## TOXICOLOGICAL PROFILE FOR

CHLORINE

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Agency for Toxic Substances and Disease Registry

November 20 10ii CHLORINE



### 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.iii CHLORINE



### UPDATE STATEMENT

A Toxicological Profile for Chlorine, Draft for Public C omment 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 30333iv CHLORINE



### This page is intentionally blank.v CHLORINE



### 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 pro file 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 nontechnica l 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 avai lable 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 adequa te 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 Federa l, 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. Staff s 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 Registryvi CHLORINE

* 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 Pr iorities 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 oth erwise

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



### QUICK REFERENCE FOR HEALTH CARE PROVIDERS

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

substance. Each profile reflec ts 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 inf ormation 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 subst ance. 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 a nd 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 followin g 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.viii CHLORINE

Managing Haza rdous 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 ho spital emergency

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

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

professionals treating patients exposed to hazardous materia ls.

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, ph ysical, 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 Cli nics (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: AO EC@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.ix CHLORINE



### 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 re views 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.x CHLORINE



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### PEER REVIEW

A p eer 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, Californi a.

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 conf ormity 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 ad ministrative 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.xii CHLORINE



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### CONTENTS

DISCLAIMER

................................................................................................ .............................................. ii

UPDATE STATEMENT

............................................................................................................................. iii

FOREWORD

................................................................................................ ................................................ v

QUICK REFERENCE FOR HEALTH CARE PROVIDERS

.................................................................... vii

C ONTRIBUTORS

................................................................................................ ....................................... 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 Developmen tal 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

............................................................................................................................ 983.2.3 Dermal Exposure.................................................................................................................100

3.2.3.1 Death

............................................................................................................................ 100

3.2.3.2 Systemic Effects

........................................................................................................... 100

3.2.3.3 Im munological 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) Mo dels ...........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

- Huma n 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 Exp o sure .............................................................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 xiv CHLO RINE5.3 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 CHLORINE xvxvi CHLORINE



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### 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 Eff ects of Chlorine Gas

................................................................. 127

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

................................................... 128

4-1. Speciation of Cl 2 , HOCl, and OCl

as a Function of pH

................................................................... 148CHLORINE xviii



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### 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 Significa nt 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

.......... 187xx CHLORINE



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## 1. PUBLIC HEALTH STATEMENT

This public health statement tells you about chlorine and the effects of expo sure 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 relea sed 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 y ou 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 (Cl 2 ), which exists as a gas under normal environmental

conditions or as a liquid when stored under pressure. Although molecular chlori ne 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 hypochl orite, 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

man ufacturing 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 (Cl 2 ) 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 i s

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

exp osure 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 deve lop 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 exce ed a critical value that is usually based on levels that

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

- to

exceed levels differ among federal organizations because they used different exposure times (an 8-hour

workday or a 24-hour day), different animal studies, or other factors.

Recommendations and regulations are also updated periodically as more information becomes available.

For the most current information, check with the federal agency or organiz ation that provides it.7 CHLORINE

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 concern s, 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 ToxProfiles TM CD

- ROM by callin g 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 Cl ifton Road NE

Mailstop F-62

Atlanta, GA 30333

Fax: 1 -770-488-41788 CHLORINE

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/9 CHLORINE



### 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 chl orine 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 dispropor tionates

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 chlor ine 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 t o 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.10 CHLORINE

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 wa ter 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

p ractices 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

sc hool 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 concentrations11 CHLORINE

2. RELEVANCE TO PUBLIC HEALTH

of chlorine (<5 ppm) are not expected to affect deep lung structur es 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 hypoxi a

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

studi es 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 case s 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

illne ss after a single acute exposure to a respiratory irritant in otherwise healthy individuals, characterized12 CHLORINE

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, incl uding 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 exam ined 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 alteration s 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 th at 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 possi ble 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 intentiona l 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 a13 CHLORINE

2. RELEVANCE TO PUBLIC HEALTH

woman who drank an unknown amount of bleach reveale d 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 in termediate -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 h ydroxide 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 wi th 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 e sophagus 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 stu dies, Sprague- Dawley rats,

F344 rats, and B6C3F 1 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 im mune or nervous system, although an 8- week study in rats14 CHLORINE

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,

howev er, 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 no t 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 wh en 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 de velop 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 t he 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.15 CHLORINE

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 availa ble 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 sensit ive 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 pot entially 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 chlori ne. Although qualitatively informative, the early data do not meet

current guidelines for use in quantitative risk assessment. More recent studies in animals, mainly rodents,16 CHLORINE

2. RELEVANCE TO PUBLIC HEALTH

have confirmed the earlier findings regarding sensory irritation and pathologic al 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 mi ce occurred with chlorine concentrations >5 ppm. Specific lowest- observed

adverse

- 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 RD 50 and is commonly used to compare the irritant potencies of

chemicals. This reflex re action 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 st udy 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 o f these studies, the17 CHLORINE

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, m ale 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, wh ereas 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 evaluate d 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 los s 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-exposur e

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 adequ ate 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:18 CHLORINE

2. RELEVANCE TO PUBLIC HEALTH

LOAEL [HEC] = LOAEL [ADJ] x RGDR TB

where:

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

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

RGDR TB = (VE/SA TB ) A / (VE/SA TB ) H

where:

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

SA TB = surface area of the tracheobronchial region (22.5 cm 2 for rats and 3,200 cm 2 for humans

[EPA 1994a])

LOAEL [HEC] = 0.09 ppm x (0.137 L/minute/22.5 cm 2 ) / (13.8 L/minute/3,200 cm 2 ) = 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 chr onic -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 stud ies of chronically

exposed 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 insuffic ient 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, h ydrogen 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, th e

most significant finding was that a subgroup of nonsmokers (n=4) had a significantly lower fixed19 CHLORINE

2. RELEVANCE TO PUBLIC HEALTH

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

1 second/forced vital capacity (FEV 1 /FVC) ratio than the control wo rkers. 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 quantit ative 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 simil ar 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 lowe st exposure concentration tested, 0.4 ppm chlorine. In general, the nasal lesions were site

specific, 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 cell20 CHLORINE

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 hypercellulari ty with loss of goblet cells and cilia. In some of

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

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

respiratory epithelial hyperplasia wa s 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. Th e 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) appr oach 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 (BMC 10 ) for nasal lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on

this concentration (BMCL 10 ) was 0.02 ppm. The monkey BMCL 10 served as the point of departure for the

chronic-duration MRL, after it was converted to a HEC (BMCL 10[HEC] ) using the EPA cross-species

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

BMCL 10[HEC] = BMCL 10[ADJ] x RGDR ET

where:

BMCL 10[ADJ] = 0.02 ppm x 6/24 hours x 5/7 days = 0.004 ppm and

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

RGDR ET = (VE/SA ET ) A / (VE/SA ET ) H

where:

VE = minute volume 2.1 m 3 /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 cm 2 (Gross and Morgan 1991); 20 m 3 /day for humans (EPA 1994a)

and

SA ET = 62 cm 2 surface area of the nasa l cavity in Rhesus monkeys weighing 7 kg (Gross and

Morgan 1991); 200 cm 2 for humans (EPA 1994a)

RGDR ET = (2.1 m 3 /day / 62 cm 2 ) / (20 m 3 /day / 200 cm 2 ) = 0.3421 CHLORINE

2. RELEVANCE TO PUBLIC HEALTH

BMCL 10[HEC] = 0.004 ppm x 0.34 = 0.00136 ppm

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

adjustment and 10 for human variability) to the BMCL 10[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. Th is 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 RGDR ET 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 chlo rine, 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 follo wing reasons. MRLs are derived

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

effect(s) for a specific duration within a given rout e 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 datab ase for hypochlorite solutions, no reliable LOAEL could

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

matter of policy of ATSDR not to derive free-sta nding 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, comme rcial hypochlorite bleach was administered through a

tube directly into the esophagus and, in some ca ses, 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; Ya rington 1970). Only three acute modern studies

in animals were available. Cunningham (1980) admini stered 0, 8, 40, or 200 ppm Cl/kg/day (as sodium22 CHLORINE

2. RELEVANCE TO PUBLIC HEALTH

hypochlorite) to Wist ar 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 B6C3F 1 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 treat ed 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 inte rmediate -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 cann ot 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 tha t 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,23 CHLORINE

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 hyp ochlorite 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 fibros is 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 c linical

chemistry. Daniel et al. (1991) conducted a similar study in male and female B6C3F 1 mice. In neither

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

both studies, water consumption was sig nificantly 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.24 CHLORINE

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 st udies 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 i n 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 co nsistently 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 B6C3F 1 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 wi de range of end points assessed.25 CHLORINE



### 3. HEALTH EFFECTS

3.1 INTRODUCTION

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

other interested individuals an d 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 gloss ary 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 p ersons 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 effe cts). 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 lowest

observed

- 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 c lassify 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

conside red 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 not26 CHLORINE

3. HEALTH EFFECTS

the effects vary with dose and/or duration, and pl ace 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 of ficials 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 sh ould aid in

the interpretation o f 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 pu blic 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 re garding 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 derm al.

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 Priestl ey (1919) reported that five deaths had occurred, three27 CHLORINE

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

abdomi nal 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 chlori ne 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.28 CHLORINE

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 caus e 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 ad ditional 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 infor mation 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 ra te, effectiveness of medical treatment, and the form

of the lethal toxic load function. The LC 50 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,

r espectively. For a 30

- minute exposure, the corresponding LC 50 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 inha lation 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 Ser vice 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 a lso 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 -1.29 CHLORINE

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 LC 50 in 53 minutes, and 250 ppm was the LC 50 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 LC 50 ,

whereas 250 ppm was a 440-minute LC 50 . 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 LC 50 in Wistar

rats, whereas 447 ppm was a 60-minute LC 50 ; in Swiss -Webster mice, 1,032 pp m was a 10 -minute LC 50

and 516 ppm was a 30- minute LC 50

.

In a different study in mice, a 10-minute LC 50 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 cardiovas cular 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 in termediate

- 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 3-1.31293271000250236881926548644735302281000250Table 3-1 Levels of Significant Exposure to Chlorine - InhalationaKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)ACUTE EXPOSUREDeath1Rat(SpragueDawley)1 hrSystemNOAEL(ppm)Less Serious(ppm)LOAELSerious(ppm)293 (1-hour LC50)ReferenceChemical FormVernot et al. 1977Comments2Rat(NS)1 min - 16 hr1000(50% killed in 53minutes)Weedon et al. 1940250 (50% killed in 440minutes)3Rat(Wistar)5-60 min688 (30-minute LC50)1926 (10-minute LC50)5486 (5-minute LC50)447 (60-minute LC50)Zwart and Woutersen 19884Mouse(SwissWebster)10 min302 M (10-minute LC50followed by 3-hourobservation period)Alarie 19815Mouse(NS)16 hr1000(50% killed in 28minutes)Weedon et al. 1940250 (50% killed in 440minutes)241032516340.510.5130.4110.510.5120.51030.56Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation(continued)aKey to SpeciesFigure (Strain)Mouse(SwissWebster)Systemic7891011HumanHumanHumanHumanHumanExposure/Duration/Frequency(Route)10-30 min4-8 hr1 hr8 hr3 d6 hr/d15 minSystemRespOcularRespRespOcularRespRespNOAEL(ppm)b0.50.50.4b0.5M0.5Mb0.5Mb0.5LOAELLess SeriousSerious(ppm)(ppm)1032 (10-minute LC50)516 (30-minute LC50)1(itching and burning ofnose and throat; alteredpulmonary function)1(eye irritation)1(transient alterations inpulmonary function tests)1 M (changes in pulmonaryfunction tests; runnynose; throat burning)1 M (eye irritation)ReferenceChemical FormZwart and Woutersen 1988Anglen 1981D'Alessandro et al. 1996Rotman et al. 1983Schins et al. 2000Shusterman et al. 1998CommentsNOAEL is forpulmonary function.NOAEL is for nasalairway resistance andpulmonary peak flow.4121252910020038121212Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(ppm)LOAELLess Serious(ppm)Serious(ppm)CommentsReferenceChemical Form12Human 15 minResp1 (increased nasal airwayresistance)Shusterman et al. 2003b13Rat(Fischer- 344)10 minResp25 M (50% decrease inrespiratory rate, RD50)Barrow and Steinhagen 198214Rat(SpragueDawley)2-10 minResp100 M200 M (slight perivascularedema in the lung)NOAEL and LOAELare for 2-minuteexposure andevaluation 72 hourslater.Demnati et al. 199515Rat(Fischer- 344)1-10 d5 d/wk6 hr/dResp12 M (swelling of the nose andwheezing)Dodd et al. 1980Ocular12 M (swelling around theeyes)Bd Wt12 M (approximately 20%weight loss)329.19.1105184442.55371330209.316171920Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation(continued)Exposure/LOAELDuration/aKey toSpeciesFrequencyNOAELLess SeriousSeriousReference(Route)Figure(Strain)System(ppm)(ppm)(ppm)Chemical FormCommentsRat 1-5 dResp9.1 M (erosion and ulceration ofJiang et al. 19836 hr/d(Fischer- 344)olfactory epithelium)Bd Wt9.1 M (13% weight loss on day5)Rat 30 minResp184 M (histological andLeustik et al. 2008(Sprague-biochemical evidence ofDawley)lung injury)18Rat(Fischer- 344)1-12 hrResp2.5 M5 M (reduced total sulfydrylcontent in nasalMcNulty et al. 1983respiratory epitheliumafter 6-hour exposure)Rat 15 minResp1330 M (pulmonary edema andYildirim et al. 2004(Sprague-hemorrhage)Dawley)Mouse 10 minResp9.3 M (50% reduction inBarrow et al. 1977(Swiss-respiratory rate, RD50)Webster)229.3393.5339.19.136100192.3104221Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation(continued)aKey to SpeciesFigure (Strain)21Mouse(SwissWebster)22Mouse(Hybrid)23Mouse(SwissWebster)24Mouse(Hybrid)25Mouse(C57BL/6N)26Mouse(C57BL/6N)Exposure/Duration/Frequency(Route)SystemNOAEL(ppm)Less Serious(ppm)LOAELSerious(ppm)ReferenceChemical FormComments5 d6 hr/dResp9.3 M (exfoliation, erosion,ulceration, necrosis ofnasal respiratoryepithelium)Buckley et al. 198460 minResp3.5 M (50% reduction inrespiratory rate, RD50)Gagnaire et al. 19941-5 d6 hr/dRespJiang et al. 19839.1 M (erosion and ulceration ofthe olfactory epithelium)Bd Wt9.1 M (21% weight loss on day5)5 minResp100 M (flattening of pulmonaryepithelium)Martin et al. 200315 minResp2.3 F (50% decrease inbreathing frequency,RD50)Morris et al. 200560 minResp221 (biochemical andhistological evidence oflung injury)Tian et al. 200826501002599193959133913139Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation(continued)Exposure/Duration/aKey toSpeciesFrequencyFigure(Strain)(Route)27Rabbit 30 min(NS)INTERMEDIATE EXPOSUREDeath28Rat 6 wk5 d/wk(Fischer- 344)6 hr/dSystemic29Rat 6 wk5 d/wk(Fischer- 344)6 hr/dSystemRespRespGastroHematoHepaticRenalOcularBd WtLOAELNOAEL(ppm)Less Serious(ppm)Serious(ppm)ReferenceChemical FormComments50100 (pulmonary edemafollowed by emphysema)Barrow and Smith 19759(death in 3/10 before day30 of exposure)Barrow et al. 19791 F (inflammation of nasalturbinates)9(erosion of nasalmucosal epithelium)Barrow et al. 197939(focal erosion of gastricmucosa)59(increased hematocrit infemales and segmentedneutrophils in males)13(cytoplasmic vacuolationof hepatocytes)39(slight to moderatekidney congestion)113 (ocular irritation)3 F (15% decreased finalweight)9 M (43% decreased finalweight)400.555550.51.550.55415425435Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(ppm)Less Serious(ppm)LOAELSerious(ppm)ReferenceChemical FormComments30Rat(Fischer- 344)62 d5 d/wk6 hr/dRespc0.5 M (loss of cilia andepithelium in thetrachea)5(severe upper respiratoryirritation)Kutzman 1983NOAELs are for organhistopathology.Cardio5HepaticRenal5 M5 MOcular0.51.5(occasional signs of eyeirritation)5(severe eye irritation)Bd Wt0.5 F(final weight 11% lowerthan controls)5 F(weight loss; final weight32% lower than controls)Immuno/ Lymphoret31Rat(Fischer- 344)62 d5 d/wk6 hr/d5Kutzman 1983NOAEL is forhistopathology ofspleen andperibronchial lymphnodes.Neurological32Rat(Fischer- 344)62 d5 d/wk6 hr/d5Kutzman 1983NOAEL is forhistopathology of thebrain.Reproductive33Rat(Fischer- 344)62 d5 d/wk6 hr/d5Kutzman 1983NOAEL is for fertility inmales and females andsperm morphology.50.12.32.32.32.32.32.32.32.30.52.32.3Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(ppm)Less Serious(ppm)LOAELSerious(ppm)ReferenceChemical FormCommentsCHRONIC EXPOSURESystemic34Monkey(Rhesus)1 yr5 d/wk6 hr/dRespd0.1 F(minimal nasal epithelialhyperplasia)Klonne et al. 1987NOAELs are for organhistopathology.Cardio2.3Gastro2.3Hemato2.3Musc/skel2.3Hepatic2.3Renal2.3Endocr2.3Dermal2.3Ocular0.52.3(conjunctival irritation)Bd Wt2.3110.42.52.52.52.52.52.52.52.52.52.5Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(ppm)Less Serious(ppm)LOAELSerious(ppm)ReferenceChemical FormComments35Rat(Fischer- 344)M: 2 yr, 5 d/wk,6 hr/dF: 2 yr, 3 d/wk,6 hr/dResp0.4 (alterations of minimalseverity in nasalepithelium)Wolf et al. 1995NOAELs are for grossand microscopicpathology of organsand tissues.CardioGastroHematoMusc/skelHepaticRenalEndocrDermalOcularBd Wt2.52.52.52.52.52.52.52.52.52.5150.42.52.52.52.52.52.52.52.52.52.562.3122.5Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation(continued)Exposure/Duration/aKey toSpeciesFrequencyFigure(Strain)(Route)36Mouse2 yr5 d/wk(B6C3F1)6 hr/dImmuno/ Lymphoret37Monkey 1 yr5 d/wk(Rhesus)6 hr/d38RatM: 2 yr, 5 d/wk,6 hr/d(Fischer- 344)F:2 yr, 3 d/wk,6 hr/dSystemRespCardioGastroHematoMusc/skelHepaticRenalEndocrDermalOcularBd WtLOAELNOAEL(ppm)Less Serious(ppm)Serious(ppm)ReferenceChemical FormComments0.4 (minimal to moderatealterations in the nasalepithelium)Wolf et al. 1995NOAELs are for grossand microscopicpathology of organsand tissues.2.52.52.52.52.52.52.52.52.52.52.3Klonne et al. 1987NOAEL is forhistopathology of lymphnodes and spleen.2.5Wolf et al. 1995NOAEL is for gross andmicroscopic pathologyof lymphoreticulartissues.162.582.3132.5172.572.3Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(ppm)Less Serious(ppm)LOAELSerious(ppm)ReferenceChemical FormComments39Mouse(B6C3F1)2 yr5 d/wk6 hr/d2.5Wolf et al. 1995NOAELs are for grossand microscopicpathology ofimmunoreticular organsand tissues.Neurological40Monkey(Rhesus)1 yr5 d/wk6 hr/d2.3Klonne et al. 1987NOAEL is forhistopathology ofcentral and peripheralcomponents of thenervous system.41Rat(Fischer- 344)M: 2 yr, 5 d/wk,6 hr/dF: 2 yr, 3 d/wk,6 hr/d2.5Wolf et al. 1995NOAEL is for gross andmicroscopic pathologyof central andperipheral componentsof the nervous system.42Mouse(B6C3F1)2 yr5 d/wk6 hr/d2.5Wolf et al. 1995NOAELs are for grossand microscopicpathology of the brain,spinal, and sciaticnerve.Reproductive43Monkey(Rhesus)1 yr5 d/wk6 hr/d2.3Klonne et al. 1987NOAEL is forhistopathology ofreproductive organsand tissues.142.5Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAELLess SeriousSeriousReferenceFigure (Strain)System(Route)(ppm)(ppm)(ppm)Chemical FormComments44Rat M: 2 yr, 5 d/wk,2.5Wolf et al. 1995NOAEL is for gross and(Fischer- 344)6 hr/dmicroscopic pathologyF: 2 yr, 3 d/wk,of reproductive organs.6 hr/da The number corresponds to entries in Figure 3-1.b Used to derive an acute-duration inhalation minimal risk level (MRL) of 0.06ppm; the MRL was derived by adjusting the NOAEL of 0.5 ppm for continuous exposure (0.5 ppm x8/24) 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 extrapolation fromanimals 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 of 30 (3 forextrapolation 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); Immuno/Lymphoret =immunological/lymphoreticular; LC50 = lethal concentration, 50% kill, LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); Musc/skel = musculoskeletal;NOAEL = no-observed-adverse-effect level; NS = not specified; occup = occupational; ppm = parts per million; RD50 = 50% decrease in respiration rate; Resp = respiratory; wk =week(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

### 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

### 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

### 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 Cancer46 CHLORINE

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 categor y 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 conce ntrations 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 hav e 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

altera tions 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 cat egories,

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.47 CHLORINE

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 Mode rate 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 198848 CHLORINE

3. HEALTH EFFECTS

The odor of chlorine was first detected at 0.06 ppm an d 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 cle an 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 3 9 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.49 CHLORINE

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 includ ed 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 show ing 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 cha nges 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 (FEV 1 ), and low forced expiratory

flow rate at 50 and 25% vital capacity (FEF 50 and FEF 25 ) and FEF 25–75% . 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 withi n 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 cases50 CHLORINE

3. HEALTH EFFECTS

that experienced nose and throat irritation, cough, shortness of breath, wheezing, chest tightness, and a

feeling of suffoc ation 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 asth ma

- 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 derai lment 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), FEV 1 , and single- breath diffusing capacity for c arbon monoxide

(DL CO ) 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 giv en 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 amo ng 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 been51 CHLORINE

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 Pro nchik (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 FEV 1 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 higher52 CHLORINE

3. HEALTH EFFECTS

among smokers and former s mokers 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 B 4 ,

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 r educed forced vital capacity (FVC) and FEV 1 . 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 o f 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 FEV 1 before and at

various times during exposure. Itching and burning of the throat were the highest responses and were

most pr evalent 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, FEV 1 , forced expired volume in 1 second as percent FVC (FEV 1 %) , peak expiratory flow

rate (PEFR), FEF 50 and FEF 25 , TLC, expiratory reserve volume (ERV), functional residual capacity

(FRC), residual volume, airway resistance (Raw), single -breath DL CO , closing volume, and difference in

nitrogen concentrations between 750 and 1,250 mL of inhaled vital capacity (ΔN 2 ). Exposure to 1 ppm

chlorine caus ed 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 and53 CHLORINE

3. HEALTH EFFECTS

were evident after 4 hours of exposure. Changes were observed in FEV 1 , PEFR, FEF 50 , FEF 25 , TLC,

Raw, and ΔN 2 . 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 o ne 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 hou rs 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 FEV 1 and FEF 25–75% 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 s ubjects

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 pulmon ary 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 effo rt

- 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 exa mined 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 n ot 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 pulmo nary function tests showed

that the only significant effect related to chlorine exposure was a difference in maximal mid expiratory54 CHLORINE

3. HEALTH EFFECTS

flow (MMEF) between 0 and 0.5 ppm exposure; however, this was attributed to an unexplained shift in

baseline values during c ontrol 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 e xposure. 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 acu te -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 hyper

responsiveness (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.55 CHLORINE

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 FEV 1 (tests were conducted without a nose clip) between the two

groups. Duration of exposure was not provided. Chlorine levels were measure d 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 and56 CHLORINE

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, FEV 1 , FEF 25–75% , and FEV 1 /FVC ratio.

Chlorine was the main contaminant in two areas of the pulp mill, the bleach plant and the mac hine 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 work ers (n=15) and machine room workers (n=22),

nonsmokers (n=4) had a significantly lower FEF 25–75% and FEV 1 /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 FEV 1 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 standar d. The results of the tests showed that in fact, over the years, VC and FEV 1 declined more in

white

- collar workers (significantly for FEV 1 ) 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 fu nction, 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 chlo rine 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 (FEV 1 /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 function57 CHLORINE

3. HEALTH EFFECTS

tests and individual m easures 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, Indi a. 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 fu nction 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, FEV 1 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 f ibrinohemorrhagic

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, al though 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 t hat 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.58 CHLORINE

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 concentratio ns 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 l ung 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 FEV 1 /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 per iod (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 FEV 1 /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 thro at (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 t o 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 mo nths 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 (FEV 1

<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 more59 CHLORINE

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 (FEV 1 , FVC,

FEV 1 /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 FEV 1 and FEV 1 /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 effec t 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, FEV 1 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 FEV 1 /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).60 CHLORINE

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 RD 50 . For

example, RD 50 values of 9.3 and 3.5 ppm were determined in mice exposed for 10 and 60 minutes,

respectively (Bar row et al. 1977; Gagnaire et al. 1994). An RD 50 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 RD 50 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 enzymat ic 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 times61 CHLORINE

3. HEALTH EFFECTS

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 studi es 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 minu tes.

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 an d

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 RD 50 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 severe62 CHLORINE

3. HEALTH EFFECTS

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 respirato ry 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 expo sure, 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 do rsal 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 RD 50 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 les ions 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. 200 8). 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 damaged63 CHLORINE

3. HEALTH EFFECTS

airways 24 hour s 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 respir atory 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 apparen t 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, incre ased

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). P ulmonary function tests (plethysmograph

- based assessment of multiple end points,

including lung and tidal volumes, breathing frequency, transpulmonary pressure, lung compliance, N 2

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, ela stin, 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 no64 CHLORINE

3. HEALTH EFFECTS

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 -du ration 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 B6C3F 1 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 site

specific, 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 met aplasia, 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 increased65 CHLORINE

3. HEALTH EFFECTS

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, th e 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 adja cent 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 o f

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 respon se

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 stressful66 CHLORINE

3. HEALTH EFFECTS

situation is not clear. Some cases in which EKGs were performed shortly after exposure found no

significant alteratio ns (C hasis 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. 20 09). 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 stu dies

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 exposu re 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 mu cosa, 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 exam ine the gastrointestinal tract.67 CHLORINE

3. HEALTH EFFECTS

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 wit h 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 af ter 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 poin ts 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 elevated68 CHLORINE

3. HEALTH EFFECTS

serum aspartate aminotransferase ( AST ) val ues. 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 s erum 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 concentration s 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 ala nine 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).69 CHLORINE

3. HEALTH EFFECTS

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 h ave 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 ano ther 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 hi gh

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 (lacr imation, 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 reported70 CHLORINE

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 st udies 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) reporte d that the spleen

and thymus from rats exposed to 9 ppm chlorine for 6 weeks had a decreased content of lymphoid71 CHLORINE

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 NOA EL 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, a nxiety, 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. I n 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 unde termined 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.

Neurobeha vioral 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 the72 CHLORINE

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

tim es, 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 wi th 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 c ompared 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 intermitte ntly 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 sacri fice 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 3-1.73 CHLORINE

3. HEALTH EFFECTS

3.2.1.5 Reprod uctive 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 f emales 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, ear ly 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 concentration

related increase i n 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 th at 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.74 CHLORINE

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 t o 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 si gnificant 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 cancer75 CHLORINE

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

re ported 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 gas trointestinal tract showed severe gross and microscopic

damage. According to unpublished information reviewed by Racioppi et al. (1994), the oral LD 50 for a76 CHLORINE

3. HEALTH EFFECTS

5.25% solution of sodium hypochlorite household bleach in rats is 13,000 mg/kg; for a 13% solution,

LD 50 values of 5,000 and 8,200 mg/kg are listed. A review of the literature by BG-Chemie (1991)

indicates that LD 50 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 NOA EL 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 wh o 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 bronchi tis.

Limited data on respiratory effects are available in animals. Ninety -day drinking water studies in

Sprague-Dawley rats (Daniel et al. 1990) and B6C3F 1 mice (Daniel et al. 1991) dosed with up to 24.9 and

39.2 mg Cl/kg/day, respectively, reported no g ross 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 r esults were

reported in chronic -duration studies in F344 rats (Hasegawa et al. 1986; NTP 1992) and B6C3F 1 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.88207920020020020080200850.40.47312Table 3-3 Levels of Significant Exposure toHypochlorite Solution-OralaKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)ACUTE EXPOSURESystemic1Rat(SpragueDawley)once(G)SystemHepaticNOAEL(mg/kg/day)LOAELLess Serious(mg/kg/day)Serious(mg/kg/day)20 M (increasedtriacylglycerols in wholeliver homogenate)ReferenceChemical FormChang et al. 1981CommentsNo other end pointswere evaluated.2Rat(Wistar)14 d(GW)Cardio200 FCunningham 1980Only organ weight wasassessed.Hepatic200 FRenal200 FNeurological3Rat(Wistar)14 d(GW)INTERMEDIATE EXPOSURESystemic4Human 4 wk(W)Bd WtHepatic200 F200 F0.4Cunningham 1980Wones et al. 1993Only brain weight wasassessed.NOAELs are for serumthyroid hormones andserum lipid profile.Endocr0.45Rat(SpragueDawley)12 mo(W)Hemato12 MAbdel-Rahman et al. 1984823.43.43.47815.76524.924.924.924.924.924.924.924.924.924.9Table 3-3 Levels of Significant Exposure toHypochlorite Solution- Oral(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical FormComments6Rat 66-76 dCarlton et al. 1986NOAELs are for bloodHemato 3.4(Long- Evans)(GW)counts and serumthyroid hormonelevels.Endocr 3.4Bd Wt 3.47Rat 6 wkBd Wt 15.7 MCunningham 1980(Wistar)(W)8Rat 90 dResp 24.9 FDaniel et al. 1990NOAELs are for gross(Sprague-(W)and microscopicDawley)evaluation of tissuesand organs, andhematology and clinicalchemistry.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 F744.1998552848585858585852650858676152305Table 3-3 Levels of Significant Exposure toHypochlorite Solution- Oral(continued)Exposure/LOAELDuration/aFrequencyReferenceKey to SpeciesNOAEL Less SeriousSerious(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical FormComments9Rat 8 wkBd Wt 4.1 MExon et al. 1987(Sprague-(W)Dawley)10Rat 92 dResp85 MFurukawa et al. 1980NOAELs are for(Fischer- 344)(W)histopathology ofhypochlorous acid and sodiumtissues and organs,hypochloriteclinical chemistry andhematology.Cardio 52 F84 F(endocardial hyperplasia;myocardial fibrosis)Gastro 85 MHemato 85 MHepatic 85 MRenal 85 MEndocr 85 MDermal 85 MBd Wt 26 M 50 M (19% reduction in final 85 M (46% reduction in finalbody weight)body weight)11Rat 13 wkOnly body weight isBd Wt 76 152 M (final body weight 305 M (final body weightHasegawa et al. 1986(Fischer- 344)(W)listed due toreduced 19%)reduced 47%)incomplete reporting ofother end points.6939.239.239.239.239.239.239.239.239.239.277266624.9Table 3-3 Levels of Significant Exposure toHypochlorite Solution- Oral(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical FormComments12Mouse 90 dDaniel et al. 1991NOAELs are for grossResp 39.2 F(B6C3F1)(W)and histologicalevaluation of tissuesand organs, adnhematology and clinicalchemistry.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 F13Gn Pig 5 wkBd Wt 26 MCunningham 1980(albino)(W)Immuno/ Lymphoret14Rat 90 dDaniel et al. 1990NOAEL is for gross and24.9 F(Sprague-(W)microscopic evaluationDawley)of lymphoreticularorgans.754.1100857039.26724.910185Table 3-3 Levels of Significant Exposure toHypochlorite Solution- Oral(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical Form15Rat 8 wk4.1 MExon et al. 1987(Sprague-(W)Dawley)16Rat 92 d85 FFurukawa et al. 1980(Fischer- 344)(W)hypochlorous acid and sodiumhypochlorite17Mouse 90 d39.2 FDaniel et al. 1991(B6C3F1)(W)Neurological18Rat 90 d24.9 FDaniel et al. 1990(Sprague-(W)Dawley)19Rat 92 d85 FFurukawa et al. 1980(Fischer- 344)(W)hypochlorous acid and sodiumhypochloriteCommentsSome reportedchanges in immuneparameters of unknowntoxicologicalsignificance were notconsidered adverse.NOAEL is for gross andmicroscopic evaluationof lymphoreticularorgans.NOAEL is for gross andhistological evaluationof lymphoreticularorgans.NOAEL is for gross andmicroscopic evaluationof the brain and sciaticnerve.NOAEL is for gross andmicroscopicexamination of thebrain.7139.2813.46824.9102857239.2833.4Table 3-3 Levels of Significant Exposure toHypochlorite Solution- Oral(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical FormComments20Mouse 90 d39.2 FDaniel et al. 1991NOAEL is for gross and(B6C3F1)(W)histological evaluationof the brain and sciaticnerve.Reproductive21Rat 66-76 dCarlton et al. 1986NOAEL is for fertility3.4(Long- Evans)(GW)and histopathology ofthe reproductive tract.22Rat 90 dDaniel et al. 1990NOAEL is for gross and24.9 F(Sprague-(W)microscopic evaluationDawley)of reproductive organs.23Rat 92 dFurukawa et al. 1980NOAEL is for gross and85 F(Fischer- 344)(W)microscopic evaluationhypochlorous acid and sodiumof reproductive organs.hypochlorite24Mouse 90 dDaniel et al. 1991NOAEL is for gross and39.2 F(B6C3F1)(W)histological evaluationof reproductive organs.Developmental25Rat 42 dCarlton et al. 1986NOAEL is for litter3.4(Long- Evans)(GW)viability and size andpup weight.5813313313313313313313313313367Table 3-3 Levels of Significant Exposure toHypochlorite Solution- Oral(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical FormCommentsCHRONIC EXPOSURESystemic26Rat 2 yrResp 133 FHasegawa et al. 1986NOAELs are for gross(Fischer- 344)(W)and microscopicalterations in organsand tissues.Cardio 133 FGastro 133 FHemato 133 FHepatic 133 FRenal 133 FEndocr 133 FDermal 133 FOcular 133 FBd Wt67 F(11% reduction in finalbody weight)4814.414.414.414.414.414.414.414.414.414.427Table 3-3 Levels of Significant Exposure toHypochlorite Solution- Oral(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical FormCommentsRat 2 yrNOAELs are forResp 14.4 FNTP 1992(Fischer- 344)(W)histopathology oftissues and organs andhematologyparameters.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 F4924.224.224.224.224.224.224.224.224.224.2591335014.4Table 3-3 Levels of Significant Exposure toHypochlorite Solution- Oral(continued)Exposure/LOAELDuration/aFrequencyReferenceKey to SpeciesNOAEL Less SeriousSerious(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical FormCommentsMouse 2 yr28NOAELs are forResp 24.2 FNTP 1992(B6C3F1)(W)histopathology oftissues and organs andhematologyparameters.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 FImmuno/ Lymphoret29Rat 2 yrHasegawa et al. 1986NOAEL is for gross and133 F(Fischer- 344)(W)microscopicappearence of thespleen.30Rat 2 yrNTP 1992NOAEL is for14.4 F(Fischer- 344)(W)histopathology oflymphoreticular organs.5324.2601335114.45424.2611335214.4Table 3-3 Levels of Significant Exposure toHypochlorite Solution- Oral(continued)Exposure/LOAELDuration/aFrequencyReferenceKey to SpeciesNOAEL Less SeriousSerious(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical FormComments31Mouse 2 yrNTP 1992NOAEL is for24.2 F(B6C3F1)(W)histopathology oflymphoreticular organs.Neurological32Rat 2 yrHasegawa et al. 1986NOAEL is for gross and133 F(Fischer- 344)(W)microscopicappearence of thebrain.33Rat 2 yrNTP 1992NOAEL is for14.4 F(Fischer- 344)(W)histopathology ofvarious brain areas.34Mouse 2 yrNTP 1992NOAELs are for24.2 F(B6C3F1)(W)histopathology ofvarious brain areas.Reproductive35Rat 2 yr133 FHasegawa et al. 1986NOAEL is for gross and(Fischer- 344)(W)microscopicappearence of thereproductive organs.Rat 2 yr3614.4 FNTP 1992NOAEL is for(Fischer- 344)(W)histopathology ofreproductive organs.5524.237Table 3-3 Levels of Significant Exposure toHypochlorite Solution- Oral(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical FormCommentsMouse 2 yrNTP 1992NOAEL is for24.2 F(B6C3F1)(W)histopathology ofreproductive organs.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 water; Hemato =hematological; Immuno/Lymphoret = immunological/lymphoreticular; LOAEL = lowest-observed-adverse-effect level; M = male; mo = month(s); Musc/skel = musculoskeletal; NOAEL= 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

### 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

### 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 Cancer91 CHLORINE

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 unr emarkable. 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 aort a 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 recei ved 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.92 CHLORINE

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 ne crosis 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, commercia l 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 cm 3 applied over a 5-minute period. A volume of

30 cm 3 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 a lterations (Daniel et al. 1990). The same

negative results were reported in F344 rats and B6C3F 1 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 B6C3F 1

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 treatm ent- 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 sugges ting that they may have not been caused by

exposure to chlorine (Abdel -Rahman et al. 1984). Red blood cell count and hematocrit were reduced93 CHLORINE

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 B6C3F 1 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 Sp rague

- 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 B6C3F 1 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

B6C3F 1 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.94 CHLORINE

3. HEALTH EFFECTS

No significant gross or microscopic alterations were seen in the liver of Sprague

- Dawley rats, F 344 rats,

or B6C3F 1 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 F 344 rats or

B6C3F 1 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 treat ment

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

(C unningham 1980). No other renal parameter was evaluated. No significant gross or microscopic

alterations were seen in the kidney of Sprague- Dawley rats, F 344 rats, or B6C3F 1 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 re ported in F344 rats or B6C3F 1 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 v olunteers 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 accompanie d

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 (hypochlor ous 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 studi es in95 CHLORINE

3. HEALTH EFFECTS

Sprague- Dawley and F 344 rats and B6C3F 1 mice administered up to 24.9, 85, and 39.2 mg Cl/k g/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 B6C3F 1 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 approximatel y 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 ani mals is that exposure of F 344 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 B6C3F 1 mice exposed to up to 24.9 and 39.2 mg

Cl/kg/day, respectively, in the drinking water for 90 d ays (Daniel et al. 1990, 1991) or in F 344 rats and

B6C3F 1 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 o r

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 st udy, 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 than96 CHLORINE

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

hypochl orite) 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 st udies Sprague- Dawley and F 344 rats and B6C3F 1 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 B6C3F 1 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 3-2.97 CHLORINE

3. HEALTH EFFECTS

3.2.2.4 Neurological Effe cts

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 ne rve of Sprague

- Dawley or F 344 rats and B6C3F 1 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 B6C3F 1 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 b rain of F 344 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 re liable 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 B6C3F 1 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 spe rm 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

st omach. 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 inte rmediate -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 microsc opic appearance of the reproductive98 CHLORINE

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 wate r 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 spe cies 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 chl orination 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 in99 CHLORINE

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 statisti cally 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 equ ivocal 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 his torical 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 we eks; 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 incr eased incidence of neoplasms or alterations in latency of neoplasms.

In the NTP (1992) study, B6C3F 1 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 tr eatment with chlorine did not induce significant treatment- related

increases in neoplasms. In a study by Kurokawa et al. (1986), groups of B6C3F 1 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 carcino genicity 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. (19 89) 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 st udied 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 sho wed

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 stratu m

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.93Percent (%)9390Percent (%)Percent (%)9091Percent (%)9192Percent (%)9289Percent (%)8996Percent (%)96Table 3-4 Levels of Significant Exposure toHypochlorous Acid and/or Sodium Hypochlorite-DermalSpecies(Strain)Exposure/Duration/Frequency(Route)ACUTE EXPOSURESystemicHuman(C)90 minSystemDermalNOAEL4FPercent (%)Less SeriousLOAELSeriousReferenceChemical FormGoffin et al. 1997CommentsInstrumental testsrevealed subclinicaldamage to the stratumcorneum.Human(C)48 hrDermal0.5Percent (%)2 (weak to moderate skinPercent (%)irritation)Habets et al. 1986Human(C)20 minDermal6 (non-immunologicPercent (%)contact urticaria)Hostynek et al. 1989Non-immunologiccontact urticariadeveloped within 20minutes of application.Human(C)24 hrDermal1Percent (%)Hostynek et al. 1990Application of 100microliters inducedirritation; 20 microlitersdid not.Human(C)4 hrDermal5.25 (severe skin irritation inPercent (%)4/7 subjects)Nixon et al. 1975(CD-1)Mouse(C)2 d8 x/dDermal0.53 F (histologic changesindicating moderateirritation response)Percent (%)Hess et al. 1991The solution wasapplied as a spray.94Percent (%)9497Percent (%)9795Percent (%)95Table 3-4 Levels of Significant Exposure toHypochlorous Acid and/or Sodium Hypochlorite-Dermal(continued)Exposure/LOAELDuration/FrequencyReferenceSpecies(Route)(Strain)System NOAEL Less SeriousSeriousChemical FormComments(Hartley)Gn Pig(C)4 hrDermal5.25Percent (%)Nixon et al. 1975(NewZealand)Rabbit(C)onceOcular5 BPercent (%)(moderate eye irritation)Griffith et al. 1980Median day to clearvaried from 7 to over21 depending onvolume applied.(NS)Rabbit(C)4 hrDermal5.25Percent (%)Nixon et al. 1975B = both male and female; (C) = capsule; d = day; F = female; Gn pig = guinea pig; hr = hour; LOAEL = lowest-observed-adverse-effect level; min = minute; NOAEL =no-observed-adverse-effect levelCHLORINE 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. I n 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 recov ery 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 irrita tion (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 timeCHLORINE 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 gene rally 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 repo rted 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 follow ing

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 Develop mental 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 applicat ions 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 ofCHLORINE 105

3. HEALTH EFFECTS

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 incr eased 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 B6C3F 1 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 hy pochlorite 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 summarizedCHLORINE 106

3. HEALTH EFFECTS



### Table 3

- 5. Genotoxicity of Sodium Hypochlorite **In Vivo**

Spe cies (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 w altl ) Micronuclei + Le Curieux et al. 1993

larvae erythrocytes

– = negative result; + = positive resultCHLORINE 107

3. HEALTH EFFECTS

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 o f 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 p eak 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 mucos a 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 L C 50 in intact mice

was 302 ppm, but in mice that breathed through a cannula in the trachea, the LC 50 was only 131 ppm. In

another study, the surgically isolated upper respiratory tract of anesthetized mice was shown to scrub

chlorine with a mean efficienc y 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).CHLORINE 108

3. HEALTH EFFECTS



### 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

Rosenkra nz 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

Human s 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 + Ishid ate 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 acidCHLORINE 109

3. HEALTH EFFECTS

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 ( 36 Cl) to fasted Sprague

- Dawley resulted in a peak 36 Cl 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 36 Cl 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

chl orine 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 36 Cl, 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

3. HEALTH EFFECTS

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

Lim ited information is available regarding the metabolism of chlorine. In a study in which rats received a

single oral gavage dose of radiolabeled ( 36 Cl) hypochlorous acid showed that, 96 hours after dosing,

81% of radioactivity detected in plasma was chlori de 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 Eli mination 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 36 Cl was studied in rats following adm inistration 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 admin istered 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 adminis tered dose. No radioactivity was recovered

in expired air during the study period. Since all or some of the amount recovered in the feces could haveCHLORINE 111

3. HEALTH EFFECTS

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 biol ogically 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 giv en 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 a nd 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 con ventional

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 substance

specific physicochemical parameters, and species

- specific physiological and biological parameters. The

numerical estimates of these model parameters are incorporated within a set of differential and algebraicCHLORINE 112

3. HEALTH EFFECTS

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 s ignificantly simplify the true

complex ities 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 proces ses. 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 pharmacokinet ic extrapolations used in risk assessm ents 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 re presentation 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 computatio nal 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 F 344 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 Ph ysiologically 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 1994CHLORINE 114

3. HEALTH EFFECTS

1999b). This means that t he 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 m entioned 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 ( 36 Cl) 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 ch loride.

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:

Cl 2 + H 2 O ↔ 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 fo r chlorine gas. However, hypochlorous acid is a stronger oxidant thanCHLORINE 115

3. HEALTH EFFECTS

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 resul t 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 dam age. 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

c onclusion 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 (Nixo n 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 endogen ous hormones. Chemicals

with this type of activity are most commonly referred to as endocrine disruptors . However, appropriateCHLORINE 116

3. HEALTH EFFECTS

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 mand ate, 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 chem icals 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 ca use 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 b reast, 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 a nd 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

3. HEALTH EFFECTS

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 t he 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

susceptibilit y 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 h azardous 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 BrozekCHLORINE 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 a dults 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 develop ing human may increase exposur e 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 counterba lanced 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 e xhibit 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 b e. 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 belo w.

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 mos t

prevalent symptoms were irritative cough (91%), nasal -pharyngeal pruritus (66%), chest pain (25%),CHLORINE 119

3. HEALTH EFFECTS

tachypnea (20%), and dyspnea (14%). Other conditions included headache, vomiting, and nausea. The

report indicates that the symptoms of most children subsided naturally upon l eaving 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 hospital ized 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 wer e 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, FEV 1 , and

FEF 25–75% . 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 an d 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, wherea s

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

3. HEALTH EFFECTS

In children, as in ad ults, 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 t han 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 foun d (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 su perficial 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 bio logic systems or samples. They have

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC

1989).

A biomarker of expos ure 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 bod y 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 mayCHLORINE 121

3. HEALTH EFFECTS

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 defi ned 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 ch anges 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 t he 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 concentration

dependent increase in 3 -chlorotyrosine (CY) and 3,5-dichlorotyrosine (d CY) 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 n otCHLORINE 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 trigemi nal 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 f orm 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 organsCHLORINE 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 asthm a, 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 FEV 1 and FEF 25 –75% than healthy subjects during exposure to 1 ppm chlorine. Shusterman et

al. (1998) report ed 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 ha ve 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 sym ptoms (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, inci dences 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 c hlorine 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

3. HEALTH EFFECTS

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 Wilkin s, 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

recom mended, but the dilution amount should be small to avoid inducing vomiting. In case of exposureCHLORINE 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 i n 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 s hown 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 oxida nt 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 concentrat ions 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 admi nistration 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 a t least some patients (Bosse 1994; Douidar 1997). NebulizedCHLORINE 126

3. HEALTH EFFECTS

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 perio dically 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 ava ilable. Where adequate information is not

available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the

init iation 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 scientis ts 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 i nhalation, 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 healt h 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

- specificSystemic t i c

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Inhalation

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Inhalation

Oral

Dermal

Animal

Existing Studies CHLORINE 127

3. HEALTH EFFECTS



### Figure 3

- 4. Existing Information on Health Effects of Chlorine GasSystemic t i c

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Inhalation

Oral

Dermal

Animal

Existing Studies CHLORINE 128

3. HEALTH EFFECTS



### Figure 3

- 5. Existing Information on Health Effects of Hypochlorite SolutionCHLORINE 129

3. HEALTH EFFECTS

information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a

data gap mor e 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 scena rio, 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 a nimals.

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 t arget 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 gastrointesti nal 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 or al 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 so dium

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

3. HEALTH EFFECTS

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 studie s 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 g as 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 dir ectly into the

esophagus and, in some cases, the distal end of the esophagus was artificially occluded to prolong andCHLORINE 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; Yaringto n 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-respons e 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 t o ≥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

necess ary 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 stu dies 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 concentrat ions 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 pr ovided informati on, 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). Non e 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 reliabl e 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 uppe r 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 mo st 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

l ocated. 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-durationCHLORINE 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 expo sed 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 byproduct s

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 on e 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 drink ing water studies in the F344 strain may be unwarranted given that: (1) mononuclear c ell

leukemia occur s with high incidence in F 344 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. Alth ough 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, chromoso mal 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 ch lorine did not observe gross or microscopicCHLORINE 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, additi onal 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 te ratogenic 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 developm ental 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 st udies 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 wer e 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 reporte d 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 b e 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 ora l 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 ascertai n 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

3. HEALTH EFFECTS

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 ce ntral 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 an d 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 numbe r 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 an d 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 ch lorine 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 hypochlo rous 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 ra ts 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 esophag eal 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 ( 36 Cl) 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 ( 36 Cl) 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 th e 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 m ost 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 an d 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 o r 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;

Gülo ğlu 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 investigatorsCHLORINE 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 pulmo nary 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 hy persensitivity

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 morta lity.

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 te st this via the following specific aims: (1) testCHLORINE 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.CHLORINE 142

3. HEALTH EFFECTS



### This page is intentionally blank.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 (Cl 2 ) is a heavier -than- air, greenish

- yellow gas with a pungent, irritat ing 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 e t 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. 20 06).

Chlorine hydrolyzes rapidly and almost completely in water to form hydrochloric acid, hypochlorous

acid, and hypochlorite as follows:



### Cl 2 

### + H 2 

### O HOCl + H + 

### + Cl 

### H + 

### + 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 Chlorine a

Characteristic Information

Chemical name Chlorine

Synonyms/trade names Chlorine gas b , Bertholite, molecular chlorine, chlorine mol, dichlorine

Chemical formula Cl 2

Chem ical structure Cl Cl

Identification numbers:

CAS registry 7782

- 50 -5

NIOSH RTECS FO2100000 c

EPA hazardous waste No data

DOT/UN/NA/IMCO shipping UN1017; IMO 2.0

HSDB 206

EINECS 231

- 959 -5 c

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 Subs tances; 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 SubstancesCHLORINE 145

4. CHEMICAL AND PHYSICAL INFORMATION



### Table 4

- 2. C ommonly 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

re acts 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 ch lorine 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 chl orine 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

m olecular 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 1998 a ; Edstrom Industries 2003; Fukayama et al. 19 86; 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 Chlorine a

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/mL c

- 35 ° C, 0.9949 atm 1.5648 g/mL c

Odor Pungent, irritating

Odor threshold:

Water Not applicable d

Air 0.2

– 0.4 ppm c,e,f

Solubility:

Wate r 14.6 g/L at 0 ° C; 7.3 g/L at 20 ° C c,g

Other solvents Glacial acetic acid, dimethylformamide, nitrobenzene, phosphoryl

chloride, carbon tetrachloride, tetrachloroethane, pentachloroethane,

hexachlorobutadiene, and chlorobenzene h

Partition coefficients:

Log K

ow Not applicable

Log K

oc Not applicable

Vapor pressure at 25 °C 5,830 mm Hg

Henry's law constant 1.17x10 - 2 atm

- m 3 /mol i

Autoignition temperature Not applicable

Flashpoint Not applicable

Reactivity Strong oxidizer; reacts explosively with ma ny materials

Conversion factors 1 ppm=2.9 mg/m 3 ; 1 mg/m 3 =0.344 ppm c

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 1996CHLORINE 147

4. CHEMICAL AND PHYSICAL INFORMATION

(2)

The relative percentage of Cl 2 , HOCl, and OCl

- at some fixed concentration of Cl

can be expressed as:

(3)

(4)

(5)

Using the expressions for the equilibrium constants in Equations 1 a nd 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 2 

### 10 K

2 

### 10 

### [ H **+** 

### ][ OCl

**−** 

### ]

K

2 

### = [ HOCl ]

][][][ ][ %

2 2

2

**−** 

### ++ **=** OCl HOCl Cl Cl Cl



### ][][][ ][ %

2 **−** 

### ++ **=** OCl HOCl Cl HOCl HOCl

][][][ ][ %

2 **− −** 

**−**



### ++

**=** OCl HOCl Cl OCl OCl

pH pH 

### KK K Cl

2 21 1 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 K 1 = 3.9x10 -4 M 2 (Cotton et al.

1999; Farr et al. 2003) and K 2 = 2.9x10 -8 M (Farr et al. 2003) at 25 °C. This figure shows theCHLORINE 148

4. CHEMICAL AND PHYSICAL INFORMATION



### Figure 4

- 1. Speciation of Cl 2 

### , 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% SpeciesCHLORINE 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



### This page is intentionally blank.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 underwen t 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, rea ching 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 asbest os 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 facil ities 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 th eCHLORINE 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 proces sed chlorine (Cl 2 )

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 chlorin e

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 manufact uring

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

Ca pacity (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 Pl astics 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

Mus cle 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

H enderson, 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 510 463,000CHLORINE 154

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



### Table 5

- 1. Companies that Produce Chlorine in the United States and Annual

Capacities for 2006

Ca pacity (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 2008CHLORINE 155

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



### Table 5

- 2. Facilit ies that Produce, Process, or Use Chlorine

Minimum Maximum

Number of amount on site amount on site

State a facilities in pounds b in pounds b Activities and uses c

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 9,999,9 99 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, 13CHLORINE 156

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



### Table 5

- 2. Facilit ies that Produce, Process, or Use Chlorine

Minimum Maximum

Number of amount on site amount on site

State a facilities in pounds b in pounds b Activities and uses c

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 9 9,999,999 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 20 07

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 2008CHLORINE 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 (H SDB 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 propo sed for inclusion on the EPA National

Priorit ies 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 ta nk 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 leve ls 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 n ot 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, there by 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 b e 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 dr inking water as a result of water sanitation

practices, even though chlorine gas may be used in these processes. Free chlorine in drinking water isCHLORINE 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 a cid 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 T RI 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 indust rial 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 Chlorine a

Reported amounts released in pounds per year b

Total release

State c RF d Air e Water f UI g Land h Other i On

- site j Off

- site k 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 54,6 53 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 52,491CHLORINE 162

6. POTENTIAL FOR HUMAN EXPOSURE



### Table 6

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

Use Chlorine a

Reported amounts released in pounds per year b

Total release

State c RF d Air e Water f UI g Land h Other i On

- site j Off

- site k 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 repor ting 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 Cl ass 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, solidificatio n/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 a pproximately

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 car rying 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 inciden t, 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 2 008). 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 ru pture. 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 isCHLORINE 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 l evels 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 S oil

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 f acilities 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 sys tem 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 -m 3 /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 gasCHLORINE 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 greenish

yellow 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 20 05a, 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 vola tilize

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 rat e. 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, mid day 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

su nlight 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 acid s 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 200 2). 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 hypoch l orite anion is

controlled by the pH of the water. Since the pK

a 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 Cl 2 are present. At pH below 2, chlorine becomes the dominant

species. Therefore, molecular chlorine will be formed in chlorinated water (containing hypochlorousCHLORINE 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 -m 3 /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 chlorin e 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 on to 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 dispr oportionate 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, biodeg radation 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 p otential 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 am ount 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 de tected 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 rega rding 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 Regist ry 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, chlor ine 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 s ince 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 hig h 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 aci ds 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 a ccident

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 adde d 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 th e 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, Childre n’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 t o 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 ofCHLORINE 171

6. POTENTIAL FOR HUMAN EXPOSURE

chlorine gas from the facility (USB 2007). Of the 865 chlorine

- only even ts 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 fro m 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 accid ent. 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 s urrounded 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 U nion Pacific train engineer,

23 local residents, and 6 emergency responders we re 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 a gencies 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

AT SDR, 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 meanCHLORINE 172

6. POTENTIAL FOR HUMAN EXPOSURE

that all data needs discussed in this section must be f illed. 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 nee d 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 fr om 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 ha zardous 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 natura lly

during the photolysis of seawater aerosols ( California Environmental Protection Agency 2002; Chang et

al. 2004). No data n eed 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 hu mans 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 trans portation 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 2009CHLORINE 176

6. POTENTIAL FOR HUMAN EXPOSURE



### This page is intentionally blank.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

Offi cial 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 BIOLOGIC AL 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 wi de 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 e nvironment, 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 aque ous 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 m easure 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 colo r 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 req uires greater operator skill to

achieve reliable results (APHA 1998 a ).

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 ai r 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 dilu te sodium hydroxide solution. Chlorine dissolves and disporportionates toCHLORINE 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 temper ature 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 chlor ide 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 a ir 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 researchCHLORINE 180

7

. ANALYTICAL METHODS



### Table 7

- 1. Analytical Methods for Determining Chlorine in Environmental Samples

Sample

matrix Preparati on 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 OAQPS

26 0.1 ppm NA EPA 2000 b

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 ID

126SGX 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/min ute );

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 an d 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 Preparati on 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 P otassium 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

- visibleCHLORINE 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 f orm 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 asso ciated 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 2000 b; 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 molecularCHLORINE 183

7

. ANALYTICAL METHODS

chlorine, hypochlorous acid, or hypochlorite (APHA 1998a, 1998b). Since hypochlorous acid and

hypochlorite are the dominant species at environmental pH, an alyzing 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 m edia 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 t o 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 ana lytical 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



### This page is intentionally blank.CHLORINE 185



### 8. REG ULATIONS, 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 conce rn 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 (BMC 10 ) for

nasal lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on this concentration (BMCL 10 )

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 F 344/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 hypoc hlorite 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 e xempt from the

requirement of a tolerance for pesticide chemicals in food when used as p re - or postharvest in solution on

all raw agricultural commodities (EPA 2007h) and sodium hypochlo rite is e xempt 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 medi a are summarized in Table 8 -1.CHLORINE 187

8. REGULATIONS, ADVISORIES, AND GUIDELINES



### Table 8

- 1. Regula tions, 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 20 00

Drinking water quality guidelines WHO 2004

Chlorine 5 mg/L a

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

- 1 b (chlorine) 1 ppm A IHA 2004

ERPG -2 b (chlorine)

ERPG

- 3 b (chlorine) 3 ppm

20 ppm

Odor threshold (chlorine) 0.08 ppm

EPA AEGL

- 1 c (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

- 2 c (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 -3 c (chlorine)

10 minutes 50 ppm

30 minutes 28 ppm

60 minutes 20 ppm

4 hours 10 ppm

8 hours 7.1 ppmCHLORINE 188

8. REGULATIONS, ADVISORIES, AND GUIDELINES



### Table 8

- 1. Regula tions, Advisories, and Guidelines Applicable to Chlorine and

Chlorine Compounds

Agency Description Information Reference

N ATIONAL (cont.)

Hazardous air pollutant (chlorine) Yes EPA 2007b

42 USC 7412

Regulated toxic substance and the 2,500 pounds d 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

(c hlorine) 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

EP A 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 Cl 2 ]) 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 poundsCHLORINE 189

8. REGULATIONS, ADVISORIES, AND GUIDELINES



### Table 8

- 1. Regula tions, 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

r equirement of a tolerance for pesticide 40 CFR 180.1095

chemicals in food when used as

p reharvest 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

addi tion 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) A4 f 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 Yes g 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) Appendi x A

Effective date of toxic chemical 01/01/87 EPA 2007g

release reporting ( chlorine) 40 CFR 372.65CHLORINE 190

8. REGULATIONS, ADVISORIES, AND GUIDELINES



### Table 8

- 1. Regula tions, Advisories, and Guidelines Applicable to Chlorine and

Chlorine Compounds

Agency Description Information Reference

NATIONAL (cont.)

EPA TSCA Master Testing List EPA 2007c

Chlorine Yes h

Sodium hypochlorite Yes i

NTP Carcinogenicity classification No data NTP 2005

a For effective disinfection, there should be a residual concentration of free chlorine of ≥0.5 mg/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 individu als 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

n early 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 es cape; 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 = Comprehe nsive 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

Occupationa l 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 = Sc reening 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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### 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 cont act.

Adsorption Coefficient (K

oc )— 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 o f 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 BMD 10 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 statistic al 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

P rofiles.

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 tim e.

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 rela tionship 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 te rms 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 investiga tion 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

irreversi ble 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) (LC LO )— The lowest concentration of a chemical in air that has been reported

to have caused death in humans or animals.

Lethal Concentration (50) (LC 50 )— 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 define d experimental animal population.

Lethal Dose (LO) (LD Lo )— 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) (LD 50 )— The dose of a chemical that has been calculated to cause death in 50% of a

defined experimental animal population.

Lethal Time (50) (LT 50 )— 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 popu lation.

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 p opulation 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, develop ment, 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 Facto r (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 bein g 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 condi tions.

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 f requency 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 (K

ow )— The equilibrium ratio of t he 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 h ealth 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 -ba sed

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 o f 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 di sease 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.

q 1 *— The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the

multistage procedure. The q 1 * 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 f or food, and

μg/m 3 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/m 3 or ppm.

Reference Dose (RfD)

— An estimate (with uncertainty spanning perhaps an order of magnitude) of the

daily ex posure 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

nonthresho ld 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 routin ely 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

- rel ated

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) conc entration 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 e xposure concentration averaged over a normal 8-hour

workday or 40-hour workweek.

Toxic Dose (50) (TD 50 )— 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 exp erimental 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 Re ference 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 sy stem.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

commonl y 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 assoc iated 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, Min imal 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 ex posure 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 pu blic health professionals decide where to

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites thatCHLORINE A-2

APPENDIX A

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of

the la ck 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 addre ss 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 laborator y 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 leve ls.

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

Minim al 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 inhal ed 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 FEV 1 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, FEV 1 , FEV 1 % forced expired volume in 1 second as %FVC (FEV1%), peak expiratory flow rate (PEFR), FEF 50

and FEF 25 , TLC, expiratory reserve volume (ERV), functional residual capacity (FRC), residual volume,

airway resistance (Raw), single -breath DL CO , closing volume, and difference in nitrogen concentr ations

between 750 and 1,250 mL of inhaled vital capacity (ΔN 2 ). Exposure to 1 ppm chlorine caused runnyCHLORINE 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 p pm exposure level and were evident after

4 hours of exposure. Changes were observed in FEV 1 , PEFR, FEF 50 , FEF 25 , TLC, Raw, and ΔN 2

. 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 t o 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, diffus ing 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 FEV 1 and FEF 25–75% and increase in airway resistance among normal and HR subjects, but the

magnitude of the effects among HR subjects was significantly greater than i n 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 interl eukin -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 significa ntly 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 in crease 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 rhin itis 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 obje ctive congestion after chlorineCHLORINE 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 pulmonar y 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

Al though 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 f actor 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 e xposure ? 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 ToddCHLORINE 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: R at

Mini mal 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, bre athing

frequency, transpulmonary pressure, lung compliance, N 2 washout, diffusing capacity for CO 2 , 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,

br ain, 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 w eight 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 group s, indicating some degree of small airway involvement. An electro

cardiogram 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 cytogen etic 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 unremarka ble. 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 histo logical 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 we re made to apply dose- responseCHLORINE 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 m inimal 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 RGDR TB

where:

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

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

RGDR TB = (VE/SA TB ) A / (VE/SA TB ) H

where:

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

SA TB = surface area of the tracheobronchial region (22.5 cm 2 for rats and 3,200 cm 2 for humans

[EPA 1994a])

LOAEL [HEC] = 0.09 ppm x (0.137 L/minute/22.5 cm 2 ) / (13.8 L/minute/3,200 cm 2 ) = 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) e valuated the respiratory response in F 344 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 difficul ty 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 mos tly 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 a lveolar 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 nasalCHLORINE A-8

APPENDIX A

turbinates of female s 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 ToddCHLORINE 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 expo sure 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 ep ithelial

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. I n 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 riskCHLORINE A-10

APPENDIX A

(BMC 10 ) for nasal lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on this

concentration (BMCL 10 ) was 0.02 ppm.

Dose and end point used for MRL derivation : BMCL 10 of 0.02 ppm for nasal lesions in monkeys.

[ ] NOAEL [ ] LOAEL [X] BMCL 10

Uncertainty Factors used in MRL derivation :

[ ] 10 for use of a LOAEL

[X] 3 for extrapolation from animal s 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 f actors used in determining human equivalent dose : The

intermediate-duration inhalation MRL was calculated using EPA’s methodology (EPA 1994a) for a

category 1 gas.

BMCL 10[HEC] = BMCL 10[ADJ] x RGDR ET

where:

BMCL 10[ADJ] = 0.02 ppm x 6/24 hours x 5/7 days = 0.004 ppm and

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

RGDR ET = (VE/SA ET ) A / (VE/SA ET ) H

where:

VE = minute volume 2.1 m 3 /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 cm 2 (Gross and Morgan 1991); 20 m 3 /day for humans (EPA 1994a)

and

SA ET = 62 cm 2 surface area of the nasa l cavity in Rhesus monkeys weighing 7 kg (Gross and

Morgan 1991); 200 cm 2 for humans (EPA 1994a)

RGDR ET = (2.1 m 3 /day / 62 cm 2 ) / (20 m 3 /day / 200 cm 2 ) = 0.34

BMCL 10[HEC] = 0.004 ppm x 0.34 = 0.00136 ppm

Was a conversion used from interm ittent to continuous exposure ? Yes, see above.

Other additional studies or pertinent info rmation that lend support to this MRL : Wolf et al. (1995)

exposed groups of F344 rats and B6C3F 1 mice (approximately 70/sex/exposure level) to 0, 0.4, 1, or

2.5 ppm chlorine gas for 2 years. Males from bot h 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 inv estigators 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; th e nasal passages were examined microscopically atCHLORINE 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- relat ed 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 site

specific, 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 inci dence 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

L OAEL for respiratory effects in rats and mice; a NOAEL was not defined.

Agency Contacts (Chemical Managers) : G. Daniel ToddCHLORINE A- 12

APPENDIX A

BENCHMARK MODELING OF NASAL LESIONS IN MONKEYS

Incidence data for nasal lesions in male and female monkeys exposed to chlorin e 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 le sion 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

BMC 10 BMCL 10

Model (ppm) (ppm) x 2 p

- value AIC

Gamma a 0.04 0.02 0.95 29.72

Logistic 0.09 0.05 0.76 30.17

Log

- logistic b 0.05 0.009 0.53 32.21

Multi

- stage c 0.04 0.02 0.95 29.72

Probit 0.08 0.05 0.77 30.14

Log

- probit b 0.06 0.03 0.81 30.09

Quantal linear 0.04 0.02 0.95 29.72

Weibull a 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. 1987CHLORINE A-13

APPENDIX A

From this model, the predicted exposure concen tration associated with a 10% extra risk (BMC 10 ) for nasal

lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on this concentration (BMCL 10 ) 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 LevelFraction 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 = 2.67521CHLORINE A- 14

APPENDIX A



### This page is intentionally blank.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 vi cinity 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 Healt h 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 o n 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 pub lic

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 hea lth 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 occ upational

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, i n 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 n o- 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 hu mans). 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.

NOAEL s 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

re gimens 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

inv estigated.

(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 lev els 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 ke y 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 t he 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) Foo tnotes . 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 expos ure 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

exis ts. 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/m 3 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 exposur e 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 upper

bound 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 (q 1 *).

(19) Key to LSE Figure . The Key explains the abbreviations and symbols used in the figure.123412**→**SAMPLETable 3-1. Levels of Significant Exposure to [Chemical x]–Inhalation**→ →** ExposureKey tofrequency/figureaSpecies durationINTERMEDIATE EXPOSURE5 6Systemic**↓ ↓** NOAELSystem(ppm)7 8**↓ ↓** LOAEL (effect)Less serious(ppm)9**↓**Serious (ppm)Reference10**↓ →** **→**18Rat13 wkResp3b10 (hyperplasia)5 d/wkNitschke et al. 19816 hr/dCHRONIC EXPOSURECancer11**↓**38Rat18 mo20(CEL, multipleWong et al. 19825 d/wkorgans)7 hr/d39Rat 89–104 wk10(CEL, lung tumors, NTP 19825 d/wknasal tumors)6 hr/d40Mouse79–103 wk10(CEL, lung tumors,NTP 19825 d/wkhemangiosarcomas)6 hr/daThe number corresponds to entries in Figure 3-1.bUsed to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3ppm; dose adjusted for intermittent exposure and dividedby an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). CHLORINE B-6

APPENDIX BCHLORINE B -7

APPENDIX BCHLORINE B-8

APPENDIX B



### This page is intentionally blank.CHLORINE C-1



### APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS

ACGIH American Conference of Govern mental 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 Ai r 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 Asso ciation

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

BMD X dose that produces a X% change in response rate of an adverse effect

BMDL X 95% lower confidence limit on the BMD X

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 Commissi on

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 LaborCHLORINE 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

F 1 first

- filial generation

FAO Food and Agricultural Organization of the United Nations

FDA Food and Drug Administration

FEMA Federal Emergency Management Agency

FIFRA Federal Inse cticide, 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

IRI S Integrated Risk Information System

Kd adsorption ratio

kg kilogram

kkg metric ton

K

oc organic carbon partition coefficient

K

ow octanol- water partition coefficient

L liter

LC liquid chromatography

LC 50 lethal concentration, 50% kill

LC Lo lethal concentr ation, low

LD 50 lethal dose, 50% kill

LD Lo lethal dose, low

LDH lactic dehydrogenase

LH luteinizing hormone

LOAEL lowest

- observed

- adverse

- effect level

LSE Levels of Significant Exposure

LT 50 lethal time, 50% kill

m meter

MA trans,trans -muconic acid

MAL max imum allowable level

mCi millicurieCHLORINE 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 parti cles 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 eryt hrocytes

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 Hea lth 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 P erformance 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 Offi ce of Toxic SubstancesCHLORINE 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 per missible 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 r ed 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 siste r 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

TD 50 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

W BC white blood cell

WHO World Health OrganizationCHLORINE 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

q 1 * cancer slope factor

– negative

+ positive

(+) weakly positive result

(–) weakly negative resultCHLORINE C-6

APPENDIX C



### This page is intentionally blank.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 e ffects

................................................................................................ ................................ 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 e ffects

.................................................................................................................. 66, 91, 138

general population

........................................................................... 9, 11, 15, 18, 46, 48, 129, 159, 169, 190

genotoxic............................................................................................................................. 25, 105, 129, 133

genotoxi city

................................................................................................ ................................. 14, 105, 133

Graniteville

................................................................................................ ............................... 163, 165, 171

groundwater ...................................................................................................................................... 164, 169

half- life

.................................................................................................................. 9, 109, 121, 159, 165, 172

h ematological e ffects

............................................................................................................................ 67, 92CHLORINE 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 syste m ................................................................................................................................... 12, 135

immunological ................................................................................................ 22, 25, 96, 104, 129, 131, 135

immunological effects......................................................................................................................... 96, 135

K

ow ................................................................................................ ............................................................146

LD 50

................................................................................................ .............................................................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