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TOXICOLOGICAL PROFILE FOR
 

TOXAPHENE
 


 


 


 


 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

September 2010 
 

TOXAPHENE 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. 

This information is distributed solely for the purpose of pre dissemination public comment under 

applicable information quality guidelines. It has not been formally disseminated by the Agency for Toxic 

Substances and Disease Registry. It does not represent and should not be construed to represent any 

agency determination or policy. 

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TOXAPHENE iii 

UPDATE STATEMENT 

A Toxicological Profile for Toxaphene was released in 1996. This present 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 and Environmental Medicine/Applied Toxicology Branch
 

1600 Clifton Road NE
 

Mailstop F-62
 

Atlanta, Georgia 30333
 

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v 

FOREWORD 


This toxicological profile is prepared in accordance with goidelines developed by the Agency for Toxic 

Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original goidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary. 

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

infonnation for these toxic substances described therein. Each peer-reviewed profile identifies and 

reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is 

also presented, but is described in less detail than the key studies. The profile is not intended to be an 

exhaustive document; however, more comprehensive sources of specialty infonnation are referenced. 

The focus of the profiles is on health and toxicologic infonnation; therefore, each toxicological profile 

begins with a public health statement that describes, in nontechnical language, a substance's relevant 

toxicological properties. Following the public health statement is infonnation concerning levels of 

sigoificant human exposure and, where known, sigoificant health effects. The adequacy ofinfonnation to 

detennine a substance's health effects is described in a health effects summary. Data needs that are of 

significance to protection ofpublic health are identified by ATSDR and EPA. 

Each profile includes the following: 

(A) 	The examination, summary, and interpretation of available toxicologic infonnation and 

epidemiologic evaluations on a toxic substance to ascertain the levels of significant human 

exposure for the substance and the associated acute, subacute, and chronic health effects; 

(B) A determination ofwhether adequate infonnation on the health effects of each substance is 

available or in the process of development to detennine levels ofexposure that present a 

significant risk to human health ofacute, subacute, and chronic health effects; and 

(C) 	Where appropriate, identification oftoxicologic testing needed to identify the types or levels 

of exposure that may present significant risk ofadverse health effects in humans. 

The principal audiences for the toxicological profiles are health professionals at the federal, state, and 

local levels; interested private sector organizations and groups; and members of the public. We plan to 

revise these documents in response to public comments and as additional data become available. 

Therefore, we encourage comments that will make the toxicological profile series ofthe greatest use. 

Comments should be sent to: 

The Agency for Toxic Substances and Disease Registry 

Division ofToxicology and Environmental Medicine 

Applied Toxicology Branch 

Regolar Mailing Address: Physical Mailing Address: 


1600 Clifton Road, N .E. 4770 Buford Highway 


Mail Stop F -62 Building 106, 8th floor, MS F-62 


Atlanta, Georgia 30333 Chamblee, Georgia 30341 


Electronic Comments should be sent to: TPPublicComments(al.cdc.gov 
VI 

The toxicological profiles are developed under the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section 

104(i)(1) directs the Administrator of ATSDR to " ... effectuate and implement the health-related 

authorities" ofthe statute. This includes the preparation of toxicological profiles for hazardous 

substances most commonly found at facilities on the CERCLA National Priorities List and that pose the 

most significant potential threat to human health, as determined by ATSDR and the EPA Section 

104(i)(3) ofCERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile 

for each substance on the list. In addition, ATSDR has the authority to prepare toxicological profiles for 

substances not found at sites on the National Priorities List, in an effort to " ...establish and maintain 

inventory of literature, research, and studies on the health effects of toxic substances" under CERCLA 

Section 104(i)(I)(B), to respond to requests for consultation under section 104(i)(4), and as otherwise 

necessary to support the site-specific response actions conducted by ATSDR. 

This profile reflects ATSDR's assessment of all relevant toxicologic testing and information that has been 

peer-reviewed. Staffs ofthe Centers for Disease Control and Prevention and other federal scientists have 

also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel 

and is being made available for public review. Final responsibility for the contents and views expressed 

in this toxicological profile resides with ATSDR. 

f"'.. ~~Thomas R. Frieden, M.D., M.P .H. 

Administrator 

Agency for Toxic Substances and 

Disease Registry 
 

 

 

 

TOXAPHENE 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: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) Fax: (770) 488-4178 

E-mail: cdcinfo@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 

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

Toxicity; and numerous chemical-specific case studies. 

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TOXAPHENE viii 

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. 

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TOXAPHENE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Nickolette Roney, MPH
 

Jona M. Ogden, B.S.
 

Robert L. Williams, Ph.D.
 

Yulia Iossifova, MD, Ph.D.
 

Malcolm Williams, DVM, Ph.D.
 

John R. Doyle, MPA
 

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA
 

David Wohlers, Ph.D.
 

Daniel Plewak, B.S.
 

SRC, Inc., North Syracuse, NY
 

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 Applied Toxicology 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. 

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TOXAPHENE xi 

PEER REVIEW
 

A peer review panel was assembled for toxaphene. The panel consisted of the following members: 

1.	 Dr. Laurie H.M. Chan, Professor, Aboriginal Environmental Health, University of Northern 

British Columbia, Prince George BC V2N 4Z9, Canada; 

2.	 Dr. Lucio G. Costa, Professor, Department of Environmental and Occupational Health Sciences, 

University of Washington, Seattle, Washington; and 

3.	 Dr. Mark Robson, Professor and Dean of Agricultural and Urban Programs, Rutgers University, 

New Brunswick, New Jersey. 

These experts collectively have knowledge of toxaphene’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. 

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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 IS TOXAPHENE?............................................................................................................. 1
 
 

1.2 WHAT HAPPENS TO TOXAPHENE WHEN IT ENTERS THE ENVIRONMENT?................ 2
 
 

1.3 HOW MIGHT I BE EXPOSED TO TOXAPHENE? .................................................................... 2
 
 

1.4 HOW CAN TOXAPHENE ENTER AND LEAVE MY BODY? ................................................. 3
 
 

1.5 HOW CAN TOXAPHENE AFFECT MY HEALTH? .................................................................. 3
 
 

1.6 HOW CAN TOXAPHENE AFFECT CHILDREN? ..................................................................... 4
 
 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO TOXAPHENE? ................. 4
 
 

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

EXPOSED TO TOXAPHENE?..................................................................................................... 4
 
 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? ................................................................................................... 5
 
 

1.10 WHERE CAN I GET MORE INFORMATION? .......................................................................... 6
 
 

2. RELEVANCE TO PUBLIC HEALTH ................................................................................................... 7
 
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO TOXAPHENE IN THE
 
 

UNITED STATES ......................................................................................................................... 7
 
 

2.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 8
 
 

2.3 MINIMAL RISK LEVELS (MRLs) ............................................................................................ 10
 
 

3. HEALTH EFFECTS.............................................................................................................................. 17
 
 

3.1 INTRODUCTION........................................................................................................................ 17
 
 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................... 17
 
 

3.2.1 Inhalation Exposure .............................................................................................................. 19
 
 

3.2.1.1 Death.............................................................................................................................. 19
 
 

3.2.1.2 Systemic Effects............................................................................................................. 19
 
 

3.2.1.3 Immunological and Lymphoreticular Effects ................................................................ 23
 
 

3.2.1.4 Neurological Effects ...................................................................................................... 23
 
 

3.2.1.5 Reproductive Effects...................................................................................................... 23
 
 

3.2.1.6 Developmental Effects................................................................................................... 23
 
 

3.2.1.7 Cancer ............................................................................................................................ 23
 

3.2.2 Oral Exposure........................................................................................................................ 24
 

3.2.2.1 Death.............................................................................................................................. 24
 

3.2.2.2 Systemic Effects............................................................................................................. 26
 

3.2.2.3 Immunological and Lymphoreticular Effects ................................................................ 52
 

3.2.2.4 Neurological Effects ...................................................................................................... 54
 

3.2.2.5 Reproductive Effects...................................................................................................... 56
 

3.2.2.6 Developmental Effects................................................................................................... 56
 

3.2.2.7 Cancer ............................................................................................................................ 58
 

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3.2.3 Dermal Exposure................................................................................................................... 60
 

3.2.3.1 Death.............................................................................................................................. 60
 

3.2.3.2 Systemic Effects............................................................................................................. 60
 

3.2.3.3 Immunological and Lymphoreticular Effects ................................................................ 63
 

3.2.3.4 Neurological Effects ...................................................................................................... 63
 

3.2.3.5 Reproductive Effects...................................................................................................... 64
 

3.2.3.6 Developmental Effects................................................................................................... 64
 

3.2.3.7 Cancer ............................................................................................................................ 64
 

3.3 GENOTOXICITY ........................................................................................................................ 64
 

3.4 TOXICOKINETICS..................................................................................................................... 68
 

3.4.1 Absorption............................................................................................................................. 68
 

3.4.1.1 Inhalation Exposure ....................................................................................................... 68
 

3.4.1.2 Oral Exposure ................................................................................................................ 68
 

3.4.1.3 Dermal Exposure ........................................................................................................... 69
 

3.4.2 Distribution ........................................................................................................................... 70
 

3.4.2.1 Inhalation Exposure ....................................................................................................... 70
 

3.4.2.2 Oral Exposure ................................................................................................................ 70
 

3.4.2.3 Dermal Exposure ........................................................................................................... 74
 

3.4.2.4 Other Routes of Exposure.............................................................................................. 74
 

3.4.3 Metabolism............................................................................................................................ 74
 

3.4.4 Elimination and Excretion..................................................................................................... 79
 

3.4.4.1 Inhalation Exposure ....................................................................................................... 79
 

3.4.4.2 Oral Exposure ................................................................................................................ 79
 

3.4.4.3 Dermal Exposure ........................................................................................................... 83
 

3.4.4.4 Other Routes of Exposure.............................................................................................. 84
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ............. 84
 

3.5 MECHANISMS OF ACTION ..................................................................................................... 87
 

3.5.1 Pharmacokinetic Mechanisms............................................................................................... 87
 

3.5.2 Mechanisms of Toxicity........................................................................................................ 87
 

3.5.3 Animal-to-Human Extrapolations......................................................................................... 89
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ............................. 89
 

3.7 CHILDREN’S SUSCEPTIBILITY.............................................................................................. 91
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ....................................................................... 92
 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Toxaphene....................................... 93
 

3.8.2 Biomarkers Used to Characterize Effects Caused by Toxaphene ......................................... 94
 

3.9 INTERACTIONS WITH OTHER SUBSTANCES..................................................................... 94
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE .............................................. 95
 

3.11 METHODS FOR REDUCING TOXIC EFFECTS.................................................................. 97
 

3.11.1 Reducing Peak Absorption Following Exposure............................................................... 98
 

3.11.2 Reducing Body Burden ..................................................................................................... 98
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects ............................................ 99
 

3.12 ADEQUACY OF THE DATABASE....................................................................................... 99
 

3.12.1 Existing Information on Health Effects of Toxaphene.................................................... 100
 

3.12.2 Identification of Data Needs............................................................................................ 100
 

3.12.3 Ongoing Studies .............................................................................................................. 108
 

4. CHEMICAL AND PHYSICAL INFORMATION.............................................................................. 109
 

4.1 CHEMICAL IDENTITY............................................................................................................ 109
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................... 109
 

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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL.......................................................... 113
 

5.1 PRODUCTION .......................................................................................................................... 113
 

5.2 IMPORT/EXPORT .................................................................................................................... 116
 

5.3 USE ............................................................................................................................................ 116
 

5.4 DISPOSAL................................................................................................................................. 117
 

6. POTENTIAL FOR HUMAN EXPOSURE ......................................................................................... 119
 

6.1 OVERVIEW............................................................................................................................... 119
 

6.2 RELEASES TO THE ENVIRONMENT................................................................................... 121
 

6.2.1 Air ....................................................................................................................................... 122
 

6.2.2 Water................................................................................................................................... 124
 

6.2.3 Soil ...................................................................................................................................... 125
 

6.3 ENVIRONMENTAL FATE ...................................................................................................... 126
 

6.3.1 Transport and Partitioning................................................................................................... 126
 

6.3.2 Transformation and Degradation ........................................................................................ 134
 

6.3.2.1 Air ................................................................................................................................ 136
 

6.3.2.2 Water............................................................................................................................ 136
 

6.3.2.3 Sediment and Soil ........................................................................................................ 137
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT.................................. 138
 

6.4.1 Air ....................................................................................................................................... 140
 

6.4.2 Water................................................................................................................................... 142
 

6.4.3 Sediment and Soil ............................................................................................................... 144
 

6.4.4 Other Environmental Media................................................................................................ 147
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ........................................ 154
 

6.6 EXPOSURES OF CHILDREN.................................................................................................. 156
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 158
 

6.8 ADEQUACY OF THE DATABASE ........................................................................................ 159
 

6.8.1 Identification of Data Needs ............................................................................................... 159
 

6.8.2 Ongoing Studies.................................................................................................................. 164
 

7. ANALYTICAL METHODS ............................................................................................................... 165
 

7.1 BIOLOGICAL MATERIALS.................................................................................................... 165
 

7.2 ENVIRONMENTAL SAMPLES .............................................................................................. 170
 

7.3 ADEQUACY OF THE DATABASE ........................................................................................ 181
 

7.3.1 Identification of Data Needs ............................................................................................... 181
 

7.3.2 Ongoing Studies.................................................................................................................. 183
 

8. REGULATIONS, ADVISORIES, AND GUIDELINES..................................................................... 185
 

9. REFERENCES .................................................................................................................................... 191
 

10. GLOSSARY ...................................................................................................................................... 235
 

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
 

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LIST OF FIGURES
 

3-1. Levels of Significant Exposure to Toxaphene - Inhalation ................................................................ 22
 

3-2. Levels of Significant Exposure to Toxaphene - Oral ......................................................................... 42
 

3-3. Proposed Metabolic Scheme for a Toxicant Isolated from Toxaphene.............................................. 75
 

3-4. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a
 

Hypothetical Chemical Substance...................................................................................................... 86
 

3-5. Existing Information on Health Effects of Toxaphene..................................................................... 101
 

4-1. Representative Carbon Skeleton Structures of the Toxaphene Congeners with Numbered 

Carbon Atoms .................................................................................................................................. 112
 

6-1. Frequency of NPL Sites with Toxaphene Contamination ................................................................ 120
 

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LIST OF TABLES
 

3-1. Levels of Significant Exposure to Toxaphene - Inhalation ................................................................ 21
 

3-2. Levels of Significant Exposure to Toxaphene - Oral ......................................................................... 27
 

3-3. Levels of Significant Exposure to Toxaphene - Dermal..................................................................... 61
 

3-4. Genotoxicity of Toxaphene In Vivo.................................................................................................... 65
 

3-5. Genotoxicity of Toxaphene In Vitro................................................................................................... 67
 

3-6. Mean Toxaphene Residues in Cows Following Oral Exposure to Toxaphene .................................. 72
 

3-7. Summary of Excretion Data: Percentage of Dose Excreted in Urine and Feces Following
 
 

Oral Administration to Rats of Radiolabeled Toxaphene and its Components.................................. 80
 

3-8. Toxaphene Levels in Milk from Cows Fed Toxaphene in Their Diet................................................ 82
 

4-1. Chemical Identity of Toxaphene ...................................................................................................... 110
 

4-2. Physical and Chemical Properties of Toxaphene ............................................................................. 111
 

5-1. Facilities that Produce, Process, or Use Toxaphene ......................................................................... 115
 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Toxaphene.................. 123
 

6-2. Food Web Total Toxaphene Concentrations (μg/g Wet Weight) Measured in Lake Superior,
 
 

Lake Huron, Lake Erie, and Lake Ontario ....................................................................................... 132
 

6-3. Names and Parlar Identification Numbers of Some Toxaphene Congeners Reported in the
 

Literature .......................................................................................................................................... 135
 

7-1. Analytical Methods for Determining Toxaphene in Biological Samples......................................... 166
 

7-2. Analytical Methods for Determining Toxaphene in Environmental Samples.................................. 171
 

8-1. Regulations and Guidelines Applicable to Toxaphene..................................................................... 187
 

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TOXAPHENE 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about toxaphene and the effects of exposure to it. 

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. Toxaphene has been found in at least 68 of the 1,699 current or former NPL 

sites. Although the total number of NPL sites evaluated for this substance is not known, the possibility 

exists that the number of sites at which toxaphene is 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 

this substance may be harmful. 

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 toxaphene, 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 it. 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 IS TOXAPHENE? 

Chlorinated camphene Toxaphene is made by reacting chlorine gas with a substance 

called camphene. The resulting product (toxaphene) is a 

mixture of hundreds of different chlorinated camphenes and 

related chemicals. 

Manufactured insecticide Toxaphene was one of the most heavily used pesticides in the 

United States in the 1970s and early 1980s. It was used 

primarily to control insect pests on cotton and other crops in the 

southern United States. Other uses included controlling insect 

pests on livestock and killing unwanted fish in lakes. 

Banned for all registered uses 

in the United States 

Toxaphene was banned for all registered uses by 1990. 

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TOXAPHENE 2 

1. PUBLIC HEALTH STATEMENT 

Form Toxaphene is usually found as a solid or gas. In its original 

form, toxaphene is a yellow to amber waxy solid that has a 

piney odor. 

1.2 WHAT HAPPENS TO TOXAPHENE WHEN IT ENTERS THE ENVIRONMENT?
 

Movement between air, water, 

soil, and sediment 

When toxaphene is released to the environment, it can enter 

the air (by evaporation), the soil (by sticking to soil particles), 

and the water (from runoff after rains). Toxaphene does not 

dissolve well in water, so it is more likely to be found in air, soil, 

or the sediment at the bottom of lakes and streams. 

Breaks down slowly Once toxaphene is in the environment, it can last for many 

years because it breaks down very slowly. 

Transported by air over long 

distances 

Toxaphene has been found in water, soil, sediment, air, and 

animals in places far from where it has been used. This shows 

that toxaphene can be carried long distances by the air. 

Bioaccumulates Toxaphene levels may be high in some predatory fish and 

mammals because toxaphene accumulates in fatty tissues. 

Even when levels are low or confined to a certain area, they 

could be high in individual animals. 

1.3 HOW MIGHT I BE EXPOSED TO TOXAPHENE?
 

Hazardous waste sites People living near a location with heavy toxaphene 

contamination, such as a hazardous waste sites, may be 

exposed to higher levels through breathing contaminated air or 

through direct skin contact with contaminated soil or water. 

Eating contaminated soil Infants and toddlers, who are likely to put things in their mouth, 

may be exposed to toxaphene by eating contaminated soil. 

Eating fish, shellfish, and wild 

game 

People who eat large quantities of fish, shellfish, or wild game 

animals from areas contaminated by toxaphene may have 

higher exposure to this substance since these animals tend 

concentrate toxaphene in their fatty tissues. 

Drinking water Individuals may be exposed to toxaphene through drinking 

water contaminated with toxaphene runoff from contaminated 

soils. 

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TOXAPHENE 3 

1. PUBLIC HEALTH STATEMENT 

1.4 HOW CAN TOXAPHENE ENTER AND LEAVE MY BODY? 

May enter your body 

through food, drinking 

water, breathing, and 

skin contact 

Toxaphene can enter your body if you eat food contaminated with 

toxaphene, such as fish caught from water where toxaphene is 

present. Toxaphene in drinking water can similarly enter your body, 

although when toxaphene has been detected in drinking water, levels 

have been generally more than 1,000 times lower than levels 

measured in toxaphene-contaminated food. Toxaphene could enter 

your body if it were to come into contact with your skin (for example, 

by bathing or showering in water contaminated with the chemical) or if 

you were to breathe air containing toxaphene. 

Leaves through bodily 

fluids 

Toxaphene is quickly broken down into other substances in your body. 

Toxaphene and its breakdown products leave your body mostly in 

urine and feces. Small amounts may leave through breast milk and 

exhaled air. 

1.5 HOW CAN TOXAPHENE AFFECT MY HEALTH? 

This section looks at studies concerning potential health effects in animal and human studies. 

Nervous system Convulsions were experienced by some people who accidentally or 

intentionally swallowed large amounts of toxaphene, including three 

women who ate collard greens contaminated with toxaphene. 

However, since toxaphene is no longer used as a pesticide, you would 

not likely eat enough toxaphene-contaminated food to affect your 

nervous system in this way. 

Immune system Effects on the immune system have been observed in laboratory 

studies of animals that were given toxaphene by mouth in amounts 

that you would not likely get by eating food or drinking water containing 

toxaphene. 

Liver Toxaphene temporarily damaged the liver of a man who attempted 

suicide by drinking a large amount of an insecticide that contained 

toxaphene. Liver damage was seen in laboratory studies of animals 

that were given toxaphene by mouth in amounts that you would not 

likely get by eating food or drinking water containing toxaphene. 

Kidneys Toxaphene temporarily damaged the kidneys of a man who attempted 

suicide by drinking a large amount of an insecticide that contained 

toxaphene. Swollen kidneys were seen in a small boy who died after 

drinking a large amount of toxaphene. Kidney damage was seen in 

laboratory studies of animals that were given toxaphene by mouth in 

amounts that you would not likely get by eating food or drinking water 

containing toxaphene. 

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TOXAPHENE 4 

1. PUBLIC HEALTH STATEMENT 

Cancer Toxaphene caused liver cancer in mice and possibly thyroid cancer in 

rats that were given toxaphene by mouth in large amounts that you 

would not likely get by eating food or drinking water containing 

toxaphene. We do not know whether toxaphene would cause cancer 

in humans. However, based on animal studies, the Department of 

Health and Human Services has determined that toxaphene may 

reasonably be anticipated to be a carcinogen. The International 

Agency for Research on Cancer has determined that toxaphene is 

possibly carcinogenic to humans. Also, the EPA has determined that 

toxaphene is a probable human carcinogen. 

1.6 HOW CAN TOXAPHENE AFFECT CHILDREN? 

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

conception to maturity at 18 years of age. 

Effects in children Toxaphene would be expected to affect children in the same manner 

as adults. It is not known whether children are more susceptible than 

adults to the effects of toxaphene. 

Developmental effects A few studies in animals have shown minor changes in fetal 

development. We do not know if toxaphene would cause 

developmental effects in humans. 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO TOXAPHENE?
 

Reduce consumption 

of foods and drinking 

water that contain 

toxaphene 

For people who live in areas where surface waters (lakes) have been 

contaminated with toxaphene, consumption of toxaphenecontaminated foods such as fish may need to be reduced. Also, do 

not drink water that has been contaminated with toxaphene. 

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

TOXAPHENE? 

Can be measured in 

blood and urine 

Toxaphene and some of its breakdown products can be measured in 

blood and urine. However, it is not likely that you would be exposed to 

enough toxaphene to make such measurements that would be 

meaningful to your health. 

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TOXAPHENE 5 

1. PUBLIC HEALTH STATEMENT 

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. These are levels of a toxic 

substance in air, water, soil, or food that do not exceed a critical value. This critical value 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 toxaphene include the following: 

Levels in drinking 

water set by EPA 

The EPA has determined that exposure to toxaphene in drinking water at 

concentrations of 0.004 mg/L for up to 10 days is not expected to cause any 

adverse effects in a child. 

The EPA has determined that lifetime exposure to 0.01 mg/L toxaphene in 

the drinking water is not expected to cause any adverse noncancer effects 

if the only source of exposure to toxaphene is the drinking water. 

EPA established a maximum contaminant level (MCL) of 0.003 mg/L for 

toxaphene in drinking water. 

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TOXAPHENE 6 

1. PUBLIC HEALTH STATEMENT 

Bottled water The FDA has determined that the toxaphene concentration in bottled 

drinking water should not exceed 0.003 mg/L. 

Levels in 

workplace air set 

by OSHA 

OSHA set a legal limit of 0.5 mg/m3 for toxaphene in air averaged over an 

8-hour work day. 

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 1-800-CDCINFO (1-800-232-4636), by e-mail at cdcinfo@cdc.gov, or by writing 

to: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine
 

1600 Clifton Road NE
 

Mailstop F-62
 

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/
 

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TOXAPHENE 7 

2. RELEVANCE TO PUBLIC HEALTH
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO TOXAPHENE IN THE 

UNITED STATES 

Toxaphene is a manufactured pesticide comprising a complex mixture of hundreds of chlorinated 

terpenes. After DDT was banned from use in the United States in 1972, toxaphene became the most 

popular substitute. Control of pests on cotton crops was the principal use of toxaphene in the United 

States, although the pesticide was used to control a variety of insects on a range of crops and to eradicate 

undesirable fish species in some aquatic environments. In November of 1982, EPA canceled the 

registration of toxaphene for most uses as a pesticide or pesticide ingredient. All registered uses of 

toxaphene mixtures in the United States and its territories were canceled in 1990. 

Toxaphene was widely released to the environment mainly as a result of its past use as an insecticide. 

Toxaphene has been transported over long distances in the atmosphere. The presence of toxaphene in 

surface waters of the Great Lakes has been attributed to aerial transport of the mixture from application 

sites in the southern United States. Atmospheric toxaphene is transported back to soil and water surfaces 

by wet and dry deposition processes. Toxaphene strongly adsorbs to particles and is relatively immobile 

in soils. In water, toxaphene is strongly adsorbed to suspended particulates and sediments and is 

bioconcentrated by aquatic organisms to fairly high levels, with bioconcentration factors (BCFs) on the 

order of 4,200–60,000. Toxaphene also appears to be biomagnified in aquatic food chains. 

The composition of technical toxaphene released to the environment has changed over time since 

toxaphene congeners degrade at different rates, resulting in what is commonly termed weathered 

toxaphene. Degradation proceeds mainly through dechlorination and dehydrochlorination resulting in a 

shift in composition toward lower chlorinated homologs. Presently, exposure to persistent toxaphene 

congeners and degradation products is the primary health concern for the general population. Toxaphene 

congeners that have been found to persist in fish, marine mammals, and human serum and breast milk 

include those identified as Parlars p-26, p-40/41, p-44, p-50, and p-62. Pooled results of studies that 

assessed levels of these congeners in human serum and/or breast milk indicate that p-26, p-50, and p-62 

comprise most of the total toxaphene body burden. 

The major source of exposure for the general population appears to be ingestion of low concentrations of 

persistent toxaphene congeners in food, particularly fish, and toxaphene-contaminated drinking water. 

Subpopulations with increased potential for significant exposure to persistent toxaphene congeners 

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TOXAPHENE 8 

2. RELEVANCE TO PUBLIC HEALTH 

include northern Native American groups that eat toxaphene-contaminated aquatic mammals, recreational 

or subsistence hunters in the southern United States that consume significant amounts of game animals 

(especially species like raccoons), and people who consume certain types of sport-caught fish (such as 

trout, salmon, herring, smelt, and walleye) from the Great Lakes. 

2.2 SUMMARY OF HEALTH EFFECTS 

This toxicological profile for toxaphene summarizes health effects information for toxaphene based on 

exposure to technical toxaphene that was formerly widely used as a pesticide in the United States. Since 

being banned for use as a pesticide in the United States in 1990, the greatest present concern for the 

general population would be exposure to persistent toxaphene congeners and degradation products of 

technical toxaphene formerly released to the environment. 

Limited information is available regarding noncancer health effects in humans or laboratory animals 

following inhalation exposure to toxaphene. Pulmonary hypersensitivity and hematological alterations 

were indicated in two Egyptian agricultural pesticide workers involved in spraying a pesticide 

formulation (68% toxaphene, 35% kerosene, 3% xylol, and 2% emulsifier). One controlled study found 

no signs of toxicity in a group of 25 volunteers exposed to an aerosol containing a maximum of 500 mg 

toxaphene/m3 30 minutes/day for 30 days. The nervous system and the liver have been identified as 

targets of toxaphene toxicity in limited animal studies that employed the inhalation exposure route. 

Ingestion of toxaphene has resulted in death in some cases of acute poisoning. Mortalities have also been 

observed in animals following single- and repeated-dose oral exposure. 

Clinical signs of central nervous system stimulation including convulsions have been reported in humans 

following accidental or intentional ingestion of toxaphene. Similar effects have been observed in animals 

following oral exposure to toxaphene. Dogs appear to be particularly sensitive to the neurological effects 

of toxaphene; convulsions were elicited at oral doses as low as 10 mg/kg/day. 

Animal studies provide evidence that toxaphene can also affect the liver, kidney, endocrine system, 

immunological system, and body weight, as well as the nervous system. Morphological and degenerative 

changes were observed in the livers of dogs, rats, and mice following repeated oral exposure to 

toxaphene; doses as low as 1.8 mg/kg/day caused nuclear changes in hepatocytes of rats. Renal tubular 

injury was reported in the kidneys of rats receiving toxaphene at 8.6 mg/kg/day for 13 weeks. 

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TOXAPHENE 9 

2. RELEVANCE TO PUBLIC HEALTH 

Histopathological evidence of effects on the thyroid gland of male rats was observed following 13 weeks 

of oral administration of toxaphene at 1.8 mg/kg/day. Significant reductions in IgM responses (indicative 

of depressed humoral immunity) were reported in female cynomolgus monkeys administered toxaphene 

by oral capsule at a dose level of 0.4 mg/kg/day during a 75-week treatment period. Pregnant animals 

may be particularly sensitive to toxaphene-induced effects on body weight; for example, average body 

weight gain of rat dams administered toxaphene by gavage at 15 mg/kg/day during pregnancy was 22% 

lower than that of pregnant control rat dams. 

Toxaphene-induced reproductive effects have not been demonstrated in animal studies. Effects such as 

decreased early postnatal body weight and increased incidences of supernumary ribs were observed in 

offspring of rat dams that were fed toxic doses of toxaphene. Decreased renal protein was noted in the 

kidneys of 21-day-old rat fetuses whose mothers had been administered toxaphene by gavage at 

12.5 mg/kg/day during gestation. Suppression of macrophage phagocytic function was reported in 

8-week-old offspring of mouse dams administered toxaphene at doses ≥2 mg/kg/day during premating 

and throughout mating, gestation, and lactation. In one developmental toxicity study, slight delays in 

successful responses to a righting reflex test were observed in nursing pups from rat dams administered 

toxaphene by gavage at 6 mg/kg/day during mating and throughout gestation. Retarded swimming ability 

and righting reflex were reported in young pups of rat dams administered toxaphene at 0.05 mg/kg/day 

during gestation and lactation; however, the effect was transient, observed only during postpartum days 

10–12 and of uncertain toxicological significance. 

Limited animal data indicate that dermal exposure to high levels of toxaphene can cause clinical signs of 

neurotoxicity, liver effects, and death at very high doses. 

Statistically significant associations between exposure to toxaphene and risk of cancers such as leukemia 

and certain types of non-Hodgkin’s lymphoma have been reported in case-control studies of groups of 

farm workers. It should be noted that all uses of toxaphene in the United States were canceled in 1990. 

Increased incidences of thyroid tumors were observed in rats administered toxaphene at approximately 

80 mg/kg/day for 80 weeks; in similarly-treated mice, increased incidences of hepatocellular tumors were 

noted at toxaphene doses of 17 and 34 mg/kg/day. One unpublished study reported increased incidences 

of hepatocellular tumors in male mice administered toxaphene orally at approximately 8.6 mg/kg/day for 

18 months. Available in vivo studies and in vitro assays provide equivocal evidence for toxapheneinduced genotoxicity. The International Agency for Research on Cancer (IARC) has classified toxaphene 

as Group 2B (possibly carcinogenic to humans). The National Toxicology Program (NTP) considers 

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TOXAPHENE 10 

2. RELEVANCE TO PUBLIC HEALTH 

toxaphene as “reasonably anticipated to be a human carcinogen”. EPA has given toxaphene a 

classification of B2 (probable human carcinogen). The cancer classifications are based on the findings of 

hepatocellular tumors in toxaphene-treated mice, thyroid tumors in toxaphene-treated rats, and evidence 

of mutagenicity in in vitro bacterial assays. 

2.3 MINIMAL RISK LEVELS (MRLs) 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for toxaphene. 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 1990a), 

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 

No inhalation MRLs were derived for toxaphene due to the lack of reliable human and animal data. One 

controlled human study found no evidence of adverse effects among 25 human subjects exposed to an 

aerosol containing a maximum of 500 mg toxaphene/m3 for 30 minutes/day for 10 days (Keplinger 1963). 

However, exposures were brief, air concentrations were not measured, and assessments were limited to 

clinical examinations and incomplete blood and urinalysis testing. Acute pulmonary insufficiency was 

noted in two agricultural workers involved in spraying a formulation consisting of (60% toxaphene, 35% 

kerosene, 3% xylol, and 2% emulsifier) for 2 months. No other information was located regarding health 

effects in humans exposed to toxaphene in the air. 

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TOXAPHENE 11 

2. RELEVANCE TO PUBLIC HEALTH 

Available animal data are limited to summaries of unpublished data cited in a secondary unpublished 

bulletin and a report of clinical signs of neurotoxicity in several animal species following repeated 

inhalation exposure to toxaphene dust (Industrial Biotest 1965). Some studies conducted by Industrial 

Biotest have been shown to be less than reliable. 

Oral MRLs 

•	 An MRL of 0.05 mg/kg/day has been derived for acute-duration oral exposure (14 days or less) to 

toxaphene. 

Information on effects of acute-duration oral exposure to toxaphene in humans is limited to reports of 

cardiac dilatation and swelling of the kidneys in a 2-year-old boy who ingested an unspecified lethal 

amount of toxaphene (McGee et al. 1952), temporarily-compromised hepatic and renal function in a 

26-year-old male who attempted suicide by ingesting an insecticide containing toxaphene as the active 

ingredient (Wells and Milhorn 1983), and signs of neurotoxicity (convulsive seizures, temporary memory 

loss, nausea) in several females who had ingested collard greens coated with toxaphene (McGee et al. 

1952). 

Available acute-duration oral toxicity animal studies include single-dose studies in rats (Garcia and 

Mourelle 1984; Peakall 1976), guinea pigs (Chandra and Durairaj 1992, 1995), and dogs (Chu et al. 1986; 

Lackey 1949); and multiple-dose studies in rats (Chernoff and Carver 1976; Chernoff et al. 1990; 

Kavlock et al. 1982; Mehendale 1978; Rao et al. 1986; Trottman and Desaiah 1980; Waritz et al. 1996), 

mice (Chernoff and Carver 1976; Hedli et al. 1998), and dogs (Chu et al. 1986; Lackey 1949). Targets of 

acute oral toxaphene toxicity include the nervous system, liver, body weight, immunological system, 

endocrine system, and development. 

Several animal studies include reports of treatment-related liver weight changes following acute-duration 

oral exposure to toxaphene. Chernoff and Carver (1976) reported 23, 25, and 32% increased mean 

relative liver weight in mouse dams administered toxaphene by gavage at 15, 25, and 35 mg/kg/day 

during gestation days 7–16; the 35 mg/kg/day dose level represented a no-observed-adverse-effect level 

(NOAEL) for liver weight in similarly-treated rat dams. Trottman and Desaiah (1980) reported 20% 

increased mean liver weight in rats receiving toxaphene from the diet at 18 mg/kg/day for 14 days; the 

NOAEL for effects on liver weight was 13.5 mg/kg/day. Hedli et al. (1998) reported 48 and 78% 

increased mean relative liver weights in mice gavaged at 50 and 100 mg/kg/day, respectively, for 7 days; 

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TOXAPHENE 12 

2. RELEVANCE TO PUBLIC HEALTH 

the NOAEL for effects on liver weight was 25 mg/kg/day. Peakall (1976) reported a 9% increase in 

relative liver weight and significantly increased microsomal enzyme activity in rats at 5 days following 

administration of a single 120 mg/kg oral dose of toxaphene. Mehendale (1978) reported decreased 

biliary excretion of imipramine metabolites from perfused livers of rats that had received toxaphene from 

the diet at an estimated dose of 10 mg/kg/day for 8 days. 

Chu et al. (1986) observed convulsions in dogs following oral administration of toxaphene at 

10 mg/kg/day for 2 days; convulsions were not elicited after the dose was reduced to 5 mg/kg/day for the 

remainder of a 13-week treatment period. Lackey (1949) reported convulsions in dogs administered a 

single 10 mg/kg dose of toxaphene. Mild tremors and nervousness were noted in rats receiving toxaphene 

by gavage at 25 mg/kg/day for 3 days (Rao et al. 1986). 

Toxaphene-induced effects on maternal body weight were observed in rat and mouse dams administered 

toxaphene via gavage during organogenesis (Chernoff and Carver 1976; Chernoff et al. 1990). The 

mouse study identified a NOAEL of 15 mg/kg/day and a serious lowest-observed-adverse-effect level 

(serious LOAEL) of 25 mg/kg/day for 22% decreased maternal body weight gain (Chernoff and Carver 

1976). The rat studies identified serious LOAELs of 32 mg/kg/day (the only dose tested by Chernoff et 

al. 1990) and 15 mg/kg/day (the lowest dose tested by Chernoff and Carver 1976) for the effect. 

Trottman and Desaiah (1980) reported a 36% decrease in mean thymus weight in rats receiving toxaphene 

from the diet at an estimated dose of 13.5 mg/kg/day for 14 days; this effect was not observed at the lower 

dose (9 mg/kg/day). The study report made no mention of histopathological evaluations. 

A greater than 2-fold increase in serum TSH and histopathologic thyroid lesions were reported in rats 

administered toxaphene by gavage at 75 mg/kg/day (the only dose tested) for 14 days (Waritz et al. 1996). 

Significantly increased incidence of supernumerary ribs (17% greater than controls) was reported in 

fetuses of rat dams administered toxaphene by gavage at 32 mg/kg/day (the only dose tested) during 

gestation days 6–15 (Chernoff et al. 1990). Significantly decreased fetal renal protein and slight, but 

statistically significant retardation in kidney development were reported in fetuses of rat dams 

administered toxaphene by gavage at 12.5 or 25 mg/kg/day during gestation days 7–16; lower dose levels 

were not tested (Kavlock et al. 1982). 

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TOXAPHENE 13 

2. RELEVANCE TO PUBLIC HEALTH 

The most sensitive effects of acute oral toxaphene toxicity were observed at doses in the range of 10– 

15 mg/kg/day and include increased liver weights, clinical signs of neurotoxicity, depressed maternal 

body weight gain, and indicators of treatment-related effects on developmental end points. There is some 

degree of uncertainty regarding the toxicological significance of the reported effects on liver weight, fetal 

renal protein, thymus weight, and biliary excretion of imipramine metabolites. The reported 22% 

decreased maternal body weight gain in the toxaphene-treated rat dams of the Chernoff and Carver (1976) 

study is clearly a serious adverse effect. However, this effect was observed at the lowest dose tested, and 

the study did not identify a NOAEL. ATSDR does not derive MRLs based on a serious LOAEL in the 

absence of an identified NOAEL. The dog study of Chu et al. (1986) identified a NOAEL (5 mg/kg/day) 

and a LOAEL (10 mg/kg/day) for clinical signs of toxaphene-induced neurotoxicity, but did not include 

histopathological investigations. To derive an acute-duration oral MRL for toxaphene, the dog study of 

Chu et al. (1986) is selected as the principal study, and the NOAEL of 5 mg/kg/day is selected as the 

critical effect and point of departure (POD) for MRL derivation. An acute-duration oral MRL derived in 

this manner is expected to be protective of toxaphene-induced effects on the nervous system, liver, 

endocrine system, and developmental end points. 

In the principal study (Chu et al. 1986), groups of male and female beagle dogs (6/sex/group) were given 

gelatin capsules containing toxaphene at 0, 0.2, 2.0, or 5.0 mg/kg daily for 13 weeks. During the first 

2 treatment days, the high-dose group received toxaphene at 10 mg/kg/day. This dose was reduced to 

5 mg/kg/day on treatment day 3 because the 10 mg/kg/day dose level elicited convulsions, salivation, and 

vomiting in 1/6 males and 2/6 females. These clinical signs were not observed in any of the toxaphenetreated dogs throughout the remainder of the scheduled 13-week treatment period. This study identified a 

serious LOAEL of 10 mg/kg/day for neurological effects elicited during the first 2 days of oral treatment 

and a NOAEL of 5 mg/kg/day. Using the NOAEL of 5 mg/kg/day as the POD, application of a total 

uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability) 

yields an acute-duration oral MRL of 0.05 mg/kg/day for toxaphene. 

•	 An MRL of 0.002 mg/kg/day has been derived for intermediate-duration oral exposure (15– 

364 days) to toxaphene. 

No human studies were located regarding the effects of intermediate-duration oral exposure to toxaphene. 

Intermediate-duration oral toxicity studies are available for rats (Chu et al. 1986, 1988; Crowder et al. 

1980; Garcia and Mourelle 1984; Kennedy et al. 1973; Koller et al. 1983; NCI 1979; Olson et al. 1980; 

Ortega et al. 1957; Peakall 1976; Waritz et al. 1996), mice (Allen et al. 1983; NCI 1979), dogs (Chu et al. 

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TOXAPHENE 14 

2. RELEVANCE TO PUBLIC HEALTH 

1986; Lackey 1949), and cynomolgus monkeys (Bryce et al. 2001; Tryphonas et al. 2000, 2001). The 

animal studies identified the nervous system, liver, kidney, thyroid gland, and immunological system as 

targets of toxaphene toxicity from intermediate-duration oral exposure. Lackey (1949) reported 

occasional convulsions in groups of dogs (2/group) administered toxaphene by capsule at 4 mg/kg/day for 

44 or 106 days, but did not include more specific details. Study limitations preclude the usefulness of this 

study for quantitative risk assessment. One developmental toxicity study reported inferior swimming 

ability at postnatal days 10–12 in pups of rat dams receiving toxaphene from the diet at 0.05 mg/kg/day 

throughout gestation and for 30 days postpartum; however, swimming behavior appeared normal by 

postnatal day 16 (Olson et al. 1980). No additional studies were located to support the finding of 

toxaphene-related effects on postnatal development at such low dose levels. 

Identified LOAELs for liver, kidney, and thyroid effects range from 0.5 to 45 mg/kg/day. A 13-week 

dietary study of male and female rats (Chu et al. 1986) identified the lowest LOAELs for these effects. 

Significantly increased incidences of histopathologic lesions of the liver (anisokaryosis) and kidney (renal 

tubular injury) were observed in the females at a 0.5 mg/kg/day dose level in the absence of an identified 

NOAEL. Similar effects were observed in the males at the dose level of 1.8 mg/kg/day; the lowest dose 

tested in the male rats (0.35 mg/kg/day) represented a NOAEL for liver and kidney effects. The same 

study identified NOAELs of 0.35 and 12.6 mg/kg/day and LOAELs of 1.8 and 63 mg/kg/day for 

morphologic lesions in the thyroid (angular collapse of follicles, increased epithelial height with 

multifocal papillary proliferation, and reduced colloid density) of the males and females, respectively. 

Chu et al. (1986) also observed hepatomegaly in dogs administered toxaphene by capsule at 5 mg/kg/day 

for 13 weeks, but no evidence of treatment-related liver effects at a daily 2 mg/kg dose level. 

Depressed humoral immune responses have been observed in rats, mice, and cynomolgus monkeys 

administered toxaphene orally for periods ranging from 8 to 52 weeks. In an enzyme-linked 

immunosorbent assay (ELISA) performed on female mice that received toxaphene from the diet at doses 

≥19 mg/kg/day for up to 8 weeks, Allen et al (1983) reported suppressed antibody production, indicating 

depressed humoral immunity; the study identified a NOAEL of 2 mg/kg/day for the effect. Koller et al. 

(1983) reported a 46% decrease in the IgG primary antibody response in male rats receiving toxaphene 

from the diet at 2.6 mg/kg/day for up to 9 weeks and challenged twice (after 8 and 15 days on test) with 

keyhole limpet hemocyanin (KLH). 

Tryphonas et al. (2001) reported a NOAEL of 0.1 mg/kg/day and a LOAEL of 0.4 mg/kg/day for 

toxaphene-induced decreased anti-SRBC (IgM) titers as an indicator of depressed humoral immunity. In 

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TOXAPHENE 15 

2. RELEVANCE TO PUBLIC HEALTH 

the study, groups of 10 female cynomolgus monkeys/dose group received toxaphene via oral capsules at 

0, 0.1, 0.4, or 0.8 mg toxaphene/kg/day for up to 75 weeks. Groups of 5 males dosed at 0 or 

0.8 mg/kg/day were included in the study. Testing for immune effects was initiated on week 33 and 

included flow cytometry, lymphocyte transformation, natural killer cell activity and determination of 

serum cortisol during weeks 33–46 and immunizations with sheep red blood cells (SRBC) treatment at 

week 44 for a primary response and week 48 for a secondary response (observations made through 

treatment week 52). Treatment with toxaphene at 0.4 mg/kg/day resulted in significant (p<0.05) 

reductions in mean primary anti-SRBC IgM responses at weeks 1 and 4 following primary immunization 

(27 and 35% lower than that of controls) and secondary anti-SRBC IgM responses at week 1 following 

secondary immunization (10% lower than that of controls). The dose level of 0.8 mg/kg/day resulted in 

significantly reduced mean primary anti-SRBC IgM responses at weeks 1–4 following primary 

immunization, significantly reduced mean secondary anti SRBC IgM response at weeks 1 and 4 following 

secondary immunization, and significantly reduced primary anti-SRBC IgG responses at weeks 2 and 3 

following primary immunization (51 and 43% lower than that of controls). In males, 0.8 mg/kg/day 

toxaphene induced a significant reduction in mean primary anti-SRBC IgM response at weeks 1–3 

following primary immunization. Flow cytometry tests showed that the only effect on leukocyte and 

lymphocyte subsets was a reduction in absolute B lymphocytes (CD20) in 0.8 mg/kg/day females (62% 

lower than controls). There were no detectable treatment-related effects on natural killer cell activity, 

lymphoproliferative response to mitogens, or serum cortisol levels. This study identified the lowest 

LOAEL (0.4 mg/kg/day for depressed humoral immunity) among reliable LOAELs for intermediateduration oral exposure to toxaphene, and is selected as the critical effect for deriving an intermediateduration oral MRL for toxaphene. 

To derive a POD for MRL derivation, BMD modeling was conducted using data for depressed humoral 

immunity from the female cynomolgus monkeys (Tryphonas et al. 2001). All continuous variable models 

in the EPA Benchmark Dose Software (Version 2.1.1) were fit to the mean anti-SRBC (IgM) titre data at 

week 1 post-immunization at treatment week 44; the modeled data are presented in Table A-3 of 

Appendix A. A default benchmark response (BMR) of 1 standard deviation (1SD) from the control mean 

was selected in the absence of a toxicological rationale for selecting an alternative BMR. As discussed in 

detail in Appendix A, the polynomial and power models converged on the linear model and provided 

identical fit to the data. These models predicted BMD1SD and BMDL1SD values of 0.34 and 

0.22 mg/kg/day, respectively. The BMDL1SD of 0.22 mg/kg/day was divided by an uncertainty factor of 

100 (10 for interspecies extrapolation and 10 for human variability). The resulting intermediate-duration 

oral MRL is 0.002 mg/kg/day. 

***DRAFT FOR PUBLIC COMMENT*** 
TOXAPHENE 16 

2. RELEVANCE TO PUBLIC HEALTH 

A chronic-duration oral MRL was not derived for toxaphene for the following reasons: 

1.	 No human studies were located regarding the effects of chronic-duration oral exposure to 

toxaphene. 

2.	 A study designed to assess the effect of toxaphene on the immune system of cynomolgus 

monkeys identified a LOAEL of 0.4 mg/kg/day for decreased anti-SRBC IgM response during 

intermediate-duration oral exposure (<52 weeks) that is lower than the LOAEL of 0.8 mg/kg/day 

for decreased anti-TT response to chronic-duration oral exposure (testing initiated after 53 weeks 

of treatment). 

3.	 Toxaphene doses used in chronic duration oral toxicity studies in rats and mice (NCI 1979) were 

2 orders of magnitude higher than doses eliciting immunological effects in cynomolgus monkeys 

treated for intermediate and chronic durations. 

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TOXAPHENE 17 

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 toxaphene. 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. 

Toxaphene is a manufactured pesticide composed of over 670 different constituents; the relative 

proportions of the major components of the pesticide are essentially the same in different formulations. 

The production and use of toxaphene have been banned in the United States and all of its territories since 

1990 (EPA 1990b). Nevertheless, because of its earlier widespread use, persistence in the environment, 

and storage in waste sites, exposure to toxaphene and its persistent congeners is still possible. 

Following its release to the environment, technical toxaphene undergoes biotic and abiotic “weathering” 

processes, resulting in congener mixtures that differ from those of technical toxaphene (EPA 2010e; 

Ruppe et al. 2003, 2004; Simon and Manning 2006). Because toxaphene has not been used as a pesticide 

in the United States since 1990, exposure to persistent toxaphene congeners from weathered toxaphene is 

of primary health concern. Major congeners of toxaphene that have been found to persist in fish, marine 

mammals, and human serum and breast milk include Parlars p-26, p-40/41, p-44, p-50, and p-62 (Simon 

and Manning 2006). Pooled results of studies that assessed levels of these congeners in human serum 

and/or breast milk (Gill et al. 1996; Polder et al. 2003; Sandanger et al. 2003; Skopp et al. 2002b; Walker 

et al. 2003) indicate that p-26, p-50, and p-62 comprise approximately 33, 55, and 6%, respectively, of the 

total toxaphene body burden (Simon and Manning 2006). 

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). 

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TOXAPHENE 18 

3. HEALTH EFFECTS 

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 

"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 toxaphene are 

indicated in Table 3-2 and Figure 3-2. Because cancer effects could occur at lower exposure levels, 

Figure 3-2 also shows a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 

10,000 to 1 in 10,000,000 (10-4 to 10-7), as developed by EPA. 

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. 

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TOXAPHENE 19 

3. HEALTH EFFECTS 

3.2.1 Inhalation Exposure 

Very little information is available regarding the health effects of toxaphene following inhalation 

exposure in humans. Most of the existing data come from case reports and long-term studies of pesticide 

workers and are of limited value. In such studies, precise levels of exposure are usually not provided, and 

concurrent exposure to several pesticides confounds the interpretation of the results. 

Limited information is available regarding health effects in animals following inhalation exposure to 

toxaphene. Secondary sources have cited unpublished results of studies for Hercules Incorporated, a 

major U.S. producer while toxaphene was registered for use as a pesticide in the United States. Although 

the primary study reports have not been made available to ATSDR, the results are presented in 

Section 3.2.1 as summarized in the Drinking Water Criteria Document for Toxaphene (EPA 1985c). 

3.2.1.1 Death 

No studies were located regarding death in humans following inhalation exposure to toxaphene. 

A 40% toxaphene dust (3,000–4,000 mg/m3

) caused death in about one-half of an exposed group of rats 

after 1 hour of exposure (EPA 1985c). Unpublished results of repeated inhalation exposure studies cited 

by EPA (1985c) include the death of all rats (number unspecified) exposed to toxaphene dust at 

250 mg/m3 for up to 1 week, unspecified numbers of deaths among rats, dogs, and guinea pigs exposed at 

12 mg/m3 for up to 3 months (but no deaths at 4 mg/m3

), and no mortality in rats and rabbits exposed at 

500 mg/m3 for 3 weeks. 

3.2.1.2 Systemic Effects 

No studies were available regarding cardiovascular, gastrointestinal, musculoskeletal, endocrine, or ocular 

effects in humans or animals following inhalation exposure to toxaphene. 

One controlled human study investigated the general effects of inhaled toxaphene. Keplinger (1963) 

reported that no toxic effects were seen in 25 human subjects (15 males, 10 females) exposed to an 

aerosol containing a maximum of 500 mg toxaphene/m3 for 30 minutes/day for 10 days. The author 

estimated the absorbed dose to be as much as 60 mg/person/day. After a 3-week period, these same 

subjects were exposed for three more 30-minute periods. Examinations of these subjects by a 

dermatologist and an internist (some of them using blood tests and urinalysis) indicated no effects. Due 

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TOXAPHENE 20 

3. HEALTH EFFECTS 

to the limited information reported in this study and the unusual exposure conditions, it is difficult to 

assess the adequacy of these data. Nevertheless, the study is referenced below for the appropriate 

systemic end points. 

The highest NOAEL values for humans for each effect are recorded in Table 3-1 and plotted in 

Figure 3-1. 

Respiratory Effects. Pulmonary hypersensitivity reactions to toxaphene were suspected in two 

Egyptian agricultural pesticide workers in 1958. In these cases, men involved in the spraying of 

toxaphene (formulated as 60% toxaphene, 35% kerosene, 3% xylol, and 2% emulsifier) for approximately 

2 months suffered from acute pulmonary insufficiency (Warraki 1963). Chest x-rays revealed extensive 

miliary shadows, and one man exhibited marked bilateral hilar lymphadenopathy. The diagnosis in both 

cases was extensive bilateral allergic bronchopneumonia as a result of insecticide exposure. Both patients 

recovered quickly and completely with cortisone, streptomycin, and isoniazid treatment. Although the 

clinical sequelae observed in these two patients could be associated with toxaphene exposure, the effects 

could have been caused by other components of the spray. No similar cases have been reported since 

1958. 

No studies were located regarding respiratory effects in animals following inhalation exposure to 

toxaphene. 

Hematological Effects. No blood abnormalities were observed in a group of volunteers exposed to 

toxaphene spray 30 minutes/day for 10 days at a maximum nominal concentration of 500 mg/m3 

(Keplinger 1963). Clinical findings in two male Egyptian agricultural pesticide workers involved in the 

spraying of toxaphene (formulated as 60% toxaphene, 35% kerosene, 3% xylol, and 2% emulsifier) for 

approximately 2 months included elevated sedimentation rates, the presence of blood eosinophilia, and 

high serum globulin (Warraki 1963). 

Hepatic Effects. No studies were available regarding hepatic effects in humans following inhalation 

exposure to toxaphene. 

Slight hepatocellular necrosis was reported in some female rats that survived inhalation exposure to 

toxaphene dust (4 or 12 mg/m3

) for 3 months (EPA 1985c). 

***DRAFT FOR PUBLIC COMMENT*** 
502

500500500500

Table 3-1 Levels of Significant Exposure to Toxaphene - Inhalation 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/m3) (mg/m3) (mg/m3) Chemical Form 

***DRAFT FOR PUBLIC COMMENT***

ACUTE EXPOSURE Systemic 

1 Human 10 d 30 min/d Resp 500 Keplinger 1963 

Hemato 500

Renal 500Dermal 500

a The number corresponds to entries in Figure 3-1.d = day(s); Hemato = hematological; LOAEL = lowest-observed-adverse-effect level; min = minute(s); NOAEL = no-observed-adverse-effect level; Resp = respirato
Respiratory 

Hematological Rena

Systemic 

mg/m3 

1000
	

1
	 1
	 1
	

100
	

l 

Dermal 

TOXAPHENE

3. HEALTH EFFECTS

22

***DRAFT FOR PUBLIC COMMENT***

Figure 3-1 Levels of Significant Exposure to Toxaphene - Inhalation 

Acute (≤14 days) 

1
	

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
 

 

 

 

 

 

TOXAPHENE 23 

3. HEALTH EFFECTS 

Renal Effects. Urinalyses were normal for a group of volunteers exposed to toxaphene spray 

30 minutes/day for 10 days at a maximum nominal concentration of 500 mg/m3 (Keplinger 1963). 

No studies were located regarding renal toxicity in animals following inhalation exposure to toxaphene. 

Dermal Effects. There were no signs of exposure-related dermal effects in a group of 25 volunteers 

exposed to an aerosol containing a maximum nominal concentration of 500 mg/m3 toxaphene for 

30 minutes/day for 10 days (Keplinger 1963). 

No studies were located regarding dermal effects in animals following inhalation exposure to toxaphene. 

Body Weight Effects. No studies were available regarding body weight effects in humans or animals 

following inhalation exposure to toxaphene. 

No studies were located regarding the following effects in humans or animals following inhalation 

exposure to toxaphene: 

3.2.1.3 Immunological and Lymphoreticular Effects 

3.2.1.4 Neurological Effects 

3.2.1.5 Reproductive Effects 

3.2.1.6 Developmental Effects 

3.2.1.7 Cancer 

Mills et al. (2005) reported a significant association (odds ratio [OR]=2.20, 95% confidence interval [CI] 

1.04–4.65) between risk of leukemia and exposure to toxaphene in a nested case-control study of 

131 lymphohematopoietic cancer cases (leukemia, multiple myeloma, non-Hodgkin’s lymphoma [NHL]) 

diagnosed between 1988 and 2001 among members of the United Farm Workers (UFW) labor union in 

California (cohort of 139,000 workers). For each case, five gender- and age-matched members of the 

UFW without any cancer diagnoses were selected as controls. Crop and pesticide exposures were 

estimated by linking job history information from union records with California Department of Pesticide 

Regulation pesticide use reports during the 20-year period prior to cancer diagnosis. There was no 

significant association between exposure to toxaphene and risk of multiple myeloma or NHL. 

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TOXAPHENE 24 

3. HEALTH EFFECTS 

Schroeder et al. (2001) reported a significant association (OR=3.7, 95% CI 1.9–7.0) between 

t(14;18)-positive NHL cases (n=5) and toxaphene exposure. The FARM (Factors Affecting Rural Men) 

case-control study included 182 NHL cases assayed for the t(14;18) translocation. This translocation is a 

common somatic mutation associated with B cell CLL/lymphoma-2 gene expression. Controls consisted 

of 30 participants who did not report use of toxaphene on farms where they worked. The study authors 

mentioned that chromosomal damage has been reported to be higher in peripheral blood lymphocytes 

during the peak spraying season (Schroeder et al. 2001). This study is limited by the small numbers of 

cases and controls. 

In an agricultural health study of 22,409 subjects assessed by interview and/or questionnaire for total 

lifetime exposure days to various pesticides, a statistically significant increased risk for rectal cancer 

(RR=2.0, 95% CI=1.1–3.5) was noted among those with self-reported exposure to toxaphene; the risk was 

independent of age (Purdue et al. 2006). However, no statistically significant association was found 

between toxaphene exposure and risk of leukemia or NHL within this study group. 

No studies were located regarding cancer effects in animals following inhalation exposure to toxaphene. 

3.2.2 Oral Exposure 

Toxaphene is toxic following short-term, high-dose oral exposure. Several cases of fatal and nonfatal 

poisoning have been reported in humans following the accidental or intentional ingestion of toxaphene or 

food contaminated with large amounts (gram quantities) of toxaphene. In such instances of acute 

poisoning, toxaphene stimulates the central nervous system like other chlorinated hydrocarbon pesticides. 

Long-term animal studies indicate that toxaphene causes central nervous system toxicosis and hepatic 

hypertrophy accompanied by increased microsomal enzyme activity and histological changes in liver 

cells. The kidneys, spleen, immunological system, and adrenal gland have also been identified as targets 

of toxaphene toxicity. 

3.2.2.1 Death 

Ingestion of large doses of toxaphene by humans can be fatal. Six case studies of acute poisoning were 

reported, three of which (all children) were fatal (McGee et al. 1952). In all cases, an unknown quantity 

of toxaphene was ingested, either alone or as a residue of spray on food. Symptoms were usually abruptly 

manifested by 7 hours post-ingestion and consisted of intermittent convulsions, generally without 

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TOXAPHENE 25 

3. HEALTH EFFECTS 

abdominal pain, vomiting, or diarrhea. Death was attributed to respiratory failure resulting from the 

seizures. An approximate minimum lethal dose in humans was estimated to be 2–7 g (CDC 1963); 

however, the available report did not provide a basis for the estimate. 

In animals, single-dose gavage administration of toxaphene resulted in estimated oral LD50 values of 80– 

293 mg/kg for rats (Boyd and Taylor 1971; Gaines 1969; Jones et al. 1968) and 25 mg/kg for dogs 

(Lackey 1949). A 300 mg/kg dose was reported to be lethal to male guinea pigs within 72 hours 

postdosing; the study authors indicated that the 300 mg/kg dose represented an LD50 dose level, but did 

not provide more detailed dosing information (Chandra and Durairaj 1995). Gavage administration of 

toxaphene to heifers (136–232 kg) at 50, 100, or 150 mg/kg resulted in 2/8, 6/7, and 5/6 deaths, 

respectively (Steele et al. 1980). 

Mortality was also reported in animals following repeated gavage dosing. Epstein et al. (1972) observed 

the death of 2/12 and 9/12 male mice administered toxaphene by daily gavage on 5 consecutive days at 

40 and 80 mg/kg, respectively. Chernoff and Carver (1976) administered toxaphene to rat and mouse 

dams on gestation days 7–16 at gavage doses of 0 (vehicle controls), 15, 25, or 35 mg/kg/day. Mortality 

was noted in 0/33, 2/39, 3/39, and 5/16 of the rat dams (0, 15, 25, and 35 mg/kg/day dose levels, 

respectively) and 1/75, 0/26, 0/45, and 07/90 of the mouse dams. In a separate study, Chernoff et al. 

(1990) observed mortality in 50% of the rat dams (n~25) administered toxaphene at 32 mg/kg/day during 

gestation days 6–15. In a 28-day oral toxicity study, Waritz et al. (1996) administered toxaphene (in corn 

oil) by daily gavage to a group of 40 male rats. An initial dose level of 100 mg/kg/day was reduced to 

75 mg/kg/day after 2/40 of the treated rats died after three doses; no additional unscheduled deaths were 

observed. No treatment-related deaths were observed in pregnant rats administered 6 mg/kg/day by 

gavage from gestational day 7 to parturition (Crowder et al. 1980). 

The vehicle used to deliver toxaphene may influence its toxicity (Lackey 1949). Among groups of dogs 

administered toxaphene once via gavage in corn oil at 15, 20, 25, 30, 40, or 50 mg/kg, mortalities were 

noted in 2/8, 1/5, 6/7, 4/7, 3/7, and 5/5 animals, respectively. However, when toxaphene was 

administered in kerosene (a poorly absorbed solvent) at 25–250 mg/kg, mortalities were observed only at 

doses ≥200 mg/kg. 

The nutritional status of an animal influences its susceptibility to the lethal effects of ingested toxaphene. 

Boyd and Taylor (1971) found that the oral LD50 for rats fed a protein-deficient diet was 80 mg/kg/day, 

whereas the oral LD50 for rats fed a control diet was 220 mg/kg/day. This has important implications for 

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TOXAPHENE 26 

3. HEALTH EFFECTS 

the possible increased susceptibility of humans who ingest a protein-deficient diet and live in areas of 

potential exposure to toxaphene. 

No treatment-related deaths were observed in a one-generational two-litter study of rats administered 

toxaphene in the diet for 48 weeks at estimated doses up to 46 mg/kg/day (Chu et al. 1988). The lack of 

lethality at a dietary dose within the range of LD50 doses noted previously is likely a reflection of 

differences in dose rate (i.e., bolus gavage dosing versus a slower dose rate from feeding). Treatmentrelated mortality was not observed in rats following gavage administration of 6 mg/kg/day for 21 days 

(Crowder et al. 1980). In a 6-week range-finding study that employed groups of male and female 

B6C3F1 mice (5/sex/group), estimated toxaphene doses of 58 and 115 mg/kg/day to males resulted in 

1/5 and 2/5 deaths, respectively; estimated toxaphene doses of 62 and 125 mg/kg/day to females resulted 

in 1/5 and 4/5 mortalities, respectively (NCI 1979). In similarly-treated Osborne-Mendel rats, estimated 

doses of 112 and 224 mg/kg/day to males resulted in 0/5 and 1/5 deaths, respectively; estimated doses of 

121 and 242 mg/kg/day to females caused 0/5 and 2/5 deaths, respectively. In a subsequent cancer 

bioassay in which toxaphene was administered in the diet to Osborne-Mendel rats and B6C3F1 mice for 

80 weeks, estimated TWA doses as high as 83 and 34 mg/kg/day, respectively, did not appear to 

significantly affect survival (NCI 1979). No treatment-related mortality was observed in parental male or 

female Sprague-Dawley rats administered toxaphene in the diet for up to 42 weeks at estimated doses up 

to 8.6 mg/kg/day (males) or 9.8 mg/kg/day (females) (Kennedy et al. 1973). 

The LD50 values and doses associated with death in each species following acute and intermediate oral 

exposure are recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.2 Systemic Effects 

No studies were located regarding musculoskeletal effects following oral exposure of humans or animals 

to toxaphene. The systemic effects of oral toxaphene exposure are described below. 

The highest NOAEL values and all reliable LOAEL values for each species and duration of exposure for 

each systemic effect are recorded in Table 3-2 and plotted in Figure 3-2. 

Respiratory Effects. Available information regarding respiratory effects in humans following oral 

exposure to toxaphene is limited to an account of congestion and edema of the lungs at autopsy of a 

2-year-old boy who ingested an unspecified but lethal amount of toxaphene (McGee et al. 1952). 

***DRAFT FOR PUBLIC COMMENT*** 
23

220

28

80

29

293

402

35

400

32

49

9080

42

283

411

35

46

40

Table 3-2 Levels of Significant Exposure to Toxaphene - Oral 

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Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

ACUTE EXPOSURE Death 

1 Rat once 220 M (Wistar) (GO) 

2 Rat once 80 M (Wistar) (GO) 3 Rat once 293 M (Wistar) (GO) 4 Rat Gd 7-16 1x/d 35 F (CD) (GO) 5 Rat Gd 6-15 1x/d 32 F (Sprague- (GO)

Dawley)

6 Rat once 90 M (Sherman) (GO) 

80 F 

7 Rat once 283 (NS) (G) 

8 Mouse Gd 7-16 1x/d 35 F (CD-1) (GO) 9 Mouse 5 d 1x/d 40 M (ICR/Ha (G)

Swiss)

(LD50 for standard 

laboratory chow diet) 

(LD50 low protein diet) (LD50 for normal-protein 

diet) 

(5/16 maternal deaths) (50% maternal lethality) (LD50) (LD50) (LD50) (7/90 maternal deaths) (death; 2/12) 

Reference Chemical Form 

Boyd and Taylor 1971 Boyd and Taylor 1971 Boyd and Taylor 1971 Chernoff and Carver 19Chernoff et al. 1990 Gaines 1969 Jones et al. 1968 Chernoff and Carver 19Epstein et al. 1972 
630

300

74

15

77

200

401

35

15

202

32

90

10

646

147

130

Table 3-2 Levels of Significant Exposure to Toxaphene - 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 

10 Gn Pig 

(NS) 

once (GO) 300 M (death) Chandra and Durairaj 1

11 Dog 

(NS) 

once (GO) 15 (death of 2/8 dogs) Lackey 1949 

12 Dog 

(NS) 

Systemic 

13 Rat 

(CD) 

once (GO) Gd 7-16 1x/d (GO) Hepatic 

Bd Wt 

35 F 

200 (death in 1/5 dogs) 

15 F (22% reduced maternal 

weight gain) 

Lackey 1949 Chernoff and Carver 19

14 Rat 

(SpragueDawley) 

Gd 6-15 1x/d (GO) Bd Wt 32 F (up to 50% depressed maternal weight gain) Chernoff et al. 1990 

15 Rat 

(SpragueDawley) 

8 d ad lib (F) Hepatic 10 M (23% decline in biliary excretion of imipramine 

metabolites) 

Mehendale 1978 

16 Rat 

(OsborneMendel) 

80 wk ad lib (F) Bd Wt 147 F 130 M (14% lower mean body weight) NCI 1979 

***DRAFT FOR PUBLIC COMMENT***
111

120

543

13.5

18

18

632

75

410

15

15

25

635

25

50

100

197

300300

Table 3-2 Levels of Significant Exposure to Toxaphene - Oral (continued) 

LOAEL 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

***DRAFT FOR PUBLIC COMMENT***

Hepatic 120 M (9% increased relative Peakall 1976 

liver weight) 

Hepatic 13.5 M 18 M (20% increased relative Trottman and Desaiah 1

liver weight) 

Bd Wt 18 M Endocr 75 M (increased TSH; thyroid Waritz et al. 1996 

histopathology) 

Hepatic 15 F (23% increased relative Chernoff and Carver 19

liver weight) 

Bd Wt 15 F 25 F (22% depressed body 

weight gain) 

Hepatic 25 M 50 M (48% increased relative Hedli et al. 1998 

liver weight) toxaphene 

Bd Wt 100 M Hepatic 300 M Chandra and Durairaj 1

Renal 300 M 

a 

Key to Species 

Figure (Strain) 

17 Rat 

(NS) 

18 Rat 

(SpragueDawley) 

19 Rat 

(SpragueDawley) 

20 Mouse 

(CD-1) 

21 Mouse 

(CD-1) 

22 Gn Pig 

(NS) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

once (C) 14 d ad lib (F) 14 d 1 x/d (GO) Gd 7-16 1x/d (GO) 7 d 1 x/d (GO) once (GO) 
121

9

13.5

117

25

636

300

611

5

10

75

5 10

527

50

201

32

Table 3-2 Levels of Significant Exposure to Toxaphene - 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 

Immuno/ Lymphoret 

23 Rat 

(SpragueDawley) 

14 d ad lib (F) 9 M 13.5 M (36% decreased relative thymus weight) Trottman and Desaiah 1

Neurological 

24 Rat 

(SpragueDawley) 

3 d 1x/d (GO) 25 M (mild tremors, nervousness) Rao et al. 1986 

25 Gn Pig 

(NS) 

once (GO) 300 M (sedation, convulsions) Chandra and Durairaj 1

26 Dog 

(Beagle) 

13 wk (C) 

b

5 10 (convulsions, salivation, 

and vomiting in 1/6 males and 2/6 females) 

Chu et al. 1986 

27 Dog 

(NS) 

once (GO) 5 10 (convulsions) Lackey 1949 

28 Bovine 

(Mixedbreed) 

Developmental 

29 Rat 

(SpragueDawley) 

once (GW) Gd 6-15 1x/d (GO) 32 (significantly increased incidence of fetal 

supernumerary ribs) 

50 (convulsions) Steele et al. 1980 

Chernoff et al. 1990 

***DRAFT FOR PUBLIC COMMENT***
10

12.5

6

35

99

224242

97

57.731.2

645

1

Table 3-2 Levels of Significant Exposure to Toxaphene - 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 

30 Rat 

(CD) 

Gd 7-16 1x/d (GO) 12.5 F (decreased fetal renal protein) Kavlock et al. 1982 

31 Mouse 

(CD-1) 

Gd 7-16 1x/d (GO) 

INTERMEDIATE EXPOSURE Death 

32 Rat 

(OsborneMendel) 

6 wk ad lib (F) 

35 F 

224 M (death in 1/5 males) 242 F (death of 2/5 females) 

Chernoff and Carver 19NCI 1979 

33 Mouse 

(B6C3F1) 

6 wk ad lib (F) 57.7 M (death of 1/5 males) 

31.2 F (death of 1/5 females) 

NCI 1979 

Systemic 

34 Monkey 

(Cynomolgus) 

52 wk 1 x/d (C) 

Ocular 1 (inflammation and/or 

enlargement of tarsal glands during treatment weeks 8-13; impacted diverticulae of eyelids during treatment weeks 10-41) 

Bryce et al. 2001 

***DRAFT FOR PUBLIC COMMENT***
643

45.9630.350.5

1.82.6

0.35 1.8

0.5

8.645.912.6

0.3512.6

1.863

45.963

Table 3-2 Levels of Significant Exposure to Toxaphene - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

35 Rat 

(SpragueDawley) 

13 wk ad lib (F) Hemato 45.9 M 

63 F 

Chu et al. 1986 

Hepatic 0.35 M 

0.5 F 

1.8 M (nuclear necrosis, 

anisokaryosis) 

2.6 F (nuclear necrosis, 

anisokaryosis) 

Renal 0.35 M 1.8 M (tubular injury) 

0.5 F (tubular necrosis, 

anisokaryosis) 

8.6 M (focally severe tubular 

injury) 

45.9 M (multiple and relatively 

severe kidney lesions) 

12.6 F (focally severe tubular 

injury) 

Endocr 0.35 M 

12.6 F 

1.8 M (moderate morphological 

changes in thyroid) 

63 F (moderate morphological 

changes in thyroid) 

Bd Wt 45.9 M 

63 F 

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12

454645469.28.5

4546

9.28.5

4546

4546

36

6

Table 3-2 Levels of Significant Exposure to Toxaphene - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

36 Rat 

(SpragueDawley) 

26 wk ad lib (F) Hemato 45 M 

46 F 

Chu et al. 1988 

Hepatic 45 M 

46 F 

Renal 9.2 M 

8.5 F 

45 M (18% increased kidney 

weight, increased incidence of tubular injury) 

46 F (increased incidence of 

renal tubular injury) 

Endocr 9.2 M 

8.5 F 

45 M (cytoplasmic vacuolation 

in thyroid) 

46 F (cytoplasmic vacuolation 

in thyroid) 

Bd Wt 45 M 

46 F 

37 Rat 

(SpragueDawley) 

21 d 1x/d (GO) Bd Wt 6 Crowder et al. 1980 

***DRAFT FOR PUBLIC COMMENT***
16

8.69.82.22.5

8.69.8

8.69.88.69.88.69.8

66

2.6

26

2626

100

224242

Table 3-2 Levels of Significant Exposure to Toxaphene - Oral (continued) 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

***DRAFT FOR PUBLIC COMMENT***

8.6 M Kennedy et al. 1973 9.8 F 

2.2 M 8.6 M (cytoplasmic vacuolation) 

2.5 F 9.8 F (cytoplasmic vacuolation) 8.6 M 9.8 F 8.6 M 9.8 F 8.6 M 9.8 F 2.6 M 26 M (24% liver weight Koller et al. 1983 

increase and hepatic degeneration) 

26 M 26 M 

224 M NCI 1979 242 F 

Exposure/ 

Duration/ 

Frequency 

(Route) 

39-42 wk ad lib (F) 6-9 wk ad lib (F) 6 wk ad lib (F) 

a 

Key to 

Figure 

38 39 40 

Species 

(Strain) 

Rat (SpragueDawley) Rat (SpragueDawley) Rat (OsborneMendel) 

System 

Cardio Hepatic Renal Endocr Bd Wt Hepatic Endocr Bd Wt Bd Wt 
107

2022.62022.6

633

75

18

3939392

19.5

393939

98

57.7

Table 3-2 Levels of Significant Exposure to Toxaphene - Oral (continued) 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

***DRAFT FOR PUBLIC COMMENT***

20 M Ortega et al. 1957 

22.6 F 

20 M 

22.6 F 

75 M (increased TSH; thyroid Waritz et al. 1996 

histopathology) 

39 F Allen et al. 1983 

39 F 39 F 

2 F 19.5 F (increased relative liver 

weight, variation in cell size with some fatty infiltration) 

39 F 39 F 39 F 

57.7 M NCI 1979 

a 

Key to Species 

Figure (Strain) 

41 Rat 

(Sherman) 

42 Rat 

(SpragueDawley) 

43 Mouse 

(Swiss Webster) 

44 Mouse 

(B6C3F1) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

up to 9 mo ad lib (F) 28 d 1 x/d (GO) 8 wk ad lib (F) 6 wk ad lib (F) 

System 

Renal Bd Wt Endocr Resp Cardio Gastro Hepatic Renal Endocr Bd Wt Bd Wt 
33

52

5

55

631

1

634

0.1

0.4

617

8.69.8

Table 3-2 Levels of Significant Exposure to Toxaphene - 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 

45 Dog 

(Beagle) 

13 wk 7 d/wk 1x/d (C) 

Hemato 5 Chu et al. 1986 

Hepatic 2 5 (increased liver weight, 

increased serum alkaline phosphatase, hepatomegaly) 

Renal 5 

Immuno/ Lymphoret 

46 Monkey 

(Cynomolgus) 

52 wk 1 x/d (C) 

Bd Wt 5 

1 Tryphonas et al. 2000 

47 Monkey 

(Cynomolgus) 

Up to 75 wk 1 x/d (C) 

0.1 F 

c

0.4 F (depressed humoral 

immunity) 

Tryphonas et al. 2001 

48 Rat 

(SpragueDawley) 

39-42 wk ad lib (F) 8.6 M 

9.8 F 

Kennedy et al. 1973 

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65

2.6

17

2

19.5

35

6

618

4

11

46

15

8.69.8

508

4.9

Table 3-2 Levels of Significant Exposure to Toxaphene - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

9 wk ad lib (F) 2.6 M (46% decreased IgG primary antibody 

response at day 15 postimmunization) 

Koller et al. 1983 

8 wk ad lib (F) 

2 F 19.5 F (depressed humoral 

immunity) 

Allen et al. 1983 

21 d 1x/d (GO) 6 Crowder et al. 1980 

44 or 106 d 1x/d (C) 

4 (convulsions) Lackey 1949 

48 wk ad lib (F) 46 Chu et al. 1988 

39-42 wk ad lib (F) 8.6 M 

9.8 F 

Kennedy et al. 1973 

multigen (F) 4.9 F Keplinger et al. 1970 

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a 

Key to Species 

Figure (Strain) 

49 Rat 

(SpragueDawley) 

50 Mouse 

(Swiss Webster) 

Neurological 

51 Rat 

(SpragueDawley) 

52 Dog 

(NS) 

Reproductive 

53 Rat 

(SpragueDawley) 

54 Rat 

(SpragueDawley) 

55 Mouse 

(Swiss) 
614

6

1

2

19.5

639

0.80.8

626

11111111

Table 3-2 Levels of Significant Exposure to Toxaphene - Oral (continued) 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

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6 (transiently delay in Crowder et al. 1980 

development of righting reflex) 

2 19.5 (suppression of Allen et al. 1983 

macrophage phagocytic function) 

0.8 F Arnold et al. 2001 

0.8 F 

1 Bryce et al. 2001 

1 

1 

1 1 1 1 

1 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

Developmental 

56 Rat Gd 7-21 1x/d 

(SpragueDawley) (GO) 

57 Mouse 9.5 wk ad lib 

(Swiss (F) Webster) 

CHRONIC EXPOSURE Systemic 

58 Monkey 75 wk 

1 x/d (Cynomolgus) (C) 

59 Monkey 52 wk 

1 x/d (Cynomolgus) (C) 

System 

Hemato Bd Wt Resp Cardio Gastro Hemato Hepatic Renal Endocr Bd Wt 
106

3939

77.983.3

3939

77.9

41.6

102

171717

34

Table 3-2 Levels of Significant Exposure to Toxaphene - 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 

60 Rat 

(OsborneMendel) 

80 wk ad lib (F) Resp 39 M (dyspnea, epistaxis) NCI 1979 

Gastro 39 M (abdominal distension, 

diarrhea) 

Hepatic 77.9 M 

83.3 F 

Renal Dermal 

39 M (hematuria) 39 M (alopecia, dermatitis, 

rough hair coats) 

Bd Wt 77.9 M 41.6 F (up to 15% lower mean 

body weight) 

61 Mouse 

(B6C3F1) 

80 wk ad lib (F) Resp 17 (dyspnea) NCI 1979 

Gastro 17 (abdominal distension, 

diarrhea) 

Dermal 17 (alopecia, rough hair 

coat) 

Bd Wt 34 

***DRAFT FOR PUBLIC COMMENT***
644

0.4

0.8

628

1

104

3941.6

619

34 17

640

0.8

629

1

Table 3-2 Levels of Significant Exposure to Toxaphene - 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 

Immuno/ Lymphoret 

62 Monkey 

(Cynomolgus) 

Up to 75 wk 1 x/d (C) 

0.4 F 0.8 F (depressed humoral 

immunity) 

Tryphonas et al. 2001 

Neurological 

63 Monkey 

(Cynomolgus) 

52 wk 1 x/d (C) 

1 Bryce et al. 2001 

64 Rat 

(OsborneMendel) 

80 wk ad lib (F) 39 M (leg paralysis, ataxia, epistaxis) NCI 1979 

41.6 F (leg paralysis, ataxia, 

epistaxis) 

65 Mouse 

(B6C3F1) 

80 wk ad lib (F) 34 F 17 M (hyperexcitability) NCI 1979 

Reproductive 

66 Monkey 

(Cynomolgus) 

75 wk 1 x/d (C) 

0.8 F Arnold et al. 2001 

67 Monkey 

(Cynomolgus) 

52 wk 1 x/d (C) 

1 Bryce et al. 2001 

***DRAFT FOR PUBLIC COMMENT***
105

41.6

404

77.983.3

405

1717

Table 3-2 Levels of Significant Exposure to Toxaphene - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

68 Rat 

(Osborne80 wk ad lib (F) 41.6 F (vaginal bleeding) 

Mendel) 

Cancer 

69 Rat 

(OsborneMendel) 

80 wk ad lib (F) 77.9 M (CEL: follicular -cell carcinomas, thyroid 

adenomas) 

83.3 F (CEL: thyroid adenomas) 

70 Mouse 

(B6C3F1) 

80 wk ad lib (F) 17 M (CEL: hepatocellular carcinoma) 

17 F (CEL: hepatocellular 

carcinoma or neoplastic nodule) 

Reference Chemical Form 

NCI 1979 NCI 1979 NCI 1979 

a The number corresponds to entries in Figure 3-2. b Used to derive an acute-duration oral minimal risk level (MRL) of 0.05 mg/kg/day; dose divided by an uncertainty factor of 100 (10 for extrapolation from animals tfor human variability). c Used to derive an intermediate-duration oral minimal risk level (MRL) of 0.002 mg/kg/day; the BMDL1SD of 0.22 mg/kg/day, based on benchmark dose analysis otiters as an indicator of humoral immunity, was divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). ad lib = ad libitum; Bd Wt = body weight; (C) = capsule; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; (F)= feed; F = Female; Gastro = gastrointestinal; Gd = gestation day; (GO) = gavage in oil; (GW) = gavage in water; Hemato = hematological; Immuno/Lymphoret = immunological/lympholethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; mo = month(s); NOAEL = no-observed-adverse-effect level; NS = not specified; x = week(s) 
D

HREBIND

1000 

mg/kg/day 

10g 3r 7r 22g 22g 25g

1r 12d 

16r 16r 17r 100 6r 21m

2r 6r 19r 

21m 28c 

9m 8m 4r 5r 13r 14r 31m 29r 

21m 20m 24r 

18r 18r 11d 20m 20m 13r 18r 23r 30r 

10 15r 26d 27d 23r 

26d 27d 

1 

0.1 

0.01 

c-Cat 

d-Dog

r-Rat 

p-Pig

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

eath 

epatic 

enal 

ndocrine 

ody Weight 

mmuno/Lymphor 

eurological 

evelopmental 

Figure 3-2 Levels of Significant Exposure to Toxaphene - Oral
	

Acute (≤14 days)
	 TOXAPHENE

3. HEALTH EFFECTS

42

***DRAFT FOR PUBLIC COMMENT***

Systemic
	

q-Cow a-Sheep g-Guinea Pig Cancer 
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Hepatic 

Systemic 

mg/kg/day 

1000 

32r 32r 

33m 35r 

35r 36r 36r 36r 36r 43m 43m 43m 33m 3

43m 

38r 3

45d 

38r 38r 

45d 

35r 38r 3 38r 45d 43m 35r 

1
	

35r
	

35r 

100

10

0.1

0.01

0.001

Renal 

TOXAPHENE

3. HEALTH EFFECTS

43

***DRAFT FOR PUBLIC COMMENT***

Figure 3-2 Levels of Significant Exposure to Toxaphene - Oral (Continued)
 

Intermediate (15-364 days)
	

35r 36r 36r 43m

9r 41r 41r 

35r 

8r 36r 38r 35r 36r 38r 

45d 

9r

35r 

35r 

35r 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Endocrine 

Ocular Body Weight Immuno/Lymphor Neurological Reproductive Developmental 

1000 

Systemic
	

mg/kg/day 

40r 40r 

100 

42r 35r 44m 35r

36r 36r 35r 36r 36r 53r 43m 43m 

39r 39r 41r 41r 50m 57m 

35r 10 36r 38r 38r 48r 54r 36r 38r 38r 48r 54r

37r 51r 56r 45d 55m 52d 

49r 

35r 50m 57m

1 34k 46k 

47k 35r 

0.1 47k 

0.01 

0.001 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

Figure 3-2 Levels of Significant Exposure to Toxaphene - Oral (Continued)
 

Intermediate (15-364 days)
	 TOXAPHENE

3. HEALTH EFFECTS

44

***DRAFT FOR PUBLIC COMMENT***
 

60r 60r 

60r 60r 60r 

61m 61m 

59k 59k 59k 59k 59k 59k 58k 

*Doses represe

response and d

-Cat 

-Dog

Rat 

-Pig

-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer E

 LOAEL, 

LOAEL, 

NOAEL - 

Respiratory Cardiovascular Gastrointestinal Hematological Hepatic Ren

100 

Systemic
	

mg/kg/day 

10 

1 

0.1 

0.01 

0.001 

0.0001 

1E-5 

1E-6 

1E-7 

1E-8 

c

d

rp

q

 

 

60r 69r 

60r 61m 60r 65m 64r 64r 68r 

61m 65m 70m 70m

59k 59k 63k 67k 58k 62k 66k 

62k 

-4 10 

-5 10 

-6 10 

-7 10 

nt the lowest dose tested per study that produced a tumorigenic 

o not imply the existence of a threshold for the cancer endpoint. 

Estimated 

Upper-Bou

Human Ca

Risk Levels

nd

ncer 

ffect Level-Animals

More Serious-Animals

Less Serious-Animals

Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk L

 for effects

 other than

 Cancer 

al 

Endocrine 

Dermal Body Weight Immuno/Lymphor Neurological Reproductive Cancer * 

Figure 3-2 Levels of Significant Exposure to Toxaphene - Oral (Continued)
 

Chronic (≥365 days)
	 TOXAPHENE

3. HEALTH EFFECTS

45

***DRAFT FOR PUBLIC COMMENT***

69r 

evel
 

 

 

 

 

 

 

 

 

TOXAPHENE 46 

3. HEALTH EFFECTS 

In rats, the acute oral administration of toxaphene has been shown to cause congestion and parenchymal 

hemorrhage, indicative of a generalized inflammatory response (Boyd and Taylor 1971). The study was 

limited by the fact that the dose was not specified. The chronic administration of toxaphene in feed to rats 

or mice at doses of 27 and 12.9 mg/kg/day, respectively, has been shown to cause dyspnea (NCI 1979). 

Bryce et al. (2001) noted no remarkable histopathology following examination of tissues (including lung 

tissue) from cynomolgus monkeys administered toxaphene by oral capsule at 1 mg/kg/day for 52 weeks. 

Cardiovascular Effects. Available information regarding cardiovascular effects in humans 

following oral exposure to toxaphene is limited to a report of dilatation of the heart at autopsy of a 

2-year-old boy who ingested an unspecified but lethal amount of toxaphene (McGee et al. 1952). 

Available information in animals is limited. Congestion and hemorrhage of cardiac capillaries were 

observed in rats that died following single gavage administration of an unspecified dose of toxaphene 

(Boyd and Taylor 1971). These effects are indicative of a generalized inflammatory response. Increased 

heart rate, in the absence of apparent effects on the vascular system, was noted in dogs following 

administration of a 10 mg/kg dose of toxaphene (Lackey 1949). Progressive neural degeneration was 

noted in the hearts of pregnant rats following daily gavage administration of toxaphene at 12 mg/kg/day 

during pregnancy (Badaeva 1976). However, the methods used to identify the lesions in this study are not 

well described and the effects were not quantitatively evaluated. 

No treatment-related effects on heart weight were observed in rats fed toxaphene in the diet for 14 days at 

10 mg/kg/day (Trottman and Desaiah 1980) or up to 42 days at 8.6 mg/kg/day (males) or 9.8 mg/kg/day 

(females) (Kennedy et al. 1973). Bryce et al. (2001) noted no remarkable histopathology following 

examination of tissues (including heart tissue) from cynomolgus monkeys administered toxaphene by oral 

capsule at 1 mg/kg/day for 52 weeks. 

Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans 

following oral exposure to toxaphene. 

Gastric ulcers and local gastroenteritis (an inflammatory reaction) were observed in rats administered a 

single unspecified oral dose of toxaphene (Boyd and Taylor 1971). In this study, animals fed a low 

protein (3.5%) diet had a greater incidence of toxaphene-induced gastritis than rats fed normal chow or a 

test diet with normal protein content, in keeping with the apparent Adiet-dependency@ of toxaphene 

toxicity. Abdominal distension and diarrhea were observed in rats and mice receiving toxaphene from the 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

TOXAPHENE 47 

3. HEALTH EFFECTS 

diet during 80 weeks at doses ≥39 mg/kg/day (rats) or ≥17 mg/kg/day (mice) (NCI 1979). These effects 

were most prominent in the high-dose (78 mg/kg/day) male rats. Bryce et al. (2001) noted no remarkable 

histopathology following examination of tissues (including esophagus, stomach, and small and large 

intestine) from cynomolgus monkeys administered toxaphene by oral capsule at 1 mg/kg/day for 

52 weeks. 

Hematological Effects. No studies were located regarding hematologic effects in humans following 

oral exposure to toxaphene. 

No adverse effects on standard hematological parameters were noted in dogs dosed with up to 

5 mg/kg/day by capsule for 13 weeks (Chu et al. 1986); dogs dosed with 4 mg/kg/day by capsule for 44 or 

106 days (Lackey 1949); male and female rats receiving toxaphene from the diet for 13 weeks at 

estimated doses of 45.9 or 63 mg/kg/day, respectively (Chu et al. 1986); or male rats receiving 

45 mg/kg/day from the diet for 26 weeks (Chu et al. 1988). There was no evidence of treatment-related 

hematological effects in cynomolgus monkeys administered toxaphene in oral capsules at 1 mg/kg/day for 

52 weeks (Bryce et al. 2001) or 0.1–0.8 mg/kg/day for up to 75 weeks (Arnold et al. 2001). 

Abnormalities in the blood-forming elements were observed in the spleens of rats that died following the 

oral administration of a single unspecified dose of toxaphene; the study authors attributed this to a 

generalized stress reaction (Boyd and Taylor 1971). 

Hepatic Effects. Little information was located regarding hepatic effects in humans following oral 

exposure to toxaphene. Transiently-elevated liver lactate dehydrogenase and serum glutamic oxaloacetic 

transaminase indicative of reversible liver injury were observed in a 26-year-old man who attempted 

suicide by ingesting the insecticide Tox-Sol, which contains toxaphene as the active ingredient (Wells and 

Milhorn 1983). 

Oral administration of toxaphene has been shown to result in increased liver weight in some studies of 

rats and mice (Allen et al. 1983; Chernoff and Carver 1976; Chu et al. 1986, 1988; Hedli et al. 1998; 

Koller et al. 1983; Peakall 1976). 

Chandra and Durairaj (1992) reported 13% increased absolute (but not relative) liver weight in guinea 

pigs administered a single gavage dose of toxaphene at 300 mg/kg (in groundnut oil) in the absence of 

indications of treatment-related histopathologic liver lesions. In a subsequent study by the same 

investigators (Chandra and Durairaj 1995), a similar exposure scenario resulted in significantly decreased 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

TOXAPHENE 48 

3. HEALTH EFFECTS 

hepatic phospholipid content and significantly increased hepatic neutral lipid content. Similar effects 

were noted in other guinea pigs receiving toxaphene by gavage at 5 mg/kg/day for 60 days (Chandra and 

Durairaj 1995). 

Inhibition of hepatobiliary function was reported in perfused livers from male rats exposed to 

5 mg/kg/day toxaphene in feed for 8 days (Mehendale 1978). Induction of hepatic microsomal enzymes 

and increased liver weights were noted in male rats given 120 mg/kg/day by capsule or 10 mg/kg/day in 

feed for 14 days (Peakall 1976; Trottman and Desaiah 1980). Increased gamma-glutamyl transpeptidase 

(GGTP) activity was observed in male rat liver plasma membranes and blood serum after a single gavage 

exposure to 110 mg/kg toxaphene (Garcia and Mourelle 1984). Increased hepatic microsomal activity 

(aminopyrene, ethoxyresorufin, and methoxyresorufin) was noted in male and female cynomolgus 

monkeys (two per sex) administered toxaphene in glycerol/corn oil via gelatin capsule at 1 mg/kg/day for 

52 weeks compared to vehicle controls (Bryce et al. 2001). However, the majority of these studies did 

not report any other evidence of hepatic toxicity. Therefore, enzyme induction in the absence of other 

signs of liver toxicity is not generally considered adverse, but enzyme induction may precede the onset of 

more serious hepatic effects. 

Morphological and degenerative changes were observed in the livers of dogs (Chu et al. 1986; Lackey 

1949), rats (Chu et al. 1988; Kennedy et al. 1973; Koller et al. 1983; Ortega et al. 1957), and mice (Allen 

et al. 1983) following intermediate-duration exposure to 4, 5–45, and 13 mg/kg toxaphene, respectively. 

These changes included generalized hydropic degenerative changes, cytoplasmic vacuolization, 

centrilobular cell hypertrophy, peripheral migration of basophilic cytoplasmic granules, and the presence 

of lipospheres. Hepatic enzyme induction was also observed in rats following intermediate exposure to 

toxaphene at 2.4 mg/kg/day (Peakall 1976) or 16.5 mg/kg/day (Garcia and Mourelle 1984). The study of 

Peakall (1976) did not include a concurrent control group. Toxaphene may also induce hypoxia and alter 

hepatic energy metabolism because it has been shown to decrease lactate dehydrogenase activity (Gertig 

and Nowaczyk 1975; Kuz'minskaya and Alekhina 1976). The intermediate-duration oral administration 

of 2 mg/kg/day toxaphene to dogs caused increased relative liver weight, hepatomegaly, and hepatocellular cytoplasmic vacuolation (Chu et al. 1986). This study is limited by the fact that the high-dose 

dogs were inadvertently fed the wrong dose for part of the study period. In rats, biochemical and 

histological evidence of toxaphene-induced liver toxicosis was observed in F0 male and female rats fed 

toxaphene at 45 mg/kg/day for at least 26 weeks (Chu et al. 1988). 

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Liver necrosis was observed in dogs chronically administered 5 mg/kg/day toxaphene in the feed (EPA 

1985c; summary of an unpublished report for Boots Hercules Agrochemicals). The unpublished report 

was not available to ATSDR. Histopathologic examinations of livers from male and female rats and mice 

receiving toxaphene from the diet for up to 80 weeks at estimated time-weighted average (TWA) doses as 

high as 78–83 mg/kg/day (rats) and 34 mg/kg/day (mice) revealed no evidence of treatment-related 

nonneoplastic lesions (NCI 1979). See Section 3.2.2.7 for discussion of cancer results from the NCI 

(1979) study. Bryce et al. (2001) noted no remarkable histopathology following examination of tissues 

(including liver) from cynomolgus monkeys administered 1 mg/kg/day of toxaphene by oral capsule for 

52 weeks. 

Renal Effects. Little information was available regarding renal effects in humans following oral 

exposure to toxaphene. Renal function was temporarily compromised in a 26-year-old man who 

attempted suicide by ingesting an unknown quantity of a toxaphene-containing pesticide (Wells and 

Milhorn 1983). Swelling of the kidney was observed in a 2-year-old boy following acute exposure to a 

lethal amount of toxaphene (McGee et al. 1952). 

Toxaphene has been shown to be nephrotoxic in laboratory animals. A single unspecified, but lethal, oral 

dose of toxaphene induced cloudy swelling of the proximal and distal convoluted tubules and congestion 

of the loop of Henle in rats (Boyd and Taylor 1971). However, no renal effects were seen in male rats 

exposed to up to 10 mg/kg/day of toxaphene in feed for 14 days (Trottman and Desaiah 1980). Renal 

injury has also been reported to occur following intermediate exposure to toxaphene. Guinea pigs given 

toxaphene orally at 2 or 5 mg/kg/day for 60 days exhibited histopathologic lesions that included intense 

vacuolation in the kidney's collection cells and glomerulus, cortical tubule cellular degeneration, and 

tubular epithelial cell vacuolation (Chandra and Durairaj 1992). Ultrastructural evaluation revealed an 

increase in the number of mitochondria in the tubular epithelial cells. However, NOAEL and LOAEL 

values for this study were not established because the study report did not include incidence data for the 

kidney lesions. Dose-dependent injuries of the proximal convoluted tubules that were focally severe were 

observed in rats fed 8.6 (males) and 12.6 (females) mg/kg/day toxaphene for 13 weeks (Chu et al. 1986). 

Chu et al. (1988) reported 18% increased kidney weight and renal tubular injury in male rats receiving 

toxaphene from the diet for 26 weeks at 45 mg/kg/day and renal tubular injury in similarly-treated female 

rats. However, Ortega et al. (1957) reported that a dose level of 10 mg/kg/day of toxaphene was not 

nephrotoxic to rats. Marked degenerative fatty changes of the kidney tubular epithelium were observed in 

dogs following intermediate-duration exposure to 4 mg/kg/day toxaphene (Lackey 1949). Eosinophilic 

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inclusions that were occasionally accompanied by focal necrosis have also been observed in dogs after 

intermediate exposure to 2 mg/kg/day toxaphene (Chu et al. 1986). 

Hematuria was reported in rats receiving toxaphene from the diet for up to 80 weeks at doses in the range 

of 39–83 mg/kg/day (NCI 1979). Bryce et al. (2001) noted no remarkable histopathology following 

examination of tissues (including kidney and urinary bladder) from cynomolgus monkeys administered 

toxaphene by oral capsule at 1 mg/kg/day for 52 weeks. 

Endocrine Effects. No information was located regarding endocrine effects in humans following 

oral exposure to toxaphene. 

Histopathological evidence of toxaphene-related effects on the thyroid gland (angular collapse of 

follicles, increased epithelial height with multifocal papillary proliferation, and reduced colloid density) 

of male rats was observed following intermediate-duration oral administration at 1.8 mg/kg/day (Chu et 

al. 1986). The morphological changes were dose-dependent, considered mild to moderate in severity, and 

adaptive in nature. The LOAEL for histopathologic thyroid lesions in female rats was 63 mg/kg/day; 

NOAELs were 0.35 mg/kg/day for males and 12.6 mg/kg/day for females. A similarly-designed study by 

Chu et al. (1988) found no evidence of treatment-related histopathological thyroid lesions at 

1.8 mg/kg/day (male rats) and 1.9 mg/kg/day (female rats). 

In a 28-day gavage study designed to assess thyroid function in toxaphene-treated male rats, Waritz et al. 

(1996) reported significant (p<0.05) time-related increases in serum TSH and histopathological evidence 

of treatment-related effects that included increased incidences of thyroid follicular cell hypertrophy, 

diffuse intrafollicular hyperplasia, and decreased follicular size (indicative of depletion of colloid stores). 

This study employed a single dose level of 75 mg toxaphene/kg (100 mg/kg/day for the first 3 treatment 

days); the thyroid effects were considered to be associated with increased excretion of T3 and/or T4 

resulting from the induction of hepatic CYPs. 

In a study of male rats receiving toxaphene from the diet for 14 days, respective mean relative thymus 

weights at estimated doses of 13.5 and 18 mg/kg/day were 36 and 27% lower than that of controls; these 

effects were not seen at doses of 4.5 or 9 mg/kg/day (Trottman and Desaiah 1980). In another rat study, 

dietary exposure at estimated doses up to and including 8.6 mg/kg/day (males) and 9.8 mg/kg/day 

(females) for 39–42 weeks did not affect spleen or thymus weights (Kennedy et al. 1973). 

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Bryce et al. (2001) noted no remarkable histopathology following examination of tissues (including 

thyroid, pituitary, and adrenal glands) from cynomolgus monkeys administered toxaphene by oral capsule 

at 1 mg/kg/day for 52 weeks. 

Dermal Effects. No information was located regarding dermal effects in humans following oral 

exposure to toxaphene. 

Alopecia and rough hair coats were reported in rats and mice receiving toxaphene from the diet for up to 

80 weeks at estimated TWA doses ≥39 and ≥17 mg/kg/day, respectively (NCI 1979). 

Ocular Effects. No information was located regarding ocular effects in humans following oral 

exposure to toxaphene. 

Available information in animals is limited to a report of inflammation and/or enlargement of tarsal 

glands of the eye in three of four cynomolgus monkeys and impacted diverticulae of the eyelid of all four 

monkeys during oral administration of toxaphene at 1 mg/kg/day for 52 weeks (Bryce et al. 2001). 

Body Weight Effects. No information was located regarding body weight effects in humans 

following oral exposure to toxaphene. 

The influence of oral toxaphene on body weight has been widely studied in laboratory animals. Some rat 

studies employed relatively low single- or multiple-dose levels (<20 mg/kg/day) and found no evidence 

of toxaphene-induced body weight effects following acute- or intermediate-duration oral exposure 

(Crowder et al. 1980; Kennedy et al. 1973; Ortega et al. 1957; Trottman and Desaiah 1980). There was 

no evidence of toxaphene-related body weight effects in intermediate-duration multiple-dose studies of 

rats or mice where the highest toxaphene doses ranged from 26 to 39 mg/kg/day (Allen et al. 1983; Chu et 

al. 1986, 1988; Koller et al. 1983). 

NCI (1979) found no evidence of a treatment-related effect on body weight in a range-finding study of 

male and female rats and mice administered toxaphene in the diet for 6 weeks at doses as high as 

242 mg/kg/day (rats) and 250 mg/kg/day (mice). However, in the subsequent chronic study that included 

80 weeks of dietary exposure to toxaphene, groups of male rats receiving toxaphene from the diet at 

131 and 270 mg/kg/day for the first 2 treatment weeks exhibited approximately 14 and 26% lower mean 

body weights, respectively, than their matched controls (NCI 1979). Throughout the remaining 78 weeks 

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of treatment, which included two 50% reductions in toxaphene concentrations (after treatment weeks 2 

and 53 due to clinical signs of neurotoxicity), body weights of the toxaphene-treated male rats appeared 

similar to those of matched controls. Estimated TWA doses of approximately 42 and 83 mg/kg/day to the 

low- and high-dose female rats resulted in lower mean body weights throughout most of the study, as 

much as 10 and 16% lower than those of matched controls (NCI 1979). In the mouse portion of the study 

(estimated toxaphene doses of 17 and 34 mg/kg/day for the low- and high-dose groups, respectively), 

mean body weights of the high-dose males were slightly lower than those of matched controls; there 

appeared to be no treatment-related effects on body weight in low-dose males or low- or high-dose 

females. 

Lackey (1949) reported weight loss during the initial portion of a study in which four dogs were 

administered toxaphene by oral capsule at 4 mg/kg/day for 44 or 106 days; convulsions were seen on 

occasion. Another dog study found no indication of treatment-related effects on body weight during oral 

dosing of toxaphene at 0.2–5 mg/kg/day for 13 weeks (Chu et al. 1986). There were no signs of 

treatment-related effects on body weight in cynomolgus monkeys administered toxaphene by oral capsule 

for 52–75 weeks, but doses were ≤1 mg/kg/day (Arnold et al. 2001; Bryce et al. 2001). 

Available animal data indicate that pregnant rats may be particularly sensitive to toxaphene-induced 

effects on body weight. Rat dams administered toxaphene by gavage at 32 mg/kg/day (the only dose 

level tested) gained only 50% of the weight gained by control rats (Chernoff et al. 1990). In another 

developmental toxicity study, rat dams administered toxaphene by gavage at 15 mg/kg/day (the lowest 

dose tested) on gestation days 7–16 exhibited 22% decreased body weight gain relative to controls 

(Chernoff and Carver 1976). Crowder et al. (1980) found no evidence of treatment-related effects on 

body weight in pregnant rats administered toxaphene at 6 mg/kg/day (the only dose tested) from gestation 

day 7 to parturition. 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects of toxaphene in humans following oral 

exposure. 

Toxaphene has been reported to induce immunosuppressive effects (primarily humoral) in laboratory 

animals. Toxaphene impaired antibody (IgG) production at some, but not all, stages of the IgG response 

in male rats receiving toxaphene from the diet for 9 weeks at an estimated dose of 2.6 mg/kg/day (Koller 

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et al. 1983). Similar results were obtained in female mice receiving toxaphene from the diet for 8 weeks 

at an estimated dose of 19.5 mg/kg/day, but not at 2 mg/kg/day (Allen et al. 1983). The study of Allen et 

al. (1983) found no evidence of a delayed hypersensitivity response. 

Immunological end points have also been assessed in cynomolgus monkeys administered toxaphene by 

oral capsule for periods up to 75 weeks (Tryphonas et al. 2001). Groups of 10 female cynomolgus 

monkeys were administered toxaphene in capsules at doses of 0 (vehicle controls), 0.1, 0.4, or 

0.8 mg/kg/day for 75 weeks. Groups of male cynomolgus monkeys (5/group) were dosed at 0 (vehicle 

controls) or 0.8 mg/kg/day. Flow cytometry, lymphocyte transformation, natural killer cell activity, and 

serum cortisol levels were evaluated during treatment weeks 33–46. Immunization with SRBC was 

performed on treatment week 44 for a primary response and week 48 for a secondary response 

(observations made through treatment week 52). Immunizations with tetanus toxoid (TT) and 

pneumococcus antigens were performed on treatment week 53 (observations made through treatment 

week 63). Delayed type hypersensitivity testing was initiated on treatment week 66 and completed on 

treatment week 70. No treatment-related effects were observed in the 0.1 mg/kg/day group of treated 

female monkeys. Treatment with toxaphene at 0.4 mg/kg/day resulted in significant (p<0.05) reductions 

in mean primary anti-SRBC IgM responses (indicative of depressed humoral immunity) at postimmunization weeks 1 and 4 (27 and 35% lower than that of controls) and secondary anti-SRBC IgM 

responses at post-immunization week 5 (10% lower than that of controls). The dose level of 

0.8 mg/kg/day resulted in significantly reduced mean primary anti-SRBC IgM responses at postimmunization weeks 1–4, significantly reduced mean secondary anti SRBC IgM response at postimmunization weeks 5 and 8, and significantly reduced primary anti-SRBC IgG responses at postimmunization weeks 2 and 3 (51 and 43% lower than that of controls). In males, 0.8 mg/kg/day 

toxaphene induced a significant reduction in mean primary anti-SRBC IgM response at postimmunization weeks 1–3. The mean anti-TT titers were significantly reduced in 0.8 mg/kg/day females 

at post-immunization weeks 2–4. Flow cytometry tests showed that the only effect on leukocyte and 

lymphocyte subsets was a reduction in absolute B lymphocytes (CD20) in 0.8 mg/kg/day females (62% 

lower than controls). There were no detectable treatment-related effects on natural killer cell activity, 

delayed type hypersensitivity, lymphoproliferative response to mitogens, or serum cortisol levels. The 

toxaphene-induced reduction in mean primary anti-SRBC IgM response served as the critical effect for 

deriving an intermediate-duration oral MRL for toxaphene. 

All reliable LOAEL values for immunological and lymphoreticular effects in each species and duration 

category are recorded in Table 3-2 and plotted in Figure 3-2. 

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3.2.2.4 Neurological Effects 

Signs of central nervous system stimulation are the hallmark of acute toxaphene intoxication in both 

humans and animals. Case reports of accidental or intentional toxaphene ingestion indicate that 

toxaphene poisoning is usually accompanied by convulsive seizures that can be controlled with 

barbiturates or diazepam (McGee et al. 1952; Wells and Milhorn 1983). The dose necessary to induce 

nonfatal convulsions in humans has been estimated to be approximately 10 mg/kg (CDC 1963). 

Contaminated collard greens coated with toxaphene, eaten on empty stomachs, caused convulsive 

seizures followed by periods of memory loss in three females between the ages of 12 and 20, as well as 

nausea in a 49-year-old woman (McGee et al. 1952). 

Convulsions and other clinical signs of toxaphene-induced neurotoxicity have been observed in laboratory 

animals. Chandra and Durairaj (1995) reported clinical signs that included convulsions and sedation in 

guinea pigs receiving a single oral dose of toxaphene at 300 mg/kg. Lackey (1949) administered single 

gavage doses of toxaphene to dogs at doses ranging from 5 to 50 mg/kg and noted convulsions at dose 

levels ≥10 mg/kg. In the same study report, occasional convulsions were noted in dogs dosed at 

4 mg/kg/day during 44- and 106-day treatment periods. Single oral administration of toxaphene to heifer 

calves at 50–150 mg/kg elicited numerous clinical signs that included hyperexcitability, nystagmus, 

convulsions, and seizures (Steele et al. 1980). In a 13-week oral toxicity dog study, clinical signs of 

neurotoxicity (convulsions, salivation, and vomiting) were elicited during the first 2 days of oral dosing at 

10 mg/kg; these clinical signs were no longer elicited after the dose was reduced to 5 mg/kg/day on 

treatment day 3 (Chu et al. 1986). Tremors and nervousness were reported in rats administered toxaphene 

by gavage for 3 days at doses ≥25 mg/kg/day; a NOAEL was not identified (Rao et al. 1986). 

Hyperreflexia was observed in rats at an unspecified dose (Boyd and Taylor 1971). 

In a chronic toxicity and carcinogenicity study of male and female rats and mice (NCI 1979), hyperexcitability was reported in high-dose male rats during the first 2 weeks of exposure to toxaphene in the 

diet when the initial concentration (2,560 ppm) delivered an estimated dose of 270 mg/kg/day; this effect 

was not observed in male rats receiving 130 mg/kg/day or in groups of similarly-treated females receiving 

toxaphene at 70 or 147 mg/kg/day during the same 2-week period. Based on the hyperexcitability in the 

high-dose male rats, dietary concentrations were reduced by 50% at treatment week 3 and another 50% at 

treatment week 55 when generalized body tremors were noted in most high-dose male and female rats. 

The study authors reported clinical signs that included tremors, leg paralysis, and ataxia from treatment 

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weeks 52 through 80, predominantly in toxaphene-treated rats. In the mouse study, hyperexcitability was 

reported during treatment weeks 60–76 in the low-dose male mice (estimated dose of 17 mg/kg/day), but 

not in the high-dose males (34 mg/kg/day); there were no signs of hyperexcitability in either dose group 

(17 and 34 mg/kg/day) of female mice. 

There were no clinical signs or histopathological evidence of toxaphene-induced neurological effects in 

male or female cynomolgus monkeys administered toxaphene in a daily capsule for 52 weeks at 

1 mg/kg/day (Bryce et al. 2001). 

The electroencephalographic (EEG) pattern of squirrel monkeys was altered by exposure to 1 mg/kg 

toxaphene (Santolucito 1975). In addition to affecting behavior, an oral dose of 120 mg/kg toxaphene 

was reported to alter brain catecholamine metabolism in rats (Kuz'minskaya and Ivanitskiĭ 1979). 

Badaeva (1976) reported brain cell death in pregnant rats gavaged with toxaphene at 12 mg/kg/day during 

gestation. However, the methods used to identify the lesions are not well described in this study and the 

effects were not quantitatively evaluated. 

Dietary administration of toxaphene to rats for 14 days at estimated doses as high as 18 mg/kg/day did not 

affect whole brain weight in rats (Trottman and Desaiah 1980), but this is a gross measure and effects on 

specific neuronal populations would not be detected by this measure. Toxaphene-related decreases in 

brain weight were reported in guinea pigs following a single oral dose of 300 mg/kg toxaphene (Chandra 

and Durairaj 1992). The same exposure scenario resulted in a significant decrease of brain phospholipid 

content and a significant increase in brain neutral lipid and cholesterol content (Chandra and Durairaj 

1995). Similar effects were observed in other guinea pigs receiving toxaphene by gavage at 5 mg/kg/day 

for 60 days (Chandra and Durairaj 1995). However, the toxicological significance of these finding is 

uncertain. 

The highest NOAEL values and all reliable LOAEL values for neurological effects for each species and 

duration category are reported in Table 3-2 and plotted in Figure 3-2. 

Oral toxicity animal studies that assessed neurodevelopmental end points are summarized in Section 3.2.6 

(Developmental Effects). 

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3.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans following oral exposure to toxaphene. 

Testicular weight was not affected in rats receiving toxaphene from the diet for 14 days at estimated doses 

as high as 18 mg/kg/day (Trottman and Desaiah 1980). Vaginal bleeding was reported in rats receiving 

toxaphene from the diet for 80 weeks at estimated TWA doses of 41.6 and 83.3 mg/kg/day; incidence 

data were not provided in the study report (NCI 1979). There were no effects on litter sizes, pup survival, 

or weanling body weights and no evidence of treatment-related teratogenic effects in a three-generation 

study of male and female rats that received toxaphene from the diet for up to 42 weeks at estimated doses 

as high as 8.6 and 9.8 mg/kg/day, respectively (Kennedy et al. 1973). In another reproductive toxicity 

study (Chu et al. 1988), fertility and offspring growth and viability were not affected by dietary exposure 

of male and female rats to toxaphene at estimated doses as high as 45–46 mg/kg/day; the treatment period 

included 13 weeks prior to mating and continued through the production of F1a and F1b litters. Plasma 

testosterone levels were not affected in male rats administered a single gavage dose of 120 mg toxaphene/ 

kg/day or in other rats dosed at 2.6 mg/kg/day for up to 6 months (Peakall 1976). 

Keplinger et al. (1970) performed a multi-generation reproductive toxicity study in which male and 

female Swiss mice received toxaphene from the diet at estimated dose of 4.5 and 4.9 mg/kg/day, 

respectively, through the production of five generations of offspring. There were no indications of 

toxaphene-related adverse effects on lactation, reproduction, average litter size, or offspring growth or on 

viability through five generations. 

Bryce et al. (2001) noted no remarkable histopathology following examination of tissues (including 

reproductive tissues) from cynomolgus monkeys administered toxaphene by oral capsule at 1 mg/kg/day 

for 52 weeks. Arnold et al. (2001) found no evidence of toxaphene-related effects on menstrual cycle in 

cynomolgus monkeys administered the chemical in capsules at daily doses ranging from 0.1 to 

0.8 mg/kg/day for up to 75 weeks. 

The highest NOAEL values 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 

No studies were located regarding developmental effects in humans following oral exposure to toxaphene. 

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Available developmental toxicity studies in animals indicate that toxaphene is not teratogenic. No major 

anatomical defects were seen in rat or mouse fetuses following gestational oral exposure of pregnant 

dams at doses in the range 0.05 to 75 mg/kg/day (Allen et al. 1983; Chernoff and Carver 1976; Chernoff 

and Kavlock 1982; Chernoff et al. 1990; Crowder et al. 1980; Kavlock et al. 1982; Kennedy et al. 1973; 

Olson et al. 1980). 

Toxaphene (15, 25, or 35 mg/kg/day) administered to mice by gavage from gestational days 7–16 

produced no adverse effects on fetal growth, viability, or gross morphology even though the toxaphenetreated dams displayed dose-dependent reductions in weight gain (Chernoff and Carver 1976). Keplinger 

et al. (1970) found no evidence of treatment-related effects on litter size or offspring growth and viability 

in mice receiving toxaphene from the diet at approximate doses of 4.5–5 mg/kg/day throughout the 

production of five generations of offspring. 

Some of the available developmental toxicity animal studies reported treatment-related effects on 

development. Chernoff and Kavlock (1982) noted transient decreases in offspring body weight on 

postnatal day 1 following gavage administration of toxaphene to rat dams at 75 mg/kg/day on gestation 

days 8B12; however, the dose was maternal toxic, as evidenced by 2/25 maternal deaths and >45% 

depressed maternal weight gain. Chernoff et al. (1990) reported significantly increased incidences of 

supernumerary ribs in fetuses from rat dams gavaged at 32 mg/kg/day during gestation days 6–15; 

however, 50% of the treated dams died. Chernoff and Carver (1976) reported significantly decreased 

numbers of sternal ossification centers in 21-day-old fetuses from rat dams administered toxaphene by 

gavage at 15 or 25 mg/kg/day during gestation days 7–16, but not at a dose level of 35 mg/kg/day. 

Kavlock et al. (1982) reported significantly decreased renal protein in the kidneys of 21-day-old rat 

fetuses whose mothers had been administered toxaphene by gavage at 12.5 or 25 mg/kg/day during 

gestation days 7–16 and significantly decreased alkaline phosphatase activity in fetal kidneys of the 

25 mg/kg/day dose group. 

Allen et al. (1983) assessed immunological end points in 8-week-old offspring of mouse dams that had 

received toxaphene from the diet at estimated doses of 2, 19.5, or 39 mg/kg/day for 3 weeks premating 

and throughout mating, gestation, and lactation. Assessment included a delayed-type hypersensitivity 

assay for cell-mediated immune response, an enzyme-linked immunosorbent assay for humoral immune 

response, and a phagocytosis assay to assess the ability of peritoneal macrophages to engulf SRBCs. 

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Toxaphene treatment resulted in significant suppression of macrophage phagocytic function in the 

offspring at all dose levels (32, 79, and 63% suppression in the 2, 19.5, and 39 mg/kg/day dose groups, 

respectively) compared to controls. The humoral antibody response was significantly suppressed at 

19.5 mg/kg/day, but was significantly enhanced at 39 mg/kg/day. The cell-mediated immune response 

was suppressed at 19.5 mg/kg/day, but was not significantly different from controls at the low- and highdose levels. These results indicate that the perinatal immunological system may be at risk for toxaphene 

toxicity. 

Crowder et al. (1980) assessed the effects of toxaphene on results of selected behavioral tests (grasp-hold, 

righting, startle, and placing reflexes; open field and maze performance) in pups from rat dams 

administered toxaphene by gavage at 6 mg/kg/day during mating and throughout gestation (Crowder et al. 

1980). Reflex testing, initiated at 7 days postpartum, revealed no significant treatment-related effects on 

performance; however, the study authors stated that 3 more days were required for 90% of the pups from 

the toxaphene-treated group to correctly respond in the righting reflex test compared to control pups 

(p≤0.05). There were no significant differences between toxaphene-treated groups and control in maze 

performance assessed beginning at 55 days postpartum. 

Olson et al. (1980) examined the effects of toxaphene on selected behavioral parameters in pups of rat 

dams ingesting the chemical at 0.05 mg/kg/day from gestation day 5 until postpartum day 30. Tests of 

swimming ability and righting reflex were performed daily on postpartum days 7–16. Significantly 

retarded swimming ability was noted on postpartum days 10 (p<0.001), 11 (p<0.0001), and 12 (p<0.05); 

however, the effect was transient and pups exhibited normal swimming ability at testing on postpartum 

day 16. The study authors stated that pups of the toxaphene treatment group also exhibited significantly 

retarded overall righting reflex (p<0.005), but quantitative data were not provided in the study report. 

Maze testing, initiated on postpartum day 70, revealed no apparent treatment-related effect. 

The highest NOAEL values and all reliable LOAEL values 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 regarding cancer in humans following oral exposure to toxaphene. 

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NCI (1979) assessed the toxicity and carcinogenicity of toxaphene in groups of male and female OsborneMendel rats and male and female B6C3F1 mice exposed to the chemical for 80 weeks via the diet 

followed by 28–30 weeks of recovery prior to terminal sacrifice. Among the mice, respective incidences 

of neoplastic liver nodules or hepatic carcinomas (combined) in concurrent controls, pooled controls, and 

low- and high-dose animals were 2/10, 7/48, 40/49, and 45/46 for males and 0/9, 0/48, 18/49, and 

40/49 for females. Incidences at the low- and high-dose levels (estimated TWA doses of 77.9 and 

83.3 mg/kg/day, respectively) were significantly higher than those of respective concurrent controls. 

Among the rats, incidences of thyroid follicular cell adenomas or carcinomas (combined) in concurrent 

controls, pooled controls, and low- and high-dose animals were 1/7, 2/44, 7/41, and 9/35 for males and 

0/6, 1/46, 1/43, and 7/42 for females. Incidences in high-dose male and female rats (estimated TWA 

doses of 77.9 and 83.3 mg/kg/day, respectively) were significantly higher than those of respective 

controls. Significantly increased incidences of hepatocellular carcinomas were observed in low- and 

high-dose (17 and 34 mg/kg/day, respectively) male mice and high-dose (34 mg/kg/day) female mice. In 

light of more contemporary diagnostic criteria for classification of histopathological liver tumors, an 

expert pathology working group (PWG) was convened to review the original liver slides from the male 

and female mice. A primary report of the PWG findings was not available to ATSDR. However, 

Goodman et al. (2000) provided a summary of the results which indicates that, although many of the 

tumors originally classified as carcinomas were reclassified as adenomas, the incidences of reclassified 

combined adenomas or carcinomas were similar to the incidences of combined neoplastic nodules or 

carcinomas presented in the original study report. 

Litton Bionetics, Inc. produced an unpublished report of a cancer bioassay in mice administered 

toxaphene in the diet. The study results were summarized by EPA in an Ambient Water Quality Criteria 

document (EPA 1980a). EPA’s Integrated Risk Information System includes a summary for toxaphene in 

which the results of the unpublished study were used by EPA to derive an oral slope factor (IRIS 2010). 

The following summary of the unpublished study was extracted from EPA (1980a) because the study was 

not available to ATSDR: Groups of male and female B6C3F1 mice (54/sex/group) were administered 

toxaphene in the diet at 0, 7, 20, or 50 ppm for 18 months followed by a 6-month observation period. 

Based on EPA (1988d) chronic reference values for body weight and food consumption in male and 

female B6C3F1 mice, respective estimated doses were 0, 1.2, 3.4, and 8.6 mg/kg/day for the males and 0, 

1.2, 3.5, and 8.6 mg/kg/day for the females. At unscheduled or terminal sacrifice, histopathological 

evaluation of major organs was initiated. A statistically significant (p=0.048) excess of hepatocellular 

tumors (adenomas plus carcinomas) was noted in the high-dose male mice (18/51 versus 10/53 in 

controls). The Cochran Armitage trend test was significant (p=0.020) for dose-related increased 

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incidence of hepatocellular tumors in the male mice. There were no significant treatment-related effects 

on the incidence of hepatocellular tumors in any group of treated female mice. 

In a study designed to assess the effect of insecticides (including toxaphene) on the induction of lung 

tumors by benzo[a]pyrene, toxaphene was given to female A/J mice (11–12/group) for 12 weeks at 0, 

100, or 200 ppm (Triolo et al. 1982). The study assessed a limited number of end points and found no 

evidence for toxaphene-related lung or stomach tumors. 

The oral doses associated with individual, lifetime upper-bound cancer risk of 10-4–10-7 are 9x10-5– 

9x10-8 mg/kg/day, assuming that a 70-kg human ingests 2 L water/day. The 10-4–10-7 risk levels are 

indicated in Figure 3-2. 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

No studies were located regarding lethal effects in humans following dermal exposure to toxaphene. 

Acute dermal LD50 values obtained in laboratory animals range from 780 to 4,556 mg/kg (Gaines 1969; 

Industrial Biotest 1973; Johnston and Eden 1953; Jones et al. 1968). All of these studies except Gaines 

(1969) reported LD50 values of 1,075 and 780 mg/kg/day for male and female Sherman rats, respectively; 

these values are plotted in Table 3-3. The other studies are limited in design and/or reporting which 

preclude their inclusion in Table 3-3. 

3.2.3.2 Systemic Effects 

No studies were located regarding cardiovascular, musculoskeletal, endocrine, or body weight effects in 

humans or animals following dermal exposure to toxaphene. The highest NOAEL values and all reliable 

LOAEL values for systemic effects in each species and duration category are recorded in Table 3-3. 

Respiratory Effects. In humans, fluoroscopic examination of the lungs following acute dermal 

exposure to 500 mg/m3 toxaphene did not reveal abnormalities (Keplinger 1963). 

Toxicosis was observed in a herd of pigs that had been treated with a 61% toxaphene solution (equivalent 

to 13.5 g/kg). The symptoms generally subsided when the animals were sprayed with warm water 

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50

mg/kgmg/kg

538 mg/kg40

mg/kg

mg/kg

39

mg/kg

Table 3-3 Levels of Significant Exposure to Toxaphene - Dermal 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE 

Death 

(Sherman) Rat once 

System NOAEL Less Serious 

LOAEL 

1075 M 

mg/kg 

Serious 

(LD50) 

Reference Chemical Form 

Gaines 1969 

780 F 

mg/kg 

(LD50) 

Systemic 

(New Zealand) Rabbit 4 hr Dermal 130 B 

mg/kg 

(erythema and edema) International Research 

Development Corporatio

(NS) Pig once Resp 13500 

mg/kg 

(lung congestion and 

presence of peribronchia 

lymphoid follicles) 

Dipietro and Haliburton 

Renal 13500 

mg/kg 

(cystic kidney cortex) 

Neurological 

(NS) Pig once 13500 

mg/kg 

(convulsions) Dipietro and Haliburton 

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B = both; hr = hour(s); LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; NS = not specifiedrespiratory 
 

 

 

 

 

 

TOXAPHENE 62 

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(DiPietro and Haliburton 1979). Various lung lesions were observed in three affected pigs that were not 

treated for toxicosis by spraying with warm water. These lesions differed in the three affected pigs 

examined and included congested cranial lung lobes, numerous peribronchial lymphoid follicles, and 

moderate congestion of the lungs. Hyperemic lungs also were observed in rabbits that died following a 

24-hour dermal application of 3,038 mg/kg toxaphene (Industrial Biotest 1973). It should be noted that 

some studies performed by Industrial Biotest have been found to be less than reliable; thus, the accuracy 

of the above data cannot be assured. 

Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans 

following dermal exposure to toxaphene. 

Dilation of veins and intestinal hemorrhage were observed in rabbits dipped in an unspecified dose 

suspension of a wettable powder of toxaphene for 2 minutes (Johnston and Eden 1953). 

Hematological Effects. In humans, blood tests conducted after acute dermal exposure to 500 mg/m3 

toxaphene did not reveal any abnormalities (Keplinger 1963). 

No studies were located regarding hematological effects in animals following dermal exposure to 

toxaphene. 

Hepatic Effects. No studies were located regarding hepatic effects in humans following dermal 

exposure to toxaphene. 

Rabbits dipped in an unspecified dose suspension of a wettable powder of toxaphene for 2 minutes had 

pale and mottled livers (Johnston and Eden 1953). Toxaphene applied to intact or burned skin of rabbits 

for 24 hours caused enlarged gall bladders in both the intact and burned groups at doses ≥3,038 mg/kg 

(Industrial Biotest 1973). 

Renal Effects. In humans, urinalysis conducted after acute dermal exposure to 500 mg/m3 toxaphene 

did not reveal any abnormalities (Keplinger 1963). 

In pigs, cysts were found in the renal cortex after acute dermal exposure to 13.5 mg/kg/day toxaphene 

(DiPietro and Haliburton 1979). 

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Dermal Effects. In humans, acute dermal exposure to 500 mg/m3 toxaphene did not produce dermal 

irritation (Keplinger 1963). 

Dermal application of 3,038 mg/kg toxaphene (90% weight to volume [w/v] ratio in xylene) to the skin of 

rabbits caused moderate to severe edema and erythema followed by severe desquamation following a 

24-hour exposure (Industrial Biotest 1973). The skin irritation may have been caused by xylene, which 

has been reported to cause dermal irritation in guinea pigs (Anderson et al. 1986). Exposure to toxaphene 

(500 mg) for 4 hours caused rabbit skin to be only mildly irritated (International Research and 

Development Corporation 1973). 

Ocular Effects. No studies were located regarding ocular effects in humans following dermal 

exposure to toxaphene. 

Mild irritation to the eyelids and loss of eyelid hair were observed after 14 applications of a 20% 

toxaphene solution in kerosene to the eyes of guinea pigs. The eyes were not affected, and the lids 

cleared completely in 10 days (EPA 1985c; summary of an unpublished report for Boots Hercules 

Agrochemicals). The unpublished report was not available to ATSDR. 

3.2.3.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological or lymphoreticular effects in humans or animals 

following dermal exposure to toxaphene. 

3.2.3.4 Neurological Effects 

No studies were located regarding neurological effects in humans following dermal exposure to 

toxaphene. 

Signs of central nervous system toxicity were observed in 40 of 150 pigs 36 hours after being sprayed 

with 300 mL of a 61% toxaphene solution in water (equivalent to 13.5 g/kg). This dose is about 10 times 

the recommended dose for treatment of sarcoptic mange (DiPietro and Haliburton 1979). Inhalation 

and/or oral exposure may have also occurred. Clinical signs included head-pressing, ataxia, depression, 

lethargy, diarrhea, and convulsive seizures. Within a day after spraying with warm water, the animals 

were much improved, and complete recovery was seen within 5 days. Muscular weakness was reported 

in rabbits exposed by 24-hour dermal application of a 90% w/v solution of toxaphene in xylene at doses 

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≥6,834 mg/kg, but not at doses ≤4,556 mg/kg (Industrial Biotest 1973); however, this study was limited in 

that the solvent, xylene, was not tested alone. Similar dermal application to burned skin resulted in 

muscular weakness at doses ≥3,038 mg/kg; there was no indication of muscular weakness at a dose of 

2,025 mg/kg. 

No studies were located regarding the following effects in humans or animals following dermal exposure 

to toxaphene: 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 

3.3 GENOTOXICITY 

Table 3-4 summarizes available in vivo genotoxicity information for toxaphene. 

A higher incidence of chromosomal aberrations was observed in cultured lymphocytes taken from the 

blood of eight women exposed to toxaphene than in lymphocytes taken from unexposed women (Samosh 

1974). The exposed women had entered a field that had recently been sprayed with an analog of 

toxaphene and were described as presenting "mild to moderate" clinical symptoms. The nature of the 

symptoms was not reported. The women were likely to have been exposed by both inhalation and dermal 

routes. 

In a dominant lethality test, toxaphene did not cause increased fetal death or decreased numbers of 

implants in mouse dams mated to males that had been administered toxaphene orally at doses of 40 or 

80 mg/kg/day for 5 days or by single intraperitoneal injection at 36 or 180 mg/kg (Epstein et al. 1972). 

Mortality was noted in 9/12 and 2/9 of the high-dose orally- and intraperitoneally-exposed males, 

respectively, indicating that sufficiently high doses were tested. 

Toxaphene did not cause liver deoxyribonucleic acid (DNA) damage in 90-day-old female 

Sprague-Dawley rats administered the chemical twice (21 and 4 hours prior to sacrifice) by gavage at up 

to 36 mg/kg/dose (Kitchin and Brown 1994). Hedli et al. (1998) found no evidence of DNA adduct 

formation in livers of male CD-1 mice administered toxaphene by gavage for 7 days at doses up to and 

including 100 mg/kg/day. 

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Table 3-4. Genotoxicity of Toxaphene In Vivo 

Species (test system) End point Results Reference 

Mammalian systems 

Human lymphocytes/occupational Chromosomal aberrations – Samosh 1974 

exposure 

Mouse dominant lethal test Gene mutation – Epstein et al. 1972 

Mouse liver cells DNA adducts – Hedli et al. 1998 

– = negative 

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Table 3-5 summarizes available in vitro genotoxicity information for toxaphene. 

Toxaphene was mutagenic in reverse mutation assays using Salmonella typhimurium strains TA98 and 

TA100 (containing the pKm101 plasmid) in the absence of metabolic activation systems (Hooper et al. 

1979; Mortelmans et al. 1986; Schrader et al. 1998; Steinberg et al. 1998). However, mutagenic 

responses were diminished or abolished with the addition of metabolic activation systems (Hooper et al. 

1979; Schrader et al. 1998). Negative or only weakly positive results were obtained in reverse mutation 

assays using S. typhimurium strains TA 1535 and TA1537 (non-plasmid containing strains). Young et al. 

(2009) reported weakly mutagenic responses in S. typhimurium strain TA100 in the presence and absence 

of exogenous metabolic activation. 

Hooper et al. (1979) determined that certain components of the mixture of chemicals making up technical 

toxaphene were much less mutagenic than the mixture as a whole. Specifically, the components that were 

considered to possess the highest insecticidal or acute mammalian toxicity activity (e.g., 

heptachlorobornane, gem-dichloro components, and nonpolar fractions) were less mutagenic to S. 

typhimurium strain TA100 than was the complete toxaphene mixture (or the polar fraction). These 

findings may have relevance to public health in that the components of complex mixtures such as 

toxaphene may distribute unevenly in the environment (see Chapter 6). 

Mortelmans et al. (1986) reported positive results for gene mutation in N. crassa in the absence of 

metabolic activation. Positive results were obtained in an assay for the induction of λ prophage in 

Escherichia coli (Houk and DeMartini 1987). Significantly increased frequency of sister chromatid 

exchanges in the presence and absence of metabolic activation (S9) were reported in a cultured cell line 

derived from human lymphoid cells; however, the increases were <2-fold greater than solvent controls 

(Sobti et al. 1983). Significantly increased frequency of sister chromatid exchanges were observed in 

toxaphene-treated Chinese hamster lung cells; the increase was slightly <2-fold higher than that of 

controls (Steinel et al. 1990). Toxaphene did not significantly increase the frequency of sister chromatid 

exchanges in Chinese hamster V79 cells with or without metabolic activation and did not significantly 

alter the frequency of HGPRT mutations at concentrations up to and including those resulting in 

cytotoxicity (Schrader et al. 1998). Bartoš et al. (2005) reported positive results for toxaphene-induced 

DNA damage in an SOS Chromotest using E. coli PQ37 in the absence of metabolic activation, but 

reported negative results in a umuC test for DNA damage in S. typhimurium strain TA1535/pSK1002 in 

the absence of metabolic activation. Both assays test induction of the SOS repair system. Toxaphene did 

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Table 3-5. Genotoxicity of Toxaphene In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

Prokaryotic organisms 

Salmonella typhimurium strain Gene mutation – + Hooper et al. 1979
 

TA100
 

S. typhimurium strain TA98	 Gene mutation ND + Hooper et al. 1979 

S. typhimurium strain TA98	 Gene mutation – + Mortelmans et al. 1986 

S. typhimurium strain TA100	 Gene mutation + + Mortelmans et al. 1986 

S. typhimurium strain TA1535	 Gene mutation – – Mortelmans et al. 1986 

S. typhimurium strain TA1537	 Gene mutation – (+) Mortelmans et al. 1986 

S. typhimurium strain TA98 Gene mutation ND + Steinberg et al. 1998 

S. typhimurium strain TA100 Gene mutation ND + Steinberg et al. 1998 

S. typhimurium strain TA100 Gene mutation + + Young et al. 2009 

S. typhimurium strain TA97 Gene mutation (+) + Schrader et al. 1998 

S. typhimurium strain TA98 Gene mutation (+) + Schrader et al. 1998 

S. typhimurium strain TA100 Gene mutation + + Schrader et al. 1998 

S. typhimurium strain TA102 Gene mutation – – Schrader et al. 1998 

S. typhimurium strain TA104	 Gene mutation (+) (+) Schrader et al. 1998 

S. typhimurium strain TA1535	 DNA damage NT – Bartoš et al. 2005
 

(umuC test)
 

Escherichia coli K-12 Λ prophage + + Houk and DeMarini
 

induction 1987
 

E. coli PQ37 DNA damage NT + Bartoš et al. 2005 

(SOS chromotest) 

Plasmid DNA isolated from E. DNA damage ND – Griffin and Hill 1978 

coli 

Fungi and plant systems Gene mutation 

Neurospora crassa Gene mutation ND + Mortelmans et al. 1986 

Mammalian cells 

Human lymphoid cells LAZ-007 Sister chromatid – – Sobti et al. 1983 

exchange 

Chinese hamster V79 fibroblasts Gene mutation – – Schrader et al. 1998 

Chinese hamster V79 fibroblasts Sister chromatid – NT Schrader et al. 1998 

exchange 

Chinese hamster lung (Don) Sister chromatid NT ± Steinel et al. 1990 

cells exchange 

ND = no data; NT = not tested; – = negative; + = positive; (+) = weakly positive; (±) = equivocal 

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not induce DNA damage in plasmid DNA isolated from E. coli in the absence of metabolic activation 

(Griffin and Hill 1978). 

In summary, the weight of evidence from available in vitro assays indicates that toxaphene is genotoxic. 

Only limited information was located regarding the potential genotoxicity of toxaphene in vivo. 

3.4 TOXICOKINETICS 

Studies in laboratory animals indicate that toxaphene is well absorbed by the intestinal tract and probably 

well absorbed by the lungs. Dermal absorption has also been demonstrated. Once absorbed, toxaphene 

distributes throughout the body. Studies using radiolabeled toxaphene indicate that distribution to fat 

predominates over distribution to other organs, and levels are detectable in fat tissue for several months 

following exposure. Toxaphene is rapidly and extensively degraded in mammals following oral 

administration. In vivo and in vitro studies indicate that the principal metabolic pathways involve 

dechlorination, dehydrodechlorination, and oxidation. Conjugation is also likely, but it is not a major 

route of metabolism. The primary route of excretion is via the feces (70% of an administered dose), but 

toxaphene is also excreted in the urine. 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

Limited human data indicate that inhaled toxaphene is absorbed (Keplinger 1963; Warraki 1963); 

however, no quantitative data are available. Limited unpublished animal data also indicate that inhaled 

toxaphene is absorbed; hepatic effects were reported in rats that survived inhalation exposure to 

toxaphene dust (4 or 12 mg/m3

) for 3 months (cited in EPA 1985c as an unpublished report for Hercules 

Incorporated; the primary report was not available to ATSDR). 

3.4.1.2 Oral Exposure 

No data were located regarding the extent of oral absorption of toxaphene in humans. However, accounts 

of death and systemic effects from accidental ingestion of toxaphene-contaminated food provide evidence 

that gastrointestinal absorption occurs (McGee et al. 1952). 

The presence of toxaphene residues in the fat of rats (Mohammed et al. 1985; Pollock and Kilgore 1980b; 

Saleh and Casida 1978; Saleh et al. 1979), mice (Crowder and Whitson 1980; Saleh et al. 1979), guinea 

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TOXAPHENE 69 

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pigs, hamsters, rabbits, monkeys, and chickens (Saleh et al. 1979) following ingestion demonstrates that 

ingested toxaphene is absorbed. The identification of toxaphene in the milk of cows following ingestion 

is also evidence of its absorption (Claborn et al. 1963; Zweig et al. 1963). 

Although there are no direct studies regarding the extent of toxaphene absorption, 56.5% of an orally 

administered dose was present in the feces and 9% of the dose was present in the urine of rats, mostly as 

metabolites. Very little was present as the parent compound, indicating that considerable metabolism had 

occurred (Chadurkar and Matsumura 1979). Less than 10% of the administered dose was detected in 

tissues 1 day after oral administration of radiolabeled toxaphene to rats, suggesting that absorption and 

redistribution may have occurred over the 24 hours following administration (Crowder and Dindal 1974). 

The proportion of the administered dose that was not redistributed may have been metabolized and 

eliminated. 

The data presented above suggest that toxaphene would be absorbed by humans following the 

consumption of drinking water or food contaminated with the chemical. Its absorption appears to be 

extensive and is enhanced when it is dissolved in a vehicle that is readily absorbed. The bioavailability of 

toxaphene is increased when it is administered in or with vegetable oils like corn oil or peanut oil, and the 

toxicity of toxaphene is potentiated (EPA 1980a). Thus, toxaphene may be more toxic when ingested in 

oily foods than when ingested in contaminated water. 

3.4.1.3 Dermal Exposure 

No studies were located in humans regarding the dermal absorption of toxaphene. 

The detection of high toxaphene levels in cow's milk (21–45 ppm) after dipping the cattle in a toxaphene 

solution (0.25% w/w toxaphene plus 0.03% w/v dioxathion) indicates that toxaphene is absorbed 

following dermal exposure (Keating 1979). Toxaphene toxicosis was reported in swine 36 hours after the 

dermal application of toxaphene in a 61% solution (equivalent to 13.5 g/kg) (DiPietro and Haliburton 

1979). 

Under conditions of high dosage, dermal absorption of toxaphene may be efficient enough to cause 

toxicosis or to produce detectable residues in cow’s milk. Toxaphene appears to be well absorbed 

following dermal exposure in animals, but the extent of absorption has not been quantified. Other 

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evidence suggests that absorption in humans may also be substantial following dermal exposure 

(Keplinger 1963). 

3.4.2 Distribution 

3.4.2.1 Inhalation Exposure 

No studies were available in humans or animals regarding the distribution of toxaphene following 

inhalation exposure. Although cases of inhalation exposure have been reported, there were no data that 

detailed distribution of toxaphene residues in various tissues. 

3.4.2.2 Oral Exposure 

Limited information is available regarding distribution in humans following oral exposure to toxaphene. 

Toxaphene residues have been detected in samples of adipose tissue taken from children (Witt and 

Niessen 2000) and in maternal and cord blood (Butler Walker et al. 2003). Ingestion of contaminated 

food, particularly fish and marine mammals, was the assumed exposure route. 

Results of tissue analysis following the oral administration of radiolabeled toxaphene to rats indicate that 

fat is the principal storage tissue (Ohsawa et al. 1975; Pollock and Kilgore 1980b). Other evidence in 

animals indicates that muscle may also be a storage site for toxaphene as suggested by the observation of 

a high distribution of toxaphene in muscle following an oral dose in rats, and by evidence that toxaphene 

residues persist in muscle for up to 20 days post-administration (Crowder and Dindal 1974). The oral 

administration of 14C-toxaphene in olive oil to rats at a dose of 10 mg/kg resulted in toxaphene residue 

levels of 6.4 mg/kg in fat 7 days following administration. Residue levels in all other tissues were 

<0.2 mg/kg (Pollock and Kilgore 1980b). The oral administration of 14C-toxaphene in corn oil to rats at 

doses of 19 and 8.5 mg/kg resulted in residue levels of 0.78 and 0.52 mg/kg, respectively, in fat 7 days 

after administration. Residue levels in all other tissues were <0.3 mg/kg (Ohsawa et al. 1975). Although 

the levels detected in fat by Pollock and Kilgore (1980b) are higher than those detected by Ohsawa et al. 

(1975), a direct comparison cannot be made because the two studies used different sized rats, analyzed 

their tissues at different times after administration, and used different vehicles. 

The highest level of activity, except for the gastrointestinal tract, was in the brown fat following 

administration of 16 mg/kg 14C-toxaphene in peanut oil to rats (Mohammed et al. 1985). High 

concentrations of toxaphene residues were also detected in the adrenal cortex, bone marrow, liver, and 

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kidney. Levels of radioactive residues peaked at 3 hours. At 24 hours after administration, most 

radioactivity was found in the white fat. Lesser amounts of the radiolabel were detected in liver and 

kidney. 

Mice that received an oral dose of 25 mg/kg 36Cl-toxaphene in corn oil retained 36Cl activity in fat, brain, 

kidney, liver, muscle, and testes. Levels were highest in fat (10.6 ppm) when tissues were analyzed 

8 days after administration (Crowder and Whitson 1980). 

Toxaphene and its metabolites were detected in the liver, kidney, bone, brain, heart, lung, muscle, spleen, 

and testes of rats 7 days after the oral administration of 8.5 and 19 mg/kg 14C-toxaphene (Ohsawa et al. 

1975). After the oral administration of a single dose of 20 mg/kg 36Cl-toxaphene to rats, the greatest 

levels of radioactivity were seen at 12 hours in almost all tissues. Levels in blood cells peaked after 

3 days. The total fat content after 12 hours was only 0.86% of the total dose, but this exceeded the 

fraction of the dose found in the kidney (0.43%), testes (0.28%), and brain (0.23%) (Crowder and Dindal 

1974). Approximately 77% of the dose was detected in the stomach at 12 hours, and <10% of the dose 

remained in the body after 1 day. At 12 hours after administration, 5.3% of the dose was present in the 

muscle. Although this was significantly more than the amount seen in fat and other tissues, the 

concentration of activity in muscle is low due to the large amount of muscle in the body. Crowder and 

Dindal (1974) only determined the fraction of the dose based on proportions of radioactivity found in 

each tissue that may have been derived from a component of the original mixture or a metabolite. 

Cynomolgus monkeys were administered toxaphene in glycerol/corn oil via gelatin capsule at 

1 mg/kg/day for 1 year (Andrews et al. 1996). At 10 weeks, the blood levels appeared to peak out at 

approximately 40 ppb; levels in adipose tissue leveled out at 4,000 ppb between weeks 15 and 20. 

Heifer calves receiving toxaphene at oral bolus doses of 50, 100, or 150 mg/kg 14C-toxaphene had 

measurable toxaphene residues in the liver, kidney, and brain 7 days after administration. These tissues 

were the only ones sampled, so it is not possible to assess the amount of toxaphene that distributed to fat 

(Steele et al. 1980). This study found that liver residues varied exponentially with dosage, as shown in 

Table 3-6. 

Furthermore, liver residue levels correlated with predicted fatality with an accuracy of about 80%. Based 

upon these tissue distribution results, the authors concluded that liver residue values could serve as a 

biomarker of toxaphene poisoning. Kidney and brain levels of toxaphene could not be used as 

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Table 3-6. Mean Toxaphene Residues in Cows Following Oral Exposure to 

Toxaphene
 

Toxaphene residue 

Liver Kidney Brain 

Dose (mg/kg) (ppm) (ppm) (ppm) 

50a 2.88 3.45 2.67 

100b 7.66 2.75 4.02 

150a 22.26 5.50 3.88 

a

Values represent mean of six animals.

b

Values represent mean of seven animals. 

Source: Steele et al. 1980 

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biomarkers, because residue levels of the pesticide in these organs did not correlate with observed 

mortality. Additionally, brain levels are not as consistent as liver values. Oral administration of 

16 mg/kg 14C-toxaphene to rats resulted in distribution of radioactivity to the adrenal cortex, primarily 

localized in the zona fasciculata. Only low levels of radioactivity were detected in the zona glomerulosa 

and the zona reticularis, and no radioactivity was found in the medulla (Mohammed et al. 1985). The 

zona fasciculata is responsible for glucocorticoid synthesis. A toxaphene-induced 50% inhibition of 

ACTH-stimulated adrenal corticosterone synthesis in vitro is supported by this pattern of toxaphene 

distribution in vivo. Pretreatment of rats with toxaphene in their diet for 5 weeks also resulted in a 

significant inhibition of corticosteroid synthesis when compared to controls. Hence, the distribution of 

toxaphene to the zona fasciculata was correlated with an adverse physiological effect. 

Administration of 14C-toxaphene in olive oil at a dose of 2.6 mg/kg to pregnant rats resulted in its 

distribution to the fat. Fetuses contained the lowest levels of radioactivity relative to other tissues 

analyzed (Pollock and Hillstrand 1982). After 1 day, the residue level in the fetus was 84 ppb; the residue 

level after 3 days averaged 28 ppb. Residue levels in the fat of the mothers exceeded 7,000 ppb. The 

authors reported that the overall amount of placental transfer was similar to that of polychlorinated 

biphenyls (PCBs), of which <1% of the dose was transferred. 

All studies reviewed consistently demonstrate that toxaphene is distributed throughout the body and 

preferentially stored in fat. Although toxaphene was identified in the fat up to 30 days after 

administration, the overall tissue activity level was very low. Apparently, toxaphene is rapidly 

metabolized, and its metabolites and components are not persistent. However, it is not known whether 

the toxaphene metabolites or the original components that persist in fat are toxic. Therefore, these 

persistent residues could theoretically reenter the circulation from the fat stores and cause additional 

delayed toxicity. Toxaphene has been shown to cross the placenta and become localized in the fetal 

adrenal. Based on the findings in all animals (Saleh et al. 1979), it would seem likely that fat would also 

be a principal storage site for toxaphene in humans following its ingestion. Toxaphene localizes in the 

liver after initial exposure but then redistributes to fat over a longer period of time. Tissue samples 

obtained from a chronic dog study demonstrated that after 2 years exposure, toxaphene (as estimated from 

tissue chlorine levels) was measurable only in fat (Hercules Research Center 1966). The levels in liver, 

kidney, and brain were negligible. Fat samples obtained at the interim periods of 6 and 12 months had 

toxaphene levels comparable to those seen at 24 months, indicating that accumulation of toxaphene in 

adipose tissue may reach a saturation point, resulting in steady-state levels, with uptake being equal to 

excretion. 

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3.4.2.3 Dermal Exposure 

No human or animal data were located regarding distribution of toxaphene following dermal exposure. 

3.4.2.4 Other Routes of Exposure 

Intravenous administration of 14C-toxaphene to mice at a dose of 16 mg/kg resulted in the appearance of 

radioactivity in the liver, fat, bile, adrenal glands, kidneys, and ovaries within 20 minutes of 

administration. The distribution significantly changed after 4 hours, with an increase in radioactivity in 

the abdominal fat and the intestinal contents. There were decreases in other tissues after 4 hours. Highest 

levels of radioactivity were still localized in the fat 16 days after administration (Mohammed et al. 1983). 

In autoradiographic studies of pregnant albino mice intravenously injected with 14C-toxaphene 

(16 mg/kg), Mohammed et al. (1983) found low levels of activity in fetal tissues. This activity was highly 

concentrated in the fetal liver and adrenal gland. These results, as after oral administration, suggest that 

the transplacental transfer of toxaphene after intravenous administration is relatively low. The tissue 

accumulation of intravenously administered 14C-toxaphene was also examined in normolipidemic and 

hypolipidemic female NMRI mice (Mohammed et al. 1990b). In normolipidemic mice, the radiolabel 

first distributed to the liver and adrenal glands 20 minutes after administration of the labeled toxaphene. 

After 4 hours, the label was primarily found in the abdominal fat. The distribution of the radiolabel in the 

hypolipidemic mice was different from the controls. After 20 minutes, the labeled toxaphene was found 

in the liver, adrenal gland, heart, and kidneys. After 4 hours, nearly all of the label was found in the liver. 

The results of the study indicate that lipid metabolism may play an important role in the tissue distribution 

of toxaphene and thus its toxicity. 

3.4.3 Metabolism 

Toxaphene is rapidly and extensively degraded in mammals following oral administration (Figure 3-3). 

In vivo and in vitro studies indicate that the principal metabolic pathways involve dechlorination, 

dehydrodechlorination, and oxidation. Conjugation is also likely, but it is not a major route of 

metabolism. Administration of 36Cl-toxaphene to rats at a dose of 13 mg/kg resulted in the excretion of 

36Cl-chloride ion in the urine. This was the only metabolite identified in the urine by Ohsawa et al. 

(1975), and it accounted for 50% of the administered radioactivity. Results obtained with 36Cl- and 

14C-toxaphene differed. With either label, the hexane extracts of urine and feces contained some 

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Toxicant B 

Cl 

Cl 

Hx 

Cl 

Hn 

Hn 

Hx 

Cl 

1 

2 

3 

4 

5 

H 

6 

7 

8 9 V 

Cl 

Cl Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

IV 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

III II 

 

TOXAPHENE 75 

3. HEALTH EFFECTS 

Figure 3-3. Proposed Metabolic Scheme for a Toxicant Isolated from Toxaphene 

Note: Toxicant B = 2,2,5-endo-6-exo-8,9,10-heptachlorobornane 

Metabolite II = 2,5-endo-6-exo-8,9,10-hexachlorobornane 

Metabolite III = 2,-exo-5-endo-6-exo-8,9,10-hexachlorogornane 

Metabolite IV = 2,5-endo-6-exo-8,9,10-heptachlorogornene 

Metabolite V = 2,5-endo-8,9,10-pentachlorotricyclene 

Source: Saleh and Casida 1978 

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unmetabolized material. The percentage of administered activity was negligible in urine and 

approximately 8–12% in feces. Hence, most excreted material consisted of metabolites from toxaphene 

components. The combined chloroform extracts of urine and feces contained a much higher proportion of 

the administered 14C-activity (27%) than of the 36Cl-activity (11.2%). These results indicate that the 

chloroform fraction consists of partially dechlorinated metabolites, and a predominance of these products 

were found in the urine. The aqueous fraction contained 11.4% of the 14C-dose and 0.5% of the 36Cl dose. 

The low amount of 36Cl activity in the aqueous extracts indicated that this fraction contained metabolites 

(5–10%) that had been completely dechlorinated (Ohsawa et al. 1975). About 2% of the 14C-activity 

appeared as expired products, probably 14C-carbon dioxide. Thus, these results indicate that toxaphene is 

metabolized mostly to partially dechlorinated products, with a small proportion being completely 

dechlorinated and a small proportion unmetabolized. 

Pollock and Kilgore (1980b) confirmed the observations of Ohsawa et al. (1975). Less than 5% of the 

total activity from an orally-administered dose of 10 mg/kg 14C-toxaphene was extractable from urine into 

hexane. Thin-layer chromatography (TLC) of the urine extract indicated that the components in the urine 

were more polar than toxaphene. No parent compound was found in the urine. These results provide 

additional evidence that most of the toxaphene absorbed is metabolized. 

The complexity of toxaphene makes it difficult to understand its metabolism fully. It appears that all of 

its components undergo rapid metabolism, yet each component has its own rate of biotransformation. A 

small fraction of fecal radioactivity that was extractable into hexane indicated that some toxaphene 

components could be excreted unchanged. However, it is possible that some metabolite residues may 

share chromatographic properties similar to the original component of toxaphene. 

Pollock and Kilgore (1980b) also extracted the lipid tissue of rats treated with either 14C-labeled 

toxaphene, Fraction 2, or Fraction 7. Fractions 2 and 7 are nonpolar and polar components, respectively, 

of toxaphene obtained from chromatographic separation of the toxaphene mixture. When compared to 

the chromatograms of extracts from fat fortified with 14C-toxaphene, the fat of treated rats had 12% more 

activity in its polar region. Chromatograms of fat extracts from rats treated with each fraction indicated 

that two additional compounds were generated that accounted for 11% of the administered activity. With 

Fraction 2, the additional compounds were of greater polarity. In contrast, the additional compounds 

generated from Fraction 7 were less polar. The decreased polarity of these metabolites may result in their 

persistence in the fat and decrease the excretion of Fraction 7. The study does not indicate whether these 

new compounds were identical. 

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Metabolism of toxicant B (2,2,5-endo-6-exo-8,9,10-heptachlorobornane), a toxic component of 

toxaphene, yielded several fecal metabolites when administered orally to mice, rats, hamsters, guinea 

pigs, rabbits, monkeys, and chickens (Saleh et al. 1979). The greatest amount of fecal metabolites was 

seen in monkeys and rabbits (20%), with 3–9% in other species, indicating that species differ with respect 

to metabolic rate and/or pathway (Saleh et al. 1979). The extensive metabolism seen in monkeys suggests 

that similar findings may result in humans; however, urinary metabolites were not monitored. 

The chromatographic pattern of these fecal metabolites was characterized by short retention times, which 

suggested that dechlorination occurred (Ohsawa et al. 1975; Saleh and Casida 1978; Saleh et al. 1979). In 

several in vitro systems, especially in rat microsomes under anaerobic conditions with NADPH, and in 

rats under in vivo conditions, toxicant B is dechlorinated at the germinal dichloro group to yield 3,5-endo6-exo-8,9,10-hexachlorobornane (II) and 2-exo-5-endo-6-exo-8,9,10-hexachlorobornane (III) 

(Figure 3-3). Toxicant B is also dehydrodechlorinated to 2,5-endo-6-exo-8,9,10-hexachloroborn-2,3-ene 

(IV) and 2,5-endo-8,9,10-pentachlorotricyclene (V) in rats in vivo and in other in vitro systems (Saleh and 

Casida 1978). There is no evidence that humans either do or do not metabolize toxaphene via this 

pathway. 

Rat liver microsomes did not transform metabolite I unless they were fortified with NADPH, indicating 

that cytochrome P-450 was required. Furthermore, the direction of metabolism was dependent upon the 

oxidative conditions. Only under anaerobic conditions did dechlorination of toxicant B occur, yielding 

metabolites II and III. Since most gastrointestinal reactions are anaerobic, it follows that metabolites II 

and III would also be present in the feces (Saleh and Casida 1978). The hexachlorobornane ratio (III/II) 

was relatively equivalent in the feces, fat, and liver of rats treated with toxicant B, in addition to the 

microsomal system. The consistency of this ratio suggested that the mechanism involved in this reaction 

was similar among tissues (Saleh and Casida 1978). An alternative (and perhaps more likely) explanation 

is that most of the metabolism occurs in the anaerobic conditions of the intestine. Then compounds II and 

III are absorbed and distributed to the various tissues, thus keeping the original ratio found in the 

intestines. 

Dechlorination of toxicant B resulted under aerobic conditions in the generation of five nonhydroxyl 

compounds in rat microsomes fortified with NADPH (Chadurkar and Matsumura 1979). As reported by 

Saleh and Casida (1978), toxicant B was metabolized to a greater extent under anaerobic conditions than 

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under aerobic conditions. It is possible that this dechlorination reaction was representative of reductive 

reactions that would be more favorably executed under anaerobic conditions. 

Metabolites II and III were not produced under aerobic conditions. However, other unidentified products 

were generated. The requirement of NADPH and anaerobic conditions for production of metabolites II 

and III suggests the involvement of the mixed function oxidase systems (Chadurkar and Matsumura 1979; 

Saleh and Casida 1978). 

Acetonitrile extracts of feces and urine from rats receiving a single oral dose of 14C-toxaphene at 

15 mg/kg confirmed previously discussed findings that most of the toxaphene was metabolized. Gasliquid chromatography/electron capture (GLC/EC) analysis of TLC fractions from urine and feces 

revealed the presence of methylation products. This showed that fecal and urinary metabolites included 

acidic and other hydroxyl compounds (Chadurkar and Matsumura 1979). Further analysis indicated that 

approximately 9 and 1% of the urinary and fecal metabolites, respectively, were sulfate conjugates. 

Glucuronide conjugates comprised 9.5 and 7.5% of the urinary and fecal metabolites, respectively. The 

presence of sulfate and glucuronide conjugates supported the conclusion that oxidative metabolism 

occurred. 

Drenth et al. (1998) noted that toxaphene induced hepatic CYP450 activity in the rat at a single oral dose 

level of 40 mg/kg, but not at lower dose levels. 

Toxaphene has been shown to induce selected CYP450 isozymes both in vitro and in vivo. Hedli et al. 

(1998) reported dose-related increased levels of total CYP450 and cytochrome b5 in hepatic microsomal 

fractions from male CD-1 mice administered toxaphene by daily gavage for 7 days at doses of 0, 10, 25, 

50, or 100 mg/kg/day. Significant, toxaphene-induced increases in immunodetectable levels of CYP2B, 

but not CYP4A1, were detected. Dehn et al. (2005) observed significantly increased CYP1A and CYP2B 

activities in human HepG2 cells exposed to toxaphene for 24 hours at high concentrations (1, 5, or 

10 mM) or 48 hours at lower concentrations (0.01–1 mM). The increases in CYP2B were of greater 

magnitude than those of CYP1A. Dehn et al. (2005) noted that glutathione levels declined when CYP2B 

activity was significantly elevated, but increased significantly in the absence of significant CYP450 

activation, suggesting that activities of glutathione and CYP450 isozymes may influence one another. 

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3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

No human or animal data were located regarding excretion following known inhalation exposure to 

toxaphene. 

3.4.4.2 Oral Exposure 

It is evident from distribution studies that toxaphene and its metabolites are not persistent in tissues; 

36Cl-labeled metabolites remained for 9 days and 14C-labeled metabolites remained for 16 days in the fat 

of animals. Metabolism studies indicate that toxaphene is rapidly and extensively biodegraded. 

Consequently, the rate of toxaphene elimination is very high. Table 3-7 summarizes excretion results 

from studies in which rats were orally administered radiolabeled toxaphene and its components. 

An average of 52.6% of an orally administered 20 mg/kg 36Cl-toxaphene dose was excreted over 9 days 

(approximate half-life of excretion). Approximately 30% of this amount was excreted in the urine and 

70% was excreted in the feces. Fecal excretion reached a plateau 2–3 days after administration. The 

cumulative urinary excretion steadily increased over the 9 days. Much of the activity in the urine and 

feces was attributable to the 36Cl-chloride ion. Therefore, dechlorination is a principal metabolic route of 

toxaphene that facilitates its elimination (Crowder and Dindal 1974). In an excretion study conducted by 

Ohsawa et al. (1975) in rats with 36Cl-toxaphene, a 13 mg/kg dose resulted in the excretion of 76% of the 

radioactivity after 14 days. Approximately 50% of the activity was detected in the urine. The amount of 

activity excreted in the urine apparently followed the pattern established by Crowder and Dindal (1974) 

where the cumulative urinary excretion of the dose steadily increased and eventually equaled the fecal 

elimination. Ohsawa et al. (1975) also found that the 36Cl-chloride ion appeared almost entirely in the 

urine. The half-time for the elimination of 36Cl was 2–3 days, a rate equivalent to the excretion of 

36Cl-sodium chloride. 

Rats treated orally with 8.5 and 19 mg/kg of 14C-toxaphene showed no dose-related differences with 

respect to the excretion of radioactivity (Ohsawa et al. 1975). After 14 days, >50% of the total activity 

was excreted in urine. Only 8–12% of the dose detected in the feces was suspected of being parent 

compound. The remainder of the activity in the urine and the feces was thought to be partially or 

completely dechlorinated products. 

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Table 3-7. Summary of Excretion Data: Percentage of Dose Excreted in
 

Urine and Feces Following Oral Administration to Rats of
 

Radiolabeled Toxaphene and its Components
 

Chemical 

Dose 

(mg/kg) Vehicle 

Days after 

administration 

Percent dose 

Urine Feces Reference 

36Cl-Toxaphene 20 Peanut oil/gum acacia 1 1.5 23.4 Crowder and Dindal 

1974 

36Cl-Toxaphene 20 Peanut oil/gum acacia 9 15.3 37.3 Crowder and Dindal 

1974 

36Cl-Toxaphene 

14C-Toxaphene 

14C-Toxaphene 

14C-Toxaphene 

14 

8.5 

19 

2.6 

Corn oil 

Corn oil 

Corn oil 

Olive oil 

14 

14 

14 

5 

49.1 

21.3 

31.8 

22.0 

26.9 

34.7 

27.8 

28.3 

Ohsawa et al. 1975 

Ohsawa et al. 1975 

Ohsawa et al. 1975 

Pollock and 

Hillstrand 1982 

14C-Toxaphene 10 Olive oil 7 22.5 35.7 Pollock and Kilgore 

1980b 

14C-Fraction 2 1 Olive oil 7 30.8 38.6 Pollock and Kilgore 

1980b 

14C-Fraction 7 0.6 Olive oil 7 23.5 32.6 Pollock and Kilgore 

1980b 

14C-Toxicant A 0.84 Corn oil 14 28.3 38.4 Oshawa et al. 1975 

14C-Toxicant B 2.6 Corn oil 9 26.7 47.8 Ohsawa et al. 1975 

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Radiolabeled toxicants A and B, obtained by chromatographic separation of 14C-toxaphene, were orally 

administered to rats at doses of 0.84 and 2.6 mg/kg, respectively. Radioactivity from the 14C-radiolabeled 

toxicants was excreted rapidly and to a slightly greater extent than toxaphene (Ohsawa et al. 1975). 

Parent compounds constituted only 8.6 and 2.6% of the fecal residues of toxicants A and B, respectively. 

However, the dosages used were lower than for toxaphene, and only one animal was tested. Rats orally 

administered 10 mg/kg 14C-toxaphene in olive oil excreted 58% of the total activity in urine and feces 

within 7 days after administration (Pollock and Kilgore 1980b). This agreed closely with the excretion 

pattern reported by Ohsawa et al. (1975). Rats were also orally administered the 14C-labeled isolated 

fractions of toxaphene, Fraction 2 and Fraction 7, which are nonpolar and polar, respectively. Of these 

three compound mixtures, the greatest percentage of excreted dose was seen with Fraction 2; the least was 

seen with Fraction 7. The metabolites derived from polar Fraction 7 were less polar, which resulted in 

greater persistence in fat and a reduced rate of excretion. In contrast, the nonpolar Fraction 2-derived 

polar metabolites were more rapidly excreted. Radioactivity measured in the urine of rats receiving 

Fraction 2 was significantly higher than from those administered Fraction 7 or toxaphene. 

Another possible explanation for the unexpected order of excretion is the unexplained contribution of 

methanol-insoluble activity in the feces. Only the methanol-extractable activity was reported. Ohsawa et 

al. (1975) reported that some fecal radioactivity was methanol-insoluble and was not detected. 

Consequently, this may have significantly altered the measurements of total excreted activity. Less polar 

metabolites from Fraction 7 may be present in the methanol-insoluble extract from feces. 

Excretion of radioactivity derived from 14C-toxaphene in pregnant rats was found to be similar to that of 

virgin female rats (Pollock and Hillstrand 1982). Although there was a weight difference between the 

pregnant and nonpregnant rats, approximately 50% of the total activity was excreted in the urine and 

feces over 5 days after the oral administration of 2.6 mg/kg in olive oil. The increased amount of fatty 

tissue had no effect on the excretion of 14C-toxaphene. 

Toxaphene fed to cows in their feed at levels of 20, 60, 100, and 140 ppm for 8 weeks was excreted at all 

dosage levels. Residues in milk increased rapidly and reached a maximum within 4 weeks after feeding 

commenced. The levels of toxaphene found in milk were dose-dependent. Upon the cessation of 

toxaphene administration, there was a rapid decrease in toxaphene residues in the milk. The rate of 

decrease was the same at all dosage levels during the 1st week. Decreases in milk levels after the first 

week were slower for animals fed toxaphene at levels >20 ppm (Claborn et al. 1963), as shown in 

Table 3-8. Detectable amounts of toxaphene were found in the milk of cows 7–9 days after feeding of 

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Table 3-8. Toxaphene Levels in Milk from Cows Fed Toxaphene in Their Diet 

Concentration of milk (ppm)a 

Weeks after cessation of 

Diet concentration Weeks of feeding toxaphene feeding 

(ppm) 1 4 8 1 3 

20 0.20 0.36 0.23 0.07 – 

60 0.56 0.68 0.48 0.13 0.07 

100 0.87 1.15 0.91 0.15 0.12 

140 1.44 1.89 1.82 0.32 0.20 

a

Values represent means of three samples. 

Source: Claborn et al. 1963 

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toxaphene at levels of 2.5–20 ppm commenced (Zweig et al. 1963). As with the higher feeding levels 

discussed above (Claborn et al. 1963), plateaus were achieved after the fourth week, except at the lowest 

dose of 2.5 ppm, where a maximum was achieved at 9 days. The animals were fed toxaphene for 1– 

2.5 months. Toxaphene was no longer detected in the milk within 14 days after cessation of toxaphene 

administration (Zweig et al. 1963). 

The high concentration of radioactivity in the gall bladder from 14C-toxaphene orally administered to 

quail confirmed the likelihood that the biliary pathway plays an important role in toxaphene excretion 

(Biessmann et al. 1983). 

The detection of toxaphene residue in human breast milk samples is testament to its pharmacokinetics in 

humans. Ingestion of contaminated food and/or water is the most likely primary source of exposure. 

Toxaphene residues were detected at a mean concentration of 67.7 ng/g fat in human milk samples 

collected between July 1996 and April 1997 from 12 residents of Kewatin, an arctic region of northern 

Canada (Newsome and Ryan 1999). Mean toxaphene residue concentrations ranging from 6.03 to 

12.1 ng/g fat were determined from human milk samples that had been collected from other regions of 

Canada at earlier times (Newsome and Ryan 1999). Toxaphene residues detected in breast milk samples 

from women living in different parts of Finland were estimated to be 10 ng/g fat (Mussalo-Rauhamaa et 

al. 1988). Toxaphene-like chlorinated bornanes have been measured in breast milk samples from women 

in areas of Russia (Polder et al. 1998, 2003), Germany (Skopp et al. 2002b), and Hong Kong and south 

China (Hedley et al. 2010). 

3.4.4.3 Dermal Exposure 

No human data were located regarding excretion following dermal exposure to toxaphene. 

Information regarding the excretion of toxaphene in animals following dermal absorption is limited. 

Evidence for the excretion of toxaphene in milk is found in a study conducted with cows that were 

sprayed twice daily with 1 ounce of 2.0% toxaphene oil solution or sprayed twice at 3-week intervals with 

0.5% sprays of toxaphene. Residues of toxaphene in milk resulting from daily oil sprays reached a 

maximum after the third day of spraying. When cows were sprayed twice at 3-week intervals, maximum 

residues in milk were detected 1 or 2 days after spraying (Claborn et al. 1963). Cows that were dipped in 

a solution containing 0.25% toxaphene also excreted toxaphene in the milk at levels of 21–45 ppm 1 day 

after dipping. Toxaphene levels fell to 5 ppm 19 days after exposure ceased (Keating 1979). The 

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absorption, distribution, and excretion of toxaphene were evident from these studies, but insufficient 

information regarding the dose of toxaphene precludes any estimation of the extent and rate of excretion. 

3.4.4.4 Other Routes of Exposure 

Mohammed et al. (1983) reported that 14C-toxaphene was rapidly distributed to most tissues and organs 

following intravenous administration in mice. Between 20 minutes and 4 hours after injection, there was 

a significant increase in the radioactivity observed in the intestinal contents. The presence of radioactivity 

in the intestine probably represented the biliary excretion of 14C-toxaphene and its metabolites. Sixteen 

days after administration, the tissue showing the highest concentration of 14C toxaphene was abdominal 

fat, which had concentrations about 10% of those found 4 hours after administration. 

Based on the rapid and extensive metabolism seen in all animals, the fate of toxaphene in humans is 

probably similar. The negligible quantities of parent compound in the excreta and the lack of persistence 

of metabolites in the tissues indicate that toxaphene and its components are readily removed from the 

body. Low-level exposure is not expected to cause significant harm to humans. Theoretically, however, 

acute high-level exposure may saturate metabolic pathways and consequently allow toxaphene to 

accumulate in the tissues for a longer period of time (>16 days). 

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 

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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 

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 3-4 shows a conceptualized representation of a PBPK model. 

If PBPK models for toxaphene 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. 

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Figure 3-4. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a
 

Hypothetical Chemical Substance
 

Inhaled chemical Exhaled chemical 

Ingestion 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax 

Km GI 

Tract 

Feces 

Urine

 Chemicals 

contacting skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

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. 

Source: adapted from Krishnan and Andersen 1994 

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Wen and Chan (2000) developed a two-compartment pharmacokinetic model to predict absorption, 

elimination, and tissue burden of toxaphene in rats; it does not incorporate data regarding 

biotransformation or clearance of toxaphene metabolites. The model includes six tissue compartments 

(blood, brain, liver, muscle, fat, and carcass) and incorporates dose-dependent flux rates and first-order 

absorption and elimination kinetics. Time-course tissue distribution data from male albino rats 

administered 36Cl-toxaphene served as basis for model development. The model was partially validated 

using time-course tissue distribution and depuration data from pregnant Sprague-Dawley rats 

administered 14C-toxaphene orally. Pharmacokinetically based dosimetry indicated that absorption of 

toxaphene was fast in fat, whole body, carcass, and blood; relatively slow in liver and muscle; and slow in 

brain. Elimination was rapid in whole body, muscle, and blood; moderate in carcass and brain; and slow 

in liver and fat. Tissue burden was highest in fat, whole body, and blood; intermediate in liver; and 

lowest in brain. In male rats, fecal and urinary excretion represented the major and minor elimination 

routes, respectively. Fecal and urinary excretion were of approximately equal magnitude in pregnant 

female rats. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Pharmacokinetic mechanisms of action for toxaphene have not been well studied. Toxaphene is rapidly 

absorbed by the gastrointestinal tract and lungs. Absorption through the skin can also occur, but appears 

to be less efficient because dermal doses that cause overt toxicity in laboratory animals are an order of 

magnitude higher than those causing similar toxicity following oral exposure. Toxaphene is more rapidly 

absorbed if it is mixed in oily (lipophilic) solvents, probably because interactions with polar areas on the 

cell membrane are reduced. Once absorbed, toxaphene rapidly distributes to all organs of the body; 

however, the pesticide tends to concentrate in fatty tissues and muscle from which it is slowly released 

over a period of weeks. Circulating toxaphene is primarily metabolized by hepatic mixed-function 

oxidases. Toxaphene and its metabolites are excreted in the feces and urine, and most of it is eliminated 

from the body within a few days. 

3.5.2 Mechanisms of Toxicity 

Toxaphene-induced neurological effects may result from a general disruption of nervous system function. 

Toxaphene has been shown to inhibit brain ATPases (Fattah and Crowder 1980; Moorthy et al. 1987; 

Morrow et al. 1986; Rao et al. 1986; Trottman and Desaiah 1979; Trottman et al. 1985). Results of in 

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vitro assays performed by Morrow et al. (1986) indicated that polar toxaphene fractions were more potent 

inhibitors of rat brain ATPase than other nonpolar or intermediate polar fractions or even toxaphene itself. 

Pollock and Kilgore (1980a) reported that nonpolar fractions of toxaphene were more toxic to houseflies 

and mice (in vivo) than polar fractions. Morrow et al. (1986) proposed that this discrepancy may be 

explained by the fact that in vivo, the ATPases are membrane-bound in a hydrophobic environment, 

whereas preparation of cell membranes in the in vitro assays could cause disruption within the 

hydrophobic environment and result in the exposure of polar groups. In any event, diminished ATPase 

activity in nervous tissue could have a profound effect on neural transmission because of the tissue's high 

metabolic rate. 

Several investigators have demonstrated that toxaphene inhibits ATPases in the liver and kidney as well 

(e.g., Fattah and Crowder 1980; Mourelle et al. 1985; Trottman and Desaiah 1979; Trottman et al. 1985). 

These enzymes are involved in all aspects of cellular activity, and their inhibition can ultimately result in 

disturbances in hepatic and renal function, which could trigger injury responses. 

Toxaphene has the potential to alter central nervous system neurotransmitter activity. Toxaphene acted as 

a noncompetitive γ-aminobutyric acid (GABA-A) antagonist at the chloride channel (also known as the 

picrotoxin binding site) in brain synaptosomes (Lawrence and Casida 1984; Matsumura and Tanaka 

1984). GABA is an inhibitory neurotransmitter; antagonism of GABAergic neurons within the central 

nervous system leads to generalized central nervous system stimulation by inhibiting chloride influx, 

leading to hyperpolarization and increased neuronal activity. Moreover, the ability of toxaphene to 

induce convulsions is closely related to its affinity for the picrotoxin binding site. Toxaphene has also 

been shown to alter catecholamine metabolism in the brain (Kuz'minskaya and Ivanitskiĭ 1979). 

Kuz'minskaya and Alekhina (1976) and Gertig and Nowaczyk (1975) reported that both short- and longterm oral administration of toxaphene to rats caused disturbances in energy metabolism as evidenced by 

changes in hepatic lactate dehydrogenase activity. However, results of Peakall (1979) indicated that these 

changes are not severe enough to have definite physiological consequences (measured as serum lactate 

and pyruvate levels) under nonstress conditions. The results of Kuz'minskaya and Alekhina (1976) and 

Gertig and Nowaczyk (1975) suggest that toxaphene exposure, coupled with stress, could result in 

detrimental effects on hepatic energy utilization and, ultimately, in hepatic injury. 

Mechanisms responsible for toxaphene-induced immunosuppressive effects in laboratory animals are not 

presently known. Gauthier and coworkers demonstrated that toxaphene induces phagocytosis, production 

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of reactive oxygen species (ROS), and apoptosis in human neutrophils in vitro (Gauthier et al. 2001), and 

that caspases and ROS are likely involved in the degradation of cytoskeletal proteins (Lavastre et al. 

2002). 

Possible modes of action for toxaphene carcinogenicity have been assessed to some extent; available 

information is summarized in reports of de Geus et al. (1999), Goodman et al. (2000), and Lamb et al. 

(2008). Results of available in vivo genotoxicity assays have not demonstrated a genotoxic response. 

Although toxaphene was mutagenic in bacterial systems in the absence of metabolic activation, the 

mutagenic effect was reduced or abolished in the presence of metabolic activation; this finding suggests 

that toxaphene may be inactivated in vivo. There was no evidence of toxaphene-induced DNA adduct 

formation or peroxisomal proliferation in hepatic DNA or microsomes from mice administered toxaphene 

at oral doses as high as 100 mg/kg; however, these mice exhibited significant increases in 

immunodetectable levels of hepatic CYP 2B (Hedli et al. 1998). Toxaphene-induced increases in hepatic 

CYP 2B levels and liver enlargement are consistent with the action of phenobarbital, a nongenotoxic 

rodent liver tumor promoter. Toxaphene and phenobarbital have each been shown to inhibit intercellular 

communication, a possible mode of nongenotoxic carcinogenicity. The weight of evidence presently 

suggests a nongenotoxic mode of action for toxaphene tumorigenicity. 

3.5.3 Animal-to-Human Extrapolations 

Due to a lack of information regarding potential interspecies differences in the toxicokinetics of 

toxaphene, it is assumed that humans and animals share similar metabolic pathways. Comparative 

information regarding the toxic effects of toxaphene is limited to findings of similar neurological effects 

in humans and laboratory animals following exposure to high levels of toxaphene. In the absence of 

information regarding other systemic effects of toxaphene toxicity in humans, it is assumed that the 

systemic effects observed in laboratory animals are of human relevance as well. 

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 Thomas and Colborn (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 

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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 

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). 

Results of some assays suggest that toxaphene may be weakly estrogenic. Toxaphene was reported to 

induce weak estrogenic effects in most assays of human breast estrogen-sensitive MCF7 cells (Jørgensen 

et al. 1997; Soto et al. 1994, 1995; Stelzer and Chan 1999) and one assay of rat uterine leiomyomaderived cells (Hodges et al. 2000). In an assay that employed human hepatoma cells transfected with 

estrogen receptor and luciferase reporter gene, Kim et al (2004) reported that toxaphene exerted an 

agonistic effect on estrogen receptor α and an antagonistic effect on estrogen receptor β. Results of 

Graham et al. (2003) indicate that toxaphene may exhibit estrogen-like activity by modulating prolactin 

mRNA levels in GH3 pituitary-derived cells. Toxaphene did not induce an estrogenic response in other 

assays using mouse uterus cells and MCF7 cells (Arcaro et al. 2000; Ramamoorthy et al. 1997) or yeastbased estrogen reporter genes (Ramamoorthy et al. 1997; Rehmann et al. 1999). Yang and Chen (1999) 

reported that toxaphene acted as an antagonist of estrogen-related receptor α-1. Drenth et al. (2000) 

reported that technical toxaphene exerted an antiestrogenic effect in stably transfected human T47D.Luc 

breast cancer cells. 

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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 

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, 

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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). 

It is not known whether children are more susceptible than adults to toxaphene toxicity. No human data 

are available regarding age-related susceptibility to toxaphene. Results of one animal study (Olsen et al. 

1980) indicate that critical stages of neurological development may be periods of increased vulnerability. 

Olson et al. (1980) reported significantly retarded swimming ability and righting reflex in 10–12-day-old 

pups of rat dams that ingested toxaphene throughout gestation and lactation; however, the effect was 

transient and pups exhibited normal swimming ability at testing on postpartum day 16. 

Immunosuppression has been demonstrated in some animals exposed to toxaphene (Allen et al. 1983; 

Koller et al. 1983; Tryphonas et al. 2001). Infants and children are especially susceptible to 

immunosuppression because their immune systems do not reach maturity until 10–12 years of age 

(Calabrese 1978). 

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). 

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, 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 

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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 

toxaphene 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 

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 toxaphene 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. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Toxaphene 

Following acute exposure to high doses, toxaphene can be readily detected in human blood (Griffith and 

Blanke 1974; Taylor et al. 1979; Tewari and Sharma 1977). If exposure is via inhalation, however, 

absorption is probably not sufficient to yield quantifiable levels in the blood (EPA 1980a). Toxaphene 

and/or toxaphene residues have been detected in breast milk, urine, stomach washings, umbilical cord 

blood, and adipose tissue samples from children (Munn et al. 1985; Tewari and Sharma 1977; Vaz and 

Blomkvist 1985; Butler Walker et al. 2003; Witt and Niessen 2000). Tissue samples taken from dogs 

sacrificed at intervals in a 2-year study demonstrated that levels of toxaphene in fat were proportional to 

the levels in the feed, and that tissue levels were essentially stable over the period of 2 years (Hercules 

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Research Center 1966). Levels detected in tissues generally reflect only very recent exposures (<1 week) 

because toxaphene is rapidly cleared from the body. Metabolites of toxaphene are excreted 

predominantly in the urine and feces; however, analytic procedures for detecting toxaphene metabolites 

are not sensitive or reliable enough to allow for screening for metabolites in the blood or excreta. 

3.8.2 Biomarkers Used to Characterize Effects Caused by Toxaphene 

Toxaphene causes a number of physiological effects including central nervous system excitation, liver 

enzyme induction, renal tubular degeneration, and immune suppression. However, none of these effects 

is specific to toxaphene exposure. 

For more information on biomarkers for renal and hepatic effects of chemicals see Agency for Toxic 

Substances and Disease Registry/CDC (1990) and for information on biomarkers for neurological effects, 

see OTA (1990). 

3.9 INTERACTIONS WITH OTHER SUBSTANCES 

Toxaphene is likely to interact with other chemicals, such as other pesticides, that also induce hepatic 

microsomal mixed-function oxidase systems. For example, Deichmann and Keplinger (1970) observed 

that the toxaphene 96-hour LD50 values were increased by about 2 times in rats pretreated with aldrin and 

dieldrin, and these values were increased by about 3 times in rats pretreated with DDT. Aldrin, dieldrin, 

and DDT are all known to induce microsomal enzymes. Equitoxic concentrations of toxaphene plus 

parathion, diazinon, or trithion yielded LD50 values that were higher than expected based on an 

assumption of additivity, indicating that toxaphene antagonized the lethal effects of these three pesticides 

(Keplinger and Deichmann 1967). 

Another example of microsomal enzyme induction by toxaphene resulting in altered activity of other 

chemicals was reported by Jeffery et al. (1976). They described the case of a farmer who was being 

treated with warfarin for thrombophlebitis and was observed to have a loss of warfarin effect that 

coincided with exposures to a toxaphene-lindane insecticide. The authors concluded that the toxaphene 

mixture induced the hepatic microsomal enzymes (for up to 3 months), thereby increasing the metabolism 

of warfarin. 

Triolo et al. (1982) investigated the effects of toxaphene administered in the diet on benzo(a)pyrene 

(BP)-induced lung tumors in mice (BP was administered by oral intubation). There was no increase in the 

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incidence of these tumors when toxaphene was administered alone, but toxaphene significantly reduced 

the incidence of BP-induced lung tumors when given in combination. This reduction correlated with a 

toxaphene-induced reduction in BP hydroxylase activity in the lung. The results of this study suggest that 

toxaphene antagonizes the tumorigenic effect of BP, possibly by inhibiting the biotransformation of BP to 

a reactive metabolite or by promoting degradative metabolism of BP to nonactive forms in the target 

tissue. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to toxaphene than will most 

persons exposed to the same level of toxaphene 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 toxaphene, or compromised function of 

organs affected by toxaphene. Populations who are at greater risk due to their unusually high exposure to 

toxaphene are discussed in Section 6.7, Populations with Potentially High Exposures. 

Subsets of the human population that may be unusually susceptible to the toxic effects of toxaphene 

include pregnant women, their fetuses, nursing babies, young children, people with neurologic diseases 

(particularly convulsive disorders), and individuals with protein-deficient diets. Others at increased risk 

include people with hepatic, renal, or respiratory diseases, those with immune system suppression, and 

those ingesting alcohol or consuming therapeutic or illicit drugs. 

Pregnant women, fetuses, nursing infants, and very young children may be at greater risk of adverse 

health effects from pesticide exposure than the general population (Calabrese 1978). Exposure to 

organochlorine insecticides, such as toxaphene, may adversely affect reproductive physiology (i.e., 

hormonal balance) in certain women (Calabrese 1978). Embryos, fetuses, and neonates up to age 2– 

3 months may be at increased risk of adverse effects following pesticide exposure because their enzyme 

detoxification systems are immature (Calabrese 1978). Animal studies suggest that detoxification of the 

toxaphene mixture may be less efficient in the immature human than the metabolism and detoxification of 

the single components such as toxicant A or B (Olson et al. 1980). Infants and children are especially 

susceptible to immunosuppression because their immune systems do not reach maturity until 10–12 years 

of age (Calabrese 1978). 

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Placental transfer of toxaphene has been documented in animals (Pollock and Hillstrand 1982). 

Toxaphene residues have also been detected in the milk of exposed cows (Claborn et al. 1963; Zweig et 

al. 1963). Adverse effects have been observed in the offspring of experimental animals exposed to 

toxaphene during gestation and nursing at doses that typically elicited maternal toxicity. Results of 

experimental studies indicate that maternal toxaphene exposure may induce behavioral effects in neonates 

and in nursing babies (Crowder et al. 1980; Olson et al. 1980). Toxaphene exposure during gestation and 

nursing has been suggested to be associated with immunosuppression in offspring (Allen et al. 1983). 

Other effects of maternal toxaphene exposure observed in the offspring were histologic changes in fetal 

liver, thyroid, and kidney tissues (Chu et al. 1988). 

Toxaphene exposure by inhalation, ingestion, or dermal application has induced neurotoxic effects 

manifested in part by seizures and other functional, biochemical, and morphological alterations (Badaeva 

1976; Dille and Smith 1964; DiPietro and Haliburton 1979; Kuz'minskaya and Ivanitskiĭ 1979; Lawrence 

and Casida 1984; McGee et al. 1952; Wells and Milhorn 1983). Persons with latent or clinical neurologic 

diseases may be at an increased risk of adverse effects following toxaphene exposure. 

Persons consuming diets deficient in protein may also be at increased risk of adverse effects from 

exposure to toxaphene. It has been estimated that 30% of women and 10% of men aged 30–60 ingest less 

than two-thirds of the required daily allowance (RDA) for protein (Calabrese 1978). An experimental 

study showed that central nervous system effects occurred sooner and at lower doses in rats ingesting 

toxaphene and diets deficient in protein (Boyd and Taylor 1971). 

People with liver disease of a genetic origin (i.e., Gilbert's syndrome) and viral infections are at increased 

risk of developing toxic effects due to insecticide exposure (Calabrese 1978). Liver effects have been 

observed in both humans and animals following acute exposure to toxaphene. Liver enzymes were 

transiently elevated in a young man who attempted suicide by ingesting toxaphene (Wells and Milhorn 

1983). Liver effects were observed in experimental studies with animals following acute, intermediate, or 

chronic exposure to toxaphene (Allen et al. 1983; Boyd and Taylor 1971; Chandra and Durairaj 1992, 

1995; Chu et al. 1986, 1988; Garcia and Mourelle 1984; Gertig and Nowaczyk 1975; Hedli et al. 1998; 

Kennedy et al. 1973; Koller et al. 1983; Kuz'minskaya and Alekhina 1976; Lackey 1949; Mehendale 

1978; Peakall 1976; Trottman and Desaiah 1980). 

Persons with diseases that affect renal, adrenal gland, or respiratory function may be at increased risk of 

adverse effects due to toxaphene exposure. Renal function was temporarily affected in a young man who 

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attempted suicide by ingesting toxaphene (Wells and Milhorn 1983). Respiratory function was adversely 

affected in two men occupationally exposed to toxaphene (Warraki 1963). The kidney (Boyd and Taylor 

1971; Chu et al. 1986; Fattah and Crowder 1980; Trottman and Desaiah 1979; Trottman et al. 1985) and 

adrenal gland (Kuz'minskaya and Ivanitskiĭ 1979; Mohammed et al. 1985) are recognized as target organs 

of toxaphene toxicity in experimental animals. 

People susceptible to the toxic effects of toxaphene may develop compromised immune function. People 

with suppressed immune systems may also be at increased risk of developing more severe effects from 

toxaphene exposure. Toxaphene has produced primarily humoral immunosuppressive effects in 

experimental animals (Allen et al. 1983; Koller et al. 1983; Tryphonas et al. 2001). 

The induction of hepatic microsomal enzymes, such as mixed function oxidases, by pesticides such as 

toxaphene may also affect the metabolism of some drugs and alcohol (Calabrese 1978). The efficacy of 

prescription drugs may be reduced because of the increased rate of metabolism. For example, Jeffery et 

al. (1976) observed a decrease in the effectiveness of warfarin in a farmer who had been exposed to a 

toxaphene-lindane insecticide. Furthermore, because toxaphene is a neurotoxic agent, neurological 

effects associated with other agents or drugs may be exacerbated in persons exposed concomitantly to 

toxaphene. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to toxaphene. 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 toxaphene. 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 toxaphene: 

Dart RC, ed. 2004. Pesticides. In: Medical toxicology. 3rd ed. Philadelphia, PA: Lippincott Williams 

& Wilkins, 1489-1496. 

Holland MG. 2002. Insecticides: Organochlorines, pyrethrins, and DEET. In: Goldfrank LR, 

Flomenbaum NE, Lewin NA, et al., eds. Goldfrank’s toxicologic emergencies. 7th ed. New York, NY: 

Mc-Graw-Hill Medical Publishing Division, 1366-1378. 

Leikin JB, Paloucek FP, eds. 2002. Leikin and Paloucek's poisoning and toxicology handbook. 3rd ed. 

Hudson, OH: Lexi-Comp, Inc., 1199. 

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Rhee JW, Aks SE. 2007. Organochlorine insecticides. In: Shannon MW, Borron SW, Burns MJ, eds. 

Haddad and Winchester’s clinical management of poisoning and drug overdose. 4th ed. Philadelphia, 

PA: Saunders Elsevier, 1231-1236. 

3.11.1 Reducing Peak Absorption Following Exposure 

Human exposure to toxaphene may occur by inhalation, ingestion, or by dermal contact. Toxaphene and 

other chlorinated hydrocarbons are efficiently absorbed from the gastrointestinal tract, particularly in the 

presence of dietary lipids. Although relatively nonvolatile, absorption following inhalation exposure to 

dusts and sprays probably occurs through mucociliary trapping and transport followed by gastrointestinal 

absorption. Toxaphene caused toxicosis following dermal application of the pesticide to farm animals; 

therefore, absorption across the skin is a health concern as well. 

For oral exposure, do not induce emesis. Gastric lavage may be considered if the patient presents in a 

timely manner. Precaution should be taken to avoid aspiration, however. Activated charcoal may be 

administered to potentially decrease absorption following ingestion, although the efficacy of this 

treatment is uncertain. 

For inhalation exposure, treatment commonly includes moving the exposed individual to fresh air, then 

monitoring for respiratory distress. Injuries to the airways and lungs are likely to be manifested as severe 

respiratory irritation and persistent cough. Provide emergency airway support and 100% humidified 

supplemental oxygen with assisted ventilation if needed. 

Decontamination is the first step in reducing absorption following dermal exposure. Contaminated 

clothing should be removed. Skin should be washed with soap and water. Decontamination includes 

irrigation of the eyes with copious amounts of water or saline (if available). 

3.11.2 Reducing Body Burden 

Once absorbed, toxaphene bioaccumulates in adipose tissue and is metabolized and excreted over several 

days to a few weeks following exposure. For organochlorines that undergo enterohepatic and 

enteroenteric recirculation, cholestyramine has been administered to potentially increase fecal 

elimination, although the efficacy of this treatment for toxaphene poisoning is uncertain. Exchange 

transfusion, peritoneal dialysis, hemodialysis, and hemoperfusion are not likely to be beneficial because 

of the large volume of distribution of toxaphene, resulting in a small proportion of removable toxin. 

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3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

The most serious toxicological effects of exposure to chlorinated hydrocarbon pesticides are central 

nervous system excitability. Organochlorine compounds are thought to interfere with the normal flux of 

sodium and potassium ions across the axon membrane, disrupting central nervous system activity and 

resulting in generalized central nervous system excitation, which may lead to convulsions and seizures in 

severe cases. Toxaphene-induced central nervous system stimulation is believed to result from the 

noncompetitive inhibition of γ-aminobutyric acid-dependent chloride ion channels that are found on the 

neuron. The putative role of γ-aminobutyric acid in the central nervous system is to suppress neuronal 

activity. Thus, if its actions are blocked, neuronal activity increases. Unchecked neuronal excitation can 

lead to tremors, convulsions, seizures, and death. 

Although mechanisms of neurotoxicity vary among individual chlorinated hydrocarbon pesticides, 

toxaphene, DDT, chlordane, lindane, heptachlor, kepone, and mirex are each considered moderately toxic 

following acute oral administration (animal LD50 >50 mg/kg). Several cases of toxaphene-induced 

seizures in humans have been reported (McGee et al. 1952; Wells and Milhorn 1983). The acute 

management of seizures with anticonvulsants such as diazepam (a γ-aminobutyric acid agonist), 

phenobarbital, and phenytoin has been recommended (Schenker et al. 1992). These drugs tend to 

suppress neuronal activity, thus counteracting the stimulatory effects of toxaphene. High exposures to 

organochlorines can lead to stimulation of the peripheral nervous system. Seizure control can be achieved 

by administration of GABA agonists such as benzodiazepines; phenobarbital or propofol may be 

considered if benzodiazepines are ineffective. 

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 toxaphene 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 toxaphene. 

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 

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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 Toxaphene 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

toxaphene are summarized in Figure 3-5. The purpose of this figure is to illustrate the existing 

information concerning the health effects of toxaphene. 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 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. 

The data describing the toxic effects of toxaphene in humans are generally limited to a small number of 

case reports of toxicity following ingestion, inhalation, or dermal contact. Some controlled studies in 

humans exist, but the data are incomplete or unreliable. Thus, although human toxicity information 

exists, animal data must be considered in order to adequately assess the risk of toxaphene exposure. The 

database for the health effects of toxaphene following ingestion in experimental animals is substantial. 

However, as can be seen in Figure 3-5, very little information is available on the effects of inhalation and 

dermal exposure to toxaphene in animals. Furthermore, the health effects associated with acute-duration 

exposure are more fully characterized than those associated with intermediate or chronic-duration 

exposure. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. Limited human and animal data are available regarding effects of acuteduration inhalation exposure to toxaphene. One controlled human study reported a NOAEL of 

500 mg/m3 for repeated 30-minute exposures to toxaphene aerosols (Keplinger 1963). Animal data are 

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TOXAPHENE 101 

3. HEALTH EFFECTS 

Figure 3-5. Existing Information on Health Effects of Toxaphene 

Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Human 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Inhalation 

Oral 

Dermal 

Animal 

Existing Studies 

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TOXAPHENE 102 

3. HEALTH EFFECTS 

restricted to secondary source accounts of death and hepatocellular necrosis in laboratory animals 

exposed to toxaphene by inhalation; the primary sources for this information were unpublished reports 

that were not available to ATSDR. Data on the acute effects of inhaled toxaphene do not appear 

necessary because all uses for toxaphene have been banned in the United States and its territories (EPA 

1990b). 

No adequate human data are available regarding the effects of acute-duration oral exposure to toxaphene. 

Available animal data include acute lethality studies in multiple laboratory species (Boyd and Taylor 

1971; Chandra and Durairaj 1995; Chernoff and Carver 1976; Chernoff et al. 1990; Epstein et al. 1972; 

Gaines 1969; Jones et al. 1968; Lackey 1949). Acute-duration oral exposure to toxaphene has resulted in 

adverse effects on the nervous system, immunological system, body weight, and liver (Chandra and 

Durairaj 1995; Chernoff and Carver 1976; Chernoff et al. 1990; Chu et al. 1986; Hedli et al. 1998; Lackey 

1949; Rao et al. 1986; Steele et al. 1980; Trottman and Desaiah 1980; Waritz et al. 1996). The study of 

Chu et al. (1986) identified the highest NOAEL (5 mg/kg/day) associated with the lowest LOAEL 

(10 mg/kg/day for clinical signs of neurotoxicity in dogs) and serves as the point of departure for deriving 

an acute-duration oral MRL for toxaphene. Additional animal studies of acute-duration oral exposure to 

toxaphene are not necessary. 

Data from animal studies indicate that dermal exposure to toxaphene can be lethal, but at doses that are an 

order of magnitude higher than those for oral administration of the pesticide (Gaines 1969; Johnston and 

Eden 1953; Jones et al. 1968). Additional acute-duration dermal studies do not appear necessary because 

all uses for toxaphene have been banned in the United States and its territories (EPA 1990b). 

Intermediate-Duration Exposure. Available information regarding intermediate-duration exposure 

to toxaphene is limited to animal studies that employed the oral exposure route and identified 

neurological, hepatic, renal, developmental, and immunological end points (Allen et al. 1983; Chu et al. 

1986, 1988; Kennedy et al. 1973; Koller et al. 1983; Lackey 1949; NCI 1979; Olsen et al. 1980; 

Tryphonas et al. 2001; Waritz et al. 1996). The study of Tryphonas et al. (2001) identified the highest 

NOAEL (0.1 mg/kg/day) associated with the lowest reliable LOAEL (0.4 mg/kg/day for depressed 

humoral immunity in cynomolgus monkeys) and served as the basis for deriving the MRL. Additional 

animal studies do not appear necessary. All uses for toxaphene have been banned in the United States 

and its territories (EPA 1990b). Monitoring of workers at waste sites where toxaphene is found and 

people living in close proximity to such sites might provide useful information. Additional information 

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TOXAPHENE 103 

3. HEALTH EFFECTS 

regarding the potential for health effects in human populations consuming food sources such as fish with 

documented levels of toxaphene residues would be useful. 

Chronic-Duration Exposure and Cancer. Available information regarding noncancer and cancer 

effects is limited to chronic-duration oral studies in animals. Neurological, immunological, and body 

weight effects were reported in rats and mice (NCI 1979) and cynomolgus monkeys (Arnold et al. 2001; 

Bryce et al. 2001; Tryphonas et al. 2001) administered toxaphene orally for chronic durations. A chronicduration oral MRL was not derived for toxaphene because the study that identified the highest NOAEL 

(0.4 mg/kg/day) associated with the lowest LOAEL (0.8 mg/kg/day for significantly depressed humoral 

immune response) after 52 weeks of toxaphene treatment identified a LOAEL of 0.4 mg/kg/day for 

another measure of humoral immune response after <52 weeks of toxaphene treatment (Tryphonas et al. 

2001). Therefore, the intermediate-duration oral MRL should be protective of immunological effects 

following chronic-duration oral exposure to toxaphene. Lifetime oral studies found increased incidences 

of thyroid tumors in rats and hepatic tumors in mice exposed to high oral doses of toxaphene (NCI 1979). 

Additional chronic-duration toxicity and carcinogenicity studies in animals do not appear necessary. All 

uses for toxaphene have been banned in the United States and its territories (EPA 1990b). Monitoring of 

workers at waste sites where toxaphene is found and people living in close proximity to such sites might 

provide useful information. Additional information regarding potential for health effects in human 

populations consuming food sources such as fish with documented levels of toxaphene residues would be 

useful. 

Genotoxicity. Limited information is available regarding the genotoxicity of toxaphene in humans. A 

higher incidence of chromosomal aberrations was observed in cultured lymphocytes taken from the blood 

of eight women exposed to toxaphene compared to lymphocytes taken from unexposed women (Samosh 

1974). Additional assessment of the genotoxic potential of toxaphene would be helpful in the unlikely 

event that populations with significant exposure to toxaphene can be identified. 

Available in vivo genotoxicity data from animals are limited to a dominant lethality test in which 

toxaphene did not cause increased fetal death or decreased numbers of implants in mouse dams mated to 

males that had been administered toxaphene orally (Epstein et al. 1972); a study that reported the lack of 

DNA damage in rats administered toxaphene once by gavage at up to 36 mg/kg/day (Kitchin and Brown 

1994); and a study that found no evidence of DNA adduct formation in livers of mice administered 

toxaphene by gavage for 7 days at doses up to and including 100 mg/kg/day (Hedli et al. 1998). 

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TOXAPHENE 104 

3. HEALTH EFFECTS 

Available in vitro assays provide positive and negative results. Bacterial reverse mutation assays provide 

evidence of a mutagenic effect in the absence of metabolic activation systems (Hooper et al. 1979; 

Mortelmans et al. 1986; Schrader et al. 1998; Steinberg et al. 1998) and diminished or abolished 

mutagenic responses with the addition of metabolic activation systems (Hooper et al. 1979; Schrader et al. 

1998). Other in vitro genotoxicity assays provide equivocal results (Bartoš et al. 2005; Griffin and Hill 

1978; Houk and DeMartini 1987; Mortelmans et al. 1986; Schrader et al. 1998; Sobti et al. 1983; Steinel 

et al. 1990). Additional in vivo data would be useful to more rigorously assess the potential genotoxicity 

of toxaphene. 

Reproductive Toxicity. No information was located regarding toxaphene-induced reproductive 

effects in humans. The available information from multigeneration studies in rats indicates that 

toxaphene does not adversely affect reproductive end points (Kennedy et al. 1973; Keplinger et al. 1970). 

Additional studies do not appear necessary. 

Developmental Toxicity. No information was located regarding toxaphene-induced developmental 

effects in humans. Toxaphene was reported to cause inferior swimming and righting ability in young 

mouse pups (9–12 days postpartum, but not at 16 days postpartum) of dams administered toxaphene by 

gavage at 0.05 mg/kg/day (the only dose tested) throughout gestation and lactation (Olson et al. 1980). 

Allen et al. (1983) reported suppression of phagocytic function in peritoneal macrophages from offspring 

of rat dams receiving toxaphene in the diet at 19.5 mg/kg/day prior to mating and during gestation and 

lactation; however, phagocytic function was enhanced at a higher dose level (39 mg/kg/day). Crowder et 

al. (1980) found no evidence of developmental toxicity following oral exposure of rat dams to toxaphene 

at 6 mg/kg/day (the only dose tested) during gestation. A comprehensive developmental toxicity study 

could be designed to provide supporting or refuting evidence to the findings of Olson et al. (1980). 

Immunotoxicity. No information was located regarding immunologic effects of toxaphene in 

humans. Toxaphene-related depressed IgG production was reported in adult rats (Koller et al. 1983). 

Depressed humoral responses were noted in rat neonates exposed via their mothers (Allen et al. 1983) and 

in cynomolgus monkeys administered toxaphene orally for up to 75 weeks (Tryphonas et al. 2001). 

Additional studies of toxaphene-induced immunotoxicity in laboratory animals do not appear necessary at 

this time. 

Neurotoxicity. Neurological effects have been reported in several cases of inadvertent or intentional 

ingestion of unknown “large amounts” of toxaphene (McGee et al. 1952; Wells and Milhorn 1983). 

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TOXAPHENE 105 

3. HEALTH EFFECTS 

Convulsions were induced in dogs (Chu et al. 1986; Lackey 1949) and heifers (Steele et al. 1980) 

following acute oral exposure to toxaphene. NCI (1979) reported clinical signs of neurotoxicity in rats 

and mice administered toxaphene orally for chronic durations. The animal data indicate that dogs are 

particularly sensitive to toxaphene neurotoxicity. Additional studies of the neurological effects in 

toxaphene-exposed animals do not appear necessary. All uses for toxaphene have been banned in the 

United States and its territories (EPA 1990b). Monitoring of workers at waste sites where toxaphene is 

found and people living in close proximity to such sites might provide useful information. Additional 

information regarding the potential for health effects in human populations consuming food sources such 

as fish with documented levels of toxaphene residues would be useful. 

Epidemiological and Human Dosimetry Studies. Most of the available information on the 

effects of toxaphene in humans comes from cases of acute poisoning following accidental or intentional 

ingestion of toxaphene and from occupational exposures in agricultural industries. Limitations inherent in 

these studies include unquantified exposure concentrations and durations, and concomitant exposure to 

other pesticides. Despite their inadequacies, those studies suggest that toxaphene can adversely affect the 

liver, kidneys, lungs, and central nervous system (McGee et al. 1952; Warraki 1963; Wells and Milhorn 

1983). All uses for toxaphene have been banned in the United States and its territories (EPA 1990b). 

Monitoring of workers at waste sites where toxaphene is found and people living in close proximity to 

such sites might provide useful information. Additional information regarding the potential for health 

effects in human populations consuming food sources such as fish with documented levels of toxaphene 

residues would be useful. 

Biomarkers of Exposure and Effect. 

Exposure. Toxaphene levels have been measured in blood, fat, urine, and feces (Ohsawa et al. 1975; 

Pollock and Kilgore 1980b). No studies demonstrate a reliable correlation between blood levels and 

levels of exposure. Fat samples contain toxaphene levels proportional to treatment levels (Pollock and 

Kilgore 1980b), but fat samples are difficult to obtain from humans. Levels of toxaphene in milk fat may 

provide a more accurate estimate of exposure than body fat or blood (Keating 1979), but these samples 

can only be obtained from a small portion of the population. Because toxaphene is rapidly eliminated 

from the body, tissue levels are a useful measure only shortly following exposure to toxaphene. 

Persistent toxaphene congeners in fat might serve as useful biomarkers of exposure and would be most 

likely associated with exposure to weathered toxaphene. 

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TOXAPHENE 106 

3. HEALTH EFFECTS 

Effect. No specific biomarkers of effects have been identified for toxaphene. Toxaphene has been 

demonstrated to cause a number of adverse health effects including central nervous system excitation, 

liver and kidney damage, and developmental and immunosuppressive effects. These effects are not 

specific for toxaphene and no studies exist that demonstrate good correlation of toxaphene levels with 

human health effects. Neurological tests such as electroencephalographic monitoring can record levels of 

central nervous system activity. Liver and kidney function tests exist that detect hepatic and renal 

impairment. Microsomal enzyme activity may indicate early effects in the liver. Effects on the immune 

system can be measured by measuring immunoglobulin levels. Although each of these tests can indicate 

the presence of disease in the systems affected by toxaphene, the effects can be caused by a number of 

other disease states. 

Absorption, Distribution, Metabolism, and Excretion. Quantitative evidence on the absorption 

of toxaphene in humans and animals following all routes of exposure is very limited. Female animals 

dipped in toxaphene excrete the substance in milk and also sometimes experience toxicosis (Claborn et al. 

1963). Humans and animals have become seriously ill following accidental or intentional ingestion of 

toxaphene. The evidence clearly indicates that toxaphene is absorbed. Reports that specifically evaluate 

its rate or extent of absorption as a result of inhalation, oral, and dermal exposure would be useful. 

No studies were located regarding the distribution of toxaphene in humans or animals following 

inhalation or dermal exposures. No evidence is available regarding the distribution of toxaphene in 

humans following ingestion. However, animal studies conducted in several species indicate that 

distribution following oral absorption is similar across species (Mohammed et al. 1983; Ohsawa et al. 

1975; Pollock and Kilgore 1980b), and it is assumed that distribution of the pesticide in humans would be 

similar. Once absorbed, toxaphene and its components are distributed initially throughout the blood 

compartment and then to fat. Studies that investigate the distribution of toxaphene following inhalation 

or dermal exposure would be helpful in order to evaluate whether toxaphene behaves similarly across all 

routes of exposure. 

Information was not available regarding the metabolism of toxaphene following dermal or inhalation 

exposure in animals or humans. This information would be useful for estimating health effects by these 

routes. Moreover, no information was available regarding the metabolites formed by humans following 

ingestion. Evidence from animals receiving toxaphene orally indicates that dechlorination, 

dehydrodechlorination, and oxidation are principal metabolic pathways (Crowder and Dindal 1974; 

Ohsawa et al. 1975). Although several metabolites have been isolated and identified (Ohsawa et al. 

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TOXAPHENE 107 

3. HEALTH EFFECTS 

1975), several others remain unknown. Their identification will help elucidate the toxaphene metabolic 

pathway(s). 

Quantitative information regarding the metabolites produced would suggest which biodegradation 

pathways are favored and provide insight into the enzyme kinetics. Information regarding the overall rate 

of metabolism and the rates of specific reactions would be useful. In addition, such studies might also 

provide information to help facilitate the metabolism of the toxaphene mixture in accidentally exposed 

humans. 

No studies in humans were found regarding the excretion of toxaphene. Excretion data from animal 

studies are available for oral and dermal exposure routes. Mice that received toxaphene intravenously 

were found to have toxaphene present in the intestinal content, suggesting biliary excretion (Mohammed 

et al. 1983). The presence of several metabolites in the urine and feces suggests that toxaphene 

degradation is extensive and complex (Ohsawa et al. 1975; Pollock and Kilgore 1980b). Though 

metabolism of toxaphene facilitates its excretion, and the kinetics of toxaphene metabolism are related to 

the kinetics of excretion, they are not the same. Since metabolites may also contribute to the toxic effects 

attributed to toxaphene, it would be beneficial to conduct studies that would establish elimination rates for 

each toxaphene metabolite or for similar metabolic products. Such studies may also provide information 

to facilitate the rapid removal of toxaphene and its metabolites in exposed people. 

Virtually all toxicokinetic properties reported in this profile were based on results from acute-duration 

exposure studies. Very limited information was available regarding intermediate- or chronic-duration 

exposure to toxaphene. Since toxaphene is known to induce hepatic enzymes, the kinetics of metabolism 

during chronic exposure probably differ from those seen during acute exposure. Thus, additional studies 

on the metabolism of toxaphene during intermediate- or chronic-duration exposure would be useful. 

Comparative Toxicokinetics. The absorption, distribution, metabolism, and excretion of toxaphene 

have been studied in animals, but only information on absorption is available in humans. In several 

mammalian species, it is evident that toxaphene is absorbed, metabolized in the liver (with some 

elimination probably occurring via the hepatobiliary system), and then possibly some parent compound 

and metabolites are distributed to fat (Ohsawa et al. 1975; Pollock and Kilgore 1980b). Very little is 

excreted unchanged. In studies of mammals, the extent of metabolism increased with the physiological 

complexity of the species. Based on this trend, humans would be expected to metabolize toxaphene 

extensively in a manner qualitatively similar to animals. 

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TOXAPHENE 108 

3. HEALTH EFFECTS 

Methods for Reducing Toxic Effects. The medical procedures used to reduce the toxic effects of 

toxaphene are well established and are those used to treat organochlorine poisoning or poisoning due to 

other chemicals with central nervous system stimulatory properties. However, data on how to best reduce 

body burden and also on how to prevent the inhibition of γ-aminobutyric acid-dependent chloride ion 

channels would be useful. 

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. 

No human data are available regarding age-related susceptibility to toxaphene. Results of one animal 

study (Olsen et al. 1980) indicate that critical stages of neurological development may be periods of 

increased vulnerability. Immunosuppression has been demonstrated in some animals exposed to 

toxaphene (Allen et al. 1983; Koller et al. 1983; Tryphonas et al. 2001), and it is known that infants and 

children are especially susceptible to immunosuppression because their immune systems do not reach 

maturity until 10–12 years of age (Calabrese 1978). As identified in the Developmental Toxicity 

subsection, a well-designed, developmental toxicity animal study could provide additional insight into 

age-related susceptibility to toxaphene. 

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 

Search of the Federal Research in Progress database (FEDRIP 2010) revealed no ongoing studies of 

toxaphene-related health effects. 

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TOXAPHENE 109 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Information regarding the chemical identity of toxaphene is located in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Information regarding the physical and chemical properties of toxaphene is located in Table 4-2. 

Toxaphene is not a single molecular substance; rather, it is a complex mixture of congeners including 

chlorinated bornanes, bornenes, bornadienes, camphenes, and dihydrocamphenes (de Geus et al. 1999). 

The congeners typically contain 6–10 chlorine atoms each (de Geus et al. 1999; Lau et al. 1996). 

Representative structures for the different types of toxaphene congeners are shown in Figure 4-1. 

Although thousands of toxaphene congeners are theoretically possible based on these structures, only a 

few hundred are expected to be present at significant concentrations in technical toxaphene (de Geus et al. 

1999; Lamb et al. 2008; Simon and Manning 2006). 

The chemical structure of specific toxaphene congeners has been described using a variety of 

nomenclature systems, some of which are summarized in de Geus et al. (1999). This Toxicological 

Profile for Toxaphene employs the nomenclature system developed by Dr. Harun Parlar to refer to 

specific congeners (Coelhan and Parlar 1996). 

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TOXAPHENE 110 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Toxaphene 

Characteristic Information Reference 

Chemical name 

Synonym(s) 

Registered trade name(s) 

Chemical formula 

Chemical structurea 

Identification numbers: 

CAS Registry 

NIOSH RTECS 

EPA Hazardous Waste 

DOT/UN/NA/IMCO 

HSDB 

Toxaphene 

Campheclor; chlorinated camphene; 

polychlorocamphene; chlorocamphene; 

octachlorocamphene; technical toxaphene 

Agricide Maggot Killer; Alltox; Camphofene 

Huilex; Geniphene; Hercules 3956; 

Hercules Toxaphene; Motox; Penphene; 

Phenicide; Phenatox; Strobane-T; 

Synthetic 3956; Toxakil 

C10H10Cl8 (approximately) 

(H3C)2 

Cl HCH 8

CH2 

8001-35-2 

XW5250000 

P123 

NA 2761/toxaphene 

1616 

ChemIDplus Advanced 

2010 

ChemIDplus Advanced 

2010 

IARC 1979 

O'Neil et al. 2006 

Paris and Lewis 1973 

ChemIDplus Advanced 

2010; NIOSH 2005 

HSDB 2010 

NIOSH 2005 

HSDB 2010 

a

Structure representative of the predominant chlorinated camphene compounds present in technical toxaphene. 

CAS = Chemical Abstracts Services; 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; IARC = International Agency for Research on Cancer; NIOSH =
 

National Institute for Occupational Safety and Health; RTECS = Registry of Toxic Effects of Chemical Substances
 

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TOXAPHENE 111 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Toxaphenea 

Property Information Reference 

Molecular weight 431.8 (approximately) BCPC 2003 

Color/form Yellow, waxy, amber NIOSH 2005; O'Neil et al. 2006 

Physical state Solid O'Neil et al. 2006 

Melting point 65B90 °C O'Neil et al. 2006 

Boiling point Not applicable O'Neil et al. 2006 

(dechlorinates at 155 °C) 

Density at 25 °C 1.65 g/cm3 BCPC 2003 

Odor Mild, piney, chlorine- and camphor- NIOSH 2005 

like odor 

Odor threshold: 

Air 

Water 

0.14 ppm (detection) 

2.4 mg/m3 

Sigworth 1965; Ruth 1986 

HSDB 2010 

0.14 ppm (detection) 

Solubility: Murphy et al. 1987 

Water 0.55 mg/L 

Organic solvent(s) Freely soluble in aromatic BCPC 2003; O'Neil et al. 2006 

hydrocarbons 

Readily soluble in organic solvents, 

including petroleum oils 

Partition coefficients: 

Log Kow 3.3–6.64 EPA 1981a; Fisk et al. 1999 

Log Koc 3–5 EPA 1981a; Soubaneh et al. 

2008; Wauchope et al. 1992 

Vapor pressure 6.69x10-6 mm Hg at 20 °C Murphy et al. 1987 

Henry's law constant 6x10-6 atm-m3/mol at 20 °C Murphy et al. 1987 

Autoignition temperature No data 

Flashpoint 135 °C (closed cup, 60% solution) HSDB 2010 

115 °C (tag closed cup, 90% 

solution) 

Flammability limits in air Solid is not flammable, but is HSDB 2010 

usually dissolved in combustible 

liquid 

Conversion factors (25 °C) 1 ppm x 17.95(average)=1 mg/m3; 

1 mg/m3 x 0.056 (average)=1 ppm 

Calculated 

Explosive limits No data 

a

Technical toxaphene is a complex mixture of hundreds of polychlorinated bicyclic terpenes consisting predominantly 

of chlorinated camphenes (Jansson and Wideqvist 1983; Paris and Lewis 1973). Toxaphene contains 67–69% 

chlorine by weight (de Geus et al. 1983). 

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TOXAPHENE 112 

4. CHEMICAL AND PHYSICAL INFORMATION 

Figure 4-1. Representative Carbon Skeleton Structures of the Toxaphene 

Congeners with Numbered Carbon Atomsa 

1

6

5 4

9 8 

1

6

5 4

9 8 

1

6

5 4

9 8
 

7
 7 7 

3 3 3
 

2 2 2
 

10 10 10 

Bornane Bornene Bornadiene 

1 

6 

5 4 

7 7 

8 8 

3 3 9 9 

2 2 

10 10 

1 

6 

5 4 

Camphene Dihydrocamphene 

a

Congeners typically contain 6–10 chlorine atoms. 

Source: de Geus et al. 1999 

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TOXAPHENE 113 

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

5.1 PRODUCTION 

Toxaphene does not occur naturally (Canada Department of National Health and Welfare 1978; EPA 

1976a; IARC 1979). It is a complex mixture of at least 670 chlorinated terpenes (Jansson and Wideqvist 

1983). Technical toxaphene can be produced commercially by reacting chlorine gas with technical 

camphene in the presence of ultraviolet radiation and catalysts, yielding chlorinated camphene containing 

67–69% chlorine by weight (EPA 1976a; Korte et al. 1979; Vetter and Scherer 1998). It has been 

available in various forms: a solid containing 100% technical toxaphene; a 90% solution in xylene or oil; 

a 40% wettable powder; 5–20 and 40% dusts; 10 and 20% granules; 4, 6, and 9% emulsifiable 

concentrates; 1% baits; a 2:1 toxaphene; DDT emulsion; and a 14% dust containing 7% DDT (IARC 

1979; IUPAC 1979; Penumarthy et al. 1976). 

In 1982, EPA canceled the registrations of toxaphene for most uses as a pesticide or pesticide ingredient, 

except for certain uses under specific terms and conditions (EPA 1982a, 1993a; USDA 1995). All 

registered uses were banned in 1990 (EPA 1990b), and existing stocks of the pesticide were not allowed 

to be sold or used in the United States after March 1, 1990 (USDA 1995). In 1976, toxaphene was 

produced primarily by Hercules Incorporated, Wilmington, Delaware (Penumarthy et al. 1976). 

Production by a total of three U.S. companies (Hercules Incorporated, Tenneco, and Vicksburg Chemical 

Co., a division of Vertac) during 1976 totaled 19 million kg, which was a 29% decline from the 

production level of 27 million kg in 1975 (IARC 1979). Montgomery and Welkom (1990) listed 

Hercules Incorporated, Brunswick, Georgia, and Sonford Chemical Company, Port Neches, Texas, as 

selected manufacturers of toxaphene; however, no production estimates were provided. Total U.S. 

production in 1977 was estimated to be 18.1 million kg (HSDB 2010). In 1982, it was estimated that 

3.7 million pounds (<2 million kg) were produced in the United States (EPA 1987a). This represents a 

decline of more than 90% from 1972, when toxaphene was the most heavily manufactured insecticide in 

the United States, with a production volume of 23,000 tons (21 million kg) (Grayson 1981). The Toxics 

Release Inventory (TRI) lists one facility in Idaho and one facility in Texas that were involved in 

toxaphene production during 2008 (TRI08 2010). No other information regarding recent production of 

toxaphene in the United States was found. 

Especially in the United States, the definition of "technical toxaphene" was patterned after the Hercules 

Incorporated product (Hercules Code Number 3956) marketed under the trademark name of 

"Toxaphene." Hercules Incorporated has essentially let the name of toxaphene lapse into the public 

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TOXAPHENE 114 

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

domain so that many products with similar properties are referred to as toxaphene (Worthing and Walker 

1987). Other companies used slightly different manufacturing processes, leading to a chlorinated 

camphene mixture with degrees of total chlorination and a distribution of specific congeners that are not 

the same as the Hercules Incorporated product. For instance, the toxaphene-like product commonly 

marketed under names like "Stroban(e)" had a slightly lowered degree of chlorination and used slightly 

different camphene or pinene feedstocks (Walter and Ballschmiter 1991). 

Since the early 2000s, efforts have been underway to eliminate the production and use of toxaphene 

worldwide. The Stockholm Convention, an international treaty designed to restrict the production and use 

of various chemical substances among its member nations, includes toxaphene on a list of persistent 

organic pollutants or POPs (Stockholm Convention 2008). Under the rules of the convention, production 

or use of toxaphene is completely banned and exemptions are not available. The convention, which 

initially went into effect in 2005, listed over 150 participating nations as of June, 2010. 

While most attention has been focused on the intentional production of polychlorinated camphenes 

(PCCs) as pesticide agents, there is evidence that PCC congeners may be an unintentional byproduct of 

manufacturing processes that use chlorination, such as those for paper and pulp (Rantio et al. 1993). 

Because toxaphene is a Priority Pollutant under the Clean Water Act, it is required to be included in the 

TRI (EPA 2005). All registered uses of toxaphene on food commodities were canceled by 1990 (EPA 

1982a, 1990b), and the sale and use of existing stocks of the pesticide in the United States were prohibited 

after March 1, 1990 (USDA 1995). Therefore, current information included in the TRI regarding the 

processing or use of toxaphene at industrial facilities is expected to be related to the storage and disposal 

of toxaphene supplies or the use of this substance in onsite processing and as a manufacturing aid. These 

facilities are not expected to be involved in production or import of toxaphene for pesticidal use in the 

United States. Table 5-1 summarizes the number of facilities in each state that processed or used 

toxaphene in 2008, the ranges of maximum amounts on site, if reported, and the activities and uses as 

reported in the TRI (TRI08 2010). The data listed in this table should be used with caution since only 

certain types of facilities are required to report. This is not an exhaustive list. 

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Table 5-1. Facilities that Produce, Process, or Use Toxaphene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 1 0 99 12 

AR 5 0 99,999 2, 5, 7, 9, 12 

CA 3 0 9,999 12 

ID 1 0 99 1, 3, 12 

IL 2 0 999 12 

IN 3 0 9,999 2, 3, 12, 13, 14 

KY 1 1,000 9,999 12 

LA 3 0 9,999 12 

MI 3 0 999 12, 14 

MS 1 1,000 9,999 2, 3, 8 

NE 3 100 999,999 12 

NJ 1 100 999 12 

NV 2 1,000 99,999 2, 3, 12 

OH 4 0 99,999 12 

OK 2 0 99,999 12 

OR 2 100 9,999 12 

PA 1 0 99 12 

SC 1 10,000 99,999 12 

TX 6 0 9,999,999 1d, 3, 12 

UT 2 0 9,999 12 

WI 1 0 99 8 

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 

d

Production is reported for only one facility in Texas. 

Source: TRI08 2010 (Data are from 2008) 

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5.2 IMPORT/EXPORT 

In 1972, a total of 8,000 metric tons (7.25 million kg) of toxaphene, or 35% of the annual production, was 

exported (EPA 1974b; SRI 1993; USITC 1991). The TRI lists four states containing facilities that were 

involved with the import of toxaphene into the United States during 2008 (TRI08 2010). No other 

information was found regarding the import of toxaphene into or the export of toxaphene from the United 

States. 

5.3 USE 

Toxaphene was formerly used as a nonsystemic stomach and contact insecticide with some acaricidal 

activity. Being nonphytotoxic (except to cucurbitus), it was used to control many insects thriving on 

cotton, corn, fruit, vegetables, and small grains and to control the Cassia obtusifola soybean pest. 

Toxaphene was also used to control livestock ectoparasites such as lice, flies, ticks, mange, and scab 

mites (Knipling and Westlake 1966; Meister 1988; Worthing 1979). Toxaphene’s relatively low toxicity 

to bees and its long persisting insecticidal effect made it particularly useful in the treatment of flowering 

plants. Toxaphene was not used to control cockroaches because its action on them is weaker than 

chlordane (IARC 1979). Toxaphene was used at one time in the United States to eradicate fish (Muirhead 

Thomson 1971). The principal use was for pest control on cotton crops (IUPAC 1979; Verschueren 

1983). In 1974, an estimated 20 million kg used in the United States was distributed as follows: 85% on 

cotton; 7% on livestock and poultry; 5% on other field crops; 3% on soybeans; and <1% on sorghum 

(IARC 1979). Based on estimates of EPA (1974b) for 1972, 75% of the toxaphene production for that 

year was for agricultural use; 24% was exported; and 1% was used for industrial and commercial 

applications. 

Toxaphene solutions were often mixed with other pesticides partly because toxaphene solutions appear to 

help solubilize other insecticides with low water solubility. Toxaphene was frequently applied with 

methyl or ethyl parathion, DDT, and lindane (IARC 1979; WHO 1974). 

Through the early 1970s, toxaphene or mixtures of toxaphene with rotenone were used widely in lakes 

and streams by fish and game agencies to eliminate biologic communities that were considered 

undesirable for sport fishing (Lockhart et al. 1992; Stern et al. 1993). This practice was especially 

prominent in parts of Canada and the northern United States for fish restocking experiments on smaller 

glacial lakes. Because the toxic effects of toxaphene may persist for many years in an aquatic system, 

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difficulties in establishing the desired sports fisheries were among the first strong indications that 

toxaphene was a persistent and bioaccumulative material. Such uses of toxaphene by fish and game 

agencies have apparently been discontinued in the United States and Canada. 

Toxaphene use in this country has declined drastically since 1975, when it was reported to be the most 

heavily used pesticide (Sanders 1975). The total used was estimated at only 9,360 tons (8.5 million kg) in 

1980 and 5,400 tons (4.9 million kg) in 1982 (WHO 1984). In November 1982, EPA canceled the 

registrations of toxaphene for most uses as a pesticide or pesticide ingredient (EPA 1982a). In the period 

following November 1982, its use was restricted to controlling scabies on sheep and cattle; grasshopper 

and army worm infestations on cotton, corn, and small grains; and specific insects on banana and 

pineapple crops in Puerto Rico and the U.S. Virgin Islands; and for emergency use only (to be determined 

on a case-by-case basis by EPA) (EPA 1982a; WHO 1984). Formulations suitable for other purposes 

could be sold or distributed until December 31, 1983, for use only on registered sites (EPA 1982a). The 

distribution or sale of remaining stocks of toxaphene formulations were permitted until December 31, 

1986, for use on no-till corn, soybeans, and peanuts (to control sicklepod), and dry and southern peas, and 

to control emergency infestations. All registered uses of toxaphene mixtures in the United States and any 

of its territories were canceled in 1990 (EPA 1990b). 

5.4 DISPOSAL 

Toxaphene may not be disposed of by water or ocean dumping or by burning in the open air. The 

recommended disposal method is incineration in a pesticide incinerator at a temperature and residence 

time combination that will result in complete destruction of the chemical (EPA 1989a). Any emissions 

generated by incineration must meet the requirements of the Clean Air Act Amendments, Title III, and 

any liquids, sludges, or solid residues produced should be disposed of in accordance with federal, state, 

and local pollution control requirements. Municipal solid waste incinerators may be used, providing that 

they meet the criterion of a new pesticide incinerator and are operated under supervision (EPA 1989a). 

Landfill has also been identified as a recommendable method of disposal of toxaphene (IRPTC 1985). 

Thermal desorption is reported to be an effective technology for treating soils contaminated with 

toxaphene (Troxler et al. 1993). Federal, state, and local regulations governing the treatment and disposal 

of wastes containing toxaphene are presented in Chapter 8. 

No information was found in the available literature on the amounts of toxaphene disposed of in the 

United States by any disposal method. 

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6.1 OVERVIEW 

Toxaphene has been identified in at least 68 of the 1,699 hazardous waste sites that have been proposed 

for inclusion on the EPA National Priorities List (NPL) (HazDat 2007). However, the number of sites 

evaluated for toxaphene is not known. The frequency of these sites can be seen in Figure 6-1. 

Toxaphene is a complex mixture of several hundred polychlorinated bicyclic terpene congeners (de Geus 

et al. 1999; Jansson and Wideqvist 1983; Lamb et al. 2008; Lau et al. 1996; Paris and Lewis 1973; Simon 

and Manning 2006). The transport and transformation of each of these components is influenced by its 

individual physical/chemical properties, in addition to those of the mixture as a whole. Although some 

data in the available literature indicate selective volatilization and metabolism of individual fractions of 

the mixture, the environmental fate of the mixture rather than of individual components has been studied 

by most investigators. 

Toxaphene has been widely dispersed to the environment mainly as a result of its past use as an 

insecticide. The mixture partitions to the atmosphere, surface water and groundwater, soil and sediment 

particulates, and adipose tissue. As a result of its volatility and environmental persistence, toxaphene 

continues to be transported over long distances in the atmosphere (Andersson et al. 1988; Bidleman and 

Olney 1975; MacLeod et al. 2002; Paasivirta et al. 2009; Swackhamer and Hites 1988; Zell and 

Ballschmiter 1980). The half-life (first-order kinetics) for reaction of atmospheric toxaphene with 

photochemically produced hydroxyl radicals has been estimated to be at least 4–5 days for vapor-phase 

components of toxaphene (Howard 1991; Kelly et al. 1994); however, many congeners exist 

predominantly in the particulate phase and subsequently have longer atmospheric residence times and 

greater potential for long-range transport. Toxaphene strongly adsorbs to particles and is relatively 

immobile in soils (EPA 1981a; Soubaneh et al. 2008; Swann et al. 1983; Wauchope et al. 1992). In 

water, toxaphene is strongly adsorbed to suspended particulates and sediments and is bioconcentrated by 

aquatic organisms to fairly high levels, with bioconcentration factors (BCFs) on the order of 4,200– 

60,000 (Sanborn et al. 1976; Schimmel et al. 1977). Toxaphene also appears to be biomagnified in 

aquatic food chains. Toxaphene is biotransformed relatively rapidly in soils and sediments under 

anaerobic conditions, with a half-life or half-disappearance time in the range of weeks to months (EPA 

1979a). However, the mixture appears to be relatively resistant to biotransformation in these media under 

aerobic conditions (half-life = years) (EPA 1979a; de Geus et al. 1999; Nash and Woolson 1967; Parr and 

Smith 1976; Smith and Willis 1978). 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with Toxaphene Contamination 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Recently, efforts have been made to differentiate between the form of toxaphene as it was formerly used 

as a pesticide, known as technical toxaphene, and the "weathered" form of this substance after years of 

environmental transport and degradation processes have had their effect (EPA 2010e). Weathered 

toxaphene is considered to be the most relevant form when assessing the current potential for human 

exposure to toxaphene. In order to achieve the best understanding of what individuals may be exposed to 

in the environment, recent studies have measured the levels of individual toxaphene congeners present in 

environmental samples. Congeners p-26, p-50, and p-62 are reported to be persistent in fish, marine 

mammals, human serum, and breast milk (Simon and Manning 2006). The toxicological implications of 

environmentally-persistent congeners of weathered toxaphene have not been adequately assessed. 

Human exposure to toxaphene currently appears to be limited to ingestion of low concentrations of the 

mixture in food, particularly fish, and possibly to inhalation of ambient air. The most probable 

populations potentially exposed to relatively high concentrations of the mixture are individuals residing in 

the vicinity of hazardous waste disposal sites contaminated with toxaphene. Other subpopulations with 

potentially higher exposure rates may be northern Native American groups that eat aquatic mammals, 

which may contain residues of toxaphene (Muir et al. 1992), recreational or subsistence hunters in the 

southern United States that consume significant amounts of game animals (especially species like 

raccoons) (Ford and Hill 1990), and people who consume certain types of sportfish caught in the Great 

Lakes (ATSDR 2009). 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report releases into the environment (EPA 2005). This is not an exhaustive list. 

Manufacturing and processing facilities are required to report information to the TRI only if they employ 

10 or more full-time employees; if their facility is included in Standard Industrial Classification (SIC) 

Codes 10 (except 1011, 1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4931 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4939 (limited to facilities that combust coal and/or oil for the purpose of generating 

electricity for distribution in commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 

42 U.S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 

7389 (limited to facilities primarily engaged in solvents recovery services on a contract or fee basis); and 

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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 2005). 

Toxaphene has been detected in the atmosphere, soils, surface waters and sediments, rainwater, aquatic 

organisms, and foodstuffs. Historically, toxaphene has been released to the environment mainly as a 

result of its past use as an agricultural insecticide (EPA 1979f). Toxaphene-like mixtures of PCC 

congeners may also be released to the environment as unintentional byproducts from manufacturing 

processes involving chlorination, such as those used for paper and pulp (Rantio et al. 1993). There are no 

known natural sources of the mixture. 

Because toxaphene is a Priority Pollutant under the Clean Water Act, it is required to be included in the 

TRI (EPA 2005). However, since most registered uses of toxaphene as a pesticide were canceled in 1982 

(EPA 1982a) and all registered uses were canceled in the United States and its territories after 1990 (EPA 

1990b), production of toxaphene for domestic use in the United States has ceased. Consequently, most 

releases of toxaphene reported to TRI for 2008 were disposals to landfills (TRI08 2010). 

Current sources of toxaphene in the environment that may result in exposure for the U.S. population is 

long-range atmospheric transport from countries currently producing or using toxaphene (e.g., Mexico 

and countries in Central America, eastern Europe, the former Soviet Union, and parts of Asia) 

(Swackhamer et al. 1993; Voldner and Li 1993) and continued releases from previously contaminated 

U.S. soils and waters. 

6.2.1 Air 

Estimated releases of 64 pounds (0.029 metric tons) of toxaphene to the atmosphere from 14 domestic 

manufacturing and processing facilities in 2008, accounted for <0.1% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI08 2010). These releases are 

summarized in Table 6-1. 

As a result of its past use as an insecticide on crops in the southern United States, toxaphene was 

dispersed directly to the atmosphere by aerial and ground application (EPA 1979f). Volatilization of the 

mixture from treated crop and soil surfaces following application also introduced substantial amounts of 

toxaphene to the atmosphere. For example, Willis et al. (1980, 1983) reported volatilization losses from 

treated cotton canopies of up to 80% of applied toxaphene within 11 days after treatment. Seiber et al. 

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Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
 

Use Toxaphenea
 

Reported amounts released in pounds per yearb 

Total release 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek On- and off-site 

AR 2 10 0 0 0 833 10 833 843 

IL 1 0 0 0 0 1 0 1 1 

LA 1 3 0 0 9 0 12 0 12 

NV 1 0 0 0 28 0 28 0 28 

OH 3 0 0 0 79 75 0 154 155 

OK 1 40 0 0 415,473 0 415,513 0 415,513 

OR 1 1 0 0 1,961 0 1,962 0 1,962 

TX 2 6 0 0 0 0 6 0 6 

UT 1 3 0 0 0 0 3 0 3 

WI 1 0 0 0 0 0 0 0 0 

Total 14 64 0 0 417,550 908 417,535 988 418,523 

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, waste water 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 onsite 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 

Source: TRI08 2010 (Data are from 2008) 

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(1979) also reported that volatilization from leaf and soil surfaces was the major removal mechanism for 

toxaphene applied to cotton crops under field conditions. These investigators reported differential 

vaporization of the mixture (i.e., selectively greater loss of the more volatile components from soil and 

leaf surfaces), which was matched by a corresponding enrichment of these components in ambient air 

samples. 

Toxaphene shows a strong tendency to sorb to particulates, and there has been a tendency to believe that 

toxaphene residuals in older hazardous waste sites would be relatively inert. Studies based primarily on 

theoretical considerations and computer screening models suggest that the PCCs could volatilize to the 

atmosphere unless a waste site has a clay cap thicker than approximately 0.3 m. The potential for 

volatilization increases if the soil matrix in which the toxaphene is buried has a significant sand fraction 

(Jury et al. 1990). These theoretical findings seem compatible with field measurements on several 

pesticides that showed the volatilization rates for toxaphene applied to soils were significantly higher than 

rates for triazine herbicides or alachlor (Glotfelty et al. 1989a). Toxaphene has been identified in air 

samples collected at 3 of the 68 NPL hazardous waste sites where it was detected in some environmental 

media (HazDat 2007). 

6.2.2 Water 

No releases of toxaphene to surface water from domestic manufacturing and processing facilities required 

to report to the TRI were reported for 2008 (TRI08 2010). Estimated releases of 988 million pounds 

(0.448 metric tons) of toxaphene off-site, which include transfers to publicly owned treatment works 

(POTWs), accounted for 0.23% of the estimated total environmental releases from facilities required to 

report to the TRI. The 2008 TRI release information is summarized in Table 6-1. 

Toxaphene has been released to surface waters as a result of its direct application to lakes as a piscicide 

(EPA 1979f), in waste water releases from manufacturing and formulation plants (Durant and Reimold 

1972), and in activities associated with the disposition of residual pesticides. For example, Mirsatari et al. 

(1987) described the release of aircraft rinse water to drainage ditches following aerial application of 

toxaphene, and the compound has been detected in surface water samples taken from disposal ponds at a 

Superfund site (EPA 1986a). NOAA (1974) reported that toxaphene concentrations in the effluent of a 

manufacturing plant decreased over a 4-year period from an average maximum monthly concentration of 

2,332 ppb in August 1970 to 6 ppb in July 1974. 

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Because neat technical toxaphene sorbs to particulates and is markedly hydrophobic, it has been argued 

that toxaphene would not be able to migrate more than about 10 cm down a soil profile and, therefore, 

would not be of concern as a groundwater contaminant. Such arguments tend to overlook the fact that 

technical toxaphene used as a pesticide was usually mixed with a hydrocarbon solvent (e.g., xylene) as a 

carrier, which increased the mobility of toxaphene in soils. Data compiled by the EPA on pesticides in 

groundwater indicates that toxaphene was found in groundwater in one state as a result of normal 

agricultural use (Ritter 1990). Also, when such pesticide preparations have been introduced at old waste 

disposal sites, the toxaphene may be able to move into groundwater with the carrier-solvent. This 

scenario has been documented at a waste disposal site in California (Jaquess et al. 1989). The authors see 

this as a possibility at many waste disposal sites containing solvent materials, with toxaphene detections 

in groundwater at NPL sites, in the Mississippi Delta, and near Houston, Texas, supporting similar 

pollution pathways. Toxaphene has been identified in surface water and groundwater samples collected 

at 14 and 27 of the 68 NPL hazardous waste sites, respectively, where it was detected in some 

environmental media (HazDat 2007). For most groundwater supplies, however, any significant residence 

time in poorly oxygenated or anaerobic subsoil vadose zones would be expected to allow for anaerobic 

biochemical degradation of toxaphene. 

6.2.3 Soil 

Estimated releases of 0.418 million pounds (189 metric tons) of toxaphene to soils from 17 domestic 

manufacturing and processing facilities in 2008, accounted for about 99.8% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI08 2010). No underground 

injection releases were reported (TRI08 2010). The TRI release data are summarized in Table 6-1. 

Toxaphene has been released directly to soils primarily as a result of its past use as an insecticide on 

agricultural crops (EPA 1979f). Disposal of spent livestock-dipping solutions (McLean et al. 1988) and 

wastes from manufacturing and formulation processes (EPA 1979f) were other significant sources of soil 

contamination. Mirsatari et al. (1987) reported that toxaphene has been found as a contaminant at 

pesticide disposal sites at concentrations in soils or sediment approaching or exceeding 100 ppm. 

Toxaphene was listed as a chemical of concern at the Crystal City Airport Superfund site in Crystal City, 

Texas. The mixture was detected in surface soil samples taken at the airport following abandonment of 

agricultural chemicals at the site by defunct aerial application operators (EPA 1987b). Toxaphene was 

also found in pesticide contaminated soils at four other Superfund sites in Litchfield, Arizona; Albany, 

Georgia; Marrianna, Florida; and Malone, Florida; concentrations in these soils ranged from 18 to 

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6. POTENTIAL FOR HUMAN EXPOSURE 

1,505 mg/kg (ppm) (Troxler et al. 1993). Toxaphene has been identified in soil and sediment samples 

collected at 40 and 22 of the 68 NPL hazardous waste sites, respectively, where it was detected in some 

environmental media (HazDat 2007). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

A combination of monitoring and modeling efforts during the 1980s has firmly established the 

importance of atmospheric pathways as a major source of PCC inputs to regions in the upper latitudes far 

removed from regions where it was heavily used as an agricultural pesticide. Adaptations to regional 

transport models initially developed to study acid rain phenomena showed the physical possibility for 

atmospheric transport of toxaphene from locations in the southern United States to the Great Lakes 

Region of the northern United States and Canada (Hoh and Hites 2004; James and Hites 2002; MacLeod 

et al. 2002; Voldner and Schroeder 1989, 1990). 

A series of studies by Canadian researchers has gathered detailed information on levels of toxaphene in 

various environmental compartments in regions ranging from Lake Baikal in Russia, to the Sargasso Sea, 

to the southeastern United States, to various areas in Canada and the Canadian Arctic (Barrie et al. 1993; 

Bidleman et al. 1989, 1992, 1993, 1995; Cotham and Bidleman 1991; Lockhart et al. 1992; McConnell et 

al. 1993; Muir et al. 1990, 1992). These studies help provide at least partial validation for the predictions 

from regional transport models and document the continued supply of PCC materials to areas in the 

northern hemisphere far removed from areas of former significant toxaphene use. 

Researchers working with the atmospheric transport of toxaphene have assembled useful time series 

observations for sites along the southern Atlantic coast in the United States, in the Canadian Maritime 

provinces, and at stations in the Canadian Arctic (Bidleman et al. 1989, 1992, 1995). Comparisons of 

levels in environmental media during the 1990s with baseline concentrations in the 1970s and early 1980s 

did not suggest declines in toxaphene contaminants, with ambient air concentrations in particular 

remaining about the same or even increasing. Especially in high latitude areas, impacts from toxaphene 

were still a matter of concern nearly a decade after the United States began phasing out the use of 

toxaphene as a pesticide agent. 

Toxaphene is a mixture of many congeners, each of which has its own unique Henry's law constant. A 

Henry's law constant of 6x10-6 atm-m3

/mol at 20 °C was measured for the mixture, which suggests that 

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many components of toxaphene will volatilize to the atmosphere from water and soil surfaces. A half-life 

(first-order kinetics) of 6 hours to 12 days has been estimated for the volatilization of toxaphene from a 

model river, one meter deep, with a flow rate of 1 m/second and a wind velocity of 3 m/second (Howard 

1991). The results of numerous field dissipation and atmospheric monitoring studies indicate that the 

atmosphere is indeed the most important environmental medium for transport of the mixture. In addition 

to the field dissipation studies cited in Section 6.2.1 (Seiber et al. 1979; Willis et al. 1980, 1983), 

significant partitioning of toxaphene to the atmosphere has been reported in a model agroecosystem study 

(Nash et al. 1977) and from fallow field soils (Glotfelty et al. 1989a). 

The persistence of toxaphene in the atmosphere allows the mixture to be transported long distances from 

the application sites. The presence of toxaphene in surface waters of the Great Lakes originated from the 

aerial transport and deposition of the mixture from application sites in the southern United States (EPA 

1984b; Hoh and Hites 2004; James and Hites 2002; Ma et al. 2005a, 2005b; MacLeod et al. 2002). 

Detection of toxaphene in the tissues of fish taken from a remote lake on Isle Royale in Lake Superior 

was also cited as evidence of long-range atmospheric transport (Swackhamer and Hites 1988). 

Numerous other investigations have reported long-range atmospheric transport of toxaphene to remote 

locations. Toxaphene was detected in ambient air samples taken over the western North Atlantic Ocean 

and Bermuda. The source of the contamination was attributed to cotton-growing areas in the southern 

United States 1,200 km away (Bidleman and Olney 1975). The presence of toxaphene in biota of the 

Barents Sea in Northern Europe has been attributed to transport via air currents from areas of historical 

use in southeastern Europe and around the rivers that flow into the Aral Sea (Paasivirta et al. 2009). 

Maximum concentrations of toxaphene found in North American peat bogs corresponded to the period of 

maximum production and use of the compound in the United States in the mid-1970s (Rapaport and 

Eisenreich 1986). The composition of the toxaphene residues in the peat cores indicated that they were 

delivered to the peat surface by atmospheric transport and deposition with the dominant wind circulation 

patterns from primary source regions in the southern and southeastern United States. The presence of 

toxaphene in the following sources has also been attributed to its long-range atmospheric transport: fish 

taken from remote lakes in northern Canada (Muir et al. 1990); fish from pristine areas in the North 

Atlantic Ocean, North Pacific Ocean, and Antarctic Ocean (Zell and Ballschmiter 1980); and fish, birds, 

and seals from the western North Atlantic Ocean, Arctic Ocean, Greenland, Canada, and Sweden 

(Andersson et al. 1988). Evidence of regional-scale transport of the mixture in the drainage basin of the 

Chesapeake Bay has also been reported (Glotfelty et al. 1989b). 

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Atmospheric toxaphene is transported back to soil and water surfaces by wet and dry deposition processes 

(Glotfelty et al. 1989b; Hoff et al. 1993a; Villeneuve and Cattini 1986). Several investigators have 

reported that washout in rain appears to be more important than the dry deposition of toxaphene 

(Bidleman et al. 1981; EPA 1984b). Hoff et al. (1993a) cited an unpublished 1992 report from the Great 

Lakes Protection Fund/Environment Canada in which the wet and dry deposition fluxes of PCCs to the 

Great Lakes were estimated to be 3.5–12.5 and 1.5–6.3 kg/year, respectively. Dry deposition accounted 

for only 15% of the input of atmospheric toxaphene into a rural estuary in South Carolina (Harder et al. 

1980). Based on a range of assumptions about the concentration of PCCs in the Great Lakes, Hoff et al. 

(1993a) estimated that the annual loading of toxaphene by gas exchange may be more than an order of 

magnitude higher than the input by wet or dry deposition. The authors noted that even though potential 

errors in the assumptions for the gas transfer of PCCs were very large, they were not large enough to 

make wet and dry deposition fluxes comparable to the estimates of the gas phase mass transfer of 

toxaphene across the air/water interface. Burniston et al. (2005) measured toxaphene concentrations in 

precipitation into Lake Ontario from 1994 to 1998. These authors reported that estimates of wet 

deposition flux were 50% of the estimated gas deposition flux based on loadings of toxaphene for Lake 

Ontario via precipitation during 1998. 

For higher latitude regions, there is more uncertainty about the importance of specific deposition 

mechanisms. Especially in Arctic areas, model estimates and available monitoring data suggest that dry 

particle deposition may be more important than scavenging through snowfall (Cotham and Bidleman 

1991). The mechanisms for toxaphene show many similarities with fate and transport processes for 

hexachlorobenzene (HCB) and perhaps several other organochlorine toxicants. The hydrophobic 

properties of these organochlorines encourage partitioning in either a volatile or semi-volatile phase or in 

forms sorbed to particulates. These properties then facilitate the incorporation of the contaminants into 

food chains starting with algae, zooplankton, and macroinvertebrates. This in turn encourages 

biomagnification at higher trophic levels (Cotham and Bidleman 1991; Hargrave et al. 1992). 

Toxaphene released to soils will persist for long periods of time. The high Koc (soil organic carbon 

partition coefficient) values for toxaphene (log Koc=3–5) (EPA 1981a; Soubaneh et al. 2008; Wauchope et 

al. 1992) suggest that the mixture should be strongly sorbed to soil particulates and, therefore, should be 

relatively immobile to leaching and inhibited from volatilizing from subsurface soils (Swann et al. 1983). 

Field studies have verified this behavior. Half-lives (first-order kinetics) ranging from approximately 

1 year (Adams 1967) to 14 years (Nash and Woolson 1967) have been reported for toxaphene in soils. In 

surface soils, where volatilization will be a significant transport process, half-lives of 2 and 4 months have 

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been reported for samples taken at the top 2.5 and 7.5 cm, respectively (Seiber et al. 1979). Between 

85 and 90% of the total toxaphene residues were found in the upper 23 cm (cultivated layer) of a sandy 

loam test soil 13 years after the last foliar application of the mixture (Nash and Woolson 1968). Following 

multiple annual applications of toxaphene to cotton crops grown in a clay soil, Swoboda et al. (1971) 

detected 90–95% of toxaphene residues in the top foot of the 5-foot profile sampled; toxaphene was not 

detected in any of the drainage water samples taken from the site. About 93% of the toxaphene found in 

runoff from a treated cotton field on a silty clay soil was bound to the sediment fraction; only 7% was 

found in the aqueous fraction of the runoff (McDowell et al. 1981). Toxaphene concentrations in runoff 

varied seasonally, and losses in two of the years studied totaled only 0.5–1% of the amount applied. 

Runoff losses from a cotton crop grown in the Mississippi Delta were found to be 0.4% of applied 

toxaphene (Lorber and Mulkey 1982). Raff and Hites (2004) measured toxaphene levels in suspended 

sediment samples along the Mississippi River. Based on these data and water discharge rates, the authors 

estimated a release of 200–1,000 kg of toxaphene into the Gulf of Mexico from the main stem of the river 

during 2002. The source of toxaphene was attributed to nonpoint source runoff from agricultural lands. 

According to the simulation models Foliar Washoff of Pesticides (FWOP), Chemical Runoff and Erosion 

from Agricultural Management Systems (CREAMS), and Pesticide Runoff Simulator (PRS), up to 3% of 

applied toxaphene may be lost in runoff and erosion from treated agricultural fields; all of the toxaphene 

would be associated with the sediment fractions (Smith and Carsel 1984). To evaluate the effects of 

toxaphene on groundwater and surface water quality under different land management practices, 

Donigian and Carsel (1987) used three models: the Pesticide Root Zone Model (PRZM); the Analytical 

Transient One-, Two-, and Three-Dimensional Simulation of Waste Transport in the Aquifer System 

(AT123D); and the Stream Transport and Agricultural Runoff of Pesticides for Exposure Assessment 

(STREAM). The dissolved mean toxaphene concentration in surface water predicted by the STREAM 

model for a 1.0 kg/ha application rate was 11.6 ppb for conventional-till, 4.9 ppb for reduced-till, and 

3.4 ppb for no-till practices. Surface water runoff loadings and concentrations of toxaphene and several 

other pesticides typically decreased under the conservation tillage scenarios, but groundwater loadings 

and concentrations generally increased as a result of decreased runoff and increased groundwater 

recharge. The authors did not provide estimates of groundwater concentrations for toxaphene because 

this pesticide did not demonstrate mean annual loadings high enough to require estimation of groundwater 

concentrations. 

The mobility of toxaphene in soils also is influenced by soil moisture status and the presence of other 

organic solvating materials (Jaquess et al. 1989). Toxaphene did leach from laboratory columns of sand 

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and sandy loam soils treated with organic solvents and emulsifiers when the columns were allowed to dry 

completely between wetting cycles. The mixture did not leach from the amended columns when a similar 

amount of water was applied on a continuous basis. Drying of the soil allowed crevices to form in the 

columns which expedited movement of the mixture. Toxaphene dissolved in the organic solvent or 

contained in the emulsifier amendment could leach through the macropores. 

There is also evidence that voltatilization is the primary route of loss from toxaphene-treated foliage. In a 

study by Seiber et al. (1979), residues of toxaphene were analyzed in cotton leaves and associated air 

samples up to 58 days after a 9 kg/ha application of toxaphene to a cotton field in the San Joaquin Valley, 

California. Analyses of the cotton leaf samples indicated a 59% loss of toxaphene at 28 days postapplication. Leaf residues declined from 661 ppm on the day of application to 135 ppm on day 50 postapplication, with an observed trend toward greater loss of the more highly volatile components. A 

corresponding enrichment of volatile toxaphene components was observed in air samples. There was no 

indication of chemical degradation in these samples in spite of the presence of abundant sunlight, oxygen, 

and atmospheric oxidant throughout the study. 

Toxaphene is highly insoluble in water (0.55 mg/L) (Murphy et al. 1987). Toxaphene in surface waters 

that is not volatilized to the atmosphere is sorbed to sediments or suspended particulates, which are 

ultimately deposited in sediments (EPA 1979a). The lower-solubility, more-chlorinated components of 

the mixture are preferentially sorbed to particulates and sediments. Paris et al. (1977) reported that the 

less soluble, more highly chlorinated fractions of toxaphene also appear to be selectively sorbed to aquatic 

microorganisms that are consumed by other organisms and, consequently, would be expected to 

bioaccumulate up the food chain. 

Uptake factors (mg toxaphene sorbed per microorganism/concentration of toxaphene in the medium) 

ranged from 3.4x103 to 1.7x104 for a variety of bacteria, fungi, and algae (Bacillus subtilis, 

Flavobacterium harrisonii, Aspergillus sp., Chlorella pyrenoidosa) (Paris et al. 1977). Direct sorption of 

toxaphene onto sediment, plankton, and other suspended solids deposited in the sediment has also been 

reported in three lakes in Wisconsin where the mixture was applied for the control of nongame fish. 

Toxaphene sorbed to sediments was not found to be readily desorbed (Veith and Lee 1971). 

Toxaphene is bioconcentrated in the tissues of aquatic organisms. The major toxaphene congeners found 

in fish from pristine environments in the Canadian Rocky Mountains have been found to be the 

Cl7–Cl9 camphenes (i.e., hepta-, octa-, and nonachlorobornenes) (Bruns and Birkholz 1993). 

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Experimentally determined bioconcentration factors (BCFs) for several aquatic organisms have been 

found to range from 4,200 to 60,000. In a flow-through bioassay conducted with the longnose killfish 

(F. similis), BCFs of up to 33,300 in fry and 60,000 in juvenile fish after 28 days of exposure were 

reported; BCFs in adults ranged from 4,200 to 6,800 after 14 days of exposure (Schimmel et al. 1977). 

Oysters (C. virginica) exposed to 1 ppb toxaphene have been found to accumulate up to 23 ppm in tissue 

after 24 weeks exposure; tissue concentrations decreased to nondetectable levels at the end of a 12-week 

depuration period (Lowe et al. 1971). In a model ecosystem study using radiolabeled toxaphene, BCFs of 

6,902 for algae, 9,600 for snails, 890 for mosquitoes, and 4,247 for fish (Gambusia affinis) were reported 

(Sanborn et al. 1976). 

Toxaphene has also been detected in the tissues of aquatic organisms in numerous field studies (see 

Section 6.4.4). For example, mean toxaphene concentrations of 11 ppm in lipid tissue for lake trout 

(Salvelinus namaycush) and 7 ppm in lipid tissue for whitefish (Coregonus clupeaformis) taken from a 

remote lake on Isle Royale in Lake Superior have been reported (Swackhamer and Hites 1988). Studies 

conducted in a natural ecosystem in northwestern Ontario on the fate of toxaphene in lake trout 

(S. namaycush) and white suckers (Catastomus commersoni) indicated depuration half-lives for total 

toxaphene ranging from 232 days (lake trout, initial intraperitoneal dose 7.0 μg/g) to 524 days (white 

suckers, initial intraperitoneal dose 3.5 μg/g), with first-order kinetics assumed (Delorme et al. 1993). 

Depuration half-lives for two of the more persistent toxaphene congeners, octachlorobornane T2 and 

nonachlorobornane T12, ranged from 294 days (lake trout; T2, initial intraperitoneal dose 7.0 μg/g) to 

716 days (white suckers; T2, initial intraperitoneal dose 3.5 μg/g) with first-order kinetics assumed. The 

overall results of this study indicated significant interspecies differences in the ability to eliminate 

toxaphene, as well as possible intraspecies differences in the ability to eliminate different toxaphene 

congeners. 

Toxaphene also appears to be biomagnified in aquatic food chains, although not to the extent of PCBs or 

other chlorinated insecticides, such as DDT. Stapleton et al. (2001) found that PCB burdens were greater 

than toxaphene burdens for each Great Lakes fish species collected during 1997–1998 with the exception 

of deepwater sculpin. Evans et al. (1991) reported trophic biomagnification of toxaphene, with toxaphene 

concentration increasing by an average factor of 4.7 from plankton (mean concentration, 0.55 ppm) to fish 

(deepwater sculpin: mean concentration, 2.57 ppm). DDE and PCBs were found to be more strongly 

biomagnified, increasing 28.7 and 12.9 times, respectively, in average concentration from plankton to 

sculpin. Whittle et al (2000) measured food web toxaphene concentrations in four of the Great Lakes 

(Table 6-2). Based on these data, toxaphene biomagnification factors were determined to be 32.03 in 

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Table 6-2. Food Web Total Toxaphene Concentrations (μg/g Wet Weight)
 

Measured in Lake Superior, Lake Huron, Lake Erie, and Lake Ontario
 

Species Lake Superior Lake Huron Lake Erie Lake Ontario 

Lake trout 1.926 0.365 0.081 0.639 

Herring 1.024 –a – – 

Sculpin 0.546 0.312 – 0.245 

Smelt 0.291 0.119 0.016 0.066 

Alewife – 0.139 – 0.049 

Diporeia 0.197 0.131 0.029 0.090 

Mysis 0.091 0.020 – 0.034 

Plankton 0.062 0.015 <0.015 0.021 

a

Not analyzed. 

Source: Whittle et al. 2000 

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Lake Superior, 24.33 in Lake Huron, 10.08 in Lake Erie, and 30.43 in Lake Ontario. In a study that 

included analyses of tissue residue levels in 16 species of fish, birds, amphibians, and reptiles, 

biomagnification of toxaphene was reported in three oxbow lakes in northeastern Louisiana (Niethammer 

et al. 1984). Tissue residue concentrations were highest in tertiary consumers (carnivores) and lowest in 

primary consumers (herbivores); toxaphene was not detected in the limited number of surface water or 

sediment samples taken from the lakes. The source of the toxaphene was apparently the surrounding 

cotton and soybean cropland, which had historically received heavy pesticide applications. 

Biomagnification was also reported in a study that included analyses of tissue residue levels in eight 

species of fish and water snakes in the area of the Yazoo National Wildlife Refuge, Mississippi (Ford and 

Hill 1991). Biomagnification of several organochlorine pesticides, including toxaphene, was apparent 

from soil sediments (geometric mean concentration, approximately 0.1 ppm) to mosquito fish, a larger 

secondary consumer and forage fish (geometric mean concentration, 0.25 ppm), to the spotted gar, a 

tertiary consumer (geometric mean concentration, 2.71 ppm). There was, however, no clear pattern of 

biomagnification in larger secondary consumers such as smallmouth buffalo and carp, or in tertiary 

consumers such as water snakes. 

Biomagnification of toxaphene in marine ecosystems appears to be species dependent (de Boer and 

Wester 1993). The two main toxaphene congeners found in marine mammals such as seals and beluga 

whales are an octa- and a nonachlorobornane, which are present only as minor constituents in technical 

toxaphene (Vetter et al. 1993, 1994). No biomagnification of toxaphene in a Canadian arctic marine food 

chain was reported in a study conducted by Muir et al. (1988a). Toxaphene was detected in the muscle 

tissue of the arctic cod (Boreogadus saida) at a mean concentration of 0.018 ppm, but not in the blubber 

and liver of the ringed seal (Phoca hispida), which preys on the cod, or the fat of the polar bear (Ursus 

maritimus), which preys on the seal. Similar results were found by Andersson et al. (1988), who 

performed limited sampling of biota from various trophic levels in marine food chains in the western 

North Atlantic Ocean, Greenland, Sweden, and Canada. They reported that toxaphene concentrations in 

fish, bird, and seal tissues ranged from 0.33 to 17 ppm in fat tissue for all trophic levels versus 0.14– 

990 ppm for DDT and PCB residues. These results were interpreted as being indicative of less 

biomagnification and/or more effective metabolism of toxaphene at higher trophic levels, as compared 

with DDT and PCB. 

In another study, however, toxaphene was found in the tissues of white-beaked dolphins (Lagenorhynchus 

albirostris) and pilot whales (Globicephala melaena) taken off the coast of Newfoundland in 1980 and 

1982 (Muir et al. 1988b). The toxaphene peaks from the gas liquid chromatography (GLC) analyses of 

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the dolphin blubber indicated considerable metabolism of the mixture, as compared with toxaphene 

residues detected in the local fish populations preyed upon by the dolphins. Other studies in the area of 

Baffin Bay, Canada, have found cetacean blubber with an average toxaphene congener concentration of 

9.2 ppm for male narwhals. Tissue concentrations in individual males ranged up to 13.2 ppm (Muir et al. 

1992). De Boer and Wester (1993) also found evidence of biomagnification of toxaphene in the marine 

food chain from fish to fish predators, and reported biomagnification factors (BMFs) of approximately 

40 for harbor porpoise/fish and 100 for whitebeaked dolphin/fish. Comparison of the chromatograms 

from whitebeaked dolphin (blubber) and fish (hake liver) indicated similar metabolism of toxaphene for 

both species. 

Tissue residue data from marine ecosystems have been used by Hargrave et al. (1993) to calculate the 

following ranges of BMFs (ng PCC/g lipid predator per ng PCC/g lipid prey) for various predator-prey 

links among arctic marine organisms. In a hypothetical food web, the following ranges in BMF values 

were reported: arctic cod and char/zooplankton (19.7–36.7); ringed seal/arctic cod and char (0.1–0.2); 

beluga/arctic cod and char (2.0–2.3); narwhal/arctic cod and char (3.3–3.4); small lysianassid amphipods/ 

arctic cod and char (0.7–2.7); small lysianassid amphipods/ringed seal (4.7–15.5); small lysianassid 

amphipods/beluga (0.4–1.1); Eurythenes gyrillus/arctic cod and char (9.1–11.1); E. gyrillus/narwhal (2.8– 

3.2); E. gyrillus/beluga (4.6–4.8); E. gyrillus/ringed seal (55.3–65.3); E. gyrillus/eelpout (4.4–19.2); and 

eelpout/small lysianassid amphipods (0.2–2.7). 

6.3.2 Transformation and Degradation 

Toxaphene is not a single molecular substance, but rather a mixture of hundreds of congeners including 

chlorinated bornanes, bornenes, bornadienes, camphenes, and dihydrocamphenes (see Section 4.2). The 

form of toxaphene as it was originally applied in the past as a pesticide is referred to as technical 

toxaphene. The composition of technical toxaphene released to the environment changes over time as the 

congeners degrade at different rates. Degradation proceeds mainly through dechlorination and 

dehydrochlorination, resulting in a shift in composition toward lower chlorinated homologs (Buser et al. 

2000; Lamb et al. 2008). The changed form of toxaphene is commonly referred to as weathered 

toxaphene (Lamb et al. 2008; Simon and Manning 2006). In order to achieve the best understanding of 

what individuals may be exposed to in the environment, recent studies have measured the levels of 

individual toxaphene congeners present in environmental samples. Some of the toxaphene congeners that 

have been reported in the literature are listed in Table 6-3. Congeners p-26, p-50, and p-62 are reported to 

be persistent in fish, marine mammals, human serum, and breast milk (Simon and Manning 2006). The 

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Table 6-3. Names and Parlar Identification Numbers of Some Toxaphene 

Congeners Reported in the Literature
 

Name CAS number Parlar number 

2,2,3-exo,8,9,10(E)-Hexachlorocamphene – p-11 

2-exo,3-endo,8,8,9,10(E)-Hexachlorocamphene – p-12 

2,2,5,5,9,10,10-Heptachlorobornane – p-21 

2-endo,3-exo,5-endo,6-exo,8,8,10,10-Octachlorobornane 142534-71-2 p-26 

2,2,5-endo,6-exo,8,9,10-Heptachlorobornane (Toxicant B) – p-32 

2,2,5,5,9,9,10,10-Octachlorobornane – p-38 

2,2,3-exo,5-endo,6-exo,8,9,10-Octachlorobornane – p-39 

2-endo,3-exo,5-endo,6-exo,8,9,10,10-Octachlorobornane 166021-27-8 p-40 

2-exo,3-endo,5-exo,8,9,9,10,10-Octachlorobornane 165820-16-6 p-41 

2,2,5-endo,6-exo,8,8,9,10-Octachlorobornane (Toxicant A1) – p-42a 

2,2,5-endo,6-exo,8,9,9,10-Octachlorobornane (Toxicant A2) – p-42b 

2-exo,5,5,8,9,9,10,10-Octachlorobornane 165820-17-7 p-44 

2-endo,3-exo,5-endo,6-exo,8,8,9,10,10-Nonachlorobornane 6680-80-8 p-50 

2,2,5,5,8,9,10,10-Octachlorobornane – p-51 

2,2,5-endo,6-exo,8,8,9,10,10-Nonachlorohornane – p-56 

2,2,5-endo,6-exo,8,9,9,10,10-Nonachlorobornane – p-59 

2,2,5,5,8,9,9,10,10-Nonachlorobornane 154159-06-5 p-62 

2-exo,3-endo,5-exo,6-exo,8,8,9,10,10-Nonachlorobornane – p-63 

2,2,5,5,6-exo,8,9,9,10,10-Decachlorobornane – p-69 

2-exo,3-endo,6-exo,8,9,10-Hexachlorobornane (Hx-Sed) – – 

2-endo,3-exo,5-endo,6-exo,8,9,10-Heptachlorobornane (Hp-Sed) – – 

2-exo,3-endo,5-exo,8,9,10,10-Heptachlorobornane (TMX-1) – – 

2-exo,3-endo,-5-exo,9,9,10,10-Octachlorobornane (B7-1453) – – 

2-endo,3-exo,5-endo,6-exo,8,8,9,10-Octachlorobornane (B8-1412) – – 

Sources: de Geus et al. 1999; EPA 2010e; Gooch and Matsumura 1985; Lau et al. 1996; Vetter et al. 2001; Xia et 

al. 2009 

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congeners Hx-Sed and Hp-Sed are known degradation products of toxaphene (Buser et al. 2000; EPA 

2010e). 

6.3.2.1 Air 

The worldwide, long-range atmospheric transport of the mixture suggests that toxaphene is relatively 

resistant to transformation in the atmosphere. Since the production of toxaphene involves exposing 

chlorinated camphenes to ultraviolet radiation, the congeners in the final mixture are resistant to 

degradation from direct photolysis (EPA 1976a; Korte et al. 1979). Consequently, toxaphene in the 

atmosphere is not expected to degrade readily by direct photolysis when attached to particulates. 

However, a half-life of approximately 4–5 days (first-order kinetics) has been estimated for the reaction 

of vapor-phase toxaphene with photochemically produced hydroxyl radicals (Howard 1991; Kelly et al. 

1994). The higher chlorinated congeners have longer half-lives since they tend to exist in the particulate 

phase rather than the vapor phase. Rapaport and Eisenreich (1986) cited an atmospheric residence time of 

46–70 days for the mixture. They noted that the toxaphene found in peat cores taken from remote regions 

in the northern United States and Canada was deposited from the atmosphere in a relatively 

untransformed state. 

6.3.2.2 Water 

Little information was found in the available literature on the biodegradation of toxaphene in aquatic 

systems. Toxaphene is resistant to chemical and biological transformation in aerobic surface waters (de 

Geus et al. 1999). It is not expected to undergo direct photolysis or photooxidation (EPA 1979a). 

Hydrolysis is also not an important fate process; a hydrolytic half-life (first-order kinetics) of >10 years 

for pH 5–8 at 25 °C has been estimated (EPA 1976d, 1979a). Detoxification of toxaphene in eight 

Wisconsin lakes was reported to be due to adsorption rather than biodegradation (EPA 1977). 

Buser et al. (2000) measured half-lives ranging from <1 day to several days for technical toxaphene 

congeners in anaerobic sewage sludge from a municipal waste water treatment plant. The non-gemchloro-substituted congeners P26 and P50 degraded less rapidly than the gem-chloro-substituted 

congeners, which is consistent with the relatively high percentage of the P26 and P50 congeners detected 

in environmental samples (Buser et al. 2000; Lamb et al. 2008). Degradation was said to proceed through 

reductive dechlorination resulting formation of Hp-Sed and Hx-Sed and other metabolites. Lacayo et al. 

(2004) studied the degradation of toxaphene in water in aerobic and anaerobic bioreactors operating in 

sequence using a mixed culture inoculum. Reported degradation was 87% after 6 weeks and 98% after 

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39 weeks, with the majority of the degradation occurring under anaerobic conditions. Levels of 

toxaphene congeners with greater chlorine substitution decreased more rapidly than those with lesser 

chlorine substitution. 

6.3.2.3 Sediment and Soil 

Toxaphene has been reported to be quite persistent in aerobic surface soils. Nash and Woolson (1967) 

reported a half-life of 11 years (first-order kinetics) in an aerobic sand loam soil that had received high 

application rates (112 and 224 kg/ha, corresponding to approximately 50 and 100 ppm) of toxaphene. 

Seiber et al. (1979) reported half-lives of approximately 2 months (top 2.5 cm) and 4 months (top 7.5 cm) 

in aerated topsoil that had been treated with toxaphene at an application rate of 9 kg/ha. While the 

observed declines in toxaphene concentrations were primarily due to vaporization, at least one toxaphene 

component was reported to be significantly degraded. The mechanism of degradation was postulated to 

be dehydrochlorination or reductive chlorination, but this was not investigated further. Studies by Parr 

and Smith (1976) and Smith and Willis (1978) in a silty loam soil indicated no transformation of 

toxaphene in moist amended (i.e., alfalfa meal added) or unamended samples incubated under aerobic 

conditions, but rapid transformation (65–96% over 4 weeks) in amended and unamended samples 

incubated under anaerobic conditions. The transformation was reported to be a dechlorination reaction. 

No transformation was observed in autoclaved samples. A 50% loss of toxaphene in 6 weeks due to 

biodegradation in anaerobic, flooded soils was reported; however, no biodegradation was found in aerobic 

sediments (EPA 1979a). 

There is conflicting information in the literature regarding the transformation of toxaphene in sediments. 

Seiber et al. (1979) found that in sediment samples taken from the bottom of a drainage ditch a year or 

more after application of toxaphene to an adjacent field (13.5 kg/ha), several major components of 

toxaphene, including toxicant B (congener p-32), were significantly degraded. Reductive dechlorination 

appeared to be a major mechanism of degradation. This mechanism results in lower weight products than 

occur in technical toxaphene, at least some of which are relatively stable in the environment. As a 

consequence, the authors emphasized that the environmental and toxicological significance of these 

products needs to be determined. Using a microcosm system, Williams and Bidleman (1978) reported 

that toxaphene transformation in an anaerobic salt marsh sediment was mediated chemically, rather than 

biologically. The transformation, believed to be a reductive dechlorination, was rapid, occurring within 

2–6 days even in sterilized samples. In contrast, Mirsatari et al. (1987) found no transformation of 

toxaphene in autoclaved (i.e., sterile) sediment and soil samples over a 60-day test period. In addition, no 

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transformation was observed in unsterile sediment samples incubated under aerobic conditions for 

6 weeks. Rapid transformation (half-life 1 week) was observed only in unsterile sediment samples 

amended with organic matter and incubated under anaerobic conditions. The microbially mediated 

transformation was apparently a reductive dechlorination. Clark and Matsumura (1979) added 

radiolabeled toxaphene to sediments and incubated them for 30 days under aerobic and anaerobic 

conditions. As in the Mirsatari et al. (1987) study, no transformation was observed in autoclaved 

samples. However, toxaphene was transformed in the aerobically incubated samples by the bacterium, 

Pseudomonas putida. Clark and Matsumura (1979) stated that toxaphene biotransformation is likely to 

proceed initially as a dechlorination reaction under anaerobic conditions followed by oxidative 

transformation of the less chlorinated products under aerobic conditions. Thus, toxaphene apparently 

undergoes some biotransformation in the sediment layers of rivers and lakes under both anaerobic and 

aerobic conditions. 

Lacayo-Romero et al. (2006) studied the degradation of toxaphene congeners in contaminated soils using 

anaerobic bioreactors. These authors reported that the congeners p-11 and p-12 were degraded while the 

concentration of p-15 increased, suggesting that the less chlorine substituent toxaphene congeners are 

formed during the degradation of the greater chlorine substituted congeners. Ruppe et al. (2004) 

identified 20 metabolites resulting from anerobic bacterial transformation of technical toxaphene in 

sediments and soils. The most recalcitrant of the toxaphene metabolites were 2-exo,3-endo, 

6-exo,8,9,10-hexachlorobornane (B6-923) and 2-endo,3-exo,5-endo,6-exo,8,9,10-heptachlorobornane 

(B7-1001). 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to toxaphene depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. Concentrations of 

toxaphene 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 toxaphene 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 bioavailable. The analytical methods available for monitoring toxaphene 

in a variety of environmental media are detailed in Chapter 7. 

As a result of its past widespread use as an insecticide and its persistence, toxaphene has been detected in 

ambient air, surface water and groundwater, soils and sediments, rainwater, and food. Data reported in 

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this section have been obtained largely from national surveys in an attempt to present a representative 

national perspective of toxaphene contamination of various environmental media. However, toxaphene 

contamination of certain media may be a more serious problem on a regional basis than indicated by these 

national averages. For example, higher soil concentration levels can be expected in cotton growing areas 

of the South, and higher tissue residue levels have been found in fish taken from the Great Lakes. 

A factor complicating the analysis of toxaphene in various environmental media is the difficulty in 

making trend comparisons for monitoring information collected before the early 1980s. Reliable 

detection of low levels of PCCs became possible only with the adoption of capillary column GC 

technology in the early 1980s. The prevailing earlier packed-column methods were usually unable to 

provide reliable total toxaphene readings for the large numbers of congeners (each present in minute 

amounts) encountered in most samples (Schmitt et al. 1990). For instance, U.S. Fish and Wildlife Service 

programs like the National Pesticide Monitoring Program (now the National Contaminant Biomonitoring 

Program or NCBP) started in the 1970s; however, due to problems in quantification with the older 

analytical technologies, results of these programs cannot be compared with toxaphene sampling results 

obtained since 1990 (Schmitt et al. 1990). These problems seriously interfere with drawing conclusions 

for such media as sediments or tissue samples, and make it almost impossible to make trend 

determinations for ambient water. 

Another complicating factor is the mounting evidence that wastes from paper and pulp operations may be 

a source of toxaphene-like materials. Much of this research comes from countries where toxaphene was 

never used as a pesticide agent, but where anomalous findings of PCC materials were encountered. There 

is a tendency in such cases to conclude that all of the PCC congeners are the result of hemispheric or 

global atmospheric transport pathways, but in some cases, PCC from paper and pulp wastes may help 

explain localized hotspots (Jarnuzi et al. 1992a, 1992b; Paasivirta and Rantio 1991; Rantio et al. 1993). 

Shanks et al. (1999) concluded that pulp and paper mills were not sources of toxaphene to Lake Superior 

or northern Lake Michigan at the time of the study based on similar concentrations measured in samples 

upstream from the mills compared with those measured in downstream samples. 

Reliable evaluation of the potential for human exposure to toxaphene depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. In reviewing data on 

toxaphene levels monitored in the environment, it should also be noted that the amount of chemical 

identified analytically is not necessarily equivalent to the amount that is bioavailable. Also, analytical 

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methods used in the past have been based on analysis of technical toxaphene and may not have detected 

some congeners that are expected to be present in the weathered form of toxaphene (EPA 2010e). 

6.4.1 Air 

Toxaphene has been detected in ambient air and rainwater samples collected at a number of sites in the 

United States; however, the available data are not current. No information was found in the available 

literature regarding ambient indoor exposure levels of toxaphene. 

Toxaphene has also been detected in ambient air samples taken at remote locations. Toxaphene 

concentrations of <0.04–1.6 ng/m3 in ambient air samples taken over the western North Atlantic Ocean 

from 1973 to 1974 have been reported (Bidleman and Olney 1975). Mean concentrations in ambient air 

samples from Bermuda were 0.81 ng/m3 (±0.45 ng/m3 standard deviation [SD]) and 0.72 ng/m3 

(±0.09 ng/m3 SD). 

In an ambient air monitoring study conducted at four urban sites (Baltimore, Maryland; Fresno, 

California; Riverside, California; and Salt Lake City, Utah) and at five rural sites (Buffalo, New York; 

Dothan, Alabama; Iowa City, Iowa; Orlando, Florida; and Stoneville, Mississippi) in the United States in 

1967–1968, toxaphene was detected only in samples taken from the three agricultural areas in southern 

states. Maximum concentrations detected were 68 ng/m3 (detected in 11 of 90 samples), 2,520 ng/m3 

(9 of 99 samples), and 1,340 ng/m3 (55 of 98 samples) in Dothan, Alabama; Orlando, Florida; and 

Stoneville, Mississippi, respectively (Stanley et al. 1971). Toxaphene was included in the ambient air 

sampling of agricultural and urban areas conducted in 14–16 states as part of the National Air Pesticide 

Monitoring Program. For the years 1970–1972, toxaphene was detected in 3.5% of the 2,479 samples 

collected at mean and maximum concentrations of 17 and 8,700 ng/m3

, respectively; the mean of the 

positive samples was 1,890 ng/m3 (Kutz et al. 1976). In 1981, toxaphene was detected at maximum 

concentrations of 9.05, 1.73, 0.44, and 0.14 ng/m3 in Greenville, Mississippi; Saint Louis, Missouri; 

Bridgeman, Michigan; and Beaver Island, Michigan, respectively (EPA 1984b; Rice et al. 1986). 

Concentrations of chlorobornanes measured in air samples from Columbia, South Caroline during 1994– 

1995 ranged from 39 to 183 pg/m3 (Bidleman et al. 1998). Air samples collected at a height of 40 cm 

above the soil at farms in Alabama, Louisiana, and Texas during June 1999 and June 2000 contained total 

toxaphene at concentrations ranging from 0.47 to 42.1 ng/m3 (Bidleman and Leone 2004). 

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The average gas-phase concentrations of toxaphene were 1,600, 280, 34, and 10 pg/m3 in air samples 

collected during 2000–2001 in Rohwer, Arkansas; Lubbock, Texas; Bloomington, Indiana; and Sleeping 

Bear Dunes, Michigan (Lake Michigan), respectively (James and Hites 2002). The average gas-phase 

concentrations of toxaphene were 61, 1,400, 60, and 23 pg/m3 in air samples collected during 2002–2003 

in Cocodrie, Louisiana; Rohwer, Arkansas; Bloomington, Indiana; and Sleeping Bear Dunes, Michigan 

(Lake Michigan), respectively (Hoh and Hites 2004). Based on these concentrations and analysis of air 

trajectories, the authors of these studies concluded that toxaphene detected in air from Indiana and the 

Great Lakes region originates in the southern United States (Hoh and Hites 2004; James and Hites 2002). 

Mean concentrations of total toxaphene and the congeners p-26 and p-50 measured in the air at locations 

over Lake Superior, Lake Huron, and Lake Erie were 28, 2.2, and 1.9 pg/L, respectively, in August 1996 

and 12, 0.32, and 0.26 pg/L, respectively, in May 1997 (Jantunen and Bidleman 2003). 

A seasonal variation in toxaphene concentrations in ambient air samples collected in Stoneville, 

Mississippi, from 1972 to 1974 was noted in a study by Arthur et al. (1976). The highest concentrations 

were observed in summer months, corresponding to the growing season, and the lowest in winter months. 

The sampling site was located in the middle of the most intensive cotton-growing area in Mississippi. 

The maximum concentration detected in weekly air samples was 1,747 ng/m3

. Average monthly levels 

were 258, 82, and 160 ng/m3 for 1972, 1973, and 1974, respectively. A similar seasonal variation was 

found in atmospheric toxaphene concentrations in southern Ontario, which was attributed to increased 

volatilization of PCCs during the warmer summer months (Hoff et al. 1993b). During this 1988–1989 

study, average monthly concentrations ranged from 0.08 pg/m3 in February to 110 pg/m3 in July; the 

overall maximum and mean concentrations (n=114) were 580 and 26 pg/m3

, respectively. Shoeib et al. 

(1999) measured total toxaphene concentrations ranging from 0.9 to 10.1 pg/m3 in the air at Point Petre, 

Ontario sampled during 1992 and from 1995 to 1997. The summer-to-winter concentration ratio was 

reported to be about 6. Glassmeyer et al. (1998) reported vapor-phase toxaphene concentrations ranging 

from 1.0 to 42 pg/m3 measured in the air at Eagle Harbor, Michigan (Lake Superior) during 1996 and 

1997. 

Toxaphene has been identified in air samples collected at 3 of the 68 NPL hazardous waste sites where it 

was detected in some environmental media (HazDat 2007). 

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6.4.2 Water 

Toxaphene has been detected very rarely in drinking water supplies. Toxaphene concentrations ranged 

from 5 to 410 ppt (0.005–0.410 ppb) in drinking water samples collected in Flint Creek, Alabama, 

between 1959 and 1963 (Faust and Suffet 1966). In an extensive water quality monitoring program 

conducted by the California Department of Health Services, toxaphene was detected (detection limit not 

specified) in only 2 of 5,279 public drinking water sources sampled from 1984 to 1992, at mean and 

maximum concentrations of 0.30 and 0.50 ppb, respectively (Storm 1994). Concentrations did not exceed 

the Maximum Contaminant Level (MCL) of 5.0 ppb. 

The median toxaphene concentration detected in ambient surface waters in the United States in 1980– 

1982, according to analyses of EPA's STORET water quality database, was 0.05 ppb (Staples et al. 1985). 

The mixture was detected in 32% of the 7,325 samples collected over that period. Toxaphene was 

detected in only 3.4% of the 708 effluent samples taken during 1980–1983 at a median concentration of 

<0.2 ppb. 

In a study of toxaphene concentrations in surface water and runoff from the Bear Creek, Mississippi, 

watershed conducted in 1976–1979, toxaphene concentrations in surface water were found to be 

measurable only after major runoff events (Cooper et al. 1987). At other times, only trace amounts of the 

compound (<0.01–1.07 ppb) were detected. However, runoff from two fields historically cultivated in 

cotton and soybeans contained toxaphene residues of 0.04–4.18 ppb and 289–2,964 ppm in the aqueous 

and particulate fractions, respectively. Petty et al. (1995) conducted studies using semipermeable 

membrane devices to determine bioavailable organochlorine pesticide residues in streams receiving 

irrigation drainwater from agricultural activity in the Lugert Altus Watershed in southwestern Oklahoma. 

Among the pesticides monitored, toxaphene was predominant, with calculated bioavailable (dissolved) 

water concentrations at six sampling sites ranging from 0.3 to 7 μg/L (ppb). In general, concentrations 

were higher in summer than in spring. The authors noted that the Kow used in these calculations was an 

average for the toxaphene mixture and that, because Kow values for individual congeners may vary by an 

order of magnitude, water concentrations of toxaphene congeners could range from 0.9 to 9 ppb. There is 

an additional uncertainty in these estimates because they were derived from the dialysate data using 

models and preliminary data on uptake kinetics. The results do indicate, however, that significant 

concentrations of bioavailable toxaphene may still be present in this aquatic ecosystem several years after 

discontinuation of its use. 

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In contrast to agricultural areas, municipal areas do not show evidence of toxaphene in water samples. 

Toxaphene was not detected in 86 samples of municipal runoff collected from 15 cities in the United 

States in 1982 as part of the Nationwide Urban Runoff Program (Cole et al. 1984). Toxaphene was not 

detected (detection limits 0.06–0.2 ppb) in surface water samples collected in 1990–1993 from 13 sites in 

the Potomac River and Upper Chesapeake Bay areas (Hall et al. 1993, 1995). Sampling sites included 

both clean reference areas and suspected polluted areas. 

Swackhamer et al. (1999) reported mean dissolved toxaphene concentrations of 1.12 ng/m3 in Lake 

Superior surface water collected in 1996 and 0.38 ng/m3 in Lake Michigan surface water collected in 

1994–1995. Surface water concentrations were estimated to be <0.5 ng/m3 in Lakes Huron, Erie, and 

Ontario. The higher levels in Lake Superior were attributed to colder temperatures (lower volatilization 

rate) and lower sedimentation rates (James et al. 2001; Swackhamer et al. 1999). The mean concentration 

of total toxaphene and the congeners p-26 and p-50 measured in surface water collected at locations 

across Lake Superior in 1996 and 1997 were 918, 3.5, and 13 pg/L, respectively (Jantunen and Bidleman 

2003). 

Toxaphene has also been detected at hazardous waste sites in surface water, groundwater, and leachates. 

Toxaphene was detected at a maximum concentration of 17 ppb in surface water samples taken from two 

of nine disposal ponds at a Superfund site (EPA 1986a). In a study of the chemical composition of 

leachates within existing landfills, toxaphene was not detected in any of the municipal landfill leachates 

examined (Brown and Donnelly 1988). However, the mixture was detected in industrial landfill leachates 

at a concentration of ≤10 ppb. In a review of groundwater monitoring data collected in 1981–1984 from 

more than 500 wells at 334 hazardous waste disposal sites (RCRA and CERCLA sites) located in all 

10 EPA regions and 42 states, Plumb (1987) reported that toxaphene was detected at 0.2% frequency at 

the 178 CERCLA sites examined and at 1.1% frequency at the 156 RCRA sites examined. Concentration 

data were not provided. Toxaphene has been identified in surface water and groundwater samples 

collected at 14 and 27 of the 68 NPL hazardous waste sites, respectively, where it was detected in some 

environmental media (HazDat 2007). 

Toxaphene has been detected in rainwater samples taken in southern France near the Mediterranean Sea 

at mean concentrations of 7.2 ppt (range: not detected to 53 ppt) and 25.2 ppt (range: not detected to 

81 ppt) in solution and sorbed to particulates, respectively (Villeneuve and Cattini 1986). Burniston et al. 

(2005) reported annual average toxaphene concentrations of 0.68–0.85 ng/L (38–47 ppt) measured in 

Lake Ontario precipitation samples collected continuously from November 1994 through December 1998. 

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No additional information was found in the literature for concentrations of toxaphene in rainwater 

samples collected in the United States. 

6.4.3 Sediment and Soil 

Toxaphene has been detected in some samples of urban and agricultural soils from throughout the United 

States. Wiersma et al. (1972a) detected the mixture in concentrations that ranged from 0.11 to 52.7 ppm 

in samples of surface soils from three of eight U.S. cities in 1969. In another study of 14 cities conducted 

in 1970, toxaphene was detected at 3 of 28 sites (10.7%) at mean and geometric mean concentrations of 

1.94 and 0.012 ppm, respectively; concentrations in the positive samples ranged from 7.73 to 33.4 ppm. 

In Sikeston, Missouri, toxaphene was detected at 1 of 27 sites at a concentration of 0.6 ppm. Carey et al. 

(1979a) monitored soils in five U.S. cities in 1971 and found toxaphene only in 11 of 43 samples (25.6%) 

taken from Macon, Georgia, at a mean concentration of 0.24 ppm (range, 0.23–4.95 ppm; geometric 

mean, 0.02 ppm). Toxaphene residues in domestic cropland soils were surveyed in the National Soils 

Monitoring Program (Carey et al. 1978, 1979b; Wiersma et al. 1972b). Toxaphene was found in 73 of 

1,729 soil samples collected in 43 states during 1969 with a mean concentration of 0.07 ppm and a range 

of 0.10–11.72 ppm (Wiersma et al. 1972b). Toxaphene was found in 76 of 1,483 soil samples collected 

in 37 states during 1972 with a mean concentration of 0.24 ppm and a range of 0.22–46.58 ppm (Carey et 

al. 1979b). 

Toxaphene was detected in 38 of 39 agricultural soil samples collected at locations across the state of 

Alabama (Harner et al. 1999). The geometric mean concentration of toxaphene in these samples was 

84 ng/g dry weight and the maximum concentration was 2,423 ng/g dry weight. The concentrations of 

toxaphene measured in soil samples collected from 32 cotton fields in southern South Carolina and 

eastern Georgia ranged from 3.3 to 2,500 ng/g dry weight (Kannan et al. 2003). The median of the 

reported concentrations was 85.3 ng/g dry weight for the South Carolina soils and 67.25 for the Georgia 

soils. Soil samples collected at farms in Alabama, Louisiana, and Texas during June 1999 and June 2000 

contained total toxaphene at concentrations ranging from 3.2 to 6,520 ng/g dry weight (Bidleman and 

Leone 2004). 

Toxaphene levels were measured in soil samples collected during 2000–2001 from three schools and one 

field ballpark in Brunswick, Georgia (Agency for Toxic Substances and Disease Registry 2005). These 

sites are all located within 0.5 miles of the Hercules, Incorporated industrial facility, which manufactured 

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toxaphene from the mid 1940s until 1982. Maximum toxaphene levels measured in the soil from the 

sampling locations were <0.010, 0.180, 0.030, and 0.380 ppm, respectively. 

Rapaport and Eisenreich (1986) found toxaphene in samples of peat from bogs located in remote regions 

of the northern United States and Canada at concentrations ranging from <1 ppb (detection limit) to 

30 ppb. Toxaphene was not detected (detection limit 0.5 ppm wet weight) in surface core samples (0– 

15 cm depth) of soils derived from dredged materials from nine confined disposal facilities in the Great 

Lakes region (Beyer and Stafford 1993). 

Toxaphene has also been detected in sediment samples throughout the United States. Toxaphene was 

detected in 2.2% of 548 sediment samples collected in the lower Mississippi River and its tributaries in 

1964 and from 1966 to 1967. Concentrations in the positive samples ranged from 0.1 to 13.18 ppm, the 

mean concentration was 6.5 ppm (Barthel et al. 1969). In southern Florida, toxaphene was detected, but 

not quantified, in 3.2% of 126 sediment samples collected from 1969 to 1972 (Mattraw 1975). 

Toxaphene was not detected in 27 sediment samples collected in Delaware and in the Raritan Canal, New 

Jersey, from 1979 to 1980 (Granstrom et al. 1984), or in sediment samples collected in Casco Bay, 

Maine, in 1991 (Kennicutt et al. 1994). At a site 1.4 miles from the outfall of a toxaphene plant on Terry 

Creek in Brunswick, Georgia, toxaphene was found at a concentration of 5.27 ppm in a 70–80-cm deep 

sediment sample collected in 1971 (IARC 1979). According to analyses of EPA's STORET water quality 

database, the median toxaphene concentration in sediment was 2.0 ppb; the compound was detected in 

25% of the 1,603 samples taken during 1980–1983 (Staples et al. 1985). 

During an investigation of organochlorine pesticides in soil sediments in the upper Steele Bayou 

watershed of Mississippi, toxaphene was found in 41% of 56 samples collected at two depths (2.54– 

7.62 and 25.4–30.48 cm) along eight different drainages (Ford and Hill 1991). The geometric mean and 

maximum wet weight toxaphene concentrations were 0.12 and 2.80 ppm for the shallow samples, and 

0.07 and 4.60 ppm for the deeper samples, respectively. There was no significant difference in toxaphene 

concentrations between corresponding shallow and deep samples. Raff and Hites (2004) measured 

toxaphene levels ranging from 0.4 to 39 ng/g in suspended sediment samples collected from 32 locations 

along the Mississippi River during 2002–2003. The concentrations of toxaphene in the sediments were 

found to increase rapidly as the river passes through the cotton-growing regions of the southern United 

States. Studies in agricultural areas of the Mississippi Delta have provided indications of the persistence 

of toxaphene in soils and sediments under what might be construed as a worst case scenario. Results of 

investigations at Moon Lake and sites within its watershed just to the east of the main levees on the 

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Mississippi River in Coahoma County, Mississippi, have been reported (Cooper 1991). In soils, which 

provide a generally aerobic redox environment, the average total toxaphene level based on 69 samples 

collected in the period 1983–1984 was 734 ppb. The toxaphene concentration in lake sediments averaged 

12.4 ppb. In core samples from wetland flats displaying marked signs of anaerobic conditions, there was 

no detectable toxaphene. These findings underscore the fact that it is only in media providing appreciable 

residence times in biologically active anoxic conditions that one can expect significant biodegradation of 

toxaphene. In even moderately aerobic environments, and especially in soil or sediments rich in clay 

colloids, the pesticide agent is persistent for many years. 

Shanks et al. (1999) reported toxaphene concentrations of 1.4–9.0 ng/g dry weight measured in sediment 

from rivers near pulp and paper mills near Lakes Michigan and Superior. These authors also measured 

toxaphene concentrations of 6.0–43 ng/g dry weight in sediments from rivers near sites where this 

pesticide was previously used. Maximum toxaphene concentrations measured in sediment cores collected 

from Lake Michigan, Lake Superior, and Lake Ontario during the early 1990s were 48, 42, and 29 ng/g, 

respectively (Pearson et al. 1997). Surficial accumulation rates of 0.097–1.01 ng/cm2

-year were 

determined (Pearson et al. 1997). Analysis of sediment cores showed that in most cases, toxaphene 

accumulations peaked in the early 1970s to early 1980s and then declined in following years (Pearson et 

al. 1997; Schneider et al. 2001). Howdeshell and Hites (1996) observed similar trends in eight Lake 

Ontario sediment cores collected in 1993 and cited contaminated flow from the Niagara River in addition 

to atmospheric deposition as sources of toxaphene in the lake. Analysis of sediment cores from two lakes 

in Canada that were treated with toxaphene during 1961–1962 revealed maximum toxaphene 

concentrations of 500 and 1,602 ng/g dry weight at depths corresponding to the time of treatment 

(Miskimmin et al. 1995). Surface concentrations in these lakes were 53 and 112 ng/g dry weight. 

Toxaphene was not detected in untreated lake sediments. Toxaphene sediment concentrations from five 

Canadian lakes previously treated with this pesticide ranged from 2.6 to 110 μg/kg dry weight (Donald et 

al. 1998). Toxaphene was also detected at 0.2 μg/kg dry weight in an oligotrophic glacial fed lake that 

had no record of treatment. 

Toxaphene has also been found in soils and sediments at hazardous waste disposal sites. Mirsatari et al. 

(1987) reported that toxaphene has been found as a contaminant at pesticide disposal sites at 

concentrations in soils or sediment approaching or exceeding 100 ppm. Toxaphene was also detected at a 

maximum concentration of 2,900 ppb (2.9 ppm) in sediment samples taken from two of nine disposal 

ponds at a Superfund site (EPA 1986a). Toxaphene was found at concentrations ranging from 18 to 

1,505 mg/kg (ppm) in pesticide contaminated soils at four other Superfund sites in Litchfield, Arizona; 

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Albany, Georgia; Marrianna, Florida; and Malone, Florida (Troxler et al. 1993). More recently, 

toxaphene has been identified in soil and sediment samples collected at 40 and 22 of the 68 NPL 

hazardous waste sites, respectively, where it was detected in some environmental media (HazDat 2007). 

6.4.4 Other Environmental Media 

Several studies conducted to determine the levels of toxaphene in food indicate that this substance is 

found only infrequently in the U.S. food supply, generally at very low residue concentrations, which have 

decreased significantly since the restriction of its use in 1982 (EPA 1982a) and its total ban in 1990 (EPA 

1990b). Except for fish and wild game animals from some areas of the United States (Agency for Toxic 

Substances and Disease Registry 2009; Ford and Hill 1990; Xia et al. 2009), the current U.S. food supply 

does not appear to contain levels of toxaphene that are of concern for human health. 

Levels of toxaphene in food have been determined as part of the Food and Drug Administration’s (FDA) 

Total Diet Studies. In a 1980–1982 survey of pesticides, toxaphene was detected in samples of food 

groups that comprised typical infant and toddler diets. Concentrations of 0.1–0.2 ppm (number positive 

samples, 3) and 0.7–0.12 ppm (number positive samples, 6) were found in the oils and fats food groups of 

infants' and toddlers' diets, respectively. The samples were collected in 13 U.S. cities. Toxaphene was 

not detected in drinking water or the other foods examined in the diet of either group. Other food groups 

examined included: whole milk; other dairy and dairy substitutes; meat, fish, and poultry; grain and 

cereal products; potatoes; vegetables; fruit and fruit juices; sugar and adjuncts; and beverages (Gartrell et 

al. 1986a, 1986b). In a summary of data from 1985 to 1991 FDA Total Diet Studies on pesticide residues 

in infant foods and adult foods eaten by infants and children, toxaphene was found only in peanut butter 

at a maximum concentration of 0.16 ppm (number of positive samples, 27 of 27) (Yess et al. 1993). 

Toxaphene was detected each year in regulatory monitoring of domestic and imported foods conducted by 

the FDA from 1988 to 1994 as part of its Pesticide Residue Monitoring Program (FDA 1989, 1990, 1991, 

1992, 1993, 1994c, 1995). Concentrations were not reported; however, <1% of the surveillance samples 

had any pesticide residue levels that were above established tolerances. Toxaphene was also detected in 

the FDA Total Diet Studies in 1987, 1988, 1989, 1990, and 1991 (FDA 1988, 1990, 1991, 1992). From 

1987 to 1990, it was listed among the most commonly found pesticides, with frequencies of detection of 

1–2% (FDA 1988, 1989, 1990, 1991). Reports of 1992–1994 FDA Total Diet Studies indicated that the 

types of pesticide residues found and their frequencies of occurrence were consistent with those in 

previous years; however, there was no explicit statement that toxaphene was detected in the years 1992– 

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1994 (FDA 1993, 1994c, 1995). Concentrations of toxaphene found in the FDA Total Diet Studies were 

not reported. However, in an overall summary for the 5-year period 1986–1991, average dietary intakes 

of toxaphene, in μg/kg body weight/day, for eight age/sex groups were reported to range from 

0.0057 (25–30-year-old females) to 0.0224 (2-year-old children) (FDA 1993). 

Overall, in 234 ready-to-eat foods tested 37 times each from 1982 to 1991 as part of the FDA Total Diet 

Studies, toxaphene was found 138 times at an average concentration of 0.04 μg/g (ppm) in 18 different 

foods: cantaloupe, raw carrots, boiled collards, corn chips, cucumbers, cooked frankfurters, dry-roasted 

peanuts, creamy peanut butter, dill pickles, cured ham, potato chips, radishes, boiled spinach, boiled 

summer squash, boiled winter squash, strawberries, tomato sauce, and cooked veal cutlet (KAN-DO 

Office and Pesticides Team 1995). Concentrations ranged from 0.0050 μg/g (ppm) (strawberries) to 

0.12 μg/g (ppm) (dry-roasted peanuts). During the period 1989–1991, estimated toxaphene intakes were 

<0.01 μg/kg body weight/day for 6–11-month-old infants, 14–16-year-old males, and 60–65-year-old 

females, with a noticeable downward trend in all age categories (FDA 1990, 1991, 1992). (See 

Section 6.5 for more detailed information on estimated daily toxaphene intakes.) While progressive 

improvements in analytical technologies complicate comparisons of older values with more recent 

collections, the FDA Total Diet Studies clearly suggest that toxaphene residue levels in food and general 

population intake levels have fallen dramatically over the last decade. 

Other studies further indicate that the occurrence of toxaphene in the U.S. food supply is very low. 

Toxaphene was not detected as a violative residue in a 1992–1993 statistically based FDA study of 

pesticide residues in more than 3,000 samples of domestic and imported pears and tomatoes (Roy et al. 

1995). A regional food basket study conducted in San Antonio, Texas, in the period from 1989 to 1991 

screened 6,970 produce items for a suite of 111 pesticide analytes. Toxaphene was not detected in any 

produce items at levels above FDA violation thresholds (Schattenberg and Hsu 1992). A summary of 

results from the FOODCONTAM database (Minyard and Roberts 1991) for the period 1988–1989 

showed no detectable toxaphene residues in food samples. This database involves 10 states that follow 

quality assurance/quality control (QA/QC) protocols consistent with those of such federal counterpart 

agencies as the USDA, EPA, and the FDA. 

Toxaphene has been found in fish and shellfish in some areas of the United States at levels of concern for 

human health and, at present, there are fourteen fish consumption advisories in effect for this compound 

(see Section 6.7) (EPA 2010d). 

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Toxaphene is of particular concern as a major contaminant of Great Lakes fish. Xia et al. (2009) detected 

the toxaphene congeners, p-26, TMX-1, p-38, p-40, p-41, p-44, p-50, and p-62, in fish composites from 

Lake Michigan, Lake Superior, Lake Huron, Lake Ontario, and Lake Erie collected during 2004. 

Reported total toxaphene concentrations were 39 ng/g wet weight in Lake Erie walleye, 155 ng/g wet 

weight in Lake Huron lake trout, 243 ng/g wet weight in Lake Michigan lake trout, 113 ng/g wet weight 

in Lake Ontario lake trout, 398 ng/g in Lake Superior lake trout, and 846 ng/g wet weight in a Lake 

Superior lake trout Standard Reference Material labeled SRM 1946. Congeners p-26, p-50, and p-62 

were reported to be the dominant peaks, together accounting for 2–44% of the amount of total toxaphene 

in the fish samples. 

Swackhamer et al. (1998) measured toxaphene in plankton from Lake Michigan and fish from Lake 

Superior. Reported mean toxaphene concentrations were 51.3 ng/g dry weight in phytoplankton, 

243 ng/g dry weight in zooplankton, 92.4 ng/g dry weight in mysis, 162 ng/g dry weight in bythotrephes, 

411 ng/g dry weight in diporeia, 225 ng/g dry weight in sculpin, and 2,373 ng/g dry weight in lake trout. 

Mean total toxaphene concentrations of 92 and 198 ng/g wet weight were measured in bloater chub and 

alewife samples, respectively, collected from Grand Traverse Bay, Lake Michigan during 1997 and 1998 

(Stapleton et al. 2002). Kucklick and Baker (1998) reported toxaphene concentrations of 99–210 ng/g 

wet weight in smelt, 560–720 ng/g wet weight in herring, 840–1,360 ng/g wet weight in bloater, 260– 

460 ng/g wet weight in sculpins, 21–40 ng/g in mysis, 110–180 ng/g wet weight in limnocatanus, 

100 ng/g wet weight in amphipod, and 250–540 ng/g wet weight in lake trout collected from Lake 

Superior during the summer of 1994. 

Whittle et al. (2000) reported toxaphene concentrations of 0.081–1.926 μg/g wet weight in lake trout, 

1.024 μg/g wet weight in herring, 0.245–0.546 μg/g wet weight in sculpin, 0.016–0.291 μg/g wet weight 

in smelt, 0.049–0.139 μg/g wet weight in alewife, 0.029–0.197 μg/g wet weight in diporeia, 0.020– 

0.091 μg/g wet weight in mysis, and <0.015–0.062 μg/g wet weight in plankton collected from Lake 

Superior, Lake Huron, Lake Erie, and Lake Ontario. Results of this study are summarized in Table 6-2. 

Levels in Lake Superior samples were consistently higher than levels in samples from the other lakes. 

Henry et al. (1998) measured toxaphene in smallmouth bass collected from Fumee Lake in the Upper 

Peninsula of Michigan. Mean toxaphene concentrations were 137 ng/g wet weight in 0–20 cm length 

fish, 255 ng/g wet weight in 20–30 cm length fish, and 312 ng/g wet weight in >30 cm length fish. 

Glassmeyer et al. (1997) measured toxaphene in lake trout, walleye, and smelt archival samples collected 

in 1982 and 1992/1994 from the Great Lakes. Reported 1982 toxaphene levels were 4.5–5.2 μg/g wet 

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weight in lake trout, 0.25 μg/g wet weight in walleye, and 0.16–0.83 μg/g wet weight in smelt. Reported 

1992/1994 levels were 0.54–6.7 μg/g wet weight in lake trout, 0.13 μg/g wet weight in walleye, and 

0.059–0.16 μg/g wet weight in smelt. While concentrations in the Lake Superior samples were not 

significantly different between the 2 years, the results showed a decline in toxaphene concentrations in the 

fish from the other Great Lakes from 1982 to 1992. 

Residues of toxaphene and other pesticides in fish were examined as part of the NCBP, formerly a part of 

the National Pesticide Monitoring Program conducted in 1984. Composite samples (n=321) of 

bottom-feeding and predatory fish were taken from 112 stations located along the major domestic rivers 

and in the Great Lakes. Toxaphene residues were detected in fish tissue samples collected at 69% of the 

stations. In earlier sampling periods, the percentages of stations where detectable residues were present 

were approximately 60% (1976–1977 and 1978–1979) and 88% (1980–1981). The maximum and 

geometric mean wet weight concentrations of the mixture in the 1984 samples were 8.2 and 0.14 ppm, 

respectively, the lowest values found in any NCBP sampling period. Maximum and geometric mean wet 

weight concentration data for earlier sampling periods were 12.7 and 0.34 ppm (1976–1977), 18.7 and 

0.28 ppm (1978–1979), and 21.0 and 0.28 ppm (1980–1981), respectively (Schmitt et al. 1985, 1990). 

Fillets of Great Lakes coho salmon collected from the five lakes in 1980 had mean concentrations of 

0.19–1.53 ppm of "apparent toxaphene" (Clark et al. 1984). Lake trout collected from Lake Michigan 

have been found to contain residues of toxicant congeners A (p-42a and p-42b) and B (p-32) that were 

approximately one-tenth or less of the estimated total toxaphene residues (Gooch and Matsumura 1985, 

1987). The percentages of toxicant A and toxicant B in the fish residues were, however, similar to those 

in the technical toxaphene, indicating that in the environment, the rates of degradation of these congeners 

are roughly the same as those of other toxaphene components. 

Toxaphene concentrations in nearshore fish collected from the mouths of rivers and embayments around 

Lake Michigan in 1983 were determined in a study conducted by Camanzo et al. (1987). In 28 composite 

whole-fish samples collected from 14 sites, toxaphene was detected at a mean concentration of 0.04– 

3.46 ppm in samples of rock bass, northern pike, common carp, smallmouth bass, lake trout, bowfin, 

pumpkinseed, channel catfish, and largemouth bass. The investigators noted that bottom-feeding species 

(e.g., common carp, channel catfish) had higher residue levels than top predatory fish (e.g., northern 

pike), possibly as a result of the bottom-feeders being older, having more fat tissue, and living in 

proximity to contaminated sediments. Most of the residues differed from the GLC peaks for the 

toxaphene standard, indicating that some metabolism/transformation of the compound had taken place. In 

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1982, toxaphene (reported as a toxaphene-like compound) was detected (detection limit 1 mg/kg [ppm] 

wet weight) in all of 10 samples of lake trout collected in Lake Michigan (mean concentration 

4.70.5 ppm), and in 9 of 10 samples of lake trout collected in Lake Superior (mean concentration 

1.6±0.2 ppm) (Miller 1993). In this same study, toxaphene was detected in all of 10 samples of chinook 

salmon collected in Lake Michigan in 1982 (mean concentration 2.0±0.2 ppm), and in 4 of 8 samples of 

chinook salmon collected in Lake Michigan in 1983 (mean concentration 1.0±0.0 ppm ). Fish fillet 

samples from 11 species of Great Lakes fish were found to have toxaphene levels ranging from not 

detected (detection limit 10 ppb [0.01 ppm] wet weight) in bass and bullhead to 936 ppb (0.936 ppm) wet 

weight in trout (Andrews et al. 1993; Newsome and Andrews 1993). The levels appeared to be species 

specific, with higher levels found in fish having higher fat content (trout, herring) than in fish having 

lower fat content (bass, bullhead, perch, pickerel, smelt, menominee). 

Levels of toxaphene in fish to which consumers are actually exposed are dependent on the type of sample 

and the method of preparation, with higher concentrations generally found in the higher fat content skinon fillets. Zabik et al. (1995a, 1995b) investigated the levels of pesticides in Great Lakes fish and the 

effects of processing and selected cooking methods on residue levels. Toxaphene was not detected 

(detection limit 0.050 ppm wet weight) in skin-on or skin-off fillets of carp from Lake Huron and Lake 

Michigan (Zabik et al. 1995a); however, in skin-on fillets of walleye and white bass from these lakes, 

concentrations ranged from not detected to 0.09 ppm (Zabik et al. 1995b). In chinook salmon, toxaphene 

was found in skin-on fillets at average concentrations of 0.41 and 0.34 ppm in Lake Huron and Lake 

Michigan, respectively; corresponding concentrations in skin-off fillets were 0.23 and 0.22 ppm (Zabik et 

al. 1995a). Baking and charbroiling significantly reduced toxaphene concentrations in both skin-on and 

skin-off fillets of salmon (38–56% reduction), while canning skin-off fillets resulted in a 77% reduction 

of toxaphene concentration. Toxaphene was not found in any samples from Lake Erie (Zabik et al. 

1995a, 1995b). 

The mean concentrations of toxaphene measured in largemouth bass at five different locations in the 

Mobile River basin in Alabama ranged from 13 to 104 ng/g in 2004 (Hinck et al. 2009). Maruya and Lee 

(1998) reported toxaphene concentrations of 0.5–1 μg/g lipid in fish collected from the Turtle/Brunswick 

River Estuary near Brunswick, Georgia. Toxaphene was found at maximum concentrations of 11 ppm in 

shellfish samples from California (4 positives in 85 samples) and 54 ppm in shellfish samples from 

Georgia (128 positives in 211 samples) in a National Pesticide Monitoring Program survey of estuarine 

molluscs conducted from 1965 to 1972, a period when toxaphene was heavily used (Butler 1973). 

Toxaphene was detected at concentrations <0.10 ppm wet weight in eggs, ovary, liver, and muscle tissue 

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of three pallid sturgeon (Scaphirnyncus albus) samples from the Missouri River in North Dakota and 

Nebraska (Ruelle and Keenlyne 1993). 

The concentrations of total toxaphene measured in 19 fish samples collected from different locations in 

the Yukon, Canada ranged from 42 to 242 ng/g with a mean of 107 ng/g (Chan and Yeboah 2000). The 

sum of the concentrations of the three congeners, p-26, p-50, and p-62, ranged from 10 to 55 ng/g. 

Donald et al. (1998) reported higher chlorobornane concentrations in fish (75.7–303 μg/kg wet weight) 

from untreated oligotrophic lakes at higher elevations than in fish (3.3–82 μg/kg wet weight) from treated 

trophic lakes at lower elevations in western Canada. Toxaphene concentrations of 1.1 ppm on a wet 

weight basis (24 ppm fat weight basis) in cod liver samples and 0.4–1.0 ppm wet weight basis (4.4– 

12 ppm fat weight basis) in herring fillets collected from the east coast of Canada were reported by 

Musial and Uthe (1983). Toxaphene was not detected in samples of deep sea scallops. 

Tuerk et al. (2005) reported total toxaphene concentrations of 13.0–10.7 μg/g wet mass measured in the 

blubber of Atlantic white-sided dolphins and 1.49–3.33 μg/g wet mass measured in the blubber of roughtoothed dolphins. The relative proportions of the toxaphene congeners, p-50, p-26, and p-62, in the 

blubber samples were approximately 50, 35, and 15%, respectively. Mean concentrations of total 

toxaphene were 11.7 and 1.03 μg/g lipid in the blubber of bottlenose dolphins from the Turtle/Brunswick 

River Estuary and the Savannah Area Estuary, respectively, along the coast of Georgia (Pulster et al. 

2009). Fourteen toxaphene congeners were identified in the blubber samples. Congener p-42a, which is 

one of the most abundant congeners in technical toxaphene, was present in the highest concentrations 

(maximum of 3,950 μg/g lipid). Toxaphene congeners, p-25, p-40, p-50, Hx-Sed, and Hp-Sed, were 

frequently detected at concentrations ranging from 100 to 1,000 ng/g lipid. 

Gouteux et al. (2003) measured toxaphene congeners in blubber samples of 26 male and 26 female beluga 

whales from the St. Lawrence Estuary. The mean concentrations of the toxaphene congeners p-26 and 

p-50 were 710 and 1,510 ng/g wet weight, respectively, in the males and 280 and 520 ng/g wet weight, 

respectively, in the females. Maximum concentrations of these congeners were 1,240 and 3,060 ng wet 

weight, respectively, in the males and 1,110 and 1,690 ng/g wet weight, respectively, in the females. The 

authors stated that on average, toxaphene concentrations decreased by a factor of two between 1988 and 

1999. Gouteux et al. (2005) measured chlorobornanes in blubber samples from six seal species in the St. 

Lawrence marine ecosystem. Toxaphene congeners, p-26, p-40/41, p-44, p-50, and p-62, were all 

detected, with p-26 and p-50 comprising 50–80% of the total chlorobornanes in each sample. The mean 

concentrations of total chlorobornanes were 49 ng/g lipid weight in gray seals, 80 ng/g lipid weight in 

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harbor seals, 18 ng/g lipid weight in ringed seals, 370 ng/g lipid weight in harp seals, and 680 ng/g lipid 

weight in hooded seals. 

Vetter et al. (2001) detected eight toxaphene congeners in the blubber of seals from the Baltic Sea, the 

North Sea, and the Antarctic. Congeners p-26, p-50, B8-1412, p-44, and p-62 were detected in the 

greatest concentrations, followed by B7-1453, p-40, and p-41. Total toxaphene concentrations ranged 

from 5 μg/kg wet weight in an Antarctic elephant seal to 1,457 μg/kg wet weight in a harp seal from the 

North Sea. Concentrations in three Weddell seals in Antarctica ranged from 161 to 489 μg/kg wet 

weight. Total toxaphene concentrations were 68–303 μg/kg in cod liver samples, 1,194 μg/kg in cod liver 

oil, and 4–98 μg/g in two penguins. 

Alder et al. (1997) measured the levels of the three toxaphene congeners, p-26, p-50, and p-62, in 

>100 samples of fish species that are consumed in Germany. Reported mean concentrations for the sum 

of these congeners were 12.1 μg/kg wet weight in herring, 0.2 μg/kg wet weight in Alaska Pollock, 

0.8 μg/kg wet weight in saithe, 15.1 μg/kg wet weight in redfish, 0.1 μg/kg wet weight in hake, 7.9 μg/kg 

wet weight in mackerel, 1.1 μg/kg wet weight in cod, 2.2 μg/kg wet weight in sardine, and 36.7 μg/kg wet 

weight in halibut. Mean concentrations of congeners p-26, p-50, and p-62 were 5.87, 8.70, and 

1.59 μg/kg fresh weight, respectively, in salmon collected along the Swedish east coast of the Baltic Sea 

(Atuma et al. 2000). 

The chief regions where bioaccumulation or biomagnification in fish or wildlife might pose a serious 

public health concern are in high latitude areas outside the contiguous United States. Studies on marine 

mammals in eastern Canada (Muir et al. 1992) suggest risks to native Inuit groups that eat blubber or 

visceral tissues such as liver. While no comparable work has been done in Alaska, this is an area of the 

United States where there could be genuine concern for Native American Inuit groups that hunt and 

consume marine mammals. 

Within the contiguous United States, there is concern for populations that regularly consume meat from 

omnivores or carnivores, such as raccoons. Studies reported in Ford and Hill (1990) on the Upper Steele 

Bayou near the Yazoo National Wildlife Refuge in Mississippi show wildlife still displaying toxaphene 

residues in adipose tissues in collections made in 1988. The residues were most pronounced for raccoons, 

where adipose concentrations of total toxaphene up to 31 ppm (weight mass basis) were observed. The 

Upper Steel Bayou region in Washington County was close to another area on the Big Sunflower River 

previously studied in 1980. Due to radical changes in the GC methods for analyzing toxaphene, 

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researchers are hesitant to make quantitative comparisons (Ford and Hill 1990). Nevertheless, in the late 

1970s, the U.S. Fish and Wildlife Service was concerned enough to issue advisories on human 

consumption of wildlife in the Mississippi Delta region. Many members of this region's rural 

subsistence-level population eat significant amounts of game meat, including raccoons. 

Toxaphene was also reported to be a contaminant of tobacco crops and products. Gibson et al. (1974) 

reported that toxaphene was a sporadic contaminant of Kentucky Burley tobacco crops during the period 

1963–1972. Toxaphene was detected in about 4% of the samples at maximum concentrations exceeding 

100 ppm. Toxaphene was also detected in six brands of cigar tobacco sampled in 1972 at an average 

concentration of 0.92 ppm; four of the six samples had toxaphene concentrations of <0.5 ppm. McDonald 

and Hites (2003) measured the concentrations of toxaphene in 46 tree bark samples collected in the 

United States and Canada. Higher concentrations (>20 ng/g bark) were found in samples collected from 

the South and Southeastern United States, between 40 and 32 degrees latitude, where toxaphene was used 

heavily in the past. Two samples had toxaphene concentrations as high as 250 and 300 ng/g bark. 

Toxaphene concentrations generally ranged from 1 to 11 ng/g bark in samples collected at locations 

further north or south. 

Toxaphene has also been found as a contaminant in anhydrous lanolin, which is used as a moisturizer in 

cosmetics and as a vehicle compound in pharmaceutical preparations (Heikes and Craun 1992). 

Toxaphene was detected (detection limit not reported) in 2 of 10 samples of anhydrous lanolin analyzed 

in 1989 at concentrations of 2.8 and 5.8 mg/kg (ppm), but not in any of 10 samples analyzed in 1991. 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Current human exposure to toxaphene in the United States appears to be very limited. Members of the 

general population may be exposed to low levels of the mixture through ingestion of contaminated 

foodstuffs and possibly through inhalation of ambient air (Kutz et al. 1991). Populations consuming large 

quantities of fish and shellfish potentially contaminated with toxaphene may be exposed to higher levels 

than the general public. Exposure to higher concentrations of toxaphene may also result from contact 

with contaminated media in the vicinity of waste disposal sites containing toxaphene-contaminated 

wastes. No information was found in the available literature regarding the size of the human population 

potentially exposed to toxaphene in the vicinity of hazardous waste sites. 

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Based on the toxaphene levels in their 1980–1982 food survey, the FDA estimated average dietary 

intakes, in μg/kg body weight/day of 0.080, 0.036, and 0.023 for infants, toddlers, and adults, respectively 

(Gartrell et al. 1986a, 1986b). However, actual intakes must be lower than the estimates because other 

reported average dietary intakes were based on the mean concentration of the positive samples. 

Toxaphene intakes, in μg/kg body weight/day, estimated for the total diet analyses were 0.0059, 0.0087, 

and 0.0046 in 1989 (FDA 1990); 0.0071, 0.0085, and 0.0093 in 1990 (FDA 1991); and 0.0033, 0.0059, 

and 0.0024 in 1991 (FDA 1992) for 6–11-month-old infants, 14–16-year-old males, and 60–65-year-old 

females, respectively. An overall summary for the 5-year period 1986–1991 of average dietary intakes of 

toxaphene, in μg/kg body weight/day, by eight age/sex groups was reported: 6–11-month-old infants, 

0.0071; 2-year-old children, 0.0224; 14–16-year-old females, 0.0062; 14–16-year-old males, 0.0089; 25– 

30-year-old females, 0.0057; 25–30-year-old males, 0.0067; 60–65-year-old females, 0.0078; and 60– 

65-year-old males, 0.0077 (FDA 1993; Gunderson 1995). These dietary intake estimates suggest a 

decreasing trend following the cancellation of most registered uses of toxaphene as an agricultural 

pesticide in the United States in 1982 (EPA 1982a) and a cancellation of all registered uses in 1990 (EPA 

1990b). 

Toxaphene has been detected at a concentration of 0.1 mg/kg on a milk fat basis in pooled human breast 

milk samples collected in Uppsala, Sweden (Vaz and Blomkvist 1985), and at an average concentration 

(n=16) of 2 mg/kg lipid weight in human breast milk samples from Nicaragua, where toxaphene is still 

being produced and used (de Boer and Wester 1993). Mean concentrations of total toxaphene and the 

toxaphene congeners p-26 and p-50 were 0.8, 0.4, and 0.6 ng/g fat, respectively, in 10 pools of human 

milk collected during 2002–2003 from 238 primiparous women living in Hong Kong and south China 

(Hedley et al. 2010). The toxaphene congener p-62 was not detected in any of the samples. Newsome 

and Ryan (1999) measured toxaphene levels in human milk samples collected from women living in 

northern and southern Canada. These authors found that toxaphene concentrations in the northern 

samples were approximately 10-fold higher than those measured in the southern samples and stated that 

this disparity may be due to differences in types of food consumed. Mean concentrations of total 

toxaphene, congener 26, and congener 50 were 6.03, 1.32, and 2.35 ng/g lipid, respectively, in samples 

collected across southern Canada in 1992 (n=58); 7.28, 1.32, and 1.15 ng/g lipid, respectively, in samples 

collected in the Great Lakes basin in 1992 (n=24); 12.1, 2.83, and 4.37 ng/g lipid, respectively, in samples 

collected across southern Canada in 1986 (n=30); and 67.7, 24.9, and 33.1 ng/g lipid, respectively, in 

samples collected in Keewatin, Northwest Territories in 1997 (n=12). Toxaphene was measured in 

pooled human milk samples collected from individuals living in sub-arctic and arctic locations in 

northwestern Russia (Polder et al. 2003). Concentrations of the toxaphene congeners p-26, p-50, and 

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p-62 measured in these samples were 2.34–4.33, 3.70–5.75, and 1.32–1.67 μg/kg milk fat, respectively. 

Polder et al. (2008) reported a mean concentration of 11 ng/g lipid weight measured in 10 human milk 

samples collected during 2000–2001 from primipara mothers living in the town of Tromso in northern 

Norway. Skopp et al. (2002b) found the sum of congeners p-26, p-41, p-44, and p-50 to range from 7 to 

24 μg/kg milk fat in breast milk samples from women in an area of northern Germany. Levels of 

toxaphene in human milk from U.S. populations are not available. 

Barr et al. (2004) measured the levels of two toxaphene congeners, p-26 and p-50, in old serum pools 

originally collected in Atlanta, Georgia in 1987, Chicago, Illinois in 1992, and Cincinnati, Ohio in 1994. 

Reported concentrations in these samples were 14.3, 3.5, and 28.9 pg/mL, respectively, for p-26 and 10.5, 

10.0, and 25.2 pg/mL, respectively, for p-50. Patel et al. (2004) measured toxaphene levels in pools of 

108 serum samples collected from pregnant women in Barrow and Bethel, Alaska. p-26 and p-50 were 

detected in >50% of the samples with geometric mean concentrations of 1.10 and 1.61 ng/g lipid-weight, 

respectively. 

When toxaphene was being manufactured and used as an insecticide, occupational exposure to toxaphene, 

particularly via the dermal and inhalation routes, may have been significant. Dermal exposures of 

22.72 and 16.56 μg/hour were reported by Munn et al. (1985) for adults and youths, respectively, 

harvesting a toxaphene-treated onion crop in the Platte River Valley of Colorado in 1982. Any farmers, 

farm workers, or pesticide applicators who formerly used the mixture to control insects on livestock and 

crops may have been exposed to relatively high concentrations via these exposure routes. 

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, 

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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 may be exposed to toxaphene by breathing contaminated air, drinking contaminated water, 

eating contaminated soil, or eating contaminated fish or animals. Children living near areas where 

toxaphene was used heavily or near hazardous waste sites contaminated with toxaphene may have higher 

exposure to this substance. Based on the maximum concentration (0.380 ppm) of toxaphene measured in 

soil from school grounds and a park located near a former production facility in Brunswick, Georgia, an 

exposure dose of 0.000015 mg/kg/day was estimated for a child if exposure through pica is excluded 

(Agency for Toxic Substances and Disease Registry 2005). The estimated exposure dose for a child rose 

to 0.0006 mg/kg/day if exposure through pica was included. Both of these values were below the 

intermediate-duration oral MRL of 0.002 mg/kg/day derived for toxaphene. 

Witt and Niessen (2000) measured levels of toxaphenes in the adipose tissue of 48 children living in 

Germany, Russia, and Kazakhstan. Median and maximum concentrations at the different sampling 

locations were 0.37–1.97 and 0.69–6.02 μg/kg, respectively, for congener p-26 and 0.65–2.36 and 1.22– 

6.12 μg/kg, respectively, for congener p-50. Levels of toxaphene measured in neonatal blood, cord blood, 

meconium fluid, or the blood or urine of children were not located. 

Nursing infants may be at risk for potentially high exposure to toxaphene; however, no data on levels of 

toxaphene congeners in breast milk from U.S. women could be located in the available literature. There 

are several documented cases of toxaphene congeners in fats from human breast milk (Hedley et al. 2010; 

Mussalo-Rauhamaa et al. 1988; Newsome and Ryan 1999; Polder et al. 1998, 2003, 2008; Skopp et al. 

2002b; Vaz and Blomkvist 1985). Toxaphene congeners were also found in the fats in human breast milk 

in Nicaragua, while toxaphene was still being produced and used (de Boer and Wester 1993). The high 

concentrations found, and the lack of correlation between the number of children a woman had and the 

toxaphene concentration in her breast milk, were cited as evidence that elimination of toxaphene via 

transfer to the infant was fully compensated for by a regular intake of toxaphene. Consequently, nursing 

infants of mothers who incur regular and potentially high exposures to toxaphene (e.g., from the 

consumption of contaminated fish or game) may be at a potentially high risk for exposure to toxaphene. 

An additional subpopulation that could experience slightly higher levels of exposure are infants and 

young children who receive vitamin supplements from cod liver oil. This is of some concern in Europe 

where fish oil products may involve catches taken in polluted areas (Walter and Ballschmiter 1991). 

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Oetjen and Karl (1998) measured levels of three toxaphene indicator congeners in fish oils from Europe 

ranging from 13 μg/kg fat in sand eel oil to 206 μg/kg fat in cod oil. While no recent literature was 

identified on fish oil products entering U.S. markets, studies conducted in the early 1980s did detect 

toxaphene residues in food products that would be part of typical toddler and infant diets (Gartrell et al. 

1986a, 1986b). Cod liver samples taken from the east coast of Canada have also shown measurable 

concentrations of toxaphene (Musial and Uthe 1983). 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Members of the general population currently having potentially higher intakes of toxaphene include 

residents living near NPL sites and other hazardous waste sites contaminated with toxaphene; populations 

that consume large quantities of fish and shellfish from waterbodies where fish consumption advisories 

for toxaphene contamination are in effect; and Native American and subsistence hunter groups that 

consume large quantities of wild game animals in their diet. No information was found in the available 

literature regarding the size of these populations. The concentrations of toxaphene in all of the 

contaminated media to which these populations might be exposed have not been adequately characterized. 

In September 2010, toxaphene was cited as the causative pollutant in three fish consumption advisories in 

Arizona (Gila River, Hassayampa River, and Salt River), two in Delaware (Army Creek and Army Pond), 

five in Georgia (Back River, Back River from Causeway to St. Simons Sound, Coastal Georgia, Middle 

and South Georgia, Terry And Dupree Creeks), one in Louisiana (Tensas River), two in Mississippi 

(Delta Region and Roebuck Lake), and one in Oklahoma (Bitter Creek) (EPA 2010d). 

EPA has identified toxaphene as a target analyte and recommended that this chemical be monitored in 

fish and shellfish tissue samples collected as part of state toxics monitoring programs. Residue data 

obtained from these monitoring programs should be used by states to conduct risk assessments to 

determine the need for issuing fish and shellfish consumption advisories (EPA 2010d). 

In much of the contiguous United States where toxaphene was once used as a pesticide agent, the 

incidence of toxaphene residues in freshwater fish appears to be declining. While changes in GC analysis 

technologies make it very hard to compare post-1980 records with analyses conducted in the 1970s, 

results from two sampling periods in the 1980s from the U.S. Fish and Wildlife Service NCBP show that 

the number of sites with detectable levels of total toxaphene in fish tissue samples dropped from 88% in 

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1980–1981 to 69% in samples collected in 1984 (Schmitt et al. 1990). There may still be the potential for 

localized contamination of fish in the vicinity of hazardous waste sites and in the Great Lakes. 

As noted in Section 6.4.4, there could also be risks of high exposures for three U.S. subpopulations that 

consume large amounts of marine mammals or game animals. The first includes Native American groups 

in Alaska, although any quantification of the risks would have to be based on data collected from such 

groups as the Inuit in the Baffin Bay area of Canada (Muir et al. 1992). The second includes people such 

as recreational or subsistence hunters in rural areas of the Southeast where historically heavy use of 

toxaphene as a pesticide agent occurred. People in this area who eat large amounts of wild game animals, 

particularly such species as raccoons, could be at risk of higher exposures (Ford and Hill 1990). The third 

includes individuals who regularly consume sport fish caught from the Great Lakes (ATSDR 2009). 

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 toxaphene 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 techniques for developing methods to determine such health 

effects) of toxaphene. 

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. In general, physical and chemical properties of toxaphene 

have been sufficiently well characterized to permit estimation of its potential environmental fate 

(Bidleman et al. 1981; Budavari et al. 1989; EPA 1981a; NIOSH/OSHA 1978; Worthing 1979). Since 

toxaphene is a complex mixture, the environmental fates of specific congeners in original product 

formulations will vary. Information on the physical and chemical properties of specific congeners is 

needed for more reliable prediction of environmental fate and transport processes for toxaphene mixtures. 

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This information, in combination with additional information on the toxicities of toxaphene congeners 

and their degradation products, is necessary to permit more quantitative estimation of exposure risks and 

analysis of environmental exposures to toxaphene. 

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 2008, became available in February of 2010. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

Recent U.S. production data for toxaphene are not available; however, it is assumed that this substance is 

no longer being produced for use as a pesticide in the United State since all registered uses were canceled 

in 1990 (EPA 1990b; USDA 1995). The most recent estimate of U.S. production levels was in 1982, the 

year that EPA first restricted the use of toxaphene (EPA 1982a). Production levels that year were less 

than 2 million kg (EPA 1987a), substantially lower than in 1972 (21 million kg) when toxaphene was the 

most widely manufactured pesticide in the United States (Grayson 1981). The TRI lists one facility in 

Idaho and one facility in Texas that were involved in toxaphene production during 2008 (TRI08 2010). 

No other information regarding recent production of toxaphene in the United States was found. 

In other parts of the world, toxaphene use continues at very high levels (Bidleman et al. 1989; Stern et al. 

1993). Although reliable information on use levels outside western European countries is almost 

impossible to obtain, many researchers feel that global use levels are quite substantial (Lahaniatis et al. 

1992; Stern et al. 1993). It has been estimated that total global usage of toxaphene from 1950 to 1993 

exceeded 1.3 million tons (Voldner and Li 1993); however, this may be a significant underestimation 

(Swackhamer et al. 1993). Since toxaphene, once volatilized, can be transported atmospherically over 

very long distances, all terrestrial and aquatic ecosystems, including those in the United States, are still 

subject to low levels of exposure. Especially in terms of atmospheric inputs, the best available 

monitoring information shows no demonstrable downward trends (Bidleman et al. 1992). More reliable 

information on global usage and atmospheric emissions of toxaphene would be useful in estimating 

potential human exposures in the United States. Additional information on the amounts of PCCs released 

to the environment as by-products of the chlorinated pulp processes involving pine oils (pinene) (Rantio 

et al. 1993; Swackhamer et al. 1993) would also be useful in developing estimates of global production 

and emissions for toxaphene. 

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The TRI lists four states containing facilities that were involved with the import of toxaphene into the 

United States during 2008 (TRI08 2010). Export of toxaphene to foreign nations for use as a pesticide is 

not expected since nations around the globe have adopted similar bans under the Stockholm Convention. 

No other information was found regarding the import of toxaphene into or the export of toxaphene from 

the United States. 

In 1982, the use of toxaphene was restricted by EPA to its use as a pesticide on livestock; to control 

grasshopper and army worm infestation on cotton, corn, and small grains (in emergency situations only); 

and on banana and pineapple crops in Puerto Rico and the Virgin Islands (EPA 1982a). After July 1990, 

the pesticide registrations for all toxaphene formulations were canceled in the United States and in all 

U.S. territories (EPA 1990b). Because of its historic use as a pesticide, toxaphene has been widely 

distributed in the air, soil, surface water and sediments, aquatic organisms, and foodstuffs. Information 

on the current distributional patterns, which may involve localized hotspots, would be helpful in 

estimating human exposure. 

Incineration in a pesticide incinerator is the preferred method of disposal for toxaphene (EPA 1989a). 

Additional information on the amount of toxaphene disposed of by this method, as well as the amount of 

toxaphene disposed of or abandoned at hazardous waste sites, would be helpful for estimating the 

potential for human exposure. 

Environmental Fate. Information on the environmental fate of toxaphene congeners (as a chemical 

group) is only sufficient to permit a general understanding of the partitioning and widespread transport, of 

toxaphene mixtures in the environment. The composition of toxaphene mixtures varies among producers 

(Walter and Ballschmiter 1991; Worthing and Walker 1987), and only limited data are available on the 

transport and transformation of individual toxaphene congeners in these mixtures. Additional information 

on the identity, physical/chemical properties, and environmental fate of toxic fractions of toxaphene 

mixtures would be useful. However, the sampling and analytical methodology limitations that have 

contributed to the lack of availability of this type of data in the past have not been completely overcome 

(Andrews et al. 1993; Bidleman et al. 1993; Bruns and Birkholz 1993; de Boer and Wester 1993; EPA 

2010e; Lamb et al. 2008; Muir and de Boer 1995; Vetter et al. 1993; Zhu et al. 1994). Therefore, the 

development of this information may be difficult. More information on the rates of biotransformation and 

abiotic reduction of toxaphene in soils and sediments under anaerobic conditions would improve the 

current understanding of toxaphene’s environmental fate. The role of biotic transformations in aerobic 

environments following initial reductive dechlorination needs to be clarified. Toxaphene metabolites 

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such as Hp-Sed and Hx-Sed have been identified (Buser et al. 2000; EPA 2010e). Further information 

regarding the identity, toxicity, and environmental fate of the major toxaphene transformation products 

will be useful in making a more critical assessment of potential human exposure. 

Bioavailability from Environmental Media. Animal studies and case reports of human exposure 

indicate that toxaphene is absorbed following inhalation, oral, and dermal exposure (Kutz et al. 1991; 

Munn et al. 1985). Pharmacokinetics data indicate that toxaphene present in water or food is extensively 

absorbed; however, the degree to which toxaphene is absorbed as a result of inhalation of contaminated 

air or dermal contact with contaminated environmental media has not been well studied. The high Koc for 

toxaphene indicates that it is adsorbed relatively strongly to soil, but it is not possible to estimate the 

extent to which toxaphene present on ingested soil would be absorbed from the gastrointestinal tract. 

Toxaphene is not expected to be available to humans via ingestion of plants unless they have been 

recently treated with the mixture. Since all registered uses of toxaphene as a pesticide were canceled in 

the United States and U.S. Territories in July 1990, ingestion of domestically grown agricultural 

commodities should no longer be a source for toxaphene. More information on the extent of absorption 

of components of the mixture following contact with contaminated air, water, or soil would be helpful in 

determining the potential health effects resulting from human exposure. 

Food Chain Bioaccumulation. Laboratory bioassay and field monitoring data clearly indicate that 

toxaphene components are bioconcentrated by aquatic organisms. Available model ecosystem and field 

monitoring studies of aquatic food chains are sufficient to indicate that toxaphene bioaccumulates in 

aquatic organisms (Lowe et al. 1971; Sanborn et al. 1976; Schimmel et al. 1977; Swackhamer and Hites 

1988; Whittle et al. 2000). However, as the result of metabolism, toxaphene is not biomagnified to the 

same degree as other chlorinated compounds, such as DDT and PCBs (Evans et al. 1991; Ford and Hill 

1991; Niethammer et al. 1984; Stapleton et al. 2001). While several studies show that toxaphene is 

biomagnified in some ecosystems, several other studies show that little or no biomagnification of 

toxaphene occurs in other ecosystems because of effective metabolism of toxaphene by higher trophic 

level mammalian species (Andersson et al. 1988; Muir et al. 1988a, 1988b, 1992). Further congenerspecific information on the bioaccumulation and biomagnification potential of toxaphene in both 

terrestrial and aquatic food chains would be desirable to resolve differences observed in different 

ecosystems. These data will be helpful in assessing the potential for human exposure as a result of 

ingestion of contaminated food. 

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Exposure Levels in Environmental Media. Reliable monitoring data for the levels of toxaphene 

in contaminated media at hazardous waste sites are needed so that the information obtained on levels of 

toxaphene in the environment can be used in combination with the known body burden of toxaphene to 

assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste 

sites. 

Although a large amount of monitoring data is available for toxaphene, most of the data were collected 

20–30 years ago when the mixture was widely used as a pesticide (Cole et al. 1984; Cooper et al. 1987; 

EPA 1984b; Faust and Suffet 1966; Kutz et al. 1976; Plumb 1987; Stanley et al. 1971; Staples et al. 

1985). Some recent monitoring data are available for air (Bidleman and Leone 2004; Hoh and Hites 

2004; James and Hites 2002; Jantunen and Bidleman 2003), surface water (Jantunen and Bidleman 2003), 

soil (Agency for Toxic Substances and Disease Registry 2005; Bidleman and Leone 2004; Harner et al. 

1999; Kannan et al. 2003), and sediment (Raff and Hites 2004; Schneider et al. 2001). Additional 

information on current levels in environmental media would be helpful in characterizing current 

concentrations to which humans could be exposed. This is particularly important for concentrations of 

toxaphene in air, soils, and surface waters in the vicinity of hazardous waste sites. The data currently 

available are too limited to be useful in estimating the exposure of populations coming into contact with 

the mixture through inhalation of contaminated air, consumption of contaminated surface water, 

groundwater, or foodstuffs, and/or contact with contaminated soil. Reliable information is needed on 

current exposure levels in all environmental matrices and food sources (fish, shellfish, and terrestrial 

wildlife) in the vicinity of hazardous waste sites. Additional biomonitoring studies of both aquatic and 

terrestrial wildlife populations near hazardous waste sites, near water bodies where fish consumption 

advisories are currently in place (EPA 2010d), and in areas where toxaphene was historically used in 

agriculture applications (Ford and Hill 1991) are needed. This information on levels of toxaphene in the 

environment would be useful in assessing the potential risk of adverse health effects in populations living 

in these areas. 

Exposure Levels in Humans. Exposure levels for the populations with either short- or long-term 

contact with hazardous waste sites are unknown. These levels currently cannot be estimated because of 

the lack of toxaphene concentration data for contaminated media in the vicinity of hazardous waste sites. 

Exposure of the general population has been estimated from levels in foodstuffs (FDA 1990, 1991, 1992, 

1993). Estimates of average dietary intakes for several age/sex categories are based on data obtained 

subsequent to the restriction of most uses of toxaphene in 1982 (EPA 1982a) and appear to be adequate. 

Inhalation is not expected to be a major exposure route for the general public; consequently, additional 

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data are not necessary. Pharmacokinetic data indicate that toxaphene rapidly redistributes to body fat and 

toxaphene has been identified in human breast milk fat from non-U.S. nursing mothers (de Boer and 

Wester 1993; Hedley et al. 2010; Mussalo-Rauhamaa et al. 1988; Newsome and Ryan 1999; Polder et al. 

2008; Vaz and Blomkvist 1985). Levels of toxaphene have been measured in serum (Barr et al. 2004; 

Patel et al. 2004). Tissue levels have not been obtained from persons exposed to toxaphene as a result of 

contact with a hazardous waste site. This information would be useful in assessing the risk to human 

health for populations living in the vicinity of hazardous waste sites. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Limited data are available regarding the exposures of children to toxaphene. 

Agency for Toxic Substances and Disease Registry (2005) assessed the potential for toxaphene exposure 

of children attending school near a former production facility. The estimated exposure dose for these 

children was calculated as 0.000015–0.0006 mg/kg/day. A few foreign studies are available that report 

toxaphene levels measured in human milk and adipose tissue of children (Hedley et al. 2010; MussaloRauhamaa et al. 1988; Newsome and Ryan 1999; Polder et al. 2003, 2008; Vaz and Blomkvist 1985; Witt 

and Niessen 2000). Levels of toxaphene in human milk, amniotic fluid, meconium, umbilical cord blood, 

neonatal blood, childhood serum, or childhood adipose tissue of individuals living in the United States 

were not located. 

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 toxaphene were located. This substance is not 

currently one of the compounds for which a sub-registry has been established in the National Exposure 

Registry. The substance will be considered in the future when chemical selection is made for subregistries to be established. The information that is 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 

No ongoing studies were located regarding the potential for human exposure to toxaphene. 

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The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring toxaphene, its metabolites, and other biomarkers of exposure and effect to 

toxaphene. 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. 

This chapter summarizes the methods available for the analysis of toxaphene in biological and 

environmental media. In designing a study and choosing a method, it is very important that adequate 

attention be paid to the extent of validation and field applicability. Some of the EPA methods have been 

validated, while some of the literature methods have not. It is the analyst’s responsibility to determine the 

data quality needed before initiating the application of a particular method. 

The analytical methods used to quantify toxaphene in biological and environmental samples are 

summarized below. 

7.1 BIOLOGICAL MATERIALS 

Table 7-1 lists the applicable analytical methods for determining toxaphene in biological samples. The 

analysis and chemical characterization of toxaphene is difficult because of the extreme complexity of the 

compound. Commercial toxaphene is a complex mixture of chlorinated camphene derivatives containing 

more than 670 components (Jansson and Wideqvist 1983). Furthermore, widespread contamination from 

ubiquitous PCBs, 1,1-dichloro-2-2-bis (chlorphenyl)-ethane (DDE), and other organochlorine pesticides, 

which are also complex multi-isomeric chemicals, often interferes with toxaphene's analysis. Hence, 

identification of toxaphene in biological and environmental samples almost invariably involves rigorous 

sample preparation and clean-up procedures prior to chromatographic analysis (de Geus et al. 1999; 

Gooch and Matsumura 1985; Matsumura et al. 1975; Nelson and Matsumura 1975). 

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Table 7-1. Analytical Methods for Determining Toxaphene in Biological Samples 

Sample 

Sample Analytical detection Percent 

matrix Preparation method method limit recovery Reference 

Human Maceration of tissue into a fine slurry; TLC 1 μg/sample 94 Tewari and 

tissues addition of anhydrous Na2SO4 and Sharma 

(toxaphene acetone; filtration of solution and 1977 

and some addition of water and saturated Na2SO4 

metabolites) solution to extract; extraction with 

chloroform; addition of 5% KOH to 

chloroform extract; extraction with 

water; water removal (Na2SO4); 

evaporation and dissolution of residue 

in acetone 

Tissues Grinding of sample (20 g, wet weight) GC/NCIMS ~10 ppb 77–107 Fowler et al. 

containing internal standards anhydrous at 40– 1993 

sodium sulfate followed by extraction 50 ppb 

with 1:1 dichloromethane:hexane, 

volume reduction; cleanup using GPC 

and Florisil 

Human Centrifugation of milk sample; freeze- GC/ECD and 100 ng/g No data Vaz and 

breast milk drying of fat concentrate; dissolution in GC/NCIMS Blomkvist 

acetone and cooling to -60 °C; re­ 1985 

dissolution of residue in hexane and 

shaking with concentrated H2SO4; 

cleanup using silica gel column 

Human Homogenization and extraction with GC/ECD No data No data Head and 

breast fat petroleum ether; removal of water from Burse 1987 

extract with anhydrous Na2SO4; volume 

reduction 

Stomach Filtration of sample and wash of residue TLC 1 μg/sample 94 Tewari and 

washings with water; addition of saturated solution Sharma 

and urine of Na2SO4 and extraction with hexane; 1977 

(toxaphene filtration of extract through anhydrous 

and some Na2SO4 and evaporation to dryness; 

metabolites) dissolution of residue in acetone 

Human Addition of 60% H2SO4 to blood sample; GC/ECDGC/ No data 10– 100 Griffith and 

blood extraction with hexane:acetone (9:1); MC 40 ppb 100 Blanke 

centrifugation and evaporation to 1974 

dryness; dissolution of residue in 

hexane 

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Table 7-1. Analytical Methods for Determining Toxaphene in Biological Samples 

Sample 

Sample Analytical detection Percent 

matrix Preparation method method limit recovery Reference 

Human Addition of sample to a solution of dilute TLC 1 μg/sample 94 Tewari and 

blood H2SO4 and 10% sodium tungstate; Sharma 

filtration of solution and wash of residue 1977 

with water; water removal with (Na2SO4) 

and extraction with hexane; filtration of 

extract through anhydrous Na2SO4 and 

evaporation to dryness; dissolution of 

residue in acetone 

ECD = electron capture detection; GC = gas chromatography; GPC = gel permeation chromatography;
 

MC = microcoulometry; NCIMS = negative chemical ionization mass spectrometry; TLC = thin-layer chromatography
 

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Cautions regarding potential transformations of toxaphene components during sample clean-up operations 

are described below in Section 7.2. The determination of trace amounts of toxaphene in human tissues 

and fluids has been restricted to a limited number of analytical techniques. These include gas 

chromatography equipped with either an electron capture detector (GC/ECD), or a microcoulometric 

detector (GC/MC), or negative ion chemical ionization mass spectrometry (GC/NCIMS), and thin-layer 

chromatography (TLC). 

The most prevalent analytical technique employed to determine trace amounts of toxaphene in biological 

and environmental samples is GC/NCIMS because it has shown the greatest sensitivity to these types of 

chlorinated compounds (Lau et al. 1996; Xia et al. 2009). Vaz and Blomkvist (1985) developed a 

GC/NCIMS method to quantitatively and selectively detect components of toxaphene at ppb (ng/g) levels 

in human breast milk. These authors demonstrated that several mass (M) fragments containing mainly 

(M-35)-ions can be identified, thereby giving relatively simple mass spectra. More important, however, 

fragmented ions from contamination by other organochlorine compounds were not detected because they 

gave weak NCIMS spectra. One disadvantage of GC/NCIMS is the potential for obtaining false negative 

results for certain congeners (Lau et al. 1996; Santos et al. 1997; Xia et al. 2009). 

An alternative method is gas chromatography/electron impact/mass spectrometry (GC/EI/MS) (Lau et al. 

1996). This method is less sensitive than GC/NCIMS; however, it is better at overcoming interferences 

(Lau et al. 1996; Xia et al. 2009). In efforts to improve sensitivity, methods using high resolution GC/EI 

coupled with tandem MS/MS have been developed (Chan et al. 1998; Gouteux et al. 2002; Skopp et al. 

2002a; Xia et al. 2009). 

GC/ECD has also been widely used as a low-cost and sensitive method for toxaphene analysis. Griffith 

and Blanke (1974) and Head and Burse (1987) employed GC/ECD for analysis of toxaphene in human 

blood and breast fat, respectively. MS detection techniques have been favored over ECD since ECD has 

lower selectivity and higher risk for the coelution of congeners (Bordajandi et al. 2006; de Geus et al. 

1999; Fowler 2000; Lau et al. 1996). A number of studies have explored multidimensional gas 

chromatography (MDGC) or similar techniques coupled with ECD as a way to increase selectivity 

(Bordajandi et al. 2006; De Boer et al. 1997; Korytar et al. 2003; Shoeib et al. 2000). Enantiomeric 

determination of chiral toxaphene congeners has been achieved using MDGC/ECD (Bordajandi et al. 

2006). 

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Detection of the individual toxaphene congener enantiomers, referred to as enantioselective 

determination, has been demonstrated using both GC/NCIMS and MDGC/ECD (Bordajandi et al. 2006; 

de Geus et al. 1999; Vetter and Luckas 1995, 2000). Enantiomers tend to show differences in biological 

behavior due to chiral-specific interactions despite their identical physical properties (Vetter and Luckas 

2000). The enantiomers of a single congener may be biodegraded or metabolized at different rates and 

they may show differences in toxicity. Therefore, analysis of the enantiomeric ratios of the congeners 

found in biological and environmental samples may provide further insight into the environmental fate 

and toxicity of toxaphene. 

Identification of low ppb levels of toxaphene in human blood was achieved by GC/MC (Griffith and 

Blanke 1974). The advantages of GC/MC are that the system is linear and more specific, and a lower 

temperature is generally required to vaporize the compound in the GC column. 

A radioreceptor assay has been described for the determination of toxaphene in whole blood (Saleh and 

Blancato 1993). The method is based on the ability of toxaphene to displace 35S tertiary butylbicyclophosphorothioate from the chloride channel of isolated gamma-aminobutyric acid receptor ionophore 

complexes. Unlike chromatographic methods, this approach requires no sample clean-up, needs only 

0.1 mL of blood, and is sensitive to toxaphene concentrations in blood of 2 ppb. An advantage of this 

method is that it assays those toxaphene isomers that are toxic to the nervous system by exploiting the 

known receptor-based mechanism of that toxicity. 

In addition to direct measurement of toxaphene in biological media, it is also possible to determine the 

level of metabolites in biological tissues and fluids. Tewari and Sharma (1977) developed a TLC method 

for determination of toxaphene and its metabolites (dechlorinated and dehydrochlorinated toxaphene) in 

urine, stomach washings, and blood. A detection limit of 1x10-6 g of toxaphene per sample was achieved. 

The authors employed a series of solvent systems and chromogenic reagents on silica gel plates 

impregnated with silver reagents and copper sulfate for separation of the pesticides. The TLC technique 

is, however, laborious and time consuming. 

Despite the availability of advanced instrumental methods, the accurate quantitative determination of the 

level of toxaphene is difficult because of inherent differences between the GC fingerprint pattern of the 

technical toxaphene standard and the pattern found in human fluid extracts containing toxaphene. These 

differences reflect changes caused by metabolism and degradation of the original compound (Lamb et al. 

2008). 

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7.2 ENVIRONMENTAL SAMPLES 

Table 7-2 lists the methods used for determining toxaphene in environmental samples. Residues of 

toxaphene are detectable in the environment because of its use as a piscicide and its use as a pesticide on 

field crops, fruits, vegetables, and uncultivated lands. The identification and quantification of toxaphene 

in environmental samples is complicated by changes in the numbers and relative sizes of constituent 

peaks (components) due to the difference in their rates of degradation, sorption, and volatilization in the 

environment. In addition, quantitative analysis can be further hindered by the lack of purified, individual 

congeners, although improvements in this area are being made (Foreid et al. 2000; Gill et al. 1996; Muir 

and de Boer 1993; Vetter et al. 2000). This is important because of the differing detector response factors 

of the different congeners, a problem of particular relevance to mass spectrometric detection methods (Xu 

et al. 1994). Most recently, the focus of analytical toxaphene research has been to develop methods 

capable of sensitive, selective, and accurate determination of the many different individual toxaphene 

congeners present in samples (Bordajandi et al. 2006; EPA 2010e; Gill et al. 1996; MacEachen and Cocks 

2002; Vander Pol et al. 2010; Vetter et al. 2005; Xia et al. 2009). 

Since the formerly used commercial form of toxaphene, called technical toxaphene, undergoes 

"weathering" through environmental transformation and degradation processes, methods that are strictly 

based on technical toxaphene analysis may not give the most accurate picture regarding the form that 

humans may be exposed to in the environment. Therefore, recent efforts have also been made to 

differentiate between the congener profiles for technical toxaphene and weathered toxaphene (EPA 

2010e). 

A number of potential problems in the procedures used to isolate toxaphene components (chlorobornanes) 

have been noted and compiled after a workshop on the analytical chemistry of toxaphene (Muir and de 

Boer 1993). Extraction/clean-up procedures that include treatments with sulfuric or nitric acid modify the 

toxaphene peak profile. Gel permeation chromatography (GPC) or column chromatography on alumina 

were judged suitable for the isolation of lipids from toxaphene and related organochlorines. The use of 

base hydrolysis for the removal of lipids would degrade chlorobornanes and is not recommended. It has 

also been reported that oxygen in the chemical ionization (CI) source during mass spectrometric detection 

can produce fragment ions from PCBs that appear to be derived from chlorobornanes and this can lead to 

errors in quantitation (Andrews et al. 1993; Muir and de Boer 1993). Other researchers claim that the 

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Table 7-2. Analytical Methods for Determining Toxaphene in Environmental
 

Samples
 

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery Reference 

Air Trapping on chromasorb 102; 

extraction with hexane 

Air Collection of air sample in an 

air sampling train equipped 

with prefilter and ethylene 

glycol; dilution of ethylene 

glycol with water and 

extraction with hexane; 

extraction of prefilter with 

hexane; pooling of extracts 

before drying and 

concentration 

Air Adsorption onto PUF using a 

high volume sampling pump; 

extraction with hexane and 

volume reduction 

Ambient air High volume sampler 

consisting of glass fiber filter 

with PUF backup adsorbent 

and flow rate approximately 

200–280 L/minute for 

24 hours; extraction of filter 

and PUF in soxhlet with 

5% ether in hexane; cleanup 

using alumina column 

chromatography and 

concentration using K-D (EPA 

Method TO4) 

Drinking water Extraction of sample with 

15% dichloromethane in 

hexane; water removal using 

anhydrous Na2SO4; extract 

volume reduction 

Drinking water	 Extraction of sample with 

dichloromethane, water 

removal and solvent exchange 

to methyl-t-butyl ether (EPA 

Method 508) 

GC/ECD 

GC/ECD 

GC/ECD; 

GC/MS 

GC/ECD (EPA 

Method 608) 

GC/ECD or 

GC/MC or 

GC/electrolytic 

conductivity 

and GC/MS 

GC/ECD 

(capillary 

column) 

0.234– 

0.926 ng/m3 

1–10 ng/m3 

0.10 pg/m3 

(10,000 m3 

sample) 

Generally 

>1 ng/m3 

0.001– 

0.01 μg/L 

(single 

component 

pesticide 

sample) 0.050– 

1.0 μg/L 

(multiple 

component 

pesticide 

sample) 

No data 

100	 Thomas 

and 

Nishioka 

1985 

No data	 Kutz et al. 

1976 

No data	 Barrie et 

al. 1993 

No data	 EPA 1984a 

No data	 EPA 1987a 

No data	 EPA 1989 

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7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Toxaphene in Environmental
 

Samples
 

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery Reference 

Drinking water, Extraction of sample with GC/ECD 0.24 μg/L No data EPA 1986f 

groundwater, organic solvent and cleanup (drinking water) 

soil, sludges, using Florisil column to 24 mg/L 

wastes (non-water 

miscible waste) 

Drinking water Extraction of sample with GC/ECD and 0.01 ng/L 100 EPA 1976b 

acetone on a water sampling GC/MS 

apparatus equipped with 

porous polyurethane plugs; 

elution of extract through 

activated Florisil column with 

diethyl ether in petroleum 

ether 

Tap water, Isolation of compounds from GC/ion trap 7.4 μg/L (ppb, 105 (18% Ho et al. 

groundwater, water using C18 SPE followed MS w:v) RSD) at 1995 

river water by recovery of adsorbed 25 μg/L 

analytes with supercritical 

carbon dioxide containing 

acetone 

Waste water Extraction with Tandem MS 5 μg/sample Hunt et al. 

dichloromethane 1985 

Waste water Extraction with GC/ECD 0.24 μg/L 96 EPA 1984c 

dichloromethane, solvent (packed 

exchange to hexane; Florisil column) 

cleanup 

Waste water Extraction with 15% dichloro- GC/ECD No data 96 EPA 1992c 

methane in hexane followed 

by water removal with sodium 

sulfate and concentration with 

K-D; additional cleanup, if 

needed, by partition with 

acetonitrile to remove fats and 

oils or fractionation using a 

Florisil column 

Municipal and Adjustment to pH=11 and GC/MS No data No data APHA 

industrial extraction with 1998a 

discharge water dichloromethane; 

concentration using K-D after 

drying 

Municipal and Extraction with GC/ECD 0.24 μg/L 80 APHA 

industrial dichloromethane (no pH 1998b 

discharges adjustment) and solvent 

exchange to hexane during 

concentration; magnesia-silica 

gel cleanup and concentration 

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Table 7-2. Analytical Methods for Determining Toxaphene in Environmental
 

Samples
 

Sample matrix Preparation method 

Analytical 

method 

Sample 

detection limit 

Percent 

recovery Reference 

Municipal and 

industrial waste 

water, sludges 

(1) If solids <1%, extraction 

with dichloromethane. (2) For 

nonsludges with solids 1–30%, 

dilution to 1% and extraction 

with methylene chloride. If 

solids >30%, sonication with 

GC with ECD, 

MC, or 

electrolytic 

conductivity 

910 ng/L (lower 

if many 

interferences) 

76–122 at 

5,000 

ng/L is 

acceptable 

EPA 1992d 

methylene chloride/acetone. 

(3) For sludges: if solids 

<30%, treatment as in 

#2 above. If solids >30%, 

sonication with acetonitrile 

then methylene chloride. Back 

extraction with 2% sodium 

sulfate. Water removal with 

sodium sulfate, concentration 

using K-D, purification using 

GPC, Florisil, and/or SPE 

Primary sludge Extraction of sample with 

hexane: dichloromethane: 

acetone (83:15:2); extract 

concentration and cleanup on 

Florisil column and elution with 

GC/ECD and 

GC/MS 

No data 85–93 EPA 1982b 

20% acetone in hexane 

Soil, water Extraction of sample with 

organic solvent or mixture of 

organic solvents, depending 

on the sample matrix, followed 

by open-column, 

chromatographic cleanup 

GC/ECD or 

GC/ELCD 

(EPA Method 

8081B) 

No data No data EPA 2007a 

Soil, water Extraction of sample with 

organic solvent or mixture of 

organic solvents, depending 

on the sample matrix, followed 

by open-column, chromatographic cleanup 

GC/NIMS 

(EPA Method 

8276) 

No data No data EPA 2010e 

Soil Addition of water and extract 

with methanol:toluene (1:1); 

loading of extract onto 

chromaflex column containing 

Florisil; concentration of 

GC/MS and 

HPLC 

0.05 μg/g 76–91 Crist et al. 

1980 

sample; addition of 43% 

methanolic KOH solution and 

refluxing followed by extraction 

with hexane and Florisil 

column cleanup 

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7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Toxaphene in Environmental
 

Samples
 

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery Reference 

Soil Soxhlet extraction using GC/EC-NIMS 100 μg/kg No data Brumley et 

methylene chloride or al. 1993 

sonication with methylene 

chloride:acetone (1:1, v/v); 

GPC or SPE cleanup 

Soil Extraction of sample (1 g) with GC/NCIMS 50 μg/kg (ppb, 90–109 Onuska et 

dichloromethane:acetone (1:1) w:w) (10% al. 1994 

using sonication; removal of RSD) 

water with a sodium sulfate 

column; solvent exchange to 

isooctane; Florisil cleanup 

Soil Extraction of soil; introduction Colorimetric 0.5 μg/g 118% EPA 1996 

of extract with enzyme­ immunoassay (0.5 ppm) >0.25– 

toxaphene conjugate into tube 5.0 μg/g 

containing immobilized 

toxaphene antibody 

Sediment, and Extraction of sample with HPLC followed <1 ng/g 95–100 Petrick et 

mussel tissue hexane; elution from alumina by GC/FID or al. 1988 

column and concentration of GC/ECD 

eluent 

Pesticide Extraction of sample using GC/ECD 1 ng/sample No data Gomes 

formulation 50% methanolic KOH; elution 1977 

with ether from Florisil 

Pesticide Removal of solvent (xylene) Open tubular No data No data Saleh and 

formulation from pesticide sample by GC column Casida 

reduced pressure; extraction and GC/TLC 1977 

with hexane 

Pesticide Extraction of sample with TLC 1 μg/sample No data Ismail and 

formulation hexane Bonner 

1974 

Pesticide Dissolution of sample in GC/ECD or No data No data Seiber et 

formulation hexane and loading onto GC/FID al. 1975 

alumina column; elution with 

hexane, then 20% methylene 

chloride in benzene and finally 

100% methanol 

Cotton leaves Extraction of sample with 

water and petroleum ether; 

TLC followed 

by GC/ECD 

0.16– 

0.45 μg/cm2 

No data Bigley et 

al. 1981 

addition of methanolic KOH 

and heat treatment; 

concentration of extract 

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7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Toxaphene in Environmental
 

Samples
 

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery Reference 

Non-fatty foods Extraction of homogenized GC/ECD <0.2 ppm >80 FDA 1994a 

sample with solvent (acetone, (PAM1 

acetonitrile, or acetonitrile/ methods 302, 

water, depending on moisture 303) 

and sugan content) followed 

by water removal and Florisil 

cleanup 

Various produce 50 g homogenized sample GC/ECD 2 ppm No data Hsu et al. 

extracted with acetonitrile, 1991 

filtered, and salt added to 

affect phase separation; 

evaporation to near dryness 

and reconstitution in benzene 

Fruits and Extraction with acetone in GC/ECD No data No data WHO 1984 

vegetables blender; filtration and 

extraction with petroleum 

ether/di-chloromethane; 

solvent evaporation and 

dissolution of residue in 

minimum amount of acetone 

Cucumber Blending of sample with GC/ECD or 4.34 ppm 113 Luke et al. 

acetone folloed by extraction FID 1975 

with petroleum ether and 

dichloromethane (1:1); water 

removal (Na2SO4) and 

concentration followed by 

Florisil column cleanup 

Fortified extracts Preparation of sample solution Spectro­ <1 ppm 69–100 Graupner 

(various foods) with acetone or hexane; photometer and Dunn 

addition of diphenylamine and (absorbance at 1960 

zinc chloride solution and 640 nm) 

evaporation to dryness; 

heating of residue (250 °C) for 

a few minutes and dissolution 

of residue complex in acetone 

Molasses Dilution of sample with water; GC/ECD 0.03 mg/kg No data WHO 1984 

extraction with hexane: 

isopropanol 

Fatty foods Extraction of fats and residues GC/ECD <0.2 ppm >80 FDA 1994b 

from homogenized sample by 

dissolution in an organic 

solvent followed by isolation of 

the residues from the fat using 

Florisil 

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7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Toxaphene in Environmental
 

Samples
 

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery Reference 

Meat Blending with ethyl acetate GC/ECD No data 76–79 Boshoff 

followed by drying (Na2SO4) and 

and filtration; treatment of Pretorius 

extract with KOH and heat; 1979 

extraction with hexane; Florisil 

column cleanup 

Bovine Dilution of blood with water GC/ECD 0.58 μg/mL 73.4 Maiorino et 

defibrinated and exatraction with hexane al. 1980 

whole blood 

Bovine Addition of sample to 88% GC/ECD 0.465 μg/mL 71.7 Maiorino et 

defibrinated formic acid and shaking on a al. 1980 

whole blood vortex mixer; extraction with 

hexane and extraction of 

hexane with 5% potassium 

carbonate; extract volume 

reduction 

Bovine Addition of sample to 88% GC/ECD 0.026 μg/mL 103.4 Maiorino et 

defibrinated formic acid followed by mixing al. 1980 

whole blood and loading onto Florisil 

column; elution with 6% diethyl 

ether in petroleum ether; 

volume reduction and washing 

with hexane 

Lard Extraction with petroleum GC/ECD 1.37 μg/g 46.5– Head and 

ether; centrifugation; removal 107.3 Burse 

of water from extract with 1987 

anhydrous Na2SO4; volume 

reduction 

Poultry fat Rendering of fat followed by GC/ECD 0.475– 92.6–96.9 Ault and 

direct analysis 0.908 ppm Spurgeon 

1984 

Milk fat Centrifugation and GC/ECD and <10 ppb (ECD) No data Cairns et 

fractionation using Florisil GC/MS 7 ppb (MS) al. 1981 

column 

Milk and butter Addition of sample to KOH GC/ECD No data 78–88 Boshoff 

followed by heat treatment and and 

extraction with hexane; Pretorius 

centrifugation and cleanup 1979 

using Florisil 

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7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Toxaphene in Environmental
 

Samples
 

Sample matrix Preparation method 

Analytical 

method 

Sample 

detection limit 

Percent 

recovery Reference 

Human breast 

milk 

Centrifugation of milk sample; 

freeze-drying of fat 

concentrate; dissolution in 

GC/ECD and 

GC/NCIMS 

100 ng/g No data Vaz and 

Blomkvist 

1985 

acetone and cooling to -60 °C; 

re-dissolution of residue in 

hexane and shaking with 

concentrated H2SO4; cleanup 

using silica gel column 

Fish (whole) Blending of frozen sample with 

dry ice and anhydrous 

Na2SO4; extraction in a column 

GC/NCIMS 75 pg/sample 98 Swackhamer et 

al. 1987 

with hexane: acetone (1:1), 

followed by methanol 

Fish tissues Extraction of tissues with a 

mixture of hexane and acetone 

GC/NCIMS No data No data Jansson 

and 

followed by a second 

extraction with hexane and 

Wideqvist 

1983 

diethyl ether; evaporation and 

dissolution of lipid extract in 

hexane; shaking of extract with 

H2SO4 to remove lipid 

Fish tissue Homogenization of 10 g 

sample with hexane:acetone 

(1:2.5) under acid condition, 

extraction twice more with 

GC/NCIMS No data 94 (RSD= 

11%) at 

19 ng/g 

Jansson et 

al. 1991 

10% diethyl ether in hexane. 

Treatment with 98% H2SO4 

and cleanup using GPC and 

silica gel chromatography 

Fish Homogenization of 20 g 

sample followed by extraction 

with hexane/acetone, addition 

of internal standards 

GC/HRMS 

(SIM) 

10 ppb (wet 

weight) 

No data Andrews et 

al. 1993 

(

13C-PCBs), and cleanup using 

GPC and Florisil 

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7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Toxaphene in Environmental
 

Samples
 

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery Reference 

Fish tissue Pulverization of tissue with GC/MS (SIM) 0.1 ng/g 90 (RSD= Jarnuzi 

anhydrous sodium sulfate and 7%) at and 

extraction with acetone; 100 ng Wakimoto 

solvent exchange to hexane 1991 

and volume reduction; cleanup 

using dry-packed Florisil, wetpacked Florisil and silica gel 

ECD = electron capture detector; ELCD = electrolytic conductivity detector; FID = flame ionization detector; 

FTIR = Fourier transform infrared spectroscopy; GC = gas chromatograph; GPC = gel permeation chromatography; 

HPLC = high performance liquid chromatography; HRMS = high resolution mass spectrometry; K-D = KudernaDanish concentration; MC = microcoulometry; MS = mass spectrometry; NCIMS = negative ion chemical ionization 

mass spectrometry; PCBs = polychlorinated biphenyls; PUF = polyurethane foam; SIM = selected ion monitoring; 

RSD = relative standard deviation; SIM = selected ion monitoring; SPE = solid phase extraction; TLC = thin-layer 

chromatography; v/v = volume/volume; wt/wt = weight/weight 

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TOXAPHENE 179 

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problem of residual oxygen in the ion source does not present a major problem (Fowler et al. 1993). In 

order to minimize problems with interferences during analysis, it is recommended that toxaphene 

components be isolated as completely as possible from PCBs and that the presence of oxygen in the ion 

source be minimized. 

GC/ECD, sometimes in combination with GC/MS, is the most frequently used analytical method for 

characterization and quantification of toxaphene in air, drinking water, fish, and other environmental 

samples (Boshoff and Pretorius 1979; Cairns et al. 1981; EPA 1976c, 1985c, 2007a; Kutz et al. 1976; 

Luke et al. 1975; Thomas and Nishioka 1985; WHO 1984; Wideqvist et al. 1984). Analysis of the sample 

includes extraction in organic solvent; a Florisil silica, gel permeation, or TLC clean-up step; and 

detection by GC (Atuma et al. 1986; Ault and Spurgeon 1984; EPA 1976b; Head and Burse 1987; Ismail 

and Bonner 1974; Maiorino et al. 1980; Saleh and Casida 1977; Seiber et al. 1975). A typical gas 

chromatogram contains a series of hills and valleys with three main peaks (EPA 1982b; Gomes 1977). 

Detection limits of toxaphene residues in fish and drinking water were 50 ng of toxaphene per g of sample 

and 1 ng of toxaphene per g of sample, respectively (EPA 1976c, 1987a). GC/ECD is the standardized 

method used by EPA (method 8081B) for determining toxaphene in water and soil samples (EPA 2007a). 

EPA method 8270c (GC/MS, electron impact ionization) is not recommended for toxaphene because of 

limitations in sensitivity arising from the multicomponent nature of toxaphene (EPA 2007b). More 

recently, EPA Method 8276 has been developed to detect congeners typically found in weathered 

toxaphene such as p-26, p-40, p-41, p-44, p-50, p-62, Hx-Sed, and Hp-Sed (EPA 2010e). This method 

uses fused-silica, open tubular capillary columns with negative ion mass spectrometry (NIMS) and is 

considered an appropriate alternative to EPA Method 8081. 

Archer and Crosby (1966) developed a confirmatory method for toxaphene analysis in environmental 

samples that involved dehydrohalogenating (in 50% methanolic potassium hydroxide) the residue extract 

prior to GC analysis. The gas chromatogram indicated one main peak and several minor peaks. Also, the 

detector response was doubled, thereby increasing the sensitivity of this procedure. While this method 

was also rapid, its main application was in samples where toxaphene was the major residue. In samples 

with multiple organochlorine pesticide residues, it would be difficult to measure accurately all of the 

residues and quantify the amount of toxaphene (Archer and Crosby 1966; Bigley et al. 1981; Crist et 

al. 1980; Gomes 1977). Recoveries from various samples are generally good with detection limits at 

levels of <1 ppm. 

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The tandem MS method has been used as an alternative to GC/MS. This method employs the technique 

of collision-activated dissociation on a triple quadruple mass spectrometer. This facilitates direct and 

rapid qualitative and semiquantitative analysis of toxaphene samples in both liquid and solid 

environmental matrices at the 10–100 ppb level (Hunt et al. 1985). Additional features of tandem MS 

include the elimination of most wet chemical and chromatographic separation steps, detection of both 

known and unknown compounds by molecular weight and functional group, and a total analysis time per 

sample of <30 minutes. A disadvantage is that tandem MS is somewhat less specific than GC/MS in the 

identification of some isomeric compounds. 

Techniques developed by Jansson and Wideqvist (1983) and modified by Swackhamer et al. (1987) 

indicated that toxaphene can be detected at 75 pg per sample (approximately 1.2 ng/g) in fish using 

methane NCIMS. The authors noted that the NCIMS technique is more specific and 100 times more 

sensitive than EI or chemical ionization (CI) mass spectrometry and GC/ECD. In combination with a 

selected ion monitoring program, specific fragment ions can be monitored without any preseparation 

column chromatography to eliminate other organochlorine pesticides that coelute with toxaphene 

(Swackhamer et al. 1987). Furthermore, NCIMS spectra are less complex than EI or CIMS spectra and 

contain higher mass ions due to successive losses of chloride and hydrochloride from the molecular ion. 

Jansson et al. (1991) reported a GC/NCIMS method for toxaphene in fish that allowed detection of levels 

below 19 ng/g. Methods based on GC/NCIMS generally give lower limits of detection than GC/ECD 

methods and thus, are recommended for the best sensitivity (Muir and de Boer 1993). 

Shafer et al. (1981) reported that the combined data of a gas chromatograph coupled to a Fouriertransform infrared spectrometer (GC/FT-IR) and GC/MS provide complementary information that leads 

to a better understanding and identification of the EPA's priority pollutants (including toxaphene) in air. 

Both GC/FT-IR and GC/MS separations were performed quickly and efficiently on wall-coated open 

tubular capillary columns. 

A semi-specific spectrophotometric method for toxaphene analysis in fortified extracts of various foods 

was developed by Graupner and Dunn (1960). It was based on measuring the absorbance at 640 nm of a 

greenish-blue diphenylamine-toxaphene complex that was formed by reacting a sample extract with 

diphenylamine in the presence of zinc chloride. Several other organochlorine pesticides also reacted 

under these conditions, but only a few formed complexes that absorbed appreciably at 640 nm, thereby 

causing some interference with toxaphene analysis. A detection limit of <1 ppm of toxaphene was 

reported (Graupner and Dunn 1960). 

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7. ANALYTICAL METHODS 

Petrick et al. (1988) employed high-performance liquid chromatography (HPLC) as a clean-up technique 

prior to GC analysis. Petrick and co-workers efficiently separated toxaphene residues from other 

organochlorinated compounds in fat-rich samples with quantitative recovery. A detection limit of less 

than 1 ng of toxaphene per gram of sample was achieved by GC/ECD. The authors noted that the HPLC 

technique is highly efficient and reproducible and has a low consumption of solvents and high sample 

loading capacity. 

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 toxaphene 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 techniques for developing methods to determine such health 

effects) of toxaphene. 

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. Methods are available for detecting and quantifying levels of toxaphene in the blood and milk 

fat of humans. The precision, accuracy, reliability, and specificity of these methods have been reported. 

These methods are sufficiently sensitive to determine background levels of toxaphene in the general 

population and levels at which adverse health effects would begin to occur. Pharmacokinetic data 

indicate that toxaphene rapidly redistributes to fat; therefore, blood levels would be useful for identifying 

very recent exposures to toxaphene. Levels in milk fat are retained somewhat longer, but these levels 

decrease within weeks of cessation of exposure. 

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7. ANALYTICAL METHODS 

A highly sensitive and specific NCIMS technique has been employed to detect components of toxaphene 

at ppb levels in breast milk without the interference of other organochlorine pesticides (Vaz and 

Blomkvist 1985). GC/ECD and GC/MS can also detect trace amounts of toxaphene in human tissues and 

fluids following an efficient sample preparation and rigorous clean-up procedures. TLC has been used for 

analysis of toxaphene metabolites (Tewari and Sharma 1977). There is a growing need for research and 

development of highly sensitive and quantitative methods for determination of toxaphene metabolites. 

These methods would be useful, since they would allow investigators to assess the risks and health effects 

of long-term, low-level exposure to toxaphene. 

Currently, no methods are available to quantitatively correlate monitored levels of toxaphene in tissues or 

fluids with exposure levels or toxic effects in humans. If methods were available, they would provide 

valuable information on systemic effects following exposure to trace levels of toxaphene. 

Effect. No specific biomarkers of effect have been clearly associated with toxaphene poisoning. Some 

biological parameters have been tentatively linked with toxaphene exposure, but insufficient data exist to 

adequately assess the analytical methods associated with measurement of these potential biomarkers. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Human exposure to toxaphene occurs primarily by inhalation of ambient air, ingestion of 

contaminated foodstuffs, and contact with contaminated soil and surface water. Reliable analytical 

methods are available to detect background levels of toxaphene in a wide range of environmental 

matrices. Toxaphene levels of 75 pg/sample (approximately 1.2 ng/g) can be detected in fish using the 

NCIMS technique (Swackhamer et al. 1987). However, there is a need to implement more refined 

software to process efficiently the data generated by the NCIMS technique. GC/ECD is the standardized 

analytical method used by EPA (2007a) to determine toxaphene in soil and water samples at ppb levels. 

A newer EPA method (8276) has been developed as an alternative to method 8081, which uses GC/NIMS 

(EPA 2010e). GC/ECD, GC/MS, and tandem MS can detect and quantify toxaphene in air, soil, plant 

material, fish, water, milk, fat, and meat at ppb levels. The MRL for intermediate oral exposure to 

toxaphene is 0.002 mg/kg/day. Assuming a 70-kg individual and oral intakes of either 2 L/day of water 

or 2 kg/day of food, analytical methods would need to have sensitivities below 70 ppb (70 μg/L or 

70 μg/kg) in either medium. The methods reported for drinking water have limits of detection far below 

this value (EPA 1976b, 1987a, 1989, 1986f; Ho et al. 1995). The needed sensitivities can be achieved for 

produce (Hsu et al. 1991; Luke et al. 1975), molasses (WHO 1984), and fish (Andrews et al. 1993; 

Jarnuzi and Wakimoto 1991; Swackhamer et al. 1987). Limits of detection in FDA methods are reported 

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TOXAPHENE 183 

7. ANALYTICAL METHODS 

as “<0.2 ppm” and are thus inadequate for these MRLs. Additional analytical methods for detecting low 

levels of toxaphene are needed for foods other than produce. 

Little is known about the toxic properties of toxaphene congener metabolites in the environment 

(Bidleman et al. 1993). Additional analytical methods specifically targeted at toxaphene metabolites and 

degradation products are needed to support such investigations. 

7.3.2 Ongoing Studies 

No ongoing studies concerning techniques for measuring and determining toxaphene in biological and 

environmental samples were reported. 

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7. ANALYTICAL METHODS 

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TOXAPHENE 185 

8. REGULATIONS, ADVISORIES, AND GUIDELINES
 

MRLs are substance specific estimates, which are intended to serve as screening levels, are used by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. 

An MRL of 0.05 mg/kg/day has been derived for acute-duration oral exposure (≤14 days) to toxaphene. 

The MRL is based on a NOAEL of 5 mg/kg/day and a serious LOAEL of 10 mg/kg/day for neurological 

effects (convulsions, salivation, and vomiting) in male and female beagle dogs (Chu et al. 1986). The 

NOAEL of 5 mg/kg/day was divided by an uncertainty factor of 100 (10 for extrapolation from animals to 

humans and 10 for human variability). 

An MRL of 0.002 mg/kg/day has been derived for intermediate-duration oral exposure (15–364 days) to 

toxaphene based on decreased anti-SRBC (IgM) titers as an indicator of depressed humoral immunity in 

monkeys. Benchmark dose (BMD) modeling was conducted using mean anti-SRBC (IgM) titre data 

collected from female cynomolgus monkeys that received toxaphene from the diet for 44 weeks prior to 

primary immunization with SRBC (Tryphonas et al. 2001). The resulting BMDL1SD of 0.22 mg/kg/day 

was divided by an uncertainty factor of 100 (10 for interspecies extrapolation and 10 for sensitive 

individuals). 

EPA (IRIS 2010) has not established an oral reference dose (RfD) or inhalation reference concentration 

(RfC) for toxaphene. 

The International Agency for Research on Cancer (IARC) has classified toxaphene as a Group 2B 

carcinogen (possibly carcinogenic to humans) (IARC 2009). The National Toxicology Program (NTP) 

has determined that toxaphene is reasonably anticipated to be a human carcinogen (NTP 2005), and EPA 

has classified toxaphene as a B2 carcinogen (probable human carcinogen) (IRIS 2010). The American 

Conference of Governmental Industrial Hygienists (ACGIH) has classified toxaphene as an 

A3 carcinogen (confirmed animal carcinogen with unknown relevance to humans) (ACGIH 2009). 

OSHA has required employers of workers who are occupationally exposed to toxaphene to institute 

engineering controls and work practices to reduce and maintain employee exposure at or below 

permissible exposure limits (PELs) (OSHA 2009). The employer must use engineering and work practice 

controls to reduce toxaphene exposures to or below 0.5 mg/m3 at any time (ceiling) (OSHA 2009). 

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TOXAPHENE 186 

8. REGULATIONS AND ADVISORIES 

EPA has designated toxaphene as a hazardous air pollutant (HAP) under the Clean Air Act (CAA) 

(EPA 2006b). Toxaphene is on the list of chemicals appearing in “Toxic Chemicals Subject to Section 

313 of the Emergency Planning and Community Right-to-Know Act of 1986" and has been assigned a 

reportable quantity (RQ) limit of 1 pound (EPA 2009e). The RQ represents the amount of a designated 

hazardous substance which, when released to the environment, must be reported to the appropriate 

authority. 

The international and national regulations, advisories, and guidelines regarding toxaphene in air, water, 

and other media are summarized in Table 8-1. 

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8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Toxaphene 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification Group 2Ba

 IARC 2009 

WHO Air quality guidelines 

Drinking water quality guidelines 

No 

Nob

WHO 2000 

 WHO 2006 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA) 

STEL (15-minute TWA) 

0.5 mg/m3 c

1 mg/m3 c 

 ACGIH 2009 

TLV-basis (critical effect) Central nervous 

system convulsions; 

liver damage 

AIHA ERPG values No AIHA 2010

 DOE TEELs DOE 2010 

TEEL-0d

PAC-1e

PAC-2f

PAC-3g

 0.5 mg/m3 

 1 mg/m3 

 20 mg/m3 

 200 mg/m3 

EPA AEGL values No EPA 2010b 

Hazardous air pollutant Yes EPA 2006b 

42 USC 7412 

NIOSH 

Regulated toxic substances and 

threshold quantities for accidental 

release prevention 

Second AEGL Chemical Priority List 

REL (10-hour TWA) 

IDLH 

No 

Yesh

Noi

200 mg/m3 

EPA 2009h 

40 CFR 68.130 

 EPA 2008 

 NIOSH 2005

Potential Occupational Carcinogen Yes 

OSHA 

 Target organs 

Category of Pesticide 

PEL (8-hour TWA) for general industry 

Central nervous 

system, skin 

Group Ij

0.5 mg/m3 i

 NIOSH 1992 

 OSHA 2009 

29 CFR 1910.1000, 

Table Z-1 

b. Water 

EPA Designated as hazardous substances in 

accordance with Section 311(b)(2)(A) of 

the Clean Water Act 

Yes EPA 2009b 

40 CFR 116.4 

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TOXAPHENE 188 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Toxaphene 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA Drinking water standards and health 

advisories 

 EPA 2009c 

1-Day health advisory for a 10-kg 

child 

0.004 mg/L 

10-Day health advisory for a 10-kg 

child 

0.004 mg/L 

DWEL 0.01 mg/L 

Lifetime No 

10-4 Cancer risk 0.003 mg/L 

Drinking water contaminants list Yes EPA 2010c 

National primary drinking water 

regulations

 EPA 2009d 

MCL 0.003 mg/L 

Potential health effects from 

exposure above the MCL 

Kidney, liver, or thyroid 

problems; increased 

risk of cancer 

Common sources of toxaphene in 

drinking water 

Runoff/leaching from 

insecticide used on 

cotton and cattle 

Public health goal Zero 

National recommended water quality 

criteria 

Yes EPA 2006a 

Freshwater 

CMC (acute) 

CCC (chronic) 

0.73 μg/L 

0.0002 μg/Lk 

Saltwater 

CMC (acute) 

CCC (chronic) 

0.21 μg/L 

0.0002 μg/Lk 

Human health for the consumption 

of: 

Water + organism 

Organism only 

0.00028 μg/Ll,m 

0.00028 μg/Ll,m 

Reportable quantities of hazardous 

substances designated pursuant to 

Section 311 of the Clean Water Act 

1 pound EPA 2009i 

40 CFR 117.3 

 Groundwater Monitoring List Yes EPA 2009a 

40 CFR 264, 

Appendix IX 

c. Food 

FDA Bottled drinking water 0.003 mg/L FDA 2010a 

21 CFR 165.110 

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8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Toxaphene 

Agency Description	 Information Reference 

NATIONAL (cont.) 

FDA EAFUSn

 No FDA 2010b 

d. Other 

 ACGIH Carcinogenicity classification A3o

 ACGIH 2009 

Biological exposure indices (end of shift No

at end of workweek) 

EPA Carcinogenicity classification B2p

 IRIS 2010 

Oral slope factor 1.1 (mg/kg-day)-1 

Drinking water unit risk 3.2x10-5 (μg/L)-1 

Inhalation unit risk 3.2x10-4 (μg/m3

)

-1

 RfC No

 RfD No 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous Yesq

 EPA 2009a 

substance 40 CFR 302.4 

 Reportable quantity 1 pound 

Effective date of toxic chemical 01/01/1987 EPA 2009g 

release reporting 40 CFR 372.65 

Extremely hazardous substances No EPA 2009f 

and its threshold planning quantity 40 CFR 355, 

Appendix A 

Toxic pollutants designated pursuant to Yes EPA 2009j 

Section 307(a)(1) of the Clean Water 40 CFR 401.15

Act 

NTP	 Carcinogenicity classification Reasonably NTP 2005 

anticipated to be a 

human carcinogenr 

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TOXAPHENE 190 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Toxaphene 

Agency Description Information Reference 

a

Group 2B: possibly carcinogenic to humans. 

b

Chemical is excluded from guideline value derivation because of determination that toxaphene is unlikely to occur in 

drinking water. 

c

Skin notation: refers to the potential significant contribution to the overall exposure by the cutaneous route, including 

mucous membranes and the eyes, and by contact with vapors, liquids, and solids. 

d

TEEL-0 is the threshold concentration below which most people will experience no adverse health effects. e

PAC-1 is the airborne concentration (expressed as or mg/m3) of a substance above which it is predicted that the 

general population, including susceptible individuals, could experience discomfort, irritation, or certain asymptomatic, 

nonsensory effects. However, these effects are not disabling and are transient and reversible upon cessation of 

exposure.

f

PAC-2 is the airborne concentration (expressed as mg/m3) of a substance above which it is predicted that the 

general population, including susceptible individuals, could experience irreversible or other serious, long-lasting, 

adverse health effects or an impaired ability to escape.
 g

PAC-3 is the airborne concentration (expressed as mg/m3) of a substance above which it is predicted that the 

general population, including susceptible individuals, could experience life-threatening health effects or death. h

Campheclor is included on the list of 371 priority chemicals that are acutely toxic and represent the selection of 

chemicals for AEGL development by the NAC/AEGL committee during the next several years. i

Skin designation: indicates the potential for dermal absorption.
 j

Group I pesticides pose a significant risk of adverse acute health effects at low concentrations, or carcinogenic, 

teratogenic, neurotoxic, or reproductive effects. 

k

This criterion is based on a 304(a) aquatic life criterion issued in 1980 or 1986, and was issued in toxaphene (EPA 

440/5-86-006). This CCC is currently based on the FRV procedure. Since the publication of the Great Lakes Aquatic 

Life Criteria Guidelines in 1995 (60 FR 15393-15399, March 23, 1995), the Agency no longer uses the Final Residue 

Value procedure for deriving CCCs for new or revised 304(a) aquatic life criteria. Therefore, the Agency anticipates 

that future revisions of this CCC will not be based on the FRV procedure (EPA 2006b). l

This criterion has been revised to reflect The EPA's q1* or RfD, as contained in IRIS as of May 17, 2002. The fish 

tissue bioconcentration factor from the 1980 Ambient Water Quality Criteria document was retained in each case 

(EPA 2006b). 

mThis criterion is based on carcinogenicity of 10-6 risk. n

The EAFUS list of substances contains ingredients added directly to food that FDA has either approved as food 

additives or listed or affirmed as GRAS. 

o

A3: confirmed animal carcinogen with unknown relevance to humans. 

p

B2: probable human carcinogen; based on increased incidence of hepatocellular tumors in mice and thyroid tumors 

in rats and supported by mutagenicity in Salmonella.
 q

Designated CERCLA hazardous substance pursuant to Section 311(b)(2) of the Clean Water Act, section 307(a) of 

the Clean Water Act, Section 112 of the Clean Air Act, and Section 3001 of RCRA. 

r

Based on sufficient evidence of carcinogenicity in experimental animals.
 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels; 

AIHA = American Industrial Hygiene Association; CERCLA = Comprehensive Environmental Response, 

Compensation, and Liability Act; CFR = Code of Federal Regulations; CCC = criterion continuous concentration; 

CMC = criterion maximum concentration; DOE = U.S. Department of Energy; DWEL = drinking water equivalent level; 

EAFUS = Everything Added to Food in the United States; EPA = U.S. Environmental Protection Agency;
 

ERPG = emergency response planning guidelines; FDA = Food and Drug Administration; FRV = final residue value; 

GRAS = generally recognized as safe; IARC = International Agency for Research on Cancer; IDLH = immediately 

dangerous to life or health; IRIS = Integrated Risk Information System; MCL = maximum contaminant level; MTL =
 

Master Testing List; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology
 

Program; OSHA = Occupational Safety and Health Administration; PAC = protective action criteria; PEL = permissible 

exposure limit; RCRA = Resource Conservation and Recovery Act; REL = recommended exposure limit; 

RfC = inhalation reference concentration; RfD = oral reference dose; STEL = short-term expsoure limit; TEEL =
 

temporary emergency exposure limit; TLV = threshold limit values; TSCA = Toxic Substances Control Act; 

TWA = time-weighted average; USC = United States Code; WHO = World Health Organization
 

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_______________________ 

TOXAPHENE 191 

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* Cited in text 

+ Cited in supplemental document 

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De Mesquita HBB, Doornobos G, van der Kuip DAM, et al. 1993. Occupational exposure to phenoxy 

herbicides and chlorophenols and cancer mortality in The Netherlands. Am J Ind Med 23:289-300. 

*Dille JR, Smith PW. 1964. Central nervous system effects of chronic exposure to organophosphate 

insecticides. Aerospace Med 35:475-478. 

+*DiPietro JA, Haliburton JC. 1979. Toxaphene toxicosis in swine. J Am Vet Med Assoc 175:452-453. 

*DOE. 2010. Chlorinated camphene. Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: 

Rev. 25 for chemicals of concern (08/2009). U.S. Department of Energy. 

http://orise.orau.gov/emi/scapa/chem-pacs-teels/default.htm. June 16, 2010. 

Domine D, Devillers J, Chastrette M, et al. 1992. Multivariate structure-property relationships (MSPR) 

of pesticides. Pestic Sci 35:73-82. 

*Donald DB, Stern GA, Muir DC, et al. 1998. Chlorobornanes in water, sediment, and fish from 

toxaphene treated and untreated lakes in western Canada. Environ Sci Technol 32(10):1391-1397. 

*Donigian AS Jr, Carsel RF. 1987. Modeling the impact of conservation tillage practices on pesticide 

concentrations in ground and surface waters. Environ Toxicol Chem 6:241-250. 

DOT. 1978. Chemical hazards response information system (CHRIS). Manual 2. Washington, DC: 

U.S. Department of Transportation, U.S. Coast Guard. 

*Dreisbach RH. 1983. Dermatitis due to contact with chemicals. In: Handbook of poisoning: 

Prevention, diagnosis, and treatment. Los Altos, CA: Lange Medical Publications, 88-89. 

*Drenth H, Van Oevelen CJC, Buitenhuis CJK, et al. 1998. Induction of hepatic cytochrome P450 

activities by toxaphene in the rat. Organohalogen Compounds 35:255-258. 

*Durant CJ, Reimold RJ. 1972. Effects of estuarine dredging of toxaphene-contaminated sediments in 

Terry Creek, Brunswick, GA-1971. Pestic Monit J 6:94-96. 

Embry TL, Morgan DP, Roan CC. 1972. Search for abnormalities of heme synthesis and 

sympathoadrenal activity in workers regularly exposed to pesticides. J Occup Med 14:918-921. 

EPA. 1974a. Procedures not recommended. Recommended procedures for the disposal of pesticides. 

U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 165.7 and 40 CFR 165.8. 

*EPA. 1974b. Case study no. 10. Toxaphene. In: Production, distribution, use and environmental 

impact potential of selected pesticides. EPA540174001. PB238795. 

*EPA. 1976a. Criteria document for toxaphene. U.S. Environmental Protection Agency, Office of 

Water Planning and Standards. EPA440976014. PB253677. 

*EPA. 1976b. Analysis and GC-MS characterization of toxaphene in fish and water. Duluth, MN: U.S. 

Environmental Protection Agency, Office of Research and Development. EPA600376076. PB257773. 

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*EPA. 1976c. A quantitative method for toxaphene by GC-CI-MS specific ion monitoring. Athens, GA: 

U.S. Environmental Protection Agency, Office of Research and Development. EPA600476010. 

PB251931. 

*EPA. 1976d. Chemical and photochemical transformation of selected pesticides in aquatic systems.
 

Athens, GA: U.S. Environmental Protection Agency, Office of Research and Development, 1-7, 47, 140.
 

EPA600376067.
 

*EPA. 1977. The degradation of selected pesticides in soil: A review of the published literature. 

Cincinnati, OH: U.S. Environmental Protection Agency. EPA600977022. PB272353.
 

EPA. 1978. Occupational exposure to toxaphene. A final report by the Epidemiologic
 

Studies Program, Human Effects Monitoring Branch, Benefits and Field Studies Division, OPP,
 

OTS.
 

*EPA. 1979a. Water-related environmental fate of 129 priority pollutants. Vol. I: Introduction and 

technical background, metals and inorganics, pesticides and PCBs. Washington, DC: U.S.
 

Environmental Protection Agency, Office of Water Planning and Standards. EPA440479029a.
 

EPA. 1979b. Instructions. Form 2C. U.S. Environmental Protection Agency. Code of Federal
 

Regulations 40 CFR 125.
 

EPA. 1979c. Criteria for classification of solid waste disposal facilities and practices. U.S.
 

Environmental Protection Agency. Code of Federal Regulations 40 CFR 257.
 

EPA. 1979d. Determination of reportable quantities for hazardous substances. U.S. Environmental
 

Protection Agency. Code of Federal Regulations 40 CFR 117.3.
 

EPA. 1979e. Toxic pollutants. U.S. Environmental Protection Agency. Code of Federal Regulations 40
 

CFR 401.15.
 

*EPA. 1979f. Review of the environmental effects of pollutants: X. Toxaphene. Cincinnati, OH: U.S. 

Environmental Protection Agency, Office of Research and Development. EPA600179044.
 

*EPA. 1980a. Toxaphene: Ambient water quality criteria for toxaphene. U.S. Environmental Protection
 

Agency, Office of Water Regulations and Standards. EPA440580076.
 

EPA. 1980b. Identification and listing of hazardous wastes. U.S. Environmental Protection Agency.
 

Code of Federal Regulations 40 CFR 261.
 

*EPA. 1981a. Aquatic fate process data for organic priority pollutants. Washington, DC: U.S. 

Environmental Protection Agency, 109-110. EPA440481014.
 

EPA. 1981b. Electroplating point source category. Total toxic organics. U.S. Environmental Protection
 

Agency. Code of Federal Regulations 40 CFR 413.
 

*EPA. 1982a. Toxaphene: Intent to cancel or restrict registrations of pesticide products containing 

toxaphene; denial of applications for registration of pesticide products containing toxaphene;
 

determination concluding the rebuttable presumption against registration; availability of decision 

document. U.S. Environmental Protection Agency. Fed Regist 47:53784-53793.
 

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*EPA. 1982b. Method development for determination of polychlorinated hydrocarbons in municipal 

sludge. Cincinnati, OH: U.S. Environmental Protection Agency, Office of Research and Development. 

EPA600482035. 

*EPA. 1984a. Method T04: Method for the determination of organochlorine pesticides and 

polychlorinated biphenyls in ambient air. In: Compendium of methods for the determination of toxic 

organic compounds in ambient air. Research Triangle Park, NC: U.S. Environmental Protection Agency, 

Quality Assurance Division, Environmental Monitoring Systems Laboratory, ORD. EPA600484041. 

*EPA. 1984b. Atmospheric transport of toxaphene to Lake Michigan. U.S. Environmental Protection 

Agency, Office of Research and Development, Duluth, MN. EPA600384101. 

*EPA. 1984c. Method 608: Organochlorine pesticides and PCBs. U.S. Environmental Protection 

Agency. Fed Regist 49:89-104. 

EPA. 1985a. Designation of reportable quantities, and notification. U.S. Environmental Protection 

Agency. Code of Federal Regulations 40 CFR 302. 

EPA. 1985b. Standards for the management of specific hazardous wastes and specific types of hazardous 

waste management facilities. U.S. Environmental Protection Agency. Code of Federal Regulations 40 

CFR 266. 

*EPA. 1985c. Drinking water criteria document for toxaphene (final draft). Cincinnati, OH: U.S. 

Environmental Protection Agency, Environmental Criteria and Assessment Office. ECAO-CIN-426. 

PB86118049. 

*EPA. 1986a. Superfund record of decision (EPA Region 4) Gallaway Ponds site, Gallaway, Tennessee, 

September 1986. Washington, DC: U.S. Environmental Protection Agency. EPARODRO486013. 

EPA. 1986b. General pretreatment regulations for existing and new sources of pollution. U.S. 

Environmental Protection Agency. Code of Federal Regulations 40 CFR 403, Appendix B. 

EPA. 1986c. Land disposal restrictions. U.S. Environmental Protection Agency. Code of Federal 

Regulations 40 CFR 268. 

EPA. 1986d. Toxaphene, tolerances for residues. U.S. Environmental Protection Agency. Code of 

Federal Regulations 40 CFR 180. 

EPA. 1986e. Ambient water quality criteria for toxaphene-1986. U.S. Environmental Protection 

Agency, Office of Water Regulations and Standards, Washington, DC. EPA440586006. 

*EPA. 1986f. Method 8080: Organochlorine pesticides and PCBs. In: Test methods for evaluating 

solid waste. Volume IB: Laboratory manual physical/chemical methods. SW 846. 3rd ed. Washington, 

DC: U.S. Environmental Protection Agency, Office of Solid Waste. 

*EPA. 1987a. Health advisories for 16 pesticides (toxaphene). Washington, DC: U.S. Environmental 

Protection Agency, Office of Drinking Water. PB87200178. 

*EPA. 1987b. Superfund record of decision (EPA region 6): Crystal City Airport, Zavala County, Texas 

(first remedial action), September 1987. U.S. Environmental Protection Agency, Washington, DC. 

EPA/ROD/RO6-87/023. 

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EPA. 1988a. Toxic chemical release reporting: Community right-to-know. U.S. Environmental 

Protection Agency. Code of Federal Regulations 40 CFR 372. 

EPA. 1988b. State water quality standards summaries. U.S. Environmental Protection Agency, Office 

of Water, Washington, DC. EPA440588031. 

EPA. 1988c. Land disposal restrictions. U.S. Environmental Protection Agency. Code of Federal 

Regulations 40 CFR 268. 

*EPA. 1988d. Recommendations for and documentation of biological values for use in risk assessment. 

Cincinnati, OH: U.S. Environmental Protection Agency, Office of Research and Development, Office of 

Health and Environmental Assessment, Environmental Criteria and Assessment Office. EPA600687008. 

ECAOCIN554. PB88179874. 

*EPA. 1989a. Pesticides and containers. Recommended procedures for the disposal of pesticides. U.S. 

Environmental Protection Agency. Code of Federal Regulations 40 CFR 165.7-165.9. 

*EPA. 1989b. Method 508: Determination of chlorinated pesticides in water by gas chromatography 

with an electron capture detector. In: Methods for the determination organic compounds in drinking 

water. Revision 3.0. Cinncinati, OH: U.S. Environmental Protection Agency, Environmental 

Monitoring Station Lab, 171-198. EPA600488039. 

*EPA. 1990a. Interim methods for development of inhalation reference concentrations. Washington, 

DC: U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Office of 

Research and Development, Environmental Criteria and Assessment Office. EPA600890066A. 

*EPA. 1990b. Notice of intent to remove certain active ingredients from reregistration list B and to 

cancel pesticides containing those ingredients. U.S. Environmental Protection Agency. Fed Regist 

55:31164-31174. 

EPA. 1992a. Drinking water regulations and health advisories. Washington DC: Office of Water. 

EPA. 1992b. National study of chemical residues in fish. Volumes I and II. Washington, DC: Office of 

Water, Office of Science and Technology. EPA 823R92008a and -008b. 

*EPA. 1992c. Method 617: The determination of organohalide pesticides and PCBs in municipal and 

industrial wastewater. In: Methods for the determination of nonconventional pesticides in municipal and 

industrial wastewater. Washington, DC: U.S. Environmental Protection Agency, 139-168. 

EPA821R92002. 

*EPA. 1992d. Method 1656. The determination of organo-halide pesticides in municipal and industrial 

wastewater. In: Methods for the determination of nonconventional pesticides in municipal and industrial 

wastewater. Washington, DC: U.S. Environmental Protection Agency, 637-677. EPA821R92002. 

*EPA. 1993a. Guidance for assessing chemical contaminant data for use in fish advisories. Vol. 1: 

Fish sampling and analysis. Washington, DC: Office of Water, U.S. Environmental Protection Agency. 

EPA823R93002. PB93237899. 

EPA. 1993b. Toxaphene: Revocation of tolerances. U.S. Environmental Protection Agency. Code of 

Federal Regulations 40 CFR 180 and 185. 

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EPA. 1995a. U.S. Environmental Protection Agency: Method 4040 soil screening for toxaphene by 

immunoassay. Test methods for evaluating solid waste, Vol IB: Laboratory manual physical/chemical 

methods. Revision 0, January 1995. 

EPA. 1995b. U.S. Environmental Protection Agency: Method 8270C semivolatile organic compounds 

by gas chromatography/mass spectrometry (GC-MS): Capillary column technique. Test methods for 

evaluating solid waste, Vol IB: Laboratory Manual Physical/Chemical methods. Revision 0, January 

1995. 

EPA. 1995c. U.S. Environmental Protection Agency: Method 8081A: Chlorine pesticides by capillary 

column gas chromatography. Test methods for evaluating solid waste, Vol IB: Laboratory Manual 

Physical/Chemical methods. Revision 0, January 1995. 

*EPA. 1996. Method 4040. Soil screening for toxaphene by immunoassay. SW-846 on-line. Test 

method for evaluating solid waste physical/chemical methods. U.S. Environmental Protection Agency. 

http://www.epa.gov/osw/hazard/testmethods/sw846/pdfs/4040.pdf. September 09, 2010. 

*EPA. 1997. Special report on environmental endocrine disruption: An effects assessment and analysis. 

Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum. EPA630R96012. 

*EPA. 1998. Announcement of the drinking water contaminant candidate list. U.S. Environmental 

Protection Agency. Fed Regist 63(40):10274-10287. http://www.gpoaccess.gov/fr/index.html. June 17, 

2010. 

*EPA. 2005. Toxic chemical release inventory reporting forms and instructions: Revised 2004 version. 

Section 313 of the Emergency Planning and Community Right-to-Know Act (Title III of the Superfund 

Amendments and Reauthorization Act of 1986). U.S. Environmental Protection Agency. Office of 

Environmental Information. EPA260B05001. 

*EPA. 2006a. National recommended water quality criteria. Washington, DC: U.S. Environmental 

Protection Agency, Office of Water. http://www.epa.gov/waterscience/criteria/wqcriteria.html. May 11, 

2009. 

*EPA. 2006b. Title 42-The public health and welfare. Chapter 85-Air pollution prevention and control. 

Sec. 7412. Hazardous air pollutants. U.S. Environmental Protection Agency. United States Code 42 

USC 7412. http://www.gpoaccess.gov/uscode/index.html. June 23, 2010. 

*EPA. 2007a. Method 8081B. Organochlorine pesticides by gas chromatography. SW-846 On-line. 

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Agency. http://www.epa.gov/osw/hazard/testmethods/sw846/pdfs/8081b.pdf. September 9, 2010. 

*EPA. 2007b. Method 8270D. Semivolatile organic compounds by gas chromatography/mass 

spectrometry (GC/MS). SW-846 On-line. Test methods for evaluating solid waste physical/chemical 

methods. U.S. Environmental Protection Agency. 

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*EPA. 2008. Acute exposure guideline levels (AEGLs). Second AEGL chemical priority list. 

Washington, DC: U.S. Environmental Protection Agency, Office of Pollution and Prevention and Toxics. 

http://www.epa.gov/oppt/aegl/pubs/priority_2.htm. May 19, 2009. 

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*EPA. 2009a. Appendix IX to Part 264-Ground-water monitoring list. U.S. Environmental Protection 

Agency. Code of Federal Regulations 40 CFR 264, Appendix IX. 

http://edocket.access.gpo.gov/cfr_2009/julqtr/pdf/40cfr264AppIX.pdf. June 18, 2010. 

*EPA. 2009b. Designation of hazardous substances. U.S. Environmental Protection Agency. Code of 

Federal Regulations 40 CFR 116.4. http://edocket.access.gpo.gov/cfr_2009/julqtr/pdf/40cfr116.4.pdf. 

June 18, 2010. 

*EPA. 2009c. 2009 Edition of the drinking water standards and health advisories. Washington, DC: 

U.S. Environmental Protection Agency, Office of Water. EPA822R09011. 

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*EPA. 2009d. National primary drinking water regulations. Washington, DC: U.S. Environmental 

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*EPA. 2009e. Superfund, emergency planning, and community right-to-know programs. Designation, 

reportable quantities, and notifications. U.S. Environmental Protection Agency. Code of Federal 

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*EPA. 2009h. Table 1 to § 68.130-List of regulated toxic substances and threshold quantities for 

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CFR 68.130. http://edocket.access.gpo.gov/cfr_2009/julqtr/pdf/40cfr68.130.pdf. June 17, 2010. 

*EPA. 2009i. Table 117.3 - Reportable quantities of hazardous substances designated pursuant to 

section 311 of the clean water act. U.S. Environmental Protection Agency. Code of Federal Regulations 

40 CFR 117.3. http://edocket.access.gpo.gov/cfr_2009/julqtr/pdf/40cfr117.3.pdf. June 18, 2010. 

*EPA. 2009j. Toxic pollutants. U.S. Environmental Protection Agency. Code of Federal Regulations 

40 CFR 401.15. http://edocket.access.gpo.gov/cfr_2009/julqtr/pdf/40cfr401.15.pdf. June 18, 2010. 

*EPA. 2010a. Basic information about toxaphene in drinking water. U.S. Environmental Protection 

Agency. http://www.epa.gov/safewater/contaminants/basicinformation/toxaphene.html. June 08, 2010. 

*EPA. 2010b. Compiled AEGLS values. AEGL Chemicals. U.S. Environmental Protection Agency. 

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*EPA. 2010d. The national listing of fish advisories. U.S. Environmental Protection Agency. 

http://oaspub.epa.gov/nlfwa/nlfwa.advrpt. September 02, 2010. 

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TOXAPHENE 235 

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. 

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. 

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TOXAPHENE 236 

10. GLOSSARY 

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. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

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TOXAPHENE 237 

10. GLOSSARY 

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. 

Maximum Contaminant Level (MCL) —The highest level of a contaminant that is allowed in drinking 

water. 

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. 

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TOXAPHENE 238 

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. 

Parlar—A system (after Dr. H. Parlar, a pioneer in toxaphene analytical chemistry) for naming 

toxaphene congeners, numbered in the order in which the chemical is detected by laboratory equipment 

(elution order). 

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. 

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TOXAPHENE 239 

10. GLOSSARY 

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. 

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, 

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TOXAPHENE 240 

10. GLOSSARY 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

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. 

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TOXAPHENE 241 

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. 

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10. GLOSSARY 

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TOXAPHENE 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. 

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 

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TOXAPHENE A-2 

APPENDIX A 

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 and Environmental Medicine, 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 and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-62, Atlanta, Georgia 30333. 

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TOXAPHENE A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Toxaphene 

CAS Numbers: 8001-35-2 

Date: September 2010 

Profile Status: Final Draft for Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 26 

Species: Dog 

Minimal Risk Level: 0.05 [X] mg/kg/day [ ] ppm 

Reference: Chu I, Villeneuve DC, Sun CW, et al. 1986. Toxicity of toxaphene in the rat and beagle dog. 

Fundam Appl Toxicol 7:406-418. 

Experimental design: (human study details or strain, number of animals per exposure/control group, sex, 

dose administration details): Groups of male and female beagle dogs (6/sex/group) were given gelatin 

capsules containing toxaphene at 0, 0.2, 2.0, or 5.0 mg/kg daily for 13 weeks. During the first 2 treatment 

days, the high-dose group received toxaphene at 10 mg/kg/day. This dose was reduced to 5 mg/kg/day on 

treatment day 3 because the 10 mg/kg/day dose level elicited convulsions, salivation, and vomiting in 

1/6 males and 2/6 females. These clinical signs were not observed in any of the toxaphene-treated dogs 

throughout the remainder of the scheduled 13-week treatment period. 

Effect noted in study and corresponding doses: Serious neurological effects (convulsions, salivation, and 

vomiting in 1/6 males and 2/6 females) were elicited during the first 2 days of oral treatment at 10 mg/kg/ 

day. These effects were not elicited after the highest dose was reduced to 5 mg/kg/day on treatment day 3 

and maintained at that level throughout the remainder of the scheduled 13-week treatment period. 

Dose and end point used for MRL derivation: NOAEL of 5 mg/kg/day for neurological effects; the 

LOAEL was 10 mg/kg/day for clinical signs (convulsions, salivation, and vomiting in 1/6 males and 

2/6 females). 

[X] NOAEL [ ] LOAEL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? No. 

Other additional studies or pertinent information that lend support to this MRL: Lackey (1949) reported 

convulsions in 4/5 fasted dogs administered toxaphene (in corn oil) once by capsule at 10 mg/kg. Higher 

single dose levels (15–50 mg/kg) resulted in convulsions and mortalities; there were no signs of 

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TOXAPHENE A-4 

APPENDIX A 

convulsions in three dogs dosed at 5 mg/kg. Seriously depressed maternal weight gain in pregnant rats 

and mice have been observed at toxaphene doses in the range of 15–32 mg/kg/day (Chernoff and Carver 

1976; Chernoff et al. 1990). The dose necessary to induce nonfatal convulsions in humans has been 

estimated to be approximately 10 mg/kg (CDC 1963). 

Agency Contacts (Chemical Managers): Nickolette Roney, MPH 

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TOXAPHENE A-5 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Toxaphene 

CAS Numbers: 8001-35-2 

Date: September 2010 

Profile Status: Final Draft for Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 47 

Species: Monkey 

Minimal Risk Level: 0.002 [X] mg/kg/day [ ] ppm 

Reference: Tryphonas H, Arnold DL, Bryce F, et al. 2001. Effects of toxaphene on the immune system 

of cynomolgus (Macaca fascicularis) monkeys. Food Chem Toxicol 39:947-958. 

Experimental design: (human study details or strain, number of animals per exposure/control group, sex, 

dose administration details): Groups of 10 female cynomolgus monkeys/dose group were administered 

toxaphene by oral capsules at 0, 0.1, 0.4, or 0.8 mg/kg/day for up to 75 weeks. Groups of five males were 

similarly dosed at 0 or 0.8 mg/kg/day. Testing for immune effects was initiated on week 33 and included 

flow cytometry, lymphocyte transformation, natural killer cell activity, and determination of serum 

cortisol during weeks 33–46 and immunizations with SRBC at treatment week 44 a primary response and 

week 48 for a secondary response (observations made through treatment week 52). 

Effect noted in study and corresponding doses: Treatment with toxaphene at 0.4 mg/kg/day resulted in 

significant (p<0.05) reductions in mean primary anti-SRBC IgM responses at weeks 1 and 4 following 

primary immunization (27 and 35% lower than that of controls) and secondary anti-SRBC IgM responses 

at week 1 following secondary immunization (10% lower than that of controls). The dose level of 

0.8 mg/kg/day resulted in significantly reduced mean primary anti-SRBC IgM responses at weeks 1–4 

following primary immunization, significantly reduced mean secondary anti SRBC IgM response at 

weeks 1 and 4 following secondary immunization, and significantly reduced primary anti-SRBC IgG 

responses at weeks 2 and 3 following primary immunization (51 and 43% lower than that of controls). In 

males, 0.8 mg/kg/day toxaphene induced a significant reduction in mean primary anti-SRBC IgM 

response at weeks 1–3 following primary immunization. Flow cytometry tests showed that the only 

effect on leukocyte and lymphocyte subsets was a reduction in absolute B lymphocytes (CD20) in 

0.8 mg/kg/day females (62% lower than controls). There were no detectable treatment-related effects on 

natural killer cell activity, lymphoproliferative response to mitogens, or serum cortisol levels. Table A-1 

shows the results of primary anti-SRBC IgM responses. 

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TOXAPHENE A-6 

APPENDIX A 

Table A-1. Mean Anti-SRBC (IgM) Titres at 1–4 Weeks Post-Immunization in 

Female Cynomolgus Monkeys Administered Toxaphene in Gelatin Capsule 

Daily for 75 Weeks Including 44 Weeks Prior to Immunization
 

Weeks post-immunization (mean log2 titres ± standard error)a

Toxaphene 

dose (mg/kg/day) 1 2 3 4 

0 7.10±0.35 6.40±0.31 5.30±0.34 4.90±0.41 

0.1 6.40±0.54 5.20±0.73 4.50±0.64 4.00±0.61 

0.4 5.20±0.79b 4.60±0.78 3.80±0.85 3.20±0.63b 

0.8 3.70±0.83b 3.00±0.88b 3.00±0.75b 2.80±0.61b 

a

Mean values calculated from 10 animals per treatment group.

b

p<0.05. 

Source: Tryphonas et al. 2001 

All continuous variable models in the EPA Benchmark Dose Software (Version 2.1.1) were fit to the 

mean anti-SRBC (IgM) titre data at week 1 post-immunization; standard error values were converted to 

standard deviation values prior to running the models. A default benchmark response (BMR) of 

1 standard deviation (1 SD) from the control mean was selected in the absence of a toxicological rationale 

for selecting an alternative BMR. Model results for the mean anti-SRBC (IgM) titre data are shown in 

Table A-2. The linear model was initially fit to the data using constant variance, but failed to meet 

conventional goodness-of-fit criteria for modeled variance (p=0.04395). Adequate fit for modeled 

variance was obtained, however, when fit to the data using non-constant variance. Therefore, nonconstant variance was selected to fit the remaining continuous variable models to the data. The Hill 

model failed the test for mean fit (degrees of freedom <0) and was not considered further. Using nonhomogeneous variance, the polynomial (2- and 3-degree), and power models converged on the linear 

model and provided identical predictions of the BMD1SD (0.34 mg/kg/day) and the 95% lower confidence 

limit on the BMD1SD (BMDL1SD; 0.22 mg/kg/day). The fit of the linear model to the malformation data is 

presented in Figure A-1. This figure is identical to those generated from the polynomial (2- and 

3-degree), and power models. 

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TOXAPHENE A-7 

APPENDIX A 

Table A-2. Model Predictions for Mean Anti-SRBC (IgM) Titre Data at
 

Week 1 Post-Immunization from Female Cynomolgus Monkeys 

Administered Toxaphene in Gelatin Capsule Daily for
 

75 Weeks Including 44 Weeks Prior to Immunization
 

Scaled 

Variance Means residual of BMD1SD BMDL1SD 

Model p-valuea p-valuea interestb AIC (mg/kg/day) (mg/kg/day) 

Constant variance 

Linearc 0.04395 0.9335 -0.15 100.43 – – 

Nonconstant variance 

Linearc 0.48 0.41 -0.16 97.45 0.34 0.22 

Polynomial (2-degree)c 0.48 0.41 -0.16 97.45 0.34 0.22 

Polynomial (3-degree)c 0.48 0.41 -0.16 97.45 0.34 0.22 

Powerd 0.48 0.41 -0.16 97.45 0.34 0.22 

Hillc 0.48 NAe 0.26 99.68 0.14 0.04 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria. b

Scaled residual at measured response closest to the benchmark response.
 c

Coefficients restricted to be negative.

d

Power restricted to ≥1.
	 e

Degrees of freedom for test of mean fit are less than or equal to 0; the χ

2 test for fit is not valid.
 

AIC = Akaike’s Information Criterion; BMD = maximum likelihood estimate of the dose/concentration associated with 

the selected benchmark response; BMDL = 95% lower confidence limit on the BMD; SD = standard deviation
 

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TOXAPHENE A-8 

APPENDIX A 

Figure A-1. Predicted and Observed Mean Anti-SRBC (IgM) Titres from Female 

Cynomolgus Monkeys Administered Toxaphene in Gelatin Capsule Daily for
 

75 Weeks Including 44 Weeks Prior to Immunization*

Linear Model with 0.95 Confidence Level 

Mean Response 

8

 7

 6

 5

 4

 3

 2

 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 

dose 

BMDL BMD

Linear 

12:15 06/09 2010 

*BMD and BMDL associated with a 10% extra risk increase over control are shown; doses given in units of 

mg/kg/day. 

Dose and end point used for MRL derivation: A BMDL1SD of 0.22 mg/kg/day for decreased anti-SRBC 

(IgM) titers as an indicator of decreased humoral immunity. 

[ ] NOAEL [ ] LOAEL [X] BMD 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable.
 

Was a conversion used from intermittent to continuous exposure? No.
 

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TOXAPHENE A-9 

APPENDIX A 

Other additional studies or pertinent information that lend support to this MRL: In an enzyme-linked 

immunosorbent assay (ELISA) performed on female mice that received toxaphene from the diet at doses 

≥19 mg/kg/day for up to 8 weeks, Allen et al. (1983) reported suppressed antibody production, indicating 

depressed humoral immunity; the study identified a NOAEL of 2 mg/kg/day for the effect. Koller et al. 

(1983) reported a 46% decrease in the IgG primary antibody response in male rats receiving toxaphene 

from the diet at 2.6 mg/kg/day for up to 9 weeks and challenged twice (after 8 and 15 days on test) with 

keyhole limpet hemocyanin (KLH). 

Agency Contacts (Chemical Managers): Nickolette Roney, MPH 

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TOXAPHENE A-10 

APPENDIX A 

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TOXAPHENE	 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 

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. 

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TOXAPHENE B-2 

APPENDIX B 

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 judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement 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. 

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TOXAPHENE	 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, 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 

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TOXAPHENE	 B-4 

APPENDIX 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. 

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TOXAPHENE	 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. 

***DRAFT FOR PUBLIC COMMENT*** 
SAMPLE

***DRAFT FOR PUBLIC COMMENT*** 

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 ↓ ↓ ↓ ↓ ↓ ↓

18 Rat 13 wk Resp 3b 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 The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 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). 
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TOXAPHENE B-8 

APPENDIX B 

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TOXAPHENE 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/C benchmark dose or benchmark concentration 

BMDX dose that produces a X% change in response rate of an adverse effect 

BMDLX 95% lower confidence limit on the BMDX 

BMDS Benchmark Dose Software 

BMF biomagnification factor 

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 

CCC criterion continuous concentration 

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 

CMC criterion maximum concentration 

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 

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TOXAPHENE C-2 

APPENDIX C 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMDG North America/Intergovernmental 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 

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TOXAPHENE C-3 

APPENDIX C 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 

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 

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TOXAPHENE C-4 

APPENDIX C 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCBs polychlorinated biphenyls 

PCCs polychlorinated camphenes 

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 

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TOXAPHENE C-5 

APPENDIX C 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 

> 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 

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TOXAPHENE C-6 

APPENDIX C 

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TOXAPHENE D-1 

APPENDIX D. INDEX
 

absorbed dose........................................................................................................................................ 19, 93
 

adipose tissue ...................................................................................... 70, 71, 73, 93, 98, 119, 153, 157, 164
 

adrenal gland............................................................................................................................. 24, 51, 74, 96
 

adsorbed ................................................................................................................................ 7, 119, 162, 172
 

adsorption.................................................................................................................................................. 136
 

aerobic................................................................................................... 77, 78, 119, 136, 137, 138, 146, 161
 

ambient air ................................................................................ 121, 124, 126, 127, 138, 140, 141, 154, 182
 

anaerobic....................................................................................... 77, 78, 119, 125, 136, 137, 138, 146, 161
 

antiestrogenic .............................................................................................................................................. 90
 

bioaccumulation................................................................................................................................ 153, 162
 

bioavailability ............................................................................................................................................. 69
 

bioconcentration factor ......................................................................................................... 7, 119, 131, 190
 

biodegradation................................................................................................................... 107, 136, 137, 146
 

biomarkers .......................................................................................... 71, 73, 92, 93, 94, 105, 106, 165, 182
 

body weight effects ................................................................................................................. 23, 51, 60, 103
 

breast milk............................................... 3, 7, 17, 83, 93, 121, 134, 155, 156, 157, 164, 166, 168, 177, 182
 

cancer .......................................................................... 4, 10, 18, 23, 24, 26, 49, 58, 59, 60, 90, 92, 103, 188
 

carcinogen............................................................................................................................... 4, 10, 185, 190
 

carcinogenic ............................................................................................................ 4, 9, 10, 17, 18, 185, 190
 

carcinogenicity................................................................................................................ 54, 59, 89, 103, 190
 

carcinomas .................................................................................................................................................. 59
 

cardiovascular ................................................................................................................................. 19, 46, 60
 

cardiovascular effects.................................................................................................................................. 46
 

chromosomal aberrations .................................................................................................................... 64, 103
 

clearance ..................................................................................................................................................... 87
 

congener...................................................................................... 17, 134, 137, 155, 157, 162, 169, 170, 183
 

death............................................................................ 8, 9, 17, 18, 19, 25, 26, 55, 64, 68, 99, 102, 103, 190
 

deoxyribonucleic acid (see DNA)............................................................................................................... 64
 

dermal effects.................................................................................................................................. 23, 51, 63
 

developmental effects ..................................................................................... 4, 23, 55, 56, 58, 64, 104, 108
 

DNA (see deoxyribonucleic acid)................................................................... 64, 65, 66, 67, 68, 89, 93, 103
 

elimination rate ......................................................................................................................................... 107
 

endocrine................................................................................................................... 8, 11, 13, 19, 50, 60, 89
 

endocrine effects ......................................................................................................................................... 50
 

erythema...................................................................................................................................................... 63
 

estrogen receptor......................................................................................................................................... 90
 

estrogenic .................................................................................................................................................... 90
 

fetal tissue ................................................................................................................................................... 74
 

fetus....................................................................................................................................................... 73, 91
 

gastrointestinal effects .......................................................................................................................... 46, 62
 

general population............................................................................... 7, 8, 95, 148, 154, 158, 163, 181, 190
 

genotoxic................................................................................................................................. 17, 68, 89, 103
 

genotoxicity........................................................................................................... 9, 64, 66, 68, 89, 103, 104
 

groundwater .............................................................................................. 119, 125, 129, 138, 143, 163, 172
 

half-life.......................................................................................................... 79, 93, 119, 127, 136, 137, 138
 

hematological effects ...................................................................................................................... 20, 47, 62
 

hepatic effects ............................................................................................................... 20, 47, 48, 62, 68, 94
 

hydrolysis.................................................................................................................................................. 170
 

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TOXAPHENE D-2 

APPENDIX D 

hydroxyl radical ................................................................................................................................ 119, 136
 

immune system ..................................................................................................... 3, 16, 92, 95, 97, 106, 108
 

immunological ........................................................................ 8, 11, 14, 16, 17, 24, 52, 53, 57, 63, 102, 103
 

immunological effects................................................................................................................... 16, 52, 103
 

Kow .................................................................................................................................................... 111, 142
 

LD50..................................................................................................................................... 25, 26, 60, 94, 99
 

leukemia............................................................................................................................................ 9, 23, 24
 

lymphoreticular..................................................................................................................................... 53, 63
 

menstrual..................................................................................................................................................... 56
 

milk ........................................... 7, 17, 69, 81, 82, 83, 96, 105, 106, 147, 155, 157, 164, 166, 177, 181, 182
 

mucociliary ................................................................................................................................................. 98
 

musculoskeletal effects ............................................................................................................................... 26
 

neonatal............................................................................................................................................. 157, 164
 

neoplastic .................................................................................................................................................... 59
 

neurobehavioral........................................................................................................................................... 90
 

neurodevelopmental.................................................................................................................................... 55
 

neurological effects................................................................. 8, 13, 23, 54, 55, 63, 87, 89, 94, 97, 105, 185
 

neurotransmitter .......................................................................................................................................... 88
 

non-Hodgkin’s lymphoma ...................................................................................................................... 9, 23
 

nuclear........................................................................................................................................................... 8
 

ocular effects................................................................................................................................... 19, 51, 63
 

odds ratio..................................................................................................................................................... 23
 

pesticide ......................................................... 3, 7, 8, 17, 19, 20, 23, 49, 73, 87, 95, 98, 102, 106, 113, 114,
 

117, 121, 122, 125, 126, 129, 133, 134, 139, 142, 146, 147,
 

148, 155, 156, 158, 159, 160, 161, 162, 163, 170, 171, 174, 179
 

pharmacodynamic ....................................................................................................................................... 84
 

pharmacokinetic............................................................................................................ 83, 84, 85, 86, 87, 91
 

photolysis.................................................................................................................................................. 136
 

placenta ....................................................................................................................................................... 73
 

renal effects..................................................................................................................................... 23, 49, 62
 

reproductive effects..................................................................................................... 9, 23, 56, 64, 104, 190
 

respiratory effects............................................................................................................................ 20, 26, 60
 

retention ...................................................................................................................................................... 77
 

salivation....................................................................................................................................... 13, 54, 185
 

serum glutamic oxaloacetic transaminase................................................................................................... 47
 

solubility ........................................................................................................................................... 116, 130
 

systemic effects........................................................................................................... 19, 26, 60, 68, 89, 182
 

T3.............................................................................................................................................. 21, 27, 50, 61
 

T4................................................................................................................................................................ 50
 

technical toxaphene................................................................ 7, 8, 17, 66, 90, 109, 110, 113, 121, 125, 133,
 

134, 136, 137, 138, 140, 150, 152, 169, 170
 

thyroid........................................................................................... 4, 9, 12, 14, 50, 51, 59, 96, 103, 188, 190
 

toxicokinetic.................................................................................................................................. 17, 89, 107
 

tremors ............................................................................................................................................ 12, 54, 99
 

tumors ......................................................................................................................... 9, 59, 60, 94, 103, 190
 

vapor phase ............................................................................................................................................... 136
 

volatility .................................................................................................................................................... 119
 

volatilization ..................................................................................... 119, 122, 124, 127, 128, 141, 143, 170
 

weanling...................................................................................................................................................... 56
 

weathered toxaphene....................................................................................... 7, 17, 105, 121, 134, 170, 179
 

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