TOXICOLOGICAL PROFILE FOR 

ALPHA-, BETA-, GAMMA-, 

AND DELTA-HEXACHLOROCYCLOHEXANE 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

Agency for Toxic Substances and Disease Registry
 

August 2005 
HEXACHLOROCYCLOHEXANE 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. 
HEXACHLOROCYCLOHEXANE iii 

UPDATE STATEMENT 

A Toxicological Profile for Hexachlorocyclohexane, Draft for Public Comment was released in 

September 2003. This edition supersedes any previously released draft or final profile. 

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

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology/Toxicology Information Branch 

1600 Clifton Road NE 

Mailstop F-32 

Atlanta, Georgia 30333 



HEXACHLOROCYCLOHEXANE vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

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

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

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

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

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

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

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

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

the general health effects observed following exposure. 

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

and assesses the significance of toxicity data to human health. 

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

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

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

reported in this section. 

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

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

following exposure. 

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

issues: 

Section 1.6 How Can (Chemical X) Affect Children? 

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

Section 3.7 Children’s Susceptibility 

Section 6.6 Exposures of Children 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

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

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

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

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

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

history is provided. Other case studies of interest include Reproductive and Developmental 
HEXACHLOROCYCLOHEXANE viii 

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

Toxicity; and numerous chemical-specific case studies. 

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

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

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

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

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

professionals treating patients exposed to hazardous materials. 

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

Other Agencies and Organizations 

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

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

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

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

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

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

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

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

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

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

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

• Phone: 800-35-NIOSH. 

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

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

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

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

Referrals 

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

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

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

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

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

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

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

Elk Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 
HEXACHLOROCYCLOHEXANE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Alfred Dorsey, DVM 

Jewell Wilson, PhD 

Annette Ashizawa, PhD 

ATSDR, Division of Toxicology, Atlanta, GA 

Stephen Bosch, BS 

Mario Citra, PhD 

Antonio Quinones-Rivera, PhD 

Michael Lumpkin, PhD 

Jennifer Rhoades, BA 

Fernando Llados, PhD 

Syracuse Research Corporation, 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 Research Implementation Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

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

HEXACHLOROCYCLOHEXANE xi 

PEER REVIEW 

A peer review panel was assembled for hexachlorocyclohexane. The panel consisted of the following 

members: 

1. C. Clifford Conaway, Ph.D., DABT, Associate Research Scientist, Institute for Cancer 

Prevention, Valhalla, NY 10595 

2. Lucio Costa, Ph.D., Professor, Department of Environmental Health, University of Washington, 

 Seattle, WA 98195 

3.	 Raghubir Sharma, Ph.D., Fred C. Davidson Distinguished Chair in Toxicology, Department 

of Physiology and Pharmacology, University of Georgia, Athens, GA 30602 

These experts collectively have knowledge of hexachlorocyclohexane '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. 

HEXACHLOROCYCLOHEXANE xiii 

CONTENTS 

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

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

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

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

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

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

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

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

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

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

1.1 WHAT IS HEXACHLOROCYCLOHEXANE? ........................................................................1 

1.2 WHAT HAPPENS TO HEXACHLOROCYCLOHEXANE WHEN IT ENTERS THE 

ENVIRONMENT? ......................................................................................................................2 

1.3 HOW MIGHT I BE EXPOSED TO HEXACHLOROCYCLOHEXANE?................................ 3 

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

1.5 HOW CAN HEXACHLOROCYCLOHEXANE AFFECT MY HEALTH?.............................. 4 

1.6 HOW CAN HEXACHLOROCYCLOHEXANE AFFECT CHILDREN? ................................. 5 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO
 

HEXACHLOROCYCLOHEXANE? ..........................................................................................6 

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

TO HEXACHLOROCYCLOHEXANE?....................................................................................7 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH?.................................................................................................7 

1.10 WHERE CAN I GET MORE INFORMATION? .......................................................................8 

2. RELEVANCE TO PUBLIC HEALTH .................................................................................................11 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO 

HEXACHLOROCYCLOHEXANE IN THE UNITED STATES ............................................11 

2.2 SUMMARY OF HEALTH EFFECTS......................................................................................12 

2.3 MINIMAL RISK LEVELS .......................................................................................................16 

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

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

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

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

3.2.1.1 Death ............................................................................................................................29 

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

3.2.1.3 Immunological and Lymphoreticular Effects...............................................................36 

3.2.1.4 Neurological Effects.....................................................................................................36 

3.2.1.5 Reproductive Effects....................................................................................................37 

3.2.1.6 Developmental Effects .................................................................................................38 

3.2.1.7 Cancer...........................................................................................................................38 

3.2.2 Oral Exposure........................................................................................................................39 

3.2.2.1 Death ............................................................................................................................39 

3.2.2.2 Systemic Effects...........................................................................................................78 
HEXACHLOROCYCLOHEXANE xiv 

3.2.2.3 Immunological and Lymphoreticular Effects...............................................................86 

3.2.2.4 Neurological Effects.....................................................................................................87 

3.2.2.5 Reproductive Effects....................................................................................................92 

3.2.2.6 Developmental Effects .................................................................................................96 

3.2.2.7 Cancer...........................................................................................................................99 

3.2.3 Dermal Exposure.................................................................................................................102 

3.2.3.1 Death ..........................................................................................................................103 

3.2.3.2 Systemic Effects.........................................................................................................103 

3.2.3.3 Immunological and Lymphoreticular Effects.............................................................111 

3.2.3.4 Neurological Effects...................................................................................................111 

3.2.3.5 Reproductive Effects..................................................................................................112 

3.2.3.6 Developmental Effects ...............................................................................................112 

3.2.3.7 Cancer.........................................................................................................................113 

3.3 GENOTOXICITY ...................................................................................................................113 

3.4 TOXICOKINETICS................................................................................................................115 

3.4.1 Absorption...........................................................................................................................115 

3.4.1.1 Inhalation Exposure....................................................................................................115 

3.4.1.2 Oral Exposure.............................................................................................................119 

3.4.1.3 Dermal Exposure ........................................................................................................119 

3.4.2 Distribution .........................................................................................................................121 

3.4.2.1 Inhalation Exposure....................................................................................................121 

3.4.2.2 Oral Exposure.............................................................................................................122 

3.4.2.3 Dermal Exposure ........................................................................................................123 

3.4.3 Metabolism..........................................................................................................................124 

3.4.4 Elimination and Excretion...................................................................................................127 

3.4.4.1 Inhalation Exposure....................................................................................................128 

3.4.4.2 Oral Exposure.............................................................................................................128 

3.4.4.3 Dermal Exposure ........................................................................................................129 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ...........129 

3.5 MECHANISMS OF ACTION ................................................................................................ 135 

3.5.1 Pharmacokinetic Mechanisms............................................................................................. 135 

3.5.2 Mechanisms of Toxicity......................................................................................................135 

3.5.3 Animal-to-Human Extrapolations.......................................................................................137 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ........................138 

3.7 CHILDREN’S SUSCEPTIBILITY.........................................................................................141 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................146 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Hexachlorocyclohexane ................147 

3.8.2 Biomarkers Used to Characterize Effects Caused by Hexachlorocyclohexane ..................148 

3.9 INTERACTIONS WITH OTHER CHEMICALS .................................................................. 149 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE............................................. 151 

3.11 METHODS FOR REDUCING TOXIC EFFECTS................................................................. 152 

3.11.1 Reducing Peak Absorption Following Exposure ............................................................153 

3.11.2 Reducing Body Burden...................................................................................................153 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects .........................................153 

3.12 ADEQUACY OF THE DATABASE......................................................................................154 

3.12.1 Existing Information on Health Effects of Hexachlorocyclohexane ..............................155 

3.12.2 Identification of Data Needs ...........................................................................................155 

3.12.3 Ongoing Studies..............................................................................................................169 
HEXACHLOROCYCLOHEXANE xv 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................173 

4.1 CHEMICAL IDENTITY.........................................................................................................173 

4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................173 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................177 

5.1 PRODUCTION .......................................................................................................................177 

5.2 IMPORT/EXPORT .................................................................................................................177 

5.3 USE..........................................................................................................................................179 

5.4 DISPOSAL..............................................................................................................................180 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................183 

6.1 OVERVIEW............................................................................................................................183 

6.2 RELEASES TO THE ENVIRONMENT................................................................................188 

6.2.1 Air .......................................................................................................................................188 

6.2.2 Water...................................................................................................................................190 

6.2.3 Soil ......................................................................................................................................191 

6.3 ENVIRONMENTAL FATE....................................................................................................191 

6.3.1 Transport and Partitioning...................................................................................................191 

6.3.2 Transformation and Degradation ........................................................................................196 

6.3.2.1 Air...............................................................................................................................196 

6.3.2.2 Water ..........................................................................................................................196 

6.3.2.3 Sediment and Soil.......................................................................................................198 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT...............................199 

6.4.1 Air .......................................................................................................................................200 

6.4.2 Water...................................................................................................................................201 

6.4.3 Sediment and Soil ...............................................................................................................202 

6.4.4 Other Environmental Media................................................................................................203 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .....................................206 

6.6 EXPOSURES OF CHILDREN...............................................................................................210 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ...........................................215 

6.8 ADEQUACY OF THE DATABASE......................................................................................216 

6.8.1 Identification of Data Needs ...............................................................................................216 

6.8.2 Ongoing Studies ..................................................................................................................220 

7. ANALYTICAL METHODS ...............................................................................................................221 

7.1 BIOLOGICAL MATERIALS.................................................................................................221 

7.2 ENVIRONMENTAL SAMPLES............................................................................................ 225 

7.3 ADEQUACY OF THE DATABASE......................................................................................234 

7.3.1 Identification of Data Needs ...............................................................................................234 

7.3.2 Ongoing Studies ..................................................................................................................236 

8. REGULATIONS AND ADVISORIES ...............................................................................................237 

9. REFERENCES ....................................................................................................................................245 

10. GLOSSARY ......................................................................................................................................319 
HEXACHLOROCYCLOHEXANE xvi 

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 
HEXACHLOROCYCLOHEXANE xvii 

LIST OF FIGURES 

3-1. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane)—Inhalation........ 32 

3-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane)—Oral................. 55 

3-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade HCH—Oral ....... 74 

3-4. The Proposed Metabolism of Hexachlorocyclohexane................................................................125
 

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

for a Hypothetical Chemical Substance .......................................................................................132
 

3-6. Structure of the PBPK Model for γ-HCH ....................................................................................133
 

3-7. Existing Information on Health Effects of α-, β-, γ-, and δ-HCH................................................156
 

6-1. Frequency of NPL Sites with α-Hexachlorocyclohexane Contamination ...................................184
 

6-2. Frequency of NPL Sites with β-Hexachlorocyclohexane Contamination ...................................185
 

6-3. Frequency of NPL Sites with γ-Hexachlorocyclohexane Contamination....................................186
 

6-4. Frequency of NPL Sites with δ-Hexachlorocyclohexane Contamination....................................187
 

HEXACHLOROCYCLOHEXANE xix 

LIST OF TABLES 

2-1. MRL Values for Hexachlorocyclohexane (HCH) .........................................................................19
 

3-1. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane)—Inhalation........ 30 

3-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane)—Oral................. 40 

3-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Tech-Grade HCH—Oral............... 59 

3-4. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane)—Dermal.......... 104 

3-5. Levels of Significant Exposure to Technical-Grade Hexachlorocyclohexane—Dermal............. 106 

3-6. Genotoxicity of Hexachlorocyclohexane Isomers In Vivo...........................................................116
 

3-7. Genotoxicity of Hexachlorocyclohexane Isomers In Vitro..........................................................117
 

3-8. Parameters for a PBPK Model for γ-Hexachlorocyclohexane in Rats ........................................134
 

3-9. Ongoing Studies on Hexachlorocyclohexane Health Effects ......................................................170
 

4-1. Chemical Identity of Hexachlorocyclohexane Isomers ...............................................................174
 

4-2. Physical and Chemical Properties of Hexachlorocyclohexane Isomers......................................176
 

5-1. Facilities that Produce, Process, or Use Hexachlorocyclohexane................................................178
 

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

Hexachlorocyclohexane...............................................................................................................189
 

6-2. Ten-year Study on the Occurrence of HCH in 234 Ready-to-eat Food Items in the 

United States................................................................................................................................204
 

6-3. Average Daily Intake (AVDI, ng/kg/day) of γ-HCH in Eight Population Groups......................207
 

6-4. Geometric Mean and Percentiles of the Serum Concentration (ng/g) of β-HCH in the U.S. 

Population ....................................................................................................................................211
 

7-1. Analytical Methods for Determining Hexachlorocyclohexane in Biological Samples ...............222
 

7-2. Analytical Methods for Determining Hexachlorocyclohexane in Environmental Samples ........226
 

8-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane and 

 Hexachlorocyclohexane Isomers.................................................................................................238
 

HEXACHLOROCYCLOHEXANE 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about alpha- (α), beta- (β), gamma- (γ), and delta- (δ) 

hexachlorocyclohexane (HCH) and the effects of exposure. 

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. α-, β-, γ-, and δ-HCH has been found in at least 146, 159, 

189, and 126, respectively of the 1,662 current or former NPL sites. Although the total number 

of NPL sites evaluated for these substances is not known, the possibility exists that the number 

of sites at which HCH 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 these 

substances may harm you. 

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

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

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

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

If you are exposed to HCH, 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 HEXACHLOROCYCLOHEXANE? 

Hexachlorocyclohexane (HCH), formally known as benzene hexachloride (BHC), is a synthetic 

chemical that exists in eight chemical forms called isomers. The different isomers are named 

according to the position of the hydrogen atoms in the structure of the chemical. One of these 

forms, gamma-HCH (or γ-HCH, commonly called lindane), is produced and used as an 
HEXACHLOROCYCLOHEXANE 2 

1. PUBLIC HEALTH STATEMENT 

insecticide on fruit, vegetables, and forest crops, and animals and animal premises. It is a white 

solid whose vapor may evaporate into the air. The vapor is colorless and has a slight musty odor 

when it is present at 12 or more parts HCH per million parts air (ppm). γ-HCH has not been 

produced in the United States since 1976. However, imported γ-HCH is available in the United 

States for insecticide use as a dust, powder, liquid, or concentrate. It is also available as a 

prescription medicine (lotion, cream, or shampoo) to treat and/or control scabies (mites) and 

head lice in humans. 

Technical-grade HCH, a mixture of several chemical forms of HCH, was also once used as an 

insecticide in the United States and typically contained about 10–15% of γ-HCH as well as the 

alpha (α), beta (β), delta (δ), and epsilon (ε) forms of HCH. Virtually all of the insecticidal 

properties reside in the gamma isomer. Technical-grade HCH has not been produced or used in 

the United States for more than 20 years. 

The scope of this profile includes information on technical-grade HCH, as well as the α, β, γ, and 

δ isomers. Available information on the ε isomer is limited and is not included in this profile. 

Chapter 4 contains more information on the chemical and physical properties of HCH. 

1.2 WHAT HAPPENS TO HEXACHLOROCYCLOHEXANE WHEN IT ENTERS THE 

ENVIRONMENT? 

Although technical-grade HCH is no longer used as an insecticide in the United States, α-, β-, γ-, 

and δ-HCH have been found in the soil and surface water at hazardous waste sites because they 

persist in the environment. In air, the different forms of HCH can be present as a vapor or 

attached to small particles such as soil and dust; the particles may be removed from the air by 

rain or degraded by other compounds found in the atmosphere. HCH can remain in the air for 

long periods and travel great distances depending on the environmental conditions. In soil, 

sediments, and water, HCH is broken down to less toxic substances by algae, fungi, and bacteria, 

but this process can take a long time. Chapter 6 contains more information about the presence of 

HCH in the environment. 
HEXACHLOROCYCLOHEXANE 3 

1. PUBLIC HEALTH STATEMENT 

1.3 HOW MIGHT I BE EXPOSED TO HEXACHLOROCYCLOHEXANE? 

You will be directly exposed to γ-HCH if you use a prescription medication that contains this 

compound in order to treat and/or control scabies and head lice. You can also be exposed to 

small amounts of γ-HCH and the other isomers (α-, β-, and δ-HCH) by eating foods that may be 

contaminated with these compounds. Exposure to the HCH isomers is also possible from 

ingesting contaminated drinking water, breathing contaminated air, or having contact with soil or 

water at hazardous waste sites that may contain these compounds. Exposure to α-, β-, and 

δ-HCH is less frequent than exposure to γ-HCH because these compounds are no longer used in 

the United States. Although γ-HCH is no longer made in the United States, it is still imported 

into the United States and formulated into products that are used here. Therefore, workers 

involved in the formulation or application of these products can be exposed to γ-HCH. 

For more information on exposure to HCH, refer to Chapter 6. 

1.4 HOW CAN HEXACHLOROCYCLOHEXANE ENTER AND LEAVE MY BODY? 

γ-HCH and the other isomers of HCH can enter your body when you eat food or drink water 

contaminated with HCH. Inhaling γ-HCH or other isomers of HCH in air can also lead to entry 

of these chemicals into the lungs. γ-HCH can be absorbed through the skin when it is used as a 

lotion, cream, or shampoo for the treatment and/or control of scabies and body lice. In general, 

HCH isomers and the products formed from them in the body can be temporarily stored in body 

fat. Among the HCH isomers, β-HCH leaves the body the most slowly. α-HCH, δ-HCH, and 

γ-HCH, and the products formed from them in the body, are more rapidly excreted in the urine; 

small amounts leave in the feces and expired air. HCH breaks down in the body to many other 

substances; these include various chlorophenols, some of which have toxic properties. Chapter 3 

gives more information on how HCH enters and leaves the body. 
HEXACHLOROCYCLOHEXANE 4 

1. PUBLIC HEALTH STATEMENT 

1.5 HOW CAN HEXACHLOROCYCLOHEXANE AFFECT MY HEALTH? 

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

ways for treating persons who have been harmed. 

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

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

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

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

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

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

laws today protect the welfare of research animals. 

In humans, breathing toxic amounts of γ-HCH and/or α-, β-, and δ-HCH can result in blood 

disorders, dizziness, headaches, and possible changes in the levels of sex hormones in the blood. 

These effects have occurred in workers exposed to HCH vapors during pesticide manufacturing. 

People who have swallowed large amounts have had seizures; some have died. A few people 

who used very large amounts of γ-HCH or used it frequently on their skin developed blood 

disorders or seizures. However, no cause-and-effect relationship between exposure to γ-HCH 

and blood disorders in humans has been established. Animals that have been fed γ- and α-HCH 

have had convulsions, and animals fed β-HCH have become comatose. All isomers can produce 

liver and kidney effects. Reduced ability to fight infection was reported in animals fed γ-HCH, 

and injury to the ovaries and testes was reported in animals given γ-HCH or β-HCH. HCH 

isomers are changed by the body into other chemical products, some of which may be 

responsible for the harmful effects. Long-term oral administration of α-HCH, β-HCH, γ-HCH, 

or technical-grade HCH to laboratory rodents has been reported to result in liver cancer. The 

Department of Health and Human Services (DHHS) has determined that HCH (all isomers) may 

reasonably be anticipated to cause cancer in humans. The International Agency for Research on 

Cancer (IARC) has classified HCH (all isomers) as possibly carcinogenic to humans. The EPA 

has determined that there is suggestive evidence that lindane (γ-HCH) is carcinogenic, but the 

evidence is not sufficient to assess its human carcinogenic potential. The EPA has additionally 
HEXACHLOROCYCLOHEXANE 5 

1. PUBLIC HEALTH STATEMENT 

classified technical HCH and α-HCH as probable human carcinogens, β-HCH as a possible 

human carcinogen, and δ- and ε-HCH as not classifiable as to human carcinogenicity. Chapter 3 

gives more information about the health effects of HCH isomers. 

1.6 HOW CAN HEXACHLOROCYCLOHEXANE AFFECT CHILDREN? 

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

conception to maturity at 18 years of age. 

The most likely source of exposure for children is from the use of shampoos and lotions 

containing HCH for the treatment of lice or scabies. HCH has also been found as a residue in 

food products; β-HCH isomer accumulates in animal tissue. In the body, α-, δ-, and γ-HCH are 

rapidly broken down and excreted. Although HCH is a restricted use pesticide in the United 

States, children could be exposed from eating foods grown in areas where HCH is still used or 

misused as a pesticide. HCH has also been detected in breast milk, resulting in a possible 

exposure pathway for infants and children. 

It is not known for sure whether children are more susceptible than adults to health effects from 

exposure to γ-HCH. Limited information is available on the specific health effects resulting 

from HCH exposure in children. Health effects observed in adults should also be of potential 

concern for children. Children can experience convulsions from exposure to γ-HCH. Eating 

enough γ-HCH can kill a child. However, in a study performed on rabbits, young animals had 

higher death rates and greater sensitivity than adults when γ-HCH was applied to the skin. 

It is not known whether HCH causes birth defects in humans. Technical-grade and γ-HCH do 

not cause significant birth defects in animals. Animals fed γ-HCH during pregnancy had an 

increased number of fetuses with extra ribs, which is a normal variation. HCH has been shown 

to cross the placenta in pregnant women. HCH is likely to be stored in fat. It has been measured 

in skin lipids and breast milk. In studies of rats, HCH has been shown to pass from the mother to 

newborns in the dam’s milk, causing neurological and hormonal effects. The male newborn 
HEXACHLOROCYCLOHEXANE 6 

1. PUBLIC HEALTH STATEMENT 

pups of female rats that had been fed HCH during lactation demonstrated a 50% reduction in 

testosterone levels and reduced testicular weight in adolescence and adulthood. 

More information on how HCH can affect the health of children can be found in Sections 3.7 

and 6.6. 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO 

HEXACHLOROCYCLOHEXANE? 

If your doctor finds that you have been exposed to substantial amounts of hexachlorocyclohexane, ask whether your children might also have been exposed. Your doctor might need to ask 

your state health department to investigate. 

There are two primary pathways through which families can be exposed to HCH. γ-HCH, which 

may be labeled as lindane, is used in shampoos and lotions for the treatment of lice. It is 

normally safe if used as directed, but may be misused. If you use shampoos or lotions containing 

γ-HCH, follow the directions carefully. Products containing lindane should never be used on 

infants. Shampoos or lotions that contain lindane should be stored out of the reach of young 

children to prevent accidental poisoning. You may expose your child to lindane if you use 

products that contain lindane to treat lice or scabies on your child’s head or skin. Alternative 

treatments are available that do not involve the use of lindane. You should consult with your 

physician to discuss appropriate alternative treatments. 

γ-HCH is a restricted use pesticide. Its allowed uses are very limited. Your children may be 

exposed to γ-HCH if an unqualified person applies pesticides containing it around your home. In 

some cases, the improper use of pesticides banned for use in homes has turned homes into 

hazardous waste sites. Make sure that any person you hire is licensed and certified to apply 

pesticides. Your state licenses each person who is qualified to apply pesticides according to EPA 

standards and further certifies each person who is qualified to apply “restricted use” pesticides. 

Ask to see their license and certification. Also ask for the brand name of the pesticide, a 

Material Safety Data Sheet (MSDS), the name of the product’s active ingredients, and the EPA 
HEXACHLOROCYCLOHEXANE 7 

1. PUBLIC HEALTH STATEMENT 

registration number. This information can be important if you or your family react to the 

product. 

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

EXPOSED TO HEXACHLOROCYCLOHEXANE? 

HCH isomers can be measured in the blood, urine, and semen of exposed persons. Samples of 

these fluids can be collected in a doctor's office and sent to a laboratory that has the special 

equipment needed to measure the levels of HCH. Although the amount of HCH isomers in 

blood, urine, or semen can be measured, it is usually not possible to determine the environmental 

levels to which the person was exposed or to predict the health effects that are likely to occur 

from specific concentrations. The products of HCH that are formed in the body and then found 

in the urine have also been measured to find out whether a person was exposed to HCH. 

However, this method cannot yet be used to determine exposure to HCH alone because other 

environmental chemicals produce the same end products. Chapter 7 contains more information 

on ways to measure HCH in human blood and tissues. 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

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

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

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

agencies that develop regulations for toxic substances. Recommendations provide valuable 

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

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

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

substances. 

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

toxic substance in air, water, soil, or food that do not exceed a critical value that is usually based 
HEXACHLOROCYCLOHEXANE 8 

1. PUBLIC HEALTH STATEMENT 

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 HCH include the following: 

γ-HCH is categorized by EPA as a restricted use pesticide. It can only be used by licensed and 

certified applicators. EPA has also recommended guidelines on how much HCH can be present 

in drinking water for specific periods without producing health effects. EPA advises that 

children should not have more than 1.2 milligrams HCH per liter of water (mg/L) for up to 

10 days. For lifetime exposure in adults, EPA recommends that there should not be more than 

0.0002 mg/L of HCH in drinking water. EPA has classified HCH as a hazardous waste that must 

meet certain disposal requirements. 

OSHA regulates levels of γ-HCH in the workplace. The maximum allowable amount in 

workplace air during an 8-hour workday in a 40-hour work week is 0.5 mg per cubic meter of 

air. 

Chapter 8 contains more information about regulations and guidelines concerning HCH. 

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. 
HEXACHLOROCYCLOHEXANE 9 

1. PUBLIC HEALTH STATEMENT 

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

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

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

atsdric@cdc.gov, or by writing to: 

Agency for Toxic Substances and Disease Registry 

 Division of Toxicology 

1600 Clifton Road NE 

 Mailstop F-32 

 Atlanta, GA 30333 

 Fax: 1-770-488-4178 

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

National Technical Information Service (NTIS) 

5285 Port Royal Road 

 Springfield, VA 22161 

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

 Web site: http://www.ntis.gov/ 

HEXACHLOROCYCLOHEXANE 11 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO HEXACHLOROCYCLOHEXANE IN THE UNITED STATES 

Hexachlorocyclohexane (HCH) is a synthetic chemical consisting of eight isomers. Only four of these 

isomers—α-HCH, β-HCH, γ-HCH, and δ-HCH—are of commercial significance. γ-HCH, commonly 

referred to as lindane, is used as seed treatment for barley, corn, oats, rye, sorghum, and wheat. It is also 

used in very small quantities as a prescription medication for the treatment of scabies and head lice in 

humans. The FDA does not recommend the use of γ-HCH in infants or in children or adults weighing 

less than 50 kg. In the past, γ-HCH was used in veterinary products to control mites, lice, and other pests, 

but recent data suggest that no products are currently registered in the United States for this use. Other 

HCH isomers, as well as technical-grade HCH, are used either as fungicides or in the synthesis of other 

chemicals. Technical-grade HCH is comprised of 60–70% α-HCH, 5–12% β-HCH, 10–15% γ-HCH, 6– 

10% δ-HCH, and 3–4% ε-HCH. Technical-grade HCH was banned for production and use in the United 

States in 1976, but still may be used in other countries in small quantities. 

Monitoring data suggest that the general population is exposed to HCH through the inhalation of ambient 

air and the consumption of contaminated food and drinking water. The relatively high stability of the 

HCH isomers in the environment and their global use for many years has led to their continued detection 

in air, soil, surface water, groundwater, and drinking water. As worldwide use of HCH declines, 

however, the frequency of detection and the levels detected in the environment should continue to 

decrease. Very low levels of α- and γ-HCH in air have been detected in a study conducted in the 1990s. 

The average air levels of α-HCH at sites along Lake Michigan, Lake Superior, and Lake Erie were in the 

range of 0.110–0.140 ng/m3 for samples collected during 1990–1997 and the average levels of γ-HCH 

were 0.024–0.062 ng/m3 at the same sites. Similarly, fairly low levels of γ-HCH were detected in 

groundwater samples. γ-HCH was detected in two groundwater samples at levels of 0.028 and 

0.032 μg/L during a groundwater monitoring study conducted in the Ozark Plateaus Province of 

Arkansas, Kansas, Missouri, and Oklahoma from April to September 1993. The estimated average daily 

dietary intakes of γ- and α-HCH were essentially the same in various adult age/sex groups in the United 

States, ranging from about 0.5 to 1.0 ng/kg/day for both isomers, whereas intake of β-HCH was 

<0.1 ng/kg/day (below the analytical detection limit in food). 
HEXACHLOROCYCLOHEXANE 12 

2. RELEVANCE TO PUBLIC HEALTH 

HCH can be detected in the blood and urine of exposed individuals. In humans, the concentration of 

β-HCH in adipose tissue is typically higher than other HCH isomers. It has been estimated that 

approximately 100% of the U.S. population had detectable levels of β-HCH in adipose tissue in 1970; in 

1980, 80% of the population had detectable levels. In a U.S. biomonitoring study conducted in 1999– 

2000, less than 50% of the studied population had detectable levels of β-HCH in serum; the geometric 

mean serum concentration was 9.68 ng/g lipid (95% confidence interval of <4.8–10.4 ng/g lipid). γ-HCH 

was only detected in 1.7% of the population surveyed in 1999–2000; the geometric mean serum 

concentration was below the detection limit of 7.5 ng/g of lipid. 

2.2 SUMMARY OF HEALTH EFFECTS 

Information on the toxicity of HCH comes from human exposure reports and experimental studies in 

animals. Most of the information on the health effects of HCH in humans comes from studies of 

individuals involved in the production or use of HCH products, reports of exposures to domestic products 

containing HCH, and intentional ingestion of HCH. Most of these studies involve exposure to technical 

HCH or γ-HCH and exposure levels are not available. Except for skin rashes observed in humans 

following topical application of γ-HCH, there is no evidence that the toxicity of HCH is route-dependent. 

In humans and animals, the main target of acute exposure to high amounts of HCH is the nervous system, 

and the effects consist of hyperexcitability, seizures, and convulsions that eventually may lead to death. 

Although the available reports on humans describe a wide array of effects associated with exposure to 

HCH, it is difficult to define a clear target organ or system for HCH toxicity, largely because of 

limitations of the studies, such as lack of exposure data and simultaneous exposure to other chemicals in 

occupational settings, or exposure to lethal or near lethal amounts, which caused generalized non-specific 

toxicities. Yet, vomiting and nausea are usual manifestations of γ-HCH ingestion and also have been 

reported after dermal exposure to γ-HCH. There are also reports of adverse hematological effects in 

humans exposed to γ-HCH following inhalation and/or dermal exposure to domestic products containing 

γ-HCH and following chronic occupational exposure. There is no evidence that HCH alters 

immunocompetence in humans, even though there is a report of increased serum IgM levels in a small 

study of workers exposed to technical-grade HCH. A study of 54 men occupationally exposed to γ-HCH 

reported an increase in serum luteinizing hormone among the exposed subjects, but this sole finding is 

clearly insufficient to make any inference regarding reproductive effects of HCH in humans. Similarly, a 

single report of an association between women with serum levels of HCH isomers and babies with intrauterine growth retardation is insufficient to draw any conclusion regarding developmental effects of HCH 
HEXACHLOROCYCLOHEXANE 13 

2. RELEVANCE TO PUBLIC HEALTH 

in humans, particularly since other organochlorine pesticides were also present. Studies of the cancer of 

HCH in humans have been inconclusive. Studies of the association between pesticide use and nonHodgkin’s lymphoma among U.S. farmers concluded that γ-HCH is not a major factor in the development 

of the disease, but may play some role. The majority of the studies of the general population have found 

no association between serum levels of HCH and breast cancer or breast tissue levels of HCH and breast 

cancer. In these studies, many other organochlorine chemicals were also detected. Results from studies 

of the genotoxic potential of HCH in humans have been inconclusive. 

Studies in animals (mostly, but not exclusively, rats exposed orally) confirm the nervous system as a 

toxicity target for acute exposure to high amounts of HCH, regardless of the route of exposure. In 

addition to hyperexcitability and convulsions, treatment of animals with HCH has produced 

neurochemical alterations in the brain, behavioral alterations in adult animals, and in the offspring of 

animals exposed to HCH. Decreased numbers of red and white blood cells and hemoglobin have been 

reported in rats following repeated administration of γ-HCH or technical-grade HCH. Most HCH isomers 

were shown to increase cytochrome P-450 content and the activities of associated enzymes in rodents and 

also produced liver necrosis and degeneration with higher doses. γ- and β-HCH produced 

immunosuppression in intermediate-duration studies in rodents. HCH isomers have altered reproductive 

parameters in male and female animals including mink, rabbits, and rats. Effects included alterations in 

estrous cycle, embryotoxicity, and testicular and sperm alterations. Exposure of female rats to γ-HCH 

during lactation altered the development of the reproductive system of male offspring. Results of studies 

aimed to test whether γ-HCH and other HCH isomers are endocrine disruptors have yielded mixed results. 

Exposure to technical-grade HCH and γ-HCH during gestation caused fetotoxicity in mice. 

Teratogenicity of HCH has not been conclusively demonstrated. Numerous studies have examined the 

carcinogenicity of HCH in animals exposed orally. α-HCH induced liver tumors in mice and rats, β-HCH 

induced liver tumors in mice, and technical grade HCH induced liver tumors in mice; inconclusive results 

have been obtained with γ- and ε-HCH, and negative results were obtained with δ-HCH. In genotoxicity 

assays, HCH isomers exhibited no genotoxic activity or weak activity at best. 

A greater detailed discussion of HCH-induced hepatic, immunological, neurological, reproductive, and 

carcinogenic effects follows. The reader is referred to Section 3.2, Discussion of Health Effects by Route 

of Exposure, for additional information on other health effects. 

Hepatic Effects. Hepatic effects, such as increased liver enzymes, have been reported in humans 

exposed to technical-grade HCH principally by inhalation in a pesticide formulating plant; but there are 
HEXACHLOROCYCLOHEXANE 14 

2. RELEVANCE TO PUBLIC HEALTH 

no liver data reported for individuals who ingested HCH or applied γ-HCH to their skin. An increase in 

cytochrome P-450 concentration has been reported in rats following inhalation exposure. Animal studies 

have also reported that ingestion of α-, β-, and γ-HCH isomers, individually or as technical-grade HCH, 

has resulted in some degree of liver toxicity including increased microsomal activity, increased liver 

weight, mild-to-moderate liver necrosis and fatty degeneration, and liver cancer. Biochemical or gross 

hepatic changes often were not accompanied by histopathological changes. Hepatic effects in animals 

following dermal exposure to γ-HCH or technical-grade HCH were similar to those observed with oral 

exposure. Although available human data are limited, effects on liver enzymes following exposure to 

technical-grade HCH were similar to those observed in animal studies. The observation of serious hepatic 

effects in animals (e.g., fatty degeneration and necrosis) suggests that the same results could potentially 

occur in workers following prolonged occupational exposure. Liver toxicity was used as the basis for an 

intermediate-duration oral MRL for β-HCH and a chronic-duration oral MRL for α-HCH. As detailed in 

Section 2.3 and Appendix A, the intermediate oral MRL for β-HCH is based on a lowest-observedadverse-effect level (LOAEL) of 0.18 mg/kg/day for liver effects in rats (centrilobular hyalinization, with 

periportal fatty changes and focal necrosis at ≥4.5 mg/kg/day) exposed for 13 weeks. The chronic oral 

MRL for α-HCH is based on a hepatic no-observed-adverse-effect level (NOAEL) of 0.8 mg/kg/day in 

rats exposed for up to 107 weeks. Liver effects at higher doses of α-HCH progressed from slight 

histological changes at 3.5–4 mg/kg/day to hepatic cell atrophy, fatty degeneration, and focal necrosis at 

56–64 mg/kg/day. 

Immunological Effects. A significant increase in the level of IgM was observed in workers exposed 

to technical-grade HCH. Although there is no evidence of an increase in immunoglobulins in animals, 

antibody response has been reported to be depressed in rats, rabbits, and mice exposed to γ-HCH. 

Biphasic effects on immunosuppression were reported in mice fed γ-HCH. This is suggestive evidence 

that HCH may affect the human immune system. 

Immunotoxicity was used as the basis for an intermediate-duration MRL for oral exposure to γ-HCH. As 

detailed in Section 2.3 and Appendix A, the intermediate oral MRL for γ-HCH is based on a LOAEL of 

0.012 mg/kg/day for immunological effects in mice exposed for up to 24 weeks. Effects observed at 

≥0.012 mg/kg/day included changes in delayed-type hypersensitivity reaction to sheep red blood cells 

(SRBC), response of IgM antibody forming cells in spleen to SRBC or lipopolysaccharide, and posttreatment histology of the spleen (reductions in lymphoid follicles and overall cellularity), lymph nodes 

(reduced lymphocyte population and size of medullary cords), and thymus (necrosis in the medulla). 
HEXACHLOROCYCLOHEXANE 15 

2. RELEVANCE TO PUBLIC HEALTH 

Neurological Effects. In humans, neurological effects, including paresthesia of the face and 

extremities, headaches, vertigo, abnormal EEG patterns, and often seizures and convulsions, have been 

reported in individuals occupationally exposed to γ-HCH or in individuals exposed accidentally or 

intentionally to large amounts of γ-HCH by ingestion or dermal application. Acute- and intermediateduration exposure of animals to high oral or dermal doses of γ- or β-HCH affects the central nervous 

system as evidenced by behavior disorders, decreased nerve conduction velocity, neurochemical changes, 

convulsions, seizures, and coma. Results of acute, intermediate, and developmental neurotoxicity test 

batteries in rats found that γ-HCH caused effects such as decreased motor activity, decreased habituation, 

and increased forelimb grip strength at lower doses and hypersensivity to touch, hunched posture, 

tremors, and convulsions at higher doses. There is evidence that exposure to γ-HCH caused functional 

impairment (reduced permeability) of the developing blood brain barrier in young rats. The effects in 

humans and animals suggest that exposure of humans to high air concentrations or large oral doses could 

potentially result in neurotoxic effects. An effect level for neurotoxicity in rats was used as the basis for 

an acute-duration oral MRL for β-HCH, as detailed in Section 2.3 and Appendix A. 

Reproductive Effects. Information on the potential reproductive toxicity of HCH in humans is 

limited. An increase in serum luteinizing hormone levels was observed in male workers, but other 

reproductive hormone levels were not significantly altered. Additionally, increased blood levels of 

γ-HCH and total HCH isomers were detected in women experiencing spontaneous abortion or premature 

delivery. Because the women were exposed to multiple organochlorine pesticides, it is difficult to 

establish a causal relationship between HCH exposure and adverse reproductive outcomes. 

Adverse reproductive effects have been observed in male and female laboratory animals orally exposed to 

γ-, β-, or technical-grade HCH. In male rats, exposure to >1 mg/kg/day γ-HCH resulted in decreases in 

the number of sperm and/or spermatids. This effect was observed following exposure of mature animals 

and in animals exposed during gestation or lactation. A decrease in sperm count was also observed in rats 

exposed to technical-grade HCH. At higher doses of γ-, β-, or technical-grade HCH, degeneration of the 

seminiferous tubules or testicular atrophy were also observed in rats and mice. An acute-duration oral 

MRL for γ-HCH is based on the reproductive effects observed in the offspring of rats exposed to γ-HCH 

during lactation, as detailed in Section 2.3 and Appendix A. 

Effects in female rats, mice, and rabbits exposed to γ- or β-HCH include ovarian atrophy, increased length 

of estrous cycle, disruption of ovarian cycling, and decreased ovulation rate. In general, the effects in the 

females occurred at higher doses than in the males. Although a number of reproductive effects have been 
HEXACHLOROCYCLOHEXANE 16 

2. RELEVANCE TO PUBLIC HEALTH 

observed in male and female rats, two multigeneration studies did not find alterations in fertility following 

exposure to 13.1 mg/kg/day γ-HCH or 32 mg/kg/day technical-grade HCH. 

Cancer. Use of γ-HCH pesticides by farmers was associated with a 50% increased risk of nonHodgkin’s lymphoma. However, a causal relationship could not be determined due to confounding 

effects such as use of other pesticides. Several studies have examined the possible relationship between 

elevated blood levels of HCH and risk of breast cancer; one study found an association and three studies 

did not find associations. With oral exposure, α-, β-, γ-, and technical-grade HCH have been found to be 

carcinogenic in mice following long-term exposure. Hepatocellular carcinoma is the most frequently 

reported tumor type, although in many studies, the liver was the only organ under investigation. Benign 

lung adenomas were also increased in mice following chronic exposure to γ-HCH. In general, mice 

appear to be more susceptible to the carcinogenic effects of HCH isomers, even though some strains have 

a high background level of liver tumors; and rats generally developed cancer following longer exposure 

or exposure to higher doses. In addition, a study reported that α-, β-, and γ-HCH promoted tumor 

development in rats exposed to a single dose of N-nitrosomorpholine. A metabolite of γ-HCH, 

2,4,6-trichlorophenol, accounts for 10–20% of γ-HCH-derived excretion products; this metabolite is 

carcinogenic in animals and might account for some or all of the carcinogenic activity observed in 

animals. A stable halogenated epoxide of another γ-HCH metabolite, pentachlorocyclohexene, could also 

contribute to the hepatocarcinogenicity of γ-HCH. 

The available animal data suggest that liver cancer may be of potential concern to individuals exposed to 

HCH isomers for prolonged periods of time. The Department of Health and Human Services (DHHS) has 

determined that γ-HCH and other HCH isomers may reasonably be anticipated to cause cancer in humans. 

The International Agency for Research on Cancer (IARC) has determined that HCH is possibly 

carcinogenic to humans. The Environmental Protection Agency (EPA) has classified technical HCH and 

α-HCH as probable human carcinogens, β-HCH as a possible human carcinogen, and δ- and ε-HCH as 

not classifiable as to human carcinogenicity. The EPA has additionally classified lindane (γ-HCH) as 

having suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential. 

2.3 MINIMAL RISK LEVELS 

The general population is predominantly exposed to HCH by consumption of contaminated food, with 

minor exposures occurring from drinking water and ambient air. Average daily dietary intakes of HCH 

isomers in the U.S. adult population have been estimated to be in the range of 0.5–1.0 ng/kg/day for 
HEXACHLOROCYCLOHEXANE 17 

2. RELEVANCE TO PUBLIC HEALTH 

α-HCH, 0.5–1.0 ng/kg/day for γ-HCH, and <0.1 ng/kg/day for β-HCH (Gunderson 1995b). Inhalation 

and dermal exposure to γ-HCH can also occur through occupational contact or at workplaces that 

formulate or use γ-HCH as a seed treatment. Additionally, a small percentage of the population can be 

dermally exposed to γ-HCH through pharmaceutical use, since this isomer is still available as a 

prescription lotion, cream, or shampoo medication for the treatment of head lice and mites. 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for HCH. An MRL 

is defined as an estimate of daily human exposure to a substance that is likely to be without an 

appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are 

derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive 

health effect(s) for a specific duration within a given route of exposure. MRLs are based on 

noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for 

acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate 

methodology does not exist to develop MRLs for dermal exposure. 

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

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

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

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

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

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

significant human exposure improve, these MRLs will be revised. 

Sufficient health effects data are available to derive oral MRLs for the α-, β-, and γ-HCH isomers. 

Technical-grade HCH and the α- and β-HCH isomers are currently unavailable in the United States; 

therefore, exposure to these isomers is likely to occur only in or near hazardous waste sites at which 

technical-grade HCH was disposed. No MRLs were derived for technical-grade HCH. HCH is not found 

in the environment as technical-grade HCH, and analytical methods do not detect or measure technicalgrade HCH, but rather, the individual isomers. When technical-grade HCH enters the environment, 

individual isomers partition into various media at different rates depending on the physical characteristics 

of each isomer. Some isomers may be more mobile in soil or water than others. Differences in 

partitioning and degradation would result in a different proportion of isomers than when initially spilled. 

Therefore, the development of an MRL(s) for technical grade HCH would not be relevant. 
HEXACHLOROCYCLOHEXANE 18 

2. RELEVANCE TO PUBLIC HEALTH 

Inhalation MRLs 

No inhalation MRLs could be developed for isomers of HCH due to insufficient data (Table 2-1). 

Information on health effects following acute inhalation of γ-HCH in animals (Klonne and Kintigh 1988; 

Oldiges et al. 1980; Ullmann 1986b) is limited. Neurological effects following acute inhalation exposure 

to γ-HCH have included excitation, sedation, ataxia, and spasms (Ullmann 1986b). Acute inhalation 

studies for the other HCH isomers and technical-grade HCH are not available. Intermediate-duration 

inhalation studies of γ-HCH have been performed in rats with mortality reported (Klonne and Kintigh 

1988). Inhalation of 5 mg/m3 of γ-HCH for 90 days has not resulted in adverse respiratory, 

hematological, hepatic, or renal effects in rats (Oldiges et al. 1983), but the data are insufficient for 

developing an intermediate-duration inhalation MRL. No chronic-duration inhalation studies in animals 

are available for any HCH isomer. Due to the limitations of the database, additional information is 

needed on thresholds, dose-response relationships, and sensitive target organs for determining levels of 

significant human exposure to HCH and associated health effects following inhalation. 

Oral MRLs 

Five oral MRLs have been derived for α-, β-, and γ-HCH isomers of HCH, as discussed below, detailed in 

Appendix A, and summarized in Table 2-1. 

α-HCH 

•	 An MRL of 0.008 mg/kg/day has been derived for chronic-duration (365 days and longer) oral 

exposure to α-HCH. 

The chronic oral MRL for α-HCH is based on a NOAEL of 0.8 mg/kg/day and LOAEL of 3.5 mg/kg/day 

for liver effects in rats (Fitzhugh et al. 1950) and an uncertainty factor of 100 (10 for extrapolation from 

animals to humans and 10 for human variability). 

The critical NOAEL was identified in a chronic toxicity study in which groups of 10 Wistar rats of each 

sex were exposed to α-HCH in the diet for up to 107 weeks at estimated doses of 0, 0.7, 3.5, 7, or 

56 mg/kg/day in males and 0, 0.8, 4, 8, or 64 mg/kg/day in females (Fitzhugh et al. 1950). End points 

included clinical signs, body weight, food consumption, organ weights, gross pathology, and 
HEXACHLOROCYCLOHEXANE 19 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-1. MRL Values for Hexachlorocyclohexane (HCH) 

Inhalation MRLs Oral MRLs (mg/kg/day) 

Isomer Acute Intermediate Chronic Acute Intermediate Chronic 

α-HCH — — — — — 0.008 

β-HCH — — — 0.05 0.0006 — 

γ-HCH — — — 0.003 0.00001 — 

δ-HCH — — — — — — 

ε-HCH — — — — — — 

Technical HCH — — — — — — 

— Insufficient data 
HEXACHLOROCYCLOHEXANE 20 

2. RELEVANCE TO PUBLIC HEALTH 

histopathology. No exposure-related changes occurred at the low dose in either sex, indicating that the 

highest NOAEL is 0.8 mg/kg/day in females. Liver effects were qualitatively described in both sexes at 

higher doses, progressing from very slight histological changes with no gross liver pathology at 3.5– 

4 mg/kg/day, slight histological changes with no gross pathology at 7–8 mg/kg/day, and moderate 

histological damage accompanied by moderate gross pathology at 56–64 mg/kg/day. The hepatic 

histopathological changes classified as moderate included hepatic cell atrophy, fatty degeneration, and 

focal necrosis. Non-hepatic effects included decreased body weight gain, slight kidney histopathology 

(focal nephritis), and reduced lifespan at 56–64 mg/kg/day. 

β-HCH 

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

β-HCH. 

The acute oral MRL for β-HCH is based on a NOAEL of 4.5 mg/kg/day and LOAEL of 22.5 mg/kg/day 

for clinical signs of ataxia in rats (Van Velsen et al. 1986) and an uncertainty factor of 100 (10 for 

extrapolation from animals to humans and 10 for human variability). 

The principal study, Van Velsen et al. (1986), is a 13-week toxicity study in which groups of 10 Wistar 

rats of each sex were exposed to estimated dietary doses of 0, 0.18, 0.9, 4.5, or 22.5 mg/kg/day in males, 

or 0, 0.2, 1.0, 5, or 25 mg/kg/day in females. At week 2 of the study, two male and two female rats 

receiving the highest dose (22.5 and 25 mg/kg/day, respectively) exhibited clinical signs of ataxia and 

became progressively inactive. Within 3 days of the first signs of ataxia, the animals became comatose 

and were sacrificed. The investigators did not report adverse clinical signs at the other dose levels; thus, 

the 4.5 mg/kg/day (in males and 5 mg/kg/day in females) dose is considered a NOAEL. 

Similar neurotoxic effects were observed in an immunotoxicity study in which groups of six female 

B6C3F1 mice were exposed to β-HCH in the diet at estimated doses of 0, 19, 57, or 190 mg/kg/day for up 

to 30 days (Cornacoff et al. 1988). Mice receiving 57 or 190 mg/kg/day showed signs of ataxia within the 

first week of exposure. The signs resolved in a few days in the 57 mg/kg/day group, whereas 

approximately 80% of the 190 mg/kg/day mice became laterally recumbent and moribund. No ataxia or 

other signs of neurotoxicity occurred at 19 mg/kg/day. Other effects in this study included 

immunological alterations at 57 mg/kg/day (e.g., decreased lymphoproliferative responses to T-cell 

mitogens and decreased natural killer cell activity), but these end points were only evaluated after 30 days 

and are therefore not considered to be consequences of acute duration exposure. Support for neuro­
HEXACHLOROCYCLOHEXANE 21 

2. RELEVANCE TO PUBLIC HEALTH 

toxicity as the critical effect for acute oral exposure to β-HCH is provided by the Cornacoff et al. (1988) 

study reporting ataxia after 1 week of exposure to 57 mg/kg/day and a study by Muller et al. (1981) 

reporting a significant reduction in tail nerve motor conduction velocity in rats exposed to 66 mg/kg/day 

β-HCH for 30 days. 

•	 An MRL of 0.0006 mg/kg/day has been derived for intermediate-duration oral exposure to 

β-HCH. 

The intermediate oral MRL for β-HCH is based on a LOAEL of 0.18 mg/kg/day for liver effects in rats 

(Van Velsen et al. 1986) and an uncertainty factor of 300 (3 for use of a minimal LOAEL, 10 for 

extrapolation from animals to humans, and 10 for human variability). 

The critical LOAEL was identified in a 13-week subchronic toxicity study in which groups of 10 Wistar 

rats of each sex were exposed to estimated dietary doses of 0, 0.18, 0.9, 4.5, or 22.5 mg/kg/day in males, 

or 0, 0.2, 1.0, 5, or 25 mg/kg/day in females (Van Velsen et al. 1986). End points that were examined 

included body weight, food consumption, hematology, blood biochemistry, organ weights, gross 

pathology, and histopathology. Hepatic effects were observed that included hyalinization of centrilobular 

cells in males at ≥0.18 mg/kg/day and females at 25 mg/kg/day; increased absolute and relative liver 

weight in both sexes at ≥0.9 mg/kg/day in males and ≥1.0 mg/kg/day in females; periportal fat 

accumulation, increased mitosis, and/or focal liver cell necrosis in males at ≥4.5 mg/kg/day and females 

at ≥5 mg/kg/day; and centrilobular hepatocytic hypertrophy, proliferation of smooth endoplasmic 

reticulum, increased microsomal activity, and/or increased glycogen content in males at 22.5 mg/kg/day 

and females at 25 mg/kg/day. Other systemic effects included increased absolute and/or kidney weight in 

females at ≥2.0 mg/kg/day and males at ≥4.5 mg/kg/day; renal medulla calcinosis in males at 

22.5 mg/kg/day; and clinical signs (ataxia progressing to inactivity and coma), hematologic and splenic 

changes indicative of anemia (decreased red blood cells and hemoglobin, increased extramedullar 

hematopoiesis), and reduced body weight in males at 22.5 mg/kg/day and females at 25 mg/kg/day. 

Due to the dose-related nature and progression in severity of the hepatic effects, and the mild, reversible 

nature of the changes at the lowest dose level, 0.18 mg/kg/day is considered to be a minimal LOAEL 

based on hyalinization of centrilobular cells. The liver is an established target of β-HCH in other 

subchronic and chronic studies in rats and mice (Fitzhugh et al. 1950; Ikegami et al. 1991a, 1991b; Ito et 

al. 1973; Schoter et al. 1987). 
HEXACHLOROCYCLOHEXANE 22 

2. RELEVANCE TO PUBLIC HEALTH 

γ-HCH (lindane) 

• An MRL of 0.003 mg/kg/day has been derived for acute-duration oral exposure to γ-HCH. 

The acute oral MRL for γ-HCH is based on a minimal LOAEL of 1 mg/kg/day for developmental/ 

reproductive effects in rats (Dalsenter et al. 1997b) and an uncertainty factor of 300 (3 for extrapolation 

from a minimal LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). 

The critical LOAEL was identified in a study that assessed reproductive toxicity in male offspring of rats 

that were exposed during lactation (Dalsenter et al. 1997b). Groups of nine Bor:spf females were 

administered γ-HCH in peanut oil by gavage as a single 6 mg/kg dose on day 9 or day 14 of lactation, or 

as daily 1 mg/kg/day doses on days 9–14 of lactation. Actual doses to the offspring were not determined. 

The control group was administered the oil vehicle alone on days 9–14 of lactation. Male offspring (10 or 

20/group) were terminated on postnatal day (pnd) 65 (puberty) or 140 (adulthood) and evaluated for the 

following end points: testis and epididymis weights, spermatid and sperm numbers, serum testosterone 

level, sexual behavior at 130 days of age during 1:1 mating with unexposed females (mount latency, 

intromission and ejaculatory latency, number and frequency of intromissions), mating index (number 

sperm positive females/number males mated x100), pregnancy index (number of males that made females 

pregnant/number of males that made females sperm-positive x100), fertility index (number of days 

elapsed until males fertilized their female partner), pregnancy end points (numbers of litters, 

implantations/litters, fetuses/litter, resorptions), and testicular histology (6 mg/kg offspring only). Effects 

observed in the 1 mg/kg/day offspring included statistically significant (p<0.05) reductions in relative 

testicular weight at pnd 140 (6.4% less than controls), relative epididymis weight at pnd 65 (7.1%), 

spermatid number at pnd 65 and 140 (29.0 and 12.8%, respectively), sperm number at pnd 140 (13.2%), 

serum testosterone at pnd 65 (30.0%), and increased number of intromissions per minute up to ejaculation 

at pnd 130 (45%). Effects were generally similar in type and magnitude in the 6 mg/kg offspring exposed 

on gestation day 9 or 14, including significantly reduced relative testicular weight at pnd 65 and 

140 (~10%), spermatid and sperm numbers at pnd 140 (~8–10%), and serum testosterone at 

pnd 140 (~50%). There were no significant effects on sexual behavior or fertility in the 1 mg/kg/day or 

6 mg/kg offspring as shown by the mating, pregnancy, and fertility indices or other pregnancy end points. 

Because no significant alterations in fertility were observed, the significant changes observed for relative 

organ weights, sperm number, hormone levels, and intromission incidence are considered minimally 

adverse. The testicular histological examinations of the 6 mg/kg/day offspring showed large areas of 

normal tissue, although some areas had distinct changes ranging from small alterations to a pronounced 
HEXACHLOROCYCLOHEXANE 23 

2. RELEVANCE TO PUBLIC HEALTH 

effect. The most affected areas were the tubules in which the effects included necrotic changes and 

reductions in Leydig cell numbers and spermatogenesis. 

Similar effects on testicular histology and sperm numbers occurred in adult male offspring of mice that 

were orally exposed to γ-HCH in doses ≥15 mg/kg/day (lower doses not tested) on gestation days 9–16 

(Traina et al. 2003). Additionally, intermediate-duration studies of γ-HCH showed that testicular and 

other reproductive effects occurred in mink exposed to 1 mg/kg/day. Female mink treated with 

1 mg/kg/day γ-HCH in their diet from 3–6 weeks before mating until weaning at 8–10 weeks of age 

showed effects on reproductive efficiency that included reduced receptivity to mating and reduced 

whelping rate (Beard et al. 1997). The decreased fertility was primarily due to embryo mortality after 

implantation. Reductions in whelping rate, litter size, and testicular size were observed in a threegeneration study of mink exposed to 1 mg/kg/day dietary γ-HCH (Beard and Rawlings 1998). Acute 

exposure to γ-HCH caused effects on neurological and other systemic end points at oral doses higher than 

the 1 mg/kg/day LOAEL for developmental/reproductive toxicity. Neurological effects of γ-HCH 

included enhanced susceptibility to kindling (induction of seizures by repeated subthreshold electrical 

stimulation of the brain) following a single 5-mg/kg dose (Gilbert and Mack 1995) or 3 mg/kg/day for 

4 days (Joy et al. 1982), reduced brain serotonin level following 3 mg/kg/day for 6 days (Attia et al. 

1991), and reduced brain barrier permeability in 10-day-old pups exposed to 2 mg/kg as a single dose or 

8 daily doses (Gupta et al. 1999). The toxicological relevance of these effects is unclear because there 

were no concurrent tests of neurobehavioral function (as well as the unnatural method of seizure 

induction). A comprehensive neurotoxicity screening study was conducted in which groups of 10 male 

and 10 female Crl:CD BR rats were administered a single dose of γ-HCH by gavage at levels of 0, 6, 20, 

or 60 mg/kg (Hughes 1999a). This study is an unpublished Confidential Business Information (CBI) 

submission summarized by EPA (2000). End points included functional observational battery (FOB) and 

motor activity (MA) tests performed prior to treatment, within 3 hours of dosing, and on post-exposure 

days 7 and 14, as well as histopathology of nervous system tissues at study termination. No clinical signs 

or any other effects were observed at 6 mg/kg. Motor activity was decreased in females at ≥20 mg/kg and 

males at 60 mg/kg. Females also had increased forelimb grip strength and decreased grooming behavior 

at 20 mg/kg, as well as an absence of grooming behavior at 60 mg/kg. Other effects at 60 mg/kg included 

clinical signs (e.g., piloerection, urine-stained fur, tremors, and/or convulsions) in both sexes and 

increased hindlimb foot splay in males. 

Other acute oral effects of γ-HCH included hematological and immunological changes in mice at 10– 

20 mg/kg/day (Hong and Boorman 1993), developmental changes in rats and mice at 20–45 mg/kg/day in 
HEXACHLOROCYCLOHEXANE 24 

2. RELEVANCE TO PUBLIC HEALTH 

rats and mice (Dalsenter et al. 1997b; Hassoun and Stohs 1996a; Rivera et al. 1991), and liver and kidney 

changes in mice at 72 mg/kg/day (Srinivasan and Radhakrishnamurty 1988; Srinivasan et al. 1984). 

•	 An MRL of 0.00001 mg/kg/day has been derived for intermediate-duration oral exposure to 

γ-HCH. 

The intermediate oral MRL for γ-HCH is based on a LOAEL of 0.012 mg γ-HCH/kg/day for 

immunological/lymphoreticular effects in mice (Meera et al. 1992) and an uncertainty factor of 

1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human 

variability). 

The critical LOAEL was identified in an immunotoxicity study in which groups of six female Swiss mice 

were exposed to γ-HCH in measured dietary doses of 0, 0.012, 0.12, or 1.2 mg/kg/day for up to 24 weeks 

(Meera et al. 1992). End points that were evaluated throughout the study included delayed-type hypersensitivity reaction to sheep red blood cells (SRBC), lymphoproliferative response to mitogenic 

stimulation by concavalin A, mixed lymphocyte reactions, response of IgM antibody forming cells in 

spleen (plaque formation) to SRBC or lipopolysaccharide (LPS), and peritoneal macrophage phagocytic 

activity in response to LPS or Staphylococcus aureus. Histology of the thymus, peripheral lymph nodes, 

and spleen was evaluated at 4, 12, and 24 weeks post-treatment. Both the cell-mediated and humoral 

components of the immune system showed a biphasic response, characterized initially by stimulation 

followed by suppression in a dose-dependent manner at all dose levels, indicating that a NOAEL was not 

identified. Effects observed at ≥0.012 mg/kg/day included biphasic changes in delayed-type hypersensitivity reaction to SRBC (increased at 4–12 weeks and decreased at 12–24 weeks), IgM plaque 

formation to SRBC (increased at 4–8 weeks and decreased at 12–24 weeks), and plaque formation to 

LPS-SRBC (increased at 4 weeks at ≥0.12 mg/kg/day and decreased at 8-24 weeks at ≥0.012 mg/kg/day). 

Histological changes occurred in lymphoid organs of treated animals and were consistent with the 

biphasic immunomodulatory responses. Effects were observed in the spleen at ≥0.12 mg/kg/day, 

including no significant reaction except for active proliferation of megakaryocytes at 4 weeks posttreatment, an apparent reduction in lymphoid follicles at 12 weeks post-treatment, and considerable 

reduction in the overall cellularity of red pulp and white pulp areas at 24 weeks post-treatment. Histopathology at 1.2 mg/kg/day included effects in lymph nodes (reduced lymphocyte population and size of 

medullary cords) and thymus (necrosis in the medulla) at 12–24 weeks post-treatment at 1.2 mg/kg/day. 

Immunotoxic effects have been observed in other oral studies of γ-HCH. Immunosuppression in the form 

of reduced antibody responses to Salmonella and typhoid vaccines occurred in rats exposed to 
HEXACHLOROCYCLOHEXANE 25 

2. RELEVANCE TO PUBLIC HEALTH 

6.25 mg/kg/day for up to 5 weeks (Dewan et al. 1980). Exposure to 10 mg/kg/day for 10 days caused 

residual bone marrow damage and suppressed granulocyte-macrophage progenitor cells in mice, and 

atrophy of the thymus was observed in mice following 40 mg/kg/day for 3 days (Hong and Boorman 

1993). Serum antibody response to SRBC was suppressed in rats exposed to 3.6 mg/kg/day for 8 weeks 

(Koner et al. 1998). 

HEXACHLOROCYCLOHEXANE 27 

3. HEALTH EFFECTS 

3.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of HCH. It contains 

descriptions and evaluations of toxicological studies and epidemiological investigations and provides 

conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an end point should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between 

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 
HEXACHLOROCYCLOHEXANE 28 

3. HEALTH EFFECTS 

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 HCH are 

indicated in Tables 3-2, 3-3, and 3-5 and Figures 3-2 and 3-3. Because cancer effects could occur at 

lower exposure levels, Figure 3-3 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. 

HCH exists as several isomers. The four major isomers discussed in this profile are alpha-HCH (α-HCH), 

beta-HCH (β-HCH), gamma-HCH (γ-HCH), and delta-HCH (δ-HCH). γ-HCH is also commonly known 

as lindane. Technical-grade HCH consists of at least five isomers (approximately 60–70% α-HCH, 5– 

12% β-HCH, 10–15% γ-HCH, 6–10% δ-HCH, and 3–4% ε-HCH). The toxicity of the isomers varies. 

With respect to acute exposure, γ-HCH is the most toxic, followed by α-, δ-, and β-HCH. With chronic 

exposure, however, β-HCH is the most toxic followed by α-, γ-, and δ-HCH. With chronic exposures, the 

increased toxicity of β-HCH is probably due to its longer biological half-life in the body and its 

accumulation in the body over time. 

3.2.1 Inhalation Exposure 

Studies examining the inhalation toxicity of HCH in humans are limited. Most of the available 

information is from case reports of acute poisoning in the home following accidental inhalation of 

pesticidal powder or from the use of γ-HCH vaporizers, whereby γ-HCH pellets are vaporized by 
HEXACHLOROCYCLOHEXANE 29 

3. HEALTH EFFECTS 

electrical warming of a ceramic jacket, and from studies of workers engaged in the manufacture and 

formulation of pesticides and fertilizers. Limitations inherent in these reports or studies include 

unquantified exposure concentrations and concomitant exposure to HCH mixtures, pyrolysis products 

from vaporizers, and other pesticides and chemicals. Studies that provide levels of significant exposure 

for inhalation exposure to γ-HCH are shown in Table 3-1 and Figure 3-1. 

3.2.1.1 Death 

γ-HCH was once used in vaporizers, resulting in human exposure to unspecified levels via inhalation and 

dermal routes. Occasional deaths associated with the use of this product for several months or years have 

been reported, but in no case is it clear that γ-HCH was responsible for the deaths (Loge 1965). Two 

fatalities resulting from pulmonary edema were reported in toddlers inhaling and ingesting unknown 

quantities of γ-HCH-containing pesticidal powder (McQueen 1968). No human deaths from inhalation 

exposure to other isomers have been reported. 

An acute study with rats exposed nose-only to γ-HCH aerosol for 4 hours, followed by a 22-day 

observation period, estimated the acute LC50 to be 1,560 mg/m3

 (Ullmann 1986b). Rats inhaling up to 

603 mg/m3 γ-HCH aerosol for 4 hours in whole-body exposure chambers exhibited no mortality 

throughout the 14-day observation period (Oldiges et al. 1980). In an intermediate-duration study with 

mice inhaling γ-HCH dust aerosol in whole-body exposure chambers, 16% mortality was observed after 

1 week of exposure to 10 mg/m3

, while exposures of up to 14 weeks resulted in 22% mortality at 

5 mg/m3

, 2% mortality at 1 mg/m3, and no mortality at 0.3 mg/m3 (Klonne and Kintigh 1988). 

The lethal concentrations reported by Ullmann (1986b) and Klonne and Kintigh (1988) are presented in 

Table 3-1 and plotted in Figure 3-1. 

3.2.1.2 Systemic Effects 

No studies were located regarding gastrointestinal, musculo/skeletal, or dermal effects in humans or 

animals following inhalation exposure to HCH. 

The highest NOAEL values and all NOAEL values from each reliable study for systemic effects in each 

species and duration category are recorded in Table 3-1 and plotted in Figure 3-1. 
211

1560

216

10

202

603603603

212

101 642

215

1

213

55555

Table 3-1 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Inhalation 

Exposure/ 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(Wistar) 

4 hr 

System 

NOAEL 

(mg/m3) 

Less Serious 

(mg/m3) 

LOAEL 

Serious 

(mg/m3) 

1560 (LC50) 

Reference Chemical Form 

Ullmann 1986b lindane 

2 Mouse 

(CD-1) 

1 wk 5 d/wk 6 hr/d 

10 (16% mortality) Klonne and Kintigh 198

lindane 

Systemic 

3 Rat 

(Wistar) 

4 hr Resp 603 Oldiges et al. 1980 

lindane 

Hepatic 603 Renal 603 

Neurological 

4 Rat 

(Wistar) 

4 hr 

INTERMEDIATE EXPOSURE Death 

5 Mouse 

(CD-1) 

14 wk 5 d/wk 6 hr/d 

101 (sedation) 642 (ataxia) 

1 (2% mortality) 

Ullmann 1986b lindane Klonne and Kintigh 198lindane 

Systemic 

6 Rat 

(Wistar) 

90 d 6 hr/d Resp 5 Oldiges et al. 1983 

lindane 

Hemato 5 Hepatic 5 Renal 5 Bd Wt 5 
616

5

Table 3-1 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/m3) (mg/m3) (mg/m3) Chemical Form 

Neurological 

7 Mouse 14 wk Other 5 Klonne and Kintigh 198

5 d/wk (CD-1) 6 hr/d lindane 

a The number corresponds to entries in Figure 3-1. Bd Wt = body weight; d = day(s); Hemato = hematological; hr = hour(s); LC50, lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s) 
Death Respiratory Hepatic Renal Neurological 

Figure 3-1 Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - In

Acute (≤14 days) 

Systemic 

mg/m3 

10000 

1r

1000

4r 3r 3r 3r 

100 4r

10 2m 

c-Cat f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans -Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil 

LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Death Respiratory Hematological Hepatic Renal Body Weight Neurological 

Figure 3-1 Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Inhalation 

Intermediate (15-364 days) 

Systemic 

mg/m3 

10 

6r 6r 6r 6r 6r 7m 

1 5m 

0.1 

c-Cat f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans -Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil 

LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
HEXACHLOROCYCLOHEXANE 34 

3. HEALTH EFFECTS 

Respiratory Effects. In humans, mucous membrane irritation of the nose and throat was observed 

after acute exposure to the HCH products dispensed by an overheated γ-HCH vaporizer (Conley 1952). 

Exposure levels were not reported and dermal exposure may also have occurred, although the observed 

irritation was probably due to direct action upon the mucous membranes. 

No respiratory effects were observed in rats exposed to up to 603 mg/m3 γ-HCH aerosol for 4 hours 

(Oldiges et al. 1980). No respiratory effects were observed in rats exposed to γ-HCH aerosol (up to 

5 mg/m3

) 6 hours/day for 90 days (Oldiges et al. 1983) or in mice similarly exposed for 14 weeks (Klonne 

and Kintigh 1988). 

Cardiovascular Effects. Cardiovascular effects of HCH have been reported in humans exposed to 

HCH. Kashyap (1986) reported electrocardiogram (ECG) abnormalities in 15% of 45 factory workers 

involved in the production of technical-grade HCH; exposure concentrations were not reported and 

dermal exposure may have occurred. 

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

HCH. 

Hematological Effects. Hematological effects have been reported in humans following acute or 

chronic inhalation exposure to γ-HCH; however, a causal relationship between exposure to γ-HCH and 

hematological effects in humans has not been established. Hypochromic anemia was reported in a 

2.5-year-old boy who was exposed to γ-HCH in a home in which a pesticide vaporizer was operated. Air 

γ-HCH concentrations measured in the basement and living room of the house were 2.4–5.5 μg/m3

; 

however, the actual concentration the child was exposed to and the duration of exposure were not 

determined (Morgan et al. 1980). Aplastic anemia was reported in a boy exposed to γ-HCH used as an 

insecticide in his home and in a man exposed at work (Rugman and Cosstick 1990). In both cases, the 

anemia was reversible and was not present in other family members. The levels and routes of exposure 

are not known, although they are presumed to be inhalation and dermal. Other hematological abnormalities, including isolated instances of leukopenia, leukocytosis, granulocytopenia, granulocytosis, 

eosinophilia, monocytosis, and thrombocytopenia, have been reported following chronic human 

occupational exposure to γ-HCH (Brassow et al. 1981; Jedlicka et al. 1958). Exposure concentrations 

were not specified in these studies and concomitant dermal exposure probably occurred. Although 

Brassow et al. (1981) reported slight changes in clinical chemistry tests in 60 human workers exposed to 
HEXACHLOROCYCLOHEXANE 35 

3. HEALTH EFFECTS 

γ-HCH, there were no cases of severe impairment of health. Granulocytopenia, aplastic anemia, and 

pancytopenia have been reported in a number of case reports of individuals following exposure to γ-HCH 

and other pesticides such as DDT in the home, during the handling of the pesticide, or from a nearby 

formulating plant (Danopoulos et al. 1953; Friberg and Martensson 1953; Gewin 1939; Loge 1965; 

Mendeloff and Smith 1955). Exposure concentrations were not reported, dermal exposure was likely, and 

in many cases, there was concomitant exposure to other pesticides; therefore, determination of a causal 

relationship between exposure and hematological effects cannot be made. 

No hematological effects were seen in rats exposed to γ-HCH aerosol (up to 5 mg/m3

) for 90 days 

(Oldiges et al. 1983). 

Hepatic Effects. In humans, statistically significant increases in the blood levels of the enzymes 

lactate dehydrogenase (33%), leucine aminopeptidase (45%), and γ-glutamyl transpeptidase (174%) were 

reported in 19 individuals occupationally exposed to technical-grade HCH for over 10 years in an HCHformulating plant (Kashyap 1986); the HCH isomer concentrations in serum showed a 10-fold increase 

compared to the control group of workers. Both inhalation and dermal exposure probably occurred. The 

large standard deviation (SD) from the mean reported for γ-glutamyl transpeptidase in exposed workers 

(mean±SD =22.2±40.31 IU/mL) suggests the increased activity of this enzyme may not be related to 

HCH exposure or that individual responses may vary. 

No hepatic effects were observed in rats after acute exposure to 603 mg/m3 γ-HCH (Oldiges et al. 1980). 

Rats exposed to γ-HCH aerosol (5 mg/m3

, 6 hours/day) exhibited increased hepatic cytochrome P-450 

concentration after 90 days, but this level returned to control values after a 4-week recovery period 

(Oldiges et al. 1983). 

Renal Effects. No studies were located regarding renal effects in humans following inhalation 

exposure to HCH. 

No renal effects were seen in rats exposed to up to 603 mg/m3 γ-HCH aerosol for 4 hours (Oldiges et al. 

1980) or up to 5 mg/m3 γ-HCH aerosol 6 hours/day for 90 days (Oldiges et al. 1983). 

Endocrine Effects. Serum luteinizing hormone levels were significantly increased in 54 men 

occupationally exposed to γ-HCH for approximately 8 years in a γ-HCH producing factory compared to a 

group of 20 control individuals (Tomczak et al. 1981). The mean serum concentration of follicle 
HEXACHLOROCYCLOHEXANE 36 

3. HEALTH EFFECTS 

stimulating hormone was increased and testosterone was decreased, but the differences relative to controls 

were not statistically significant (Tomczak et al. 1981). 

No studies were located regarding endocrine effects in animals following inhalation exposure to HCH. 

Ocular Effects. No studies were located regarding ocular effects in humans following inhalation 

exposure to HCH. 

Mice exposed to γ-HCH aerosol (up to 5 mg/m3

) 6 hours/day for 14 weeks exhibited no ophthalmic 

effects (Klonne and Kintigh 1988). 

Body Weight Effects. No studies were located regarding body weight effects in humans following 

inhalation exposure to HCH. 

No body weight effects were seen in rats exposed to up to 5 mg/m3 γ-HCH aerosol 6 hours/day for 

90 days (Oldiges et al. 1983). 

3.2.1.3 Immunological and Lymphoreticular Effects 

A statistically significant increase (approximately 18%) in the level of immunoglobulin M (IgM) was 

noted in 19 workers occupationally exposed to technical-grade HCH during pesticide formulation as 

compared to 14 nonexposed workers (Kashyap 1986). The HCH isomer concentrations in serum showed 

a 10-fold increase when compared to the control group. Both inhalation and dermal exposure probably 

occurred, and the measurement of IgM alone is not a reliable measure of immune function in adults. 

No studies were located regarding immunological or lymphoreticular effects in animals following 

inhalation exposure to HCH. 

3.2.1.4 Neurological Effects 

Paresthesia of the face and extremities, headache, and vertigo have been reported in a group of 

45 workers occupationally exposed during manufacture and formulation of technical-grade HCH for 

several years (Kashyap 1986); exposure concentrations were not reported. Both inhalation and dermal 
HEXACHLOROCYCLOHEXANE 37 

3. HEALTH EFFECTS 

exposure probably occurred. Abnormal electroencephalographic (EEG) patterns (increased variation in 

the frequency and amplitude of wave pattern or more serious changes without specific EEG signs) have 

been reported in 16 of 37 workers following exposure to γ-HCH for 0.5–2 years in a fertilizer plant 

(Czegledi-Janko and Avar 1970). Exposure concentrations were not reported; however, these EEG 

changes were found to correlate with blood levels of γ-HCH. Weakness of the left and right limbs, 

dysarthria, and dysphagia were seen in an agricultural worker exposed by inhalation and dermal contact to 

unspecified levels of several organochlorine pesticides, including γ-HCH (Fonseca et al. 1993). 

Rats exposed to various concentrations of 99.6% γ-HCH aerosol via nose-only inhalation for 4 hours 

exhibited concentration-related neurological effects when observed for up to 22 days after exposure 

(Ullmann 1986b). Slight-to-moderate sedation was observed after exposure to 101 mg/m3

; slight-tosevere sedation was noted after exposure to 378 mg/m3

; restlessness, excitation, and ataxia were seen 

after exposure to 642 and 2,104 mg/m3

; and spasms were also noted at the highest concentration 

(2,104 mg/m3

). Rats exposed to 0.02–5 mg/m3 γ-HCH aerosol for 90 days exhibited a "slightly disturbed 

general condition" beginning at day 15 (Oldiges et al. 1983). Mice were similarly exposed for 14 weeks 

and exhibited no clinical signs of neurotoxicity (Klonne and Kintigh 1988). 

NOAELs and LOAELs for neurological effects in animals following inhalation exposure are listed in 

Table 3-1 and plotted in Figure 3-1. 

3.2.1.5 Reproductive Effects 

Statistically significant increases in the levels of serum luteinizing hormone were reported in a group of 

54 men occupationally exposed to unspecified concentrations of γ-HCH for approximately 8 years in a 

γ-HCH-producing factory (Tomczak et al. 1981). Although the mean serum concentration of follicle 

stimulating hormone was increased and testosterone was decreased, these differences were not 

statistically significant compared to mean values determined in a control group. These hormonal changes 

may have resulted in diminished reproductive capability. 

No studies were located regarding reproductive effects in animals following inhalation exposure to HCH. 
HEXACHLOROCYCLOHEXANE 38 

3. HEALTH EFFECTS 

3.2.1.6 Developmental Effects 

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

exposure to HCH. 

3.2.1.7 Cancer 

There is no clear evidence of increased risk of non-Hodgkin’s lymphoma among farmers from Kansas, 

Nebraska, Iowa, and Minnesota who used γ-HCH (Blair et al. 1998). Results of four case control studies 

conducted in the 1980s were pooled for analysis of a combined data set of 987 men with non-Hodgkin’s 

lymphoma and 2,895 population-based controls. Odds ratios (ORs) indicated that reported use of γ-HCH 

significantly increased the odds of developing non-Hodgkin’s lymphoma by 50% (OR=1.5, 95% 

confidence interval (CI) 1.1–2.0). Some use characteristics suggested a dose-response relationship, 

although differences between cases and controls were not statistically significant. For example, ORs were 

greater among individuals who first used γ-HCH ≥20 years before diagnosis (OR=1.7, 95% CI 1.1–2.5) 

compared to those with <20 years of use (OR=1.3, 95% CI 0.7–2.3), and among persons who reported 

≥5 days per year of γ-HCH use (OR=2.0, 95% CI 0.6–6.4) compared with those with <5 days per year of 

use (OR=1.6, 95% CI 0.6–4.0). Other factors reduced apparent risk, including adjustment for potential 

confounding by use of other pesticides such as 2,4-D and diazinon, which reduced the OR associated with 

γ-HCH use from 1.5 (95% CI 1.1–2.0) to 1.2 (95% CI 0.5–2.2) and 1.3 (95% CI 0.9–1.9), respectively. 

The authors concluded that γ-HCH is not a major factor in the development of non-Hodgkin’s lymphoma 

but may play some role. There was also no clear evidence of an increased risk of non-Hodgkin’s 

lymphoma in a population-based study of Canadian men of varying occupations. There was a 

significantly increased risk of non-Hodgkin’s lymphoma with exposure to γ-HCH; however, after 

additional multivariate analysis to factor in exposure to other chemicals, history of cancer among firstdegree relatives, and personal history of measles and allergy sensitization, γ-HCH was not considered a 

significant independent predictor (McDuffie et al. 2001). 

No studies were located regarding carcinogenic effects in animals following inhalation exposure to HCH. 
HEXACHLOROCYCLOHEXANE 39 

3. HEALTH EFFECTS 

3.2.2 Oral Exposure 

The Levels of Significant Exposure for oral exposure to γ-HCH are presented in Table 3-2 and Figure 3-2. 

Levels of Significant Exposure for α-, β-, δ-, and technical-grade HCH are presented in Table 3-3 and 

Figure 3-3. 

3.2.2.1 Death 

Case reports have described deaths in humans (usually children, some suicidal adults) following ingestion 

of γ-HCH, often from the tablets intended for γ-HCH vaporizers (Storen 1955; Sunder Ram Rao et al. 

1988). The amounts of γ-HCH associated with these deaths are not known. 

γ-HCH has been shown to be lethal to animals following single gavage administration (Gaines 1960; Liu 

and Morgan 1986; Tusell et al. 1987). The LD50 value for female rats is 91 mg/kg, and the LD50 value for 

male rats is 88 mg/kg (Gaines 1960). One of seven male Wistar rats died following a single oral 

administration of 60 mg/kg γ-HCH (Martinez et al. 1991). DBA/2 strain mice, recognized as being 

"unresponsive" to microsomal enzyme induction, are more sensitive to the acute lethal effects of γ-HCH 

than C57BL/6 strain mice when exposed to 20 mg/kg/day for 10 days (Liu and Morgan 1986). In a 

15-week study, 2 of 12 F-344 rats treated with 20 mg/kg/day died (Chadwick et al. 1988). A 2-year study 

in rats fed γ-HCH in their diets (32 mg/kg/day) also found a significantly increased mortality rate 

compared with controls (Amyes 1990). The oral LD50 for technical-grade HCH in CFT-Wistar rats 

treated once by gavage was 2,428 mg/kg (Joseph et al. 1992a). Exposure to 5 mg/kg/day of technicalgrade HCH for 90 days resulted in the deaths of 6/12 male rats and 4/12 female rats (Dikshith et al. 

1991b). Exposure to low levels (0.4 mg/kg/day) of technical-grade HCH in the diet for 360 days resulted 

in deaths of 4/20 rats (Dikshith et al. 1991a). However, the deaths occurred late in the study and were 

accompanied by other changes, indicating that they were due to pathogenic infection rather than HCH 

exposure. The LD50 for rats and the LOAEL values from the intermediate-duration studies are recorded 

in Tables 3-2 and 3-3 and plotted in Figures 3-2 and 3-3. 
400

8891

402

60

945

2.5

5

936

30

640

72

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

ACUTE EXPOSURE Death 

1 Rat once 

(Sherman) (GO) 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

88 M (LD50) 91 F (LD50) 

Reference Chemical Form 

Gaines 1960 lindane 

2 Rat 

(Wistar) 

Systemic 

3 Rat 

(Wistar) 

once (GO) 1 x/d 5-21 d (G) 

Hepatic 2.5 M 5 M (increased EROD, 

PROD, and NDMA-d enzyme levels) 

60 M (1/7 deaths) Martinez et al. 1991 

lindane Parmar et al. 2003 lindane 

4 Rat 

(SpragueDawley) 

48h 1x/d (F) 

Hepatic 30 (Reduced number of 

cells per field; increased cell, nucleus, and nucleolus size; slight cellular disorganization) 

Shahid Ali and Rauf Sh1998 lindane 

5 Rat 2wks 

(F) Hepatic 72 (Altered activities of serum 

aminotransferases, alkaline phosphatase, altered soluble enzymes and altered carbohydrate metabolism) 

Srinivasan and Radhakrishnamurty 198lindane 
482

72

900

202020

10

202020

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species 

Figure (Strain) 

Frequency 

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

6 Rat 

(Wistar) 

14 d ad libitum (F) 

Renal 72 M (10% increase in kidney 

weight, altered excretion patterns, distention of glomeruli, swelling of tubular epithelia) 

7 Mouse 

(B6C3F1) 

10 d 1 x/d (GO) 

Resp 20 M 

Cardio 20 M Gastro 20 M Hemato 10 M (Transient decrease in 

marrow progenitor cell numbers) 

Hepatic Renal 

20 M 20 M 

Bd Wt 20 M 

Reference Chemical Form 

Srinivasan et al. 1984 lindane Hong and Boorman 199lindane 
901

404040

20

40404040

221

10

20 40

222

10

411

3

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

Exposure/ 

Duration/ 

Key to 

a 

Species Frequency 

Figure (Strain) (Route) System 

Resp Cardio Gastro Hemato Hepatic Renal Endocr Bd Wt 

NOAEL 

(mg/kg/day) 

40 M 40 M 40 M 40 M 40 M 40 M 40 M 10 M 

LOAEL 

Less Serious 

(mg/kg/day) 

20 M (Transient reduction in 

marrow progenitor cell number) 

20 M (decreased thymus 

weights) 

10 M (Dose-related decrease 

in relative thymus and spleen weights) 

3 M (increased pineal 

N-acetyltransferase, decreased serotonin levels) 

Serious 

(mg/kg/day) 

40 M (Atrophy of thymus 

cortex) 

Reference Chemical Form 

Hong and Boorman 199lindane Hong and Boorman 199lindane Hong and Boorman 199lindane 

Attia et al. 1991 lindane 

8 Mouse 

(B6C3F1) 

Immuno/ Lymphoret 

9 Mouse 

(B6C3F1) 

10 Mouse 

(B6C3F1) 

Neurological 

11 Rat 

(SpragueDawley) 

3 d 1x/d (GO) 3 d 1x/d (GO) 10 d 1x/d (GO) 6 d 1x/d (GO) 
320

5 10

924

6

20

60

408

3

10

315

60

403

60

948

5

10

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

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

10 M (myoclonic jerks and 

single clonic seizures in naive animals) 

60 (Clinical signs of 

neurotoxicity including tremors and convulsions) 

10 M (seizures) 60 (convulsions) 60 M (tonic-clonic seizures) 

Reference Chemical Form 

Gilbert and Mack 1995 lindane Hughes 1999a lindane Joy et al. 1982 lindane Martinez and Martinez-C1995 lindane Martinez et al. 1991 lindane Parmar et al. 2003 lindane 

12 Rat 

(Long- Evans) 

13 Rat 14 Rat 

(SpragueDawley) 

15 Rat 

(Wistar) 

16 Rat 

(Wistar) 

17 Rat 

(Wistar) 

once (GO) 5 M once (G) 6 20 4 d 1x/d 3 M (GO) once (GO) once (GO) 1 x/d 5 d 5 M 10 M (G) 

(myoclonic jerks and single clonic seizure in kindled animals) 

(Decreased motor activity 

and grooming behavior, increased forelimb grip strength) (increased kindling acquisition) 

(increased EROD, 

PROD, and NDMA-d enzyme levels in the brain) 
950

35

923

20

904

5

88

15 20

409

30

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

18 Rat 

(Wistar) 

19 Rat 20 Rat 

(Wistar) 

21 Rat 

(Wistar) 

22 Rat 

(SpragueDawley) 

Exposure/ LOAEL 

Duration/ 

Frequency NOAEL Less Serious Serious Reference (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

1 d (G) 35 M (convulsions in 4/10 animals) Parmar et al. 2003 lindane 

once (G) 20 (altered acquisition of a passive avoidance task 

in 15-day-old pups) 

Rivera et al. 1998 lindane 

3 d 1x/d (GO) 

5 (decreased myelin and 

2',3'-cyclic nucleotide 3'-phosphodiesterase activity in brains) 

Serrano et al. 1990a lindane 

once (GO) 15 M 20 M (convulsions) Vendrell et al. 1992a lindane 

once (GO) 30 M (seizures) Wooley and Griffith 198

lindane 
370

1

371

6

306

40

658

25

25 26 

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

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

Reproductive 

23 Rat Ld 9-14 

1x/d (GO) 

b

1 M (Reduced relative 

testicular and epididymis weight (~10%), spermatid and sperm counts (~10%), and testosterone levels (30-50%) at maturity with no effect on fertility) 

Dalsenter et al. 1997b lindane 

24 Rat Ld 9 or 14 

once (GO) 

6 M (Reduced relative testical 

and epidymis weight (~10%), spermatid and sperm counts (~8-10%), testosterone levels 

Dalsenter et al. 1997b lindane 

(~30-50%), Leydig cell numbers and spermatogenisis at maturity with no effect on fertility) 

Rat 7 d 40 F Laws et al. 1994 1x/d (Long- Evans) lindane (GO) 

Rat once 25 (increased length of Uphouse and Williams 1

(CDF-F344) estrous cycle) lindane 
939

15

25

940

15

921

30

412

25

413

20

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

27 Mouse 

(CD-1) 

28 Mouse 

(CD-1) 

Developmental 

29 Rat 

(Wistar) 

30 Rat 

(Wistar) 

31 Rat 

(CFY) 

Exposure/ LOAEL 

Duration/ 

Frequency NOAEL Less Serious Serious Reference (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

3 d 1 x/d (GO) 7 d Gd 9-16 1 x/d (GO) Pc 15 1x (GO) Gd 6-15 1x/d (GO) Gd 6-15 1x/d (GW) 

15 F 25 F (increase in degenerating 

two-cell embryos following preovulatory exposure) 

Scascitelli and Pacchier2003 lindane 

15 M (Reduced testicular 

sperm head count and concentration and other effects on spermatogenesis in adult F1 males exposed during gestation) 

Traina et al. 2003 lindane 

30 (reduction of serum 

testosterone concentration in adult offspring) 

Dalsenter et al. 1997a lindane 

25 F Khera et al. 1979 

lindane 

20 F Palmer et al. 1978a 

lindane 
410

20

916

30

917

45

414

20

415

20

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

Key to 

a 

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 

32 Rat 

(Wistar) 

once (GO) 20 (regional changes in brain noradrenaline and 

serotonin levels in suckling rats) 

Rivera et al. 1991 lindane 

33 Mouse 

C57BL/6J 

Single oral dose on day 12 of gestation (GI) 

30 (decrease in fetal weight, 

fetal thymus weight) 

Hassoun and Stohs 199lindane 

34 Mouse 

DBA/2J 

Single oral dose on day 12 of gestation (GI) 

45 (decrease in fetal and 

placental weight) 

Hassoun and Stohs 199lindane 

36 35 Rabbit Gd 6-18 

(New 1x/d Zealand) (GW) 

INTERMEDIATE EXPOSURE Death 

Rat 15 wk (Fischer- 344) 1x/d 

(GO) 

20 F 

20 F (2/12 deaths) 

Palmer et al. 1978a lindane Chadwick et al. 1988 lindane 
952

3

418

1.8

419

1.8

641

50

5

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Systemic 

37 Rat 

(albino) 

38 Rat 

(Wistar) 

39 Rat 

(Wistar) 

40 Rat 

(Wistar) 

Exposure/ LOAEL 

Duration/ 

Frequency NOAEL Less Serious Serious Reference (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

1x d 6 wks (G) 

Cardio 3 M (tachycardia, increase in 

blood pressure, plasma calcium levels, 

Anand et al. 1995 gamma 

myocardial calcium influx. Decreased Ca,K-ATPase activity. ECG changes: increase in ST segment, T-wave amplitude; reduced R-R interval, P-wave 

15 d ad libitum (F) 

Hepatic 1.8 M (Increases in lipid 

peroxidation, level of cytochrome P-450, and activities of superoxide dismutase) 

Barros et al. 1991 lindane 

30 d ad libitum (F) 

Hepatic 1.8 M (Increases in lipid 

peroxidation, level of cytochrome P-450, and activities of superoxide dismutase) 

Barros et al. 1991 lindane 

40d (F) Hepatic 50 Desi 1974 lindane 

Renal 5 (increased kidney weight) 
947

2.5

937

18

217

100.4

2

0.4

2

454

90

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

41 Rat 

(Wistar) 

42 Rat 

(SpragueDawley) 

43 Rat 

(Wistar) 

44 Mouse 

(dd) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

1 x/d 5-21 d (G) 15d 1x/d (F) 12 wk ad libitum (F) 24 wk ad libitum (F) 

System 

Hepatic Hepatic Hemato Hepatic Renal Hepatic 

NOAEL 

(mg/kg/day) 

10 

0.4 0.4 

Less Serious 

(mg/kg/day) 

2.5 M (increased liver 

weight;increased P-450 content and P-450 dependent enzymes) 

18 (Reduced number of 

cells per field; incresed cell, nucleus, and nucleolus size; vacuoles in the cytoplasm and granulation; apparent fatty degeneration) 

2 (centrilobular 

hypertrophy) 

2 (tubular distension, 

basophilic tubules) 

90 M (centrilobular 

hypertrophy) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Parmar et al. 2003 lindane Shahid Ali and Rauf Sh1998 lindane Suter 1983 lindane Ito et al. 1973 lindane 
922

3.6

420

0.012

1.2

303

90

318

10

319

10

925

7.9 30.2

316

2

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

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

Immuno/ Lymphoret 

45 Rat 8 wk 

ad libitum (F) 

3.6 (reduced serum antibody 

response to SRBC) 

46 Mouse 

(Swiss albino) 

24 wk ad libitum (F) 

c

0.012 F (changes in cell- and 

humoral-mediated immune system) 

1.2 F (necrosis of thymus) 

Neurological 

47 Rat 

(Wistar) 

90 d ad libitum (F) 

90 M (tonic convulsions) 

48 Rat 

(Long- Evans) 

30 d 1x/d (GO) 

10 M (myoclonic jerks and 

clonic seizures) 

49 Rat 

(Long- Evans) 

10 wk 3 d/wk (GO) 

10 M (myoclonic jerks and 

clonic seizures) 

50 Rat 

(CD) 

13 wk ad libitum (F) 

7.9 F 30.2 F 

51 Rat 

(Wistar) 

30 d (GO) 2 (decreased dopamine levels) 

Reference Chemical Form 

Koner et al. 1998 lindane Meera et al. 1992 lindane 

Arisi et al. 1994 lindane Gilbert 1995 lindane Gilbert 1995 lindane Hughes 1999b lindane Martinez and Martinez-C1995 lindane 
478

12.3

25.4

926

1.2

5.6

949

2.5

416

5

10

321

0.8

304

0.8

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

Key to 

a 

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 

52 Rat 

(Wistar) 

30 d ad libitum (F) 

12.3 M 25.4 M (reduced tail nerve 

conduction velocity) 

Muller et al. 1981 lindane 

53 Rat 

(Wistar) 

25 d GD 6 - LD 10 ad libitum (F) 

1.2 F 5.6 F (increased motor activity 

and decreased motor activity habituation in pups at postnatal days 11 and 65) 

Myers 1999 lindane 

54 Rat 

(Wistar) 

1 x/d 15 d (G) 

2.5 M (increased EROD, 

PROD, and NDMA-d enzyme levels in the brain) 

Parmar et al. 2003 lindane 

Reproductive 

55 Rat 

(Fischer- 344) 

15 wk 1x/d (GO) 

5 F 10 F (disrupted ovarian 

cycling, antiestrogenic effects) 

Chadwick et al. 1988 lindane 

56 Rabbit 

(hybrid) 

12 wk 3 d/wk (GO) 

0.8 F (reduced ovulation rate) Lindenau et al. 1994 

lindane 

57 Rabbit 

(New Zealand) 

12-15 wk 3 d/wk (GO) 

0.8 F Seiler et al. 1994 

lindane 
943

1

941

1

942

1

662

25

305

0.8

625

32

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) System NOAEL (mg/kg/day) 

LOAEL 

Less Serious Serious Reference 

(mg/kg/day) (mg/kg/day) Chemical Form 

58 Mink 3 generations 

(NS) (F) 1 (reduced litter size in F2 females, reduced testis 

size in F3 males) 

Beard and Rawlings 19lindane 

59 Mink 12 wk 

(NS) 3 wk premating - 8 wk 

postpartum (F) 

1 F (reduced mating 

receptivity and whelping rate) 

Beard et al. 1997 lindane 

60 Mink 17 wk 

(NS) 6 wk premating - 10 wk 

postpartum (F) 

1 F (reduced whelping rate 

and increased post-implantation embryo loss) 

Beard et al. 1997 lindane 

Developmental 

61 Rat Gd 0-21 

(Wistar) Ld 1-28 

(F) 

25 (Increased liver weight 

and decreased kidney weight in pups exposed during gestatino and lactation) 

Srinivasan et al. 1991a lindane 

62 Rabbit 12-15 wk 

(New 3 d/wk 

Zealand) (GO) 

CHRONIC EXPOSURE Death 

63 Rat up to 52 weeks 

(Wistar) ad libitum 

(F) 

0.8 F 

32 F (increased mortality rate) 

Seiler et al. 1994 lindane 

Amyes 1990 lindane 
201

7

32

474

4

7

112

4 764

112

938

9

421

13.6

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Systemic 

64 Rat 

(Wistar) 

65 Rat 

(Wistar) 

66 Rat 

(SpragueDawley) 

Cancer 

67 Mouse 

(B6C3F1) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

up to 2 yr ad libitum (F) 107 weeks (F) 18mo 1x/d (F) 80 wk ad libitum (F) 

System 

Hepatic Renal Hepatic Renal Bd Wt Hepatic 

NOAEL 

(mg/kg/day) 

32 F 

4 F 4 F 

64 F 

Less Serious 

(mg/kg/day) 

7 M (periacinar hepatocytic 

hypertrophy) 

7 M (Very slight microscopic 

liver damage in the absence of gross liver damage) 

7 M (focal nephritis) 

112 M (17% decrease in body 

weight gain) 

9 (Increased cell, nucleus, 

and nucleolus size; extensive cytoplasmolysis; slight cytoplasmic degeneration; incresing nuclear distortion) 

LOAEL 

Serious 

(mg/kg/day) 

112 M (Moderate microscopic 

damage [hepatic cell atrophy, fatty degeneration, and focal necrosis] in the presence of slight-to-moderate gross liver damage) 

13.6 M (CEL: hepatocellular 

carcinoma) 

Reference Chemical Form 

Amyes 1990 lindane Fitzhugh et al. 1950 lindane Shahid Ali and Rauf Sh1998 lindane NCI 1977 lindane 
422

27.2

Table 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

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

68 Mouse 

(F-1 hybrid) 

24 mo ad libitum Wolff et al. 1987 

lindane 

27.2 F (CEL: hepatocellular 

carcinoma, lung tumors) (F) 

a The number corresponds to entries in Figure 3-2. b Used to derive an acute-duration oral minimal risk level (MRL) of 0.003 mg/kg/day for gamma-HCH; based on a minimal LOAEL of 1 mg/kg/day divided by an unc300 (3 for use of a LOAEL, 10 for extrapolation from animals to humans, 10 for human variability) c Used to derive an intermediate-duration minimal risk level (MRL) of 0.00001 mg/kg/day for gamma-HCH; 0.012 mg/kg/day divided by an uncertainty factor of 100LOAEL, 10 for extrapolation from animals to humans, 10 for human variability) Bd Wt = body weight; cardio = cardiovascular; CEL = cancer effect level; d = day(s); endocr = endocrine; EROD = 7-ethoxyresorufin-O-deethylase; F = female; (F) gavage; (GO) = gavage in oil; (GW) = gavage in water; Gd = gestation day(s); GI = gastric intubation; gastro = gastrointestinal; Hemato = hematological; hr = hour(day; LD50, lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; mo = month(s); NDMA-d = N-nitrosodimethylamine demethylase; NOAEno-observed-adverse-effect level; Pc = post conception; PROD = 7-pentoxyresorufin-O-dealkylase; Resp = respiratory; wk = week(s); x = time(s); yr = year(s) 
Death Respiratory Cardiovascular Gastrointestinal Hem Hepati Renal Endocrine Body atological c Weight 

Figure 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - 

Acute (≤14 days)
 

Systemic 

mg/kg/day 

100 1r 1r

5r 6r 2r 

8m 8m 8m 8m 8m 8m 8m 

4r 

7m 7m 7m 8m 7m 7m 7m 

10 7m 

3r 3r 

1 

0.1 

0.01 

0.001 

c-Cat f-Ferret n-Mink Cancer Effect Level-Animals -Humans Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Im Neurological Reproductive Developm ental muno/Lymphor 

Figure 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral 

Acute (≤14 days) 

mg/kg/day 

100 

13r 15r 16r 

34m 9m 25r 18r 22r 33m 29r 27m 26r 30r 

9m 13r 19r 21r 31r 32r 35h

21r 27m 28m 

10 9m 10m 12r 14r 17r 

13r 24r 12r 17r 20r 11r 14r 

1 23r 

0.1 

0.01 

0.001 

c-Cat f-Ferret n-Mink Cancer Effect Level-Animals -Humans Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Death 

Cardiovascular HemHepatiRenal ImNeurological Reproductive Developm

10 

100 

atological 

c 

muno/Lymphor 

ental 

Figure 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (Continued)
	

Intermediate (15-364 days)
	

Systemic 

mg/kg/day 

44m 47r 

40r 

50r 52r 61r 36r 42r 

52r 43r 48r 49r 50r 55r 

53r 40r 55r 

45r 37r 41r 54r

38r 39r 43r 43r 51r

46m 53r 1 58n 59n 60n 56h 57h 62h 

43r 43r 

0.1 

46m 0.01 

0.001 

0.0001 

1E-5 

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

 for effects

 other than

 Cancer 

Level 
Death Hepati Renal Body Cancer * c Weight 

Figure 3-2 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Oral (Co

Chronic (≥365 days) 

mg/kg/day Systemic

1000 

65r 65r 100 

65r 

63r 64r 

68m 67m 

10 66r 

64r 65r 65r 

65r 65r 

*Doses represent the lowest dose tested per study that produced a tumorigenic 1 response and do not imply the existence of a threshold for the cancer endpoint. 

c-Cat f-Ferret n-Mink Cancer Effect Level-Animals -Humans Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
79

2428

326

100

75

90

76

90

1

72

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - Oral 

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(CFT-Wistar) 

once (GO) 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

2428 M (LD50) 

Systemic 

2 Rat 

(NS) 

once (GO) Metab 100 F (increased phosphoinositide 

turnover in erythrocyte membranes) 

3 Rat 

(SpragueDawley) 

2 wk ad libitum (F) 

Hepatic 90 M (increased triglycerides, 

phospholipids and cholesterol, increased cytochrome C reductase and decreased glutathione peroxidase) 

4 Rat 

(SpragueDawley) 

2 wk ad libitum (F) 

Hepatic 90 M (increased relative liver 

weight and cytochrome P-450 levels and decreased hepatic vitamin A levels) 

5 Rat 

(Wistar) 

14 d ad libitum (F) 

Renal 72 M (tubular degeneration, 

distention of glomeruli, swelling of tubular epithelia, 22% increase in kidney weight, altered excretion patterns) 

Reference Chemical Form 

Joseph et al. 1992a technical 

Agrawal et al. 1995 technical Ikegami et al. 1991a beta Ikegami et al. 1991b beta Srinivasan et al. 1984 beta 
903

5

39

5050

38

72

46

72

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

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

6 Mouse 

(Swiss albino) 

Gd 9 once (GO) 

Hepatic 5 F (significantly decreased 

GOT and lactate dehydrogenase (LD) activities) 

7 Mouse 

(NS) 

1, 5, 15 d 1x/d (GO) 

Hepatic 50 (congestion of portal 

vessels and central vein, fatty changes, granular degeneration) 

Renal 50 (congestion of blood 

vessels and glomeruli, fatty changes, interstitial hemorrhaging) 

8 Mouse 

(Swiss albino) 

2 wk ad libitum (F) 

Hepatic 72 M (127% increase in 

relative liver weight, increased serum alanine and aspartate aminotransferases and 

ALP, increased hepatic 

phosphatases and acid cathepsin) 

9 Mouse 

(Swiss albino) 

2 wk ad libitum (F) 

Hepatic 72 M (cellular hypertrophy, 

centrilobular degeneration, focal necrosis) 

Reference Chemical Form 

Dikshith et al. 1990 technical Philip et al. 1989 technical Ravinder et al. 1989 technical Ravinder et al. 1990 technical 
951

54.5

22.525

453

19 57 190

44

5

25

65

0.4

47

5

327

5

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) System 

Exposure/ 

Duration/ 

Frequency 

(Route) NOAEL (mg/kg/day) 

LOAEL 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Neurological 

10 Rat 

(Wistar) 

2 wk ad libitum (F) 5 M b

4.5 F 

22.5 M (ataxia, inactivity) 

25 F (ataxia, inactivity) 

Van Velsen et al. 1986 beta 

11 Mouse 

(B6C3F1) 

1 wk ad libitum (F) 

Reproductive 

12 Mouse 

(Swiss albino) 

Gd 9 once (GO) 

19 F 

5 F 

57 F (ataxia) 190 F (lateral recumbancy) 

25 F (increased fetal 

resorptions) 

Cornacoff et al. 1988 beta Dikshith et al. 1990 technical 

INTERMEDIATE EXPOSURE Death 

13 Rat 

(NS) 

360 d ad libitum (F) 

0.4 M (4/20 deaths) Dikshith et al. 1991a 

technical 

14 Rat 

(NS) 

90 d 1x/d (GO) 

Systemic 

15 Metab Rat (NS) 3-6 mo 5 d/wk 

(GO) 

5 (6/12 M, 4/12 F died) 

5 F (significant reductions in 

phosphoinositide levels in erythocyte membranes and cerebrum) 

Dikshith et al. 1991b technical Agrawal et al. 1995 technical 
94

1.8

95

1.8

51

60

60

60

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - 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 

16 Rat 

(Wistar) 

15 d ad libitum (F) 

Hepatic 1.8 M (increased cytochrome 

P-450 level, superoxide dismutase, catalase, and lipid peroxidation activities) 

Barros et al. 1991 alpha 

17 Rat 

(Wistar) 

30 d ad libitum (F) 

Hepatic 1.8 M (increased cytochrome 

P-450 level, superoxide dismutase, catalase, NADPH-cytochrome P-450 reductase activities, and lipid peroxidation) 

Barros et al. 1991 alpha 

18 Rat 

(NS) 

30 d 1x/d (GO) 

Hemato 60 M Dikshith et al. 1989a 

technical 

Hepatic 60 M (decreased GOT and 

LDH activities, increased 

ALP activity, 65% 

increase in liver weight) 

Renal 60 M 
67

0.4 2

20

2

20

80

5

477

3

89

90

77

90

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

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

19 Rat 

(NS) 

360 d ad libitum (F) 

Hepatic 0.4 M 2 M (increased liver weight) 20 M (focal necrosis, 

enlargement of hepatocytes, nuclear pyknosis, vacuolation, margination) 

Renal 2 M 20 M (tubular necrosis, 

glomerular degeneration) 

20 Rat 

(NS) 

90 d 1x/d (GO) 

Hepatic 5 M (decreased liver and 

serum GOT and alkaline phosphatase activities) 

21 Rat 

(Charles Foster) 

180 d 1x/d (G) 

Bd Wt 3 M (17% decrease in body 

weight gain) 

22 Rat 

(CFT-Wistar) 

7 wk ad libitum (F) 

Hepatic 90 M (Decreased hepatic 

vitamin A content, increased GPT and beta-GLR activities, 56% increase in liver weight) 

23 Rat 

(CFT-Wistar) 

7 wk ad libitum (F) 

Hemato 90 M (decreased white blood 

cell counts) 

Reference Chemical Form 

Dikshith et al. 1991a technical Dikshith et al. 1991b technical Gautam et al. 1989 technical Joseph et al. 1992b technical Joseph et al. 1992c technical 
48

5050

330

20

4

5

22.50.18

4.5

4.5 22.55

22.5

8

20

54

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

24 Rat 

(NS) 

25 Rat 

(Wistar) 

26 Rat 

(Wistar) 

27 Mouse 

(dd) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

30 d 1x/d (GO) 90 d ad libitum (F) 13 wk ad libitum (F) 32 wk ad libitum (F) 

System 

Hepatic Renal Bd Wt Hemato Hepatic Renal Bd Wt Hepatic 

NOAEL 

(mg/kg/day) 

50 M 50 M 

5 F 

4.5 M 

5 F 

20 F 

Less Serious 

(mg/kg/day) 

20 F (significantly decreased 

body weight gain) 

22.5 M (decreased red blood 

cells, leukocyte and hemoglobin concentrations) 

c

0.18 M (hyalinization of 

centrilobular cells) 

22.5 M (calcinosis in males) 22.5 M (15% decrease in body 

weight) 

54 M (nuclear irregularities in 

foci of enlarged hepatocytes) 

LOAEL 

Serious 

(mg/kg/day) 

4.5 M (hyalinization of 

centrilobular cells, focal cell necrosis, increased mitoses) 

Reference Chemical Form 

Khanna et al. 1990 technical Nagaraja and Desiraju 1technical Van Velsen et al. 1986 beta Hanada et al. 1973 beta 
455

45

456

90

7

18

55

90

9

90

208

5

22.5

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

28 Mouse 

(dd) 

24 wk ad libitum (F) 

Hepatic 

29 Mouse 

(dd) 

24 wk ad libitum (F) 

Hepatic 

30 Mouse 

(dd) 

24 wk ad libitum (F) 

Hepatic 

31 Mouse 

(Swiss) 

2-8 mo ad libitum (F) 

Hepatic 

32 Mouse 

(HPB) 

Immuno/ Lymphoret 

33 Rat 

(Wistar) 

50 wk ad libitum (F) 13 wk ad libitum (F) 

Hepatic 

5 F 

LOAEL 

Less Serious Serious 

(mg/kg/day) (mg/kg/day) 

45 M (centrilobular 

hypertrophy) 

90 M (centrilobular 

hypertrophy) 

18 M (centrilobular 

hypertrophy) 

90 (100% increase in liver 

weight, decreased G6P and FDP activity, glycogen accumulation, smooth endoplasmic reticulum proliferation) 

90 M (hyperplastic nodules) 

22.5 M (cortical atrophy in 

thymus) 

Reference Chemical Form 

Ito et al. 1973 beta Ito et al. 1973 delta Ito et al. 1973 alpha Karnik et al. 1981 technical Tryphonas and Iverson alpha Van Velsen et al. 1986 beta 
43

20

60

87

50

91

0.04

0.4

96

50

10

106.2

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

34 Mouse 

(B6C3F1) 

Neurological 

35 Rat 

(NS) 

36 Rat 

(NS) 

37 Rat 

(NS) 

38 Rat 

(Wistar) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

30 d ad libitum (F) 

20 F 60 F (decreased 

lymphoproliferative responses to T-cell mitogens, decreased natural killer cytolytic activity) 

Cornacoff et al. 1988 beta 

90 d 6 d/wk 1x/d (GO) 

50 M (increased dopamine and 

decreased serotonin and norepinephrine. Behavioral changes, increased brain wave frequency) 

Anand et al. 1991 technical 

360 d 1x/d (F) 

0.04 M 0.4 M (convulsions, tremors, 

hindlimb paralysis, salivation) 

Dikshith et al. 1991a technical 

120 d 1x/d (GO) 

50 M (increased motor activity, 

decreased resting stereotypic time) 

Gopal et al. 1992 technical 

30 d ad libitum (F) 

106.2 M Muller et al. 1981 

alpha 
12

66.3

313

20

11

5 22.5

92

2 20

40

3

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

39 Rat 

(Wistar) 

40 Rat 

(Wistar) 

41 Rat 

(Wistar) 

Reproductive 

42 Rat 

(NS) 

43 Rat 

(Charles Foster) 

Exposure/ LOAEL 

Duration/ 

Frequency NOAEL Less Serious Serious Reference (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

30 d 66.3 M (reduced tail nerve Muller et al. 1981 ad libitum conduction velocity) beta (F) 

90 d ad libitum (F) 

20 F (increased GABA levels, 

increased GAD activity, decreased glutamate levels) 

Nagaraja and Desiraju 1technical 

13 wk ad libitum (F) 

5 F 22.5 M (ataxia, coma) Van Velsen et al. 1986 

beta 

360 d 1x/d (F) 

2 M 20 M (testicular degeneration) Dikshith et al. 1991a 

technical 

180 d 1x/d (GO) 

3 M (6% decrease in vas 

deferens weight, degeneration of inner muscle and cell layers) 

Gautam et al. 1989 technical 
41

3

6

13

0.90.2

4.51

22.525

42

60

14

90

314

10

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - 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 

44 Rat 

(Charles Foster) 

45 Rat 

(Wistar) 

46 Mouse 

(B6C3F1) 

47 Mouse 

(Swiss) 

Developmental 

48 Rat 

(Wistar) 

180 d 1x/d (G) 13 wk ad libitum (F) 30 d ad libitum (F) 3 mo ad libitum (F) 60 d ad libitum 

0.9 M 

d

0.2 F 

60 F 

3 M (decreased seminiferous 

tubular diameter and Leydig cell nuclear population) 

4.5 M (decreased testes 

weight) 

d

1 F (increased absolute 

ovary and uterus weights) 

10 F (alterations in levels of 

dopamine, serotonin, and noradrenaline in pup brains) 

6 M (seminiferous tubular 

degeneration) 

d

22.5 M (atrophy of testes) 

25 F (atrophy of ovary; 

hyperplastic and vacuolized endometrium epithelium in uterus) 

90 M (increased testis weight, 

degeneration of seminiferous tubules, decreased spermatocytes) 

Roy Chowdhury and Ga1990 technical Van Velsen et al. 1986 beta Cornacoff et al. 1988 beta Nigam et al. 1979 technical Nagaraja and Desiraju 1technical 
661

5

20

470

2

471

3

22

18

17

45

21

90

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

Frequency 

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

Gd 0-21 Ld 1-28 (F) 

5 (increased liver weight in 

pups exposed during gestation and lactation) 

20 (increased pup mortaility) 

20 wk ad libitum (F) 

2 F (CEL: increase in 

preneoplastic hepatic foci) 

20 wk ad libitum (F) 

3 F (CEL: increase in 

preneoplastic hepatic foci) 

32 wk ad libitum (F) 

18 M (CEL: hepatoma) 

24 wk ad libitum (F) 

45 M (CEL: hepatocellular 

carcinoma) 

16-36 wk ad libitum (F) 

90 M (CEL: hepatocellular 

carcinoma) 

Reference Chemical Form 

Srinivasan et al. 1991a beta Schroter et al. 1987 alpha Schroter et al. 1987 beta Hanada et al. 1973 alpha Ito et al. 1973 alpha Ito et al. 1976 alpha 

a 

Key to 

Figure 

49 

Cancer 

50 51 52 53 54 

Species 

(Strain) 

Rat (Wistar) Rat (Wistar) Rat (Wistar) Mouse (dd) Mouse (dd) Mouse (DDY) 
847

90

18

90

19

90

20

90

23

90

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

55 Mouse 

(Swiss) 

56 Mouse 

(DDY, ICR, DBA/2, C57BL/6, C3H/He) 

57 Mouse 

(Swiss) 

58 Mouse 

(HPB) 

59 Mouse 

(DD) 

Exposure/ LOAEL 

Duration/ 

Frequency 

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

2-4 mo ad libitum (F) 24 wk ad libitum (F) 

90 F (CEL: hepatocellular 

carcinoma) 

90 M (CEL: hepatocellular 

carcinoma) 

2-8 mo ad libitum (F) 50 wk ad libitum (F) 

90 (CEL: hepatocellular 

carcinoma) 

90 M (CEL: hyperplastic 

nodules and adenomas in liver) 

16-36 wk ad libitum (F) 

90 M (CEL: hepatoma) 

Reference Chemical Form 

Karnik et al. 1981 technical Nagasaki et al. 1975 alpha Thakore et al. 1981 technical Tryphonas and Iverson alpha Tsukada et al. 1979 alpha 
472

0.8

5664

8 56560.8

8

473

0.8

3.5

56

8 568

56

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

CHRONIC EXPOSURE 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Systemic 

60 Rat 

(Wistar) 

107 weeks ad libitum (F) 

Hepatic 0.8 F (Very slight microscopic 

damage in the absence of gross liver damage, 33% increase in liver weight) 

d

56 M (Moderate microscopic 

damage [hepatic cell atrophy, fatty degeneration, and focal necrosis] in the presence of marked gross liver damage) 

Fitzhugh et al. 1950 beta 

64 F 

Renal 8 F 56 M (focal nephritis) Bd Wt 56 M 

d

0.8 F 

8 F (12% decrease in body 

weight gain) 

61 Rat 

(Wistar) 

107 weeks ad libitum (F) 

Hepatic 0.8 F 3.5 M (very slight to slight 

microscopic damage in the absence of gross liver damage) 

56 M (Moderate microscopic 

damage [hepatic cell atrophy, fatty degeneration, and focal necrosis] in the presence of moderate gross liver damage. 36% increase in liver weight) 

Fitzhugh et al. 1950 technical 

Renal 8 F 56 M (focal nephritis) 

Bd Wt 8 F 56 M (decreased body weight 

gain) 
5

0.8

3.5

56

8 568

56

30

17

479

10

25

75

28

10

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - 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 

62 Rat 

(Wistar) 

107 weeks ad libitum (F) 

Hepatic 

e

0.8 F 3.5 M (very slight to slight 

microscopic damage in the absence of gross liver damage; 32% increased liver weight) 

56 M (Moderate microscopic 

damage [hepatic cell atrophy, fatty degeneration, and focal necrosis] in the presence of moderate gross liver damage) 

Renal 8 F 56 M (focal nephritis) 

Bd Wt 8 F 56 M (18% decrease in body 

weight gain) 

Neurological 

63 Mouse 

(Swiss) 

80 wk ad libitum (F) 

17 (convulsions) 

64 Mouse 

(Swiss) 

80 wk 1x/d (GO) 

10 (convulsions) 

Cancer 

65 Rat 

(NS) 

72 wk ad libitum (F) 

75 M (CEL: hepatocellular 

carcinoma) 

66 Mouse 

(Swiss) 

80 wk 1x/d (GO) 

10 (CEL: hepatocellular 

carcinoma) 

Fitzhugh et al. 1950 alpha Kashyap et al. 1979 technical Kashyap et al. 1979 technical Ito et al. 1975 alpha Kashyap et al. 1979 technical 
29

17

26

21.3

27

34

Table 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, And Tech-grade HCH - 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 

67 Mouse 

(Swiss) 

68 Mouse 

(Swiss) 

69 Mouse 

(CF1) 

80 wk ad libitum (F) 20 mo ad libitum (F) 104 wk ad libitum (F) 

17 (CEL: hepatocellular 

carcinoma) 

21.3 M (CEL: hepatocellular 

carcinoma) 

34 (CEL:hepatocellular 

carcinoma) 

Kashyap et al. 1979 technical Munir et al. 1983 technical Thorpe and Walker 197beta 

a The number corresponds to entries in Figure 3-3. b Used to derive an acute-duration oral minimal risk level (MRL) of 0.05 mg/kg/day for beta-HCH; 19 mg/kg/day divided by an uncertainty factor of 100 (10 for extraanimals to humans, 10 for human variability). c Used to derive an intermediate-duration oral minimal risk level (MRL) of 0.0006 mg/kg/day for beta-HCH; 0.18 mg/kg/day divided by an uncertainty factor of 300 (minimal LOAEL, 10 for extrapolation from animals to humans, 10 for human variability). d Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-3. Where such differences exist, only the levels most sensitive gender are presented. e Used to derive a chronic-duration oral minimal risk level (MRL) of 0.008 mg/kg/day for alpha-HCH; 0.8 mg/kg/day divided by an uncertainty factor of 100 (10 for eanimals to humans, 10 for human variability). 

ALP = alkaline phosphatase; Bd Wt = body weight; CEL = cancer effect level; d = day(s); (F)= feed; F = female; FDP = fructose-1,6-diphosphatase; (G) = gavage; 

oil; Gd = gestation day; GABA = gamma-aminobutyric acid; GAD = glutamate decarboxylase; GLR = glucorinidase; GOT = glutamate oxaloacetate transaminase; Gglucose-6-phosphatase; GPT = glutamate pyruvate transaminase; Hemato = hematological; Ld = lactation day; LD50, lethal dose, 50% kill; LDH = lactate dehydroglowest-observed-adverse-effect level; M = male; metab = metabolism; mo = month(s); NOAEL = no-observed-adverse-effect level; NS = not specified; Resp = respweek(s); x = time(s) 
Death 

HepatiRenal MNeurological Reproductive 

c 

etabolic 

Figure 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Tech-grade HCH - Oral 

Acute (≤14 days) 

mg/kg/day Systemic 

10000 

t 1r 

1000 

β 11m 

100 β t 2r 3r β 4r t 8m t 9m β 5r 

t 7m t 7m β 11m

β 10r t 12m

β 11m 

10 

t 6m β 10r β 10r t 12m

1 

0.1 

0.01 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbi l 

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

 for effects

 other than

 Cancer 

Level 
Death 

HemHepatiRenal Body 

Metabolic 

Im

atological 

c 

Weight 

muno/Lymphor 

Figure 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Tech-grade HCH - Oral (Continued) 

Intermediate (15-364 days) 

Systemic mg/kg/day 

1000 

100 t δ t α t 23r 29m 31m 32m 22r 

t 18r β 27m t 18r t t 18r t β 34m β 24r 24r 28m 

β 26r β β β β 26r t 26r β 33r 27m α 30m t 19r t 19r 25r 34m

10 

t 14r β 26r t 20r β β 26r t 15r β 33r 26r β 26r 

t 21r 

α 16r α 17r t 19r t 19r

1 

t 13r t 19r 

β 26r 

0.1 

0.01 

0.001 

0.0001 

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

 for effects

 other than

 Cancer 

Level 
Neurological 

Reproductive DevelopmCancer * 

ental 

Figure 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Tech-grade HCH - Oral (Continued) 

Intermediate (15-364 days) 

mg/kg/day 

1000 

100 α 38r t 47m α 54m t 55m α 56m t 57m α 58m α 59m β t 39r β 46m 35r t 37r α 53m 

t 40r β 41r t 42r β 45r β 49r α 52m 

10 t 48r

t 44r β 41r β 49r 

t 43r t 44r β 51r 

t 42r α 50r 

1 β 45r

t 36r 

β 45r 

0.1 

t 36r 

0.01 

0.001 

*Doses represent the lowest dose tested per study that produced a tumorigenic 

0.0001 response and do not imply the existence of a threshold for the cancer endpoint. 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbi l 

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

 for effects

 other than

 Cancer 

Level 
Hepati

Renal 

c 

Body Weight 

Neurological 

Cancer * 

Figure 3-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Tech-grade HCH - Oral (Continued) 

Chronic (≥365 days) 

mg/kg/day 

100 α 65r β 60r t 61r α 62r β 60r t 61r α 62r t 61r α 62r β 69m 

t t t 68m 63m 67m

10 t 64m t 66m β 60r t 61r α 62r β 60r t 61r α 62r 

t 61r α 62r
	

1
	 β 60r 61r t α 62r β 60r 

0.1 

0.01 

0.001 

0.0001 -4 -4 10 10 

Estimated Estimated -4 10

1E-5 Upper-Bound Upper-Bound -5 -5 Estimated 10 Human Cancer 10 Human Cancer Upper-Bound Risk Levels Risk Levels -5 10 Human Cancer 1E-6 For beta-HCH For technical-HCH -6 -6 Risk Levels 10 10 

For alpha-HCH -6 10 

1E-7 -7 -7 10 10 

*Doses represent the lowest dose tested per study that produced a tumorigenic 10-7 

1E-8 response and do not imply the existence of a threshold for the cancer endpoint. 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbi l 

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

 for effects

 other than

 Cancer 

Level 
HEXACHLOROCYCLOHEXANE 78 

3. HEALTH EFFECTS 

3.2.2.2 Systemic Effects 

No studies were located regarding respiratory, dermal, or ocular effects in humans or animals following 

oral exposure to HCH. The animal studies in which systemic effects of HCH were examined, in most 

cases, used isomers of >99% purity. 

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each 

species and duration category are recorded in Tables 3-2 and 3-3 and plotted in Figures 3-2 and 3-3. 

Gastrointestinal Effects. Decreased appetite, vomiting, nausea, and diarrhea have been observed in 

humans following ingestion of food contaminated with unknown amounts of γ-HCH; exposure was 

inferred from levels of γ-HCH measured in urine (Nantel et al. 1977). Vomiting and nausea are usual 

manifestations of γ-HCH ingestion (Sunder Ram Rao et al. 1988). 

γ-HCH has been shown to affect the absorption of substances such as glucose, glycine, and calcium in the 

gastrointestinal tract of rats (Labana et al. 1997), and the effect depends on the nutritional status of the 

animals. Additional reports of gastrointestinal effects after oral administration of γ-HCH were not 

located; however, γ-HCH administered subcutaneously at 20 mg/kg/day to rats for 15 days reduced 

(Na+

-K+)-ATPase activity in the rat jejunum (Moreno et al. 1996). 

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans 

following inhalation exposure to HCH. 

Rats receiving gavage doses of 3 mg/kg/day γ-HCH for 6 weeks exhibited tachycardia, increased blood 

pressure and plasma calcium levels, an increase in myocardial calcium influx, and decreased 

Ca,K-ATPase activity. Electrocardiographic changes included increased ST segment and T-wave 

amplitude and reduced R-R interval and P-wave (Anand et al. 1995). 

Hematological Effects. A woman who committed suicide by drinking γ-HCH was found to have 

disseminated (dispersed) intravascular coagulation during the period when serum γ-HCH levels were 

elevated (Sunder Ram Rao et al. 1988). No other reports were found on the possible effect of γ-HCH on 

blood-clotting factors in humans. 
HEXACHLOROCYCLOHEXANE 79 

3. HEALTH EFFECTS 

No hematological effects were noted in beagle dogs exposed to 12.5 mg γ-HCH/kg/day in the diet for 

32 weeks or to 2.9 mg γ-HCH/kg/day in the diet for 104 weeks (Rivett et al. 1978). A 12-week study in 

rats using 10 mg γ-HCH/kg/day, support this finding (Suter 1983). However, exposure to 22.5 mg 

β-HCH/kg/day in the diet for 13 weeks in rats was found to be more toxic, resulting in a statistically 

significant decrease in numbers of red blood cells and white blood cells and reduced hemoglobin and 

packed cell volume values (Van Velsen et al. 1986). Significant decreases in total white blood cell counts 

and clotting time were reported in rats fed vitamin A-free diets containing technical-grade HCH at a dose 

level of 90 mg/kg/day for 7 weeks (Joseph et al. 1992c). In rats fed a vitamin A-supplemented diet 

containing the same dose level of technical-grade HCH, a significant reduction in total white blood cell 

count, but not red blood cell count, was observed (Joseph et al. 1992c). Significant suppression in bone 

marrow cellularity, erythrocyte precursors, and granulocyte-macrophage progenitor cells, and residual 

progenitor cell damage were reported in male B6C3F1 mice given 20 or 40 mg γ-HCH/kg/day by gavage 

in corn oil for 3 days (Hong and Boorman 1993). Following 10 days of exposure to 10 or 20 mg 

γ-HCH/kg/day, dose-dependent decreases in bone marrow cellularity, granulocyte-macrophage progenitor 

cells, and pluripotent bone marrow stem cells were noted (Hong and Boorman 1993). 

No hematological effects were seen in rats following oral exposure to 60 mg/kg/day technical-grade HCH 

for 30 days (Dikshith et al. 1989a). 

Musculoskeletal Effects. In humans, ingestion of a single dose of approximately 15–30 mL γ-HCH 

powder (amount not reported by weight) was associated with seizures and limb muscle weakness and 

necrosis in an adult man (Munk and Nantel 1977); a muscle biopsy conducted 15 days after ingestion 

showed no evidence of denervation or neuropathy. Widespread striatal muscle necrosis was seen in a 

woman who died 11 days after intentionally ingesting 8 ounces of a 20% γ-HCH solution (Sunder Ram 

Rao et al. 1988). 

Decreased cross-sectional bone area was found in young rats treated with 20 mg/kg/day of γ-HCH by 

gavage for 10 weeks (Andrews and Gray 1990). Myelotoxicity, manifested as significant, dosedependent decrease in marrow progenitor numbers, was seen in mice exposed to 10 or 20 mg/kg/day 

γ-HCH for 10 days (Hong and Boorman 1993). 

Hepatic Effects. No studies were located regarding hepatic effects in humans following oral exposure 

to HCH. 
HEXACHLOROCYCLOHEXANE 80 

3. HEALTH EFFECTS 

Significantly increased liver microsomal 7-ethoxycoumarin-O-dealkylase activity was found in OsborneMendel rats exposed to 11.2 mg γ-HCH/kg/day and in CF1 and B6C3F1 strain mice exposed to 23.6 and 

50.5 mg/kg/day in the diet for 3 days (Oesch et al. 1982). Although no histopathological examinations 

were performed to confirm the presence or absence of toxicity, no significant increase in liver weight or 

other adverse effects were noted in rats exposed to 10 mg γ-HCH/kg/day for a minimum of 4 days (Joy et 

al. 1982). Rats exposed to 15 mg γ-HCH/kg/day for 5 days, and 2.5 mg γ-HCH/kg/day for 21 days, 

showed a significant increase in absolute liver weight (Parmar et al. 2003). A dose- and time-dependent 

increase of P-450 and P-450-dependent enzyme levels was observed in the liver of rats exposed to γ-HCH 

(Parmar et al. 2003). P-450 content was significantly increased in rats exposed to 10 mg γ-HCH/kg/day 

for 5 days, and in rats exposed to 2.5 mg γ-HCH/kg/day for 15 and 21 days. There was no significant 

increase in P-450 content in rats exposed to <10 mg γ-HCH/kg/day for 5 days. Several P-450- dependent 

enzymes, 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-dealkylase (PROD), and 

N-nitrosodimethylamine demethylase (NDMA-d), significantly increased in rats exposed to 5 mg 

γ-HCH/kg/day for 5 days, and in rats exposed to 2.5 mg γ-HCH/kg/day for 15 and 21 days (Parmar et al. 

2003). Hepatocellular damage as indicated by elevation in serum aminotransferases and decrease in 

hepatic soluble enzymes was found in rats given 72 mg/kg/day γ-HCH for 2 weeks (Srinivasan and 

Radhakrishnamurty 1988). Significant increases in hepatic microsomal cytochrome P-450 levels and 

increases in hepatic microsomal superoxide anion production and cytoplasmic superoxide dismutase 

activity and lipid peroxidation were found in Wistar rats fed diets containing 1.8 mg/kg/day γ-HCH for 

15 or 30 days (Barros et al. 1991). Male Wistar rats fed 13.5 mg γ-HCH/kg/day in their diet for 12 days 

exhibited decreased activities of liver lipogenic enzymes and increased levels of serum triglycerides (Boll 

et al. 1995). 

Focal degeneration of hepatocytes was noted in rabbits given γ-HCH at a dose of 7 mg/kg/day by gavage 

for 4 weeks (Grabarczyk et al. 1990; Kopec-Szlezak et al. 1989). Rabbits treated with 4.21 mg 

γ-HCH/kg/day by gavage for 28 days exhibited a significant increase of plasma alkaline phosphatase and 

alanine aminotransferase (ALT) activities immediately following initiation of dosing; these activities 

returned to control levels by day 14 (Cerón et al. 1995). Activity of aspartate aminotransferase (AST) 

also increased immediately following dosing and remained elevated up to 7 days postexposure (day 35). 

γ-HCH residues were detected in the fat 28 days after dosing. 

Treatment of female rats with ≥10.6 mg γ-HCH/kg/day or of male and female mice with ≥21.1 mg/kg/day 

in the diet for 3 months resulted in increases in liver microsomal mixed-function oxidase activity and in 
HEXACHLOROCYCLOHEXANE 81 

3. HEALTH EFFECTS 

significant increases in absolute and relative liver weights; histopathological examinations were not 

performed (Oesch et al. 1982). A dose-dependent increased incidence of liver centrilobular hypertrophy 

was reported in Wistar rats dosed with ≥0.4 mg γ-HCH/kg/day in the diet for 12 weeks (Suter 1983). 

Liver cell lipospheres were reported in rats fed 2.5 mg γ-HCH/kg/day in the diet for 32 weeks (Ortega et 

al. 1957). In mice, administration of 90 mg γ-HCH/kg/day in the diet for 24 weeks was reported to result 

in centrilobular hypertrophy (Ito et al. 1973). Other studies of intermediate-duration exposure (3– 

48 weeks) have reported slight liver effects or increased liver weight in mice exposed to 18 mg/kg/day of 

α-HCH, 45 mg/kg/day of β-HCH, and 90 mg/kg/day for δ-HCH and γ-HCH (Ito et al. 1973). These 

studies were limited by either a small sample size or lack of statistical analysis. 

Chronic exposure of rats to 112–128 mg/kg/day γ-HCH in the diet for 107 weeks resulted in liver necrosis 

and fatty degeneration (Fitzhugh et al. 1950). A dose-related increase in periacinal hepatocytic 

hypertrophy was seen in Wistar rats given 7–8 mg γ-HCH/kg/day in the diet for 104 weeks (Amyes 

1990). No liver effects were reported in dogs exposed to 2.9 mg/kg/day for 104 weeks (Rivett et al. 

1978). In mice, chronic administration of 13.6–27.2 mg γ-HCH/kg/day in the diet was associated with an 

increased incidence of liver cancer (NCI 1977; Wolff et al. 1987) (see Section 3.2.2.8). 

Similar liver effects were reported in animals following intermediate- or chronic-duration exposure to 

α-HCH in the diet. Administration of 1.8 mg/kg/day α-HCH in the diet to rats for 15 or 30 days resulted 

in increases in hepatic cytochrome P-450 content, hepatic lipid peroxidation, and hepatic microsomal 

superoxide production (Barros et al. 1991). Ito et al. (1975) reported liver cell hypertrophy and 

hyperplasia in rats exposed to 45 mg/kg/day α-HCH for 24–48 weeks. Hypertrophied liver cells were 

reported in mice fed 18 mg/kg/day α-HCH and 45 mg/kg/day β-HCH for 24 weeks (Ito et al. 1973), and 

hepatomegaly was reported in mice exposed to 90 mg/kg/day in the diet for 50 weeks (Tryphonas and 

Iverson 1983). Liver cancer has also been reported in mice given 18–90 mg α-HCH/kg/day for 16– 

36 weeks (Hanada et al. 1973; Ito et al. 1973, 1976; Nagasaki et al. 1975; Tsukada et al. 1979) (see 

Section 3.2.2.8). Long-term exposure to lower doses of α-HCH was reported to result in fatty 

degeneration and focal necrosis in rats exposed to 56–64 mg/kg/day for 107 weeks (Fitzhugh et al. 1950), 

and liver cancer was reported in rats administered 50 mg/kg/day in the diet for 72 weeks (Ito et al. 1975). 

Significant increases in liver weight and in the levels of hepatic cytochrome P-450, triglycerides, 

phospholipids, and cholesterol were observed in rats administered 90 mg/kg/day β-HCH in the diet for 

2 weeks (Ikegami et al. 1991a, 1991b); decreases in cytochrome c reductase activity were also reported. 

Intermediate and chronic exposure to β-HCH in the diet is also associated with liver effects in animals. A 
HEXACHLOROCYCLOHEXANE 82 

3. HEALTH EFFECTS 

dose-dependent increase in liver weight was noted in rats exposed for 13 weeks to 0.18–4.5 mg 

β-HCH/kg/day; the increase was significant at doses of >1 mg/kg/day (Van Velsen et al. 1986). Liver cell 

hypertrophy was reported in rats fed 25 or 50 mg/kg/day in the diet for 24 or 48 weeks (Ito et al. 1975). 

In mice, exposure to 45 mg/kg/day for 24 weeks resulted in liver cell hypertrophy (Ito et al. 1973), and 

exposure to 54–57 mg/kg/day for 32 weeks resulted in hepatic foci of degeneration (Hanada et al. 1973). 

β-HCH was not found to be carcinogenic in rats or mice exposed for 24–48 weeks (Hanada et al. 1973; 

Ito et al. 1975). Chronic exposure to lower doses of β-HCH resulted in fatty degeneration and necrosis in 

the liver of mice fed 56–64 mg/kg/day for 107 weeks (Fitzhugh et al. 1950), and Thorpe and Walker 

(1973) reported liver cancer in mice fed 34 mg/kg/day for 26 months. 

Liver hypertrophy was observed in rats fed with 45 mg/kg/day of α-, β-, or δ-HCH in the diet for 24 or 

48 weeks (Ito et al. 1975) and in mice fed 18 mg/kg/day α-HCH in the diet for 24 weeks (Ito et al. 1973). 

The toxicity of ingested δ-HCH has not been investigated following chronic exposure. 

Technical-grade HCH was reported to cause increases in liver weight and enzymatic activity (e.g., 

alkaline phosphatase, aminotransferases) in male Swiss mice given 72 mg/kg in the diet for 2 weeks 

(Ravinder et al. 1989). The same dosing regime also caused significantly increased serum triglycerides, 

phospholipids, and cholesterol, as well as hypertrophy of hepatocytes with enlargement of nuclei, 

centrilobular degeneration, and focal necrosis (Ravinder et al. 1990). Statistically significant decreases in 

the liver activity of glutamic oxaloacetate transaminase (GOT), also known as aspartate 

aminotransferease (AST), and lactate dehydrogenase (LD) were observed in pregnant mice administered a 

single dose of technical-grade HCH (5 mg/kg) on gestation day 9 (Dikshith et al. 1990). Pregnant mice 

dosed with 25 mg/kg technical-grade HCH experienced a statistically significant decrease in glutamic 

pyruvic transaminase (GPT), also known as alanine aminotransferase (ALT), and alkaline phosphatase 

(AP) activity. Virgin mice administered a single dose of 5–200 mg/kg technical-grade HCH had 

statistically significant decreases in liver activity of ALT and AST. Statistically significant increases in 

liver AP activity were observed in the virgin mice administered 25–200 mg/kg technical-grade HCH. 

However, with the exception of AST activity in pregnant mice, the dose response relationships were 

questionable (Dikshith et al. 1990). There were also no corresponding pathological changes in the liver. 

Similar effects were seen in male, but not female, rats given 5 or 25 mg/kg/day by gavage for 90 days 

(Dikshith et al. 1991b). A 65% decrease in liver weight, decreased liver aspartate aminotransferase and 

lactate dehydrogenase activities, and increased alkaline phosphatase activity were noted in male rats given 

60 mg/kg by gavage for 30 days, but animals had normal liver histology (Dikshith et al. 1989a). 

However, enlargement of hepatocytes, nuclear pyknosis, margination, and vacuolation were observed in 
HEXACHLOROCYCLOHEXANE 83 

3. HEALTH EFFECTS 

rats fed 20 mg/kg/day technical-grade HCH in the diet for 360 days (Dikshith et al. 1991a). No adverse 

hepatic effects were seen in rats treated with 50 mg/kg/day technical-grade HCH for 30 days (Khanna et 

al. 1990). 

Technical-grade HCH was reported to deplete the hepatic vitamin A content in male rats fed a diet 

containing 90 mg/kg/day HCH for 7 weeks (Joseph et al. 1992b). Pronounced fatty degeneration and 

necrosis of the liver were found in rats exposed to 56–64 mg/kg/day of technical-grade HCH for 

107 weeks (Fitzhugh et al. 1950). Mice treated daily with 50 mg/kg/day technical-grade HCH for 1, 5, or 

15 days by oil gavage exhibited congestion of hepatic portal vessels and central vein, swollen hepatic 

cells with vacuolar or parenchymatous degeneration, and fatty changes in periportal and centrilobular 

cells (Philip et al. 1989). Mice fed diets containing 90 mg/kg/day of HCH for 8 months exhibited 

increased liver weight, glycogen accumulation, and decreased glucose-6-phosphatase and fructose-1,6-diphosphatase activities (Karnik et al. 1981). Technical-grade HCH was also reported to cause liver cancer 

in mice following exposure to 90 mg/kg/day in the diet for 2–8 months (Karnik et al. 1981; Thakore et al. 

1981) or exposure to 10–50 mg/kg/day for 80–88 weeks (Kashyap et al. 1979; Munir et al. 1983) (see 

Section 3.2.2.8). 

Based on the occurrence of hepatic effects in rats and mice exposed to β-HCH, an intermediate MRL of 

0.0006 mg/kg/day has been calculated from the LOAEL of 0.18 mg β-HCH/kg/day (Van Velsen et 

al. 1986), as described in the footnote in Table 3-3. 

An MRL of 0.008 mg/kg/day has been derived for chronic-duration oral exposure to α-HCH, based on a 

NOAEL of 0.08 mg/kg/day for hepatic effects in female rats (Fitzhugh et al. 1950). 

Renal Effects. Progressive renal failure was seen in a woman who died 11 days after intentionally 

ingesting 8 ounces of a 20% γ-HCH solution (Sunder Ram Rao et al. 1988). The myoglobin release 

resulting from muscle lysis in this case led to kidney shutdown, which was the ultimate cause of death. 

Male Fischer-344 rats receiving gavage doses of 10 mg/kg/day of γ-HCH for 4 days showed 

α-2μ-globulin staining in the kidney cortex. Histopathological changes in the proximal tubule epithelial 

cells included accumulation of protein droplets, hypertrophy and necrosis, pyknotic nuclei, cellular 

exfoliation, and regenerative epithelium (Dietrich and Swenberg 1990, 1991). These effects did not occur 

or were seen to a very slight extent in Fischer-344 male controls, Fischer-344 female exposed rats, or 

exposed NBR rats (a strain that does not synthesize α-2μ-globulin). These results indicate that damage to 
HEXACHLOROCYCLOHEXANE 84 

3. HEALTH EFFECTS 

male rat kidneys by γ-HCH may be caused by α-2μ-globulin, a protein that is not present in humans. 

Thus, it is unlikely that humans are at risk for developing this type of pathology from γ-HCH (EPA 

1991a). Other biochemical changes indicative of kidney injury, such as significantly increased excretion 

of glucose in urine, and histological changes, such as hypertrophy and degeneration of the renal tubular 

epithelia, were observed in Wistar rats exposed to 72 mg/kg/day of γ-HCH for up to 2 weeks (Srinivasan 

and Radhakrishnamurty 1988; Srinivasan et al. 1984). 

However, no renal effects other than significantly increased kidney weight were observed in rats exposed 

to up to 5–50 mg γ-HCH/kg/day in the diet for up to 40 days (Desi 1974); histological examination of the 

kidney did not reveal any changes. Slight kidney damage (calcified tubular casts) was reported in rats 

exposed to 9–10 mg γ-HCH/kg/day for an average of 39.7 weeks (Fitzhugh et al. 1950); the results of this 

study are limited by poor survival in control and treated animals at all doses. Male rats exposed for 

2 years to γ-HCH in their diet exhibited hyaline droplets in the renal proximal tubules at 0.07 mg/kg/day, 

and pale kidneys, increased kidney weights and urine volumes, and higher urinary protein excretions and 

tubular necrosis at 7 mg/kg/day (Amyes 1990). Hyaline droplet formation also occurred in a dosedependent manner in rats treated with 0.02–10 mg γ-HCH/kg/day in their diets for 12 weeks (Suter 1983). 

Dose-dependent incidents of renal tubular distension and degeneration were seen in this study beginning 

at a dose of 2 mg γ-HCH/kg/day. 

Fitzhugh et al. (1950) reported kidney damage (nephritis and basal vacuolation) in rats fed 72–80 mg 

α-HCH/kg/day for an average of 35.9 weeks; no such effects were observed in rats fed 5 mg/kg/day. Poor 

survival was noted in both control and treated animals. 

Renal effects have also been noted in rats exposed to β-HCH in the diet. Srinivasan et al. (1984) reported 

significantly increased excretion of glucose in urine and increased excretion of creatinine and urea as well 

as hypertrophy and degeneration of the renal tubular epithelia in rats exposed to 72 mg β-HCH/kg/day for 

up to 2 weeks. Van Velsen et al. (1986) reported significantly increased kidney weights in female rats 

exposed to 0.18 mg β-HCH/kg/day for 13 weeks; males did not show a significant increase until they 

were exposed to a dose of 4.5 mg/kg/day. At 22.5 mg/kg/day, both males and females exhibited renal 

calcinosis in the outer medulla; however, the female controls also exhibited calcinosis. The study authors 

noted that renal calcinosis is common in female rats but that this finding was of significance in males 

(Van Velsen et al. 1986). Fitzhugh et al. (1950) also examined the renal effects of exposure to β-HCH in 

rats that died after an average of 4.4 weeks and found nephritis and basal vacuolation similar to that 
HEXACHLOROCYCLOHEXANE 85 

3. HEALTH EFFECTS 

described in rats exposed to α-HCH; poor survival due to unspecified causes was reported in both control 

and treated animals. 

Nephritis, pigmentation, and basal vacuolation were also observed in rats fed 56–64 mg technical-grade 

HCH/kg/day (64% α-HCH, 10% β-HCH, 13% γ-HCH, 9% δ-HCH, and 1.3% ε-HCH) in the diet for an 

average of 32.9–64.6 weeks (Fitzhugh et al. 1950); poor survival (for which there was no explanation) 

was noted in both control and treated animals. Tubular necrosis and glomerular degeneration was seen in 

animals exposed for 360 days to 20 mg/kg/day of technical-grade HCH (Dikshith et al. 1991a), but no 

renal effects were seen in rats exposed to 60 mg/kg/day technical-grade HCH for 30 days by oil gavage 

(Dikshith et al. 1989a). Mice treated daily with 50 mg/kg/day technical-grade HCH for 1, 5, or 15 days 

by oil gavage exhibited congestion of blood vessels and glomerular tufts, swollen tubules with hyaline 

casts, cystic dilation, fatty changes, some interstitial hemorrhaging in the medulla, and epithelial cell 

vacuolation (Philip et al. 1989). No adverse effects were seen in rats treated with 50 mg/kg/day technicalgrade HCH for 30 days (Khanna et al. 1990). 

Endocrine Effects. No studies were located regarding endocrine effects in humans following oral 

exposure to HCH. 

The endocrine effects of γ-HCH were reported in ewe lambs (Beard and Rawlings 1999) and young rams 

(Beard et al. 1999a) given 1 mg/kg/day in treated feed from conception to sexual maturity. In ewes, 

effects included increased pulse frequency of serum luteinizing hormone, slower increase and earlier 

decrease of progesterone levels, and lower T4 levels. In young rams, observed endocrine effects included 

lower serum luteinizing hormone and estrodiol concentrations. While serum testosterone levels were 

similar across treatment groups, the γ-HCH treated rams showed attenuated testosterone response to 

stimulation with gonadotropin releasing hormone. 

Body Weight Effects. No studies were located regarding body weight effects in humans following 

oral exposure to HCH. 

Significantly decreased body weight gain has been seen in rats treated orally with 800 ppm α-HCH 

(Fitzhugh et al. 1950), 250 mg/kg β-HCH (Fitzhugh et al. 1950; Van Velsen et al. 1986), 40 mg/kg/day 

γ-HCH (Fitzhugh et al. 1950; Laws et al. 1994), and 3 or 20 mg/kg/day technical-grade HCH (Gautam et 

al. 1989; Nagaraja and Desiraju 1994). 
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Metabolic Effects. No studies were located regarding metabolic effects in humans following oral 

exposure to HCH. 

Increased phosphoinositide turnover and generation of second messengers from phosphoinositides were 

seen in erythrocyte membranes from female rats treated by gavage with a single dose of 100 mg/kg 

technical-grade HCH, or with doses of 5 mg/kg/day technical-grade HCH for 3–6 months, 5 days/week 

(Agrawal et al. 1995). The latter exposure regime also resulted in a significant decrease in 

phosphatidylinositol, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-bisphosphate in 

erythrocyte membrane and cerebrum; the levels decreased with increased time of treatment (3–6 months). 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological or lymphoreticular effects in humans following oral 

exposure to HCH. 

Some evidence of possible immunotoxic effects of γ-HCH is available from acute- and intermediateduration studies in animals. Dose-related decreases in thymus and spleen weights were observed in mice 

gavaged with 10–20 mg/kg/day γ-HCH for 10 days and decreased thymus weight was observed in mice 

gavaged with 20–40 mg/kg/day γ-HCH for 3 days (Hong and Boorman 1993). Immunosuppression, as 

measured by decreased agglutinin titers against typhoid vaccine and Salmonella vaccine, was reported in 

rats exposed by gavage to 6.25 and 25 mg γ-HCH/kg/day for 5 weeks (Dewan et al. 1980) and in rabbits 

exposed by capsules 5 times each week to 1.5, 6, and 12 mg/kg/day for 5–6 weeks (Desi et al. 1978). 

Humoral immune response, as indicated by serum antibody response to injected sheep red blood cells 

(SRBC), was suppressed in rats that were exposed to γ-HCH in estimated dietary doses of 3.6 or 

7 mg/kg/day for 8 weeks (Koner et al. 1998). The primary antibody response to SRBC was also 

suppressed in albino mice after exposure to 9 mg/kg/day γ-HCH in the diet for 12 weeks (Banerjee et al. 

1996). Suppression of secondary antibody response was also observed after 3 weeks of exposure to 

9 mg/kg/day γ-HCH and after 12 weeks of 5.4 mg/kg/day γ-HCH exposure. Decreased lymphoproliferative responses to mitogens were seen in mice exposed to 60 mg/kg/day β-HCH in the diet for 

30 days (Cornacoff et al. 1988). There were no associated changes in immunoglobulins, red blood cell 

counts, or histology of the thymus, spleen, or lymph nodes. Cortical atrophy of the thymus was observed 

in rats fed 22.5–25 mg/kg/day β-HCH (Van Velsen et al. 1986). A biphasic dose-dependent 

immunological effect of γ-HCH on components of cell- and humoral-mediated immunity, characterized 

by initial stimulation followed by immunosuppression, was reported in mice fed 0.012, 0.12, or 1.2 mg 
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3. HEALTH EFFECTS 

γ-HCH/kg/day for 24 weeks (Meera et al. 1992). In addition, histological examinations revealed 

decreased lymphocyte populations in the thymus and lymph nodes and a reduction in overall cellularity in 

the spleen and necrosis of the thymus at 1.2 mg/kg/day. Cell-mediated immune response, as measured by 

delayed type hypersensitivity reaction to dinitroflurobenzene antigen, was suppressed in sheep that were 

exposed to 1.25 ppm γ-HCH in the diet for 6 months (Khurana et al. 1999). The LOAEL values for 

immunological effects are recorded in Tables 3-2 and 3-3 and plotted in Figures 3-2 and 3-3. 

Based on immunological effects of γ-HCH on components of cell- and humoral-mediated immunity in 

mice, an intermediate MRL of 1x10-5 mg/kg/day has been calculated from the LOAEL of 0.012 mg 

γ-HCH/kg/day (Meera et al. 1992), as described in the footnote in Table 3-2. 

3.2.2.4 Neurological Effects 

In humans, the most commonly reported effects associated with oral exposure to γ-HCH are neurological. 

Most of the information is from case reports of acute γ-HCH poisoning. No studies were located 

regarding neurological effects in humans following long-term ingestion of α-, β-, γ-, or δ-HCH. Seizures 

and convulsions have been observed in individuals who have accidentally or intentionally ingested 

γ-HCH in insecticide pellets, liquid scabicide, or contaminated food (Davies et al. 1983; Harris et al. 

1969; Munk and Nantel 1977; Nordt and Chew 2000; Powell 1980; Starr and Clifford 1972; Storen 

1955). Several case studies of acute γ-HCH exposure to children ingesting liquid scabicide report similar 

neurological effects, including vomiting, tremors, and tonic/clonic seizures (Aks 1995; Lifshitz et al. 

2002; Wheeler 1977). In these cases, the affected children returned to normal health in 6–48 hours 

following exposure. In most cases, exposure to γ-HCH was inferred from the presence of γ-HCH in the 

urine or blood. Also, the actual amount of γ-HCH ingested could not be determined because the γ-HCH 

was present in solution or in pellets in which other substances were present. Liquid scabicide has been 

reported to contain approximately 1% γ-HCH (Davies et al. 1983; Powell 1980). 

Neurotoxic effects have been reported in several species of animals exposed to γ-HCH. The most serious 

effects were seizures following a single intragastric administration of approximately 15–60 mg/kg in rats 

(Martinez and Martinez-Conde 1995; Martinez et al. 1991; Tilson et al. 1987; Tusell et al. 1987; Vendrell 

et al. 1992a, 1992b; Woolley and Griffith 1989). Less-serious effects in rats included increased anxiety 

following a single gavage dose of 20 mg/kg (Llorens et al. 1990b) and increased spontaneous motor 

behavior observed at 10 mg/kg (Llorens et al. 1989). 
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Kindling, the induction of seizures with repeated application of subthreshold electrical or chemical stimuli 

to the brain, has been used as a method of investigating neurological response to HCH poisoning. A 

single oral dose of 5–20 mg γ-HCH/kg to rats previously kindled by electrical stimulus produced 

incidences of myoclonic jerks and clonic seizures, which increased in a dose-dependent manner (Gilbert 

and Mack 1995). Nonkindled animals displayed these symptoms at a dose of 10 mg γ-HCH/kg. 

Enhanced susceptibility to kindled seizures brought on by electrical stimulation was seen in rats exposed 

for 10 weeks to 10 mg γ-HCH/kg/day, 3 days/week (Gilbert 1995). Increased rates of acquisition of 

kindled seizures were observed following dosing of rats with 3–10 mg γ-HCH/kg/day for 4 days (Joy et 

al. 1982). 

Epileptiform seizures have been reported in male rats fed milk, from dams that were gavaged with 20 mg 

γ-HCH/kg, on postnatal days 3–15 (Albertson et al. 1985). These data suggest that γ-HCH can be 

transferred in the dam’s milk and can elicit neurological effects in offspring. It is not possible to 

determine the doses received by the pups. Avoidance response latency was statistically increased in rats 

administered a single dose of 15 mg/kg by gavage (Tilson et al. 1987). Acquisition of a passive 

avoidance task was improved in 15-day-old rat pups that were treated with non-convulsant levels of 

γ-HCH by gavage as either a single 20 mg/kg dose or 7-day repeated 10 mg/kg/day doses, although 

changes in motor activity and brain monoaminergic levels (e.g., ratios of 5-HIAA/serotonin and 

DOPAC/dopamine) depended on the treatment schedule (Rivera et al. 1998). No clinical signs of 

behavioral effects were seen in suckling Wistar rats treated once with 20 mg/kg γ-HCH by gavage at 

postnatal days 8, 15, 22, or 29, although regional changes in brain noradrenaline and serotonin were seen, 

with differential effects depending on age at the time of exposure (Rivera et al. 1991). 

Changes in levels of brain norepinephrine (Rivera et al. 1991) and serotonin (Attia et al. 1991; Rivera 

et al. 1991) have also been reported in rats administered acute oral doses of γ-HCH. Decreased dopamine 

levels were seen in rats treated by gavage with 10 doses totaling 60 mg γ-HCH/kg (half the LC50) over a 

period of 30 days (Martinez and Martinez-Conde 1995). Increase in the levels of brain catecholamines, 

particularly norepinephrine and dopamine, and associated signs of toxicity such as mild tremor, 

lacrimation, salivation, and dysnea were observed in female rats given oral doses of 100 mg/kg/day of 

technical-grade HCH for 7 days (Raizada et al. 1993). The activity of monoamine oxidase (MAO) in the 

cerebrum showed a marginal decrease, while the cerebellum and spinal cord indicated a significant 

increase and decrease in MAO, respectively. Rats treated with 20 mg technical-grade HCH/kg/day in 

food for 90 days exhibited increased γ-aminobutyric acid (GABA) levels, increased glutamate 

decarboxylase (GAD) activity, and decreased glutamate levels in the brain (Nagaraja and Desiraju 1994). 
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No significant changes were seen in lipid peroxidation in brain tissue from rats treated for 90 days with 

90 mg γ-HCH/kg/day in food, indicating that the tonic convulsions observed throughout the exposure 

period were probably not brought on by oxidative stress in the brain (Arisi et al. 1994). Decreased myelin 

basic protein was observed in rats exposed to 5 mg/kg/day by gavage for 3 days (Serrano et al. 1990a). 

The neurotoxicity of γ-HCH has also been assessed in acute, subchronic, and developmental exposure 

screening batteries in rats (Hughes 1999a, 1999b; Myers 1999). In the acute study, a single 0, 6, 20, or 

60 mg/kg dose of γ-HCH was administered to Crl:CDBR rats (Hughes 1999a). End points included 

functional observational battery (FOB) and motor activity (MA) tests performed prior to treatment, within 

3 hours of dosing (time of peak effect), and on post-exposure days 7 and 14, as well as histopathology of 

nervous system tissues at study termination. No clinical signs or other effects were observed at 6 mg/kg. 

Exposure to 20 mg/kg caused decreased motor activity 3 hours post-treatment in females at ≥20 mg/kg 

and in males at 60 mg/kg. Females also had increased forelimb grip strength and decreased grooming 

behavior at 20 mg/kg, and an absence of grooming behavior at 60 mg/kg. Other effects at 60 mg/kg, 

included clinical signs (e.g., piloerection, urine-stained fur, tremors, and/or convulsions) in both sexes and 

increased hindlimb foot splay in males. Gavage administration of 2.5, 5, 10, or 15 mg γ-HCH/kg/day for 

5 days produced a dose-dependent increase in the activities of EROD, PROD, and NDMA-d in the brain 

of Wistar rats (Parmar et al. 2003). Compared with the liver, the magnitude of the induction of the P-450 

enzymes in the brain was much smaller. In the same study, Parmar et al. (2003) examined the effect of 

metabolism on the convulsive effect of γ-HCH in rats. A single dose of 35 mg/kg of γ-HCH induced 

convulsions in 4 out of 10 animals. Pretreatment of the rats with 3-methylcholanthrene (MC), an inducer 

of P-4501A1/1A2, had no significant effect in the incidence of convulsions induced by γ-HCH. However, 

pretreatment with phenobarbitol (PB), an inducer of P-4502B1/2B2, or ethanol, an inducer of P-4502E1, 

or blocking P-450-mediated metabolism with cobalt chloride, significantly increased the incidence of 

convulsions caused by γ-HCH. Taken together, the results suggest that the convulsive activity is due to 

γ-HCH per se and/or to metabolites formed by PB- or ethanol-inducible P-450 isoenzymes. 

In the subchronic neurotoxicity screening battery, Crl:CDBR rats were exposed to 0, 20, 100, or 500 ppm 

γ-HCH in the diet for 13 weeks (Hughes 1999b). Due to severe toxicity, the high concentration was 

reduced to 400 ppm on day 11. Reported average daily intake levels of γ-HCH for the entire study were 

0, 1.4, 7.1, and 28.1 mg/kg/day for the males and 0, 1.6, 7.9, and 30.2 mg/kg/day for the females. End 

points included FOB and MA tests performed prior to administration and after 4, 8, and 13 weeks of 

treatment, and histopathology of nervous system tissues at study termination. No clinical signs or other 

changes were observed in females at 1.6 mg/kg/day or males at ≤7.1 mg/kg/day. Effects in females at 
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3. HEALTH EFFECTS 

7.9 mg/kg/day included decreased body weight gain and food consumption (40 and 16% lower than 

controls, respectively, during the first week). Both systemic and neurotoxic effects occurred in both sexes 

at the high dose, including clinical signs (e.g., staining of urogenital region, piloerection, abnormal 

grooming behavior), increased rearing, walking on tiptoes, hypersensitivity to touch, hunched posture, 

weight loss, and several deaths. 

In the developmental neurotoxicity study, Han Wistar rats were exposed to 0, 10, 50 or 120 ppm γ-HCH 

in the diet from gestation day 6 through lactation day 10 (Myers 1999). Reported daily maternal dose 

levels were 0, 0.8–0.9, 4.2–4.6, or 8.0–10.5 mg/kg/day during gestation, and 0, 1.2–1.7, 5.6–8.3, or 13.7– 

19.1 mg/kg/day during lactation. The F1 offspring were evaluated for FOB, motor activity, auditory 

startle response, learning and memory, developmental landmarks (e.g., vaginal perforation and 

balanopreputial separation), and brain end points (weight, histology, and morphometrics) on postpartum 

days 11 and 65. Maternal toxicity occurred at 13.7 mg/kg/day as shown by effects that included 

decreased body weight gain (64–79% less than controls on gestation days 6–20), decreased food 

consumption, and increased reactivity to handling. The offspring showed effects at the two highest dose 

levels, including increased motor activity (both sexes), decreased habituation of motor activity (females), 

decreased body weights (12–20% less than controls), and decreased body weight gains (60–84% less than 

controls) during lactation days 1–11 (both sexes) at ≥5.6 mg/kg/day. Effects observed at 13.7 mg/kg/day 

included reduced auditory startle response habitation in both sexes, increased stillbirths (live birth index 

of 77% compared to 99% in controls), and increased neonatal mortality (postnatal day 4 viability index of 

71% compared to 89% in controls). This study was classified as an unacceptable developmental 

neurotoxicity study by EPA (2000) because there was no laboratory validation of the neurobehavioral 

tests and the number of animals (six per dose level) was insufficient. 

There is evidence that γ-HCH exposure causes functional impairment of the developing blood brain 

barrier (BBB) in young rats (Gupta et al. 1999). The integrity (permeability) of the BBB was studied by 

assessing uptake of sodium fluorescein (a micromolecular tracer dye) into the brain of neonatal rats 

following single or repeated acute gavage doses of γ-HCH. The brain uptake index of fluorescein was 

significantly increased in 10-day-old pups treated with a single 2 mg/kg dose (72 and 23% higher than 

controls after 2 hours and 3 days, respectively), as well as in those treated with 2 mg/kg/day for 8 days 

(50% higher than controls 7 days after the first exposure, with recovery 20 days after the first exposure). 

The effect appeared to be age-related because the brain uptake index was lower when rats were 

administered a single 2 mg/kg dose at 15 days of age (20% higher than controls after 2 hours) or a higher 

dose of 4 mg/kg/day for 3 days as adults (no effect on brain permeability). 
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Longer exposures to lower doses of γ-HCH were reported to result in significantly altered Skinner box 

behavior (operant conditioning) in a small number of rats exposed to 2.5 mg/kg/day for 40 days (Desi 

1974), and significantly decreased nerve conduction velocity in rats exposed to 25.4 mg/kg/day for 

30 days (Muller et al. 1981). The latter study did not examine any behavioral parameters. 

Similar neurological effects have not been reported in animals treated with α-HCH. Muller et al. (1981) 

reported no delay in tail nerve conduction velocity in rats fed 5.1, 54.2, or 106.2 mg α-HCH/kg/day for 

30 days. However, neurological effects have been reported in rats exposed to β-HCH. Mice treated with 

57 or 190 mg/kg/day β-HCH for 30 days developed ataxia within 1 week of treatment (Cornacoff et al. 

1988). Muller et al. (1981) reported a significant delay in tail nerve conduction velocity in rats fed 

66.3 mg β-HCH/kg/day for 30 days. An acute-duration oral MRL of 0.05 mg/kg/day was derived based 

on a NOAEL of 4.5 mg/kg/day for ataxia, progressive inactivity, and coma in male rats exposed to 25 mg 

β-HCH/kg/day for 2 weeks (Van Velsen et al. 1986). 

Behavioral and neurochemical changes were evaluated in rats that were administered technical-grade 

HCH in doses of 10 or 20 mg/kg/day in oil by gavage for 7–30 days (Sahoo et al. 1999). Assessment of 

open-field behavior (horizontal motor activity, vertical exploratory rearing, and grooming activities) and 

brain biochemistry (ATPases and acetylcholinesterase) showed effects that included reduced brain total 

ATPase and Na+

-, K+-, and/or Mg2+-ATPase activities after 7–30 days at ≥10 mg/kg/day, reduced brain 

acetylcholinesterase activity after 15 and 30 days at 20 mg/kg/day, increased motor activity after 7 days at 

20 mg/kg/day, and reduced grooming behavior after 30 days at 20 mg/kg/day. Increase motor activity 

was also observed in rats exposed to technical-grade HCH at a level of 50 mg/kg/day for 120 days (Gopal 

et al. 1992). Alterations in neurotransmitter levels, increased brain wave frequency, and behavioral 

changes were reported in male rats administered 50 mg/kg/day technical-grade HCH by gavage for 1 or 

3 months (Anand et al. 1991b). Exposure to 0.4 mg/kg/day technical-grade HCH for 360 days resulted in 

convulsions, tremors, and paralysis in male rats after 270 days, although the number of animals affected 

or the severity of the symptoms were not reported (Dikshith et al. 1991a). This study also found 

degeneration of the cerebellum and cerebellar cortex in animals sacrificed after a 1-year exposure to 

20 mg/kg/day. Seizures were noted in mice exposed to technical-grade HCH through feed or gavage at 

levels of 10–17 mg/kg/day in the feed for 80 weeks (Kashyap et al. 1979). 
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3.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans following oral exposure to HCH. 

Increased length of estrous cycle and decreased sexual receptivity were found in female rats treated with a 

single dose of γ-HCH (25 mg/kg) given by gavage (Uphouse and Williams 1989). Inhibition of the 

formation of estradiol-receptor complex in the rat uterus cytosol was reported in female rats administered 

30 mg γ-HCH/kg/day by oral intubation for 7 days (Tezak et al. 1992). Female mink treated with 

1 mg/kg/day γ-HCH in their diet from 3–6 weeks before mating until weaning at 8–10 weeks postpartum 

showed effects on reproductive efficiency that included reduced receptivity to a second mating and 

reduced whelping rate, although litter size was not affected (Beard et al. 1997). This decreased fertility 

effect was primarily a result of embryo mortality after implantation. Mouse dams treated with γ-HCH 

(6.2 mg/kg) during gestation period days 6–12 had increased numbers of resorbed fetuses (Sircar and 

Lahiri 1989). A lack of implantation sites and pups death were observed following treatment with 

10.8 mg/kg/day on gestation days 1–4 and 3.6 mg/kg/day on gestation days 14–19, respectively. 

Statistically significant increases in the glycogen content of the uterus, cervix, and vagina (but no increase 

in organ weight) were reported in female rats exposed to 20 mg γ-HCH/kg/day in the diet for 30 days 

(Raizada et al. 1980). Antiestrogenic properties were found in female rats given oral gavage doses of 

10 mg/kg/day γ-HCH for 15 weeks (Chadwick et al. 1988). These responses were not seen at 

5 mg/kg/day. Ovariectomized rats exposed for 5 days and sexually immature female rats exposed for 

7 days to 40 mg γ-HCH/kg/day showed no effects on the number of estrogen and estrogen-dependent 

progesterone receptors (Laws et al. 1994). Thus, γ-HCH's antiestrogenic effects in reproductive tissue do 

not appear to be due to direct action on estrogen receptors or its induction of progesterone receptors. 

Acute preovulatory exposure to γ-HCH caused embryonic effects in mice (Scascetelli and Pacchierotti 

2003). Three consecutive daily doses of γ-HCH in olive oil were administered to female mice either 

before mating (during the preovulatory period) or immediately after mating. Oocyte maturation, 

ovulation, and fertilization were evaluated by assessing percentage of vaginal plug positive females, 

number of embryos/female, percentage of one-cell embryos (corresponding to unfertilized oocytes or 

zygotes that did not undergo cleavage), and gross morphologic alterations of two-cell embryos. 

Preimplantation embryonic development was evaluated by morphological examinations of morulae for 

determinations of one-cell embryos (unfertilized eggs or zygotes that did not undergo cleavage), embryos 

retarded in their cleavage, and abnormal embryos, as well as by cytological examinations of morulae for 

determinations of interphase nuclei, meta-anaphases, apoptotic nuclei, micronuclei, and mitotic index. 
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Preovulatory exposure caused a significant increase of degenerating two-cell embryos (lysis or 

fragmentation of blastomeres), but there were no exposure-related effects of post-fertilization treatment. 

Female rabbits exposed to 0.8 mg γ-HCH/kg/day, 3 days/week for 12 weeks, had a reduced ovulation rate 

(Lindenau et al. 1994). However, rabbits given the same treatment regime followed by artificial 

insemination exhibited no effects on the fertilization rate or on pre- or postimplantation losses (Seiler et 

al. 1994). 

Gavage administration of 15 mg γ-HCH/kg/day (only dose tested) in corn oil to pregnant CD-1 mice on 

gestational days 9–16 did not affect the relative or absolute weights of the uterus, ovaries, or mammary 

gland, monitored on postnatal day 23 (Maranghi et al. 2003). Microscopic examination of sections from 

these organs showed no significant treatment-related alterations. Female offspring from treated mice 

exhibited a slight increase (4.3%) in relative uterus weight when sacrificed on postnatal day 60. In 

addition, earlier vaginal opening (2 days) and increased branching of villi and oedema in the endometrial 

stroma was observed in the offspring from treated mice when compared to controls. Neither the ovary 

nor mammary glands from female offspring showed significant alterations (Maranghi et al. 2003). 

In male rats, oral administration of 6 mg/kg for 5 days or a single dose of 30 mg/kg of γ-HCH resulted in 

a reduction in the number of testicular spermatids and epididymal sperms of both treated groups 2 weeks 

after treatment (Dalsenter et al. 1996). γ-HCH was detected in the testes of both groups 24 hours and 

2 weeks after the last treatment. Histological examination by electron microscopy revealed ballooning of 

the Sertoli cells with fragmentation or loss of organelles. Similarly, Shivanandappa and Krishnakumari 

(1983) reported testicular atrophy, degeneration of seminiferous tubules, and disruption of 

spermatogenesis in male rats fed 75 mg γ-HCH/kg/day for 90 days. Significant reductions in the relative 

weight of testicles and epididymis, spermatid and sperm counts, and testosterone levels were observed in 

pubescent or adult rats fed milk as neonates from dams gavaged with 6 mg/kg γ-HCH on lactation day 

9 or 14 or 1 mg/kg γ-HCH on lactation days 9–14 (Dalsenter 1997b). Histopathological observations 

included a reduction in Leydig cell numbers and spermatogenesis, but fertility, as measured by 

impregnation of female rats, was unaffected. The results of another study with γ-HCH, reported only as 

an abstract, indicate that the male reproductive system may be a particularly sensitive target of toxicity in 

rats (Pages et al. 2000). Male Sprague-Dawley rats were exposed to γ-HCH in drinking water for 

12 weeks from the beginning of gestation, lactation, or weaning at concentrations that provided estimated 

doses of 0.000075, 0.00015, or 0.0003 mg/kg/day. Body weight gain, plasma testosterone, sperm 

number, and sperm mobility values were approximately 18, 38, 40, and 52% reduced compared to 

controls, respectively, in groups exposed to 0.0003 mg/kg/day during gestation or lactation. The pup rate 
HEXACHLOROCYCLOHEXANE 94 

3. HEALTH EFFECTS 

was normal when treated males were mated with untreated females, although the rate decreased and 

newborn mortality was higher when treated males were exposed to treated females. Given the lack of a 

complete report, the results of this study cannot be regarded as conclusive. 

Effects of prenatal exposure on spermatogenesis were evaluated in adult offspring of mice that were 

administered 15 or 25 mg/kg/day doses of γ-HCH in olive oil by gavage on gestation days 9–16 (Traina et 

al. 2003). F1 offspring were assessed on postnatal day (pnd) 60 (both dose levels) and pnd 100 

(25 mg/kg/day); end points included litter size, growth and sexual maturation indices, and male 

reproductive indices (e.g., sperm number and concentration, testicular biochemistry and histology, and 

testicular cytotoxicity and germ cell damage). Statistically significant effects included testicular 

histological alterations at ≥15 mg/kg/day on pnd 60 (increased number and size of Leydig cells), reduced 

sperm head count (sperm/testis) at ≥15 mg/kg/day on pnd 60, reduced sperm head concentration (sperm/g 

testis) at 25 mg/kg/day on pnds 60 and 100, reduced activities of testicular serum sorbitol dehydrogenase 

(SDH) at ≥ 15 mg/kg/day and lactate dehydrogenase (LDH) at 25 mg/kg/day (only evaluated on pnd 60), 

altered testicular germ cell distribution at 25 mg/kg/day on pnds 60 and 100, and increased number of 

epididymal sperm with chromatin abnormalities at ≥15 mg/kg/day on pnd 60. 

Multigeneration reproduction studies were conducted in rats exposed to technical HCH or γ-HCH (King 

1991; Srivastava and Raizada 2000). In the study with technical HCH, male and female Druckrey rats 

were exposed via diet and drinking water to estimated total daily doses of 0, 16, or 32 mg/kg/day 

throughout three generations (Srivastava and Raizada 2000). Toxicity occurred in the P0 parental animals, 

as shown by effects that included reduced body weight gain in both sexes at ≥16 mg/kg/day, and hepatic 

histopathological changes and some deaths at 32 mg/kg/day. There were no signs of toxicity in the 

subsequent parental generations (F1b or F2b), no exposure-related effects on reproduction in any of the 

three parental generations, and no morphological or teratological changes in any of the offspring 

generations (F1b, F2b, or F3b). In the study with γ-HCH, Charles River CD rats were exposed to estimated 

dietary doses of 0, 0.09, 1.7, or 13.1 mg/kg/day for two generations during the mating periods only (King 

1991). No treatment-related clinical signs of toxicity, effects on body weight or food consumption were 

observed in the F0 or F1 males or females during premating. Body weight gain decreased in the high-dose 

F0 parental females during gestation, however, indicating that systemic toxicity occurred at 

13.1 mg/kg/day. Other indications of systemic toxicity included renal histopathological changes 

characteristic of alpha 2μ globulin accumulation in F0 and F1 males at ≥1.7 mg/kg/day; however, this 

syndrome is specific to male rats and not relevant to humans. No gross or histopathological changes were 

observed in females in either generation. There were no effects on mating, fertility, gestation survival, 
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liveborn indices, or mean litter sizes in either generation, although offspring toxicity occurred at 

13.1 mg/kg/day, as shown by reduced body weight and decreased viability in pups of both generations 

and delayed maturation of F2 pups. Body weights of the high-dose pups of both generations were 

significantly lower than controls on lactation days 1 and 25. Viability indices (survival on lactation day 

4) for the high dose F1 and F2 pups were 81 and 85%, respectively, compared with ≥96% for the controls. 

The onset and completion of tooth eruption and completion of hair growth were 10.5, 11.6, and 24% 

delayed in the high dose F2 pups, respectively, compared to controls. 

A two-generation reproduction study of γ-HCH was also conducted in mink that were exposed to dietary 

doses of 0 or 1 mg/kg/day (Beard and Rawlings 1998). The parental (P0) generation was exposed from 

3 weeks before breeding until weaning of the offspring. Following weaning, the F1 females were exposed 

throughout growth and mating (to untreated males), and subsequently throughout pregnancy and lactation 

until 3 months post-lactation. The F2 females were exposed until they reached full adult body size at 

30 weeks of age. The F1 and F2 males were exposed until the time their testis development was maximal 

(sexual maturity) at about 42 weeks of age. In addition to standard reproductive indices, serum hormone 

levels (estradiol, thyroxine, cortisol, testosterone) and histology, including male and female reproductive 

and endocrine tissues (e.g., thyroid, parathyroid, adrenal, pituitary, and pancreas), were evaluated in 

offspring of both generations. There were no overt signs of toxicity or effects on mating percentage. 

Fertility was reduced in both generations, as shown by reductions in whelping rate and litter size, such 

that exposed mink produced approximately 60% fewer kits than controls. Other effects included reduced 

testis size and serum thyroxine concentration in F2 males. 

Oral exposure to 60 mg β-HCH/kg for 30 days resulted in normal uteri and reproductive cycling in female 

mice (Cornacoff et al. 1988). Atrophy of the ovaries and testes, hyperplastic and vacuolized endometrial 

epithelium, degeneration of the seminiferous tubules, and disruption of spermatogenesis were seen in rats 

exposed to 22.5–25 mg β-HCH/kg/day in the diet for 13 weeks (Van Velsen et al. 1986). Technical-grade 

HCH caused transient changes in testes’ weights and decreased sperm counts in a 7-week study (Pius et 

al. 1990), degeneration of seminiferous tubules and Leydig cells (Roy Chowdhury and Gautam 1990), 

and changes in the muscle layer of the vas deferens (Gautam et al. 1989). None of these studies provide 

adequate evidence for the effects of technical-grade HCH on sperm function in animals or humans. 

Testicular oxidative stress was studied in immature (15-day-old) and mature (90-day-old) rats that were 

administered technical-grade HCH in doses of 10 or 20 mg/kg/day in oil by gavage for 7, 15, or 30 days 

(Samanta et al. 1999). End points that were evaluated included testicular protein and lipid peroxidation, 
HEXACHLOROCYCLOHEXANE 96 

3. HEALTH EFFECTS 

testicular levels of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, 

glutathione reductase) and non-enzymatic antioxidants (reduced glutathione, ascorbic acid, hydrogen 

peroxide), weights of testis and accessory sex organs, and testicular histology including epididymal sperm 

counts and sperm anomalies. Exposure to ≥10 mg/kg/day for 7 days caused effects that included reduced 

epididymis weight in immature rats and reduced seminal vesicle and ventral prostate weights in adult rats. 

Effects observed following exposure to ≥10 mg/kg/day for 7–30 days included reduced total sperm count 

and increased frequencies of damaged sperm and sperm with anomalous heads in adult rats. Testes from 

immature and adult rats exposed to ≥10 mg/kg/day for 7–30 days also showed increased lipid 

peroxidation and changes in glutathione peroxidase, ascorbic acid, and hydrogen peroxide levels. In 

mice, exposure to 90 mg technical-grade HCH/kg/day (isomer composition unknown) for 3 months led to 

increased testicular weight and degeneration of seminiferous tubules (Nigam et al. 1979). Testicular 

degeneration was reported in male rats exposed to 20 mg/kg/day technical-grade HCH in the diet for 

360 days (Dikshith et al. 1991a). A dose-related increase in fetal resorptions was seen in pregnant female 

mice treated once with 25–200 mg/kg technical-grade HCH by gavage on the ninth gestation day 

(Dikshith et al. 1990). 

The reproductive effects of γ-HCH were reported in ewe lambs (Beard and Rawlings 1999) and young 

rams (Beard et al. 1999a) given 1 mg/kg/day in treated feed from conception to sexual maturity. In estrus 

synchronized ewes, treated animals had significantly shorter estrous cycle length and lower number and 

less total volume of corpus lutea. No other detrimental fertility effects were observed. The subjectivelyscored sexual behavior in young rams was significantly reduced in treated animals presented with estrous 

ewes. 

3.2.2.6 Developmental Effects 

In a study of women from India, 30 pregnant women diagnosed with intra-uterine fetal growth retardation 

(IUGR) had higher mean serum levels of γ-HCH (OR=1.38, 95% CI 1.05–1.80), α-HCH (OR=1.22, 95% 

CI 1.02–1.46), δ-HCH (OR=1.61, 95% CI 1.01–2.54), and total HCH (OR=1.07, 95% CI 1.01–1.13) than 

24 mothers of non-IUGR babies after adjusting for potential confounders (Siddiqui et al. 2003). 

Similarly, γ-HCH, δ-HCH, and total HCH cord blood levels of IUGR babies were higher than the cord 

blood levels in the normal-weight babies (OR=1.14, 95% CI 1.00–1.31; OR=1.31, 95% CI 1.00–1.75; and 

OR=1.07, 95% CI 1.00–1.14, respectively) (Siddiqui et al. 2003). Since other organochlorine pestides, 

including DDT and its metabolites, were also present in the blood, the role of HCH, if any, cannot be 

ascertained. In this study, exposure is likely due to consumption of the pesticides in food; however, other 
HEXACHLOROCYCLOHEXANE 97 

3. HEALTH EFFECTS 

environmental contamination pathways, including inhalation and dermal exposure, may be possible routes 

of exposure as well. 

A single oral dose of 25 mg/kg technical-grade HCH caused increased resorptions of the fetus in female 

mice, but fetal development was normal (Dikshith et al. 1990). Srivastava and Raizada (1993) further 

studied the prenatal effect of orally administered technical-grade HCH. While mice exposed to HCH 

during the preimplantation period (days 2–6 of gestation) did not show fetolethality, exposure during the 

postimplantation period (days 6–12 of gestation) to 25 and 50 mg/kg/day HCH produced significant 

increases in resorption of fetuses, inhibition of maternal serum progesterone levels, and higher levels of 

HCH in fetal tissues. Oral exposure to Benesan (a pesticidal formulation containing 50% γ-HCH) given 

at doses of 6.25, 12.5, or 25 mg/kg/day by gavage on days 6–15 of gestation failed to produce teratogenic 

effects in rats (Khera et al. 1979). When minks were treated with 1 mg/kg/day γ-HCH in their diet (Beard 

et al. 1997), the proportion of embryos lost after implantation was increased. A multigeneration study in 

mink exposed to 1 mg/kg/day γ-HCH in the diet observed that testis size was reduced in F3 males, 

although there were no effects on testicular development in the second generation (Beard and Rawlings 

1998). 

Another study of γ-HCH was conducted in which the compound was administered to pregnant mice by 

gastric intubation on day 12 of gestation (Hassoun and Stohs 1996a). At doses of 30 and 45 mg/kg body 

weight in C57BL/6J mice, significant decreases in fetal weight, fetal thymic weight, and placental weight 

were observed. When given to DBA/2J mice at a dose of 45 mg/kg body weight, γ-HCH caused 

significant reductions in fetal and placental weight. No malformations in the fetuses of both strains of 

mice were observed, even though the administered doses caused maternal deaths. Increases in the 

production of lipid metabolites in maternal sera and the amniotic fluids were found to parallel the 

observed fetotoxicities (Hassoun et al. 1996). Superoxide production, lipid peroxidation and DNA-single 

strand breaks were increased in fetal and placental tissues 48 hours after administration of single dose of 

30 mg/kg γ-HCH to pregnant mice on day 12 of gestation (Hassoun and Stohs 1996b). Significant 

increases in lipid peroxidation also occurred in fetal livers collected on day 18 of gestation. Thus, it was 

suggested that fetotoxic effects of γ-HCH may be due to induced oxidative stress, enhanced lipid 

peroxidation, and DNA-single strand breaks in the fetal and placental tissues of mice. 

Developmental/reproductive effects of γ-HCH were studied in male offspring of rats that were exposed 

during lactation (Dalsenter et al. 1997b). Females were treated with γ-HCH in peanut oil by gavage as a 

single 6 mg/kg dose on day 9 or day 14 of lactation, or as daily 1 mg/kg/day doses on days 9–14 of 
HEXACHLOROCYCLOHEXANE 98 

3. HEALTH EFFECTS 

lactation. Male offspring were evaluated on pnd 65 (puberty) or 140 (adulthood) and evaluated for testis 

and epididymis weights, spermatid and sperm numbers, serum testosterone level, sexual behavior at 

130 days of age during mating with unexposed females, reproductive indices (mating, pregnancy and 

fertility), pregnancy end points (numbers of litters, implantations/litters, fetuses/litter, resorptions), and 

testicular histology (6 mg/kg offspring). The 1 mg/kg/day offspring had statistically significant 

reductions in relative testicular weight at pnd 140, relative epididymis weight at pnd 65, spermatid 

number at pnds 65 and 140, sperm number at pnd 140, and serum testosterone at pnd 65. Effects were 

generally similar in type and magnitude in the 6 mg/kg offspring exposed on lactation day 9 or 14. There 

were no significant effects on sexual behavior or fertility in the 1 mg/kg/day or 6 mg/kg offspring. The 

testicular histological examinations of the 6 mg/kg/day offspring showed large areas of normal tissue, 

although some areas had distinct changes ranging from small alterations to a pronounced effect, including 

necrotic changes and reductions in Leydig cell numbers and spermatogenesis. An acute oral MRL of 

0.003 mg/kg/day has been derived for γ-HCH based on the 1 mg/kg/day minimal LOAEL for 

reproductive effects in rats (Dalsenter et al. 1997b). 

An isomer comparison study in rats found that dietary exposure to 25 mg/kg/day of γ-HCH during 

gestation and lactation did not cause developmental effects in pups, whereas 20 mg/kg/day of β-HCH 

during gestation caused increased fetal deaths within 5 days of birth and 5 mg/kg/day of β-HCH during 

gestation and lactation resulted in increased liver weights of pups (Srinivasan et al. 1991a). A doserelated increase in the incidence of fetuses with an extra 14th rib was reported in CFY rats exposed to 5, 

10, or 20 mg/kg γ-HCH by gavage during gestation days 6–15; statistical significance was attained only at 

20 mg/kg (Palmer et al. 1978a). The incidence of fetuses with an extra 13th rib was statistically increased 

in rabbits exposed to 20 mg/kg γ-HCH by gavage during gestation days 6–18 (Palmer et al. 1978a). In 

both rats and rabbits, the incidences of extra ribs were within or just greater than the ranges recorded for 

the control groups, and therefore, may not be sufficient evidence of teratogenicity of γ-HCH. Maternal 

toxicity (reduced body weight gain and food consumption) occurred at doses ≥10 mg/kg/day in the rats, 

but not in rabbits (highest tested dose 20 mg/kg/day). No effects on embryonic development were seen in 

rabbits treated by oral gavage with 0.8 mg γ-HCH/kg, 3 times/week for 12–15 weeks before artificial 

insemination and throughout gestation (Seiler et al. 1994). A two-generation study of γ-HCH was 

conducted in rats exposed to estimated dietary doses of 0, 0.09, 1.7, or 13.1 mg/kg/day (King 1991). As 

detailed in Section 3.2.2.5 (Reproductive Effects), developmental toxicity occurred at 13.1 mg/kg/day, as 

shown by reduced body weight and decreased viability in pups of both generations and delayed 

maturation of F2 pups. 
HEXACHLOROCYCLOHEXANE 99 

3. HEALTH EFFECTS 

Regional changes in brain noradrenaline, serotonin and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) levels were noted in suckling rats treated with 20 mg/kg/day γ-HCH, as a single 

dose (Rivera et al. 1991). Alterations in levels of brain dopamine, serotonin, gamma-aminobutyric acid 

(GABAB), glutamate, glutamate decarboxylase, and noradrenaline were seen in various areas of the brains 

of female rat pups treated with 10 mg technical-grade HCH/kg/day for 60 days (Nagaraja and Desiraju 

1994). 

3.2.2.7 Cancer 

In a study of women from India, blood levels of HCH, and its isomers (α, β, and γ), were found to be 

higher in women with breast cancer when compared to healthy women without the disease (Mathur et al. 

2002). In this study, 135 breast cancer patients and 50 females without cancer filled out questionnaires 

and were evaluated for their body burden of pesticides through blood testing. α- and γ-HCH blood levels 

were significantly higher in breast cancer patients, 41–50 years of age, compared to women of the same 

age without the disease. β-HCH blood levels were significantly higher in breast cancer patients, 31– 

50 years of age, compared to those without the disease (Mathur et al. 2002). Other organochlorine 

pesticides, including DDT and its metabolites, were also present in the blood and could have contributed 

to the incidence of breast cancer. In contrast to the Mathur et al. (2002) findings, there were no positive 

associations between serum levels of β-HCH and incidence of breast cancer in studies of 95 Mexican 

women (Lopez-Carrillo et al. 2002), 150 Norwegian women (Ward et al. 2000), or 240 women from 

Denmark (Hoyer et al. 1998). In addition, Hoyer et al. (1998) did not find an association between serum 

levels of γ-HCH and the incidence of breast cancer. The risk for endometrial cancer was also not 

associated with β-HCH serum concentrations in a study of 90 women from the United States (Sturgeon et 

al. 1998). Levels of β- and γ-HCH in surgically removed breast tissue samples from 65 women in 

Germany were not indicative of malignant breast disease; there was no significant difference between the 

levels of β- and γ-HCH in the breast tissue surrounding malignant and benign breast disease (Guttes et al. 

1998). Exposure to HCH, and other organochlorine pesticides, to the populations of these studies is 

mainly through food where the pesticides are primarily used for agricultural applications; however, other 

possible environmental contamination pathways include inhalation and dermal routes of exposure. 

α-HCH, β-HCH, γ-HCH, and technical-grade HCH have been shown to be liver carcinogens in rats and 

mice; however, in some studies, the liver was the only organ examined. Ito et al. (1973) examined the 

carcinogenicity of HCH isomers in dd mice exposed to 45 mg/kg/day of each isomer (total dosage was 

90 mg/kg/day) for 24 weeks. Exposure to β-, γ-, or δ-HCH alone did not result in hepatocellular 
HEXACHLOROCYCLOHEXANE 100 

3. HEALTH EFFECTS 

carcinoma. However, when these isomers were mixed with α-HCH, hepatocellular carcinoma was 

observed. These results suggest that α-HCH is itself a hepatocellular carcinogen or acts synergistically 

with the other isomers. 

In Wistar rats, exposure to 25 mg γ-HCH/kg/day in the diet for 24 or 48 weeks did not result in any 

identifiable carcinogenic effect (Ito et al. 1975); however, high mortality in the control and treatment 

groups precludes determination that γ-HCH is not carcinogenic to rats under this experimental protocol. 

Mice (dd strain) exposed to as much as 90 mg γ-HCH/kg/day in the diet for 24 weeks did not exhibit any 

carcinogenic effects (Ito et al. 1973). Although an increased incidence of malignant hepatomas was 

reported in male dd mice exposed to 108–120 mg/kg/day in the diet for 32 weeks (Hanada et al. 1973), 

this dose level may have exceeded the maximum tolerated dose (MTD), based on effects of γ-HCH on 

survival. Liver nodules developed following doses of 39 mg/kg/day. The study was limited by the lack 

of statistical analysis (Hanada et al. 1973). 

Information concerning the cancer effects of γ-HCH following chronic-feeding exposure is equivocal. No 

statistically significant increases in endocrine, thyroid, pituitary, adrenal gland, liver, or ovary tumors 

were observed in male and female Osborne-Mendel rats fed 10.8–33 mg/kg/day in the diet for 80 weeks 

(NCI 1977) and in Wistar rats fed 0.07–32 mg γ-HCH/kg/day in the diet for 104 weeks (Amyes 1990); 

however, poor survival rates limit the significance of these results. On the other hand, hepatocellular 

carcinomas have been reported in F1 and B6C3F1 mice exposed to 13.6–27.2 mg/kg/day in the diet for 

80 or 104 weeks, respectively (NCI 1977; Wolff et al. 1987). Hepatocellular carcinomas were also 

increased in yellow (YS/UY)F-1 mice exposed to 27.2 mg/kg/day in the diet for 96 weeks (Wolff et al. 

1987); this strain of mouse has a dominant mutation at the agouti locus (Avy) that results in an increased 

susceptibility to formation of strain-specific neoplasms. Chronic dietary studies of γ-HCH additionally 

showed that incidences of benign lung adenomas were increased in female Agouti and Pseudoagouti mice 

exposed to 27.2 mg/kg/day for 24 months (Wolff et al. 1987) and in female CD-1 mice exposed to 

≥26.8 mg/kg/day for 78 weeks (Chase 2000; Huntington Life Sciences Ltd. 2001). The EPA has 

classified γ-HCH (lindane) into the category “suggestive evidence of carcinogenicity, but not sufficient to 

assess human carcinogenic potential” (EPA 2001a, 2002b). No cancer potency factors have been 

estimated for γ-HCH or γ-HCH (EPA 2001a, 2002b; IRIS 2005). 

No evidence of liver carcinogenicity was reported in Wistar rats exposed to 45 or 90 mg α-HCH/kg/day in 

the diet for 24 or 48 weeks (Ito et al. 1975; Nagasaki et al. 1975); high mortality was observed in both the 

treated and control groups. However, α-HCH appears to be carcinogenic in mice following intermediate­
HEXACHLOROCYCLOHEXANE 101 

3. HEALTH EFFECTS 

duration exposure. Hepatomas and hepatocellular carcinomas have been reported in a number of strains 

of mice exposed to 13–95 mg/kg/day for 16–36 weeks (Hanada et al. 1973; Ito et al. 1973, 1976; 

Nagasaki et al. 1975; Tsukada et al. 1979). Tryphonas and Iverson (1983), however, reported no 

evidence of a carcinogenic effect in male mice exposed to 90 mg α-HCH/kg/day in the diet for 50 weeks. 

Ito et al. (1975) reported an increased incidence of hepatocellular carcinoma in male rats exposed to 

50 and 75 mg α-HCH/kg/day in the diet for 72 weeks, suggesting that α-HCH may be carcinogenic in rats 

after long-term exposure. A study of enzyme-altered liver foci in rats treated first with the tumor initiator 

N-nitrosomorpholine, and then 20 mg α-HCH/kg/day in food for 49 weeks, found that the tumor promoter 

activity of HCH is apparently due to increased cell proliferation caused by a lowering of the cell death 

(apoptosis) rate (Luebeck et al. 1995). In another study in rats, additional administration of 35 mg/kg/day 

of α-HCH in the diet for 65 weeks inhibited the induction of liver tumors by 0.07 mg/kg/day of aflatoxin 

B1 (Angsubhakorn et al. 1981). IRIS (2005) lists α-HCH as a probable human carcinogen and estimated 

an oral cancer potency factor for α-HCH of 6.3 (mg/kg/day)-1 based on the incidence of hepatic nodules 

and hepatocellular carcinomas observed in male mice administered α-HCH in the diet (Ito et al. 1973). 

The doses corresponding to cancer risk levels ranging from 10-4 to 10-7 are 1.6x10-5–1.6x10-8 mg/kg/day, 

respectively, as indicated in Figure 3-3. The oral cancer potency factor is a plausible upper-bound 

estimate of the lifetime probability of an individual developing cancer as a result of oral exposure per unit 

intake of the chemical. 

β-HCH has not been found to be carcinogenic in Wistar rats exposed to 25 or 50 mg/kg/day in the diet for 

24 or 48 weeks (Ito et al. 1975) or in dd mice exposed to 18–120 mg/kg/day in the diet for 24 or 32 weeks 

(Hanada et al. 1973; Ito et al. 1973). However, Thorpe and Walker (1973) reported an increased 

incidence of hepatocellular carcinomas in CF1 mice exposed to 26 mg/kg/day in the diet for 104 weeks. 

The studies with negative results were, in general, of short duration, used a small number of animals, or 

failed to examine all of the animals. IRIS (2005) lists β-HCH as a possible human carcinogen and 

estimated an oral cancer potency factor for ingested β-HCH of 1.8 (mg/kg/day)-1 based on the incidence 

of hepatic nodules and hepatocellular carcinomas observed in male mice administered β-HCH at a single 

dose level in the diet (Thorpe and Walker 1973). The doses corresponding to cancer risk levels ranging 

from 10-4 to 10-7 are 5.6x10-5–5.6x10-8 mg/kg/day, respectively, as indicated in Figure 3-3. This is the 

only chronic study from which to estimate cancer risk from exposure to β-HCH. The study is limited by 

the use of only one nonzero dose group. Also, the use of incidence of liver tumors alone in mice to 

predict a compound’s carcinogenicity in humans may be equivocal (Vesselinovitch and Negri 1988). 

Diversity of factors has been shown to influence the development of liver cell tumors in mice, such as the 
HEXACHLOROCYCLOHEXANE 102 

3. HEALTH EFFECTS 

strain of the mice (Nagasaki et al. 1975), the protein or calorific value of the diet (Tannenbaum and 

Silverstone 1949), and the microbial flora of the animals (Roe and Grant 1970). 

δ-HCH has not been found to be carcinogenic in male Wistar rats exposed to 45 or 90 mg/kg/day in the 

diet for 24 or 48 weeks (Ito et al. 1975) or in male dd mice exposed to 18–90 mg/kg/day in the diet for 

24 weeks (Ito et al. 1973). However, these studies were of relatively short-exposure duration. δ-HCH is 

structurally related to carcinogenic HCH isomers, but it is currently listed as not classifiable for human 

carcinogenicity (IRIS 2005). 

Increased incidence of carcinoma was reported in Swiss mice following exposure to 90 mg technicalgrade HCH/kg/day in the diet for 8–32 weeks (Thakore et al. 1981). Increased incidences of 

hepatocellular carcinoma were also reported in Swiss mice exposed to 21.3–85 mg/kg/day in the diet for 

20 months (Munir et al. 1983) and in Swiss mice exposed to 10 or 17 mg/kg/day through gavage or the 

diet, respectively, for 80 weeks (Kashyap et al. 1979). The EPA has derived a cancer potency estimate 

for oral exposure to technical HCH (IRIS 2005). The oral slope factor is 1.8 per (mg/kg)/day and the 

doses corresponding to risk levels ranging from 10-4 to 10-7 are 5.6x10-5–5.6x10-8 mg/kg/day, respectively, 

as indicated in Figure 3-3. 

The DHHS has determined that γ-HCH and other HCH isomers may reasonably be anticipated to cause 

cancer in humans (NTP 2002). IARC has determined that HCH is possibly carcinogenic to humans 

(IARC 2003). As previously mentioned, the EPA has classified technical HCH and α-HCH as probable 

human carcinogens, β-HCH as a possible human carcinogen, and δ- and ε-HCH as not classifiable as to 

human carcinogenicity (IRIS 2005). The EPA has additionally classified γ-HCH into the category 

“suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential” (EPA 

2001a, 2002b). 

3.2.3 Dermal Exposure 

Studies examining the dermal toxicity of HCH in humans are limited. Most of the available information 

is derived from cases in which γ-HCH was dermally applied as a scabicide. γ-HCH in topical creams and 

lotions is efficiently absorbed through the skin (Ginsburg et al. 1977). Although it has been reported that 

these lotions contain 1% γ-HCH, it is not possible to quantify the amount of γ-HCH to which these 

individuals were exposed, because of the different areas of skin treated. 
HEXACHLOROCYCLOHEXANE 103 

3. HEALTH EFFECTS 

3.2.3.1 Death 

No studies were located regarding lethal effects in humans following dermal exposure to α-, β-, or 

δ-HCH. An acute whole-body dermal application of 1% γ-HCH lotion to a 2-month-old infant for the 

treatment of scabies was reported to result in death (Davies et al. 1983), and a concentration of 110 ppb 

γ-HCH was identified in the brain. The death of an elderly woman was reported following a 6-hour 

dermal application of γ-HCH-containing lotion (approximately 40 mg total γ-HCH) to the head for the 

treatment of scabies (Katsumata and Katsumata 2003). No data were reported for blood or tissue levels of 

γ-HCH. The causal association between HCH exposure and death is difficult to establish since the 

women had numerous pre-existing health problems. In general, most humans dermally poisoned with 

γ-HCH have recovered with no apparent adverse effects (Fagan 1981). 

In animals, acute dermal exposures to high doses of γ-HCH were reported to result in death. The dermal 

LD50 values for γ-HCH are 900 mg/kg in female rats and 1,000 mg/kg in male rats (Gaines 1960). Rats 

exposed to moistened γ-HCH for 24 hours exhibited no mortality at 250 mg/kg, 20% mortality at 

600 mg/kg, 40% mortality at 1,000 mg/kg, and 30% mortality at 2,000 mg/kg (Ullmann 1986a). 

Significant lethality (47%) was seen in female rats, but not male rats, exposed dermally to 400 mg 

γ-HCH/kg/day for 6 hours/day, 5 days/week, for 13 weeks (Brown 1988). Calves dermally exposed to 

33.3 mg/kg γ-HCH died within 5 months (Venant and Sery 1991). Dikshith et al. (1978) reported that 

guinea pigs dermally exposed to 200 mg technical-grade HCH/kg died within 5–12 days. Four of 20 rats 

died from exposure to technical-grade HCH at 100 mg/kg/day for 15–30 days (Dikshith et al. 1991c). 

Weanling rabbits were more sensitive to γ-HCH treatment than young adults, as seen by increased 

mortality rates accompanied by excitement and convulsions after a single whole-body treatment with a 

1% solution at a dose of 60 mg γ-HCH/kg (Hanig et al. 1976). This suggests that children might be at a 

greater risk than adults for toxic responses to dermal absorption of HCH. Rabbits treated with 

25 mg/kg/day technical-grade HCH for 30 days by skin painting on shaved dorsal, ventral, or thigh areas 

exhibited no deaths in the group exposed by dorsal application, but two of eight rabbits died in the group 

exposed by ventral application, and four of eight died in the group exposed by thigh application (Dikshith 

et al. 1989b). These and other values are in Tables 3-4 and 3-5. 

3.2.3.2 Systemic Effects 

No studies were located regarding musculoskeletal, endocrine, ocular, or body weight effects in humans 

or animals after inhalation exposure to inorganic tin or organotin compounds. Reliable LOAELs for 
401

mg/kg/daymg/kg/day

208

mg/kg/day

210

mg/kg/day mg/kg/day

204 mg/kg/day203 mg/cm2/kg209

mg/kg/day mg/kg/day mg/kg/day

Table 3-4 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Dermal 

Exposure/ 

Duration/ 

Species Frequency 

(Strain) (Route) 

ACUTE EXPOSURE 

Death 

Rat (Sherman) 

10 d (GO) once 

System NOAEL Less Serious 

LOAEL 

1000 M 

mg/kg/day 

Serious 

(LD50) 

Reference Chemical Form 

Gaines 1960 lindane 

900 F 

mg/kg/day 

(LD50) 

Rat (Wistar) 

24 hr once 1000 

mg/kg/day 

(LD50) Ullmann 1986a 

lindane 

Systemic 

Rat (Wistar) 

24 hr once Resp 600 

mg/kg/day 

1000 

mg/kg/day 

(dyspnea) Ullmann 1986a 

lindane 

Rabbit (New Zealand) 

once Ocular 40 

mg/kg/day 

(mild eye irratation) Ullmann 1986c 

lindane 

Rabbit (New Zealand) 

4 hr once 

Dermal 200 

mg/cm2/kg 

Ullmann 1986d lindane 

Neurological 

Rat (Wistar) 

24 hr once 600 

mg/kg/day 

1000 

mg/kg/day 

(slight sedation) 2000 F 

mg/kg/day 

(severe spasms) Ullmann 1986a 

lindane 
218

mg/kg/day mg/kg/day

220

mg/kg/day

mg/kg/day mg/kg/day

mg/kg/day mg/kg/day

mg/kg/day

668

mg/kg

219

mg/kg/day mg/kg/day

Table 3-4 Levels of Significant Exposure to Gamma-hexachlorocyclohexane (lindane) - Dermal (continued) 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

INTERMEDIATE EXPOSURE 

Death 

(Crl:(WI)BR) Rat 13 wk 

5 d/wk 6 hr/d 

NOAEL 

60 F 

mg/kg/day 

Less Serious 

LOAEL 

400 F 

mg/kg/day 

Serious 

(23 deaths out of 49) 

Reference Chemical Form 

Brown 1988 lindane 

Systemic 

(Crl:(WI)BR) Rat 13 wk 

5 d/wk 6 hr/d 

Resp 10 

mg/kg/day 

(rapid respiration or 

wheezing) 

Brown 1988 lindane 

Hepatic 10 

mg/kg/day 

60 

mg/kg/day 

(centrilobular 

hypertrophy) 

Renal 10 F 

mg/kg/day 

10 M 

mg/kg/day 

(hyaline droplet formation) 

60 F 

mg/kg/day 

(basophilic tubules) 

Rat once for 25 days 180 F 

mg/kg 

(mild dermatitis) Dikshith et al. 1973 

lindane 

Neurological 

(Crl:(WI)BR) Rat 13 wk 

5 d/wk 6 hr/d 

10 

mg/kg/day 

(hyperactivity) 60 F 

mg/kg/day 

(ataxia, tremors, convulsions) 

Brown 1988 lindane 

d = day(s); F = female; hr = hour(s); LD50, lethal dose; LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect level; Resp = week(s) 
31

mg/kg/day

98

mg/kg/day

61

mg/kg/day

Table 3-5 Levels of Significant Exposure to Technical - Grade Hexachlorocyclohexane - Dermal 

Exposure/ LOAEL 

Duration/ 

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

ACUTE EXPOSURE 

Death 

Gn Pig 5-12 d (NS) 1x/d 

INTERMEDIATE EXPOSURE 

Death 

Rat 15 d (Wistar) 1x/d Rabbit 30 d (NS) 1x/d 

Dikshith et al. 1978 200 M (24/24 deaths) 

mg/kg/day technical - grade

Dikshith et al. 1991c 100 F (2/10 deaths) 

mg/kg/day technical - grade

Dikshith et al. 1989b 25 M (6/24 deaths) 

mg/kg/day technical - grade
58

mg/kg/day

mg/kg/day

mg/kg/day

32

mg/kg/day

mg/kg/day

Table 3-5 Levels of Significant Exposure to Technical - Grade Hexachlorocyclohexane - Dermal (continued) 

Exposure/ LOAEL 

Duration/ 

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

Systemic 

(Wistar) Rat 30 d 

1x/d Hepatic 100 F 

mg/kg/day 

(hypertrophy, fatty degeneration, nuclear pyknosis of hepatocytes, diffuse and focal liver necrosis) 

Dikshith et al. 1991c technical - grade 

Renal 100 F 

mg/kg/day 

(tubular necrosis) 

Dermal 100 F 

mg/kg/day 

(hyperkeratosis, epidermal cell vacuolization, thickening 

of collagen fibers) 

(NS) Gn Pig 30 d 

1x/d Hepatic 100 M 

mg/kg/day 

(38% increase in liver weight, hepatic hypertrophy, pycnotic nuclei in cytoplasm, foca 

fatty inclusions, increased GOT and ALP activity) 

Dikshith et al. 1978 technical - grade 

Renal 100 M 

mg/kg/day 
60

mg/kg/day

mg/kg/day

mg/kg/day

34

mg/kg/day

Table 3-5 Levels of Significant Exposure to Technical - Grade Hexachlorocyclohexane - Dermal (continued) 

Exposure/ LOAEL 

Duration/ 

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

(NS) Rabbit 30 d 

1x/d Hepatic 25 M 

mg/kg/day 

Renal Dermal 25 M 

mg/kg/day 

CHRONIC EXPOSURE 

Cancer 

(Swiss) Mouse 80 wk 

2 d/wk 

(hepatocyte degeneration, pycnotic nuclei, enlarged liver, altered GOT, GPT, LDH and ALP activities) 

25 M 

mg/kg/day 

(thickened epidermis, hyperkeratinization, and infiltration of mononuclear cells) 

2.4 

mg/kg/day 

(altered epithelial lining o 

proximal convoluted tubules, loss of brush borders of tubules, atrophy of glomerular capsules) 

(CEL: liver tumors) 

Dikshith et al. 1989b technical - grade Kashyap et al. 1979 technical - grade 

ALP = alkaline phosphatase; CEL = cancer effect level; d = day(s); F = female; Gn pig = guinea pig; GOT = glutamate oxaloacetate transaminase; GPT = glutamat

transaminase; LDH = lactate dehydrogenase; LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect level; NS = not specweek(s); x = time(s) 
HEXACHLOROCYCLOHEXANE 109 

3. HEALTH EFFECTS 

respiratory, hepatic, and renal effects in animals after acute and intermediate exposure to γ-HCH are 

shown in Table 3-4. Reliable LOAELs for hepatic, renal, and dermal effects in animals after intermediate 

exposure to technical-grade HCH are shown in Table 3-5. 

Respiratory Effects. An acute dermal poisoning of a 2-month-old infant exposed to a whole-body 

application of 1% γ-HCH lotion resulted in death. The autopsy revealed pulmonary petechiae (tiny 

reddish spots that contain blood) (Davies et al. 1983). Slight dyspnea was observed in rats exposed 

dermally for 24 hours to 1,000 or 2,000 mg γ-HCH/kg on a shaved patch of dorsal skin (Ullmann 1986a). 

The dyspnea was severe in one female administered the high dose. Rapid respiration or wheezing was 

noted in rats exposed dermally to 10 mg γ-HCH/kg/day for 13 weeks (Brown 1988). 

Cardiovascular Effects. An acute dermal poisoning of a 2-month-old infant exposed to a wholebody application of 1% γ-HCH lotion resulted in death. The autopsy findings were minimal but revealed 

epicardial petechiae (Davies et al. 1983). 

No studies were located regarding cardiovascular effects in animals following dermal exposure to HCH. 

Gastrointestinal Effects. Vomiting and diarrhea occurred in a child (Ramchander et al. 1991) and a 

woman (Hall and Hall 1999) who had 1% γ-HCH applied to the skin to treat a rash and to treat scabies. 

No studies were located regarding gastrointestinal effects in animals following dermal exposure to HCH. 

Hematological Effects. Aplastic anemia was documented in a man who applied γ-HCH to his skin 

for 3 weeks for treatment of scabies (Rauch et al. 1990). Excessive dermal exposure to HCH was 

reported to result in aplastic anemia and bone marrow hyperplasia in a woman who bathed her dog once a 

week for 2 years in a preparation that reportedly contained 2% HCH (Woodliff et al. 1966). Reduced 

hemoglobin and hematocrit values and a nearly complete absence of red blood cell precursors in bone 

marrow were reported in a 2-year-old boy exposed to a family dog that was dipped regularly in mange 

treatment containing 12% γ-HCH (Vodopick 1975). 

No studies were located regarding hematological effects in animals following dermal exposure to any of 

the HCH isomers. 
HEXACHLOROCYCLOHEXANE 110 

3. HEALTH EFFECTS 

Hepatic Effects. No studies were located regarding hepatic effects in humans following dermal 

exposure to HCH. 

Liver pathology, including dilation of sinusoids, focal fatty inclusions, hypertrophy of hepatocytes, 

thickened blood vessels, swelling, and proliferation of epithelial cells of bile ducts, was observed in 

guinea pigs treated with 100 mg technical-grade HCH/kg/day for 30 days (Dikshith et al. 1978). The 

patch of the abdomen on which the HCH was applied was not covered to prevent licking, so oral exposure 

may also have occurred. In rabbits exposed to 25 mg technical-grade HCH/kg/day for 30 days, there 

were degenerative changes in hepatocytes along with increased liver and serum GPT and alkaline 

phosphatase (Dikshith et al. 1989b). Liver cell hypertrophy, fatty degeneration, nuclear pyknosis, and 

focal and diffuse necrosis were found in female rats treated with 100 mg/kg/day technical-grade HCH for 

7–30 days, but the time that it took for these lesions to occur, the severity, and the number of animals 

affected were not reported (Dikshith et al. 1991c). Centrilobular hypertrophy was reported in male and 

female rats exposed dermally to 60 mg γ-HCH/kg/day for 6 hours/day, 5 days/week, for 13 weeks (Brown 

1988). 

Renal Effects. No studies were located regarding renal effects in humans following dermal exposure 

to HCH. 

Female rats treated with 100 mg/kg/day of technical-grade HCH for 7, 15, or 30 days had necrosis and 

atrophy of the renal tubules and glomeruli, although the number of animals affected and the severity of 

the lesions were not reported (Dikshith et al. 1991c). Similar effects were noted in male rabbits treated 

with 25 mg/kg/day technical-grade HCH (Dikshith et al. 1989b). Male rats treated dermally with 

10 mg/kg/day γ-HCH for 13 weeks exhibited hyaline droplet formation, and urinalysis showed increased 

cast formation and positive scores for protein, blood, and turbidity in treated males (Brown 1988). 

Females in the same study exhibited a slight increase in the incidence of tubular basophilia at 

60 mg/kg/day. 

Dermal Effects. Rashes were observed in a boy following treatment with shampoo containing γ-HCH 

(Fagan 1981). No exposure level was reported, but the shampoo was rinsed over the boy's entire body. 

Mild dermatitis was observed in rats after 15 skin paintings with 180 mg/kg/day γ-HCH/kg for 25 days 

(Dikshith et al. 1973). Rabbits exposed to 200 mg/kg moistened γ-HCH for 4 hours showed no primary 

skin irritation or other toxic symptoms (Ullmann 1986d). Rabbits exposed to technical-grade HCH 
HEXACHLOROCYCLOHEXANE 111 

3. HEALTH EFFECTS 

(25 mg/kg/day for 30 days) had hyperkeratinization of the epidermal layer and swollen collagen fibers in 

the dermis, but no scoring level was provided (Dikshith et al. 1989b). Dermal treatment of rats with 

100 mg/kg/day technical-grade HCH for 7–30 days resulted in hyperkeratosis, epidermal cell 

vacuolization, and thickening of collagen fibers (Dikshith et al. 1991c). 

Ocular Effects. No studies were located regarding ocular effects in humans following dermal 

exposure to HCH. 

Mild eye irritation was seen in rabbits exposed to 40 mg/kg γ-HCH in the conjunctival sac for up to 

72 hours, giving a primary irritation score of 0.6 out of a maximum possible cumulative score of 16 

(Ullmann 1986c). 

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 HCH. 

3.2.3.4 Neurological Effects 

There have been several reports of human intoxication involving convulsions in adults and children after 

excessive topical application of γ-HCH (Boffa 1995; Fischer 1994; Hall and Hall 1999; Lee and Groth 

1977; Matsuoka 1981; Ramchander et al. 1991; Telch and Jarvis 1982; Tenenbein 1991); exposure levels 

were not reported. Heiberg and Wright (1955) reported convulsions in a woman who had treated calves 

with an insecticide containing 11% γ-HCH and 16% other HCH isomers. Central nervous systems 

symptoms of severe γ-HCH poisoning, including incontrollable shaking and myoclonic jerking and tonicclonic movements of the extremities, developed in a woman following three dermal applications of a 

considerable amount (not quantified) of an antiscabies product over a period of approximately 2 weeks 

(Hall and Hall 1999). Fever, tachycardia, grand mal seizure, and hallucinations were reported in a 

teenager treated with a 1% γ-HCH lotion for 3 consecutive nights (Boffa 1995). Weakness of the left and 

right limbs, dysarthria, and dysphagia were seen in an agricultural worker exposed by inhalation and 

dermal contact to unspecified levels of several organochlorine pesticides, including γ-HCH (Fonseca et al. 

1993). A man with human immunodeficiency virus (HIV) exhibited generalized tonic-clonic seizure 

activity after a single topical application of a 1% γ-HCH lotion to treat scabies (Solomon et al. 1995). 
HEXACHLOROCYCLOHEXANE 112 

3. HEALTH EFFECTS 

Studies in animals have substantiated the neurological symptoms resulting from γ-HCH application. 

Manifestations such as excitability, seizures, and convulsions have been observed in rabbits following a 

single topical application of 60 mg γ-HCH/kg in a 1% solution (Hanig et al. 1976); young rabbits were 

more susceptible than older rabbits. Slight sedation was observed in rats exposed once for 24 hours to 

1,000 mg/kg γ-HCH through shaved dorsal skin (Ullmann 1986a). Sedation was severe in one female 

receiving the highest dose (2,000 mg/kg). This female also showed severe spasms. Damage to Purkinje 

cells in the cerebellum and tremors were found in female Wistar rats treated with 100 mg/kg/day 

technical-grade HCH for 7–30 days (Dikshith et al. 1991c). Aggressiveness or hyperactivity was noted in 

female rats exposed dermally for 13 weeks to 10 mg γ-HCH/kg/day, while ataxia and tremors were seen 

at 60 mg/kg/day (Brown 1988). 

3.2.3.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans following dermal exposure to HCH. 

Dikshith et al. (1978) reported testicular hypertrophy and atrophy and complete inhibition of 

spermatogenesis in guinea pigs dermally treated with technical-grade HCH for 7, 15, or 30 days at doses 

as low as 100 mg/kg/day. The patch of the abdomen on which the HCH was applied was not covered to 

prevent licking, so oral exposure more than likely occurred. In a similar study, the backs of male rats 

were sprayed with 50 or 100 mg/kg/day technical-grade HCH for 120 days and the rats were housed in 

separate cages to prevent licking (Prasad et al. 1995). Depletion of germ cells and impaired function of 

Leydig and Sertoli cells was suggested by significant dose-related changes in activities of testicular 

enzymes such as sorbitol dehydrogenase, glucose-6-P-dehydrogenase, γ-glutamyl transpeptidase, and 

β-glucoronidase. Significant reductions in sperm count and motility and increased percentages of 

abnormal sperm were also observed in both groups. A significant reduction in testosterone level was 

observed in the high dose group. 

3.2.3.6 Developmental Effects 

No studies were located regarding developmental effects in humans or animals following dermal 

exposure to HCH. 
HEXACHLOROCYCLOHEXANE 113 

3. HEALTH EFFECTS 

3.2.3.7 Cancer 

A case-control study surveying childhood brain cancer cases among Missouri residents found that the 

odds ratios for the use of Kwell, a shampoo containing γ-HCH for lice control, were slightly elevated 

during the first 7 months of age to diagnosis (Davis et al. 1992). Thus, Kwell use was significantly 

associated with childhood brain cancer compared to controls. However, this study was limited by small 

sample sizes, potential recall bias in questionnaires, multiple comparisons, and the lack of detailed 

exposure information. 

In mice, dermal exposure to a 0.5% solution of γ-HCH in acetone applied twice a day for 60 days was 

reported to result in no treatment-related tumors (Orr 1948). Increases that were not statistically 

significant were reported in the incidences of hyperplastic and preneoplastic areas in the liver and hepatic 

tumors in Swiss mice exposed to 2.4 mg technical-grade HCH/kg/day for 80 weeks (Kashyap et al. 1979). 

Limitations of these studies, including less-than-lifetime exposure and study duration, the testing of only 

one dose, and the potential for ingestion of some of the compound from the skin, preclude determination 

that dermally applied HCH is noncarcinogenic in mice. 

3.3 GENOTOXICITY 

The available genotoxicity data indicate that γ-HCH and other individual HCH isomers have some 

genotoxic potential, but the evidence for this is not conclusive. 

No appreciable increase in the frequency of chromosome aberrations was observed in humans exposed 

primarily to γ-HCH by inhalation in a pesticide production factory (Kiraly et al. 1979). These individuals 

had been exposed for 8 hours/day for at least 6 months. Other studies are available regarding genotoxic 

effects in humans exposed to a wide variety of pesticides, including γ-HCH, when they were used on 

farms (Rupa et al. 1988, 1989a, 1989b, 1989c). The specific effects of HCH, apart from the effects due to 

the other exposures, are not known. 

In animals, ingestion of technical-grade HCH was reported to induce dominant-lethal mutations in mice 

(Lakkad et al. 1982). It did not induce chromosome aberrations in bone marrow cells of Syrian hamsters 

(Dzwonkowska and Hubner 1986), but positive results were reported in bone marrow cells of rats 

exposed to β-HCH (Shimazu et al. 1972). Oral exposure to α-HCH was reported to result in mitotic 

disturbances including an increased mitotic rate and an increased frequency of polyploid hepatic cells in 
HEXACHLOROCYCLOHEXANE 114 

3. HEALTH EFFECTS 

rats (Hitachi et al. 1975). γ-HCH has also been tested in vivo in animals. Incidence of chromosome 

clastogeny in bone marrow cells was increased in mice exposed to 1.6 mg γ-HCH/kg body weight/day by 

gavage for 7 days (Kumar et al. 1995). γ-HCH was negative in a micronucleus assay in mice (Jenssen 

and Ramel 1980). α-HCH produces DNA fragmentation in primary cultures of rat and human 

hepatocytes, but not in mouse hepatocytes (Mattioli et al. 1996). DNA repair induction was absent in 

hepatocytes from all three species. Both α- and γ-HCH have been observed to bind to mouse liver DNA 

at a low rate (Iverson et al. 1984). 

γ-HCH has been tested in several in vitro genotoxicity studies. In bacteria, it was not observed to induce 

gene mutations in assays with or without a metabolic activation system (Moriya et al. 1983; Nagy et al. 

1975), and it did not produce DNA damage, although a mammalian metabolic activation system was not 

present (Shirasu et al. 1976). γ-HCH was also not mutagenic in yeast (Shahin and von Borstel 1977) or 

algae (Kar and Singh 1979a). Mitotic disturbances (c-mitosis which is characterized by spindle 

breakdown as that produced by colchicine) and chromosome aberrations were observed in onion root tip 

cells exposed to commercial γ-HCH (Nybom and Knutsson 1947). In mammalian cells, γ-HCH (purity 

not reported) induced a marginal increase in the frequency of chromosome aberrations (including 

chromosomal gaps) in Chinese hamster cells, which was interpreted by the authors of the study as 

providing suggestive, but not conclusive, evidence of an effect (Ishidate and Odashima 1977). DNA 

damage was observed in cultures of rat nasal and gastric mucosa cells, and human nasal mucosa cells 

(Pool-Zobel et al. 1994). γ-HCH (NTP 1984) and technical-grade γ-HCH (Murli 1990) were both 

reported to be negative for cytogenetic effects in Chinese hamster ovary cells. α-HCH and γ-HCH were 

reported to bind to calf thymus DNA in the presence of metabolic activation (Iverson et al. 1984). γ-HCH 

was found inactive for inducing unscheduled DNA synthesis in human SV-40 fibroblasts, with and 

without activation (Ahmed et al. 1977), while it was found to induce unscheduled DNA synthesis in 

human peripheral lymphocytes (Rocchi et al. 1980). More recent studies by Kalantzi et al. (2004) with 

human mammary carcinoma MCF-7 and human prostate carcinoma PC-3 cell lines showed that 

incubation of the cells with low concentrations of γ-HCH (10-12–10-10 M) induced increases in 

micronuclei in both cell lines in the absence of DNA damage or cytotoxicity, suggesting a clastogenic 

effect for this chemical. The α- and β- stereoisomers were less active than γ-HCH. Cultured human 

lymphocytes taken from three healthy males showed a dose-dependent increase in chromosomal 

aberrations (gaps, breaks, and fragments) with significant increases at 0.1 μL/mL technical-grade HCH 

(6.5% γ-HCH) for 48-hour treatment and at 0.05 and 0.1 μL/mL for 72-hour treatment (Rupa et al. 

1989d). In addition, sister chromatid exchanges increased in a dose-dependent manner with the high dose 

(0.1 μL/mL) producing the only significant result. These results suggest mild mutagenic activity at high 
HEXACHLOROCYCLOHEXANE 115 

3. HEALTH EFFECTS 

doses in humans (Rupa et al. 1989d). Technical-grade γ-HCH was also found inactive for inducing 

unscheduled DNA synthesis in rat primary hepatocytes in vitro (Cifone 1990). 

Tables 3-6 and 3-7 present the results of in vivo and in vitro genotoxicity studies on HCH isomers, 

respectively. 

3.4 TOXICOKINETICS 

Absorption of the various HCH isomers following inhalation, oral, or dermal exposure has been inferred 

from humans who have become ill or who had increased serum levels of the various isomers following 

exposure by these routes. No animal data are available from the inhalation route to quantify the extent or 

rate of absorption. Technical-grade HCH has been shown to be well absorbed from the gastrointestinal 

tract of animals (Albro and Thomas 1974). The distribution of HCH isomers in humans and animals is 

primarily to the adipose tissue but also to the brain, kidney, muscle, blood, and other tissues (Baumann 

et al. 1980; Siddiqui et al. 1981a). β-HCH accumulates to a much greater extent than γ-HCH. The 

excretion of HCH isomer metabolites is primarily through the urine. The isomers have also been detected 

in breast milk (Ejobi et al. 1996; Schoula et al. 1996) and semen (Szymczynski and Waliszewski 1981). 

The primary urinary metabolites are chlorophenols and 1,2,4-trichlorocyclohexane-4,5-epoxide. The 

conversion occurs mainly by the action of hepatic enzymes. 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

Evidence exists that humans absorb γ-HCH vapor or dusts via inhalation. This can be inferred from 

occupational studies in which adverse health effects, including hematological abnormalities and 

neurological effects, have been reported in workers exposed to γ-HCH in workplace air (Brassow et 

al. 1981; Czegledi-Janko and Avar 1970; Kashyap 1986; Samuels and Milby 1971). In addition, α-, β-, 

γ-, and δ-HCH have been detected in the blood serum, adipose tissue, and semen of occupationally and 

environmentally exposed individuals, indicating that absorption does take place (Baumann et al. 1980; 

Czegledi-Janko and Avar 1970; Kashyap 1986; Nigam et al. 1986; Saxena et al. 1980, 1981a, 1981b). 

There are no specific studies that have quantified the rate or extent of absorption of the HCH isomers 

following inhalation exposure. No information is available on the absorption of α-, β-, γ-, and δ-HCH 

following inhalation exposure in experimental animals. 
HEXACHLOROCYCLOHEXANE 116 

3. HEALTH EFFECTS 

Table 3-6. Genotoxicity of Hexachlorocyclohexane Isomers In Vivo 

Species (test system) End point Results Isomer Reference 

Mammalian cells: 

 Human (peripheral 

lymphocytes) 

Chromosomal 

aberrations 

– Gamma Kiraly et al. 1979 

Human hepatocytes DNA fragmentation + Alpha Mattioli et al. 1996 

Syrian hamster (bone 

marrow) 

Chromosomal 

aberrations 

– Gamma Dzwonkowska and 

Hubner 1986 

Rat (bone marrow) Chromosomal 

aberrations 

+ Beta Shimazu et al. 1972 

Rat (primary cultures) DNA fragmentation + Alpha Mattioli et al. 1996 

Mouse (germ cells) Dominant lethal + Technical Lakkad et al. 1982 

Mouse Micronuclei – Gamma Jenssen and Ramel 1980 

 Mouse (bone marrow) Chromosomal 

aberrations 

+ Gamma Kumar et al. 1995 

Mouse (liver) DNA binding (+) Alpha/ 

gamma 

Iverson et al. 1984 

Mouse (hepatocytes) DNA fragmentation – Alpha Mattioli et al. 1996 

Rat (liver) Mitotic disturbances + Alpha Hitachi et al. 1975 

– = negative result; + = positive result; (+) = weakly positive result; DNA = deoxyribonucleic acid 
HEXACHLOROCYCLOHEXANE 117 

3. HEALTH EFFECTS 

Table 3-7. Genotoxicity of Hexachlorocyclohexane Isomers In Vitro 

Results 

With Without 

Species (test system) End point activation activation Isomer Reference 

Prokaryotic organisms: 

Salmonella typhimurium Gene mutation – – Gamma Moriya et al. 1983 

(TA100, TA98, TA1535, 

TA1537, TA1538) 

Escherichia coli (WP2/spot Gene mutation NT – Gamma Nagy et al. 1975 

test) 

E. coli (WP2 hcr) Gene mutation – – Gamma Moriya et al. 1983 

Bacillus subtilis (rec assay) DNA damage NT – Gamma Shirasu et al. 1976 

Eukaryotic organisms: 

Fungi and plant cells: 

Saccharomyces cerevisiae Gene mutation – – Gamma Shahin and von 

Borstel 1977 

Nostoc muscorum Gene mutation NT – Gamma Kar and Singh 1979a 

Allium cepa Mitotic NT + Gamma Nybom and Knutsson 

disturbances 1947 

Mammalian cells: 

Human (SV-40 fibroblasts) Unscheduled – – Gamma Ahmed et al. 1977 

DNA synthesis 

 Human (peripheral Unscheduled NT + Gamma Rocchi et al. 1980 

lymphocytes) DNA synthesis 

 Human (mammary Micronuclei NT + Gamma Kalantzi et al. 2004 

carcinoma MCF-7) 

Human (prostate carcinoma Micronuclei NT + Gamma Kalantzi et al. 2004 

PC-3) 

 Human (mammary DNA damage NT – Gamma Kalantzi et al. 2004 

carcinoma MCF-7) 

Human (prostate carcinoma DNA damage NT – Gamma Kalantzi et al. 2004 

PC-3) 

 Human (peripheral Sister chromatid NT + Technical Rupa et al. 1989d 

lymphocytes) exchange 

 Human (peripheral Chromosomal NT + Technical Rupa et al. 1989d 

lymphocytes) aberrations 

Chinese hamster (CHL Chromosomal NT (+) Gamma Ishidate and 

cells) aberrations Odashima 1977 

Chinese hamster (CHL Chromosomal NT – Gamma NTP 1984 

cells) aberrations 

Chinese hamster (CHL Sister chromatid NT – Gamma NTP 1984 

cells) exchange 

Chinese hamster (CHL Chromosomal – – Technical Murli 1990 

cells) aberrations 
HEXACHLOROCYCLOHEXANE 118 

3. HEALTH EFFECTS 

Table 3-7. Genotoxicity of Hexachlorocyclohexane Isomers In Vitro 

Results 

With Without 

Species (test system) End point activation activation Isomer Reference 

Rat (primary hepatocytes) Unscheduled NT – Technical Cifone 1990 

DNA synthesis 

Calf (thymus DNA) DNA binding (+) NT Alpha/ Iverson et al. 1984 

gamma 

– = negative result; + = positive result; (+) = weakly positive result; DNA = deoxyribonucleic acid; NT = not tested 
HEXACHLOROCYCLOHEXANE 119 

3. HEALTH EFFECTS 

3.4.1.2 Oral Exposure 

In humans, HCH is absorbed following oral exposure. Many accidental poisonings have occurred in 

humans as a result of γ-HCH ingestion, and high blood concentrations have been demonstrated in a 

number of acute poisoning cases (Berry et al. 1987; Harris et al. 1969; Khare et al. 1977; Munk and 

Nantel 1977; Nantel et al. 1977; Powell 1980; Starr and Clifford 1972). 

HCH is similarly absorbed following oral exposure in animals. Information concerning the rate of 

absorption from the gastrointestinal tract can be inferred from studies conducted in mice and rats. These 

studies indicated that γ-HCH is readily absorbed from the gastrointestinal tract (Ahdaya et al. 1981; 

Turner and Shanks 1980). Ahdaya et al. (1981) demonstrated that half of the administered dose was 

absorbed from the gastrointestinal tract of fasting mice approximately 14 minutes after administration of 

radiolabelled γ-HCH by stomach tube. Although this study demonstrates the rapid absorption of γ-HCH 

from the gastrointestinal tract, the use of fasted animals prevents an assessment of the effect of stomach 

contents on the rate of absorption. Turner and Shanks (1980) studied the rate of absorption of γ-HCH 

from the gastrointestinal tract and intestinal lymphatic system using rat intestinal loop preparations. 

Prepared loops were injected with γ-HCH, and the blood and lymph were sampled for 30 minutes. 

γ-HCH was readily absorbed from the intestine into the blood; however, only a small amount of γ-HCH 

entered the lymphatic system from the intestine. 

Absorption of technical-grade HCH following oral exposure has been quantified in rats. The extent of 

absorption of technical-grade HCH has been estimated to be 95.8% in rats within 4 days following the 

oral administration of single doses of the substance (Albro and Thomas 1974). Variation of the dosages 

from 30 to 125 mg/kg had no effect on the percentage of absorption. The overall degree of absorption of 

technical-grade HCH administered in the feed for 14 days was similar (94.9%), but the average 

absorption values of α-, β-, γ-, and δ-HCH were 97.4, 90.7, 99.4, and 91.9%, respectively (Albro and 

Thomas 1974). 

3.4.1.3 Dermal Exposure 

The ready absorption of γ-HCH across human skin, due to its lipid solubility, has been demonstrated in 

several studies that examined the absorption of γ-HCH from an antiscabies lotion (Feldmann and Maibach 
HEXACHLOROCYCLOHEXANE 120 

3. HEALTH EFFECTS 

1974; Franz and Lehman 1996; Lange et al. 1981). Maximum serum levels in healthy volunteers and 

scabies patients were reported within 4–6 hours following whole-body application (Lange et al. 1981). 

However, the maximum serum levels of γ-HCH in scabies patients were greater than those reported for 

normal volunteers. Studies involving a single topical application of γ-HCH to the forearm, which was left 

for 24 hours before washing, indicate that at least 9% of the applied dose was absorbed; maximum 

absorption occurred during the first 12 hours after application of γ-HCH to the skin, but absorption 

continued for at least 5 days (Feldmann and Maibach 1974). 

The absorption of γ-HCH through the skin was studied following application of two different preparations 

to the forearm of volunteers (Dick et al. 1997a). One with 120 mg γ-HCH/mL in acetone as the vehicle 

and the other, a commercial product, consisted of 3 mg γ-HCH/mL formulation, which primarily 

contained white spirit as the solvent base. The proportion of the applied dose absorbed into the systemic 

circulation in 6 hours was 5% for the dose applied in acetone and 60% of the applied dose in white spiritbased formulation. Thus, the white spirit enhanced the absorption of γ-HCH relative to acetone as the 

vehicle. The absorption of γ-HCH through human skin was also assessed in an in vitro study (Dick et al. 

1997b). γ-HCH absorption was reported to be 15–25% in 24 hours for the two formulations that 

contained white spirit as the predominant solvent, 3% in 24 hours from an aqueous spray dilution, and 

<1% in 24 hours for the acetone preparation. 

γ-HCH is similarly absorbed through the skin of animals. Toxicity was observed in guinea pigs and 

rabbits following dermal exposure to γ-HCH and following dermal exposure to technical-grade HCH 

(Dikshith et al. 1978; Hanig et al. 1976). Male rats treated dermally with radiolabelled γ-HCH (20% 

emulsifiable concentrate) on a 4.9 cm2

 shaved dorsal area exhibited absorption of radiolabel, which 

increased with time of exposure (Bosch 1987a). After 4 hours, 10.1, 5.3, and 2.0% were absorbed from 

doses of 0.06, 0.6, and 6 mg/cm2

/kg, respectively. After 24 hours, 27.7, 20.9, and 5.1% were absorbed 

from doses of 0.06, 0.6, and 6 mg/cm2

/kg, respectively. Male rabbits treated dermally with radiolabelled 

γ-HCH (20% emulsifiable concentrate) in a 28.3-cm2

 shaved dorsal area absorbed, after 4 hours, 29.6, 

18.3, and 7.3% radiolabel from doses of 0.005, 0.05, and 0.5 mg/cm2

/kg, respectively, and, after 24 hours, 

55.7, 40.0, and 16.6% from the same respective doses (Bosch 1987b). 

The absorption of γ-HCH in infants and children who had received dermal treatment with 1% γ-HCH 

lotion was investigated in one study (Ginsburg et al. 1977). Maximum blood concentrations of γ-HCH 

were observed in 6 hours, and averaged at 0.028 μg/mL for the group infected with scabies and 

0.024 μg/mL for the noninfected group. 
HEXACHLOROCYCLOHEXANE 121 

3. HEALTH EFFECTS 

3.4.2 Distribution 

Placental transfer of HCH in humans has been well documented (Saxena et al. 1981a). The levels of 

HCH and other organochlorine insecticides were found to be higher in the maternal blood, placenta, and 

umbilical-cord blood of stillborn cases than those of live-born cases (Saxena et al. 1983). Similarly, γ-, 

α-, δ-, and total HCH maternal blood and umbilical-cord blood levels were higher in mothers who gave 

birth to IUGR babies than in women who gave birth to normal weight babies (Siddiqui et al. 2003). HCH 

has been shown to accumulate in amniotic fluid, placenta, and fetal tissues after oral treatment of pregnant 

mice (Srivastava and Raizada 1993) and can be related to fetolethality. HCH isomers have been detected 

in human breast-milk, particularly in developing countries that still use HCH as a pesticide. Detected 

concentrations in these studies are discussed in Section 6.6. In a study on rats, γ-HCH has been reported 

to be transferred in the breastmilk and to elicit neurological effects in neonates. Epileptiform seizures 

have been reported in male rats fed maternal milk for 12 days beginning on the third day after birth, from 

dams exposed daily to 20 mg γ-HCH/kg by gavage (Albertson et al. 1985). In another study, in which 

lactating females were treated orally with a single dose of 6 mg/kg of γ-HCH on days 9 or 14 of lactation, 

the testosterone level of the male offspring was reduced 50% when puberty was reached (day 65) when 

compared to the control group (Dalsenter et al. 1997b). When the offspring reached adulthood (postnatal 

day 140), the relative testicular weight was significantly lower (Dalsenter et al. 1997b). The number of 

sperm and spermatids was also significantly reduced. α-, β-, and γ-HCH have been found to be 

bioconcentrated and excreted in breast milk of women who have been exposed to technical-grade HCH in 

pesticide residues (Nair et al. 1996). 

3.4.2.1 Inhalation Exposure 

Information on the distribution of the HCH isomers, following inhalation by humans, comes from studies 

of humans exposed to HCH in the workplace. Air concentrations of α-HCH (0.002–1.99 mg/m3

), β-HCH 

(0.001–0.38 mg/m3

), and γ-HCH (0.004–0.15 mg/m3) were associated with concurrent mean blood serum 

levels in workers of 69.6, 190.3, and 36.9 μg/L, respectively (Baumann et al. 1980). Serum levels of total 

HCH of 0.14–0.60 ppm were found in workers with unknown levels of exposure to technical-grade HCH 

(Nigam et al. 1986). HCH isomers have also been detected in the adipose tissues of workers 

occupationally exposed and individuals exposed via the ambient environment (Baumann et al. 1980; 

Siddiqui et al. 1981a). Accumulation of β-HCH has been shown to increase approximately linearly with 
HEXACHLOROCYCLOHEXANE 122 

3. HEALTH EFFECTS 

time of exposure (Baumann et al. 1980). Siddiqui et al. (1981a) found adipose levels of 0.1–1.5, 0.06– 

0.9, 0.7–3.0, and 0.97–5.8 ppm of α-, β-, γ-, and total HCH, respectively, in the tissues collected during an 

autopsy case study conducted in India. 

In a study with Wistar rats exposed to air concentrations of 0.02–5 mg/m3 γ-HCH for 90 days, male rats 

exhibited higher serum γ-HCH levels than females, but females had higher liver, brain, and fat levels 

(Oldiges et al. 1983). The organ levels of γ-HCH were dose-dependent, but had returned to baseline 

levels after a 4-week recovery period. 

3.4.2.2 Oral Exposure 

Information on the distribution of the HCH isomers following ingestion by humans comes from case 

reports. A fatal poisoning case confirmed that γ-HCH is, in part, distributed to the central nervous 

system. γ-HCH was detected in the cerebrospinal fluid of a young boy following ingestion of an 

unknown quantity of γ-HCH (Davies et al. 1983). 

More detailed information on the distribution of HCH or its isomers is available from studies in which 

laboratory animals were exposed by ingestion (Chand and Ramachandran 1980; Eichler et al. 1983; 

Srinivasan and Radhakrishnamurty 1983b). These studies examined the overall distribution pattern of 

HCH isomers. γ- and β-HCH are primarily stored in the fat of rats acutely exposed for 5, 10, or 15 days 

(Srinivasan and Radhakrishnamurty 1983b). The overall distribution of γ-HCH was greatest in fat, 

followed by brain, kidney, muscle, lungs, heart, spleen, liver, and blood. More recently, γ-HCH has also 

been found in the adrenal glands of rats (Lahiri et al. 1990; Sulik et al. 1988). In an experiment lasting 

12 days, the accumulation of γ-HCH in the brain of rats gavaged with 5 or 12 mg/kg/day began to decline 

after 8 days. This reduction was not observed in rats gavaged with 20 mg/kg/day (Tusell et al. 1988). In 

rats gavaged with γ-HCH on lactation days 9 or 14, γ-HCH levels were higher in their milk than plasma 

(Dalsenter et al. 1997b). Levels of γ-HCH in the offspring of those rats were approximately twice as high 

in kidneys and liver than in brain and testes. In the brain of rats, α-HCH has been found to accumulate 

preferentially in the white matter, an area containing lipid-rich myelin, as opposed to gray matter (Portig 

et al. 1989). However, the same brain distribution pattern was not noted for γ-HCH in mice, despite the 

fact that it is equally lipophilic. Differences in distribution of γ-HCH and α-HCH are most likely due to 

stereospecific forces. 
HEXACHLOROCYCLOHEXANE 123 

3. HEALTH EFFECTS 

The distribution pattern for β-HCH was found to be in the following order: fat > kidney > lungs > liver > 

muscle > heart > spleen > brain > blood. For γ-HCH, the distribution pattern was as follows: fat > 

brain > kidney > muscle > lungs > heart > spleen > liver > blood. β-HCH accumulates in tissues to a 

greater degree than γ-HCH except in the brain, where the γ-HCH accumulates at a higher concentration 

(Srinivasan and Radhakrishnamurty 1983b). This accumulation increases with increasing dose and 

treatment period for β-HCH more so than for γ-HCH. The greater accumulation of β-HCH in tissues is 

expected since this isomer is known to be metabolized more slowly. In addition, γ-HCH is known to 

induce the liver mixed-function oxygenase system, and thus, self-induced metabolism is an important 

factor that minimizes the accumulation of γ-HCH residues in animal tissues. 

The preferential accumulation of HCH in fatty tissues is also observed following intermediate-duration 

exposure of rats to HCH (isomer unspecified) in the diet (overall distribution: fat > liver > serum) (Chand 

and Ramachandran 1980) or exposure to α- or γ-HCH by gavage (overall distribution: fat > kidney > 

liver > brain > blood) (Eichler et al. 1983). 

3.4.2.3 Dermal Exposure 

Information on the distribution of the HCH isomers in exposed humans comes from case reports. A fatal 

poisoning case indicated that γ-HCH is, in part, distributed to the brain following topical application. The 

isomer was detected in brain tissue (110 ppb) and heart blood (33.3 ppb) collected during the autopsy of 

an infant who was treated with a whole-body application of a 1% γ-HCH lotion after a hot bath (Davies et 

al. 1983). In another study, blood levels of γ-HCH peaked 6 hours following topical application of a 1% 

solution to 20 children (12 infected with scabies, 8 noninfected) (Ginsburg et al. 1977). Mean 

concentrations did not differ statistically between the two groups at 6 hours and were 0.024 μg/mL in 

healthy children and 0.028 μg/mL in infected children. The half-lives in blood were 17.9 and 21.4 hours 

in infected and healthy children respectively. Differences in dosage between the two groups of children 

were considered marginally significant (p=0.11). However, the infected children were younger. The 

mean ages for the infected and noninfected groups were 32.5 and 64.3 months, respectively. 

The distribution of γ-HCH through the skin was studied following application of two different 

preparations to the forearm of volunteers (Dick et al. 1997a). The mean peak plasma concentrations of 

γ-HCH following exposure to the acetone and white-spirit based applications were 0.91 and 0.47 ng/mL, 

respectively; although the preparation in acetone contained a 40-fold higher concentration of γ-HCH. 

About 30% of the applied dose for the white-spirit based formulation was observed in the stratum 
HEXACHLOROCYCLOHEXANE 124 

3. HEALTH EFFECTS 

corneum at 6 hours of exposure and decreased by 90% at 24 hours. Fifteen percent of the applied dose 

for the acetone-based application was located in the stratum corneum. 

Some information on the distribution of γ-HCH is available from studies in which laboratory animals 

were exposed by dermal application (Bosch 1987a, 1987b; Hanig et al. 1976; Solomon et al. 1977a, 

1977b). A study on the distribution of γ-HCH in guinea pigs following acute dermal exposure indicates 

that accumulation of γ-HCH in the brain is greater than in the blood after single and multiple topical 

applications (Solomon et al. 1977a, 1977b); the levels in both tissues increased with the number of 

applications. Experiments with radiolabelled γ-HCH in dermally treated rats (Bosch 1987a) and rabbits 

(Bosch 1987b) found that absorption of radiolabel increased with time of exposure, with greater 

absorption and subsequent excretion in the urine occurring at the lower treatment doses. In weanling 

rabbits, which appear to be more sensitive to γ-HCH toxicity from dermal exposure than young adults, 

levels of γ-HCH in the blood after a single application of a 1% solution (60 mg γ-HCH/kg) were 1.67 and 

2.48 μg/mL in two rabbits that had been shaved and depilated, then stripped to remove the keratin layer 

(Hanig et al. 1976). In contrast, a blood level of only 0.67 μg/mL was seen in a rabbit that had only been 

shaved and depilated, indicating that absorption increases with loss of skin integrity. 

Following dermal treatment of rats with 50 or 100 mg/kg/day technical-grade HCH for 120 days, α-, β-, 

γ-, and δ-HCH were accumulated in testicular tissue and sperm in a dose-related manner (Prasad et al. 

1995). β-HCH was present at the highest concentration in testicular tissue and sperm. 

3.4.3 Metabolism 

The metabolism of γ-HCH is illustrated in Figure 3-4. Angerer et al. (1983) determined that 

chlorophenols were the primary urinary metabolites of γ-HCH excreted by workers involved in γ-HCH 

production. In the study, glucuronides and sulfates of chlorophenols were cleaved by acidic hydrolysis of 

urine samples. The metabolites 2,3,5-, 2,4,6-, and 2,4,5-trichlorophenol accounted for almost 57.7% of 

the γ-HCH metabolites identified in the urine collected during the last 2 hours of the workers' shifts. 

Other urinary metabolites identified included other trichlorophenols, dichlorophenols, tetrachlorophenols, 

and dihydroxychlorobenzenes. Pentachlorophenol has also been identified as a urinary metabolite in 

humans following occupational exposure (Engst et al. 1979). In vitro investigations indicate that human 

liver microsomes convert γ-HCH by dechlorination, dehydrogenation, dehydrochlorination, and 

hydroxylation to five primary metabolites: 3,6/4,5-hexachlorocyclohexene, pentachlorocyclohexene, 

2,4,6-trichlorophenol, 2,3,4,6-tetrachlorophenol, and pentachlorobenzene (Fitzloff et al. 1982). Similar in 
HEXACHLOROCYCLOHEXANE 125 

3. HEALTH EFFECTS 

Figure 3-4. The Proposed Metabolism of Hexachlorocyclohexane* 

Mercapturic Acid Conjugates 

RS (Cl)n 

OH

OH

O 

O 

OH 

(Cl)n SR

OH

OH 

OH 

OH 

OH 

OH 

OH OH

O 

OH 

OH

3,4,5-PCCOL 

3,4,6,5-PCCH 

1,2,3,4-TTCB 

cis B-PCCH 

Oxide 1,2,4-TCB 

2,4,5-TCB 

3,6,4,5-PCCH 

1,2,4-TCB 

2,3,5-TCB 

Glucuronide and Sulfate Conjugates 

3,4,6,5-TCCH 

1,2,4,6-TCCOL 

2,4,5,6-TCCOL 

2,4,5,6-TCCOL 

CO2 

HCH 

PCCHA 

2,4,6-TCP 

3,6/4,5-HCCH 

HCCOL 

+ 

2,3,4,5-TTCP 2,3,4,5-TTCP 

1,2,4-TCB 

PCB 

HCB 

HCCHD 

1,2,4-TCB-5,b-epoxide 

1,2,4-TCB5,b-epoxide 

PCCOL 

Abbreviations: 

HCB: Hexachlorobenzene 

HCCHD: Hexachlorocyclohexadiene 

HCCOL: Hexachlorocyclohexenol 

HCH: Hexachlorocyclohexane 

PCCHA: Pentachlorocyclohexane 

PCCOL: Pentachlorocyclohexenol 

PCCH: Pentachlorocyclohexene 

PCB: Pentachlorobenzene 

TCCOL: Tetrachlorocyclohexenol 

TCCH: Tetrachlorobenzene 

TTCP: Tetrachlorophenol 

TCB: Trichlorobenzene 

TCP: Trichlorophenol 

3,6/4,5-HCCH: 3,6/4,5-Hexachlorocyclohexene 

*Adapted from Chadwick et al. 1979, 1985; Fitzloff and Pan 1984; Fitzloff et al. 1982 
HEXACHLOROCYCLOHEXANE 126 

3. HEALTH EFFECTS 

vitro studies have demonstrated that an epoxide forms during the metabolism of pentachlorocyclohexene. 

This stable halogenated hydrocarbon epoxide metabolite may be responsible for the mutagenic and 

carcinogenic effects of γ-HCH (Fitzloff and Pan 1984). 

In animals, γ-HCH appears to be transformed by hepatic enzymes to form chlorophenols, chlorobenzene, 

chlorocyclohexanes, chlorocyclohexanols, and conjugates of mercapturic acid, glucuronide, and sulfate 

(Chadwick and Freal 1972a; Chadwick et al. 1978a; Engst et al. 1979; Kujawa et al. 1977). These 

metabolites have been identified in various tissues and in the urine of laboratory animals. Metabolites 

found in the liver of rats following intermediate exposure to γ-HCH via gavage or diet include di-, tri-, 

tetra-, and pentachlorobenzenes; pentachlorocyclohexenes; and pentachloro-2-cyclohexen-1-ol 

(Chadwick and Freal 1972a; Kujawa et al. 1977). Metabolites identified in the blood of these rats include 

di-, tri-, tetra-, and pentachlorophenols and pentachloro-2-cyclohexen-1-ol (Kujawa et al. 1977). Di-, tri-, 

and tetrachlorophenols; pentachlorocyclohexenes; and pentachloro-2-cyclohexen-1-ol have been 

identified in samples of kidney, spleen, heart, and brain tissue from rats fed γ-HCH (Kujawa et al. 1977). 

Metabolites found in the urine include tri-, tetra-, and pentachlorophenol; pentachloro-2-cyclohexen-1-ol; 

and isomers of tetrachloro-2-cyclohexen-1-ol (Chadwick and Freal 1972a; Chadwick et al. 1978c; 

Kujawa et al. 1977). The metabolism of γ-HCH in the intestine was reported to be very minor, or the 

metabolites were completely absorbed. No metabolites were detected in the feces or in the adrenal gland 

(Kujawa et al. 1977). In vitro preparations using rat liver slices have also found that γ-HCH is converted 

to hexachlorobenzene (Gopalaswamy and Aiyar 1984). However, these findings have not yet been 

confirmed in in vivo experiments. 

The major urinary metabolites formed in rats, following intermediate oral exposure to α- or β-HCH, were 

identified as tri- and tetrachlorophenols; pentachlorocyclohexene was also identified as a metabolite of 

γ-HCH in kidney tissue (Macholz et al. 1982a, 1982b). 

The toxicity of γ-HCH appears to be dependent on the P-450 oxidative system. Intermediate exposure to 

γ-HCH resulted in greater toxicity in DBA/2 (D2) mice than in C57BL/6 (B6) mice; the former are 

unresponsive to microsomal enzyme induction by γ-HCH (Liu and Morgan 1986). Increased toxicity was 

associated with higher blood and brain concentrations in D2 mice than in B6 mice at the time of sacrifice. 

In addition, D2 mice were found to have more 2,4,6-trichlorophenol in the liver, kidney, and spleen than 

the less-susceptible B6 mice. The inability of D2 mice to undergo enzyme induction to increase the rate 

of detoxification led to γ-HCH's enhanced toxicity in this strain. Other investigators have demonstrated 

the importance of the hepatic microsomal enzymes in the toxicity of γ-HCH (Baker et al. 1985; Chadwick 
HEXACHLOROCYCLOHEXANE 127 

3. HEALTH EFFECTS 

and Freal 1972a; Chadwick et al. 1981; Chand and Ramachandran 1980; Tanaka et al. 1979). Chadwick 

et al. (1981) demonstrated that pretreatment of rats with inducers of hepatic enzymes significantly 

influenced the metabolism and excretion of γ-HCH and its metabolites by altering specific metabolic 

pathways; excretion of γ-HCH metabolites in the urine increased nearly 4-fold following pretreatment 

with Aroclor 1254 or phenobarbitol. Following pretreatment with Aroclor 1254, a 7-fold increase in 

expired metabolites was observed. Naphthoflavone had no effect on the excretion rate. 

Metabolic transformations also affect the neurotoxicity of γ-HCH. Experiments in rats pretreated with 

3-methylcholanthrene (MC), an inducer of P-4501A1/1A2, phenobarbitol (PB), an inducer of 

P-4502B1/2B2, or ethanol, an inducer of P-4502E1, suggested that the convulsive activity of γ-HCH is 

due to γ-HCH per se and/or to metabolites formed by PB- or ethanol-inducible P-450 isoenzymes (Parmar 

et al. 2003). 

Metabolism of HCH has not been studied in children. However, although it is unknown whether the 

ability to metabolize HCH specifically differs between children and adults, some enzymes that belong to 

the enzyme superfamilies involved in phase II HCH metabolism are developmentally regulated in 

humans. The development of UDP-glucuronosyltransferase (responsible for glucuronide conjugation) 

depends on the enzyme isoform but, in general, adult activity is attained by 6–18 months of age (Leeder 

and Kearns 1997). Development of sulfotransferase (responsible for sulfate conjugates) activity is also 

substrate specific and is usually earlier than UDP-glucuronosyltransferase. In fact, levels of some 

sulfotransferases may be greater during infancy and early childhood than during adulthood (Leeder and 

Kearns 1997). A series of enzymes are involved in the production of mercapturic acid conjugates: 

γ-glutamyltranspeptidase, glutathione S-transferase, cysteinyl glycinase, and N-acetyl transferase (Sipes 

and Gandolfi 1991). There are two superfamilies of N-acetyltransferases, and one (i.e., the N-acetyltransferase 2 superfamily) has members that are developmentally regulated in humans. There is some 

N-acetyltransferase 2 activity in fetuses by 16 weeks of gestation. Infants up to 2 months of age have the 

slow metabolizer phenotype (there is a genetic polymorphism in this enzyme in adults). The adult 

distribution of slow and fast metabolizer phenotypes is reached by 4–6 months of age and full adult 

activity is achieved at 1–3 years of age (Leeder and Kearns 1997). 

3.4.4 Elimination and Excretion 

Excretion of hexachlorocyclohexane has not been studied in children. 
HEXACHLOROCYCLOHEXANE 128 

3. HEALTH EFFECTS 

3.4.4.1 Inhalation Exposure 

Humans excrete γ-HCH and its metabolites in urine, milk, and semen (Angerer et al. 1981). 

Chromatographic analysis of urine from humans occupationally exposed to HCH showed the presence of 

chlorinated phenols and all isomers of di-, tri-, and tetrachlorophenol (Angerer et al. 1981). In another 

study, the elimination of β-HCH was investigated in a group of 40 former workers of a γ-HCH-producing 

plant by analyzing at least two blood specimens from different time points between 1952 and 1980. The 

median half-life of β-HCH was 7.2 years, calculated by concentrations in whole blood, and 7.6 years, 

calculated by concentrations in extractable lipids (Jung et al. 1997), assuming first order kinetics for 

excretion. HCH is commonly detected in low concentrations (0.015 mg/kg fat) in the breastmilk of 

women exposed to HCH in the environment (Fytianos et al. 1985). All five of the HCH isomers 

discussed in this profile have been detected in human semen following environmental exposure, 

suggesting another route of elimination (Szymczynski and Waliszewski 1981). No animal studies using 

the inhalation route of exposure were located. 

3.4.4.2 Oral Exposure 

Excretion of γ-HCH and its metabolites in laboratory animals has been well documented. Data indicate 

that its major route of elimination is via the urine following intermediate and chronic oral feeding in mice 

(Chadwick et al. 1985). Very little is eliminated in exhaled air (Ahdaya et al. 1981; Chadwick et al. 

1985) or in feces (Chadwick et al. 1985) following acute, intermediate, and chronic oral administration in 

rodents. Because of its high lipid solubility, γ-HCH is excreted through the dam’s milk (Dalsenter et al. 

1997b). 

Very little γ-HCH is excreted unaltered. Various phenylmercapturic acid derivatives have been detected 

in the urine of rats, formed by the conjugation of γ-HCH metabolites with glutathione subsequent to 

dechlorinations and dehydrochlorinations (Allsup and Walsh 1982; Kurihara et al. 1979). In vitro 

investigations using rat liver cells indicate that β-HCH seems to resist, to some extent, conversion to the 

glutathione derivative; γ-HCH and α-HCH are readily conjugated (Fitzloff and Pan 1984; Fitzloff et al. 

1982). γ-HCH derivatives are not only excreted in the form of phenylmercapturic acids; there is ample 

evidence that they are also excreted in the form of glucuronides and sulfate conjugates (Chadwick et al. 

1978a). 
HEXACHLOROCYCLOHEXANE 129 

3. HEALTH EFFECTS 

No studies were located regarding genotoxic effects in animals following oral exposure, in humans 

following inhalation exposure, or in humans or animals following dermal exposure to HCH. 

3.4.4.3 Dermal Exposure 

Nonmetabolized γ-HCH was excreted in the urine and feces of healthy volunteers and scabies patients 

acutely exposed to a 0.3% γ-HCH emulsion by whole-body application. The cumulative excretion of 

nonmetabolized γ-HCH was almost the same in the healthy volunteers and the scabies patients (Zesch et 

al. 1982). 

The elimination of γ-HCH was studied following application of two different preparations to the forearm 

of volunteers (Dick et al. 1997a). The elimination half-life was between 50 and 111 hours for the 

acetone-based application, and 25–58 hours for the white-spirit based formulation. Absorbed γ-HCH was 

excreted in the urine as conjugates of 2,4,6-; 2,3,5-; and 2,4,5-trichlorophenol. Only 0.01–0.15% of the 

dose was excreted in the urine in 72 hours following dermal exposure for 6 hours. 

In a study in which children infected with scabies and their noninfected siblings were treated dermally 

with 1% γ-HCH lotion, the blood level was found to diminish rapidly after application, with a half-life of 

17.9 hours in infected children and 21.4 hours in noninfected children. 

In male rats treated dermally with radiolabelled γ-HCH, 0.28, 0.08, and 0.02% radiolabel were excreted in 

urine 4 hours after doses of 0.06, 0.6, and 6 mg/cm2

/kg, respectively (Bosch 1987a). After 24 hours, 4.4, 

3.2, and 0.6% radiolabel were excreted in urine from the same respective doses. In a similar study with 

male rabbits, 3.8, 2.6, and 1.3% radiolabel were excreted in urine 4 hours after doses of 0.005, 0.05, and 

0.5 mg/cm2

/kg, respectively (Bosch 1987b). After 24 hours, 25.5, 11.6, and 6.8% radiolabel were 

excreted in urine from the same respective doses. 

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 
HEXACHLOROCYCLOHEXANE 130 

3. HEALTH EFFECTS 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parametrization, (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. 
HEXACHLOROCYCLOHEXANE 131 

3. HEALTH EFFECTS 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-5 shows a conceptualized representation of a PBPK model. 

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. 

DeJongh and Blaauboer (1997) simulated the toxicokinetics of γ-HCH in rats with a PBPK model. A 

five-compartment model for the rat as presented in Figure 3-5 was constructed, including (1) the liver, 

serving as the metabolizing organ; (2) blood; (3) fat; (4) brain; and (5) a lumped compartment 

representing all other tissues, consisting mainly of muscle tissue. Values for the physiological 

parameters, tissue-blood partition coefficients, were obtained from the literature and are presented in 

Figure 3-6 and Table 3-8. The model was calibrated on a dataset from the literature on the disposition of 

γ-HCH from blood in vivo after single oral dosage and first-order biotransformation and gastrointestinal 

absorption constants for γ-HCH were obtained. 

The model was validated by simulating the disposition of γ-HCH in vivo after single intraperitoneal and 

chronic oral dosing and comparing simulated with experimental results. Simulated γ-HCH concentrations 

in blood, brain, muscle, and fat after single intraperitoneal and chronic oral dosage compared adequately 

well with experimental results. However, the model is not validated via biological evaluation of kinetic 

parameters. 

There are no PBPK models for HCH in children. 

Currently, the Agency of Toxic Substances and Disease Registry is assessing the feasibility of using tools 

such as PBPK modeling and pharmacodynamic modeling to extrapolate data across routes or durations of 

exposure. Such extrapolation may be done on a substance-by-substance basis after adequate toxicokinetic 

information has been collected. 
HEXACHLOROCYCLOHEXANE 132 

3. HEALTH EFFECTS 

Figure 3-5. 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 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax Km 

GI 

Tract 

Feces 

Urine

 Chemicals in air 

contacting skin 

Source: adapted from Krishnan et al. 1994 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 
HEXACHLOROCYCLOHEXANE 133 

3. HEALTH EFFECTS 

Figure 3-6. Structure of the PBPK Model for γ-HCH* 

blood 

fat 

other tissue (SPT) 

brain 

liver 

Qc 

Qf 

Qs 

Qb 

Ql 

biotransformation oral or intraperitoneal uptake 

Source: DeJongh and Blaauboer (1997) 

*Model parameters are described in Table 3-8. 
HEXACHLOROCYCLOHEXANE 134 

3. HEALTH EFFECTS 

Table 3-8. Parameters for a PBPK Model for γ-Hexachlorocyclohexane in Rats 

Parameter Value Scaling factor 

Body weight (kg) 0.135–0.313 

Cardiac output (L/hour kg)a

 14 

BW0.74 

Blood flow fractionsa

 Liver 0.25 – 

Fat 0.09 – 

Other tissues (SPT) 0.63 – 

Brain 0.03 – 

Tissue group volume fractions 

Blooda

 0.06 – 

Livera

 0.04 – 

Braina

 0.0006 – 

Fatb

 0.2xBW+0.0166 – 

Remaining tissues (SPT) 0.894-VFC – 

Partition coefficients for lindane 

Liver-bloodc

 4.2 – 

 Fat-bloodc

 95.3 – 

SPT-bloodc

 1.6 – 

 Brain-bloodd

 4.1 – 

Metabolic and uptake constants 

BW-0.3 Biotransformation ratee

 (hour-1kg-1) 4.5 

Oral/intraperitoneal uptake ratee 0.035 – 

(hour-1) 

 Oral/intraperitoneal uptake 0.8 – 

efficiencyd 

Source: DeJongh and Blaauboer 1997 

BW = body weight; SPT = slowly perfused tissue; VFC = relative adipose tissue mass where VFC=0.2*BW+0.0166 

a

Reference values (Arms and Travis 1988) 

b

Calculated as a function of body weight (Bailey et al. 1980)
 c

Measured in vitro (Jepson et al. 1994) d

Measured in vivo (Oshiba 1972) e

Value obtained by calibration 
HEXACHLOROCYCLOHEXANE 135 

3. HEALTH EFFECTS 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Information is available to assess the extent and rate of HCH absorption following oral and dermal 

exposure (Ahdaya et al. 1981; Albro and Thomas 1974; Turner and Shanks 1980). However, inhalation 

absorption of HCH can only be inferred from toxicity studies and studies assessing the distribution and 

excretion of γ-HCH. No quantitative information is available to assess the rate and extent of inhalation 

absorption. 

Following oral exposure to γ-HCH in rats, little, if any, metabolism was observed in the gut as indicated 

by the absence of metabolites in the feces (Kujawa et al. 1977). Rather, it is readily absorbed, where the 

majority is transported via the blood rather than the lymphatics (Turner and Shanks 1980). HCH, a 

lipophilic compound, is well distributed in adipose tissue, though whether these compounds are absorbed 

into tissues via active or passive mechanisms is unknown. HCH metabolism is mediated primarily in the 

liver by the cytochrome P-450 oxygenase system. The many metabolites of HCH, mostly 

polychlorophenols, are eliminated primarily in the urine. 

Additional data concerning the mechanisms of inhalation and dermal absorption of HCH in animals may 

provide information to assist in characterizing absorption of HCH in humans. 

3.5.2 Mechanisms of Toxicity 

In the nervous system, γ-HCH is thought to interfere with GABA neurotransmitter function by interacting 

with the GABAA receptor-chloride channel complex at the picrotoxin binding site (Abalis et al. 1985; 

Anand et al. 1998; Casida and Lawrence 1985; Lawrence and Casida 1984; Pomès et al. 1994). Thus, the 

seizures caused by γ-HCH can be antagonized by GABAA mimetics. The δ-HCH isomer has also been 

shown to act at the picrotoxin binding site, but to a lesser extent (Fishman and Gianutsos 1988). 

Intraparataneal doses of γ-HCH or picrotoxin administered to rats resulted in epileptic events, but 

different levels of extracellular excitatory amino acids were observed in the hippocampus, suggesting a 

difference in mechanism of action (Nyitria et al. 2002). In rat cortical neurons, expression of the 

protooncogene c-fos, which is associated with seizure activity and is induced by elevated intracellular 

calcium levels, was increased by γ-HCH treatment but decreased by δ-HCH treatment (Barrón et al. 

1995). Treatment-related changes in c-fos expression suggested that γ-HCH induces seizures through the 
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activation of calcium channels, while inhibition of calcium channels by δ-HCH results in anticonvulsant 

effects. The α-HCH isomer, another nonconvulsant, has been shown, like δ-HCH, to suppress c-fos 

induction (Vendrell et al. 1992a). In a study on the cytotoxic action of δ-HCH and γ-HCH in cultured rat 

cerebellar granule neurons (Rosa et al. 1997), both isomers were found to induce an increase in the free 

intracellular Ca2+ concentration. However, the γ-isomer mainly caused this increase by a release from 

intracellular Ca2+ stores. On the other hand, δ-HCH may exert its action by stimulating a large influx of 

Ca2+. δ-HCH was found to be more potent and active as a cytotoxic agent than γ-HCH, and the 

differences in cytotoxicity and neurotoxic action may be related to their action on the different Ca2+ pools. 

Other suggestive data concerning mechanisms by which HCH causes neurological effects in animals 

include enhanced synaptic activity (Joy 1982; Joy and Albertson 1985) altered GABA functional activity 

(Bhatt and Panchal 1994; Cattabeni et al. 1983; Fishman and Gianutsos 1987, 1988; Hulth et al. 1978; Joy 

and Albertson 1985), and inhibition of (McNamara and Krop 1948a; Nakajima 1983; Uchida et al. 1974) 

or oxidative damage to Na+

-K+-ATPase activity (Sahoo and Chainy 1998). In general, the mechanism of 

toxicity of HCH on the nervous system appears to be similar to those of other neurotoxic organochlorine 

insecticides. 

γ-HCH interacts with cellular membranes and may produce several generalized cytotoxic effects 

associated with impaired membrane function. In rat renal cortical tubules, glucose uptake and cyclic 

AMP accumulation were altered by γ-HCH treatment (López-Aparicio et al. 1994). Transport of 

D-galactose and L-leucine across enterocytes was decreased in chickens injected daily with γ-HCH for 

7 days (Moreno et al. 1994). Rats exposed orally to 5 mg/kg/day technical-grade HCH 5 days/week, for 

3–6 months, exhibited significantly decreased levels of phosphatidylinositol, phosphatidylinositol 

4-phosphate, and phosphatidylinositol 4,5-bisphosphate in the erythrocyte membrane and cerebrum 

(Agrawal et al. 1995). An in vitro study showed that γ-HCH altered the action potential and 

transmembrane currents in frog heart (atrial) myocytes (Sauviat et al. 2002). γ-HCH also has been shown 

to block gap junctional intercellular communication in Sertoli cells by inducing the aberrant endocytosis 

of Connexin 43 and zonula occludens-1 within Rab5 positive endosomes via the activation of the 

extracellular signal-regulated kinases (Defamie et al. 2001; Mograbi et al. 2003). Inhibition of 

intercellular communication could potentially lead to uncontrolled cell growth and tumor promotion. 

γ-HCH inhibited gap junction and intercellular communication in myometrial cell cultures isolated from 

rats on gestation day 10 by creating an oxidative stress environment (Kreiger and Loch-Caruso 2001; 

Loch-Caruso et al. 2003). γ-HCH also inhibited spontaneous phasic contractions in late gestation rat 

uterus (Loch-Caruso et al. 2003). 
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Oxidative stress in the liver has been suggested as a mechanism of γ-HCH-induced hepatotoxicity 

(Azzalis et al. 1995; Barros et al. 1988, 1991; Junqueira et al. 1997; Puri and Kohli 1995; Srinivasan and 

Radhakrishnamurty 1983a; Videla et al. 1991). This condition is characterized in the rat liver by a 

reduction in hepatic glutathione content, lipid peroxidation, the microsomal generation of superoxide 

radical coupled to cytochrome P-450 induction, and a decrement in superoxide dismutase and catalase 

activity (Junqueira et al. 1993). Dose-dependent inhibition of intercellular communication in cultured rat 

hepatocytes, with subsequent reversal by addition of vitamin E or superoxide dismutase, indicates 

oxidative stress as a hepatotoxic mechanism (Leibold and Schwarz 1993). Species differences exist in the 

activities of hepatic metabolizing enzymes, and it has been demonstrated that γ-HCH at a dose of 

10 mg/kg/day for 6 days increased the hepatic cytochrome P-450 as well as glutathione-S-transferase in 

the rat, but not in the rabbit or monkey (Puri and Kohli 1995). Thus, oxidative stress and hepatotoxicity 

are produced with γ-HCH treatment in rats, but not in the rabbit and monkey (Puri and Kohli 1995). 

Inhibition of Mg2+-ATPase activity has also been observed in rat liver tissue, suggesting an ATPase 

enzyme sensitivity to the action of γ-HCH (Gopalaswamy and Aiyar 1984). The researchers suggested 

that some toxic effects appearing in mammals as a result of γ-HCH exposure may arise from its influence 

on this ATPase activity (Gopalaswamy and Aiyar 1984). An in vitro study in mammalian CHO-K1 cells 

indicated that both γ-HCH and an unspecified HCH isomer mixture induced glutathione peroxidase and 

glutathione reductase activities as a defense mechanism against oxidative stress (Garcia-Fernandez et al. 

2002). 

The toxic mechanisms acting on prenatal development are poorly understood. Some studies of γ-HCH in 

rodents suggest that oxidative stress and depletion of GSH may be developmentally significant. Mouse 

fetal and placental tissues exhibited increased superoxide production, lipid peroxidation, and DNA-single 

strand breaks at 48 hours after administration of single dose of 30 mg/kg γ-HCH to pregnant dams on 

day 12 of gestation (Hassoun and Stohs 1996b). In vitro exposures of rat conceptuses to γ-HCH solutions 

of ≥50 μM on gestational day 10 resulted in significantly lower intracellular levels of GSH compared to 

controls (McNutt and Harris 1994). Data were not available, however, to determine whether a 

relationship exists in the prenatal rat between oxidative stress and GSH depletion. 

3.5.3 Animal-to-Human Extrapolations 

Extrapolating animal toxicity data to predict human risk from HCH exposure appears to be reasonable 

since similar effects are seen in both species. 
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Metabolism of HCH isomers is believed to be carried out primarily by the P-450 monooxygenase system 

in humans and rodents. The presence of chlorophenols and chlorobenzenes in urine of workers 

occupationally exposed to γ-HCH (Angerer et al. 1983; Engst et al. 1979) was similar to observations of 

rats experimentally exposed to γ-HCH (Chadwick and Freal 1972a; Chadwick et al. 1978a; Engst et 

al. 1976; Kujawa et al. 1977). In vitro investigations indicate that human liver microsomes convert 

γ-HCH to chlorocyclohexenes, chlorophenols, and chlorobenzenes (Fitzloff et al. 1982). Both human and 

rat microsomes have been shown to form an identical epoxide in vitro following γ-HCH exposure 

(Fitzloff and Pan 1984). An important difference in interspecies metabolism of γ-HCH is the production 

of α-2μ-globulin in the male rat (Dietrich and Swenberg 1990, 1991), a protein not present in humans, 

which is well known for its role in renal toxicity. 

Similar clinical toxic effects resulting from HCH exposure have been observed in laboratory animals 

dosed experimentally and humans experiencing occupational, therapeutic, and accidental domestic 

exposures to HCH. These include neurological, hepatic, hematological, and dermatological effects. 

Though reproductive, immunological, and carcinogenic effects have been reported in occupationally 

exposed humans and in animals, the human cases (Blair et al. 1998; Kashyap 1986; Tomczak et al. 1981) 

lack both quantitative exposure data and strong causal associations and also involve concurrent exposures 

to other chemicals. While rodents appear to be adequate models for a variety of human effects of HCH 

exposure, care must be taken in interpreting data from reproductive toxicity feeding studies in sheep 

(Beard and Rawlings 1999; Beard et al. 1999a), since significant differences exist in the gastrointestinal 

physiology of ruminants and humans. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Colborn and Clement (1992), was also used in 1996 when Congress mandated the EPA 

to develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 
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3. HEALTH EFFECTS 

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). 

Studies indicating that γ-HCH may act as an endocrine disruptor are summarized below. The amount of 

evidence is limited and further investigation is necessary to ascertain the relevance and impact to public 

health. 

Estrogen influences the growth, differentiation, and functioning of various target tissues, including male 

and female reproductive systems such as mammary gland, uterus, vagina, ovary, testes, epididymis, and 

prostate. Findings indicative of antiestrogenic activity of oral exposure to γ-HCH include reduced 

embryo implantation in mice (Sircar and Lahiri 1989), reduced ovulation rate in rabbits (Lindenau et al. 

1994), and delayed vaginal opening, disrupted estrous cycling, and reduced uterine weight in rats 

(Chadwick et al. 1988). Conversely, Raizada et al. (1980) indicated induction of estrogenic activity by 

γ-HCH based on increased glycogen content of the uterus, cervix, and vagina. Inconsistencies in the 

classification of estrogenic activity for γ-HCH may have been due to variations in experimental protocols, 

examination of different end points, and controversy in the interpretation of hormonal effects (Chadwick 

et al. 1988). Ovariectomized rats exposed for 5 days and sexually immature female rats exposed for 

7 days to 40 mg γ-HCH/kg/day showed no effects on the number of estrogen and estrogen-dependent 

progesterone receptors (Laws et al. 1994), indicating that the antiestrogenic effects of γ-HCH in rat 

reproductive tissues do not appear to be due to direct action on estrogen receptors or the induction of 
HEXACHLOROCYCLOHEXANE 140 

3. HEALTH EFFECTS 

progesterone receptors. This is consistent with in vitro tests showing that γ-HCH had no significant 

agonistic action on the estrogen receptor (ER) in the MCF-7 human cell line (Soto et al. 1995), or activity 

in ER-mediated assays with luciferase reporter systems transfected to MCF-7 and HeLa human cells 

(Balaguer et al. 1999). 

Nativelle-Serpentini et al. (2003) showed that γ-HCH can modulate the activity of human aromatase, the 

enzyme that catalyzes the aromatization of androgens to estrogens, thus potentially affecting sexual 

maturation in developing organisms. The study showed that short-term (10 minutes to 18 hours) 

incubation of human placental JEG-3 cells with γ-HCH increased aromatase activity, whereas longer-term 

(18 hours) incubation produced dose-related inhibition (Nativelle-Serpentini et al. 2003). This occurred 

at dose levels that were not cytotoxic. Because aromatase is an enzyme that catalyzes the aromatization 

of androgens to estrogens, alterations in aromatase activity can have widespread consequences, 

particularly in developing organisms. 

Studies with β-HCH in ovariectomized mice showed that mobilization of this isomer from fat during 

fasting produced estrogenic effects including stimulation of uterine growth in mice (Bigsby et al. 1997), 

and that blood and fat levels of the isomer were correlated with the estrogenic end points uterine epithelial 

height and vaginal epithelial thickness (Ulrich et al. 2000). The blood concentrations of β-HCH that 

induced these effects in mice were within the same order of magnitude of blood levels of this isomer in 

some subjects in the general human population. β-HCH has estrogenic action in transfected MCF-7 cells, 

although there is evidence that this activity is mediated through ligand-independent activation of the ER 

(Hatakeyama et al. 2002). 

The male gonad is a highly sensitive target organ for γ-HCH in animals as discussed in Section 3.2.2.5 

(Reproductive Effects). For example, spermatogenesis was reduced in rats as shown by reductions in 

serum testosterone levels, testicular weight, and/or spermatid and sperm counts, following exposure as 

adults (6 mg/kg/day for 5 days or a single 30 mg/kg dose) or during gestation (1 mg/kg/day for 5 days or 

a single 6 or 30 mg/kg dose) (Dalsenter et al. 1996, 1997a, 1997b). Similarly, oral exposure of rats to 

15 mg/kg/day γ-HCH for 5 days during gestation caused effects in adult male offspring that included 

testicular histological alterations, reduced sperm head counts, and increased chromatin abnormalities in 

epididymal sperm (Traina et al. 2003). Oral exposure to β- or technical-grade-HCH also caused 

degenerative changes in male reproductive tissues and sperm abnormalities in rats and mice (Dikshith et 

al. 1991a; Gautam et al. 1989; Nigam et al. 1979; Pius et al. 1990; Roy Chowdhury and Gautam 1990; 

Van Velsen et al. 1986), and similar effects on male reproductive tissues and spermatogenesis occurred in 
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3. HEALTH EFFECTS 

rats and guinea pigs following dermal treatment with technical-grade HCH (Dikshith et al. 1978; Prasad 

et al. 1995). 

In vitro exposure to γ-HCH caused depolarization, influx of extracellular Ca2+, and other cell membrane 

changes in rat testis peritubular myoid cells (PMCs, the smooth muscle cell layer surrounding the 

seminiferous tubules), suggesting that interference with hormone-regulated PMC function might be 

involved in testicular toxicity of γ-HCH (Silvestroni et al. 1999). Other in vitro effects of γ-HCH 

included altered sperm responsiveness to progesterone (Silvestroni and Palleschi 1999) and inhibition of 

testicular steroidogenesis in rat Leydig cells (Ronco et al. 2001). Testing of HCH isomers for activity in 

an in vitro androgen receptor assay using a human PC-3 LUCAR- prostate carcinoma cell line showed 

that α- and β-HCH interacted with the human androgen receptor as agonists, whereas γ- and β-HCH had 

no agonist or antagonist activity (Schrader and Cooke 2000). Another isomer comparison study found 

that in vitro exposure to γ-, α-, and δ-HCH (only isomers tested) inhibited (Bu2) cAMP-stimulated 

progesterone production by mouse MA-10 Leydig tumor cells (Walsh and Stocco 2000). 

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 
HEXACHLOROCYCLOHEXANE 142 

3. HEALTH EFFECTS 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

Limited information is available on the specific health effects resulting from HCH exposure in children. 

Generally, health effects observed in adults should also be of potential concern in children. Occasional 

deaths of children have been reported following ingestion of γ-HCH (Storen 1955). Although a causal 

relationship between exposure to γ-HCH and hematological effects in humans has not been established, 

there is one case report of hypochromic anemia and another of aplastic anemia in children exposed to 

γ-HCH by inhalation (Morgan et al. 1980; Rugman and Cosstick 1990). There are also sporadic reports 

of adverse effects of γ-HCH including convulsions in children after excessive topical application of 

γ-HCH (Lee and Groth 1977; Matsuoka 1981; Nordt and Chew 2000; Ramchander et al. 1991; Telch and 
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3. HEALTH EFFECTS 

Jarvis 1982; Tenebien 1991). Based on animal data as discussed below, it can be inferred that children 

may be more susceptible than adults to some effects of HCH isomers. 

Neurological effects have been observed in immature animals exposed to γ-HCH via gestation and/or 

lactation. A developmental neurotoxicity study found several changes, including increased motor activity 

and reduced auditory startle response habituation, in 11-day-old offspring of maternal rats that were 

exposed to ≥5.6 mg/kg/day doses of γ-HCH (γ-HCH) in the diet from gestation day 6 through lactation 

day 10 (Myers 1999). Epileptiform seizures occurred in rat pups that were exposed to maternal milk from 

dams that were exposed to 20 mg γ-HCH/kg by gavage for 12 days on postnatal days 3–15 (Albertson et 

al. 1985). Weanling rabbits were more sensitive to γ-HCH than young adults, as seen by increased 

mortality rates accompanied by excitement and convulsions after a single whole-body treatment with a 

1% solution (60 mg γ-HCH/kg) that was absorbed dermally (Hanig et al. 1976). Although the data from 

these studies suggest that γ-HCH can be transferred via the placenta and maternal milk and elicit 

functional neurological effects in offspring, the actual doses received by the young animals is not known. 

There is evidence that γ-HCH caused functional impairment of the developing blood brain barrier (BBB) 

in young rats (Gupta et al. 1999). The integrity (permeability) of the BBB was studied by assessing 

uptake of sodium fluorescein (a micromolecular tracer dye) into the brain of neonatal rats following 

single or repeated acute gavage doses of γ-HCH. The brain uptake index of fluorescein was significantly 

increased in 10-day-old pups treated with a single 2 mg/kg dose (72 and 23% higher than controls after 

2 hours and 3 days, respectively), as well as in those treated with 2 mg/kg/day for 8 days (50% higher 

than controls 7 days after the first exposure, with recovery 20 days after the first exposure). The effect 

appeared to be age-related because the brain uptake index was lower when rats were administered a single 

2 mg/kg dose at 15 days of age (20% higher than controls after 2 hours) or a higher dose of 4 mg/kg/day 

for 3 days as adults (no effect on brain permeability). 

Alterations in cerebral levels of noradrenaline, serotonin, and dopamine were observed in suckling rats 

treated intragastrically with a single dose of 20 mg/kg γ-HCH during the postnatal period (Rivera et al. 

1991). Levels of noradrenalin were reduced in the mesencephalon. Concentrations of a serotonin 

metabolite were increased in the frontal cortex primarily on postnatal days 8 and 15, but the results were 

not statistically significant. Levels of a dopamine metabolite were decreased in the mesencephalon, but 

statistical significance was only obtained on postnatal day 15 (+44%, p<0.05). According to the authors, 

earlier experiments demonstrated that higher doses of γ-HCH were required to increase serotonin in adult 

rats. Alterations in levels of brain dopamine, serotonin, GABA, glutamate, glutamate decarboxylase, and 
HEXACHLOROCYCLOHEXANE 144 

3. HEALTH EFFECTS 

noradrenaline were seen in various areas of the brains of female rat pups treated orally with 10 mg 

technical-grade HCH/kg/day for 60 days (Nagaraja and Desiraju 1994). Acquisition of a passive 

avoidance task was improved in 15-day-old rat pups that were orally treated with γ-HCH as either a single 

20 mg/kg dose or 7-day repeated 10 mg/kg/day doses, although changes in motor activity and brain 

monoaminergic levels (e.g., ratios of 5-HIAA/serotonin and DOPAC/dopamine) depended on the 

treatment schedule (Rivera et al. 1998). 

No direct information is available regarding the effects of HCH on the developmental process in humans. 

However, developmental studies in animals indicated few effects from exposure to γ-HCH (Khera et al. 

1979; Hassoun and Stohs 1996a; Srinivasan et al. 1991a); significant teratogenic effects were not 

observed (Khera et al. 1978). The proportion of embryos lost after implantation was increased after 

minks were treated with 1 mg/kg/day γ-HCH in the diet (Beard et al. 1997). An increase in the incidence 

of fetuses with extra ribs was reported in rats exposed to 20 mg/kg/day γ-HCH during gestation days 6–16 

and in rabbits exposed during days 6–18 (Palmer et al. 1978a). However, the incidence of extra ribs were 

within or just greater than the ranges recorded for the control groups, and therefore, may not be 

significant evidence of teratogenicity caused by exposure to γ-HCH (Hassoun and Stohs 1996a). β-HCH 

given to rat dams at 20 mg/kg/day during gestation caused increased fetal deaths within 5 days of birth 

(Srinivasan et al. 1991a). In another study, cadmium interacted with γ-HCH to cause significant 

embryotoxic and teratogenic effects in the developing rat fetus when administered together at a dosage 

that for either toxin alone is insufficient to cause any deleterious effects in development (Saxena et al. 

1986). 

β-HCH is lipophilic and accumulates in maternal adipose tissue and may be mobilized during pregnancy 

and lactation. HCH residues have been measured in human skin lipids (Dua et al. 1998) and in breastmilk 

(Czaja et al. 1997; Dua et al. 1997; Nair et al. 1996); HCH also crosses the placenta (Saxena et al. 1981b). 

Its levels in placenta, maternal blood, and umbilical-cord blood were higher in cases of stillbirths than in 

live-born cases; however, many other organochlorine pesticides were present that could have contributed 

to stillbirths (Saxena et al. 1983). γ-, α-, δ-, and total HCH maternal blood and umbilical-cord blood 

levels were also higher in mothers who gave birth to IUGR babies (Siddiqui et al. 2003). Similar to the 

Saxena et al. (1983) study, other organochlorine pestides were also present in the blood that could have 

contributed to the IUGR. In a study in rats, γ-HCH has been reported to be transferred in the maternal 

milk and to elicit neurological effects in neonates. Following intraperitoneal dosing of dams with γ-HCH 

on days 12–17 of gestation, GABAA receptors in rat fetuses were studied with radiolabelled 

t-butylbicyclophosphorothionate (TBPS), a ligand that binds to the GABAA receptor (Brannen et al. 
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3. HEALTH EFFECTS 

1998). Treatment with γ-HCH significantly reduced the TBPS binding affinity in fetal brainstems and it 

was concluded that the effect could potentially lead to abnormal brain activity, increased susceptibility to 

seizures, and behavioral effects. Also noted in the study, was reduced TBPS binding in brains of fetuses 

when compared to adults. In another study, lactating female rats were treated orally with a single dose of 

6 mg/kg of γ-HCH on days 9 or 14, or with 1 mg/kg on days 9–14 of lactation; the testosterone level of 

the male offspring was reduced 50% at puberty (day 65) when compared to the control group (Dalsenter 

et al. 1997b). When the offspring reached adulthood (day 140 postnatal), the relative testicular weight 

was significantly lower (Dalsenter et al. 1997b). The number of sperm and spermatids was also 

significantly reduced. 

Differences in oxidative effects have been observed in the testes of young versus mature rats, 15 and 

90 days old respectively, following intrapertitoneal injection with 10 or 20 mg/kg technical-grade HCH 

(Samanta and Chainey 1997b). Lipid peroxidation occurred to a greater extent in mature rats. However, 

the percent decrease in cytosolic superoxide dismutase activity was greater in young rats, which have 

increased baseline activity of the enzyme. Based on the findings of this study, it does not appear that 

young rats are at increased risk of oxidative testicular damage. 

Although it is unknown whether the ability to metabolize HCH specifically differs between children and 

adults, some enzymes, which belong to the enzyme superfamilies involved in phase II HCH metabolism, 

are developmentally regulated in humans. The development of UDP-glucuronosyltransferase 

(responsible for glucuronide conjugation) depends on the enzyme isoform, but, in general, adult activity is 

attained by 6–18 months of age (Leeder and Kearns 1997). Development of sulfotransferase (responsible 

for sulfate conjugates) activity is also substrate specific and is usually earlier than UDP-glucuronosyltransferase. In fact, levels of some sulfotransferases may be greater during infancy and early childhood 

than during adulthood (Leeder and Kearns 1997). A series of enzymes are involved in the production of 

mercapturic acid conjugates: γ-glutamyltranspeptidase, glutathione S-transferase, cysteinyl glycinase, 

and N-acetyl transferase (Sipes and Gandolfi 1991). There are two superfamilies of N-acetyltransferase, 

and the N-acetyltransferase 2 superfamily has members that are developmentally regulated in humans. 

There is some N-acetyltransferase 2 activity in fetuses by 16 weeks of gestation. Infants up to 2 months 

of age have the slow metabolizer phenotype (there is a genetic polymorphism in this enzyme in adults). 

The adult distribution of slow and fast metabolizer phenotypes is reached by 4–6 months of age and full 

adult activity is achieved at 1–3 years of age (Leeder and Kearns 1997). 
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3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic 

substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target 

molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The 

preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in 

readily obtainable body fluid(s) or excreta. However, several factors can confound the use and 

interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures 

from more than one source. The substance being measured may be a metabolite of another xenobiotic 

substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic 

compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental 

conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the 

body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous 

substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as 

copper, zinc, and selenium). Biomarkers of exposure to HCH 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 HCH 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 
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3. HEALTH EFFECTS 

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 Hexachlorocyclohexane 

There are few quantitative data to correlate levels of any of the HCH isomers in human tissue or fluids 

with environmental levels. A study in which children infected with scabies and their noninfected siblings 

were treated dermally with 1% γ-HCH lotion found no correlation between the dose applied and the 

subsequent level of γ-HCH in blood (Ginsburg et al. 1977). The blood level was also seen to diminish 

rapidly after application, with a half-life of 17.9 hours in infected children and 21.4 hours in noninfected 

children. 

In contrast, β-HCH persists in the blood for a longer period of time than the other isomers. A study of 

workers in a γ-HCH -producing factory found that levels of β-HCH in blood serum were higher than 

those of other isomers, and there was a significant correlation between serum levels of β-HCH and length 

of employment (Baumann et al. 1980). Studies of populations with general HCH exposure have 

consistently found the level of the β-isomer to be higher than those of the other isomers (Kashyap 1986; 

Nigam et al. 1986; Ramachandran et al. 1984). This is probably due to the greater tendency of β-HCH to 

persist and accumulate in the body, while the other isomers are more rapidly metabolized or excreted. A 

survey of epidemiological studies involving workers occupationally exposed to "crude benzene 

hexachloride" as much as 10–15 years prior to sampling reported serum levels of 20–348 μg/L β-HCH 

(Morgan and Lin 1978). Unfortunately, none of the above studies specified exposure levels, so it is still 

questionable whether blood HCH levels can be used as biomarkers to quantify exposure. 

There is also a direct correlation between HCH levels in the blood and human adipose tissue and semen 

(Baumann et al. 1980; Radomski et al. 1971a, 1971b; Szymczynski and Waliszewski 1981); 

concentrations of β-HCH in subcutaneous adipose tissues were found to be 300 times higher than blood 

levels (Baumann et al. 1980). Levels of β-HCH detected in skin lipids correlated with those found in 

human adipose tissue (Sasaki et al. 1991b). Although exposure levels were not known, the results of this 

study indicate that measuring β-HCH in skin lipids can be an easy means of determining relative levels or 

times of individual exposure. The method of collecting the skin lipid samples was noninvasive, involving 

washing the face with soap and wiping 3–4 hours later with fat-free cotton soaked in 70% ethanol. β- and 

γ-HCH have also been found in samples of human maternal adipose tissue, maternal blood, cord blood, 

and breast milk in women who were exposed to unknown levels of various organochlorine pesticides in 
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Kenya (Kanja et al. 1992). The metabolites of γ-HCH have been detected in human urine (Angerer et al. 

1981). However, such findings are not specific to γ-HCH exposure, and these findings could follow from 

exposure to both γ-HCH and a number of structurally related compounds. 

3.8.2 Biomarkers Used to Characterize Effects Caused by Hexachlorocyclohexane 

The individual isomers of HCH can be detected in the blood serum, urine, adipose tissue, and semen of 

exposed individuals. However, the concentrations measured in these biological tissues have not been 

exclusively correlated with the degree of adverse health effects observed. Additionally, there are no 

general biomarkers of effect for HCHs analogous to red blood cell or plasma cholinesterase for 

organophosphorous insecticides. 

Adverse effects such as neurophysiological and neuropsychological disorders and gastrointestinal 

disturbances have been reported in workers exposed to HCH during pesticide or fertilizer formulation. 

Nigam et al. (1986) and Kashyap (1986) reported that nonhandlers indirectly exposed and handlers 

directly exposed to HCH during pesticide manufacture and formulation were found to have mean serum 

levels of 0.27 ppm (nonhandlers) and 0.6 ppm (handlers) total HCH. As much as 60–100% of the total 

HCH measured in serum was β-HCH. The ranges of serum HCH levels measured in all exposed workers 

were 0.07–0.72 ppm β-HCH, 0.004–0.18 ppm α-HCH, 0–0.17 ppm γ-HCH, and 0–0.16 ppm δ-HCH. 

Both handlers and nonhandlers complained of paresthesia of the face and extremities, headache, and 

giddiness; other symptoms included malaise, vomiting, tremors, apprehension, confusion, loss of sleep, 

impaired memory, and loss of libido. Similar but less-severe effects were noted in 19 maintenance 

workers who visited the plant frequently. Serum HCH levels measured in these workers were 0.004– 

0.1 ppm α-HCH, 0.02-0.2 ppm β-HCH, 0–0.32 ppm γ-HCH, and 0–0.04 ppm δ-HCH. Kashyap (1986) 

also reported higher serum enzyme levels of alkaline phosphatase, lactate dehydrogenase, ornithine 

carbamyl transferase, γ-glutamyl transpeptidase, and leucine aminopeptidase and increased IgM in the 

handlers as compared with the nonhandlers and a control population of 14 workers with no occupational 

contact with HCH. Czegledi-Janko and Avar (1970) reported that γ-HCH blood levels of 0.024–0.16 ppm 

were associated with clinical symptoms including muscle jerking and variations in EEG in 37 workers 

exposed to γ-HCH in a fertilizer plant. 

HCH and other organochlorine pesticides have been found in the blood serum of some individuals in a 

population of men attending an infertility clinic in Israel. Serum levels of organochlorine pesticides, 

including γ-HCH, have been found in men with low sperm counts to be two times higher than that of 
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fertile men (Pines et al. 1987). Maternal mean serum γ-HCH levels were reported to be higher in cases of 

premature delivery and spontaneous abortions than in controls (Saxena et al. 1980; Wassermann et 

al. 1982). Saxena et al. (1980) reported HCH levels of 69.3–550.4 ppb and γ-HCH levels of 30.8– 

113.6 ppb in the blood of women in India who had experienced spontaneous abortions or premature labor 

compared with blood HCH levels of 22.2–85.5 ppb and γ-HCH levels of 7.1–32.5 ppb in women who had 

undergone full-term pregnancy. β-HCH levels were significantly higher in German women with a history 

of miscarriages (Gerhard et al. 1999). Serum levels of a number of other pesticides including aldrin, PCP, 

PCB, HCB, DDE, DDT, and DDD were also found to be higher in cases of premature labor and 

spontaneous abortions. It was, therefore, not possible to establish a quantitative, causal relationship 

between the serum HCH levels and these adverse effects. 

Blood serum levels of 1–17 ppb β-HCH were not found to be associated with the incidence of colorectal 

adenocarcinoma in 10 families (Caldwell et al. 1981). Serum levels of 0–49.5 ppb γ-HCH were not found 

to be associated with the occurrence of hematological syndromes such as pancytopenia, thrombocytopenia, plasma cell myoma, acute leukemia, chronic lymphocytic leukemia, and anemia in 103 patients 

(Traczyk et al. 1977). 

For more information on biomarkers for renal and hepatic effects of chemicals, see ATSDR/CDC 

Subcommittee Report on Biological Indicators of Organ Damage (1990) and for information on 

biomarkers for neurological effects, see OTA (1990). 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

Guinea pigs maintained on diets deficient in vitamin C and protein showed altered γ-HCH metabolism 

and excretion. Vitamin C deficiency decreased the amount of γ-HCH and its metabolites excreted in the 

urine and increased the amount stored in the kidney (Chadwick et al. 1972c). Vitamin A supplements 

decreased HCH-induced toxicity in the rat testes, while deficiencies in vitamin A potentiated the toxicity 

(Pius et al. 1990). 

Cadmium, which is known to inhibit hepatic drug-metabolizing enzymes in mammals, also inhibited the 

metabolism of γ-HCH in adult male Wistar rats exposed to the compound after short- and long-term 

pretreatment with cadmium (Chadwick et al. 1978b). Liver microsomal enzymes affected by exposure 

were γ-HCH dehydrogenase, γ-HCH dechlorinase, and hepatic cytochrome P-450 content. This action 

altered the profile of metabolites excreted in the urine. Cadmium may inhibit γ-HCH metabolism 
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indirectly by increasing levels of zinc and reducing levels of copper in the liver (Chadwick et al. 1978b). 

The addition of cadmium to the diet also increased the concentration of γ-HCH measured in the plasma 

and liver (Khanna et al. 1988). Cadmium also interacts with γ-HCH to cause significant embryotoxic and 

teratogenic effects in the developing rat fetus when administered together at a dosage that, for either toxin 

alone, is insufficient to cause any deleterious effects on development (Saxena et al. 1986). 

A low-protein diet potentiated the effects of γ-HCH on reducing the weights of various organs in male 

rats (Khanna et al. 1990). Serum and liver lipid contents and cholesterol levels were increased in animals 

fed low-protein diets. The low-protein diet increased the levels of γ-HCH found in the various organ 

tissues. 

The combined application of HCH (mixed isomers) and malathion to the skin of guinea pigs for 30 days 

showed no significant influence of either chemical on neurological signs of toxicity before dying (e.g., 

tremors, dyspnea, salivation, convulsions, and paralysis of the hind limbs) or mortality induced by the 

other (Dikshith et al. 1987). The study suggests that HCH isomers and malathion did not elicit any 

potentiation effects at the doses tested (50 and 100 mg/kg HCH, 200 and 400 mg/kg malathion). 

γ-HCH is a central nervous system stimulant, whereas the α-, β-, and δ-isomers of HCH are mainly 

depressants (McNamara and Krop 1948a; Smith 1991). Isomeric interactions can occur, such that α-, β-, 

and δ-HCH counteract the effects of the γ-isomer (lindane); neurotoxicity is reduced when a dose of 

δ-HCH is accompanied by an equal or higher dose of the other isomers. These interactions likely account 

for differences in the neurotoxicity of γ-HCH and technical HCH, the majority of which is comprised of 

isomers other than γ-HCH (60–70% α-HCH, 5–12% β-HCH, 10–15% γ-HCH, 6–10% δ-HCH, and 3–4% 

ε-HCH [Baumann et al. 1980; Kutz et al. 1991]). 

The metabolism of γ-HCH can be altered by exposure to other chlorinated hydrocarbon insecticides such 

as DDT. Exposure to various chlorinated hydrocarbon insecticides, including γ-HCH, is thought to 

produce generalized nonspecific induction of microsomal enzymes, including cytochrome P-450. 

Induction of these enzymes could affect the toxicokinetics of a variety of xenobiotics that are metabolized 

through microsomal oxidation. Induction of mixed-function oxidase activity by other chlorinated 

hydrocarbon insecticides stimulates the selective effect on the oxidative degradation of γ-HCH to the 

tetrachlorophenols and enhances its elimination in the urine (Chadwick and Freal 1972b). In addition, 

since HCH is hepatotoxic, therapeutic agents, which can produce liver toxicity, such as acetaminophen, 

might also enhance the symptoms of HCH exposure. 
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Single daily doses of 20 mg/kg γ-HCH in mice significantly reduced the convulsive threshold, as 

measured by the dose of pentylenetetrazol required to induce seizures 1–4 hours after treatment, but 

increased the convulsive threshold 48 hours following treatment (Hulth et al. 1978). A dose of 50 mg/kg 

γ-HCH significantly increased the convulsive threshold 2, 4, and 10 days following dosing. A single dose 

of α-HCH significantly increased the convulsive threshold 3 and 24 hours after dosing and resulted in a 

significant 17% increase in brain levels of γ-aminobutyric acid (GABA) 24 hours after dosing. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to HCH than will most persons 

exposed to the same level of HCH 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 HCH, or compromised function of organs affected by 

HCH. Populations who are at greater risk due to their unusually high exposure to HCH are discussed in 

Section 6.7, Populations with Potentially High Exposures. Based on information from animal studies as 

discussed in Section 3.7, Children’s Susceptibility, it can be inferred that children may be more 

susceptible than adults to some effects of HCH isomers. Individuals possessing genetic polymorphisms 

affecting HCH metabolism and elimination may be more susceptible, though supporting data do not exist. 

People with excoriated (peeling) skin exhibited higher levels in blood of γ-HCH following dermal 

exposure to γ-HCH lotion than those with normal skin (Ginsburg et al. 1977). It was not known if there 

were any increased toxic effects to individuals with excoriated skin. It is also not known with certainty if 

children are unusually susceptible to the toxic effects of HCH, but case reports of acute neurotoxicity in 

children treated for scabies with γ-HCH suggest that it should not be used on infants and young children 

(Telch and Jarvis 1982). The potential hazards of using γ-HCH dermal preparations on infants and young 

children are underscored by the fact that the very young have a large surface area-to-volume ratio, 

possibly less efficient hepatic detoxification abilities, and are more likely to lick treated skin (Kramer et 

al. 1980). Therefore, the use of γ-HCH as a scabicide on infants and very young children, especially 

those who have very little body fat, has been discouraged (Telch and Jarvis 1982). 

Evidence suggests that pregnant women should exercise extreme caution in their exposure to γ-HCH 

(Ginsburg et al. 1977; Kramer et al. 1980; Solomon et al. 1977a). Refer to Section 3.7 for more detailed 

explanation. In pregnant animals and humans, γ-HCH crosses the placenta. HCH and γ-HCH body tissue 
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3. HEALTH EFFECTS 

levels have also been associated with premature labor, spontaneous abortions, and IUGR in babies 

(Rasmussen 1980; Saxena et al. 1980, 1981a, 1981b; Siddiqui et al. 2003; Wassermann et al. 1982). 

However, no causal relationship has been established between blood and tissue levels of γ-HCH and 

premature termination of pregnancy. 

Nair et al. (1996) demonstrated that there is a significant bioconcentration of the α-, β-, and γ- isomers of 

HCH in the breastmilk of mothers exposed to technical-grade HCH. 

People with lowered convulsion thresholds due to epilepsy (treated or untreated), cerebrovascular 

accidents, or head injuries may be at greater risk of the central nervous system effects of γ-HCH toxicity 

and may suffer increased risk of or severity of seizures (Kramer et al. 1980; Matsuoka 1981). Those 

individuals suffering from malnutrition (e.g., low protein, low fiber, and low vitamin intake) may be more 

susceptible than the general public to the toxic effects of γ-HCH (Rasmussen 1987). Individuals with 

liver and/or kidney disease may be at risk because of compromised detoxification mechanisms in the liver 

and impaired excretory mechanisms in the kidney. Additionally, individuals with existing or suspected 

immunodeficiencies may be at risk because HCH isomers may enhance immunosuppression. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to HCH. 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 HCH. 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 

HCH: 

Reigart JR, Roberts JR. 1999. Recognition and management of pesticide poisonings. 5th edition. 

Washington, DC: U.S. Environmental Protection Agency, 55-61. 

Goldfrank L, Flomenbaum N, Lewin N, et al. 2002. Goldfrank’s toxicologic emergencies. 7th edition. 

New York, NY: McGraw-Hill, 1366-1378. 

Ellenhorn MJ, Barceloux DG. 1988. Medical toxicology: Diagnosis and treatment of human poisoning. 

New York, NY: Elsevier, 1078-1080. 
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3.11.1 Reducing Peak Absorption Following Exposure 

When a large amount of HCH has been swallowed, emetics have been used to induce vomiting. One of 

the problems with inducing vomiting is that the insecticidal form of HCH is often dissolved in an organic 

solvent, which presents an aspiration hazard. Activated charcoal can also be used to decrease 

gastrointestinal absorption. To avoid skin absorption after exposure, clothing should be removed, and the 

skin should be washed with water and mild soap (Ellenhorn and Barceloux 1988). There are no known 

methods for reducing absorption following inhalation exposure. 

3.11.2 Reducing Body Burden 

The traditional methods of increasing elimination or decreasing distribution (e.g., dialysis, diuresis, and 

hemoperfusion) are not useful because of the high volume of distribution of HCH into adipose tissue 

(Ellenhorn and Barceloux 1988). HCH accumulates in adipose tissue following all routes of exposure. 

However, peritoneal dialysis may be required if rhabdomyolysis (muscle necrosis) leads to myoglobinuria 

and kidney shutdown (Sunder Ram Rao et al. 1988). 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

Possible mechanisms of action of HCH on some of the target organs have been described. In the nervous 

system, γ-HCH is thought to interfere with the GABA system by interacting with the GABAA receptorionophore complex at the picrotoxin binding site (Portig and Schnorr 1988; Rivera et al. 1991; Sunol et 

al. 1988). Thus, the seizures caused by γ-HCH can be antagonized by GABAA mimetics; diazepam is the 

anticonvulsant of choice (Ellenhorn and Barceloux 1988). Phenobarbital and/or phenytoin or 

fosphenytoin may be used if seizures are uncontrollable (HSDB 1998). Use of anticonvulsants 

(especially in children and other susceptible individuals) should include careful monitoring of 

hypotension, respiratory depression, and the need for endotracheal interbation. In the liver, γ-HCH is 

thought to produce oxidative stress by inducing oxidative enzymes such as cytochrome P-450 and 

depleting hepatic glutathione content (Barros et al. 1988, 1991; Srinivasan and Radhakrishnamurty 1988; 

Videla et al. 1991). Another possible mechanism for hepatic toxicity is increased lipid metabolism 

(Ravinder et al. 1990; Srinivasan and Radhakrishnamurty 1988). It is possible that interfering with these 

mechanisms can decrease the toxicity of HCH. 
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3. HEALTH EFFECTS 

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 HCH is available. Where adequate information is not 

available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the 

iniiation of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of HCH. 

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. 

Most of the literature reviewed concerning the health effects of inhaled α-, β-, γ-, or δ-HCH in humans 

consists of case reports of individuals occupationally exposed or exposed in the home by a γ-HCH 

vaporizer. The predominant route of exposure in occupational studies is presumed to be inhalation, 

although dermal exposure is also likely. The health effects in humans associated with ingested HCH are 

reported primarily in case studies in which individuals ingested pesticide pellets or therapeutic lotions 

containing γ-HCH to control scabies, and in several epidemiological studies where exposure is likely 

through ingestion of pesticide residues in the diet. Information concerning the health effects of HCH in 

humans following dermal exposure is limited to case studies of individuals who have misused therapeutic 

lotions containing γ-HCH to control scabies and head and body lice. The duration and level of exposure 

to HCH generally cannot be quantified from the information presented in these reports. In addition, the 

case study reports in humans are limited because concomitant exposure to other toxic substances or other 

substances present in the atmosphere may have occurred. 

Limited information was found regarding the health effects of γ-HCH following inhalation exposure in 

animals. The health effects of α-, β-, γ-, and δ-HCH following oral exposure have been well documented 

in a variety of species. Limited information is available concerning the health effects of technical-grade 

HCH and γ-HCH following dermal exposure. 
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3. HEALTH EFFECTS 

γ-HCH is the isomer most thoroughly tested in intermediate- and chronic-duration studies. The 

carcinogenic effects of technical-grade HCH and α-, β-, and γ-HCH have been examined, but the 

carcinogenic potential of δ-HCH has not been as well studied. Studies on the long-term effects of dermal 

exposure to γ-HCH are inadequate for the determination of carcinogenicity status. 

3.12.1 Existing Information on Health Effects of Hexachlorocyclohexane 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

HCH are summarized in Figure 3-7. The purpose of this figure is to illustrate the existing information 

concerning the health effects of HCH. 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. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. Occasional case reports are available for humans who have had adverse 

health effects, including irritation of the nose and throat and death, from excessive inhalation exposure 

from γ-HCH vaporizers (Conley 1952; Loge 1965). Oral exposure to large amounts has resulted in a few 

human deaths (Storen 1955; Sunder Ram Rao et al. 1988) and adverse neurological, musculoskeletal, and 

renal effects (Munk and Nantel 1977; Sunder Ram Rao et al. 1988). When applied dermally, γ-HCH has 

also been shown to have adverse effects such as pulmonary and epicardial petechiae, aplastic anemia, and 

rashes in a few humans (Davis et al. 1992; Fagan et al. 1981; Rauch et al. 1990). The level of exposure in 

the human studies generally cannot be quantified because the information is derived from anecdotal case 

reports. Therefore, there is little reliable information in humans associating dose with effect. Such 

information might allow investigators to establish thresholds for systemic toxicity due to acute exposure, 

although it is not necessarily a priority data need. 
HEXACHLOROCYCLOHEXANE 156 

3. HEALTH EFFECTS 

Figure 3-7. Existing Information on Health Effects of α-, β-, γ-, and δ-HCH 

Inhalation 

Oral 

Dermal 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Existing Studies 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Animal 
HEXACHLOROCYCLOHEXANE 157 

3. HEALTH EFFECTS 

Information on health effects (death and neurological) following acute inhalation of γ-HCH in animals 

(Klonne and Kintigh 1988; Oldiges et al. 1980; Ullmann 1986b) is limited. Neurological effects 

following acute inhalation exposure to γ-HCH include excitation, sedation, ataxia, and spasms (Ullmann 

1986b). Acute inhalation studies for the other HCH isomers and technical-grade HCH are not available. 

No acute inhalation MRL was developed because of insufficient data. Additional acute inhalation data 

are needed for all isomers (e.g., threshold, dose-response, and target organ). This information is 

necessary for determining levels of significant human exposure to hexachlorocyclohexane and the 

associated effects following exposure. 

Acute oral studies in animals exposed to γ-HCH have reported death in rats (Gaines 1960) and mice (Liu 

and Morgan 1986); neurological effects in rats including enhanced susceptibility to kindling (Gilbert and 

Mack 1995; Joy et al. 1982), reduced brain serotonin level (Attia et al. 1991), reduced brain barrier 

permeability in 10-day-old pups (Gupta et al. 1999), and neurobehavioral changes (Hughes 1999a); 

increased hepatic microsomal mixed-function oxidase activity in mice (Oesch et al. 1982); increased 

hepatic cytochrome P-450 and P-450-dependent enzyme levels and increased absolute liver weight 

(Parmar et al. 2003), and degeneration of renal tubular epithelia in rats (Srinivasan et al. 1984). Oral 

exposure to β-HCH has resulted in an increase in hepatic cytochrome P-450 levels, and renal tubular 

degeneration in rats (Ikegami et al. 1991b; Srinivasan et al. 1984). Exposure to technical-grade HCH has 

resulted in hepatic focal necrosis, fatty changes, and enzyme activation and renal hemorrhage (Dickshith 

et al. 1990; Phillip et al. 1989; Ravinder et al. 1989). An acute oral MRL of 0.5 mg/kg/day for β-HCH 

has been developed based on ataxia in mice (Van Velsen et al. 1986). Additional studies that examine 

systemic effects (e.g., cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, and renal) 

following acute oral exposure to all HCH isomers would be helpful. Acute dermal studies in rats are 

available on γ-HCH and technical-grade HCH (Dikshith et al. 1991c; Gaines 1960). Acute dermal 

exposure of rats to γ-HCH (Gaines 1960) or of guinea pigs to technical-grade HCH (Dikshith et al. 1978) 

was associated with lethality. Additional acute dermal data in animals are needed, for example, threshold, 

dose-response, and target organs. This information is necessary for determining levels of significant 

human exposure to HCH and the associated health effects following dermal exposure, and is particularly 

important for γ-HCH given the use of γ-HCH in shampoos and lotions for the pharmaceutical treatment of 

scabies and head lice. 

Intermediate-Duration Exposure. Information on human health effects of repeated exposure to 

HCH is available from studies of occupationally exposed individuals (Kashyap 1986); no information is 
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3. HEALTH EFFECTS 

available on the effects of repeated oral or dermal exposure in humans. EEG abnormalities and increased 

liver enzymes have been observed in factory workers involved in the production of technical-grade HCH 

(Kashyap 1986). The exact duration and level of exposure in the human studies are often not provided in 

the studies. Such information would allow investigators to determine health effects associated with 

known levels of exposure. 

Intermediate-duration inhalation studies of γ-HCH have been performed in rats with mortality reported 

(Klonne and Kintigh 1988). Inhalation of 603 mg/m3 γ-HCH for 4 hours or 5 mg/m3

 for 90 days has not 

resulted in adverse respiratory, hematological, hepatic, or renal effects in rats (Oldiges et al. 1983). 

However, the data are insufficient for developing an intermediate-inhalation MRL. Additional 

intermediate-inhalation data in animals are needed (e.g., threshold, dose-response, and target organs). 

This information is necessary for determining levels of significant human exposure to HCH and the 

associated health effects following inhalation. 

Intermediate-duration oral studies have been performed in animals. Oral γ-HCH did not affect the 

hematological parameter in rats (Suter 1983) and dogs (Rivett et al. 1978). A decrease in blood cell 

numbers was observed in rats fed β-HCH (Van Velsen et al. 1986) and technical-grade HCH (Joseph et 

al. 1992c). The endocrine effects of γ-HCH exposure were reported in ewe lambs (Beard and Rawlings 

1999) and young rams (Beard et al. 1999a) given 1 mg/kg/day in treated feed from conception to sexual 

maturity. In ewes, effects included increased pulse frequency of serum luteinizing hormone, slower 

increase and earlier decrease of progesterone levels, and lower T4 levels. In young rams, observed 

endocrine effects included lower serum luteinizing hormone and estrodiol concentrations. While serum 

testosterone levels were similar across treatment groups, the γ-HCH treated rams showed attenuated 

testosterone response to stimulation with gonadotropin releasing hormone. Hepatic effects in animals 

following γ-HCH exposure included an increase in P-450-dependent enzymes, hypertrophy, necrosis, and 

cancer (Hanada et al. 1973; Ito et al. 1973; Parmar et al. 2003; Suter 1983). Hepatic effects in animals, 

following exposure to β-HCH, included cellular hypertrophy and necrosis (Hanada et al. 1973; Ito et al. 

1973; Van Velsen et al. 1986); α-HCH induced hepatic effects included enzyme activation, hypertrophy, 

necrosis, and cancer (Barros et al. 1991; Hanada et al. 1973; Ito et al. 1973). Hepatic effects from 

technical-grade HCH exposure in animals included changes in enzyme activities and enlargement of 

hepatocytes, nuclear pyknosis, and vacuolation (Dikshith et al. 1989a, 1991a; Fitzhugh et al. 1950; Karnik 

et al. 1981; Joseph et al. 1992b). Renal effects from γ-HCH exposure included nephritis, accumulation of 

protein droplets, hypertrophy, and necrosis (Suter 1983); nephritis was observed following α-HCH 

exposure (Fitzhugh et al. 1950). Exposure to β-HCH has resulted in calcinosis and nephritis (Fitzhugh et 
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3. HEALTH EFFECTS 

al. 1950; Van Velsen et al. 1986); technical-grade HCH exposure has resulted in nephritis and tubular 

necrosis (Dikshith et al. 1991a; Fitzhugh et al. 1950). Two MRLs have been derived for intermediateduration oral exposure in animals. An intermediate oral MRL of 0.0006 mg/kg/day for β-HCH has been 

developed based on hepatic effects in rats (Van Velsen et al. 1986). An intermediate oral MRL for 

γ-HCH of 0.00001 mg/kg/day has also been developed based on immunological effects in mice (Meera et 

al. 1992). Insufficient data are available to derive an intermediate-duration oral MRL for α-HCH; 

additional studies using known or possible sensitive end points, including reproductive and 

immunological indices, could address this data need. 

Intermediate-duration dermal studies have been performed in rabbits, guinea pigs, and rats; some deaths 

were observed following exposure to γ-HCH (Brown 1988). There are limited data pertaining to systemic 

effects (e.g., increased respiratory rate and wheezing, hepatic hypertrophy, and basophilic renal tubules) 

and neurological effects (e.g., hyperactivity, ataxia, and convulsions) in rats following intermediateduration dermal exposure to γ-HCH (Brown 1988). Death and systemic effects (e.g., hepatic hypertrophy 

and fatty degeneration and renal tubular necrosis) have been observed in rats (Dikshith et al. 1991c); 

hepatic hypertrophy and enzyme activation were observed in guinea pigs (Dikshith et al. 1978) following 

intermediate-duration dermal exposure to technical-grade HCH. Additional intermediate-dermal data in 

animals are needed (e.g., threshold, dose-response, and target organs). This information is necessary for 

determining levels of significant human exposure to HCH and the associated health effects following 

dermal exposure. 

Chronic-Duration Exposure and Cancer. Controlled epidemiological studies have been 

conducted in humans exposed to HCH, but are few in number and limited in scope. Hematological 

effects have been observed in persons exposed to γ-HCH in the workplace via the inhalation and/or 

dermal route (Brassow et al. 1981; Jedlicka et al. 1958). A number of case reports are available from 

individuals who had exposure to γ-HCH in the home, during the handling of the pesticide, or from a 

nearby formulating plant (Danopoulos et al. 1953; Friberg and Martensson 1953; Gewin 1939; Loge 

1965; Mendeloff and Smith 1955). Effects that have been described in these case reports include 

hematological effects including granulocytopenia, aplastic anemia, paramyeloblastic leukemia, and 

pancytopenia. Blood levels of HCH, and its isomers (α, β, and γ), were found to be higher in women with 

breast cancer when compared to healthy women without the disease (Mathur et al. 2002). α- and γ-HCH 

blood levels were significantly higher in breast cancer patients, 41–50 years of age, compared to women 

of the same age without the disease. β-HCH blood levels were found significantly higher in breast cancer 

patients, 31–50 years of age, compared to those without the disease (Mathur et al. 2002). Other 
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organochlorine pesticides, including DDT and its metabolites, were also present in the blood and could 

have contributed to the incidence of breast cancer. Exposure to HCH, and other organochlorine 

pesticides, to the population is likely through food where the pesticides are primarily used for agricultural 

applications; however, other possible environmental contamination pathways include inhalation and 

dermal routes of exposure. 

No chronic-duration inhalation studies in animals are available for any isomer. Altered renal excretions 

and hepatic hypertrophy and have been observed in chronic oral studies on rats with γ-HCH (Amyes 

1990). A chronic oral MRL of 0.008 mg/kg/day for α-HCH has been developed based on hepatic effects 

in rats (Fitzhugh et al. 1950). Chronic dermal studies in animals are not available. Since there are 

insufficient data to develop inhalation and dermal chronic-duration MRLs, further data from the 

inhalation and dermal routes are needed (e.g., threshold, dose-response, and target organs). This 

information is needed for determining levels of significant human exposure to HCH and the associated 

health effects. However, the need for dermal studies is not a priority as data on skin absorption can be 

used to calculate equivalent oral doses. 

Use of γ-HCH pesticides by farmers was associated with a 50% increased risk of non-Hodgkin’s 

lymphoma (Blair et al. 1998). However, a causal relationship could not be determined due to 

confounding effects such as use of other pesticides. Limited chronic dermal data in humans are available 

(Davis et al. 1993), but chronic oral data in humans are not available. There are no inhalation studies in 

animals. Several chronic toxicity/carcinogenicity bioassays have been conducted in animals following 

oral exposure to technical-grade HCH and α-, β-, γ-, and δ-HCH (Hanada et al. 1973; Ito et al. 1975; 

Karnik et al. 1981; Kashyap et al. 1979; Munir et al. 1983; NCI 1977; Thorpe and Walker 1973; Wolff et 

al. 1987). Chronic dermal exposure to technical-grade HCH caused liver cancer in mice (Kashyap et al. 

1979). However, the results were not useful in determining carcinogenic potential because of limitations 

of these studies, such as testing only one dose and the potential for oral ingestion. 2,4,6-Trichlorophenol, 

a metabolite of γ-HCH, may be responsible for some or all of the carcinogenic activity observed in mice. 

This metabolite has been classified by EPA as a group B2 carcinogen. Pentachlorocyclohexene epoxide, 

a metabolite of γ-HCH that has been identified in the liver of rats, may also be responsible for the 

carcinogenic effects of γ-HCH. Cancer classifications of several HCH isomers have been made by the 

U.S. Department of Health and Human Services (DHHS) and the EPA. EPA has classified technicalgrade HCH, α-HCH, β-HCH, and δ-HCH as B2, B2, C, and D, carcinogens, respectively (EPA 1998a). 

γ-HCH has not been assigned a cancer classification by EPA. Additional carcinogenicity information 

would not be needed at this time. DHHS has classified γ-HCH and other HCH isomers as “reasonably 
HEXACHLOROCYCLOHEXANE 161 

3. HEALTH EFFECTS 

anticipated to be human carcinogen” in the 8th Report on Carcinogens (DHHS 1998). The International 

Agency for Research on Cancer (IARC) has classified HCH isomers as Group 2B, possibly carcinogenic 

to humans. 

Genotoxicity. HCH did not produce chromosomal aberrations in humans exposed primarily by 

inhalation (Kiraly et al. 1979). Dominant lethal mutations occurred in mice orally exposed to technicalgrade HCH (Lakkad et al. 1982). Increased frequency of polyploid cells occurred in rats exposed orally 

to α-HCH (Hitachi et al. 1975). Information on the genotoxic effects of γ-HCH is also obtained from in 

vitro studies. Gene mutations were observed in bacteria treated with γ-HCH (with and without metabolic 

activation) (Moriya et al. 1983; Nagy et al. 1975). γ-HCH was not mutagenic in yeast (Shahin and von 

Borstel 1977) or algae (Kar and Singh 1979a). Results of chromosomal aberration tests in γ-HCH-treated 

hamster cells were questionable (Ishidate and Odashima 1977). Technical-grade HCH produced 

chromosomal aberrations in cultured human lymphocytes (Rupa et al. 1989d) but did not produce 

cytogenetic effects in Chinese hamster cells (Murli 1990) or unscheduled DNA synthesis in rat 

hepatocytes (Cifone 1990). Human mammary carcinoma MCF-7 and human prostate carcinoma PC-3 

cell lines showed that low concentrations of γ-HCH induced increases in micronuclei in both cell lines in 

the absence of DNA damage or cytotoxicity, suggesting a clastogenic effect for this chemical (Kalantzi et 

al. 2004). In general, the available information suggests that α-, β-, and γ-HCH may have some genotoxic 

potential; however, the evidence is not conclusive. Further testing in clastogenicity and genotoxicity tests 

in vivo would be valuable. 

Reproductive Toxicity. The only available human data are from one study on hormone levels in 

pesticide workers in which increases in the levels of serum luteinizing hormone were noted following 

exposure to γ-HCH for 8 years (Tomczak et al. 1981). There are no inhalation data in animals for any 

HCH isomer. Anti-estrogenic properties were found in female rats given γ-HCH by the oral route 

(Chadwick et al. 1988), and female rabbits treated orally with γ-HCH had a reduced ovulation rate 

(Lindenau et al. 1994). γ-HCH exposure in female mice and their offspring on gestational days 9–16 

resulted in slightly increased relative uterus weight in F1 females, and earlier vaginal opening and 

increased branching of villi and oedema in the endometrial stroma in treated mice (Maranghi et al. 2003). 

Reductions in testicular and epididymis weights, spermatid and sperm numbers, and serum testosterone 

level were found in male rats exposed to relatively low doses of γ-HCH during lactation and evaluated at 

puberty and adulthood (Dalsenter et al. 1997b). Effects on testicular histology and sperm numbers 

similarly occurred in adult male offspring of mice that were exposed to γ-HCH during gestation (Traina et 

al. 2003). Reproductive effects of γ-HCH exposure were reported in ewe lambs (Beard and Rawlings 
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3. HEALTH EFFECTS 

1999) and young rams (Beard et al. 1999a) given 1 mg/kg/day in treated feed from conception to sexual 

maturity. In estrus synchronized ewes, treated animals had significantly shorter estrous cycle length and 

lower number and less total volume of corpus lutea. No other detrimental fertility effects were observed. 

The subjectively-scored sexual behavior in young rams was significantly reduced in treated animals 

presented with estrous ewes. Developmental/reproductive effects in male rats were used as the basis for 

an acute-duration MRL for oral exposure to γ-HCH. Results of single and multigeneration reproduction 

studies in rats and mink indicate that exposure to γ-HCH or technical HCH caused effects, such as 

decreased numbers of offspring at birth, reduced neonatal viability, and delayed maturation of pups, that 

were primarily results of prenatal and/or postnatal developmental toxicity (Beard and Rawlings 1998; 

Beard et al. 1997; King 1991; Srivastava and Raizada 2000). Oral exposure of rats and mice to β- or 

technical-grade-HCH has resulted in degeneration of male reproductive organs and sperm abnormalities 

(Dikshith et al. 1991a; Gautam et al. 1989; Nigam et al. 1979; Pius et al. 1990; Roy Chowdhury and 

Gautam 1990; Van Velsen et al. 1986), and ovarian atrophy was observed in rats exposed to β-HCH for 

13 weeks (Van Velsen et al. 1986). Similar effects were also observed in reproductive organs of rats 

following dermal treatment with technical-grade HCH for 120 days (Prasad et al. 1995). The 

reproductive effects on guinea pigs after dermal exposure to technical-grade HCH (100–500 mg/kg/day) 

have also been investigated (Dikshith et al. 1978). Testicular hypertrophy and atrophy and complete 

inhibition of spermatogenesis were observed in the guinea pigs. Studies via the inhalation and dermal 

routes would provide information regarding the reproductive effects of HCH in animals for these 

exposure routes and could be useful in the assessment of potential reproductive effects in humans. 

Pharmacokinetic data suggest that HCH isomers might have the potential to affect reproduction across 

routes of exposure, although data are insufficient to predict effect levels. 

Developmental Toxicity. Developmental effects in humans, specifically IUGR, may result from oral 

exposure to HCH (Siddiqui et al. 2003). The blood of mothers with IURG babies had higher levels of γ-, 

α-, δ-, and total HCH. Similarly, γ-, δ-, and total HCH cord blood levels of IUGR babies were higher 

than the cord blood levels in the normal-weight babies (Siddiqui et al. 2003). Other organochlorine 

pestides, including DDT and its metabolites, were also present in the blood, and could have contributed to 

IUGR. There are no inhalation data in animals for any isomer. No adverse prenatal developmental 

effects of γ-HCH from oral exposure have been found in rats or rabbits (Khera et al. 1979; Palmer et al. 

1978a; Seiler et al. 1994) or from exposure to technical-grade HCH in mice (Dikshith et al. 1990). 

Alterations in neurotransmitter levels were noted in suckling rats treated once with γ-HCH by gavage 

(Rivera et al. 1991). γ-HCH exposure in F1 females of female mice treated on gestational days 9–16, 

resulted in slightly increased relative uterus weight (Maranghi et al. 2003). An acute oral MRL of 
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3. HEALTH EFFECTS 

0.003 mg/kg/day has been developed from data on developmental/reproductive effects in mature male 

offspring of rats that were exposed to γ-HCH during lactation; these effects included reduced testicular 

and epididymis weights, reduced spermatid and sperm numbers, and alterations in mating behavior 

(Dalsenter et al. 1997b). Decreases in fetal weight, fetal thymic weight, and placental weight have been 

reported in mice exposed to a single oral dose of γ-HCH on day 12 of gestation (Hassoun and Stohs 

1996a). No effects on embryonic development were seen in rabbits treated orally with γ-HCH (Seiler et 

al. 1994). 

Alterations in neurotransmitter levels were observed in female rat pups treated orally with technical-grade 

HCH (Nagaraja and Desiraju 1994). No data on the developmental effects of α-, β-, or δ-HCH were 

located for the oral or dermal route and there is no information for dermal exposure to technical-grade 

HCH. Due to the lack of developmental toxicity studies in humans, as well as the lack of inhalation and 

dermal data in animals, insufficient information is available to indicate whether HCH affects development 

via all three routes of exposure. Pharmacokinetic data suggest that HCH isomers might have the potential 

to affect development across routes of exposure. Additional developmental studies in animals exposed to 

α-, β-, or δ-HCH would provide useful information concerning possible fetotoxic and teratogenic effects 

in animals, which might be relevant to humans. 

Immunotoxicity. A statistically significant increase (approximately 18%) in IgM has been reported in 

individuals occupationally exposed to technical-grade HCH (Kayshap 1986). The HCH isomer 

concentrations in serum showed a 10-fold increase when compared to the control. There are no oral or 

dermal data in humans. Also, there are no inhalation or dermal data in animals. Depressed antibody 

response to Salmonella antigens was reported in rats (Dewan et al. 1980) and rabbits (Desi et al. 1978) 

exposed to γ-HCH via the oral route. γ-HCH exposure has been shown to result in thymus cortex 

atrophy, suppressed bone marrow cellularity, erythrocyte precursors, and granulocyte-macrophage 

progenitor cells in mice (Hong and Boorman 1993). Based on immunological effects of γ-HCH on 

components of cell- and humoral-mediated immunity in mice, an intermediate oral MRL has been 

developed (Meera et al. 1992). Decreased lymphoproliferative responses to T-cell mitogens were 

observed in mice treated by the oral route with β-HCH (Cornacoff et al. 1988). No immunological effects 

were observed in rats treated with β-HCH by the oral route for 13 weeks (Van Valsen et al. 1986). There 

are no immunotoxicity data for technical-grade HCH. The biological significance of increased 

immunoglobulin levels remains to be established. In addition, exposure to technical-grade or γ-HCH may 

also affect the immune system in humans (Kashyap 1986) and animals (Desi et al. 1978; Dewan et al. 
HEXACHLOROCYCLOHEXANE 164 

3. HEALTH EFFECTS 

1980). Further studies on all isomers using all three routes of exposure would be useful in the assessment 

of potential immunotoxic effects in humans. 

Neurotoxicity. Exposure to γ-HCH and other isomers has been shown to be associated with 

neurological effects in both humans and animals, and there is no basis to suspect that these effects may be 

route-, species-, or age-dependent. Paresthesia has been reported in workers exposed via the inhalation or 

dermal routes (Fonseca et al. 1993; Kashyap 1986). Abnormal EEG patterns have also been noted in 

workers (Czegledi-Janko and Avar 1970). Seizures and coma have been observed in individuals who 

have ingested large amounts of γ-HCH (Davies et al. 1983; Harris et al. 1969; Munk and Nantel 1977; 

Nantel et al. 1977; Powell 1980; Starr and Clifford 1972; Storen 1955). Convulsions have been reported 

in children following dermal application of γ-HCH (Ramchander et al. 1991; Tenebein 1991). 

Neurological effects including sedation, restlessness, excitation, and ataxia were seen in rats exposed by 

inhalation to γ-HCH for 4 hours (Ullmann 1986b). Mice exposed via the inhalation route to γ-HCH in a 

chronic study did not display any neurotoxic signs (Klonne and Kintigh 1988). Convulsions have been 

observed in rats and mice following oral exposure to γ-HCH (Arisi et al. 1994; Attia et al. 1991; Gilbert 

1995; Gilbert and Mack 1995; Joy et al. 1982; Martinez and Martinez-Conde 1995; Martinez et al. 1991; 

Parmar et al. 2003; Vendrell et al. 1992a; Wooley and Griffith 1989). Less serious neurological effects of 

oral exposure to γ-HCH in rats included reduced brain serotonin level, reduced brain barrier permeability 

in pups, decreased myelin and enzyme activity in brain, reduced tail nerve conduction velocity, enhanced 

susceptibility to kindling, motor activity changes, and other neurobehavioral alterations (Attia et al. 1991; 

Hughes 1999a; Joy et al. 1982; Muller et al. 1981; Serrano et al. 1990a). Oral exposure of mice and rats 

to β-HCH has resulted in lateral recumbency, coma, and reduced tail nerve conduction velocity 

(Cornacoff et al. 1988; Muller et al. 1981; Van Velsen et al. 1986). Rats and mice exposed orally to 

technical-grade HCH experienced convulsions, increased motor activity, and variations in 

neurotransmitter levels (Anand et al. 1991; Dikshith et al. 1991a; Gopal et al. 1992; Kashyap et al. 1979). 

Neurological effects were not observed in rats following oral exposure to α-HCH (Muller et al. 1981). 

Information is available on the neurotoxic effects of α-, β-, and γ-HCH in experimental animals following 

acute-duration oral exposure (Tilson et al. 1987; Tusell et al. 1987; Woolley and Griffith 1989) and 

intermediate-duration oral exposure (Desi 1974; Muller et al. 1981; Van Velsen 1986). An acute oral 

MRL of 0.2 mg/kg/day for β-HCH was developed based on ataxia in mice (Cornacoff et al. 1988). 

Studies in animals have substantiated the neurological symptoms resulting from dermal application of 

γ-HCH. Effects in rats included sedation, spasms (Ullmann 1986a), tremors, and convulsions (Brown 

1988). Neurochemical and neurophysiological studies in animals exposed via the oral route would 

provide useful information regarding the mechanisms of HCH-related neurotoxic effects. Because an 
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3. HEALTH EFFECTS 

MRL could not be developed for inhalation exposures and dermal data are limited, additional studies for 

all isomers for these two exposure routes are needed. 

Epidemiological and Human Dosimetry Studies. Information on the adverse health effects of 

HCH in groups of humans comes from reports of occupationally exposed individuals (Brassow et al. 

1981; Jedlicka et al. 1958; Kayshap 1986). Adverse health effects include EEG abnormalities, increased 

liver enzymes, and changes in hematological parameters. Limitations inherent in these studies include 

unquantified exposure concentrations and durations and concomitant exposure to HCH mixtures and other 

chemicals and pesticides. The few industrial surveys and studies of exposed individuals generally 

reported blood levels of HCH following exposure and the health effects associated with these levels 

(Czegledi-Janko and Avar 1970). However, the reported blood levels of HCH have not been 

quantitatively correlated with ambient HCH levels or health effects. Studies that provide information 

correlating exposure levels with body levels of HCH would allow investigators to monitor humans for 

exposure, including populations living near hazardous waste sites. Well-conducted studies are needed to 

determine and quantifying the effects of inhalation, oral, or dermal HCH exposure on human health 

including neurological, hematologic, and hepatic effects. However, considering the magnitude of the 

needed studies, possible difficulty in identifying a suitable potentially exposed subpopulation in the 

general populace or workplace, and lowered likelihood of exposure in present day society, the value of 

such studies is questionable. 

Biomarkers of Exposure and Effect. 

Exposure. Methods exist for the analysis of HCH in blood and urine (Angerer et al. 1981). Thus, 

biological monitoring for exposure to HCH is possible by measuring the levels of HCH in the blood or 

urine. In an occupational study, abnormal EEG changes were found to correlate with blood levels of 

γ-HCH (Czegledi-Janko and Avar 1970). Measurements of γ-HCH represent short-term exposure 

because it is metabolized and excreted rapidly. Due to its high lipid solubility and persistence, β-HCH 

level represents long-term exposures. β-HCH has been measured in numerous human tissues and is the 

isomer that is consistently detected at the highest concentration (Baumann et al. 1980; Kashyap 1986; 

Morgan and Lin 1978; Nigam et al. 1986; Ramachandran et al. 1984). However, the reported blood 

levels of HCH have not been quantitatively correlated with ambient HCH levels. Methods that measure 

the levels of HCH metabolites in urine are not specific enough to detect exposure to HCH alone. More 

information could be provided by studies designed to correlate biomarkers of exposure with exposure 

levels. 
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3. HEALTH EFFECTS 

Effect. No biomarkers of effect, specific for HCH, have been identified in the literature. Nonspecific 

biomarkers of effect include EEG abnormalities, increases in liver enzymes, hematological effects, 

seizures and convulsions, neuropsychological, and gastrointestinal effects (Kashyup 1986; Nigam et al. 

1986). Muscle spasms and EEG abnormalities have also been observed in workers exposed to γ-HCH 

(Czegledi-Janko and Avar 1970). High levels of HCH and other organochlorine insecticides have been 

detected in men with low sperm counts and in women who miscarry or deliver prematurely (Pines et al. 

1987; Saxena et al. 1980; Wassermann et al. 1982). No quantitative correlation can be made between 

body levels of HCH and adverse health effects based on the existing data. Studies quantitatively 

correlating HCH exposure with body levels of HCH and the occurrence of specific adverse health effects 

are needed to monitor populations possibly exposed near hazardous waste sites. Studies designed to 

identify specific biomarkers of effect for HCH would be useful. 

Absorption, Distribution, Metabolism, and Excretion. Information is available to assess the 

extent and rate of HCH absorption following oral exposure in animals and humans (Ahdaya et al. 1981; 

Albro and Thomas 1974; Turner and Shanks 1980). High blood concentrations of γ-HCH have been 

demonstrated in a number of acute poisoning cases in which humans were exposed to γ-HCH as the result 

of ingestion (Berry et al. 1987). Animal studies indicate that γ-HCH is readily absorbed from the 

gastrointestinal tract (Ahdaya et al. 1981). Both in vivo and in vitro studies that evaluate dermal 

absorption of γ-HCH in humans are available (Dick et al. 1997a, 1997b). However, absorption of HCH 

via inhalation can only be inferred from toxicity studies and studies assessing the distribution and 

excretion of γ-HCH. No quantitative information is available to assess the rate and extent of inhalation 

absorption in humans or animals. Additional data concerning the absorption of HCH in animals may 

provide information to assist in characterizing absorption of HCH in humans. 

Information on the distribution of HCH isomers in humans is inferred from case studies, clinical studies, 

and industrial surveys (Baumann et al. 1980; Nigam et al. 1986; Siddiqui et al. 1981a). Air 

concentrations of α-, β-, and γ-HCH have been found to be associated with blood serum levels in workers 

(Baumann et al. 1980). HCH isomers have been detected in the adipose tissue of workers (Baumann et al. 

1980). γ-HCH was detected in the cerebral spinal fluid of a young boy following ingestion of γ-HCH 

(Davies et al. 1983). γ-HCH was detected in brain tissue collected during the autopsy of an infant who 

was treated with a whole-body application of γ-HCH lotion (Davies et al. 1983). The distribution of HCH 

in animals following oral exposure has been well documented (Chand and Ramachandran 1980; Eichler et 

al. 1983; Srinivasan and Radhakrishnamurty 1983b). γ- and β-HCH were found to be primarily stored in 
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3. HEALTH EFFECTS 

the fat of rats after acute oral exposure. Except in the brain, β-HCH accumulates in tissues to a greater 

degree than γ-HCH. α-HCH has been shown to accumulate preferentially in the white matter of the brain 

(Portig et al. 1989). Data exist on the rate and overall distribution of HCH in animals following dermal 

application. In guinea pigs, the accumulation of γ-HCH in the brain was greater than in the blood 

following acute dermal exposure (Solomon et al. 1977a, 1977b). 

The metabolism of γ-HCH has been studied in mice and rats (Chadwick and Freal 1972a; Chadwick et 

al. 1978a; Engst et al. 1979; Kujawa et al. 1977). Researchers have identified the primary metabolites 

(di-, tri-, and tetrachlorophenols) in humans, rats, and mice. In humans, this information is obtained from 

urinary excretion studies in which individuals were occupationally exposed to γ-HCH (Angerer et al. 

1983; Engst et al. 1979). In vitro studies using rat liver microsomes have helped to delineate the major 

metabolic processes and have demonstrated the formation of a reactive epoxide that may be indicative of 

similar processes in other mammals and humans (Fitzloff and Pan 1984). Investigations have not been 

conducted to examine the epoxide formation in vivo or its role in inducing mutagenic and carcinogenic 

effects. Extensive metabolic studies have been conducted in animals, and adequate studies exist 

identifying major metabolites in the tissues and urine (Chadwick and Freal 1972a; Kujawa et al. 1977; 

Macholz et al. 1982a, 1982b). Multiple detoxification pathways have been delineated (Chadwick et al. 

1978a, 1981; Kujawa et al. 1977). Further information on the possible role of epoxide formation in 

carcinogenesis in vivo, as well as its rate of formation under various conditions, would be useful. 

Information from occupational studies and studies in which γ-HCH was used as a therapeutic lotion is 

available to conclude that humans excrete HCH, principally as metabolites, in urine, breast milk, and 

semen (Angerer et al. 1981). Urinary excretion of γ-HCH metabolites by humans has been documented 

(Angerer et al. 1983). The primary urinary metabolites of γ-HCH are chlorophenols. Quantitative 

information also exists to conclude that the primary route of HCH excretion in animals, following oral 

exposure, is urine (Chadwick et al. 1985). There are no inhalation studies that have examined the 

excretion of HCH. In male rats treated dermally with radiolabelled γ-HCH, radiolabel was detected in the 

urine (Bosch 1987a). 

Comparative Toxicokinetics. Evidence is available to suggest that rats and humans absorb HCH 

and store the isomers primarily in the fat and other body tissues (Chand and Ramachandran 1980; Eichler 

et al. 1983; Srinivasan and Radhakrishnamurty 1983b). Similar metabolites have been identified in the 

urine of exposed individuals and treated rodents, and in both, the primary route of excretion is the urine 

(Angerer et al. 1981; Chadwick et al. 1985). 
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Exposure to γ-HCH has been shown to be associated with neurological effects in both humans and 

animals (Czegledi-Janko and Avar 1970; Kashyap 1986; Van Velsen et al. 1986). The available human 

and animal data also suggest that HCH isomers may affect the blood system. In addition, HCH isomers 

may also affect the immune system in humans (Kashyap 1986) and animals (Desi et al. 1978; Dewan 

et al. 1980). Further studies are not needed at this time. 

Methods for Reducing Toxic Effects. Seizures caused by γ-HCH can be antagonized by GABAA 

mimetics; diazepam is the anticonvulsant of choice (Ellenhorn and Barceloux 1988). Information is 

available to assess the extent and rate of absorption of HCH following oral and dermal exposure (Ahdaya 

et al. 1981; Albro and Thomas 1974; Turner and Shanks 1980), although the mechanism(s) of absorption 

is inadequately characterized. The available data indicate some ways in which peak absorption of HCH 

might be reduced following oral or dermal exposure (Ellenhorn and Barceloux 1988). Intestinal 

absorption can be reduced with activated charcoal, while washing with soap and water can decrease skin 

absorption. There are no known methods for reducing absorption following inhalation exposure. 

Because of the high volume of distribution of HCH into adipose tissue, traditional methods of increasing 

elimination or decreasing distribution are not useful. Development of methods to enhance the excretion 

of HCH from adipose tissue, while minimizing toxicity, is needed for reducing the body burden. 

There is some information on the mechanism (see Section 3.4) for the toxic effects of HCH on the brain 

(e.g., interference with the GABA system) (Abalis et al. 1985; Casida and Lawrence 1985; Lawrence and 

Casida 1984) and liver (e.g., disruption of oxidative defense mechanisms) (Barros et al. 1988, 1991; 

Srinivasan and Radhakrishnamurty 1988; Videla et al. 1991). Further studies in these areas might be 

helpful for developing methods for reducing toxic effects. 

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. 

Limited data are available on the health effects of HCH on exposed children. 

It has been demonstrated that weanling rabbits were more sensitive to γ-HCH than young adults, as seen 

by increased mortality rate and associated excitement and convulsions after treatment (Hanig et al. 1976). 
HEXACHLOROCYCLOHEXANE 169 

3. HEALTH EFFECTS 

There is, however, no actual evidence that children are more sensitive to the neurotoxicity of γ-HCH. It 

would be useful to follow up on the weanling rabbits study and conduct additional studies on immature 

postnatal animals as an experimental model. Data needs relating to developmental effects are discussed 

above in developmental toxicity section. Replicating the Dalsenter et al. (1997b) study on lactational 

exposure and adult testosterone levels should be a priority. There is inadequate experimental evidence to 

determine if pharmacokinetics of HCH in children are different from adults. There is no experimental 

evidence to indicate whether metabolism of HCH or its mechanism of action is different in children 

compared with adults. Generally, it would be difficult to have data on the metabolism and mechanism of 

action of HCH in children (except in accidentally exposed children) to determine whether children are 

more vulnerable than adults to adverse health effects from exposure to HCH. There are no biomarkers of 

exposure or effect that have been validated in children or adults exposed as children. There are no data to 

determine whether there are any interactions with other chemicals that are unique to children or whether 

interactions observed in adults also occur in children. Although HCH is shown to have some genotoxic 

potential, it is not known whether parental exposure to HCH may affect children via parental germ cells, 

or whether HCH may indirectly affect the fetus during maternal exposure. Additional data are needed to 

determine the potential for genotoxicity in germ cells and adverse developmental effects. 

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 

Federally sponsored research regarding health effects of HCH that was reported in the CRIS/USDA 

(2003), CRISP (2003), and FEDRIP (2004) databases is summarized in Table 3-9. 
HEXACHLOROCYCLOHEXANE 170 

3. HEALTH EFFECTS 

Table 3-9. Ongoing Studies on Hexachlorocyclohexane Health Effects 

Investigator Affiliation Research area	 Reference 

Adler, SR Washington University 

Alavanja, M Not available 

Bloomquist, JR Virginia Polytechnic 

Institute 

Casida, JE University of California 

at Berkeley 

Clark, JM University of 

Massachusetts Amherst 

Dietert, RR Cornell University, 

Center for the 

Environment 

MacDonald, JF Cornell University, 

Center for the 

Environment 

Misra, HP Virginia Polytechnic 

Institute, College of 

Veterinary Medicine 

Naeher, LP University of Georgia, 

Environmental Health 

Sciences 

Examination of the regulatory potential of 

insecticides, plasticizers, and dioxins in 

estrogenic and non-estrogenic pathways 

Epidemiologic investigations to identify 

and clarify cancer risks from pesticide 

exposure 

Assessment of the ability of insecticide 

exposure to cause biomarkers indicating 

Parkinsonism 

Modes of toxic action, biochemical 

targets, mechanisms of selective toxicity, 

and health implications of exposure of 

selected insecticides 

Detection of pyrethroid and γ-HCH 

resistance in head lice 

Expansion of the database of Critical 

Evaluations on the current evidence of 

carcinogenicity for selected agricultural 

chemicals 

Establishment of a database of critical 

evaluations on evidence of breast 

carcinogenicity of selected pesticides 

Assessment of the role of pesticide 

mixtures in potentiating the genotoxicity 

in immune cells in vitro 

Environmental and dietary monitoring for 

organophosphate and pyrethroid 

pesticides in children 

Narahashi, T Northwestern University Determination of the mechanism by 

Oman, GM Department of Veteran 

Affairs, Medical Center 

Ostrea, EM Wayne State University 

Schwartz, SM Fred Hutchinson Cancer 

Research Center 

Wong, PS University of California 

at Davis 

which neuroactive insecticides exert their 

toxic actions on mammals 

Assessment of the impacts of metal and 

organochlorine contaminants indigenous 

to Saginaw Bay, Lake Huron, on human 

and fish immune systems 

Meconium analysis of fetal exposure to 

environmental toxins and infant outcome 

Determination of risk of testicular germ 

cell carcinoma in relation to serum levels 

of persistent organochlorines 

Establishment of the existence of "ligand 

independent" activation mechanism for 

various chlorinated pesticides in human 

cell systems (BG-1 ovarian cancer cells, 

and Ishikawa endometrial cells) 

CRISP 2004 

FEDRIP 2004 

CRIS/USDA 2003; 

FEDRIP 2004 

CRIS/USDA 2003 

FEDRIP 2004 

FEDRIP 2004 

FEDRIP 2003 

FEDRIP 2004 

CRIS/USDA 2003; 

FEDRIP 2004 

CRIS 2003; 

CRISP 2004 

FEDRIP 2003 

CRISP 2003; 

FEDRIP 2004 

CRISP 2004 

FEDRIP 2004 
HEXACHLOROCYCLOHEXANE 171 

3. HEALTH EFFECTS 

Table 3-9. Ongoing Studies on Hexachlorocyclohexane Health Effects 

Investigator Affiliation Research area Reference 

Woolley, DE University of California 

at Davis, Neurology, 

Physiology, and 

Behavior 

Investigation of the neurotoxic effects and 

mechanisms of action produced by acute 

and chronic exposure to heptachlor and 

γ-HCH 

CRIS/USDA 2003; 

FEDRIP 2004 

Matsumura, F University of California 

at Davis, Environmental 

Toxicology 

Identification of the action of mechanism 

of selected pesticides and study of the 

basis of their differential toxicities against 

mammalian, insect, and acerine large 

proteins 

FEDRIP 2004 

Matsumura, F University of California 

at Davis, Environmental 

Toxicology 

Determination of whether c-Neu plays a 

pivotal role in mediating the estrogenic 

action of OC in MCF-7 cell transformation 

FEDRIP 2004 

Molony, D University of Texas, 

Health and Science 

Explanation of some of the cellular 

events and molecular mechanisms that 

FEDRIP 2004 

Center, Houston participate in the induction of apoptosis of 

renal tubular epithelial cell in response to 

the inhibition of specific ion channels by 

toxicants 

CRIS = Current Research Information System; CRISP = Computer Retrieval of Information on Science Projects; 

FEDRIP = Federal Research in Progress; OC = Organochlorine; USDA = U.S. Department of Agriculture 

HEXACHLOROCYCLOHEXANE 173 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

HCH consists of eight isomers (Safe 1993). Only γ-HCH, α-HCH, β-HCH, and δ-HCH are of 

commercial significance and considered in this profile. The pesticide lindane refers to products that 

contain >99% γ-HCH. The α-, β-, and δ-isomers, as well as technical-grade HCH are not synonymous 

with γ-HCH (Farm Chemicals Handbook 1993). Technical-grade HCH is not an isomer of HCH, but 

rather a mixture of several isomers; it consists of approximately 60–70% α-HCH, 5–12% β-HCH, 10– 

15% γ-HCH, 6–10% δ-HCH, and 3–4% ε-HCH (Kutz et al. 1991). Information regarding the chemical 

identities of γ-HCH, α-HCH, β-HCH, and δ-HCH is located in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Information regarding the physical and chemical properties of γ-HCH, α-HCH, β-HCH, and δ-HCH is 

located in Table 4-2. 
HEXACHLOROCYCLOHEXANE 174 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Hexachlorocyclohexane Isomersa 

Characteristic γ-hexachlorocyclohexane α-hexachlorocyclohexane 

Synonym(s) Lindane; 1-alpha, 2-alpha, 3-beta, 1-alpha, 2-alpha, 3-beta, 4-alpha, 

4-alpha, 5-alpha, 6-beta-hexachloro­ 5-beta, 6-beta-benzene-transcyclohexane; benzene hexachloridegamma-isomer; BHC; cyclohexane 

1,2,3,4,5,6-hexachloro-gammaisomer; ENT 7796; gamma-benzene 

hexachloride; gamma-BHC; gammahexachlorocyclohexane; gamma1,2,3,4,5,6-hexachlorocyclohexane; 

gamma-HCH; gamma-lindane; HCH; 

HCCH; hexachlorocyclohexane, 

hexachloride; alpha-1,2,3,4,5,6-hexachlorocyclohexane; alpha-benzene 

hexachloride; alpha-BHC; alpha-HCH; 

alpha-hexachloran; alpha-hexachlorane; alpha-hexachlorocyclohexane; alpha-lindane; benzenehexachloride-alpha-isomer; cyclohexane 

1,2,3,4,5,6-(alpha, DL); cyclohexane 

1,2,3,4,5,6-hexachloro, alpha-; cyclogamma-isomer; 1,2,3,4,5,6-hexa

chlorocyclohexane, gamma-isomerb 

­ hexane 1,2,3,4,5,6-hexachloro-, alphaRegistered trade name(s) Etan 3G (Diachem S.P.A.); Forlin; 

Gamaphex; Isotox (Chevron 

Chemical Co.); Germate Plus 

(Gustafson Inc.); Gamma-Mean 400 

and Gamma Mean L. (OregonCalifornia Chemicals, Inc.); Hammer 

(Exsin Industries); Lindagam; 

Novigam; Silvanolc

; Kwell 

(pharmaceutical shampoo/lotion)d 

Chemical formula C6H6Cl6 

Chemical structure 

Cl Cl

Cl Cl 

Cl Cl 

Cl Cl 

Cl 

Cl 

Identification numbers: 

 CAS registry 58-89-9 

 NIOSH RTECS GV4900000 

EPA hazardous waste U129; D013 

 OHM/TADS 7216531 

 DOT/UN/NA/IMCO NA 2761 lindane; IMCO 6.1 lindane; 

shipping UN 2761, organochlorine pesticides, 

solid toxic, not otherwise specified 

HSDB 646 

NCI C00204 

isomer; cyclohexane, alpha1,2,3,4,5,6-hexachloro; ENT 9232b 

No data 

C6H6Cl6

b 

Cl 

Cl 

319-84-6 

GV3500000 

No data 

810002 

No data 

6029 

No data 
Cl Cl Cl Cl

Cl Cl Cl Cl

Cl Cl 

HEXACHLOROCYCLOHEXANE 175 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Hexachlorocyclohexane Isomersa 

Characteristic β-hexachlorocyclohexane δ-hexachlorocyclohexane 

Synonym(s) 1-alpha, 2-beta, 3-alpha, 4-beta, 1-alpha,2-alpha,3-alpha, 4-beta, 

5-aplha, 6-beta-hexachlorocyclo­ 5-alpha, 6-beta-hexachlorocyclohexane; beta 1,2,3,4,5,6-hexachloro- hexane; cyclohexane, 

cyclohexane; beta-benzenehexa- 1,2,3,4,5,6-hexachloro-, deltachloride; beta-BHC; beta HCH; beta- isomer; cyclohexane, deltahexachloran; beta-hexachloro- 1,2,3,4,5,6-hexachloro-; deltabenzene; beta-lindane; cyclohexane, (AEEEEE)- 1,2,3,4,5,6-hexachloro1,2,3,4,5,6-hexachloro-, beta-; cyclo- cyclohexane; delta-benzenehexahexane, 1,2,3,4,5,6-hexachloro-, chloride; delta-BHC; delta-HCH; 

beta-isomer; cyclohexane, delta-1,2,3,4,5,6-hexachlorocyclo

hexane; delta-lindane; ENT 9234b 

­

1,2,3,4,5,6-hexachloro-, trans-; 

cyclohexane, beta-1,2,3,4,5,6-hexa

chloro-; ENT 9233; trans-alphabenzenehexachlorideb 

­

Registered trade name(s) No data No data 

Chemical formula C6H6Cl6 C6H6Cl6 

Chemical structure Cl Cl

Identification numbers: 

 CAS registry 319-85-7 319-86-8 

 NIOSH RTECS GV4375000 GV4550000 

EPA hazardous waste No data No data 

OHM/TADS No data No data 

DOT/UN/NA/IMCO shipping No data No data 

HSDB 6183 6184 

NCI No data No data 

a

All information obtained from HSDB 1997 except where noted. 

b

RTECS 1993 

c

Farm Chemicals Handbook 1993 

d

Budavari et al. 1989 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; HSDB = 

Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for Occupational 

Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; RTECS = Registry 

of Toxic Effects of Chemical Substances 
HEXACHLOROCYCLOHEXANE 176 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Hexachlorocyclohexane Isomers 

γ-hexachlorocyclo- α-hexachlorocyclo- β-hexachlorocyclo- δ-hexachlorocycloProperty hexane hexane hexane hexane 

Molecular weight 290.83a 290.83a 290.83a 290.83a 

Color Whiteb Brownish to whitec No data No data 

Physical state Crystalline solidd

; 

monoclinic prismsb 

Crystalline solidc

; 

monclinic prismsa 

Crystalline solida,d Fine platesa,b 

Melting point 112.5 °Ca,e 159–160 °Ca

 314–315 °Ca 141–142 °Ca 

Boiling point 323.4 °C at 

760 mmHgc 

288 °C at 

760 mmHgc 

60 °C at 0.5 mmHga 60 °C at 

0.36 mmHga 

Density (g/cm3

) 1.89 at 19 °Cf 1.87 at 20 °Ca 1.89 at 19 °Ca No data 

Odor Slightly musty odorc

 Phosgene-like odorc No data No data 

Odor threshold: 

Water 12 mg/kgg 0.88 ppm for 

unspecified purityh 

0.00032 mg/kgg

 No data 

Air No data No data No data No data 

Solubility: 

 Water 17 ppmi

; insoluble in 

waterc 

10 ppmj

; 69.5 mg/L 

at 28 °Ck 

5 ppmj

 10 ppmj

 Organic 6.4 g/100 g in Soluble in alcoholk

; 1.1 g/100 g in ethanol; 24.4 g/100 g in 

solvents ethanol; 

20.8 g/100 g in 

ether; 28.9 g/100 g 

in benzenej 

1.8 g/100 g in 

ethanolj

; 6.2 g/100 g 

in etherj 

1.8 g/100 g in ether; 

1.9 g/100 g in 

benzenej 

ethanol; 

35.4 g/100 g in 

ether; 41.4 g/100 g 

in benzenej 

Partition coefficients: 

 Log Kow 3.72l 3.8l

 3.78l 4.14l

 Log Koc 3.0m; 3.57f

 3.57f 3.57m 3.8f 

Vapor pressure 4.2x10-5 mmHg at 

20 °Cc 

4.5x10-5 mmHg at 

25 °Cc 

3.6x10-7 at 20 °Cc

 3.5x10-5 at 25 °Cc 

Henry’s law 3.5x10-6c 6.86x10-6c 4.5x10-7m,n 2.1x10-7o,p 

constant 

Autoignition Not flammablec No data No data No data 

temperature 

Flashpoint Approximately 

150 °F (closed cup)c 

No data No data No data 

Flammability Not flammablec No data No data No data 

limits 

Conversion ppm to mg/m3

 in air (20°C): ppm x 4.96 = mg/m3; 

factorsq mg/m3

 to ppm in air (20°C): mg/m3 x 0.20 = ppm 

Explosive limits No data No data No data No data 

a

Lide 1991 eBudavari et al. 1989 iHollifield 1979 lHansch and Leo 1995 oPankow et al. 1984 b

Kirk-Othmer 1985 fWeiss 1986 jClayton and Clayton mRipping 1972 pEPA 1982 c

HSDB 2003 gVerschueren 1983 1981 nVeith et al. 1979 qSame for all isomers d

IARC 1979 hFazzalari 1978 kKuihara et al. 1973 
HEXACHLOROCYCLOHEXANE 177 

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

5.1 PRODUCTION 

Table 5-1 lists the facilities in each state that process hexachlorocyclohexane, the intended use, and the 

range of maximum amounts of hexachlorocyclohexane that are stored on site. These data only pertain to 

γ-HCH (lindane) and reflect the amounts that are formulated into various pesticide products, 

pharmaceuticals (shampoos or lotions to treat lice), or seed treatments. The data listed in Table 5-1 are 

derived from the Toxics Release Inventory (TRI02 2004). Only certain types of facilities were required 

to report. Therefore, this is not an exhaustive list. 

HCH does not occur as a natural substance. The manufacturing of technical-grade HCH involves the 

photochlorination of benzene, which yields an isomeric mixture consisting of α-HCH, β-HCH, γ-HCH, 

δ-HCH, ε-HCH, and inerts (IARC 1979); this reaction can be started by free-radical initiators such as 

visual or ultraviolet light, X-rays, or γ-rays (Kirk-Othmer 1985). Treatment with methanol or acetic acid, 

followed by fractional crystallization, concentrates γ-HCH to the 99.9% required in the technical-grade of 

γ-HCH (IARC 1979); nitric acid is used to remove odor (SRI 1987). None of the isomers or technicalgrade HCH are currently produced in the United States. The production of γ-HCH exceeded 2.27x106

 g 

in 1976 (HSDB 2003); commercial γ-HCH production in the United States reportedly ended in that year 

(EPA 1989b). However, the Directory of Chemical Producers for 1987 and 1988 lists one producer of 

γ-HCH, Drexel Chemical Company (SRI 1987, 1988); subsequent volumes (1989–1991) give no listings 

of γ-HCH producers. 

γ-HCH is available in emulsifiable and flowable concentrates, soluble concentrates/liquids, wettable 

powders, dusts, ready-to-use liquids, pressurized liquids and impregnated materials, oil base and aerosol 

sprays, granules, and as a smoke generator (Berg 1988; EPA 1985a). γ-HCH is sold separately or in 

combination with fungicides, fertilizers, other insecticides, or wood preservatives (Hayes 1982). 

5.2 IMPORT/EXPORT 

γ-HCH is not produced in the United States. It is imported from France, Germany, Spain, Japan, and 

China (EPA 1985a). Once in the United States, it can be formulated in various pesticide products and 

exported. The U.S. imports of γ-HCH declined from 1.52x105

 kg in 1977 to 8.53x104 kg in 1982 (HSDB 
HEXACHLOROCYCLOHEXANE 178 

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

Table 5-1. Facilities that Produce, Process, or Use Hexachlorocyclohexane 

Number of Minimum amount Maximum amount on site in 

Statea facilities on site in poundsb poundsb Activities and usesc 

AL 1 10,000 99,999 2, 4 

AR 2 1,000 99,999 12 

CO 1 10,000 99,999 7 

FL 2 No data 99,999 2, 4, 7 

GA 9 1,000 999,999 2, 3, 4, 7, 9 

ID 5 10,000 999,999 2, 3, 7 

IL 2 1,000 99,999 7, 12 

IN 1 100,000 999,999 12 

KS 1 1,000 9,999 7 

KY 2 10,000 99,999 7, 12 

MO 3 10,000 999,999 2, 3, 7 

MS 2 No data 999,999 2, 3, 7, 12 

ND 7 10,000 999,999 1, 2, 3, 4, 7, 9, 10, 11 

NE 4 1,000 999,999 7, 12 

NJ 3 100 99,999 9, 12 

OH 2 100 9,999 12 

OR 1 100 999 12 

SC 1 10,000 99,999 12 

TX 6 1,000 999,999 2, 5, 7, 8, 12 

Source: TRI02 2004 (Data are from 2002) 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 
HEXACHLOROCYCLOHEXANE 179 

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

2003). In 2002, it was estimated that 90 metric tons (9.0x104 kg) of γ-HCH were imported into the 

United States (Hauzenberger et al. 2002). Facilities that import γ-HCH for use as a formulation 

component are shown in Table 5-1. Up until 2001, it was estimated that 500 metric tons of γ-HCH 

containing pesticide products were exported annually by the United States (primarily to Canada) 

(Hauzenberger et al. 2002). That export volume dropped to 25 metric tons in 2001 and is expected to 

decline significantly as the use of γ-HCH decreases in other countries. 

5.3 USE 

γ-HCH was initially registered by the USDA (U.S. Department of Agriculture) in the 1940s and over the 

years, was approved for use on a wide variety of fruit and vegetable crops (including seed treatment), 

tobacco, greenhouse vegetables and ornamentals, forestry (including Christmas tree plantations), farm 

animal premises, and other uses. In February 1977, EPA issued a notice of Rebuttal Presumption Against 

Registration (RPAR), now called a Special Review, and continued registration of pesticide products 

containing γ-HCH. EPA took this action in response to indications of γ-HCH's potential carcinogenic 

effect, possible developmental and reproductive effects, possible blood dyscrasias, and delayed toxic 

effects, as well as its acute toxic effects seen in aquatic wildlife (IARC 1979). In October of 1983, EPA 

issued a “Notice of Intent to Cancel Pesticide Products Containing γ-HCH.” The contentions concerning 

developmental and reproductive effects were successfully challenged by industry. EPA no longer permits 

the use of γ-HCH for purposes involving direct aerial application (EPA 1985b). The notice restricted 

certain applications of γ-HCH on livestock, structures, and domestic pets to certified applicators or 

persons under their direct supervision (EPA 1985b). In November 1993, EPA issued a "Notice of Receipt 

of a Request for Amendments to Delete Uses" for several formulations of γ-HCH powder, 99.5% 

technical-grade HCH, and dust concentrate, which would delete from the pesticide label most uses of 

γ-HCH for agricultural crops and use on animals and humans (EPA 1993). According to the EPA’s most 

recent Registration Eligibility Decision (RED), the only current food/feed use of γ-HCH that is being 

supported for re-registration is seed treatment on barley, corn, oats, rye, sorghum, and wheat (EPA 

2002b). Since the 1998 and 1999 use deletions, the registrants are no longer interested in supporting the 

seed treatment use on broccoli, Brussel sprouts, celery, cabbage, cauliflower, collards, kale, kohlrabi, 

mustard greens, lettuce, radishes, spinach, and Swiss Chard (EPA 2002b). 

γ-HCH is also available, and regulated by the U.S. Food and Drug Administration (FDA), for the 

pharmaceutical treatment of scabies and head lice (EPA 2002b). A 1% γ-HCH lotion is available for the 

treatment of scabies, and a 1% shampoo is available for the treatment of head lice. Both uses have been 
HEXACHLOROCYCLOHEXANE 180 

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

on the market since 1947, but were labeled as a second line therapy in 1995 after a review by the FDA. 

The FDA is revising the label for the treatment of scabies, which would effectively prohibit its use on 

infants and children weighing less than 60 kg (EPA 2002b). In the past, γ-HCH was used in veterinary 

products to control mites and other pests, but recent data suggest that no products are currently registered 

in the United States for this use (Hauzenberger et al. 2002). Based on EPA estimates from 1996 to 2001, 

about 233,000 pounds of γ-HCH are used annually as a seed treatment (EPA 2002b). 

5.4 DISPOSAL 

Hexachlorocyclohexane is listed as a toxic substance under Section 313 of the Emergency Planning and 

Community Right to Know Act (EPCRA) under Title III of the Superfund Amendments and 

Reauthorization Act (SARA) (EPA 1995). Disposal of wastes containing hexachlorocyclohexane is 

controlled by a number of federal regulations (see Chapter 8). 

While current disposal techniques may be adequate, new methods provide increased efficiency and 

quality of disposal at a greatly reduced cost. The use of demulsification, sorption, and filtration in 

combination with chemical and biological degradation of pesticide waste waters is being examined. This 

process is divided into two phases. First, demulsification agents (lignocellulosic materials, peat moss, 

wood products, etc.) are utilized in the removal of solubilized pesticides. In the second phase II, the solid 

matter (pesticide-saturated sorbents and suspended particulates) is physically separated from the aqueous 

material through a variety of filtration techniques. The aqueous phase is either recycled or discarded, and 

the solid phase, in which the concentration of the pesticide is most significant, is further treated through 

composting (Mullins et al. 1992). 

In order to facilitate the composting process, it is important to use sorption agents that provide a 

beneficial environment for the pesticide-degrading microorganisms. Peat moss, ground pine bark mulch, 

and steam-exploded wood fibers are excellent demulsifiers because they are highly sorbent, readily 

available, and inexpensive. They also provide the nutrients required by the degrading microorganisms, 

although the peat moss media require some carbohydrate enrichment. The solid waste can be either 

directly metabolized or co-metabolized by multiple species of microbes. The number of compost cycles, 

and therefore the amount of energy input required, depends on the pesticide concentration and on how 

easily the pesticide can be biodegraded. In preliminary studies by Mullins and coworkers, this process 

has reduced the concentration of γ-HCH in waste materials significantly, with <1% of the original 

pesticide remaining after 24-hour incubation (Mullins et al. 1992). 
HEXACHLOROCYCLOHEXANE 181 

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

Additional work is required, but the benefits of this disposal technique are clear. It is cost effective, 

reliable, and can be adapted to the variety of disposal challenges presented by the multitude of pesticides 

that are currently used. The use of microbial consortia ensures that each pesticide will be degraded 

rapidly. This method can also be used on pesticide mixtures (Mullins et al. 1992). 

Disposal methods are currently subject to significant revision by EPA (HSDB 1997). 

HEXACHLOROCYCLOHEXANE 183 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

α-, β-, γ-, and δ-HCH have been identified in at least 146, 159, 189, and 126, respectively of the 

1,662 hazardous waste sites that have been proposed for inclusion on the EPA National Priorities List 

(NPL) (HazDat 2005). However, the number of sites evaluated for these substances is not known. The 

frequency of these sites can be seen in Figures 6-1, 6-2, 6-3, and 6-4. Of these sites, all are located within 

the United States with the exception of three sites located in the Virgin Islands, two sites in the 

Commonwealth of Puerto Rico, and one site in Guam (not shown). 

HCH has been released to the environment during its formulation process and through its use. Although 

technical-grade HCH and none of the isomers are manufactured in the United States any longer, γ-HCH 

(lindane) is still imported into the United States and formulated into various products. Most of these 

formulated products are pesticides that can still be used as a seed treatment for barley, corn, oats, rye, 

sorghum, and wheat. However, γ-HCH is also used in very small quantities as a prescription medication 

for the treatment of scabies and head lice. According to the EPA, approximately 233,000 pounds of 

γ-HCH were used annually from 1996 to 2001 as a seed treatment, which accounts for nearly all γ-HCH 

used in the United States (EPA 2002b). By contrast, in 1977, over 900,000 pounds of γ-HCH were used 

in the United States, with roughly half that amount being applied as a seed treatment (EPA 2002b). Once 

released to the environment, HCH can partition to all environmental media. Although its atmospheric 

lifetime is long, HCH can be degraded by reacting with photochemically produced hydroxyl radicals or 

can be removed from the air by wet and dry deposition. Biodegradation is believed to be the dominant 

decomposition process for HCH in soil and water, although hydrolysis and photolysis may also occur to a 

lesser extent. The rates of degradation depend on the ambient environmental conditions. Although 

technical-grade HCH has essentially been banned in the United States for many years, α-, β-, and δ-HCH 

continue to be detected in environmental media because of the long environmental persistence of these 

compounds. HCH has been detected in air, surface water, groundwater, sediment, soil, fish and other 

aquatic organisms, wildlife, food, and humans. Human exposure results primarily from medicinal use and 

from ingestion of contaminated plants, animals, and animal products. HCH has not been found to be a 

major contaminant of drinking water supplies. 
HEXACHLOROCYCLOHEXANE 184 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with α-Hexachlorocyclohexane 

Contamination 

Frequency of 

NPL Sites 

1

2-4

5

6-8

Derived from HazDat 2005 13

16
HEXACHLOROCYCLOHEXANE 185 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-2. Frequency of NPL Sites with β-Hexachlorocyclohexane 

Contamination 

Frequency of 

NPL Sites 

1

2-4

5-6

8-9

Derived from HazDat 2005 11-12 

17 
HEXACHLOROCYCLOHEXANE 186 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-3. Frequency of NPL Sites with γ-Hexachlorocyclohexane 

Contamination 

Frequency of 

NPL Sites 

1

2

3-5

6-9

Derived from HazDat 2005 12-15

20
HEXACHLOROCYCLOHEXANE 187 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-4. Frequency of NPL Sites with δ-Hexachlorocyclohexane 

Contamination 

Frequency of 

NPL Sites 

1

2-3

4-5

7-8

Derived from HazDat 2005 11

12
HEXACHLOROCYCLOHEXANE 188 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.2 RELEASES TO THE ENVIRONMENT 

This is not an exhaustive list. Manufacturing and processing facilities are required to report information 

to the Toxics Release Inventory only if they employ 10 or more full-time employees; if their facility is 

classified under Standard Industrial Classification (SIC) codes 20–39; and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI 

chemical in a calendar year (EPA 1997). 

According to the Toxic Chemical Release Inventory, in 2002, total on-site and off-site releases of γ-HCH 

to the environment from 10 processing facilities were 231 pounds (TRI02 2004). Table 6-1 lists amounts 

released from these facilities. The TRI data should be used with caution because only certain types of 

facilities are required to report (EPA 1997). 

γ-HCH and other isomers of HCH do not occur naturally in the environment. Most current releases of 

γ-HCH in the United States are related to its formulation and its use as an insecticide/acaricide. 

6.2.1 Air 

Estimated releases of 11 pounds of γ-HCH to the atmosphere from four domestic manufacturing and 

processing facilities in 2002, accounted for about 5% of the estimated total environmental releases from 

facilities required to report to the TRI (TRI02 2004). These releases are summarized in Table 6-1. 

Historically, the largest source of γ-HCH releases to the air resulted from agricultural application of the 

pesticide γ-HCH. Other air releases occurred during the manufacture of the pesticide. Aerial applications 

of γ-HCH are now prohibited in the United States as its use as a pesticide was restricted (EPA 1985b), 

and atmospheric releases from these sources are not expected. α-HCH and γ-HCH were detected in 60– 

90% of the air samples collected in the vicinity of formulation plants in Arkansas and Tennessee in 1971 

at mean levels of 1.0 and 1.3 mg/m3

, respectively (Lewis and Lee 1976). Quantitative estimates of the 

total quantities of γ-HCH released to the air from these sources were not located. 

In addition to releases from industrial facilities, γ-HCH is present in the environment as a result of its use 

or disposal. For example, wind erosion of contaminated soil may distribute pesticides into the 
HEXACHLOROCYCLOHEXANE 189 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or 

Use Hexachlorocyclohexanea
 

Reported amounts released in pounds per yearb 

Total release 

Statec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek 

On- and offsite 

AR 1 2 0 0 0 0 2 0 2 

ID 1 0 0 0 0 0 0 0 0 

IL 2 2 0 0 55 43 2 98 100 

ND 2 0 0 0 0 0 0 0 0 

NE 1 5 0 0 0 0 5 0 5 

OH 1 0 0 0 5 0 0 5 5 

OR 1 0 0 0 117 0 117 0 117 

TX 1 2 0 0 0 0 2 0 2 

Total 10 11 0 0 177 43 128 103 231 

Source: TRI02 2004 (Data are from 2002) 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used. 

d

Number of reporting facilities.
 e

The sum of fugitive and point source releases are included in releases to air by a given facility. f

Surface water discharges, wastewater treatment-(metals only), and publicly owned treatment works (POTWs) (metal 

and metal compounds). 

g

Class I wells, Class II-V wells, and underground injection. 

h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills. i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for 

disposal, unknown 

j

The sum of all releases of the chemical to air, land, water, and underground injection wells. k

Total amount of chemical transferred off-site, including to POTWs. 

RF = reporting facilities; UI = underground injection 
HEXACHLOROCYCLOHEXANE 190 

6. POTENTIAL FOR HUMAN EXPOSURE 

atmosphere. γ-HCH can also be released to the atmosphere via volatilization from treated agricultural 

soils and plant foliage (Lewis and Lee 1976). Evaporative loss of γ-HCH from water is not considered a 

significant source of atmospheric γ-HCH because of its relatively high water solubility (Mackay and 

Leinonen 1975). Quantitative estimates of the amount of γ-HCH released from these sources were not 

located in the literature. 

Atmospheric release of γ-HCH from disposal sites or hazardous waste sites has not been documented but 

is likely, considering the physical and chemical properties of γ-HCH. 

α-, β-, γ-, and δ-HCH have been detected in air at 7, 4, 9, and 4 of the 1,662 current or former EPA NPL 

hazardous waste sites, respectively (HazDat 2005). 

6.2.2 Water 

There were no estimated releases of γ-HCH to water from facilities that formulated γ-HCH (TRI02 2004). 

γ-HCH can be released to surface water via surface runoff (as the dissolved chemical or adsorbed to 

particulates) or via wet deposition of rain and snow (Tanabe et al. 1982; Wheatley and Hardman 1965). 

For example, Lake Ontario received 7 kg/year of α-HCH and <2 kg/year of γ-HCH because of suspended 

sediment loading from the Niagara River between 1979 and 1981 (Kuntz and Warry 1983). The Great 

Lakes in general receive from 0.77 to 3.3 metric tons/year of α-HCH and from 3.7 to 15.9 metric 

tons/year of γ-HCH because of atmospheric deposition of these contaminants (Eisenreich et al. 1981). In 

1982, α-HCH and γ-HCH were detected in samples of urban stormwater runoff from Denver, Colorado, 

and Washington, DC, at 0.0027–0.1 and 0.052–0.1 μg/L in 20% and 11%, respectively, of the 86 samples 

collected; β-HCH was detected only in runoff from Washington, DC, in 5% of the samples at a 

concentration of 0.1 μg/L (Cole et al. 1984). 

γ-HCH can be released to groundwater via soil leachate. Although available adsorption data indicate that 

γ-HCH has a low mobility in soils, the results of monitoring studies suggest that γ-HCH does migrate to 

groundwater (Page 1981; Sandhu et al. 1978). In water tested from 1,076 wells throughout New Jersey, 

γ-HCH was not detected in at least half of the samples, but a maximum concentration of 0.9 ppb γ-HCH 

was detected (Page 1981). 
HEXACHLOROCYCLOHEXANE 191 

6. POTENTIAL FOR HUMAN EXPOSURE 

α-, β-, γ-, and δ-HCH have been detected in groundwater at 72, 69, 91, and 65 of the 1,662 current or 

former EPA NPL sites, respectively (HazDat 2005). α-, β-, γ-, and δ-HCH have been detected in surface 

water at 34, 18, 33, and 12 of the 1,662 current or former EPA NPL sites, respectively (HazDat 2005). 

6.2.3 Soil 

Estimated releases of 177 pounds of γ-HCH to soils from three domestic manufacturing and processing 

facilities in 2002, accounted for about 77% of the estimated total environmental releases from facilities 

required to report to the TRI (TRI02 2004). According to the TRI database, there were no underground 

injections in 2002 (TRI02 2004). These releases are summarized in Table 6-1. 

γ-HCH can be released to the soil by direct application of the pesticide to soil or by direct or indirect 

releases during formulation, storage, and/or disposal. Hazardous waste sites where γ-HCH has been 

disposed of in the past are sources of γ-HCH in soils. However, the application of γ-HCH to laboratory 

refuse columns simulating municipal landfills indicated that γ-HCH did not volatilize or leach from the 

refuse surface, and movement through the column was slight, suggesting that codisposal of γ-HCH with 

municipal refuse will result in minimal releases (Reinhart and Pohland 1991; Reinhart et al. 1991). 

α-, β-, γ-, and δ-HCH have been detected in sediment at 17, 19, 36, and 28 of the 1,662 current or former 

EPA NPL sites, respectively (HazDat 2005). α-, β-, γ-, and δ-HCH have been detected in soil at 63, 78, 

90, and 58 of the 1,662 current or former EPA NPL sites, respectively (HazDat 2005). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

HCH present in soil can leach to groundwater, sorb to soil particulates, or volatilize to the atmosphere. In 

general, the leaching of organic chemicals through soil is governed by the water solubility of the 

chemicals and their propensity to bind to soil. The Koc of γ-HCH in a mineral soil containing 1.26% 

organic carbon content was measured as 832 (Chiou et al. 1998). Based on the results of a number of 

laboratory soil column leaching studies that used soils of both high and low organic carbon content as 

well as municipal refuse, γ-HCH generally has low mobility in soils (Hollifield 1979; Melancon et al. 

1986; Rao and Davidson 1982; Reinhart et al. 1991). Adsorption of γ-HCH to soil particulates is 

generally a more important partitioning process than leaching to groundwater. However, groundwater 
HEXACHLOROCYCLOHEXANE 192 

6. POTENTIAL FOR HUMAN EXPOSURE 

sediments, which have low organic carbon content, are not sufficient to adsorb γ-HCH to the extent that 

groundwater contamination is prevented (Nordmeyer et al. 1992). In a study involving a laboratory 

sediment/water system (pH=7.42; 2.18% organic carbon), α- and γ-HCH isomers were highly adsorbed 

on sediments under both aerobic and anaerobic conditions and few differences were noted in the 

adsorption behavior of each isomer (Wu et al. 1997). Under aerobic and anaerobic conditions, the Koc 

values of α-HCH were 681 and 617, respectively, while the Koc values for γ-HCH were 641 and 694, 

respectively. Using sediment obtained from a sugar-cane growing region of Australia, the Koc of γ-HCH 

was measured as 2,164 (Just et al. 1990). 

γ-HCH sorbed to the soil can partition to the atmosphere by wind erosion of surface soil particulates 

(Stanley et al. 1971) and via volatilization from treated agricultural soils and plant foliage (Lewis and Lee 

1976). In tests conducted in a model laboratory system at 10 and 20 °C, volatilization half-lives of 

γ-HCH from soil and oat plant surfaces of 2.3–24.8 and 0.29–0.73 days, respectively, were reported 

(Dorfler et al. 1991a); half-lives were greater on dry, sandy soils versus peat soils; however, when 

moisture was added to the soils, the half-life was greater for the peat soil, while the warmer temperature 

decreased the half-life under all soil and moisture conditions (Dorfler et al. 1991b). In tests performed 

with a wind tunnel, a volatilization rate of >20% for γ-HCH from soil surfaces within a 24-hour period 

was determined (Rüdel 1997). The volatilization rate from plant surfaces was 55% for γ-HCH. 

Application of γ-HCH to fields of sunflowers and sugarbeets resulted in a 54% evaporative loss of the 

pesticide within 24 hours (Neururer and Womastek 1991). A 6-fold increase in γ-HCH volatilization 

from soil was seen in laboratory experiments when the temperature increased from 15 to 45 °C; flooding 

the soil also increased the volatilization (Samuel and Pillai 1990). A field study conducted in south 

central Saskatchewan, Canada in 1997–1998 in which γ-HCH was applied as a seed treatment to canola, 

determined that between 12 and 30% of the initial amount applied volatilized to the atmosphere (Waite et 

al. 2001). 

An analysis of the concentrations of α-HCH to γ-HCH in air over southern Ontario suggested that high 

levels of γ-HCH were indicative of recent γ-HCH usage (Hoff et al. 1992a). The levels of α-HCH were 

less variable throughout the year, ranging from 77 to 260 pg/m3

. During the winter, higher ratios of 

α-HCH to γ-HCH reflect the movement of air containing the more persistent α-HCH isomer from the 

colder Arctic regions to the south, while the lower ratios in the summer reflect both increased γ-HCH 

usage in the region and the lack of movement of Arctic air (Hoff et al. 1992a). γ-HCH is also seen to 

move with warm air during the summer months from the lower United States (or areas even further to the 

south) to the Great Lakes region, although a similar trajectory cannot be identified for the more 
HEXACHLOROCYCLOHEXANE 193 

6. POTENTIAL FOR HUMAN EXPOSURE 

ubiquitous α-HCH. Levels of α-HCH in air are not dominated by volatilization or partitioning to surfaces, 

but are dependent on local temperature changes (Hoff et al. 1992b). α-HCH appears to have a long 

residence time in the atmosphere and is controlled primarily by transport. 

γ-HCH in the atmosphere is likely to be subject to rain-out and dry deposition. γ-HCH removal rates by 

rainfall and dry deposition were 2.5%/week and 3.3%/week, respectively, and the estimated residence 

time of γ-HCH in the atmosphere was 17 weeks in a study by Atkins and Eggleton (1971). Rain-out and 

dry deposition of atmospheric γ-HCH results in the contamination of surface soil and water in areas not 

directly exposed via pesticide application. γ-HCH concentrations were positively correlated with ambient 

air temperature, although concentrations of α-HCH were not. The dry deposition flux rate of α-HCH 

ranged from 0.1 to 5.1 ng/m2

-day in deposition samples collected in June–August 1997 near the southern 

Baltic Sea (Wiberg et al. 2001). The flux rate of γ-HCH was 0.9–32.6 ng/m2

-day over the same time 

frame. Seasonal variation resulted in lower dry deposition rates during the winter months. In samples 

collected between February and March 1998, the flux rate for α-HCH ranged from 0.25 to 

0.54 ng/m2

/day, and the dry deposition flux rate for γ-HCH was 3.4–14.1 ng/m2/day (Wiberg et al. 2001). 

The dry deposition flux rate of γ-HCH in south central Saskatchewan in 1998 where it had been used as a 

seed treatment in a canola field ranged from <29 to 2,203 ng/m2

-day, and the amount in rainfall over the 

same period ranged from <10 to 200 ng/L (Waite et al. 2001). 

In surface waters, γ-HCH has a tendency to dissolve and remain in the water column. Although γ-HCH 

has a relatively high vapor pressure and Henry’s law constant compared with many other organochlorine 

insecticides, evaporative loss of γ-HCH from water is not considered to be significant. Mackay and 

Leinonen (1975) calculated theoretical losses of several pesticides from saturated water solutions and 

predicted a volatilization half-life of 191 days for γ-HCH. 

γ-HCH released to water may undergo adsorption/desorption with sediments and other materials in the 

water. Adsorption and desorption studies of γ-HCH in natural water-sediment systems performed by 

Saleh et al. (1982) indicate that a diversity of the natural water-sediment characteristics may affect the 

sorption-desorption behavior of γ-HCH in addition to the organic carbon content of the sediments. 

γ-HCH is sorbed to silt solutions with a slow desorption rate, indicating that transport through the 

environment is most likely to be particle mediated (Noegrohati and Hammers 1992c). Biosorption of 

γ-HCH was seen for the fungus Rhizopus arrhizus and activated sludge, with equilibrium being reached 

within 1 and 4 hours, respectively. Death of the sludge biomass resulted in rapid desorption with zeroorder kinetics, suggesting that adsorbed γ-HCH can be released back into the environment (Tsezos and 
HEXACHLOROCYCLOHEXANE 194 

6. POTENTIAL FOR HUMAN EXPOSURE 

Wang 1991a). The sorption of γ-HCH from water using wood charcoal has been described 

(Keerthinarayana and Bandyopadhyay 1998); it was found to be a good sorbent for the sorption of γ-HCH 

from water. 

γ-HCH that is adsorbed to sediments may be recycled to the atmosphere as gas bubbles are formed in the 

sediment by the methanogenesis and denitrification processes of bacteria. In one case studied, it is 

estimated that 85% of the γ-HCH associated with the sediment gas bubbles will be released to the 

atmosphere, with the remaining 15% being dissolved in the water column as the bubble rises toward the 

surface (Fendinger et al. 1992). 

γ-HCH is bioconcentrated to high levels following uptake from surface waters by a number of aquatic 

organisms. However, uptake from soils and bioconcentration by plants and terrestrial organisms appear 

to be limited. For example, bioconcentration factors (BCFs) for γ-HCH from surface waters include 

183 in brine shrimp (Matsumura and Benezet 1973), 319 in rainbow trout fry (Ramamoorthy 1985), 84 in 

pink shrimp, 218 in pinfish, 63 in grass shrimp, and 490 in sheepshead minnows (Schimmel et al. 1977). 

Introduction of γ-HCH onto sand resulted in a BCF of 95 in brine shrimp and 1,613 in northern brook 

silverside fish (Matsumura and Benezet 1973). A BCF of 1,273 (lipid basis) in prawns (crustacean) was 

seen to be 0.58 times the γ-HCH concentration in the underlying sediment, indicating that although 

aquatic organisms may accumulate γ-HCH from the water column, uptake from contaminated sediment 

alone may not be extensive (Just et al. 1990). BCFs for the isomers of HCH, using zebra-fish under 

steady-state conditions, were 1,100 for α-HCH, 1,460 for β-HCH, 850 for γ-HCH, and 1,770 for δ-HCH; 

BCFs determined by uptake and clearance rate constants were slightly lower (Butte et al. 1991). BCFs on 

a wet weight basis for γ-HCH in different fish species were positively correlated with their lipid content 

(Geyer et al. 1997). The bioaccumulation of γ-HCH by tubificide oligochaetes from a static system 

consisting of sediment and water has been reported (Egeler et al. 1997). 

γ-HCH applied to an aquatic mesocosm (i.e., a small, artificial ecosystem) at 61.3 μg/L was reduced by 

50% at 24 hours postapplication, while at 19 weeks postapplication, the concentration in the water was 

only 0.2%; no γ-HCH was detected at 21 weeks. The biological half-life was estimated to be 16.7 days. 

Movement through the water column was shown by increasing sediment concentrations up to a maximum 

of 75.4 μg/kg at 96 hours postapplication; however, sediment concentrations decreased to below the 

detection limit at 23 weeks to give a half-life in sediment of 48.1 days. Rooted aquatic macrophytes have 

a BCF of 56 at a maximum concentration of 1.7 mg/kg at 24 hours postapplication; however, at 14 weeks, 

all residues were below the detection limit for a half-disappearance time of 18 days. Gastropods in the 
HEXACHLOROCYCLOHEXANE 195 

6. POTENTIAL FOR HUMAN EXPOSURE 

system had a maximum γ-HCH concentration of 7.2 mg/kg at 24 hours posttreatment, yielding a BCF of 

232.4 and a half-disappearance time of 13.7 days with all residues eliminated by 13 weeks (Caquet et al. 

1992). 

In tests with radiolabeled γ-HCH, grain, maize, and rice plants accumulated 0.95, 0.11, and 0.04%, 

respectively, of the amount of bound residues following 14–20 days growth in a sandy loam soil. 

Bioconcentration increased by 4–10 times when the plants were grown in test soils containing both bound 

and extractable residues of γ-HCH (Verma and Pillai 1991). Plants and grains grown on soil treated with 

γ-HCH showed α-HCH as the predominant isomer although all isomers were found to some extent; 

amounts decreased with increasing time after application (Singh et al. 1991). 

Uptake of γ-HCH by earthworms from a treated humus soil has also been reported. Following exposure 

to 5 ppm of the compound for up to 8 weeks, the test organisms bioconcentrated γ-HCH by a factor of 

2.5. The earthworms biotransformed more than 50% of the accumulated γ-HCH; the main degradation 

product was γ-2,3,4,5,6-pentachlorocyclohex-1-ene (Viswanathan et al. 1988). 

γ-HCH and the other isomers of HCH do not appear to undergo biomagnification in terrestrial food chains 

to a great extent, although there is a moderate potential for transfer of γ-HCH to animal tissue as a result 

of soil ingestion or ingestion of contaminated foliage (Wild and Jones 1992). Clark et al. (1974) found 

that γ-HCH levels in the adipose tissue of cattle were 10 times higher than in the feed (0.002 mg/kg). 

Szokolay et al. (1977) examined relative accumulation of HCH isomers including γ-HCH and various 

components in the food chain in Czechoslovakia. Lower γ-HCH residues were found in tissues of 

animals (chickens, sheep, pigeons) feeding entirely on plant material, whereas carnivores had higher 

concentrations. 

The effect of soil loading (the amount of soil deposited per unit area of skin) on the dermal bioavailability 

of γ-HCH from contaminated soils has been examined (Duff and Kissel 1996). A static in vitro diffusion 

apparatus and abdominal skin from human cadavers were used. It was shown that the dermal absorption 

of γ-HCH from soil is dependent on soil loading and was estimated to be 0.45–2.35%. Dermal absorption 

of γ-HCH increased significantly with decreases in soil loading, provided that monolayer or greater 

coverage of the skin was maintained. 
HEXACHLOROCYCLOHEXANE 196 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

HCH is degraded in the atmosphere by reacting with photochemically produced hydroxyl radicals. The 

rate of this reaction is not very rapid however, and all of the HCH isomers have rather long atmospheric 

lifetimes. The rate constants for the reaction of γ-HCH and α-HCH with hydroxyl radicals were measured 

as 1.9x10-13 and 1.4x10-13 cm3

/molecule-second, respectively (Brubaker and Hites 1998). Using an 

average hydroxyl radical concentration of 5x105

 molecule/cm3, the corresponding half-lives are about 

84 and 115 days for γ-HCH and α-HCH, respectively. In locations where the atmospheric hydroxyl 

radical concentration is very low, the persistence times of these compounds are much longer. Cortes and 

Hites (2000) estimated that the average half-life of γ-HCH and α-HCH around the Great Lakes region 

ranged from about 3 to 4 years. Since HCH does not absorb light >290 nm, direct photolysis in the 

atmosphere is not expected to be an important environmental fate process. However, Chen et al. (1984), 

reported photodegradation half-lives of 91, 152, 104, and 154 hours for thin films of α-HCH, β-HCH, 

γ-HCH, and δ-HCH, respectively when irradiated with light of wavelength 295–305 nm. No absorption 

bands were observed in this spectral region, however, for any of the HCH isomers, and the mechanism of 

photodegradation and its environmental significance are uncertain. 

6.3.2.2 Water 

Biodegradation is believed to be the dominant degradative process for γ-HCH in aquatic systems, 

although hydrolysis and indirect photolysis may also occur. Sharom et al. (1980) found that <30% of the 

applied γ-HCH remained in unsterilized natural waters in capped bottles after 16 weeks. Biodegradation 

was concluded to be responsible for these results, although it was unclear to what extent hydrolysis or 

adsorption to the glass bottles may have contributed to the results. Zoetemann et al. (1980) estimated 

river, lake, and groundwater half-lives for γ-HCH from degradation data in these environments to be 3– 

30, 30–300, and >300 days, respectively. In natural lake water with a pH of 9.0 and a hardness of 

>600 mg calcium carbonate/L, the half-life of γ-HCH was estimated to be 65 hours (Ferrando et al. 1992). 

γ-HCH, applied at concentrations of 50 or 500 μg/L to aerobic batch cultures of microorganisms with 

sodium acetate as a carbon source, was initially removed by adsorption and followed by desorption onto 

the biomass with subsequent decomposition (McTernan and Pereira 1991). Approximately 56–62% of 

the γ-HCH was removed from the water column in 23 days, with 26% removal by adsorption onto the 

biological solids produced in these batch reactors. Microbial growth, using γ-HCH in the absence of 
HEXACHLOROCYCLOHEXANE 197 

6. POTENTIAL FOR HUMAN EXPOSURE 

sodium acetate, increased as the microorganisms became acclimated; the pesticide still showed toxic 

properties, as evidenced by a concurrent increase in microbial death rates. 

It has been shown that γ-HCH is degraded by nitrogen-fixing blue-green algae. These algae reduce the 

toxic effects of γ-HCH following repeated inoculations (Kar and Singh 1979b). The degradation of 

γ-HCH became more efficient with time, thus reducing the pesticide's toxicity in cultures of nitrogenfixing blue-green algae. Dechlorination of γ-HCH to γ-pentachlorocyclohexene was also shown to occur 

with fungi in aqueous suspensions (Machholz and Kujawa 1985) and in algal cultures (Sweeney 1969). 

Hydrolysis is not considered an important degradation process for γ-HCH in aquatic environments under 

neutral pH conditions. However, under alkaline conditions, γ-HCH is hydrolyzed fairly rapidly. Saleh et 

al. (1982) tested rates of hydrolysis of γ-HCH in sterilized natural waters at 25 °C and found that 

hydrolysis of γ-HCH followed first-order kinetics with half-lives of 92 hours at pH 9.3, 648 hours at 

pH 7.8, and 771 hours at pH 7.3. EPA (1989d) reported a hydrolysis half-life of 207 days at pH 7 and 

25 °C using distilled water. 

Somewhat conflicting information is available on the rate of photolysis of γ-HCH in water. Since HCH 

does not contain chromophores that absorb light >290 nm, direct photolysis is not expected to occur. 

However indirect photolysis, whereby a photosensitizing agent may absorb light and then transfer its 

excitation energy to HCH, may occur. Humic and fulvic acids are well-known photosensitizing agents 

and are practically ubiquitous in natural waters. In the study by Saleh et al. (1982) the authors reported 

γ-HCH first-order photolysis half-lives of 169, 1,791, and 1,540 hours in pond water, lake water, and 

water from a quarry at pH 9.3, 7.3, and 7.8, respectively when solutions were exposed to direct sunlight. 

However, the rapid rate of degradation at pH 9.3 may have been enhanced by hydrolysis reactions rather 

than by photolysis. In another study, α-HCH and γ-HCH were shown to undergo enhanced photolysis 

when aqueous solutions were spiked with 5 and 25 ppm of soil fulvic acid, and irradiated with natural 

sunlight (Malaiyandi et al. 1982). Hamada et al. (1981) found that γ-HCH underwent photodegradation to 

form two isomers of tetrachlorohexene and pentachlorohexene in propanol solution when irradiated with 

ultraviolet light produced by a low-pressure mercury lamp. Oxidants commonly found in natural waters, 

such as peroxy radicals, hydroxyl radicals, and singlet oxygen species, can degrade HCH in water. Mill 

(1999) estimated that the indirect photolysis half-life of HCH in natural waters is about 270 days, and the 

dominant oxidant for HCH was the hydroxyl radical. Photolysis of γ-HCH in aqueous solution in the 

presence of polyoxomethallate, a strong oxidizing agent, has also been demonstrated (Hiskia et al. 1997). 
HEXACHLOROCYCLOHEXANE 198 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3.2.3 Sediment and Soil 

γ-HCH in soil or sediment is degraded primarily by biodegradation, although hydrolysis may occur in 

moist soils under alkaline conditions. Tu (1976) reported that 71 of 147 microorganisms isolated from a 

loamy sand soil were able to utilize a γ-HCH solution as the sole carbon source. White rot fungus 

degraded radiolabeled γ-HCH in aerobic pure culture laboratory tests. In a silt loam soil/corncob test 

matrix, 34.7% of the compound was degraded over a 60-day test period, whereas 53.5% degradation was 

observed in liquid cultures over a 30-day test period (Kennedy et al. 1990). The results of this study have 

been confirmed by more recent studies (Mougin et al. 1996, 1997). The isolation of γ-HCH-degrading 

bacteria, classified as Sphingomonas paucimobilis, from contaminated soils has been reported (Thomas 

et al.1996). A Pseudomonas species has also been isolated from pretreated soil that is able to degrade 

γ-HCH and α-HCH, but not β-HCH, within 10–20 days under both flooded (anaerobic) and unflooded 

(aerobic) conditions; greater degradation rates were observed under aerobic conditions (Sahu et al. 1993). 

However, the concentrations and persistence of γ-HCH in soil are dependent on soil types. An analysis of 

two soil types, loamy sand (approximately 1–2% organic matter) and muck (approximately 27–56% 

organic matter), for γ-HCH residues showed that mean residues in the loamy sand soil had decreased 

from 95 ppb dry weight in 1971 to below the detection limit of 10 ppb in 1989; however, in muck, 

residues had decreased from 426 ppb in 1971 to 168 ppb in 1989 (Szeto and Price 1991). The presence of 

crops on the soils also affects the persistence of HCH residues, with half-lives of 58.8 and 83.8 days for 

cropped and uncropped plots, respectively. β-HCH was the most persistent isomer, with half-lives of 

184 and 100 days, respectively, on cropped and uncropped plots; γ-HCH was next at 107 and 62.1 days, 

followed by α-HCH at 54.4 and 56.1 days, and finally, δ-HCH at 33.9 and 23.4 days. Only trace amounts 

of the isomers were found to leach below 20 cm soil depth (Singh et al. 1991). The β-HCH isomer 

comprised 80–100% of the total HCH residues found in soil or vegetation on land surrounding an 

industrial landfill in Germany 10 years after the final HCH input (Heinisch et al. 1993). 

Most available information suggests that γ-HCH transformation is favored in biologically rich, anaerobic 

environments (EPA 1979b; Haider 1979; Kalsch et al. 1998). In bench-scale anaerobic digestion tests 

designed to assess the fate of semivolatile organic pollutants in primary and secondary sludges, γ-HCH 

was found to undergo 98% degradation at 120 days. Sorption of the compound to the digester solids 

accounted for 2% of the initial feed; none of the compound was lost by volatilization. The digesters were 

operated at 35 °C with a 30-day solids retention time (Govind et al. 1991). Similar results were seen with 

live activated sludge where initially reversible biosorption dominates the removal process followed by an 

increased aerobic biodegradation after approximately 10 hours of acclimation. The biodegradation 
HEXACHLOROCYCLOHEXANE 199 

6. POTENTIAL FOR HUMAN EXPOSURE 

process includes hydrolytic dechlorination with subsequent ring cleavage and finally, partial or total 

mineralization (Tsezos and Wang 1991b). Adaptation of sewage sludge is slow and may take 1– 

2 months; however, once acclimation occurs, 70–80% biodegradation of γ-HCH may occur, with the 

percentage of degradation decreasing with increasing sludge age (Nyholm et al. 1992). Co-oxidation and 

reductive dechlorination are the probable degradation mechanisms (Jacobsen et al. 1991; Nyholm et al. 

1992). 

Numerous diverse studies on biological degradation have shown that γ-HCH was transformed to 

tetrachlorohexene; tri-, tetra-, and pentachlorinated benzenes; penta- and tetra cyclohexanes; other 

isomers of HCH; and other related chemicals. The products varied depending on what organisms were 

present, what products were sought, and when the sample was analyzed (EPA 1979b). Laboratory studies 

have demonstrated the bioisomerization of γ-HCH to α-, β-, and δ-HCH but bioisomerization in the 

environment was considered to be nonsignificant by an investigator who conducted a field study 

(Waliszewski 1993). Levels of individual isomers were approximately 0.1–1.4 and 0.8–4.0% of the 

γ-HCH concentrations at 3–31 and 34–46 weeks, respectively, following γ-HCH treatment of soil. An 

inability to control all environmental conditions in the laboratory was discussed as a possible reason for 

differences in results between laboratory and field studies. 

Abiotic transformation and degradation processes of γ-HCH in soil/sediment are not thought to be 

significant pathways. As discussed earlier for water, photolysis or hydrolysis are not considered 

important degradation pathways of γ-HCH and other isomers; the exception being hydrolysis under 

alkaline conditions. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to hexachlorocyclohexane depends in part on the 

reliability of supporting analytical data from environmental samples and biological specimens. 

Concentrations of hexachlorocyclohexane 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 

hexachlorocyclohexane 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 hexachlorocyclohexane in a variety of environmental 

media are detailed in Chapter 7. 
HEXACHLOROCYCLOHEXANE 200 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.1 Air 

γ-HCH was detected in ground level ambient air samples collected in College Station, Texas, in 1979– 

1980 at a mean concentration of 0.23 ng/m3

 (range, 0.01–1.60 ng/m3) (Atlas and Giam 1988). The 

compound has also been detected in troposphere air samples collected over the Adirondack Mountains in 

New York State in 1985 at a mean concentration of 0.509 ng/m3

 and over Newport News, Virginia, in 

1988 at a mean concentration of 0.021 ng/m3

 (Knap and Binkley 1991). α-HCH and γ-HCH were 

detected in the air of Alabama during an air monitoring program (January–October 1996 and May 1997) 

at mean concentrations of 0.092 and 0.050 ng/m3

, respectively (Jantunen et al. 2000). The average level 

of α-HCH at Eagle Harbor, Michigan; Sleeping Bear Dunes State Park, Michigan; and Sturgeon Point, 

New York ranged from 0.110 to 0.140 ng/m3

 for samples collected between 1990 and 1997 and the 

average levels of γ-HCH were 0.024–0.062 ng/m3

 at the same sites (Cortes and Hites 2000). Air 

monitoring over southern Ontario, Canada, from July 1988 to July 1989 showed annual mean air 

concentrations of α-, β-, and γ-isomers to be 0.145, 0.0018, and 0.06 ng/m3

, respectively with a total HCH 

annual mean concentration of 0.21 ng/m3

 and with the greatest total HCH concentrations during the 

summer months (Hoff et al. 1992a). The maximum concentration of γ-HCH measured at a site 2 km 

away from a canola field in south central Saskatchewan, Canada where γ-HCH had been applied as a seed 

treatment was 2.9 ng/m3

 in 1997, and 2.7 ng/m3 in 1998 (Waite et al. 2001). 

In a study of global distribution and atmospheric transport of chlorinated hydrocarbons in the West 

Pacific, Eastern Indian, and Antarctic Oceans, Tanabe et al. (1982) confirmed the widespread distribution 

of HCH isomers. HCH residues were detected in all 79 air and water samples collected. The 

concentrations ranged from 1.1 to 2.0 ng/m3

 in air and from 3.1 to 7.3 ng/L in water. Other monitoring 

studies include the detection of γ-HCH in the lower troposphere over the Southern Indian Ocean in 1986 

at a mean concentration of 0.406 ng/m3

 (Wittinger and Ballschmiter 1990), in the lower troposphere over 

Bermuda in 1988 at a mean concentration of 0.012 ng/m3

 (Knap and Binkley 1991), and in ambient air 

samples collected at Axel Hieberg Island in the Canadian arctic at 0.017–0.07 ng/m3

 (Hargrave et al. 

1988). 

γ-HCH has also been detected in rainfall samples collected in College Station, Texas, in 1979–1980 at a 

weighted mean concentration of 2.81 ng/L (range, 0.30–7.8 ng/L) (Atlas and Giam 1988) and in Bermuda 

in 1983–1984 at a mean concentration of 0.126 ng/L (range, 0.001–0.936 ng/L) (Knap et al. 1988). In 

rainfall samples collected at four sites in Canada in 1984, γ-HCH concentrations ranged from 0.46 to 

34 ng/L (Strachan 1988). The mean concentration in rainfall samples collected at Lake Superior during 
HEXACHLOROCYCLOHEXANE 201 

6. POTENTIAL FOR HUMAN EXPOSURE 

the 1984 wetfall season was 3.0 ng/L, with an annual loading of 2.0 μg/m2/year (Strachan 1988). These 

values were less than those determined in the years 1977, 1981, and 1983 (Strachan 1988). γ-HCH has 

been detected in rain and snow water in Portland, Oregon in 1982 at mean concentrations ranging from 

0.45 to 11 ng/L (Pankow et al. 1984). Rainwater collected in Hawaii in 1970–1971 had a mean γ-HCH 

concentration of 5 ng/L, with concentrations ranging from 1 to 19 ng/L (Bevenue et al. 1972). Snow and 

ice samples collected at Axel Hiberg Island in the Canadian Arctic in 1986 contained γ-HCH at 

concentrations of 0.211–0.644 and 0.186 ng/L, respectively (Hargrave et al. 1988). Rain samples 

collected in Germany between June 1990 and August 1991 contained γ-HCH at a mean concentration of 

208 ng/L (range, 20–833 ng/L) in 39 of 41 samples (Scharf et al. 1992). 

6.4.2 Water 

Surface water concentrations of γ-HCH have been measured in many areas across the United States. 

Concentrations of γ-HCH in the range of 0.052–0.1 μg/L were observed in Washington, DC, and Denver, 

CO (Cole et al. 1984). The majority of the available monitoring studies were conducted in the early to 

mid 1970s. A comprehensive monitoring study was conducted in 1980–1981 in the Niagara River near 

its entry into Lake Ontario. In that study, γ-HCH was detected in 99% of all samples at a mean 

concentration of 2.1 ng/L (Kuntz and Warry 1983). γ-HCH concentration in Lake Michigan tributary 

streams ranged from undetected to 0.15 μg/L (EPA 1974c). According to EPA's STORET (short for 

STOrage and RETrieval) database, γ-HCH was detected in 27% of 4,505 surface water samples collected 

in the United States at a median concentration of 0.020 μg/L (Staples et al. 1985). γ-HCH concentrations 

in groundwater samples were greatest in the West South Central region (Phillips and Birchard 1991). The 

compound was also found in water samples collected in Lake Ontario in 1983 at 0.806–1.85 ng/L 

concentration (Biberhofer and Stevens 1987). γ-HCH was detected in the Patuxent River (a tributary to 

the Chesapeake Bay) in 1995 at a mean concentration of 1.0 ng/L (Harmon-Fetcho et al. 1999). 

γ-HCH has been detected in more than 10% of urban stormwater runoff samples in two U.S. cities at 

concentrations between 0.052 and 0.1 ng/L (Cole et al. 1984). In urban runoff samples collected in the 

Canadian Great Lakes Basin, γ-HCH was detected at mean concentrations of 0.0065 μg/L and 

0.0035 mg/kg in the aqueous and sediment portions, respectively; the mean annual loading of the 

compound in runoff in the basin was reported to be 4.1 kg/year (Marsalek and Schroeter 1988). 

γ-HCH has been detected in drinking water in Chesterfield County, South Carolina, and Hampton, South 

Carolina at mean concentrations of 23 ng/L (0–193 ng/L, range) and 147 ng/L (0–319 ng/L, range), 
HEXACHLOROCYCLOHEXANE 202 

6. POTENTIAL FOR HUMAN EXPOSURE 

respectively (Sandhu et al. 1978). γ-HCH has also been detected in drinking water from Cincinnati, Ohio 

(Keith et al. 1976), and Oahu, Hawaii (Bevenue et al. 1972), at mean concentrations of 0.01 ng/L, and 

0.2 ng/L, respectively. In a study of α-HCH and γ-HCH in Saskatchewan, Canada, these HCH isomers 

were not detected frequently in surface waters that originate from ground water (Donald et al. 1997). A 

comprehensive groundwater monitoring study was conducted in the Ozark Plateaus Province of Arkansas, 

Kansas, Missouri, and Oklahoma from April to September 1993 (Adamski et al. 1996). γ-HCH was 

identified in two groundwater samples collected from domestic wells and springs at concentrations of 

0.028 and 0.032 μg/L. γ-HCH was detected in a drinking water well in Connecticut at a concentration of 

0.06 μg/L (Eitzer and Chevalier 1999). Isomers of HCH were detected in drinking water from Southern 

Spain between 1991 and 1994 at concentrations of 0.008–0.199 μg/L (α-HCH ), 0.005–0.021 μg/L 

(β-HCH), and 0.002–0.228 μg/L (γ-HCH) (Garcia-Repetto and Repetto 1997). 

6.4.3 Sediment and Soil 

γ-HCH was detected at trace levels (<0.1 mg/kg) in surface soils from five counties in western Alabama 

(Albright et al. 1974). γ-HCH was detected in soil from Alabama, Arkansas, Georgia, Illinois, and Iowa 

at concentrations of 0.01, 0.01, 0.07, 0.02, and 0.15 mg/kg, respectively (Crockett et al. 1974). A survey 

of soils from six regions of Alabama showed that α-HCH was present in 24 out of 39 soils analyzed at 

concentrations of 0–0.269 μg/kg and γ-HCH was present in 26 out of 39 soils analyzed at concentrations 

of 0–1.07 μg/kg (Harner et al. 1999). γ-HCH was detected in agricultural soils from Canada at levels of 

0.36–2.2 μg/kg (Webber and Wang 1995). β-HCH, γ-HCH, and δ-HCH were detected in rice growing 

and industrial soils in South Korea at the following concentration ranges: 0.25–0.80 μg/kg, β-HCH; 0.17– 

0.56 μg/kg, γ-HCH; 0.76–2.97 μg/kg, δ-HCH (Kim and Smith 2001). 

According to EPA's STORET database, γ-HCH was detected in 0.5% of 596- sediment samples collected 

throughout the United States at a median concentration of <2.0 μg/kg (Staples et al. 1985). According to 

data collected in STORET between 1978 and 1987, γ-HCH was found in the greatest concentration in 

sediment from the West North Central census region of the United States, followed by the Mountain 

region and the East South Central region (Phillips and Birchard 1991). γ-HCH was detected in 33% of 

suspended sediment samples collected from the Niagara River; the average concentration was 2 μg/kg 

(Kuntz and Warry 1983). The average γ-HCH concentration in settling particulates from Lake Ontario 

was 2.4 ppb in 1982 (Oliver and Charlton 1984). Sediment samples from Lake St. Francis on the St. 

Lawrence River contained a mean total HCH concentration of 0.6 μg/kg dry weight (range, <0.1– 

2.0 μg/kg), suggesting that deposition of contaminated materials from Lake Ontario was of less 
HEXACHLOROCYCLOHEXANE 203 

6. POTENTIAL FOR HUMAN EXPOSURE 

importance than local inputs of HCH (Sloterdijk 1991). γ-HCH concentrations in creek sediments 

collected in 1976 near the James River in Virginia ranged from 7.3 to 8.5 μg/kg (Saleh et al. 1978). 

γ-HCH was included in the analytes monitored in the National Oceanic and Atmospheric Administration's 

(NOAA) Status and Trends Mussel Watch Program conducted in the Gulf of Mexico. The compound 

was detected in 19% of the sediment samples collected in 1987 at a mean concentration of 0.07 μg/kg 

(median, <0.02 μg/kg; range, <0.02–1.74 μg/kg) (Sericano et al. 1990). Sediment samples collected 

around the Great Lakes in May 1989 contained γ-HCH concentrations ranging from below the detection 

limit (0.10 μg/kg) to 0.99 μg/kg (wet weight) (Verbrugge et al. 1991). Thirty-three sediment samples 

from 11 impoundments along the Indian River Lagoon in Florida contained γ-HCH at concentrations 

ranging from 34.4 μg/kg in the top layer of sediment at one impoundment to 9.4 μg/kg in the bottom layer 

at the same site (Wang et al. 1992). The pesticide γ-HCH had been used for mosquito control in the area 

from the late 1950s to the mid 1960s. Interstitial water samples from the impoundment sites did not 

contain detectable levels of the pesticide. 

6.4.4 Other Environmental Media 

γ-HCH was detected in 5 out of 612 imported rice samples at a maximum concentration of 0.03 ppm 

during an FDA pesticide monitoring study conducted in 1993–1994 (Roy et al. 1997). A 10-year (1982– 

1991) FDA study of ready-to-eat foods commonly consumed in the United States showed that α-, β-, δ-, 

and γ-HCH were frequently detected (Rogers et al. 1995). The results of this study pertinent to the 

isomers of HCH are summarized in Table 6-2. γ-HCH residues were detected in fat samples of domestic 

farm animals collected in Ontario, Canada, in 1986–1988. Mean concentrations in fat from chickens, 

turkeys, beef, lamb, and pork ranged from 0.012 to 0.032 ppm; the mean concentration in hen eggs was 

0.008 ppm (Frank et al. 1990b). γ-HCH was detected at levels of ≤10 ppm in 6 out of 5,784 fruit and 

vegetable commodities analyzed in Canada from 1992 to 1994 (Neidert and Saschenbrecker 1996). α-, 

β-, and γ-HCH were detected in butter samples from the United States at mean levels of 0.38, 0.42, and 

0.78 ppb, respectively (Kalantzi et al. 2001). HCH isomers were also detected in butter samples from 

20 other countries, with the highest levels being observed in a single butter sample from India with 

reported concentrations of 98, 108, and 164 ppb for α-, β- and γ-HCH, respectively (Kalantzi et al. 2001). 

γ-HCH residues on tomatoes decreased by 23.9% 15 days after application of the pesticide (from 

0.1956 ppm to 0.1488 ppm). Processing the tomatoes (e.g., pureeing, making tomato juice) reduced the 
HEXACHLOROCYCLOHEXANE 204 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Ten-year Study on the Occurrence of HCH in 234 Ready-to-eat 

Food Items in the United States
 

HCH isomer Na Foodsb Average concentration (μg/g) 

α-HCH 584 88 0.0010 

β-HCH 14 9 0.0027 

δ-HCH 1 1 0.0030 

γ-HCH 369 81 0.0012 

a

Number of samples in which residue was detected (17,050 total samples). 

b

Number of foods in which residue was detected (234 total ready-to-eat foods; 230 foods with detectable pesticide
 

levels). 
HEXACHLOROCYCLOHEXANE 205 

6. POTENTIAL FOR HUMAN EXPOSURE 

residue levels by 100% after the waiting period; however, washing the tomatoes reduced the residues by 

up to 55.9% (Bessar et al. 1991). A pesticide residue screening program carried out by the H.E.B. Food 

Stores of San Antonio between 1989 and 1991 detected γ-HCH in 4 of 429 onion samples (detection 

limit, 0.02 ppm); however, none of the positive samples exceeded the action level for this commodity 

(Schattenberg and Hsu 1992). 

As part of NOAA's Status and Trends Mussel Watch Program conducted in the Gulf of Mexico, γ-HCH 

was detected in 80% of the oyster samples collected in 1987 at a mean concentration of 1.74 ppb (median, 

1.20 ppb; range, <0.25–9.06 ppb) (Sericano et al. 1990). Samples taken in 1992 from Mexico's Palizada 

River, located in a major agricultural area with substantial pesticide use, contained an average γ-HCH 

concentration of 0.08 ppb in shrimp but no detectable levels in oysters or mussels (Gold-Bouchot et al. 

1995). Combined concentrations of other HCH isomers were found to be 1.18 ppb in shrimp, 1.04– 

1.97 ppb in oysters, and 1.68 ppb in mussels. Schmitt et al. (1985) reported the results of a monitoring 

study of fish tissues from 107 freshwater stations in the United States. A decline in tissue occurrence of 

detectable α- and γ-HCH residues was observed from 1976 to 1981. During 1980–1981, whole body 

residues of γ-HCH exceeded 0.01 ppb at only one station, where levels were 0.02–0.03 ppb. Tissue 

concentrations of α-HCH were higher than γ-HCH. The highest concentrations for α-HCH were 0.03– 

0.04 ppb and were found in fish from the southwestern and Midwestern United States. An analysis of 

fish from the Upper Steele Bayou in Mississippi in 1988 indicated that β-HCH concentrations ranged 

from undetected to 0.02 ppm wet weight in fish; no β-HCH was detected in snakes or sediments taken 

from the same area (Ford and Hill 1991). Atlantic cod taken from relatively isolated stock in the southern 

Gulf of St. Lawrence showed declining tissue concentrations of α-HCH between 1977 (1.865 ppb) and 

1985 (1.792 ppb). α-, β-, δ, and γ-HCH were detected in the tissue of adult green frogs from 

southwestern Michigan at mean concentrations of 0.02, 0.01, 0.03, and 0.07 ppb, respectively, during a 

1998 monitoring study (Gilliland et al. 2001). Only α-HCH was detected in juvenile frogs obtained from 

the same locations at a mean concentration of 0.04 ppb. 

An analysis of pesticide residues in green coffee and after roasting indicated that technical-grade HCH 

was found in green coffee at concentrations ranging from <0.005 to 0.204 ppm. However, storage and 

roasting reduced the pesticide residues by 60–67% and up to 98%, respectively, with darker roasting 

resulting in the greatest reduction (McCarthy et al. 1992). 
HEXACHLOROCYCLOHEXANE 206 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Human exposures to γ-HCH can result from the ingestion of plants, animals, animal products, milk, and 

water containing the pesticide. Farm animals may be exposed to the compound through feed, air, or water 

or cutaneous application for protection from ectoparasites. Lipophilic pesticides such as γ-HCH 

accumulate in adipose tissue. Clark et al. (1974) found that γ-HCH levels in the adipose tissue of cattle 

were 10 times higher than in the feed (0.002 mg/kg). An analysis of data from 238 families in Missouri 

between June 1989 and March 1990, indicated that 9.2% of the families reported using Kwell shampoo 

(contains γ-HCH) for lice control on children (Davis et al. 1992). 

The most likely route of non-medicinal human exposure to γ-HCH is ingestion of food containing the 

pesticide. A smaller degree of exposure may result from ingestion of drinking water containing γ-HCH. 

For example, γ-HCH was detected in 6% of the foods collected in eight market basket surveys from 

different regions of the United States during the period of April 1982 to April 1984 (Gunderson 1988), in 

4% of the foods surveyed from June 1984 to April 1986 (Gunderson 1995a), and in 4% of the foods 

surveyed from July 1986 to April 1991 (Gunderson 1995b). Foods representative of eight infant and 

adult population groups were prepared for consumption prior to analysis in a revision to FDA's Total Diet 

Studies methodology. The estimated mean daily intakes (ng/kg body weight/day) of α-, β-, and γ-HCH 

for these groups in 1982–1984, 1984–1986, and 1986–1991 are shown in Table 6-3. HCH isomers have 

been detected in the following feed types formulated for infants and toddlers: whole milk and other dairy 

products; meat, fish, and poultry; oils and fats; vegetables; and sugars and adjuncts (Gartrell et al. 1986a). 

HCH isomers were also detected in adult diet foodstuffs, including dairy products; meat, fish, and 

poultry; garden fruits; oils and fats; leafy and root vegetables; and sugar and adjuncts (Gartrell et al. 

1986b). Daily intake values of HCH isomers in adult diets in 1981–1982 were reported to be 

0.010 μg/kg/day for total HCH; 0.008 μg/kg/day for α-HCH; <0.001 μg/kg/day for β-HCH and δ-HCH; 

and 0.002 μg/kg/day for γ-HCH. In the Total Diet Study conducted by FDA in 1990 on 936 food items, 

γ-HCH was detected in 23 items, while α-HCH and β-HCH (combined) were detected in 11 items. 

Information on the amount of levels found were not provided (Yess 1991). The average concentrations of 

α-, β-, δ-, and γ-HCH in 234 ready-to-eat foods were 0.0010, 0.0027, 0.0030, and 0.0012 μg/g, 

respectively (see Table 6-2) (Rogers et al. 1995). 

Studies, in which soils containing 10 ppm radiolabeled γ-HCH were added to human skin samples at 

quantities that exceeded monolayer coverage (5 mg soil/cm2

 skin), demonstrated mean γ-HCH 
HEXACHLOROCYCLOHEXANE 207 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Average Daily Intake (AVDI, ng/kg/day) of γ-HCH in 

Eight Population Groups 

Date 

Infants 

(6–11 months) 

Toddlers 

(2 years) 

14–16­

year-old 

females 

14–16­

year-old 

males 

25–30­

year-old 

females 

25–30­

year-old 

males 

60–65­

year-old 

females 

60–65­

year-old 

males 

α-HCH 

1982– 

1984a 

7.2 16.1 6.1 7.3 4.5 5.9 3.3 3.7 

1984– 

1986b 

3.3 7.1 2.7 3.3 2.0 2.5 1.5 1.6 

1986– 

1991c 

0.8 2.7 1.1 1.1 0.7 0.8 0.5 0.5 

β-HCH 

1982– 

1984a 

<0.1 0.3 0.2 0.2 0.2 0.4 0.2 0.2 

1984– 

1986b 

No data <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 

1986– 

1991c 

<0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 

γ-HCH 

1982– 1.9 7.9 3.1 3.4 2.0 2.5 1.6 1.8 

1984a 

1984– 0.7 2.8 1.1 1.3 0.7 0.9 0.6 0.6 

1986b 

1986– 0.8 3.2 1.4 1.5 0.8 1.0 0.6 0.6 

1991c 

a

Gunderson 1988 

b

Gunderson 1995a 

c

Gunderson 1995b 
HEXACHLOROCYCLOHEXANE 208 

6. POTENTIAL FOR HUMAN EXPOSURE 

absorptions of 1.04% from sandy soils and 1.64% from silt soils (Duff and Kissel 1996). However, data 

from soil absorption studies can vary due to factors such as the amount of soil added to skin, the exposure 

time, and possible evaporation of the contaminant. 

The results of biomonitoring studies can be used as indicators of human exposures to HCH. The National 

Human Adipose Tissue Survey (NHATS) conducted in 1982 showed that β-HCH (the most prevalent 

HCH isomer in fatty tissue) was detected in 87% of 46 composite samples at <19–570 ng/g (ppb) 

concentrations (EPA 1986d). It was detected most often in postmortem samples collected from 

individuals from the southern United States. In another survey conducted in 1970–1975, β-HCH was 

detected in more than 90% of the postmortem human adipose tissue samples at an average level of 

300 ppb (Kutz et al. 1979). In a review of the NHATS data available from 1970 to 1983, EPA (1985c) 

reported that the estimated 1983 national median level of β-HCH was 80 ppb, in comparison to the 

historic level of 140 ppb. The median level has decreased over time, but the compound has continued to 

be detected in nearly 100% of the population surveyed. Median levels are highest in the South census 

region and tend to increase with age but have not been found to differ across the sexes or racial groups. A 

further analysis of the NHATS data indicated that average β-HCH concentrations in fat had decreased 

from 0.45 ppm in 1970 to approximately 0.16 ppm since 1981 (Kutz et al. 1991). 

A comparison of the levels of α-HCH and β-HCH in the whole blood and biopsy fat of 25 patients 

showed median levels of 0.04 ng/g (maximum, <0.04 ng/g) and 0.13 ng/g (maximum, 2.60 ng/g) for the 

blood and 1.1 ng/g (maximum, 9.6 ng/g) and 18.0 ng/g (maximum, 748.6 ng/g) for the fat tissue, 

respectively (Mes 1992). A further comparison of β-HCH levels in breastmilk and adipose tissue samples 

was made for populations living near the Great Lakes (Canada only) and in other Canadian regions. 

Mean β-HCH levels in breast milk (0.6 ng/g) and adipose tissue (23.4 ng/g) were lower near the Great 

Lakes than in other parts of Canada (0.8 and 30.8 ng/g, respectively) (Mes and Malcolm 1992). Levels of 

HCHs in the adipose tissue of Japanese males increased from the late 1940s to 1966, coinciding with an 

increased annual production of HCH (Loganathan et al. 1993). Levels have been dropping since HCHs 

were banned in 1971, from a maximum level of 28 μg/g to present levels of <1 μg/g. Since 1974, only 

the more persistent β-HCH isomer has been found (Loganathan et al. 1993). 

γ-HCH was one of the most frequently detected pesticides in the blood of Virginia residents, although the 

number of individuals sampled was not identified (Griffith and Blanke 1975). γ-HCH blood 

concentrations were the highest in residents of the middle age group (41–60 years). Some of the 

frequency of γ-HCH occurrence in the state was attributed to its common use in commercial vaporizers 
HEXACHLOROCYCLOHEXANE 209 

6. POTENTIAL FOR HUMAN EXPOSURE 

and its presence in cigarette smoke (Griffith and Blanke 1975). The National Health and Nutrition 

Examination Survey (NHANES) analyzed blood and urine specimens for the presence of HCH isomers. 

β-HCH was detected in approximately 13.9% of the U.S. population (12–74 years) in the Northeast, 

Midwest, and South. The median level for the 91% quantifiable positive results was 1.7 ppb (Murphy 

and Harvey 1985). 

Factors such as age, dietary habits, and residence can influence the body burden of γ-HCH in exposed 

individuals. In one study, it was shown that women between the ages of 26 and 34 years who lived in a 

rural area of India and were nonvegetarians tended to show higher body levels of γ-HCH than other 

Indian women who lived in an urban area or who were vegetarians (Saxena et al. 1981a). The higher 

levels of γ-HCH in women at an older child-bearing age suggest that a longer life span may cause a 

greater accumulation of pesticide in the body. Higher pesticide levels are found in mutton, eggs, and 

chicken, which are common in nonvegetarian meals; therefore, there tends to be a higher level of γ-HCH 

in the bodies of nonvegetarians. Individuals living in rural areas are more likely to be exposed to γ-HCH 

because agricultural fields are the primary site of application of pesticides. In addition, studies indicate 

that γ-HCH is also present in breastmilk at an average level of 0.006 ppm in Alberta, Canada (Currie et al. 

1979). In a study of 50 donors of breastmilk in Oahu, Hawaii, Takahashi et al. (1981) demonstrated HCH 

in 82% of the samples at a mean level of 81 ppb within a range of 0–480 ppb, expressed in terms of 

extractable lipid. 

A study conducted in Colorado indicated, in general, that no quantitative relationships were demonstrated 

between pesticide levels in household dust and pesticide levels in blood. However, γ-HCH levels in 

blood sera in a pesticide formulator (16.8 ppb) and his wife (5 ppb) were found to be elevated in a 

household in which dust levels measured 5.85 ppb (Starr et al. 1974). It is possible that the γ-HCH found 

in the wife's blood and in the household came from the clothes and person of the pesticide formulator. 

The Nonoccupational Pesticide Exposure Study (NOPES) conducted by EPA was based on the Total 

Exposure Assessment Methodology (TEAM) approach to exposure estimation. NOPES was designed to 

provide estimates of nonoccupational exposure to 32 household pesticides in the United States. Samples 

were collected at two locations: (1) Jacksonville, Florida, an area representative of high pesticide usage; 

and (2) Springfield/Chicopee, Massachusetts, an area of low-to-moderate pesticide usage. Detectable 

levels of γ-HCH were found in the personal air samples of 32–70% of the Jacksonville sample population; 

the range of mean concentrations in the air samples was 7–22 ng/m3

. For the Springfield population, 
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6. POTENTIAL FOR HUMAN EXPOSURE 

detectable levels of γ-HCH were found in personal air samples collected from 8 to 10% of the population, 

with mean concentrations of 0.7–5 ng/m3

 (EPA 1990c). 

A study on occupational pesticide exposure of commercial seed-treating applicators was conducted in 

Montana (Grey et al. 1983). No exposure was detectable on the chest and arm pads, but γ-HCH was 

detected on the hands and on the respirator pads. Workers involved with γ-HCH application complained 

of nasal irritation if they did not wear a respirator or mask. The α-, β-, γ-, and δ-isomers of HCH have 

been detected in the blood serum and adipose tissue of individuals occupationally exposed to HCH in 

pesticide formulation. Serum levels of <0.5 ppb–1 ppm α-HCH, <0.9 ppb–0.72 ppm β-HCH, <0.7 ppb– 

0.17 ppm γ-HCH, and 0.002–0.16 ppm δ-HCH have been detected in exposed workers (Baumann et al. 

1980; Kashyap 1986; Morgan and Lin 1978; Nigam et al. 1986). Mean adipose tissue levels of 5.8 mg 

α-HCH/kg, 45.6 mg β-HCH/kg, and 3.1 mg γ-HCH/kg have also been reported in exposed workers 

(Baumann et al. 1980). 

The Centers for Disease Control and Prevention (CDC) has recently completed its Second National 

Report on Human Exposure to Environmental Chemicals that was derived from data obtained from the 

National Health and Nutrition Examination Survey (NHANES) (CDC 2003). The first report on 

27 chemicals was issued in March 2001. This second report, released in January 2003, presents blood and 

urine levels of 116 environmental chemicals from a sample of people who represent the noninstitutionalized, civilian U.S. population during the 2-year period of 1999–2000. Lipid serum levels of β- and 

γ-HCH are summarized in Table 6-4. 

In general, accidental or intentional ingestion would lead to the highest exposures. Worker exposure 

constitutes the next highest exposure population although worker exposure is decreasing in both the 

number of workers exposed and the levels of exposure. Lastly, the general population receives the lowest 

levels, which occur mainly from ingestion of foods and water with γ-HCH residues. Living near a waste 

disposal site contaminated with γ-HCH will also increase the likelihood of exposure. 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Geometric Mean and Percentiles of the Serum Concentration (ng/g) of 

β-HCH in the U.S. Populationa 

Geometric Selected percentiles Sample 

Age mean 10th 25th 50th 75th 90th 95th size 

β-HCH 

12 and older 9.68 <LODb

 <LOD <LOD 19.0 42.0 68.9 1,893 

 12–19 NAc <LOD <LOD <LOD <LOD <LOD 11.4 653 

20 and older 10.9 <LOD <LOD <LOD 21.0 46.0 73.4 1,240 

Males NA <LOD <LOD <LOD 14.5 29.8 44.6 901 

Females 11.1 <LOD <LOD <LOD 22.0 51.3 81.1 992 

 Mexican Americans 16.7 <LOD <LOD 15.5 37.5 97.9 139.0 632 

Non-Hispanic Blacks NA <LOD <LOD <LOD 14.7 36.6 48.9 403 

Non-Hispanic Blacks NA <LOD <LOD <LOD 17.5 34.4 51.3 702 

γ-HCH 

12 and older 9.68 <LOD <LOD <LOD <LOD <LOD <LOD 1,799 

12–19 NA <LOD <LOD <LOD <LOD <LOD <LOD 660 

20 and older NA <LOD <LOD <LOD <LOD <LOD <LOD 1,139 

Males NA <LOD <LOD <LOD <LOD <LOD <LOD 863 

Females NA <LOD <LOD <LOD <LOD <LOD <LOD 936 

Mexican Americans NA <LOD <LOD 15.5 <LOD <LOD <LOD 631 

Non-Hispanic Blacks NA <LOD <LOD <LOD <LOD <LOD <LOD 380 

Non-Hispanic Blacks NA <LOD <LOD <LOD <LOD <LOD <LOD 646 

b

LOD = level of detection; 4.8 ng/g (β-HCH) and 7.5 ng/g (γ-HCH). c

NA = not available; proportion of results below limit of detection was too high to provide a valid result. 

a

Source: CDC 2003 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

Prenatal exposure of children to HCH can occur. β-HCH and γ-HCH have been found in samples of 

human maternal adipose tissue, maternal blood, cord blood, and breastmilk in women who were exposed 

to unknown levels of various organochlorine pesticides in Kenya (Kanja et al. 1992). Placental transfer of 

HCH in humans has been well documented (Saxena et al. 1981b). Higher levels of total HCH and γ-HCH 

were found in specimens of maternal blood, placenta, and umbilical-cord blood from women 

experiencing premature labor, spontaneous abortions, and stillbirths when compared to matched controls 

(Saxena et al. 1980; Saxena et al. 1983). Saxena et al. (1980) reported HCH levels of 69.3–550.4 ppb and 

γ-HCH levels of 30.8–113.6 ppb in the blood of women in India who had experienced spontaneous 

abortions or premature labor compared with blood HCH levels of 22.2–85.5 ppb and γ-HCH levels of 

7.1–32.5 ppb in women who had undergone full-term pregnancy. Serum levels of a number of other 

pesticides including aldrin, DDE, DDT, and DDD were also found to be higher in cases of premature 

labor and spontaneous abortions. It was, therefore, not possible to establish a causal relationship between 

the serum HCH levels and these adverse effects. However, HCH has been shown to accumulate in 

amniotic fluid, placenta, and fetal tissues after treatment of pregnant mice (Srivastava and Raizada 1993) 

and can be related to fetolethality. 

HCH is commonly detected in low concentrations (0.015 mg/kg fat) in the breastmilk of women exposed 

to HCH in the environment (Fytianos et al. 1985). Levels of HCH isomers in breastmilk have been 

reported, particularly in developing countries that still use HCH as a pesticide. Studies indicate the 

γ-HCH is present in breastmilk at an average level of 6 ppb in Alberta, Canada (Currie et al. 1979). In a 

study of 50 donors of breastmilk in Oahu, Hawaii, Takahashi et al. (1981) demonstrated HCH in 82% of 

the samples at a mean level of 81 ppb within a range of 0–480 ppb, expressed in terms of extractable 

lipids. Breastmilk concentrations of α-, β-, γ-, and δ-HCH were determined from samples obtained from 

two areas of India that were under malaria control (Dua et al. 1997). The mean concentrations of α-, γ-, 
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6. POTENTIAL FOR HUMAN EXPOSURE 

β-, and δ-HCH in one area were 0.002, 0.002, 0.022, and 0.001 (mg/kg), while in the second area, 

concentrations were 0.003, 0.006, 0.078, and 0.002, respectively. Another study performed in a different 

region of India also demonstrated the presence of HCH isomers in breastmilk (Nair et al. 1996). Mean 

breastmilk concentrations of α-, β-, and γ-HCH were 0.045, 0.198, and 0.084 (mg/L), respectively. 

δ-HCH was not detected in the breastmilk samples. In a study designed to quantify the levels of 

organochlorine residues in the breastmilk of mothers in Uganda, Africa, the milk fat concentrations of 

α-HCH, β-HCH, and γ-HCH ranged from 0.006–0.46, 0.005–0.25, and 0.01–0.87 mg/kg, respectively 

(Ejobi et al. 1996). The concentration of β-HCH in breastmilk samples from three regions in the Czech 

Republic ranged from 71 to 80 ng/g (Schoula et al. 1996). A comparison of β-HCH levels in breastmilk 

and adipose tissue samples was made for populations living near the Great Lakes (Canada only) and the 

rest of Canada. Mean β-HCH levels in breastmilk (0.6 ng/g) and adipose tissue (23.4 ng/g) were lower 

near the Great Lakes than in other parts of Canada (0.8 and 30.8 ng/g, respectively) (Mes and Malcolm 

1992). γ-HCH was identified in 27 out of 115 samples of breast milk obtained from mothers in Al-Kharj, 

Saudi Arabia at mean concentrations of 1.061 μg/L and 23.3 μg/kg milkfat (Al-Saleh et al. 1998). HCH 

isomers were detected in breast milk of mothers from six regions of Belarus at concentrations of 2– 

93 μg/L and 14–2,470 μg/kg milkfat (Barkatina et al. 1998). 

As mentioned previously, exposures to HCH can result from the ingestion of plants, animals, animal 

products, milk, and water containing the pesticide. A smaller degree of exposure may result from 

ingestion of drinking water containing HCH. There is also the possibility of exposure to γ-HCH from 

medical usage (e.g., shampoos for control of lice and lotion for treatment of scabies). Numerous studies 

have documented the effects in humans overexposed to γ-HCH through misuse or accidental ingestion of 

products used to treat head lice (Davies et al. 1983; Jaeger et al. 1984; Lee and Groth 1977). Although 

some controversy exists as to whether γ-HCH is a safe therapeutic agent when used in accordance with 

the manufacturers’ guidelines, it is clear that most exposures occur through misuse of products 

(Rasmussen 1980, 1981, 1987). Besides medical usage, children are likely to be exposed to HCH from 

the ingestion of food containing the pesticide. Based on FDA’s Total Diet Analyses, γ-HCH intakes 

(body weight/day) are 0.8 ng/kg for 6–11-month-old infants, 3.2 ng/kg for 2-year-old toddlers, and 

1.5 and 1.4 ng/kg for 14–16-year-old males and females, respectively (Gunderson 1995b). HCH isomers 

have been detected in the following food types formulated for infants and toddlers: whole milk and other 

dairy products; meat, fish, and poultry; oils and fats; vegetables; and sugars and adjuncts (Gartrell et al. 

1986a). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

HCH isomers have also been detected in cow’s milk in those countries that still use the chemical as a 

pesticide. In a study performed in Uganda, Africa, the concentrations of α- HCH, β-HCH, and γ-HCH in 

cow’s milk were 0.002–0.014, 0.003–0.018, and 0.006–0.036 mg/kg milkfat, respectively (Ejobi et al. 

1996). Mean levels of HCH isomers analyzed in cow’s milk samples from two separate areas in India 

were 0.0045 and 0.012 mg/kg α-HCH, 0.002 and 0.015 mg/kg γ-HCH, 0.0105 and 0.028 mg/kg β-HCH, 

and 0.002 and 0.003 mg/kg δ-HCH (Dua et al. 1997). A monitoring study of 192 samples of cow’s milk 

from Mexico revealed 0.001–0.201 mg/kg α-HCH, 0.008–0.253 mg/kg β-HCH, and 0.002–0.187 mg/kg 

γ-HCH (Waliszewski 1993). HCH isomers have also been detected in buttermilk and butter prepared 

from cow’s milk contaminated with these isomers (Sreenivas et al. 1983). 

HCH is bioavailable from soil and can be absorbed both orally and dermally (Duff and Kissel 1996). 

γ-HCH exhibited mean 24-hour dermal absorption values from 0.45 to 2.35% varying with different soil 

types and soil loadings of 1, 5, and 10 mg/cm3

. Some children intentionally eat dirt and most 

inadvertently ingest dirt by putting fingers or other objects in their mouths while playing outdoors. Thus, 

they are more likely than adults to be exposed to HCH via ingestion or direct contact of soil contaminated 

with HCH. 

Children may also be exposed to a significant amount of HCH from household dust; parents’ work 

clothes, skin, hair, tools, and other objects removed from the workplace are a likely source of exposure to 

children. An analysis of environmental contribution to pesticide body burden indicated household dust 

can be a major source of environmental HCH exposure (Starr et al. 1974), as indicated by elevated 

γ-HCH levels in blood sera in a pesticide formulator (16.8 ppb) and his wife (5 ppb) in a household in 

which dust levels measured 5.85 ppb. It is possible that the γ-HCH found in the wife’s blood and in the 

household came from the clothes and person of the pesticide formulator. 

Children can be exposed to γ-HCH if it is used as a prescription medication for the treatment of scabies 

and/or head lice. A study was conducted where nine patients aged 3.5–18 years of age were prescribed a 

1% γ-HCH shampoo for the treatment of head lice at label rates, but at longer than label-specified 

treatment durations. The maximum level of γ-HCH measured in the blood following treatment was 

6.13 μg/L (EPA 2002b). This concentration is significantly lower than 320 μg/L, the blood level 

associated with acute accidental ingestion, which resulted in short-term adverse effects (EPA 2002b). 

EPA also has published a study on blood levels of γ-HCH in infants and children who had received 

scabies treatment with 1% topical γ-HCH lotion. In this study, serum concentrations of γ-HCH were 

determined in infants and children with and without scabies infection following application of the topical 
HEXACHLOROCYCLOHEXANE 215 

6. POTENTIAL FOR HUMAN EXPOSURE 

preparation to the body surface area as prescribed by the label. Studies were performed on 20 infected 

and non-infected patients who averaged 33–64 months of age. The maximum blood level observed in the 

treated children was reported as 64 μg/L (EPA 2002b). 

Analyses of blood samples of 186 children living in an area contaminated with HCH, which was used as 

an insecticide in Brazil, revealed the presence of α-, γ-, and β-, HCH isomers (Brilhante and Oliveira 

1996). The authors reported that 24% of the children showed 0.89 ppb average concentrations of β-HCH 

in the blood. α- and γ-isomers were detected in only three and one children, respectively, at mean 

concentrations of 1.8 and 0.95 ppb, respectively. Lipid serum levels of β-, and γ-HCH for children 12 or 

older were summarized in table 6-4 (CDC 2003). 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

The populations with the most potential for chronic exposure to HCH are workers who either formulate or 

routinely use γ-HCH. Exposure of the general population to γ-HCH tends to be low because federal 

regulations limiting its use have taken effect. However, γ-HCH is available in some prescription 

medications (e.g., shampoos, lotions), and the possibility of exposure may arise from use of these 

products. Individuals living near hazardous waste sites contaminated with HCH may also be exposed. 

Numerous studies have documented the effects in humans overexposed to γ-HCH through misuse or 

accidental ingestion of products used to treat scabies and head lice (Davies et al. 1983; Jaeger et al. 1984; 

Lee and Groth 1977). Although some controversy exists as to whether γ-HCH is a safe therapeutic agent 

when used in accordance with the manufacturers' guidelines, it is clear that most exposures occur through 

misuse of products (Rasmussen 1980, 1981, 1987). In addition, other studies have described cases in 

which patients have shown neurotoxic effects following excess exposure or ingestion of pesticides (Harris 

et al. 1969; Hayes 1976; West 1967). 

Exposure to the other isomers of HCH (as in the technical-grade HCH) is limited in the United States as a 

result of regulations restricting their use. However, persons traveling or living in areas where the use of 

HCH is legal (e.g., South America, Eastern Europe, and Asia) should be wary of exposure to isomers of 

HCH through food and drinking water sources (Krauthacker et al. 1986; Radomski et al. 1971a; Saxena et 

al. 1980, 1981a, 1981b). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

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 HCH 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 HCH. 

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. Sufficient information is available on the physical and 

chemical properties of γ-HCH and the other HCH isomers (see Chapter 4) to permit an assessment of the 

environmental fate of these compounds. No additional studies are required at this time. 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2002, became available in May of 2004. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

Production methods for HCH are well described in the literature (IARC 1979). γ-HCH is used as an 

insecticide and as a therapeutic scabicide and pediculicide for treatment of ectoparasite in humans and 

animals (Budavari et al. 1989). The production and use of γ-HCH as a pesticide has been restricted in the 

United States, and the use of technical-grade HCH was voluntarily canceled in 1976 (EPA 1978). Recent 

data suggest that the uses and import/export volumes of γ-HCH are decreasing (Hauzenberger et al. 

2002). Release of γ-HCH to environmental media has been primarily from its use as a pesticide. Wastes 

containing γ-HCH must be contained, incinerated, and disposed of in landfills (EPA 1991g). Carbon 
HEXACHLOROCYCLOHEXANE 217 

6. POTENTIAL FOR HUMAN EXPOSURE 

absorption or flocculation are useful treatment methods for the removal of HCH from aqueous effluent 

streams, except when methanol is also contained in the effluents (HSDB 1993). Disposal methods are 

currently subject to revision under EPA guidance. 

Environmental Fate. HCH released to the environment partitions to the atmosphere, soils, and 

sediments (Atkins and Eggleton 1971; Lewis and Lee 1976; Melancon et al. 1986; Saleh et al. 1982; 

Stanley et al. 1971). HCH is transported in the atmosphere, surface water, and groundwater (Mackay and 

Leinonen 1975; Nordmeyer et al. 1992; Stanley et al. 1971). HCH is transformed via biodegradation in 

soils and surface waters (Govind et al. 1991; Kar and Singh 1979b; Kennedy et al. 1990; Macholz and 

Kujawa 1985; Sharom et al. 1980; Tu 1976). Wet and dry deposition are significant removal processes 

for HCH in the atmosphere (Atkins and Eggleton 1971; Hamada et al. 1981; Wiberg et al. 2001). 

Additional information on the transport, transformation, and persistence of the individual isomers in soils 

and groundwater, particularly at hazardous waste sites, are needed to identify the most important routes of 

human exposure to HCH. There is information regarding the half-lives for γ-HCH in water (3–30, 30– 

300, and >300 days for river, lake, and groundwater, respectively [Zoetemann et al. 1980]). Hydrolysis 

occurs slowly under most environmental conditions, but the rate is much more rapid under alkaline 

conditions. At 25 °C, hydrolysis half-lives of 92, 648, and 771 hours were observed for γ-HCH at pH 9.3, 

7.8, and 7.3, respectively (Saleh et al.1982). The degradation of HCH in the atmosphere occurs through 

the reaction with photochemically generated hydroxyl radicals, and half-lives of γ-HCH and α-HCH are 

around 100 days, but can be much longer based upon environmental conditions (Brubaker and Hites 

1998). 

Bioavailability from Environmental Media. Evidence of absorption following inhalation and 

dermal exposure is available for workers involved in the formulation of pesticide products containing 

HCH isomers and in the use of γ-HCH (Baumann et al. 1980; Grey et al. 1983). Dietary intake is a major 

route of exposure for the general population (Gunderson 1988, 1995a, 1995b). Additional information on 

the absorption of γ-HCH, following ingestion of foods containing residues of the compound, would be 

helpful. As mentioned in Section 6.3.1, Duff and Kissel (1996) showed that bioavailability of γ-HCH via 

dermal exposure depended upon levels of soil loading. Dermal absorption ranged from 0.45 to 2.35%. 

For populations living in the vicinity of hazardous waste sites, additional information on absorption 

following dermal contact with, or ingestion of, contaminated soil are needed, given the expected strong 

sorption of the compound to soil particulates. Besides γ-HCH, other isomers of HCH have been detected 

in adult diet foodstuffs (Gartrell et al. 1986b; Rogers et al. 1995). Additional information on the 

absorption of these other HCH isomers following ingestion of foods containing residues of these isomers 
HEXACHLOROCYCLOHEXANE 218 

6. POTENTIAL FOR HUMAN EXPOSURE 

is needed. Because of the potential of HCH to contaminate air, drinking water, and soil, further 

information on the bioavailability of the HCH isomers from these environmental media are needed for 

assessing possible health concerns for humans. 

Food Chain Bioaccumulation. γ-HCH in surface waters and soils is taken up and bioconcentrated 

by terrestrial and aquatic organisms (Just et al. 1990; Matsumura and Benezet 1973; Ramamoorthy 1985; 

Verma and Pillai 1991; Viswanathan et al. 1988). γ-HCH is bioconcentrated to high levels following 

uptake from surface waters by a number of aquatic organisms (Matsumura and Benezet 1973; 

Ramamoorthy 1985; Schimmel et al. 1977). Uptake from soils and bioconcentration by plants and 

terrestrial organisms appears to be limited (Verma and Pillai 1991; Wild and Jones 1992). Limited 

information suggests that the compound is not biomagnified in terrestrial food chains because of its 

metabolism by terrestrial organisms (Schmitt et al. 1985). Bioconcentration values in zebra-fish for 

α-HCH and β-HCH are reported (Butte et al. 1991). Among the HCH isomers, β-HCH accumulates the 

most in the food chain (Szokolay et al. 1977). Additional information on the potential bioaccumulation of 

α-, β-, and δ-HCH isomers in terrestrial and aquatic food chains is needed. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of HCH in 

contaminated media at hazardous waste sites are needed so that the information obtained on levels of 

HCH in the environment can be used in combination with the known body burden of HCH to assess the 

potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. 

Environmental monitoring data are available predominantly for γ-HCH in air (Atlas and Giam 1988; 

Knap and Binkley 1991), surface water (Sandhu et al. 1978; Staples et al. 1985), groundwater (Sandhu et 

al. 1978), soil (Carey et al. 1978; Staples et al. 1985), and foods (FDA 1989b; Gunderson 1988; Kutz et 

al. 1976). γ-HCH has been detected in air, surface water and groundwater, and sediment and soil. The 

widespread distribution of HCH isomers in air has been confirmed (Tanabe et al. 1982). Although the use 

of γ-HCH has been restricted and the use of technical-grade HCH was voluntarily canceled in 1976 (EPA 

1978), it is not likely that new environmental measurements will show considerably lower levels of 

γ-HCH in these media since there are remaining impacts from importing and processing HCH. Therefore, 

additional information on the levels of γ-HCH and α-, β-, and δ-HCH isomers is needed to assess the 

current potential human exposure to the chemicals from environmental media, particularly near hazardous 

waste sites. 
HEXACHLOROCYCLOHEXANE 219 

6. POTENTIAL FOR HUMAN EXPOSURE 

Reliable monitoring data for the levels of hexachlorocyclohexane in contaminated media at hazardous 

waste sites are needed so that the information obtained on levels of hexachlorocyclohexane in the 

environment can be used in combination with the known body burdens of hexachlorocyclohexane to 

assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste 

sites. 

Exposure Levels in Humans. HCH can be detected in the blood (Baumann et al. 1980; Griffith and 

Blanke 1975; Murphy and Harvey 1985), urine (Murphy and Harvey 1985), adipose tissue (Baumann et 

al. 1980; EPA 1986d), breastmilk (Takahasi et al. 1981), and semen (Stachel et al. 1989) of exposed 

individuals. Most of the data on the body burden of HCH are from adipose tissue and blood serum 

analyses conducted postmortem or on occupationally exposed individuals. The disadvantage of using 

postmortem blood is that the HCH concentration may change after death. The occupational studies often 

do not report environmental levels; therefore, it is not possible to correlate body HCH levels with 

environmental levels. The results of the NHATS conducted in 1982 showed that β-HCH, the most 

prevalent isomer in fatty tissue, was detected most often in postmortem samples collected from 

individuals from the southern United States. Samples of human milk that were collected over the years in 

certain populations and used to monitor other contaminants (e.g., PCBs) could be tested for HCHs 

content. Additional information is needed on exposure to γ-HCH and α-, β-, and δ-HCH isomers in 

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. The different pathways for exposure of children to HCH have been 

discussed in Section 6.6. Prenatal exposure of children to HCH has been demonstrated; it is well 

documented that placental transfer of HCH occurs, and HCH levels have been measured in placenta and 

cord blood in humans (Nair et al. 1996; Saxena et al. 1981b) and in amniotic fluid and fetal tissues in 

mice (Srivastava and Raijada 1993). Infants may also be exposed via ingestion of breastmilk and cow’s 

milk. Exposure may also occur via ingestion of water containing HCH, food and animal products, and 

possibly through incidental ingestion of household dust. It has been demonstrated that household dust 

can be an important source of environmental HCH (Starr et al. 1974). This occurs especially if the 

parents work in facilities that process or use HCH and can bring home residues of HCH via their work 

clothes, skin, hair, tools, or other objects removed from the workplace. A take-home exposure study on 

pesticide applicators might be useful if such occupational exposure settings occur. Limited studies 

conducted on exposure of infants and children to γ-HCH from application of 1% γ-HCH lotion as 
HEXACHLOROCYCLOHEXANE 220 

6. POTENTIAL FOR HUMAN EXPOSURE 

scabicide indicated dermal absorption occurred (Ginsberg et al. 1977). Adipose tissue is a major storage 

depot for HCH. Although data from a national human adipose tissue survey exist (EPA 1986d), no 

quantitative data are currently available on the body burden of HCH in children. These studies are needed 

because unique exposure pathways for children exist, and children may be different from adults in their 

weight-adjusted intake of HCH because of their higher surface area to volume ratio and higher ingestion 

rate of household dust. 

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 HCH 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 sub-registries 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 

The Federal Research Programs In Progress (FEDRIP 2004), Current Research Information System 

(CRIS/USDA 2003), and Computer Retrieval of Information on Scientific Projects (CRISP 2003) 

databases were searched for ongoing projects that may fill some existing data gaps. Carolyn Childress of 

the U.S. Geological Survey (USGS) is conducting a regional water-quality study for the Research 

Triangle area of North Carolina that contains monitoring data of chlorinated pesticides including γ-HCH 

(FEDRIP 2004). Dr. Rebecca Dickhut of the College of William and Mary is conducting long-range 

transport studies using isotopically labeled γ-HCH in order to distinguish between long-range and shortrange sources of persistent organic pollutants (POPs) (FEDRIP 2004). Dr. Y.P. Chin of Ohio State 

University and Dr. Diane McKnight of the University of Colorado are conducting joint research to 

determine the level of γ-HCH in Arctic surface waters and the role that dissolved organic matter (DOM) 

plays in the direct and indirect photolysis of γ-HCH and other POPs in the Arctic (FEDRIP 2004). 

Dr. E.M. Ostrea is investigating fetal exposure to environmental toxins, including γ-HCH, through the 

analysis of meconium, cord blood, and neonatal hair attempting to determine the degree of agreement 

among these three methods (CRISP 2003). Dr. J.A. Bloomquist of Virginia Polytechnic University is 

investigating the links between insecticide exposure including exposure to γ-HCH (CRIS/USDA 2003). 
HEXACHLOROCYCLOHEXANE 221 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring α-, β-, γ-, and δ-HCH, its metabolites, and other biomarkers of exposure 

and effect to α-, β-, γ-, and δ-HCH. The intent is not to provide an exhaustive list of analytical methods. 

Rather, the intention is to identify well-established methods that are used as the standard methods of 

analysis. Many of the analytical methods used for environmental samples are the methods approved by 

federal agencies and organizations such as EPA and the National Institute for Occupational Safety and 

Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as 

the Association of Official Analytical Chemists (AOAC) and the American Public Health Association 

(APHA). Additionally, analytical methods are included that modify previously used methods to obtain 

lower detection limits and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

The α-, β-, γ-, and δ-isomers of HCH, and/or their phenolic metabolites have been measured in biological 

samples such as adipose tissue, serum, urine, milk, semen, and the brain by gas chromatographic methods 

listed in Table 7-1. 

The most commonly used methods for measuring α-, β-, γ-, and δ-HCH in serum, semen, adipose tissue, 

and milk are gas chromatography (GC) or high-resolution gas chromatography (HRGC) combined with 

electron capture detection (ECD) and mass spectrometry (GC/MS) (Barquet et al. 1981; Burse et al. 1990; 

Butte and Fooken 1990; EPA 1980c; Gupta et al. 1978; LeBel and Williams 1986; Liao et al. 1988; 

Prapamontol and Stevenson 1991; Saady and Poklis 1990; Stachel et al. 1989; Waliszewski and 

Szymczynski 1983; Williams et al. 1988). The EPA GC/ECD method is capable of detecting γ-HCH and 

other HCH isomers in blood serum at the ppb level (EPA 1980c). Using HRGC, method detection limits 

for measuring HCH isomers in serum and milk are in the sub-ppm to low-ppb range (Butte and Fooken 

1990; Prapamontol and Stevenson 1991; Saady and Poklis 1990); recovery and precision are acceptable 

(Butte and Fooken 1990; Prapamontol and Stevenson 1991; Saady and Poklis 1990). The use of capillary 

(high-resolution) GC enhances chromatographic separation of compounds with similar retention 

characteristics (Saady and Poklis 1990). Although GC has also been used in measuring the isomers in 

blood serum, recovery problems (i.e., low recoveries) have been encountered because of the volatility of 

the HCH isomers (Burse et al. 1990); sensitivity and precision data were not reported (Burse et al. 1990). 
HEXACHLOROCYCLOHEXANE 222 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Hexachlorocyclohexane 

in Biological Samples 

Sample 

matrix Preparation method 

Analytical 

method Isomer 

Sample 

detection limit 

Percent 

recovery Reference 

Urine Hydrolyze sample; acidify; 

extract with hexane; 

derivatize for GC/ECD or 

evaporate to a small 

volume for TLC 

GC/ECD, 

TLC 

Phenolic 

metabolites of 

γ-HCH 

1 ppb 

(GC/ECD) 

1 ppm (TLC) 

95% 

NR 

Balikova et al. 

1988 

Urine Hydrolyze acidified 

sample; extract with 

diethyl ether; concentrate 

phenol conjugates 

GC/ECD 4.9–18.6 ppb 87–119% Angerer et al. 

1981 

Serum Extract and concentrate 

serum using solid-phase 

extraction; elute with 

isooctane; inject 

HRGC/ 

ECD 

α-HCH 

γ-HCH 

0.18 ppm 

0.33 ppm 

70–75% Saady and 

Poklis 1990 

Serum Extract serum with 

organic solvents; sample 

and acid cleanup on 

Florisil column; sample 

cleanup using silica gel 

chromatography 

GC/ECD α-HCH 

γ-HCH 

NR 

NR 

57.2– 

58.2% 

47.7– 

50.4% 

Burse et al. 1990 

Serum Extract with hexane GC/ECD α-HCH 1 ppb NR EPA 1980a 

β-HCH 1 ppb NR 

γ-HCH 1 ppb NR 

Serum Separate plasma from 

blood containing 

anticoagulant 

GC/ECD β-HCH 0.8 ppb 85% Barquet et al. 

1981 

Serum Hexane or hexaneacetone extraction GC/ECD α-HCH 

β-HCH 

NR 82–83% 

73–77% 

Gupta et al. 1978 

γ-HCH 90–96% 

Semen Liquid-liquid extraction; 

cleanup with Florisil 

GC/ECD 

GC/MS 

(NCI) 

α-HCH 

β-HCH 

0.02 ppb 

0.32 ppb 

72.5% 

94.7% 

Stachel et al. 

1989 

Semen Extract with acetic acid; 

cleanup with Florisil; elute 

with petroleum-diethyl 

ether 

GC/ECD α-HCH 

β-HCH 

γ-HCH 

δ-HCH 

NR 86.3% 

101.3% 

951.0% 

101.6% 

Waliszewski and 

Szymczynski 

1983 

Adipose 

tissue 

Extract with organic 

solvents; reextract lipids 

on Florisil column; elute 

with hexane and 

GC/MS α-HCH 

β-HCH 

 >100% 5–50 ppb 

80–100% 

Liao et al. 1988 

concentrate 
HEXACHLOROCYCLOHEXANE 223 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Hexachlorocyclohexane 

in Biological Samples 

Sample Analytical Sample Percent 

matrix Preparation method method Isomer detection limit recovery Reference 

Adipose Extract fat from tissue HRGC/ α-HCH 1.2 ppb >89 LeBel and 

tissue with acetone-hexane; ECD Williams 1986 

fractionate from fat by gel GC/MS γ-HCH 1.4 ppb >88% permeation chromato­ β-HCH 3.0 ppb >91% graphy with methylene 

chloride-cyclohexane; 

cleanup on Florisil 

column; inject 

Adipose Grind sample; isolate fat, GC/ECD α-HCH 10 ppb NR EPA 1980a 

tissue extract residue in β-HCH 20 ppb NR petroleum ether γ-HCH 20 ppb NR 

Adipose Grind tissue; extract with GC/ECD β-HCH 80 ppb 98% Barquet et al. 

tissue acetonitrile and acetone; 1981 

evaporate; extract with 

hexane 

Milk Solvent extract with ethyl- HRGC/ α-HCH 0.5 ppb 83–105% Prapamontol and 

acetate-methanol- ECD β 91–119% Stevenson 1991 -HCH 1 ppb acetone; cleanup and γ-HCH 0.5 ppb 80–96% concentrate using solidphase extraction; elute 

with isooctane 

Milk Homogenize sample; HRGC/ α-HCH 0.002 ppb 125% Butte and 

extract and cleanup using ECD β Fooken 1990 -HCH 0.009 ppb 114% silica gel; elute with γ-HCH 0.004 ppb 125% hexane/dichloromethane; 

concentrate; inject 

Brain Homogenize sample in GC/MS γ-HCH and 3 pg/L NR Artigas et al. 

hexane; centrifuge; inject (NCI) meta- 1988b 

bolites 

α-HCH = alpha-hexachlorocyclohexane; β-HCH = beta-hexachlorocyclohexane; γ-HCH = gammahexachlorocyclohexane; δ-HCH = delta-hexachlorocyclohexane; ECD = electron capture detection; GC = gas 

chromatography; HRGC = high-resolution gas chromatography; MS = mass spectrometry; NCI = negative chemical 

ionization; NR = not reported; TLC = thin-layer chromatography 
HEXACHLOROCYCLOHEXANE 224 

7. ANALYTICAL METHODS 

GC/ECD combined with identification by GC/MS is a reliable method for quantitation and identification 

of HCH isomers in semen (Stachel et al. 1989); sensitivity of GC/ECD is in the sub-ppb range with 

acceptable recoveries (Stachel et al. 1989). HRGC/ECD and GC/MS have also been used for detection 

and identification of HCH isomers in adipose tissue (LeBel and Williams 1986; Liao et al. 1988). During 

sample preparation, the use of gel permeation chromatography is effective for separation of the isomers 

from adipose tissue (LeBel and Williams 1986). This method is sensitive (low- to sub-ppb range) and has 

good recoveries (>88%) and precision (≤0.12% RSD). Although sensitivity is not quite as good as that of 

GC/ECD, GC/MS is more specific. GC/MS is usually used as a confirmatory method, but it can be 

reliably used alone and produces excellent recoveries and good precision (Liao et al. 1988). 

γ-HCH and its metabolites have also been detected in brain tissue using GC/MS in the chemical 

ionization mode (Artigas et al. 1988a). The use of GC/MS with negative ion chemical ionization (NICI) 

is preferred over electron impact mass spectrometry (EIMS) because the sensitivity using NICI is orders 

of magnitude better than with EIMS. GC/MS with NICI is also more selective than GC/MS with EI or 

GC/ECD (Artigas et al. 1988a). Another advantage of GC/MS with NICI is that identification and 

quantitation are performed without any purification or extraction procedures (Artigas et al. 1988a). 

The phenolic metabolites of γ-HCH and the other HCH isomers have been measured in urine samples 

using GC/ECD (Angerer et al. 1981; Balikova et al. 1988). Sensitivity for this method is in the low-ppb 

range and recovery is excellent (95%); however, precision was not reported (Balikova et al. 1988). Thin 

layer chromatography (TLC) has also been used in conjunction with GC/ECD for identification of HCH 

isomers (Balikova et al. 1988). Although TLC does not achieve the same sensitivity (ppm range) as 

GC/ECD, sensitivity can be increased by extraction of a larger volume of urine. The combination of GC 

and TLC was reported to be a reliable confirmation tool for identifying compounds (Balikova et al. 1988). 

Angerer et al. (1981) developed a sensitive and specific gas chromatographic method for the simultaneous 

detection of 10 chlorinated phenols that appear in the urine of individuals exposed to γ-HCH. However, 

the study authors noted that both HCH and chlorobenzene compounds are commonly used as pesticides 

and that both are metabolized to chlorophenols. This suggests that detection of these metabolites does not 

distinguish between HCH, chlorobenzene, or pentachlorophenol (PCP) exposure. Edgerton et al. (1979) 

detected chlorinated phenol metabolites of HCH and PCP in the urine of experimental animals and 

exposed individuals by using GC/ECD. Discrimination between HCH and PCP exposure was possible 

through comparisons of metabolite profiles. However, detection of PCP in the urine may also be an 

indication of exposure to PCP or other compounds similar to HCH. 
HEXACHLOROCYCLOHEXANE 225 

7. ANALYTICAL METHODS 

7.2 ENVIRONMENTAL SAMPLES 

HCH residues are present in the environment because γ-HCH is used as an insecticide on a wide variety 

of vegetables, fruits, field crops, and on uncultivated land. The most commonly used methods for 

measuring HCH isomers in environmental samples is GC or HRGC combined with ECD or MS. 

Table 7-2 presents details on selected analytical methods. 

HCH isomers have been measured in air using GC/ECD, HRGC/ECD, or GC with dual detection by ECD 

and electrolytic conductivity detection (ELCD) (Durell and Sauer 1990; Kurtz and Atlas 1990; NIOSH 

1984; Stein et al. 1987; Zaranski et al. 1991). Polyurethane foam or Florisil adsorbent tubes are suitable 

for collecting air samples. The use of a simultaneous dual-column, dual-detector method (ECD and 

ELCD) was found to reduce the risk of false positive identifications without increasing the cost or time of 

analysis (Durell and Sauer 1990). Both columns were able to separate a large number of analytes with 

good reproducibility. Although ECD is more sensitive for halogenated compounds and has a lower 

detection limit (sub-ppb to low-ppm) than ELCD (low ppb), ELCD can greatly reduce matrix 

interferences. Precision and recovery were not reported for either detector (Durell and Sauer 1990; Kurtz 

and Atlas 1990). 

The most commonly used methods for detecting HCH isomers in water (e.g., surface water, drinking 

water, sea water, groundwater, waste water, and rain) include GC or HRGC combined with ECD or MS 

(Allchin 1991; Barquet et al. 1981; Durell and Sauer 1990; EPA 1984, 1986a; Goosens et al. 1990; Kurtz 

and Atlas 1990; Lopez-Avila et al. 1989a, 1990b; Reding 1987; van der Hoff et al. 1991). To improve 

sample extraction and cleanup, the most current EPA method (Method 8120) used commercially available 

disposable Florisil cartridges instead of conventional Florisil cleanup (Lopez-Avila et al. 1989a). The 

disposable Florisil cartridges were simpler to use, shortened the analysis time, and reduced the overall 

cost of the analysis. The excellent precision, accuracy, and sensitivity (ppt range) of the results indicated 

that the revised method is reliable (Lopez-Avila et al. 1989a). Automated solid-phase extraction 

cartridges filled with silica and coupled on-line to GC/ECD have been effectively used to measure HCH 

isomers in water at low levels (ppt) (van der Hoff et al. 1991). This method is efficient and reproducible, 

with good recovery (>95%) and precision (<12% coefficient of variance [CV]) (van der Hoff et al. 1991). 

On-line liquid-liquid extraction coupled with HRGC/ECD is also a sensitive (ppb level) and reliable 

method (Goosens et al. 1990). A method validation study, conducted on EPA Method 508, for 

determining HCH isomers in finished drinking water using GC/ECD indicated the method was reliable, 

repeatable, and reproducible (Lopez-Avila et al. 1990b). Precision was good; recovery (>90%) was 
HEXACHLOROCYCLOHEXANE 226 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Hexachlorocyclohexane 

in Environmental Samples 

Sample Analytical Sample Percent 

matrix Preparation method method Isomer detection limit recovery Reference 

Air Collect air using filters HRGC/ 0.9 pg/μL NR Durell and Sauer 

and polyurethane ECD 1990 

foam; Soxhlet 

extraction; column 

HRGC/ 

ELCD 

15.3 pg/μL NR 

cleanup and isolation; 

concentration; dual 

column detection 

Air Collect sample in HRGC/ Low pg/m3 NR Kurtz and Altas 

Florisil adsorbent ECD 1990 

tubes; elute with 

methylene chloride in 

pentane; concentrate in 

Kuderna-Danish 

evaporative 

concentrator; solvent 

exchange to hexane 

Air Trap in isooctane GC/ECD 3 μg/sample NR NIOSH 1984 

(method 5502) 

Air Adsorb air sample on GC/ECD α-HCH 0.25 pg/m3 83% Stein et al. 1987 

Florisil; elute with 10% β-HCH 88% 

2-propanol in hexane γ-HCH 81% 

δ-HCH 87% 

Surface Extract with hexane; GC/ECD α-HCH 7 ppt 95.6% Van der Hoff et 

water concentrate; cleanup 

using automated solidphase extraction 

technique 

β-HCH 

γ-HCH 

δ-HCH 

10 ppt 

7 ppt 

6 ppt 

98.2% 

95.6% 

95.9% 

al. 1991 

Water Extract twice with GC/ECD α-HCH 11 ppt 96% Lopez-Avila et 

methylene chloride; dry 

with anhydrous sodium 

sulfate; concentrate; 

add hexane and 

β-HCH 

γ-HCH 

δ-HCH 

31 ppt 

23 ppt 

20 ppt 

103% 

96% 

103% 

al. 1989a 

(modified EPA 

method 8120) 

concentrate by 

evaporation; cleanup 

on disposable Florisil 

cartridge and elute with 

hexane-acetone 

Drinking Extract with methylene GC/ECD α-HCH 0.025 ppb 94.6% Lopez-Avila et 

water chloride; solvent 

exchange to methyl 

tert-butyl ether; 

concentrate 

β-HCH 

γ-HCH 

δ-HCH 

0.010 ppb 

0.010 ppb 

0.015 ppb 

93.4% 

94.2% 

92.0% 

al. 1989a 

(modified EPA 

method 508) 
HEXACHLOROCYCLOHEXANE 227 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Hexachlorocyclohexane 

in Environmental Samples 

Sample Analytical Sample Percent 

matrix Preparation method method Isomer detection limit recovery Reference 

Drinking Stripping for water with HRGC/ 0.003 ppb 93–130% Reding 1987 

water an inert gas-helium ECD (method 505) (EPA methods 

505, 508) 0.006 ppb 

(method 508) 

Drinking Separation with GC/ECD β-HCH 0.025 ppb 88% Barquet et al. 

water Na2SO4; extraction 1981 

CH3Cl2 

Water and Extraction with GC/ECD α-HCH 0.003 ppb NR EPA 1984 

waste methylene chloride β (method 608) -HCH 0.006 ppb NR water 

γ-HCH 0.004 ppb NR 

δ-HCH 0.009 ppb NR 

Water and Extraction with GC/MS β-HCH 4.2 ppb NR EPA 1984 

waste methylene chloride (method 625) δ-HCH 3.1 ppb NR water 

Water and Extraction with GC/ECD α-HCH 0.003 ppb NR EPA 1986b 

waste methylene chloride β (method 8080) -HCH 0.006 ppb NR water 

γ-HCH 0.004 ppb NR 

δ-HCH 0.009 ppb NR 

Sea water Extract twice with GC/ECD α-HCH 1 ppt >85% Allchin 1991 

hexane; dry over γ-HCH 

anhydrous sodium 

sulfate; concnetrate; 

cleanup using column 

chormatography with 

5% deactivated 

alumina; concentrate 

Ground- On-line liquid-liquid HRGC/ α-HCH 0.1 ppb 112% Goosens et al. 

water extraction of sample ECD 1990 δ-HCH 119% 

with isooctane and 

separation of aqueous 

and organic phases by 

a sandwich phase 

separator 

Sea water, Liquid-liquid extraction; HRGC/ Lindane 0.9 ppb NR Durrell and 

rain column cleanup and ECD Sauer 1990 

isolation; concnetration HRGC/ 15.3 ppb NR 

ELCD 

Sea water Extract with methylene HRGC/ α-HCH Low pg/L NR Kurtz and Atlas 

chloride; solvent ECD 1990 γ-HCH 

exchange to hexane; 

cleanup on Florisil 
HEXACHLOROCYCLOHEXANE 228 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Hexachlorocyclohexane 

in Environmental Samples 

Sample Analytical Sample Percent 

matrix Preparation method method Isomer detection limit recovery Reference 

Soil Extract with 

supercritical carbon 

dioxide or carbon 

dioxide modified with 

10% methanol 

Soil Dry sample with 

anhydrous sodium 

sulfate; extract twice 

with methylene 

chloride-acetone by 

sonication; filter; dry; 

concentrate; cleanup 

on disposable Florisil 

cartridge and elute with 

hexane-acetone 

Soil Equilibrate with water; 

extract with acetone 

and hexane (1:1); wash 

with water and sodium 

chloride disiccate with 

anhydrous sodium 

sulfate; concentrate; 

add hexane; cleanup 

with SPE Florisil 

cartridge 

Soil, Extract sample with 

sediment, methylene chloridewaste acetone by sonication; 

sludge cleanup using gel 

permeation chromatography processing of 

extracts dissolved in 

1+1 butyl chloridemethylene chloride or 

100% methylene 

chloride 

Soil Hexane-acetone 

extraction 

Soil Extraction with 

methylene chloride 

followed by cleanup on 

Florisil column 

GC/ECD α-HCH NR 

GC/MS β-HCH 

γ-HCH 

δ-HCH 

GC/ECD α-HCH <40 ng/L 

β-HCH 

γ-HCH 

δ-HCH 

GC Lindane 5 ppm 

HRGC/ γ-HCH NR 

ECD, 

HRGC/MS 

GC/ECD NR 

GC/ECD, α-HCH 3.0 ppm 

HSD β-HCH 6.0 ppm 

δ-HCH 4.0 ppm 

δ-HCH 9.0 ppm 

77.43–93.6% Lopez-Avila et 

79.28–93.6% al. 1990a 

80.63–121% 

72.4–103% 

96% Lopez-Avila et 

al. 1989b 103% 

(modified EPA 96% method 8120) 103% 

108% Noegrohati and 

Hammers 1992a 

83–91% Czuczwa and 

Alford-Stevens 

1989 

NR AOAC 1984 

(method 29.013) 

NR EPA 1986b 

NR (method 8080) 

NR 

NR 
HEXACHLOROCYCLOHEXANE 229 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Hexachlorocyclohexane 

in Environmental Samples 

Sample Analytical Sample Percent 

matrix Preparation method method Isomer detection limit recovery Reference 

Sediment Extract using vapor GC/ECD α-HCH 2.42 ppb 76% Schuphan et al. 

phase distillation 1990 γ-HCH 4.98 ppb 40% technique; dry 

isooctane extract; 

concentrate 

Milk Selective extraction of GC/ECD α-HCH NR 94% DiMuccio et al. 

HCH isomers on solid­ 1988 γ-HCH 105% 

matricx disposable 

column by means of 

acetonitrile-saturated 

light petroleum; 

concnetrate; cleanup 

extract on Florisil 

minicolumn 

Milk Extract fortified milk 

samples with acetone 

and n-hexane; 

centrifuge; evaporate 

organic phase; dissolve 

residues in ether 

Soil, water, Extract HCH from 

wheat, sample by activated 

rice, beans charchal; 

dechlorination of HCH 

to benzene; nitration of 

benzene to m-dinitrobenzene; reduction to 

m-phenylene diamine; 

diazotization and 

coupling to form azo 

dye 

Mussels	 Extract with 

acetonitrile; separate 

form coextractives by 

liquid-liquid partition 

between acetonitrile 

and water/hexane; 

cleanup on Sep-Pak 

Florisil cartridge; elute 

in second eluate with 

15% ethyl ether in 

hexane 

Fish Extract residue using 

one-step matrix solid 

phase dispersion 

combined with Florisil 

column cleanup; inject 

into GC 

β-HCH 113% 

GC/ECD α-HCH NR 95.7% Kapoor et al. 

β-HCH 99.9% 1981 

γ-HCH 83.4% 

δ-HCH 89.7% 

Spectro­ γ-HCH NR ≥89% Raju and Gupta 

photo­ 1988 

metry 

GC/ECD Lindane 0.02 μg/kg 92–102% Muino et al. 

1991 

GC/ECD Lindane 10 ng/g 82% Long et al. 

1991a 
HEXACHLOROCYCLOHEXANE 230 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Hexachlorocyclohexane 

in Environmental Samples 

Sample Analytical Sample Percent 

matrix Preparation method method Isomer detection limit recovery Reference 

Fish Petroleum ether 

extraction 

Fish Combine with 

anhydrous Na2SO4; 

extract with petroleum 

ether/ethyl acetate; 

separate lipids with 

GPC; solvent 

exchange to isooctane; 

add dry N2 gas 

Fruits and Extract samples with 

vegetables acetonitrile; partition 

with sodium chloride 

saturated aqueous 

solution; concentrate 

Vegetables Extract with methanol; 

partition with sodium 

chlrodie and hexane; 

wash hexane layer with 

sodium chloride 

solution; disccate with 

anhydrous sodium 

sulfate; concentrate; 

cleanup on SPE SilFlorisil cartridge 

Beef fat Extract residue using 

one-step matrix solid 

phase dispersion 

combined with Florisil 

column cleanup; inject 

into GC 

Animal fat For dairy products, 

and dairy extract fat with hexane; 

products	 for animal fat, melt 

sample and remove fat; 

cleanup with gel 

permeation chromatography; further cleanup 

with Florisil if 

necessary; inject 

Root Extract with CO2 collect 

vegetables with n-hexane/dichloroand dairy methane; evaporate; 

products dissolve in n-hexane 

Beef Extract with acetonehexane; cleanup on 

Florisil column, inject 

GC/ECD NR 

GC/MS Lindane 1.6 ppb 

(NCI) 

HRGC/MS α-HCH 0.05 μg/g (all 

isomers) β-HCH 

γ-HCH 

δ-HCH 

GC Lindane ppb range 

GC/ECD Lindane Low ppb 

GC/ECD HCH Low to sub 

ppm 

GC/ECD α-HCH NR 

γ-HCH NR 

GC/ECD β-HCH Sub ppm 

NR AOAC 1984 

(method 20.029) 

115% Schmidt and 

Hesselberg 1992 

88% Liao et al. 1991 

93% 

93% 

112% 

87–137% Neogrohati and 

Hammers 1992a 

85% Long et al. 

1991b 

82% Venant et al. 

1989 

10–100% Bernal et al. 

1992 12–98% 

78.1–88.3% Tonogai et al. 

1989 
HEXACHLOROCYCLOHEXANE 231 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Hexachlorocyclohexane 

in Environmental Samples 

Sample Analytical Sample Percent 

matrix Preparation method method Isomer detection limit recovery Reference 

Tobacco Soak in acetonitrile GC/ECD α-HCH 1.0 ppm 98.2% Waliszewksi and 

water mixture, extract Szymczynski β-HCH 2.0 ppm 92.9% with petroleum ether; 1986

γ-HCH 2.0 ppm 96.2% shake with H2SO4 δ-HCH 2.0 ppm 88.2% 

Wood Extract with toluene; GC/MS 10 ppb NR Butte and 

(rasped) sonicate and Walker 1992 

centrifuge; inject 

α-HCH = alpha-hexachlorocyclohexane; β-HCH = beta-hexachlorocyclohexane; γ-HCH = gammahexachlorocyclohexane; δ-HCH = delta-hexachlorocyclohexane; CH2Cl2 = methylene chloride; ECD = electron 

capture detection; ELCD = electrolytic conductivity detector; GC = gas chromatography; GPC = gas permeation 

chromatography; H2SO4 = sulfuric acid; HRGC = high-resolution gas chromatography; HSD = halogen specific 

detector; MS = mass spectrometry; Na2SO4 = sodium sulfate; NCI = negative chemical ionization; NR = not reported; 

SPE = solid phase extraction 
HEXACHLOROCYCLOHEXANE 232 

7. ANALYTICAL METHODS 

excellent. Sensitivity was in the ppb range (Lopez-Avila et al. 1990b). The EPA-established analytical 

test procedures to analyze water, waste water, and drinking water samples use GC coupled with MS. 

EPA methods 608 and 625 are recommended to detect γ-HCH and other HCH isomers in surface water 

and municipal and industrial discharges (EPA 1984). 

GC/ECD, HRGC/ECD, and HRGC/MS are the most commonly used methods to measure HCH isomers 

in soil, sediments, and solid wastes (AOAC 1984; Czuczwa and Alford-Stevens 1989; EPA 1986b; 

Lopez-Avila et al. 1989b, 1990a; Noegrohati and Hammers 1992b; Schuphan et al. 1990). More efficient 

extraction of the isomers from soil was obtained using a disposable Florisil cartridge (modified EPA 

Method 8120) prior to detection by GC/ECD (Lopez-Avila et al. 1989b). The method yielded excellent 

recoveries (>95%), and sensitivity was in the ppt range. Sample cleanup using a disposable solid phase 

extraction (SPE) cartridge with detection by GC yielded a higher recovery (108%) with excellent 

precision (4% CV). Although sample detection limits were not reported, sensitivity was in the ppm range 

(Noegrohati and Hammers 1992b). Sample cleanup using gel permeation chromatography and detection 

and identification by HRGC/ECD and HRGC/MS resulted in good recoveries (83–91%) and good 

precision (≤5.1% relative standard deviation [RSD]) (Czuczwa and Alford-Stevens 1989); sensitivity was 

not reported (Czuczwa and Alford-Stevens 1989). A new technique, supercritical fluid extraction (SFE), 

has been applied to the analysis of soil samples (Lopez-Avila et al. 1990a). Recovery (>75%) and 

precision (<26% CV) are adequate. Because this is a relatively new method, the cost is higher than other 

accepted techniques. The vapor phase extraction technique has also been applied to the analysis of trace 

residues of HCH in sediments (Schuphan et al. 1990). The efficiency of this method was compared with 

conventional Soxhlet extraction and Florisil cleanup procedures. The results showed that recovery using 

the Soxhlet extraction method (73–81%) was better than with vapor-phase extraction (40–76%). The low 

recovery of γ-HCH (40%) was due to sample loss during concentration of the iso-octane extract 

(Schuphan et al. 1990); sensitivity was in the low-ppb range; precision was excellent (0.01–0.03% 

coefficient of variation). 

GC/ECD and HRGC/ECD are the most commonly used methods for measuring HCH isomers in milk 

(DiMuccio et al. 1988; Kapoor et al. 1981), dairy products (Bernal et al. 1992; Venant et al. 1989), 

seafood (mussels and fish) (AOAC 1984; Long et al. 1991a; Muino et al. 1991; Schmidt and Hesselberg 

1992), fruits and vegetables (Liao et al. 1991; Noegrohati and Hammers 1992), beef (Tonogai et al. 

1989), and beef fat (Long et al. 1991b). Gel permeation chromatography is a suitable method for the 

cleanup of HCH residues in animal fats and dairy products (Venant et al. 1989); recoveries are good 

(82%). Although specific detection limits were not reported, sensitivity is in the low-to-sub-ppm range. 
HEXACHLOROCYCLOHEXANE 233 

7. ANALYTICAL METHODS 

Additional cleanup with Florisil is needed when residue levels are below 0.1 ppm; precision was not 

reported. High-pressure soxhlet extraction coupled with Florisil column cleanup yielded recoveries up to 

100% for α-HCH and γ-HCH in butter, if pressure, time, and sample volume in the extractor were 

optimized; detection limits and precision values were not reported. This method has also been used to 

detect γ-HCH residues in potatoes with similar recoveries (Bernal et al. 1992). A reliable and 

reproducible method has been developed to determine HCH residues in milk (DiMuccio et al. 1988). The 

procedure involves a single-step, selective extraction of residues from milk on a solid-matrix disposable 

column, clean-up with Florisil, and detection by GC/ECD. Although specific detection limits were not 

reported, sensitivity is in the low-ppb range. With this extraction procedure, the HCH residues are more 

readily extracted than milk lipids, and the addition of a small amount of acetonitrile to the milk 

significantly improved recoveries without increasing the amount of fat in the extracts (diMuccio et al. 

1988). A reliable, rapid screening technique for extraction of residues from a complex biological matrix 

such as fat uses matrix solid-phase dispersion (MSPD) extraction, Florisil column cleanup, and detection 

by GC/ECD (Long et al. 1991a, 1991b). This method has been used to measure HCH residues in beef fat 

and fish. Recovery (82–85%) is good; sensitivity is in the low-ppb range. The MSPD method overcomes 

many of the complications associated with traditional pesticide isolation techniques because it uses small 

sample volumes and involves few steps (Long et al. 1991a, 1991b). GC/MS with negative ion chemical 

ionization (NCI) with GPC cleanup is a rapid, accurate, and simple method to quantify γ-HCH in fish. 

Recoveries were excellent (115%) with good precision (8.9% RSD), and a detection limit of 1.6 ppb 

(Schmidt and Hesselberg 1992). An HRGC/MS screening method has been developed for the 

determination of pesticide residues in a variety of crop samples (fruits and vegetables) (Liao et al. 1991). 

This technique is a useful tool because it offers simultaneous detection and confirmation, which are not 

provided by ECD. This method, however, lacks the sensitivity achieved by ECD. Spectrophotometry has 

been used to measure HCH isomers in cereals (e.g., wheat, rice, and beans) with good recoveries (≥89%) 

(Raju and Gupta 1988). This technique has also been used for other matrices such as soil and water (Raju 

and Gupta 1988). An accurate and simple extraction and cleanup method has been developed for 

capillary GC analysis of γ-HCH in vegetables. The sample was extracted with methanol and cleanup was 

executed on disposable SPE cartridges. Recoveries ranged from 87 to 137% (average 100%) with good 

precision (CV ≤5%). Although no specific detection limits were reported, sensitivity is expected to be in 

the ppb range (Noegrohati and Hammers 1992b). 

HCH residues have also been detected in tobacco using GC/ECD (Waliszewski and Szymczynski 1986). 

Sensitivity is in the low-ppm range and recovery is excellent (88–98%) (Waliszewski and Szymczynski 

1986). 
HEXACHLOROCYCLOHEXANE 234 

7. ANALYTICAL METHODS 

GC/MS has been used to determine γ-HCH residues in wood preserving fluids on the surface of wood; the 

detection limit is 10 ppb. No recovery or precision values were reported (Butte and Walker 1992). 

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 α-, β-, γ-, and δ-HCH 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 α-, β-, γ-, and δ-HCH. 

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 measuring HCH residues and/or their metabolites in blood serum 

(Barquet et al. 1981; Burse et al. 1990; Gupta et al. 1978; EPA 1980c; Saady and Poklis 1990), urine 

(Angerer et al. 1981; Balikova et al. 1988), semen (Stachel et al. 1989; Waliszewski and Szymczynski 

1983), adipose tissue (Barquet et al. 1981; EPA 1980c; LeBel and Williams 1986; Liao et al. 1988), 

breastmilk (Butte and Fooken 1990; Prapamontol and Stevenson 1991), and brain tissue (Artigas et al. 

1988a). However, examination of blood and urine is most frequently conducted to determine exposure 

because of the ease of sample collection with these media. The available methods are accurate and 

reliable for most of the media. However, sensitivity and precision data for measuring HCH residues in 

serum are needed. Although available methods can detect and quantify background levels of HCH in the 

population, there is no information to quantitatively correlate levels in these fluids with exposure levels. 
HEXACHLOROCYCLOHEXANE 235 

7. ANALYTICAL METHODS 

Additional quantitative information regarding the relationship between body and environmental levels of 

HCH might allow investigators to predict environmental exposure levels from measured body levels. 

Methods are available to detect the chlorinated phenol metabolites present in the urine as a result of 

exposure to HCH (Angerer et al. 1981; Balikova et al. 1988). However, similar metabolites are detected 

following exposure to other pesticides. The identification of a specific urinary metabolite of HCH alone 

(e.g., chlorophenol) would not allow investigators to determine whether an individual has been exposed to 

HCH. 

Effect. The individual isomers of HCH can be detected in serum, urine, adipose tissue, and semen of 

exposed individuals as indicated above in Section 3.8.1 Biomarkers of Exposure and Effect. Since no 

quantitative correlation has been made between body levels of HCH and adverse health effects based on 

existing data, we do not know if the methods are sensitive enough to measure levels at which biological 

effects occur. Further studies need to be undertaken to quantitatively correlate body levels resulting from 

HCH exposure and the occurrence of specific adverse health effects. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Methods are available to detect HCH in air (Durell and Sauer 1990; Kurtz and Atlas 1990; 

NIOSH 1984; Stein et al. 1987; Zaranski et al. 1991), water (Allchin 1991; Barquet et al. 1981; Durell 

and Sauer 1990; EPA 1984, 1986a; Goosens et al. 1990; Kurtz and Atlas 1990; Lopez-Avila et al. 1989a, 

1990b; Reding 1987; van der Hoff et al. 1991), soil (AOAC 1984; Czuczwa and Alford-Stevens 1989; 

EPA 1986b; Lopez-Avila et al. 1989a, 1990b; Noegrohati and Hammers 1992a; Schuphan et al. 1990), 

food (AOAC 1984; Bernal et al. 1992; Liao et al. 1991; Long et al. 1991a, 1991b; Muino et al. 1991; 

Noegrohati and Hammers 1992b; Schmidt and Hesselberg 1992; Tonogai et al. 1989; Venant et al. 1989), 

milk (DiMuccio et al. 1988; Kapoor et al. 1981), tobacco (Waliszewski and Szymczynski 1986), and 

wood preserving fluid (Butte and Walker 1992). These methods are sensitive enough to measure 

background levels in environmental media. The precision, accuracy, reliability, and specificity of these 

methods are sufficiently documented. Research investigating the relationship between levels measured in 

air, water, soil, and food and observed health effects could increase our confidence in existing methods 

and/or indicate where improvements are needed. 
HEXACHLOROCYCLOHEXANE 236 

7. ANALYTICAL METHODS 

7.3.2 Ongoing Studies 

The Federal Research Programs In Progress (FEDRIP 2004), Current Research Information System 

(CRIS/USDA 2003), and Computer Retrieval of Information on Scientific Projects (CRISP 2003) 

databases were searched for ongoing projects that may fill some existing data gaps. 
HEXACHLOROCYCLOHEXANE 237 

8. REGULATIONS AND ADVISORIES 

The international, national, and state regulations and guidelines regarding α-, β-, δ-, γ-, and ε-HCH in air, 

water, and other media are summarized in Table 8-1. 

Five oral MRLs have been derived for the α-, β-, and γ-HCH isomers of HCH, as summarized below and 

detailed in Section 2.3 and Appendix A. 

An MRL of 0.008 mg/kg/day was derived for chronic-duration (365 days and longer) oral exposure to 

α-HCH. The chronic oral MRL for α-HCH is based on a NOAEL of 0.8 mg/kg/day and LOAEL of 

3.5 mg/kg/day for liver effects in rats (Fitzhugh et al. 1950), and an uncertainty factor of 100 (10 for 

extrapolation from animals to humans and 10 for human variability). 

An MRL of 0.05 mg/kg/day was derived for acute-duration (14 days or less) oral exposure to β-HCH. 

This MRL is based on a NOAEL of 4.5 mg/kg/day and LOAEL of 22.5 mg/kg/day for ataxia, progressive 

inactivity, and coma in rats exposed to β-HCH for 2 weeks (Van Velsen et al. 1986), and an uncertainty 

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

An MRL of 0.0006 mg/kg/day was derived for intermediate-duration oral exposure to β-HCH (Van 

Velsen et al. 1986). This MRL is based on a minimal LOAEL of 0.18 mg/kg/day for liver effects in rats 

(Van Velsen et al. 1986) and an uncertainty factor of 300 (3 for use of a minimal LOAEL, 10 for 

extrapolation from animals to humans, and 10 for human variability). 

An MRL of 0.003 mg/kg/day was derived for acute-duration oral exposure to γ-HCH (lindane). This 

MRL is based on a minimal LOAEL of 1 mg/kg/day for reproductive effects in male offspring of rats 

exposed during lactation (Dalsenter et al. 1997b), and an uncertainty factor of 300 (3 for use of a minimal 

LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). 

An MRL of 1x10-5 mg/kg/day was derived for intermediate-duration oral exposure to γ-HCH. This MRL 

is based on a LOAEL of 0.012 mg/kg/day for immunological/lymphoreticular effects in mice (Meera et 

al. 1992), and an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to 

humans, and 10 for human variability). 
HEXACHLOROCYCLOHEXANE 238 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane and
 

Hexachlorocyclohexane Isomers 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

 IARC Carcinogenicity classification 

HCH (including isomers) 

WHO Drinking water guideline 

γ-HCH 

 Temporary ADI 

γ-HCH 

Proposed drinking water 

guideline 

γ-HCH 

NATIONAL 

Regulations and 

Guidelines: 

a. Air: 

ACGIH TLV (8-hour TWA) 

γ-HCHb 

NIOSH REL (10-hour TWA) 

γ-HCHc

 IDLH 

OSHA PEL (8-hour TWA) for general 

industry 

γ-HCHd 

PEL (8-hour TWA) for 

construction industry 

γ-HCHd 

PEL (8-hour TWA) for shipyard 

industry 

γ-HCHd
 

USC Hazardous air pollutant 

b. Water 

EPA Drinking water health 

advisories for γ-HCH 

1-day (10-kg child) 

10-day (10-kg child) 

DWELe 

Lifetimef 

 Hazardous substance 

designation in accordance with 

Section 311 (b)(2)(A) of the 

Clean Water Act 

Interim primary drinking water 

standard 

γ-HCH 

Group 2Ba 

2.0 μg/L 

0–0.001 mg/kg bw 

0.3 μg/L 

0.5 mg/m3 

0.5 mg/m3 

50 mg/m3 

0.5 mg/m3 

0.5 mg/m3 

0.5 mg/m3 

γ-HCH 

1.0 mg/L 

1.0 mg/L 

0.01 mg/L 

2.0x10-4 mg/L 

γ-HCH 

0.004 mg/L 

IARC 2003 

WHO 1993 

WHO 1998 

ACGIH 2003 

NIOSH 2003 

OSHA 2003a 

29 CFR 1910.1000, 

Table Z-1 

OSHA 2003c 

29 CFR 1926.55, 

Appendix A 

OSHA 2003b 

29 CFR 1915.1000 

USC 2003 

42 USC 7412 

EPA 2002a 

EPA 2003p 

40 CFR 116.4 

EPA 2003f 

40 CFR 265, 

Appendix III 
HEXACHLOROCYCLOHEXANE 239 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane and
 

Hexachlorocyclohexane Isomers 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA Lifetime cancer risks (oral) in 

water (μg/L) 

 HCH (technical) 

α-HCH 

β-HCH 

MCL for criteria for classification of solid waste disposal 

facilities and practices 

γ-HCH 

Pollutants of initial focus of the 

Great Lakes Water Quality 

Initiative; pollutants that are 

bioaccumulative chemicals of 

concern 

Primary drinking water 

standards (MCL) 

γ-HCH 

Primary drinking water 

standards (MCLG) 

γ-HCH 

Reportable quantity of 

hazardous substances 

designated pursuant to 

Section 311 of the Clean Water 

Act 

γ-HCH 

c. Food 

EPA Residue Tolerances for γ-HCH 

Cattle, goat, horse, and 

sheep (fat of meat) 

Hog (fat of meat) 

Cucumber, lettuce, melon, 

mushroom, pumpkin, 

squash, summer, and 

tomato 

Apple, apricot, asparagus, 

avocado, broccoli, Brussels 

sprouts, cabbage, 

cauliflower, celery, cherry, 

collards, eggplant, grape, 

guava, kale, kohlrabi, 

mango, mustard greens, 

nectarine, okra, onion (dry 

bulb only), peach, pear, 

pepper, pineapple, plum, 

prune, quince, spinach, 

strawberry, and Swiss chard 

10-4 

2.0 

0.6 

2.0 

10-5 

0.2 

0.06 

0.2 

0.004 mg/L 

HCH (technical) 

α-HCH 

β-HCH 

δ-HCH 

γ-HCH 

2.0x10-3 mg/L 

2.0x10-3 mg/L 

10-6 

0.02 

0.006 

0.02 

IRIS 2005 

EPA 2003a 

40 CFR 257, 

Appendix I 

EPA 2003q 

40 CFR 132, 

Table 6 

EPA 2003i 

40 CFR 141.61 

EPA 2003h 

40 CFR 141.50 

EPA 2003j 

40 CFR 117.3 

1 pound 

7 ppm 

EPA 2003n 

40 CFR 180.133 

4 ppm 

3 ppm 

1 ppm 
HEXACHLOROCYCLOHEXANE 240 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane and
 

Hexachlorocyclohexane Isomers 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA Residue Tolerances for γ-HCH 

Pecans 

FDA Bottled drinking water 

allowable level 

γ-HCH 

d. Other 

 ACGIH Carcinogenicity classification 

γ-HCH 

EPA Carcinogenicity classification 

 HCH-technical 

α-HCH 

β-HCH 

δ-HCH 

ε-HCH 

γ-HCH 

γ-HCH 

RfD 

 HCH-technical 

α-HCH 

β-HCH 

δ-HCH 

ε-HCH 

γ-HCH 

 Community right-to-know; 

release report; effective date of 

reporting 

α-HCH 

γ-HCH 

 Extremely hazardous 

substance for (γ-HCH)

 Reportable quantity 

Threshold planning quantity 

Identification and listing of 

hazardous waste; maximum 

concentration for the toxicity 

characteristic 

γ-HCH 

Land disposal restrictions; 

universal treatment standards 

α-HCH 

β-HCH 

δ-HCH 

γ-HCH 

EPA 2003n 

0.01 ppm 40 CFR 180.133 

FDA 2003 

21 CFR 165.110 

2.0x10-3 mg/L 

ACGIH 2003 

A3g 

IRIS 2005 

B2h 

B2h 

Ci 

Dj 

Dj 

Not available 

Suggestive evidencek EPA 2002b 

IRIS 2005 

Not available 

Not available 

Not available 

Not available 

Not available 

3.0x10-4 mg/kg/day 

EPA 2003o 

40 CFR 372.65 

01/01/95 

01/01/87 

EPA 2003d 

40 CFR 355, 

1 pound Appendix A 

1,000/10,000 pounds 

EPA 2003e 

40 CFR 261.24 

0.4 mg/L 

Non-waste EPA 2003g 

Waste water water 40 CFR 268.48 

14x10-3 mg/L 0.066 mg/kg 

14x10-3 mg/L 0.066 mg/kg 

0.023 mg/L 0.066 mg/kg 

0.0017 mg/L 0.066 mg/kg 
HEXACHLOROCYCLOHEXANE 241 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane and
 

Hexachlorocyclohexane Isomers 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA Municipal solid waste landfills; 

hazardous constituents 

α-HCH 

β-HCH 

δ-HCH 

γ-HCH 

Reportable quantity of 

hazardous substance in 

accordance with Section 

307(a) of the Clean Water Act 

for all isomers of HCH 

Reportable quantity of 

hazardous substance in 

accordance with Section 311 

(b)(2) and 307(a) of the Clean 

Water Act, Section 112 of 

RCRA, and Section 112 of the 

Clean Air Act for γ-HCH 

Standards for owners or 

operators of hazardous waste 

TSD facilities; maximum 

concentration for groundwater 

protection 

α-HCH 

β-HCH 

δ-HCH 

γ-HCH 

Standards for owners or 

operators of hazardous waste 

TSD facilities; maximum 

concentration for groundwater 

protection 

γ-HCH 

Suggested EPA 2003b 

method PQL (μg/L) 40 CFR 258, 

8080 0.05 Appendix II 

8270 10 

8080 0.05 

8270 20 

8080 0.1 

8270 20 

8080 0.05 

8270 20 

Not assigned to the generic EPA 2003c 

or broad class 40 CFR 302.4 

1 pound EPA 2003c 

40 CFR 302.4 

EPA 2003l 

40 CFR 264, 

Appendix IX 

Suggested 

method PQL (μg/L) 

8080 0.05 

8250 10 

8080 0.05 

8250 40 

8080 0.1 

8250 30 

8080 0.05 

8250 10 

EPA 2003k 

40 CFR 264.94 

0.004 mg/L 
HEXACHLOROCYCLOHEXANE 242 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane and
 

Hexachlorocyclohexane Isomers 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA Standards for the management 

of specific hazardous waste 

and types of hazardous waste 

management facilities 

 HCH (technical) 

α-HCH 

Risk specific doses (μg/m3

) 

2.0x10-2 

5.6x10-3 

EPA 2003m 

40 CFR 266, 

Appendix V 

β-HCH 1.9x10-2 

γ-HCH 2.6x10-2 

NTP Carcinogenicity classification 

for γ-HCH and other HCH 

isomers 

Reasonably anticipated to be 

a human carcinogen 

NTP 2002 

STATE 

a. Air No data 

b. Water 

Arizona Drinking water guideline 

γ-HCH 0.2 μg/L 

HSDB 2003 

California Drinking water guideline 

α-HCH 

β-HCH 

0.7 μg/L 

0.3 μg/L 

HSDB 2003 

Florida Drinking water guideline 

α-HCH 

β-HCH 

δ- HCH 

0.05 μg/L 

0.1 μg/L 

0.05 μg/L 

HSDB 2003 

Maine Drinking water guideline 

γ-HCH 0.2 μg/L 

HSDB 2003 

New Hampshire Drinking water guideline 

 HCH 

α-HCH 

β-HCH 

0.02 μg/L 

0.006 μg/L 

0.02 μg/L 

HSDB 2003 

c. Food No data 
HEXACHLOROCYCLOHEXANE 243 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane and
 

Hexachlorocyclohexane Isomers 

Agency Description Information Reference 

STATE (cont.) 

d. Other No data 

a

Group 2B: possibly carcinogenic to humans 

b

Skin notation: refers to the potential significant contribution to the overall exposure by the cutaneous route, including 

mucous membranes and the eyes, either by contact with vapors or, of probable greater significance, by direct skin 

contact with the substance. 

c

Skin designation: indicates the potential for dermal absorption; skin exposure should be prevented as necessary 

through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment. d

Skin designation 

e

DWEL: a lifetime exposure concentration protective of adverse, non-cancer health effects, that assumes all of the 

exposure to a contaminant is from drinking water. 

f

Lifetime: the concentration of a chemical in drinking water that is not expected to cause any adverse 

noncarcinogenic effects for a lifetime of exposure. The Lifetime HA is based on exposure of a 70-kg adult consuming 

2 L water/day. 

g

A3: confirmed animal carcinogen with unknown relevance to humans 

h

B2: probable human carcinogen; sufficient evidence of carcinogenicity from animal studies and inadequate 

evidence from epidemiological studies. 

i

C: possible human carcinogen 

j

D: not classifiable as to human carcinogenicity 

k

Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential. 

ACGIH = American Conference of Governmental Industrial Hygienists; ADI = allowable daily intake; CFR = Code of 

Federal Regulations; DWEL = drinking water equivalent level; EPA = Environmental Protection Agency; FDA = Food 

and Drug Administration; HCH = hexachlorocyclohexane; HSDB = Hazardous Substances Data Bank; 

IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or health; 

IRIS = Integrated Risk Information System; MCL = maximum contaminant level; MCLG = maximum contaminant level 

goal; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; 

OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; PQL = practical 

quantitation level; RCRA = Resource Conservation and Recovery Act; REL = recommended exposure limit; 

RfD = reference dose; TLV = threshold limit values; TSD = treatment, storage, and disposal; TWA = time-weighted 

average; USC = United States Code; WHO = World Health Organization 
HEXACHLOROCYCLOHEXANE 244 

8. REGULATIONS AND ADVISORIES 

EPA derived an oral reference dose (RfD) of 0.0003 mg/kg/day for γ-HCH (IRIS 2005). The RfD is 

based on a NOAEL of 0.33 mg/kg/day for liver and kidney toxicity in female rats (Zoecon Corporation 

1983), and uses an uncertainty factor of 1,000 (10 for use of a subchronic versus a lifetime assay, 10 to 

account for interspecies variation, and 10 to protect sensitive human subpopulations). 

EPA has classified HCH in the following cancer weight-of-evidence classifications: technical HCH and 

α-HCH, Group B2 (probable human carcinogen); β-HCH, Group C (possible human carcinogen); and 

δ-HCH and ε-HCH, Group D (not classifiable as to human carcinogenicity) (IRIS 2005). γ-HCH is 

classified as having “suggestive evidence of carcinogenicity, but not sufficient to assess human 

carcinogenic potential” (EPA 2002b). 

EPA estimates that concentrations of HCH (technical) in water of 2.0, 0.2, and 0.02 μg/L are associated in 

humans with excess lifetime cancer risks of 10-4, 10-5, and 10-6, respectively. α-HCH in water at 

concentrations of 0.6, 0.06, and 0.006 μg/L are associated in humans with excess lifetime cancer risks of 

10-4, 10-5, and 10-6, respectively, and concentrations of β-HCH in water of 2.0, 0.2, and 0.02 μg/L are 

associated in humans with excess lifetime cancer risks of 10-4, 10-5, and 10-6, respectively (IRIS 2005). 

δ-HCH and γ-HCH are on the list of chemicals appearing in "Toxic Chemicals Subject to Section 313 of 

the Emergency Planning and Right-to-Know Act of 1986" (EPA 2003o). 

Tolerances are established for γ-HCH in or on raw agricultural commodities as follows: 7 ppm in or on 

the fat of meat from cattle, goats, horses, and sheep; 4 ppm in or on the fat of meat from hogs; 3 ppm in or 

on cucumbers, lettuce, melons, mushrooms, pumpkin, squash, summer, and tomatoes; 1 ppm in or on 

apples, apricots, asparagus, avocado, broccoli, Brussels sprouts, cabbage, cauliflower, celery, cherry, 

collards, eggplant, grape, guava, kale, kohlrabi, mango, mustard greens, nectarine, okra, onion (dry bulb 

only), peach, pear, pepper, pineapple, plum, prune, quince, spinach, strawberry, and Swiss chard; and 

0.01 ppm in or on pecans (EPA 2003n). 

The use of γ-HCH has been restricted by EPA since 1977 and is to be applied only by a certified 

applicator following label directions (EPA 1985b). 
_______________________ 

HEXACHLOROCYCLOHEXANE 245 

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HEXACHLOROCYCLOHEXANE 246 

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HEXACHLOROCYCLOHEXANE 319 

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. 
HEXACHLOROCYCLOHEXANE 320 

10. GLOSSARY 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 
HEXACHLOROCYCLOHEXANE 321 

10. GLOSSARY 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(Lo) (LCLo)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(Lo) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a 

chemical is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 
HEXACHLOROCYCLOHEXANE 322 

10. GLOSSARY 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 
HEXACHLOROCYCLOHEXANE 323 

10. GLOSSARY 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3

 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 
HEXACHLOROCYCLOHEXANE 324 

10. GLOSSARY 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 
HEXACHLOROCYCLOHEXANE 325 

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. 

HEXACHLOROCYCLOHEXANE 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 
HEXACHLOROCYCLOHEXANE 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, expert panel peer reviews, and agency-wide MRL Workgroup reviews, with 

participation from other federal agencies and comments from the public. They are subject to change as 

new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in 

the most recent toxicological profiles supersede previously published levels. For additional information 

regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease 

Registry, 1600 Clifton Road NE, Mailstop F-32, Atlanta, Georgia 30333. 
HEXACHLOROCYCLOHEXANE A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: α-HCH 

CAS Number: 319-84-6 

Date: June 2005 

Profile Status: Final Post-Public Comment Draft 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 61 

Species: Rat 

Minimal Risk Level: 0.008 [X] mg/kg/day [ ] ppm 

Reference: Fitzhugh OG, Nelson AA, Frawley JP. 1950. The chronic toxicities of technical benzene 

hexachloride and its α, β and γ isomers. J Pharmacol Exp Ther 100:59-66. (Table 2 of the article). 

Experimental design: Groups of 10 male and 10 female Wistar rats were treated with 0, 10, 50, 100, or 

800 ppm α-HCH in food for life. Estimated doses were 0, 0.7, 3.5, 7, or 56 mg/kg/day in males and 0, 

0.8, 4, 8, or 64 mg/kg/day in females. The mean age at death was 54.6 weeks for the 10 ppm group 

(NOAEL) and 58.3 weeks for the control group. The lifetime of the animals sacrificed at the end of the 

experiment was taken as 107 weeks. End points included clinical signs, body weight, food consumption, 

organ weight, gross pathology, and histopathology. 

Effects noted in study and corresponding doses: No exposure-related changes occurred at the low dose in 

either sex, indicating that the highest NOAEL is 0.8 mg/kg/day in females. Liver effects were 

qualitatively described in both sexes at higher doses, progressing from very slight histological changes 

with increased liver weight but no gross liver pathology at 3.5–4 mg/kg/day, slight histological changes 

with no gross pathology at 7–8 mg/kg/day, and moderate histological damage accompanied by moderate 

gross pathology at 56–64 mg/kg/day. The hepatic histopathological changes classified as moderate 

included hepatic cell atrophy, fatty degeneration, and focal necrosis. Non-hepatic effects included 

decreased body weight gain (18 and 13% less than controls in males and females), slight kidney 

histopathology (focal nephritis), and reduced lifespan (38% less than controls) at 56–64 mg/kg/day. 

Dose and end point used for MRL derivation: 0.8 mg/kg/day (10 ppm); no hepatic effects. 

[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 used from ppm in food or water to a mg/body weight dose? Yes. 

If so, explain: Food factor of 0.07 and 0.08 kg feed/kg body weight/day for male and female Wistar rats, 

respectively, were used to convert dose from ppm food to mg/kg body weight as follows: 

10 ppm x 0.07 (male rat food factor) = 0.7 mg/kg/day; 50 ppm=3.5 mg/kg/day; 100 ppm=7 mg/kg/day; 

800 ppm=56 mg/kg/day; 10 ppm x 0.08 (female rat food factor)=0.8 mg/kg/day; 50 ppm=4 mg/kg/day; 

100 ppm=8 mg/kg/day; 800 ppm=64 mg/kg/day.
 
HEXACHLOROCYCLOHEXANE A-4 

APPENDIX A 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

NA. 

Other additional studies or pertinent information which lend support to this MRL: Other studies have 

observed various hepatic effects after chronic-duration oral exposure to α-HCH and other HCH isomers 

(Amyes et al. 1990; Ito et al. 1975; Kashyap et al. 1979; Munir et al. 1983; NCI 1977; Thorpe and Walker 

1973; Wolff et al. 1987). Amyes et al. 1990 observed periacinar hypertrophy in male and female Wistar 

rats treated with 8 mg/kg/day γ-HCH in their diet for up to 52 weeks. The NOAEL was determined to be 

0.8 mg/kg/day. Hepatocellular carcinoma was observed in rats fed 50 mg/kg/day α-HCH in their diet for 

72 week (Ito et al. 1975). Hepatocellular carcinoma was also reported in mice treated with 34 mg/kg/day 

β-HCH in their diet for 104 weeks (Thorpe and Walker 1973). 

Agency Contact (Chemical Manager): Alfred Dorsey, D.V.M. 
HEXACHLOROCYCLOHEXANE A-5 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: β-HCH 

CAS Number: 319-85-7 

Date: June 2005 

Profile Status: Final Post-Public Comment Draft 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 10 

Species: Mouse 

Minimal Risk Level: 0.05 [X] mg/kg/day [ ] ppm 

Reference: Van Velsen FL, Danse LHJC, Van Leeuwen FXR, et al. 1986. The subchronic oral toxicity 

of the β-isomer of hexachlorocyclohexane in rats. Fundam Appl Toxicol 6:697-712. 

Experimental design: Groups of 10 male and 10 female Wistar rats were exposed to diets containing 0, 2, 

10, 50, or 250 ppm β-HCH in food for 13 weeks and then sacrificed. Estimated dietary doses are 0, 0.18, 

0.9, 4.5, or 22.5 mg/kg/day in males, and 0, 0.2, 1.0, 5, or 25 mg/kg/day in females. End points that were 

examined included clinical signs, body weight, food consumption, hematology, blood biochemistry, 

organ weights, gross pathology, and histopathology. 

Effects noted in study and corresponding doses: At the end of week 2, two male and two female rats 

receiving the highest dose (22.5 and 25 mg/kg/day, respectively) exhibited clinical signs of ataxia and 

became progressively inactive. Within 3 days of the first signs of ataxia, the animals became comatose 

and were sacrificed 

Dose and end point used for MRL derivation: 4.5 mg/kg/day; no reported signs of neurotoxicity (ataxia, 

inactivity, coma). 

[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 used from ppm in food or water to a mg/body weight dose? Yes. 

If so, explain: A food factor of 0.1 kg feed/kg body weight/day for female Wistar rats was used to 

convert from ppm in food to mg/kg as follows: 2 ppm x 0.1 (rat food factor)=0.02 mg/kg/day;
 

10 ppm=1.0 mg/kg/day; 50 ppm=5.0 mg/kg/day; 250 ppm=25 mg/kg/day.
 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

NA. 

Other additional studies or pertinent information which lend support to this MRL: Support for 

neurotoxicity as the critical effect for acute oral exposure to β-HCH is provided by other studies of this 

isomer identifying the nervous system as a target of toxicity. Rats exposed to 66 mg/kg/day of β-HCH in 

food for 30 days (Muller et al. 1981) exhibited significantly reduced tail nerve motor conduction velocity. 
HEXACHLOROCYCLOHEXANE A-6 

APPENDIX A 

Agency Contact (Chemical Manager): Alfred Dorsey, D.V.M. 
HEXACHLOROCYCLOHEXANE A-7 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: β-HCH 

CAS Number: 319-85-7 

Date: June 2005 

Profile Status: Final Post-Public Comment Draft 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 25 

Species: Rat 

Minimal Risk Level: 0.0006 [X] mg/kg/day [ ] ppm 

Reference: Van Velsen FL, Danse LHJC, Van Leeuwen FXR, et al. 1986. The subchronic oral toxicity 

of the β-isomer of hexachlorocyclohexane in rats. Fundam Appl Toxicol 6:697-712. 

Experimental design: Groups of 10 male and 10 female Wistar rats were exposed to diets containing 0, 2, 

10, 50, or 250 ppm β-HCH in food for 13 weeks and then sacrificed. Estimated dietary doses are 0, 0.18, 

0.9, 4.5, or 22.5 mg/kg/day in males, and 0, 0.2, 1.0, 5, or 25 mg/kg/day in females. End points that were 

examined included body weight, food consumption, hematology, blood biochemistry, organ weights, 

gross pathology, and histopathology. 

Effects noted in study and corresponding doses: Hepatic effects were observed that included 

hyalinization of centrilobular cells in males at ≥0.18 mg/kg/day and females at 25 mg/kg/day; increased 

absolute and relative liver weight in both sexes at ≥0.9 mg/kg/day in males and ≥1.0 mg/kg/day in 

females; periportal fat accumulation, increased mitosis and/or focal liver cell necrosis in males at 

≥4.5 mg/kg/day and females at ≥5 mg/kg/day; and centrilobular hepatocytic hypertrophy, proliferation of 

smooth endoplasmic reticulum, increased microsomal activity, and/or increased glycogen content in 

males at 22.5 mg/kg/day and females at 25 mg/kg/day. Other systemic effects included increased 

absolute and/or kidney weight in females at ≥2.0 mg/kg/day and males at ≥4.5 mg/kg/day; renal medulla 

calcinosis in males at 22.5 mg/kg/day; and clinical signs (ataxia progressing to inactivity and coma), 

hematologic and splenic changes indicative of anemia (decreased red blood cells and hemoglobin, 

increased extramedullar hematopoiesis), and reduced body weight in males at 22.5 mg/kg/day and 

females at 25 mg/kg/day. Due to the dose-related nature and progression in severity of the hepatic 

effects, and the mild, reversible nature of the changes at the lowest dose level, 0.18 mg/kg/day is 

considered to be a minimal LOAEL based on hyalinization of centrilobular cells, which indicates the 

inititation of hepatic effects. The liver is an established target of β-HCH in other subchronic and chronic 

studies in rats and mice (Fitzhugh et al. 1950; Ikegami et al. 1991a, 1991b; Ito et al. 1973; Schoter et al. 

1987). 

Dose and end point used for MRL derivation: 0.18 mg/kg/day; hyalinization of centrilobular cells. 

[ ] NOAEL [X] LOAEL 

Uncertainty Factors used in MRL derivation: 

[X] 3 for use of a minimal LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 
HEXACHLOROCYCLOHEXANE A-8 

APPENDIX A 

Was a conversion used from ppm in food or water to a mg/body weight dose? Yes. 

If so, explain: A food factor of 0.09 kg feed/kg body weight/day for male Wistar rats was used to convert 

from ppm in food to mg/kg as follows: 2 ppm x 0.09 (rat food factor)=0.18 mg/kg/day;
 

10 ppm=0.9 mg/kg/day; 50 ppm=4.5 mg/kg/day; 250 ppm=22.5 mg/kg/day. 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

NA. 

Other additional studies or pertinent information which lend support to this MRL: Significant increases 

in liver weight and the levels of hepatic cytochrome P-450, triglycerides, phospholipids, and cholesterol 

were seen in rats fed 50 mg/kg/day β-HCH for 2 weeks (Ikegami et al. 1991a, 1991b). Liver hypertrophy 

was seen in rats fed 25 mg/kg/day for 24 weeks (Ito et al. 1975), and in mice fed 32.5 mg/kg/day for 

24 weeks (Ito et al. 1973). Fatty degeneration and necrosis were seen in liver of rats fed 0.5– 

40 mg/kg/day for up to 53 weeks (Fitzhugh et al. 1950). Schöter et al. (1987) also observed an increase in 

hepatic foci in rats exposed to 3 mg/kg/day in the diet for 20 weeks. 

Agency Contact (Chemical Manager): Alfred Dorsey, D.V.M. 
HEXACHLOROCYCLOHEXANE A-9 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: γ-HCH 

CAS Number: 58-89-9 

Date: June 2005 

Profile Status: Final Post-Public Comment Draft 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 23 

Species: Rat 

Minimal Risk Level: 0.003 [X] mg/kg/day [ ] ppm 

Reference: Dalsenter PR, Faqi AS, Webb J, et al. 1997b. Reproductive toxicity and toxicokinetics of 

lindane in the male offspring of rats exposed during lactation. Hum Exp Toxicol 16:146-153. 

Experimental design: Reproductive toxicity was evaluated in male offspring of groups of 9 Bor:spf 

female rats that were administered γ-HCH in peanut oil by gavage as a single 6 mg/kg dose on day 9 or 

day 14 of lactation, or as daily 1 mg/kg/day doses on days 9-14 of lactation (Dalsenter et al. 1997b). A 

group of 9 controls was administered the vehicle alone on days 9-14 of lactation. Male offspring (10 or 

20/group) were terminated on postnatal day (pnd) 65 (puberty) or 140 (adulthood) and evaluated for the 

following end points: testis and epididymis weights, spermatid and sperm numbers, serum testosterone 

level, sexual behavior at 130 days of age during 1:1 mating with unexposed females (mount latency, 

intromission and ejaculatory latency, number and frequency of intromissions), mating index (number 

sperm positive females/number males mated x100), pregnancy index (number of males that made females 

pregnant/number of males that made females sperm-positive x100), fertility index (number of days 

elapsed until males fertilized their female partner), pregnancy end points (numbers of litters, 

implantations/litters, fetuses/litter, resorptions), and testicular histology (6 mg/kg offspring only). 

Effects noted in study and corresponding doses: Effects occurred in all treated groups. Findings in the 

1 mg/kg/day offspring included statistically significant (p<0.05) reductions in relative testicular weight at 

pnd 140 (6.4% less than controls), relative epididymis weight at pnd 65 (7.1%), spermatid number at pnd 

65 and 140 (29.0 and 12.8%, respectively), sperm number at pnd 140 (13.2%), serum testosterone at pnd 

65 (30.0%), and increased number of intromissions per minute up to ejaculation at pnd 130 (45%). 

Effects were generally similar in type and magnitude in the 6 mg/kg offspring following exposure on 

gestation day 9 or 14, including significantly reduced relative testicular weight at pnd 65 and 140 (~10%), 

spermatid and sperm numbers at pnd 140 (~8–10%), and serum testosterone at pnd 140 (~50%). There 

were no significant effects on sexual behavior or fertility in the 1 mg/kg/day or 6 mg/kg offspring as 

shown by the mating, pregnancy, and fertility indices or other pregnancy end points. Thus, the significant 

changes observed for relative organ weights, sperm number, hormone levels, and intromission incidence 

are considered minimally effective for reproduction; their associated dose levels are considered minimal 

LOAELs. The testicular histological examinations of the 6 mg/kg/day offspring showed large areas of 

normal tissue, although some areas had distinct changes ranging from small alterations to a pronounced 

effect. The most affected areas were the tubules in which the effects included necrotic changes and 

reductions in Leydig cell numbers and spermatogenesis. 

Concentration and end point used for MRL derivation: 1 mg/kg/day LOAEL for 

developmental/reproductive effects in male offspring exposed during lactation. 
HEXACHLOROCYCLOHEXANE A-10 

APPENDIX A 

Calculations: 1 mg/kg/day x 1/300 UF = 0.003 mg/kg/day. 

 [ ] NOAEL [X] LOAEL 

Uncertainty Factors used in MRL derivation: 

[X] 3 for use of a minimal 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 

concentration: NA. 

Was a conversion used from intermittent to continuous exposure? No. 

Other additional studies or pertinent information which lend support to this MRL: Similar adverse effects 

on testicular histology and sperm numbers occurred in adult male offspring of mice that were orally 

exposed to γ-HCH in doses ≥15 mg/kg/day (lower doses not tested) on gestation days 9–16 (Traina et al. 

2003). Testicular and other reproductive effects occurred in intermediate-duration studies of lindane in 

mink at the same dose as the acute LOAEL for developmental/reproductive toxicity in rats. Female mink 

treated with 1 mg/kg/day γ-HCH in their diet from 3–6 weeks before mating until weaning at 8–10 weeks 

postpartum showed effects on reproductive efficiency that included reduced receptivity to a second 

mating and reduced whelping rate, although litter size was not affected (Beard et al. 1997). This 

decreased fertility effect was primarily a result of embryo mortality after implantation. Reductions in 

litter size as well as whelping rate were observed in a three-generation study of mink exposed to 

1 mg/kg/day γ-HCH in the diet (Beard and Rawlings 1998). Neurological effects of γ-HCH occurred at 

acute doses similar to and higher than the 1 mg/kg/day LOAEL for developmental/reproductive toxicity. 

Neurological responses included enhanced susceptibility to kindling (induction of seizures by repeated 

subthreshold electrical stimulation of the brain) following a single 5-mg/kg dose (Gilbert and Mack 1995) 

or 3 mg/kg/day for 4 days (Joy et al. 1982), reduced brain serotonin level following 3 mg/kg/day for 

6 days (Attia et al. 1991), and reduced brain barrier permeability in 10-day-old pups exposed to 2 mg/kg 

as a single dose or 8 daily doses (Gupta et al. 1999). The toxicological relevance of these effects is 

unclear because there were no concurrent tests of neurobehavioral function (as well as the unnatural 

method of seizure induction). 

A comprehensive neurotoxicity screening study was conducted in which groups of 10 male and 10 female 

Crl:CD BR rats were administered a single dose of γ-HCH by gavage at levels of 0, 6, 20, or 60 mg/kg 

(Hughes 1999a). This study is an unpublished CBI submission summarized by EPA (2000). End points 

included functional observational battery (FOB) and motor activity (MA) tests performed prior to 

treatment, within 3 hours of dosing, and on post-exposure days 7 and 14, as well as histopathology of 

nervous system tissues at study termination. No clinical signs or any other effects were observed at 

6 mg/kg. Motor activity was decreased in females at ≥20 mg/kg and males at 60 mg/kg. Females also 

had increased forelimb grip strength and decreased grooming behavior at 20 mg/kg, as well as an absence 

of grooming behavior at 60 mg/kg. Other effects at 60 mg/kg included clinical signs (e.g., piloerection, 

urine-stained fur, tremors, and/or convulsions) in both sexes and increased hindlimb foot splay in males. 

Other acute effects of γ-HCH included hematological and immunological changes in mice at 10– 

20 mg/kg/day (Hong and Boorman 1993), developmental changes in rats and mice at 20–45 mg/kg/day in 

rats and mice (Dalsenter et al. 1997b; Hassoun and Stohs 1996a; Rivera et al. 1991), and liver and kidney 

changes in mice at 72 mg/kg/day (Srinivasan and Radhakrishnamurty 1988; Srinivasan et al. 1984). 
HEXACHLOROCYCLOHEXANE A-11 

APPENDIX A 

Agency Contact (Chemical Manager): Alfred Dorsey, D.V.M. 
HEXACHLOROCYCLOHEXANE A-12 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: γ-HCH 

CAS Number: 58-89-9 

Date: June 2005 

Profile Status: Final Post-Public Comment Draft 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 45 

Species: Mouse 

Minimal Risk Level: 0.00001 [X] mg/kg/day [ ] ppm 

Reference: Meera P, Rao PR, Shanker R, et al. 1992. Immunomodulatory effects of γ-HCH (lindane) in 

mice. Immunopharmacol Immunotoxicol 14:261-282. 

Experimental design: Groups of six female Swiss mice were exposed to γ-HCH in measured dietary 

doses of 0, 0.012, 0.12, or 1.2 mg/kg/day for up to 24 weeks in an immunotoxicity study. End points that 

were evaluated throughout the study included delayed-type hypersensitivity reaction to sheep red blood 

cells (SRBC), lymphoproliferative response to mitogenic stimulation by concavalin A, mixed lymphocyte 

reactions, response of IgM antibody forming cells in spleen (plaque formation) to SRBC or 

lipopolysaccharide (LPS), and peritoneal macrophage phagocytic activity in response to LPS or 

Staphylococcus aureus. Histology of the thymus, peripheral lymph nodes, and spleen was evaluated at 4, 

12, and 24 weeks post-treatment. 

Effects noted in study and corresponding doses: Both cell-mediated and humoral components of the 

immune system showed a biphasic response, characterized initially by stimulation followed by 

suppression in a dose-dependent manner at all dose levels, indicating that a NOAEL was not identified. 

Effects observed at ≥0.012 mg/kg/day included biphasic changes in delayed-type hypersensitivity reaction 

to SRBC (increased at 4–12 weeks and decreased at 12–24 weeks), IgM plaque formation to SRBC 

(increased at 4–8 weeks and decreased at 12–24 weeks), and plaque formation to LPS-SRBC (increased at 

4 weeks at ≥0.12 mg/kg/day and decreased at 8–24 weeks at ≥0.012 mg/kg/day). Histological changes 

occurred in lymphoid organs of treated animals and were consistent with the biphasic immunomodulatory 

responses. Effects were observed in the spleen at ≥0.12 mg/kg/day, including no significant reaction 

except for active proliferation of megakaryocytes at 4 weeks post-treatment, an apparent reduction in 

lymphoid follicles at 12 weeks post-treatment, and considerable reduction in the overall cellularity of red 

pulp and white pulp areas at 24 weeks post-treatment. Histopathology at 1.2 mg/kg/day included effects 

in lymph nodes (reduced lymphocyte population and size of medullary cords) and thymus (necrosis in the 

medulla) at 12–24 weeks post-treatment at 1.2 mg/kg/day. 

Dose and end point used for MRL derivation: 0.012 mg/kg/day; reduced activity of lymphoid follicles 

with prominent megakaryocytes and delayed hypersensitivity to immune challenge. 

[ ] NOAEL [X] LOAEL 
HEXACHLOROCYCLOHEXANE A-13 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[X] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

NA. 

Other additional studies or pertinent information which lend support to this MRL: Immunotoxic effects 

have been observed in other oral studies of γ-HCH. Immunosuppression in the form of reduced antibody 

responses to Salmonella and typhoid vaccines occurred in rats exposed to 6.25 mg/kg/day for up to 

5 weeks (Dewan et al. 1980). Exposure to 10 mg/kg/day for 10 days caused residual bone marrow 

damage and suppressed granulocyte-macrophage progenitor cells in mice, and atrophy of the thymus was 

observed in mice following 40 mg/kg/day for 3 days (Hong and Boorman 1993). Serum antibody 

response to SRBC was suppressed in rats exposed to 3.6 mg/kg/day for 8 weeks (Koner et al. 1998). 

Agency Contact (Chemical Manager): Alfred Dorsey, D.V.M. 

HEXACHLOROCYCLOHEXANE 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. 
HEXACHLOROCYCLOHEXANE 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. 
HEXACHLOROCYCLOHEXANE 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"). 
HEXACHLOROCYCLOHEXANE 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. 
HEXACHLOROCYCLOHEXANE 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. 
3 4 

SAMPLE 

1 → Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

LOAEL (effect) Exposure 

Key to frequency/ NOAEL Less serious Serious (ppm) 

figurea Species duration System (ppm) (ppm) Re

2 → INTERMEDIATE EXPOSURE 

5 

→ Systemic ↓

18 Rat 

→

CHRONIC EXPOSURE 

Cancer 38 Rat 39 Rat 40 Mouse 

6 7 8 9 

↓ ↓ ↓ ↓

3b 13 wk Resp 10 (hyperplasia) 

5 d/wk 6 hr/d 

11 ↓

18 mo 20 5 d/wk 7 hr/d 89–104 wk 10 5 d/wk 6 hr/d 79–103 wk 10 5 d/wk 6 hr/d 

(CEL, multiple organs) (CEL, lung tumors, nasal tumors) (CEL, lung tumors, hemangiosarcomas) 

10 

↓

NitWNTNT

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). 


HEXACHLOROCYCLOHEXANE C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD benchmark dose 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 

DOT Department of Transportation 
HEXACHLOROCYCLOHEXANE C-2 

APPENDIX C 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/International Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 
HEXACHLOROCYCLOHEXANE C-3 

APPENDIX C 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

OW Office of Water 
HEXACHLOROCYCLOHEXANE C-4 

APPENDIX C 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
HEXACHLOROCYCLOHEXANE C-5 

APPENDIX C 

> greater than ≥ greater than or equal to 

= equal to 

< less than ≤ less than or equal to 

% percent α alpha β beta γ gamma δ delta μm micrometer μg microgram q1 

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 

HEXACHLOROCYCLOHEXANE D-1 

APPENDIX D. INDEX 

absorbed dose ............................................................................................................................................................146 

acetylcholinesterase.....................................................................................................................................................91 

adenocarcinoma.........................................................................................................................................................149 

adipose tissue...................................................................... 12, 115, 121, 134, 135, 144, 147, 148, 153, 166, 168, 195, 

206, 208, 210, 212, 213, 219, 220, 221, 224, 234, 235
 

adrenal gland .............................................................................................................................................100, 122, 126 

adsorbed.....................................................................................................................................................190, 192, 194 

adsorption ..........................................................................................................................................190, 192, 193, 196 

aerobic ...............................................................................................................................................192, 196, 198, 199 

alanine aminotransferase (see ALT)......................................................................................................................80, 82 

ALT (see alanine aminotransferase)......................................................................................................................80, 82 

ambient air.............................................................................................................................................11, 16, 193, 200 

anaerobic............................................................................................................................................................192, 198 

androgen receptor ......................................................................................................................................................141 

anemia ...........................................................................................................................21, 34, 109, 142, 149, 155, 159
 

antiestrogenic.......................................................................................................................................................92, 139 

aspartate aminotransferase (see AST)....................................................................................................................80, 82 

AST (see aspartate aminotransferase)....................................................................................................................80, 82 

bioaccumulation ................................................................................................................................................194, 218 

bioavailability ....................................................................................................................................................195, 217 

bioconcentration factor ..............................................................................................................................................194 

biodegradation ...........................................................................................................................................198, 199, 217 

biomarkers ................................................................................................. 146, 147, 148, 149, 165, 166, 169, 170, 221
 

blood cell count .....................................................................................................................................................79, 86 

body weight effects........................................................................................................................................36, 85, 103 

breast milk ............................................................................................................. 5, 115, 121, 147, 167, 208, 212, 213
 

cancer........................4, 13, 14, 16, 28, 38, 81, 82, 83, 99, 100, 101, 102, 113, 142, 158, 159, 160, 170, 239, 243, 244
 

carcinogen........................................................................................................ 5, 16, 100, 101, 102, 160, 242, 243, 244
 

carcinogenic..................................4, 13, 16, 17, 27, 28, 38, 82, 100, 101, 102, 126, 138, 155, 160, 167, 179, 243, 244 

carcinogenicity ............................................................................ 5, 13, 16, 99, 100, 101, 102, 155, 160, 170, 243, 244
 

carcinoma .................................................................................................... 16, 100, 101, 102, 114, 117, 141, 161, 170
 

cardiovascular........................................................................................................................................34, 78, 109, 157 

cardiovascular effects ....................................................................................................................................34, 78, 109 

cholinesterase ............................................................................................................................................................148 

chromosomal aberrations...................................................................................................................................114, 161 

clearance....................................................................................................................................................................194 

death .............................................................................................. 5, 12, 27, 83, 92, 101, 103, 109, 155, 157, 197, 219
 

deoxyribonucleic acid (see DNA)......................................................................................................................116, 118 

dermal effects ..............................................................................................................................................29, 109, 110 

DNA (see deoxyribonucleic acid)........................................................................ 97, 114, 116, 117, 118, 137, 146, 161
 

dopamine .......................................................................................................................................................88, 99, 143 

endocrine ........................................................................................................... 13, 36, 85, 95, 100, 103, 138, 139, 158
 

endocrine effects......................................................................................................................................35, 36, 85, 158 

estrogen receptor..................................................................................................................................................92, 140 

estrogenic...................................................................................................................................139, 140, 161, 170, 171 

fetal tissue............................................................................................................................................97, 121, 212, 219 

fetus .............................................................................................................................................97, 141, 144, 150, 169 

follicle stimulating hormone..................................................................................................................................36, 37 

gastrointestinal effects .................................................................................................................................78, 109, 166 

general population ...........................................................................................................11, 13, 16, 146, 210, 215, 217 

genotoxic ...............................................................................................................................13, 27, 113, 129, 161, 169 

genotoxicity .................................................................................................................13, 113, 114, 115, 161, 169, 170
 
HEXACHLOROCYCLOHEXANE D-2 

APPENDIX D 

groundwater................................................................................. 11, 183, 190, 191, 196, 201, 202, 217, 218, 225, 241
 

growth retardation..................................................................................................................................................12, 96 

half-life ................................................................................................ 28, 128, 129, 146, 147, 192, 193, 194, 196, 197
 

hematological effects........................................................................................... 12, 34, 35, 78, 79, 109, 142, 159, 166 

hepatic effects.................................................................................. 13, 14, 20, 21, 35, 79, 83, 110, 149, 158, 160, 165
 

hydrolysis .................................................................................................................. 124, 183, 196, 197, 198, 199, 217
 

hydroxyl radical.................................................................................................................................183, 196, 197, 217 

immune system..............................................................................................................................14, 24, 163, 168, 170 

immunological..................................................................... 13, 14, 20, 23, 24, 27, 36, 86, 87, 111, 138, 159, 163, 237
 

immunological effects ...........................................................................................................................14, 87, 159, 163 

Kow .............................................................................................................................................................................176 

LD50 .....................................................................................................................................................................39, 103 

leukemia ............................................................................................................................................................149, 159 

leukopenia....................................................................................................................................................................34 

lymphatic ...................................................................................................................................................................119 

lymphoreticular................................................................................................................................24, 36, 86, 111, 237 

metabolic effects..........................................................................................................................................................86 

micronuclei..................................................................................................................................................92, 114, 161 

milk.............................................................5, 88, 93, 121, 122, 128, 143, 144, 206, 213, 214, 219, 221, 229, 232, 235
 

musculoskeletal effects................................................................................................................................................79 

neonatal ...............................................................................................................................................90, 143, 162, 220 

neurobehavioral .............................................................................................................................23, 90, 139, 157, 164 

neurochemical..................................................................................................................................................13, 15, 91 

neurophysiological.............................................................................................................................................148, 164 

neurotransmitter...........................................................................................................................91, 135, 162, 163, 164 

non-Hodgkin’s lymphoma.......................................................................................................................13, 16, 38, 160 

norepinephrine.............................................................................................................................................................88 

nuclear .........................................................................................................................................................82, 110, 158 

ocular effects .................................................................................................................................................36, 78, 111 

odds ratio ...................................................................................................................................................................113 

pancytopenia................................................................................................................................................35, 149, 159 

partition coefficients..................................................................................................................................................131 

pharmacodynamic..............................................................................................................................................130, 131 

pharmacokinetics...............................................................................................................129, 130, 131, 132, 142, 169
 

photolysis...................................................................................................................................183, 196, 197, 199, 220 

placenta.......................................................................................................................... 5, 121, 143, 144, 151, 212, 219
 

rate constants .....................................................................................................................................................194, 196 

renal effects ......................................................................................................... 18, 35, 83, 84, 85, 109, 110, 155, 158 

retention.............................................................................................................................................................198, 221 

salivation..............................................................................................................................................................88, 150 

solubility....................................................................................................................................119, 128, 165, 190, 191 

T4.........................................................................................................................................................................85, 158 

thrombocytopenia ................................................................................................................................................34, 149 

thyroid .................................................................................................................................................................95, 100 

thyroxine......................................................................................................................................................................95 

toxicokinetics...............................................................................................................................................27, 131, 150 

tremors................................................................................................................. 15, 23, 87, 89, 91, 112, 148, 150, 164 

tumors............................................................................................................................................13, 16, 100, 101, 113 

vapor phase........................................................................................................................................................229, 232 

vapor pressure............................................................................................................................................................193 

volatility.....................................................................................................................................................................221 

volatilization......................................................................................................................................190, 192, 193, 198 

weanling ............................................................................................................................................................124, 168