TOXICOLOGICAL PROFILE FOR
 

CHLORINE
 


 


 


 


 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

November 2010 
 

CHLORINE 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. 
 


 


 


 


 


 


 

CHLORINE iii 

UPDATE STATEMENT
 

A Toxicological Profile for Chlorine, Draft for Public Comment was released in October 2007. 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 and Environmental Medicine/Applied Toxicology Branch
 

1600 Clifton Road NE
 

Mailstop F-62
 

Atlanta, Georgia 30333
 
CHLORINE iv 

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CHLORINE v 

FOREWORD
 

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

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

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

and republished as necessary. 

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

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

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

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

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

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

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

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

significant human exposure and, where known, significant health effects. The adequacy of information to 

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

significance to protection of public health are identified by ATSDR. 

Each profile includes the following: 

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

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

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

(B) A determination of whether adequate information on the health effects of each substance 

is available or in the process of development to determine levels of exposure that present a 

significant risk to human health of acute, subacute, and chronic health effects; and 

(C) Where appropriate, identification of toxicologic testing needed to identify the types or 

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

The principal audiences for the toxicological profiles are health professionals at the Federal, State, and 

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

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

peer-reviewed. Staffs of the Centers for Disease Control and Prevention and other Federal scientists have 

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

and was made available for public review. Final responsibility for the contents and views expressed in 

this toxicological profile resides with ATSDR. 

Thomas R. Frieden, M.D., M.P.H.
 

Administrator
 

Agency for Toxic Substances and
 

Disease Registry
 
 

 

 

CHLORINE vi 

*Legislative Background 

The toxicological profiles are developed under the Comprehensive Environmental Response, 

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

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

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

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

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

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

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

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

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

Section 104(i)(1)(B), to respond to requests for consultation under section 104(i)(4), and as otherwise 

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

 

 

 

 

 

 

 

 

 


 


 


 


 

CHLORINE vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

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

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

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

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

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

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

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

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

the general health effects observed following exposure. 

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

and assesses the significance of toxicity data to human health. 

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

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

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

reported in this section. 

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

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

following exposure. 

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

issues: 

Section 1.6 How Can (Chemical X) Affect Children?
 

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

Section 3.7 Children’s Susceptibility
 

Section 6.6 Exposures of Children
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

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

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

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

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

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

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

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

Toxicity; and numerous chemical-specific case studies. 
 

 

 

 

 

 

 

 

 

CHLORINE viii 

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

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

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

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

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

professionals treating patients exposed to hazardous materials. 

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

Other Agencies and Organizations 

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

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

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

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

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

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

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

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

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

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

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

• Phone: 800-35-NIOSH. 

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

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

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

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

Referrals 

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

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

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

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

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

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

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

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

 

 

 

 

 

 

 

 

 


 


 


 


 


 


 


 


 


 


 

	 

	 

	 

	 

CHLORINE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

G. Daniel Todd, Ph.D.
 

Patricia Ruiz, Ph.D.
 

Larry Cseh, R.S.
 

Pam Tucker, M.D.
 

John Doyle, M.P.A.
 

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

Fernando T. Llados, Ph.D.
 

Daniel J. Plewak, B.S.
 

Mario Citra, Ph.D.
 

SRC, Inc., North Syracuse, NY
 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

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

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

end points. 

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

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

profile, and makes recommendations for derivation of MRLs. 

3.	 Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

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

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CHLORINE xi 

PEER REVIEW
 

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

1.	 John Balmes, M.D., Professor in Residence, Department of Medicine, University of California, 

San Francisco, San Francisco, California; 

2.	 Meryl Karol, Ph.D., Professor Emeritus, Associate Dean for Academic Affairs and Research, 

University of Pittsburgh, Pittsburgh, Pennsylvania; and 

3.	 Dennis Shusterman, M.D., MPH, Professor Emeritus, Department of Medicine, University of 

California, San Francisco, California. 

These experts collectively have knowledge of chlorine'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. 
CHLORINE xii 

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CHLORINE 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 CHLORINE?.................................................................................................................2
 

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

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

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

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

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

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO CHLORINE? .....................5
 

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

TO CHLORINE?............................................................................................................................6
 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? ...................................................................................................6
 

1.10 WHERE CAN I GET MORE INFORMATION?..........................................................................7
 

2. RELEVANCE TO PUBLIC HEALTH ...................................................................................................9
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CHLORINE IN THE
 

UNITED STATES .........................................................................................................................9
 

2.2 SUMMARY OF HEALTH EFFECTS.........................................................................................10
 

2.3 MINIMAL RISK LEVELS (MRLs) ............................................................................................14
 

3. HEALTH EFFECTS..............................................................................................................................25
 

3.1 INTRODUCTION........................................................................................................................25
 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE .....................................25
 

3.2.1 Inhalation Exposure ..............................................................................................................26
 

3.2.1.1 Death..............................................................................................................................26
 

3.2.1.2 Systemic Effects.............................................................................................................46
 

3.2.1.3 Immunological and Lymphoreticular Effects................................................................70
 

3.2.1.4 Neurological Effects ......................................................................................................71
 

3.2.1.5 Reproductive Effects......................................................................................................73
 

3.2.1.6 Developmental Effects...................................................................................................73
 

3.2.1.7 Cancer............................................................................................................................74
 

3.2.2 Oral Exposure........................................................................................................................75
 

3.2.2.1 Death..............................................................................................................................75
 

3.2.2.2 Systemic Effects.............................................................................................................76
 

3.2.2.3 Immunological and Lymphoreticular Effects................................................................96
 

3.2.2.4 Neurological Effects ......................................................................................................97
 

3.2.2.5 Reproductive Effects......................................................................................................97
 

3.2.2.6 Developmental Effects...................................................................................................98
 

3.2.2.7 Cancer............................................................................................................................98
 
 

 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 

3.2.3 Dermal Exposure.................................................................................................................100
 

3.2.3.1 Death............................................................................................................................100
 

3.2.3.2 Systemic Effects...........................................................................................................100
 

3.2.3.3 Immunological and Lymphoreticular Effects ..............................................................104
 

3.2.3.4 Neurological Effects ....................................................................................................104
 

3.2.3.5 Reproductive Effects....................................................................................................104
 

3.2.3.6 Developmental Effects.................................................................................................104
 

3.2.3.7 Cancer..........................................................................................................................104
 

3.3 GENOTOXICITY......................................................................................................................105
 

3.4 TOXICOKINETICS...................................................................................................................107
 

3.4.1 Absorption...........................................................................................................................107
 

3.4.1.1 Inhalation Exposure .....................................................................................................107
 

3.4.1.2 Oral Exposure ..............................................................................................................109
 

3.4.1.3 Dermal Exposure .........................................................................................................109
 

3.4.2 Distribution .........................................................................................................................109
 

3.4.2.1 Inhalation Exposure .....................................................................................................109
 

3.4.2.2 Oral Exposure ..............................................................................................................109
 

3.4.2.3 Dermal Exposure .........................................................................................................110
 

3.4.3 Metabolism..........................................................................................................................110
 

3.4.4 Elimination and Excretion...................................................................................................110
 

3.4.4.1 Inhalation Exposure .....................................................................................................110
 

3.4.4.2 Oral Exposure ..............................................................................................................110
 

3.4.4.3 Dermal Exposure ......................................................................................................... 111
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ...........111
 

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

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

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

3.5.3 Animal-to-Human Extrapolations.......................................................................................115
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS...........................115
 

3.7 CHILDREN’S SUSCEPTIBILITY............................................................................................117
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT .....................................................................120
 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Chlorine.........................................121
 

3.8.2 Biomarkers Used to Characterize Effects Caused by Chlorine...........................................122
 

3.9 INTERACTIONS WITH OTHER CHEMICALS .....................................................................122
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ............................................122
 

3.11 METHODS FOR REDUCING TOXIC EFFECTS................................................................124
 

3.11.1 Reducing Peak Absorption Following Exposure.............................................................124
 

3.11.2 Reducing Body Burden ...................................................................................................125
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects..........................................125
 

3.12 ADEQUACY OF THE DATABASE.....................................................................................126
 

3.12.1 Existing Information on Health Effects of Chlorine........................................................126
 

3.12.2 Identification of Data Needs............................................................................................130
 

3.12.3 Ongoing Studies ..............................................................................................................139
 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................143
 

4.1 CHEMICAL IDENTITY............................................................................................................143
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES.........................................................................143
 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................151
 

5.1 PRODUCTION .......................................................................................................................... 151
 

5.2 IMPORT/EXPORT ....................................................................................................................152
 

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5.3 USE ............................................................................................................................................152
 

5.4 DISPOSAL.................................................................................................................................158
 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................159
 

6.1 OVERVIEW...............................................................................................................................159
 

6.2 RELEASES TO THE ENVIRONMENT...................................................................................160
 

6.2.1 Air .......................................................................................................................................160
 

6.2.2 Water...................................................................................................................................163
 

6.2.3 Soil ......................................................................................................................................164
 

6.3 ENVIRONMENTAL FATE ......................................................................................................164
 

6.3.1 Transport and Partitioning...................................................................................................164
 

6.3.2 Transformation and Degradation ........................................................................................165
 

6.3.2.1 Air................................................................................................................................165
 

6.3.2.2 Water............................................................................................................................166
 

6.3.2.3 Sediment and Soil ........................................................................................................167
 

6.3.2.4 Other Media .................................................................................................................167
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT..................................167
 

6.4.1 Air .......................................................................................................................................168
 

6.4.2 Water...................................................................................................................................168
 

6.4.3 Sediment and Soil ...............................................................................................................168
 

6.4.4 Other Environmental Media................................................................................................168
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE........................................169
 

6.6 EXPOSURES OF CHILDREN..................................................................................................170
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 170
 

6.8 ADEQUACY OF THE DATABASE ........................................................................................171
 

6.8.1 Identification of Data Needs ...............................................................................................172
 

6.8.2 Ongoing Studies..................................................................................................................174
 

7. ANALYTICAL METHODS................................................................................................................177
 

7.1 BIOLOGICAL MATERIALS....................................................................................................177
 

7.2 ENVIRONMENTAL SAMPLES ..............................................................................................177
 

7.3 ADEQUACY OF THE DATABASE ........................................................................................179
 

7.3.1 Identification of Data Needs ...............................................................................................182
 

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

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

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

10. GLOSSARY ......................................................................................................................................213
 

APPENDICES 

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

B. USER’S GUIDE.................................................................................................................................. B-1
 

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

D. INDEX ................................................................................................................................................D-1
 

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CHLORINE xvii 

LIST OF FIGURES
 

3-1. Levels of Significant Exposure to Chlorine – Inhalation ................................................................... 42
 

3-2. Levels of Significant Exposure to Hypochlorite Solution – Oral....................................................... 88
 

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

Hypothetical Chemical Substance....................................................................................................113
 

3-4. Existing Information on Health Effects of Chlorine Gas .................................................................127
 

3-5. Existing Information on Health Effects of Hypochlorite Solution...................................................128
 

4-1. Speciation of Cl2, HOCl, and OClas a Function of pH...................................................................148
 
CHLORINE xviii
 

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CHLORINE xix 

LIST OF TABLES
 

3-1. Levels of Significant Exposure to Chlorine – Inhalation ................................................................... 30
 

3-2. Acute Effects of Chlorine Exposure on the Respiratory Tract of Humans.........................................47
 

3-3. Levels of Significant Exposure to Hypochlorite Solution – Oral....................................................... 77
 

3-4. Levels of Significant Exposure to Hypochlorous Acid and/or Sodium Hypochlorite
 

Chlorine - Dermal............................................................................................................................. 101
 

3-5. Genotoxicity of Sodium Hypochlorite In Vivo.................................................................................106
 

3-6. Genotoxicity of Sodium Hypochlorite In Vitro ................................................................................108
 

4-1. Chemical Identity of Chlorine ..........................................................................................................144
 

4-2. Commonly Used Terms Related to Chlorinated Water....................................................................145
 

4-3. Physical and Chemical Properties of Chlorine .................................................................................146
 

5-1. Companies that Produce Chlorine in the United States and Annual Capacities for 2006 ................153
 

5-2. Facilities that Produce, Process, or Use Chlorine.............................................................................155
 

5-3. U.S. Chlorine Imports and Exports by Year in Metric Tons............................................................157
 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Chlorine .....................161
 

6-2. Ongoing Studies Regarding the Potential for Human Exposure to Chlorine ...................................175
 

7-1. Analytical Methods for Determining Chlorine in Environmental Samples......................................180
 

8-1. Regulations, Advisories, and Guidelines Applicable to Chlorine and Chlorine Compounds ..........187
 
CHLORINE xx 

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CHLORINE 1 

1. PUBLIC HEALTH STATEMENT 

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

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

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

federal clean-up activities. Chlorine gas is too reactive to be detected in environmental media at 

hazardous waste sites. Any chlorine gas released at these sites would be quickly converted to other 

substances whose primary source may or may not have been chlorine. 

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. Since chlorine is highly reactive, you are unlikely to 

be exposed directly to it unless there has been a large scale accidental release in the nearby vicinity. 

If you are exposed to chlorine, 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. 

The subject of this profile is molecular chlorine (Cl2), which exists as a gas under normal environmental 

conditions or as a liquid when stored under pressure. Although molecular chlorine is used in some water 

disinfection processes, the resulting solution, commonly referred to as chlorinated water, does not actually 

contain molecular chlorine. Therefore, water disinfection and the chemicals present in chlorinated water, 

such as hypochlorite, are not the main focus of this document and are only discussed where relevant. 
 

 

 

 

 

 

 

 

 

 

CHLORINE 2 

1. PUBLIC HEALTH STATEMENT 

1.1 WHAT IS CHLORINE? 

Chlorine is a gas 

with a very 

irritating odor 

It is very unstable and quickly reacts with many substances to form other 

chemicals. 

Used in Chlorine is an extremely important industrial chemical that is used in the 

manufacturing production of thousands of products. 

and water 

disinfection It is also used for water disinfection, although the chlorine itself is quickly 

transformed into other chemicals at the beginning of the process. 

Chlorine gas is A common misconception is that molecular chlorine (Cl2) is present in 

not present in chlorinated water. During water chlorination, molecular chlorine gas may be 

chlorinated water added to the water at first; however, the chlorine is quickly transformed into 

other chemicals, which actually disinfect the water. Hypochlorous acid and 

hypochlorite anion are two of these chemicals that disinfect the water. 

The terms “free chlorine” and “aqueous chlorine” in drinking water usually 

refer to the amount of hypochlorous acid and hypochlorite in the water. It is 

important to recognize that these compounds are different from molecular 

chlorine. 

Bleach is not One of the important products that chlorine is used to make is bleach, and 

chlorine people sometimes confuse chlorine with bleach. Bleach contains a 

compound called sodium hypochlorite. If you mix acidic chemicals with 

bleach, chlorine can be formed and given off as a gas. 

For more information on the sources, properties, and uses of chlorine, see Chapters 4 and 5. 

1.2 WHAT HAPPENS TO CHLORINE WHEN IT ENTERS THE ENVIRONMENT? 

Chlorine is very 

unstable in the 

environment 

Chlorine is very unstable, and reacts with a variety of chemicals and water 

when it is released into the environment. 

Rapidly broken 

down 

• Air 

• Water 

Chlorine is broken down by sunlight within a matter of several minutes. 

Chlorine dissolves in water and is converted into chloride and hypochlorous 

acid. 

Chlorine can 

travel from its 

source 

If chlorine is spilled into water or onto soil or if it is released from a tank into 

the air, the chlorine will evaporate very quickly forming a greenish-yellow 

cloud that can be carried by the wind from the source. 

For more information on chlorine in the environment, see Chapter 6. 
 

 

 

 

 

 

 

 

 

 

CHLORINE 3 

1. PUBLIC HEALTH STATEMENT 

1.3 HOW MIGHT I BE EXPOSED TO CHLORINE? 

Most people are 

not expected to 

be exposed to 

chlorine 

Because chlorine is so reactive, it is not normally detected in the 

environment except for very low levels in the air above seawater. 

Accidental You may be exposed through breathing, skin contact, and eye contact if an 

exposure to accident involving chlorine takes place nearby, such as a liquid chlorine spill, 

chlorine a leak from a chlorine tank, or a leak from a facility that produces or uses 

chlorine. 

You may also be exposed to chlorine if you mix household chemicals such 

as toilet cleaner with bleach. 

Hypochlorous acid is used to treat swimming pool water. You may be 

exposed to chlorine gas through the improper use of swimming pool 

chemicals. 

Workplace air People who work in places where chlorine is made or used may be exposed 

to low levels over a period of time. 

People may be exposed to high levels if a large amount of chlorine is 

released during an accident. 

For more information on human exposure to chlorine, see Chapter 6. 

1.4 HOW CAN CHLORINE ENTER AND LEAVE MY BODY? 

Chlorine gas 

enters your body 

only when you 

breathe it in. 

Chlorine gas can enter your body through your nose or your mouth. 

At low concentrations (less than 10 ppm), almost all of the chlorine is 

removed from the air in the upper part of the respiratory airways and only a 

very small amount may reach your lungs. 

If you drink hypochlorite solution, it may react with the acids in your 

stomach and possibly form chlorine gas. 

Immediately 

reacts with other 

chemicals 

Chlorine gas reacts with the water in the cells located in the surface of the 

respiratory airways and forms other compounds that produce irritation of the 

airways. 

Most of these compounds eventually are transformed into chloride ions, 

which are normal components of the body. 

For more information on how chlorine enters and leaves the body, see Chapter 3. 
 

 

 

 

CHLORINE 4 

1. PUBLIC HEALTH STATEMENT 

1.5 HOW CAN CHLORINE AFFECT MY HEALTH? 

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

The effect of chlorine on human health depends on how much chlorine is present, how you are exposed to 

it, and the length of exposure. 

Short-term 

exposure to 

chlorine in air 

The following effects have been observed in humans briefly exposed to 

chlorine: 

• mild nose irritation at 1–3 ppm 

• eye irritation at 5 ppm 

• throat irritation at 5–15 ppm 

• immediate chest pain, vomiting, changes in breathing rate, and 

cough at 30 ppm 

• lung injury (toxic pneumonitis) and pulmonary edema (fluid in the 

lungs) at 40–60 ppm 

• death after 30 minute exposure to 430 ppm 

• death after a few minute exposure to 1,000 ppm 

The concentrations listed above are approximate; the effects will depend 

also on exposure duration. In general, people who suffer from respiratory 

conditions such as allergies or hay fever, or who are heavy smokers, tend to 

experience more severe effects than healthy subjects or nonsmokers. 

Long-term 

exposure to 

chlorine in air 

No significant harmful health effects were observed in workers exposed for 

years to relatively low concentrations of chlorine (around 1 ppm). 

The tissues inside the nose were principally affected in animals exposed to 

chlorine for longer durations. 

Short-term 

exposure to 

hypochlorite 

solution by 

ingestion 

Drinking small amounts of hypochlorite solution (less than a cup) can 

produce irritation of the esophagus. Drinking concentrated hypochlorite 

solution can produce severe damage to the upper digestive tract and even 

death. These effects are most likely caused by the caustic nature of the 

hypochlorite solution and not from exposure to molecular chlorine. 

Long-term 

exposure to 

hypochlorite 

solution by 

ingestion 

There is no information on long-term ingestion of hypochlorite solution in 

humans. Animals that drank hypochlorite solution in water for up to 2 years 

did not show any significant health effects. The amount of hypochlorite 

solution in the water that the animals drank was much smaller than what is 

found in household bleach. 

Skin exposure to 

hypochlorite 

solution 

Spilling hypochlorite solution on the skin can produce irritation. The severity 

of the effects depends on the concentration of sodium hypochlorite in the 

bleach. 

Further information on the health effects of chlorine in humans and animals can be found in Chapters 2 

and 3. 
 

 

 

 

 

 

 

 

 


 

CHLORINE 5 

1. PUBLIC HEALTH STATEMENT 

1.6 HOW CAN CHLORINE AFFECT CHILDREN? 

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

conception to maturity at 18 years of age. 

Children are likely 

to have similar 

effects as adults, 

but may be more 

sensitive than 

adults 

Short-term exposures (minutes) to high concentrations of chlorine affect 

children in the same manner they affect adults (i.e., mucous membrane and 

respiratory tract irritation). We do not know what the effects could be in 

children following longer-term (weeks or longer), low-level exposure to 

chlorine gas, but this type of exposure occurs only in workers and is not 

relevant to children. We also do not know what the effects could be in 

children following longer-term, low-level exposure to hypochlorite solution. 

Birth defects We do not know whether exposure to chlorine gas during pregnancy can 

result in damage to unborn babies because there are no studies of pregnant 

women or pregnant animals exposed to chlorine gas. 

One study of rats exposed to hypochlorite solution during pregnancy found 

no evidence of birth defects or any other developmental alteration in the 

baby rats. The amount of chlorine that the rats consumed was many times 

higher than what people are normally exposed to through drinking water. 

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

Do not mix bleach 

with household 

cleaners 

Chlorine gas can be released to the air when bleach is mixed with other 

cleaning solutions that contain an acid like some toilet cleaners. Mixing 

bleach with ammonia also produces very hazardous gases, such as 

chloramines. 

Store household 

chemicals out of 

reach of young 

children 

Always store household chemicals in their original labeled containers out of 

reach of young children to prevent accidental poisonings. Never store 

household chemicals in containers children would find attractive to eat or 

drink from, such as old soda bottles. 

Follow 

instructions for 

swimming pool 

disinfection 

Chlorine gas can also be released to the air when chemicals used to 

chlorinate swimming pools are mishandled. If you have a swimming pool at 

home, read the labels of the chlorination products carefully and do not let 

children play with these products. 
 

 

 

 

 

 

 

 

 

 

CHLORINE	 	 6 

1. PUBLIC HEALTH STATEMENT 

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

CHLORINE? 

There are no 

medical tests 

available for 

chlorine 

There are no medical tests to determine whether you have been exposed 

specifically to chlorine. 

Chlorine is transformed in the body into chloride ions, which are normal 

components of the body. An enormous amount of chlorine has to be 

inhaled or ingested in order to detect a significant increase in chloride ions 

in the blood. This has occurred in a few cases of ingestion of large amounts 

of hypochlorite solution and one of them was a fatal case. 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

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

can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the 

Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic 

substances. Recommendations provide valuable guidelines to protect public health, but cannot be 

enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National 

Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop 

recommendations for toxic substances. 

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

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

affect animals; they are then adjusted to levels that will help protect humans. Sometimes these not-toexceed 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. 
 

 

 

 

 

 

 

 

 

 

 

 


 


 


 


 


 


 

CHLORINE 7 

1. PUBLIC HEALTH STATEMENT 

Some regulations and recommendations for chlorine include the following: 

Levels in air set 

by EPA 

EPA established an environmental air limit of 0.5 ppm. Exposure to higher 

levels could result in discomfort and irritation. Dependent on the 

concentration, these effects may be reversible when exposure ends. 

Levels in 

workplace air set 

by OSHA 

OSHA set a legal limit of 1 ppm chlorine in air as a ceiling limit. At no time 

should a worker’s exposure exceed this limit. 

Levels in drinking 

water set by EPA 

EPA established a maximum contaminant level (MCL) and maximum 

residual disinfectant level (MRDL) of 4 mg/L for free chlorine in drinking 

water. 

1.10 WHERE CAN I GET MORE INFORMATION? 

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

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

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

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

substances. 

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

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

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

to: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine
 

1600 Clifton Road NE
 

Mailstop F-62
 

Atlanta, GA 30333
 

Fax: 1-770-488-4178
 
 

 

 

 

 

 

 

CHLORINE 8 

1. PUBLIC HEALTH STATEMENT 

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/ 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 9 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CHLORINE IN THE 

UNITED STATES 

Chlorine is a greenish-yellow gas with a pungent, irritating odor. It is stored and transported as a liquid 

under pressure. Chlorine is transported as either a liquid or a gas through pipelines within chemical plants 

or over distances of several kilometers. When chlorine is released into the environment, it reacts with 

both organic and inorganic substances that it comes into contact with. When chlorine gas is released into 

water, such as during water chlorination, it quickly dissolves in the water and then disproportionates 

within seconds to form chloride and hypochlorous acid. Chlorine may be released into the environment 

from facilities where it is produced or used, or during accidents, such as a chlorine tank rupture or a liquid 

chlorine spill. Most of the chlorine released during these types of incidents is expected to volatilize into 

the air forming a greenish-yellow chlorine gas cloud. Because chlorine is approximately 2.5 times 

heavier than air, the chlorine cloud remains near the ground. This cloud can be carried away from the site 

of release by the wind. Chlorine undergoes direct photolysis in the air and its half-life in the troposphere 

is on the order of several minutes. 

Because it is so reactive, chlorine gas is normally not detected in the environment except at low levels in 

seawater aerosols. Therefore, background exposure of the general population to chlorine is not expected 

to represent a health concern. Human biomonitoring data are not available for chlorine. Analyzing 

human biological tissue and fluids for chlorine is not relevant because >95% of the chlorine that is 

inhaled (over a 1–5 ppm range) is removed in the upper respiratory tract and eventually joins the chloride 

pool in the body. The amount of chlorine that would need to be inhaled to induce a significant increase in 

extracellular chloride in the body is probably a lethal amount. 

There are two primary means by which the general population may be exposed to chlorine. Individuals 

located near an accidental release of chlorine, either from a manufacturing facility or the transportation of 

liquefied chlorine may be exposed to high levels of this gas through inhalation and dermal contact if the 

cloud travels in their direction. In addition, people who mix acidic solutions with hypochlorite solutions, 

such as bleach or certain types of swimming pool chemicals, may accidentally be exposed to chlorine gas. 

Children may be exposed to chlorine through the same routes that affect adults, except for occupational 

exposures. Occupational exposure to low levels of chlorine gas in air may occur for individuals who 

work at facilities that produce or use chlorine. These individuals may also be exposed to high chlorine 

concentrations if an accidental release occurs inside the facility. 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 10 

2. RELEVANCE TO PUBLIC HEALTH 

Exposure to chlorine through drinking water is expected to be very low. Free chlorine in drinking water 

is defined as the sum of dissolved chlorine gas, hypochlorous acid, and hypochlorite anion. As discussed 

in Chapters 4 and 6, the level of dissolved chlorine in water is extremely low, except under acidic 

conditions; therefore, the term free chlorine in public water systems typically refers to the concentration 

of hypochlorous acid and hypochlorite anion. The term total chlorine as it pertains to water sanitation 

practices usually refers to the amount of free chlorine plus chloroamines (sometimes called combined 

chlorines) produced during the sanitation process. It is important to recognize that these compounds are 

different from molecular chlorine even though the terminology is often used interchangeably. 

2.2 SUMMARY OF HEALTH EFFECTS 

Chlorine Gas. The principal targets of exposure to chlorine gas are the respiratory airways and the eyes. 

Exposure can occur only by direct contact of inhaled chlorine gas with the respiratory epithelium or via 

direct contact of the eyes with the gas. The skin seems to be a less sensitive target to direct contact with 

chlorine gas possibly because it lacks the moisture of mucous membranes. The effects of acute-duration 

exposures to high concentrations of chlorine have been known for almost a century, starting with its use 

as a chemical weapon at Ypres, Belgium, during World War I. Additional information regarding the 

effects of brief high-level exposures to chlorine has been collected from accidental exposures following 

leaks during transport of tanks containing liquid chlorine, leaks from storage tanks, domestic accidents 

involving bleach solutions, mishandling of chemicals used at swimming pools, and even accidents in high 

school science experiments. These and many additional studies, including studies in volunteers exposed 

to controlled concentrations of chlorine, indicate that exposures to 1–3 ppm produce mild irritation of the 

nose that can be tolerated for about 1 hour; 5 ppm may produce eye irritation; headache and throat 

irritation may occur at concentrations of 5–15 ppm; 30 ppm produces immediate chest pain, nausea and 

vomiting, dyspnea, and cough; 40–60 ppm produces toxic pneumonitis and pulmonary edema; 430 ppm 

usually causes death in 30 minutes, and 1,000 ppm is fatal within a few minutes. In most cases, death is 

the result of pulmonary edema. Accidental releases of chlorine have affected adults and children, and a 

few reports suggested that children might be more susceptible than adults to the effects of chlorine. This 

may be due to the smaller diameter of the airways of children compared to adults. 

The effects of exposure to chlorine seem to depend, at least above a certain minimal exposure 

concentration, on the duration of exposure and exposure concentration, and the moisture content of the 

surface contacted by the gas (i.e., the respiratory epithelium). Exposures to relatively low concentrations 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 11 

2. RELEVANCE TO PUBLIC HEALTH 

of chlorine (<5 ppm) are not expected to affect deep lung structures since most of the inhaled chlorine 

(>95%) is scrubbed in the upper portion of the respiratory tract, whether breathing is through the nose or 

through the mouth. With the exception of cough, substernal pain, and respiratory distress, the symptoms 

occurring after exposure to moderate concentrations of chlorine generally subside within 24 hours. 

Edema, observed following high exposures, is caused by marked alveolar capillary congestion followed 

immediately by focal and confluent area of fluid with a high content of fibrinogen. Pulmonary edema 

peaks in 12–24 hours and the resulting hypoxia further increases capillary permeability, which creates a 

vicious cycle. Initially, the pulmonary fluid is interstitial, but if it overwhelms the capacity of the 

lymphatic system to drain it, the alveoli become filled. A further complication is the formation of hyaline 

membranes from the alveolar fluid with high-fibrinogen content, which along with developing areas of 

atelectasis (collapse), and right to left shunting of blood, explains the poor oxygen diffusion with resultant 

hypoxemia and later hypercapnea. Subjects surviving the acute phase of exposure to high concentrations 

of chlorine may still be in danger of delayed death due to bronchial pneumonia or pneumonia. The 

complications of chlorine inhalation fit the histological condition known as diffuse alveolar damage that 

is associated with the clinical condition known as the adult respiratory distress syndrome. 

Not all of the signs and symptoms exhibited by subjects exposed to moderate to high concentrations of 

chlorine gas are caused directly by chlorine. In general, it is believed that effects such as nausea and 

vomiting are reflex in origin, and headache and loss of consciousness are probably due to the hypoxia 

caused by pulmonary edema. Leukocytosis is almost always found in subjects admitted to emergency 

departments following exposure to high chlorine gas and is most likely a general response to 

inflammation. Anxiety and changes in blood pressure and heart rate also are commonly mentioned in 

case reports. While cardiovascular alterations can be due in part to a ventilation perfusion mismatch, they 

may also represent a general response to the stress and anxiety of having been involved in a chemical 

accident and being admitted to a health facility. 

Prolonged exposures to relatively low concentrations of chlorine in occupational settings have not given 

indications of respiratory or other health problems among the workers, but additional better-controlled 

studies are necessary to add confidence to these early findings. Workers occasionally experience brief 

episodes of high exposure (“gassing” incidents), in some cases to concentrations high enough to warrant a 

visit to the emergency room. In some of these cases and also in some cases of high exposure of the 

general population, long-term follow-up has shown persistent respiratory alterations that included airway 

obstruction and reactive airway dysfunction syndrome (RADS). RADS is defined as an asthma-like 

illness after a single acute exposure to a respiratory irritant in otherwise healthy individuals, characterized 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 12 

2. RELEVANCE TO PUBLIC HEALTH 

by increased responsiveness to methacholine challenge. There are many factors that can play a role in 

whether residual effects will be present, including exposure level and duration of exposure, medical 

treatment following exposure, length of the follow-up, underlying respiratory disease, and smoking status. 

A series of reports by Kilburn suggested that acute exposure to high concentrations of chlorine produced 

long-term neurobehavioral effects (i.e., memory loss, slow reaction time, impaired balance, hearing loss, 

visual alterations). No other study of chlorine-exposed subjects has included neurobehavioral testing, but 

this could potentially be examined in animal models. It is not known whether exposure to chlorine gas 

can affect reproduction or development in humans. Only one early study reported that pregnancy 

outcome was not affected among female workers at a chlorine plant. There is also no relevant 

information regarding effects of chlorine exposure on the immune system. A few studies of workers in 

the chemical industry did not find any evidence that chlorine gas is carcinogenic. The EPA, the 

International Agency for Research on Cancer (IARC), and the Department of Health and Human Services 

(DHHS) have not classified chlorine gas as to its carcinogenicity. 

The respiratory system is also the target of chlorine toxicity in animals. Animals exposed briefly to high 

concentrations of chlorine gas have shown respiratory effects similar to those observed in humans, with 

the added observations of severe gross and microscopic changes in the respiratory airways. Chlorine, in 

relatively low concentrations (1–3 ppm), also induced histological alterations in the respiratory tract, 

particularly the upper portion, in intermediate- and chronic-duration inhalation studies in animals. In 

these studies, there was no indication that chlorine exposure affects reproductive parameters. No studies 

are available that evaluated whether chlorine affects immunocompetence or the development of young 

organisms. Chlorine gas was not carcinogenic in rats and mice exposed to up to 2.5 ppm for 2 years. 

Hypochlorite Solutions. At very low pH (<2), it is theoretically possible that chlorine gas can be formed; 

therefore, exposures to hypochlorite solutions are briefly discussed even though, under normal pH, the 

predominant species are expected to be hypochlorous acid and hypochlorite (for a detailed discussion and 

definitions of terms related to the chemistry of chlorine in water, please see Chapter 4). The principal 

targets of exposure to hypochlorite solutions are the upper gastrointestinal tract and the skin. Exposure to 

hypochlorite can occur via accidental or intentional ingestion of chlorine bleach or via direct contact of 

the skin with hypochlorite solutions. In most cases, ingestion of small amounts (less than a cup) of 

sodium hypochlorite bleach (approximately 5.25% sodium hypochlorite, 52,250 ppm, or 52,250 mg/L) 

(ppm in water = mg/L) can produce esophageal irritation without permanent consequences. However, 

fatalities due to ingestion of sodium hypochlorite have been reported. In a reported case, an autopsy of a 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 13 

2. RELEVANCE TO PUBLIC HEALTH 

woman who drank an unknown amount of bleach revealed esophageal and gastric mucosal erosions, 

perforations at the gastroesophageal junction, and extensive necrosis of adjacent soft tissue. Aspiration of 

hypochlorite bleach into the lungs following ingestion of bleach also has been reported as a cause of 

death. The lethal dose of sodium hypochlorite in adults has been reported to be approximately 200 mL of 

a solution containing 3–6% chlorine. No significant additional toxicities have been reported in humans 

following oral exposure to hypochlorite. Two intermediate-duration studies in which volunteers were 

exposed to known amounts of chlorine in water provided no evidence of adverse effects. In one of them, 

consumption of water containing 5 mg/L chlorine (approximately 0.036 mg Cl/kg/day) had no significant 

effect on hematology, serum chemistry, urinalysis, or additional physiological parameters. Another study 

of limited scope showed that consumption of water containing 20 ppm chlorine (approximately 0.4 mg 

Cl/kg/day) had no significant effect on serum lipids or serum levels of thyroid hormones. It is not known 

whether oral exposure to chlorine can affect the immune and nervous systems, or reproduction or 

development in humans. There are no studies of cancer in humans exposed to chlorine itself. Based on 

inadequate evidence for carcinogenicity of hypochlorite salts in animals and no data from studies in 

humans, a study determined that hypochlorite salts are not classifiable as to their carcinogenicity in 

humans. 

Direct contact of the skin with household chlorine bleach can cause skin irritation in humans. Although 

sodium hypochlorite generally is not considered a contact sensitizer, several cases of allergic contact 

dermatitis have been reported. Commercial household bleaches are prepared with sodium hydroxide and 

are typically very alkaline; it is this property that may result in the irritant contact dermatitis. The limited 

information regarding ocular effects of direct contact of the eye with hypochlorite solutions suggest that 

splashes in the eye with house solutions of sodium hypochlorite rarely result in serious consequences. 

For the most part, the results of oral and dermal studies of chlorine in animals support the observations in 

humans. Studies in which hypochlorite bleach was placed in the esophagus of animals reproduced the 

observations following high exposure in humans. Additional intermediate- and chronic-duration studies 

that examined hematology and clinical chemistry parameters and conducted gross and microscopic 

examination of tissues from rats and mice following exposure to chlorinated water provided little 

evidence of chlorine-related toxicity. In the intermediate-duration studies, Sprague-Dawley rats, 

F344 rats, and B6C3F1 mice were dosed for 90 days with up to 24.9, 85, and 39.2 mg Cl/kg/day, 

respectively. In the chronic-duration studies, rats were exposed for 2 years to up to 14.4 mg Cl/kg/day 

and mice to up 24.2 mg Cl/kg/day. Studies in animals have provided no evidence that exposure to 

hypochlorite ions adversely affects the immune or nervous system, although an 8-week study in rats 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 14 

2. RELEVANCE TO PUBLIC HEALTH 

reported alterations in some immune parameters of unknown toxicological significance (reduced delayedtype hypersensitivity reaction, increased prostaglandin E2 synthesis by macrophages, and reduced 

oxidative metabolism by macrophages following stimulation with phorbol myristate acetate). Exposure 

of male and female rats to hypochlorite before and during breeding and of the females during gestation 

and lactation did not cause reproductive effects in either sex or adverse developmental effects in the 

offspring. Cancer bioassays in rats and mice have been negative except for equivocal evidence of 

increased incidence of leukemia in female F344 rats in one study’s bioassay. It should be mentioned, 

however, that one study considered the overall evidence only weakly supportive of an association 

between the occurrence of mononuclear cell leukemia and the consumption of chlorinated water based on 

the following: (1) the increase in leukemia was slight and not clearly dose-related, (2) there was no 

decrease in tumor latency, and (3) the incidence in concurrent controls was less than in historical controls. 

A limited number of studies of in vivo genotoxicity of hypochlorite ion provided negative results. 

2.3 MINIMAL RISK LEVELS (MRLs) 

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

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

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

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

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

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

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

methodology does not exist to develop MRLs for dermal exposure. 

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

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

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

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

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

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

significant human exposure improve, these MRLs will be revised. 
 

 

 

 

 

 

 

 

 

 

 

 

 

	 

CHLORINE 15 

2. RELEVANCE TO PUBLIC HEALTH 

Inhalation MRLs 

•	 An MRL of 0.06 ppm has been derived for acute-duration inhalation exposure (14 days or less) to 

chlorine gas. 

The effects of acute-exposure of humans and animals to chlorine have been well characterized (see 

Sections 2.2 and 3.2.1.2). Chlorine is a sensory irritant (substance capable of eliciting sensory irritation) 

and the most sensitive target for chlorine toxicity in humans and in animals is the respiratory system. 

Information that could be used for quantitative risk assessment regarding effects from acute exposure of 

humans to chlorine is available from studies of volunteers exposed to chlorine gas for 15 minutes to 

8 hours (Anglen 1981; D’Alessandro et al. 1996; Rotman et al. 1983; Schins et al. 2000; Shusterman et al. 

1998, 2003b). Some of these studies, as detailed below, also included sensitive individuals. Collectively, 

the results of these studies suggest that brief exposures to concentrations of chlorine ≤0.5 ppm do not 

cause sensory irritation or significant alterations in pulmonary function tests, but exposure to ≥1 ppm 

chlorine can induce transient respiratory and eye irritation and slight alterations in pulmonary function 

tests. Evaluations of soldiers gassed during World War I provide information on the effects of acute 

exposure to very high concentrations of chlorine and also on potentially persistent effects of acute 

exposure (Berghoff 1919; DOA 1933; Meakins and Priestley 1919). Similar information is available in 

many reports of accidental exposures to chlorine gas of workers and members of the general population 

(i.e., Agabiti et al. 2001; Agency for Toxic Substances and Disease Registry 1998; Bonetto et al. 2006; 

CDC 1991, 2005; Chasis et al. 1947; Chester et al. 1977; Hasan et al. 1983; Schönhofer et al. 1996; 

Sexton and Pronchik 1998; Weill et al. 1969). In both the war cases and the accidental exposures to 

chlorine gas, the concentrations of chlorine were generally not known. These high exposure cases have 

provided data on respiratory effects and on additional signs and symptoms of intoxication with chlorine 

that are not due to a direct action of chlorine, but that probably represent reflex responses and/or general 

responses to inflammation and stress that were caused by products of chlorine’s reaction with bodily 

fluids. Some of these responses include nausea, vomiting, headache, anxiety, alterations in blood 

pressure, and leukocytosis. 

The acute-duration database in animals is extensive, and includes a great number of studies conducted 

after the use of chlorine as a chemical weapon during World War I (for review, see DOA [1933] and 

Withers and Lees [1985b]). Most of the early studies provide information regarding lethal concentrations 

of chlorine as well as descriptions of the pathology of the respiratory tract caused by exposure to 

relatively high concentrations of chlorine. Although qualitatively informative, the early data do not meet 

current guidelines for use in quantitative risk assessment. More recent studies in animals, mainly rodents, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 16 

2. RELEVANCE TO PUBLIC HEALTH 

have confirmed the earlier findings regarding sensory irritation and pathological changes in the 

respiratory tract (Barrow and Smith 1975; Buckley et al. 1984; Demnati et al. 1995; Jiang et al. 1983; 

Leustik et al. 2008; Tian et al. 2008; Yildirim et al. 2004). In general, morphological alterations in the 

nasal mucosa of rats and mice occurred with chlorine concentrations >5 ppm. Specific lowest-observedadverse-effect levels (LOAELs) for sensory irritation in rodents are not available. However, in response 

to exposure to irritant substances, a reflex mechanism allows rodents to decrease the respiratory rate as a 

protective response (Alarie 1973). The concentration of the irritant that induces a 50% decrease in 

respiratory rate has been termed RD50 and is commonly used to compare the irritant potencies of 

chemicals. This reflex reaction has also been demonstrated in humans, dogs, and cats (Alarie 1973). 

Acute-duration inhalation studies provided very little information regarding end points other than those 

involving the respiratory system. Body weight loss, which is due to reduced food consumption, was 

reported in some studies (Dodd et al. 1980; Jiang et al. 1983). 

Evaluation of the acute-duration inhalation database summarized above indicates that sensory irritation 

and pulmonary function in humans are the most sensitive end points for exposure to chlorine and will 

serve as the basis for derivation of an acute-duration inhalation MRL for chlorine. These findings were 

reported in a group of studies that can serve as co-principal studies (Anglen 1981; D’Alessandro et al. 

1996; Rotman et al. 1983; Schins et al. 2000; Shusterman et al. 1998, 2003b). A detailed description of 

these studies is provided in Appendix A. 

Collectively, this group of studies provides evidence of sensory irritation and transient pulmonary 

changes occurring in humans exposed to 1 ppm chlorine for up to 8 hours/day. The pulmonary changes 

indicated increased airway resistance and reduced air flow. No such changes were reported in volunteers 

exposed to 0.5 ppm chlorine (0.4 ppm in the D’Alessandro et al. [1996]) study. The longest exposure 

duration was 8 hours (Anglen 1981; Rotman et al. 1983). These studies also included sensitive 

individuals: an atopic subject in the study by Rotman et al. (1983), subjects showing methacholine 

hyperresponsiveness in the study by D’Alessandro et al. (1996), and subjects exhibiting seasonal allergic 

rhinitis (Shusterman et al. 1998). Also of significance is the fact that Rotman et al. (1983) reported that 

exposure to 1 ppm for 8 hours induced greater changes in pulmonary function tests than exposure to the 

same concentration for 4 hours, suggesting that the response was related to duration in addition to 

concentration. Given this information, an acute-duration inhalation MRL for chlorine can be derived by 

duration adjustment of the no-observed-adverse-effect level (NOAEL) of 0.5 ppm for continuous 

exposure (0.5 ppm x 8 hours/24 hours = 0.167 ppm) (8 hours was the longest period of exposure for 

which there is information). Although sensitive individuals were tested in some of these studies, the 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

	 

CHLORINE 17 

2. RELEVANCE TO PUBLIC HEALTH 

number of individuals tested at the region of the NOAEL (0.4–0.5 ppm) was small. Therefore, an 

uncertainty factor of 3 is used to account for sensitive populations. The resulting acute-duration 

inhalation MRL for chlorine is 0.06 ppm (0.167 ppm/3). 

•	 An MRL of 0.002 ppm has been derived for intermediate-duration inhalation exposure (15– 

364 days to chlorine gas. 

No human studies were available that could serve as the basis for derivation of an intermediate-duration 

inhalation MRL. The animal database for intermediate-duration exposure to chlorine is limited to two 

studies. In one study, male and female F344 rats were exposed to 0, 1, 3, or 9 ppm chlorine 6 hours/day, 

5 days/week for 6 weeks (Barrow et al. 1979). In the other study, male and female F344 rats were 

exposed to 0, 0.5, 1.5, or 5 ppm chlorine 6 hours/day, 5 days/week for 62 days (Kutzman 1983). Aside 

from a reduction in final body weight of approximately 11% relative to controls in female rats exposed to 

0.5 ppm chlorine (most likely due to reduced food consumption) in the Kutzman (1983) study, the most 

sensitive target for chlorine exposure was the respiratory tract. Barrow et al. (1979) described 

inflammation of the nasal turbinates in rats exposed to ≥1 ppm chlorine, whereas loss of cilia and 

epithelium in the trachea was seen in rats exposed to ≥0.5 ppm in the Kutzman (1983) study. No 

NOAELs for respiratory effects were established in either study. Since incidences of animals with 

respiratory lesions were presented in the Kutzman (1983) study, but not in the Barrow et al. (1979) study, 

the Kutzman (1983) study was selected as the principal study for derivation of an intermediate-duration 

inhalation MRL for chlorine (more complete descriptions of the end points evaluated and the reported 

results in these studies can be found in Section 3.2 and Appendix A). 

There were no significant exposure-related increases in the incidences of animals with histological lesions 

in any of the examined tissues with the exception of a loss of cilia in the trachea (Kutzman 1983). The 

incidences of slight to moderate loss of tracheal cilia were 1/23, 12/23, 4/23, and 13/23 in the 0, 0.5, 1.5, 

and 5 ppm exposure groups, respectively. Although the incidence for this lesion in the mid-exposure 

group was not significantly different from the control incidence, a statistically significant (p=0.0055) 

Cochran-Armitage trend test for these data can be demonstrated. However, when attempts were made to 

apply dose-response models to the data, no adequate fits of EPA Benchmark Dose Software (BMDS) 

models to the data were obtained (p-values for chi-square goodness of fit statistics were <0.1). Thus, the 

LOAEL of 0.5 ppm was used as the point of departure for deriving an intermediate-duration inhalation 

MRL for chlorine, after it was converted to a human equivalent concentration (HEC) using the EPA 

cross-species dosimetric methodology (EPA 1994a) for a category 1 gas, as follows: 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

	 

CHLORINE 18 

2. RELEVANCE TO PUBLIC HEALTH 

LOAEL[HEC] = LOAEL[ADJ] x RGDRTB 

where: 

LOAEL[ADJ] = 0.5 ppm x 6/24 hours x 5/7 days = 0.09 ppm and 

RGDRTB = ratio of the regional gas dose in rats to that of humans for the tracheobronchial region 

RGDRTB = (VE/SATB)A / (VE/SATB)H 

where: 

VE = minute volume (0.137 L/minute for rats, 13.8 L/minute for humans [EPA 1994a]) and 

SATB = surface area of the tracheobronchial region (22.5 cm2 for rats and 3,200 cm2 for humans 

[EPA 1994a]) 

LOAEL[HEC] = 0.09 ppm x (0.137 L/minute/22.5 cm2

) / (13.8 L/minute/3,200 cm2) = 0.14 ppm 

Applying an uncertainty factor of 90 (3 for extrapolation from animals to humans with dosimetric 

adjustment, 3 for the use of a minimal LOAEL, and 10 for human variability) to the LOAEL[HEC] yields 

an intermediate-duration inhalation MRL of 0.002 ppm for chlorine. 

•	 An MRL of 0.00005 ppm has been derived for chronic-duration inhalation exposure (365 days or 

more) to chlorine gas. 

There is no information regarding chronic-duration exposure of the general population to chlorine 

because this type of exposure occurs only in occupational settings. There are few studies of chronicallyexposed workers in which there is some documentation regarding exposure levels and in which there is no 

evidence, at least explicitly mentioned in the studies, of the workers having being subjected to acute 

episodes of high exposure or “gassing” incidents. One of these studies involved 600 workers from 

25 plants producing chlorine subjected to an evaluation of medical and occupational histories, blood and 

urine tests, pulmonary function tests, and electrocardiogram (Patil et al. 1970). Exposure data were 

available for 332 workers and showed a time-weighted average (TWA) 8-hour mean of 0.15±0.29 ppm 

(range, 0.006–1.42 ppm). Evaluation of the 332 workers who had exposure data showed that none of the 

end points examined (those subjected to recall or measured) showed a dose-response relationship. The 

mean concentration of 0.15 ppm may be considered a NOAEL for the study, but limitations such as 

unclear analytical methodology, no clear definition of the case/control populations, and insufficient detail 

regarding the method of analysis render the NOAEL questionable. A respiratory health assessment of 

392 male pulp mill workers exposed predominantly to a mean 8-hour TWA of 0.18 ppm chlorine (other 

possible exposures included, sulfur dioxide, hydrogen sulfide, and methylmercaptan, in addition to 

various particulates) found that, relative to a control group, the pulp mill workers complained more 

frequently of usual phlegm, wheeze without cold, and chest illness (Enarson et al. 1984). However, the 

most significant finding was that a subgroup of nonsmokers (n=4) had a significantly lower fixed 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 19 

2. RELEVANCE TO PUBLIC HEALTH 

expiratory flow rate at 25–75% vital capacity (FEF25–75%) and forced expiratory volume in 

1 second/forced vital capacity (FEV1/FVC) ratio than the control workers. Given the small number of 

workers involved and the possibility of exposure to multiple chemicals, the validity of the 0.18 ppm as an 

effect level is questionable. An additional issue to consider is that neither one of these studies seemed 

adequate to detect possible mild alterations in the nasal cavity, a sensitive target of chlorine exposure in 

humans and animals, as described in Sections 2.2 and 3.2.1.2. Due to the limitations mentioned above, 

these long-term studies are insufficient for quantitative risk assessment. 

There are only two chronic-duration inhalation studies of chlorine in animals. One is a 1-year study in 

monkeys (Klonne et al. 1987) and the other is a 2-year bioassay in rats and mice (Wolf et al. 1995). Both 

studies tested similar concentrations of chlorine (up to 2.3 ppm in monkeys and 2.5 ppm in rats and mice) 

and evaluated multiple end points including respiratory tract histopathology, hematology, and clinical 

chemistry. In both studies, the upper respiratory tract was the target for chlorine toxicity. In general, 

lesions were less severe in the monkeys than in rats and mice, but extended more distally in the 

respiratory tract. In rats and mice, an increased incidence of minimal to moderate alterations occurred 

with the lowest exposure concentration tested, 0.4 ppm chlorine. In general, the nasal lesions were sitespecific, but the severity and/or incidence were not always concentration-dependent. Lesions observed 

included respiratory and olfactory epithelial degeneration, septal fenestration, mucosal inflammation, 

respiratory epithelial hyperplasia, squamous metaplasia, and goblet cell hypertrophy and hyperplasia, and 

secretory metaplasia of the transitional epithelium of the lateral meatus. For the most part, monkeys 

exhibited only mild concentration-related respiratory epithelial hyperplasia with focal loss of cilia over 

the range of concentrations tested (0, 0.1, 0.5, and 2.3 ppm) and showed no evidence of the major nasal 

lesions seen in rats and mice. These differences are probably related to species-specific respiratory-tract 

airflow characteristics (Ibanes et al. 1996), which in turn, are determined by anatomical differences. 

Moreover, rats and mice are obligatory nose breathers with a greater surface-area-to-volume ratio of the 

upper respiratory tract than primates. Therefore, exposure of rodents and primates to equal concentrations 

for equal amounts of time will likely result in greater pathological changes in the nasal area of the rodent 

(Barrow et al. 1979). It appears, therefore, that primates are a better model to evaluate potential 

respiratory effects in humans than rodents. For these reasons, the study in monkeys (Klonne et al. 1987) 

was selected for deriving a chronic-duration inhalation MRL for chlorine. 

In the principal study, male and female Rhesus monkeys (4/sex/exposure level) were exposed to 0, 0.1, 

0.5, or 2.3 ppm chlorine 6 hours/day, 5 days/week for 1 year (Klonne et al. 1987). The only treatmentrelated histopathological effects consisted of focal epithelial hyperplasia characterized by increased cell 
 

 

CHLORINE 20 

2. RELEVANCE TO PUBLIC HEALTH 

numbers and loss of cilia and goblet cells in the respiratory epithelium of the nose and trachea. The 

affected areas of the nasal passages showed hypercellularity with loss of goblet cells and cilia. In some of 

these areas, the nuclei showed altered polarity. Lesions were more frequent on the angular margins of the 

turbinates and less frequent on the lateral wall or septum adjacent to these margins. In some cases, the 

respiratory epithelial hyperplasia was associated with mild suppurative inflammatory response. Lesions 

in the trachea resembled those in the nose, but were less severe and involved only a small circumferential 

section of the ventral and ventrolateral trachea. The combined incidences of hyperplasia in the nasal 

epithelium with loss of goblet cells and cilia, characterized as trace and mild in males and females, were 

1/8, 3/8, 6/8, and 8/8 in the control, 0.1, 0.5, and 2.3 ppm exposure groups, respectively. The exposure 

concentration of 0.1 ppm is considered a minimal LOAEL for nasal lesions in monkeys. 

Incidence data for nasal lesions in male and female monkeys exposed to chlorine gas (Klonne et al. 1987) 

were analyzed using the benchmark dose (BMD) approach for MRL derivation (further details of the 

modeling are presented in Appendix A) (EPA 2008a). Models in the EPA BMDS (version 1.4.1) (i.e., 

Gamma, Logistic, Log-logistic, Multi-stage, Probit, Log-probit, Quantal linear, and Weibull) were fit to 

the nasal lesion data to determine potential points of departure for the MRL. A Quantal linear model 

provided the best fit to the data. From this model, the predicted exposure concentration associated with a 

10% extra risk (BMC10) for nasal lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on 

this concentration (BMCL10) was 0.02 ppm. The monkey BMCL10 served as the point of departure for the 

chronic-duration MRL, after it was converted to a HEC (BMCL10[HEC]) using the EPA cross-species 

dosimetric methodology (EPA 1994a) for a category 1 gas, as follows: 

BMCL10[HEC] = BMCL10[ADJ] x RGDRET 

where: 

BMCL10[ADJ] = 0.02 ppm x 6/24 hours x 5/7 days = 0.004 ppm and 

RGDRET = ratio of the regional gas dose in rats to that of humans for the extrathoracic region 

RGDRET = (VE/SAET)A / (VE/SAET)H 

where: 

VE = minute volume 2.1 m3

/day for monkeys, calculated using the allometric equation for 

monkeys in EPA (1988) assuming a body weight of 7 kg for Rhesus monkeys with nasal 

cavity surface area of 62 cm2

 (Gross and Morgan 1991); 20 m3/day for humans (EPA 1994a) 

and 

SAET = 62 cm2

 surface area of the nasal cavity in Rhesus monkeys weighing 7 kg (Gross and 

Morgan 1991); 200 cm2

 for humans (EPA 1994a) 

RGDRET = (2.1 m3

/day / 62 cm2) / (20 m3/day / 200 cm2) = 0.34 
CHLORINE 21 

2. RELEVANCE TO PUBLIC HEALTH 

BMCL10[HEC] = 0.004 ppm x 0.34 = 0.00136 ppm 

Applying an uncertainty factor of 30 (3 for extrapolation from animals to humans with dosimetric 

adjustment and 10 for human variability) to the BMCL10[HEC] yields a chronic-duration inhalation MRL of 

0.00005 ppm for chlorine. 

For the purpose of comparison, using the NOAEL/LOAEL approach would yield a chronic-duration 

inhalation MRL of 0.00007 ppm for chlorine. This results from duration-adjusting the LOAEL of 

0.1 ppm (0.1 ppm x 6/24 x 5/7 = 0.02 ppm) and then multiplying the LOAEL[ADJ] by the RGDRET of 

0.34 calculated above (LOAEL[HEC] = 0.02 ppm x 0.34 = 0.007 ppm). Applying an uncertainty factor of 

100 (10 for extrapolation from a LOAEL to NOAEL, 3 for animal to human extrapolation using 

dosimetric adjustments, and 3 for human variability) to the LOAEL[HEC] of 0.007 ppm would result in a 

chronic-duration inhalation MRL of 0.00007 ppm for chlorine, which is very close to the MRL calculated 

by benchmark analysis. If the LOAEL is considered a minimal LOAEL, then the composite uncertainty 

factor would be 30 and the resulting MRL would be 0.0002 ppm, which is 4 times higher than the MRL 

calculated by benchmark analysis. 

Oral MRLs 

Oral MRLs were not derived for hypochlorite solutions for the following reasons. MRLs are derived 

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

effect(s) for a specific duration within a given route of exposure. Scientifically, as part of having 

sufficient and reliable data, it is important to be able to see the full, or at least a significant range, of the 

dose-response curve. In the case of the oral database for hypochlorite solutions, no reliable LOAEL could 

be identified at levels of hypochlorite that could reasonably be encountered in the environment. It is a 

matter of policy of ATSDR not to derive free-standing MRLs. A summary of the oral database is 

presented below. 

Earlier acute-duration studies in animals tried to reproduce the lesions to the esophagus and/or stomach 

due to ingestion of bleach. In most studies, commercial hypochlorite bleach was administered through a 

tube directly into the esophagus and, in some cases, the distal end of the esophagus was artificially 

occluded to prolong and control the contact time between the solution and the mucosa (Hook and Lowry 

1974; Landau and Saunders 1964; Strange et al. 1951; Yarington 1970). Only three acute modern studies 

in animals were available. Cunningham (1980) administered 0, 8, 40, or 200 ppm Cl/kg/day (as sodium 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 22 

2. RELEVANCE TO PUBLIC HEALTH 

hypochlorite) to Wistar rats (10 females/dose group) by gavage in milk for 14 days and reported that this 

treatment had no significant effect on growth or on the weight of the brain, liver, kidney, or heart. No 

other end points were evaluated. In a limited scope study, Meier et al. (1985) exposed male B6C3F1 mice 

(10/dose group) to 0, 1.6, 4, or 8 mg Cl/kg/day (from sodium hypochlorite or hypochlorous acid) for 

5 days and reported that in mice treated with sodium hypochlorite and sacrificed 3 weeks after exposure, 

there were significant increases in sperm abnormalities at 1.6, 4, and 8 mg Cl/kg/day (not clearly doserelated), but no such increases were seen in mice sacrificed 1 or 5 weeks after exposure. In addition, no 

increases in sperm abnormalities were seen in mice treated with hypochlorous acid, which the 

investigators considered “somewhat surprising since hypochlorite should be converted to hypochlorous 

acid in the acid pH of the stomach.” Furukawa et al. (1980) administered sodium hypochlorite in the 

water to male and female F344 rats for 14 days and reported weight loss at approximately ≥36 mg 

Cl/kg/day accompanied by marked reductions in water consumption. No histological evaluations were 

conducted in this study. 

Two human studies were located in the available intermediate-duration oral database. A study of limited 

scope evaluated serum lipid profile and serum levels of thyroid hormones in volunteers who drank 

1.5 L/day of distilled water containing 0 or 20 ppm chlorine (0 or 0.4 mg Cl/kg/day based on a mean body 

weight of 71 kg from the study) for 4 weeks (Wones et al. 1993). No significant deviations from 

normality were found. In the other study, consumption of water containing 5 mg/L chlorine 

(approximately 0.036 mg Cl/kg/day) for 12 weeks by 10 volunteers had no significant effect on 

hematology, serum chemistry, urinalysis, and additional physiological parameters (Lubbers et al. 1982). 

Since the study did not control for non-experimental ingestion of chlorine by the volunteers, the actual 

dose of chlorine cannot be estimated, but is likely to have been higher than 0.036 mg Cl/kg/day. 

Few intermediate-duration studies in animals were located that examined a wide range of end points 

following exposure to hypochlorite solutions chlorine. These studies showed that the main effect of 

exposure to solutions of hypochlorous acid or sodium hypochlorite, particularly at the higher 

concentrations levels, is a reduction of water intake that is due to taste aversion. The available 

intermediate-duration oral studies evaluated systemic toxicity (body weight, tissue and organ 

histopathology, hematology, clinical chemistry) (Abdel-Rahman et al. 1984; Cunningham 1980; Daniel et 

al. 1990, 1991; Furukawa et al. 1980) and also provided information, albeit limited, on immunological/ 

lymphoreticular (organ weight and histopathology and limited immunocompetence) (Daniel et al. 1990, 

1991; Exon et al. 1987), neurological (weight and histopathology of the brain and sciatic nerve) (Daniel et 

al. 1990, 1991), reproductive (male and female reproductive organ weight and histopathology, fertility, 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 23 

2. RELEVANCE TO PUBLIC HEALTH 

and sperm parameters) (Carlton et al. 1986; Daniel et al. 1990, 1991), and developmental effects (fetal 

viability and fetal weight in a gestation exposure study) (Carlton et al. 1986). None of the available 

studies reported effects that could be attributed directly to chlorine or only reported effects that were 

considered of unknown toxicological significance. LOAELs were not identified in the intermediateduration studies, but in one of these studies, rats exposed to 4.1 mg Cl/kg/day (the highest dose tested) for 

8 weeks showed a statistically significant reduction in delayed-type hypersensitivity reaction (DTH) to 

bovine serum albumin, increased prostaglandin E2 synthesis by macrophages, and reduced oxidative 

metabolism (Exon et al. 1987). The toxicological significance of these findings is unknown. 

The highest NOAEL identified in intermediate-duration oral studies is 76 mg Cl/kg/day for reduction in 

body weight gain in rats dosed with sodium hypochlorite in the drinking water for 13 weeks (Hasegawa et 

al. 1986). Doses of 152 and 305 mg Cl/kg/day were associated with reductions in final body weight of 

19 and 47%, respectively, relative to controls. This study, however, has serious limitations including no 

reporting of food or water consumption and lack of presentation of data on other end points. Three other 

13-week studies are available. Furakawa et al. (1980) administered up to approximately 85 mg Cl/kg/day 

(from sodium hypochlorite) to F344 rats for 92 days and reported significant reductions in final body 

weight males at 85 and 50 mg Cl/kg/day (19 and 46%, respectively) and in females at 84 mg Cl/kg/day 

(30%) relative to controls. This was accompanied by significant reductions of up to 66% in water 

consumption. For the most part, clinical chemistry hematology tests were unremarkable. Gross necropsy 

showed bladder abnormalities (no further description) among all groups, while microscopic examination 

showed endocardial hyperplasia and fibrosis of the myocardium in males and females dosed with 84 mg 

Cl/kg/day. Daniel et al. (1990) exposed male and female Sprague-Dawley rats to chlorine in the drinking 

water and evaluated a number of end points including organ histopathology, hematology, and clinical 

chemistry. Daniel et al. (1991) conducted a similar study in male and female B6C3F1 mice. In neither 

study were there significant toxic effects that could be attributed to exposure to chlorine. However, in 

both studies, water consumption was significantly decreased, particularly in the high-dose groups. In 

high-dose male (16.7 mg/ Cl/kg/day) and female (24.9 mg Cl/kg/day) rats, water consumption was 

reduced 36 and 38%, respectively; in high-dose male (34.4 mg Cl/kg/day) and female (39.2 mg 

Cl/kg/day) mice, water intake was reduced 30 and 20%, respectively. The decrease in water intake, 

which resulted in dehydration and possibly altered electrolyte balance, could explain the reductions in 

weight gain and sporadic changes in hematological parameters, clinical chemistry, and organ weights 

observed in both rats and mice. In the absence of effects that could be clearly attributed to chlorine 

toxicity, the highest doses tested represent the NOAELs for the studies; no LOAELs were defined. 
 

 

 

 

 

 

 

 

 

 

CHLORINE 24 

2. RELEVANCE TO PUBLIC HEALTH 

No chronic-duration human study of exposure to hypochlorous acid or sodium hypochlorite was located; 

thus, a target for long-term exposure to chlorine in humans has not been identified. Three chronicduration studies were available, two in rats (Hasegawa et al. 1986; NTP 1992) and one in mice (NTP 

1992). In the NTP (1992) study, the only treatment-related effect was a reduction in water consumption, 

particularly at the higher dose levels of chlorine, which, as generally agreed, is due to taste aversion. All 

three studies evaluated a comprehensive number of end points including hematology and clinical 

chemistry and tissue and organ histopathology. The highest NOAEL was 133 mg Cl/kg/day for female 

rats in the Hasegawa et al. (1986) study. However, final body weight in low- and high-dose females at 

termination (104 weeks) was 11 and 20% lower, respectively, than in controls. Hasegawa et al. (1986) 

stated that in females, the daily water intake was “somewhat lower” (no data provided) than in the other 

groups during the first year, but that this trend was not observed during the second year. In addition, the 

investigators indicated that in males, water intake was comparable among groups, except during the last 

20 weeks of the study, during which time water intake was consistently 10–20% higher in the 

experimental groups than in the controls. The latter seems to be inconsistent with findings in other 

studies that reported marked reductions in water consumption at lower chlorine concentrations (i.e., 

Daniel et al. 1990, 1991; NTP 1992). In the NTP (1992) studies, F344 rats received doses of up to 

14.4 mg Cl/kg/day and B6C3F1 mice up to 24.2 mg Cl/kg/day for up to 2 years. No significant alterations 

attributable to chlorine exposure were noticed in either species for a wide range of end points assessed. 
 

 

 

 

 

 

 

 

 

 

CHLORINE 25 

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 chlorine. 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 

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 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 26 

3. HEALTH EFFECTS 

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. 

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. 

This toxicological profile discusses health effects that result from exposure to chlorine gas. However, 

ATSDR feels there is a need to inform the public about the role of chlorine in the process of disinfection 

of water, namely, the production of hypochlorous acid and hypochlorite ion when chlorine is introduced 

in water. As a way to inform the public, ATSDR has decided to include some information regarding the 

health effects of hypochlorite solutions in the Profile for chlorine. For chlorine gas, the most important 

route of exposure is inhalation. For hypochlorous acid and sodium hypochlorite, the most important 

routes of exposure are oral and dermal. 

3.2.1 Inhalation Exposure 

3.2.1.1 Death 

There is extensive information regarding the lethal effects of exposure to high concentrations of chlorine. 

Much of the information available is derived from the use of chlorine gas as a chemical weapon at the 

battle of Ypres, Belgium, during World War I. Approximately 150 tons of chlorine released from 

6,000 cylinders killed, by some accounts, 800 soldiers and incapacitated 2,500–3,000 (Joy 1997). In a 

review of the effects of warfare gases, the U.S. Department of Army (DOA 1933) stated that of the total 

70,752 casualties from gas poisoning in the American Expeditionary Forces, 1,843 were gassed with 

chlorine. A study of 838 of these subjects revealed that 4 deaths were due to later-developing effects of 

chlorine gassing. The causes of death were broncho-pneumonia, lobar pneumonia, purulent pleurisy, and 

tuberculous meningitis. In an evaluation of the after effects of chlorine gassing in 700 members of the 

First Canadian Division, Meakins and Priestley (1919) reported that five deaths had occurred, three 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 27 

3. HEALTH EFFECTS 

apparently due to an acute pneumonic condition. One death occurred 5 months after exposure to chlorine 

and, although the exact cause of death was unknown, the symptoms recorded were pain in the left chest, 

dyspnea, orthopnea, and pronounced cyanosis. The concentration of chlorine to which the soldiers were 

exposed during the gas attacks is unknown. 

DOA (1933) summarized the pathology of chlorine exposure leading to death in 24 hours as follows: an 

acute inflammation of the trachea and bronchi is followed by congestion and edema of the entire 

respiratory tract. The edema and consolidation of the lungs lead to acute dilation followed by passive 

congestion of the abdominal viscera. Acute death is the result of the pulmonary edema and respiratory 

and cardiovascular failure. Subacute death is generally due to pulmonary infection with resulting 

bronchitis and pneumonia (DOA 1933). Postmortem findings include: acute conjunctivitis, congestion of 

abdominal organs (especially the liver), increased lung volume, fluid in the pleural cavity, mottled 

appearance on lung surface with scattered areas of emphysema, pleural hemorrhage, perivascular edema, 

and dilation of blood vessels, frothy fluid filling the trachea and bronchi, red mucous membranes, and 

heart enlargement and dilated heart chambers (especially the right side) (DOA 1933). 

There are also reports of deaths due to spills of chlorine gas to the environment following railroad 

accidents. CDC (2005) reported that in January 2005, a train in South Carolina carrying chlorine tanker 

cars collided with another train and an estimated 11,500 gallons of chlorine gas were immediately 

released to the air causing the death of nine persons. The primary cause of death of those who died at the 

scene was asphyxia (Van Sickle et al. 2009). Reported findings included congested lungs, pulmonary 

edema, and tracheal and bronchial erythema. CDC (2005) also reported that a similar accident on 

June 2004 in Texas released approximately 90,000 pounds of chlorine gas resulting in two fatalities 

among residents near the site. Eight people died as a direct result of lung injury caused by exposure to 

chlorine following a freight train accident in Florida in February 1978 (Jones et al. 1986). A train 

accident in San Luis Potosí, Mexico, in August 1981 caused the release of an unspecified amount of 

chlorine gas, which caused the death of 14 people (Costero and Falcón Escobedo 1983). An 11-monthold infant died after liquid chlorine spilled as a result of a derailment in La Barre, Louisiana, in January 

1961 (Joyner and Durel 1962). The child died hours after exposure and the cause of death presumably 

was massive pulmonary edema. Joyner and Durel (1962) indicate that 7 hours after the accident, levels of 

400 ppm chlorine were measured in areas 75 yards from the wreck. Citing an unpublished report, Baxter 

et al. (1989) stated that the rupture of a chlorine storage vessel in Romania in 1939 caused the death of 

68 people. 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 28 

3. HEALTH EFFECTS 

Dixon and Drew (1968) reported the case of a worker at a factory producing chlorine who was exposed to 

chlorine gas that leaked from a faulty valve for about 30 minutes and died 3–3.5 hours later; postmortem 

examination showed that pulmonary edema was the prime cause of death. Adelson and Kaufman (1971) 

reported the death of two healthy adults 25 and 76 hours after being exposed to chlorine gas that leaked 

into their home from a nearby water filtration plant while they were sleeping. An autopsy of the earlier 

death showed congested and edematous lungs whose cut surfaces released substantial amounts of water 

and frothy liquid on pressure, and injected tracheobronchial mucosa. Postmortem examination of the later 

death showed a similar picture of the lungs with the additional findings of swollen brain with flattening of 

convolutions and subarachnoid hemorrhage. Suzuki et al. (2001) reported the case of a worker who 

inhaled concentrated chlorine gas and died from pulmonary thrombosis 6 days after exposure. 

Using information on lethal effects of chlorine in animals and humans from the literature, Withers and 

Lees (1985a) developed probit equations to derive a revised estimate of the lethal toxicity of chlorine that 

considers physical activity, particularly inhalation rate, effectiveness of medical treatment, and the form 

of the lethal toxic load function. The LC50 values for a 10-minute exposure with standard level of activity 

were estimated at 433, 173, and 364 ppm for the regular, vulnerable, and average population, 

respectively. For a 30-minute exposure, the corresponding LC50 values were estimated at 250, 100, and 

210 ppm, respectively. Prater (1990) indicates that concentrations of 400 ppm can be lethal to humans in 

30 minutes and that immediate death follows inhalation of a concentration of 1,000 ppm. Concentrations 

between 1,000 and 1,200 ppm for 30 minutes are lethal to humans according to a review of earlier data 

from various American authors by Withers and Lees (1985b). 

Even more abundant information exists regarding lethal effects of chlorine in animals. For data regarding 

work beginning with World War I, the reader is referred to a review by Withers and Lees (1985b). Work 

conducted at the U.S. Army’s Medical Research Laboratory of the Chemical Warfare Service cited by 

DOA (1933) indicates that acute exposures to concentrations >870 ppm were usually lethal to dogs, 

whereas concentrations below 656 ppm were rarely fatal. Additional studies also in dogs, also 

summarized by DOA (1933), indicate that dogs that died within 24 hours of gassing showed severe injury 

to the mucous membranes of the upper respiratory tract, congestion, and edema of the entire respiratory 

tract including the peribronchial tissues and the sheaths of the large blood vessels. There was also acute 

inflammatory reaction of the lungs that developed into pneumonia. In dogs dying 2–5 days after gassing, 

the most important feature was the inflammatory process, whereas in dogs dying 5–14 days after gassing 

death was due to pulmonary infection. Since the original sources were not available, these studies in dogs 

are not listed in Table 3-1. 
 

 

 

 

 

 

CHLORINE 29 

3. HEALTH EFFECTS 

Weedon et al. (1940) conducted lethality studies in unspecified strains of rats and mice. In a group of 

eight rats exposed to 1,000 ppm chlorine, the first death occurred in 20 minutes and all were dead in 

1.7 hours. The exposure level of 1,000 ppm was the LC50 in 53 minutes, and 250 ppm was the LC50 in 

440 minutes. Rats that died immediately after exposure showed slight brain congestion; lungs distended 

and hemorrhagic with cut surfaces wet and foamy; distended heart; liver congestion; distended and 

hemorrhagic stomach; distended intestines; and congested kidneys. In mice, the first death occurred in 

21 minutes, and all eight were dead in 50 minutes. The 1,000 ppm exposure level was a 28-minute LC50, 

whereas 250 ppm was a 440-minute LC50. Mice that died immediately after exposure had slight brain 

congestion; lungs partly collapsed and hemorrhagic; moderately distended heart; liver congestion; 

distended and hemorrhagic stomach; slightly distended intestines, and congested kidneys. 

In lethality studies conducted by Zwart and Woutersen (1988), 5,484 ppm was a 5-minute LC50 in Wistar 

rats, whereas 447 ppm was a 60-minute LC50; in Swiss-Webster mice, 1,032 ppm was a 10-minute LC50 

and 516 ppm was a 30-minute LC50. 

In a different study in mice, a 10-minute LC50 of 302 ppm was calculated in intact mice and 131 ppm in 

mice that were exposed via a cannula placed in the trachea, suggesting that the nose is an effective 

scrubber of chlorine (Alarie 1981). In a study in mechanically-ventilated pigs, exposure to 140 ppm 

chlorine for 10 minutes caused the death of four out of five pigs within 6 hours of exposure (Gunnarsson 

et al. 1998). Death was caused by cardiovascular failure triggered by a severe mismatching of ventilation 

and perfusion. Additional information on lethal concentrations of chlorine in various animal species can 

be found in World Health Organization (WHO 1982). 

Lethality was also reported in an intermediate-duration study in rats (10/sex/exposure level) exposed to 1, 

3, or 9 ppm 6 hours/day, 5 days/week for 6 weeks (Barrow et al. 1979). Three rats from the 9 ppm 

exposure level group died before day 30 and had lesions consistent with chlorine exposure (widespread 

inflammation of the respiratory tract with hyperplasia and hypertrophy of epithelial cells of the respiratory 

bronchioles, alveolar ducts, and alveoli). The specific times of death were not reported. 

The LOAEL values for death in each species and duration category are recorded in Table 3-1 and plotted 

in Figure 3-1. 
31

293

27

1000250

23

68819265486447

35

302

28

1000250

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

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(SpragueDawley) 

1 hr 

System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

LOAEL 

Serious 

(ppm) 

293 (1-hour LC50) 

Reference Chemical Form 

Vernot et al. 1977 

2 Rat 

(NS) 

1 min - 16 hr 1000 (50% killed in 53 

minutes) 

Weedon et al. 1940 

250 (50% killed in 440 

minutes) 

3 Rat 

(Wistar) 

5-60 min 688 (30-minute LC50) 

1926 (10-minute LC50) 5486 (5-minute LC50) 

447 (60-minute LC50) 

Zwart and Woutersen 1

4 Mouse 

(SwissWebster) 

10 min 302 M (10-minute LC50 

followed by 3-hour observation period) 

Alarie 1981 

5 Mouse 

(NS) 

16 hr 1000 (50% killed in 28 

minutes) 

Weedon et al. 1940 

250 (50% killed in 440 

minutes) 
24

1032516

34

0.5

1

0.5 1

3

0.4

1

1

0.5

1

0.5 1

2

0.5

103

0.5

6 

Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

Mouse (SwissWebster) 

Systemic 

7 8 9 10 11 

Human Human Human Human Human 

Exposure/ 

Duration/ 

Frequency 

(Route) 

10-30 min 4-8 hr 1 hr 8 hr 3 d 6 hr/d 15 min 

System 

Resp 

Ocular 

Resp Resp 

Ocular Resp Resp 

NOAEL 

(ppm) 

b

0.5 0.5 

0.4 

b

0.5 M 0.5 M 

b

0.5 M 

b

0.5 

LOAEL 

Less Serious Serious 

(ppm) (ppm) 

1032 (10-minute LC50) 

516 (30-minute LC50) 

1 (itching and burning of

nose and throat; alteredpulmonary function)

1 (eye irritation) 1 (transient alterations in

pulmonary function tests)

1 M (changes in pulmonary

function tests; runnynose; throat burning)

1 M (eye irritation) 

Reference Chemical Form 

Zwart and Woutersen 1

Anglen 1981 D'Alessandro et al. 199Rotman et al. 1983 Schins et al. 2000 Shusterman et al. 1998 
4

1

21

25

29

100

200

38

1212

12

Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) 

LOAEL 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

12 Human 15 min Resp 1 (increased nasal airway 

resistance) 

Shusterman et al. 2003

13 Rat 

(Fischer- 344) 

10 min Resp 25 M (50% decrease in 

respiratory rate, RD50) 

Barrow and Steinhagen 

14 Rat 

(SpragueDawley) 

2-10 min Resp 100 M 200 M (slight perivascular 

edema in the lung) 

Demnati et al. 1995 

15 Rat 

(Fischer- 344) 

1-10 d 5 d/wk 6 hr/d 

Resp 12 M (swelling of the nose and 

wheezing) 

Dodd et al. 1980 

Ocular 12 M (swelling around the 

eyes) 

Bd Wt 12 M (approximately 20% 

weight loss) 
32

9.19.1

105

184

44

2.5

5

37

1330

20

9.3

16 17 19 20 

Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

a 

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

Rat 1-5 d Resp 9.1 M (erosion and ulceration of Jiang et al. 1983 6 hr/d (Fischer- 344) olfactory epithelium) 

Bd Wt 9.1 M (13% weight loss on day 

5) 

Rat 30 min Resp 184 M (histological and Leustik et al. 2008 (Sprague- biochemical evidence of Dawley) lung injury) 

18 Rat 

(Fischer- 344) 

1-12 hr Resp 2.5 M 5 M (reduced total sulfydryl 

content in nasal 

McNulty et al. 1983 

respiratory epithelium after 6-hour exposure) 

Rat 15 min Resp 1330 M (pulmonary edema and Yildirim et al. 2004 (Sprague- hemorrhage) Dawley) 

Mouse 10 min Resp 9.3 M (50% reduction in Barrow et al. 1977 (Swiss- respiratory rate, RD50) Webster) 
22

9.3

39

3.5

33

9.19.1

36

100

19

2.3

104

221

Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

21 Mouse 

(SwissWebster) 

22 Mouse 

(Hybrid) 

23 Mouse 

(SwissWebster) 

24 Mouse 

(Hybrid) 

25 Mouse 

(C57BL/6N) 

26 Mouse 

(C57BL/6N) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

5 d 6 hr/d Resp 9.3 M (exfoliation, erosion, ulceration, necrosis of 

nasal respiratory epithelium) 

Buckley et al. 1984 

60 min Resp 3.5 M (50% reduction in 

respiratory rate, RD50) 

Gagnaire et al. 1994 

1-5 d 6 hr/d Resp 9.1 M (erosion and ulceration of Jiang et al. 1983 the olfactory epithelium) 

Bd Wt 9.1 M (21% weight loss on day 

5) 

5 min Resp 100 M (flattening of pulmonary 

epithelium) 

Martin et al. 2003 

15 min Resp 2.3 F (50% decrease in 

breathing frequency, RD50) 

Morris et al. 2005 

60 min Resp 221 (biochemical and 

histological evidence of lung injury) 

Tian et al. 2008 
26

50

100

25

9

9

1 9

3

9

5

9

1

3

3

9

1 31

3 9

Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

27 Rabbit 30 min 

(NS) 

INTERMEDIATE EXPOSURE Death 

28 Rat 6 wk 

5 d/wk (Fischer- 344) 6 hr/d 

Systemic 

29 Rat 6 wk 

5 d/wk (Fischer- 344) 6 hr/d 

System 

Resp Resp Gastro Hemato Hepatic Renal Ocular Bd Wt 

LOAEL 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

50 100 (pulmonary edema 

followed by emphysema) 

Barrow and Smith 1975 

9 (death in 3/10 before day 

30 of exposure) 

Barrow et al. 1979 

1 F (inflammation of nasal 

turbinates) 

9 (erosion of nasal 

mucosal epithelium) 

Barrow et al. 1979 

3 9 (focal erosion of gastric 

mucosa) 

5 9 (increased hematocrit in 

females and segmented neutrophils in males) 

1 3 (cytoplasmic vacuolation 

of hepatocytes) 

3 9 (slight to moderate 

kidney congestion) 

1 1 

3 (ocular irritation) 3 F (15% decreased final 

weight) 

9 M (43% decreased final 

weight) 
40

0.5

5

5550.5

1.5

5

0.5 5

41

5

42

5

43

5

Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

30 Rat 

(Fischer- 344) 

62 d 5 d/wk 6 hr/d 

Resp 

c

0.5 M (loss of cilia and 

epithelium in the trachea) 

5 (severe upper respiratory 

irritation) 

Kutzman 1983 

Cardio 5 Hepatic Renal 

5 M 5 M 

Ocular 0.5 1.5 (occasional signs of eye 

irritation) 

5 (severe eye irritation) 

Bd Wt 0.5 F (final weight 11% lower 

than controls) 

5 F (weight loss; final weight 

32% lower than controls) 

Immuno/ Lymphoret 

31 Rat 

(Fischer- 344) 

62 d 5 d/wk 6 hr/d 

5 Kutzman 1983 

Neurological 

32 Rat 

(Fischer- 344) 

62 d 5 d/wk 6 hr/d 

5 Kutzman 1983 

Reproductive 

33 Rat 

(Fischer- 344) 

62 d 5 d/wk 6 hr/d 

5 Kutzman 1983 
5

0.1

2.32.32.32.32.32.32.32.30.5 2.32.3

Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

CHRONIC EXPOSURE Systemic 

34 Monkey 

(Rhesus) 

1 yr 5 d/wk 6 hr/d 

Resp 

d

0.1 F (minimal nasal epithelial 

hyperplasia) 

Klonne et al. 1987 

Cardio 2.3 Gastro 2.3 Hemato 2.3 Musc/skel 2.3 Hepatic 2.3 Renal 2.3 Endocr 2.3 Dermal 2.3 Ocular 0.5 2.3 (conjunctival irritation) 

Bd Wt 2.3 
11

0.4

2.52.52.52.52.52.52.52.52.52.5

Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

35 Rat 

(Fischer- 344) 

M: 2 yr, 5 d/wk, 6 hr/d F: 2 yr, 3 d/wk, 6 hr/d 

Resp 0.4 (alterations of minimal 

severity in nasal epithelium) 

Wolf et al. 1995 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 

2.5 

2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 

2.5 
15

0.4

2.52.52.52.52.52.52.52.52.52.5

6

2.3

12

2.5

Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

36 Mouse 2 yr 

5 d/wk (B6C3F1) 6 hr/d 

Immuno/ Lymphoret 

37 Monkey 1 yr 

5 d/wk (Rhesus) 6 hr/d 

38 Rat M: 2 yr, 5 d/wk, 

6 hr/d (Fischer- 344) F: 2 yr, 3 d/wk, 6 hr/d 

System 

Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 

LOAEL 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

0.4 (minimal to moderate 

alterations in the nasal epithelium) 

Wolf et al. 1995 

2.5 

2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 

2.5 

2.3 Klonne et al. 1987 2.5 Wolf et al. 1995 
16

2.5

8

2.3

13

2.5

17

2.5

7

2.3

Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

39 Mouse 

(B6C3F1) 

2 yr 5 d/wk 6 hr/d 

2.5 Wolf et al. 1995 

Neurological 

40 Monkey 

(Rhesus) 

1 yr 5 d/wk 6 hr/d 

2.3 Klonne et al. 1987 

41 Rat 

(Fischer- 344) 

M: 2 yr, 5 d/wk, 6 hr/d F: 2 yr, 3 d/wk, 6 hr/d 

2.5 Wolf et al. 1995 

42 Mouse 

(B6C3F1) 

2 yr 5 d/wk 6 hr/d 

2.5 Wolf et al. 1995 

Reproductive 

43 Monkey 

(Rhesus) 

1 yr 5 d/wk 6 hr/d 

2.3 Klonne et al. 1987 
14

2.5

Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) System (Route) (ppm) (ppm) (ppm) Chemical Form 

44 Rat M: 2 yr, 5 d/wk, 2.5 Wolf et al. 1995 

(Fischer- 344) 6 hr/d 

F: 2 yr, 3 d/wk, 6 hr/d 

a The number corresponds to entries in Figure 3-1. b Used to derive an acute-duration inhalation minimal risk level (MRL) of 0.06 ppm; the MRL was derived by adjusting the NOAEL of 0.5 ppm for continuous exposu8/24) and dividing by an uncertainty factor of 3 to account for human variability. c Used to derive an intermediate-duration MRL of 0.002 ppm; the MRL was derived by dividing the LOAEL[HEC] of 0.14 ppm by an uncertainty factor of 90 (3 for exanimals to humans with dosimetric adjustment, 3 for use of a minimal LOAEL, and 10 for human variability). d Used to derive a chronic-duration inhalation MRL of 0.00005 ppm; the MRL was derived by dividing the BMCL10[HEC] of 0.00136 ppm by an uncertainty factor oextrapolation from animals to humans with dosimetric adjustment and 10 for human variability). Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = Female; Gastro = gastrointestinal; Hemato = hematological; hr = hour(s); Immunimmunological/lymphoreticular; LC50 = lethal concentration, 50% kill, LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); Musc/skel = muscNOAEL = no-observed-adverse-effect level; NS = not specified; occup = occupational; ppm = parts per million; RD50 = 50% decrease in respiration rate; Resp = reweek(s); yr = year(s) 
Figure 3-1 Levels of Significant Exposure to Chlorine - Inhalation
	

Acute (≤14 days)
	

Systemic 

Death 

Respiratory 

Ocular 

Body Weight 

ppm 

10000 

3r 

3r 

19r 

1000 5m 6m 2r 

3r 

6m 3r 

4m 1r 5m 2r 26m 14r 17r
	

100
	 24m 14r 27h 

27h 

13r 

15r 15r 15r 10 20m 21m 23m 16r 23m 16r 

18r 

22m 

25m 18r
	

1
	 7 8 9 12 7 9 

7 9 10 11 7 9 8 

0.1 

0.01 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

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

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

CHLORINE

3. HEALTH EFFECTS

42
Figure 3-1 Levels of Significant Exposure to Chlorine - Inhalation (Continued)
 

Intermediate (15-364 days)
	

Systemic
	

Death 

Respiratory 

Cardiovascular 

Gastrointestinal 

Hematological 

Hepatic 

Renal 

Ocular 

ppm
	 Body Weight 

Immuno/Lymphor 

Neurological 

Reproductive 

10
	 28r 29r 29r 29r 29r 29r 

30r 30r 29r 30r 30r 30r 30r 31r 32r 33r 

29r 29r 29r 29r 29r 

30r
	

1
	 29r 29r 29r 29r 

30r 30r 30r 

0.1 

0.01 

0.001 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

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

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

CHLORINE

3. HEALTH EFFECTS

43
Figure 3-1 Levels of Significant Exposure to Chlorine - Inhalation (Continued)
 

Chronic (≥365 days)
	

Systemic 

Respiratory 

Cardiovascular 

Gastrointestinal 

Hematological 

Musculoskeletal 

Hepatic 

Renal 

ppm
	

10
	

34k 36m 35r 34k 36m 35r 34k 36m 35r 34k 36m 35r 34k 36m 35r 34k 36m 35r

1 

36m 35r 

0.1 34k 

0.01 

0.001 

0.0001 

1E-5 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

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

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

CHLORINE

3. HEALTH EFFECTS

44
Figure 3-1 Levels of Significant Exposure to Chlorine - Inhalation (Continued)
 

Chronic (≥365 days)
	

Systemic
	

Endocrine 

Dermal 

Ocular 

ppm
	 Body Weight 

Immuno/Lymphor 

Neurological 

Reproductive 

10
	

34k 36m 35r 34k 36m 35r 34k 36m 35r 34k 36m 35r 37k 39m 38r 40k 42m 41r 43k 44r

1 

34k 

0.1 

0.01 

0.001 

0.0001 

1E-5 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

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

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

CHLORINE

3. HEALTH EFFECTS

45
 

 

 

 

 

 

 

 

 

 

CHLORINE 46 

3. HEALTH EFFECTS 

3.2.1.2 Systemic Effects 

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

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

Respiratory Effects. The respiratory system, particularly the upper portion of the respiratory system, 

is the target for exposure to chlorine gas, and there is a considerable amount of information to support this 

observation. Chlorine is a respiratory irritant and its effects depend on its concentration, as well as the 

duration of exposure and the water content of the tissue involved. 

Table 3-2 lists clinical effects associated with exposure concentrations compiled from epidemiological 

and toxicological studies by Ellenhorn and Barceloux (1988). Whether acute exposure to high levels of 

chlorine induces long-term respiratory effects is still a matter of debate. As mentioned below, some 

studies have reported a clinical picture of persistent airflow obstruction as well as increased bronchial 

reactivity, while many others have not found significant persistent alterations. There are many factors 

that can determine whether residual effects are detected, including exposure level and duration of 

exposure, medical treatment following exposure, length of the follow-up, underlying respiratory disease, 

and smoking status. The preponderance of the evidence suggests that no serious long-term respiratory 

alterations result from acute exposure to low to moderate (up to approximately 20 ppm) concentrations of 

chlorine gas. 

Effects caused by several types of exposures are summarized below including exposure to high 

concentrations as it occurred during gassing attacks in World War I, accidental exposures of the general 

population, occupational exposures, and acute, low-level, controlled exposure in volunteers. Information 

on odor perception is also summarized. Due to the high volume of studies in some of these categories, 

representative examples are presented. 

Odor Perception. A study in which a trained odor panel of four members was exposed to chlorine under 

controlled laboratory conditions reported that the first concentration at which all members cold detect the 

odor was 0.314 ppm (Leonardos et al. 1968). Ryazanov (1962) reported that the odor threshold of a 

group of volunteers was 0.3–0.4 ppm. In a study by Rupp and Henschler (1967), chlorine was slowly 

introduced to a test room so that the concentration increased from 0 to 1.3 ppm in a 50-minute period. 
 

 

 


 


 

CHLORINE 47 

3. HEALTH EFFECTS 

Table 3-2. Acute Effects of Chlorine Exposure on the Respiratory Tract of
 

Humans
 

Concentration (ppm) Effects 

0.2–3.5 Odor detection 

1–3 Mild mucous membrane irritation tolerated up to 1 hour 

5–15 Moderate irritation 

30 Immediate chest pain, dyspnea, cough 

40–60 Toxic pneumonitis and pulmonary edema 

430 Lethal over 30 minutes 

1,000 Lethal within minutes 

Source: Ellenhorn and Barceloux 1988 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 48 

3. HEALTH EFFECTS 

The odor of chlorine was first detected at 0.06 ppm and all the subjects (number not specified) could 

smell 0.2 ppm chlorine. In a summary of information on odor perception, NIOSH (1976) states that 

Stayzhkin reported a threshold of 0.2 ppm for chlorine in a group of 12 subjects who were asked to 

discern clean air from chlorine by inhaling from two tanks and that Beck found that subjects who were 

exposed to increasing concentrations of chlorine the length of time of perception was positively related to 

the exposure concentrations (i.e., the perception of higher concentrations lasted longer than that of low 

concentrations suggesting that tolerance to low chlorine concentrations may develop). In general, there 

seems to be consensus that the mean odor threshold lies between 0.2 and 0.4 ppm, which is between 

1/25 and 1/50 of the concentration considered to represent immediate danger to life and health of 10 ppm 

(NIOSH 2005). This means that individuals with a normal sense of smell should be able to take 

appropriate avoidance measures before serious health effects due to chlorine exposure can occur. 

War Exposures. A review of the effects of chlorine as a result of its use during World War I indicates 

that subjects exposed to very high concentrations (not specified, but presumably >100 ppm) experienced 

burning of the throat, cough, and feeling of suffocation, dyspnea, and usually death within 24 hours of 

acute pulmonary edema (DOA 1933). Those surviving 48 hours usually recovered, but bronchitis 

persisted for weeks and, in some cases, there was evidence of pulmonary emphysema. Data summarized 

by DOA (1933) on studies that evaluated residual effects indicate that bronchitis and asthma were 

common months to years after gassing. Dyspnea and chest pain after exercise were also frequent 

complaints. Citing a study of 838 U.S. soldiers who had been subjected to chlorine gassing, DOA (1933) 

states that 9 soldiers were discharged due to conditions attributable to gassing; these conditions included 

pulmonary tuberculosis, bronchitis, pleurisy, and dyspnea. An additional 39 cases were found to have 

been disabled at the time of discharge, and bronchitis and pleurisy were among the disabling conditions. 

The extent to which these residual effects were truly due to chlorine gassing is difficult to ascertain due to 

lack of information on pre-existing conditions, smoking status, and even factors such as the climatic 

conditions that existed at the time. 

Exposures of the General Population. There is considerable information on the effects of exposures of 

the general population to chlorine derived from various types of situations, including storage tank leaks, 

railroad accidents, mishandling of bleach cleaning solutions, accidents involving swimming pool 

chemicals, and accidents in high school chemistry laboratories. Representative examples are summarized 

below. 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 49 

3. HEALTH EFFECTS 

Chasis et al. (1947) provided a comprehensive description of immediate and delayed respiratory effects in 

a group of subjects exposed to chlorine that leaked from a defective cylinder that was carried in a truck in 

Brooklyn, New York. The accident involved several hundred people. Although the exposure 

concentration was not known, it was high enough to cause a visible cloud. Chasis et al. (1947) report on 

33 persons admitted to a local hospital. Immediate symptoms included rhinorrhea, cough, choking 

sensation, and substernal burning, pain, and constriction. Substernal pain, burning, and constriction, and 

choking sensation were present within 2 hours of exposure and, in most patients, subsided completely 

within 72 hours. Respiratory distress subsided within 3 days in 27 patients and within 6 days in 

5 patients. During the first week, almost all 33 patients complained of substernal soreness, which was 

interpreted as indicating the presence of tracheobronchitis. Physical examination on admission revealed 

acutely ill patients in moderate to marked respiratory distress, increased respiratory rate of costal 

abdominal type, and both dry and moist rales. Laboratory data showed sputum with large numbers of 

epithelial cells showing pronounced degenerative changes. Most cultures showed microorganisms 

representative of the normal pharyngeal flora. Chest x-rays showed mottling of the lungs and patches of 

irregular density and differences in the degree of aeration between the two pulmonary fields. Spirometry 

was conducted on 8 patients 48 hours after exposure and showed markedly reduced vital capacity (VC) 

and maximal breathing capacity (1 minute); these changes showed improvement in subsequent days. The 

diagnosis of pulmonary changes was: pulmonary edema, tracheobronchitis, and pneumonia. In 

29 patients who were followed for up to 16 months after exposure, there was no evidence of permanent 

pulmonary disease. 

Hasan et al. (1983) reported that exposure of 28 subjects to chlorine that leaked from a storage tank 

caused cough, dyspnea, and nasopharyngeal irritation. Pulmonary tests conducted 18 hours after 

exposure showed diminished forced expiratory volume in 1 second (FEV1), and low forced expiratory 

flow rate at 50 and 25% vital capacity (FEF50 and FEF25) and FEF25–75%. These abnormalities were still 

present 14 days after exposure in subjects whose chief initial complaint was dyspnea. Evaluation of nine 

subjects 5 months after chlorine exposure showed pulmonary parameters within normal limits. 

In contrast to the findings of the above two studies, some studies have reported long-term effects of acute 

high chlorine exposure. For example, Chester et al. (1977) reported the case of a woman who was 

exposed following a leak in a liquid storage tank and suffered severe cough and chest pain within minutes 

after exposure. Chest x-rays at the time showed bilateral infiltrates in the midpulmonary zones, but 1 year 

after the accident x-rays were normal. However, dyspnea and chronic cough with occasional production 

of white to yellow sputum persisted over the next 4 years. Schönhofer et al. (1996) studied three cases 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 50 

3. HEALTH EFFECTS 

that experienced nose and throat irritation, cough, shortness of breath, wheezing, chest tightness, and a 

feeling of suffocation minutes after exposure to chlorine gas that leaked from a tank. Chest x-rays 

showed no evidence of pulmonary edema. Four months after the accident, bronchoalveolar lavage 

showed inflammatory changes, but no such changes were seen 16 months later. However, moderate to 

severe bronchial hyperresponsiveness was observed up to 30 months after the accident. Schönhofer et al. 

(1996) noted that the condition showed the typical feature of the reactive airways dysfunction syndrome 

(RADS), defined as an asthma-like occupational illness after an acute exposure to concentrated 

respiratory irritants characterized by increased responsiveness to methacholine (Brooks et al. 1985). 

Weill et al. (1969) studied 12 subjects who were exposed to chlorine after the derailment of a tank car 

containing 30 tons of liquid chlorine near the town of Morganza, Louisiana. Chlorine concentrations of 

400 ppm were measured 75 yards from the wreck 7 hours after the accident. Immediate effects included 

shortness of breath, cough, and x-rays revealed pulmonary edema. Three and/or 7 years after the 

accident, all patients were free of respiratory symptoms and pulmonary tests, including total lung capacity 

(TLC), VC, residual volume (RV), FEV1, and single-breath diffusing capacity for carbon monoxide 

(DLCO) were within 2 standard deviations of the predicted value. Weill et al. (1969) concluded that acute 

exposure to chlorine does not result in significant permanent lung damage. A previous account of this 

accident was given by Joyner and Durel (1962). 

The Agency for Toxic Substances and Disease Registry (1998) conducted a health assessment of a 

population in Alberton, Montana after tanker cars derailed and released chlorine gas, solid sodium 

chlorate, and potassium cresylate. Readings at the site of the accident occasionally reached 1,000 ppm, 

but it was estimated that members of the community had been exposed to up 20 ppm chlorine. Analysis 

of soil and wipe samples determined that chemicals other than chlorine had not migrated offsite. A total 

of 682 persons were interviewed within 2 weeks of the accident. The most frequent conditions were 

cough, nose and throat irritation, and difficulty breathing. The report also indicates that children aged 0– 

5 years had the highest prevalence of respiratory infections, that persons who had previous respiratory 

problems (i.e., asthma, chronic bronchitis, hay fever) reported a higher prevalence of respiratory health 

problems, and that the reported frequencies of respiratory symptoms were higher among current and 

former smokers than in nonsmokers. 

Accidental domestic exposure to chlorine gas can occur when bleach (sodium hypochlorite) is mixed with 

other cleaning substances that contain an acid, for example, phosphoric acid cleaners (used to remove 

hard water deposits); the chemical reaction generates chlorine gas. Many such incidents have been 
 

 

 

 

 

 

 

 

 

 

CHLORINE 51 

3. HEALTH EFFECTS 

reported. For example, CDC (1991) reported five episodes in which subjects experienced nose irritation, 

sore throat, chest tightness, cough, and difficulty breathing; in most cases, respiratory symptoms subsided 

within a day. Gapany-Gapanavičius et al. (1982) reported two similar cases in which subjects inhaled 

chlorine after mixing bleach and hydrochloric acid and immediately experienced a burning sensation in 

the throat, cough, and shortness of breath. Chest x-rays taken hours after the accident showed air in the 

mediastinal space (space in the middle of the chest separating the two pleurae), probably the result of 

severe coughing, which resolved 7–10 days after the accident. None of these cases were followed to 

evaluate possible long-term effects. Additional information from similar exposure scenarios can be found 

in a review by Mrvos et al. (1993). 

Chlorine gas can be released around swimming pools when chlorinating agents are handled improperly or 

due to malfunction of the chlorination equipment, which underscores a strong need for training pool 

owners and operators in pool maintenance. Pertinent information can be found in CDC (2009). 

Sexton and Pronchik (1998) described the effects of such an exposure on 13 children who presented to the 

emergency department. On admission to the emergency department, most patients complained of throat 

irritation, chest pain, shortness of breath, wheezing, and chest tightness. Five patients who were admitted 

to the hospital had normal chest x-rays. At follow-up interviews 2 weeks later, the patients did not 

complain of residual respiratory symptoms. Ploysongsang et al. (1982) studied four patients who inhaled, 

for 2–5 minutes, an undetermined amount of chlorine gas that leaked from a container at a public 

swimming pool and experienced cough, a feeling of irritation of the upper respiratory tract, and tightness 

in the chest. Pulmonary function studies conducted 12–14 hours after the accident showed values within 

normal ranges. However, tests done 1 month later showed a significant increase in measurements of 

volumes, suggesting that there had been an acute reduction of lung volumes after the exposure. 

Ploysongsang et al. (1982) concluded that exposure to chlorine had produced an insignificant and 

inconsistent obstruction in large airways. Agabiti et al. (2001) reported the effects of accidental 

inhalation of chlorine gas among a total of 282 subjects attending a pool. Cough and shortness of breath 

were common acute symptoms after the accident and 27% reported some respiratory symptoms 15– 

30 days after exposure. Lung function measurements at that time revealed a tendency to lower levels 

among those with the highest perceived exposure, but only a decrease in FEV1 was significant. The study 

also found that among children (approximately half the sample), the incidences of all symptoms tended to 

be higher among those who had a history of chronic respiratory disease, among those who were engaged 

in physical exercise when the accident occurred, among those who were slow to evacuate the pool, and 

among those who reported higher exposure (as judged by eye irritation). Also, incidences were higher 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 52 

3. HEALTH EFFECTS 

among smokers and former smokers than among never smokers. A recent study of 18 children exposed to 

chlorine in a swimming pool accident found that a biomarker of pulmonary inflammation, leukotriene B4, 

was still significantly increased in exhaled breath condensate 2 months after exposure, long after 

pulmonary function parameters had returned to normal values (Bonetto et al. 2006). Immediately after 

exposure, the children had experienced dyspnea and burning of the throat and spirometry tests done 

within the first 24 hours showed reduced forced vital capacity (FVC) and FEV1. The authors also found 

that hours after exposure a Clara cell-specific protein, CC16, was significantly elevated in serum 

compared to non-exposed children, and suggested that this may be interpreted as a sign of injury to the 

lung epithelial permeability barrier. Transient increases in serum CC16 have been reported following 

exposure to certain pulmonary irritants (see Lakind et al. 2007 for review). Additional information 

regarding swimming pool accidents can be found in Almagro et al. (2008), Babu et al. (2008), Grasemann 

et al. (2007), and Thomas and Murray (2008). 

Controlled Low-level Exposure of Volunteers. Anglen (1981) exposed up to 29 male and female 

volunteers to 0, 0.5, 1, or 2 ppm chlorine for either 4 or 8 hours. Sensations were recorded before and 

during exposure and pulmonary function was monitored by measuring FVC and FEV1 before and at 

various times during exposure. Itching and burning of the throat were the highest responses and were 

most prevalent by the end of an 8-hour exposure to 1 ppm chlorine. Responses for sensations of itching 

or burning of the nose and eyes were also prevalent at 1 ppm chlorine. In general, males provided 

stronger irritation responses than females. Exposure to 1 or 2 ppm chlorine for 8 hours produced 

significant changes in pulmonary function but similar exposures to 0.5 ppm did not. Exposure to 2 ppm 

for up to 30 minutes produced no increase in subjective irritation and exposure to 2 ppm for 2 hours did 

not alter pulmonary function. In another study from the same group of investigators (it is unclear whether 

a follow-up to Anglen [1981] or a separate study), eight healthy male volunteers exposed to target 

concentrations of 0, 0.5, or 1 ppm chlorine (Rotman et al. 1983). Pulmonary tests were conducted before 

exposure, after a 4- and 8-hour exposure period and again 2 and 24 hours after exposure ceased. During 

exposure, the subjects exercised on a treadmill for 15 minutes of each hour to simulate light-to-moderate 

work that raised the heart rate to 100 beats per minute. Specific respiratory parameters measured 

included FVC, FEV1, forced expired volume in 1 second as percent FVC (FEV1%), peak expiratory flow 

rate (PEFR), FEF50 and FEF25, TLC, expiratory reserve volume (ERV), functional residual capacity 

(FRC), residual volume, airway resistance (Raw), single-breath DLCO, closing volume, and difference in 

nitrogen concentrations between 750 and 1,250 mL of inhaled vital capacity (ΔN2). Exposure to 1 ppm 

chlorine caused runny nose and mild burning in the throat, but no such effects were reported at 0.5 ppm. 

Significant changes in pulmonary function tests were mostly restricted to the 1 ppm exposure level and 
 

 

 

 

 

 

 

 

 

CHLORINE 53 

3. HEALTH EFFECTS 

were evident after 4 hours of exposure. Changes were observed in FEV1, PEFR, FEF50, FEF25, TLC, 

Raw, and ΔN2. Greater changes in some of these parameters were seen after 8 hours of exposure. Few 

changes were still evident 24 hours after exposure, but most parameters had returned to pre-exposure 

values by that time. It should be noted that one volunteer who was atopic experienced severe distress 

during exposure to 1 ppm and was forced to exit the chamber before the full 8-hour period due to 

shortness of breath and wheezing. 

D’Alessandro et al. (1996) evaluated pulmonary function in subjects with (n=10) and without (n=5) 

airway hyperresponsiveness (HR, defined by baseline methacholine hyperresponsiveness). The HR 

subjects were exposed to 0.4 or 1.0 ppm chlorine, whereas the healthy subjects were exposed to 1.0 ppm 

chlorine. All exposures lasted 60 minutes. Airflow and airway resistance were measured immediately 

before and immediately after exposure. Also, lung volumes, airflow, diffusing capacity, airway 

resistance, and responsiveness to methacholine were measured 24 hours before and 24 hours after 

exposure. Exposure of the HR group to 0.4 ppm chlorine resulted in no significant change in airflow or 

resistance either immediately or 24 hours after exposure. Exposure to 1.0 ppm chlorine resulted in an 

immediate decrease in FEV1 and FEF25–75% and increase in airway resistance among normal and HR 

subjects, but the magnitude of the effects among HR subjects was significantly greater than in healthy 

subjects. Twenty-four hours after exposure, there were no significant changes for healthy or HR subjects 

in airflow, lung volumes, diffusing capacity, resistance, or methacholine responsiveness. Comparing 

relative changes from baseline immediately after exposure between normal and HR subjects showed that 

HR subjects had much greater changes in pulmonary function tests. 

A similar study was conducted in eight volunteers exposed to chlorine 6 hours/day on 3 consecutive days 

to each of the four exposure conditions, 0, 0.1, 0.3, and 0.5 ppm chlorine (Schins et al. 2000). Pulmonary 

function including effort-dependent parameters and effort-independent parameters were evaluated before 

and after exposures. In addition, nasal lavage measurements were performed before and after each 

exposure and 1 and 4 days after each exposure. The nasal lavage fluid was examined for total cells, 

epithelial cells, neutrophils, lymphocytes, eosinophils, monocytes, albumin (an indicator of epithelial 

permeability), and interleukin-8 (indicator of inflammatory response). Subjective complaints by the 

subjects were judged to be not treatment-related, but objective physiological measures of nasal irritant 

response were not included. Examination of the nasal lavages gave no indication of an inflammatory 

response or irritant effects on the nasal epithelium. The results of the pulmonary function tests showed 

that the only significant effect related to chlorine exposure was a difference in maximal mid expiratory 
 

 

 

 

 

 

CHLORINE 54 

3. HEALTH EFFECTS 

flow (MMEF) between 0 and 0.5 ppm exposure; however, this was attributed to an unexplained shift in 

baseline values during control exposure (0 ppm). 

Shusterman et al. (2003b) measured nasal airway resistance in 52 healthy adults (24 males and 

28 females) before and after exposure to 0 or 1 ppm chlorine for 15 minutes. Subjects were stratified on 

age (18–34, 35–51, 52–69 years), gender, and allergic rhinitis status (27 were positive). Nasal airway 

resistance was measured by active posterior rhinomanometry. Exposures to air and chlorine were a week 

apart. Subjects with allergic rhinitis showed a significantly greater increase in nasal airway resistance 

(49% increase from baseline) than healthy subjects (10% increase from baseline) 15 minutes after 

exposure. The increase in nasal airway resistance was most pronounced in older subjects and least 

pronounced in the youngest group. No significant differences were seen between males and females. In 

an earlier study, the same group of investigators had reported that subjects with SAR exposed to 0.5 ppm 

chlorine for 15 minutes experienced a much greater increase in nasal airway resistance than subjects 

without SAR, as measured by active posterior rhinomanometry (Shusterman et al. 1998). However, when 

subjective responses to odor, nasal irritation, and nasal congestion were analyzed separately by rhinitis 

status, no significant exposure-related changes were observed for rhinorrhea, postnasal drip, or headache 

either on a pool or stratified basis. In addition, within either the SAR or non-SAR group, there was no 

relationship between subjective and objective congestion after chlorine exposure. Pulmonary peak flow 

tests showed that none of the subjects exhibited clinically significant changes in peak flow, nor did they 

complain of cough, wheezing, or chest tightness on chlorine exposure days. 

As a whole, these studies indicate that acute-duration exposures to 1 ppm chlorine can induce upper 

respiratory tract irritation and transient alterations in parameters of respiratory function and exposure 

concentrations of 0.5 ppm are generally devoid of such effects and, therefore, 0.5 ppm can be considered 

an acute (1–8 hours) NOAEL for sensory irritation and pulmonary function. The 0.5 ppm level caused no 

significant effects in an atopic subject (Rotman et al. 1983) or in subjects with airway hyperresponsiveness (D’Alessandro et al. 1996), and, while increased nasal airway resistance measured 

instrumentally in subjects with SAR, the latter did not clearly perceive the effect as an adverse effect 

(Shusterman et al. 1998). These studies also show that individuals with compromised respiratory 

function constitute a susceptible group for exposure to chlorine. The NOAEL of 0.5 ppm and LOAEL of 

1 ppm from these studies as a group, serve as the basis for derivation of an acute-duration inhalation MRL 

for chlorine. 
 

 

 

 

 

 

 

 

CHLORINE 55 

3. HEALTH EFFECTS 

Long-term, Low-level Occupational Exposures. Relatively few studies have examined the effects of 

long-term exposure to low levels of chlorine in humans, and the ones that have done so have not provided 

conclusive answers largely because of study limitations. 

Patil et al. (1970) studied the health effects of chlorine in 600 workers from 25 plants producing chlorine 

in North America. A group of 382 workers not considered to be routinely exposed to chlorine served as 

controls. The average duration of exposure was 11.9 years. Each worker received one physical 

examination that included evaluation of medical and occupational histories, blood and urine tests, 

pulmonary function tests and electrocardiogram (EKG). Tobacco and alcohol use were also monitored. 

The concentration of chlorine was monitored in each plant every 2 months over a period of 1 year in 

several representative areas, but otherwise unspecified. Exposure data were available for 332 workers 

and showed a time-weighted average (TWA) 8-hour mean of 0.15±0.29 ppm (range, 0.006–1.42 ppm). It 

also showed that almost all workers were exposed to <1 ppm chlorine, 94% were exposed to ≤0.5 ppm, 

and 70% were exposed to ≤0.2 ppm. Evaluation of the 332 workers who had exposure data showed that 

none of the end points examined (those subjected to recall or measured) showed a dose-response 

relationship. The mean concentration of 0.15 ppm may be considered a NOAEL for the study, but there 

are limitations such as unclear analytical methodology, no clear definition of the case/control populations, 

and insufficient detail regarding the method of analysis that render the NOAEL questionable; thus, it is 

not included in Table 3-1. 

Ferris et al. (1967) examined the prevalence of chronic respiratory disease among 147 workers in a pulp 

mill and 124 controls who worked in a paper mill and found no significant differences in respiratory 

symptoms or in tests for FVC and FEV1 (tests were conducted without a nose clip) between the two 

groups. Duration of exposure was not provided. Chlorine levels were measured on three different 

occasions in 3 years; in one occasion, the mean was 7.4 ppm and only traces were reported in the other 

two occasions. The limit of detection of the method was 1 ppm. Examination of the same cohort 

10 years later did not reveal any increased mortality or increased specific cause of death (Ferris et al. 

1979). Evaluation of 200 men seen at both times did not reveal any differences in respiratory symptoms 

or chronic nonspecific respiratory disease. 

Enarson et al. (1984) evaluated respiratory effects and pulmonary function in a group of 392 male pulp 

mill workers exposed to chlorine, sulfur dioxide, hydrogen sulfide, and methylmercaptan, in addition to 

various particulates (i.e., wood dust, ash, lime dust), for a mean duration of 101.5±86.6 months. A 

control, unexposed group, consisted of 310 male rail yard workers who lived in the same community and 
 

 

 

 

 

 

 

 

 

CHLORINE 56 

3. HEALTH EFFECTS 

who performed similar manual labor. End points examined included prevalence of respiratory symptoms 

(usual cough, usual phlegm, wheezing without a cold, dyspnea when hurrying, chest tightness, and chest 

illness). Pulmonary function tests conducted included FEC, FEV1, FEF25–75%, and FEV1/FVC ratio. 

Chlorine was the main contaminant in two areas of the pulp mill, the bleach plant and the machine room 

(mean 8-hour TWA 0.18 and 0.02 ppm, respectively). Overall, pulp mill workers complained more 

frequently of usual phlegm, wheeze without cold, and chest illness than rail workers. However, the most 

significant finding was that among bleach workers (n=15) and machine room workers (n=22), 

nonsmokers (n=4) had a significantly lower FEF25–75% and FEV1/FVC ratio than rail yard workers. Given 

the small number of workers involved, the possibility of exposure to multiple chemicals, and the lack of 

information on chlorine peak exposure levels, the validity of the 0.18 ppm as an effect level is 

questionable. 

A study at a chlorine plant in Sweden compared the changes in vital capacity (VC) and FEV1 that 

occurred between measurements separated by 10 years among 44 workers exposed to chlorine and 

33 white-collar workers matched for age and smoking status (Hyback 1999). The author stated that the 

concentration of chlorine was measured continuously over the years and was always below 0.5 ppm, as a 

set standard. The results of the tests showed that in fact, over the years, VC and FEV1 declined more in 

white-collar workers (significantly for FEV1) than in the workers exposed to chlorine. Hyback (1999) 

speculated that perhaps the low concentrations of chlorine gas may protect workers from contracting 

respiratory infections that over time contribute to a decline in respiratory function. 

The limited information available does not suggest that long-term exposure to low levels of chlorine gas 

affects respiratory function, but additional, better-conducted studies are necessary to confirm this view. 

High-level Occupational Exposure. Schwartz et al. (1990) studied a group of 20 workers who were 

briefly (minutes) exposed in a pulp mill to chlorine gas when liquid chlorine leaked from a tank and 

evaporated. Acute symptoms included burning of the nose and throat, and dry cough with chest tightness. 

Pulmonary tests were conducted within 24 hours of exposure and several times over the next 12 years. 

The most significant findings were a high prevalence of airflow obstruction (FEV1/VC ratio <65%) that 

persisted over the observation period and a prevalence of low residual volume (RV) that increased during 

the follow-up period. Schwartz et al. (1990) also found that 5 of 13 subjects tested at year 12 had 

increased airway reactivity to inhaled methacholine. While the findings were suggestive of long-term 

pulmonary complication, the investigators acknowledged that without pre-exposure pulmonary function 
 

 

 

 

 

 

 

 

 

 

CHLORINE 57 

3. HEALTH EFFECTS 

tests and individual measures of exposure, it is difficult to determine whether the changes were due to 

chlorine exposure. 

Moulick et al. (1992) evaluated 82 patients exposed to approximately 66 ppm chlorine that leaked from a 

storage tank at a chemical factory in Bombay, India. Acute symptoms of exposure included dyspnea, 

cough, and irritation of the throat. Pulmonary tests performed in 62 cases within 48 hours of exposure 

indicated obstruction in 17 cases, restriction in 2 cases, and a mixed pattern in 33 cases. Also, 

bronchoscopy showed tracheobronchial mucosal congestion and hemorrhagic spots. Four out of 

16 patients who were followed for 1 year showed persistent cough 4–6 weeks after exposure, but after 

1 year, there were no residual symptoms and x-rays and pulmonary function tests were normal. 

Evaluation of five nonsmoking patients 3 years after exposure did not reveal any residual symptoms and 

pulmonary function tests were normal (tests were not specified). 

Lemière et al. (1997) reported the case of a nonsmoking worker at a water-filtration plant man who was 

exposed to chlorine levels high enough to induce immediate burning of the nose and throat and 

retrosternal burning and wheezing. Five years earlier, he experienced similar symptoms after chlorine 

inhalation, but the symptoms had been transient. Two days after exposure, FEV1 was significantly 

reduced (66% of predicted) and the response to methacholine provocation was slightly abnormal. A 

bronchial biopsy showed almost complete replacement of the epithelium by a fibrinohemorrhagic 

exudate. Subsequent biopsies taken over a 5-month period showed considerable epithelial desquamation 

15 days after exposure followed by signs of regeneration 5 weeks after exposure and considerable 

improvement 5 months after exposure, although an inflammatory infiltrate was still present. The airway 

responsiveness to methacholine paralleled the inflammatory changes, but could be significantly improved 

by inhaled steroids. 

Kowitz et al. (1967) described the effects of chlorine exposure that occurred when a cylinder containing 

chlorine that was being unloaded from a freighter leaked. Neither exposure concentration nor exposure 

duration was available. At least 150 men were involved and almost all experienced acute symptoms. 

Eleven of 17 subjects who were admitted to a hospital were evaluated over a 3-year period. All showed 

respiratory distress on admission; other common signs included rales, wheeze, or rhonchi, or both, and 

pulmonary edema. Pulmonary function testing conducted over the 3-year evaluation period showed a 

persistent decrease in lung volume and diffusing capacity and increased airway resistance. According to 

Kowitz et al. (1967), these alterations were compatible with an alveolar-capillary injury. 
 

 

 

 

 

 

 

 

 

CHLORINE 58 

3. HEALTH EFFECTS 

There are also a number of studies that describe the effects of occasional occupational exposures to 

elevated concentrations of chlorine over a background of low level exposure (“gassing” incidents). Some 

examples are summarized below. 

In a study of 321 workers at a British Columbia pulp mill, 189 reported one or more gassing incidents, 

although no data were available to determine the severity of the exposure incidents (Kennedy et al. 1991). 

The average chlorine levels in the pulp mill were <1 ppm, but estimates of concentrations during the 

gassing incidents are not available. Pulp mill workers who reported having being gassed were 

significantly more likely to report wheezing on occasion than individuals who had not been gassed. 

While there were no significant differences in lung function tests between the overall pulp mill group and 

a control group, nonsmoking and formerly smoking pulp mill workers who reported being gassed had 

significantly lower MMEF and FEV1/FVC ratio than those who had not been gassed. Kennedy et al. 

(1991) hypothesized that the first accidental high exposure incident may cause an inflammatory reaction 

in the small airways that does not completely resolve because of continuous or repeated presence of the 

stimulus. A longitudinal analysis over a 7-year period (1981–1988) of 67 pulp mill workers that 

underwent pulmonary function tests both in 1981 and 1988 reported that there was a significantly greater 

decline in FEV1/FVC ratio and MMEF in the gassed group than in the unexposed group matched for age 

and smoking status (Salisbury et al. 1991). 

In a survey of 281 construction workers involved in renovation work at a pulp mill, 257 workers reported 

an average of 24 gassing episodes over a 3–6-month period (Courteau et al. 1994). Exposure data during 

the gassings were not available, but 36% of 483 air samples taken in the bleach plant after the episodes 

showed chlorine concentrations of <0.5 ppm, 58% were between 0.5 and 8 ppm, and 6% were >8 ppm. 

The most commonly reported symptoms were irritation of the throat (78%), cough (67%), and shortness 

of breath (54%); the latter was not associated with age, smoking state, or history of asthma or chronic 

bronchitis. Over 60% of the workers described a flu-like syndrome that lasted for an average of 11 days. 

Visits to the first aid department were associated with greater reporting of most symptoms including 

dyspnea and cough. Seventy-one workers identified as having moderate to high risk based on exposure 

data and onset of respiratory symptoms were evaluated 18–24 months later (Bhérer et al. 1994). At this 

time, a questionnaire completed by 64 workers (90%) suggested that 58 (91%) still had respiratory 

symptoms and 51 underwent spirometry and methacholine challenge tests. Bronchial obstruction (FEV1 

<80% predicted) was observed in 16 workers, whereas 29 showed significantly increased airway 

responsiveness. Based on the fact that workers who had been to an emergency room were more likely to 

be left with airway hyper-responsiveness, Bhérer et al. (1994) speculated that severity of one or more 
 

 

 

 

 

 

 

 

 

CHLORINE 59 

3. HEALTH EFFECTS 

gassing episodes may be a more significant determinant of the likelihood of developing permanent 

alterations than the number of episodes. 

In a study of 300 pulp and paper workers in New Hampshire, 105 reported ever having experienced an 

episode of high exposure to chlorine gases (Henneberger et al. 1996). Spirometry (FEV1, FVC, 

FEV1/FVC, MMEF) showed that the prevalence of obstructive pattern was >3 times greater for the gassed 

subjects compared with the others. For workers who had 26-pack years of cigarette smoking, an 

obstructive pattern (abnormally low FEV1 and FEV1/FVC) was observed only among those with a history 

of gassing. In addition, the combination of high cigarette smoking and gassing had a greater-thanadditive effect on obstruction. Monitoring data were not available in this report. 

Gautrin et al. (1999) evaluated 239 workers in a metal production plant who, 3 years earlier, had taken 

part in a cross-sectional study (Gautrin et al. 1995). In the first evaluation, the authors reported that FVC 

was higher in workers who had no symptoms after a gassing episode compared with those who had mild 

symptoms. Also, FEV1 and FVC were significantly lower in workers who experience >10 gassing 

incidents with mild symptoms than in workers who experienced no symptoms. In both cases, the 

differences were significant only in workers who had ever smoked. Increased airway responsiveness was 

also found in subjects who experienced >10 gassing incidents with mild symptoms. In 98% of the 

accidental exposures, chlorine was reported as the gas involved. Among 211 workers seen at follow-up 

(Gautrin et al. 1999), heavy smokers showed a decrease in FEV1/FVC% that was predicted by the number 

of gassing episodes causing mild symptoms between the two evaluations. Nineteen workers showed 

increased airway responsiveness which was associated with accidents reported to the first aid unit during 

the previous 2 years. The same group of investigators also reported that chronic rhinitis reported in the 

second assessment was significantly associated with acute exposure to chlorine and that chronic lower 

airway symptoms were more frequent in the second assessment among workers reporting chronic rhinitis 

on both assessments than in others (Leroyer et al. 1999). 

Effects in Animals. The studies in animals support the findings in humans, particularly the nature of the 

acute effects of exposure to high concentrations of chlorine gas. A great deal of information regarding the 

toxicity of chlorine in animals was generated during World War I and the years that followed triggered by 

the use of chlorine as a chemical weapon during the war. A summary of the earlier studies conducted in 

various European countries as well as in the United States and Russia can be found in Withers and Lees 

(1985b). Additional information on the early literature, particularly from extensive studies in dogs, can 

be found in DOA (1933). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 60 

3. HEALTH EFFECTS 

More recently, studies in rodents have confirmed the earlier observations regarding high exposures and 

have provided valuable information regarding the irritant properties of chlorine. 

Acute exposure to low-to-moderate concentrations of chlorine induces a reduction in the respiratory rate, 

a protective reflex response mediated by stimulation of trigeminal nerve endings in the nasal mucosa. 

The concentration of the chemical that induces a 50% decrease in respiratory rate is termed RD50. For 

example, RD50 values of 9.3 and 3.5 ppm were determined in mice exposed for 10 and 60 minutes, 

respectively (Barrow et al. 1977; Gagnaire et al. 1994). An RD50 of 25 ppm was determined in male 

F344 rats exposed to chlorine for 10 minutes (Barrow and Steinhagen 1982). This study also 

demonstrated the development of tolerance to chlorine since in rats pre-exposed to chlorine at 1, 5, or 

10 ppm intermittently for 32 weeks, the RD50 values were 90, 71, and 454 ppm, respectively, measured 

16–24 hours after the last day of pre-exposure. Barrow and Steinhagen (1982) speculated that the 

mechanism of tolerance may involve reactions of chlorine with sulfhydryl groups in the receptors or that 

chlorine exposure may damage the free nerve endings in the respiratory nasal mucosa. Rats pre-exposed 

to chlorine also developed cross-tolerance to formaldehyde (Chang and Barrow 1984). Interestingly, rats 

pre-exposed to 15 ppm formaldehyde did not develop tolerance to formaldehyde, but did develop crosstolerance to chlorine, which suggested the existence of different reactive sites for the two gases (Chang 

and Barrow 1984). 

A study by the same group of investigators examined the effects of chlorine on lung -SH content and on 

the enzymes that maintain non-protein -SH levels, glucose-6-phosphate dehydrogenase (G6PD) and 

glutathione reductase (GSSG-RED) in rats exposed to 0 or 12 ppm chlorine for up to 2 weeks and 

sacrificed at various times after cessation of exposure (Dodd et al. 1980). The results showed no 

significant alterations in lung protein -SH, non-protein -SH, G6PD, or GSSG-RED in rats sacrificed 

immediately after 1, 5, or 10 days of exposure. Rats sacrificed 3 or 6 days after exposure showed an 

increase in lung -SH, G6PD, and GSSG-RED. These parameters returned to control values after 10 days 

of recovery. The investigators concluded that the increase in lung -SH and enzymatic activities observed 

during the recovery periods may reflect reparative processes subsequent to damage induced by chlorine. 

A different study by the same group showed that exposures to up to 10 ppm chlorine for 12 hours did not 

alter the total sulfhydryl content (TSH) of the olfactory mucosa but lower concentrations did reduce TSH 

in the respiratory mucosa, suggesting that inhaled chlorine can oxidize tissue sulfhydryl groups at the 

point of entry, but not at deeper regions of the respiratory tract (McNulty et al. 1983). McNulty et al. 

(1983) also found that exposure to 5 ppm for 6 hours or 10 ppm for 3 hours (concentration times 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 61 

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exposure=30) produced similar reductions in TSH, but exposure to 2.5 ppm for up to 12 hours did not 

significantly affect TSH content. The investigators speculated that a threshold concentration may be 

needed to overwhelm the protective mechanism in the respiratory mucosa (perhaps the mucociliary flow) 

allowing chlorine to penetrate deeper into the underlying tissue. 

Acute studies also have examined respiratory function in animals. 

Barrow and Smith (1975) evaluated inspiratory-expiratory flow rate ratios (Vi/Ve) and volume-pressure 

relationships (lung compliance) in rabbits exposed to 0, 50, 100, and 200 ppm chlorine for 10 minutes. 

The tests were conducted 0.5 hours after exposure and after 3, 14, and 60 days without exposure. After 

the last test, the rabbits were killed and the lungs were removed for gross and microscopic examination. 

Rabbits exposed to 50 ppm showed mild pneumonitis, which was also observed in control animals; this 

exposure level did not induce significant changes in air flow ratios, but transiently decreased lung 

compliance. Exposure to 100 or 200 ppm induced transient concentration related increases in Vi/Ve and 

a decrease, followed by an increase, in pulmonary compliance; these changes are related to gross signs of 

pulmonary edema and microscopic changes characterized by chronic pneumonitis and anatomic 

emphysema. Rabbits allowed to recover for 14 or 60 days showed no “specific airway pathology.” 

In another study, mice exposed for 15 minutes to 0.8, 2, 3.1, or 3.8 ppm chlorine showed concentrationrelated decreases in respiratory frequency and increases in specific airway resistance (Morris et al. 2005). 

Pretreatment with atropine did not alter the increase in airway resistance, suggesting that this response 

does not involve parasympathetic cholinergic endings. However, pretreatment with capsaicin, a sensory 

nerve toxin, dramatically reduced respiratory irritation and the obstructive response, suggesting the 

involvement of sensory nerves. Mice exposed to much higher concentrations of chlorine (100–800 ppm) 

for 15 minutes showed increased airways resistance and increased responsiveness to methacholine and 

microscopic examination of the lungs showed flattening of the epithelium and epithelial cell loss and 

changes associated with oxidative stress (Martin et al. 2003). Since the increased responsiveness to 

methacholine could be prevented by inhibition of nitric oxide synthase, it appeared that nitric oxide (NO) 

production may have contributed to the airway response to inhaled chlorine. 

Jiang et al. (1983) studied the time course of the histopathological alterations in the respiratory tract of 

rats and mice exposed to the RD50 of 9.1 ppm chlorine 6 hours/day for 1–5 days. The animals were killed 

immediately after the last exposure and the nose, larynx, trachea, and lungs were processed for 

microscopic examination. In both species, lesions were seen in the nasal passages with less severe 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 62 

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changes in the nasopharynx, larynx, trachea, and lungs. The lesions in the nasal passages involved both 

the olfactory and respiratory epithelia; the nasal squamous epithelium showed minimal change. Lesions 

in the respiratory epithelium included acute epithelial degeneration with epithelial cell exfoliation, 

erosion, and ulceration after 1 and 3 days of exposure, infiltration by neutrophils after 3 and 5 days, and 

squamous metaplasia after 5 days. After 3 and 5 days of exposure, the epithelial lesions and 

inflammatory response found in the respiratory and olfactory mucosa became progressively more severe 

and extended more posteriorly. The most severe changes occurred in the olfactory mucosa of the anterior 

portion of the dorsal meatus, which showed extensive epithelial erosion and ulceration. Less severely 

affected areas showed necrosis and variable loss of sensory cells. Scanning electron microscopy showed 

loss of olfactory cilia and cellular exfoliation. The larynx and trachea showed acute degeneration of 

respiratory epithelial cells, whereas the lungs showed moderate to severe peribronchiolitis. Exposure of 

mice to the RD50 of 9.3 ppm for 5 days induced severe exfoliation, erosion, ulceration, and necrosis of the 

nasal respiratory epithelium (Buckley et al. 1984). It also induced minimal inflammation and squamous 

metaplasia. In the olfactory epithelium, chlorine induced severe ulcerations and necrosis and 

degeneration of sensory nerve endings. In the trachea, the lesions ranged from mild to moderate epithelial 

exfoliation, hyperplasia, and squamous metaplasia. In the lungs, chlorine induced a moderately severe 

terminal bronchiolitis with occlusion of affected bronchioles by serocellular exudate. Mice killed 

72 hours after the last exposure had reduced inflammation and exudate, but there was little difference in 

the extent of ulceration and degenerative lesions, suggesting that the 3-day period was insufficient for 

complete repair of the lesions. 

Exposure of rats to much higher concentrations of chlorine (50–1,500 ppm for 1–10 minutes) induced 

increasing lung damage that partially resolved within 24 hours of exposure (Demnati et al. 1995). In rats 

exposed to 1,330 ppm chlorine for 15 minutes, pulmonary changes observed 45 days after exposure 

included interstitial fibrosis and thickening of the alveolar septa due to thickening of the basement 

membrane (Yildirim et al. 2004). Exposure of rats to ≥184 ppm chlorine for 30 minutes induced 

hypoxemia, respiratory acidosis, and hypercapnia, and increased the surfactant surface tension and protein 

content of the bronchoalveolar lavage fluid, suggesting alveolar epithelial injury (Leustik et al. 2008). 

Less evidence of lung injury was seen in rats that were injected before exposure to chlorine with a 

mixture of ascorbate, deferoxamine, and N-acetyl-L-cysteine, suggesting that damage could be 

ameliorated by low-molecular antioxidants (Leustik et al. 2008). Exposure of mice to 221–289 ppm 

chlorine for 60 minutes caused severe lung inflammation as evidenced by widespread neutrophil influx 

into the lung parenchyma 6 hours after exposure followed by a clustering of neutrophils around damaged 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 63 

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airways 24 hours after exposure (Tian et al. 2008). Histologically, chlorine caused massive sloughing of 

the airway epithelium that was evident 6 hours after exposure. 

Two intermediate-duration studies in animals were located. 

Barrow et al. (1979) evaluated the respiratory response in F344 rats exposed to 0, 1, 3, or 9 ppm chlorine 

6 hours/day, 5 days/week for 6 weeks. Nasal discharge was seen occasionally in rats exposed to 1 ppm, 

but was common in rats exposed to 3 and 9 ppm. Respiratory difficulty was also apparent in some rats 

exposed to 9 ppm. At termination, gross necropsy revealed accumulation of inflammatory reactions in 

the upper nasal passages in rats exposed to 3 and 9 ppm chlorine. Microscopic evaluations showed 

indications of inflammatory reactions in the upper and lower respiratory tract of high-dose males and 

females. The nasal turbinates showed mucopurulent inflammation with secretory material and erosions of 

the mucosal epithelium. Changes in the trachea and bronchi consisted mostly of hyperplasia of the 

epithelial lining and inflammatory reactions. The alveolar sacs contained macrophages and secretory 

material and epithelial cells showed necrosis, hypertrophy and hyperplasia. Alterations in rats exposed to 

1 and 3 ppm were less extensive and were limited to focal mucopurulent inflammation of the nasal 

turbinates in females. Males exposed to 1 or 3 ppm showed deeper pulmonary changes consisting of 

slight to moderate inflammatory reaction around the respiratory bronchioles and alveolar ducts, increased 

alveolar macrophages, and isolated areas of atelectasis (incomplete expansion). A LOAEL of 1 ppm for 

respiratory effects can be defined in this study based on the presence of inflammatory changes in the nasal 

turbinates of females and in the lungs of males; no NOAEL was established. 

A similar study examined clinical signs, lung function, and histopathology of the nasal turbinates and 

lungs from F344 rats exposed to 0, 0.5, 1.5, or 5 ppm chlorine 6 hours/day, 5 days/week for 62 days 

(Kutzman 1983). Pulmonary function tests (plethysmograph-based assessment of multiple end points, 

including lung and tidal volumes, breathing frequency, transpulmonary pressure, lung compliance, N2 

washout, diffusing capacity for CO, maximum expiratory flow volume, peak expiratory flow, and airway 

resistance) were conducted in 21–24 anesthetized males 6 hours after the last exposure. Respiratory 

tissues from these rats were prepared for histopathology. The lungs from some of these rats were also 

examined for collagen, elastin, total protein, and DNA. Exposure to 5 ppm cause severe upper respiratory 

irritation; exposure to 1.5 ppm showed occasionally less severe signs of irritation, whereas exposure to 

0.5 ppm caused no obvious signs of irritation or discomfort. The tests of pulmonary function did not 

reveal marked abnormalities. The most significant effect was a reduction in airflow at 75% of exhaled 

vital capacity in all exposed groups, indicating some degree of small airway involvement. There were no 
 

 

 

 

 

 

 

 

 

 

CHLORINE 64 

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histopathological alterations in the lungs and nasal turbinates, but there was a tendency in the trachea for 

loss of cilia and epithelium at 0.5 and 5 ppm chlorine. The lung biochemistry only showed an increased 

collagen concentration at 1.5 and 5 ppm. Based on upper respiratory irritation and loss of cilia and 

epithelium in the trachea, the exposure level of 0.5 ppm can be defined as a LOAEL for respiratory 

effects; no NOAEL was defined in this study. This study was used as the basis for derivation of an 

intermediate-duration inhalation MRL for chlorine. 

Two studies have examined the effects of chronic exposure to chlorine on respiratory parameters in 

animals. 

Wolf et al. (1995) exposed groups of F344 rats and B6C3F1 mice (approximately 70/sex/exposure level) 

to 0, 0.4, 1, or 2.5 ppm chlorine gas for 2 years. Males from both species and female mice were exposed 

6 hours/day, 5 days/week, whereas female rats were exposed 6 hours/day, 3 days/week. The reduced 

exposure of female rats was based on unpublished data from the investigators that showed female rats to 

have a greater sensitivity to repeated long-term exposure to chlorine. End points evaluated included gross 

and microscopic examination of the respiratory tract; the nasal passages were examined microscopically 

at five different levels. Both in rats and mice, there were no gross lesions attributable to exposure to 

chlorine, and microscopic evaluation of the respiratory tract showed that chlorine-related effects were 

restricted to the nasal passages. In the study, the incidences were presented as percentages of all animals 

for which the nasal passages were adequate for microscopic examination, but the numbers of animals 

examined were not provided. No lesions were seen in the larynx, trachea, bronchi, or bronchioles. In 

general, rats and mice exhibited similar types of lesions. For the most part, the nasal lesions were sitespecific, but the severity and/or incidence were not always concentration-dependent. The majority of the 

nasal responses exhibited a rostral-to-caudal severity gradient. The lesions rarely extended to the 

nasopharyngeal meatus. Lesions observed included respiratory and olfactory epithelial degeneration, 

septal fenestration, mucosal inflammation, respiratory epithelial hyperplasia, squamous metaplasia, and 

goblet cell (rats only) hypertrophy and hyperplasia, and secretory metaplasia of the transitional epithelium 

of the lateral meatus. Also observed was intracellular accumulation of eosinophilic proteinaceous 

material involving the respiratory, transitional, and olfactory epithelia. Lesions were also observed in 

controls, but the incidences were significantly lower than in the treated groups. One of the lesions with 

the lowest incidence in controls was goblet cell hyperplasia in female rats (4%); the respective incidences 

in the 0.4, 1, and 2.5 ppm group were 71, 90, and 91%. In mice, olfactory epithelium atrophy exhibited 

one of the lowest incidences in controls (3%); the respective incidences in the 0.4, 1, and 2.5 ppm group 

were 20, 21, and 39%. In both cases, severity also was concentration-related. Based on the increased 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 65 

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incidence of various types of lesions in the nasal passages, the exposure level of 0.4 ppm constitutes a 

LOAEL for respiratory effects in rats and mice; a NOAEL was not defined. 

Klonne et al. (1987) exposed Rhesus monkeys to 0, 0.1, 0.5, or 2.3 ppm chlorine 6 hours/day, 

5 days/week for 1 year. Pulmonary diffusing capacity for CO and distribution of ventilation were 

evaluated monthly during the study. At termination, the nasal tissues (at the first palatine ridge and just 

posterior to the third, fifth, and seventh palatine ridges), trachea, and lungs were examined. There was no 

evidence of treatment-related effects on pulmonary function at any interval during the study. The only 

treatment-related histopathological effects consisted of focal epithelial hyperplasia characterized by 

increased cell numbers and loss of cilia and goblet cells in the respiratory epithelium of the nose and 

trachea. The affected areas of the nasal passages showed hypercellularity with loss of goblet cells and 

cilia. In some of these areas, the nuclei showed altered polarity. Lesions were more frequent on the 

angular margins of the turbinates and less frequent on the lateral wall or septum adjacent to these margins. 

In some cases, the respiratory epithelial hyperplasia was associated with mild suppurative inflammatory 

response. Lesions in the trachea resembled those in the nose, but were less severe and involved only a 

small circumferential section of the ventral and ventrolateral trachea. The combined incidences of lesions 

in the nasal mucosa, characterized as trace and mild in males and females, were 1/8, 3/8, 6/8, and 8/8 in 

the control, 0, 0.1, 0.5, and 2.3 ppm exposure groups, respectively. The lowest exposure concentration of 

0.1 ppm chlorine is a LOAEL for nasal lesions in monkeys. This study was used as the basis for 

derivation of a chronic-duration inhalation MRL for chlorine. 

Ibanes et al. (1996) re-examined the respiratory tissues from the chronic studies in monkeys, rats, and 

mice summarized above to better characterize the lesions and to improve human risk assessments based 

on these data sets. In general, the re-evaluation found a good correlation between the subjective scores of 

tissue responses in the original studies and quantitative analyses in the re-evaluation. The investigators 

also noted that the lesions in monkeys and rodents exhibited both differences and similarities. One 

notable difference was that monkeys showed less severe lesions, but extended more distally in the 

respiratory tract. The investigators concluded that respiratory tract airflow characteristics play a major 

role in lesion distributions in monkeys and rodents. Yet, with appropriate exposure and response 

adjustments, both rodents and Rhesus monkeys appear to be valid models for human risk assessment. 

Cardiovascular Effects. It is not uncommon to find reports of tachycardia and elevated blood 

pressure in individuals admitted to emergency rooms following accidental exposure to high 

concentrations of chlorine, but how much of this can be attributed to chlorine exposure or to a stressful 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 66 

3. HEALTH EFFECTS 

situation is not clear. Some cases in which EKGs were performed shortly after exposure found no 

significant alterations (Chasis et al. 1947; Güloğlu et al. 2002; Ramachandran et al. 1990). Tachypnea 

and hypertension were frequently observed in persons who were hospitalized following a train derailment 

that released chlorine gas in South Carolina in 2005 (Van Sickle et al. 2009). In most persons in whom 

the conditions were observed, tachypnea and tachycardia persisted across examination. No specific 

mention of cardiovascular effects was found in studies that evaluated possible long-lasting effects of 

chlorine exposure. 

Rats and mice that were exposed to lethal concentrations of chlorine had distended hearts (Weedon et al. 

1940), but little additional information is available regarding cardiovascular effects in animals following 

exposure to chlorine. It is reasonable to assume that some cardiovascular parameters would be affected 

after acute exposure to high concentrations of chlorine as a result of the severe ventilation-perfusion 

mismatching and hypoxia caused by pulmonary edema; however, no evaluations were made in the studies 

available. 

In an intermediate-duration study, rats exposed to 5 ppm chlorine for 62 days had no significant gross or 

microscopic alterations in the heart (Kutzman 1983). Intermittent exposure of monkeys to 2.3 ppm 

chlorine for 1 year (Klonne et al. 1987) or of rats and mice to 2.5 ppm chlorine for 2 years (Wolf et al. 

1995) did not cause any significant gross or microscopic alterations in the heart and aorta. 

Gastrointestinal Effects. Nausea and vomiting are common acute symptoms following exposure to 

high concentrations of chlorine and are believed to be reflex reactions and not a specific effect of 

chlorine. 

Barrow et al. (1979) reported that rats exposed to 9 ppm chlorine 6 hours/day, 5 days/week for 6 weeks 

had focal erosion of the gastric mucosa, which was usually accompanied by focal inflammation of the 

adjacent submucosal areas. No such effects were seen in rats exposed to 3 ppm chlorine. The 

investigators suggested that general stress or perhaps ingestion of hydrochloric acid and/or hypochlorous 

acid as a result of grooming or deposition in the oral cavity may have caused the condition. The results of 

Barrow et al. (1979) could not be confirmed or refuted in a study of very similar design by Kutzman 

(1983) because the latter did not examine the gastrointestinal tract. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 67 

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Intermittent exposure of monkeys to up to 2.3 ppm chlorine for 1 year or of rats and mice to up to 

2.5 ppm for 2 years did not produce gross or microscopic alterations in the gastrointestinal tract (Klonne 

et al. 1987; Wolf et al. 1995). 

Hematological Effects. Leukocytosis is a common finding in individuals acutely exposed to high 

concentrations of chlorine, and is most likely a clinical manifestation of acute inflammation and tissue 

destruction rather than a specific effect of chlorine. Hypoxemia is also characteristic of exposures high 

enough to cause pulmonary edema and consequently, interference in gas exchange. 

Experiments in dogs conducted by Underhill (1920) following World War I showed that following 

gassing with high concentrations of chlorine, there was a relative increase in red blood cells and 

hemoglobin that reached a peak approximately 5 hours after exposure and was due to a decrease in 

intravascular fluid content. He also observed that in dogs exposed to relatively low concentrations of 

chlorine, there was slight leukocytosis, which was caused solely by an increase in polymorphonuclear 

cells. An intermediate-duration study in rats reported that exposure to 9 ppm chlorine for 6 weeks 

induced a significant increase in hematocrit (females) and segmented neutrophils (males and females) 

(Barrow et al. 1979). No significant changes in hematological parameters were observed in monkeys, 

rats, or mice exposed to 2.3–2.5 ppm chlorine in chronic duration studies (Klonne et al. 1987; Wolf et al. 

1995). 

Musculoskeletal Effects. The only information regarding musculoskeletal effects and exposure to 

chlorine is a report in which a 25-year-old man was diagnosed with myasthenia gravis manifested as 

laryngeal stridor after accidental exposure to chlorine gas (Foulks 1981). Myasthenia gravis is an 

autoimmune disorder that causes a reduction in the number and/or sensitivity of acetylcholine receptors at 

the neuromuscular junction resulting in muscle weakness. Foulks (1981) speculated that the massive 

exposure of the laryngeal muscles to chlorine may have altered the neuromuscular junction in a way that 

caused an autoimmune stimulus that resulted in myasthenia gravis. 

Exposure of monkeys to up to 2.3 ppm chlorine for 1 year or of rats and mice to up to 2.5 ppm for 2 years 

did not produce gross or microscopic alterations in skeletal muscle (Klonne et al. 1987; Wolf et al. 1995). 

Hepatic Effects. Very limited information was located regarding evaluation of liver end points in 

patients after acute high exposure to chlorine. Leube and Kreiter (1971) reported that 1 day after exposure 

to chlorine, 26 out of 65 patients (40%) had elevated serum ALT and 2 out of 13 (15%) had elevated 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 68 

3. HEALTH EFFECTS 

serum aspartate aminotransferase (AST) values. Without any information on other factors that impact the 

levels of these enzymes in serum, such as alcohol consumption, it is difficult to ascertain the toxicological 

significance of this finding. Moulick et al. (1992) mention that measurements of serum AST activity in 

patients admitted to the hospital following exposure to chlorine did not show any significant abnormality. 

The exposure concentration was not known, but 2 hours after the massive leak, the level of chlorine was 

found to be 66 ppm. Hasan et al. (1983) reported that subjects exposed to chlorine gas following a leak 

from a liquid storage tank had normal liver function tests; the tests were not specified. 

Liver congestion has been observed in rodents exposed to acute lethal concentrations of chlorine (i.e., 

Weedon et al. 1940), but generally, other low-concentration, acute-duration studies did not examine the 

liver, or if they did, the findings were not reported. In an intermediate-duration study, rats exposed to 

≥3 ppm chlorine, but not 1 ppm, 6 hours/day, 5 days/week for 6 weeks had cytoplasmic vacuolation in the 

hepatocytes (Barrow et al. 1979). This was accompanied by a significant increase in serum alkaline 

phosphatase at 3 and 9 ppm in males and females and an increase in serum alanine aminotransferase 

(ALT) in females exposed to 9 ppm. In contrast, in a study of very similar design, rats exposed to up to 

5 ppm chlorine 6 hours/day, 5 days/week for 62 days showed no significant histological alterations in the 

liver (Kutzman 1983). The reason for this apparent discrepancy is not apparent. 

Intermittent exposure of monkeys to up to 2.3 ppm chlorine for 1 year or of rats and mice to up to 

2.5 ppm for 2 years did not produce gross or microscopic alterations in the liver (Klonne et al. 1987; Wolf 

et al. 1995). 

Renal Effects. No reports were located of renal effects in humans following inhalation exposure to 

chlorine. However, it would have not been unexpected to find some abnormal indices of renal function in 

individuals acutely exposed to high levels of chlorine as a consequence of severe cardiopulmonary 

alterations. 

Slight to moderate congestion of the kidneys was reported in male and female rats exposed intermittently 

to 9 ppm chlorine for 6 weeks, but no significant alterations were seen in rats exposed to 3 ppm (Barrow 

et al. 1979). Kutzman (1983) examined the kidneys of rats exposed to up to 5 ppm chlorine for 62 days 

and reported no significant gross or microscopic alterations. Intermittent exposure of monkeys to up to 

2.3 ppm chlorine for 1 year or of rats and mice to up to 2.5 ppm for 2 years did not produce gross or 

microscopic alterations in the kidney (Klonne et al. 1987; Wolf et al. 1995). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 69 

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Endocrine Effects. No information was located regarding endocrine effects in humans following 

inhalation exposure to chlorine. No gross or microscopic alterations were reported in the adrenals, 

pancreas, parathyroid, pituitary, or thyroid gland from monkeys exposed to up to 2.3 ppm chlorine for 

1 year (Klonne et al. 1987). Similarly, no gross or histological alterations were found in the pancreas, 

parathyroid, pituitary, or thyroid from rats and mice exposed to up to 2.5 ppm chlorine for 2 years (Wolf 

et al. 1995). No further information on endocrine effects in animals exposed to chlorine was located in 

the literature. 

Dermal Effects. Considering that chlorine is an irritating gas, very few reports have described skin 

effects in subjects exposed to high concentrations of the gas. A health assessment of a population that 

may have been exposed to up to 200 ppm chlorine after tanker cars derailed reported that skin rashes and 

skin burns affected 16–25% of a total of 682 persons interviewed 2 weeks after the accident (Agency for 

Toxic Substances and Disease Registry 1998). In another train derailment, some exposed subjects had 

minor first-degree skin burns resulting from the vapor exposure (Joyner and Durel 1962). A health 

evaluation report of firefighters that responded to a chlorine gas leak in Henderson, Nevada, mentions that 

many of the firefighters complained of skin irritation (NIOSH 1995). During the incident, chlorine 

concentrations in the air ranged from <0.2 to 17 ppm. 

Studies in animals have not described skin alterations following exposure to chlorine gas, even in high 

exposure acute-duration studies in which animals experienced whole-body exposures. In monkeys 

exposed to up 2.3 ppm chlorine for 1 year, histological examination of samples of skin did not reveal any 

significant exposure-related alterations (Klonne et al. 1987). The same negative observations were made 

in rats and mice exposed to up to 2.5 ppm chlorine for 2 years (Wolf et al. 1995). 

Ocular Effects. Almost all reports of acute exposure to high concentrations of chlorine mention eye 

irritation (lacrimation, conjunctivitis, burning sensation) as one of the most prevalent complains among 

the patients. These effects usually resolve within a few days after exposure. In a controlled exposure 

study with volunteers, complaints of itching or burning of the eyes were significantly greater during 

exposures to 1 ppm chlorine than during control exposures (Anglen 1981). 

Swelling around the eyes was reported in rats exposed to 12 ppm chlorine 6 hours/day, 5 days/week for 

10 days, but not for 5 days (Dodd et al. 1980). Ocular irritation was also reported in rats exposed 

intermittently to 3 ppm chlorine for 6 weeks, but no irritation was apparent at 1 ppm (Barrow et al. 1979). 

This is more or less consistent with the results of another intermediate-duration study that reported 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 70 

3. HEALTH EFFECTS 

occasional signs of eye irritation in rats exposed to 1.5 ppm for 62 days and severe irritation in rats 

exposed to 5 ppm chlorine (Kutzman 1983). Monkeys exposed intermittently to 2.3 ppm for 1 year 

showed conjunctival irritation with some exudation at the end of the study, but there was no gross or 

microscopic evidence of chronic changes in the conjunctiva or in the cornea (Klonne et al. 1987). No 

ocular effects were observed in rats or mice exposed to up to 2.5 ppm chlorine for 2 years (Wolf et al. 

1995). 

Body Weight Effects. No relevant information was located regarding body weight effects in humans 

following inhalation exposure to chlorine. Reduced body weight gain or weight loss has been commonly 

reported in acute high-exposure studies in animals of enough duration to allow evaluation of weight 

changes. Although rarely reported, the reduced growth or weight loss is largely due to reduced food 

consumption. For example, rats exposed to 12 ppm chlorine 5 days/week for 2 weeks lost approximately 

20% of their body weight during the second week relative to their starting weight (Dodd et al. 1980). 

Pair-fed rats also lost weight, confirming that the effect in the chlorine-exposed rats was due to reduced 

food intake. In another acute-duration study, rats exposed to 9.1 ppm chlorine for 3 or 5 days lost 11 and 

13%, respectively, of the initial body weight (Jiang et al. 1983). Under the same exposure conditions, 

mice lost 17 and 21% of the initial body weight (Jiang et al. 1983). 

Similar results have been obtained in intermediate-duration studies. Final body weight of rats exposed to 

9 ppm chlorine for 6 weeks (Barrow et al. 1979) or to 5 ppm for 62 days (Kutzman 1983) were >30% 

lower than controls. Even a relatively low concentration of chlorine of 0.5 ppm for 62 days lowered body 

weight in female rats by approximately 11% relative to controls (Kutzman 1983). Neither study provided 

information on food or water consumption. Exposure of monkeys to 2.3 ppm chlorine for 1 year (Klonne 

et al. 1987) or of rats and mice to 2.5 ppm for 2 years (Wolf et al. 1995) reduced body weight gain during 

the studies, but the final weights, judging by figures in the papers, appeared to be <10% lower than the 

respective controls. 

3.2.1.3 Immunological and Lymphoreticular Effects 

No studies were located that evaluated immunocompetence or effects on lymphoreticular organs in 

humans following exposure to chlorine gas. 

Minimal information is available from studies in animals. Barrow et al. (1979) reported that the spleen 

and thymus from rats exposed to 9 ppm chlorine for 6 weeks had a decreased content of lymphoid 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 71 

3. HEALTH EFFECTS 

elements, but no such changes were seen in rats exposed to 1 or 3 ppm. According to the investigators, 

this may have been a function of the poor physical condition and decreased nutritional state of the rats in 

that dosing group. In a very similar study, no histological alterations were reported in the spleen and 

peribronchial lymph nodes from rats exposed to up to 5 ppm chlorine for 62 days (Kutzman 1983). 

Studies in monkeys, rats, and mice also have found no gross or microscopic lesions in lymphoreticular 

organs and tissues following intermittent chronic exposure to 2.3–2.5 ppm chlorine (Klonne et al. 1987; 

Wolf et al. 1995). 

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

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

3.2.1.4 Neurological Effects 

Symptoms effects such as headache, dizziness, anxiety, and syncope are commonly reported following 

acute high exposures to chlorine and are thought to be due, at least in part, to asphyxia induced by 

chlorine. 

In a case of high exposure to chlorine that resulted in the death of the patient, postmortem examination 

showed a swollen brain with flattening of convolutions and subarachnoid hemorrhage (Adelson and 

Kaufman 1971). The investigators speculated that the lesions could have been caused by hypoxia that 

resulted from the severe pulmonary effects. In another case report, a 60-year-old man who accidentally 

inhaled chlorine gas in a swimming pool accident had a magnetic resonance scan of the head conducted 

2 years after the accident that showed multiple areas of decreased signal in the periventricular white 

matter (Levy et al. 1986). Other neurological tests showed no evidence of cranial nerve abnormalities or 

sensory deficits. This brief communication does not mention what might have prompted the subject to 

undergo the scan. 

Kilburn (1995, 2000, 2003b) published a series of reports describing long-lasting neurological effects in 

subjects accidentally exposed to high concentrations of chlorine gas under various scenarios. The earliest 

study (Kilburn 1995) reported that six subjects exposed to an undetermined concentration of chlorine for 

3 minutes to 5 hours had difficulty concentrating and sleeping, dizziness, loss of balance, excessive 

fatigue, loss of strength, depression, and irritability during a period of 1–3 years after the accident. 

Neurobehavioral tests were conducted 15–50 months after exposure and the results were compared to a 

control group matched for sex, age, and education. It should be noted that the testers were aware of the 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 72 

3. HEALTH EFFECTS 

exposure status of the subjects. The results showed impaired balance with the eyes closed and hearing 

loss in all of the exposed subjects. Five had decreased vibration sensitivity, color discrimination, and 

verbal recall; four had prolonged blink reflex latency; three had prolonged simple and choice reaction 

times, and three had nerve defects or constricted visual fields. In a subsequent study, 22 patients exposed 

briefly (the reports mentions seconds to a few minutes in one section and minutes to a few hours in 

another section) to chlorine gas were evaluated with a battery of tests 7–48 months after exposure. A 

total of 296 unexposed subjects served as controls. The results showed significant impairment among the 

exposed group in a number of areas including balance, reaction time, color identification, visual field 

performance, blink latency, cognition, verbal recall, and making trails. A similar study was conducted 

with subjects exposed to chlorine as a result of a train derailment (see Agency for Toxic Substances and 

Disease Registry [1998] under Respiratory Effects) (Kilburn 2003b). Ninety-seven subjects were tested 

7 weeks after exposure and 57 were tested 3 years later; 26 were tested on both occasions. Seven weeks 

after exposure, the exposed subjects showed impairment in five neurobehavioral functions compared with 

unexposed subjects recruited for the 3-year testing. At 3 years, the patients showed impairment in seven 

additional tests compared with controls. Because of lack of exposure data, these studies are not listed in 

Table 3-1. 

There are no studies in animals that could confirm or refute Kilburn’s findings mentioned above. The 

only information regarding neurological effects of chlorine in animals is limited to reports of no gross or 

microscopic alterations in the brain of rats exposed intermittently to up to 5 ppm chlorine for 62 days 

(Kutzman 1983), or in the brain, spinal cord, and sciatic nerve of rats and mice exposed to up to 2.5 ppm 

chlorine for 2 years (Wolf et al. 1995). Also, in monkeys exposed intermittently for 1 year to up to 

2.3 ppm chlorine, there were no gross or histological alterations in central or peripheral nervous system 

tissues (Klonne et al. 1987). The investigators also mentioned that clinical observational neurological 

examinations conducted in the monkeys prior to sacrifice were unremarkable, but the scope of these tests 

was not specified. 

The highest NOAEL values from each reliable study for neurological effects in each species and duration 

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

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 73 

3. HEALTH EFFECTS 

3.2.1.5 Reproductive Effects 

The only information available regarding effect in humans is that evaluation of the outcome of 

15 pregnancies among female workers at a chlorine plant in 1932–1933 did not provide any evidence of 

reproductive toxicity (Skljanskaya et al. 1935). 

In an intermediate-duration inhalation study, male and female rats were exposed intermittently to up to 

5 ppm chlorine for 62 days (Kutzman 1983). At the end of the exposure period, 8 exposed males were 

mated with unexposed females and 10 exposed females were mated with unexposed males and all females 

were sacrificed on gestation day 19 for evaluation of reproductive end points. The results showed no 

significant effects of chlorine exposure on fertility, number of corpora lutea, viable embryos, early or late 

deaths, or pre-implantation loses. In addition, in males exposed for 62 days, there were no histological 

alterations in the testes, and sperm morphology was unremarkable. 

In chronic-duration studies, exposure of male and females monkeys for 1 year or male and female rats and 

male mice for 2 years to up to 2.5 ppm chlorine did not result in gross or microscopic alterations of the 

reproductive organs (Klonne et al. 1987; Wolf et al. 1995). Female mice developed a concentrationrelated increase in ovarian abscesses and of suppurative inflammation of the uterus. Without a further 

discussion, the investigators stated that it was unlikely that chlorine induced the inflammatory response, 

but no alternative explanation was provided. 

The highest NOAEL values from each reliable study for reproductive effects in each species and duration 

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

3.2.1.6 Developmental Effects 

In a summary of the limited information available, WHO (1982) reports that early studies from the 

Russian literature found no evidence of teratogenic in offspring from effects female workers at a chlorine 

plant in 1932–1933 and that rabbits exposed to low chlorine concentrations (0.6–1.6 ppm) during 

pregnancy gave birth to healthy offspring. No additional information was located regarding 

developmental effects in animals following inhalation exposure to chlorine. 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 74 

3. HEALTH EFFECTS 

3.2.1.7 Cancer 

There are several studies of cancer in humans that involve exposure to chlorine, among other chemicals, 

in occupational settings. 

A study of 28 employees at a Texas chemical plant who had died of primary intracranial neoplasms found 

no evidence that exposure to chlorine may have played a role (Bond et al. 1983). Chlorine was one of the 

chemicals to which cases and controls had the most frequent potential for exposure. Bond et al. (1985) 

conducted a case-control study of 26 renal cancer deaths among employees of a multiple process 

chemical production facility. Although an increased odds ratio (OR) for renal cancer was found in a 

chlorine production area, it was not attributed to chlorine exposure, but to asbestos and caustic materials. 

In addition, in the magnesium processing area, where large amounts of chlorine were used, there was a 

decreased risk of renal cancer. A nested case-control study of 306 lung cancer deaths among 

19,608 employees of a chemical plant provided no evidence that chlorine had a role in the deaths (Bond et 

al. 1986). The OR for chlorine exposure was 1.08 (95% confidence interval [CI], 0.81–1.44). 

A study of 51 lung cancer cases at a dye and resin manufacturing plant reported an increased OR for lung 

cancer for employees who were seen at the plant infirmary for acute exposure to chlorine after adjusting 

for smoking (OR=27; 95% CI, 3.5–205) (Barbone et al. 1992). However, the number of cases was small 

(6 cases versus 3 out of 102 controls), and four of the six cases worked in the anthraquinone dye and 

epichlorohydrin production area. Barbone et al. (1992) stated that based on small number of cases, the 

small association between lung cancer and acute exposure to chlorine may be due to chance or to 

confounding by other unidentified exposures. 

In a larger study of 2,391 male workers producing magnesium metal, Heldaas et al. (1989) found 4 cases 

of lung cancer versus 1.3 expected in a subset of workers who experienced chlorine intoxication and had 

at least 20 years since first employment (95% CI, 0.8–7.8). However, the rate ratios for lung cancer were 

higher in those workers who were not registered in the chlorine exposure list. The authors speculated that 

the use of respiratory protective gear (mouthpieces) may have been a reason for the difference. 

In a study of 1,190 workers at chlor alkali plants, there was a marginally significant excess of lung 

cancers (10 observed versus 4.9 expected; 95% CI, 1.0–3.8) which, according to the authors, was possibly 

due to previous use of asbestos (Barregård et al. 1990). Jäppinen et al. (1987) conducted a retrospective 

cohort study of 3,545 workers in the Finnish pulp and paper industry and found 78 cases of lung cancer 
 

 

 

 

 

 

 

 

 

 

CHLORINE 75 

3. HEALTH EFFECTS 

versus 62.6 expected (95% CI, 98–155). The excess was most prominent in board mill workers 

(40 observed versus 18.1 expected; 95% CI, 158–302), particularly after 20 years of latency (25 observed 

versus 7.8 expected; 95% CI, 209–476). However, there is no mention in the study of the chemicals to 

which the various subcohorts (based on work histories) may have been more intensely exposed. 

Only the study by Wolf et al. (1995) provided information on carcinogenicity of inhaled chlorine in 

animals. In that study, male and female rats and mice were exposed intermittently to up to 2.5 ppm 

chlorine for 2 years. Gross and histological examination of all major tissues and organs, including the 

nasal cavity at five levels did not show any biologically or statistically significant increase in neoplasms. 

The EPA, the International Agency for Research on Cancer (IARC), and the Department of Health and 

Human Services (DHHS) have not classified chlorine gas as to its carcinogenicity. 

3.2.2 Oral Exposure 

Studies that used tap water as the medium for delivery of chlorine to experimental animals are not 

included in this section to eliminate potential confounding effects of chlorination byproducts. 

Although people are not likely to be exposed to chlorine itself through oral routes, there are reports of 

accidental or intentional exposure to bleach (typically a 3–6% solution of sodium hypochlorite). 

Information from some of those reports is also included in this section. 

3.2.2.1 Death 

Human deaths have been reported following ingestion of sodium hypochlorite. In a review of the 

literature, Racioppi et al. (1994) state that the lethal dose of sodium hypochlorite in adults has been 

reported to be approximately 200 mL of a solution containing 3–6% chlorine. Racioppi et al. (1994) also 

indicate that the aspiration of bleach in the lungs following ingestion as been reported as the cause of 

fatalities. Ross and Spiller (1999) described a fatal case of a 66-year-old woman who ingested an 

unknown quantity of bleach and died of cardiac arrest 4.5 hours after the bleach ingestion. Autopsy 

revealed esophageal and gastric mucosal erosions, perforations at the gastroesophageal junction, and 

extensive necrosis of adjacent soft tissue. Jakobsson et al. (1991) reported the case of a fatal poisoning in 

a 1-year-old girl after ingestion of a household cleanser containing 4.5% sodium hypochlorite in an 

alkaline solution. Examination of the upper gastrointestinal tract showed severe gross and microscopic 

damage. According to unpublished information reviewed by Racioppi et al. (1994), the oral LD50 for a 
 

 

 

 

 

 

 

 

CHLORINE 76 

3. HEALTH EFFECTS 

5.25% solution of sodium hypochlorite household bleach in rats is 13,000 mg/kg; for a 13% solution, 

LD50 values of 5,000 and 8,200 mg/kg are listed. A review of the literature by BG-Chemie (1991) 

indicates that LD50 values of 6,800 and 5,800 mg/kg were determined for male and female ddY rats, 

respectively. 

3.2.2.2 Systemic Effects 

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

species and duration category are recorded in Table 3-3 and plotted in Figure 3-2. 

Respiratory Effects. Respiratory rate was not altered in a group of 10 volunteers who drank 

0.5 L/day of drinking water containing 5 mg/L chlorine for 12 weeks (Lubbers et al. 1982). This 

corresponds approximately to doses of 0.036 mg Cl/kg/day, assuming a body weight of 70 kg. 

Evaluations of the respiratory rate were done weekly during the dosing period and continued for an 

additional 8 weeks post-dosing. Since the study did not control for non-experimental ingestion of 

chlorine by the volunteers, the total daily dose of chlorine consumed is likely to have been higher than 

0.036 mg Cl/kg/day. In a review of the literature, Racioppi et al. (1994) mention the case of a woman 

who developed aspiration pneumonitis after ingesting an unknown amount of hypochlorite bleach. 

Bracco et al. (2005) described a similar case. In this case, chest x-rays performed 2 hours after 

intoxication showed bilateral bibasal infiltrate suggestive of aspiration pneumonia. Over the next 

24 hours, the patient’s respiratory condition declined and she required ventilatory support. The patient 

eventually recovered after 26 days of mechanical ventilation. In the fatal case of bleach ingestion 

described by Jakobsson et al. (1991), microscopic examination of the lungs showed aspiration of 

epithelium derived from the upper respiratory tract, and signs of acute bronchitis. 

Limited data on respiratory effects are available in animals. Ninety-day drinking water studies in 

Sprague-Dawley rats (Daniel et al. 1990) and B6C3F1 mice (Daniel et al. 1991) dosed with up to 24.9 and 

39.2 mg Cl/kg/day, respectively, reported no gross or microscopic alterations in the lungs, trachea, and 

nasal turbinates. Furukawa et al. (1980) also reported no significant histological alterations in the lungs 

and bronchial tube of F344 rats dosed with up to 85 mg Cl/kg/day for 92 days. Similar results were 

reported in chronic-duration studies in F344 rats (Hasegawa et al. 1986; NTP 1992) and B6C3F1 mice 

(NTP 1992). Rats received doses of up to 133 mg Cl/kg/day and mice received doses up to 24.2 mg 

Cl/kg/day for 2 years. 
88

20

79

200200200200

80

200

85

0.40.4

73

12

Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - Oral 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Systemic 

1 Rat 

(SpragueDawley) 

once (G) 

System 

Hepatic 

NOAEL 

(mg/kg/day) 

LOAEL 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

20 M (increased 

triacylglycerols in whole liver homogenate) 

Reference Chemical Form 

Chang et al. 1981 

2 Rat 

(Wistar) 

14 d (GW) Cardio 200 F Cunningham 1980 

Hepatic 200 F Renal 200 F 

Neurological 

3 Rat 

(Wistar) 

14 d (GW) 

INTERMEDIATE EXPOSURE Systemic 

4 Human 4 wk 

(W) 

Bd Wt Hepatic 

200 F 200 F 

0.4 

Cunningham 1980 Wones et al. 1993 

Endocr 0.4 

5 Rat 

(SpragueDawley) 

12 mo (W) Hemato 12 M Abdel-Rahman et al. 19
82

3.43.43.4

78

15.7

65

24.924.924.924.924.924.924.924.924.924.9

Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - 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 

6 Rat 66-76 d Carlton et al. 1986 

Hemato 3.4 (Long- Evans) (GW) 

Endocr 3.4Bd Wt 3.4

7 Rat 6 wk Bd Wt 15.7 M Cunningham 1980 (Wistar) (W)

8 Rat 90 d Resp 24.9 F Daniel et al. 1990 

(Sprague- (W) Dawley) 

Cardio 24.9 FGastro 24.9 FHemato 24.9 FMusc/skel 24.9 FHepatic 24.9 FRenal 24.9 FEndocr 24.9 FDermal 24.9 FBd Wt 24.9 F
74

4.1

99

8552

84

85858585858526

50 85

86

76

152 305

Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - Oral (continued) 

Exposure/ LOAEL

Duration/

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

9 Rat 8 wk Bd Wt 4.1 M Exon et al. 1987 (Sprague- (W)

Dawley)

10 Rat 92 d Resp 85 M Furukawa et al. 1980 

(Fischer- 344) (W) 

hypochlorous acid and shypochlorite 

Cardio 52 F 84 F (endocardial hyperplasia;

myocardial fibrosis)

Gastro 85 M Hemato 85 M Hepatic 85 M Renal 85 M Endocr 85 M Dermal 85 M Bd Wt 26 M 50 M (19% reduction in final 85 M (46% reduction in final 

body weight) body weight) 

11 Rat 13 wk 

Bd Wt 76 152 M (final body weight 305 M (final body weight Hasegawa et al. 1986 (Fischer- 344) (W) 

reduced 19%) reduced 47%) 
69

39.239.239.239.239.239.239.239.239.239.2

77

26

66

24.9

Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - 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 

12 Mouse 90 d Daniel et al. 1991 

Resp 39.2 F (B6C3F1) (W) 

Cardio 39.2 FGastro 39.2 FHemato 39.2 FMusc/skel 39.2 FHepatic 39.2 FRenal 39.2 FEndocr 39.2 FDermal 39.2 FBd Wt 39.2 F

13 Gn Pig 5 wk Bd Wt 26 M Cunningham 1980 (albino) (W)

Immuno/ Lymphoret 

14 Rat 90 d Daniel et al. 1990 

24.9 F (Sprague- (W) 

Dawley) 
75

4.1

100

85

70

39.2

67

24.9

101

85

Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - 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 

15 Rat 8 wk 4.1 M Exon et al. 1987 

(Sprague- (W) Dawley) 

16 Rat 92 d 85 F Furukawa et al. 1980 (Fischer- 344) (W) hypochlorous acid and s

hypochlorite 

17 Mouse 90 d 39.2 F Daniel et al. 1991 (B6C3F1) (W) 

Neurological 

18 Rat 90 d 24.9 F Daniel et al. 1990 (Sprague- (W) 

Dawley) 

19 Rat 92 d 85 F Furukawa et al. 1980 (Fischer- 344) (W) hypochlorous acid and s

hypochlorite 
71

39.2

81

3.4

68

24.9

102

85

72

39.2

83

3.4

Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - 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 

20 Mouse 90 d 39.2 F Daniel et al. 1991 

(B6C3F1) (W) 

Reproductive 

21 Rat 66-76 d Carlton et al. 1986 

3.4 (Long- Evans) (GW) 

22 Rat 90 d Daniel et al. 1990 

24.9 F (Sprague- (W) 

Dawley) 

23 Rat 92 d Furukawa et al. 1980 

85 F (Fischer- 344) (W) 

hypochlorous acid and shypochlorite 

24 Mouse 90 d Daniel et al. 1991 

39.2 F (B6C3F1) (W) 

Developmental 

25 Rat 42 d Carlton et al. 1986 

3.4 (Long- Evans) (GW) 
58

133133133133133133133133133

67

Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - 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 

CHRONIC EXPOSURE Systemic 

26 Rat 2 yr Resp 133 F Hasegawa et al. 1986 

(Fischer- 344) (W) 

Cardio 133 F Gastro 133 F Hemato 133 F Hepatic 133 F Renal 133 F Endocr 133 F Dermal 133 F Ocular 133 F Bd Wt 67 F (11% reduction in final

body weight)
48

14.414.414.414.414.414.414.414.414.414.4

27 

Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - 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 

Rat 2 yr 

Resp 14.4 F NTP 1992 (Fischer- 344) (W) 

Cardio 14.4 FGastro 14.4 FHemato 14.4 FHepatic 14.4 FRenal 14.4 FEndocr 14.4 FDermal 14.4 FBd Wt 14.4 FOther 14.4 F
49

24.224.224.224.224.224.224.224.224.224.2

59

133

50

14.4

Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - Oral (continued) 

Exposure/ LOAEL

Duration/

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

28 Mouse 2 yr 

Resp 24.2 F NTP 1992 (B6C3F1) (W) 

Cardio 24.2 FGastro 24.2 FHemato 24.2 FHepatic 24.2 FRenal 24.2 FEndocr 24.2 FDermal 24.2 FBd Wt 24.2 FOther 24.2 F

Immuno/ Lymphoret 

29 Rat 2 yr Hasegawa et al. 1986 

133 F (Fischer- 344) (W) 

30 Rat 2 yr NTP 1992 

14.4 F

(Fischer- 344) (W) 
53

24.2

60

133

51

14.4

54

24.2

61

133

52

14.4

Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - Oral (continued) 

Exposure/ LOAEL

Duration/

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

31 Mouse 2 yr NTP 1992 

24.2 F

(B6C3F1) (W) 

Neurological 

32 Rat 2 yr Hasegawa et al. 1986 

133 F (Fischer- 344) (W) 

33 Rat 2 yr NTP 1992 

14.4 F

(Fischer- 344) (W) 

34 Mouse 2 yr NTP 1992 

24.2 F

(B6C3F1) (W) 

Reproductive 

35 Rat 2 yr 133 F Hasegawa et al. 1986 

(Fischer- 344) (W) 

36 Rat 2 yr 14.4 F NTP 1992 

(Fischer- 344) (W) 
55

24.2

37 

Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - 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 

Mouse 2 yr NTP 1992 

24.2 F

(B6C3F1) (W) 

a The number corresponds to entries in Figure 3-2. Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = Female; Gastro = gastrointestinal; Gn pig = guinea pig; (GW) = gavage in waterhematological; Immuno/Lymphoret = immunological/lymphoreticular; LOAEL = lowest-observed-adverse-effect level; M = male; mo = month(s); Musc/skel = muscu= no-observed-adverse-effect level; Resp = respiratory; (W) = drinking water; wk = week(s); yr = year(s) 
Figure 3-2 Levels of Significant Exposure to Hypochlorite Solution - Oral 

Acute (≤14 days) 

Systemic 

mg/kg/day Cardiovascular 

Hepatic 

Renal 

Body Weight 

Neurological 

1000 

2r 2r 2r 2r 3r 

100 

1r 

10 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

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

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

CHLORINE

3. HEALTH EFFECTS

88
Figure 3-2 Levels of Significant Exposure to Hypochlorite Solution - Oral (Continued)
 

Intermediate (15-364 days)
	

Systemic
	

mg/kg/day Respiratory 

Cardiovascular 

Gastrointestinal 

Hematological 

Musculoskeletal 

Hepatic 

Renal 

Endocrine 

Dermal 

Body Weight 

Immuno/Lymphor 

Neurological 

Reproductive 

Developmental 

1000 

11r 

11r 

100 

10r 10r 10r 10r 10r 10r 10r 10r 10r 16r 19r 23r 11r 

10r 10r 

12m 12m 12m 12m 12m 12m 12m 12m 12m 12m 17m 20m 24m 

8r 8r 8r 8r 8r 8r 8r 8r 8r 13g 8r 10r 14r 18r 22r 

7r 

5r 

10 

9r 15r 

6r 6r 6r 21r 25r 

1 

4 4 

0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

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

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

CHLORINE

3. HEALTH EFFECTS

89
Figure 3-2 Levels of Significant Exposure to Hypochlorite Solution - Oral (Continued)

Chronic (≥365 days) 

Systemic
	

mg/kg/day Respiratory 

Cardiovascular 

Gastrointestinal 

Hematological 

Hepatic 

Renal 

Endocrine 

Dermal 

Ocular 

Body Weight 

Other 

Immuno/Lymphor 

Neurological 

Reproductive 

1000 

26r 26r 26r 26r 26r 26r 26r 26r 26r 29r 32r 35r 

100 

26r 

28m 28m 28m 28m 28m 28m 28m 28m 28m 28m 31m 34m 37m 

27r 27r 27r 27r 27r 27r 27r 27r 27r 27r 30r 33r 36r 

10 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

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

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

CHLORINE

3. HEALTH EFFECTS

90
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 91 

3. HEALTH EFFECTS 

Cardiovascular Effects. In the study by Lubbers et al. (1982) in volunteers mentioned above, 

drinking water that provided 0.036 mg Cl/kg/day for 12 weeks did not alter systolic or diastolic blood 

pressure or pulse rate, and electrocardiograms were unremarkable. No additional relevant information 

was located regarding cardiovascular effects in humans following oral exposure to hypochlorite solutions. 

A 14-day study in which Wistar rats were dosed by gavage with sodium hypochlorite in milk (up to 

200 mg Cl/kg/day) reported no significant alterations in heart weight, but no additional cardiovascular 

parameters were examined (Cunningham 1980). Two intermediate-duration studies reported no 

significant gross or microscopic alterations in the heart and aorta from rats and mice exposed to up to 

24.9 and 39.2 mg Cl/kg/day, respectively, for 90 days (Daniel et al. 1990, 1991). Furukawa et al. (1980) 

reported that endocardial hyperplasia and fibrosis of the myocardium were observed in male and female 

F344 rats dosed with approximately 84 mg Cl/kg/day in the drinking water for 92 days. No such effects 

were seen in rats dosed with approximately 50 mg Cl/kg/day. Two-year studies also did not find 

histological alterations in the heart from rats and mice that received doses of up to 133 and 24.2 mg 

Cl/kg/day, respectively (Hasegawa et al. 1986; NTP 1992). 

Gastrointestinal Effects. In general, ingestion of small amounts (less than a cup) of sodium 

hypochlorite bleach (approximately 5.3% sodium hypochlorite) does not cause serious or permanent 

damage to the upper gastrointestinal tract. Pike et al. (1963) reviewed 129 cases of children who ingested 

Clorox® and reported that no complications of consequences were found. Sixty-five cases were examined 

by esophagoscopy within 96 hours of the ingestion and only 2 showed evidence of esophageal injury. 

The children were between 12 month and 7 years old and the amounts of bleach ingested ranged from 

“1⁄2 ounce to 1 cup.” Landau and Saunders (1964) state that among 393 children who ingested bleach and 

were seen at a hospital, there were no esophageal strictures or perforations, and about 50% of the patients 

received no treatment. Hook and Lowry (1974) reported that among 23 definite cases of children who 

ingested Clorox®, severe irritation of the esophageal mucosa was observed in only 1 case. Minor 

transient irritation was observed in some of the patients. A report from the German literature of 

23 children who accidentally ingested 3–5% sodium hypochlorite indicates that there was only 1 case 

with signs of superficial burns in the esophagus, which had disappeared 2 weeks later when controlled by 

esophagoscopy (Mühlendahl et al. 1978). Liquid bleach is a strong emetic, which helps reduce the time 

of residence in the stomach, but on the other hand, it increases the potential for aspiration. 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 92 

3. HEALTH EFFECTS 

Examination of fatal cases following ingestion of unknown quantities has revealed esophageal and gastric 

mucosal erosions, perforations at the gastroesophageal junction, and extensive necrosis of adjacent soft 

tissue (Ross and Spiller 1999). In a fatal case of a child who drank 4.5% sodium hypochlorite in an 

alkaline solution (pH 12), severe gross lesions were seen in the mouth, tongue, glottis, epiglottis, 

esophagus, and stomach (Jakobsson et al. 1991). Glottic and subglottic edema was described by Babl et 

al. (1998) in a child who drank household bleach from a cup. 

In some earlier studies in animals, commercial bleach was administered through a tube directly into the 

esophagus and, in some cases, the distal end of the esophagus was artificially occluded to prolong and 

control the contact time between the solution and the mucosa (Hook and Lowry 1974; Landau and 

Saunders 1964; Strange et al. 1951; Yarington 1970). For example, commercial bleach placed in the 

esophagus of 151 dogs for several minutes caused the immediate death of 8 dogs from perforations into 

their pleural cavities (Landau and Saunders 1964). Necropsy performed 3 months later on the seven dogs 

that survived revealed no abnormalities. Yarington (1970) reported that, in dogs, the minimum amount of 

bleach that caused a burn in the esophagus was 10 cm3 applied over a 5-minute period. A volume of 

30 cm3 applied for 2 minutes caused minimal edema of the esophagus. 

Few more recent studies are available. Gross and microscopic examination of multiple levels of the 

gastrointestinal tract of Sprague-Dawley rats that drank water that provided up to 24.9 mg Cl/kg/day for 

90 days did not reveal any significant gross or microscopic alterations (Daniel et al. 1990). The same 

negative results were reported in F344 rats and B6C3F1 mice that drank water with up to 85 mg Cl/kg/day 

or 39.2 mg Cl/kg/day, respectively, for 90 days (Daniel et al. 1991; Furukawa et al. 1980). Two-year 

studies also did not find histological alterations in the gastrointestinal tract from F344 rats and B6C3F1 

mice that received doses of up to 133 and 24.2 mg Cl/kg/day, respectively (Hasegawa et al. 1986; NTP 

1992). 

Hematological Effects. No significant treatment-related alterations in a comprehensive number of 

hematological parameters were reported in volunteers who drank 0.5 L/day of drinking water containing 

5 mg/L chlorine (approximately 0.036 mg Cl/kg/day) for 12 weeks (Lubbers et al. 1982). 

A 12-month study in Sprague-Dawley rats exposed to approximately 12 mg Cl/kg/day reported alterations 

in red blood cell fragility at various times during the study; however, the alterations were sporadic and not 

dose- or duration-related, and varied in direction suggesting that they may have not been caused by 

exposure to chlorine (Abdel-Rahman et al. 1984). Red blood cell count and hematocrit were reduced 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 93 

3. HEALTH EFFECTS 

significantly after 3 months of treatment with 12 mg Cl/kg/day, but not at lower doses of chlorine 

(0.12 and 1.2 mg Cl/kg/day). Evaluations conducted after 6 months of treatment showed no significant 

difference in hematology parameters between treated and control groups (Abdel-Rahman et al. 1984). In 

another intermediate-duration study, exposure of male and female Long-Evans rats to up to 3.4 mg 

Cl/kg/day did not induce significant alterations in blood cell counts (Carlton et al. 1986). In yet 

additional studies, standard hematology parameters were not significantly altered in rats or mice dosed 

with up to 85 and 39.2 mg Cl/kg/day, respectively, for 90 days (Daniel et al. 1990, 1991; Furukawa et al. 

1980). Hematology parameters were also evaluated in F344 rats and B6C3F1 mice after 14–15 and 

66 months of treatment with chlorine in the 2-year drinking water bioassay (NTP 1992) and at termination 

in the Hasegawa et al. (1986) study in F344 rats. The results showed no significant treatment-related 

alterations in rats dosed with ≤133 mg Cl/kg/day or in mice dosed with ≤24.2 mg Cl/kg/day. 

Musculoskeletal Effects. No information was located regarding musculoskeletal effect in humans 

following oral exposure to hypochlorite and limited information is available in animals. No significant 

gross or microscopic alterations were seen in skeletal muscle and sternebrae from Sprague-Dawley rats 

following exposure to up to 24.9 mg Cl/kg/day in the drinking water for 90 days (Daniel et al. 1990). 

Similar results were reported in B6C3F1 mice exposed to up to 39.2 mg Cl/kg/day for 90 days (Daniel et 

al. 1991). The 2-year NTP (1992) study reported no significant alterations in the femur from F344 rats or 

B6C3F1 mice that received up to 14.4 or 24.2 mg Cl/kg/day, respectively, in the drinking water. 

Hepatic Effects. Serum chemistry tests used to evaluate liver function did not reveal any significant 

alteration in volunteers during 12 weeks of exposure to approximately 0.036 mg Cl/kg/day in the drinking 

water and during a period of 8 weeks after exposure ceased (Lubbers et al. 1982). In another study of 

controlled exposure in volunteers, exposure to approximately 0.4 mg Cl/kg/day in the drinking water for 

4 weeks had no significant effect on the lipid profile in serum (Wones et al. 1993). 

Very limited information is available regarding liver effects in acute-duration oral studies in animals. 

Liver weight was not significantly altered in Wistar rats after 14 days of daily gavage doses of sodium 

hypochlorite in milk (up to 200 mg Cl/kg/day) (Cunningham 1980); no other liver parameter was 

monitored in this study. In another study of limited scope, triacylglycerols were significantly increased in 

whole liver homogenates from rats 2 days after a single gavage dose of approximately 20 mg Cl/kg 

(Chang et al. 1981). Ten days after dosing, the levels of triacylglycerols had returned to pre-dosing 

levels. 
 

 

 

 

 

 

 

 

 

 

CHLORINE 94 

3. HEALTH EFFECTS 

No significant gross or microscopic alterations were seen in the liver of Sprague-Dawley rats, F344 rats, 

or B6C3F1 mice exposed to up to 24.9, 85, and 39.2 mg Cl/kg/day, respectively, in the drinking water for 

90 days (Daniel et al. 1990, 1991; Furukawa et al. 1980). Levels of serum liver enzymes also were not 

significantly affected by treatment. Similarly, no significant hepatic effects were reported in F344 rats or 

B6C3F1 mice that received up to 133 or 24.2 mg Cl/kg/day, respectively, in the drinking water for 2 years 

(Hasegawa et al. 1986; NTP 1992). Clinical chemistry tests conducted at termination in rats in the 

Hasegawa et al. (1986) study did not provide any indication of liver toxicity. 

Renal Effects. The only relevant information regarding renal effects in humans following oral 

exposure to hypochlorite is that urinalysis performed weekly on volunteers during a 12-week controlled 

intake of approximately 0.036 mg Cl/kg/day and during a subsequent period of 8 weeks after treatment 

was unremarkable (Lubbers et al. 1982). 

The only information available in acute-duration oral studies in animals is that kidney weight was not 

altered in rats in a 14-day study in which received daily doses of up to 200 Cl/kg/day by gavage in milk 

(Cunningham 1980). No other renal parameter was evaluated. No significant gross or microscopic 

alterations were seen in the kidney of Sprague-Dawley rats, F344 rats, or B6C3F1 mice exposed to up to 

24.9, 85, and 39.2 mg Cl/kg/day, respectively, in the drinking water for 90 days (Daniel et al. 1990, 1991; 

Furukawa et al. 1980). However, Furukawa reported increased incidence of gross abnormalities (no 

further details provided) in the bladder of rats in all treated groups (8–85 mg Cl/kg/day) in the 90-day 

study. No significant kidney effects were reported in F344 rats or B6C3F1 mice that received up to 133 or 

24.2 mg Cl/kg/day, respectively, in the drinking water for 2 years (Hasegawa et al. 1986; NTP 1992). 

Endocrine Effects. A study in male and female volunteers who consumed daily for 4 weeks 1.5 L of 

distilled water that provided a dose of approximately 0.4 mg Cl/kg/day reported that there was a slight 

reduction in serum levels of thyroxine (T4) and triiodothyronine (T3) in men, which was not accompanied 

by any meaningful change in thyroid-stimulating hormone (TSH) levels (Wones et al. 1993). In another 

study in volunteers, ingestion of approximately 0.036 mg Cl/kg/day in the drinking water for 12 weeks 

did not significantly alter serum levels T3 or T4 (Lubbers et al. 1982). 

No information was located regarding endocrine effects in acute-duration studies in animals. In an 

intermediate-duration reproductive study in male and female Long-Evans rats, dosing with up to 

3.4 mg Cl/kg/day by gavage (hypochlorous acid) had no significant effect on serum thyroid hormone 

(unspecified) levels in males or females (Carlton et al. 1986). In the 90-day drinking water studies in 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 95 

3. HEALTH EFFECTS 

Sprague-Dawley and F344 rats and B6C3F1 mice administered up to 24.9, 85, and 39.2 mg Cl/kg/day, 

respectively, there were no gross or microscopic alterations in the pancreas, adrenals, pituitary, thyroid, 

and parathyroid glands (Daniel et al. 1990, 1991; Furukawa et al. 1980). Similar results were obtained in 

the 2-year drinking water bioassay in F344 rats and B6C3F1 mice (NTP 1992). Rats were exposed to up 

to 14.4 mg Cl/kg/day and mice were exposed to up to 24.2 mg Cl/kg/day. Hasegawa et al. (1986) also 

reported no alterations in the adrenal glands from F344 rats exposed to up 133 mg Cl/kg/day in the 

drinking water for 2 years. 

Dermal Effects. No information was located regarding dermal effects in humans following oral 

exposure to hypochlorite solutions. The skin of rats and mice was examined in the 90-day (Daniel et al. 

1990, 1991; Furukawa et al. 1980) and 2-year drinking water studies (Hasegawa et al. 1986; NTP 1992) 

and no significant gross or microscopic alterations related to treatment with chlorine were reported. In 

the 90-day studies, high doses in rats and mice were approximately 85 and 39.2 mg Cl/kg/day, 

respectively. In the 2-year studies, high doses in rats and mice were 133 and 24.2 mg Cl/kg/day. 

Ocular Effects. No studies were located regarding ocular effects in humans following oral exposure 

to hypochlorite solutions. The only information from studies in animals is that exposure of F344 rats to 

up to 133 mg Cl/kg/day for 2 years did not increase the incidence of cataracts (Hasegawa et al. 1986). 

The eyes were not examined in rats or mice in the 90-day studies (Daniel et al. 1990, 1991) or in the NTP 

(1992) 2-year study. 

Body Weight Effects. No studies were located regarding body weight effects in humans following 

oral exposure to hypochlorite solutions. Reduced growth was not observed in Wistar rats that received 

200 mg Cl/kg/day (from sodium hypochlorite) by gavage in milk for 14 days (Cunningham 1980). Body 

weight was also not affected in Sprague-Dawley rats and B6C3F1 mice exposed to up to 24.9 and 39.2 mg 

Cl/kg/day, respectively, in the drinking water for 90 days (Daniel et al. 1990, 1991) or in F344 rats and 

B6C3F1 mice exposed to up to 14.4 and 24.2 mg Cl/kg/day, respectively, in the drinking water for 2 years 

(NTP 1992). Hasegawa et al. (1986) reported that male Fisher-24 rats exposed to approximately 152 or 

305 mg Cl/kg/day (from sodium hypochlorite) in the drinking water for 90 days had reductions of 19 and 

47% in final body weight compared with control rats; however, neither food nor water consumption data 

were provided in the study. In another 90-day study, male F344 dosed with approximately 50 mg 

Cl/kg/day (as sodium hypochlorite) in water had a final body weight 19% lower than controls; this group 

of rats also consumed 42% less water daily than controls (Furukawa et al. 1980). Rats dosed with 84 mg 

Cl/kg/day consumed 66% less water than controls and their final body weight was 46% lower than 
 

 

 

 

 

 

 

 

CHLORINE 96 

3. HEALTH EFFECTS 

controls (Furukawa et al. 1980). In the 2-year study conducted by the same investigators, final body 

weights were reduced 11 and 20% in female rats dosed with 67 and 133 mg Cl/kg/day, respectively. The 

investigators stated that in high-dose females water intake was somewhat lower (no quantitative data 

provided) during the first year, but not in the second year. 

Metabolic Effects. Hypernatremia and hyperchloremic acidosis were reported in a woman who 

intentionally drank about 500 mL of a strong bleach solution (10% sodium hypochlorite) (Ward and 

Routledge 1988). Treatment with 5% dextrose gradually improved her electrolytes and 5 days later, she 

had recovered. Hyperchloremic metabolic acidosis also was reported in a woman who intentionally 

ingested an unknown amount of bleach (5.25% sodium hypochlorite, pH 11.4) and eventually died of 

cardiac arrest 4.5 hours after ingestion of the bleach solution (Ross and Spiller 1999). No other relevant 

information was located regarding metabolic effects in humans or animals following oral exposure to 

hypochlorite solutions. 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects in humans following oral exposure to 

hypochlorite solutions. Limited information is available in animals. In an 8-week study in SpragueDawley rats, exposure to 4.1 mg Cl/kg/day (the highest dose tested) in the drinking water (as sodium 

hypochlorite) resulted in alterations in several immunological parameters including reduced delayed-type 

hypersensitivity (DTH) reaction, increased prostaglandin E2 synthesis by macrophages, and reduced 

oxidative metabolism by macrophages following stimulation with phorbol myristate acetate (Exon et al. 

1987). In the absence of systemic toxicity in rats dosed with much higher dose of chlorine in longer-term 

studies, the toxicological significance of these changes is unknown. In 90-day (Daniel et al. 1990, 1991; 

Furukawa et al. 1980) and 2-year (Hasegawa et al. 1986; NTP 1992) studies in rats and mice dosed with 

chlorine in the drinking water, there were no significant gross or microscopic alterations in the spleen, 

thymus, and lymph nodes. In the 90-day studies Sprague-Dawley and F344 rats and B6C3F1 mice were 

exposed to up to 24.9, 85, and 39.2 mg Cl/kg/day, respectively. In the 2-year studies, high-doses in 

F344 and rats and B6C3F1 mice were 133 and 24.2 mg Cl/kg/day, respectively. In none of these longterm studies was immunocompetence evaluated. 

The highest NOAEL values from each reliable study for immunological and lymphoreticular effects in 

each species and duration category are recorded in Table 3-3 and plotted in Figure 3-2. 
 

 

 

 

 

 

 

 

 

 

CHLORINE 97 

3. HEALTH EFFECTS 

3.2.2.4 Neurological Effects 

No studies were located regarding neurological effects in humans following exposure to hypochlorite 

solutions. One acute-duration study reported that exposure of Wistar rats to up to 200 mg Cl/kg/day (as 

sodium hypochlorite) by gavage in milk had no significant effect on brain weight, but no other 

neurological end point was evaluated in this study (Cunningham 1980). No gross or microscopic 

alterations were reported in the brain and sciatic nerve of Sprague-Dawley or F344 rats and B6C3F1 mice 

in 90-days drinking water studies (Daniel et al. 1990, 1991; Furukawa et al. 1980). In these studies, rats 

and mice received doses of up to 85 and 39.2 mg Cl/kg/day, respectively. In the NTP (1992) 2-year 

drinking water study in F344 rats and B6C3F1 mice, gross and microscopic examination of several brain 

areas did not show any significant alteration that could be attributed to treatment with chlorine. 

Hasegawa et al. (1986) also reported no histological alterations in the brain of F344 rats dosed with up to 

133 mg Cl/kg/day (as sodium hypochlorite) in the drinking water for 2 years. None of these studies 

reported any adverse neurological sign in the animals throughout the studies, but no neurological tests 

were performed. 

The highest NOAEL values from each reliable study for neurological effects in each species and duration 

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

3.2.2.5 Reproductive Effects 

No information was located regarding reproductive effects in humans following oral exposure to 

hypochlorite solutions. In an acute-duration drinking water study, exposure of male B6C3F1 mice to 

≥1.6 mg Cl/kg/day (as sodium hypochlorite) for 5 days resulted in significant increases in sperm 

abnormalities in mice sacrificed 3 weeks after dosing ceased, but not in mice sacrificed 1 or 5 weeks after 

dosing (Meier et al. 1985). In addition, no sperm abnormalities were seen in mice that were treated in the 

same manner with hypochlorous acid. According to the investigators, the results were somewhat 

surprising since sodium hypochlorite should be converted in to hypochlorous acid in acid pH of the 

stomach. In the absence of corroborating information from other studies and lack of internal consistency 

of the results, the toxicological significance of these results is difficult to ascertain; therefore, this study is 

not listed in Table 3-3. 

In an intermediate-duration study, exposure of male and female Long-Evans rats to up to 3.4 mg 

Cl/kg/day (as hypochlorous acid) by gavage before and during breeding and of the females throughout 

gestation and lactation did not affect fertility, the gross and microscopic appearance of the reproductive 
 

 

 

 

 

 

 

 

 

 

CHLORINE 98 

3. HEALTH EFFECTS 

organs of males or females, and did not induce sperm abnormalities (Carlton et al. 1986). Neither the 

90-day (Daniel et al. 1990, 1991; Furukawa et al. 1980) nor the 2-year (Hasegawa et al. 1986; NTP 1992) 

drinking water studies reported any gross or histological alterations in the reproductive organs of male 

and female rats and mice. These studies, however, did not assess fertility. 

The highest NOAEL values from each reliable study for reproductive effects in each species and duration 

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

3.2.2.6 Developmental Effects 

No information was located regarding developmental effects in humans following oral exposure to 

hypochlorite solutions. Abdel-Rahman et al. (1982) exposed female Sprague-Dawley rats to 0, 0.1, 1, or 

10 mg Cl/kg/day (as hypochlorous acid) in the drinking water for 2.5 months before mating with 

untreated males and continuing throughout pregnancy until sacrifice on gestation day 20. Exposure to 

chlorine had no significant effects on fetal viability or on mean fetal body weight. Skeletal anomalies 

were increased at 1 and 10 mg/kg/day and total soft tissue defects at 10 mg/kg/day relative to controls. 

However, since neither maternal body weight nor water consumption data were provided in the study, it 

also appeared that the incidence of fetal anomalies in the control group were higher than in the low-dose 

group, interpretation of these results is problematic; therefore, this study is not listed in Table 3-3. In the 

study by Carlton et al. (1986) mentioned above under Reproductive Effects, exposure of rats during 

gestation to maternal doses of 3.4 mg Cl/kg/day had no significant effect on neonate viability, weight 

gain, or on the incidence of gross external abnormalities. Pups sacrificed at 21 days of age had normal 

blood counts and serum levels of thyroid hormones. Developmental landmarks such as mean day of eye 

opening and average day of observed vaginal patency were unaltered in pups evaluated at age 28 and 

40 days. The developmental NOAEL of 3.4 mg Cl/kg/day is listed in Table 3-3 and plotted in Figure 3-2. 

3.2.2.7 Cancer 

Studies of the carcinogenicity of trihalomethanes or other organic chemicals that form in water as a result 

of the chlorination of drinking water are not discussed in this section since these studies were not intended 

to assess whether chlorine itself is responsible for cancer. For reviews on this issue, the reader is referred 

to IARC (1991), Koivusalo and Vartiainen (1997), and EPA (1994b). 

Cancer bioassays of chlorine in drinking water have been conducted in rats and mice. In the NTP (1992) 

bioassay, F344 rats (70/sex/dose group) were exposed to 0, 70, 140, or 275 ppm sodium hypochlorite in 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 99 

3. HEALTH EFFECTS 

the drinking water for 103–104 weeks. This provided doses of 0, 4.2, 7.3, or 13.6 mg Cl/kg/day to males 

and 0, 4.2, 7.8, or 14.4 mg Cl/kg/day to females. The water used in the study was deionized charcoalfiltered water. Interim sacrifices (10 rats/sex/dose) were conducted at 14 and 66 weeks. The only 

significant finding was an increased incidence of leukemia in female rats. The incidences were: 8/50, 

7/50/, 19/51, and 16/50 in the control, low-, mid-, and high-dose females, respectively. Pair-wise 

comparison showed a statistically significant difference between controls and the mid-dose (p=0.014) and 

a trend test was also significant (p=0.037). In males, the respective incidences were 25/51, 25/51, 27/50, 

and 29/51. These results led NTP (1992) to conclude that there was equivocal evidence of 

carcinogenicity in female rats based on the fact that there was no clear dose-related response or reduced 

latency, there was no decrease in tumor latency, and the incidence in concurrent controls (16%) was 

significantly lower than in historical controls (25%). In a similar study, Hasegawa et al. (1986) 

administered sodium hypochlorite in distilled water to groups of F344 rats (50/sex/dose) in concentrations 

of 0, 500, or 1,000 ppm to males and 0, 1,000, or 2,000 ppm to females for 104 weeks; this was followed 

by a period of 8 weeks of drinking untreated water. This corresponds to doses of approximately 0, 33, or 

67 mg Cl/kg/day for males and 0, 67, or 133 mg Cl/kg/day for females. The results showed no significant 

treatment-related increased incidence of neoplasms or alterations in latency of neoplasms. 

In the NTP (1992) study, B6C3F1 mice (70/sex/dose group) drank water with 0, 70, 140, or 275 ppm 

sodium hypochlorite for 103–104 weeks. This corresponds to doses of approximately 0, 7.4, 14, or 24 mg 

Cl/kg/day for males and 0, 7.6, 14.2, or 24.2 mg Cl/kg/day for females. The water used in the study was 

deionized charcoal-filtered water. Interim sacrifices (10 mice/sex/dose) were conducted at 15 and 

66 weeks. The results showed that treatment with chlorine did not induce significant treatment-related 

increases in neoplasms. In a study by Kurokawa et al. (1986), groups of B6C3F1 mice (50/sex/dose) were 

exposed to sodium hypochlorite in drinking water in concentrations of 0, 0.5, or 1% for 103 weeks. 

These concentrations provided doses of approximately 0, 33, or 55 mg Cl/kg/day to males and 0, 27, or 

52 mg Cl/kg/day to females. Controls consisted of 73 males and 72 females. At termination, 

examination of tissues and organs did not show any statistically significant differences in tumor 

incidences between controls and treated mice. 

Neither the EPA nor the DHHS has classified chlorine (elemental) or hypochlorite salts as to their 

carcinogenicity. Based on inadequate evidence for carcinogenicity of hypochlorite salts in animals and 

no data from studies in humans, IARC determined that hypochlorite salts are not classifiable as to their 

carcinogenicity in humans (Group 3) (IARC 1991). 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 100 

3. HEALTH EFFECTS 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

No studies were located regarding death in humans or in animals following dermal exposure to 

hypochlorite solutions. 

3.2.3.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological, 

musculoskeletal, hepatic, renal, endocrine, and body weight effects in humans or in animals following 

dermal exposure to hypochlorite solutions. 

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

species and duration category are recorded in Table 3-4. 

Dermal Effects. Nixon et al. (1975) reported that patch application of bleach containing 5.25% 

sodium hypochlorite, pH 10.7, to intact human skin for 4 hours was severely irritating. Habets et al. 

(1986) reported that a solution of 2% sodium hypochlorite in water caused weak to moderate skin 

irritation in 15 out of 69 individuals tested; the volume applied was not disclosed. Twenty individuals 

who were tested with 0.1 and 0.5% solutions showed no irritation. Hostynek et al. (1989) tested 

10 subjects with 100 μL of a 6% strength sodium hypochlorite solution (pH 11.2) and 4 of them 

developed a non-immunologic form of contact urticaria within 20 minutes of the application to skin of the 

forehead. The same group of investigators studied the skin irritation of 20 or 100 μL of hypochlorite 

bleach containing 1% sodium hypochlorite and various amounts of sodium hydroxide following 24 hours 

exposure under occluded patch conditions in 50 volunteers (Hostynek et al. 1990). The results showed 

that 20 μL 1% sodium hypochlorite and 1% sodium hydroxide produced no irritation, whereas 100 μL 

produced significant irritation. Goffin et al. (1997) reported that patch test exposure of 15 women to 

150 μL of a commercial bleaching agent containing 4% sodium hypochlorite and 0.2% sodium hydroxide 

for up to 90 minutes produced no clinical signs of irritation. However, instrumental tests (reflectance 

colorimetry, transepidermal water loss, and skin conductance) revealed subclinical damage to the stratum 

corneum. The investigators concluded that a 4% solution of sodium hypochlorite can alter the superficial 

part of the stratum corneum without modifying the barrier function of the skin. 
93

Percent (%)

90

Percent (%) Percent (%)

91

Percent (%)

92

Percent (%)

89

Percent (%)

96

Percent (%)

Table 3-4 Levels of Significant Exposure to Hypochlorous Acid and/or Sodium Hypochlorite - Dermal 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE 

Systemic 

Human 

(C) 90 min 

System 

Dermal 

NOAEL 

4F 

Percent (%) 

Less Serious 

LOAEL 

Serious 

Reference Chemical Form 

Goffin et al. 1997 

Human 

(C) 48 hr Dermal 0.5 

Percent (%) 

2 (weak to moderate skin 

Percent (%) irritation) 

Habets et al. 1986 

Human 

(C) 20 min Dermal 6 (non-immunologic 

Percent (%) contact urticaria) 

Hostynek et al. 1989 

Human 

(C) 24 hr Dermal 1 

Percent (%) 

Hostynek et al. 1990 

Human 

(C) 4 hr Dermal 5.25 (severe skin irritation in 

Percent (%) 4/7 subjects) 

Nixon et al. 1975 

(CD-1) Mouse 

(C) 2 d 8 x/d Dermal 0.53 F (histologic changes 

indicating moderate irritation response) Percent (%) 

Hess et al. 1991 
94

Percent (%)

97 Percent (%)95

Percent (%)

Table 3-4 Levels of Significant Exposure to Hypochlorous Acid and/or Sodium Hypochlorite - Dermal 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

(Hartley) Gn Pig 

(C) 4 hr Dermal 5.25 

Percent (%) 

Nixon et al. 1975 

(New Zealand) Rabbit 

(C) once Ocular 5 B 

Percent (%) 

(moderate eye irritation) Griffith et al. 1980 

(NS) Rabbit 

(C) 4 hr Dermal 5.25 

Percent (%) 

Nixon et al. 1975 

B = both male and female; (C) = capsule; d = day; F = female; Gn pig = guinea pig; hr = hour; LOAEL = lowest-observed-adverse-effect level; min = minute; NOAEno-observed-adverse-effect level 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 103 

3. HEALTH EFFECTS 

Nixon et al. (1975) conducted 4-hour patch tests with a 5.25% hypochlorite bleach solutions in rabbits 

and guinea pigs and reported that in both species, hypochlorite caused only slight irritation to both intact 

and abraded skin and concluded that neither species provide an accurate model for human skin. Strange 

et al. (1951) studied the effect of Clorox® mixed with various biological media on the skin of rabbits and 

rats. Clorox® was mixed with water, saliva, gastric juice, or plasma in ratios of 2:1, 1:1, and 1:2 and 

applied to the shaved abdominal skin of anesthetized rabbits in inverted tubes for 15 and 30 minutes. The 

mixtures with saliva and water were the most damaging, whereas the mixture with plasma was the least 

damaging, regardless of the dilution. Strange et al. (1951) speculated that the proteins in solutions 

containing plasma had a buffer effect on the harmful action of Clorox® on tissue. Strange et al. (1951) 

also reported that submerging the feet of anesthetized rats for 15 minutes into Clorox® mixed with 

proteins (plasma, egg white, milk) protected the tissue from the action of Clorox®. Mixtures of Clorox® 

with saliva or Clorox® with water induced edema, bleeding, and actual ulceration and destruction of 

tissue. 

Hess et al. (1991) sprayed 0.8 mL of a 1:10 dilution of a commercial bleach solution onto a shaved 

abdominal area of female CD-1 mice 8 times/day for 2 consecutive days. Eighteen to 24 hours after the 

last application, the mice were sacrificed and the skin was processed for microscopic examination of the 

epidermis, dermis, and hypodermis. Exposure to bleach caused a “moderate” response. Grossly, the skin 

appeared dry with scattered brown crusty patches. Acanthosis, intraepithelial edema, hyperkeratosis, and 

atypical epithelial cells were seen in the epidermis. The dermis showed some evidence of edema, 

whereas the hypodermis showed a mild infiltration of neutrophils, macrophages, and lymphocytes. 

Ocular Effects. Very limited information was located regarding ocular effects of direct contact of the 

eye with hypochlorite solutions. In their text Toxicology of the Eye, Grant and Schuman (1993) state that 

“because most accidental splashes in the eye have been with the relatively weak 5% household solutions 

of sodium hypochlorite, very few human eye injuries have been reported, and recovery has been rapid and 

complete.” 

Experiments conducted in male and female New Zealand albino rabbits showed that instillation of 0.1 mL 

of household bleach directly to the central corneal surface and followed over a 21-day period produced 

moderate irritation (Griffith et al. 1980). The median day to clear was 7 days. In a review of the 

literature, Racioppi et al. (1994) mention unpublished data indicating that in rabbits, 0.1 mL of an 8% 

solution of sodium hypochlorite (without rinsing) caused moderate irritation and that the recovery time 
 

 

 

 

 

 

 

CHLORINE 104 

3. HEALTH EFFECTS 

was 7 days; under similar conditions, 0.01 mL of the same solution had low irritation potential and the 

recovery time was 3 days. 

3.2.3.3 Immunological and Lymphoreticular Effects 

Although sodium hypochlorite generally is not considered a contact sensitizer, several cases of allergic 

contact dermatitis have been reported. Osmundsen (1978) reported that case of a woman had a strong 

reaction to patch testing with 0.5% sodium hypochlorite in water years after having had dermal contact 

with chloramine. Further tests showed positive reactions to sodium hypochlorite in 3 out of 225 patients. 

Habets et al. (1986) reported two cases of hand dermatitis related to sodium hypochlorite allergy, as 

diagnosed by patch tests. Both patients showed a positive reaction to sodium hypochlorite up to a 

concentration of 0.1%. Van Joost et al. (1987) reported one additional case among 40 housewives who 

apparently had used bleaching agents for long periods. Eun et al. (1984) also reported a case of allergic 

contact dermatitis in a veterinarian who occasionally washed his hands with a commercial solution 

containing 4–6% sodium hypochlorite. 

No information was located regarding immunological and lymphoreticular effects in animals following 

dermal exposure to hypochlorite solutions. 

No studies were located regarding the following effects in humans or animals after dermal exposure to 

hypochlorite solutions. 

3.2.3.4 Neurological Effects 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 

No information was located regarding cancer in humans due to dermal exposure to hypochlorite solutions. 

No bioassays have been conducted in animals by the dermal route of exposure, but the co-carcinogenic 

properties of hypochlorite have been examined. In a two-stage study in female ddN mice using 

4-nitroquinoline 1-oxide in benzene as initiator, application of a commercial sodium hypochlorite solution 

(45 times) to a shaved area in the back of the mice after 20 applications of the nitroquinoline solution 

resulted in an incidence of 9/32 skin tumors compared with 0/29 in the nitroquinoline alone group and 

0/27 in the hypochlorite group alone (Hayatsu et al. 1971). Although there is suggestive evidence of 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 105 

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promotion activity for sodium hypochlorite, the study is limited by insufficient information on dose, 

survival, and age at termination. In another initiation-promotion study, skin application of single 

initiating doses of 7,12-dimethylbenz[a]anthracene in acetone to female Sencar mice followed by twice 

weekly applications of sodium hypochlorite resulted in squamous cell carcinomas in one mouse initiated 

with 7,12-dimethylbenz[a]anthracene followed by sodium hypochlorite applications (Kurokawa et al. 

1984). No skin carcinomas were seen in uninitiated mice promoted with sodium hypochlorite or in 

control groups. In yet another study, application of sodium hypochlorite to the shaved back of female 

NMRI mice twice per week for 10 weeks before the mice were applied benzo[a]pyrene twice per week 

for 10 weeks resulted in a decrease (approximately 40%) in the number of skin carcinomas induced by 

benzo[a]pyrene (Pfeiffer 1978). Mice that were treated with sodium hypochlorite during or after 

benzo[a]pyrene had tumor incidences comparable to benzo[a]pyrene alone. 

3.3 GENOTOXICITY 

No studies were located regarding genotoxic effects of chlorine gas in humans. The only information 

available in animals exposed to chlorine gas is that from an intermediate-duration study by Kutzman 

(1983). In that study, rats were exposed to 0, 0.5, 1.5, or 5 ppm chlorine 6 hours/day, 5 days/week for 

62 days. At termination, samples of blood and bone marrow were collected and evaluated for cytogenetic 

effects. The results showed no evidence on increased incidence of sister chromatid exchanges or of 

cellular proliferation in the bone marrow from exposed rats. There was also no evidence of increased 

sister chromatid exchanges or of chromosomal aberrations in peripheral lymphocytes. 

There is limited information regarding the in vivo genotoxicity of hypochlorite ions. A study in which 

male B6C3F1 mice were administered chlorine in the drinking water as sodium hypochlorite or 

hypochlorous acid for 5 days and that provided doses of up to 8 mg Cl/kg/day found no evidence of 

increased incidences of chromosomal aberrations or micronuclei in bone marrow (Meier et al. 1985). In 

another study, administration of a single intraperitoneal dose of up to 2,500 mg/kg sodium hypochlorite 

(1,175 mg Cl/kg/day) to male ddY mice did not increase the incidence of micronuclei in bone marrow 

evaluated 24 hours after dosing (Hayashi et al. 1988). Exposure of newt larvae to sodium hypochlorite in 

the surrounding water (0.12 or 0.25 μg/mL) for 12 days increased the frequency of micronuclei in blood 

erythrocytes (Le Curieux et al. 1993). However, the study did not specify in what type of water the larvae 

were kept. If the larvae were kept in tap water, it is possible that chlorination byproducts rather than 

chlorine or the hypochlorite anion were the clastogenic agents. Table 3-5 summarizes the genotoxicity of 

sodium hypochlorite in vivo. Studies of the genotoxicity of sodium hypochlorite in vitro are summarized 
 

 


 


 


 


 


 


 


 

CHLORINE 106
 

3. HEALTH EFFECTS 

Table 3-5. Genotoxicity of Sodium Hypochlorite In Vivo 

Species (test system) End point Results Reference 

Mice bone marrow cells Micronuclei − Meier et al. 1985
 

Mice bone marrow cells Chromosomal aberrations − Meier et al. 1985
 

Mice bone marrow Micronuclei − Hayashi et al. 1988
 

erythrocytes
 

Newt (Pleurodeles waltl) Micronuclei + Le Curieux et al. 1993
 

larvae erythrocytes
 

– = negative result; + = positive result 
 

 

 

 

 

 

 

CHLORINE 107 

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in Table 3-6. As the table shows, the results have been mixed and no general statements can be made. 

The variability of the results may be due to differences in the experimental protocols used. 

3.4 TOXICOKINETICS 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

Nodelman and Ultman (1999a) measured the fraction of an inspired chlorine bolus cleared during a single 

breath as a function of the bolus penetration into the respiratory system of five nonsmoker males and 

females during both nasal and oral breathing at a respiratory flow of 250 mL/second using a noninvasive 

procedure. Measurements of the chlorine concentrations were made by means of a fast-responding 

thermionic chlorine analyzer. Peak concentrations of 0.5 and 3 ppm chlorine were used in nasal breathing 

experiments and 3 ppm in oral breathing experiments. The results indicated that almost all of the chlorine 

inhaled was absorbed in the upper airways (above the cords) whether the subjects inhaled through the 

nose or through the mouth. By comparing mass transfer parameters, the investigators also determined 

that total absorption rates for the mouth and nose were similar. When the peak concentration in the nasal 

breathing experiments was increased from 0.5 to 3 ppm, the mass transfer parameters remained 

unchanged, indicating that the dissolution, diffusion, and chemical reactions governing the absorption of 

the gas by the nasal mucosa are all linear processes. In other words, over the 0.5–3 ppm concentration 

range, absorption appeared to be non-saturable. In a separate experimental series, the investigators 

determined the longitudinal distribution of a bolus of 3 ppm chlorine as a function of the flow rate 

(Nodelman and Ultman 1999b). Using flow rates of 150, 250, or 1,000 mL/second, the authors 

determined that irrespective of the mode of breathing, nasal or oral, and respiratory flow rate, >95% of 

the inspired chlorine was absorbed in the upper airways and <5% was delivered to the lower airways. 

Some studies in animals also have provided indirect evidence that the upper respiratory tract is an 

efficient scrubber of chlorine. For example, Alarie (1981) reported that the 10-minute LC50 in intact mice 

was 302 ppm, but in mice that breathed through a cannula in the trachea, the LC50 was only 131 ppm. In 

another study, the surgically isolated upper respiratory tract of anesthetized mice was shown to scrub 

chlorine with a mean efficiency of approximately 98% (Morris et al. 2005). Preliminary studies in F344 

rats similar to those conducted by Nodelman and Ultman (1999a, 1999b) in humans also showed that 

>90% of a chlorine dose (0.5, 1.0, 2.5 ppm) is cleared in the upper respiratory tract (Roberts et al. 2007). 
 

 

 

 

 

 

 

 

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Table 3-6. Genotoxicity of Sodium Hypochlorite In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

Salmonella typhimurium 

(TA100, TA102, TA98) 

Gene mutation Not tested − Le Curieux et al. 1993 

S. typhimurium (TA100) Gene mutation Not tested + Ishidate et al. 1984 

S. typhimurium (TA1530) Gene mutation Not tested + Wlodkowski and 

Rosenkranz 1975 

S. typhimurium (TA1538) Gene mutation Not tested − Wlodkowski and 

Rosenkranz 1975 

Escherichia coli (PQ37) DNA repair Not tested − Le Curieux et al. 1993 

E. coli (DNA polymerase 

deficient) 

DNA damage Not tested + Rosenkranz 1973 

Human fibroblasts cell line 

HE2144 

Sister chromatid 

exchange 

Not tested + Sasaki et al. 1980 

Humans fibroblasts cell line 

HE1244 

Chromosome 

breakage 

Not tested − Sasaki et al. 1980 

Syrian hamster embryo cells Sister chromatid 

exchange 

Not tested + Miyachi and Tsutsui 2005 

Chinese hamster fibroblast cell 

line 

Chromosomal 

aberrations 

Equivocal + Ishidate et al. 1984 

Chinese hamster lung cell line Chromosomal 

aberrations 

Toxic + Matsuoka et al. 1979 

Syrian hamster embryo cells Chromosomal 

aberratons 

+ − Hagiwara et al. 2006 

C = negative result; + = positive result; DNA = deoxyribonucleic acid 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 109 

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3.4.1.2 Oral Exposure 

No relevant data were located regarding oral absorption of hypochlorite ions in humans and limited 

information exists in studies in animals. Administration of a single dose of approximately 3.3 mg/kg of 

radiolabeled hypochlorous acid (36Cl) to fasted Sprague-Dawley resulted in a peak 36Cl in plasma of 

7.9 μg/mL 2 hours after dosing (Abdel-Rahman et al. 1983). In non-fasted rats, administration of the 

same dose resulted in a peak concentration of 10.7 μg/mL 36Cl in plasma 4 hours after dosing, suggesting 

that food residues slow down absorption perhaps due to the reaction of chlorine with food components 

(Fukayama et al. 1986). For both fasted and non-fasted rats, the absorption half-life was 2.2 hours. The 

elimination half-life from plasma was 44.1 and 88.5 hours in fasted and non-fasted rats, respectively. 

3.4.1.3 Dermal Exposure 

No information was located regarding absorption of hypochlorite ions in humans or in animals after 

dermal exposure to hypochlorite solutions. Studies of dermal exposure of humans or animals to aqueous 

chlorine have focused almost exclusively of effects on the skin; therefore, no systemic effects have been 

described that could provide indirect evidence of dermal absorption of hypochlorite ions. 

3.4.2 Distribution 

3.4.2.1 Inhalation Exposure 

No information was located regarding distribution of chlorine following inhalation exposure to chlorine 

gas. 

3.4.2.2 Oral Exposure 

In rats, 96 hours after the administration of a single gavage dose of approximately 3 mg/kg of 

hypochlorous acid labeled with 36Cl, the plasma had the highest amount of radioactivity (1.92 μg/g) 

followed by whole blood, bone marrow, testes, skin, kidneys, lungs, packed cells, duodenum, stomach, 

spleen, thyroid, thymus, liver, carcass, and fat (0.09 μg/g) (Abdel-Rahman et al. 1983). Examination of 

the subcellular distribution of radioactivity in the liver 24 hours after dosing with hypochlorous acid 

showed that 75% of the total radioactivity of the whole homogenate was associated with the cytosol, 

2.5% with the microsomal fraction, 1.5% with the nuclear fraction, and <0.1% with the mitochondrial 

fraction. 
 

 

 

 

 

 

 

 

CHLORINE 110 

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3.4.2.3 Dermal Exposure 

No information was located regarding distribution of chlorine following dermal exposure to chlorine gas 

or hypochlorite ions. 

3.4.3 Metabolism 

Limited information is available regarding the metabolism of chlorine. In a study in which rats received a 

single oral gavage dose of radiolabeled (36Cl) hypochlorous acid showed that, 96 hours after dosing, 

81% of radioactivity detected in plasma was chloride ion (Abdel-Rahman et al. 1983). 

Hypochlorous acid is a very reactive chemical and has been shown to react with biomolecules found in 

food (Fuyakama et al. 1986). Hypochlorous acid reacts with proteins, amino acids, and unsaturated lipids 

to form chlorinated compounds, whereas the reaction with carbohydrates yields oxidation products. 

Scully et al. (1986) reported that chlorination of the stomach from rats resulted in the production of 

N-chloramines, tentatively identified as N-chloroalanine, N-chloroglycine, and N-chlorophenylalanine. 

Chemicals such as chloroform, dichloroacetonitrile and di- and trichloroacetic acids were shown to form 

in vivo in the stomach of rats following oral administration of sodium hypochlorite (Mink et al. 1983). 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

No information was located regarding elimination and excretion of chlorine following inhalation exposure 

to the gas. 

3.4.4.2 Oral Exposure 

The excretion of 36Cl was studied in rats following administration of a single gavage dose of 

approximately 2.6 mg/kg of radiolabeled hypochlorous acid (Abdel-Rahman et al. 1983). Urine, feces, 

and expired air were collected over a 4-day period after dosing. During the first 24 hours, 7 and 7.5% of 

the administered radioactivity was excreted in the urine and feces, respectively. At the end of the 4-day 

period, 36 and 15% of the administered radioactivity had been recovered in the urine and feces, 

respectively, for a combined total of about 51% of the administered dose. No radioactivity was recovered 

in expired air during the study period. Since all or some of the amount recovered in the feces could have 
 

 

 

 

 

 

 

 

 

 

CHLORINE 111 

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been un-absorbed radioactivity, the 36% recovered in the urine represents the minimum that was 

absorbed. 

3.4.4.3 Dermal Exposure 

No information was located regarding elimination and excretion of chlorine gas or hypochlorite ions in 

humans or in animals following dermal exposure to these chemicals. 

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

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 112 

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equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-3 shows a conceptualized representation of a PBPK model. 

If PBPK models for chlorine exist, the overall results and individual models are discussed in this section 

in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations. 

A computational fluid dynamics-physiologically based pharmacokinetic model is being developed for 

chlorine (Jarabek et al. 2007). The model is intended to address experimental dosimetry data on chlorine 

in rats, including uptake of chlorine delivered unidirectionally at various flow rates and concentrations 

measured in the isolated upper respiratory tract of F344 rats, and measurement of chlorotyrosines (as 

biomarkers) in samples taken from four regions from the respiratory and olfactory tissues. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Chlorine is a strong oxidizer that hydrolyzes in water forming hydrochloric and hypochlorous acids. 

Because of the high water content of the epithelial lining fluid and the local concentration of chloride and 

pH, the hydrolysis reaction of chlorine has a large equilibrium constant, such that the concentration of 

chlorine in the form of hypochlorite is 120,000 times that of chlorine gas (Nodelman and Ultman 1999a, 
 


 


 


 

CHLORINE 113 

3. HEALTH EFFECTS 

Figure 3-3. Conceptual Representation of a Physiologically Based
 

Pharmacokinetic (PBPK) Model for a Hypothetical
 

Chemical Substance
 

Inhaled c hem ic al E x ha led c hem ic al 

Inges tion 

Lungs 

Liv er 

V m a x GI K m T ra c t A 

V R 

E F at T 

N E 

O R 

U I S lo w ly S perfus ed A 

tis s ues L 

R ic h ly B perfus ed L B tis s ues O L F ec es O O 

D O K idney D 

U rin e

S k in 

 C h e m ic a ls 

contacting skin 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: Adapted from Krishnan and Andersen 1994 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 114 

3. HEALTH EFFECTS 

1999b). This means that the effective solubility of chlorine between the inhaled gas and the mucus phase 

is 5 orders of magnitude larger than the physical solubility, which explains why >95% of the inhaled 

chlorine was absorbed in the upper airways in the studies with volunteers mentioned above (Nodelman 

and Ultman 1999a). 

In a review of the toxicological significance of the chemical reactions of hypochlorite ions, Scully et al. 

(1989) point out that because hypochlorite is a potent oxidant, pharmacokinetic studies of radiolabeled 

hypochlorous acid (36Cl) in animals do not reveal what happens to the parent compound, but rather to the 

product of the reactions of these compounds in vivo. However, as discussed by Scully et al. (1986), since 

hypochlorous acid undergoes rapid isotope exchange with unlabeled chloride, it is unclear whether the 

radioactive chloride detected in plasma of rats in the study by Abdel-Rahman et al. (1983) is due to 

complete reduction of the hypochlorous acid or to isotope exchange followed by elimination of chloride. 

3.5.2 Mechanisms of Toxicity 

Chlorine Gas. The toxicity of chlorine is strongly related to its oxidizing capacity. Chlorine reacts with 

water in the epithelial lining of the upper respiratory airways according to the following equation: 

Cl2 + H2O ↔ HCl + HOCl 

Chlorine gas has been shown to be 33 times more potent as a sensory irritant in mice than hydrochloric 

acid (HCl) (Barrow et al. 1977), which led the investigators to suggest that, in terms of sensory irritation, 

the response observed must be due to hypochlorous acid (HOCl) rather than to hydrochloric acid. More 

recently, Morris et al. (2005) reported that in mice, (a) an aerosol of sodium hypochlorite and (b) chlorine 

gas, at equivalent air concentrations, induced similar decreases in respiratory rate and increases in specific 

airway resistance, which suggested to the investigators that the oxidant properties of chlorine alone are 

sufficient to account for the observed responses. The precise mechanism by which this might occur is not 

known, but the assumption is that products of the reaction of chlorine with water are able to interact with 

functional groups in components from cells in the respiratory epithelium. At low concentrations, only 

sensory receptors may be affected, triggering only changes in respiratory dynamics, but higher 

concentrations produce frank tissue damage due to disruption of cellular components. 

Hypochlorous Acid/Hypochlorite. The mechanism of toxicity of hypochlorous acid/hypochlorite is 

basically the same as that for chlorine gas. However, hypochlorous acid is a stronger oxidant than 
 

 

 

 

 

 

 

 

CHLORINE 115 

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chlorine gas as reflected by its higher redox potential. Damage to the upper gastrointestinal tract, as may 

occur following ingestion of sodium hypochlorite bleach, is likely the result of oxidation reactions of 

hypochlorous acid with a range of biological molecules. Exposure to dilute solutions of bleach usually 

result in only minor esophageal irritation, but ingestion of concentrated solutions of bleach can produce 

serious tissue damage. These properties of hypochlorous acid form the basis for the use of this chemical 

as a disinfectant (i.e., Lapenna and Cuccurullo 1996; Schraufstätter et al. 1990; Wang et al. 2007). Due to 

its high reactivity, ingested hypochlorous acid also reacts with organic compounds present in the stomach 

fluid such as proteins, polysaccharides, lipids, and vitamins, which may result in the formation of 

potentially harmful compounds (for review, see Fukayama et al. 1986; Mink et al. 1983; Scully et al. 

1989). 

3.5.3 Animal-to-Human Extrapolations 

The respiratory system is the target for exposure to chlorine gas in humans and animals, and for the most 

part, humans and animals exhibit similar effects, particularly following acute-duration high exposures. 

Less is known regarding long-term effects of acute high exposures and of prolonged low level exposures, 

especially with regard to pulmonary function parameters. An evaluation of respiratory lesions in 

monkeys, rats, and mice following chronic exposure to comparable concentrations of chlorine noted that 

respiratory tract airflow characteristics play a major role in the distribution of the lesions and that the 

lesions in monkeys and rodents exhibited both differences and similarities (Ibanes et al. 1996). The 

conclusion was that with appropriate exposure and response adjustments, both rodents and Rhesus 

monkeys appear to be valid models for human risk assessment. 

The gastrointestinal tract is the target for oral exposure to hypochlorite in humans and animals. Ingestion 

of concentrated solutions of hypochlorite bleach induces similar effects in humans and animals, and no 

single animal species has emerged as a preferred animal model for human gastric toxicity. A comparative 

study of dermal exposure of humans, rabbits, and guinea pigs to a 5.25% hypochlorite bleach solution 

reported that rabbits and guinea pigs were much more sensitive to the irritating properties of sodium 

hypochlorite, and therefore, neither species provide an accurate model for human skin (Nixon et al. 1975). 

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 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 116 

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terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 

There are no studies that have tested whether chlorine gas has properties of endocrine disruptor, but given 

its mechanism of toxicity, such effects are very unlikely. 

Oral exposure to hypochlorite solutions has provided no evidence of endocrine disruption in humans or in 

animals, but the available studies have not been designed to carefully evaluate that possibility. A study in 

male and female volunteers who consumed for 4 weeks 1.5 L of distilled water that provided a dose of 

approximately 0.4 mg Cl/kg/day reported that there was a slight reduction in serum levels of T4 and T3 in 

men which was not accompanied by any meaningful change in thyroid-stimulating hormone levels 

(Wones et al. 1993). In another study in volunteers, ingestion of approximately 0.036 mg Cl/kg/day in 

the drinking water for 12 weeks did not significantly alter serum levels T3 or T4 (Lubbers et al. 1982). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 117 

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Relevant information in animals is very limited. Exposure of rats during gestation to maternal doses of 

up to 3.4 mg Cl/kg/day (as hypochlorous acid) had no significant effect on pups’ serum levels of thyroid 

hormones at 21 days of age (Carlton et al. 1986). In addition, developmental landmarks such as mean day 

of eye opening and average day of observed vaginal patency were unaltered in pups evaluated at 

age 28 and 40 days. Studies in rats and mice found no significant gross or microscopic alterations in 

endocrine glands following long-term exposure to chlorine the drinking water (Daniel et al. 1990, 1991; 

Furukawa et al. 1980; Hasegawa et al. 1986; NTP 1992). 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 
 

 

 

 

 

 

 

 

CHLORINE 118 

3. HEALTH EFFECTS 

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). 

The respiratory tract is also the target for chlorine gas toxicity in children, and children exposed to 

chlorine exhibit the same signs and symptoms observed in adults detailed in Section 3.2.1.2. Whether 

children are more susceptible than adults to the effects of chlorine exposure is not known with certainty, 

but there are some reports that suggest that they might be. There are many reports of intoxication of 

children following a variety of exposure scenarios: tank explosions, train derailments, accidents at 

swimming pools, and accidents during school science class. Some representative examples are 

summarized below. 

Following a train derailment in which members of a community, including over 100 children, may have 

been exposed to up 20 ppm chlorine, the most frequent conditions were coughing, headache, throat 

irritation, and a burning sensation in the eyes (Agency for Toxic Substances and Disease Registry 1998). 

Children aged 0–5 years had the highest prevalence of respiratory infections, rash, and vomiting. Fleta et 

al. (1986) reported the case of a leak of chlorine from a tank that exposed 76 children. The most 

prevalent symptoms were irritative cough (91%), nasal-pharyngeal pruritus (66%), chest pain (25%), 
 

 

 

 

 

 

 

 

 

 

 

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tachypnea (20%), and dyspnea (14%). Other conditions included headache, vomiting, and nausea. The 

report indicates that the symptoms of most children subsided naturally upon leaving the center of 

contamination. Seventy of the 76 children were released within 2 hours of the accident. In a similar case, 

106 individuals were affected and 60 of them were children and adolescents <18 years (Güloğlu et al. 

2002). Of those hospitalized due to their severe condition, patients 0–1 and 2–7 years had the longest 

duration of hospitalization, suggesting an increased susceptibility among children than adults. 

Sexton and Pronchik (1998) described the case of 13 children, ages 6–18, who were overcome by chlorine 

gas at two swimming pools. On admission to the Emergency Department, most children complained of 

eye and throat irritation, chest pain, anxiety, shortness of breath, wheezing, and chest tightness. Five 

patients were admitted to the hospital with hypoxia, but all were released after 2 days. Two weeks after 

the exposures, no patients complained of residual symptoms. In another swimming pool accident, 

134 children inhaled chlorine vapors and acute respiratory symptoms occurred in 72% (Agabiti et al. 

2001). The incidence of all symptoms tended to be higher among those who had a history of chronic 

respiratory disease and among those who were engaged in physical exercise during the accident. 

Lung function tests conducted in 82 children 15–30 days after exposure showed lower FVC, FEV1, and 

FEF25–75%. A study of 10 children exposed to chlorine gas at a swimming pool reported that all children 

had respiratory distress and reduced lung function on admission to the hospital (Bonetto et al. 2006). 

Although lung function returned to normal values 15 days after the accident, biochemical markers of 

pulmonary inflammation were still elevated in exhaled breath condensate several months after the 

accident. Persistent respiratory alterations were also observed in a child who developed dyspnea, 

hypoxemia, and pneumonitis approximately 12 hours after exposure to chlorine gas (Vohra and Clark 

2006). Pulmonary testing 4 months after the episode revealed the presence of mild obstructive reactivity 

of the airways. After being exposed to excess chlorine in an indoor pool, 18 children were followed for 

up to 28 days (Grasemann et al. 2007). Fractional exhaled NO (a measure of airway inflammation) was 

significantly increased on day 1 compared to days 8 and 28 in 13 of the children who had lower airway 

symptoms with cough or shortness of breath on day 1, but not in the total study group or in asymptomatic 

children. In the total group of children, FVC was decreased on day 1 compared to days 8 and 28, whereas 

a marker of pulmonary hyperinflation was elevated on day 1 compared to day 8 or 28. 

There are no studies in animals that addressed possible differential susceptibilities to exposure to chlorine 

gas between young and older animals. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 120 

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In children, as in adults, the gastrointestinal tract is the target for oral exposure to hypochlorite bleach. 

Children usually constitute a significant percentage of the reported cases of accidental ingestion of 

chlorine bleach. In general, ingestion of small amounts (less than a cup) of household bleach (5– 

5.5% sodium hypochlorite) does not result in serious effects, but fatalities have been reported. For 

example, a review of 129 cases of children who ingested Clorox® reported that no complications of 

consequences were found (Pike et al. 1963). Sixty-five cases were examined by esophagoscopy within 

96 hours of the ingestion and only 2 showed evidence of esophageal injury. Another review of 

393 children seen at a hospital who ingested bleach reported that there were no esophageal strictures or 

perforations and that about 50% of the patients received no treatment (Landau and Saunders 1964). Hook 

and Lowry (1974) reported that among 23 definite cases of children who ingested Clorox®, severe 

irritation of the esophageal mucosa was observed in only one case. Minor transient irritation was 

observed in some of the patients. A report from the German literature of 23 children who accidentally 

ingested 3–5% sodium hypochlorite indicates that there was only one case with signs of superficial burns 

in the esophagus, which had disappeared 2 weeks later when controlled by esophagoscopy (Mühlendahl 

et al. 1978). Severe gross lesions were seen in the mouth, tongue, glottis, epiglottis, esophagus, and 

stomach in a child who died after drinking an unknown amount of a 4.5% sodium hypochlorite solution in 

alkali (pH 12.0) (Jakobsson et al. 1991). The information available does not suggest that children are 

more or less sensitive to oral exposure to chlorine than adults. 

There are no studies in animals that have examined whether young animals are more susceptible to the 

effects of ingestion of hypochlorite bleach than adult animals. 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 

A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction 

between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment 

of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance 

itself, substance-specific metabolites in readily obtainable body fluid(s), or excreta. However, several 

factors can confound the use and interpretation of biomarkers of exposure. The body burden of a 

substance may be the result of exposures from more than one source. The substance being measured may 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 121 

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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 chlorine 

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 chlorine are discussed in Section 3.8.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10, Populations That Are Unusually Susceptible. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Chlorine 

There are no biomarkers that can be used to quantify exposure to chlorine gas or sodium hypochlorite in 

humans. However, a recent study documented a statistically significant exposure concentrationdependent increase in 3-chlorotyrosine (CY) and 3,5-dichlorotyrosine (dCY) in nasal tissue from 

F344 rats exposed to chlorine gas concentrations ranging from 0.5 to 2.5 ppm for 90 minutes (Sochaski et 

al. 2008). Preferential formation of CY and dCY was found in the respiratory and transitional epithelium 

versus the olfactory epithelium of the nasal cavity. The investigators point out that the method presented 

in the study is only applicable to animals, as the collection of tissue samples would be too invasive for use 

in humans; nevertheless, it represents a good starting point for future method development. It is not 
 

 

 

CHLORINE 122 

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known whether exposure to other chlorinated compounds could also produce CY and dCY, thus 

compromising the specificity of these biomarkers. 

3.8.2 Biomarkers Used to Characterize Effects Caused by Chlorine 

There are no specific biomarkers that can be used to characterize the effects of chlorine. Chlorine gas is a 

sensory and pulmonary irritant, and similar effects can be observed after exposure to many other irritants. 

Ingestion of sodium hypochlorite can irritate the upper gastrointestinal tract, but this effect is not specific 

to chlorine. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

The only relevant information is that exposure to chlorine gas may result in the development of crosstolerance to other chemicals. A study showed rats pre-exposed to chlorine developed cross-tolerance to 

formaldehyde and vice versa, and the development of tolerance was a function of the duration of pretreatment (Chang and Barrow 1984). Slight loss of cross-tolerance was observed following a recovery 

period of a few days. Interestingly, exposure of rats to 15 ppm formaldehyde did not induce tolerance to 

formaldehyde, but resulted in cross-tolerance to chlorine and, according to Chang and Barrow (1984), 

suggested the existence of different reactive sites at the trigeminal nerve endings. 

As previously mentioned, hypochlorous acid is a very reactive chemical and has been shown to react with 

biomolecules found in food (Fuyakama et al. 1986). Hypochlorous acid reacts with proteins, amino acids, 

and unsaturated lipids to form chlorinated compounds, whereas the reaction with carbohydrates yields 

oxidation products. Scully et al. (1986) reported that chlorination of the stomach from rats resulted in the 

production of N-chloramines, tentatively identified as N-chloroalanine, N-chloroglycine, and N-chlorophenylalanine. Chemicals such as chloroform, dichloroacetonitrile, and di- and trichloroacetic acids were 

shown to form in vivo in the stomach of rats following oral administration of sodium hypochlorite (Mink 

et al. 1983). 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to chlorine than will most persons 

exposed to the same level of chlorine 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 chlorine, or compromised function of organs 
 

 

 

 

 

 

 

 

 

CHLORINE 123 

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affected by chlorine. Populations who are at greater risk due to their unusually high exposure to chlorine 

are discussed in Section 6.7, Populations with Potentially High Exposures. 

Populations unusually susceptible to chlorine gas exposure include individuals with respiratory conditions 

such as asthma, hay fever, and chronic bronchitis, heavy smokers, and children. Rotman et al. (1983) 

described the case of an atopic individual who experienced severe distress during exposure to 1 ppm 

chlorine, a concentration that was tolerated by healthy subjects. D’Alessandro et al. (1996) also reported 

that subjects with airway hyperresponsiveness to methacholine exhibited a much more pronounced 

decrease in FEV1 and FEF25–75% than healthy subjects during exposure to 1 ppm chlorine. Shusterman et 

al. (1998) reported that subjects with seasonal allergic rhinitis experienced a significantly greater increase 

in nasal airway resistance (congestion) than non-rhinitic subjects following exposure to 0.5 ppm chlorine 

for 15 minutes. Following an accidental leak of chlorine, individuals who had a more prevent history of 

smoking and asthma exhibited more hypoxemia and were more likely to have tachypnea, crackles, and 

wheezes during examination than subjects without asthma and/or who smoked less (Hasan et al. 1983). 

In the former, signs and symptoms of chlorine intoxication resolved more slowly reduced and flow rates 

and lung volumes were still evident 2 weeks after acute exposure to chlorine. Similar observations 

regarding smokers have been made in studies of workers who have experienced occasional high 

exposures or “gassing” episodes (Chester et al. 1969; Gautrin et al. 1999; Henneberger et al. 1996). 

In a swimming pool accident involving 126 adult and 134 children, among both children and adults, the 

incidences of all symptoms (eye, nose, and throat irritation) and respiratory problems (shortness of breath, 

wheezing, cough) were higher among those who had a history of chronic respiratory disease than among 

healthy people (Agabiti et al. 2001). In addition, in adults, incidences were higher among smokers and 

former smokers than among never smokers. 

Some reports in which adults and children were accidentally exposed to high concentrations of chlorine 

have suggested that children might be more susceptible to the effects of chlorine than adults. For 

example, in a case involving 106 individuals, 60 of whom were children and adolescents <18 years old, of 

those hospitalized due to their severe condition, patients 0–1 and 2–7 years old had the longest duration of 

hospitalization, suggesting an increased susceptibility among children than adults (Güloğlu et al. 2002). 

In another case in which over 100 children may have been exposed to up 20 ppm chlorine, children aged 

0–5 years had the highest prevalence of respiratory infections, rash, and vomiting (Agency for Toxic 

Substances and Disease Registry 1998). 
 

 

 

 

 

 

 

 

 

CHLORINE 124 

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No information was located regarding populations unusually susceptible to exposure to hypochlorite 

bleach. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to chlorine. 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 chlorine. 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 chlorine: 

Ellenhorn MJ, Barceloux DG. 1988. Medical Toxicology: Diagnosis and Treatment of Human 

Poisoning. New York, NY: Elsevier, 878-879. 

Ellenhorn MJ. 1997. Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2th ed. 

Philadelphia, PA: Williams and Wilkins, 1521. 

Goldfrank LR, Flomenbaum NE, Lewin NA, et al. 2002. Goldfrank’s Toxicologic Emergencies. 7th ed. 

New York, NY: McGraw-Hill, 1458-1459. 

Viccellio P, Bania T, Brent J, et al. 1998. Chlorine gas. In: Emergency toxicology. 2nd ed. 

Philadelphia, PA: Lippincott-Raven Press, 444-445. 

Additional information can be found in ATSDR’s Medical Management Guideline for chlorine (ATSDR 

2007). 

3.11.1 Reducing Peak Absorption Following Exposure 

There are no specific methods for reducing absorption of chlorine gas other than removing the patient 

from the source of the chlorine gas to fresh air and monitor for respiratory distress. It should be noted 

that rescuers should wear self-contained breathing apparatus and have protective clothing, if needed. 

Sodium hypochlorite or hypochlorous acid is not absorbed in the gastrointestinal tract as such. Either 

substance will react with the acid in the stomach to form chlorine gas and/or with organic compounds 

present in the stomach fluid to form chlorinated compounds (Mink et al. 1983; Scully et al. 1989). 

Gastrointestinal decontamination procedures such as emesis, gastric lavage, and activated charcoal should 

be avoided following ingestion of chlorine bleach. However, dilution with water or milk is 

recommended, but the dilution amount should be small to avoid inducing vomiting. In case of exposure 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 125 

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of the skin to hypochlorite solutions, flushing with copious amounts of plain tepid water is recommended. 

In case of exposure of the eyes, irrigation with saline or Ringer’s lactate is recommended. 

3.11.2 Reducing Body Burden 

There are no standard methods for reducing chlorine body burden. Studies in humans have shown that 

under low exposure conditions (<5 ppm), >95% of the inspired chlorine is absorbed in the upper airways 

and <5% is delivered to the lower airways (Nodelman and Ultman 1999a, 1999b). Chlorine that reacts 

with the mucosa of the upper respiratory airways eventually joins the pool of chloride ions in the body. 

Studies in animals also have shown that most of the chlorine ingested as hypochlorous acid is transformed 

and eliminated as chloride (Abdel-Rahman et al. 1983). 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

The toxic effects of chlorine gas are due to its oxidant properties and also to the added tissue damage 

caused by the hypochlorous and hydrochloric acids that result from the reaction of chlorine with water. 

There are no established methods to interfere with the oxidant properties of chlorine, but nebulized 

sodium bicarbonate has been used to neutralize the acid (Bosse 1994; Douidar 1997). 

The treatment of exposure to chlorine gas is symptomatic, exposure to low concentrations may require 

only treatment for sensory irritation, but exposure to high concentrations may cause serious respiratory 

symptoms including pulmonary edema and respiratory failure and death. The information below has been 

extracted from the texts listed above and also from Baxter et al. (1989). 

Before any treatment, the patient should be assessed for signs of corrosive injury to mucous membrane, 

eyes, and skin. The assessment should also include a check for lung sounds, peak flow, and vital signs. 

Patients heavily exposed who show breathing difficulties at rest should undergo baseline x-ray 

examination. The initial treatment consists of irrigation with water or saline and vasoconstrictive 

ophthalmic solutions for eye irritation, but eye damage may require referral to a health care facility. 

Nausea may be treated with Phenergan® and administration of clear liquids, whereas sore throat can be 

treated with throat lozenges or spray or a humidifier. Decongestants are recommended for rhinitis and 

antitussive agents for the treatment of cough. Skin burns should be treated as thermal burns. Patients 

exhibiting respiratory effects should receive 100% humidified oxygen, unless it is contraindicated by the 

medical history. As mentioned above, 5% nebulized bicarbonate has been used in patient with respiratory 

effects with favorable responses in at least some patients (Bosse 1994; Douidar 1997). Nebulized 
 

 

 

 

 

 

 

 

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bronchodilators may be used to treat bronchospasm. Therapy with corticosteroids has not been proved to 

produce improvement in chlorine gas poisoning (Baxter et al. 1989). Monitoring of respiratory function 

and arterial blood gases in important because pulmonary edema may occur up to 24 hours after exposure. 

If pulmonary edema occurs, emergent treatment and monitoring in an intensive care unit is often required. 

Caution should be exercised with the administration of intravenous fluids and because fluid overload is 

extremely dangerous in such patients. If fluid overload occurs, diuretics such as furosemide may be 

useful as indicated. Survivors of high chlorine exposure should be monitored periodically to determine 

possible persistent loss of pulmonary function. 

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 chlorine 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 chlorine. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.12.1 Existing Information on Health Effects of Chlorine 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

chlorine gas and hypochlorite solutions chlorine are summarized in Figures 3-4 and 3-5, respectively. 

The purpose of these figures is to illustrate the existing information concerning the health effects of 

chlorine. 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 
 

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CHLORINE 127 

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CHLORINE 128 

3. HEALTH EFFECTS 

Figure 3-5. Existing Information on Health Effects of Hypochlorite Solution 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 129 

3. HEALTH EFFECTS 

information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a 

data gap more broadly as any substance-specific information missing from the scientific literature. 

The existing information on the health effects of chlorine gas in humans comes from accounts of soldiers 

exposed during gas attacks in World War I, subjects exposed to chlorine at work, and members of the 

general population accidentally exposed due to leaks or explosions of storage tanks or due to the 

mishandling of bleach solutions or swimming pool chemicals. Regardless of the exposure scenario, the 

target for chlorine gas toxicity is the respiratory system. Effects of exposure to low concentrations may 

be limited to irritation of the eyes, upper respiratory tract, and skin, whereas exposure to high 

concentrations may cause serious pulmonary effects and death. There is limited information on 

neurological effects in humans exposed to chlorine gas. Oral exposure is not a relevant route of exposure 

to chlorine gas in humans or animals. 

Acute-, intermediate-, and chronic inhalation studies of chlorine gas in animals are available. In these 

studies, the respiratory tract was also established as the target for chlorine toxicity. There are minimal 

data on neurological, lymphoreticular, reproductive, and genotoxic effects, as well as cancer, in animals. 

The available information on health effects of hypochlorous acid or sodium hypochlorite in humans is 

derived almost exclusively from cases of accidental or intentional ingestion of chlorine bleach. These 

observations indicate that the principal target for oral exposure to hypochlorite is the upper 

gastrointestinal tract. Ingestion of small amounts of chlorine bleach may only cause esophageal irritation, 

but ingestion of strong solutions of bleach can cause severe damage to the upper gastrointestinal tract and 

even death. There are no data on long-term exposure of humans to hypochlorite bleach. Since no target 

for chlorine toxicity has been identified in oral studies of various durations with dose levels much higher 

than those that could be generally encountered by the general population, oral MRLs for hypochlorite 

were not derived. Additional oral studies are not considered necessary except for the few exceptions 

indicated in Section 3.12.2 below. 

Information is available from acute-duration oral studies with hypochlorous acid or sodium hypochlorite 

in animals, which also indicates that the upper gastrointestinal tract is the main target of toxicity for 

concentrated bleach. Intermediate- and chronic-duration studies with hypochlorous acid or sodium 

hypochlorite in animals have examined systemic end points and also have provided limited information 

on immunological, neurological, reproductive, and developmental effects. There are cancer bioassays 

available with sodium hypochlorite in rats and mice. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 130 

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There are data that indicate that dermal exposure to hypochlorite bleach can cause skin irritation in 

humans and in animals. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. Information regarding health effects of acute exposure to chlorine gas is 

available from studies with volunteers (Anglen 1981; D’Alessandro et al. 1996; Rotman et al. 1983; 

Schins et al. 2000; Shusterman et al. 1998, 2003b), from exposures of soldiers during World War I (i.e., 

Berghoff 1919; DOA 1933; Joy 1997; Meakins and Priestley; Sandall 1922), and from accidental 

exposures of workers and the general public following chlorine leaks in a variety of scenarios (i.e., 

Agabiti et al. 2001; Agency for Toxic Substances and Disease Registry 1998; Bhérer et al. 1994; Bonetto 

et al. 2006; CDC 1991, 2005; Chasis et al. 1947; Chester et al. 1977; Edwards et al. 1983; Hasan et al. 

1983; Jones et al. 1986; Kowitz et al. 1967; Moulick et al. 1992; Salisbury et al. 1991; Schönhofer et al. 

1996; Sexton and Pronchik 1998; Weill et al. 1969). These and many additional studies showed that the 

respiratory tract is the target for chlorine toxicity and that the effects range from sensory irritation at low 

exposures (<5 ppm) to severe pulmonary effects (40–60 ppm) and possibly death (>100 ppm). 

Information is also available regarding long-term effects of acute high exposures to chlorine; some studies 

did not find persistent effects (i.e., Chasis et al. 1947; Jones et al. 1986; Moulick et al. 1992; Weill et al. 

1969), whereas others did (i.e., Bhérer et al. 1994; Kowitz et al. 1967; Salisbury et al. 1991). Further 

research on this issue is needed. The studies in volunteers provided sufficient information for derivation 

of an acute-duration inhalation MRL for chlorine gas. The studies in animals support the findings in 

humans and provided additional information regarding histopathological changes in the respiratory tract 

and duration and reversibility of the effects. Standard additional acute-duration inhalation studies of 

chlorine gas in animals do not seem necessary at this time. 

Information regarding health effects of hypochlorous acid and sodium hypochlorite in humans is derived 

exclusively from cases of accidental or intentional ingestion of hypochlorite bleach. These reports 

indicate that the upper gastrointestinal tract is the main target of toxicity for the oral route of exposure 

(Landau and Saunders 1964; Pike et al. 1963; Ross and Spiller 1999). The animal data support the 

findings in humans, but the available studies are inadequate for constructing dose-response relationships. 

Earlier studies in animals tried to reproduce the lesions to the esophagus and/or stomach due to ingestion 

of bleach. In most of these studies, commercial bleach was administered through a tube directly into the 

esophagus and, in some cases, the distal end of the esophagus was artificially occluded to prolong and 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 131 

3. HEALTH EFFECTS 

monitor the contact time between the solution and the mucosa (Hook and Lowry 1974; Landau and 

Saunders 1964; Strange et al. 1951; Yarington 1970). Two more recent studies were of very limited 

scope (Cunningham 1980) or reported ambiguous results (Meier et al. 1985). 

Dermal effects have been reported in a few cases of direct acute contact of the skin with high 

concentrations of chlorine gas in humans (Agency for Toxic Substances and Disease Registry 1998; 

Joyner and Durel 1962; NIOSH 1995), and eye irritation was reported in volunteers exposed to 1 ppm 

chlorine for up to 8 hours (Anglen 1981; Rotman et al. 1983). Information on dose-response for sensory 

irritation was used along with data on pulmonary effects to derive the acute-duration inhalation MRL for 

chlorine. Additional studies of sensory irritation with chlorine gas do not appear necessary at this time. 

Chlorine gas is not absorbed through the skin, so systemic effects due to contact of the skin with chlorine 

are not expected to occur. Dermal effects of hypochlorite bleach have been reported in humans and in 

animals (Habets et al. 1986; Hostynek et al. 1989, 1990; Nixon et al. 1975; Strange et al. 1951); therefore, 

additional dermal studies do not seem necessary at this time. 

Intermediate-Duration Exposure. No studies of humans exposed specifically for intermediate 

duration to chlorine gas were located. However, it is likely that in many of the occupational studies 

available, some workers were exposed for intermediate durations. Only two intermediate-duration studies 

in animals are available (Barrow et al. 1979; Kutzman 1983). Both studies utilized rats and in both 

studies, the most sensitive target for chlorine exposure was the respiratory tract. Barrow et al. (1979) 

described inflammation of the nasal turbinates in rats exposed to ≥1 ppm chlorine, whereas loss of cilia 

and epithelium in the trachea was seen in rats exposed to ≥0.5 ppm in the Kutzman (1983) study. The 

Kutzman (1983) study was selected as the principal study for derivation of an intermediate-duration 

inhalation MRL for chlorine. Additional intermediate-duration inhalation studies in animals do not seem 

necessary at this time. 

Two intermediate-duration studies in which volunteers were exposed to known amounts of total chlorine 

from chlorinated water provided no evidence of adverse effects (Lubbers et al. 1982; Wones et al. 1993). 

Few intermediate-duration studies in animals were located that examined a wide range of end points 

following exposure to hypochlorite. These studies showed that the main effect of exposure to solutions of 

hypochlorous acid or sodium hypochlorite, particularly at the higher concentrations levels, is a reduction 

of water intake that is due to taste aversion. The available intermediate-duration oral studies evaluated 

systemic toxicity (Abdel-Rahman et al. 1984; Cunningham 1980; Daniel et al. 1990, 1991; Furukawa et 

al. 1980) and also provided information, albeit limited, on immunological/lymphoreticular (Daniel et al. 
 

 

 

 

 

 

 

 

 

CHLORINE 132 

3. HEALTH EFFECTS 

1990, 1991; Exon et al. 1987), neurological (Daniel et al. 1990, 1991), reproductive (Carlton et al. 1986; 

Daniel et al. 1990, 1991), and developmental effects (Carlton et al. 1986). None of the available studies 

reported effects that could be attributed directly to chlorine or only reported effects that were considered 

of unknown toxicological significance. Additional intermediate-duration oral studies with hypochlorite 

do not seem necessary. It is also unclear what needed information would be provided in additional 

intermediate-duration dermal studies. 

Chronic-Duration Exposure and Cancer. There are relatively few long-term studies in workers 

exposed to chlorine gas (Enarson et al. 1984; Ferris et al. 1967, 1979; Hyback 1999; Patil et al. 1970). 

Health evaluations of the workers in these studies, including pulmonary function monitoring, did not 

provide evidence of significant health problems. In the Enarson et al. (1984) and Patil et al. (1970) 

studies, it was estimated that the workers were exposed to a TWA mean of 0.15–0.18 ppm chlorine. Yet, 

due to limitations, these long-term studies were insufficient for quantitative risk assessment. In none of 

the studies available was the nasal cavity, a sensitive target of chlorine exposure in humans and animals, 

examined. Therefore, evaluations of workers currently exposed to chlorine should include examination of 

the nasal cavity. In addition, future studies should include more reliable methods to estimate exposure. 

Two chronic-duration inhalation studies in animals are available. One of them studied the effects of 

chlorine inhalation in monkeys (Klonne et al. 1987) and the other in rats and mice (Wolf et al. 1995). In 

both, the upper respiratory tract was most sensitive end point and the study in monkeys was selected as 

basis for derivation of a chronic-duration inhalation MRL for chlorine gas. These studies also evaluated 

hematology and clinical chemistry parameters and, for the most part, no significant alterations were 

found. Additional chronic-duration inhalation studies of chlorine gas in animals do not seem necessary at 

this time. 

No chronic-duration human studies of exposure to hypochlorous acid or sodium hypochlorite were 

located. Three chronic-duration studies were available in rats and mice (Hasegawa et al. 1986; NTP 

1992). All three studies evaluated a comprehensive number of end points including hematology and 

clinical chemistry and tissue and organ histopathology and did not find any significant toxicity attributed 

to exposure to hypochlorite solutions. Additional chronic-duration oral studies with hypochlorite 

solutions are not necessary at this time. 

There are several studies of cancer in humans exposed to chlorine gas, and probably simultaneously to 

other chemicals that did not find any evidence that chlorine gas is carcinogenic (Barbone et al. 1992; 

Barregård et al. 1990; Bond et al. 1983, 1985, 1986; Heldaas et al. 1989). The chronic-duration 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 133 

3. HEALTH EFFECTS 

inhalation study in rats and mice exposed to chlorine for 2 years found no evidence of carcinogenicity at 

termination (Wolf et al. 1995). It is unclear what useful information additional studies with chlorine gas 

would provide. There are no studies of cancer in humans exposed to hypochlorite ions, and it is unlikely 

that such a cohort can ever be found. Studies of cancer in humans exposed to chlorinated water have been 

conducted, but the focus of these studies has not been the hypochlorite ion but the chlorinated byproducts 

derived from the reaction of chlorine with organic matter in the water (see Kantor [1994] for review). 

Long-term drinking water bioassays have been conducted in rats (Hasegawa et al. 1986; NTP 1992) and 

mice (Kurokawa et al. 1986; NTP 1992) and, with one exception, the results were negative. Equivocal 

evidence of increased leukemia was reported in female rats in the NTP (1992) study. A need to conduct 

additional drinking water studies in the F344 strain may be unwarranted given that: (1) mononuclear cell 

leukemia occurs with high incidence in F344 rats; (2) the increase in leukemia was slight and not clearly 

dose-related; (3) there was no decrease in tumor latency; and (4) the incidence in concurrent controls was 

less than in historical controls. Although an option would be to conduct a study in a different strain of rat, 

the need would still have to be balanced with the fact that epidemiologic data do not suggest such an 

effect in humans. 

Genotoxicity. No studies were located regarding genotoxic effects of chlorine gas in humans. The 

only information available in animals is that from a study in which blood and bone marrow from rats 

exposed to chlorine gas for 62 days showed no evidence on increased incidence of sister chromatid 

exchanges, chromosomal aberrations, or of cellular proliferation (Kutzman 1983). It does not appear that 

there is a need for additional genotoxicity studies for chlorine gas. Studies examining the in vivo 

genotoxicity of hypochlorite ions in mammals gave negative results (Hayashi et al. 1988; Meier et al. 

1985) and studies in vitro in animal cells and bacteria gave mixed results (Hagiwara et al. 2006; Ishidate 

et al. 1984; Le Curieux et al. 1993; Miyachi and Tsutsui 2005; Sasaki et al. 1980). It is unlikely that 

additional studies with hypochlorite will settle the issue. 

Reproductive Toxicity. The only information available regarding effect of chlorine gas in humans is 

that evaluation of the outcome of 15 pregnancies among female workers at a chlorine plant in 1932–1933 

did not provide any evidence of reproductive toxicity (Skljanskaja et al. 1935). Pre-exposure of male or 

female rats to up to 5 ppm chlorine for 62 days followed by mating with untreated rats resulted in no 

significant effects on fertility, number of corpora lutea, viable embryos, early or late deaths, or preimplantation loses. In addition, in males exposed for 62 days there were no histological alterations in the 

testes, and sperm morphology was unremarkable (Kutzman 1983). Chronic-duration inhalation studies 

with monkeys, rats, and mice exposed to up to 2.5 ppm chlorine did not observe gross or microscopic 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 134 

3. HEALTH EFFECTS 

lesions in the reproductive organs (Klonne et al. 1987; Wolf et al. 1995). It is plausible that accidental 

exposure of pregnant women to concentrations of chlorine high enough to produce severe hypoxia may 

affect pregnancy outcomes (i.e., stillbirth, abortions). Therefore, identification and evaluation of women 

who were pregnant during past chlorine accidents may provide valuable information. This can also be 

tested in animal models. 

There is no information regarding reproductive effects in humans exposed to hypochlorite solutions and 

there are limited data in animals. An acute-duration study reported sperm abnormalities in mice treated 

with sodium hypochlorite, but not in mice treated with hypochlorous acid (Meier et al. 1985). This and 

other internal inconsistencies make this finding of unknown toxicological significance. A study in rats 

exposed to hypochlorous acid by gavage before and during breeding reported no significant effects on 

fertility or on histopathology of the reproductive organs of males or females (Carlton et al. 1986). Sperm 

was examined in this study and no significant alterations were reported. Long-term drinking water 

studies in rats and mice did not report any gross or microscopic alterations in the reproductive organs of 

males and females (Daniel et al. 1991, 1991; Furukawa et al. 1980; Hasegawa et al. 1986; NTP 1992). 

Although 2-generation reproductive studies with sodium hypochlorite (in water devoid of organic matter 

to eliminate the formation of chlorination byproducts) have not been conducted, the available information 

does not suggest that reproductive parameters are sensitive targets for hypochlorite. Thus, additional oral 

studies do not appear necessary at this time. There are no studies that evaluated reproductive parameters 

in humans or animals following dermal exposure to hypochlorite. However, dermal exposure to 

hypochlorite bleach is expected to affect only the site of exposure. 

Developmental Toxicity. The only information available in humans exposed to chlorine gas is that 

evaluation of the outcome of 15 pregnancies among female workers at a chlorine plant in 1932–1933 did 

not provide any evidence of teratogenic effects (Skljanskaja et al. 1935). The same investigators reported 

that rabbits exposed to low chlorine concentrations (0.6–1.6 ppm) during pregnancy gave birth to healthy 

offspring (Skljanskaja and Rappoport 1935). There are no modern developmental studies of chlorine gas 

in animals. As mentioned in the preceding paragraph, exposure to high concentrations of chlorine gas 

during pregnancy could affect fetal or neonatal development, although so far, no study has examined that 

possibility. Therefore, identification and evaluation of women that were pregnant during past accidents in 

which chlorine gas was released may provide valuable information. Again, this can also be tested in 

animal models. 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 135 

3. HEALTH EFFECTS 

There is no information regarding developmental effects in humans exposed to hypochlorite. Only one 

reliable study in animals was available. In that study, exposure of pregnant rats to hypochlorous acid by 

gavage had no effect on neonate viability, weight gain, incidence of gross external abnormalities, or 

developmental landmarks (Carlton et al. 1986). Additional studies using a relevant means of 

administering chlorine, such as drinking water rather than gavage, may be necessary to confirm or refute 

the results of Carlton et al. (1986). There are no studies that evaluated developmental parameters in 

humans or animals following dermal exposure to hypochlorite bleach. However, as mentioned above, 

dermal exposure to bleach is expected to affect only the site of exposure. 

Immunotoxicity. No studies were located that evaluated immunocompetence or effects on 

lymphoreticular organs in humans following exposure to chlorine gas. Studies in workers did not provide 

any evidence that exposure to chlorine gas may affect immunocompetence. A 6-week study reported that 

the spleen and thymus from rats exposed to 9 ppm chlorine showed decreased content of lymphoid 

elements, but according to the investigators, this may have been a function of the poor physical condition 

and decreased nutritional state of the rats in that dosing group (Barrow et al. 1979). Chronic-duration 

inhalation studies in moneys, rats, and mice found no gross or microscopic lesions in lymphoreticular 

organs and tissues (Klonne et al. 1987; Wolf et al. 1995). The immune system does not seem to be a 

sensitive target for chlorine gas toxicity; additional studies of the immune system in animals exposed by 

inhalation to chlorine gas are not necessary at this time. 

There is no information regarding effects on the immune system in humans following oral exposure to 

chlorine. One study reported that exposure of rats to chlorine in the drinking water for 8 weeks resulted 

in alterations in some immune parameters (Exon et al. 1987). The toxicological significance of these 

findings is difficult to ascertain because there is no known mechanism by which oral administration of 

chlorine could induce immunological effects and no additional studies that could corroborate these 

findings. It is possible that oxidative reactions play a role in the effects reported by Exon et al. (1987). 

Other intermediate-duration studies and chronic-duration studies in rats and mice dosed with much higher 

doses of chlorine in the drinking water found no gross or microscopic alterations in lymphoreticular 

organs, but did not examine immunocompetence (Daniel et al. 1990, 1991; Furukawa et al. 1980; 

Hasegawa et al. 1986; NTP 1992). It would be useful to try to replicate the findings from Exon et al. 

(1987) adding to the protocol challenges with microorganisms to determine whether the reported 

alterations translate into decreased immunity. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 136 

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Sodium hypochlorite is generally not considered a skin sensitizer, but several cases of allergic contact 

dermatitis have been reported (Eun et al. 1984; Habets et al. 1986; Osmundsen 1978; Van Joost et al. 

1987). Additional dermal studies are not necessary 

Neurotoxicity. A series of studies by Kilburn (1995, 2000, 2003b) suggested that brief exposures to 

high concentrations of chlorine gas can result in long-term neurological alterations in humans. No other 

high-exposure studies in humans have reported similar effects, but no neurobehavioral tests have been 

conducted in these studies. Therefore, it would be useful to conduct neurobehavioral evaluations in 

subjects known to have been exposed to high concentrations of chlorine to confirm or refute Kilburn’s 

findings. The study should include comparison populations matched for the prior occurrence of a nonchemically related traumatic event. In addition, there are several validated animal models that have been 

used to test for neurobehavioral effects of chemicals (i.e., lead) that could be used to test for possible 

chlorine effects. The available studies in animals have provided no evidence of gross or microscopic 

alterations in tissues of the central or peripheral nervous system following exposure to chlorine gas. 

There is no information regarding neurological effects in humans following exposure to hypochlorite 

bleach. The only information relevant information in animals is that from 90-day and 2-year studies that 

found no gross or microscopic alterations in the brain from rats and mice exposed to chlorine in the 

drinking water (Daniel et al. 1990, 1991; Furukawa et al. 1980; Hasegawa et al. 1986; NTP 1992). No 

further neurological end points were evaluated in these studies. Since the nervous system does not seem 

to be a sensitive target for oral chlorine, there is no compelling reason to conduct additional studies. 

Epidemiological and Human Dosimetry Studies. There is a considerable number of studies of 

humans exposed to chlorine gas (see Section 3.2.1.2 for representative references). The effects of acute 

exposure to high concentrations of chlorine gas are known and concentration-response relationships have 

been established (Ellenhorn and Barceloux 1988). However, less is known about long-term effects of 

high acute exposures to chlorine gas and low-level, long-term exposure. As previously mentioned, some 

studies have described persistent pulmonary alterations following acute exposure to chlorine gas (i.e., 

Bhérer et al. 1994; Kowitz et al. 1967; Salisbury et al. 1991), whereas others have not (i.e., Chasis et al. 

1947; Jones et al. 1986; Moulick et al. 1992; Weill et al. 1969). Better exposure data and baseline health 

information would seem necessary to establish reliable correlations between exposure and effects. Also, 

evaluation of the nasal cavity of low-level, long-term exposure to chlorine gas seems warranted in light of 

the findings of Klonne et al. (1987) in monkeys exposed to chlorine for 1 year. 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 137 

3. HEALTH EFFECTS 

Exposure to hypochlorous acid or sodium hypochlorite can occur by accidental or intentional ingestion of 

chlorine bleach. This type of exposure is generally of acute duration and, in most cases, the effects are 

restricted to esophageal irritation without long-term consequences (Hook and Lowry 1974; Landau and 

Saunders 1964; Pike et al. 1963). As discussed in Chapters 4 and 6, the level of dissolved chlorine in 

drinking water is extremely low and most of the free chlorine is as hypochlorous acid at the normal pH of 

drinking water. The highest level of chlorine allowed in drinking water is 4 ppm (EPA 2006a), which is 

considerably lower than the maximal concentration of chlorine used in long-term studies (275 ppm 

available chlorine) in rats and mice (NTP 1992), which caused no significant toxicity. Therefore, it seems 

unlikely that free chlorine in drinking water will represent a health concern for humans. It should be 

noted, however, that chlorinated water contains a variety of chlorinated byproducts whose biological 

effects continue to be studied. 

Biomarkers of Exposure and Effect. 

Exposure. There are no specific biomarkers of exposure for chlorine in humans. Chlorine gas that enters 

the airways or chlorine ingested as sodium hypochlorite eventually joins the chloride pool in the body. 

A recent study showed that exposure of rats to chlorine gas (0.5–2.5 ppm) for 90 minutes resulted in 

dose-related formation of 3-chlorotyrosine and 3,5-dichlorotyrosine in nasal tissue (Sochaski et al. 2008). 

Since the method could not be used in humans due to the invasive nature of the tissue collection, 

additional research needs to be conducted to make the method less invasive. In addition, it would be 

valuable to determine whether exposure to other chlorinated compounds also result in the formation of 

these potential biomarkers. 

Effect. There are no biomarkers of effect specific for chlorine. The sensory irritation and respiratory 

alterations caused by exposure to chlorine gas or the esophageal irritation caused by ingestion of 

hypochlorite bleach can also be caused by other chemicals. 

Absorption, Distribution, Metabolism, and Excretion. The only information regarding 

pharmacokinetics of chlorine gas is that from experiments in volunteers conducted by Nodelman and 

Ultman (1999a, 1999b) that showed that almost all (>95%) of a bolus dose of chlorine gas inhaled 

through the mouth or the nose is cleared by the upper respiratory tract and none reaches the lungs. This 

was observed over a 0.5–3 ppm exposure range. The methodology used to generate the bolus and to 

monitor the concentrations of chlorine in the airways could probably be adapted to studies in animals, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 138 

3. HEALTH EFFECTS 

particularly monkeys, to test a wider range of concentrations and to correlate internal concentrations of 

chlorine with lesions in the respiratory tract. 

There is only one study of the pharmacokinetics of hypochlorite, the study by Abdel-Rahman et al. (1983) 

that evaluated absorption, metabolism, distribution, and excretion of chlorine in rats following gavage 

doses or radiolabeled (36Cl) hypochlorous acid. Additional studies may be useful to confirm or refute the 

findings of Abdel-Rahman et al. (1983). On the other hand, as Scully et al. (1989) pointed out, because 

hypochlorite is a potent oxidant, pharmacokinetic studies of radiolabeled hypochlorous acid (36Cl) in 

animals do not reveal what happens to the parent compound, but rather to the product of the reactions of 

these compounds in vivo. Therefore, the usefulness of additional studies is questionable. As previously 

mentioned, a computational fluid dynamics-physiologically based pharmacokinetic model is being 

developed for chlorine (Jarabek et al. 2007). 

Comparative Toxicokinetics. The nature and distribution of lesions in the respiratory tract of 

monkeys were compared with those in rats and mice following chronic exposure to comparable 

concentrations (Ibanes et al. 1996). The investigators noted that monkeys and rodents exhibited both 

differences and similarities that were most likely related to the differences in airflow characteristics. 

Intuitively, it would seem that monkeys are a better model for human risk assessment because rodents are 

obligate nose breathers, whereas humans and monkeys are not. However, Ibanes et al. (1996) concluded 

that with appropriate exposure and response adjustments, both rodents and Rhesus monkeys appear to be 

valid models for human risk assessment. 

An animal model for human exposure to hypochlorite has not been identified. Studies in rats and mice 

exposed to sodium hypochlorite by the oral route for 90 days or 2 years showed practically no toxicity of 

at the concentrations of chlorine tested (Daniel et al. 1990, 1991; NTP 1992). The gastrointestinal effects 

observed in humans after ingestion of high amounts of hypochlorite bleach (i.e., Ross and Spiller 1999) 

are similar to those described in earlier studies in dogs and rabbits exposed also to high amounts of 

hypochlorite bleach (Landau and Saunders 1964; Strange et al. 1951; Yarington 1970). Additional 

comparative studies do not seem necessary at this time. 

Methods for Reducing Toxic Effects. The treatment of chlorine exposure is mostly supportive of 

respiratory and cardiovascular functions. The efficacy of some specific agents such as corticosteroids or 

nebulized sodium bicarbonate for the treatment of respiratory alterations due to exposure to chlorine gas 

has not been properly documented and further studies in animal models would be valuable. 
 

 

 

 

 

 

 

 

CHLORINE 139 

3. HEALTH 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. 

Children exposed to high concentrations of chlorine gas or hypochlorite solutions have experienced 

effects similar to those observed in adults, although some reports have suggested that children may more 

susceptible to chlorine gas toxicity than adults (Agency for Toxic Substances and Disease Registry 1998; 

Güloğlu et al. 2002). Children may be at increased risk for exposure to chlorine gas because they have a 

greater lung surface area:body weight ratio and an increased minute volume:weight ratio. Children may 

also be more vulnerable than adults because of the smaller diameter of their airways. Prolonged low-level 

exposures to chlorine gas are not relevant to children since this type of exposure occurs only in 

occupational settings. There are no studies that have examined whether young animals are more or less 

susceptible than adults to chlorine gas or hypochlorite toxicity. Additional information on this issue 

would be useful. 

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 

The following ongoing studies pertaining to chlorine were identified in the Federal Research in Progress 

database (FEDRIP 2009): 

Dr. M.D. Gunn and coworkers at Duke University, plan to conduct a series of murine studies to determine 

the extent to which specific pulmonary inflammatory cell types contribute to chlorine-induced lung injury 

and the consequent epithelial damage, bronchial reactivity, morbidity, and mortality. He will then 

examine the ability of the chemokine receptor antagonist to reduce these toxicities. The research is 

sponsored by the National Institute of Environmental Health Sciences (NIEHS). 

Dr. S-E. Jordt and coworkers at the University of Alabama, Birmingham, intend to develop 

pharmacological approaches for the treatment of asthma patients after exposure to chlorine. Based on 

preliminary results indicating that the TRPA1, an ion channel of the transient receptor potential (TRP) 

gene family, is strongly activated by chlorine in primary and heterologous cells, the investigators 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 140 

3. HEALTH EFFECTS 

hypothesized that post-exposure administration of TRP channel antagonist, in combination with 

adrenergic agonists and antioxidants, will counteract life-threatening hypersensitivity responses in asthma 

patients to chlorine and other pulmonary chemical threats. Specifically the investigators intend to 

(1) compare responses of wild-type and TRP-channel deficient mice to chlorine in the background of the 

ovalbumin asthma model, (2) establish pharmacological measures to counteract chlorine hypersensitivity 

responses and chlorine-induced tissue damage in asthma, and (3) analyze the mechanism of TRPA1 

activation and sensitization by chlorine, and its reversal. The research is sponsored by the NIEHS. 

Dr. S. Matalon and associates at the University of Alabama, Birmingham, plan to test the hypothesis that 

the toxic effects of C12 will be heightened in animals infected with respiratory syncytial virus (RSV) or 

challenged with ova albumin. For that purpose, they will perform a number of biochemical, biophysical, 

physiological, and morphometric measurements in RSV infected and ova albumin challenged mice as 

well as normal rats prior to and following chlorine exposure to document the onset and progression of 

injury to lung epithelia and pulmonary and systemic vasculature. They will then treat the mice with 

antioxidants, TRP antagonists, and nitrite administered at various intervals post chlorine exposure either 

intratracheally or via aerosolization, or intraperitoneally (antioxidants and nitrite) and quantify recovery 

by specific functional measurements. The research is sponsored by the NIEHS. 

Dr. S. Matalon and coworkers at the University of Alabama, Birmingham, also plan to determine whether 

systemic administration of reactive species scavengers, as well as agents that augment surfactant levels, 

ion transport and paracellular resistance, and a recently described peptide based on the lectin region of 

TNFa (tip peptide), shortly after exposure to chlorine will decrease lung injury, morbidity and mortality. 

This hypothesis will be tested by exposing either confluent monolayers of rat alveolar type II (ATII) 

epithelial cells or rats to chlorine (50–200 ppm for 30 minutes) and measuring a number physiological 

and biochemical indices of lung function 0.5, 6, 12, and 24 hours post exposure. The measurements will 

be repeated following intravenous injections of NAC, ascorbate, and deferoxamine as well as albuterol 

and the tip peptide. They will also assess the efficacy of intratracheally instilled ascorbate, NAC, 

deferoxamine, Infasurf (a surfactant replacement mixture), albuterol and the tip peptide, as well as 

aerosolized albuterol, in prolonging survival of rats with respiratory failure following chlorine exposure. 

The research is sponsored by the NIEHS. 

Dr. P.R. Patel and coworkers at the University of Alabama, Birmingham, hypothesize that chlorine gas 

exposure induces both pulmonary and systemic vascular injury, which will be inhibited by nitritedependent NO formation. The investigators propose to test this via the following specific aims: (1) test 
 

 

 

CHLORINE 141 

3. HEALTH EFFECTS 

the hypothesis that inactivation of eNOS leads to compromised pulmonary and systemic vascular 

function, (2) establish protective effects of nitrite administration to rats following chlorine gas exposure 

on cardiopulmonary function, and (3) determine the mechanism by which nitrite therapy protects against 

C12 gas induced cardiopulmonary toxicity. 
 

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CHLORINE 143 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Information regarding the chemical identity of chlorine is located in Table 4-1. This information includes 

synonyms, chemical formula and structure, and identification numbers. For the purpose of 

disambiguation, terms that are commonly used in reference to chlorinated water are defined in Table 4-2. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Information regarding the physical and chemical properties of chlorine is located in Table 4-3. 

Chlorine (Cl2) is a heavier-than-air, greenish-yellow gas with a pungent, irritating odor (HSDB 2009). 

The odor threshold for chlorine in air is generally between 0.2 and 0.4 ppm (Amoore and Hautala 1983; 

The Chlorine Institute 1998). Perceivable sensory irritation occurs at 1.0 ppm in air (EPA 1999). 

Chlorine is a nonflammable gas; however, it is a very strong oxidizing agent, reacting explosively or 

forming explosive compounds or mixtures with many common chemicals (O'Neil et al. 2001). Chlorine 

reacts directly with nearly all of the elements to form chlorides (Lide 2005; O'Neil et al. 2001). Chlorine 

is stored and transported as a liquid in pressurized containers (EPA 1999). Chlorine is transported as 

either a liquid or a gas through pipelines within chemical plants or over distances of several kilometers 

(Schmittinger et al. 2006). 

Chlorine hydrolyzes rapidly and almost completely in water to form hydrochloric acid, hypochlorous 

acid, and hypochlorite as follows: 

Cl2 + H2O HOCl + H+ + ClH+ + OCl- HOCl 

The equilibrium constants for these reactions are represented by: 

[ HOCl ][H + ][Cl − ] K 1 = [ Cl 2 ] (1)
 
 

 

 


 


 


 


 


 


 


 

CHLORINE 144 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Chlorinea 

Characteristic Information 

Chemical name Chlorine 

Synonyms/trade names Chlorine gasb, Bertholite, molecular chlorine, chlorine mol, dichlorine 

Chemical formula Cl2 

Chemical structure Cl Cl 

Identification numbers: 

CAS registry 7782-50-5
 

NIOSH RTECS FO2100000c
 

EPA hazardous waste No data
 

DOT/UN/NA/IMCO shipping UN1017; IMO 2.0
 

HSDB 206
 

EINECS 231-959-5c
 

NCI No data
 

a

All information obtained from HSDB 2009 except where noted.

b

EPA 1999 

c

IPCS 1996 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMO = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EINECS = European Inventory of Existing Commercial 

Chemical Substances; EPA = Environmental Protection Agency; HSDB = Hazardous Substances Data Bank; NCI = 

National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; RTECS = Registry of Toxic 

Effects of Chemical Substances 
 

 

 

 

 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

CHLORINE	 145 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Commonly Used Terms Related to Chlorinated Water 

Term	 Meaning 

Chlorinated water	 The solution that results when molecular chlorine or a hypochlorite salt is 

added to water for the purpose of water disinfection. Molecular chlorine 

reacts rapidly with water under environmental conditions to form 

hypochlorous acid, hypochlorite, and hydrochloric acid; therefore, 

chlorinated water does not contain molecular chlorine under normal 

conditions. Some other substances that are commonly formed in 

chlorinated water include oxidized inorganics, chloramines, and 

trihalomethanes. 

Free chlorine	 The combination of the equilibrium species molecular chlorine, 

hypochlorous acid, and the hypochlorite ion in chlorinated water. Since 

molecular chlorine is usually not present in water samples, this term 

usually refers to the amount of hypochlorous acid and hypochlorite in 

water. 

Combined chlorine	 The amount of chloramines (chlorine combined with nitrogen) present in 

chlorinated water. 

Total chlorine	 The amount of free chlorine (hypochlorous acid and hypochlorite) plus 

combined chlorine (chloramines) present in chlorinated water. 

Available chlorine	 A measure of the oxidizing strength of a solution. It is equal to the 

amount of molecular chlorine that when added to water would produce a 

solution with equivalent oxidizing power. It is commonly reported as 

weight percent. 

Residual chlorine	 The amount of free chlorine remaining in a chlorinated water sample that 

has been collected at a point of use. This indicates whether the water 

has retained its disinfection properties. 

Aqueous chlorine	 A term that usually has a meaning similar to that of free chlorine. In this 

sense, “aqueous chlorine” should not be misunderstood as the amount of 

molecular chlorine in water (aqueous molecular chlorine). The term 

“aqueous chlorine” is commonly used in reference to a prepared aqueous 

solution of hypochlorite and hypochlorous acid. 

Sources: APHA 1998a; Edstrom Industries 2003; Fukayama et al. 1986; IARC 1991; The Chlorine Institute 2006; 

Westerhoff et al. 2004; WHO 2007. 
 

 

 

 

 

 


 


 

CHLORINE 146 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-3. Physical and Chemical Properties of Chlorinea 

Property Information 

Molecular weight 70.905 

Color Greenish-yellow 

Physical state Gas 

Melting point -101.00 °C 

Boiling point -34.04 °C 

Density in air 2.482 (air=1)b 

Density, as liquid 

20 °C, 6.864 atm 1.4085 g/mLc 

-35 °C, 0.9949 atm 1.5648 g/mLc 

Odor Pungent, irritating 

Odor threshold: 

Water Not applicabled
 

Air 0.2–0.4 ppmc,e,f
 

Solubility: 

Water 14.6 g/L at 0 °C; 7.3 g/L at 20 °Cc,g 

Other solvents Glacial acetic acid, dimethylformamide, nitrobenzene, phosphoryl 

chloride, carbon tetrachloride, tetrachloroethane, pentachloroethane, 

hexachlorobutadiene, and chlorobenzeneh 

Partition coefficients: 

Log Kow Not applicable 

Log Koc Not applicable 

Vapor pressure at 25 °C 5,830 mm Hg 

Henry's law constant 1.17x10-2 atm-m3/moli 

Autoignition temperature Not applicable 

Flashpoint Not applicable 

Reactivity Strong oxidizer; reacts explosively with many materials 

Conversion factors 1 ppm=2.9 mg/m3; 1 mg/m3=0.344 ppmc 

a

All information obtained from HSDB 2009, except where noted.

b

O'Neil et al. 2001 

c

EPA 1999 

d

Amoore and Hautala (1983) reported an odor threshold of 0.002 ppm for chlorine in water; however, these authors 

state that this solution lacks enough persistence for this value to be used for reference purposes. 

e

Amoore and Hautala 1983 

f

CI 1998 

g

EPA 1994b 

h

Schmittinger et al. 1996 

i

Staudinger and Roberts 1996 
 

 

 

CHLORINE 147 

4. CHEMICAL AND PHYSICAL INFORMATION 

(2) 

The relative percentage of Cl2, HOCl, and OCl- at some fixed concentration of Clcan be expressed as: 

(3) 

(4) 

(5) 

Using the expressions for the equilibrium constants in Equations 1 and 2 and the relationship that pH is 

equivalent to the negative logarithm of the hydronium ion concentration, Equations 3–5 can be re-written 

as: 

(6) 

1+ 10 + 10 

[Cl − ] [Cl − ] 

(7) 

− 1 %OCl = − (8) [Cl ] 1 1+ + 2 pH pH K K 1 210 K210 

[ H + ][OCl − ] K 2 = [ HOCl ]

][][][ 

][ % 

2 

2 

2 − ++ = Cl HOCl OCl 

Cl Cl 

][][][ 

][ % 

2 

− ++ = Cl HOCl OCl 

HOCl HOCl 

][][][ 

][ % 

2 

−

−

−

++ = Cl HOCl OCl 

OCl OCl 

K pH KK pH

Cl 

1 21 2

2 

1 % =

pH 

pH K 

K 

Cl 

HOCl 

10 

10 

][ 1 

1 % 

2 

1 

++

= −

Figure 4-1 illustrates the speciation as a function of pH using values for K1 = 3.9x10-4 M2 (Cotton et al. 

1999; Farr et al. 2003) and K2 = 2.9x10-8 M (Farr et al. 2003) at 25 °C. This figure shows the 

 


 


 


 


 


 


 


 


 


 


 


 

CHLORINE 148 

4. CHEMICAL AND PHYSICAL INFORMATION 

Figure 4-1. Speciation of Cl2, HOCl, and OCl- as a Function of pH 

100
 

90
 

80
 

70
 

60
 

50
 Cl2 

HOCl 40
 

OCl­ 30
 

20
 

10
 

0
 

pH 

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
 

% Species 
 

CHLORINE 149 

4. CHEMICAL AND PHYSICAL INFORMATION 

pH-dependant relationship between molecular chlorine, hypochlorous acid, and hypochlorite in aqueous 

solution. Sodium hypochlorite bleach solutions typically have a pH of 11–13 (The Chlorine Institute 

2006). As illustrated in Figure 4-1, the addition of acid to a hypochlorite solution (e.g., mixing of sodium 

hypochlorite bleach with acid drain cleaner) can drive the pH low enough to result in the release of 

dangerous amounts of molecular chlorine gas. 
CHLORINE 150
 

4. CHEMICAL AND PHYSICAL INFORMATION 

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CHLORINE 151 

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

5.1 PRODUCTION 

The element chlorine was discovered in 1774, and the first patent for its use as a bleaching agent came as 

early as 1799 (Deutsch 1947). However, it wasn't until the late 1800s that adequate electrolytic 

equipment became available to produce chlorine on an industrial scale. Chlorine production increased 

steadily from 5,400 metric tons in 1900 to 63,500 metric tons in 1920 (Deutsch et al. 1963). U.S. chlorine 

production then underwent an extremely dramatic increase over the next 50 years. Production volumes in 

1930, 1940, 1950, 1960, and 1970 were 181,000, 608,000, 1,814,000, 4,172,000, and 8,800,000 metric 

tons, respectively (Curlin et al. 1991; Deutsch et al. 1963; Robertson 1978). Reasons for this increase 

were the demand for use of chlorine as a bleaching agent, the demand for its use in the manufacture of 

other important industrial chemicals, and the further development of electrolytic cell technology, which 

improved plant production capacities by almost 200% (Bommaraju et al. 2004; Deutsch et al. 1963). 

Growth during this period was supported by the widespread construction of chlorine-producing plants by 

alkali producers who were interested in manufacturing chlorine and caustic soda (sodium hydroxide) as 

co-products, an effort that gave birth to the chlor-alkali industry (Bommaraju et al. 2004; Deutsch et al. 

1963; Schmittinger et al. 2006). In 1915, there were only 15 chlorine-producing factories in the United 

States; by 1960, there were 240 (Deutsch et al. 1963). 

During the 1970s and 1980s, U.S. chlorine production fluctuated between 11,200,000 metric tons in 1979 

and 8,300,000 metric tons in 1982 (Curlin et al. 1991). Chlorine production rose steadily through the 

1990s, reaching 12,100,000 metric tons in 1999 (The Chlorine Institute 2008). With the exception of a 

spike to 12,300,000 metric tons in 2004, production has steadily declined over the past decade (The 

Chlorine Institute 2008). The 2008 U.S. production volume for chlorine was reported to be 

10,600,000 metric tons by the U.S. Census Bureau (2009). Environmental pressures have strained the 

chlorine market since the 1970s. Regulations have contributed to such changes as moving away from the 

use of mercury and asbestos in chlorine production, ending the use of chlorine in pulp and paper 

bleaching, and curtailing the production of certain chlorinated end products (Bommaraju et al. 2004; 

CMR 1977, 1980, 1989, 1992, 1995, 2000, 2003, 2006; Robertson 1978; Schmittinger et al. 2006). 

Negative effects on the market have been balanced by the development of alternative chlorine production 

methods and increases in demand for other chlorine end products, especially polyvinyl chloride. 

Although there are still operational facilities that use the older mercury and asbestos production methods, 

the newer chlorine production facilities are based on the more efficient membrane technology 

(Bommaraju et al. 2004; The Chlorine Institute 2008). The companies that produced chlorine in the 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 152 

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

United States, their production sites, and their annual capacities for 2008 (the most recent year for which 

figures are available) are shown in Table 5-1 (SRI 2008). 

Table 5-2 summarizes the number of facilities in each state that manufactured or processed chlorine (Cl2) 

in 2006, the ranges of maximum amounts on site, if reported, and the activities and uses as reported in the 

Toxics Release Inventory (TRI) (TRI06 2008). The data listed in this table should be used with caution 

since only certain types of facilities are required to report. This is not an exhaustive list. 

5.2 IMPORT/EXPORT 

Annual U.S. chlorine import and export quantities reported for different years are listed in Table 5-3. The 

available data indicate that annual imports of chlorine into the United States have increased steadily over 

the past 20 years, rising from 251,000 metric tons in 1984 to 429,000 metric tons in 2007 (CMR 1989, 

1992, 2000; HSDB 2009; ITA 2007; U.S. Census Bureau 2008). The decline in U.S. chlorine exports 

during the early 2000s (24,200 metric tons in 2000 to 10,400 metric tons in 2004) has been attributed to 

increasing energy costs, which have rendered the chlorine produced in the United States uncompetitive, 

especially in the Asian market (CMR 2006; ITA 2007). However, U.S. chlorine exports in 2006 were 

bolstered by a 9-fold increase in shipments to Mexico, accounting for approximately 82% (32,201 metric 

tons) of the 39,481 metric tons of chlorine exported during that year (ITA 2007). U.S. exports of chlorine 

fell to 25,740 in 2007 (US Census Bureau 2008). 

5.3 USE 

The major uses of chlorine during 2006 were the manufacturing of vinyl chloride to make polyvinyl 

chloride (PVC) plastics (36%), the manufacturing of other organic compounds (41%), the manufacturing 

of inorganic chemicals (15%), water treatment (4%), and pulp and paper bleaching (1%) (CMR 2006). 

Other miscellaneous uses accounted for 3% of total chlorine use during 2006. Chlorine is used in the 

production of a large number of commercial products (Bommaraju et al. 2004; Schmittinger et al. 2006). 

Some of the important end products for which chlorine plays a role in the production stream include 

refrigerants, aerosols, silicones, silicone rubber, plastics, solvents, polyethers, varnishes, foams, 

chlorinated rubber, polyurethane, detergents, dyes, insecticides, pesticides, disinfectants, bleaches, and 

white pigment enamel (Schmittinger et al. 2006). Chlorine has been used in the food industry as a 

bleaching agent for flour (Fukayama et al. 1986). Chlorine was used as a war gas during World War I 

(Compton 1987). Chlorine is also used to manufacture phosgene (O’Neil et al. 2001). 
 

 

 

 

 


 


 

CHLORINE 153 

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

Table 5-1. Companies that Produce Chlorine in the United States and Annual
 

Capacities for 2006
 

Capacity (thousands Capacity 

Company Location of short tons)a (metric tons)a 

ASHTA Chemicals, Inc. Ashtabula, Ohio 44 40,000 

Bayer MaterialScience LLC Baytown, Texas 400 363,000 

The Dow Chemical Company Freeport, Texas 3,240 2,939,000 

Plaquemine, Louisiana 1,070 971,000 

E.I. du Pont de Nemours and Niagara Falls, New York 85 77,000 

Company; DuPont Coatings and 

Color Technologies; DuPont 

Performance Coatings 

Equa-chlor LLC Longview, Washington 87 79,000 

ERCO Worldwide, Inc. Port Edwards, Wisconsin 106 96,000 

Formosa Plastics Corporation Point Comfort, Texas 811 736,000 

Georgia Gulf Corporation Plaquemine, Louisiana 450 408,000 

Georgia-Pacific Chemicals LLC Green Bay, Wisconsin 9 8,000 

Muskogee, Oklahoma 6 5,000 

Rincon, Georgia 7 6,000 

Kuehne Chemical Corporation Delaware City, Delaware 16 15,000 

Occidental Chemical Corporation; Convent, Louisiana 389 353,000 

Chloro-Vinyls Group Corpus Christi, Texas 604 548,000 

Geismar, Louisiana 268 243,000 

Hahnville, Louisiana 750 680,000 

Mobile, Alabama 50 45,000 

Muscle Shoals, Alabama 150 136,000 

New Castle, Delaware 90 82,000 

Niagara Falls, New York 335 304,000 

Wichita, Kansas 263 239,000 

Olin Corporation; Olin Chlor Alkali Augusta, Georgia 120 109,000 

Products Division Charleston, Tennessee 245 222,000 

Henderson, Nevada 152 138,000 

McIntosh, Alabama 735 667,000 

Niagara Falls, New York 286 259,000 

St. Gabriel, Louisiana 180 163,000 

OxyVinyls, L.P. La Porte, Texas 580 526,000 

PPG Industries, Inc.; Lake Charles, Louisiana 1,375 1,247,000 

Chemical Group Natrium, West Virginia 510 463,000 
 


 


 

CHLORINE 154 

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

Table 5-1. Companies that Produce Chlorine in the United States and Annual
 

Capacities for 2006
 

Capacity (thousands Capacity 

Company Location of short tons)a (metric tons)a 

SABIC Innovative Plastics Burkville, Alabama 90 82,000 

Mount Vernon, Indiana 96 87,000 

Titanium Metals Corporation Henderson, Nevada 5 5,000 

Trans Carolina Products LLC Hamlet, North Carolina Not available Not available 

U.S. Magnesium, LLC Rowley, Utah 47 43,000 

Westlake Vinyls, Inc. Calvert City, Kentucky 205 186,000 

Total 13,856 12,570,000 

a

Much of the capacity is consumed captively. 

Source: SRI 2008; The Chlorine Institute 2008 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 155 

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

Table 5-2. Facilities that Produce, Process, or Use Chlorine 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AK 13 0 9,999,999 1, 2, 3, 5, 6, 7, 10, 11, 12, 13, 14 

AL 134 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AR 67 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

AS 2 1,000 9,999 11, 12 

AZ 44 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 

CA 143 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

CO 19 0 49,999,999 1, 2, 3, 4, 5, 6, 9, 10, 11, 12 

CT 28 0 999,999 1, 2, 3, 4, 5, 6, 7, 10, 11, 12 

DC 1 100,000 999,999 12 

DE 31 100 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 

FL 109 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

GA 105 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13 

GU 2 10,000 999,999 9, 12 

HI 18 0 9,999,999 1, 2, 3, 4, 6, 8, 10, 11, 12 

IA 46 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 10, 11, 12 

ID 36 0 9,999,999 1, 2, 3, 5, 6, 7, 10, 11, 12, 13, 14 

IL 72 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

IN 67 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

KS 37 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12 

KY 81 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

LA 180 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MA 25 0 999,999 1, 2, 3, 5, 6, 7, 9, 10, 11, 12 

MD 41 100 49,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13 

ME 63 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13 

MI 104 0 499,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13 

MN 67 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

MO 55 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MS 76 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MT 11 1,000 9,999,999 1, 4, 5, 7, 10, 11, 12, 13 

NC 118 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

ND 9 100 999,999 1, 2, 3, 5, 6, 10, 11, 12 

NE 18 100 49,999,999 1, 2, 3, 4, 6, 9, 10, 11, 12 

NH 12 0 9,999,999 1, 2, 3, 5, 6, 9, 12, 13 

NJ 66 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NM 19 0 9,999,999 1, 2, 3, 4, 5, 6, 9, 11, 12 

NV 31 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 156 

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

Table 5-2. Facilities that Produce, Process, or Use Chlorine 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

NY 106 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

OH 120 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

OK 48 0 49,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13 

OR 55 0 9,999,999 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13 

PA 102 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

PR 27 0 49,999,999 2, 3, 4, 6, 7, 10, 11, 12 

RI 15 100 9,999,999 1, 2, 3, 4, 6, 9, 10, 11, 12 

SC 94 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

SD 9 100 999,999 7, 10, 11, 12 

TN 99 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

TX 197 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 40 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

VA 66 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

VT 2 1,000 9,999 11, 12 

WA 102 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

WI 107 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WV 52 0 499,999,999 1, 2, 3, 4, 5, 6, 9, 10, 11, 12, 13 

WY 13 1,000 999,999 1, 2, 3, 5, 10, 11, 12, 13 

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 

Source: TRI06 2008 (Data are from 2006) 
 

CHLORINE 157 

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

Table 5-3. U.S. Chlorine Imports and Exports by Year in Metric Tons 

Year Imports Exports Reference 

1975 67,000 15,000 Robertson 1978 

1984 251,000 39,500 HSDB 2007 

1986 298,739 Not available HSDB 2007 

1987 Not available 3,787 HSDB 2007 

1988 280,840 58,073 CMR 1989 

1991 272,160 Not available CMR 1992 

1998 373,766 22,680 CMR 2000 

1999 325,685 21,773 CMR 2000 

2000 358,015 24,231 ITA 2007 

2001 358,060 20,964 ITA 2007 

2002 409,695 18,566 ITA 2007 

2003 412,117 15,361 ITA 2007 

2004 470,884 10,448 ITA 2007 

2005 476,103 12,306 ITA 2007 

2006 454,414 39,481 ITA 2007 

2007 429,440 25,740 U.S. Census Bureau 2008 
 

 

 

CHLORINE 158 

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

5.4 DISPOSAL 

Chlorine is disposed of via a salt-forming reaction followed by neutralization (HSDB 2009). Chlorine 

gas is first introduced into a large volume solution of a reducing agent such as sodium thiosulfate, 

bisulfite, or ferrous salts or aqueous sodium hydroxide (HSDB 2009). The resulting salt solution is then 

neutralized and routed to a sewage treatment plant (HSDB 2009). 
 

 

 

 

 

 

 

 

 

 

CHLORINE 159 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Although it has multiple uses and is released to the environment, chlorine is too reactive to be identified 

in any of the 1,704 hazardous waste sites that have been proposed for inclusion on the EPA National 

Priorities List (NPL) (HazDat 2007). 

Chlorine may be released into the environment during accidents such as a chlorine gas leak from an 

industrial facility or a chlorine tank spill or rupture. Low concentrations of chlorine gas (<600 ppt) 

appear to be produced by the photolysis of seawater aerosol. Chlorine gas injected into the water during 

water chlorination quickly dissolves and forms chloride and hypochlorous acid within seconds. Liquid 

chlorine in a ruptured tank or spilled onto the ground or into water during an accident is expected to 

volatilize rapidly, forming a greenish-yellow cloud of chlorine gas. This gas cloud can be carried several 

miles away from the source of release while maintaining dangerous levels of chlorine. 

Since chlorine gas is so reactive, it is not expected to remain in the environment very long after it is 

released. Chlorine immediately reacts with both organic and inorganic materials that it comes into 

contact with. As mentioned above, it is converted within seconds once it dissolves in water. Chlorine 

undergoes direct photolysis in the air and its half-life in the troposphere is on the order of several minutes. 

Chlorine levels in the ambient atmosphere, water, soil, or sediment are not available. 

Exposure of the general population to chlorine gas is not expected except in the case of an accidental spill 

or industrial mishap. There have been several documented incidents in which large amounts of chlorine 

gas have been released, thereby exposing workers and the members of the general population following 

the derailment of trains carrying liquefied chlorine gas (Agency for Toxic Substances and Disease 

Registry 1998; NTSB 1998, 2005, 2006). Other accidental exposures may occur when individuals mix 

acidic household chemicals with bleach or pool sanitizing agents (see Section 6.3.2.2). Occupational 

exposure to low levels of chlorine gas may occur for individuals who work at facilities where it is 

produced or used. These individuals may be exposed to higher levels if an accidental release occurs 

within the facility. Children are expected to be affected by the same routes of exposure as adults, except 

for occupational exposure. 

The general public is not exposed to molecular chlorine in drinking water as a result of water sanitation 

practices, even though chlorine gas may be used in these processes. Free chlorine in drinking water is 
 

 

 

 

 

 

 

 

 

 

CHLORINE 160 

6. POTENTIAL FOR HUMAN EXPOSURE 

defined as the sum of dissolved chlorine gas, hypochlorous acid, and hypochlorite anion. As discussed in 

Chapter 4 and in Section 6.3.2.2, the level of dissolved chlorine in water is very low, except under acidic 

conditions. As a consequence, the term free chlorine in public water systems or swimming pools usually 

refers to the concentration of hypochlorous acid and hypochlorite anion (APHA 1998a, 1998b). 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ 10 or more full-time 

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI 

chemical in a calendar year (EPA 2005). 

6.2.1 Air 

Estimated releases of 5,050,000 pounds (2,290 metric tons) of chlorine to the atmosphere from 

915 domestic manufacturing and processing facilities in 2006, accounted for about 88% of the estimated 

total environmental releases from facilities required to report to the TRI (TRI06 2008). These releases are 

summarized in Table 6-1. 

Chlorine may be released into the air in fugitive emissions from industrial facilities where it is produced 

or used. It may also be released into the air as a result of a spill or tank rupture (Henry et al. 2005; Horton 

et al. 2002). Between January 1993 and December 2000, 952 chlorine-related events (865 involved 

chlorine only) were reported to the ATSDR's Hazardous Substances Emergency Events Surveillance 

system (Horton et al. 2002). Of the 865 chlorine-only events, 592 (68.4%) involved air emissions. Of the 

564 events for which release amount information was available in pounds, 511 events involved releases of 

≤250 pounds. Examples of some recent large scale accidents involving the release of chlorine gas follow. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 
 

CHLORINE 161 

6. POTENTIAL FOR HUMAN EXPOSURE 

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

Use Chlorinea
 

Reported amounts released in pounds per yearb 

Total release 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek On- and off-site 

AK 2 0 No data 0 0 0 0 0 0 

AL 39 43,765 1,208 0 0 0 44,973 0 44,973 

AR 23 54,016 637 0 0 0 54,653 0 54,653 

AZ 10 668 250 0 517 0 1,435 0 1,435 

CA 28 3,192 0 0 8,100 0 11,292 0 11,292 

CO 9 45,635 0 0 0 0 45,635 0 45,635 

CT 4 972 816 0 0 0 1,788 0 1,788 

DC 2 1,008 0 0 0 0 1,008 0 1,008 

DE 5 4,662 No data 0 0 0 4,662 0 4,662 

FL 34 5,749 22 0 27,734 0 18,055 15,450 33,505 

GA 34 5,332 2,702 0 0 0 8,034 0 8,034 

HI 1 5 No data 0 0 0 5 0 5 

IA 16 12,873 16,825 0 1,620 0 31,318 0 31,318 

ID 6 8,965 250 0 5 0 9,215 5 9,220 

IL 31 186,356 121,209 0 0 0 307,565 0 307,565 

IN 34 77,356 1,501 0 278 0 78,862 273 79,135 

KS 10 2,681 0 146,240 0 0 148,921 0 148,921 

KY 21 78,635 490 0 0 0 79,125 0 79,125 

LA 63 179,943 13,056 0 269 72 192,999 341 193,340 

MA 5 385 No data 0 0 0 385 0 385 

MD 9 781 0 0 0 0 781 0 781 

ME 5 1,510 0 0 0 0 1,510 0 1,510 

MI 26 30,950 679 0 0 0 31,628 0 31,628 

MN 16 12,165 0 0 0 0 12,165 0 12,165 

MO 20 15,545 1,157 0 0 0 16,702 0 16,702 

MS 18 61,839 676 0 0 0 62,515 0 62,515 

NC 23 121,870 12,308 0 8 0 134,186 0 134,186 

ND 4 715 0 0 0 0 715 0 715 

NE 9 2,126 220 0 0 0 2,346 0 2,346 

NH 2 11 0 0 0 0 11 0 11 

NJ 12 8,251 6,431 0 0 0 14,682 0 14,682 

NM 6 3,133 No data 3,166 0 109 6,299 109 6,408 

NV 9 5,246 No data 0 252,035 0 257,281 0 257,281 

NY 23 61,884 1,209 0 0 694 63,093 694 63,787 

OH 42 51,278 1,206 0 0 7 52,484 7 52,491 
 

 

 

 

 

 

 

 

 


 
 


 


 


 


 


 


 


 


 


 

CHLORINE 162 

6. POTENTIAL FOR HUMAN EXPOSURE 

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

Use Chlorinea
 

Reported amounts released in pounds per yearb 

Total release 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek On- and off-site 

OK 12 1,448 250 0 0 0 1,698 0 1,698 

OR 10 10,744 301 0 0 0 11,045 0 11,045 

PA 31 68,834 2,919 0 0 0 71,753 0 71,753 

PR 7 3,644 No data 0 0 0 3,644 0 3,644 

RI 3 1,796 No data 0 0 0 1,796 0 1,796 

SC 18 12,836 23 0 0 0 12,859 0 12,859 

SD 2 0 186 0 144 0 330 0 330 

TN 26 138,054 0 0 0 0 138,054 0 138,054 

TX 116 242,531 31,610 13,908 160 0 288,209 0 288,209 

UT 6 3,330,619 0 0 0 0 3,330,619 0 3,330,619 

VA 25 31,766 11,173 0 0 0 42,939 0 42,939 

VT 1 0 No data 0 0 0 0 0 0 

WA 18 2,268 17,006 0 5 0 19,279 0 19,279 

WI 21 40,691 3,540 0 14 0 44,245 0 44,245 

WV 14 17,997 4,000 0 0 0 21,997 0 21,997 

WY 4 57,019 0 0 114 0 57,133 0 57,133 

Total 915 5,049,751 253,859 163,314 291,003 882 5,741,931 16,879 5,758,810 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used.
 d

Number of reporting facilities.
 e

The sum of fugitive and point source releases are included in releases to air by a given facility.
 f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal
 

and metal compounds).
 g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other 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 

Source: TRI06 2008 (Data are from 2006) 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 163 

6. POTENTIAL FOR HUMAN EXPOSURE 

A freight train derailment, which took place on April 11, 1996, 2 miles west of Alberton, Montana 

resulted in a spill releasing 64.8 tons of chlorine into the environment (Agency for Toxic Substances and 

Disease Registry 1998; NTSB 1998). On January 6, 2005, a train carrying sodium hydroxide, cresol, and 

liquefied chlorine collided with another train in Graniteville, South Carolina releasing approximately 

120,000 pounds of chlorine gas to the surrounding atmosphere (NTSB 2005). On June 28, 2004, a 

westbound Union Pacific Railroad freight train collided with an eastbound freight train in Macdona, 

Texas (NTSB 2006). Consequently, a tank car carrying 180,000 pounds of liquefied chlorine was 

punctured, releasing a cloud of chlorine gas to the immediate area (NTSB 2006). An accident involving a 

broken cargo transfer pipe at the ATOFINA Chemicals plant in Riverview, Michigan, resulted in the 

release of flammable methyl mercaptan gas (NTSB 2002). A subsequent fire resulted in damage to an 

adjacent tank car loaded with chlorine. It was estimated that approximately 26,500 of the 178,560 pounds 

of chlorine in the tank car were released in this incident, which occurred in July 2001 (NTSB 2002). 

Chlorine appears to be generated in very low concentrations by the photolysis of seawater aerosols above 

seawater (California Environmental Protection Agency 2002; Chang et al. 2004; Knipping and Dabdub 

2003). 

Based on its instability and reactivity, it is not expected to be identified in air at any of the 

1,704 hazardous waste sites that have been proposed for inclusion on the EPA National Priorities List 

(NPL) (HazDat 2007). 

6.2.2 Water 

Estimated releases of 254,000 pounds (115 metric tons) of chlorine to surface water from 915 domestic 

manufacturing and processing facilities in 2006, accounted for about 4% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI06 2008). These releases are 

summarized in Table 6-1. 

Activities at industrial facilities where chlorine is produced or used may result in its unintentional release 

to surface water. Chlorine may also be released into water as a result of a spill or tank rupture. Chlorine 

gas is injected directly into water during certain disinfection processes; however, these processes take 

place under controlled conditions within treatment facilities to prevent the release of chlorine into the 

environment (Das 2002; Tchobanoglous and Schroeder 1985). Furthermore, the chlorine gas is 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 164 

6. POTENTIAL FOR HUMAN EXPOSURE 

immediately converted into hypochlorous acid, chloride ion, and hypochlorite as soon as it enters the 

water. Chlorine may be formed in waters containing hypochlorite if the pH is lowered to levels below 4 

(Farr et al. 2003). 

Chlorine is too reactive to be identified in surface water or groundwater at any of the 1,704 hazardous 

waste sites that have been proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 

2007). 

6.2.3 Soil 

Estimated releases of 291,000 pounds (132 metric tons) of chlorine to soils from 915 domestic 

manufacturing and processing facilities in 2006, accounted for about 5% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI06 2008). An additional 

163,000 pounds (74 metric tons), constituting about 3% of the total environmental emissions, were 

released via underground injection (TRI06 2008). These releases are summarized in Table 6-1. 

Activities at industrial facilities where chlorine is produced or used may result in its release to soil. 

Chlorine may also be released onto soil as a result of a spill. Of the 865 chlorine-only events reported to 

the ATSDR's Hazardous Substances Emergency Events Surveillance system between January 1993 and 

December 2000, 134 (15.5%) involved spills (Horton et al. 2002). 

Chlorine is too reactive to be identified in soil or sediment at any of the 1,704 hazardous waste sites that 

have been proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 2007). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

The boiling point of chlorine is -34.04 °C; therefore, chlorine is a gas under environmental conditions 

(HSDB 2009). Chlorine gas dissolves in water (7.3 g/L at 20 °C) and is immediately converted to 

hypochlorous acid and chloride ion at environmental pH. However, this conversion is hindered under 

very acidic conditions (pH<4). Molecular chlorine in water at this low pH is expected to volatilize 

rapidly based on a Henry's law constant of 1.17x10-2 atm-m3

/mol (Staudinger and Roberts 1996). 

Chlorine is not expected to bioaccumulate in plants or animals since it reacts with the moist tissues of 

living systems (Compton 1987; Schreuder and Brewer 2001; Schmittinger et al. 2006). Schreuder and 

Brewer (2001) observed severe damage to the foliage of two conifer species exposed to a chlorine gas 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 165 

6. POTENTIAL FOR HUMAN EXPOSURE 

cloud released during an accidental spill. All buds on exposed trees located within 50 m of the release 

were killed. 

If a large amount of liquid chlorine is released to a body of water, such as during a spill or an underwater 

release from a ruptured tank, some of the chlorine is expected to escape into the air before it can mix and 

react with the water. Similarly, when liquid chlorine is spilled onto the ground or when a tank containing 

liquid chlorine is ruptured, much of the chlorine will volatilize rapidly into the air creating a greenishyellow cloud of chlorine gas (Agency for Toxic Substances and Disease Registry 1998; DOE 2005b). 

Since chlorine gas is heavier than air, a chlorine gas cloud will remain low to the ground. Movement and 

dissipation of the gas cloud is determined by such factors as the release volume, type of release, terrain, 

topography, temperature, humidity, atmospheric stability, and wind speed and direction (DOE 2005b; 

U.S. Chemical Safety and Hazard Investigation Board 2003). 

Analysis of the chlorine gas cloud released during the 2005 Graniteville, South Carolina train derailment 

indicates that the dense cloud was initially driven southwest by gravity toward lower elevation, but was 

later dispersed by the wind toward the north and northeast as the boundary layer of the plume grew and as 

the gas began to mix with the surrounding air (DOE 2005a, 2005b). Wenck et al. (2007) reported that 

there were approximately 40 severe outcomes (≥3 nights of hospitalization and 9 deaths) and 

approximately 120 less severe outcomes (≤2 nights hospitalization) that occurred within a half-mile 

radius of the incident (Wenck et al. 2007). According to these authors, only a few less severe outcomes 

occurred between a half-mile and three-quarters of a mile from incident. 

Movement of chlorine through soil is not expected to be relevant since chlorine will react and volatilize 

so quickly when spilled onto the ground (Agency for Toxic Substances and Disease Registry 1998; 

Schulte 1999). 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

The primary removal mechanism for chlorine in air is direct photolysis (EPA 1993; Graedel 1978; 

Graedel et al. 1986). Sunlight at tropospheric wavelengths (<430 nm) breaks apart the chlorine molecule 

to form two chlorine radicals. These radicals then react with any available organic molecule to form 

hydrochloric acid. The mean atmospheric lifetime of chlorine has been reported as 440 seconds (the 

atmospheric half-life can be approximated by multiplying the lifetime by the natural logarithm of 2) 
 

 

 

 

 

 

 

 

 

 

CHLORINE 166 

6. POTENTIAL FOR HUMAN EXPOSURE 

(Graedel 1978). A tropospheric lifetime of <15 minutes was calculated by Tanaka et al. (2003) under 

smog conditions in Houston, Texas. The rate of direct photolysis for any chemical species is dependent 

upon the intensity of sunlight, and therefore, factors such as time of year, geographic location, and time of 

day affect the photolysis rate. Hov (1985) discussed the diurnal variation of the photolysis rate of 

chlorine in an analysis of the effect that atmospheric chlorine had on the formation of various 

photochemical oxidants in southern Telemark, Norway. It was generally concluded that the 

photodissociation rate is rapid under both winter and summer sunlight conditions. Using absorption cross 

section data for chlorine at 330 nm, a maximum photodissociation rate constant of approximately 

1.6x10-3 second-1 was calculated for midsummer, midday sunlight conditions. This corresponds to a 

tropospheric half-life of approximately 7.2 minutes and a mean lifetime of slightly over 10 minutes. 

Using a photodissociation rate constant of approximately 0.2x10-3 second-1 calculated for midday winter 

sunlight conditions, a half-life of 58 minutes is estimated. 

Chlorine is also expected to react with cloud particulates and rain drops that it comes into contact with in 

the atmosphere, forming hydrochloric and hypochlorous acids (Vetrano 2001). These acids can then be 

washed out of the atmosphere by precipitation (Vetrano 2001). 

6.3.2.2 Water 

Water disinfection through chlorination has been in regular use since the early 1900s; consequently, the 

fate of chlorine in water has been well studied (Das 2002). Chlorine gas released into water first 

dissolves and then undergoes a disproportionation within seconds at environmental pH to form 

hydrochloric (H+ + Cl-

) and hypochlorous acid (HOCl) (Cotton et al. 1999; Das 2002; EPA 1999; Farr et 

al. 2003; Morris 1946; Snoeyink and Jenkins 1980; Tchobanoglous and Schroeder 1985; Wang and 

Margerum 1994). The equilibrium that exists between hypochlorous acid and the hypochlorite anion is 

controlled by the pH of the water. Since the pKa of hypochlorous acid is 7.49 (O’Neil et al. 2001), the 

formation of the conjugate base (hypochlorite anion) is favored under alkaline conditions and the 

protonated species (hypochlorous acid) is favored under neutral and mildly acidic conditions. Under 

strongly acidic conditions (pH≤2), the formation of molecular chlorine is possible (see Chapter 4). 

As illustrated in Figure 4-1, the equilibrium between chlorine, hypochlorous acid, and hypochlorite acid is 

dependant on the pH of the solution (Farr et al. 2003). As the pH is lowered to 4, the equilibrium begins 

to shift to the left, and small amounts of Cl2 are present. At pH below 2, chlorine becomes the dominant 

species. Therefore, molecular chlorine will be formed in chlorinated water (containing hypochlorous 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 167 

6. POTENTIAL FOR HUMAN EXPOSURE 

acid) that has been made very acidic. Under these conditions, chlorine is expected to react rapidly with 

both organic and inorganic mater that it comes into contact with in the water; it is also expected to 

volatilize rapidly into the air based on a Henry's law constant of 1.17x10-2 atm-m3

/mol (Staudinger and 

Roberts 1996). Chlorine is toxic to microbial communities; therefore, biodegradation is not considered to 

be a relevant fate process (Vetrano 2001). The hypochlorous acid formed during the disproportionation 

of chlorine in natural waters reacts with organic and inorganic materials, ultimately forming chloride, 

oxidized inorganics, chloramines, trihalomethanes, oxygen, and nitrogen (IARC 1991; Vetrano 2001). 

6.3.2.3 Sediment and Soil 

If liquid chlorine is spilled onto soil, it will react with both organic and inorganic mater in the soil; 

however, much of the chlorine is expected to volatilize immediately (Agency for Toxic Substances and 

Disease Registry 1998; Schulte 1999). Chlorine is expected to dissolve and disproportionate in the water 

of moist soils to form chloride and hypochlorite (Cotton et al. 1999). Chlorine in a gas cloud is expected 

to react with soil surfaces that it comes into contact with. Chlorine is toxic to microbial communities; 

therefore, biodegradation is not considered to be a relevant fate process (Vetrano 2001). 

When released into water, chlorine is expected to react with suspended solids and sediments that it comes 

into contact with. 

6.3.2.4 Other Media 

Specific information on the transformation of chlorine in other media is not available; however, chlorine 

is very unstable and is expected to react with most substances that it comes into contact with. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to chlorine depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. Concentrations of 

chlorine 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 chlorine 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 chlorine in 

a variety of environmental media are detailed in Chapter 7. 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 168 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.1 Air 

Levels of chlorine monitored in the ambient atmosphere have not been located. Scientists have proposed 

that chlorine is generated during the photolysis of seawater aerosol (California Environmental Protection 

Agency 2002; Chang et al. 2004; Knipping and Dabdub 2003). According to California Environmental 

Protection Agency (2002), chlorine was detected in the air at a New York coastal site with a maximum 

concentration of 150 ppt. Chang et al. (2004) reported a maximum chlorine concentration of 580 ppt in 

air samples collected from coastal locations in Taiwan. 

Little information is available regarding the levels of chlorine measured in air surrounding areas of 

accidental release. The concentrations of chlorine monitored in the air surrounding a chlorine release 

from a railroad tank car near Festus, Missouri were >1,000 ppm (U.S. Chemical Safety and Hazard 

Investigation Board 2003). Chlorine concentrations as high as 1,000 ppm were measured in the air at a 

train derailment chemical spill near Alberton, Montana that released chlorine gas in April 1996 (Agency 

for Toxic Substances and Disease Registry 1998). 

6.4.2 Water 

Levels of chlorine monitored in water are not available. Chlorine is not a predominant species in water at 

environmental pH since it disproportionates within seconds to form chloride anion and hypochlorous 

acid; therefore, chlorine is not expected to be detected in the aquatic environment (Das 2002; Morris 

1946; Wang and Margerum 1994). 

6.4.3 Sediment and Soil 

Levels of chlorine monitored in sediment and soil are not available. Chlorine is not expected to be found 

in soil since it reacts and volatilizes so rapidly. 

6.4.4 Other Environmental Media 

Levels of chlorine monitored in food, animals, vegetation, and consumer products are not available. 

Chlorine is not expected to be found in these media because of its very high reactivity. 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 169 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Chlorine is not normally detected in ambient air, soil, surface water, groundwater, or drinking water. 

Therefore, background exposure of the general population to chlorine is not expected. Greater than 

95% of the chlorine that is inhaled (over a 1–5 ppm range) reacts in the upper respiratory tract (Nodelman 

and Ultman 1999a, 1999b; Winder 2001) and eventually joins the chloride pool in the body. Therefore, 

analysis of human biological materials such as blood, urine, and body tissue for chlorine is not considered 

relevant. The amount of chlorine that needs to be inhaled to induce a significant increase in extracellular 

chloride in the body is probably a lethal amount. Current procedures for gauging an individual's exposure 

to chlorine gas involve analysis of the lungs and respiratory airways for physical and functional damage 

(Lawson 1981; Winder 2001). 

Members of the general population may be exposed to chlorine if they mix an acid with a solution 

containing sodium hypochlorite (CDC 1991). Examples include mixing toilet bowl cleaners containing 

hydrochloric, phosphoric, or oxalic acid with bleach (Becker and Forrester, 2008; CDC 1991; GapanyGapanavicius et al. 1982; Howard et al. 2007; Mrvos et al. 1993). If enough acid is added to lower the 

pH of the hypochlorite solution to below 4, chlorine gas will be released (Farr et al. 2003). Individuals 

may also be exposed to chlorine if swimming pool chemicals are accidentally mixed with acids or too 

much sodium hypochlorite is added to the water over a short period of time (Agabiti et al. 2001; Becker 

and Forrester 2008; Bonetto et al. 2006; Ngo et al. 2007; Sexton and Pronchik 1998). On 

October 22, 1998, hydrochloric acid accidentally spilled onto chlorinated swimming pool water at a 

recreational facility in Rome, Italy causing the liberation of chlorine gas to the entire center and exposing 

nearly 300 people to the gas (Agabiti et al. 2001). The exact amount of chlorine released in this accident 

was not reported. A similar accident occurred on February 17, 2004 in Parma, Italy in which 18 children 

were exposed to chlorine gas (Bonetto et al. 2006). In this case, the improper addition of an excessive 

amount of sodium hypochlorite was added to a chlorinated swimming pool to shock the system, resulting 

in the emission of chlorine gas. 

Occupational exposure to low levels of chlorine gas in air may occur for individuals who work at 

facilities that produce, transport, or use chlorine (Gautrin et al. 1995). These individuals may also be 

exposed to high chlorine concentrations if an accidental release occurs at the facility (Beach et al. 1969; 

Chester et al. 1969; Gautrin et al. 1999; Kennedy et al. 1991; NTSB 2002, 2005, 2006; USB 2007). 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 170 

6. POTENTIAL FOR HUMAN EXPOSURE 

Of the 865 chlorine-only events reported to the ATSDR's Hazardous Substances Emergency Events 

Surveillance system between January 1993 and December 2000, 275 events involved victims 

(1,071 individuals) (Horton et al. 2002). Of these, 759 were occupational exposures and 68 were first 

responders. 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

As with adults, biomonitoring is not considered relevant for assessing childhood exposure to chlorine. 

Therefore, information on chlorine levels in blood, urine, tissue, breast milk, neonatal blood, cord blood, 

and meconium fluid is not available. Children may be exposed to chlorine through the same routes that 

affect adults, except for occupational exposures. Children located near an accidental release of chlorine 

such as a leak from a factory or a chlorine tank spill or rupture may be exposed to high concentrations of 

chlorine through inhalation, skin contact, or eye contact. Children may be exposed to high levels of 

chlorine if they are in an area where swimming pool chemicals are being improperly used or where 

certain household chemicals are mixed together. Mixing an acid, such as toilet cleaner, with bleach can 

generate chlorine gas if the pH of the bleach is lowered to below 4. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Individuals located near an accidental release of chlorine may be exposed to high concentrations of this 

gas through inhalation, skin contact, and eye contact if the cloud travels in their direction (Horton et al. 

2002; Wenck et al. 2007). Individuals who live near industrial facilities where chlorine gas is produced 

or used may be exposed to high concentrations if there is an accidental release of a large amount of 
 

 

 

 

 

 

 

 

 

 

CHLORINE 171 

6. POTENTIAL FOR HUMAN EXPOSURE 

chlorine gas from the facility (USB 2007). Of the 865 chlorine-only events reported to ATSDR's 

Hazardous Substances Emergency Events Surveillance system between January 1993 and December 

2000, 275 events involved victims (1,071 individuals) (Horton et al. 2002). Of these, 235 were members 

of the general public. A train derailment near Alberton, Montana on April 11, 1996 released 

approximately 130,000 pounds of chlorine gas to the atmosphere (NTSB 1998). According to the 

National Transportation Safety Board (NTSB), approximately 350 people were treated for chlorine 

inhalation. Nine people, including members of the train crew, were hospitalized. The NTSB reported 

that a transient riding the train died from acute chlorine toxicity (NTSB 1998). On January 6, 2005, a 

northbound Norfolk Southern Railway Company freight train traveling through Graniteville, South 

Carolina, encountered an improperly lined switch that diverted the train from the main track onto an 

industrial track, where it struck an unoccupied, parked train releasing approximately 120,000 pounds of 

chlorine gas from one of the cars of the northbound train (NTSB 2005). The train engineer and 8 other 

people died as a result of chlorine gas exposure and an additional 554 nearby residents were treated at 

local hospitals for respiratory illness as a result of this accident. On June 28, 2004 a westbound Union 

Pacific Railroad freight train collided with an eastbound freight train in Macdona, Texas (NTSB 2006). 

Consequently, a tank car loaded with liquefied chlorine was punctured, releasing a cloud of chlorine gas 

that surrounded the accident area. Three persons, including the conductor of the Union Pacific train and 

two local residents, died as a result of acute chlorine gas inhalation. The Union Pacific train engineer, 

23 local residents, and 6 emergency responders were treated for respiratory illness or other injuries related 

to the collision and derailment. 

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 chlorine is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of chlorine. 

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 
 

 

 

 

 

 

 

 

 

 

CHLORINE 172 

6. POTENTIAL FOR HUMAN EXPOSURE 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The important chemical and physical properties for elemental 

chlorine are available (EPA 1999; HSDB 2009; Staudinger and Roberts 1996), as well as the important 

equilibrium constants describing the equilibrium reaction of chlorine in water (Cotton et al. 1999; Farr et 

al. 2003). No data need is identified 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 2005, became available in May of 2007. This database is updated yearly and should provide a list of 

industrial production facilities and emissions. 

Current production and U.S. import/export volumes are available for chlorine (CMR 2006; HSDB 2009; 

ITA 2007; The Chlorine Institute 2008; U.S. Census Bureau 2008), as well as adequate disposal methods 

(HSDB 2009). No data need is identified at this time. 

Environmental Fate. The environmental fate of chlorine is understood. Chlorine is extremely 

reactive and will not remain in environmental media for long periods of time. The important equilibrium 

properties of chlorine in water are understood (Cotton et al. 1999; Farr et al. 2003). Scientists have 

proposed that minute quantities of chlorine are generated naturally during the photolysis of seawater 

aerosols (California Environmental Protection Agency 2002; Chang et al. 2004; Knipping and Dabdub 

2003). Sunlight at tropospheric wavelengths (<430 nm) dissociates the chlorine molecule to form two 

chlorine radicals; a lifetime of <15 minutes (half-life of <11 minutes) was calculated for this reaction 

(Tanaka et al. 2003). No data need is identified at this time. 

Bioavailability from Environmental Media. Chlorine is too reactive to be bioavailable from soil, 

water, or other environmental media. No data need is identified at this time. 

Food Chain Bioaccumulation. Chlorine is too reactive to bioaccumulate in the food chain. No data 

need is identified at this time. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 173 

6. POTENTIAL FOR HUMAN EXPOSURE 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of chlorine in 

contaminated media at hazardous waste sites are needed so that the information obtained on levels of 

chlorine in the environment can be used in combination with the known body burden of chlorine to assess 

the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. 

Chlorine is too reactive to monitor for background levels in the environment. In the case of an accidental 

spill, levels >1,000 ppm have been observed in air around the accident site (U.S. Chemical Safety and 

Hazard Investigation Board 2003). Very low levels of chlorine (parts per trillion) are generated naturally 

during the photolysis of seawater aerosols (California Environmental Protection Agency 2002; Chang et 

al. 2004). No data need is identified at this time. 

Exposure Levels in Humans. Humans can be exposed to chlorine following the accidental release 

at a manufacturing facility or an accident involving the transportation of liquefied chlorine gas (NTSB 

1998, 2002, 2005, 2006); however, molecular chlorine levels in human tissues cannot be quantitatively 

assessed (see Chapter 7). In addition, people may be exposed to chlorine if they mix common household 

chemicals that are acidic with bleach or pool sanitizing chemicals (Agabiti et al. 2001; Bonetto et al. 

2006). Continued monitoring of accidental chlorine releases and the health affects observed in humans is 

necessary. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Similar to adults, exposure of children to chlorine gas primarily occurs from 

accidental industrial or transportation releases (NTSB 1998, 2002, 2005, 2006), or the inadvertent mixing 

of common household chemicals with bleach or pool sanitizing chemicals, resulting in the liberation of 

chlorine (Agabiti et al. 2001; Bonetto et al. 2006). Continued monitoring of accidental chlorine releases 

and the health affects observed in children is necessary. 

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 chlorine 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-
 

 

 

 

CHLORINE 174 

6. POTENTIAL FOR HUMAN EXPOSURE 

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 

Two ongoing studies have been located in the Federal Research in Progress Database (FEDRIP 2009) that 

will measure levels of chlorine in the marine atmosphere. These are listed in Table 6-2. No other 

ongoing studies regarding the potential for human exposure to chlorine were located. 
 


 

CHLORINE 175 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Ongoing Studies Regarding the Potential for Human Exposure to 

Chlorine
 

Investigator Affiliation Research description Sponsor 

R. Talbot and 

A. Pszenny 

University of New 

Hampshire 

Study of reactive halogens in the marine 

boundary layer overlying the eastern 

tropical north Atlantic Ocean. This 

research will include measurement of 

National Science 

Foundation 

inorganic chlorine gases. 

E. Saltzman University of 

California-Irvine 

Study of the source, presence, and 

distribution of inorganic dihalogen gases in 

the marine atmosphere. This research will 

include measurement of chlorine gas in 

coastal and marine air. 

National Science 

Foundation 

Source: FEDRIP 2009 
CHLORINE 176
 

6. POTENTIAL FOR HUMAN EXPOSURE 

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CHLORINE 177 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring chlorine, its metabolites, and other biomarkers of exposure and effect to 

chlorine. 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 

Inhaled chlorine gas forms hypochlorous acid and hydrochloric acid upon contact with the moist mucous 

membranes of the upper respiratory tract (Vetrano 2001; Winder 2001). Since molecular chlorine reacts 

so quickly inside living systems, it is not found in biological materials. Therefore, analysis of these 

materials for chlorine is not relevant. Once they have been absorbed into the body, hypochlorous and 

hydrochloric acid are expected to react with proteins and nucleotides to produce a wide variety of 

chlorinated organic compounds (EPA 1999; Winder 2001). Based on a study that traced radiolabeled 

chlorine (as hypochlorite) through metabolism inside rats, it is expected that chlorine is ultimately 

converted to chloride in the blood and eliminated in the urine and feces of humans and animals primarily 

as the chloride ion (Abdel-Rahman et al. 1982, 1983; EPA 1999; Suh and Abdel-Rahman 1983). 

Chloroform has also been detected in the blood of rats exposed to hypochlorous acid (Abdel-Rahman et 

al. 1984). Since chloride is a natural component of blood, urine, and feces, monitoring chloride 

concentrations in these materials would not be helpful for assessing exposure to chlorine. 

7.2 ENVIRONMENTAL SAMPLES 

When chlorine is released into the environment, it reacts very quickly with both organic and inorganic 

matter forming chloride ion and chlorinated compounds. Therefore, aside from low levels in marine 

aerosols above the open ocean, and higher concentrations in the areas surrounding recent spills and leaks, 

molecular chlorine is not found in the environment. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 178 

7. ANALYTICAL METHODS 

Standardized methods have been established for analyzing chlorinated water for free chlorine (APHA 

1998a, 1998b). Free chlorine refers to the combination of the equilibrium species aqueous molecular 

chlorine, hypochlorous acid, and the hypochlorite ion. These methods do not differentiate between the 

molecular chlorine and the hypochlorite species. Since molecular chlorine is usually not present in water 

samples, these tests typically measure the amounts of hypochlorous acid, hypochlorite, and chlorinated 

derivatives. The most popular of these tests is the DPD (N,N-diethyl-p-phenyldiamine) test (APHA 

1998a, 1998b). A small amount of DPD is added to a water sample, which is immediately oxidized by 

free chlorine to produce a relatively stable free radical and results in a reddish-colored solution. The total 

chlorine is measured spectrophotometrically at 515 nm (APHA 1998a, 1998b). Some important residuals 

of water disinfection can also quantified by this method. Since chloramines are slow to react with DPD, 

they are quantified by the subsequent addition of potassium iodide. The iodide ion acts catalytically 

causing color production by monochloramine and dichloramine (APHA 1998a, 1998b). The free chlorine 

and the chloroamines are often referred to as the total chlorine content of the water. 

Aside from the DPD test, free chlorine can be measured using the amperometric titration method or the 

starch-iodide titration method (APHA 1998a). The amperometric titration method involves the titration 

of the buffered sample with phenylarsine oxide (APHA 1998a). The decrease of free chlorine during the 

titration is detected by applying an electric potential across two electrodes and measuring the change in 

current through the solution. The starch-iodide titration method involves addition of potassium iodide 

and a starch indicator to the sample followed by titration with sodium thiosulfate (APHA 1998a). The 

end point is reached when the blue color of the solution disappears. 

It should be noted that the free chlorine test methods described here work by detecting the presence of 

oxidizing species and are not actually specific and selective to free chlorine (hypochlorite and 

hypochlorous acid) (APHA 1998a). Therefore, care must be taken to avoid interference due to non-free 

chlorine oxidizing or reducing agents. The amperometric titration method is less affected by interference, 

temperature variations, turbidity, and color; however, this method requires greater operator skill to 

achieve reliable results (APHA 1998a). 

Four standardized methods have been located that describe procedures for measuring molecular chlorine 

in air (EPA 2000b; NIOSH 1994; OSHA 2007a, 2007b). In EPA Method OAQPS-26, the air sample is 

passed through a particulate filter followed by a dilute sulfuric acid solution (EPA 2000b). Hydrogen 

chloride dissolves to form chloride in the acid solution, while chlorine, which is relatively insoluble in the 

acid, passes through to a dilute sodium hydroxide solution. Chlorine dissolves and disporportionates to 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 179 

7. ANALYTICAL METHODS 

form both chloride and hypochlorous acid. Sodium thiosulfate is then added to the alkaline solution to 

ensure complete reaction with the hypochlorous acid, freeing the second chloride ion. Analysis is 

performed using ion chromatography. 

OSHA Methods ID-101 and ID-126SGX are based on the reaction between chlorine and iodide to form 

iodine and chloride (OSHA 2007a, 2007b). In Method ID-101, chlorine is collected in a sulfamic acid 

solution, which is then reacted with potassium iodide and analyzed using a residual chlorine ion specific 

electrode. In Method ID-126SGX, chlorine is collected into a neutral solution of potassium iodide, which 

is then titrated with sodium thiosulfate. A second titration involving chlorine dioxide is performed next. 

The concentrations of chlorine and chlorine dioxide are determined using stoichiometric calculations. 

Disadvantages of this method are that it suffers from many interferences and that temperature and strong 

light affect solution solubility. Both of the OSHA methods recommend using a filter to eliminate 

particulates that may cause interference. 

NIOSH Method 6011 describes a way to measure chlorine in air samples via collection onto a silver 

membrane filter, desorption into sodium thiosulfite, and subsequent analysis using ion chromatography 

(NIOSH 1994). This method is subject to positive interference from hydrogen chloride and negative 

interference from hydrogen sulfide. Also, silver chloride is photosensitive; therefore, the silver filter must 

be transferred to an amber bottle in the dark. Once the silver chloride has desorbed, it is no longer 

photosensitive. The detection limit for chlorine listed in this method is 0.007 ppm for a 90L air sample 

collected at a flow rate of 0.3–1 L per minute; however, Chang et al. (2004) was able to measure chlorine 

in air to a detection limit of 50 ppt (parts per trillion) using a Dionex DX-120 analyzer and longer 

sampling times. 

Standardized methods for measuring chlorine in air and water including accuracy, detection limits, and 

additional details are listed in Table 7-1. Methods that analyze soil and sediment for chlorine are not 

available. 

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 chlorine is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 
 

 

 

 

 

 

 

 

 

 

CHLORINE 180 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Chlorine in Environmental Samples 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection limit 

Percent 

recovery Reference 

Air Sample is passed through a 

particulate filter into a dilute 

sulfuric acid solution followed 

EPA OAQPS26 

0.1 ppm NA EPA 2000b 

by a dilute sodium hydroxide 

solution. Analysis is performed 

using IC. 

Air Sample is passed through a 

teflon prefilter and dissolved in 

a sulfamic acid solution. 

OSHA ID-101 0.14 ppm NA OSHA 2007b 

Potassium iodide is added to 

the acid solution. Analysis is 

performed using RCE. 

Air Sample is passed through a 

glass giber pre-filter and 

collected into a potassium 

iodide solution. The solution is 

OSHA ID126SGX 

0.3 ppm NA OSHA 2007a 

then titrated with sodium 

thiosulfate in two steps to 

determine concentrations of 

chlorine and chlorine dioxide. 

Air Sample is passed through a 

silver membrane filter. Silver 

chloride is desorbed from the 

membrane into a sodium 

NIOSH 6011 0.007–0.5 ppm 

for a 90 L air 

sample (flow 

rate 0.3– 

98.6% NIOSH 1994; 

Chang et al. 

2004 

thiosulfate solution, which is 

then analyzed using IC. 

1.0 L/minute); 

50 ppt 

Water Acetic acid and potassium 

iodide are added to the sample 

to create an acidic solution, 

APHA 4500-Cl 

B 

40 μg as free 

chlorine/L 

NA APHA 1998a, 

1998b 

which is then titrated using 

sodium thiosulfate. 

Water Acetic acid and potassium 

iodide are added to the sample 

to create an acidic solution, 

which is then titrated using 

sodium thiosulfate or 

EPA 330.3 250–4,020 μg 

as free 

chlorine/L 

NA CAS 1978c 

phenylarsine oxide. 
 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

CHLORINE	 181 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Chlorine in Environmental Samples 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Water	 Phenylarsine oxide, potassium 

iodide, and acetate buffer are 

combined with the sample. For 

starch iodide determination, a 

starch indicator is added 

followed by titration with iodine 

solution. For amperometric 

determination, titrate with an 

iodine solution using an 

amperometric titrator. 

Water	 Phosphate buffer is added to 

the sample, which is then 

titrated with phenylarsine oxide 

using a microammeter to 

observe current changes. 

Water	 Potassium iodide and acetate 

buffer are added to the sample, 

which is then titrated with 

phenylarsine oxide or sodium 

thiosulfate using an 

amperometer to determine the 

end point. 

Water	 Add 10 mL of water to 0.5 mL of 

phosphate buffer solution and 

0.5 mL of DPD reagent. 

Quantify by UV-VIS at 515 nm 

EPA 330.2	 250–4,020 μg NA CAS 1978b 

as free 

chlorine/L 

APHA 4500-Cl 200 μg as free NA APHA 1998a 

D chlorine/L 

EPA 330.1	 380–3,500 μg NA CAS 1978a 

as free 

chlorine/L 

APHA 4500-Cl 10 μg as free NA APHA 1998a, 

G chlorine/L 1998b 

DPD = N,N-diethyl-p-phenyldiamine; IC = ion chromatography; NA = not available; RCE = residual chlorine ion specific 

electrode; UV-VIS = ultraviolet-visible 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 182 

7. ANALYTICAL METHODS 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of chlorine. 

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. There are no biomarkers of exposure that are specific to chlorine. Chlorine reacts very 

quickly inside the body; therefore, analyzing for this substance in biological materials is not relevant. The 

chlorine reacts to form many chlorinated compounds that are ultimately broken down into chloride ion. 

Chloride is a natural component of blood, urine, and feces. Monitoring for chloride in biological 

materials would not be helpful in gauging exposure to chlorine. 

Effect. There are no biomarkers of effect that are unique to chlorine exposure. The most obvious effect 

of exposure to high levels of chlorine is damage to the moist mucous membranes of the lungs and 

respiratory pathways. Other health effects that have been associated with exposure to chlorine include 

bronchitis, asthma, pulmonary edema, dermatitis, and conjunctivitis. The odor threshold for chlorine in 

air is 0.2–0.4 ppm and the lowest concentration in air at which there is perceivable sensory irritation is 

1 ppm (EPA 1999; The Chlorine Institute 1998; WHO 1982). Current standardized methods for 

measuring chlorine in air have detection limits ranging from 0.007 to 0.3 ppm, which are below 

concentrations at which biological effects occur (EPA 2000b; NIOSH 1994; OSHA 2007a, 2007b). 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Methods sensitive enough to measure background chlorine concentrations in ocean air are 

available. Chang et al. (2004) used a more sensitive analyzer and larger sampling volumes with the silver 

membrane filter method (NIOSH Method 6011) to lower the detection limit from 0.007 ppm to 50 ppt. 

Background chlorine concentrations measured were <600 ppt. Methods are also available for measuring 

chlorine in water; however, these methods do not distinguish between the equilibrium species molecular 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 183 

7. ANALYTICAL METHODS 

chlorine, hypochlorous acid, or hypochlorite (APHA 1998a, 1998b). Since hypochlorous acid and 

hypochlorite are the dominant species at environmental pH, analyzing water for molecular chlorine is not 

relevant except under very acidic conditions (pH<4) (APHA 1998a, 1998b; Farr et al. 2003). Methods 

that analyze for chlorine in soil or sediment were not located. Chlorine is not expected to be found in 

these media since it is so reactive, rapidly oxidizing both organic and inorganic materials that it comes 

into contact with. 

Among the analytical methods referred to in this chapter, only the detection limits reported for NIOSH 

Method 6011 are sensitive enough to detect chlorine in air at levels at or below the MRL values derived 

in Chapter 3. For reference, the acute, intermediate, and chronic MRLs derived for chlorine in air are 

0.06 ppm, 0.002 ppm, and 50 ppt, respectively. Detection limits reported for NIOSH Method 6011 range 

from 0.007–0.5 ppm, while a detection limit of 50 ppt was achieved for a modification of this method 

(NIOSH 1994; Chang et al. 2004). The other detection methods for measuring chlorine levels in air 

report detection limits of >0.1 ppm (EPA 2000b). Based on the lack of sensitivity of the available 

methods relative to the derived MRL values, the development of standardized analytical methods that can 

detect chlorine in air at levels below the MRL values (below 50 ppt) is a data need. 

7.3.2 Ongoing Studies 

One ongoing study has been located in the Federal Research in Progress Database (FEDRIP 2009) related 

to the development of analytical methods for chlorine. This study will be led by investigator Eric 

Saltzman of the University of California-Irvine and is sponsored by the National Science Foundation 

(NSF). The study will explore the source, presence, and distribution of inorganic dihalogen gases in the 

marine atmosphere and will include the validation and further development of analytical methods for 

dihalogens, including chlorine, in air. No other ongoing studies regarding the development of methods 

for analyzing for chlorine in the environment were located in the available literature. 
 

CHLORINE 184
 

7. ANALYTICAL METHODS 

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CHLORINE 185 

8. REGULATIONS, ADVISORIES, AND GUIDELINES
 

MRLs are substance specific estimates, which are intended to serve as screening levels, are used by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. 

ATSDR has derived an acute-duration inhalation MRL of 0.06 ppm for chlorine based on a NOAEL of 

0.5 ppm for sensory irritation and pulmonary effects in volunteers exposed for up to 8 hours/day (Anglen 

1981; D’Alessandro et al. 1996; Rotman et al. 1983; Schins et al. 2000; Shusterman et al. 1998, 2003b). 

The NOAEL was duration-adjusted for continuous exposure. An uncertainty factor of 3 was used to 

account for sensitive populations. 

ATSDR has derived an intermediate-duration inhalation MRL of 0.002 ppm for chlorine based on a 

minimal LOAEL of 0.5 ppm for tracheal lesions in rats exposed 6 hours/day, 5 days/week for 62 days 

(Kutzman 1983). An uncertainty factor of 90 was used (3 for extrapolation from animals to humans with 

dosimetric adjustment, 3 for use of a minimal LOAEL, and 10 for human variability). 

ATSDR has derived a chronic-duration inhalation MRL of 0.00005 ppm for chlorine based on an 

increased incidence of nasal lesions in monkeys exposed to chlorine 6 hours/day, 5 days/week for 1 year 

(Klonne et al. 1987). The MRL was derived using benchmark modeling of incidence data for nasal 

lesions in monkeys. The predicted exposure concentration associated with a 10% extra risk (BMC10) for 

nasal lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on this concentration (BMCL10) 

was 0.02 ppm. An uncertainty factor of 30 was used (3 for extrapolation from animals to humans with 

dosimetric adjustment and 10 for human variability). 

Oral MRLs were not derived for aqueous chlorine for the following reasons. MRLs are derived when 

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

for a specific duration within a given route of exposure. Scientifically, as part of having sufficient and 

reliable data, it is important to be able to see the full, or at least a significant range, of the dose-response 

curve. In the case of the oral database for aqueous chlorine, no reliable LOAEL could be identified at 

levels of aqueous chlorine that could reasonably be encountered in the environment. It is a matter of 

policy of ATSDR not to derive free-standing MRLs. 
 

 

 

 

 

 

 

 

 

 

CHLORINE 186 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

EPA (IRIS 2007) has established an oral reference dose (RfD) for chlorine of 0.1 mg/kg/day based on a 

NOAEL of 14.4 mg/kg/day for systemic effects in F344/N rats exposed to chlorine in the drinking water 

for 2 years (NTP 1992). The uncertainty factor used in this assessment was 100 (10 for interspecies 

extrapolation and 10 for the protection of sensitive human subpopulations). 

EPA has not derived an inhalation reference concentration (RfC) for chlorine gas. 

The International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), and 

EPA has not classified chlorine, sodium hypochlorite, or hypochlorous acid for human carcinogenicity 

(IARC 2006; IRIS 2007; NTP 2005). The American Conference of Governmental Industrial Hygienists 

(ACGIH) has classified chlorine as an A4 carcinogen (not classifiable as a human carcinogen) (ACGIH 

2006). 

OSHA has required employers of workers who are occupationally exposed to chlorine to institute 

engineering controls and work practices to reduce and maintain employee exposure at or below 

permissible exposure limits (PELs) (OSHA 2006c). The employer must use engineering and work 

practice controls to reduce exposures to not exceed 1 ppm for chlorine at any time (ceiling) (OSHA 

2006c). 

EPA has designated chlorine as a hazardous air pollutant (HAP) under the Clean Air Act (CAA) (EPA 

2007b). Chlorine and sodium hypochlorite are on the list of chemicals appearing in “Toxic Chemicals 

Subject to Section 313 of the Emergency Planning and Community Right-to-Know Act of 1986" and has 

been assigned a reportable quantity (RQ) limit of 10 and 1 pounds, respectively (EPA 2007e). Chlorine is 

also considered to be an extremely hazardous substance (EPA 2007f). The RQ represents the amount of a 

designated hazardous substance which, when released to the environment, must be reported to the 

appropriate authority. 

Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), chlorine gas is exempt from the 

requirement of a tolerance for pesticide chemicals in food when used as pre- or postharvest in solution on 

all raw agricultural commodities (EPA 2007h) and sodium hypochlorite is exempt from the requirement 

of a tolerance for residues in food (EPA 2007k). 

The international and national regulations, advisories, and guidelines regarding chlorine in air, water, and 

other media are summarized in Table 8-1. 
 

 

 

 

 

 

 

 


 

CHLORINE 187 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Chlorine and 

Chlorine Compounds
 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification No data IARC 2006 

WHO Air quality guidelines No data WHO 2000 

Drinking water quality guidelines WHO 2004 

Chlorine 5 mg/La 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA) (chlorine) 0.5 ppm ACGIH 2006 

STEL (15-minute TWA) (chlorine) 1 ppm 

AIHA ERPG-1b (chlorine) 1 ppm AIHA 2004 

ERPG-2b (chlorine) 

ERPG-3b (chlorine) 

3 ppm 

20 ppm 

Odor threshold (chlorine) 0.08 ppm 

EPA AEGL-1c (chlorine) EPA 2007a 

10 minutes 0.5 ppm 

30 minutes 0.5 ppm 

60 minutes 0.5 ppm 

4 hours 0.5 ppm 

8 hours 0.5 ppm 

AEGL-2c (chlorine) 

10 minutes 2.8 ppm 

30 minutes 2.8 ppm 

60 minutes 2.0 ppm 

4 hours 1.0 ppm 

8 hours 0.71 ppm 

AEGL-3c (chlorine) 

10 minutes 50 ppm 

30 minutes 28 ppm 

60 minutes 20 ppm 

4 hours 10 ppm 

8 hours 7.1 ppm 
 

 

 

 

 

 

 

 

 

 

 


 

CHLORINE 188 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Chlorine and 

Chlorine Compounds
 

Agency Description Information Reference 

NATIONAL (cont.) 

Hazardous air pollutant (chlorine) Yes EPA 2007b 

42 USC 7412 

Regulated toxic substance and the 2,500 poundsd EPA 2007d 

threshold quantity for accidental release 40 CFR 68.130 

prevention (chlorine) 

NIOSH REL (ceiling) (chlorine) 0.5 ppm NIOSH 2005 

IDLH (chlorine) 10 ppm 

OSHA PEL (ceiling) for general industry 1 ppm OSHA 2006c 

(chlorine) 29 CFR 1910.1000 

PEL (ceiling) for shipyard industry 1 ppm OSHA 2006a 

(chlorine) 29 CFR 1915.1000 

PEL (ceiling) for construction industry 1 ppm OSHA 2006b 

(chlorine) 29 CFR 1926.55, 

Appendix A 

Toxic and reactive highly hazardous 1,500 pounds OSHA 2006d 

chemical which presents a potential for 29 CFR 1910.119 

a catastrophic event at or above the 

threshold quantity (chlorine) 

b. Water 

EPA Designated as hazardous substances in Yes EPA 2007i 

accordance with Section 311(b)(2)(A) of 40 CFR 116.4 

the Clean Water Act (chlorine) 

Drinking water standards and health EPA 2006 

advisories (chlorine) 

1-day health advisory for a 10-kg 3 mg/L 

child 

10-day health advisory for a 10-kg 3 mg/L 

child 

DWEL 5 mg/L 

Lifetime 4 mg/L 

10-4 Cancer risk No data 

National primary drinking water 

regulations (chlorine [as Cl2])e EPA 2003 

MRDL 4.0 mg/L 

Public health goal (MRDLG) 4.0 mg/L 

Reportable quantities of hazardous EPA 2007j 

substances designated pursuant to 40 CFR 117.3 

Section 311 of the Clean Water Act 

Chlorine 10 pounds 

Sodium hypochlorite 100 pounds 
 

 

 

 

 

 

 

 

 


 

CHLORINE 189 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Chlorine and 

Chlorine Compounds
 

Agency Description Information Reference 

NATIONAL (cont.) 

c. Food 

EPA Chlorine is exempt from the Yes EPA 2007h 

requirement of a tolerance for pesticide 40 CFR 180.1095 

chemicals in food when used as 

preharvest or postharvest in solution on 

all raw agricultural commodities 

Sodium hypochlorite is exempt from the Yes EPA 2007k 

requirement of a tolerance for residues 40 CFR 180.1235 

in food 

FDA EAFUS (ingredient added directly to Yes FDA 2007a 

food that FDA has either approved as a 

food additive or listed or affirmed as 

GRAS) (chlorine and sodium 

hypochlorite) 

Food additives permitted for direct Yes FDA 2007b 

addition to food for human consumption 21 CFR 172 

(sodium hypochlorite) 

Indirect food additives: adhesives and Yes FDA 2006 

components of coatings (sodium 21 CFR 175 

hypochlorite) 

d. Other 

ACGIH Carcinogenicity classification (chlorine) A4f ACGIH 2006 

EPA Carcinogenicity classification (chlorine) No data IRIS 2007 

RfD (chlorine) 0.1 mg/kg/day 

RfC (chlorine) No data 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous Yesg EPA 2007e 

substance (chlorine and sodium 40 CFR 302.4 

hypochlorite) 

Reportable quantity 

Chlorine 10 pounds 

Sodium hypochlorite 1 pound 

Extremely hazardous substance and 100 pounds EPA 2007f 

the threshold planning quantity 40 CFR 355, 

(chlorine) Appendix A 

Effective date of toxic chemical 01/01/87 EPA 2007g 

release reporting (chlorine) 40 CFR 372.65 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 

CHLORINE 190 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Chlorine and 

Chlorine Compounds
 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA TSCA Master Testing List EPA 2007c 

Chlorine Yesh 

Sodium hypochlorite Yesi 

NTP Carcinogenicity classification No data NTP 2005 

a

For effective disinfection, there should be a residual concentration of free chlorine of ≥0.5mg/litre after at least 

30 minute contact time at pH <8.0 (WHO 2004). b

ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for 

up to 1 hour without experiencing or developing other than mild, transient adverse health effects or without perceiving 

a clearly defined objectionable odor; ERPG-2 is the maximum airborne concentration below which it is believed 

nearly all individuals could be exposed for up to 1 hour without experiencing or developing irreversible or other 

serious health effects or symptoms that could impair an individual’s ability to take protective action; and ERPG-3 is 

the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 

1 hour without experiencing or developing life-threatening health effects (AIHA 2004). c

AEGL-1 is the airborne concentration of a substance above which it is predicted that the general population, 

including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic nonsensory 

effects, however, the effects are not disabling and are transient and reversible upon cessation of exposure; AEGL-2 

is the airborne concentration of a substance above which it is predicted that the general population, including 

susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an 

impaired ability to escape; and AEGL-3 is the airborne concentration of a substance above which it is predicted that 

the general population, including susceptible individuals, could experience life-threatening health effects or death 

(EPA 2007a).

d

Regulated toxic and flammable substance under Section 112 of the Clean Air Act e

Potential health effects from exposure above the MCL include anemia and nervous system effects in infants and 

young children; the common source of the contaminant in drinking water is the use of chlorine as a water additive 

used to control microbes (EPA 2003).

f

A4: not classifiable as a human carcinogen 

g

Designated CERCLA hazardous substance pursuant to Section 112 of the Clean Air Act.

h

The Office of Air and Radiation recommended chlorine for acute toxicity testing for health effects. Chlorine is a 

hazardous air pollutant and was added to the Master Testing List in 1995. EPA is initiating development of a testing 

action via TSCA Section 4 FRM, a TSCA Section 4 ECA, or a VTA (EPA 2007c).

i

The Organization for Economic Cooperation and Development recommended sodium hypochlorite for a "base set" of 

screening level test data (SIDS), which include health effects and environmental effects and fate. Sodium 

hypochlorite was added to the Master Testing List in 1995 and EPA is initiating development of a testing action via 

CTPU-VTA (EPA 2007c). 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = Acute Exposure Guideline Levels; 

AIHA = American Industrial Hygiene Association; CERCLA = Comprehensive Environmental Response, 

Compensation, and Liability Act; CFR = Code of Federal Regulations; CTPU = Chemical Testing Program Underway; 

DWEL = drinking water equivalent level; EAFUS = Everything Added to Food in the United States; 

ECA = Enforceable Consent Agreement; EPA = Environmental Protection Agency; ERPG = Emergency Response 

Planning Guidelines; FDA = Food and Drug Administration; FRM = Final Rule-Making; GRAS = Generally 

Recognized As Safe; IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or 

health; IRIS = Integrated Risk Information System; MCL = Maximum Contanimant Level; MRDL = Maximum Residual 

Disinfectant Level; MRDLG = Maximum Residual Disinfectant Level Goal; NIOSH = National Institute for 

Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health 

Administration; PEL = permissible exposure limit; REL = recommended exposure limit; RfC = inhalation reference 

concentration; RfD = oral reference dose; SIDS = Screening Information Data Set; STEL = short-term expsoure limit; 

TLV = threshold limit values; TSCA = Toxic Substances Control Act; TWA = time-weighted average; USC = United 

States Code; VTA = Voluntary Testing Agreement; WHO = World Health Organization 
 

 

 

 

 

 

 

_______________________ 


 

CHLORINE 191 

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Wang L, Najafi R, Najafi K, et al. 2007. Hypochloroous acid as a potential wound care agent. J Burns 

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Wang TZ, Margerum DW. 1994. Kinetics of reversible chlorine hydrolysis: Temperature dependence 

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Ward MJ, Routledge PA. 1988. Hypernatraemia and hyperchloraemic acidosis after bleach ingestion. 

Hum Toxicol 7:37-38. 

Weedon FR, Hartzell A, Setterstrom C. 1940. Toxicity of ammonia, chlorine, hydrogen cyanide, 

hydrogen sulphide, and sulphur dioxide gasses. V. Animals. Contrib Boyce Thompson Inst 11:365-385. 

Wegman DH, Eisen EA. 1990. Acute irritants: More than a nuisance. Chest 97(4):773-775. 

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Wenck MA, van Sickle D, Drociuk D, et al. 2007. Rapid assessment of exposure to chlorine released 

from a train derailment and resulting health impact. Public Health Rep 122(6):784-792. 

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Winder C. 2001. The toxicology of chlorine. Environ Res 85(2):105-114. 

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CHLORINE 212 

9. REFERENCES 

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Wolf DC, Morgan KT, Gross EA, et al. 1995. Two-year inhalation exposure of female and male 

B6C3F1 mice and F344 rats to chlorine gas induces lesions confined to the nose. Fundam Appl Toxicol 

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Wones RG, Deck CC, Stadler B, et al. 1993. Lack of effect of drinking water chlorine on lipid and 

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Yarington CT. 1970. The experimental causticity of sodium hypochlorite in the esophagus. Ann Otol 

Rhinol Laryngol 79:895-899. 

Yildirim C, Kocoglu H, Goksu S, et al. 2004. Long-term pulmonary histopathologic changes in rats 

following acute experimental exposure to chlorine gas. Inhal Toxicol 16(14):911-915. 

Ziegler EE, Edwards BB, Jensen RL, et al. 1978. Absorption and retention of lead by infants. Pediatr 

Res 12(1):29-34. 

Zwart A, Woutersen RA. 1988. Acute inhalation toxicity of chlorine in rats and mice: Timeconcentration-mortality relationships and effects on respiration. J Hazard Mater 19(2):195-208. 
 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 213 

10. GLOSSARY 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 214 

10. GLOSSARY 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 
 

 

 

 

 

 

 

 

 

CHLORINE 215 

10. GLOSSARY 

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. 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 
 

 

 

 

 

 

 

 

 

 

CHLORINE 216 

10. GLOSSARY 

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. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE 217 

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. 

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. 
 

 

 

 

 

 

 

CHLORINE 218 

10. GLOSSARY 

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. 

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. 
 

 

 

 

 

 

 

 

 

 

CHLORINE 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 
 

 

 

 

 

 

CHLORINE A-2 

APPENDIX A 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-62, Atlanta, Georgia 30333. 
 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Chlorine gas 

CAS Numbers: 7782-50-5 

Date: June 2010 

Profile Status: Final Draft Post-Public Comment 

Route: [X] Inhalation [ ] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 7, 9, 10, 11 

Species: Human 

Minimal Risk Level: 0.06 [ ] mg/kg/day [X] ppm 

References: Anglen DA. 1981. Sensory response of human subjects to chlorine in air. Ann Arbor, MI: 

University of Michigan. 

D’Alessandro A, Kuschner W, Wong H, et al. 1996. Exaggerated responses to chlorine inhalation 

among persons with nonspecific airway hyperreactivity. Chest 109:331-337. 

Rotman HH, Fliegelman MJ, Moore T, et al. 1983. Effects of low concentrations of chlorine on 

pulmonary function in humans. J Appl Physiol 54:1120-1124. 

Schins RPF, Emmen H, Hoogendijk L, et al. 2000. Nasal inflammatory and respiratory parameters in 

human volunteers during and after repeated exposure to chlorine. Eur Respir J 16:626-632. 

Shusterman D, Murphy, MA, Balmes J. 1998. Subjects with seasonal allergic rhinitis and nonrhinitic 

subjects react differentially to nasal provocation with chlorine gas. J Allergy Clin Immunol 101:732-740. 

Shusterman D, Murphy, MA, Balmes J. 2003b. Influence of age, gender, and allergy status on nasal 

reactivity to inhaled chlorine. Inhal Toxicol 15:1179-1189. 

Experimental design and effects noted in each study: Anglen (1981) exposed up to 29 male and female 

volunteers to 0, 0.5, 1, or 2 ppm chlorine for either 4 or 8 hours. Sensations were recorded before and 

during exposure, and pulmonary function was monitored by measuring FVC and FEV1 before and at 

various times during exposure. Itching and burning of the throat were the highest responses and were 

most prevalent by the end of an 8-hour exposure to 1 ppm chlorine. Responses for sensations of itching 

or burning of the nose and eyes were also prevalent at 1 ppm chlorine. In general, males provided 

stronger irritation responses than females. Exposure to 1 or 2 ppm chlorine for 8 hours produced 

significant changes in pulmonary function, but similar exposures to 0.5 ppm did not. Exposure to 2 ppm 

for up to 30 minutes produced no increase in subjective irritation and exposure to 2 ppm for 2 hours did 

not alter pulmonary function. 

Rotman et al. (1983) studied eight healthy male volunteers exposed to target concentrations of 0, 0.5, or 

1 ppm chlorine (Rotman et al. 1983). Pulmonary tests were conducted before exposure, after a 4- and 

8-hour exposure period and again 2 and 24 hours after exposure ceased. During exposure, the subjects 

exercised on a treadmill for 15 minutes of each hour to simulate light-to-moderate work that raised the 

heart rate to 100 beats per minute. Specific respiratory parameters measured included FVC, FEV1, 

FEV1% forced expired volume in 1 second as %FVC (FEV1%), peak expiratory flow rate (PEFR), FEF50 

and FEF25, TLC, expiratory reserve volume (ERV), functional residual capacity (FRC), residual volume, 

airway resistance (Raw), single-breath DLCO, closing volume, and difference in nitrogen concentrations 

between 750 and 1,250 mL of inhaled vital capacity (ΔN2). Exposure to 1 ppm chlorine caused runny 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE A-4 

APPENDIX A 

nose and mild burning in the throat, but no such effects were reported at 0.5 ppm. Significant changes in 

pulmonary function tests were mostly restricted to the 1 ppm exposure level and were evident after 

4 hours of exposure. Changes were observed in FEV1, PEFR, FEF50, FEF25, TLC, Raw, and ΔN2. 

Greater changes in some of these parameters were seen after 8 hours of exposure. Few changes were still 

evident 24 hours after exposure, but most parameters had returned to pre-exposure values by that time. It 

should be noted that one volunteer who was atopic experienced severe distress during exposure to 1 ppm 

and was forced to exit the chamber before the full 8-hour period due to shortness of breath and wheezing. 

D’Alessandro et al. (1996) evaluated pulmonary function in subjects with (n=10) and without (n=5) 

airway hyperreactivity (HR, defined by baseline methacholine hyperresponsiveness). The HR subjects 

were exposed to 0.4 or 1.0 ppm chlorine, whereas the healthy subjects were exposed to 1.0 ppm chlorine. 

All exposures lasted 60 minutes. Airflow and airway resistance were measured immediately before and 

immediately after exposure. Also, lung volumes, airflow, diffusing capacity, airway resistance, and 

responsiveness to methacholine were measured 24 hours before and 24 hours after exposure. Exposure of 

the HR group to 0.4 ppm chlorine resulted in no significant change in airflow or resistance either 

immediately or 24 hours after exposure. Exposure to 1.0 ppm chlorine resulted in an immediate decrease 

in FEV1 and FEF25–75% and increase in airway resistance among normal and HR subjects, but the 

magnitude of the effects among HR subjects was significantly greater than in healthy subjects. Twentyfour hours after exposure, there were no significant changes for healthy or HR subjects in airflow, lung 

volumes, diffusing capacity, resistance, or methacholine responsiveness. Comparing relative changes 

from baseline immediately after exposure between normal and HR subjects showed that HR subjects had 

much greater changes in pulmonary function tests. 

Schins et al. (2000) studied eight volunteers exposed to chlorine 6 hours/day on 3 consecutive days to 

each of the four exposure conditions, 0, 0.1, 0.3, and 0.5 ppm chlorine (Schins et al. 2000). Pulmonary 

function including effort-dependent parameters and effort-independent parameters were evaluated before 

and after exposures. In addition, nasal lavage measurements were performed before and after each 

exposure and 1 and 4 days after each exposure. The nasal lavage fluid was examined for total cells, 

epithelial cells, neutrophils, lymphocytes, eosinophils, monocytes, albumin (an indicator of epithelial 

permeability), and interleukin-8 (indicator of inflammatory response). Subjective complaints by the 

subjects were judged to be not treatment-related. Examination of the nasal lavages gave no indication of 

an inflammatory response or irritant effects on the nasal epithelium. The results of the pulmonary 

function tests showed that the only significant effect related to chlorine exposure was a difference in 

maximal mid expiratory flow (MMEF) between 0 and 0.5 ppm exposure; however, this was attributed to 

an unexplained shift in baseline values during control exposure (0 ppm). 

Shusterman et al. (2003b) measured nasal airway resistance in 52 healthy adults (24 males and 

28 females) before and after exposure to 0 or 1 ppm chlorine for 15 minutes. Subjects were stratified on 

age (18–34, 35–51, 52–69 years), gender, and allergic rhinitis status (27 were positive). Nasal airway 

resistance was measured by active posterior rhinomanometry. Exposures to air and chlorine were a week 

apart. Subjects with allergic rhinitis showed a significantly greater increase in nasal airway resistance 

(49% increase from baseline) than healthy subjects (10% increase from baseline) 15 minutes after 

exposure. The increase in nasal airway resistance was most pronounced in older subjects and least 

pronounced in the youngest group. No significant differences were seen between males and females. In 

an earlier study, the same group of investigators had reported that subjects with SAR (n=8) exposed to 

0.5 ppm chlorine for 15 minutes experienced a much greater increase in nasal airway resistance than 

subjects without SAR (n=8), as measured by active posterior rhinomanometry (Shusterman et al. 1998). 

However, when subjective responses to odor, nasal irritation, and nasal congestion were analyzed 

separately by rhinitis status, no significant exposure-related changes were observed for rhinorrhea, 

postnasal drip, or headache either on a pool or stratified basis. In addition, within either the SAR or nonSAR group, there was no relationship between subjective and objective congestion after chlorine 
 

 

 

 

 

 


 


 

CHLORINE A-5 

APPENDIX A 

exposure. Pulmonary peak flow tests showed that none of the subjects exhibited clinically significant 

changes in peak flow, nor did they complain of cough, wheezing, or chest tightness on chlorine exposure 

days. The increased nasal airway resistance instrumentally detected in subjects with SAR is not 

considered an adverse effect since the subjects did not perceive it as such. 

Collectively, this group of studies provides evidence of sensory irritation and transient pulmonary 

changes occurring in humans exposed to 1 ppm chlorine for up to 8 hours/day. The pulmonary changes 

indicated increased airway resistance and reduced air flow. No such changes were reported in volunteers 

exposed to 0.5 ppm chlorine 

Dose and end point used for MRL derivation: 0.5 ppm is a NOAEL for sensory irritation and pulmonary 

function. 

The MRL is derived by adjusting for continuous exposure based on the fact that Rotman et al. (1983) 

reported that exposure to 1 ppm for 8 hours induced greater changes in pulmonary function tests than 

exposure to the same concentration for 4 hours, suggesting that the response was related to some function 

of concentration and duration rather than to concentration alone. 

MRL = 0.5 ppm (8 hours/24 hours) = 0.167 ppm 

8 hours was the longest period of exposure for which there is information. 

[X] NOAEL [ ] LOAEL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL
 

[ ] 10 for extrapolation from animals to humans
 

[X] 3 for human variability 

Although sensitive individuals were tested in some of these studies, the number of individuals tested at 

the region of the NOAEL (0.4–0.5 ppm) was small. Therefore, an uncertainty factor of 3 is used to 

account for sensitive populations. 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Yes, see above. 

Other additional studies or pertinent information that lend support to this MRL: Results from the five 

studies summarized above are supportive of each other. 

Agency Contacts (Chemical Managers): G. Daniel Todd 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE A-6 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Chlorine gas 

CAS Numbers: 7782-50-5 

Date: June 2010 

Profile Status: Final Draft Post-Public Comment 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 30 

Species: Rat 

Minimal Risk Level: 0.002 [ ] mg/kg/day [X] ppm 

Reference: Kutzman RS. 1983. A study of Fisher-344 rats subchronically exposed to 0, 0.5, 1.5, or 

5.0 ppm chlorine. Upton, NY: Brookhaven National Laboratory. BNL 32710. 

Experimental design: Groups of F344 rats (24 males, 10 females) were exposed to 0, 0.5, 1.5, or 5 ppm 

chlorine 6 hours/day, 5 days/week for 62 days (Kutzman 1983). Pulmonary function tests 

(plethysmograph-based assessment of multiple end points, including lung and tidal volumes, breathing 

frequency, transpulmonary pressure, lung compliance, N2 washout, diffusing capacity for CO2, maximum 

expiratory flow volume, peak expiratory flow, and airway resistance) were conducted in 21– 

24 anesthetized males 6 hours after the last exposure. Respiratory tissues from these rats were prepared 

for histopathology. The lung from some of these rats was also examined for collagen, elastin, total 

protein, and DNA. Histopathology of selected organs (nasal turbinates, lungs, peribronchial lymph node, 

brain, kidney, liver, spleen, testes, and heart) was evaluated in eight males per group. Also, 8 males were 

mated with untreated females and 10 exposed females were mated with untreated males for reproductive 

studies on females sacrificed on GD 19. In addition, 1 day after the last exposure, samples of blood and 

bone marrow from 10 males per group were prepared for analysis of chromosomal aberrations and sister 

chromatid exchanges. 

Effects noted in study and corresponding doses: Exposure to 5 ppm cause severe eye and upper 

respiratory irritation, whereas rats exposed to 1.5 ppm showed occasionally less severe signs of irritation, 

and exposure to 0.5 ppm caused no obvious signs of irritation or discomfort. Female rats exposed to 

5 ppm lost weight. Final weight was approximately 32% lower than controls; at 1.5 and 0.5 ppm, final 

weight was approximately 15 and 11% lower than in control rats, respectively. In males exposed to 

5 ppm, final weight was approximately 15% lower than controls. No information was provided regarding 

food and water intake. Changes in organ weights were unremarkable. The tests of pulmonary function 

did not reveal marked abnormalities. The most significant effect was a reduction in airflow at 25% vital 

capacity in all exposed groups, indicating some degree of small airway involvement. An electrocardiogram did not reveal any significant cardiac alterations due to chlorine exposure. The lung 

biochemistry only showed an increased collagen concentration at 1.5 and 5 ppm. The cytogenetic studies 

showed no increased incidence of sister chromatid exchange or cellular proliferation in bone marrow and 

no increase in sister chromatid exchanges or chromosomal aberrations in peripheral lymphocytes. 

Analysis of sperm morphology was unremarkable. Results of the reproductive studies showed no effects 

on fertility, number of corpora lutea, viable embryos, early or late deaths, or preimplantation loses. There 

were no significant exposure-related increases in the incidences of animals with histological lesions in 

any of the examined tissues with the exception of a loss of cilia in the trachea. The incidences of slight to 

moderate loss of tracheal cilia were 1/23, 12/23, 4/23, and 13/23 in the 0, 0.5, 1.5, and 5 ppm exposure 

groups, respectively. Although the incidence for this lesion in the mid-exposure group was not 

significantly different from the control incidence, a statistically significant (p=0.0055) Cochran-Armitage 

trend test for these data can be demonstrated. However, when attempts were made to apply dose-response 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE A-7 

APPENDIX A 

models to the data, no adequate fits of EPA Benchmark Dose Software models to the data were obtained 

(p-values for chi-square goodness of fit statistics were <0.1). 

Dose and end point used for MRL derivation: 0.5 ppm is a minimal LOAEL for tracheal lesions. 

Uncertainty Factors used in MRL derivation: 

[X] 3 for use of a minimal LOAEL 

[X] 3 for extrapolation from animals to humans with dosimetric adjustment 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: The 

intermediate-duration inhalation MRL was calculated using EPA’s methodology (EPA 1994a) for a 

category 1 gas. 

LOAEL[HEC] = LOAEL[ADJ] x RGDRTB 

where: 

LOAEL[ADJ] = 0.5 ppm x 6/24 hours x 5/7 days = 0.09 ppm and 

RGDRTB = ratio of the regional gas dose in rats to that of humans for the tracheobronchial region 

RGDRTB = (VE/SATB)A / (VE/SATB)H 

where: 

VE = minute volume (0.137 L/minute for rats, 13.8 L/minute for humans [EPA 1994a]) and 

SATB = surface area of the tracheobronchial region (22.5 cm2 for rats and 3,200 cm2 for humans 

[EPA 1994a]) 

LOAEL[HEC] = 0.09 ppm x (0.137 L/minute/22.5 cm2

) / (13.8 L/minute/3,200 cm2) = 0.14 ppm 

Was a conversion used from intermittent to continuous exposure? Yes, see above. 

Other additional studies or pertinent information that lend support to this MRL: In a similar study, 

Barrow et al. (1979) evaluated the respiratory response in F344 rats exposed to 0, 1, 3, or 9 ppm chlorine 

6 hours/day, 5 days/week for 6 weeks. Nasal discharge was seen occasionally in rats exposed to 1 ppm, 

but was common in rats exposed to 3 and 9 ppm. Respiratory difficulty was also apparent in some rats 

exposed to 9 ppm. At termination, gross necropsy revealed accumulation of inflammatory reactions in 

the upper nasal passages in rats exposed to 3 and 9 ppm chlorine. Microscopic evaluations showed 

indications of inflammatory reactions in the upper and lower respiratory tract of high-dose males and 

females. The nasal turbinates showed mucopurulent inflammation with secretory material and erosions of 

the mucosal epithelium. Changes in the trachea and bronchi consisted mostly of hyperplasia of the 

epithelial lining and inflammatory reactions. The alveolar sacs contained macrophages and secretory 

material and epithelial cells showed necrosis, hypertrophy, and hyperplasia. Alterations in rats exposed to 

1 and 3 ppm were less extensive and were limited to focal mucopurulent inflammation of the nasal 

turbinates in females. Males exposed to 1 or 3 ppm showed deeper pulmonary changes consisting of 

slight to moderate inflammatory reaction around the respiratory bronchioles and alveolar ducts, increased 

alveolar macrophages, and isolated areas of atelectasis (incomplete expansion). A LOAEL of 1 ppm for 

respiratory effects can be defined in this study based on the presence of inflammatory changes in the nasal 
 

CHLORINE A-8 

APPENDIX A 

turbinates of females and in the lungs of males; no NOAEL was established. Incidences of animals with 

respiratory lesions were not presented in this study. 

Agency Contacts (Chemical Managers): G. Daniel Todd 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CHLORINE A-9 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Chlorine gas 

CAS Numbers: 7782-50-5 

Date: June 2010 

Profile Status: Final Draft Post-Public Comment 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 34 

Species: Monkey 

Minimal Risk Level: 0.00005 [ ] mg/kg/day [X] ppm 

Reference: Klonne DR, Ulrich CE, Riley MG, et al. 1987. One-year inhalation toxicity study of chlorine 

in Rhesus monkeys (Macaca mulatta). Fundam Appl Toxicol 9:557-572. 

Experimental design: Male and female Rhesus monkeys (4/sex/exposure level) were exposed to 0, 0.1, 

0.5, or 2.3 ppm chlorine 6 hours/day, 5 days/week for 1 year (Klonne et al. 1987). Pulmonary diffusing 

capacity of CO and distribution of ventilation, body weights, urinalysis, EKG, hematology, and clinical 

chemistry were evaluated monthly during the study. At termination, the heart, lungs plus trachea, liver, 

gonads, kidneys, spleen, and brain were weighed. Histological evaluations were done on all major tissues 

and organs. The nasal tissues (at the first palatine ridge and just posterior to the third, fifth, and seventh 

palatine ridges), trachea, and lungs were also examined. 

Effects noted in study and corresponding doses: Exposure to chlorine did not significantly affect body 

weight, hematology and clinical chemistry parameters, urinalysis, or the EKG. At approximately week 6 

of exposure, monkeys in the 2.3 ppm group showed overt signs of ocular irritation (tearing, reddened 

eyes, rubbing the eyes) during the daily exposures; no signs of irritation were seen in the other exposure 

groups. Examination of the eyes at termination showed irritation of the conjunctiva at 2.3 ppm, but no 

evidence of gross changes; the corneas were not affected. During the study, there was a statistically 

significant trend in each group, including controls, for increasing pulmonary diffusing capacity and 

distribution of ventilation. However, there was no evidence of treatment-related effects at any interval 

during the study. The only treatment-related histopathological effects consisted of focal epithelial 

hyperplasia characterized by increased cell numbers and loss of cilia and goblet cells in the respiratory 

epithelium of the nose and trachea. The affected areas of the nasal passages showed hypercellularity with 

loss of goblet cells and cilia. In some of these areas, the nuclei showed altered polarity. Lesions were 

more frequent on the angular margins of the turbinates and less frequent on the lateral wall or septum 

adjacent to these margins. In some cases, the respiratory epithelial hyperplasia was associated with mild 

suppurative inflammatory response. Lesions in the trachea resembled those in the nose, but were less 

severe and involved only a small circumferential section of the ventral and ventrolateral trachea. The 

combined incidences of hyperplasia in the nasal epithelium with loss of goblet cells and cilia, 

characterized as trace and mild in males and females, were 1/8, 3/8, 6/8, and 8/8 in the control, 0.1, 0.5, 

and 2.3 ppm exposure groups, respectively. The exposure concentration of 0.1 ppm is considered a 

LOAEL for nasal lesions in monkeys. 

Incidence data for nasal lesions in male and female monkeys exposed to chlorine gas (Klonne et al. 1987) 

were analyzed using the BMD approach for MRL derivation. Models in the EPA BMDS (version 1.4.1) 

(i.e., Gamma, Logistic, Log-logistic, Multi-stage, Probit, Log-probit, Quantal linear, Weibull) were fit to 

the nasal lesion data to determine potential points of departure for the MRL. A Quantal linear model 

provided the best fit to the data. The predicted exposure concentration associated with a 10% extra risk 
 

 

CHLORINE A-10 

APPENDIX A 

(BMC10) for nasal lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on this 

concentration (BMCL10) was 0.02 ppm. 

Dose and end point used for MRL derivation: BMCL10 of 0.02 ppm for nasal lesions in monkeys. 

[ ] NOAEL [ ] LOAEL [X] BMCL10 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 3 for extrapolation from animals to humans with dosimetric adjustment 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: The 

intermediate-duration inhalation MRL was calculated using EPA’s methodology (EPA 1994a) for a 

category 1 gas. 

BMCL10[HEC] = BMCL10[ADJ] x RGDRET 

where: 

BMCL10[ADJ] = 0.02 ppm x 6/24 hours x 5/7 days = 0.004 ppm and 

RGDRET = ratio of the regional gas dose in rats to that of humans for the extrathoracic region 

RGDRET = (VE/SAET)A / (VE/SAET)H 

where: 

VE = minute volume 2.1 m3

/day for monkeys, calculated using the allometric equation for 

monkeys in EPA (1988) assuming a body weight of 7 kg for Rhesus monkeys with nasal 

cavity surface area of 62 cm2

 (Gross and Morgan 1991); 20 m3/day for humans (EPA 1994a) 

and 

SAET = 62 cm2 surface area of the nasal cavity in Rhesus monkeys weighing 7 kg (Gross and 

Morgan 1991); 200 cm2

 for humans (EPA 1994a) 

RGDRET = (2.1 m3

/day / 62 cm2) / (20 m3/day / 200 cm2) = 0.34 

BMCL10[HEC] = 0.004 ppm x 0.34 = 0.00136 ppm 

Was a conversion used from intermittent to continuous exposure? Yes, see above. 

Other additional studies or pertinent information that lend support to this MRL: Wolf et al. (1995) 

exposed groups of F344 rats and B6C3F1 mice (approximately 70/sex/exposure level) to 0, 0.4, 1, or 

2.5 ppm chlorine gas for 2 years. Males from both species and female mice were exposed 6 hours/day, 

5 days/week, whereas female rats were exposed 6 hours/day, 3 days/week. The reduced exposure of 

female rats was based on unpublished data from the investigators that showed female rats to have a 

greater sensitivity to repeated long-term exposure to chlorine. End points evaluated included gross and 

microscopic examination of the respiratory tract; the nasal passages were examined microscopically at 
 

 

 

 

 

CHLORINE A-11 

APPENDIX A 

five different levels. Both in rats and mice, there were no gross lesions attributable to exposure to 

chlorine, and microscopic evaluation of the respiratory tract showed that chlorine-related effects were 

restricted to the nasal passages. In the study, the incidences were presented as percentages of all animals 

for which the nasal passages were adequate for microscopic examination, but the number of animals 

examined was not provided. No lesions were seen in the larynx, trachea, bronchi, or bronchioles. In 

general, rats and mice exhibited similar types of lesions. For the most part, the nasal lesions were sitespecific, but the severity and/or incidence were not always concentration-dependent. The majority of the 

nasal responses exhibited a rostral-to-caudal severity gradient. The lesions rarely extended to the 

nasopharyngeal meatus. Lesions observed included respiratory and olfactory epithelial degeneration, 

septal fenestration, mucosal inflammation, respiratory epithelial hyperplasia, squamous metaplasia, and 

goblet cell (only rats) hypertrophy and hyperplasia, and secretory metaplasia of the transitional epithelium 

of the lateral meatus. Also observed was intracellular accumulation of eosinophilic proteinaceous 

material involving the respiratory, transitional, and olfactory epithelia. Lesions were also observed in 

controls, but the incidences were significantly lower than in the treated groups. One of the lesions with 

the lowest incidence in controls was Goblet cell hyperplasia in female rats (4%); the respective incidences 

in the 0.4, 1, and 2.5 ppm group were 71, 90, and 91%. In mice, olfactory epithelium atrophy exhibited 

one of the lowest incidences in controls (3%); the respective incidences in the 0.4, 1, and 2.5 ppm group 

were 20, 21, and 39%. In both cases, severity also was concentration-related. Based on the increased 

incidence of various types of lesions in the nasal passages, the exposure level of 0.4 ppm constitutes a 

LOAEL for respiratory effects in rats and mice; a NOAEL was not defined. 

Agency Contacts (Chemical Managers): G. Daniel Todd 
 

 

 


 


 


 


 


 

CHLORINE A-12 

APPENDIX A 

BENCHMARK MODELING OF NASAL LESIONS IN MONKEYS 

Incidence data for nasal lesions in male and female monkeys exposed to chlorine gas (Klonne et al. 1987) 

were analyzed using the BMD approach for MRL derivation (Table A-1). Models in the EPA BMDS 

(version 1.4.1) (i.e., Gamma, Logistic, Log-logistic, Multi-stage, Probit, Log-probit, Quantal linear, 

Weibull) were fit to the nasal lesion data to determine potential points of departure for the MRL. A 

Quantal linear model provided the best fit to the data (Table A-2). 

Table A-1. Incidence of Nasal Lesions Observed in Monkeys Exposed to
 

Chlorine for 1 Year
 

Dose (ppm) Total number of monkeys Number of monkeys with lesions 

0 8 1 

0.1 8 3 

0.5 8 6 

2.3 8 8 

Source: Klonne et al. 1987 

Table A-2. Modeling Predictions for the Incidence of Nasal Lesions Observed in 

Monkeys Exposed to Chlorine for 1 Year 

BMC10 BMCL10 

Model (ppm) (ppm) x2 p-value AIC 

Gammaa 0.04 0.02 0.95 29.72 

Logistic 0.09 0.05 0.76 30.17 

Log-logisticb 0.05 0.009 0.53 32.21 

Multi-stagec 0.04 0.02 0.95 29.72 

Probit 0.08 0.05 0.77 30.14 

Log-probitb 0.06 0.03 0.81 30.09 

Quantal linear 0.04 0.02 0.95 29.72 

Weibulla 0.04 0.02 0.95 29.72 

a

Restrict power ≥1.
 b

Slope restricted to >1.
 c

Restrict betas ≥0; lowest degree polynomial with an adequate fit is reported; degree of polynomial = 1.
 

Source: Klonne et al. 1987 
 

 

 

 

CHLORINE A-13 

APPENDIX A 

From this model, the predicted exposure concentration associated with a 10% extra risk (BMC10) for nasal 

lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on this concentration (BMCL10) was 

0.02 ppm (Figure A-1). 

Figure A-1. Predicted and Observed incidence of Nasal Mucosal Lesions in 

Monkeys Exposed to Chlorine for 1 Year 

Quantal Linear Model with 0.95 Confidence Level 

Fraction Affected 

1 

0.8 

0.6 

0.4 

0.2 

0 

BMDL BMD 

Quantal Linear 

0 0.5 1 1.5 2 

dose 

10:34 03/30 2007 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(-slope*dose)] 

Background = 0.135767 

Slope = 2.67521 
CHLORINE A-14
 

APPENDIX A 

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CHLORINE	 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. 
 

 

 

 

 

 

 

 

 

 

 

CHLORINE 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. 
 

 

 

 

 

 

 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

CHLORINE	 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"). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

CHLORINE	 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. 
 

 

 

	 

	 

	 

CHLORINE	 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. 
1 2 3 4 12 

→

SAMPLE 

Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

→→

Exposure 

Key to frequency/ figurea Species duration 

INTERMEDIATE EXPOSURE 

5 6 

Systemic ↓ ↓

NOAEL 

System (ppm) 

7 8 ↓ ↓

LOAEL (effect) Less serious (ppm) 

9 

↓

Serious (ppm) 

Re

10 

↓

→→

18 Rat 13 wk Resp 3b 10 (hyperplasia) 

5 d/wk Nit6 hr/d 

CHRONIC EXPOSURE 

Cancer 11 

↓

38 Rat 18 mo 20 (CEL, multiple Wo

5 d/wk organs) 7 hr/d 

39 Rat 89–104 wk 10 (CEL, lung tumors, NT

5 d/wk nasal tumors) 6 hr/d 

40 Mouse 79–103 wk 10 (CEL, lung tumors, NT

5 d/wk hemangiosarcomas) 6 hr/d 

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). 

CHLORINE B-8
 

APPENDIX B 

This page is intentionally blank. 
CHLORINE C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD/C benchmark dose or benchmark concentration 

BMDX dose that produces a X% change in response rate of an adverse effect 

BMDLX 95% lower confidence limit on the BMDX 

BMDS Benchmark Dose Software 

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 
 

 

CHLORINE C-2 

APPENDIX C 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMDG North America/Intergovernmental Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 
 

 

CHLORINE C-3 

APPENDIX C 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 
 

 

CHLORINE C-4 

APPENDIX C 

OW Office of Water 

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 
 

CHLORINE 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 
CHLORINE C-6
 

APPENDIX C 

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CHLORINE D-1 

APPENDIX D. INDEX
 

absorbed dose............................................................................................................................................121
 

acetylcholine ...............................................................................................................................................67
 

adrenal gland...............................................................................................................................................95
 

adrenals ................................................................................................................................................. 69, 95
 

alanine aminotransferase (see ALT) ...........................................................................................................68
 

Alberton .............................................................................................................................. 50, 163, 168, 171
 

ALT (see alanine aminotransferase) ..................................................................................................... 67, 68
 

ambient air ................................................................................................................................................169
 

anemia.......................................................................................................................................................190
 

aspartate aminotransferase (see AST).........................................................................................................68
 

AST (see aspartate aminotransferase).........................................................................................................68
 

asthma ......................................................................................................... 11, 14, 48, 50, 58, 123, 139, 182
 

atropine .......................................................................................................................................................61
 

biodegradation...........................................................................................................................................167
 

biomarker ............................................................................................ 52, 112, 120, 121, 122, 137, 177, 182
 

bleach..................................... 2, 3, 4, 5, 9, 10, 12, 13, 21, 48, 50, 56, 58, 75, 76, 91, 92, 96, 100, 103, 115,
 

120, 124, 129, 130, 131, 134, 135, 136, 137, 138, 149, 159, 169, 170, 173
 

blood cell count..................................................................................................................................... 92, 93
 

body weight effects....................................................................................................................... 70, 95, 100
 

breast milk.................................................................................................................................................170
 

cancer.............................................................................................................. 13, 74, 98, 104, 118, 129, 132
 

carcinogen......................................................................................................................................... 186, 190
 

carcinogenic .................................................................................................................... 12, 14, 25, 104, 132
 

carcinogenicity.................................................................................................... 12, 13, 75, 98, 99, 133, 186
 

carcinomas ................................................................................................................................................105
 

cardiovascular ..................................................................................................... 11, 27, 29, 66, 91, 100, 138
 

cardiovascular effects...................................................................................................................... 65, 66, 91
 

chemical weapon....................................................................................................................... 10, 15, 26, 59
 

chromosomal aberrations.................................................................................................................. 105, 133
 

cleaning solutions.................................................................................................................................... 5, 48
 

death.............................................. 4, 10, 11, 13, 25, 26, 27, 28, 29, 48, 55, 71, 92, 100, 125, 129, 130, 190
 

deoxyribonucleic acid (see DNA).............................................................................................................108
 

dermal effects................................................................................................................................ 69, 95, 100
 

dermatitis ............................................................................................................................ 13, 104, 136, 182
 

disinfection.............................................................................................. 1, 2, 5, 26, 145, 163, 166, 178, 190
 

DNA (see deoxyribonucleic acid)............................................................................................... 63, 108, 121
 

endocrine............................................................................................................... 69, 94, 100, 115, 116, 117
 

endocrine effects ................................................................................................................................... 69, 94
 

erythema......................................................................................................................................................27
 

fetus...........................................................................................................................................................117
 

gassing ................................................................................................ 11, 18, 26, 28, 46, 48, 58, 59, 67, 123
 

gastrointestinal effects .................................................................................................................. 66, 91, 138
 

general population........................................................................... 9, 11, 15, 18, 46, 48, 129, 159, 169, 190
 

genotoxic............................................................................................................................. 25, 105, 129, 133
 

genotoxicity................................................................................................................................. 14, 105, 133
 

Graniteville ............................................................................................................................... 163, 165, 171
 

groundwater ...................................................................................................................................... 164, 169
 

half-life.................................................................................................................. 9, 109, 121, 159, 165, 172
 

hematological effects ............................................................................................................................ 67, 92
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 

CHLORINE D-2 

APPENDIX D 

hepatic effects ................................................................................................................................. 67, 93, 94
 

household chemicals ......................................................................................................... 3, 5, 159, 170, 173
 

hydrolysis..................................................................................................................................................112
 

hypochlorite ..............1, 2, 3, 4, 5, 6, 9, 10, 12, 13, 21, 22, 23, 24, 26, 50, 75, 76, 91, 92, 93, 94, 95, 96, 97, 

98, 99, 100, 103, 104, 105, 109, 110, 111, 112, 114, 115, 116, 120, 121, 122, 

124, 126, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 143, 

145, 149, 160, 164, 166, 167, 169, 177, 178, 183, 186, 188, 189, 190
 

hypochlorous...................................... 2, 9, 10, 12, 22, 24, 26, 66, 94, 97, 98, 105, 109, 110, 112, 114, 117, 

122, 124, 125, 129, 130, 131, 132, 134, 135, 137, 138, 143, 

145, 149, 159, 160, 164, 166, 168, 177, 178, 179, 183, 186
 

immune system ................................................................................................................................... 12, 135
 

immunological ................................................................................................ 22, 25, 96, 104, 129, 131, 135
 

immunological effects......................................................................................................................... 96, 135
 

Kow ............................................................................................................................................................146
 

LD50.............................................................................................................................................................75
 

leukemia........................................................................................................................................ 14, 99, 133
 

lymphatic ....................................................................................................................................................11
 

lymphoreticular......................................................................................... 22, 70, 71, 96, 104, 129, 131, 135
 

Macdona............................................................................................................................................ 163, 171
 

metabolic effects .........................................................................................................................................96
 

micronuclei ...............................................................................................................................................105
 

milk ............................................................................................................... 21, 91, 93, 94, 95, 97, 103, 124
 

mucociliary .................................................................................................................................................61
 

musculoskeletal effects ......................................................................................................................... 67, 93
 

neonatal............................................................................................................................................. 134, 170
 

neurobehavioral..................................................................................................................... 12, 72, 116, 136
 

nuclear.......................................................................................................................................................109
 

ocular effects........................................................................................................................... 13, 70, 95, 103
 

odds ratio.....................................................................................................................................................74
 

pharmacodynamic.....................................................................................................................................111
 

pharmacokinetic........................................................................................ 111, 112, 113, 114, 117, 137, 138
 

photolysis...................................................................................................... 9, 159, 163, 165, 168, 172, 173
 

pneumonia..................................................................................................................... 11, 26, 27, 28, 49, 76
 

pulmonary edema.......................................... 4, 10, 11, 27, 28, 47, 48, 49, 50, 57, 61, 66, 67, 125, 126, 182
 

railroad.......................................................................................................................... 27, 48, 163, 168, 171
 

rate constant ..............................................................................................................................................166
 

reactive airway dysfunction syndrome .......................................................................................................11
 

renal effects........................................................................................................................................... 68, 94
 

solubility ........................................................................................................................................... 114, 179
 

South Carolina .............................................................................................................. 27, 66, 163, 165, 171
 

spirometry ............................................................................................................................................. 52, 58
 

storage tank................................................................................................................. 10, 48, 49, 57, 68, 129
 

swimming pool...................................................... 3, 5, 9, 10, 48, 51, 71, 118, 119, 123, 129, 160, 169, 170
 

T3.................................................................................................................................... 30, 77, 94, 101, 116
 

T4........................................................................................................................................................ 94, 116
 

thyroid......................................................................................................... 13, 22, 69, 94, 98, 109, 116, 117
 

thyroxine .....................................................................................................................................................94
 

toxicokinetic................................................................................................................................................25
 

triiodothyronine...........................................................................................................................................94
 

TSH....................................................................................................................................................... 60, 94
 

tumors .......................................................................................................................................................104