene and 2-methylnaphthalene are also 

produced from coal tar by first extracting the heteroaromatics and phenols, then filtering off the 

crystallized 2-methylnaphthalene and redistilling the filtrate to yield 1-methylnaphthalene (GDCH 1992; 

Sax and Lewis 1987). 

Since 1960, recovery of naphthalene from petroleum by dealkylation of methyl naphthalenes in the 

presence of hydrogen at high temperature and pressure has become a commercial production process. 

The naphthalene is then recovered by fractionation, decolorized, and purified by crystallization. 

Naphthalene produced from petroleum is about 99% pure. In the United States, most naphthalene is 

produced from petroleum (EPA 1982d; Hughes et al. 1985). 

The production volume of naphthalene in the United States decreased significantly from a peak of 

900 million pounds (409,000 metric tons) in 1968 to 222 million pounds (101,000 metric tons) in 1994. 

Production capacity has remained relatively stable in recent years, with estimated capacity for 2004 at 

215 million pounds (97,700 metric tons) (Hughes et al. 1985; Mason 1995; SRI 2002). 

There are currently two companies in the United States producing naphthalene: Advanced Aromatics, 

L.P., Baytown, Texas and Koppers Industries, Inc., Follansbee, West Virginia. Koppers Industries, Inc. 

produces 1-methylnaphthalene; Flint Hills Resources L.P., Corpus Christi, Texas, produces 2-methylnaphthalene; and Crowley Chemical Company, Inc., Kent, Ohio and Oklahoma City, Oklahoma, produces 

1-methylnaphthalene/2-methylnaphthalene (mixed isomers) (SRI 2004). No data on production volume 

of 1-methylnaphthalene or 2-methylnaphthalene were located. 

Table 5-1 lists information on United States companies that reported the manufacture and use of 

naphthalene in 2002 (TRI02 2004). The Toxics Release Inventory (TRI) data should be used with caution 

since only certain types of facilities are required to report. TRI is not an exhaustive list. 1-Methyl 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 164 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Naphthalene 

Number Minimum Maximum 

of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AK 9 1,000 9,999,999 1, 3, 4, 5, 7, 8, 9, 12 

AL 79 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AR 36 0 49,999,999 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AZ 12 100 999,999 3, 6, 7, 8, 9, 10, 11, 12 

CA 141 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CO 21 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 12, 13 

CT 16 100 49,999,999 2, 3, 6, 7, 8, 9, 10, 11, 12, 13 

DE 12 10,000 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13 

FL 28 0 9,999,999 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

GA 36 0 999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13 

GU 4 0 9,999,999 9, 12 

HI 16 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14 

IA 32 100 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 14 

ID 2 10,000 999,999 1, 5, 12 

IL 96 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

IN 76 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

KS 40 100 499,999,999 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KY 53 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

LA 117 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MA 15 1,000 49,999,999 2, 3, 6, 7, 9, 10, 11, 12 

MD 20 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 14 

ME 7 1,000 49,999,999 2, 3, 8, 9, 11, 12 

MI 70 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MN 25 100 49,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14 

MO 35 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 

MS 44 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MT 20 10,000 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 

NC 34 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

ND 8 100 9,999,999 1, 2, 3, 4, 6, 7, 9, 10, 11, 12 

NE 9 0 99,999 2, 7, 10, 11, 12 

NJ 65 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

NM 12 1,000 9,999,999 1, 3, 4, 7, 8, 9, 12, 13 

NV 3 1,000 999,999 2, 3, 4, 9, 12 

NY 31 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 13 

OH 97 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OK 46 100 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

OR 21 100 499,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 12, 13, 14 

PA 87 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 165 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Naphthalene 

Number Minimum Maximum 

of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

PR 24 100 

RI 4 1,000 

SC 30 0 

SD 7 100 

TN 48 0 

TX 247 0 

UT 46 0 

VA 35 100 

VI 5 1,000 

VT 1 100,000 

WA 50 0 

WI 30 0 

WV 43 0 

WY 33 0 

99,999,999 

9,999,999 

9,999,999 

999,999 

49,999,999 

99,999,999 

49,999,999 

9,999,999 

49,999,999 

999,999 

499,999,999 

9,999,999 

99,999,999 

49,999,999 

1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 13, 14 

1, 5, 9, 10, 12 

1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13 

7, 8, 12 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

1, 2, 3, 4, 6, 7, 9, 12 

12 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

Source: TRI02 2004 (Data are from 2002) 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 166 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

naphthalene and 2-methylnaphthalene are not included in the list of chemicals for which reporting is 

required for the TRI. 

5.2 IMPORT/EXPORT 

In 1978, about 7 million pounds (3,260 metric tons) of naphthalene were imported to the United States 

and 9 million pounds (3,960 metric tons) were exported from the United States (EPA 1982d). More 

recently, imports increased to about 8 million pounds (3,600 metric tons), while exports increased to 

38 million pounds (17,000 metric tons) in 2002 (USITC 2003). In 1986, 24,400 pounds of 1-methylnaphthalene were imported in the United States (HSDB 2004). No recent information was located for 

1-methylnaphthalene. No information was located on import or export quantities of 2-methylnaphthalene. 

5.3 USE 

The U.S. consumption of naphthalene was 238 million pounds (108,000 metric tons) in 1996 (Lacson et 

al. 2000; EPA 2002b). The principal end use for naphthalene is as an intermediate in the production of 

phthalic anhydride (more than 60% of consumption), which is used as an intermediate in the production 

of phthalate plasticizers, resins, phthaleins, dyes, pharmaceuticals, insect repellents, and other materials. 

It is also used in the production of the insecticide carbaryl, synthetic leather-tanning agents and surface 

active agents (naphthalene sulfonates and derivatives, which are used as dispersants or wetting agents in 

paint, dye, and paper-coating formulations), and miscellaneous organic chemicals, including dyes and 

resins. Crystalline naphthalene is also used as a moth repellent. In 1989, about 12 million pounds 

(5,500 metric tons) of naphthalene were used for this purpose (CEH 1993; HSDB 2004). Crystalline 

naphthalene has also been used as a solid block deodorizer for diaper pails and toilets (Haggerty 1956). 

Also, in the early 1900s naphthalene was used in medicine as an antiseptic, expectorant, and anthelmintic 

(Grant 1986; Lezenius 1902). It was commonly administered for diseases of the gastrointestinal tract and 

applied externally for treatment of skin disorders (Lezenius 1902). 

It is anticipated that consumption of naphthalene for phthalic anhydride and production of naphthalene 

sulfonates will increase due to increased demand for these products. About 15–16 million pounds 

(6,800–7,300 metric tons) of naphthalene were expected to be used for moth repellents by 1994 (CEH 

1993). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 167 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

1-Methylnaphthalene is used in the synthesis of 1-methylnaphthoic acid and, to a lesser degree, as a 

dyeing agent and as a test substance for determining the ignition capability of diesel fuels. 2-Methylnaphthalene is used in vitamin K production by oxidation to 2-methyl-1,4-naphthoquinone, which can 

then be reacted to yield phytomenadione (vitamin K). It can also be chlorinated and oxidized to form 

dyes and small amounts in sulfonated form are used as textile aids, wetting agents, and emulators (GDCH 

1992). 

5.4 DISPOSAL 

Naphthalene and waste containing naphthalene are classified as hazardous wastes by EPA. Generators of 

waste containing this contaminant must conform to EPA regulations for treatment, storage, and disposal 

(see Chapter 8). Rotary kiln or fluidized bed incineration methods are acceptable disposal methods for 

these wastes (EPA 1988a, 1989e). 

According to the TRI, about 306,345 pounds of naphthalene were transferred off-site, including to 

publicly owned treatment works (POTW) in 2002 (TRI02 2004). Although data on quantities of 

naphthalene disposed of by various disposal methods in the past were not located, it was estimated that 

about 524,000 pounds (238 metric tons) of naphthalene were disposed of on land and 504,000 pounds 

(229 metric tons) were discharged to POTWs from production and inadvertent sources in 1978 (EPA 

1982d). 

No information was located on disposal methods or quantities of wastes containing 1-methylnaphthalene 

or 2-methylnaphthalene. However, these chemicals have been detected at hazardous waste sites (see 

Section 6.1). 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 169 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene have been identified in at least 654, 36, and 

412, respectively, of the 1,662 hazardous waste sites that have been proposed for inclusion on the EPA 

National Priorities List (NPL) (HazDat 2005). However, the number of sites evaluated for naphthalene, 

1-methylnaphthalene, and 2-methylnaphthalene is not known. The frequency of these sites can be seen in 

Figures 6-1, 6-2, and 6-3, respectively. Of these sites, 654, 36, and 410, respectively, are located within 

the United States and 0, 0, and 2, respectively, are located in the Virgin Islands (not shown). 

Most of the naphthalene entering the environment is discharged to the air. The largest releases result 

from the combustion of wood and fossil fuels and the off-gassing of naphthalene-containing moth 

repellents. Smaller amounts of naphthalene are introduced to water as the result of discharges from coaltar production and distillation processes. The coal-tar industry is also a major source of the small 

amounts of naphthalene that are directly discharged to land. A large amount of naphthalene (often 

considerably more than 1,000 mg/kg) is present in soils contaminated with wastes from manufactured-gas 

plants. 

Naphthalene in the atmosphere is subject to a number of degradation processes, including reaction with 

photochemically produced hydroxyl radicals. Naphthalene has a short half-life in most natural waters and 

soils because of its tendency to volatilize and biodegrade. As a consequence of these processes, there is 

little tendency for naphthalene to build up in the environment over time. 

The concentration of naphthalene in air tends to be low in rural areas, but is elevated in urban areas. The 

highest atmospheric concentrations have been found in the immediate vicinity of specific industrial 

sources and hazardous waste sites. Naphthalene is also a common indoor contaminant in households 

using naphthalene-containing moth repellents or where tobacco is smoked. Sidestream smoke from one 

cigarette contained 46, 30, and 32 μg of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene, 

respectively. Levels in water, sediments, and soil tend to be low, except in the immediate vicinity of 

point sources of release, such as chemical waste sites. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 170 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with Naphthalene Contamination 

Frequency of 

NPL Sites 

1-5
 

6-10
 

11-20
 

21-30
 

31-48 Derived from HazDat 2005
 64
 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 171 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-2. Frequency of NPL Sites with 1-Methylnaphthalene Contamination 

Frequency of 

NPL Sites 

1
 

2
 

3
 

4
 

Derived from HazDat 2005
 11
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 172 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-3. Frequency of NPL Sites with 2-Methylnaphthalene Contamination 

Frequency of 

NPL Sites 

1-2
 

3-4
 

5-7
 

9-14
 

15-18 Derived from HazDat 2005
 

31-35
 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 173 

6. POTENTIAL FOR HUMAN EXPOSURE 

The most likely pathway by which the general public is exposed to naphthalene is by inhalation due to the 

release of this substance from combustion fuels, moth repellents, and cigarette smoke. The estimated 

average per capita daily intake from ambient air is 19 μg. Exposure by other routes is not likely. 

High naphthalene exposure levels could occur near industrial sources or chemical waste sites, but the 

extent of such exposure to individuals can only be evaluated on a site-by-site basis. High naphthalene 

exposure levels could also occur in certain work environments in industries that produce and use 

naphthalene such as wood preserving, tanning, coal distillation, and ink and dye production. 

Based on limited data, potential human exposure to 1-methylnaphthalene or 2-methylnaphthalene is 

expected to be mainly by inhalation from ambient air. Exposure to these chemicals from tobacco smoke 

is likely. 

1-Methylnaphthalene and 2-methylnaphthalene have also been detected in the environment, particularly 

in air. These are released from many of the same natural and industrial sources as naphthalene 

(combustion of wood and fossil fuels, tobacco smoke, coal distillation), but in smaller quantities. 

Naphthalene has been identified in at least 654 of the 1,662 hazardous waste sites that have been proposed 

for inclusion on the EPA National Priorities List (NPL) (HazDat 2005). 1-Methylnaphthalene has been 

identified in at least 36 of these sites, and 2-methylnaphthalene has been identified in at least 412 of these 

sites. However, the number of sites evaluated for these chemicals is not known. The frequency of the 

sites at which naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene have been identified within 

the United States can be seen in Figures 6-1 through 6-3. 

6.2 RELEASES TO THE ENVIRONMENT 

The TRI data should be used with caution because only certain types of facilities are required to report 

(EPA 1997). This is not an exhaustive list. Manufacturing and processing facilities are required to report 

information to the Toxics Release Inventory only if they employ 10 or more full-time employees; if their 

facility is classified under Standard Industrial Classification (SIC) codes 20–39; and if their facility 

produces, imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds 

of a TRI chemical in a calendar year (EPA 1997). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 174 

6. POTENTIAL FOR HUMAN EXPOSURE 

Most of the naphthalene entering environmental media is from combustion, mainly residential wood 

heating, or from the use of naphthalene in moth repellents. About 10% of environmental releases are 

attributable to coal production and distillation, while naphthalene production losses contribute <1% of 

environmental releases (EPA 1982d). Methylnaphthalenes are released from similar sources, including 

fuel combustion and industrial discharges (GDCH 1992). Smoking tobacco also releases small amounts 

of naphthalene and methylnaphthalenes into the environment. 

6.2.1 Air 

Estimated releases of 2.07 million pounds (940.2 metric tons) of naphthalene to the atmosphere from 

781 domestic manufacturing and processing facilities in 2002, accounted for about 72% of the estimated 

total environmental releases from facilities required to report to the TRI (TRI02 2004). These releases are 

summarized in Table 6-1. 

Nearly all naphthalene entering the environment is released directly to the air (92.2%). The largest source 

of emission (more than 50%) is through inadvertent releases due to residential combustion of wood and 

fossil fuels (EPA 1982d). Naphthalene emissions from unvented kerosene space heaters have been 

reported (Traynor et al. 1990). 

The second greatest contribution comes from the use of naphthalene as a moth repellent (EPA 1982d). 

Because it volatilizes appreciably at room temperature, virtually all of the naphthalene contained in moth 

repellent is emitted to the atmosphere. Thus, in 1989, about 12 million pounds of naphthalene were 

released to air from moth repellent use (see Section 5.3). 

Naphthalene may also enter the atmosphere during coal-tar production and distillation processes, through 

volatilization processes (aeration) in publicly owned treatment works (POTWs), from the use of 

naphthalene in the manufacture of phthalic anhydride, during the production of naphthalene, and from 

tobacco smoke. Methylnaphthalenes may be released to air in stack emissions and from fuel combustion, 

forest fires, and tobacco smoke (GDCH 1992; HSDB 2004; IARC 1993). 1-Methylnaphthalene and 

2-methylnaphthalene were reported in jet exhaust at average concentrations of 421 and 430 μg/m3

, 

respectively, and in the gas phase of diesel motor exhaust at 1.57 μg/m3 each (GDCH 1992). The smoke 

of an American unfiltered cigarette contains 2.8 μg of naphthalene, 1.2 μg of 1-methylnaphthalene, and 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 175 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, 

or Use Naphthalenea 

Reported amounts released in pounds per yearb 

Total release 

On- and offStatec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek site 

AK 1 52 0 0 12 0 52 12 64 

AL 22 108,624 58 0 221,582 5 295,685 34,585 330,270 

AR 8 6,113 7 0 42 250 6,120 292 6,412 

AZ 1 14 No data 0 0 0 14 0 14 

CA 44 13,482 89 0 17,729 439 28,581 3,158 31,739 

CO 7 2,106 0 0 0 0 2,106 0 2,106 

CT 4 17,579 0 0 0 0 17,579 0 17,579 

DE 2 721 0 0 0 0 721 0 721 

FL 15 515,776 5 0 0 0 515,781 0 515,781 

GA 13 18,576 0 0 9 0 18,576 9 18,585 

GU 1 288 No data 0 0 0 288 0 288 

HI 2 623 20 0 50 0 643 50 693 

IA 11 13,873 0 0 11 0 13,873 11 13,884 

IL 42 161,983 88 0 24,504 2,509 162,071 27,013 189,084 

IN 35 166,075 526 26,140 29,037 17 221,609 186 221,795 

KS 11 6,607 16 0 2 31,587 6,626 31,587 38,213 

KY 20 23,003 840 0 323 0 24,103 63 24,166 

LA 51 89,494 1,072 3 4,722 0 92,701 2,590 95,291 

MA 7 4,948 0 0 5 262 4,948 267 5,215 

MD 11 13,018 0 0 0 0 13,018 0 13,018 

ME 3 6,208 No data 0 0 17 6,208 17 6,225 

MI 26 104,586 0 0 463 2,040 104,836 2,253 107,089 

MN 4 5,369 0 0 6 70 5,371 74 5,445 

MO 20 59,389 6 0 8 84 59,400 87 59,487 

MS 8 46,209 277 0 0 0 46,487 0 46,487 

MT 4 1,192 8 0 17 0 1,216 1 1,217 

NC 11 5,273 21 0 2,405 32 6,981 750 7,731 

ND 4 1,934 2 0 0 893 1,936 893 2,829 

NE 1 1,465 No data 0 9,853 0 1,465 9,853 11,318 

NJ 21 17,753 629 0 712 5 18,382 717 19,099 

NM 11 10,637 5 5 0 1,199 10,647 1,199 11,846 

NV 1 8,075 No data 0 0 0 8,075 0 8,075 

NY 19 6,141 0 0 0 500 6,141 500 6,641 

OH 47 51,153 37 0 12,718 667 51,198 13,376 64,574 

OK 10 28,605 299 0 6,801 48 35,327 426 35,753 

OR 3 16,276 0 0 0 3 16,276 3 16,279 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 176 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, 

or Use Naphthalenea 

Reported amounts released in pounds per yearb 

Total release 

Statec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek 

On- and offsite 

PA 55 95,520 643 0 9,646 4,065 96,174 13,700 109,874 

PR 12 1,745 0 0 0 0 1,745 0 1,745 

SC 11 37,030 22,000 0 0 0 59,030 0 59,030 

SD 3 52 No data 0 1 0 52 1 53 

TN 6 4,706 No data 0 260 0 4,706 260 4,966 

TX 127 282,582 738 204,570 11,548 9,282 470,932 37,788 508,720 

UT 8 3,999 5 0 250 0 4,003 250 4,253 

VA 11 1,357 8 0 2 0 1,365 2 1,367 

VI 3 1,667 0 0 25 0 1,667 25 1,692 

VT 1 4 No data 0 0 600 4 600 604 

WA 15 4,840 0 0 1,087 0 5,537 390 5,927 

WI 9 15,802 39 0 1,929 9 15,840 1,938 17,778 

WV 10 85,154 63 0 10,983 110,190 85,221 121,169 206,390 

WY 9 676 No data 0 1 250 677 250 927 

Total 781 2,068,353 27,502 230,718 366,742 165,023 2,551,993 306,345 2,858,337 

Source: TRI02 2004 (Data are from 2002) 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number. 

b

Data in TRI are maximum amounts released by each facility. 

c

Post office state abbreviations are used. 

d

Number of reporting facilities. 

e

The sum of fugitive and point source releases are included in releases to air by a given facility. f

Surface water discharges, wastewater treatment-(metals only), and publicly owned treatment works (POTWs)
 

(metal and metal compounds).
 g

Class I wells, Class II-V wells, and underground injection. 
 h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 
 

impoundments, other land disposal, other landfills. 
 i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for 
 

disposal, unknown 
 j

The sum of all releases of the chemical to air, land, water, and underground injection wells. 
 k

Total amount of chemical transferred off-site, including to POTWs. 
 

RF = reporting facilities; UI = underground injection 
 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 177 

6. POTENTIAL FOR HUMAN EXPOSURE 

1.0 μg of 2-methylnaphthalene. Smoke from an equivalently filtered "little cigar" contains 1.2 μg of 

naphthalene, 0.9 μg of 1-methylnaphthalene, and 0.7 μg of 2-methylnaphthalene (Schmeltz et al. 1976). 

As shown in Table 6-1, an estimated total of 2.1 million pounds of naphthalene, amounting to about 72% 

of the total environmental release under the TRI program, was discharged to the air from manufacturing 

and processing facilities in the United States in 2002 (TRI02 2004). The TRI data should be used with 

caution since only certain types of facilities are required to report. TRI is not an exhaustive list. 

6.2.2 Water 

Estimated releases of 27.5 thousand pounds (21.5 metric tons) of naphthalene to surface water from 

781 domestic manufacturing and processing facilities in 2002, accounted for about 1% of the estimated 

total environmental releases from facilities required to report to the TRI (TRI02 2004). These releases are 

summarized in Table 6-1. 

About 5% of all naphthalene entering the environment is released to water (EPA 1982d). Most of that 

amount is attributable to coal-tar production and distillation processes. Some naphthalene (about 60%) 

from these sources is discharged directly to surface waters; the remainder is distributed to POTWs. The 

effluent and oil-spills from the wood-preserving industry is the only other source of consequence that 

releases naphthalene into the nation's waterways, 

Naphthalene was detected in 1.6% of effluent samples reported on the STORET database from 1980 to 

1982 (Staples et al. 1985). Analysis of STORET data for 1978–1981 indicated that the range of 

detectable naphthalene concentrations in effluents was <1–36,000 μg/L (EPA 1982d). 

The detection of naphthalene and methylnaphthalenes in groundwater in the vicinity of industrial facilities 

and landfills (see Section 6.4.2) (Brown and Donnelly 1988; Rosenfeld and Plumb 1991) indicates that 

these chemicals are released to water from these sources. Methylnaphthalenes have been detected in 

effluents from industrial sources (GDCH 1992; HSDB 2004). 1-Methylnaphthalene and 2-methylnaphthalene were reported in process sewage and production water samples from coal gasification plants 

at concentrations ranging from 78 to 278 μg/L and from 66 to 960 μg/L, respectively (GDCH 1992). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 178 

6. POTENTIAL FOR HUMAN EXPOSURE 

As shown in Table 6-1, an estimated total of 27,502 pounds of naphthalene, amounting to about 1.0% of 

the total environmental release, was discharged to surface water from manufacturing and processing 

facilities in the United States in 2002 (TRI02 2004). An additional 230,718 pounds (8.0% of the total) 

was discharged by underground injection. The TRI data should be used with caution since only certain 

types of facilities are required to report. 

6.2.3 Soil 

Estimated releases of 366 million pounds reported under the TRI program (166.7 metric tons) of 

naphthalene to soils from 781 domestic manufacturing and processing facilities in 2002, accounted for 

about 12.8% of the estimated total environmental releases from facilities required to report to the TRI 

(TRI02 2004). An additional 0.231 million pounds (104.8 metric tons), constituting about 8.0% of the 

total TRI environmental emissions, were released via underground injection from facilities required to 

report to the TRI (TRI02 2004). These releases are summarized in Table 6-1. 

It is estimated that only about 2.7% of the environmental releases of naphthalene are discharged to land 

(EPA 1982d). Sources include coal-tar production and minor contributions from naphthalene production, 

POTW sludge disposal, and the use of organic chemicals that include naphthalene. 

The residuals produced in gas production by coal carbonization, carbureted water gas production, or oil 

gas production at manufactured gas plants (MGPs) included PAHs (naphthalene, anthracene, 

phenanthrene and benzo[1]pyrene). These residuals were deposited on site in tar wells, sewers, nearby 

pits, or streams resulting in widespread soil and groundwater contamination (Luthy et al. 1994). 

As shown in Table 6-1, an estimated 366,742 pounds of naphthalene, amounting to about 8.1% of the 

total environmental release, was discharged to land from manufacturing and processing facilities 

producing and using naphthalene in the United States in 2002 (TRI02 2004). The TRI data should be 

used with caution since only certain types of facilities are required to report. 

No information was located on releases of 1-methylnaphthalene or 2-methylnaphthalene to soil. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 179 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

Naphthalene released to the atmosphere may be transported to surface water and/or soil by wet or dry 

deposition. Since most airborne naphthalene is in the vapor phase, deposition is expected to be very slow 

(about 0.04–0.06 cm/sec). It has been estimated that about 2–3% of naphthalene emitted to air is 

transported to other environmental media, mostly by dry deposition (EPA 1982d). 

Naphthalene in surface water may volatilize to the atmosphere. With a vapor pressure of 0.087 mm Hg at 

25 EC, solubility in water of 31.7 mg/L at 20 EC, and a Henry's law constant of 4.6x10-4 (EPA 1982e), it 

is likely that volatilization will be an important route of naphthalene loss from water. The rate of 

volatilization also depends upon several environmental conditions, including temperature, wind velocity, 

and mixing rates of the air and water columns (EPA 1982d). The half-life of naphthalene in the Rhine 

River was 2.3 days, based on monitoring data (Zoeteman et al. 1980). In an experiment using a 

mesocosm, that simulated Narragansett Bay, the half-life in water was 12 days during winter, with loss 

primarily due to volatilization (Wakeham et al. 1983). 

Log octanol/water partition coefficients (Kow) for naphthalene range from 3.29 to 3.37 and log organic 

carbon coefficients (Koc) range from 2.97 to 3.27 (Bahnick and Doucette 1988; EPA 1982e; Howard 

1989; Klecka et al. 1990; Thomann and Mueller 1987). These values include both experimentally 

determined and calculated values. The reported experimentally determined log Koc is 3.11 (Bahnick and 

Doucette 1988). Based on the magnitude of these values, it is expected that only a small fraction (<10%) 

of naphthalene in typical surface water would be associated with particulate matter (Thomann and 

Mueller 1987). Thus, naphthalene discharged to surface waters would remain largely in solution, with 

smaller quantities being associated with suspended solids and benthic sediments. 

Naphthalene is easily volatilized from aerated soils (Park et al. 1990) and is adsorbed to a moderate extent 

(10%) (Karickhoff 1981; Schwarzenbach and Westall 1981). The extent of sorption depends on the 

organic carbon content of the soil, with rapid movement expected through sandy soils (Howard 1989). 

The estimated soil adsorption coefficient for naphthalene in a soil with <0.6% organic carbon is 

1.8 (Klecka et al. 1990). Because it adsorbs to aquifer material (Ehrlich et al. 1982), naphthalene's 

passage through groundwater will be somewhat retarded. Nevertheless, naphthalene frequently appears in 

effluent drainage from disposal sites (Rittman et al. 1980; Roberts et al. 1980; Schwarzenbach et al. 

1983). However, sorption of naphthalene to aquifer materials with low organic carbon content (<0.03%) 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 180 

6. POTENTIAL FOR HUMAN EXPOSURE 

may be enhanced by the presence of nonionic low-polarity organics, such as tetrachloroethene, commonly 

found at hazardous waste sites (Brusseau 1991a). 

Bioconcentration factors (BCFs) for naphthalene have been measured and calculated from the Kow, Koc, or 

water solubility. The values reported for log BCF range from 1.6 to 3 (Banerjee and Baughman 1991; 

Bysshe 1982; Geyer et al. 1982; Kenaga 1980; Southworth et al. 1978; Veith et al. 1979), indicating 

moderate bioconcentration in aquatic organisms. Naphthalene is reported to be rapidly eliminated from 

invertebrates when the organisms are placed in pollutant-free water (Eastmond et al. 1984; Tarshis 1981), 

and naphthalene is readily metabolized in fish (Howard 1989). Based on the magnitude of the Kow, 

bioaccumulation in the food chain is not expected to occur (Thomann 1989). However, naphthalene 

exposure of cows and chickens could lead to the presence of naphthalene in milk and eggs (Eisele 1985). 

Limited data were located on transport and partitioning of methylnaphthalenes in the environment. The 

respective vapor pressures (0.054 and 0.068 mmHg), water solubilities (25.8 and 24.6 mg/L), and Henry's 

law constants (3.60x10-4 and 4.99x10-4 atm-m3

/mol) for 1-methylnaphthalene and 2-methylnaphthalene 

are of similar magnitude to these properties for naphthalene (HSDB 2004; Yaws et al. 1991). Thus, it is 

likely that loss of methylnaphthalenes from ambient water occurs by volatilization. In a mesocosm 

experiment, that simulated Narragansett Bay, the half-life of 2-methylnaphthalene in water was 13 days in 

winter, with loss primarily due to volatilization (Wakeham et al. 1983). Based on the magnitude of log 

Kow for 1-methylnaphthalene and 2-methylnaphthalene (3.87 and 3.86, respectively) (HSDB 2004) and 

the experimental log Koc for 2-methylnaphthalene (3.93) (Bahnick and Doucette 1988), these chemicals 

may partition similarly to naphthalene in environmental media and are expected to be slightly mobile to 

immobile in soils (HSDB 2004). Log BCFs calculated for 2-methylnaphthalene range from 2 to 

2.8 (Kenaga 1980) and measured log BCFs for 1-methylnaphthalene and 2-methylnaphthalene in oysters 

ranged from 2.7 to 4.1 (GDCH 1992). Methylnaphthalenes are also metabolized and excreted rapidly by 

fish and shellfish when they are removed from polluted waters (Breger et al. 1981; GDCH 1992). 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

The most important atmospheric removal process for naphthalene is reaction with photochemically 

3 produced hydroxyl radicals (Howard 1989). The rate for this reaction is 2.17x10-11 cm /molecule-sec 

(Atkinson et al. 1987) and the atmospheric half-life for naphthalene based on this reaction is <1 day. The 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 181 

6. POTENTIAL FOR HUMAN EXPOSURE 

major products of this reaction are 1- and 2-naphthol and 1- and 2-nitronaphthalene (Atkinson et al. 

1987). Naphthalene also reacts with N2O5, nitrate radicals, and ozone in the atmosphere (Atkinson et al. 

1984, 1987) and photolysis is expected to occur, although no experimental data were located (Howard 

1989). 

Methylnaphthalenes also react with hydroxyl radicals. The reported rate constants are 5.30x10-11 and 

5.23x10-11 cm3

/molecule-sec for 1-methylnaphthalene and 2-methylnaphthalene, respectively. Based on 

an atmospheric hydroxyl radical concentration of 1x106

/cm3, the corresponding atmospheric half-lives are 

3.6 and 3.7 hours (GDCH 1992). Reactions of 1-methylnaphthalene and 2-methylnaphthalene with 

N2O5 radicals have half-lives of 24 and 19 days, respectively (GDCH 1992). These chemicals also react 

with atmospheric ozone. 

6.3.2.2 Water 

Naphthalene and methylnaphthalenes are degraded in water by photolysis and biological processes. The 

half-life for photolysis of naphthalene in surface water is estimated to be about 71 hours, but the half-life 

in deeper water (5 m) is estimated at 550 days (Zepp and Schlotzhauer 1979). The half-lives for 

photolysis of 1-methylnaphthalene and 2-methylnaphthalene were estimated at 22 and 54 hours, 

respectively (GDCH 1992). 

Biodegradation of naphthalene is sufficiently rapid for it to be a dominant fate process in aquatic systems 

(Tabak et al. 1981). Data on biodegradation of naphthalene in biodegradability tests and natural systems 

suggest that biodegradation occurs after a relatively short period of acclimation (rapidly, half-life about 

7 days] in oil-polluted water) and the biodegradation rate increases with the naphthalene concentration. 

The biodegradation occurs slowly (half-lives up to 1,700 days) in unpolluted water (Herbes 1981; Herbes 

and Schwall 1978; Herbes et al. 1980; Howard 1989; Kappeler and Wuhrmann 1978). Reported 

biodegradation half-lives range from 3 to 1,700 days in various water systems (Howard 1989). In a staticflask-screening test, naphthalene showed rapid acclimation and 100% loss from the test medium in 7 days 

(Tabak et al. 1981). In an experiment with Narragansett Bay seawater, the half-life of naphthalene in late 

summer was reported at 0.8 days, mainly due to biodegradation (Wakeham et al. 1983). The half-life of 

2-methylnaphthalene was 0.7 days in the same experiment. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 182 

6. POTENTIAL FOR HUMAN EXPOSURE 

Methylnaphthalenes are biodegraded under aerobic conditions after adaptation. The highest degradation 

rates were reported in water constantly polluted with petroleum (GDCH 1992). 

6.3.2.3 Sediment and Soil 

Naphthalene biodegradation rates are about 8–20 times higher in sediment than in the water column 

above the sediment (Herbes and Schwall 1978). Half-lives reported in sediment include 4.9 hours and 

>88 days in oil-contaminated and uncontaminated sediment, respectively (Herbes and Schwall 1978), 

9 days in sediment near a coal-coking discharge (Herbes 1981), 3, 5, and >2,000 hours in sediments with 

high, medium, and low PAH levels, respectively (Herbes et al. 1980), and ranging from 2.4 weeks in 

sediments exposed to petroleum hydrocarbons to 4.4 weeks in sediments from a pristine environment 

(Howard 1989). Methylnaphthalenes biodegrade more slowly. Reported half-lives in sediments were 

46 weeks for 1-methylnaphthalene and ranged from 14 to 50 weeks for 2-methylnaphthalene (GDCH 

1992). 

In soils, biodegradation potential is important to biological remediation of soil. Studies on biodegradation 

of PAHs suggest that adsorption to the organic matter significantly reduces the bioavailability for 

microorganisms, and thus the biodegradability, of PAHs, including naphthalene (Heitzer et al. 1992; 

Weissenfels et al. 1992). There is considerable variability in reported naphthalene soil half-lives. The 

estimated half-life of naphthalene reported for a solid waste site was 3.6 months (Howard 1989). In less 

contaminated soils, more rapid biodegradation is expected to occur (Howard 1989). In soils with 0.2– 

0.6% organic carbon and 92–94% sand, the half-lives were 11–18 days (Klecka et al. 1990). In another 

study, sandy loams with 0.5–1% organic carbon had naphthalene half-lives of 2–3 days (Park et al. 1990). 

Biodegradation is accomplished through the action of aerobic microorganisms and declines precipitously 

when soil conditions become anaerobic (Klecka et al. 1990). Studies indicate that naphthalene 

biodegrades to carbon dioxide in aerobic soils, with salicylate as an intermediate product (Heitzer et al. 

1992). 

Abiotic degradation of naphthalene seldom occurs in soils. In one study only about 10% of the 

naphthalene added to two soil samples treated with mercuric chloride to kill microorganisms was 

degraded over a 105- or 196-day period (Park et al. 1990). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 183 

6. POTENTIAL FOR HUMAN EXPOSURE 

In contaminated subsurface soils often found at former MGP sites, naphthalene is present as a component 

coal tar, a dense nonaqueous-phase liquid (DNAPL). It may exist in the subsurface in the form of trapped 

pools of organic liquid or as immobilized macroporous ganglia. Slow dissolution of naphthalene and 

other PAHs from DNAPLs into the aqueous phase causes them to be unavailable to the microorganism, 

thus resulting in the dissolution of the PAHs being the rate-limiting step in their biodegradation (Thomas 

et al. 1986). Using phenanthrene as a test substance, Birman and Alexander (1996) showed that the 

viscosity of the NAPL may reflect a slower diffusion of the aromatic substrate in the more viscous 

NAPLs and its subsequent slower mass transfer to water. Ghoshal and Luthy (1996) demonstrated that a 

very large fraction of naphthalene can be biodegraded from an accessible coal-tar-NAPL (free flowing) 

by microorganisms in bioslurry systems. Metabolically active microflora were detected beneath the water 

table at a former MGP sites from 2.6 to 30.8 m below the ground surface. The subsurface micorflora 

appeared to be acclimated to the presence of PAHs and were found to mineralize naphthalene (8–55%) in 

sediment-water microcosms under aerobic conditions. Naphthalene biodegradation half-lives ranged 

from 18 to 480 days (Durrant et al. 1994). 

Naphthalene remaining in soil for extended periods of time was shown to become less available to 

bacteria and earthworms (Kelsey and Alexander 1997). 

The behavior of 1-methylnaphthalene in sandy loam was very similar to that of naphthalene. 1-Methylnaphthalene was easily volatilized from aerated soil, and the biodegradation half-life averaged between 

1.7 and 2.2 days (Park et al. 1990). No data were identified on the biodegradation of 2-methylnaphthalene in soil. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to naphthalene, 1-methylnaphthalene, and 

2-methylnaphthalene depends in part on the reliability of supporting analytical data from environmental 

samples and biological specimens. Concentrations of naphthalene, 1-methylnaphthalene, and 

2-methylnaphthalene in unpolluted atmospheres and in pristine surface waters are often so low as to be 

near the limits of current analytical methods. In reviewing data on naphthalene, 1-methylnaphthalene, 

and 2-methylnaphthalene levels monitored or estimated in the environment, it should also be noted that 

the amount of chemical identified analytically is not necessarily equivalent to the amount that is 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 184 

6. POTENTIAL FOR HUMAN EXPOSURE 

bioavailable. The analytical methods available for monitoring naphthalene, 1-methylnaphthalene, and 

2-methylnaphthalene in a variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

Naphthalene has been reported in ambient air at several locations in the United States. The average 

reported concentration for 67 samples was 5.19 μg/m3

, with most (60) of the samples and the highest 

concentrations at source-dominated locations (EPA 1988g). A median naphthalene level in urban air in 

11 U.S. cities of 0.94 μg/m3 has been reported (Howard 1989). An average naphthalene concentration of 

170 μg/m3 in outdoor air was reported in a residential area of Columbus, Ohio (Chuang et al. 1991), and 

naphthalene was measured in ambient air in Torrance, California at a concentration of 3.3 μg/m3 (Propper 

1988). Average naphthalene concentrations ranging from 10 to 888 ng/m3 were measured in several sites 

in Phoenix and Tucson, Arizona from 1994 to 1996 (Zielinska et al. 1998). A mean naphthalene 

concentration of 0.129 ng/m3 was detected in ambient air at the Mississippi Sandhill Crane National 

Wildlife Refuge, Jackson County from May to September 1991 (White and Hardy 1994). 

Average naphthalene concentrations detected in ambient air at five hazardous waste sites and one landfill 

in New Jersey ranged from 0.42 to 4.6 μg/m3 (LaRegina et al. 1986). 

Naphthalene concentrations in indoor air may be higher than outdoors, with reported average indoor 

concentrations in various areas of homes ranging from 0.860 to 1,600 μg/m3 (Chuang et al. 1991; Hung et 

al. 1992; Wilson et al. 1989). However, based on a careful analysis of Chuang et al. (1991), the reported 

upper range value may be in error. A more representative upper limit concentration for indoor air may be 

32 μg/m3

, recorded in buildings in heavily trafficked urban areas of Taiwan (Hung et al. 1992). 

Concentrations of naphthalene detected in indoor and outdoor air measured in 24 low-income homes in 

North Carolina ranged from 0.33 to 9.7 and from 0.57 to1.82 μg/m3 respectively (Chuang et al. 1999). In 

homes with smokers, indoor and outdoor air concentrations were measured to be 2.2 and 0.3 μg/m3

, 

respectively. Comparable values in homes without smokers were 1.0 and 0.1 μg/m3

, respectively (EPA 

1991e; IARC 1993). The average reported concentration of naphthalene inside automobiles in commuter 

traffic is about 4.5 μg/m3 (Lofgren et al. 1991). 

Naphthalene has also been detected in air in industrial facilities. Reported naphthalene vapor levels 

ranged from 11 to 1,100 μg/m3 in a coke plant and from 0.72 to 310 μg/m3 in an aluminum reduction plant 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 185 

6. POTENTIAL FOR HUMAN EXPOSURE 

(Bjorseth et al. 1978a, 1978b). Reported particulate levels for the same facilities ranged from nondetected 

to 4.4 μg/m3

, and from 0.9 to 4 μg/m3, respectively. 

Naphthalene has been detected in the emissions from motor vehicles. Mean concentrations of 104.3, 

31.9, and 54.1 μg/m3 of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene, respectively, were 

measured in the air samples collected from the Caldecott Tunnel located in San Francisco (Zielinska and 

Fung 1994). Mean concentrations of 1,709, 131, and 162.5 mg/m3

 of naphthalene, 1-methylnaphthalene, 

and 2-methylnaphthalene, respectively, were measured in the air samples collected from the Van Nuys 

Tunnel in Los Angeles (Fraser et al. 1998a). Mean concentration ranges of 0–589.2, 0–188.6, and 0– 

333.3 μg/m3 of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene, respectively, were measured 

in the air samples collected from the Fort McHenry Tunnel in Baltimore. Mean concentration ranges of 

16.2–68.9, 9.4–20.0, and 21.9–35.7 μg/m3 of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene, respectively, were measured in the air samples collected from the Tuscarora Tunnel on the 

Pennsylvania Turnpike (Zielinska et al. 1996). Average concentrations of 137–1714, 92–1,458, and 154– 

2,129 ng/m3 of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene, respectively, were detected 

during various flight related and ground-support activities of C-130H aircraft at an Air National Guard 

base (Childers et al. 2000). 

Shauer et al. (2002) compared the tailpipe emissions of catalyst- and noncatalyst-converter-equipped 

motor vehicles. Approximately 1,000 μg/km-1 of naphthalene and 2-methylnaphthalene and 500 μg/km-1 

of 1-methylnaphthalene were detected in the catalyst-equipped vehicles. Approximately 50,000 μg/km-1 

of naphthalene and 2-methylnaphthalene and 30,000 μg/km-1 of 1-methylnaphthalene were detected in the 

noncatalyst converter-equipped vehicles. 

1-Methylnaphthalene and 2-methylnaphthalene have been reported in ambient air at average 

concentrations of 0.51 and 0.065 μg/m3

, respectively (EPA 1988g). Most of the data reported are from 

source-dominated areas, where the highest concentrations were detected. Methylnaphthalene (isomer not 

specified) was detected (concentration not reported) in ambient air at a hazardous waste site in New 

Jersey (LaRegina et al. 1986). 2-Methylnaphthalene was also reported in indoor air at an average 

concentration of 1.5 μg/m3 (EPA 1988g). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.2 Water 

Naphthalene has been detected in surface water and groundwater in the United States. An analysis of 

1980–1982 data from the STORET database indicates that naphthalene was detectable in 7% of 

630 ambient water samples (Staples et al. 1985). The median concentration for all samples was <10 μg/L. 

Analysis of earlier (1978–1980) STORET data for naphthalene showed concentrations in positive samples 

ranging from 0.005 to 17 μg/L (EPA 1982d). Naphthalene was also detected in 11% of 86 urban runoff 

samples at concentrations ranging from 0.8 to 2.3 μg/L (Cole et al. 1984). In a study of contaminants of 

an urban watershed of Chesapeake Bay, naphthalene was detected in the northeast and northwest 

branches of Anacostia River (an urban watershed of Chesapeake Bay) at a concentration range of 0.18– 

21.6 ng/L. 2-Methylnaphthalene was also detected at a concentration of 0.57–62.7 ng/L (Foster et al. 

2000). The mean concentration of naphthalene found in the water samples taken from 31 freshwater and 

estuarine sites adjacent to, nearby, or downstream from potential pollutant sources in Florida was 

33 mg/L (Miles and Delfino 1999). 

Naphthalene was detected in fewer than 5% of the 208 wells sampled from a variety of urban setting 

across the United States (Koplin et al. 1997). Naphthalene was detected in 3% of the samples taken from 

urban and rural wells from 1985 to 1995 (Squillace et al. 1999). 

Naphthalene is rarely detected in drinking water. Naphthalene was reported in drinking water supplies in 

one area in the United States at levels up to 1.4 μg/L (EPA 1982d). Low levels of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene were detected in drinking water samples taken from a chlorine 

dioxide disinfection pilot plant in Evansville, Indiana. These compounds were identified as organic 

disinfection byproducts produced by chlorine dioxide treatment (Richardson et al. 1994). 

Naphthalene and 2-methylnaphthalene were detected in groundwater at five wood treatment facilities 

(Rosenfeld and Plumb 1991). Naphthalene was reported in 35% of samples at all five sites at an average 

concentration of 3,312 μg/L. 2-Methylnaphthalene was reported in 27% of samples at four sites at an 

average concentration of 563 μg/L. Naphthalene was reported in leachate or groundwater plume from 

industrial and municipal landfills at concentrations ranging from <10 to 18.69 mg/L and from 0.11 to 

19 mg/L, respectively. The methylnaphthalene (isomer not specified) concentration reported at a 

municipal landfill was 0.033 mg/L (Brown and Donnelly 1988). Naphthalene was detected in the 

groundwater in 12.7% of the 479 U.S. waste disposal sites (Barbee 1994). Naphthalene was also reported 

in the leachate of a household hazardous waste disposal in sanitary landfill. The 4-year mean 
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6. POTENTIAL FOR HUMAN EXPOSURE 

concentrations of naphthalene ranged from 128.9 to 496.6 μg/L (Kinman et al. 1995). Naphthalene, 

1-methylnaphthalene, and 2-methylnaphthalene have been detected in groundwater at gas Works Park, 

Seattle, Washington, in the range of 0.02–12, 0.02–1.1, and 0.03–1.4 mg/L, respectively (Turney and 

Goerlitz 1990). Gas Works Park is located on the site of a coal and oil gasificaton plant that ceased 

operation in 1956. 

1-Methylnaphthalene and 2-methylnaphthalene were reported in an urban snow-pack in Michigan at 

concentrations of <0.05–0.177 and <0.05–0.251 μg/L, respectively (Boom and Marsalek 1988). 

Naphthalene has been reported at a mean concentration of 6.3 ng/L in seawater in the south Atlantic 

Ocean (Cripps 1992). 

6.4.3 Sediment and Soil 

Naphthalene and methylnaphthalenes have been reported at low concentrations in uncontaminated soils 

and sediments and at higher concentrations near or within sources of contamination. Naphthalene has 

been reported in untreated agricultural soils at levels ranging from 0 to 3 μg/kg (Wild et al. 1990). 

Naphthalene was detected in urban soil samples taken from Boston, Massachusetts, Providence, Rhode 

Island, and Springfield, Massachusetts at a mean concentration of 0.125 mg/kg (Bradley et al. 1994). 

Reported naphthalene concentrations in contaminated soils included 6.1 μg/g in coal-tar contaminated soil 

(Yu et al. 1990), 16.7 mg/kg in soil from a former tar-oil refinery (Weissenfels et al. 1992) and up to 

66 μg/kg in sludge-treated soils (Wild et al. 1990). Methylnaphthalenes (isomer not specified) were 

reported at a concentration of 2.9 μg/g in coal-tar contaminated soil (Yu et al. 1990). Hawthrone et al. 

have reported concentration of naphthalene to be 48 mg/kg in the soil from an unspecified manufactured 

gas plant in Midwestern United States (Hawthrone et al. 2001). Naphthalene and 2-methylnaphthalene 

have been detected in groundwater at Gas Works Park, Seattle, Washington, in the range of 0–46 and 0– 

6.3 mg/L, respectively (Turney and Goerlitz 1990). Gas Works Park is located on the site of a coal and 

oil gasificaton plant that ceased operation in 1956. 

Naphthalene was reported as detectable in 7% of 267 sediment samples entered into the STORET 

database (1980–1982), with the median concentration for all samples of <500 μg/kg (Staples et al. 1985). 

Another analysis of STORET data indicated that concentrations in positive sediment samples ranged from 

0.02 to 496 μg/kg (EPA 1982d). Naphthalene and methylnaphthalenes (isomers not specified) were 
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6. POTENTIAL FOR HUMAN EXPOSURE 

detected in contaminated and noncontaminated estuarine sediments (Brooks et al. 1990). Average 

concentrations of naphthalene detected in samples taken at 10 and 25 miles from an offshore coastal 

multiwell drilling platform were 54.7 and 61.9 μg/kg, respectively while concentrations of methylnaphthalenes were 50.4 and 55.3 μg/kg, respectively. Naphthalene and methylnaphthalenes 

concentrations in nearby noncontaminated estuarine sediments were 2.1 and 1.9 μg/kg, respectively. 

Naphthalene was detected in 7% of 496 streambed sediment sites across the United States tested for the 

presence of semivolatile organic compounds. The maximum concentration of naphthalene measured was 

4,900 μg/kg dry weight (Lopes and Furlong 2001). Concentration of naphthalene detected decreased 

from 33 to 2.1 ng/g dry weight with increasing depth (0–148 cm) in the sediment core in Richardson Bay 

and from 18–4.1 ng/g dry weight with increasing depth (0–239 cm) in the sediment core in San Pablo Bay 

(Pereira et al. 1999). These bays are located in the San Francisco Bay which is the larges urbanized 

estuary on the west coast of the United States. 

6.4.4 Other Environmental Media 

Naphthalene is not generally reported in fish, but has been detected in shellfish in the United States. 

Naphthalene was not detected in 83 biota samples (median detection limit 2.5 mg/kg) reported from 

1980–1982 in the STORET database (Staples et al. 1985). Reported naphthalene concentrations ranged 

from 5 to 176 ng/g in oysters, from 4 to 10 ng/g in mussels, and from <1 to 10 ng/g in clams from U.S. 

waters (Bender and Huggett 1989). In shore crabs collected from the San Francisco Bay area, average 

naphthalene concentrations were 7.4 ng/g (Miles and Roster 1999). Naphthalene constituted 75–80% of 

total polyaromatic hydrocarbons (PAHs) found in the muscle, liver, and gonads of American plaice and 

yellow tail flounder caught off the coast of Newfoundland (Hellou and Warren 1996). Naphthalene and 

methylnaphthalene (isomer not specified) were detected in the muscle (1.5–3.1 ng/g wet weight), kidney 

(1.4–4.3 ng/g wet weight), liver (1.4–4.7 ng/g wet weight), and blubber (8.3–23.5 ng/g wet weight) of 

harp seals caught in southern Labrador on the eastern coast of Canada (Zitko et al. 1998). Naphthalene 

and methylnaphthalenes (isomer not specified) were detected at concentrations of 7.15 and 65.11 μg/kg of 

salmon tissue, respectively, and at 12.9 and 17.3 μg/kg of mussels, respectively. Both the salmon and 

mussels were caught in Exxon Valdez spill affected Snug Harbor in the Prince William Sound (Neff and 

Burns 1996). Methylnaphthalenes have occasionally been detected in fish from polluted waters. 

2-Methylnaphthalene was reported at concentrations ranging from 0.4 to 320 μg/g in fish from Ohio 

waters, but neither isomer of methylnaphthalene was detected in muscle tissue of fish from polluted areas 

of Puget Sound (GDCH 1992). Methylnaphthalenes were also detected in oysters in Australia at <0.3– 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 189 

6. POTENTIAL FOR HUMAN EXPOSURE 

2 μg/g. Naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene were detected at mean 

concentrations of 1.98, 0.96, and 1.98 ng/g, respectively, in farmed salmon and at 2.15, 1.53, and 

2.93 ng/g, respectively, in wild salmon from the Pacific coast (Easton et al. 2002). 

Naphthalene was detected in 2 of 13,980 samples of foods analyzed in six states (Minyard and Roberts 

1991). In a Lower Rio Grande Valley environmental study, naphthalene (median concentration, 

2.159 μg/kg body weight) was detected in five of the nine duplicate-diet samples (Berry et al. 1997). 

Naphthalene (1–7 μg/kg) was also detected in fresh tree-ripened apricots, plums, and their interspecific 

hybrids (Gomez et al. 1993). Naphthalene concentrations from vegetables grown in an industrial area of 

Thessaloniki, Greece were measured to be 0.37–15 μg/kg dry weight in cabbage; 8.9–30 μg/kg dry weight 

in carrots; 6.3–35 μg/kg dry weight in leeks; 4.9–53 μg/kg dry weight in lettuce; and 27–63 μg/kg dry 

weight in endive (Kipopoulou et al. 1999). Naphthalene was among the volatile organic compounds 

identified in whole and ground sorghum (Seitz et al. 1999). 

Naphthalene levels in sterilized milk drinks contained in low-density polyethylene (LDPE) bottles were 

shown to be low (0.02 μg/mL) at the time of purchase, increasing to 0.1 μg/mL 30 days later, and 

averaging 0.25 μg/mL at the expiration date of the milk (Lau et al. 1994). Residual naphthalene present 

in the LDPE packaging was hypothesized to be the source of naphthalene contamination. A later study by 

the same authors observed that the level of naphthalene in LDPE milk bottle material had been reduced to 

0.1–0.4 μg/g due to the use of new packaging material (Lau et al. 1995). 

No information was located that documented methylnaphthalenes in food products. 

Naphthalene was detected in the gas phase (5,860 μg/kg of meat cooked) as well as the particle phase 

(1,440–1,690 μg/kg of cooked meat) in the emissions from the process of charbroiling hamburger meat 

over a natural gas grill (Schauer et al. 1999a). Naphthalene was detected at a concentration of 227 mg/kg 

of wood burned from the fireplace combustion of pine wood. 1-Methylnaphthalene was detected at 

concentrations of 10.6, 6.39, and 4.31 mg/kg of wood burned from the combustion of pine, oak, and 

eucalyptus wood respectively. 2-Methylnaphthalene was detected at concentrations of 15.0, 9.31, and 

5.69 mg/kg of wood burned from combustion of pine, oak, and eucalyptus wood, respectively. 

Naphthalene was not measured from the oak and eucalyptus fires (Schauer et al. 2001). In another study, 

the respective median concentrations of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene 

were determined to be 22.57, 4.14, and 4.76 mg/kg of burned soft wood in the fireplace; 60.86, 12.71, and 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 190 

6. POTENTIAL FOR HUMAN EXPOSURE 

15.55 mg/kg for hardwood in the fireplace; and 34.96, 5.23 and 6.32 mg/kg for hardwood burned in a 

woodstove (McDonald et al. 2000). 

Reported levels of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene in measured in the smoke 

from U.S. commercial unfiltered cigarettes were 3, 1, and 1 μg, respectively (Schmeltz et al. 1978). 

Levels in sidestream smoke were found to be higher; 46, 30, and 32 μg/cigarette, respectively (Schmeltz 

et al. 1976). 

Naphthalene has been detected in ash from municipal refuse and hazardous waste incinerators (EPA 

1989g; Shane et al. 1990). Naphthalene was detected in 7 of 8 municipal refuse ash samples at 6– 

28,000 μg/kg (Shane et al. 1990) and in 5 of 18 hazardous waste incinerator ash samples at 0.17– 

41 mg/kg (EPA 1989g). Higher concentrations were detected in bottom ash than in fly ash (Shane et al. 

1990). 

Naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene were among the chemicals detected in 

Lower Manhattan in the aftermath of the destruction of the World Trade Center, New York City, New 

York on September 11th, 2001. Concentration of naphthalene ranged from 699 ng/m-3 on 9/26–9/27 to 

42 ng/m-3 on 10/21–10/22. The concentration of 1-methylnaphthalene ranged from 178 to 100 ng/m-3 and 

that of 2-methylnaphthylene ranged from 267 to 165 ng/m-3 for the same days (Swartz et al. 2003). 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The general population is exposed to naphthalene mainly by inhalation of ambient and indoor air. The 

use of naphthalene-containing moth repellents and smoke from cigarettes are the main sources of 

naphthalene in indoor air. Other sources include kerosene heaters. Based on an urban/suburban average 

air concentration of 0.95 μg/m3 and an inhalation rate of 20 m3

/day, it has been estimated that the average 

daily intake from ambient air is 19 μg (Howard 1989). Intake from indoor air may be higher, depending 

on the presence of indoor sources. 

The estimated average daily intake from ambient air may be about 10 μg for 1-methylnaphthalene and 

1 μg for 2-methylnaphthalene. These estimates are based on ambient air samples taken from 

64 (1-methylnaphthalene) and 17 (2-methylnaphthalene) locations (EPA 1988g) and an assumed human 

daily intake of 20 m3

. Naphthalene was one of the PAHs detected in an 8-home pilot study that was 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 191 

6. POTENTIAL FOR HUMAN EXPOSURE 

conducted in Columbus, Ohio to measure the PAH concentration profiles in house-dust. The average 

concentration of naphthalene was found to be dependant upon the method of extraction (2.8 mg/m3 by 

soxhlet extraction and 1.8 mg/m3 by sonication extraction) (Chuang et al. 1995). Concentrations of 

naphthalene detected in the indoor and outdoor air measured in 24 low-income homes in North Carolina 

ranged from 0.33 to 9.7 and from 0.57 to1.82 μg/m3

, respectively (Chuang et al. 1999). In a study 

reporting the concentrations of volatile organic compounds (VOCs) in a wide range of environments (i.e., 

homes, offices, restaurants, pubs, department stores, train and bus stations, heavily trafficked roadside 

locations, buses, trains and automobiles) in Birmingham, United Kingdom, naphthalene concentrations 

were found to range from 0.1 μg/m3 (labs) to 12.1 μg/m3 (heavily trafficked roadside) (Kim et al. 2001). 

A mean concentration of naphthalene was found to be 2.3 μg/m3 in a German environmental survey that 

monitored 113 adults aged 25–69 years, selected at random, for personal exposure to VOCs including 

naphthalene (Hoffman et al. 2000). Low levels of naphthalene (average concentration, 0.44 μg/m3

) and 

1-methylnaphthalene (average concentration 0.08 μg/m3

) were found in the indoor air of 92 and 81% of 

single family homes and apartments monitored, respectively (Kostianen 1995). Naphthalene has been 

detected in the smoke from charbroiling meat (Schauer et al. 1999a) and from the smoke from domestic 

fireplaces and wood burning stoves (McDonald et al. 2000; Schauer et al. 2001). 

Exposure to naphthalene may occur from ingestion of drinking water and/or food, but these exposures are 

expected to be much less than inhalation exposures for the general population. Estimated exposure from 

drinking water, assuming a water concentration range of 0.001–2 μg/L, is 0.002–4 μg/day (Howard 1989). 

Estimates for food were not calculated. In a Lower Rio Grande Valley environmental study, naphthalene 

(median concentration, 2.159 μg/kg body weight) was detected in five of the nine duplicate-diet samples 

(Berry et al. 1997). Naphthalene was also detected in fresh tree-ripened apricots, plums, and their 

interspecific hybrids (Gomez et al. 1993), in vegetables such as cabbage, carrots, leeks, lettuce, and 

endive (Kipopoulou et al. 1999), and in whole and ground sorghum (Seitz et al. 1999). It has also been 

found in fish such as American plaice, yellow tail flounder (Hellou and Warren 1996), and salmon (Neff 

and Burns 1996). 

Accidental ingestion of household products containing naphthalene such as mothballs or deodorant blocks 

frequently occurs in children. In 1990, 2,400 cases of accidental naphthalene ingestion were reported to 

72 Poison Control Centers in the United States (Woolf et al. 1993). Nearly 90% of these cases occurred 

in children under 6 years of age. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 192 

6. POTENTIAL FOR HUMAN EXPOSURE 

Dermal exposure to naphthalene may occur from handling or wearing clothing stored in naphthalenecontaining moth repellents. However, no data were located concerning the level of human exposure to 

naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene via this exposure route. Experimental studies 

have shown that naphthalene can be dermally absorbed and systemically metabolized in rats (Turkall et 

al. 1994). 

Naphthalene was detected in 40% of human adipose tissue samples at concentrations ranging from <9 to 

63 μg/kg in a National Human Adipose Tissue Survey (NHATS) (EPA 1986g). Naphthalene was also 

detected (concentrations not reported) in six of eight selected breast milk samples from women in four 

U.S. cities (Pellizzari et al. 1982). 

Naphthalene exposure may also occur in the workplace. Bjorseth et al. (1978a, 1978b) have reported 

vapor levels of 11–1,100 μg/m3 and from 0 (nondetected) to 44 μg/m3 for naphthalene-containing 

particulate in a coke plant. Similar measurements in an aluminum reduction plant yielded somewhat 

lower levels of 0.72–310 μg/m3 for vapor and 0.08–4 μg/m3 for particulates. Higher levels would be 

anticipated in naphthalene-producing industries and naphthalene-using industries such as wood 

preserving, tanning, and ink and dye production. A NIOSH (1980) survey of worker exposures to 

polyaromatic hydrocarbons at a petroleum refinery in Tulsa, Oklahoma reported air concentrations of 

naphthalene as high as 10.2 μg/m3 in an area sample and 19.3 μg/m3 for a personal sample. For 2-methylnaphthalene, 17.6 μg/m3 was the maximum area concentration reported and 31.9 μg/m3 was the highest 

value for a personal sample. A National Occupational Exposure Survey (NOES) conducted by NIOSH 

estimated that 112,702 and 4,358 workers are potentially exposed to naphthalene and 2-methylnaphthalene, respectively (NIOSH 1991). The workers at greatest risk of exposure included mining 

machine operators, aircraft engine mechanics, and miscellaneous machine operators. The NOES data 

have become progressively dated, and as a consequence, less representative of current exposure 

situations. The number of workers exposed to naphthalene during its manufacture and subsequent use is 

estimated to be 250–500 in the UK and 1,500–2,000 in the European Union (EU). These estimates do not 

include operators handling creosote treated lumber or brush applicators or users of tar paints/membranes 

(EU 2002). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 193 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

Children are likely to be exposed to naphthalene via the same routes that affect adults, such as inhalation 

of contaminated air, ingestion of contaminated groundwater used as a source of drinking water, ingestion 

of contaminated food, and dermal contact with contaminated soils or products treated with the compound. 

The EPA (1996c) calculated an estimated intake range of 0.0002–0.043 mg/kg/day of naphthalene for a 

10-kg child, assuming an ingestion of 100 mg of soil per day. Assuming food ingestion of approximately 

0.5–2.3 kg/day for children, an estimated daily intake of 204–940 ng/kg-day was calculated for a 10-kg 

child. An estimated average daily dose of 1,127 ng/kg-day was calculated, assuming an inhalation rate of 

8.7 m3

/day for a 10-kg child. 

Small children are more likely than adults to come into intimate contact with yard dirt, lawns, and dust 

from carpets. Dislodgeable pesticide residues in carpets or on uncovered floors may present a relatively 

important exposure route for infants and toddlers through dermal contact and oral ingestion. The 

tendency of young children to ingest soil, either intentionally through pica or unintentionally through 

hand-to-mouth activity, is well documented. These behavioral traits can result in ingestion of naphthalene 

present in soil and dust. Naphthalene has been detected in the house-dust in an 8-home pilot study 

(Chuang et al. 1995). 

Dermal exposure to naphthalene may occur from handling or wearing clothing stored in naphthalenecontaining moth repellents. No studies are available that describe the dermal absorption of naphthalene in 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 194 

6. POTENTIAL FOR HUMAN EXPOSURE 

children. Experimental studies have shown that naphthalene can be dermally absorbed and systemically 

metabolized in rats (Turkall et al. 1994). 

Inhalation exposure is a major source of exposure in both adults and children. Naphthalene has been 

detected in the indoor air of homes (Chuang et al. 1995, 1999; Kostianen 1995). Naphthalene has been 

detected in the smoke from charbroiling meat (Schauer et al. 1999a) and from the smoke from domestic 

fireplaces and wood burning stoves (McDonald et al. 2000; Schauer et al. 2001). 

Naphthalene was among the chemicals detected at nine day care centers in Durham, Raleigh, and Chapel 

Hill, North Carolina (Wilson et al. 1999). Indoor and outdoor air was found to contain naphthalene at 

concentrations of 205 and 89.6 ng/m-3, respectively. The concentrations were 0.011 ppm in soil, 

0.008 ppm in dust, 0.94 ppb in liquid food, and 0.25 ppb in solid food samples. The differences in PAH 

concentrations between day care centers serving low-income clients and those serving middle-income 

clients were found to be small. 

Naphthalene (mothballs) is commonly used as a moth repellant in clothes during storage and as a 

deodorizer in diaper pails. Acute hemolysis was reported in 21 children following a period of inhalation 

exposure of naphthalene. The source of naphthalene was woolen clothes and blankets that had been 

stored with mothballs over the summer (Valaes et al. 1963). 

A potential source of exposure in infants is from the presence of naphthalene in breast milk or formula. 

Naphthalene was detected (concentrations not reported) in six of eight breast milk samples from women 

in four U.S. cities (Pellizzari et al. 1982). 

Children may also be exposed to naphthalene from milk drinks that have been stored in LDPE bottles. 

Naphthalene concentrations of 0.02 μg/mL were found in milk drinks stored in LDPE bottles at the time 

of purchase, but increased to 0.1 μg/mL 30 days later and averaged 0.25 μg/mL at the expiration date of 

the milk drink (Lau et al. 1994). Residual naphthalene present in the LDPE packaging was hypothesized 

to be the source of naphthalene contamination. A later study by the same authors observed that the level 

of naphthalene in LDPE milk bottle material had been reduced to 0.1–0.4 μg/g due to new packaging 

material (Lau et al. 1995). 

Accidental ingestion of household products containing naphthalene, such as mothballs or deodorant 

blocks, can occur in children. In 1990, 2,400 cases of accidental naphthalene ingestion were reported to 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 195 

6. POTENTIAL FOR HUMAN EXPOSURE 

72 Poison Control Centers in the United States (Woolf et al. 1993). Nearly 90% of these cases occurred 

in children under 6 years of age. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Members of the general population most likely to have high levels of exposure to naphthalene are users of 

naphthalene-containing moth repellents (including infants exposed to blankets or clothing stored in 

naphthalene-containing mothballs), smokers, and those in proximity to smokers. Workers in naphthaleneproducing or naphthalene-using industries could be subject to heightened exposure, and individuals living 

or working near hazardous waste sites at which naphthalene has been detected could also be exposed to 

higher naphthalene concentrations if they came into contact with contaminated media. 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene are available. Where adequate information is not available, ATSDR, in conjunction with 

NTP, is required to assure the initiation of a program of research designed to determine the health effects 

(and techniques for developing methods to determine such health effects) of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of naphthalene that are 

required to evaluate its behavior in the environment have been determined (EPA 1982e; HSDB 2004). 

Information that documented the physical and chemical properties of 1-methylnaphthalene and 2-methyl-
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 196 

6. POTENTIAL FOR HUMAN EXPOSURE 

naphthalene are also available (HSDB 2004). However, measured Henry's law constants and log Koc 

values for methylnaphthalenes would allow more accurate prediction of environmental fate processes. 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2002, became available in May of 2004. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

Naphthalene producers, production locations and volumes, uses, releases, and disposal practices are well 

documented (Lacson et al. 2000; SRI 2004; TRI02 2004). Disposal of naphthalene-containing wastes are 

regulated by EPA, and major spills or accidental releases must be reported to EPA. No data were located 

on production volume, releases, and disposal practices for 1-methylnaphthalene or 2-methylnaphthalene. 

This information would be helpful to predict the potential for human exposure to these chemicals. 

Environmental Fate. Existing information indicates that most naphthalene is released to the 

atmosphere and undergoes rapid reaction with hydroxyl radicals (Atkinson et al. 1987; EPA 1982d; 

Howard 1989). Available data indicate that volatilization and biodegradation are important removal 

processes from water and soil (EPA 1982d; Howard 1989; Tabak et al. 1981; Wakeham et al. 1983). 

Additional studies on the rates of volatilization, degradation, and transport in groundwater would be 

helpful in assessing potential human exposure in the vicinity of industrial sources and chemical waste 

sites. Data describing the volatilization, biodegradation, and transport of 1-methylnaphthalene and 

2-methylnaphthalene would be useful in predicting the potential for human exposure. 

Bioavailability from Environmental Media. No studies were located on the bioavailability of 

naphthalene in various environmental media. Available toxicity data indicate that naphthalene present in 

contaminated air and ingested in drinking water or soil is probably absorbed. Confirmatory, quantitative 

data would be useful. Data on infants indicate that toxicologically significant amounts of naphthalene 

may be absorbed dermally from residues left on stored clothing, especially under circumstances where 

baby oil was used on the infants' skin (Schafer 1951). Quantitative studies of the dermal absorption of 

naphthalene from water and soil would be useful in determining potential exposure for populations living 

near hazardous waste sites. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 197 

6. POTENTIAL FOR HUMAN EXPOSURE 

No data have been located pertaining to the bioavailability of 1-methylnaphthalene or 2-methylnaphthalene in environmental media. Studies in laboratory animals to assess the absorption of this 

compound via the oral, inhalation, and dermal routes would be useful before bioavailability from each 

medium can be reasonably estimated. 

Food Chain Bioaccumulation. Naphthalene is often readily degraded in the environment and is 

easily metabolized by a wide variety of organisms. Studies indicate that although naphthalene may 

bioconcentrate to a moderate degree for brief periods, it will not significantly bioaccumulate in organisms 

due to metabolism, and thus, is unlikely to biomagnify through the food chain (Howard 1989; Thomann 

1989). Naphthalene has been found to be present in fish and shellfish (Bender and Huggett 1989; Hellou 

and Warren 1996; Miles and Roster 1999; Minyard and Roberts 199l; Neff and Burns 1996; Zitko et al. 

1998). It has also been located in the flesh of fresh fruits and vegetables (Gomez et al. 1993; Kipopoulou 

et al. 1999; Seitz et al. 1999). Data were not located on 1-methylnaphthalene and 2-methylnaphthalene 

levels in foods. Additional data on naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene 

concentrations in foods and processed foods would be useful to assess the extent of human exposure via 

the food chain. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of 

naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene in contaminated media at hazardous waste 

sites are needed so that the information obtained on levels of naphthalene, 1-methylnaphthalene, and 

2-methylnaphthalene in the environment can be used in combination with the known body burden of 

naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene to assess the potential risk of adverse health 

effects in populations living in the vicinity of hazardous waste sites. 

The concentrations of naphthalene in the air, water, and soil have been documented (Bradley et al. 1994; 

Chuang et al. 1999; EPA 1988g; Howard 1989; Miles and Delfino 1999; Richardson et al. 1994; 

Squillace et al. 1999; Wild et al. 1990; Yu et al. 1990; Zielinska et al 1998). In addition, indoor air levels 

have been measured (Chuang et al. 1991; Hung et al. 1992; Wilson et al. 1989). Additional information 

regarding exposure levels of 1-methylnaphthalene and 2-methylnaphthalene in environmental media 

would be useful for deriving exposure estimates for the general population. 

Reliable monitoring data for the levels of naphthalene in contaminated media at hazardous waste sites are 

needed so that the information obtained on levels of naphthalene in the environment can be used in 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 198 

6. POTENTIAL FOR HUMAN EXPOSURE 

combination with the known body burden of naphthalene to assess the potential risk of adverse health 

effects in populations living in the vicinity of hazardous waste sites. 

Exposure Levels in Humans. A national survey of adipose tissue samples indicates that about 40% 

of the study subjects had measurable levels of naphthalene (EPA 1986g). Naphthalene was also detected 

in six of eight samples of human milk (Pellizzari et al. 1982). Data on the effect of cigarette filters on 

naphthalene uptake by the adipose tissues would be useful. Naphthalene has been detected in house dust 

(Chuang et al. 1995). 

No data on exposure levels in humans were located for 1-methylnaphthalene or 2-methylnaphthalene. 

This information would be useful to determine whether any significant exposure to these chemicals 

occurs. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. No monitoring studies have been performed to investigate the exposure to, 

and the body burden of, naphthalene in children. No studies are available on the dermal absorption of 

naphthalene in infants and toddlers due to activities such as crawling, which will result in contact with the 

floor (carpet) and soil or from exposure to clothes stored with mothballs. Since naphthalene is likely to 

be adsorbed to these materials, more information would allow the estimation of a child’s exposure to 

naphthalene to be more rigorously determined. Naphthalene has been detected in house dust (Chuang et 

al. 1995). The EPA has calculated estimated amounts of naphthalene inhaled and naphthalene ingested 

via the intake of food and soil for a 10-kg child (EPA 2002b). No studies on amounts of naphthalene 

present in foods eaten by children are available. Such studies may help to identify childhood-specific 

means of decreasing exposure to naphthalene. 

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data 

Needs: Children’s Susceptibility. 

Exposure Registries. No exposure registries for naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene were located. These substances are not currently one of the compounds for which a subregistry has been established in the National Exposure Registry. These substances will be considered in 

the future when chemical selection is made for sub-registries to be established. The information that is 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 199 

6. POTENTIAL FOR HUMAN EXPOSURE 

amassed in the National Exposure Registry facilitates the epidemiological research needed to assess 

adverse health outcomes that may be related to exposure to this substance. 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2004) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. These 

studies are summarized in Table 6-2. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 200 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Ongoing Studies on the Potential for Human Exposure to 

Naphthalenea 

Investigator Affiliation Research description Sponsor 

Nylander French LA 	 University of North 

Carolina, Chapel Hill, 

North Carolina 

Aitken MD 	 University of North 

Carolina, Chapel Hill, 

North Carolina 

Atkinson R; Winer University of California, 

AM Riverside, California 

Boyd SA 	 Michigan State 

University, East 

Lansing, Michigan 

Bryers JD	 University of 

Connecticut Health 

Center, Farmington, 

Connecticut 

Kilduff JE 	 Rensselaer Polytechnic 

Institute, Troy, New 

York 

Thompson AF	 Connecticut Agricultural 

Experimental Station, 

New Haven, 

Connecticut 

Pulliam Holoman TR 	 University of Maryland, 

College Park, Maryland 

Sayler GS 	 University of 

Tennessee, Knoxville, 

Tennessee 

Zylstra GJ	 Rutgers University, New 

Brunswick, New Jersey 

Dermal exposure to benzene 

and naphthalene 

Bacterial chemotaxis to 

naphthalene desorbing from 

non-aqueous phase liquid 

Photochemical and thermal 

reactions of combustion 

related particulate organic 

matter: A combined 

chemical and microbiological 

approach 

Physicochemical and 

microbiological factors 

influencing the bioavailability 

of organic contaminants in 

subsoils 

Substrata surface chemistry, 

conformation of contaminant 

upon absorption, and 

availability for biodegradation 

Collaborative research: 

Sorption reversibility of 

hydrophobic compounds in 

geosorbents investigated 

with model sorbents 

Collaborative research: 

Sorption reversibility of 

hydrophobic compounds in 

geosorbents investigated 

with model sorbents 

Anaerobic degradation of 

polycyclic aromatic 

hydrocarbons in marine 

harbor sediments 

On-line monitoring of aerobic 

bioremediation with 

bioluminescent reporter 

microbes 

Molecular analysis of 

polycyclic aromatic 

hydrocarbon degradation by 

mycobacteria 

National Institutes of 

Environmental Health 

Science 

National Science 

Foundation, 

Environmental 

Remediation Program 

ER-74 

Office of Scientific and 

Technical Information 

U.S. Department of 

Energy, Energy Research 

National Science 

Foundation, 

Environmental 

Remediation Program 

National Science 

Foundation, 

Environmental 

Remediation Program 

National Science 

Foundation, 

Environmental 

Remediation Program 

National Science 

Foundation, 

Environmental 

Remediation Program 

U.S. Department of 

Energy, Energy Research 

National Science 

Foundation, Biomolecular 

Processes Cluster 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 201 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Ongoing Studies on the Potential for Human Exposure to 

Naphthalenea 

Investigator Affiliation Research description Sponsor 

Pignatello JJ 	 Connecticut Agricultural Chain-transfer complexation U.S. Department of 

Experimental Station, of aromatic compounds with Agriculture 

New Haven, soil organic matter 

Connecticut 

Inskeep WP 	 Montana State Fate and transport of U.S. Department of 

University, Bozeman, chemicals in soils: linking Agriculture 

Montana chemical transformations 

Madsen EL Cornell University, Observing microbial diversity U.S. Department of 

Ithaca, New York and horizontal gene transfer Agriculture 

in a shallow aquifer 

Haggblom MM Rutgers University, New Microbial degradation of U.S. Department of 

Brunswick, New Jersey PAHs in the rhizosphere of Agriculture 

salt-marsh plants 

Pignatello JJ 	 Connecticut Agricultural Nonideal (specific) sorption U.S. Department of 

Experimental Station, of organic chemicals in soil Agriculture 

New Haven, organic matter 

Connecticut 

Ogram AV; Hornsby	 University of Florida, Pesticides and other toxic U.S. Department of 

AC Gainesville, Florida 	 organics in soil and their Agriculture 

potential for ground and 

surface water contamination 

Huang W 	 Drexel University, Black carbon in soils and U.S. Department of 

Philadelphia, sediments and its Agriculture 

Pennsylvania interactions with organic 

pollutants 

Huwe JK; Hakk H; Agricultural Research Dioxins and other U.S. Department of 

Shappell NW; Service, Fargo, South environmental contaminants Agriculture 

Shlever WL; Larsen Dakota in food 

GL; Smith DJ 

Xing B 	 University of Effects of long-term tillage U.S. Department of 

Massachusetts, and cover crop systems on Agriculture 

Amrherst, soil organic matter and 

Massachusetts pesticide sorption 

Chorover JD 	 Pennsylvania State Effects of mineral-organic U.S. Department of 

University, University interactions on chemical Agriculture 

Park, Pennsylvania processes in soils 

Thompson ML; Iowa State University, Human impacts on soil; a U.S. Department of 

Sandor JA; Burras Ames, Iowa pedogenic perspective Agriculture 

Hyman MR	 North Carolina State Physiology, biochemistry, U.S. Department of 

university, Raleigh, and enzymology of microbial Agriculture 

North Carolina cometabolism 

Larson RA; Sims GK University of Illinois, Phytoremediation of U.S. Department of 

Urbana, Illinois agrochemicals with aquatic Agriculture 

and terrestrial plants 

CL 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 202 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Ongoing Studies on the Potential for Human Exposure to 

Naphthalenea 

Investigator Affiliation Research description Sponsor 

Simkins S University of 

Massachusetts, 

Amherst, 

Quantification of pesticidederived organic carbon in 

microbial biomass and soil 

U.S. Department of 

Agriculture 

Massachusetts humic substances 

Pignatello JJ Connecticut Agricultural 

Experimental Station, 

New Haven, 

Connecticut 

Reducing the potential for 

environmental contamination 

by pesticides and other 

organic chemicals 

U.S. Department of 

Agriculture 

Scow KM University of California, 

Davis, California 

Reducing the potential for 

environmental contamination 

by pesticides and other 

organic chemicals 

U.S. Department of 

Agriculture 

Maier RM; Brusseau 

ML 

University of Arizona, 

Tucson, Arizona 

Reducing the potential for 

environmental contamination 

by pesticides and other 

organic chemicals 

U.S. Department of 

Agriculture 

Xing B University of 

Massachusetts, 

Amherst, 

Massachusetts 

Sorption of organic 

contaminants in soils; 

mechanisms and implications 

for desorption and 

bioavailability 

U.S. Department of 

Agriculture 

Rolston DE University of California, 

Davis, California 

Transport and transformation 

of trace gases in soil 

U.S. Department of 

Agriculture 

a

FEDRIP 2004 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 203 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring naphthalene, 1-methylnaphthalene, 2-methylnaphthalene,, its metabolites, 

and other biomarkers of exposure and effect to naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is 

to identify well-established methods that are used as the standard methods of analysis. Many of the 

analytical methods used for environmental samples are the methods approved by federal agencies and 

organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other 

methods presented in this chapter are those that are approved by groups such as the Association of 

Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). 

Additionally, analytical methods are included that modify previously used methods to obtain lower 

detection limits and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

Naphthalene is moderately volatile with a boiling point of 218 °C and low water solubility of 31.7 mg/L 

(20 °C). Its log octanol/water partition coefficient is 3.29, implying a moderate affinity for lipid tissues. 

It undergoes short-term bioaccumulation in tissues, but biochemical processes lead to its biodegradation 

and eventual elimination. Methylnaphthalenes have similar properties (see Table 4-2). All of these 

properties have implications for determination of naphthalene and methylnaphthalenes in biological 

materials. 

Historically, diethyl ether has been a widely used solvent for the extraction of lipophilic organic analytes 

such as naphthalene from biological fluids (Zlatkis and Kim 1976). Homogenization of tissue with the 

extractant and lysing of cells improves extraction efficiency. When, as is often the case, multiple analytes 

are determined using solvent extraction, selective extraction and loss of compounds that have a low 

boiling point can cause errors. The commercial availability of highly purified solvents has largely 

eliminated problems with solvent impurities, although high costs, solvent toxicities, and restrictions on 

spent solvent disposal must be considered. Extraction is the first step in the overall cleanup process that 

places the analyte in a form and matrix suitable for introduction into the instrument used to quantitate it. 

Cleanup of biological samples may often be complex and involve a number of steps (Walters 1986). 

Directly coupled supercritical fluid extraction (SFE)-gas chromatography has been used for the 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 204 

7. ANALYTICAL METHODS 

determination of polychlorinated biphenyls (Hawthorne 1988) and might also be applicable to 

determination of naphthalene and methylnaphthalenes in biological samples. 

Naphthalene metabolites are less lipophilic than naphthalene itself. Metabolites are isolated from body 

fluids and tissue homogenates by extraction and separated by thin layer chromatography (TLC) and 

HPLC (Horning et al. 1980; Melancon et al. 1982; Stillwell et al. 1982). Final identification of 

metabolites, which include numerous oxygenated and sulfur-containing species, is accomplished by gas 

chromatography (GC) and mass spectrometry (MS). 

New immunological methods are being developed for detecting selected naphthalene metabolites in urine 

or naphthalene protein adducts in the blood of lung lavage specimens (Cho et al. 1994b; Marco et al. 

1993). Additional work in perfecting these techniques is necessary before they will be useful in research 

and clinical practice. 

Analytical methods for the determination of naphthalene and for 1-methylnaphthalene and 2-methylnaphthalene in biological samples are given in Table 7-1. A method for the determination of 

radiolabelled 2-methylnaphthalene in rat urine has been described by Melancon et al. (1982). TLC and 

HPLC were used to characterize 2-methylnaphthalene and its metabolites, including 2-naphthoylglycine, 

2-naphthoic acid, and others. 

7.2 ENVIRONMENTAL SAMPLES 

Gas chromatography and HPLC are the analytical methods most commonly used for detection of 

naphthalene and methylnaphthalenes in environmental samples. Several variations of these methods 

using different collection, extraction, and/or cleanup procedures and different detection methods have 

been approved by EPA and NIOSH for analysis of naphthalene in ambient water, drinking water, waste 

water, soil, and air (EPA 1982a, 1982b, 1986a, 1986b, 1986c, 1986d, 1990a, 1990b, 1990c, 1990d, 

1990e; NIOSH 1984a, 1984b). The American Public Health Association (APHA) has recommended 

standard methods for analysis of naphthalene in water and waste water, each of which has been accepted 

by EPA as equivalent to one of the EPA-approved methods (APHA 1992a, 1992b, 1992c, 1992d, 1992e, 

1992f). Analytical methods for naphthalene and 2-methylnaphthalene are presented in Tables 7-2 

and 7-3, respectively. Although no standard methods were located that provided information on detection 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 205 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Naphthalene, 1-Methylnaphthalene, and 2-Methylnaphthalene in Biological Samplesa 

Sample 

Analytical detection Percent 

Sample matrix Preparation method method limit recovery Reference 

Adipose tissue Extract; bulk lipid removal; HRGC/MS 9 ng/g No data Stanley 1986 

Florisil7 fractionation 

Adipose tissue Extract with hexane; Florisil7 Capillary 10 ng/g 90 (human) Liao et al. 

(human and cleanup column 

bovine) GC/MS 

63 (bovine) 1988 

Human milk Purge with helium; desorb Capillary No data No data Pellizzari et al. 

thermally column 1982 

GC/MS 

Human urine No data TLC or GS/ No data No data Bieniek 1994 

(1-naphthol unspecified 

analysis spectroscopy 

Fish tissue Purge and trap to carbon HRGC/FID <10 μg/L 43–51 Murray and 

adsorption tube; extract with Lockhart 1988 

carbon disulfide 

Fish tissue Saponification with potassium Capilliary 20 ng/g 76–202 Lebo et al. 

hydroxide; extraction with column (naphthalene) 1991 

cyclopentane-dichloro- GC/PID 77–82 

methane; adsorption (1-methylenrichment with potassium naphthalene) 

silicate/silica gel; gel 75–131 

permeation chromatography (2-methylenrichment naphthalene) 

Rat urine Extract with ammonium GC/MS No data No data Horning et al. 

carbonate/ethyl acetate; 1980 

evaporate under nitrogen 

stream; dissolve in pyridine 

Mouse urine Extract with ethyl acetate; GC/MS No data No data Stillwell et al. 

evaporate under nitrogen 1982 

stream; dissolve in pyridine 

Burned tobacco Extract with methanol/water GLC/MS No data 85–95 Schmeltz et al. 

and cyclohexane; enrich in 1976 

dimethyl sulfoxide; fractional 

distillation and evaporation 

under dry nitrogen 

a

Data are for naphthalene only unless otherwise specified. 

FID = flame ionization detector; GC = gas chromatography; GLC = gas-liquid chromatography; HRGC = high 

resolution gas chromatography; MS = mass spectrometry; PID = photoionization detector; TLC = thin layer 

chromatography 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 206 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Naphthalene in 

Environmental Samples 

Sample matrix 

Air 

Analytical 

Preparation method method 

Collect in charcoal tube; elute GC/FID 

with carbon disulfide 

Sample 

detection limit 

15 mg/m3 

Percent 

recovery

No data 

 Reference 

NIOSH 1977 

Air Collect in charcoal tube; elute GC/FID 

with carbon disulfide 

10 μg/sample No data NIOSH 1984a 

Air Collect in charcoal tube; elute GC/FID 

with organic solvent 

0.5 μg/sample No data NIOSH 1984b 

Air Collection filter or tube; 

extract with acetonitrile 

HPLC/FD 0.080 μg/filter or No data 

0.070 μg/tube 

Hansen et al. 

1991 

Indoor air Medium flow rate samples; 

extract with methylene 

chloride; exchange to 

cyclohexane; clean up; 

exchange to acetonitrile 

HPLC/UV 250 pg/μL No data EPA 1990a 

Indoor air Medium flow rate samples; 

extract with methylene 

chloride 

GC/MS No data No data EPA 1990a 

Water Purge and trap HRGC/PID 0.06 μg/L 102±6.3 Ho 1989 

Water Extract with methylene 

chloride; exchange to 

cyclohexane; clean up; 

exchange to acetonitrile 

HPLC/UV 1.8 μg/L 78±8.3 EPA 1982a 

Water Extract with methylene 

chloride at pH 11 and 2; 

concentrate 

GC/MS 1.6 μg/L 75±35 EPA 1982b 

Water Adsorb on small bed volume 

Tenax® cartridges; thermally 

desorb 

GC/MS No data No data Pankow et al. 

1988 

Drinking water Liquid-liquid extraction with HPLC/UV 

methylene chloride; exchange 

to acetonitrile 

3.3 μg/L 76–96 EPA 1990d 

Drinking water Liquid-solid extraction with HPLC/UV 

methylene chloride; exchange 

to acetonitrile 

2.2 μg/L 49.6–75.2 EPA 1990e 

Drinking water Purge and trap Packed 

column 

0.01–0.05 μg/L 92 APHA1992e 

GC/PID 

Drinking water Purge and trap Capillary 

column 

0.02–0.2 μg/L 98–104 APHA 1992d 

GC/MS 

Drinking water Purge and trap Capillary 

column 

No data 102 APHA 1992f 

GC/PID 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 207 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Naphthalene in 

Environmental Samples 

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery Reference 

Wastewater 	 Extract with methylene Isotope 10 μg/L 75–149 EPA 1990c 

chloride 	 dilution, 
 

capillary 
 

column
 

GC/MS 
 

Wastewater 	 Extract with methylene HPLC/UV 1.8 μg/L 21.5–100 APHA 1992b 

chloride; exchange to 

cyclohexane; clean up; 

exchange to acetonitrile 

Water 	 Extract with methylene Capillary 10 μg/La No data EPA 1986c 

chloride column 

GC/MS 

Wastes, non- Extract with methylene Packed 160 mg/kg No data EPA 1986b 

water miscible chloride column 

GC/MS 

Soil Extract with methylene Packed 1 mg/kg No data EPA 1986b 

chloride column 

GC/MS 

Soil, sediment Extract with methylene Capillary 660 μg/kg No data EPA 1986c 

chloride column 

GC/MS 

Wastes, soil Extract with methylene GC/FTIR 20 μg/La, b No data EPA 1986d 

chloride 

a

Identification limit in water. Detection limits for actual samples are several orders of magnitude higher, depending 
 

upon the sample matrix and extraction procedure employed.
 b

Based on a 2 μL injection of a 1 L sample that was extracted and concentrated to a volume of 1 mL. 
 

FD = fluorescence detection; FID = flame ionization detector; FTIR = Fourier transform infrared spectrometry; 
 

GC = gas chromatography; HPLC = high performance liquid chromatography; HRGC = high resolution gas 
 

chromatography; MS = mass spectroscopy; PID = photoionization detection; UV = ultraviolet spectrometry
 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 208 

7. ANALYTICAL METHODS 

Table 7-3. Analytical Methods for Determining 2-Methylnaphthalene in 

Environmental Samplesa 

Sample Percent 

Sample matrix Preparation method Analytical method detection limit recovery 

Soil, sediment Extract with methylene chloride Capillary column GC/MS 660 μg/kg No data 

Water Extract with methylene chloride Capillary column GC/MS 10 μg/kg No data 

a

EPA 1986c 

GC = gas chromatography; MS = mass spectroscopy 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 209 

7. ANALYTICAL METHODS 

limits or accuracy for 1-methylnaphthalene, this compound may be analyzed in environmental media by 

GC and HPLC methods (HSDB 1995). 

Air samples for analysis may be collected on filters or charcoal tubes. Since naphthalene may exist in 

both the vapor phase and the particle phase in air (Harkov 1986), collection on a charcoal tube is the 

preferred method for sampling naphthalene from air for analysis (NIOSH 1977, 1984a, 1984b). 

Naphthalene is usually extracted from the matrix with organic solvents (liquid-liquid or liquid-solid 

extraction) or by purge and trap with an inert gas. SFE techniques for extraction of organic compounds 

from environmental matrices are currently being studied by EPA. A protocol for SFE with carbon 

dioxide for many organic compounds, including naphthalene, from soils and sediments has been 

developed (EPA 1991f). 

A technique for the detection of naphthalene in PAH-contaminated media has been developed (Heitzer et 

al. 1994). The technique measures bioluminescence in the genetically engineered microorganism 

Pseudomonas fluorescens HK44, which carries a transcriptional gene for naphthalene and salicylate 

metabolism. After the addition of the bacteria to sterile water, naphthalene was detected down to 

1.55 μg/L, the lowest concentration studied. In an experiment using JP-4 jet fuel, naphthalene was 

detected down to 0.55 μg/L in the effluent of the biosensor (Heitzer et al. 1994). 

Detectors used for identification and quantification of naphthalene and methylnaphthalenes include the 

flame ionization detector (FID), photoionization detector (PID), ultraviolet detection (UV), Fourier 

transform infrared detection (FTIR), and fluorescence detection (FD). Mass spectrometry is used for 

confirmation. 

7.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene is available. Where adequate information is not available, ATSDR, in conjunction with NTP, 

is required to assure the initiation of a program of research designed to determine the health effects (and 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 210 

7. ANALYTICAL METHODS 

techniques for developing methods to determine such health effects) of naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Sensitive and selective methods are available for the qualitative and/or quantitative 

measurement of naphthalene and many of its metabolites present in biological materials such as adipose 

tissue and urine (EPA 1986g; Horning et al. 1980; Liao et al. 1988). In contrast to the relative ease of 

measuring naphthalene once it has been isolated from its sample matrix, the development of improved 

techniques for sample preparation would be beneficial. 

Metabolites of naphthalene in biological materials are not readily determined in routine practice because 

of the lack of standard methods for their quantification. Furthermore, there is a need for modern validated 

standard methods for analysis of naphthalene itself in biological materials. It would also be helpful to 

have a method that can be used to associate levels of naphthalene or its metabolites in biological media 

with levels of naphthalene exposure in the environment. 

A method for the determination of 2-methylnaphthalene and its degradation products in rat urine has been 

reported (Melancon et al. 1982). It would be useful to determine if this method could also be applied to 

human urine and other biological samples. 

Effect. There are currently no methods that can be used to correlate levels of naphthalene, 2-methylnaphthalene, or their metabolites in biological tissues or fluid with the probable onset of adverse health 

effects. The development of such methods would be useful insofar as they estimate the doses required to 

produce cataracts and hemolytic effects. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 211 

7. ANALYTICAL METHODS 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Methods for determining naphthalene in water, air, and waste samples with excellent selectivity 

and sensitivity have been developed and are undergoing constant improvement (EPA 1982a, 1982b, 

1986a, 1986b, 1986c, 1986d, 1990a, 1990b, 1990c, 1990d, 1990e; NIOSH 1984a, 1984b). For each 

medium, the existing methods are adequate to measure background levels in the environment and levels at 

which health effects occur. Standard methods for 1-methylnaphthalene and 2-methylnaphthalene would 

be helpful in assessing data comparability. 

It would be useful to have the means to rapidly and directly measure organic compounds such as 

naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene in water and other environmental media 

without the necessity for tedious sample processing. The recently developed bioluminescent probe for 

naphthalene (Heitzer et al. 1994) may help satisfy this data need. 

Degradation products of naphthalene in environmental media are difficult to determine. This difficulty is 

not so much an analytical problem as it is a problem of knowing the fundamental environmental 

chemistry of these compounds in water, soil, air, and biological systems. 

There are some difficulties associated with sampling naphthalene from the atmosphere, where it is 

partially associated with particulate matter. High-volume sampling with glass fiber filters provides 

conditions conducive to artifact formation (Harkov 1986), thus introducing errors into the analysis of 

atmospheric naphthalene. This is an area in which further improvements would be useful. 

7.3.2 Ongoing Studies 

No ongoing studies involving analytical techniques of naphthalene, 1-methylnaphthalene, or 2-methylnaphthalene were found in a search of the Federal Research in Progress database (FEDRIP 2003). 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 213 

8. REGULATIONS AND ADVISORIES 
 

The international, national, and state regulations and guidelines regarding naphthalene, 1-methylnaphthalene, and 2-methynaphthalene in air, water, and other media are summarized in Table 8-1. 

As discussed in Chapter 2 and Appendix A, several MRLs for naphthalene (chronic-duration inhalation, 

acute-duration oral, and intermediate-duration oral) and chronic-duration oral MRLs for 1-methylnaphthalene and 2-methylnaphthalene have been derived. 

An MRL of 0.0007 ppm (3x10-3 mg/m3

) for chronic inhalation exposure to naphthalene is based on a 

LOAEL for nasal lesions in rats (Abdo et al. 2001; NTP 2000; LOAEL[human equivalent concentration]= 0.2 ppm), 

and a total uncertainty factor of 300 (10 for the use of a LOAEL, 3 for extrapolation from animals to 

humans using dosimetric adjustment, and 10 for human variability). An MRL of 0.6 mg/kg/day for acute 

oral exposure to naphthalene is based on a minimal LOAEL of 50 mg/kg/day for clinical signs of toxicity 

in pregnant rats and a total uncertainty factor of 90 (3 for the use of a minimal LOAEL, 10 for 

extrapolation from animals to humans, and 3 for human variability). The acute-duration oral MRL of 

0.6 mg/kg/day is adopted as the intermediate-duration oral MRL for naphthalene. 

For chronic-duration oral exposure to 1-methylnaphthalene, an MRL of 0.07 mg/kg/day was derived 

based on a LOAEL of 71.6 mg/kg/day for pulmonary alveolar proteinosis in female mice exposed to 

1-methylnaphthalene in the diet for 81 weeks and an uncertainty factor of 1,000 (10 for using a LOAEL, 

10 for extrapolating from animals to humans, and 10 for human variability). 

For chronic-duration oral exposure to 2-methylnaphthalene, an MRL of 0.04 mg/kg/day was derived 

based on the lower 95% confidence limit on a benchmark dose associated with 5% extra risk 

(BMDL05=4 mg/kg/day) for pulmonary alveolar proteinosis in male mice exposed to 

2-methylnaphthalene in the diet for 81 weeks and an uncertainty factor of 100 (10 for extrapolation from 

animals to humans and 10 for human variability). 

The EPA calculated an oral exposure RfD of 2x10-2 mg/kg/day for naphthalene based on a NOAEL of 

100 mg/kg/day for the absence of decreased mean terminal body weight in male rats exposed by gavage 

for 13 weeks (IRIS 2005; NTP 1980b). An inhalation RfC of 3x10-3 mg/m3

 for naphthalene was derived 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 214 

8. REGULATIONS AND ADVISORIES 

based on a LOAEL of 10 ppm (LOAEL[human equivalent concentration]=9.3 mg/m3) for nasal lesions in mice 

exposed by inhalation for 2 years (IRIS 2005; NTP 1992a). 

The EPA (2003r) calculated an oral exposure RfD of 0.004 mg/kg-day for 2-methylnaphthalene based on 

a value of 3.5 mg/kg-day for a 95% lower confidence limit on a dose associated with 5% extra risk 

(BMDL05) for pulmonary alveolar proteinosis in mice exposed to 2-methylnaphthalene in the diet for 

81 weeks. 

The EPA is currently conducting a comprehensive review of the available environmental and toxicity data 

of naphthalene as part of its FIFRA re-registration process. The results of this review are expected in 

March 2008. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 215 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Naphthalene, 

1-Methylnaphthalene, and 2-Methylnaphthalene 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC 	 Carcinogenicity classification Group 2Ba

 IARC 2002 

WHO Drinking water guideline No data 

NATIONAL 

Regulations and 

Guidelines: 

a. Air: 

ACGIH TLV (8-hour TWA) 

 Naphthaleneb 10 ppm 

ACGIH 2003 

STEL 
 15 ppm 

EPA 	 Hazardous air pollutant Naphthalene EPA 2003g 

40 CFR 63, Table 1 

National emission standards for EPA 2003h 

hazardous air pollutants 40 CFR 61.134 

 Naphthalene processing, final No (zero) emissions are 

coolers, and final-cooler 
 allowed 

cooling towers at coke by-
 

product recovery plants 
 

NIOSH REL (10-hour TWA) NIOSH 2003 

 Naphthalene 
 10 ppm 

STEL 
 15 ppm 

IDLH 
 250 ppm 

OSHA 	 PEL (8-hour TWA) for general 
 OSHA 2003a 

industry 29 CFR 1910.1000, 

 Naphthalene 
 10 ppm 	 Table Z-1 

PEL (8-hour TWA) for 
 OSHA 2003c 

construction industry 29 CFR 1926.55, 

 Naphthalene 
 10 ppm 	 Appendix A 

PEL (8-hour TWA) for shipyard 
 OSHA 2003b 

industry 29 CFR 1915.1000 

 Naphthalene 
 10 ppm 

USC Hazardous air pollutant Naphthalene USC 2003 

42 USC 7412 

b. Water 

EPA Drinking water health advisories EPA 2002a 

 1-day (10-kg child) 0.5 mg/L 
 

10-day (10-kg child) 

DWELc 

Life-timed 

0.5 mg/L 
 

0.7 mg/L 
 

0.1 mg/L 

Effluent guidelines and standards; Naphthalene EPA 2003c 

toxic pollutants pursuant to 40 CFR 401.15 

Section 307(a)(1) of the Clean 

Water Act 

Hazardous substance designated Naphthalene EPA 2003p 

in accordance with Section 311 40 CFR 116.4 

(b)(2)(A) of the Clean Water Act 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 216 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Naphthalene, 

1-Methylnaphthalene, and 2-Methylnaphthalene 

Agency Description Information Reference 

NATIONAL (cont.) 

Pollutants of initial focus in the 

Great Lakes Water Quality 

Initiative 

Reportable quantities of 

hazardous substances 

(naphthalene) designated 

pursuant to Section 311 of the 

Clean Water Act 

c. Food No data 

d. Other 

 ACGIH Carcinogenicity classification 

EPA Carcinogenicity classification 

 RfD (oral) 

 RfC (inhalation) 

Community right-to-know; release 

reporting; effective date of 

reporting 

Criteria for municipal solid waste 

landfills; hazardous constituent 

Identification and listing of 

hazardous waste; hazardous 

waste number

 Naphthalene 

Land disposal restrictions; 

universal treatment standards for 

naphthalene 

 Waste water standard 

 Non-waste water standard 

EPA 	 Landfills point source effluent 

limitations attainable by the 

application of the best practicable 

control technology currently 

available 

 Maximum daily 

Maximum monthly average 

Reportable quantity of hazardous 

substance in accordance with 

Section 311 (b)(2) and 307(a) of 

the Clean Water Act, Section 112 

of RCRA, and Section 112 of the 

Clean Air Act for naphthalene 

Standards for owners and 

operators of hazardous waste 

TSD facilities; groundwater 

monitoring 

 Naphthalene 

 2-Methylnaphthalene 

Naphthalene 

100 pounds 	 

A4e 

Group Cf

2.0x10-2 mg/kg/day 

3.0x10-3 mg/m3

01/01/87 

Naphthalene and 	 

2-Methylnaphthalene 	 

U165 

0.059 mg/L 

5.6 mg/L TCLP 

0.059 mg/L 

0.022 mg/L 

100 pounds 

Suggested 

Method PQL 

8100 200 μg/L 

8270 10 μg/L 

8270 10 μg/L 

EPA 2003q 

40 CFR 132, 

Table 6 

EPA 2003j 

40 CFR 117.3 

 IRIS 2005 

IRIS 2005 

 IRIS 2005 

EPA 2003m 

40 CFR 372.65 

EPA 2003a 

40 CFR 258, 

Appendix II 

EPA 2003d 

40 CFR 261, 

Appendix VIII 

EPA 2003e 

40 CFR 268.48 

EPA 2003f 

40 CFR 445.11 

EPA 2003b 

40 CFR 302.4 

EPA 2003k 

40 CFR 264, 

Appendix IX 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 217 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Naphthalene, 

1-Methylnaphthalene, and 2-Methylnaphthalene 

Agency Description 	 Information Reference 

NATIONAL (cont.) 

Standards for owners and 10 mg/kg EPA 2003l 

operators of hazardous waste 40 CFR 266, 

TSD facilities; health-based limits Appendix VII 

for exclusion of waste-derived 

residues; residue concentration 

limit 

TSCA chemical information rules; EPA 2003n 

health and safety data reporting 40 CFR 712.30 

for naphthalene 

 Effective date 	 08/04/95 

 Reporting dateg 10/03/95 

TSCA health and safety data EPA 2003o 

reporting for naphthaleneh 40 CFR 716.120 

 Effective date 08/04/95 

 Sunset date 10/03/95 

NTP Carcinogenicity classification 	 Naphthalene is reason- NTP 2005 
 

ably anticipated to be a 
 

human carcinogen 
 

(Group 2)
 

STATE 

a. Air No data 

b. Water 

Maine Drinking water guideline 25 μg/L HSDB 2004 

Minnesota Drinking water guideline 300 μg/L HSDB 2004 

New Jersey Drinking water standard 300 μg/L HSDB 2004 

Washington Drinking water guideline 14 μg/L HSDB 2004 

Wisconsin Drinking water guideline 40 μg/L HSDB 2004 

Florida Drinking water guideline 6.8 μg/L HSDB 2004 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 218 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Naphthalene, 

1-Methylnaphthalene, and 2-Methylnaphthalene 

Agency Description Information Reference 

STATE (cont.) 

c. Food No data 

d. Other No data 

a

Group 2B: possibly carcinogenic to humans 

b

Skin notation: refers to the potential significant contribution to the overall exposure by the cutaneous route, including 

mucous membranes and the eyes, either by contact with vapors or, of probable greater significance, by direct skin 

contact with the substance. 

c

DWEL: a lifetime exposure concentration protection of adverse, non-cancer health effects, that assumes all of the 

exposure to a contaminant is from drinking water. 

d

Life-time: the concentration of a chemical in drinking water that is not expected to cause any adverse 

noncarcinogenic effects for a lifetime of exposure. The lifetime HA is based on exposure of a 70-kg adult consuming 

2 L water/day. 

e

A4: not classifiable as a human carcinogen 

f

Group C: a possible human carcinogen 
 g

Reporting date: manufacturers and importers of naphthalene must submit a Preliminary Assessment Information 
 

Manufacturer’s Report for each site at which they manufacture or import naphthalene by the reporting date. 
 h

TSCATS health and safety data reporting: naphthalene is subject to all provisions of part 716. Manufacturers, 
 

importers, and processors of naphthalene are subject to the reporting requirements of subpart A. 
 

ACGIH = American Conference of Governmental Industrial Hygienists; CFR = Code of Federal Regulations; 
 

DWEL = drinking water equivalent level; EPA = Environmental Protection Agency; HSDB = Hazardous Substances 
 

Data Bank; IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or health; 
 

IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health; 
 

NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; PEL = permissible 
 

exposure limit; PQL = practical quantitation level; RCRA = Resource Conservation and Recovery Act; 
 

REL = recommended exposure limit; RfC = reference concentration; RfD = reference dose; STEL = short-term 
 

exposure limit; TCLP = toxicity characteristic leachate procedure; TLV = threshold limit values; TSCA = Toxic 
 

Substances Control Act; TSD = treatment, storage, and disposal; TWA = time-weighted average; USC = United 
 

States Code; WHO = World Health Organization 
 
_______________________ 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 219 

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NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 285 

10. GLOSSARY 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 286 

10. GLOSSARY 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 287 

10. GLOSSARY 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 288 

10. GLOSSARY 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 289 

10. GLOSSARY 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3

 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 290 

10. GLOSSARY 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE 291 

10. GLOSSARY 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-2 

APPENDIX A 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology, expert panel peer reviews, and agency-wide MRL Workgroup reviews, with 

participation from other federal agencies and comments from the public. They are subject to change as 

new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in 

the most recent toxicological profiles supersede previously published levels. For additional information 

regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease 

Registry, 1600 Clifton Road NE, Mailstop F-32, Atlanta, Georgia 30333. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Naphthalene 

CAS Number: 91-20-3 

Date: June 2005 

Profile Status: Final Post-Public Comment 

Route: [x] Inhalation [ ] Oral 

Duration: [ ] Acute [ ] Intermediate [x] Chronic 

Graph Key: 6 

Species: Rat 

Minimal Risk Level: 0.0007 [ ] mg/kg/day [x] ppm 

Reference(s): Abdo KM, Grumbein S, Chou BJ, et al. 2001. Toxicity and carcinogenicity study in 

F344 rats following 2 years of whole-body exposure to naphthalene vapors. Inhal Toxicol 13:931-950. 

NTP. 1992a. Toxicology and carcinogenesis studies of naphthalene (CAS No. 91-20-3) in B6C3F1 mice 

(inhalation studies). Research Triangle Park, NC: U.S. Department of Health and Human Services, 

Public Health Service, National Institutes of Health. National Toxicology Program. NIH Publication No. 

92-3141. Technical report series no. 410. 

NTP. 2000. Toxicology and carcinogenesis studies of naphthalene (CAS No. 91-20-3) in F344/N rats 

(inhalation studies). National Toxicology Program. NTP TR 500, NIH Publ. No. 01-4434. 

Experimental design: NTP 1992a: Groups of 75 B6C3F1mice of each sex were exposed by inhalation at 

concentrations of 0, 10, or 30 ppm. Exposure occurred 5 times/week, 6 hours/day for 104 weeks. 

Abdo et al. 2001; NTP 2000: Groups of 49 male and 49 female F344/N rats were exposed to naphthalene 

at concentrations of 0, 10, 30, or 60 ppm for 6 hours/day, 5 days/week for 105 weeks. 

Effects noted in study and corresponding doses: In mice, exposure to 10 or 30 ppm of naphthalene 

resulted in inflammation of the nose (males: 0/70, 67/69, 133/135; females: 1/69, 65/65, 135/135) and 

lungs (males: 0/70, 21/69, 56/135; females: 3/69, 13/65, 52/135), metaplasia of the olfactory epithelium 

(males: 0/70, 66/69, 134/135; females: 0/69, 65/65, 135/135), and hyperplasia of the nasal respiratory 

epithelium (males: 0/70, 66/69, 134/135; females: 0/69, 65/65, 135/135). Increased incidences of 

neoplastic lesions were restricted to the lung in females: alveolar/bronchiolar adenomas (5/69, 2/65, 

28/135) and alveolar/bronchiolar carcinomas (0/69, 0/65, 1/135). 

In rats, increased incidences of nonneoplastic and neoplastic lesions were restricted to the nose as shown 

in Table A-1. 

Dose and end point used for MRL derivation: The lowest exposure level in both studies, 10 ppm, was a 

LOAEL in both sexes of both species for nonneoplastic lesions in nasal olfactory epithelium and 

respiratory epithelium. Applying EPA inhalation dosimetry (see below), a human equivalent LOAEL of 

0.2 ppm, based on the rat LOAEL, was selected as the point of departure for the chronic inhalation MRL. 

Benchmark dose analyses were not conducted on the incidence data for nonneoplastic nasal lesions, 

because the data provided insufficient information on the shape of the dose-response relationship. The 

lowest exposure level in the principal study induced nasal lesions in essentially all of the rats. 

[ ] NOAEL [x] LOAEL 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-4 

APPENDIX A 

Modifying Factors used in MRL derivation: N/A 

Table A-1. Nonneoplastic and Neoplastic Lesions of the Nose in Male and 
 

Female F344/N Rats Exposed to Naphthalene 6 Hours/Day,
 

5 Days/Week for 105 Weeks 
 

Concentration (ppm) 

0 10 30 60 

Lesion M F M F M F M F 

Nonneoplastic lesions 

Olfactory epithelium 

Hyperplasia 0/49 0/49 48/49 48/49 45/48 48/49 46/48 43/49 

Atrophy 3/49 0/49 49/49 49/49 48/48 49/49 47/48 47/49 

Chronic inflammation 0/49 0/49 49/49 47/49 48/48 47/49 48/48 45/49 

Hyaline degeneration 3/49 13/49 46/49 46/49 40/48 49/49 38/48 45/49 

Respiratory epithelium 

Hyperplasia 3/49 0/49 21/49 18/49 29/48 22/49 29/48 23/49 

Squamous metaplasia 0/49 0/49 15/49 21/49 23/48 17/49 18/48) 15/49 

Hyaline degeneration 0/49 8/49 20/49 33/49 19/48 34/49 19/48 28/49 

Goblet cell hyperplasia 0/49 0/49 25/49 16/49 29/48 29/49 26/48 20/49 

Gland hyperplasia 1/49 0/49 49/49 48/49 48/48 48/49 48/48 42/49 

Gland squamous metaplasia 0/49 0/49 3/49 2/49 14/48 20/49 26/48 20/49 

Neoplastic lesions 

Respiratory epithelial 0/49 0/49 6/49 0/49 8/48 4/49 15/48 2/49 

adenoma 

Olfactory epithelial 0/49 0/49 0/49 2/49 4/48 3/49 3/48 12/49 

neuroblastoma 

F = female; M = male 

Uncertainty Factors used in MRL derivation: Total Uncertainty Factor = 10x3x10=300 

[x] 10 for use of a LOAEL 

[x] 3 for extrapolation from animals to humans with dosimetric adjustment 

[x] 10 for human variability 

Was a conversion used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

10 ppm x 6 hours/24 hours x 5 days/7 days=1.8 ppm (duration-adjusted LOAEL for nasal effects in rats 

or mice) 

1.8 ppm x 128.18/24.45=9.4 mg/m3 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-5 

APPENDIX A 

Following EPA (1994d) Methods for Derivation of Inhalation Reference Concentrations and Application 

of Inhalation Dosimetry, equations for a category 1 gas producing nasal effects were used to derive 

human equivalent concentrations: HEC=Animal Concentration x RGDRET; 

RGDRET= regional gas dose ratio in the extrathoracic (ET) region 

 = (DoseET)A/(DoseET)H= [minute volume/ETsurface area]A÷[minute volume/ETsurface area]H; 

Reference minute volumes (L/min): 13.8 human, 0.137 rat, 0.0368 mouse; 

Reference ET surface area (cm2 ): 200 human, 15 rat, 3 mouse; 

RGDRET(Rat to Human)=[0.137/15]÷[13.8/200]=0.132; 

LOAELHEC=duration-adjusted LOAEL x 0.132=1.8 ppm x 0.132=0.2 ppm 

RGDRET(Mouse to Human)=[0.0368/3]÷[13.8/200]=0.178; 

LOAELHEC=duration-adjusted LOAEL x 0.132=1.8 ppm x 0.178=0.3 ppm 

Using public health protection reasoning, the LOAELHEC based on the rat data was selected as the point of 

departure for the chronic inhalation MRL. 

Other additional studies or pertinent information which lend support to this MRL: Uncertainty in the 

MRL would likely be decreased with the development and application of hybrid computational fluid 

dynamics and physiologically based pharmacokinetic models that would estimate regional tissue doses of 

naphthalene metabolites in rats and humans. The models can incorporate species-specific information on 

nasal geometry, breathing patterns, and metabolism, as well as chemical-specific information on 

reactivity, partition coefficients, and diffusivity of the vapor in air and tissue. Such models have been 

developed for other gases that induce nasal lesions (see Frederick et al. 2001), but have not yet been 

developed for naphthalene. 

Reactive naphthalene metabolites (1,2-naphthalene oxide, 1,2-naphthoquinone, 1,4-naphthoquinone, and 

1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydronaphthalene) have been proposed to be involved in 

naphthalene’s toxic modes of action (Buckpitt et al. 2002). CYP isozymes, which might be involved in 

naphthalene metabolism and bioactivation, have been demonstrated to exist in nasal respiratory epithelial 

and olfactory epithelial tissue from rodents and humans (Thornton-Manning and Dahl 1997). Studies 

designed to specifically characterize metabolism of naphthalene in nasal tissue, however, have not been 

conducted (e.g., which CYP isozymes catalyze naphthalene transformations in nasal tissue?, are there 

species differences in nasal tissue efficiencies and capabilities for metabolism and/or bioactivation of 

naphthalene?), with the exception of a single study that examined in vitro rates of metabolism of 

naphthalene to naphthalene oxides in postmitochondrial supernatants from mouse, rat, and hamster 

olfactory tissue (Buckpitt et al. 1992). In this study, metabolic rates (units of nmol/min/mg protein) 

showed the following order: mouse (87.1) > rat (43.5) > hamster (3.9). This order did not correspond 

with species differences in susceptibility to single intraperitoneal injections of naphthalene in a 

companion study (Plopper et al. 1992a). Rat nasal epithelial tissue (olfactory and respiratory epithelium) 

was more sensitive than tissue from mice and hamsters, which showed equivalent sensitivities. 

Agency Contacts (Chemical Managers): Hisham El-Masri, Ph.D.; Moiz Mumtaz, Ph.D.; and G. Daniel 

Todd, Ph.D. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-6 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Naphthalene 

CAS Number: 91-20-3 

Date: June 2005 

Profile Status: Final Post-Public Comment 

Route: [ ] Inhalation [x] Oral 

Duration: [x] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 16 

Species: Rat 

Minimal Risk Level: 0.6 [x] mg/kg/day [ ] ppm 

Reference: NTP. 1991a. Developmental toxicity of naphthalene (CAS No. 91-20-3) administered by 

gavage to Sprague-Dawley (CD) rats on gestational days 6 through 15. Research Triangle Park, NC: 

National Toxicology Program, National Institute of Environmental Health Sciences, U.S. Department of 

Health and Human Services, Public Health Service, National Institutes of Health. TER91006. 

Experimental design: Groups of 25–26 pregnant female Sprague-Dawley rats received doses of 0, 50, 

150, and 450 mg/kg/day by gavage on gestation days 6–15. There were two replicate groups of 12– 

13 animals. 

Effects noted in study and corresponding doses: Rat dams in exposed groups showed one or more of 

several clinical signs of toxicity (slow respiration, lethargy, or prone body posture) on the first day of 

dosing (81, 96, and 96% of rats in the 50-, 150-, and 450-mg/kg/day groups). By the third day of dosing, 

these signs did not occur in any of the 50-mg/kg/day rats. A similar trend was noted in the 

150-mg/kg/day group, but apparent tolerance did not develop until the sixth day of dosing. In the 

450-mg/kg/day group, the incidence of rats exhibiting these signs of toxicity also declined during the 

exposure period, but did not fall below 15%. With the development of “tolerance”, the slow respiration, 

lethargy, and prone body posture were replaced with rooting behavior, a common behavior of rodents 

following gavage administration of chemicals with strong odors or irritant properties. At the end of the 

exposure period (gestation day 15), incidence of rats showing rooting behavior was 0% for the control 

and 50-mg/kg/day groups, compared with 24 and 92% of dams in the 150- and 450-mg/kg/day groups, 

respectively. Weight gain during exposure (gestation days 6–15) was similar between the control and 

50-mg/kg/day group, but was decreased by 31 and 53% in the 150- and 450-mg/kg/day groups, compared 

with controls. From these results, 50 mg/kg/day was judged to be a minimal less serious LOAEL for 

transient clinical signs of maternal toxicity in pregnant rat dams. At higher doses (150 and 

450 mg/kg/day), these effects were more persistent and were accompanied by decreased weight gain. 

No statistically significant exposure-related effects were observed on the average number of corpora lutea 

per dam, implantation sites per litter, live fetuses per litter, or average fetal body weight. The percent of 

fetuses malformed per litter (4, 4, 7, and 10% for control through 450 mg/kg/day) and the percent of 

litters with malformed fetuses (23, 27, 33, and 50%) both showed a statistically significant trend test, but 

pairwise comparisons between individual exposure groups and the control were not statistically 

significant. The investigators concluded that naphthalene was not fetotoxic or teratogenic in this assay. 

Dose and end point used for MRL derivation: A minimal LOAEL of 50 mg/kg/day for transient clinical 

signs of toxicity in pregnant rat dams. 

[] NOAEL [x ] minimal LOAEL 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-7 

APPENDIX A 

Modifying Factors used in MRL derivation: N/A 

Uncertainty Factors used in MRL derivation: Total Uncertainty Factor= 3x10x3=90 

[x] 3 for use of a minimal LOAEL 

[x] 10 for extrapolation from animals to humans 

[x] 3 for human variability 

An uncertainty factor of 3 was selected for the use of a minimal LOAEL of 50 mg/kg/day. At this dose 

level, the only adverse effects observed in the pregnant rat dams were signs of maternal toxicity, which 

were only observed on the first 2 days of exposure. 

An uncertainty factor of 10 was used for extrapolating from animals to humans. 

An uncertainty factor of 3 was used for human variability because the critical effect is based on effects in 

a sensitive animal subpopulation. Pregnant rats appear to be more sensitive for the effects observed 

(clinical signs and decreased body weight gain) than nonpregnant rats. In 13-week gavage studies with 

nonpregnant rats (NTP 1980b), similar persistent clinical signs were not observed following administration of doses as high as 200 mg/kg/day, but were observed at 400 mg/kg/day. In nonpregnant rats 

exposed for 13 weeks, significant body weight decreases occurred at 200 mg/kg/day throughout exposure, 

but not at 100 mg/kg/day (NTP 1980b) or in nonpregnant mice exposed for 13 weeks to 133 mg/kg/day 

(Shopp et al. 1984) or 200 mg/kg/day (NTP 1980a). Mice in the NTP (1980a) study showed transient 

signs of toxicity (lethargy, rough hair coats, and decreased food consumption), but these only occurred 

between weeks 3 and 5 in the 200-mg/kg/day group. 

Was a conversion used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

N/A 

Other additional studies or pertinent information which lend support to this MRL: Neurologic symptoms 

have been reported in humans following ingestion of naphthalene at unknown, but presumably high dose 

levels. These include confusion (Ojwang et al. 1985) and listlessness and lethargy (Bregman 1954; 

Chusid and Fried 1955; Kurz 1987; Macgregor 1954; Zuelzer and Apt 1949), as well as decreased 

responses to painful stimuli and coma prior to death (Gupta et al. 1979; Kurz 1987). Persistent neurologic 

symptoms were not recorded in 13-week studies with rats or mice exposed to doses as high as 

200 mg/kg/day (NTP 1980a, 1980b), but the highest exposure level tested in these studies, 

400 mg/kg/day, produced lethargy in exposed rats (only rats were exposed to 400 mg/kg/day). 

Hemolytic anemia has been identified in many human cases of acute accidental or intentional ingestion of 

naphthalene (e.g., Gidron and Leurer 1956; MacGregor 1954). Estimations of dose levels involved in 

these cases, however, are limited to a report (Gidron and Leurer 1956) of hemolytic anemia in a 16-yearold girl who swallowed 6 g of naphthalene (estimated dose=109 mg/kg, assuming body weight of 55 kg). 

Laboratory animals do not appear to be susceptible to the hemolytic activity of naphthalene. No 

pronounced changes in red-cell-related hematologic parameters were observed following 13-week oral 

exposures to doses up to 200 mg/kg/day in mice (NTP 1980a) and 400 mg/kg/day in rats (NTP 1980b), or 

in mice exposed by inhalation for 14 days to air concentrations as high as 30 ppm (NTP 1992a). 

Naphthalene-induced hemolytic anemia has been observed in dogs exposed to a single dose of 

1,525 mg/kg or 263 mg/kg/day for 7 days (Zuelzer and Apt 1949), but more information on the doseresponse relationship for hemolytic anemia in humans or animals acutely exposed to naphthalene is not 

available. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-8 

APPENDIX A 

Another effect associated with acute or repeated oral exposure to naphthalene in animals is cataracts 

(Kojima 1992; Murano et al. 1993; Van Heyningen and Pirie 1976; Xu et al. 1992b). These effects, 

however, appear to occur at dose levels (in the range of 500–1,000 mg/kg/day) much higher than the 

lowest dose level (150 mg/kg/day) producing body weight gain decreases and clinical signs of toxicity in 

pregnant rats. 

Agency Contacts (Chemical Managers): Hisham El-Masri, Ph.D.; Moiz Mumtaz, Ph.D.; and G. Daniel 

Todd, Ph.D. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-9 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Naphthalene 

CAS Number: 91-20-3 

Date: June 2005 

Profile Status: Final Post-Public Comment 

Route: [ ] Inhalation [x] Oral 

Duration: [ ] Acute [x] Intermediate [ ] Chronic 

Graph Key: 16 

Species: Rat 

Minimal Risk Level: 0.6 [x] mg/kg/day [ ] ppm 

Reference: NTP. 1991a. Developmental toxicity of naphthalene (CAS No. 91-20-3) administered by 

gavage to Sprague-Dawley (CD) rats on gestational days 6 through 15. Research Triangle Park, NC: 

National Toxicology Program, National Institute of Environmental Health Sciences, U.S. Department of 

Health and Human Services, Public Health Service, National Institutes of Health. TER91006. 

Experimental design: See the worksheet for the acute-duration oral MRL. 

Effects noted in study and corresponding doses: See the worksheet for the acute-duration oral MRL. 

Dose and end point used for MRL derivation: A minimal LOAEL of 50 mg/kg/day for transient clinical 

signs of toxicity in pregnant rat dams. 

[ ] NOAEL [x] minimal LOAEL 

Modifying Factors used in MRL derivation: N/A 

Uncertainty Factors used in MRL derivation: Total Uncertainty Factor =3x10x3=90 

[x] 3 for use of a minimal LOAEL 

[x] 10 for extrapolation from animals to humans 

[x] 3 for human variability 

See the worksheet for the acute-duration oral MRL for explanations of the uncertainty factors. 

Was a conversion used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

N/A 

Other additional studies or pertinent information which lend support to this MRL: 

There are three intermediate-duration oral toxicity studies in laboratory animals that were considered for 

deriving the intermediate oral MRL for naphthalene. A 13-week comprehensive oral toxicity study in 

Fischer 344 rats found no adverse exposure related effects other than decreased body weight (NTP 

1980b). This study identified 100 mg/kg/day as a NOAEL and 200 mg/kg/day as a LOAEL for decreased 

body weight in male and female rats. Another 13-week comprehensive oral toxicity study in B6C3F1 

mice found no adverse effects in mice exposed to doses as high as 200 mg/kg/day (NTP 1980a). Another 

90-day gavage study in mice focused on immune system variables and other toxicity variables (e.g., body 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-10 

APPENDIX A 

weight, organ weight, haematological parameters) and identified 133 mg/kg/day as a LOAEL and 

53 mg/kg/day as a NOAEL for weight decreases in several organs (brain, liver, and spleen), but found no 

biologically significant exposure-related changes in other end points evaluated (Shopp et al. 1984). This 

study, however, did not include histopathological examination of tissues. 

More detailed descriptions of the intermediate-duration oral toxicity studies follow. After the description 

of the studies, an analysis of their usefulness for MRL derivation is presented. 

NTP. 1980b. Subchronic toxicity study: Naphthalene (C52904), Fischer 344 rats. Research Triangle 

Park, NC: U.S. Department of Health and Human Services, National Toxicology Program. 

Naphthalene (>99% pure) in corn oil was administered by gavage to groups of 10 male and 10 female 

Fischer 344 rats at dose levels of 0, 25, 50, 100, 200, or 400 mg/kg/day, 5 days/week for 13 weeks (NTP 

1980b). End points included weekly measurement of food consumption and body weight, twice daily 

observation for clinical signs of toxicity, measurement of hematological parameters for blood collected at 

termination (hemoglobin, hematocrit, total and differential white blood cell count, red blood cell count, 

mean cell volume, mean cell hemoglobin concentration), necropsy of all rats in the study, and complete 

histopathological examination of 27 organs and tissues (including the eyes, lungs, stomach, liver, 

reproductive organs, thymus, and kidneys) from all control and 400-mg/kg rats. Male kidneys and female 

thymuses from the 200-mg/kg group were also examined histopathologically (according to the 

histopathology tables; however, the report text states that the 100 mg/kg group was examined). Organ 

weight data were not reported. 

At the highest dose level, two male rats died during the last week of treatment, and rats of both sexes 

displayed diarrhea, lethargy, hunched posture, and rough coats at intermittent intervals throughout the 

study. Food consumption was not affected by exposure. Mean terminal body weights were decreased by 

more than 10% relative to the controls in several groups (28 and 12% decrease in the 400- and 200-mg/kg 

males, respectively and 23% decrease in 400-mg/kg females). The terminal body weights at 13 weeks’ 

exposure were 250.6, 306.7, 333.4, 351.2, 353.4, and 348.9 g for males and 156.7, 190.5, 197.2, 203.5, 

197.8, and 203.4 g for females for the 400, 200, 100, 50, 25, and 0 dose groups, respectively. Differences 

between mean values of hematological parameters in exposed groups and those in control groups were 

<10% of control values, except for a 94% increase in numbers of mature neutrophils and a 25.1% 

decrease in numbers of lymphocytes in male 400 mg/kg rats and a 37.2% increase in mature neutrophils 

in 400 mg/kg females. Due to a lack of a consistent pattern of change in the hematologic parameters, the 

observed changes are not considered adverse. Histological examinations revealed low incidences of 

lesions in exposed male kidneys and exposed female thymuses; no lesions were observed in respective 

control kidneys or thymuses. Focal cortical lymphocytic infiltration or focal tubular regeneration were 

observed in kidneys in 2/10 male rats exposed to 200 mg/kg naphthalene, and diffuse renal tubular 

degeneration occurred in 1/10 male rats exposed to 400 mg/kg naphthalene. Lymphoid depletion of the 

thymus occurred in 2/10 females exposed to 400 mg/kg naphthalene, but not in any other females or in 

males. No other tissue lesions were detected. In this study, 100 mg/kg/day was a NOAEL, 

200 mg/kg/day was a LOAEL, and 400 mg/kg/day was a serious LOAEL for decreased body weight in 

rats orally exposed to naphthalene for 13 weeks. 

NTP. 1980a. Subchronic toxicity study: Naphthalene (C52904), B6C3F1 mice. Research Triangle Park, 

NC: U.S. Department of Health and Human Services, National Toxicology Program. 

Ten male and 10 female B6C3F1 mice were administered gavage doses of naphthalene in corn oil at 

levels of 0, 12.5, 25, 50, 100, or 200 mg/kg, 5 days/week for 13 weeks (NTP 1980a). Seven mice (three 

males and two females of the 200 mg/kg group, one female of the 25 mg/kg group, and one control male) 

died during the second, third, and fourth weeks from gavage trauma or accident. Transient signs of 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-11 

APPENDIX A 

toxicity (lethargy, rough hair coats, and decreased food consumption) occurred between weeks 3 and 5 in 

the 200-mg/kg groups. Due to their transient nature, these effects are not considered to be adverse. All 

exposed male mice gained more weight during the study than did control males (weight gains expressed 

as a percentage of control weight gain were 154.3, 116.0, 125.9, 122.2, and 107.4 for the 12.5–200 mg/kg 

groups, respectively). In contrast, exposed female mice displayed decreased weight gain compared with 

controls (weight gains expressed as a percentage of control weight gain were 97.5, 81.5, 81.5, 77.8, and 

76.5% for the 12.5–200 mg/kg groups, respectively). The average change in body weight between day 0 

and the 13th week was 6.2 g/mouse for the 200-mg/kg female mice compared with 8.1 g/mouse for the 

control females. The investigators believed that a difference in weight gain of 1.9 g over a 13-week 

period “was not large enough to conclusively indicate a toxic effect.” Respective mean terminal body 

weights (g) for control through the 200-mg/kg group were: 33.2, 37.7, 34.7, 34.7, 36.0, and 34.7 for 

males, and 26.7, 26.8, 25.4, 26.0, 26.1, and 25.6 for females. Mean terminal body weight values in 

exposed females were ≥95% of control values. 

All mice were necropsied, and 27 organs (including the eyes, thymus, reproductive organs, and lungs) 

from the mice in the control and high-dose groups were examined histologically. No exposure-related 

lesions were observed in any organs. The highest incidence of lesions observed was for minimal to mild, 

focal or multifocal, subacute pneumonia in both controls (4/10 males and 2/10 females) and high-dose 

mice (4/10 males and 5/10 females). Organ weight data were not reported. Hematological analyses were 

performed on all groups. Exposed groups displayed mean values that were within 10% of the control 

means for the following parameters: hemoglobin, hematocrit, total white blood cells, and total red blood 

cells. An increase in lymphocytes (18% increase) and a decrease in segmented neutrophils (38.8% 

decrease) in high-dose males were not considered biologically significant by the authors. The highest 

dose in this study, 200 mg/kg/day, is judged to be a NOAEL for nonneoplastic lesions, hematologic 

changes, and adverse neurologic symptoms. 

Shopp GM, White KL JR, Holsapple MP, et al. 1984. Naphthalene toxicity in CD-1 mice: General 

toxicology and immunotoxicology. Fundam Appl Toxicol 4:406-419. 

Groups of male and female albino CD-1 mice (approximately 6 weeks old at the start) were administered 

gavage doses of 0, 5.3, 53, or 133 mg/kg naphthalene (99.3% pure) in corn oil for 90 consecutive days 

(Shopp et al. 1984). A naive control group and the 5.3 and 53 mg/kg dose groups each contained 76 male 

mice and 40 female mice. The vehicle control group contained 112 male mice and 76 female mice. The 

high-dose group contained 96 male mice and 60 female mice. Statistical analysis consisted of a one-way 

analysis of variance of means and Dunnett’s t-test to compare control and treatment means using a 

significance level of p<0.05. Statistically significant chemical-related decreases in terminal body weights 

or survival were not observed in either sex. Respective mean terminal body weight values were (naïve, 

vehicle, 5.3, 53, and 133 mg/kg/day groups): 39.3, 37.3, 37.2, 36.2, and 36.8 g for male mice and 29.2, 

29.0, 27.9, 27.0, and 27.1 g for female mice. No significant alterations in absolute or relative organ 

weights occurred in exposed male mice. Significant decreases in absolute weights of brain (9%), liver 

(18%), and spleen (28%) and relative weight of spleen (24%) occurred in high-dose females compared 

with controls. Histopathological examination of organs was not conducted, but the authors noted that 

cataracts were not formed in exposed mice (methods used to assess the presence of cataracts were not 

specified). 

Examination of hematological parameters (including numbers of leucocytes, erythrocytes, and platelets 

and determination of hematocrit and hemoglobin) at termination revealed only slight, but statistically 

significant, increases in hemoglobin in high-dose females only; however, the hematological data were not 

shown in the available report. Chemical analysis of serum showed statistically significant decreased 

blood urea nitrogen in all exposed female groups. Compared with vehicle controls, the percent decreases 

in BUN were 16, 20, and 34% for the 5.3, 53, and 133 mg/kg/day groups, respectively. Increased serum 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-12 

APPENDIX A 

globulin (about 55%) and protein (about 40%) occurred in the two highest female dose groups compared 

with vehicle control values. Hepatic microsomal activities of aniline hydroxylase and aminopyrine 

N-demethylases were not statistically significantly changed in exposed versus control mice, but 

benzo[a]pyrene hydroxylase activities were statistically significantly decreased in exposed groups 

compared with control values (0.8, 0.62*, 0.55* and 0.41* nmol/min/mg protein for males in the control 

through high-dose group, and 1.40, 1.24, 1.13*, and 0.89* nmol/min/mg protein for females; statistically 

significant differences from control noted with *). The toxicological significance of the statistically 

significant changes in hematological parameters, hepatic enzyme activities, and serum chemical 

parameters is not clear, and these changes are not considered to be adverse. 

No exposure-related responses were found in a battery of immunological assays (humoral immune 

response, lymphocyte responsiveness, delayed-type hypersensitivity response, popliteal lymph node 

response, and bone marrow function); immunotoxic responses were observed in positive controls given 

intraperitoneal injections of 50 mg/kg cyclophosphamide on days 87, 88, 89, and 90. The study identified 

a LOAEL of 133 mg/kg/day and a NOAEL of 53 mg/kg/day for statistically significant decreases in 

absolute weight of brain, liver, and spleen and relative weight of spleen in female mice, but not male 

mice. The biological significance of these changes, however, is uncertain because the effects were only 

observed in female mice, and histological changes in these organs were not observed in Fischer 344 rats 

(NTP 1980b) or B6C3F1 mice (NTP 1980a) exposed to naphthalene for 13 weeks. 

Intermediate-Duration Oral MRL Derivation Considerations 

The findings from the three intermediate-duration oral toxicity studies (one in rats and two in mice) do 

not collectively identify a clear, biologically significant, toxicity target other than body weight changes in 

rats. Consideration was given to basing the MRL on the NOAEL of 53 mg/kg/day and LOAEL of 

133 mg/kg/day for decreases in absolute weight of brain, liver, and spleen, and in relative weight of 

spleen, in female mice (Shopp et al. 1984). However, the biological significance of these effects is 

uncertain because (1) small changes in organ weights are difficult to consistently measure in mice; (2) the 

effects were only observed in females; and (3) histological effects in the affected organs were not 

observed in the other 13-week oral studies with rats and mice. The biological significance of these effects 

in female, but not male, mice was less clearly biologically significant than the naphthalene-induced body 

weight changes observed in male and female rats. 

In deriving a potential intermediate-duration MRL, the NOAEL of 100 mg/kg/day for decreased body 

weight in male and female rats should be adjusted to a continuous duration dose 

(100x5 days/7 days=71 mg/kg/day). The use of this adjusted dose and a total uncertainty factor of 

100 (10 for extrapolating from rats to humans and 10 for human variability) arrives at a potential 

intermediate-duration oral MRL of 0.7 mg/kg/day, which is slightly larger than the acute-duration oral 

MRL for naphthalene, 0.6 mg/kg/day. Thus, the acute-duration oral MRL of 0.6 mg/kg/day is expected to 

be protective for intermediate-duration exposure scenarios and was adopted as the intermediate-duration 

oral MRL. 

Agency Contacts (Chemical Managers): Hisham El-Masri, Ph.D.; Moiz Mumtaz, Ph.D.; and G. Daniel 

Todd, Ph.D. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-13 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1-Methylnaphthalene 

CAS Number: 90-12-0 

Date: June 2005 

Profile Status: Final Post-Public Comment 

Route: [ ] Inhalation [x] Oral 

Duration: [ ] Acute [ ] Intermediate [x] Chronic 

Graph Key: 46 

Species: Mouse 

Minimal Risk Level: 0.07 [x] mg/kg/day [ ] ppm 

Reference: Murata Y, Denda A, Maruyama H, et al. 1993. Chronic toxicity and carcinogenicity studies 

of 1-methylnaphthalene in B6C3F1 mice. Fundam Appl Toxicol 21:44-51. 

Experimental design: Groups of 50 B6C3F1 mice ingested the following doses (in mg/kg/day) over an 

81-week period: 0 (M/F), 71.6 (M), 75.1 (F), 140.2 (M), and 143.7 (F). Tissues were examined 

histologically: brain, salivary glands, heart, thymus, lung, liver, pancreas, spleen, kidneys, testis, 

adrenals, trachea, stomach, small intestine, seminal vesicle, ovary, uterus, vagina, mammary gland, 

skeletal muscle, eye, Harderian glands, spinal cord, bone, and skin. 

Effects noted in study and corresponding doses: Exposure-related lesions were restricted to the lung. 

Incidences for pulmonary alveolar proteinosis were (control through high-dose groups): 5/50, 23/50, and 

17/49 for females and 4/49, 23/50, and 19/50 for males. 

The only other exposure-related lesions found were lung tumors. Incidences for mice with adenomas 

were 4/50, 2/50, and 4/49 in females, and 2/49, 13/50, and 12/50 for males. Combined incidences for 

mice with lung adenomas or adenocarcinomas were: 5/50, 2/50, and 5/50 for females, and 2/49, 13/50, 

and 15/50 for males. 

Dose and end point used for MRL derivation: Because the lowest exposure level was a LOAEL for 

increased incidence of alveolar proteinosis in male and female mice, benchmark dose analyses of the 

incidence data were conducted to determine a point of departure (POD) for the chronic-duration oral 

MRL. Available models in the EPA Benchmark Dose Software were fit to the incidence data for males 

and females, separately. None of the models provided adequate fit of the incidence data for females or for 

males, as assessed by chi-square goodness of fit statistics (p-values were <0.1). These results indicate 

that the data provide insufficient information to model the shape of the dose-response relationship. The 

lack of fit of the models to the data appears to be due to the apparent plateau of the response between the 

low- and high-dose levels. Thus, the LOAEL of 71.6 mg/kg/day for increased incidence of alveolar 

proteinosis in male mice was selected as the POD for the MRL. 

[ ] NOAEL [x] LOAEL 

Modifying Factors used in MRL derivation: N/A 

Uncertainty Factors used in MRL derivation: Total Uncertainty Factor=10x10x10=1,000 

[x] 10 for use of a LOAEL 

[x] 10 for extrapolation from animals to humans 

[x] 10 for human variability 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-14 

APPENDIX A 

Was a conversion used from ppm in food or water to a mg/body weight dose? If so, explain: Groups of 

50 male and 50 female B6C3F1 mice were fed 0, 0.075, or 0.15% 1-methylnaphthalene (1-MN) in their 

diet for 81 weeks (567 days). Cumulative dose equivalents were provided by the investigators included: 

males: 0.075%=40,600 mg 1-MN/kg/body weight/567 days=71.6 mg/kg/day; 0.15%=79,500 mg 

1-MN/kg/body weight/567 days=140.2 mg/kg/day; females: 0.075%=42,600 mg 1-MN/kg body 

weight/567 days=75.1 mg/kg/day; 0.15%=81,500 mg 1-MN/kg body weight/567 days=143.7 mg/kg/day. 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

N/A 

Other additional studies or pertinent information which lend support to this MRL: Increased incidence of 

pulmonary alveolar proteinosis has also been reported in B6C3F1 mice exposed to 2-methylnaphthalene 

in the diet for 81 weeks at dose levels of 50–54 and 108–114 mg/kg/day (Murata et al. 1997), and in mice 

dermally exposed to 30 or 119 mg/kg of methylnaphthalene for 30–61 weeks (a mixture of 1- and 

2-methylnaphthalene) (Emi and Konishi 1985; Murata et al. 1992). 

Goodness-of-fit statistics [p-values for chi-square goodness of fit and the Akaike Information Criteria 

(AIC)] from the benchmark dose analyses of the incidence data for pulmonary alveolar proteinosis are 

summarized in the table below. 

Table A-2. Goodness-of-fit Statistics From Benchmark Dose Analyses of 

Incidence Data for Male and Female Mice Exposed to 1-Methylnaphthalene in the Diet for 81 Weeks (Murata et al. 1993). 

Male mouse data Female mouse data 

chi-square chi-square 

Model p-value AIC p-value AIC 

Log-logisticb 0.024 172.13 0.014 174.71 

Gammaa

 0.01 173.57 0.007 175.88 

Multi-stagec

 0.01 173.57 0.007 175.88 

Quantal linear 0.01 173.57 0.007 175.88 

Weibulla

 0.01 173.57 0.007 175.88 

Log-probitb

 0.002 176.68 0.001 179.07 

Probit 0.002 177.06 0.002 178.42 

Logistic 0.001 177.45 0.002 178.71 

Quantal quadratic 0.0002 181.03 0.0002 182.00 

a c = Restrict power >=1; b = Slope restricted to >1; = Restrict betas >=0, Degree of polynomial = 1 

Agency Contacts (Chemical Managers): Hisham El-Masri, Ph.D.; Moiz Mumtaz, Ph.D.; and G. Daniel 

Todd, Ph.D. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-15 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 2-Methylnaphthalene 

CAS Number: 91-57-6 

Date: June 2005 

Profile Status: Final Post-Public Comment 

Route: [ ] Inhalation [x] Oral 

Duration: [ ] Acute [ ] Intermediate [x] Chronic 

Graph Key: 47 

Species: Mouse 

Minimal Risk Level: 0.04 [x] mg/kg/day [ ] ppm 

Reference: Murata Y, Denda A, Maruyama H, et al. 1997. Chronic toxicity and carcinogenicity studies 

of 2-methylnaphthalene in B6C3F1 mice. Fundam Appl Toxicol 36(1):90-93. 

Experimental design: Groups of 50 male and 50 female B6C3F1 mice were exposed to dietary levels of 

0, 0.075, or 0.15% 2-MN for 81 weeks. Average intakes were reported as 0, 54.3, or 113.8 mg/kg/day for 

males and 0, 50.3, or 107.6 mg/kg/day for females. 

Effects noted in study and corresponding doses: Survival and food consumption were not affected by 

exposure. Mean final body weights were decreased by 7.5 and 4.5% in high-dose males and females, 

respectively; these changes are not considered to be biologically significant. Histopathology only found 

exposure-related changes in the lung. Tissues examined were brain, heart, kidney, liver, lung, pancreas, 

salivary glands, spleen, testis, adrenals, bone, eye, Harderian glands, mammary gland, ovary, seminal 

vesicle, skeletal muscle, skin, small and large intestine, spinal cord, stomach, trachea, uterus, and vagina. 

No evidence of bronchiolar Clara cell necrosis or sloughing was found. Females showed statistically 

significantly decreased differential counts of stab and segmented form neutrophils and increased 

lymphocytes compared to controls, but biological significance of these changes is not clear due to a lack 

of reporting of the data (i.e., the report did not specify the response magnitudes or the dose levels at which 

they occurred). 

Incidences for mice with pulmonary alveolar proteinosis were (control through high-dose groups): 5/50, 

27/49, and 22/48 for females, and 4/49, 21/49, and 23/49 for males. 

Incidences for mice with lung adenomas were: 4/50, 4/49, and 5/48 in females, and 2/49, 9/49, and 

5/49 in males. Only the incidence in the male 54.3-mg/kg/day groups was significantly different from the 

control incidence. Combined incidences for lung adenomas or adenocarcinomas were: 5/50, 4/49, and 

6/48 for females, and 2/49, 10/49, and 6/49 for males. 

Dose and end point used for MRL derivation: Because the lowest exposure level was a LOAEL for 

increased incidence of alveolar proteinosis in male and female mice, benchmark dose (BMD) analyses of 

the incidence data were conducted to determine a point of departure (POD) for the chronic-duration oral 

MRL. Available models in the EPA Benchmark Dose Software were fit to the incidence data for males 

and females, separately. None of the models provided adequate fit of the incidence data for females, as 

assessed by chi-square goodness of fit statistics (p-values were <0.1). These results indicate that the 

female data provide insufficient information to model the shape of the dose-response relationship. The 

apparent plateau of the response between the low- and high-dose levels appears to contribute to the lack 

of fit of the models to the data. In contrast, the log-logistic and multi-stage models provided marginally 

adequate fits (p-values >0.1) to the male data, showing p-values of 0.23 and 0.11, respectively, for the 

chi-square goodness-of-fit statistic (Table A-3). The fitting algorithms for the gamma, quantal-linear, and 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-16 

APPENDIX A 

Weibull models provided identical model parameters and fit statistics as the multi-stage model. The 

Akaike Information Criteria (AIC) for the log-logistic model was lower than that for the multi-stage 

model indicating a better fit; thus the log-logistic model of the male data was selected to calculate the 

BMD POD for the MRL. 

A benchmark response of 5% extra risk was selected over a default value of 10% extra risk in order to 

provide protection for children who may develop pulmonary alveolar proteinosis. This selection is 

supported by reports that children with pulmonary alveolar proteinosis (albeit of unknown etiology) 

experience more severe symptoms of respiratory dysfunction than do adults (EPA 2003r; Mazzone et al. 

2001). 

To derive the MRL of 0.04 mg/kg/day, the BMDL05 of 4.3 mg/kg/day was divided by an 

uncertainty factor of 100 (10 for extrapolation from mice to humans and 10 for human variability). 

An alternative NOAEL/LOAEL approach arrives at a similar value for the MRL. In the alternative 

approach, the LOAEL of 50.3 mg/kg/day for pulmonary alveolar proteinosis in female mice would be 

divided by an uncertainty factor of 1000 (10 for extrapolation from mice to humans, 10 for human 

variability, and 10 for extrapolation from a LOAEL to a NOAEL), arriving at a value of 0.05 mg/kg/day. 

Table A-3. Benchmark Doses and Goodness-of-Fit Statistics from Modeling of 

Incidence Data for Pulmonary Alveolar Proteinosis in Male Mice Exposed to 

2-Methylnaphthalene in the Diet for 81 Weeks (Murata et al. 1997) 

Benchmark doses 

(mg/kg/day) Goodness-of-fit statistics 

chi-square 

Model BMD (ED05) BMDL (LED05) p-value AIC 

Log-logisticb 6.47 4.30 0.23 167.81 

Gammaa

 8.76 6.4 0.11 168.93 

Multi-stagec

 8.76 6.4 0.11 168.93 

Quantal linear 8.76 6.4 0.11 168.93 

Weibulla

 8.76 6.4 0.11 168.93 

Log-probitb

 20.92 15.95 0.03 170.99 

Probit 17.23 13.8 0.01 172.4 

Logistic 18.43 14.62 0.01 172.84 

Quantal quadratic 32.73 26.51 0.001 175.87 

a c = Restrict power >=1; b = Slope restricted to >1; = Restrict betas >=0, Degree of polynomial = 1 

BMD(ED05) = predicted benchmark dose associated with 5% extra risk; BMDL (LED05) = 95% lower confidence limit 

on benchmark dose associated with 5% extra risk 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-17 

APPENDIX A 

Figure A-1. Observed and Predicted Incidence of Pulmonary Alveolar Proteinosis 

in Male Mice Exposed to 2-Methylnaphthalene in the Diet for 81 Weeks 

(Murata et al. 1997): Log-Logistic Model 

BMD=ED05; BMDL=LED05 

Log-Logistic Model with 0.95 Confidence Level 

Fraction Affected 

0.6 

0.5 

0.4 

0.3 

0.2 

0.1 

0 BMDL BMD 

Log-Logistic 

0 20 40 60 80 100 120 

dose 

16:22 01/11 2005 

Observed and predicted incidences of olfactory epithelial neuroblastomas in male rats exposed to 

naphthalene: Weibull model. BMD=EC10; BMDL=LEC10; dose unit= ppm. 

[ ] NOAEL [ ] LOAEL [ x] BMDL = 

Modifying Factors used in MRL derivation: N/A 

Uncertainty Factors used in MRL derivation: Total Uncertainty Factor=10x10=100 

[ ] 10 for use of a LOAEL 

[x] 10 for extrapolation from animals to humans 

[x] 10 for human variability 

Was a conversion used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

N/A 

Other additional studies or pertinent information which lend support to this MRL: Increased incidence of 

pulmonary alveolar proteinosis has also been reported in B6C3F1 mice exposed to 1-methylnaphthalene 

in the diet for 81 weeks at dose levels as low as 71.6 mg/kg/day (Murata et al. 1993), and in mice 

dermally exposed to 30 or 119 mg/kg of methylnaphthalene for 30–61 weeks (a mixture of 1- and 

2-methylnaphthalene) (Emi and Konishi 1985; Murata et al. 1992). 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE A-18 

APPENDIX A 

In a range-finding study, groups of B6C3F1 mice (10/sex/group) were fed diets containing 2-methylnaphthalene for 13 weeks delivering approximate average daily doses of 0, 31, 92, 276, 827, or 

2,500 mg/kg/day (Murata et al. 1997). No histopathologic lesions were found in tissues and organs of 

male or female mice exposed to 827 or 2,500 mg/kg-day; tissues from mice in lower dose groups were 

not examined histologically. Decreased body weights, compared with control values, were seen at the 

three highest dose levels in both males and females, and were attributed to food refusal (Murata et al. 

1997). The absence of pulmonary alveolar proteinosis in the prechronically exposed mice, which were 

exposed to much higher doses than those experienced by mice with this lesion in the chronic study, 

suggests that the development of pulmonary alveolar proteinosis from oral exposure to 2-methylnaphthalene requires chronic-duration exposure. The limited reporting of experimental details and results 

from this intermediate-duration study, however, precludes its use as the basis of an intermediate oral 

MRL for 2-methylnaphthalene. 

The EPA (2003r) Toxicological Review of 2-Methylnaphthalene calculated an oral exposure RfD of 

0.004 mg/kg-day for 2-methylnaphthalene based on a value of 3.5 mg/kg-day for a 95% lower confidence 

limit on a benchmark dose associated with 5% extra risk (BMDL05) for pulmonary alveolar proteinosis in 

mice exposed to 2-methylnaphthalene in the diet for 81 weeks (Murata et al. 1992). The combined 

incidence data for this lesion in male and female mice in the control and low-dose groups were modeled 

with the quantal-linear model algorithm in the BMDS software (the high-dose data were excluded from 

the analysis, because when they were included adequate fit of models to the data were not obtained). A 

total uncertainty factor of 1,000 was used to derive the RfD: 10 for interspecies variability, 10 for 

interindividual variability, and 10 for database deficiencies. 

Agency Contacts (Chemical Managers): Hisham El-Masri, Ph.D.; Moiz Mumtaz, Ph.D.; and G. Daniel 

Todd, Ph.D. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1.	 What effects are known to occur in humans? 

2. 	 What effects observed in animals are likely to be of concern to humans? 

3. 	 What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE B-2 

APPENDIX B 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgment, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgment or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1) Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2) Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3) Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4) Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5) Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6) Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7) System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8) NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE B-4 

APPENDIX B 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 

(9) LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10) Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11) CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12) Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13) Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14) Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)	 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3

 or ppm and oral exposure is reported in 

mg/kg/day. 

(16) NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17) CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE B-5 

APPENDIX B 

(18) Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19) Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 
SAMPLE 

1 →	 Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

LOAEL (effect) Exposure 

Key to frequency/ NOAEL Less serious Serious (ppm) 

figurea Species duration System (ppm) (ppm) Re

2 3 4 

→ INTERMEDIATE EXPOSURE 

5 6 7 8 9 10

→ Systemic ↓ ↓ ↓ ↓ ↓	 ↓

3b 18 Rat	 13 wk Resp 10 (hyperplasia) 

→	 5 d/wk Nit

6 hr/d 

CHRONIC EXPOSURE Cancer 11 

↓

38 Rat 18 mo 20 (CEL, multiple W

5 d/wk organs) 7 hr/d 

39 Rat 89–104 wk 10 (CEL, lung tumors, NT

5 d/wk nasal tumors) 6 hr/d 

40 Mouse 79–103 wk 10 (CEL, lung tumors, NT

5 d/wk hemangiosarcomas) 6 hr/d 

12 a → i 	 The number corresponds to entries in F gure 3-1. b Used to derive an intermediate inha ation Minimal Risk Level (MRL) of l 5x10-3 ppm; dose adjusted for intermittent ex

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 


NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD benchmark dose 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 

DOT Department of Transportation 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE C-2 

APPENDIX C 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/International Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE C-3 

APPENDIX C 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

OW Office of Water 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE C-4 

APPENDIX C 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE C-5 

APPENDIX C 

> greater than ≥ greater than or equal to 

= equal to 

< less than ≤ less than or equal to 

% percent α alpha β beta γ gamma δ delta 

μm micrometer 

μg microgram q1 

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 

NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE D-1 

APPENDIX D. INDEX 
 

absorbed dose ............................................................................................................................................................139 
 

adenocarcinomas ...................................................................................................................................................26, 81 
 

adipose tissue..................................................................................................... 103, 104, 140, 145, 162, 203, 209, 222
 

adrenals........................................................................................................................................................................26 
 

adsorbed..................................................................................................................................... 116, 122, 163, 190, 209 
 

adsorption ..........................................................................................................................................116, 190, 193, 217 
 

aerobic .......................................................................................................................................................193, 194, 211 
 

ambient air ........................................................................................................................... 13, 183, 195, 196, 201, 202 
 

anaerobic....................................................................................................................................................................193 
 

anemia ......................................................................................... 43, 44, 70, 71, 87, 104, 136, 141, 143, 161, 162, 166
 

aspartate aminotransferase...........................................................................................................................................71 
 

bioaccumulation ................................................................................................................................................191, 215 
 

bioavailability ............................................................................................................................ 193, 207, 208, 211, 213 
 

biodegradation ................................................................................................................... 192, 193, 194, 207, 211, 215
 

biomarker...........................................................................................................................................138, 139, 140, 141 
 

biomarkers ................................................................................................................................. 138, 139, 140, 162, 215 
 

blood cell count ...............................................................................................................................................44, 71, 87 
 

blood cell counts....................................................................................................................................................44, 71 
 

body weight effects................................................................................................................................................16, 75 
 

breast milk .....................................................................................................................................5, 136, 203, 204, 205 
 

cancer............................................................................................................. 6, 7, 14, 20, 129, 135, 151, 156, 161, 230
 

carcinogen..................................................................................................................................................7, 19, 20, 230 
 

carcinogenic............................................................................................... 7, 18, 19, 20, 21, 22, 29, 30, 48, 49, 81, 230
 

carcinogenicity ............................................................................ 7, 15, 19, 20, 21, 22, 49, 81, 129, 151, 156, 157, 161 
 

carcinoma ..........................................................................................................................................14, 16, 42, 48, 156 
 

carcinomas ...................................................................................................................................................................21 
 

cardiovascular..................................................................................................................................................43, 69, 87 
 

cardiovascular effects ......................................................................................................................................43, 69, 87 
 

cataract................................................................................................................... 46, 89, 110, 124, 125, 126, 142, 161 
 

chromosomal aberrations.........................................................................................................................18, 97, 98, 158 
 

clearance ..............................................................................................................................................................68, 131 
 

death ............................................................................................................................................29, 46, 78, 97, 98, 101 
 

dermal effects ..................................................................................................................................................31, 50, 88 
 

DNA .......................................................................................................... 18, 77, 90, 93, 94, 95, 96, 97, 127, 139, 158 
 

enantiomer .................................................................................................................................................107, 109, 127 
 

endocrine ...........................................................................................................................................................133, 134 
 

erythema ......................................................................................................................................................................88 
 

fetus .......................................................................................................................................................15, 80, 134, 152 
 

gastrointestinal effects .....................................................................................................................................43, 69, 87 
 

general population ..................................................................................................... 138, 140, 162, 201, 202, 206, 209
 

genotoxic ................................................................................................................................... 18, 29, 90, 98, 129, 158 
 

genotoxicity ........................................................................................................................... 18, 19, 129, 130, 158, 159 
 

groundwater ................................................................................................. 14, 188, 189, 190, 197, 198, 204, 207, 229
 

half-life ...................................................................................... 105, 106, 114, 126, 139, 179, 190, 191, 192, 193, 194
 

hematological effects .......................................................................................................................................43, 70, 87 
 

hemolytic anemia............................................... 6, 7, 8, 14, 15, 43, 70, 80, 82, 102, 136, 143, 151, 153, 159, 162, 165
 

hepatic effects ..................................................................................................................................................45, 71, 88 
 

hydroxyl radical.................................................................................................................................127, 179, 192, 207 
 

immune system ............................................................................................................................................................24 
 

immunological.............................................................................................................................29, 46, 77, 89, 90, 216 
 

Kow .............................................................................................................................................................171, 190, 191 
 

LD50 ...............................................................................................................................................49, 50, 68, 70, 82, 95 
 
NAPHTHALENE, 1-METHYLNAPHTHALENE, AND 2-METHYLNAPHTHALENE D-2 

APPENDIX D 

lymphoreticular....................................................................................................................................46, 77, 78, 89, 90 
 

mass spectroscopy .............................................................................................................................................219, 220 
 

micronuclei ....................................................................................................................................................19, 98, 158 
 

milk...................................................................................................... 3, 7, 10, 103, 104, 136, 191, 200, 205, 209, 217
 

musculoskeletal effects..........................................................................................................................................45, 82 
 

neonatal ...............................................................................................................................................80, 137, 166, 167 
 

neoplastic......................................................... 15, 16, 17, 18, 20, 31, 42, 121, 123, 127, 128, 129, 133, 151, 156, 158
 

neurobehavioral .........................................................................................................................................................134 
 

nuclear .......................................................................................................................................................................143 
 

octanol-water partition coefficient.............................................................................................................................120 
 

ocular effects .............................................................................................................................................102, 125, 151 
 

odds ratio ...................................................................................................................................................................137 
 

olfactory epithelial neuroblastoma.................................................................................................17, 18, 20, 22, 42, 48 
 

olfactory epithelium..................................................................................................... 16, 17, 22, 42, 48, 109, 122, 156 
 

partition coefficients ..................................................................................................................................................190 
 

passive transport ........................................................................................................................................................163 
 

pharmacodynamic......................................................................................................................................................117 
 

pharmacokinetic.................................................................................................................................117, 118, 119, 135 
 

photolysis...................................................................................................................................................................192 
 

placenta......................................................................................................................................................................104 
 

placental barrier .........................................................................................................................................136, 159, 166 
 

pulmonary alveolar proteinosis..................... 8, 20, 21, 25, 26, 27, 68, 69, 77, 123, 130, 131, 132, 138, 155, 157, 162, 
 

165, 225, 226 
 

rate constant.......................................................................................................................................................120, 192 
 

rate constants .....................................................................................................................................................120, 192 
 

renal effects .....................................................................................................................................................45, 72, 88 
 

respiratory epithelial adenoma.......................................................................................................17, 18, 20, 22, 42, 48 
 

SGOT...........................................................................................................................................................................72 
 

SGPT ...........................................................................................................................................................................72 
 

solubility ....................................................................................................................................................190, 191, 215 
 

toxicokinetic .................................................................................................... 29, 98, 99, 118, 136, 137, 164, 165, 166
 

tumors ...................................7, 8, 16, 19, 20, 22, 25, 42, 48, 49, 81, 118, 120, 121, 129, 138, 141, 161, 163, 164, 166
 

vapor phase........................................................................................................................................................190, 221 
 

vapor pressure....................................................................................................................................................190, 191 
 

volatilization ................................................................................................................................ 13, 184, 190, 191, 207