## TOXICOLOGICAL PROFILE FOR

PHENOL

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service Agency for Toxic Substances and Disease Re gistry

September 200 8ii PHENOL



### 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 PHENOL



### UPDATE STATEMENT

A Toxicological Profile for Phen ol , Draft for Public Comment was released in October 2006 . 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 previous ly 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-32 Atlanta, Georgia 30333iv PHENOL



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### 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 the hazardous substance described therein. Each peer

- reviewed profile identifies and reviews the key literature that describes a hazardous substance’s toxicologic properties. Other pertinent literature is also presented, but is described in less detail than the key studies. The profile is not in tended to be an exhaustive document; however, more comprehensive sources of specialty information are

referenced.

The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile begins with a public health statement that describes, in nontechnical language, a substance’s relevant toxicological properties. Following the public health statement is information concerning levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance’s health effects is described in a health effects summary. Data needs that are of significance to protection of public health are identified by ATSDR and EPA.

Each profile includes the following:

(A) The examination, summary, and interpretation of available toxicologic information and epidemiologic evaluations on a hazardous substance to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects;

(B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure that present a significant risk to human health of acute, subacute, and chroni c 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 pr ofiles are health professionals at the Federal, State, and local levels; interested private sector organizations and groups; and members of the public.

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

peer

- reviewed. Staff 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 panelvi PHENOL

and was made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR.

Howard Frumkin M.D., Dr.P.H. Julie Lo uise Gerberding, M.D., M.P.H.

Director Administrator

National Center for Environmental Health/ Agency for Toxic Substances and Agency for Toxic Substances and Disease Registry Disease Registry

* Legislative Background

The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99 499) which amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed ATSDR to prepare 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. The availability of the revised priority list of 275 hazardous substances was announced in the Federal Register on Dec ember 7, 2005 (70 FR 72840). For prior versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866); October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17,1990 (55 FR 42067); October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); February 28, 1994 (59 FR 9486); April 29, 1996 (61 FR 18744); November 17, 1997 (62 FR 61332); October 21, 1999(64 FR 56792); October 25, 2001 (66 FR 54014) and November 7, 2003 (68 FR 63098). Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on

the list.vii PHENOL



### QUICK REFERENCE FOR HEALTH CARE PROVIDERS

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation of available toxicologic and epidemiologic information on a substance. Health care providers treating patients potentially exposed to hazard ous substances will find the following information helpful for fast

answers to often -asked questions.

Primary Chapters/Sections of Interest

Chapter 1: Public Health Statement : The Public Health Statement can be a useful tool for educating patients ab out possible exposure to a hazardous substance. It explains a substance’s relevant toxicologic properties in a nontechnical, question-and- answer format, and it includes a review of the general health effects observed following exposure.

Chapter 2: Relev ance 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 Intere st:
Section 3.8 Biomarkers of Exposure and Effect

Section 3.11 Methods for Reducing Toxic Effects

ATSDR Information Center

Phone: 1-800- CDC

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

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

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

Case Studies in Environmental Medicine: Taking an Exposure History

— The importance of taking an exposure history and how to conduct one are described, and an example of a thorough exposure history is provided. Other case studies of interest include Reproductive and Developmental Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide Toxicity ; and numerous chem ical

- specific case studies.PHENOL viii

Managing Hazardous Materials Incidents is a three

- volume set of recommendations for on

- scene (prehospital) and hospital medical management of patients exposed during a hazardous materials incident. Volumes I and II are plannin g guides to assist first responders and hospital emergency department personnel in planning for incidents that involve hazardous materials. Volume III— Medical Management Guidelines for Acute Chemical Exposure s— is a guide for health care professionals trea ting patients exposed to hazardous materials.

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

Other Agencies and Organizations

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, injury, and disability related to the interactions between people and their environment outside the workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta,

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

Th e 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 Occupa tional 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

biomedic al research on the effects of chemical, physical, and biologic environmental agents on human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, Research Triangle Park, NC 27709 • Phone: 919-541-3212.

Referrals

The Associa tion of Occupational and Environmental Clinics (AOEC) has developed a network of clinics in the United States to provide expertise in occupational and environmental issues. Contact: AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976

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

The American College of Occupational and Environmental Medicine (ACOEM) is an association of physicians and other health care providers specializing in the field of o ccupational 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 PHENOL



### CONTRIBUTORS

CHEMICAL MANAGER(S)/AUTHOR(S):

Jewel Crawford, M.D. Obaid Faroon, DVM, Ph.D. Jewell Wilson, Ph.D. ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, Georgia

Fernando T. Llados, Ph.D. Kristina Garber, M.S. Sari J. Paikoff, Ph.D. Michael H. Lumpkin, Ph.D. Syracuse Research Corporation, North Syracuse, NY Syracuse Research Corporation, Arlington, VA

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:

1. Health Effects Review. The Health Effects Review Committee examines the health effects chapter of each profile for consistency and accuracy in interpreting health effects and classifying end points.

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

substance- specific Minimal Risk Levels (MRLs), reviews the health effects database of each profile , and makes recommendations for derivation of MRLs.

3. Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure consistency across profiles and adherence to instructions in the Guidance.

4. Green Border Review. Green Borde r review assures the consistency with ATSDR policy.x PHENOL



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### PEER REVIEW

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

1. Marlissa Campbell, Ph.D., Private Consultant, Pacific a, California;

2. F. Peter Guengerich, Ph.D., Director, Center in Molecular Toxicology, Professor of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee; and

3. Thomas Zoeller, Ph.D., Professor, Department of Biology, Universit y of Massachusetts at Amherst, Amherst, Massachusetts;

These experts collectively have knowledge of phenol’ s physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of r isk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as

amended.

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers' comments and determined which comments will be included in the profile. A listing of the peer reviewers' comments not incorporated in the profile, with a brief explanation of the rati onale for their exclusion, exists as part of the administrative record for this compound.

The citation of the peer review panel should not be understood to imply its approval of the profile's final content. The responsibility for the content of this pr ofile lies with the ATSDR.xii PHENOL



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### CONTENTS

DISCLAIMER

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

UPDATE STATEMENT

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

FOREWORD

................................................................................................ ................................................ v QUICK REFERENCE FOR HEALTH CARE PROVIDERS

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

CONTRIBUTORS

................................................................................................ ....................................... ix

PEER REVIEW

................................................................................................ ........................................... xi

CONTENTS

................................................................................................ ............................................... xiii

LIST OF FIGURES

................................................................................................ .................................. xvii

LIST OF TABLES

................................................................................................ ..................................... xix

1. PUBLIC HEALTH STATEMENT

.......................................................................................................... 1

1.1 WHAT IS PHENOL?

..................................................................................................................... 1

1.2 WHAT HAPPENS TO PHENOL WHEN IT ENTERS THE ENVIRONMENT?

........................ 2

1.3 HOW MIGHT I B E EXPOSED TO PHENOL?

............................................................................ 2

1.4 HOW CAN PHENOL ENTER AND LEAVE MY BODY?

......................................................... 3

1.5 HOW CAN PHENOL AFFECT MY HEALTH?

.......................................................................... 4

1.6 HOW CAN PHENOL AFFECT CHILDREN?

.............................................................................. 5

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

......................... 5

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

TO PHENOL?

................................................................................................ ................................ 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 EX POSURES TO PHENOL IN THE

UNITED STATES

......................................................................................................................... 9

2.2 SUMMARY OF HEALTH EFFECTS

......................................................................................... 10

2.3 MINIMAL RISK LEVELS (MRLs)

............................................................................................ 14

3. HEALTH EFFECTS

.............................................................................................................................. 21

3.1 INTRODUCTION

........................................................................................................................ 21

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

..................................... 21

3.2.1 Inhalation Exposure

.............................................................................................................. 22

3.2.1.1 Death

.............................................................................................................................. 22

3.2.1.2 Systemic Effects

............................................................................................................. 23

3.2.1.3 Immunological and Lymphoreticular Effects

................................................................ 40

3.2.1.4 Neurological Effects

...................................................................................................... 41

3.2.1.5 Reproductive Effects

...................................................................................................... 43

3.2.1.6 Developmental Effects

................................................................................................... 43

3.2.1.7 Cancer

............................................................................................................................ 44

3.2.2 Oral Exposure

........................................................................................................................ 44

3.2.2.1 Death

................................................................ .............................................................. 44

3.2.2.2 Systemic Effec ts

............................................................................................................. 61

3.2.2.3 Immunological and Lymphoreticular Effects

................................................................ 69

3.2.2.4 Neurological Effects

...................................................................................................... 70

3.2.2.5 Reproductive Effects

...................................................................................................... 71

3.2.2.6 Developmental Effects

................................................................................................... 72

3.2.2.7 Cancer

............................................................................................................................ 75PHENOL xiv

3.2.3 Dermal Exposure

................................................................................................................... 75

3.2.3.1 Death

.............................................................................................................................. 75

3.2.3.2 Systemic Effects

............................................................................................................. 77

3.2.3.3 Immunological and Lymphoreticular Effects

................................................................ 85

3.2.3.4 Neurological Effects

...................................................................................................... 85

3.2.3.5 Reproductive Effects

...................................................................................................... 86

3.2.3.6 Developmental E ffects

................................................................................................... 86

3.2.3.7 Cancer

............................................................................................................................ 86

3.3 GENOTOXICITY

........................................................................................................................ 87

3.4 TOXICOKINETICS

..................................................................................................................... 93

3.4.1 Absorption

............................................................................................................................. 93

3.4.1.1 Inhalation Exposure

....................................................................................................... 93

3.4.1.2 Oral Exposure

................................................................................................................ 94

3.4.1.3 Dermal Exposure

........................................................................................................... 95

3.4.1.4 Other Routes of Exposure

.............................................................................................. 97

3.4.2 Distribut ion

........................................................................................................................... 97

3.4.2.1 Inhalation Exposure

....................................................................................................... 97

3.4.2.2 Oral Exposure

................................................................................................................ 98

3.4.2.3 Dermal Exposure

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

3.4.2.4 Other Routes of Exposure

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

3.4.3 Metabolism

.......................................................................................................................... 101

3.4.4 Elimination and Excretion

................................................................................................... 105

3.4.4.1 Inhalation Exposure

..................................................................................................... 105

3.4.4.2 Oral Exposure

.............................................................................................................. 106

3.4.4.3 Dermal Exposure

......................................................................................................... 107

3.4.4.4 Other Routes of Exposure

............................................................................................ 108

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

........... 108

3.4.5.1 Summary of PBPK Models

............................................................................................. 109

3.4.5.2 Discussion of Models

...................................................................................................... 111

3.5 MECHANISMS OF ACTION

................................................................................................... 113

3.5.1 Pharmacokinetic Mechanisms

............................................................................................. 113

3.5.2 Mechanisms of Toxicity

...................................................................................................... 114

3.5.3 Animal

- to -Human Extrapolations

....................................................................................... 115

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS

........................... 115

3.7 CHILDREN’S SUSCEPTIBILITY

............................................................................................ 117

3.8 BIOMARKERS OF EXPOSURE AND EFFECT

..................................................................... 122

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Phenol

........................................... 123

3.8.2 Biomarkers Used to Characterize Effects Caused by Phenol

.............................................. 123

3.9 INTERACTIONS WITH OTHER CHEMICALS

..................................................................... 124

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

............................................ 124

3.11 METHODS FOR REDUCING TOXI C EFFECTS

................................................................ 125

3.11.1 Reducing Peak Absorption Following Exposure

............................................................. 125

3.11.2 Reducing Body Burden

................................................................................................... 126

3.11.3 Interfering with the Mechanism of Action for Toxic E ffects

.......................................... 126

3.12 ADEQUACY OF THE DATABASE

..................................................................................... 126

3.12.1 Existing Information on Health Effects of Phenol

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

3.12.2 Identification of Data Needs

............................................................................................ 129

3.12.3 Ongoing Studies

.............................................................................................................. 138PHENOL xv

4. CHEMICAL AND PHYSICAL INFORMATION

.............................................................................. 139

4.1 CHEMICAL IDENTITY

............................................................................................................ 139

4.2 PHYSICAL AND CHEMICAL PROPERTIES

......................................................................... 139

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

.......................................................... 143

5.1 PRODUCTION

.......................................................................................................................... 143

5.2 IMPORT/EXPORT

.................................................................................................................... 143

5.3 USE

................................................................................................ ............................................ 143

5.4 DISPOSAL

................................................................................................ ................................. 147

6. POTENTIAL FOR HUMAN EXPOSURE

......................................................................................... 149

6.1 OVERVIEW

............................................................................................................................... 149

6.2 RELEASES TO THE ENVIRONMENT

................................................................................... 151

6.2.1 Air

................................................................................................ ....................................... 151

6.2.2 Water

................................................................................................ ................................... 154

6.2.3 Soil

................................................................................................ ...................................... 155

6.3 ENVIRONMENTAL FATE

...................................................................................................... 155

6.3.1 Transport and Partitioning

................................................................................................... 155

6.3.2 Tr ansformation and Degradation

........................................................................................ 157

6.3.2.1 Air

................................................................................................ ................................ 157

6.3.2.2 Water

............................................................................................................................ 157

6.3.2.3 Sediment and Soil

........................................................................................................ 158

6.4 LEVELS MONITORED OR ESTIMAT ED IN THE ENVIRONMENT

.................................. 159

6.4.1 Air

................................................................................................ ....................................... 159

6.4.2 Water

................................................................................................ ................................... 160

6.4.3 Sediment and Soil

............................................................................................................... 163

6.4.4 Other Environmental Media

................................................................................................ 163

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

........................................ 164

6.6 EXPOSURES OF CHILDREN

.................................................................................................. 166

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

.............................................. 167

6.8 ADEQUACY OF THE DATABASE

........................................................................................ 168

6.8.1 Identification of Data Needs

............................................................................................... 168

6.8.2 Ongoing Studies

.................................................................................................................. 172

7. ANALYTICAL METHODS

................................................................................................................ 173

7.1 B IOLOGICAL MATERIALS

.................................................................................................... 173

7.2 ENVIRONMENTAL SAMPLES

.............................................................................................. 176

7.3 ADEQUACY OF THE DATABASE

........................................................................................ 176

7.3.1 Identification of Data Needs

............................................................................................... 181

7.3.2 Ongoing Studies

.................................................................................................................. 182

8. REGULATIONS AND ADVISORIES

............................................................................................... 185

9. REFERENCES

................................................................................................ .................................... 191

10. GLOSSARY

................................................................................................ ...................................... 221PHENOL xvi

APPENDICES

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS

............................................................. A-1

B. USER’S GUIDE

................................................................................................ .................................. B-1

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS

...................................................................... C-1

D. INDEX

................................................................................................ ................................................ D-1PHENOL xvii



### LIST OF FIGURES

3-1. Levels of Significant Exposure to Phenol – Inhalation

...................................................................... 30

3-2. Levels of Significant Exposure to Phenol - Oral

................................................................................ 58

3-3. Metabolism of Phenol

....................................................................................................................... 102

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

.................................................................................................... 110

3-5. Existing Information on Health Effects of Phenol

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

6-1. Frequency of NPL Sites with Phenol Contamination

....................................................................... 150PHENOL xviii



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### LIST OF TABLES

3-1. Levels of Significant Exposure to Phenol - Inhalation

....................................................................... 24

3-2. Levels of Significant Exposure to Phenol - Oral

................................................................................ 46

3-3. Levels of Significant Exposure to Phenol - Dermal

........................................................................... 78

3-4. Genotoxicity of Phenol In Vivo

.......................................................................................................... 88

3-5. Genotoxicity of Phenol In Vitro

......................................................................................................... 89

4-1. Chemical Identity of Phenol

............................................................................................................. 140

4- 2. Physical and Chemical Properties of Phenol

.................................................................................... 141

5- 1. Facilities that Produce, Process, or Use Phenol

................................................................................ 144

5-2. Current U.S. Producers of Phenol

..................................................................................................... 146

6- 1. Releases to the Environment from Facilities that Pr oduce, Process, or Use Phenol

........................ 152

6-2. Estimated Exposure To Phenol At Various Industry Sites

............................................................... 169

7-1. Analytical Methods for Determining Phenol in Biological Samples

................................................ 174

7-2. Analytical Methods for Determining Phenol in Environmental Samples

........................................ 177

8-1. Regulations and Guidelines Applicable to Phenol

........................................................................... 186xx PHENOL



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## 1. PUBLIC HEALTH STATEMENT

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

The Environmental Protection Agency (EPA) identifi es 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. Phenol has been found in at least 595 of the 1,678 current or former NPL

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

exists that the number of sites at which phenol is found may increase in the future as more sites are

evaluated. This information is important because th ese sites may be sources of exposure, and exposure to

this substance may be harmful.

When a substance is released either from a large area, such as an indus trial plant, or from a container,

such as a drum or bottle, it enters the environment. Su ch a release does not always lead to exposure. You

can be exposed to a substance only when you come in contact with it. You may be exposed by breathing,

eating, or drinking the substance, or by skin contact.

If you are exposed to phenol, 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, fa mily traits, lifestyle, and

state of health.

1.1 WHAT IS PHENOL?

Description Phenol is a colorless-to-white solid when pure. Commercial phenol is a liquid that evaporates more slowly than water.

Phenol has a distinct odor that is sickeningly sweet and tarry.

Uses • Manufacturing

• Consumer products Phenol is both a manufactured chemical and produced naturally. Large amounts of phenol are produced in the United States.

Phenol is used to make plastics. Phenol is also used as a disinfectant in household cleaning products and in consumer products such as:

• mouthwashes

• gargles

• throat spraysPHENOL 2

1. PUBLIC HEALTH STATEMENT

For more information on the physical and chemical pr operties of phenol, and its production, disposal and

use, see Chapters 4 and 5.

1.2 WHAT HAPPENS TO PHENOL WHEN IT ENTERS THE ENVIRONMENT?

Sources Phenol can be found in air and water after release from the manufacture, use, and disposal of products containing phenol. Phenol in soil is likely to move to groundwater.

Break down

• Air

• Water

• Soil Phenol is quickly broken down in the air, usually within 1–2 days.

Phenol may persist in water for a week or more.

Phenol that remains in soil may be broken down by bacteria or other microorganisms.

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

1.3 HOW MIGHT I BE EXPOSED TO PHENOL?

Air The primary way you can be exposed to phenol is by breathing air containing it. Releases of phenol into the air occur from:

• industries using or manufacturing phenol

• automobile exhaust

• cigarette smoke, and

• wood burning

Recent data on levels of phenol in air are lacking.

Water and soil Phenol has been detected in surface wate rs, rainwater, sediments, drinking water, groundwater, industrial and urban runoff, and at hazardous waste sites. Phenol in soil is likely to move to groundwater.

Workplace Workers in the following industries may be exposed to phenol:

• petroleum industry

• manufacture of nylon, epoxy resins and polycarbonates, herbicides, wood preservatives, hydraulic fluids, heavy-du ty surfactants, lube-oil additives, tank linings and coatings, and intermediates for plasticizers and other specialty chemicals

Exposure occurs through breathing and dermal contact with contaminated air or by skin contact with products containing phenol.PHENOL 3

1. PUBLIC HEALTH STATEMENT

Food Low levels of phenol have been found in foods such as smoked summer sausage, smoked pork belly, mountain cheese, fried bacon, fried chicken,

and black fermented tea.

Consumer products Dermal contact can occur through t he use of general disinfectants and ointments containing phenol.

Ingestion can occur through the use of products such as throat lozenges or sore throat sprays that contain phenol.

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

1.4 HOW CAN PHENOL ENTER AND LEAVE MY BODY?

Enter your body

• Inhalation

• Ingestion

• Dermal contact When you breathe air containing phenol, most of the phenol will rapidly enter your body through your lungs.

Phenol in food or water may also rapidly enter your body through the digestive tract.

A significant amount may enter through your skin when you come into contact with phenol vapor, liquid phenol or liquids containing phenol.

Leave your body Once in your body, phenol is transf ormed into other chemicals called
metabolites. Most of these other c hemicals leave your body in the urine within few days.

For more information on how phenol enters and leaves the body, see Chapter 3.PHENOL 4

1. PUBLIC HEALTH STATEMENT

1.5 HOW CAN PHENOL AFFECT MY HEALTH?

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

Workers
• Inhalation/

dermal Long-term exposure to phenol at work has been associated with cardiovascular disease, but the wo rkers were also exposed to other

chemicals at the same time.

General population

• Oral Ingestion of liquid products contai ning concentrated phenol can cause serious gastrointestinal damage and even death.

General population

• Dermal Application of concentrated phenol to the skin can cause severe skin damage.

Laboratory

animals

• Inhalation Short-term exposure to high levels of phenol has caused irritation of the respiratory tract and muscle twitching in animals.

Longer-term exposure to high levels of phenol caused damaged to the heart, kidneys, liver, and lungs in animals.

Laboratory

animals

• Oral Drinking water with extremely high concentrations of phenol has caused muscle tremors, difficulty walking, and death in animals.

Laboratory

animals

• Dermal Short-term application of phenol to the skin has produced blisters and burns

in animals.

Cancer There is no evidence that phenol causes cancer in humans.

The International Agen cy for Research on Ca ncer (IARC) and the EPA determined that phenol is not classifiable as to human carcinogenicity.

Further information on the health effects of phenol in humans and animals can be found in

Chapters 2 and 3.PHENOL 5

1. PUBLIC HEALTH STATEMENT

1.6 HOW CAN PHENOL AFFECT CHILDREN?

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

conception to maturity at 18 years of age.

Effects in children Vomiting and lethargy were the main symptoms observed in children following accidental ingestion of a disi nfectant containing phenol. We do not

know whether children would be more s ensitive than adults to the effects of phenol.

Birth defects Two studies of women exposed to phenol and other chemicals during pregnancy did not provide evidence of birth defects.

Some birth defects have been observed in animals born to females exposed to phenol during pregnancy. This generally occurred at exposure levels that

were also toxic to the mothers.

Breast milk There is no information on levels of phenol in human breast milk.

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

Tobacco smoke Phenol is a component of tobacco sm oke. Avoid smoking in enclosed spaces like inside the home or car in order to limit exposure to children and other family members.

Consumer products Household products and over-the-counter medications containing phenol

should be stored out of the reach of young children to prevent accidental poisonings and skin burns.PHENOL 6

1. PUBLIC HEALTH STATEMENT

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

PHENOL?

Detecting

exposure Phenol can be measured in blood and uri ne. Phenol is a normal constituent

of human urine.

Measuring

exposure A higher-than-normal concentration of phenol in the urine may suggest recent exposure to phenol or to substa nces that are converted to phenol in the body.

The detection of phenol and/or its meta bolites in your urine cannot be used to predict the kind of health effects t hat might develop from that exposure.

Information about tests for detecting phenol in the body is given in Chapters 3 and 7.

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH?

The federal government develops regul ations and recommendations to prot ect public health. Regulations

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

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

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

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

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

recommendations for toxic substances.

Regulations and recommendations can be expressed as “not-to-exceed” levels. These are levels of a toxic

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

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

these not-to-exceed levels differ among federal organi zations 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 periodi cally as more information becomes available.

For the most current information, check with the federal agency or organization that provides it.PHENOL 7

1. PUBLIC HEALTH STATEMENT

Some regulations and recommendations for phenol include the following:

Drinking water The EPA has determined that exposure to phenol in drinking water at a concentration of 6 milligrams per liter (mg/L) for up to 10 days is not expected to cause any adverse effects in a child.

The EPA has determined that lifetime ex posure to 2 mg/L phenol in drinking water is not expected to cause any adverse effects.

Bottled water The FDA has determined that the phenol concentration in bottled drinking water should not exceed 0.001 mg/L.

Workplace air OSHA set a legal limit of 5 parts per million (ppm) phenol in air averaged over an 8-hour work day.

For more information on regulations and advisories, see Chapter 8.

1.10 WHERE CAN I GET MORE INFORMATION?

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

environmental quality department, or contact A TSDR 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 trea ting 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 calling the toll-free information and technical

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

to:

Agency for Toxic Substances and Disease Registry Division of Toxicology and Environmental Medicine

1600 Clifton Road NE Mailstop F-32 Atlanta, GA 30333

Fax: 1-770-488-4178PHENOL 8

1. PUBLIC HEALTH STATEMENT

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

National Technical Information Service (NTIS) 5285 Port Royal Road Springfield, VA 22161

Phone: 1-800-553-6847 or 1-703-605-6000 Web site: http://www.ntis.gov/9 PHENOL



### 2. RELEVANCE TO PUBLIC HEALTH

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO PHENOL IN THE UNITED
STATES

Phenol is a naturally occurrin g and manufactured chemical that is widely distributed in the environment.

It is found in various consumer products including throat lozenges, mouthwashes, and antiseptic lotions.

The most likely route of exposure to phenol is through dermal contact either in the work environment or

at home using ointments and other household products containing phenol.

Phenol is a product of combustion of coal wood and municipal solid waste; therefore, residents near coal

and petroleum fueled facilities as well as residents near municipal waste incinerators may have increased

exposure to phenol. Phenol is also a product of auto exhaust, and therefore, areas of high traffic likely

contain increased levels of phenol. Recent data on concentrations of phenol in air are lac king; it was

found at a median concentration of 30 parts per trillion (ppt) in 7 samples from one U.S. urban/suburban

site in 1974 and at a median concentration of 5,000 ppt in 83 samples from seven sites between 1974 and

1978. The individual medians of t he seven source sites ranged from 520 to 44,000 ppt. Higher phenol

concentrations may occur when there is smog or in highly contaminated air.

Phenol has been detected in surface waters, rainwater, sediments, drinking water, groundwater, industrial

efflue nts, urban runoff, and at hazardous waste sites. Levels of up to 1 ppb have been detected in

unpolluted groundwater and concentrations ranging from 0.01 to 1 ppb were detected in unpolluted rivers.

Phenol has been detected in Lake Huron water at 3 –24 ppb and industrial rivers in the United States at 0

–
5 ppb.

Phenol generally does not adhere very strongly to soils and tends to filter rapidly through soil, which may

account for the lack of monitoring data, since any phenol released to soils is likely to mo ve to

groundwater. In addition, phenol is readily biodegraded under both aerobic and anaerobic conditions,

which is expected to attenuate its levels in soil.

Phenol is degraded rapidly in air (half -life of approximately 15 hours), but may persist in wat er for a

somewhat longer period. In soil, phenol will biodegrade rapidly; the half- life in soil is generally <5 days.

Although low levels of phenol have been detected in certain foods and tap water, these levels do not

constitute major sources of exposur e for most people. Phenol has been reported at concentrations ofPHENOL 10

2. RELEVANCE TO PUBLIC HEALTH

7 and 28.6 ppm in smoked summer sausage and smoked pork belly, respectively, and was identified but

not quantified in mountain cheese, fried bacon, fried chicken, and black fermented tea.

Since plants can metabolize phenol readily, exposure through eating food derived from plants grown in

phenol-containing soil is probably minimal. Due to rapid biodegradation in water and soil, this

contamination should be limited. People with contaminated tap water can be exposed from drinking the

water or eating foods prepared with it. In addition, inhalation can occur during showering, bathing, and

cooking with contaminated water. People can also be exposed to phenol through dermal contact due to

bathing or showering with contaminated water.

There are no known unique sources of exposure to children. No reports of phenol in breast milk or baby

foods were found. Children are likely to be exposed to phenol through inhalation of contaminated air

from wood, coal, and waste incineration as well as from second-hand smoke. Nonsmokers who live with

smokers may be exposed to 6 –14 μg/day of phenol.

2.2 SUMMARY OF HEALTH EFFECTS

Information about the health effects of phenol in humans is derived from studies of workers and members

of the general population following inhalation, oral, and dermal exposure. These studies indicate that

phenol is an irritating and corrosive substance, making the skin and mucosal membranes targets of

toxicity, but other effects have also been reported. However, the data for humans exposed to phenol by

inhalation or ingestion are inadequate to establish concentration -response relationships, which are needed

to identify adverse effects levels. Fatalities due to ingestion or contact with a significant area of the skin

have been reported. A minimal lethal oral dose of approximately 70 mg/kg has been estimated in adults.

Other estimates indicate that an oral dose as low as 1,000 mg could be fatal in humans, but patients

occasionally survived doses as high as 65,000 mg. Postmortem examination typically showed serious

mucosal alterations in the gastrointestinal tract. Other than the skin and mucosal membranes, the liver

and cardiovascular system might by c onsidered targets for phenol toxicity. In an epidemiological study of

workers from the rubber industry exposed to multiple chemicals (phenol among them), phenol showed the

strongest association with mortality due to ischemic heart disease. Electrocardiog raphic alterations have

been reported following acute oral and dermal exposure to phenol, as well as vomiting and lethargy.

Studies of populations whose drinking water was contaminated with phenol found increased incidences of

nausea and d iarrhea, but exp osure to chloro phenols may have also occurred. Also, liver effects, as judged

by increased serum activities of alanine aminotransferase (ALT) and aspartate amino transferase (AST),PHENOL 11

2. RELEVANCE TO PUBLIC HEALTH

were reported in a case of prolonge d inhalation exposure to phenol and in workers in an oil- refining plant,

but exposure to other solvents could not be ruled out in the latter case. An increased incidence of

headaches was reported among people who used drinking water contaminated with phenol and probably

chlorophenols also. There is no evidence that phenol is a reproductive or developmental toxicant in

humans. The Development and Reproductive Toxicant Identification Committee of the California EPA’s

Office of Environmental Health Hazard Assessment examined the weight of evidence on the reproductive

toxicity of phenol and concluded that phenol had not been clearly shown to cause reproductive toxicity.

There is only one modern study of inhalation exposure of animals to phenol. The rest of the inhalation

database for phenol is outdated and not useful for risk assessment, although it serves to identify some

targets for phenol toxicity. However, no single especially sensitive target emerged from these studies.

Short- term (5 minutes) exposure of mice to phenol caused respiratory i rritation, as judged by the animals’

reflex reduction in respiratory rate; a lowest

- observed

- effect level (LOEL) was not defined; but the

exposure concentration that reduced the respiratory rate by 50% was 166 ppm. In rats exposed nose-only

intermittently to concentrations up to 25 ppm for 2 weeks, phenol caused no gross or microscopic

alterations in major tissues and organs, including the nasal cavity, but some rats showed an increased

incidence in a red nasal discharge possibly due to the irritating properties of phenol. Phenol caused

pneumonia, necrosis of the myocardium, centrilobular degeneration, and necrosis of the liver and renal

lesions in rabbits and guinea pigs, but not in rats, exposed whole- body intermittently to 26 ppm phenol for

intermediate durations. In yet another study in rats, continuous whole-body exposure to 26 ppm phenol

for 15 days caused signs of neurological impairment including muscle tremors, twitching, and gait

disturbances during the first 3 –5 days of exposure. At termination , serum transaminases were elevated

suggesting liver damage, but no histological examination was conducted. Neurological effects, including

loss of coordination and tremors, were also observed in rats exposed to 234 ppm phenol for 8 hours. In

summary, in haled phenol can affect several organs and tissues and produce neurological effects, but few

generalizations can be made from the available studies due to the different exposure protocols used (i.e.,

nose-only vs. whole-body; intermittent vs. continuous) and incomplete reporting. Toxicokinetics

information indicates that phenol is readily absorbed through the skin of humans and animals, so that

whole-body exposure may result in considerably more absorbed phenol than in nose-only exposures.

Application of phenol to the skin of animals has caused edema, erythema, necrosis, and death; the cause

of death was not provided in the studies available. The effects of phenol on the skin are due to its

property to impair the stratum corneum and produce coagulation necrosis by denaturing and precipitating

proteins. Lethality is influenced by the surface area exposed as well as the concentration of the appliedPHENOL 12

2. RELEVANCE TO PUBLIC HEALTH

solution. Systemic effects also have been described in animals following dermal exposure to phenol.

Rabbits that received a dose of phenol of 24 mg/cm 2 /kg suffered cardiac arrhythmia. Tremors leading to

convulsions were reported in rats following application of 107 mg/kg of phenol to an unspecified surface

area.

In contrast to the limited inhalation databas e, there is an extensive database of oral studies in animals; yet,

it is not easy to characterize the toxicity of orally administered phenol. A key factor contributing to the

inability to do so is that phenol administered by oral gavage is much more toxic than when it is

administered in the drinking water, a phenomenon that is related to the toxicokinetics of phenol. Studies

have shown that the toxicity of phenol is correlated with peak blood concentration rather than with total

dose, such as the area under the blood concentration curve (AUC). Thus, end points that appear sensitive

to phenol administered by oral gavage are not affected by the same total daily dose given via the drinking

water.

Results from a 28 -day drinking water study in mice provided the lowest effect levels in the oral database

for phenol and suggested that hematological, neurochemical, and immunological end points may be

particularly sensitive to phenol toxicity. However, since the effects reported in that study occurred at

dose lev els much lower than in any other study available, these findings should be interpreted with

caution until supporting results are available. In one study, phenol induced a s ignificant decrease in red

blood cell counts in mice at ≥1.8 mg/kg/day. While this finding could have been due to macrocytosis, the

study did not provide enough information to evaluate this possibility. Only two additional studies

provided information on hematological parameters after phenol exposure. In pregnant mice, a single

gavage dose of 265 mg/kg of phenol (only dose tested) on gestation day (GD) 13 induced a reduction in

the ratio of poly/normochromatic erythrocytes in the bone marrow, whereas phe nol administered to rats in

doses of up to 320 mg/kg/day in the drinking water for 10 weeks did not significantly affect a

comprehensive number of hematological parameters monitored. Other long-term drinking water studies

in rats and mice did not evaluate hematological parameters.

The neurochemical effects caused by phenol in a study also occurred at ≥1.8 mg/kg/day and consisted of

alterations in the levels of neurotransmitters in various brain areas. This is difficult to interpret in light of

the absenc e of clinical signs and lack of supporting evidence from other studies. Phenol, however, did

induce neurological effects in other studies. Short- term oral gavage administration of doses

≥120 mg/kg/day of phenol caused muscle twitching and tremors in rats and mice, but no effects were

observed at <40 mg/kg/day. Decreased motor activity was reported in female rats dosed withPHENOL 13

2. RELEVANCE TO PUBLIC HEALTH

360 mg/kg/day of phenol in the drinking water for 13 weeks, but no effects were seen at 107 mg/kg/day.

No neurochemical evaluations were conducted in these studies. Other long- term drinking water studies in

rats and mice that used much higher doses of phenol did not observe significant changes in gross or

microscopic appearance of the brain of the animals, but no neurological tests or neurochemical

evaluations were conducted in these studies.

Phenol caused a significant decrease in antibody response to immunization with sheep red blood cells

(SRBC) in mice at ≥6.2 mg/kg/day in a drinking water study. Lymphoproliferative responses t o T and

B cell mitogens were also significantly suppressed at 33.6 mg/kg/day. A study in which the plaqueforming cell assay to SRBC (but not the antibody titer) and lymphoreticular organs of rats exposed to up

to 321 mg/kg/day of phenol in the drinking w ater for 10 weeks were evaluated found no significant

alterations. In another study, a single dose of 224 mg/kg of phenol administered to rats by oral gavage

caused necrosis or atrophy of the spleen or thymus, but no other immunological end point was evaluated.

Long- term drinking water studies in rats and mice did not report any significant gross and histological

alteration in lymphoreticular organs and tissues at phenol doses >1,000 mg/kg/day.

Other effects of phenol observed in oral studies include re nal tubular necrosis in rats treated with a single

gavage dose of 224 mg/kg or with 40 mg/kg/day for 14 days. However, long-term drinking water studies

in rats and mice that received much higher doses of phenol do not suggest that the kidney is a particul arly

sensitive target for phenol. Phenol also induced decreases in body weight in rats and mice in 13- week

and 2-year drinking water studies that were associated with significant reductions in water consumption

due probably to poor palability. Phenol reduced body weight gain in pregnant mice treated by oral

gavage with 280 mg/kg/day, a dose level that also caused frank neurotoxicity. Doses of 120 mg/kg/day of

phenol administered to pregnant rats during GDs 6–15 using a divided dosing protocol to minimize the

adverse effects of a bolus dose caused a significant reduction in weight gain in the dams; the no

- observed

adverse

- effect level (NOAEL) was 60 mg/kg/day. The latter findings suggest that weight gain during

pregnancy is a sensitive end point for pheno l toxicity and the dose of 120 mg/kg/day was the lowest

LOAEL in acute -duration oral studies in which no overt signs of toxicity (other than reduced maternal

weight gain) were observed following administration of phenol.

Phenol has induced developmental effects in rodents, but, with one exception, it appears that this occurs

at dose levels that also affect the mothers. In one study, doses of 120 mg/kg/day of phenol on GDs 6–15

produced a 7% decrease in average fetal body weight in the absence of materna l effects. In the study that

used the divided dosing protocol mentioned above, there were no developmental effects atPHENOL 14

2. RELEVANCE TO PUBLIC HEALTH

120 mg/kg/day, but decreased ossification sites were seen at the highest dose level, 360 mg/kg/day. In a

two

- generation reproductive stu dy in which the parental generation received doses of up to 301–

321 mg/kg/day of phenol via the drinking water, decreased pup weight and percent live pups on postnatal

day 4 was reported at a dose level that also significantly decreased maternal water cons umption, including

during gestation and lactation. In pregnant mice, doses of 280 mg/kg/day on GDs 6–15 produced a

significant decrease in fetal weight and also caused tremors and ataxia in the dams.

A study of phenol-exposed wood industry workers repo rted a small, nonsignificant excess of respiratory

cancers and a study of phenol production workers reported a small, non- significant excess of Hodgkin’s

disease and of lung, esophageal, rectal, and kidney cancers. However, the interpretation of these fin dings

is complicated due to lack of dose-response and potential for confounding. Phenol has been tested for

carcinogenicity in long- term drinking water bioassays in rats and mice. Statistically significant increased

incidences of pheochromocytomas of the adrenal gland and leukemia or lymphomas were observed in

male rats exposed to the low dose of phenol, but not to the high dose of phenol. No significant effects

were seen in female rats or in mice. Phenol has consistently been found to be a promoter in initiation

promotion studies in mouse skin. Based on inadequate evidence in humans and in animals, EPA assigned

phenol to Group D, not classifiable as to human carcinogenicity. Under updated guidelines, the data

regarding carcinogenicity of phenol are: “inadequate for an assessment of human carcinogenic potential.”

2.3 MINIMAL RISK LEVELS (MRLs)

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

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

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

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

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

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

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

methodology does not exist to develop MRLs for dermal exposure.

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

uncertainties are associated with these techniques. Fur thermore, ATSDR acknowledges additional

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

example, acute inhalation MRLs may not be protective for health effects that are delayed in developmentPHENOL 15

2. RELEVANCE TO PUBLIC HEALTH

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 revise d.

Inhalation MRLs

An acute-duration inhalation MRL was not derived for phenol due to inadequacies of the limited database

available. The database includes a few animal studies of limited scope (Aranyi et al. 1986; De Ceaurriz et

al. 1981; Flickinger 1976) and a well-conducted study that used modern methodology to evaluate a

number of relevant end points (Hoffman et al. 2001). No relevant human studies were located. In the

animal studies, a target for phenol toxicity was not clearly defined; however, f or an irritant substance such

as phenol, it is reasonable to assume that portals of entry, such as the respiratory tract, could be potential

targets. Of the studies mentioned above, only Hoffman et al. (2001) conducted a careful evaluation of the

respirat ory tract. Hoffman et al. (2001) exposed rats to various exposure levels for 2 weeks and evaluated

a number of end points including histopathology, hematology, and clinical chemistry and reported no

adverse effects. De Ceaurriz et al. (1981) exposed mice to various concentrations of phenol in air for

5 minutes and determined an RD 50 (concentration that reduced the respiratory rate by 50%, a protective

reflex response in rodents) of 166 ppm. Aranyi et al. (1986) also exposed mice to 5 ppm phenol

3 hours/d ay for 5 days and reported no significant changes in susceptibility to airborne bacterial agents

relative to mice exposed to filtered air. Flickinger (1976) observed loss of coordination and tremors in

rats exposed to 234 ppm phenol for 8 hours; a 1-hour exposure was without effect. No other exposure

concentration was tested and no control group was used. Fourteen days later, the rats were sacrificed and

subjected to gross necropsy. Flickinger (1976) indicated that no gross lesions were observed, but th e

scope of the examination was not specified. Of all the studies available, the one conducted by Hoffman et

al. (2001) is the most complete, better-reported, and used modern methodology, but, as indicated above,

because no adverse effects were reported, it is not a suitable basis for an MRL.

An intermediate-duration inhalation MRL was not derived for phenol due to lack of adequate data. No

relevant human data were located and the available animal studies had numerous limitations including

poor control of exposure levels, unclear scope of the evaluations, and limited reporting. The

intermediate -duration database consists of only three studies (Dalin and Kristoffersson 1974; Deichmann

et al. 1944; U.S. Air Force 1961). Dalin and Kristoffersson (1974) exposed a small number of rats to 0 or

26 ppm phenol continuously for 15 days and reported mild motor disorders (impaired balance, abnormal

gait, muscle twitching) during the first few days of exposure. At termination, the activities of serumPHENOL 16

2. RELEVANCE TO PUBLIC HEALTH

transaminases were significantly increased indicating liver damage, but no histopathology examination

was conducted. Because the exposure chamber was not of modern design, there is some uncertainty as to

the actual exposure levels. Deichmann et al. (1944) exposed guin ea pigs, rats, and rabbits intermittently

for 6 –12 weeks to a concentration of phenol in air that apparently could not be controlled with any

precision, but could have ranged from 26 to 52 ppm. No controls were used and no actual data were

presented; the paper contains only a narrative of the results. Exposure to phenol caused serious

histological alterations in the lungs, heart, liver, and kidneys in rabbits and guinea pigs, but no significant

changes were reported in rats. U.S. Air Force (1961) exposed monkeys, rats, and mice continuously to

0 or 5 ppm phenol for 90 days. No information was provided regarding the frequency of monitoring the

test atmosphere, but the concentration of phenol was reported to remain in the range of 4.5–5.5 ppm after

the fir st few days of the experiment. Although the report indicates that there were no significant

histological alterations in organs and tissues, incomplete reporting of the results suggests that there may

have been some lung, liver, and kidney pathology. In addition, no data were presented to support the

assertion that there were no effects on hematology (three species), blood chemistry (monkeys only),

urinalysis (three species), and kidney function tests (monkeys and rats).

A chronic- duration inhalation MR L for phenol was not derived due to lack of data for this duration.

Occupational studies in humans are limited by lack of exposure data and simultaneous exposure to

multiple chemicals. No chronic inhalation study in animals was located.

Oral MRLs

No re liable human data were located for derivation of oral MRLs for phenol. As mentioned in

Section 2.2, effects of phenol administered to animals by oral gavage are different than those observed in

drinking water studies. Administration of phenol by oral gavage, as was done in almost all acute -duration

oral studies, results in adverse effect levels that are much lower than those identified in drinking water

studies. For example, tremors were reported in rats administered a single gavage dose of 120 mg/kg

(Berman et al. 1995) and in pregnant mice administered 140 mg/kg/day during gestation (NTP 1983b),

but no adverse neurological signs were reported in rats administered 360 mg/kg/day in the drinking water

for 13 weeks (Beyrouty 1998) or i n rats or mice administered phenol in the drinking water in doses

exceeding 700 mg/kg/day for up to 103 weeks (NCI 1980). This differential toxicity is related to the

toxicokinetics of phenol. A study by Hiser et al. (1994) showed that the toxicity of ph enol is correlated

with peak blood concentration rather than with total dose, such as the AUC. Hiser et al. (1994) observed

that rats given phenol by oral gavage developed a cluster of behaviors that the investigators termedPHENOL 17

2. RELEVANCE TO PUBLIC HEALTH

“phenol twitching behavior” consisting of tremors, sudden jerks, hyper-reactivity to stimulus, and

excessive blinking, none of which occurred in groups dosed via the drinking water. Hiser et al. (1994)

also noticed that the twitching behavior developed almost immediately after gavage dosing, a time that

also coincided with peak blood levels of phenol, and disappeared by 37 minutes after dosing. Also, for a

given daily dose, peak levels of phenol in blood were much higher following gavage dosing than

following continuous administration in the drinking water. Additional information that supports the idea

of toxicity being associated with peak blood levels of phenol was provided by experiments done by NTP

(1983a). These investigators treated pregnant rats with phenol by gavage in different volumes during

GDs 6 –15. In a group dosed with 125 mg/kg/day in a volume of 1 mL/kg, 7 of 10 rats died. Deaths were

preceded by dose-related signs of toxicity, including tremors, convulsions, and respiratory distress, and

necropsy revealed mottled li ver and congested lungs. However, in a group treated with 160 mg/kg/day in

a volume of 5 mL/kg only one of six rats died, as a larger dosing volume would be expected to decrease

the absorption rate. Based on the information discussed in this paragraph, only drinking water studies and

divided dose gavage studies were considered appropriate for MRL derivation.

**•** An MRL of 1 mg/kg/day has been derived for acute- duration oral exposure (1 –14 days) to phenol.

All of the acute

- duration oral studies available ad ministered phenol to the animals by gavage. As

indicated in the preceding paragraph, dosing volume in oral gavage studies is important in the

manifestation of phenol toxicity. Acute-duration studies that used a relatively low dosing volume of

1 mL/kg are those by Berman et al. (1995), Moser et al. (1995), and Narotsky and Kavlock (1995). These

studies were not considered for MRL derivation even though they identified adverse effects at dose levels

lower than studies that used divided gavage dosing or dri nking water studies. The remaining database is

essentially limited to two developmental studies, which were considered for MRL derivation. In one of

these studies, rats were gavaged with phenol in doses of up to 120 mg/kg/day in a dosing volume of

5 mL/k g during GDs 6–15 (NTP 1983a). There was no maternal toxicity, but mean fetal body weight at

this dose level was approximately 7% lower than controls. However, since historical control data showed

that the concurrent control fetal weight for the CD rat w as much higher (22%) than the historical control

weight and a larger litter size in the high -dose group may have contributed to the smaller fetal weight in

the high -dose group, the dose of 120 mg/kg/day can be considered an equivocal LOAEL for

developmenta l effects; the NOAEL was 60 mg/kg/day. In the other developmental study, which used a

divided dosing protocol and a dosing volume of 10 mL/kg, there was a dose

- related decrease in maternal

body weight gain during treatment days and beyond, which achieved statistical significance at

120 mg/kg/day ( York 1997). Maternal body weight was also reduced, but differences with controlPHENOL 18

2. RELEVANCE TO PUBLIC HEALTH

achieved statistical significance only at 360 mg/kg/day (see details below). No fetal toxicity was seen at

120 mg/kg/day. The decr ease in maternal body weight gain during gestation was the most sensitive end

point and the dose level of 120 mg/kg/day is considered a LOAEL; the NOAEL is 60 mg/kg/day. Since

the York (1997) study identified the most sensitive end point and utilized a do sing protocol that resembles

more closely a potential environmental exposure scenario to phenol, it was selected as the principal study

for the derivation of an acute- duration oral MRL for phenol.

In the York (1997) study, groups of pregnant Sprague- Dawl ey rats (25/dose group) were dosed 3 times

daily with 0, 20, 40, or 120 mg phenol/kg in water (total daily doses of 0, 60, 120, or 360 mg/kg) by

gavage on GDs 6 –15; the dosing volume was 10 mL/kg. Maternal end points evaluated included clinical

signs, body weight, and food consumption. Dams were also observed for abortions and premature

deliveries. Dams were sacrificed on GD 20 and a gross necropsy was conducted. The uterus was

examined for pregnancy, number and distribution of implantations, live and d ead fetuses, and early and

late resorptions. Fetuses were weighed and examined for sex and gross external alterations. Half of the

fetuses were examined for soft tissue alterations and the remaining fetuses were examined for skeletal

alterations. One dam in the 360 mg/kg/day group died on GD 11 and the death was attributed to phenol

treatment. Clinical signs considered treatment

- related included excess salivation and tachypnea in rats

exposed to 360 mg/kg/day. Gross necropsy of the dams did not reveal any treatment

- related alterations.

In the 120 mg/kg/day group, maternal body weight gain was significantly reduced for GDs 6– 16 (11%)

and for GDs 12–16 (19%), whereas in the 360 mg/kg/day group, body weight gain was reduced 38% for

GDs 6 –16. Maternal final body weight in the 360 mg/kg/day group was reduced, but <10% relative to

controls. Food consumption was reduced in the 360 mg/kg/day group by 16% for GDs 6–20 and by 15%

for GDs 0

– 20; in the 120 mg/kg/day group, food consumption for GDs 6–16 was reduced 11%. Fetal

body weight at the 360 mg/kg/day level was reduced 5

– 7% relative to controls. There was a significant

decrease in ossification sites on the hindlimb metatarsals in the 360 mg/kg/day group, which was

considered of minimal biological significa nce. At the 120 and 360 mg/kg/day dose levels, there were

increases in litters with fetuses with "any alteration" and with "any variation", but neither reached

statistical significance and there were no clear dose

- response relationships. There were no si gnificant

effects on corpora lutea, implantations, litter sizes, live fetuses, early and late resorptions, or percent

resorbed conceptuses. Based on decreased fetal body weight and delayed ossification, the dose of

360 mg/kg/day is a LOAEL for development al effects; the NOAEL is 120 mg/kg/day. Based on

decreased weight gain during gestation, the dose of 120 mg/kg/day is a LOAEL for decreased maternal

body weight gain; the NOAEL is 60 mg/kg/day.PHENOL 19

2. RELEVANCE TO PUBLIC HEALTH

Data from York (1997) were analyzed using the BMD approach for MRL derivation. BMD models in the

EPA Benchmark Dose Software (BMDS version 2.0) ( linear, polynomial, power, and Hill models) were

fit to the maternal body weight gain data to determine potential points of departure for the MRL (details

of the modeling are presented in Appendix A). The linear model with homogeneous variance (which was

identical to the power model), was selected because it was the simplest model and provided the best fit.

In the absence of a clear criteria as to what level of change in weight gain during pregnancy should be

considered adverse, the BMR was defined as a change in mean body weight gain equal to one standard

deviation from the control mean (EPA 2000c). The corresponding BMD was 152 mg/kg/day; the

corresponding benchmark dose limit (BMDL) was 125 mg/kg/day. Applying an uncertainty factor of 100

(10 for animal to human extrapolation and 10 for human variability) to the BMDL results in an acuteduration oral MRL of 1 mg/kg/day.

An intermediate-duration oral MRL for pheno l was not derived. Several studies are available that provide

information on the effects of phenol following intermediate -duration exposure and all of them used

drinking water to administer the test material. With the exception of one study (Hsieh et al. 1992, see

below), doses tested in intermediate -duration oral studies were higher than doses tested in acute-duration

oral studies. A 13- week drinking water study in rats and mice evaluated clinical signs and gross and

microscopic appearance of a number of organs and tissues and found little evidence of toxicity (NCI

1980). Reduction in body weight gain was observed in both rats and mice at the highest dose levels

tested (1,556 mg/kg/day in rats, 2,468 mg/kg/day in mice), which was most likely due to sign ificant

decreases in water consumption. Also available is a two -generation reproduction study that found no

evidence of reproductive effects in male and female rats (301 and 321 mg/kg/day, respectively), but

reported decreased pup weight and reduced viability at 301/321 mg/kg/day (Ryan et al. 2001).

Significantly reduced water consumption was also reported in the Ryan et al. (2001) study, particularly in

the 301/321 mg/kg/day males and females. A specialized 13 -week neurotoxicity study in rats reported

d ecreased motor activity in females dosed with 360 mg/kg/day, but not with 107 mg/kg/day (Beyrouty

1998). However, the most significant findings among the intermediate- duration database were reported in

a 28-day study in mice (Hsieh et al. 1992). These in vestigators found hematological and neurochemical

effects in mice at 1.8 mg/kg/day and immunological effects at ≥6.2 mg/kg/day. Hsieh et al. (1992) dosed

CD -1 mice (five per dose group) with phenol in the drinking water for 28 days. At termination, there was

a dose- related decrease in red cell counts, statistically significant at all dose levels. The hematocrit was

decreased only at the highest dose level. In the absence of a change in hematocrit, the decrease in red

blood cells may have been due to mac rocytosis, but the study did not provide sufficient information to

evaluate this possibility. Ryan et al. (2001), in a two-generation study, conducted a comprehensivePHENOL 20

2. RELEVANCE TO PUBLIC HEALTH

evaluation of hematological parameters in rats exposed to up to 321 mg/kg/day for 10 wee ks and found

no significant alterations. Similarly, in the inhalation experiments of U.S. Air Force (1961) in mice

exposed continuously for 90 days, no hematological alterations were observed. Hsieh et al. (1992) also

reported significant dose- related al terations in various neurotransmitters in the brain (i.e., dopamine,

norepinephrine). In the absence of clinical effects, this is difficult to interpret. Beyrouty (1998) exposed

rats to doses of 308 mg/kg/day of phenol for 13 weeks and found no significant neurological alterations,

although neurochemical evaluations were not conducted. Hsieh et al. (1992) also found a significant

decrease in antibody response to immunization with SRBCs at ≥6.2 mg/kg/day, detected by two different

assays (plaque -forming cell assay and antibody titer). At the highest dose level tested, 33.6 mg/kg/day,

lymphoproliferative responses to T and B cell mitogens were also significantly suppressed. Ryan et al.

(2001) also conducted the plaque-forming cell assay to SRBC (but not the antibody titer) and evaluated

lymphoreticular organs of rats in the two -generation study and found no significant alterations, although it

is not uncommon to find differences in immune responses between rats and mice. The Hsieh et al. (1992)

study was not used for derivation of an intermediate- duration oral MRL largely due to the unconfirmed

nature of findings observed at relatively very low doses and because only five mice comprised each dose

group. Hsieh’s findings need to be replicated before the da ta can be used for risk assessment.

A chronic-duration oral MRL for phenol was not derived. The only chronic-duration animal studies are

the NCI (1980) 103-week studies in rats and mice. NCI (1980) evaluated clinical signs, organ weights,

and gross and microscopic appearance of organs and tissues. The lowest doses tested were

322 mg/kg/day in rats and 590 mg/kg/day in mice. Under the conditions of the study, phenol showed

essentially no systemic toxicity, but neither hematology nor clinical chemistry tests were conducted. The

only reported effect was a significant decrease in body weight in male ( ≥322 mg/kg/day) and female

( ≥721 mg/kg/day) rats associated with significant decreases in water intake; food consumption was

comparable among all groups. It would not be appropriate to use the LOAEL of 322 mg/kg/day as the

basis for an MRL since the effect (reduced final body weight) was likely due to decreased water intake.

An additional reason for not deriving a chronic- duration oral MRL for phenol is the intermediate data

from Hsieh et al. (1992) suggesting that immunosuppression may be the most sensitive effect, which

leaves open the possibility that it could do the same in longer- term studies. Tests of immunocompetence

were not conducted in the standard 2- year bioassays available.PHENOL 21



### 3. HEALTH EFFECTS

3.1 INTRODUCTION

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

other interested individuals and g roups with an overall perspective on the toxicology of phenol. 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.

It should be noted that phenol is the simplest form, or parent compound, of the class of chemicals

commonly referred to as phenols or phenolics, many of which are natural substances widely distributed

throughout the environment. There is some confusion in the literature as to the use of the term ‘phenol’;

in some cases, it has been used to refer to a particular phenolic compound that is more highly substituted

than the parent com pound (Doan et al. 1979), whereas in other cases, it has been used to refer to the class

of phenolic compounds (Beveridge 1997). This chapter, however, addresses only those health effects that

can be directly attributable to the parent compound, monohydroxybenzene, or phenol. As Deichmann and

Keplinger (1981) note: “It cannot be overemphasized that the structure- activity relationships of phenol

and phenol derivatives vary widely, and that to accept the properties of individual phenolic compounds as

being those of phenol is a misconception and leads to error and confusion.”

A glossary and list of acronyms, abbreviations, and symbols can be found in Appendix C at the end of

this profile.

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

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

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

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

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

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

Levels of significant exposure for each r oute 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 thatPHENOL 22

3. HEALTH EFFECTS

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

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

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

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

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

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

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

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

"less serious" and "serious" effects. The distinction between "less serious" effects and "s erious" effects is

considered to be important because it helps the users of the profiles to identify levels of exposure at which

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not

the effects vary with dose and/or duration, and place into perspective the possible significance of these

effects to human health.

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and

figures may differ depending on the user's perspective. Public health officials and others concerned with

appropriate actions to take at hazardous waste sites may want information on levels of exposure

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which n o

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike.

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs.

3.2.1 Inhalation Exposure

3.2.1.1 Death

A cohort mortality study of workers in five formaldehyde-resin manufacturing facilities was conducted to

evaluate whether excess mortality could be attributed to occupational exposure to phenol (Dosemeci et al.

1991). Workers (exposed and non- exposed) had a mortality rate, from all causes, similar to that of the

general U.S. population. Compared to either the general population or unexposed workers, exposed

workers had small statistically non

- significant excesses in mortality due to Hodgkin’s disease

(standardized mortality ratio [SMR], 1.7; 95% confidence interval [CI], 0.8–3.1) and esophageal (SMR,

1.6; 95% CI, 0.9–2.6), renal (SMR, 1.3; 95% CI, 0.7–2.1), and rectal (SMR, 1.4; 95% CI, 0.8–2.2)PHENOL 23

3. HEALTH EFFECTS

cancers. They also had small reductions in mortality due to: cancer of the stomach, testes, pancreas,

buccal cav ity/pharynx and brain; lymphosarcoma; liver cirrhosis; emphysema; diseases of the

cardiovascular, circulatory, and digestive systems; motor vehicle accidents; and all accidents. The

ambiguity of these data, as well as the fact that dose

- related trends occurred only for those diseases

showing reductions in mortality, makes it difficult to assess the impact on mortality of long- term

occupational exposure to phenol.

Deichmann et al. (1944) exposed guinea pigs, rabbits, and rats to phenol vapor at levels ranging from

26 to 52 ppm for 28–88 days. After 28 days of exposure, 5 of 12 guinea pigs died, but no deaths occurred

in rabbits or rats. Since only a range was given for the exposure level, the exact level of phenol in air that

resulted in death of guinea pigs was not established and may be as low as 26 ppm or as high as 52 ppm.

Interpretation of this study is further complicated by an apparent lack of controls. However, since the

effects observed in guinea pigs and rabbits (described in subsequent secti ons in Chapter 3) were so

severe, it is difficult to ascribe the mortality to any source other than the phenol exposure. The lower

limit of the exposure range, 26 ppm, is recorded as a serious LOAEL in Table 3- 1 and plotted in

Figure 3-1. No deaths were reported in Rhesus monkeys, rats, or mice exposed to 5 ppm phenol

continuously for 90 days ( U.S. Air Force 1961).

3.2.1.2 Systemic Effects

The highest NOAEL values and all LOAEL values from each reliable study for systemic effect s in each

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

Respiratory Effects. Slight increases in mortality associated with respiratory cancers were seen in

two epidemiological studies of worker s exposed to phenol (Dosemeci et al. 1991; Kauppinen et al. 1986).

However, after adjusting for smoking

- related behavior, these increases became nonsignificant in the

Kauppinen et al. (1986) study, and neither study showed a dose- related trend; thus, the relevance of these

findings to respiratory disease per se is somewhat uncertain. Indeed in the latter study, there were slight,

yet nonsignificant reductions in mortality associated with emphysema among exposed workers, leading

the i nvestigators to suggest that exposure to phenol could have a protective effect for diseases involving

free radical damage.

A case -control study of office workers was conducted by Baj et al. (1994) to evaluate the risks of

chronic exposures to “inhaled formaldehyde, phenol, and isomers of organic chlorohydrocarbons from

KsylamitTM ...” which is a widely used liquid wood preservative. It should be noted that in the report,25225252525250861662532509851234Table 3-1 Levels of Significant Exposure to Phenol - InhalationaKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)ACUTE EXPOSURESystemic1Rat(Fischer- 344)2 wk5 d/wk6 hr/dSystemRespNOAEL(ppm)25Less Serious(ppm)LOAELSerious(ppm)ReferenceChemical FormHoffman et al. 2001CommentsNOAELs are for organweights andhistopathology.Hemato25HepaticRenal2525Bd Wt252Mouse(Swiss OF1)5 minResp166 M (50% decrease inrespiration rate)De Ceaurriz et al. 1981Immuno/ Lymphoret3Rat(Fischer- 344)2 wk5 d/wk6 hr/d25Hoffman et al. 2001NOAEL is forhistopathology of thespleen.4Mouse(CD-1)5 d3 hr/d5 FAranyi et al. 1986NOAEL is for nochange in susceptibilityto infectious agents.Neurological5RatHarlanWistar1 hr234 FFlickinger 1976NOAEL is for noadverse neurologicalsigns.22340652610655555145262626Table 3-1 Levels of Significant Exposure to Phenol - Inhalation(continued)aKey toFigureSpecies(Strain)SystemExposure/Duration/Frequency(Route)NOAEL(ppm)Less Serious(ppm)LOAELCommentsSerious(ppm)ReferenceChemical Form6Rat(HarlanWistar)8 hrFlickinger 1976234 F (loss of coordination andtremors)INTERMEDIATE EXPOSUREDeath7Gn Pig(NS)6 wk5 d/wk7 hr/dSystemic8RespMonkey(Rhesus)90 d24 hr/d5 MDeichmann et al. 194426 (5/12 deaths)NOAELs are for organhistopathology.U.S. Air Force 1961HematoHepaticRenalBd Wt5 M5 M5 M5 M9HematoRat(White)15 d24 hr/d26Dalin and Kristoffersson 1974Hepatic26 (serum activities of ALT,AST, LDH, and GLDHincreased 2-6-fold;increased serummagnesium)Bd Wt26064262626261075555510855555Table 3-1 Levels of Significant Exposure to Phenol - Inhalation(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(ppm)Less Serious(ppm)LOAELSerious(ppm)ReferenceChemical FormComments10Rat(NS)10 wk5 d/wk7 hr/dResp26Deichmann et al. 1944NOAELs are forhistopathology oftissues.CardioHepaticRenal26262611Rat(SpragueDawley)90 d24 hr/dResp5 MU.S. Air Force 1961NOAELs are forhistopathology oftissues.HematoHepaticRenalBd Wt5 M5 M5 M5 M12Mouse(NS)90 d24 hr/dResp5 MU.S. Air Force 1961NOAELs are forhistopathology oftissues.HematoHepaticRenalBd Wt5 M5 M5 M5 M06826262626Table 3-1 Levels of Significant Exposure to Phenol - Inhalation(continued)Exposure/LOAELDuration/aKey toSpeciesFrequencyNOAELLess SeriousSeriousReference(Route)Figure(Strain)System(ppm)(ppm)(ppm)Chemical FormComments13Gn Pig(NS)6 wk5 d/wk7 hr/dResp26Deichmann et al. 1944(acute lobular pneumoniawith occasionalabscesses and vasculardamage)Cardio26(necrosis of themyocardium, extensivereactive inflammation)Hepatic26(fatty changes,centrolobulardegeneration andnecrosis)Renal26(edema of the convolutedtubules, slightlyadvanced focal corticallesions, glomerulardegeneration)06326262626224514626Table 3-1 Levels of Significant Exposure to Phenol - Inhalation(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(ppm)Less Serious(ppm)LOAELSerious(ppm)ReferenceChemical FormComments14Rabbit(NS)12 wk5 d/wk7 hr/dResp26(confluent lobularpneumonia, chronicpurulent bronchitis,hyperplastic peribronchialtissue, degenerativechanges in pulmonaryvessels)Deichmann et al. 1944Cardio26(myocardialdegeneration, necrosis ofmuscle bundles,interstitial fibrosis,lymphocytic infiltration)Hepatic26(centrilobulardegeneration andnecrosis)Renal26(edema of the convolutedtubules, focal corticallesions, glomerulardegeneration)Neurological15Monkey(Rhesus)90 d24 hr/d5 MU.S. Air Force 196116Rat(White)15 d24 hr/d26(mild motor disordersduring the first 4 days ofexposure, 4.4 degreesdecrease in sliding angle)Dalin and Kristoffersson 19742265228515426Table 3-1 Levels of Significant Exposure to Phenol - Inhalation(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(ppm)Less Serious(ppm)LOAELSerious(ppm)ReferenceChemical FormComments17Rat(SpragueDawley)90 d24 hr/d5 MU.S. Air Force 1961NOAEL is for brainhistopathology andresults of a swimmingtest.18Mouse(NS)90 d24 hr/d5 MU.S. Air Force 1961NOAEL is for brainhistopathology andresults of a swimmingtest.19Gn Pig(NS)6 wk5 d/wk7 hr/d26(hindlimb paralysis)Deichmann et al. 1944a The number corresponds to entries in Figure 3-1.ALT = alanine aminotransferase; AST = aspartate aminotransferase; Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = Female; Gastro =gastrointestinal; GLDH = glutamate dehydrogenase; Gn pig = guinea pig; Hemato = hematological; hr = hour(s); Immuno = immunological; LDH = lactate dehydrogenase; LOAEL =lowest-observed-adverse-effect level; M = male; min = minute(s); NOAEL = no-observed-adverse-effect level; NS = not specified;Resp = respiratory; wk = week(s); yr = year(s)Respiratory Hematological Hepatic Body Weight Immuno/Lymphor Neurological

1000 Renal 

### Figure 3-1 Levels of Significant Exposure to Phenol - Inhalation

Acute (≤14 days)

Systemic

ppm

5r 6r

2m

100

1r 1r 1r 1r 1r 3r

10

4m

1

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50 Minimal Risk Level for effects other than CancerDeath Respiratory Cardiovascular Hematological Hepatic Renal Body Weight 

### Figure 3-1 Levels of Significant Exposure to Phenol - Inhalation (Continued)

Intermediate (15-364 days)

Systemic

ppm

100

7g 13g 10r 14h 13g 10r 14h 9r 13g 9r 10r 14h 13g 10r 14h 9r

10

8k 12m 11r 8k 12m 11r 8k 12m 11r 8k 12m 11r 8k 12m 11r

1

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50

for effects other than Cancer Minimal Risk LevelNeurological 

### Figure 3-1 Levels of Significant Exposure to Phenol - Inhalation (Continued)

Intermediate (15-364 days)

ppm

100

19g 16r

10

15k 18m 17r

1

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50

for effects other than Cancer Minimal Risk LevelPHENOL 33

3. HEALTH EFFECTS

KsylamitTM is indicated to consist of “...a mixture of chlorinated benzenes , pentachlorophenol,

alpha-chloronaphthalene, chloroparaffin and kerosene...”, and that the authors provide no discussion of

how phenol and formaldehyde are produced through the use of such a mixture. Twenty- two workers

(18 women and 4 men) exposed for at least 6 months were the cases, and 29 non-exposed, nonsmoking

volunteers matched for age, sex, and place of residence were the controls. The investigators indicate that

all exposed workers developed chronic complaints, among them cough and sore throat, b ut that no

remarkable increase in morbidity was found during the 6 months of exposure to KsylamitTM nor during

the 3-year follow-up study (details of which were not provided). The investigators attribute these

symptoms to the irritant effect of the inhaled KsylamitTM probably (based on the references provided) due

to the formaldehyde vapor they assert emanates from the wood -preserving liquid.

In laboratory animals, phenol is a respiratory irritant. De Ceaurriz et al. (1981) reported a dose

- response

function for reflex apnea, an index of respiratory irritation, in mice exposed to phenol vapor. From the

log dose-response function for decreased breathing rate, the RD 50 (RD designates respiratory depression),

or level of phenol in air that resulted in a 50% decrease in breathing rate during a 5-minute head-only

exposure, was established as 166 ppm. Based on the RD 50 , the study authors estimated that a

concentration of 17 ppm (0.1xRD 50 ) would be a LOAEL for respiratory irritation in humans, and a

concentration of 2 ppm (0.01xRD 50 ) would be a NOAEL.

In a study in which female Harlan Wistar rats were exposed for 1 hour to a phenol aerosol at a

concentration of 234 ppm, then held for 2 weeks postexposure, Flickinger (1976) observed signs of nasal

irritation during exposure. However, all animals exhibited normal behavior by postexposure day 1, and

no abnormal lesions were observed upon gross autopsy. No histopathology was performed; thus, this

study is not presented as a LOAEL for rats. A more recent study in whi ch rats were exposed

intermittently nose-only to up to 25 ppm phenol for 2 weeks found no significant gross or microscopic

alterations in the respiratory tract, including the nasal turbinates (Hoffman et al. 2001).

Inflammation, cellular infiltration, p neumonia, bronchitis, endothelial hyperplasia, and capillary

thrombosis occurred in guinea pigs exposed by inhalation to 26– 52 ppm phenol for 41 days (Deichmann

et al. 1944). Rabbits exhibited qualitatively similar but less severe effects after 88 days of similar

exposure. Rats exposed similarly showed no gross or microscopic alterations in the respiratory tract.

Since only a range was given for the exposure level (26 –52 ppm), the exact level of phenol in air that

resulted in respiratory effects was not established and may be as low as 26 ppm or as high as 52 ppm.

Interpretation of this study is further complicated by an apparent lack of controls. However, the lungPHENOL 34

3. HEALTH EFFECTS

pathology was so severe, particularly in the guinea pigs, that it is difficult to ascribe the effects to any

source other than the phenol exposure. The lower limit of the exposure range, 26 ppm, can be considered

a LOAEL for respiratory effects in guinea pigs and rabbits and a NOAEL for rats.

No significant histological abnormalities of the lungs were detected in Rhesus monkeys, rats, or mice

exposed to 5 ppm phenol continuously for 90 days ( U.S. Air Force 1961).

Cardiovascular Effects. In a cohort mortality study of workers in a large rubber and tire

manufacturi ng plant, Wilcosky and Tyroler (1983) found a significant increase in mortality from ischemic

heart disease in phenol exposed workers. Of the 25 solvents used in the plant, phenol exposure showed

the strongest association with mortality from heart disease , greater even than that observed for exposure

to carbon disulfide, the only known occupational cause of atherosclerosis.

In a cohort-mortality study of workers from five phenol- formaldehyde resin plants, Dosemeci et al.

(1991) found a slight reduction in mortality due to heart disease. These investigators hypothesized a

protective effect of phenol exposures; however, these results clearly conflict with those of Wilcosky and

Tyroler (1983). As a consequence, without more definitive studies, it is difficu lt to assess the

cardiovascular risk to humans, if any, posed by occupational exposure to phenol.

Myocardial injury was reported in guinea pigs exposed to 26 –52 ppm for 41 days, rabbits exhibited

qualitatively similar but less severe effects after 88 days of similar exposure, and rats showed no

significant alterations after 54 exposures (Deichmann et al. 1944). The injury was characterized by

myocardial inflammation, degeneration, and necrosis, interstitial fibrosis, and lymphocyte infiltration.

Since on ly a range was given for the exposure level (26 –52 ppm), the exact level of phenol in air that

resulted in myocardial injury was not established and may be as low as 26 ppm or as high as 52 ppm.

Interpretation of this study is further complicated by an apparent lack of controls. However, the heart

pathology was so severe that it is difficult to ascribe the effects to any source other than the phenol

exposure. The lower limit of the exposure range, 26 ppm, can be considered a LOAEL for myocardial

injury in guinea pigs and rabbits and a NOAEL for rats

.

Gastrointestinal Effects. Historical information in a case report (Merliss 1972) indicates that

‘carbol marasmus’ was a common occupational disorder of physicians and their assistan ts during the mid

19th Century when carbolic acid sprays (1:40 phenol in water) were commonly used for antisepsis in

operating rooms. Among the characteristics of this disorder was anorexia leading to progressive weightPHENOL 35

3. HEALTH EFFECTS

loss and excess production of saliv a. Similar gastrointestinal effects were observed in one of the author’s

patients who was involved in the daily distillation of phenol over a 13.5-year period. Exposed both via

inhalation of the vapors and dermally from frequent spills, the patient’s symptoms included both loss of

appetite and weight loss.

A cohort mortality study of workers in five phenol-formaldehyde resin manufacturing plants found that

exposed workers showed a slight reduction in death rate due to cancers of the digestive system as

compared to both non-exposed workers and the general population (Dosemeci et al. 1991).

In a study of rats exposed continuously for 15 days to 26 ppm phenol vapor, Dalin and Kristoffersson

(1974) noted the absence of alterations in the digestive system and attributed this to the relatively low

exposure levels (as compared to studies using oral dosing), but no further discussion was provided.

Hematological Effects. A case

- control study of office workers was conducted by Baj et al . (1994) to

evaluate the ris ks of chronic exposures to “inhaled formaldehyde, phenol and isomers of organic chlorohydrocarbons from KsylamitTM” which is a widely used liquid wood preservative. It should be noted that

in the report, KsylamitTM is indicated to consist of “a mixture of chlorinated benzenes, pentachlorophenol,

alpha-chloronaphthalene, chloroparaffin and kerosene,” and that the authors provide no discussion of how

phenol and formaldehyde are produced through the use of such a mixture. Twenty- two workers

(18 women and 4 me n) exposed for at least 6 months were the cases, and 29 non-exposed, nonsmoking

volunteers matched for age, sex, and place of residence were the controls. Using blood and urine samples

drawn after 6 months of exposure, cases and controls were compared on a variety of biochemical,

hematological, and immunological parameters. The exposed group showed no differences in any of the

blood chemistry parameters examined, serum bilirubin, alanine, and aspartate aminotransferase activity,

but had about a 30% increa se in eosinophils, a 25% increase in monocytes, and a 70% decrease in

erythrocytes. Measure ment of the office air at the end of the 6 -month period revealed a level of phenol of

0.34 ppm. Although the authors contend that their observations support the concern that chronic exposure

to phenol could adversely affect the hematopoietic system, it is important to consider not only that other

volatile chemicals, chlorinated organics, were present in the wood -preserving liquid, but also that the

chemical composi tion provided for KsylamitTM opens up the possibility that the effects being evaluated

result from exposure to pentachlorophenol rather than to phenol. This is particularly true since it was not

possible to determine from the information presented if the analytical methods used would differentiate

between phenol and pentachlorophenol.PHENOL 36

3. HEALTH EFFECTS

Workers (n=20) at an oil -refining plant in Egypt exposed to a time-weighted mean concentration of

5.4 ppm of phenol in air for a mean exposure period of 13.15 years showed sm all but significant increases

in hemoglobin, hematocrit, mean corpuscular hemoglobin, and mean corpuscular volume, but red blood

cell counts were not significantly altered relative to a group of 30 unexposed controls (Shamy et al. 1994).

Other small, but significant changes relative to controls included increased basophils and neutrophils,

decreased monocytes, and increased clotting time.

Hematocrit and hemoglobin concentrations were not affected in rats exposed to 26 ppm phenol in air

continuously for 15 days (Dalin and Kristoffersson 1974). Detailed hematological evaluations including

red and white blood cell, reticulocyte, and platelet counts; white cell differential; hemoglobin and

sulfhemoglobin, and red cell fragility tests, as well as corpuscular volume, corpuscular hemoglobin, and

corpuscular hemoglobin concentrations, did not reveal any effects in Rhesus monkeys, rats, or mice

exposed continuously to 5 ppm phenol in air for 90 days ( U.S. Air Force 1961). Comprehensive

hematology testing of rats e xposed nose -only to up to 25 ppm of phenol 6 hours/day, 5 days/week for

2 weeks showed no significant exposure-related deviations from control values (Hoffman et al. 2001).

Musculoskeletal Effects. A case of muscle pain and weakness was described in an individual after

intermittent chronic inhalation and dermal exposure to vapors and solutions of phenol, cresol, and xylenol

for >10 years (Merliss 1972). The symptoms lessened when the subject was removed from exposure.

Although t he exposure concentrations were not reported, the study author stated that the patient often

detected heavy odors, and that phenol was often spilled on his clothes resulting in skin irritation. Since

phenol is absorbed readily from the skin, dermal absorption of phenol may have contributed to the

systemic effects that were observed. The above symptoms may represent neurological effects rather than

injury to the muscle tissue.

Hepatic Effects. Enlarged liver and elevated serum levels of hepatic enzymes indicative of liver

injury (lactate dehydrogenase, 2 times above normal; aspartate aminotransferase (AST), 21 times above

normal; alanine aminotransferase (ALT), 100 times above normal) were observed in an individual

following chronic daily exposure to vapors and spills of phenol for >10 years (Merliss 1972). The

symptoms lessened when the individual was removed from the site of exposure. Although the exposure

concentrations were not reported, the study author stated that the patient often detected heavy odors and

that phenol was often spilled on his clothes resulting in skin irritation. Since phenol is absorbed readily

from the skin, dermal absorption may have contributed to the systemic effects that were observed. A

study of 20 w orkers at an oil -refining plant in Egypt exposed to a time- weighted average concentration ofPHENOL 37

3. HEALTH EFFECTS

phenol of 5.4 ppm for a mean exposure duration of 13.15 years found small, but significant increases in

ALT and AST activities (approximately 65 and 54%, respectiv ely) in serum collected at the end of the

shift of the last working day of the week relative to 30 unexposed controls (Shamy et al. 1994).

No effects on activities of liver enzymes (ALT, AST, γ

- glutamyltranspeptidase, alkaline phosphatase) in

the serum or changes in serum bilirubin or ceruloplasmin were noted in 22 workers exposed for 6 months

to vapors from a wood- treatment liquid containing phenol, formaldehyde, and organic chlorohydrocarbons (Baj et al. 1994). Although the study authors considered a significant increase in serum iron to

reflect an adverse effect on the liver that they attributed to phenol exposure, it is important to con sider not

only that other volatile chemicals, chlorinated organics, were present in the wood-preserving liquid, but

also that the chemical composition provid ed for KsylamitTM opens up the possibility that the effects being

evaluated result from exposure to pentachlorophenol rather than phenol. Dosemeci et al. (1991) saw a

dose- related decrease in mortality from liver cirrhosis in a cohort of workers occupation ally exposed to

phenol during their employment at five phenol-formaldehyde resin plants. These findings are

complicated by the fact that workers were also exposed to other chemicals; however, the authors

hypothesize that exposure to phenol could have a pr otective effect for diseases involving free radical

damage.

Centrilobular degeneration and necrosis of the liver were reported in guinea pigs exposed intermittently

by inhalation to 26–52 ppm phenol for 41 days, rabbits exhibited qualitatively similar b ut less severe

effects after 88 days of similar exposure, whereas rats showed no significant alterations after 54 exposures

(Deichmann et al. 1944). Since only a range was given for the exposure level (26–52 ppm), the exact

level of phenol in air that res ulted in hepatic injury was not established and may be as low as 26 ppm or as

high as 52 ppm. Interpretation of this study is further complicated by an apparent lack of controls.

However, the liver pathology was so severe, particularly in the guinea pigs , that it is difficult to ascribe

the effects to any source other than the phenol exposure.

Elevated activities of liver enzymes (lactate dehydrogenase, AST, ALT, glutamate dehydrogenase) were

found in the serum of rats exposed continuously to 26 ppm phenol vapor for 15 days (Dalin and

Kristoffersson 1974). Increased concentration of these enzymes in serum is often associated with liver

injury, but is not conclusive evidence for the type or severity of injury. Therefore, 26 ppm can be

considered a less serious LOAEL in rats. Serum levels of magnesium were also increased in these rats, an

effect the study authors suggested may also be a sign of liver injury. In a more recent study, rats exposed

nose-only to up to 25 ppm of phenol 6 hours/day, 5 days/week for 2 weeks showed no evidence of liverPHENOL 38

3. HEALTH EFFECTS

effects as monitored by clinical chemistry tests and histopathological examination of the liver (Hoffman

et al. 2001). No significant histological abnormalities were detected in the livers of Rhesus monkeys,

rats, or mice exposed continuously to 5 ppm phenol in air for 90 days ( U.S. Air Force 1961).

Renal Effects. In a case of chronic phenol poisoning, dark urine and glucose in the urine were noted

in a man following intermittent exposure to vapors and solutions of phenol (Merliss 1972). The urine

tested negative for protein and urobilinogen. The urine cleared 2–3 months after removal from exposure.

Although the exposure concentrations were not reported, the study author stated that heavy odors were

often detectable, and that phenol was often spilled on the patient’s clothes resulting in skin irritation.

Since phenol is absorbed readily from the skin, dermal absorption may have contributed to the systemic

effects that were observed.

Rena l proximal tubule and glomerular injury was reported in guinea pigs exposed intermittently by

inhalation to 26 –52 ppm phenol for 41 days, and rabbits exhibited qualitatively similar but less severe

effects after 88 days of similar exposure; rats exposed si milarly for 54 days showed no significant effects

(Deichmann et al. 1944). Since only a range was given for the exposure level (26–52 ppm), the exact

level of phenol in air that resulted in renal injury was not established and may be as low as 26 ppm or a s

high as 52 ppm. Interpretation of this study is further complicated by an apparent lack of controls.

However, the kidney pathology was so severe, particularly in the guinea pigs, that it is difficult to ascribe

the effects to any source other than the phenol exposure. The lower limit of the exposure range, 26 ppm,

can be considered a LOAEL for renal injury in guinea pigs and rabbits. No significant histological

abnormalities were detected in the kidneys of Rhesus monkeys, rats, or mice exposed continu ously to

5 ppm phenol in air for 90 days ( U.S. Air Force 1961). No kidney pathology was reported in a study in

rats exposed intermittently nose -only to up to 25 ppm of phenol for 2 weeks (Hoffman et al. 2001);

specific end points monitored included kidney histopathology, blood urea nitrogen (BUN), and serum

creatinine and electrolytes.

Dermal Effects. Historical information in a case report (Merliss 1972) indicates that ‘carbol

marasmus’ was a common occupational disorder of physi cians and their assistants during the mid -19th

Century. Among the characteristics of this disorder was an odd form of pigmentation, which commonly

occurred in the urine, but also occasionally colored the sclera of the eyes, the skin over the nose, and the

cheek bones. NIOSH (1983) conducted a survey in an Oregon hospital in response to concerns about

respiratory problems and contact dermatitis in housekeeping staff members who were exposed frequently

to germicidal solutions containing phenol and other solvents (formaldehyde, cellosolve, ethanolamine).PHENOL 39

3. HEALTH EFFECTS

According to the survey, the housekeeping staff reported significantly more symptoms of cough, itching,

sinus problems, and dermatitis than other employees. Air concentrations of phenol in the work areas we re

below the limit of detection (<0.01 ppm). Urinary phenol levels in housekeeping staff were not

significantly different from those of other employees. Thus, while it is likely that the employees came

into contact with irritants, the cause of the report ed symptoms could not be assigned to phenol or any

other specific substance in the work environment.

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

Ocular Effects. A case -control study of office workers was conducted by Baj et al. (1994) to evaluate

the risks of chronic exposures to “inhaled formaldehyde, phenol and isomers of organic

chlorohydrocarbons from KsylamitTM” which is a widely used liquid wood preservative reported to

consist of “a mixture of chlorinated benzenes, pentachlorophenol, alpha-chloronaphthalene,

chloroparaffin, and kerosene.” Twenty- two workers (18 women and 4 men) exposed for at least 6 months

were the cases, and 29 non-exposed, nonsmoking volunteers matc hed for age, sex, and place of residence

were the controls. The authors indicate that all of the exposed workers developed chronic complaints,

among them burning eyes, but that no remarkable increase in morbidity was found during the 6 months of

exposure to KsylamitTM, nor during the 3- year follow -up study (details of which were not provided). The

authors attribute these symptoms to the irritant effect of the inhaled KsylamitTM probably (based on the

references provided) due to the formaldehyde vapor they a ssert emanates from the wood

- preserving

liquid.

In a study in which female Harlan Wistar rats were exposed for 1 hour to a phenol aerosol at a

concentration of 234 ppm, then held for 2 weeks postexposure, Flickinger (1976) observed signs of ocular

irritat ion during exposure. However, all animals were normal by postexposure day 1, and no abnormal

lesions were observed upon gross autopsy.

Body Weight Effects. Historical information in a case report (Merliss 1972) indicates that ‘carbol

marasmus’ was a c ommon occupational disorder of physicians and their assistants during the mid-19th

Century. Among the characteristics of this disorder were anorexia accompanied by progressive weight

loss. The author reported that his patient, a 44

- year -old man involved in the daily distillation of phenol,

showed many of the symptoms of this condition, including lack of appetite and severe weight loss,

probably due to his daily workplace exposures to phenol vapors. Although the exposure concentrations

were not reported, the report indicated that the patient often detected heavy odors, and that phenol wasPHENOL 40

3. HEALTH EFFECTS

often spilled on his clothes resulting in skin irritation. Since phenol is absorbed readily from the skin,

dermal absorption may have contributed to the systemic effects that were observed.

Body weight effects were not observed in adult female Harlan Wistar rats exposed to an aerosol

containing 234 ppm phenol for 8 hours (Flickinger 1976), in rats exposed continuously to 26 ppm phenol

in air for 15 days (Dalin and Kristoffersson 1974), in Rhesus monkeys, rats, or mice exposed

continuously to 5 ppm phenol in air for 90 days ( U.S. Air Force 1961), or in rats exposed intermittently

nose-only for 2 weeks to up to 25 ppm of phenol vapor (Hoffman et al. 2001).

Metabolic Effects. Dalin and Kristoffersson (1974) reported elevated serum concentrations of

potassium and magnesium in rats exposed to 26 ppm phenol vapor continuously for 15 days. While not

necessarily adverse, this effect may be related to the muscle tremors and neurological effects observed

following inhalation exposure to phenol (see Section 3.2.1.4). No further information was located

regarding metabolic effects of inhaled phenol in animals.

3.2.1.3 Immunological and Lymphoreticular Effe cts

A case -control study of office workers was conducted by Baj et al. (1994) to evaluate the risks of chronic

exposures to “inhaled formaldehyde, phenol and isomers of organic chlorohydrocarbons from

KsylamitTM” which is a widely used liquid wood preservative. Twenty -two workers (18 women and

4 men) exposed for at least 6 months were the cases, and 29 non- exposed, nonsmoking volunteers

matched for age, sex, and place of residence were the controls. Using blood samples drawn after

6 months of exposure, cases and controls were compared on a variety of immunological parameters. The

exposed group showed significantly decreased (p<0.05) levels of the CD3+, CD4+, and CD8+ subsets of

T-lymphocytes, a significant decrease (p<0.001) in lymphocyte responsiveness to the mitogen

phytohemagglutinin (PHA), a significant decrease (p<0.05) in natural killer (NK) cell cytotoxicity, and a

significant decrease (p<0.0001) in the mixed lymphocyte response assay. Measurement of the office air

at the end of the 6-month period revealed a level of phenol of 0.34 ppm. Although the authors contend

that their observations support the concern that chronic exposure to phenol could adversely affect the

immune system, it is important to consider not only that other volatile chemicals, chlor inated organics,

were present in the wood -preserving liquid, but also that the chemical composition provided for

KsylamitTM opens up the possibility that the effects being evaluated resulted from exposure to

pentachlorophenol rather than phenol. This is p articularly true since it was not possible to determine fromPHENOL 41

3. HEALTH EFFECTS

the informa tion presented if the analytical methods used would differentiate between phenol and

pentachlorophenol.

An increased susceptibility to Streptococcus zooepidemicus aerosol was not ob served in mice exposed to

5 ppm phenol for 3 hours, or for 5 daily 3 -hour periods (Aranyi et al. 1986). Neither did the phenol

exposures affect pulmonary bactericidal activity towards Klebsiella pneumonia . Although tests for

vulnerability to infectious a gents do not represent a comprehensive evaluation of immunological

competence, the 5 -ppm level can be considered a NOAEL for this specific immunological effect, and is

recorded in Table 3-1 and plotted in Figure 3-1. Gross and microscopic examination of t he spleen of rats

exposed nose-only to up to 25 ppm phenol intermittently for 2 weeks did not reveal any significant

exposure-related alterations (Hoffman et al. 2001). This exposure concentration is listed as a NOAEL for

lymphoreticular effects in Table 3-1.

3.2.1.4 Neurological Effects

Historical information in a case report (Merliss 1972) indicates that ‘carbol marasmus’ was a common

occupational disorder of physicians and their assistants during the mid-19th Century. Among the

characteristics of this disorder were anorexia, headache, and vertigo. The author reported that his patient,

the subject of the case report, showed many of the symptoms of this condition, although his chief

complaints were weakness and muscle pain in his arms and legs, progressive weight loss, and excess

production of saliva. The symptoms lessened when the subject was removed from the site of exposure.

Although it is possible that these symptoms resulted from injury to the muscle, it is more likely that they

represent a neurological effect. No information on exposure concentrations was presented; however, the

report indicated that the patient often detected heavy odors and that phenol was often spilled on his

clothes resulting in skin irritation. Since phenol is absorbed readily from the skin, dermal absorption may

have contributed to the systemic effects that were observed.

A case -control study of office workers was conducted by Baj et al. (1994) to evaluate the risks of chronic

exposures to “inha led formaldehyde, phenol and isomers of organic chlorohydrocarbons from

KsylamitTM” which is a widely used liquid wood preservative. Twenty -two workers (18 women and

4 men) exposed for at least 6 months were the cases, and 29 non- exposed, nonsmoking volunt eers

matched for age, sex, and place of residence were the controls. The workers complained of a variety of

chronic symptoms, among them headache and fatigue. Measurement of the office air at the end of the

6 month period revealed a level of phenol of 0.34 ppm. Although these symptoms could be a sign thatPHENOL 42

3. HEALTH EFFECTS

chronic inhalation exposure to phenol could adversely affect the neurological system, it is important to

consider not only that other volatile chemicals, chlorinated organics, were present in the wood -p reserving

liquid, but also that the chemical composition provided for KsylamitTM opens up the possibility that the

effects being evaluated resulted from exposure to pentachlorophenol rather than phenol. This is

particularly true since it was not possible t o determine from the information presented if the analytical

methods used would differentiate between phenol and pentachlorophenol.

Female Harlan Wistar rats exposed for 1 or 8 hours to 234 ppm phenol delivered in an aerosol

demonstrated no neurological e ffects at 1 hour, a slight loss of coordination with spasm of the muscle

groups at 4 hours, and frank tremors leading to a severe loss of coordination by 8 hours (Flickinger 1976).

All animals were normal by postexposure day 1, and no abnormal lesions were observed upon gross

autopsy performed at the end of a 14- day observation period. These exposure levels are recorded in

Table 3-1 and are plotted in Figure 3- 1 as a NOAEL, a less serious LOAEL, and a serious LOAEL.

Rats exposed continuously to 26 ppm sh owed numerous symptoms and signs of neurological impairment,

including muscle tremors, twitching, and disturbances in walking rhythm and posture during the first 3–

5 days of exposure, and impaired performance (4.4° decrease in sliding angle) on a tilting p lane test after

15 days of exposure (Dalin and Kristoffersson 1974). These effects are indicative of neurological

impairment. Because the tremors did not last during the whole exposure period, the effects were not

considered severe.

Hindlimb paralysis was reported in guinea pigs exposed to 26–52 ppm phenol for 41 days (Deichmann et

al. 1944). Rabbits and rats exhibited no overt neurological effects after 88 and 74 days of similar

exposure, respectively. Since only a range was given for the exposure lev el (26

– 52 ppm), the exact level

of phenol in air that resulted in hindlimb paralysis was not established and may be as low as 26 ppm or as

high as 52 ppm. Interpretation of this study is further complicated by an apparent lack of controls.

However, the n eurological effect was so severe in the guinea pigs that it is difficult to ascribe the effects

to any source other than the phenol exposure. The lower limit of the exposure range, 26 ppm, is recorded

in Table 3- 1 and plotted in Figure 3- 1 as a LOAEL for serious neurological effects in guinea pigs. Since

the presence or absence of overt neurological effects such as paralysis is not a sensitive end point for

detecting neurological effects, 26–52 ppm is not considered a reliable NOAEL for neurological effec ts in

rats and rabbits.PHENOL 43

3. HEALTH EFFECTS

There are several differences in the experimental designs of the Dalin and Kristoffersson (1974) and

Deichmann et al. (1944) studies that may account for the different results regarding neurological effects in

rats. Dalin and Kr istoffersson (1974) reported subtle effects that may have been overlooked in the

Deichmann et al. (1944) study. Furthermore, Dalin and Kristoffersson (1974) subjected the rats to a

specific test for neurological impairment, the tilting plane test. Althou gh exposure concentrations were

the same in both studies, Dalin and Kristoffersson (1974) exposed rats continuously, while Deichmann et

al. (1944) exposed rats intermittently. Because phenol is metabolized quite rapidly (see Section 3.4.3),

rats exposed i ntermittently may not develop neurological effects.

Histopathological changes in the brain were not observed in Rhesus monkeys, rats, or mice exposed

continuously to 5 ppm phenol in air for 90 days (U.S. Air Force 1961).

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

each species for acute and intermediate

- duration exposure are recorded in Table 3-1 and plotted in

Figure 3-1.

3.2.1.5 Reproductive Effects

The only relevant information located is that from a retrospective study of pregnancy outcome among

university laboratory employees in Sweden (Axelsson et al. 1984). No significant increase in the rate of

miscarriage was found in a group of 576 women exposed to organic solvent relative to 576 unexpo sed

pregnancies. Specific mention of phenol was reported in only five cases, all of which were normal

deliveries. No relevant information was found in animal inhalation studies.

3.2.1.6 Developmental Effects

Neither perinatal death rates nor prevalence of malformations were significantly increased in the study of

laboratory workers conducted by Axelsson et al. (1984) mentioned above. An abstract by Hernberg et al.

(1983) on data from personal interviews of 1,047 Finnish mothers exposed to disinfecta nts (including

phenol) during early pregnancy did not indicate significant associations between exposure to disinfectants

and the occurrence of congenital defects. No further relevant information in humans was located. No

developmental inhalation studies in animals were located.PHENOL 44

3. HEALTH EFFECTS

3.2.1.7 Cancer

In a nested case

- control study of cancers associated with chemical exposures in the wood industry,

Kauppinen et al. (1986) found a significantly increased risk of respiratory system cancer associated with

exposure to phenol and phenol in wood dust. As is often the case in occupational settings, these

exposures were confounded by smoking and exposures to other materials like pesticides; in addition,

information on direct phenol measureme nts was not provided. The increased risk observed for exposure

to phenol was almost 5-fold (odds ratio of 4.94), but showed no dose- related increase. This risk dropped

to 4-fold with adjustments for smoking history, and <3- fold (and non

- significant) when workers exposed

to both phenols and pesticides were excluded from the analysis.

Similar to the findings of Kauppinen et al. (1986), a large (14,861) cohort mortality study of workers in

the phenol-formaldehyde resin manufacturing industry found nondose-r elated increases in the risk of

several respiratory system cancers in workers exposed to phenol (Dosemeci et al. 1991). The authors

develop a semiquantitative exposure assessment by assigning exposure levels (none, low, medium, and

high) to each job categ ory. The increased risks were small; for instance, for cancer of the larynx or lung,

standard mortality ratios (SMRs) of 1.1 were less than those found for non-exposed workers. For a

number of other cancers, including those of the esophagus, rectum, bladder, kidney, and Hodgkin’s

disease, the SMRs found for phenol

- exposed workers were slightly elevated, but none of the increases

were statistically significant when compared with those in the general population. Furthermore, none of

these increases had dos e-response relationships with cumulative exposure to phenol.

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

3.2.2 Oral Exposure

3.2.2.1 Death

There have been numerous reports of s uicide or suicide attempts involving ingestion of large amounts of

phenol. However, the lack of accurate documentation of dose levels in these cases makes it difficult to

identify a minimal dose at which lethality occurs. Deichmann and Keplinger (1981), in summarizing the

literature, indicated that an oral dose as low as 1 g could be fatal in humans, but that occasionally patients

had survived doses as high as 65 g. Assuming that these patients were male with an average weight of

70 kg, the lower limit o n the dose for death would be 14 mg/kg and the upper limit would bePHENOL 45

3. HEALTH EFFECTS

approximately 930 mg/kg. In a review of the toxicology of phenol, Bruce et al. (1987) summarized

human oral lethality data from numerous case reports and estimated 140 mg/kg to be the min imal dose at

which death occurs. Stajduhar-Caric (1968) reported a case in which a woman ingested ≈10 –20 g of

phenol and died within hours. The lower limit of the ingested dose was converted to 172 mg/kg,

assuming a 58 kg body weight, to derive a dose fo r death, which is recorded in Table 3-2 and plotted in

Figure 3-2. Boatto et al. (2004) described the case of a male who ingested a solution containing phenol

and cresol and died approximately 30 minutes after ingestion. Toxicology tests revealed that th e stomach

content, blood, and urine of the individual contained 115.0, 58.3, and 3.3 μg/mL of phenol, respectively.

Similar blood concentrations (56–130 μg/mL) were measured in fatal cases reported by Tanaka et al.

(1998), Soares and Tift (1982), and Lo Dico et al. (1989).

The oral LD 50 has been determined in rats treated by gavage with phenol in water; the LD 50 was found to

decrease with increasing concentration of phenol in the gavage fluid. The reported LD 50 values were

340 mg/kg in rats gavaged with a solution of 200,000 ppm phenol and 530 mg/kg in rats gavaged with a

solution of 20, 000 ppm phenol (Deichmann and Witherup 1944). After rats were treated by gavage with

600 mg/kg in a 5% solution, 9 of 30 5- week -old rats, 18 of 20 10-day-old rats, and 12 of 20 adult rats died

indicating that the 10 -day-old rat is more sensitive to phenol than rats in the other age groups tested

(Deichmann and Witherup 1944). In pregnant rats treated on gestation days (GDs) 6–15, 7 of 10 rats died

at a dose of 125 mg/kg/day when treated with a volume of 1 mL/kg, while 1 of 6 rats died at a dose of

160 mg/ kg/day when treated with a volume of 5 mL/kg (NTP 1983a). In a 1-day dosing regimen study,

female rats were given 0, 12, 40, 120, or 224 mg/kg in order to determine a single-dose oral LD 50 of

400 mg/kg (Berman et al. 1995). Mortality was observed only at the highest dose where two of eight rats

treated died. All female rats treated for 14 days with a dose of 120 mg/kg/day died (Berman et al. 1995;

Moser et al. 1995). In a 14-day dosing regimen with the same doses (except the 224 mg/kg), all animals

died at the dose of 120 mg/kg.

The oral LD 50 of phenol has been estimated as 300 mg/kg in mice (von Oettingen and Sharpless 1946).

Five of 10 rabbits treated with an oral dose of 420 mg/kg died (Deichmann and Witherup 1944). In

pregnan t mice treated on GDs 6–15, four of 35 mice died at a dose of 280 mg/kg/day (NTP 1983b).

Flickinger (1976) gave male Harlan

- Wistar albino rats single doses of 0, 200, 398, 795, and 1,580 mg/kg

phenol by gavage and held the animals for 14 days postdosing i n order to determine an oral LD 50 . No

animals died following the 0, 200, or 398 mg/kg doses; four of five animals died the first day following059172115400119120073340166125100280104300075420Table 3-2 Levels of Significant Exposure to Phenol - OralaKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)ACUTE EXPOSUREDeath1Human onceSystemNOAEL(mg/kg/day)Less Serious(mg/kg/day)LOAELSerious(mg/kg/day)172 F (death)ReferenceChemical FormStajduhar-Caric 1968Comments2Rat(Fischer- 344)once(GW)400 F(LD50)Berman et al. 19953Rat(Fischer- 344)14 d1 x/d(GW)120 F(8/8 died)Berman et al. 1995Dosing volume was 1mL/kg.4Rat(Wistar)once(GW)340 (LD50)Deichmann and Witherup 19445Rat(CD)10 dGd 6-151 x/d(GW)125 F (7/10 maternal deaths)NTP 1983aDosing volume was 1mL/kg.6Mouse(CD-1)10 dGd 6-151 x/d(GW)280 F (4/35 maternal deaths)NTP 1983bDosing volume was 10mL/kg.7Mouse(NS)once(GO)300 M (5/10 deaths)Von Oettingen and Sharpless19468Rabbit(White)once(GW)420 (5/10 deaths)Deichmann and Witherup 194411722412022412022422412040124040401954040Table 3-2 Levels of Significant Exposure to Phenol - Oral(continued)Exposure/Duration/aKey toSpeciesFrequencyFigure(Strain)(Route)Systemic9Rat once(Fischer- 344)(GW)10Rat14 d1 x/d(Fischer- 344)(GW)11Rat14 dGd 6-19(Fischer- 344)(GW)SystemHepaticRenalEndocrBd WtHepaticRenalEndocrBd WtRespBd WtLOAELNOAEL(mg/kg/day)Less Serious(mg/kg/day)Serious(mg/kg/day)ReferenceChemical FormComments224 FBerman et al. 1995Dosing volume was 1mL/kg.120 F224 F (renal tubular necrosis,protein casts, papillaryhemorrhage)120 F224 F (unspecified changes inthe adrenal gland)224 F40 FBerman et al. 1995Dosing volume was 1mL/kg.12 F40 F (renal tubular necrosis,protein casts, papillaryhemorrhage in 3/8)40 F40 F40 F (dyspnea, rales)Narotsky and Kavlock 1995Dosing volume was 1mL/kg.40 F (20% decrease inmaternal body weightgain)16812012025760120140265171280140280118120224Table 3-2 Levels of Significant Exposure to Phenol - Oral(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(mg/kg/day)Less Serious(mg/kg/day)LOAELSerious(mg/kg/day)ReferenceChemical FormComments12Rat(CD)10 dGd 6-151 x/d(GW)Hepatic120 FNTP 1983aDosing volume was 5mL/kg.Bd Wt120 F13Rat(SpragueDawley)10 dGd 6-153 x/d(GW)Bd Wtb60 F120 F (11% reduced maternalbody gain on Gd 6-16)York 1997Dosing volume was 10mL/kg.14Mouse(Swiss CD-1)onceGd 13(GW)Hemato265 F(30-60% reduction in theratio of poly/normochromatic erythrocytes inthe bone marrow ofpregnant dams)Ciranni et al. 198815Mouse(CD-1)10 dGd 6-151 x/d(GW)Hepatic280 FNTP 1983bDosing volume was 10mL/kg.Bd Wt140 F280 F (67% decrease inabsolute maternal bodyweight gain)Immuno/ Lymphoret16Rat(Fischer- 344)once(GW)120 F224 F(necrosis or atrophy ofthe spleen or thymus)Berman et al. 1995Dosing volume was 1mL/kg.12140105207190401201931240101701402801964053.3Table 3-2 Levels of Significant Exposure to Phenol - Oral(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemLOAELNOAEL(mg/kg/day)Less Serious(mg/kg/day)Serious(mg/kg/day)ReferenceChemical FormComments17Rat(Fischer- 344)14 d1 x/d(GW)Berman et al. 199540 FNOAEL is for weightand histopathology ofthe spleen.Neurological18Rat(SpragueDawley)once(G)Liao and Oehme 1981207 M (muscle twitching,convulsions, coma)Dosing volume notreported.19Rat(Fischer- 344)once(GW)Moser et al. 199540 F120 F (mild-to-severewhole-body tremors,decreased motor activity)Dosing volume was 1mL/kg.20Rat(Fischer- 344)14 d1 x/d(GW)Moser et al. 199512 F 40 F (increased rearing)Dosing volume was 1mL/kg.21Mouse(CD-1)10 dGd 6-151 x/d(GW)Developmental22Rat(Fischer- 344)14 dGd 6-19(GW)NTP 1983b70 F 140 F (mild tremors on the first3 days of dosing)280 F (tremors, ataxia inpregnant dams)Narotsky and Kavlock 199540 F53.3 F (significant decrease inthe number of live-bornpups, associated withsevere respiratory effectsin the dams)Dosing volume was 10mL/kg.Dosing volume was 1mL/kg.10360120254120360046140280Table 3-2 Levels of Significant Exposure to Phenol - Oral(continued)Exposure/LOAELDuration/aFrequencyKey to SpeciesNOAEL Less SeriousSerious(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)23Rat 10 d60 F 120 F (7% decrease in averageGd 6-15(CD)fetal body weight)1 x/d(GW)24Rat 10 d120 360 (decreased fetal weightGd 6-15(Sprague-and decrease ossification3 x/dDawley)sites)(GW)25Mouse 10 d140 F280 FGd 6-15(CD-1)1 x/d(GW)(18% decreased fetalbody weight, cleft palate8/214)ReferenceChemical FormCommentsNTP 1983aDosing volume was 5mL/kg.York 1997Dosing volume was 10mL/kg.NTP 1983bDosing volume was 10mL/kg.1981694169416941694169416941694169446750815561694251321321321Table 3-2 Levels of Significant Exposure to Phenol - Oral(continued)Exposure/Duration/aKey toSpeciesFrequencyFigure(Strain)(Route)INTERMEDIATE EXPOSURESystemic26Rat 13 wkad lib(Fischer- 344)(W)27Rat10 wk2-gen(Spraguead libDawley)(W)SystemRespCardioGastroMusc/skelHepaticRenalEndocrDermalBd WtHematoHepaticRenalLOAELNOAEL(mg/kg/day)Less Serious(mg/kg/day)Serious(mg/kg/day)ReferenceChemical FormComments1694 FNCI 1980NOAELs are for organweight andhistopathology.1694 F1694 F1694 F1694 F1694 F1694 F1694 Fc467 M508 F1556 M (16% decrease in bodyweight gain associatedwith decreased waterintake)1694 F(26% decrease in bodyweight gain associatedwith decreased waterintake)321 FRyan et al. 2001NOAELs are forhistopathology of liverand kidney.321 F321 F16133.633.61.833.633.633.6Table 3-2 Levels of Significant Exposure to Phenol - Oral(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(mg/kg/day)Less Serious(mg/kg/day)LOAELSerious(mg/kg/day)ReferenceChemical FormComments28Mouse(CD-1)28 dad lib(W)Resp33.6 MHsieh et al. 1992NOAELs are forhistopathology.Cardio33.6 MHemato1.8 M (32% decrease in RBCcount)HepaticRenal33.6 M33.6 MBd Wt33.6 M2032642264226422642264226422642264274124682503210151.86.2Table 3-2 Levels of Significant Exposure to Phenol - Oral(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(mg/kg/day)Less Serious(mg/kg/day)LOAELSerious(mg/kg/day)ReferenceChemical FormComments29Mouse(B6C3F1)13 wkad lib(W)Resp2642 FNCI 1980NOAELs are for organweight andhistopathology.Cardio2642 FGastro2642 FMusc/skel2642 FHepatic2642 FRenal2642 FEndocr2642 FDermal2642 FBd Wt741 M2468 M (80% decrease in bodyweight gain associatedwith decreased waterintake)Immuno/ Lymphoret30Rat(SpragueDawley)10 wkad lib(W)321 FRyan et al. 2001NOAEL is for spleenand thymus histologyand antibodyproduction againstimmunization withSRBC.31Mouse(CD-1)28 dad lib(W)1.8 M6.2 M (decreased antibodyproduction response toSRBC)Hsieh et al. 19922551073600141.8201155616942483013212062468264224993321Table 3-2 Levels of Significant Exposure to Phenol - Oral(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemLOAELNOAEL(mg/kg/day)Less Serious(mg/kg/day)Serious(mg/kg/day)ReferenceChemical FormCommentsNeurological32Rat(SpragueDawley)13 wkad lib(W)Beyrouty 1998107 F 360 F (decreased motor activityon week 4)33Mouse(CD-1)28 dad lib(W)Hsieh et al. 19921.8 M (decreased levels ofdopamine in the corpusstriatum)Reproductive34Rat(Fischer- 344)13 wkad lib(W)NCI 1980c1556 M1694 FNOAEL is forhistopathology ofreproductive organs.35Rat(SpragueDawley)10 wk2-genad lib(W)Ryan et al. 2001c301 M321 FNOAEL is for P malessperm parameters andF1 reproductive organhistology.36Mouse(B6C3F1)13 wkad lib(W)NCI 1980c2468 M2642 FNOAEL is forreproductive organhistopathology.Developmental37Rat(SpragueDawley)10 wk2-genad lib(W)Ryan et al. 200193 F321 F (decreased pup weightand percent live on day4)050721721721721721721721721322721Table 3-2 Levels of Significant Exposure to Phenol - Oral(continued)Exposure/Duration/aKey toSpeciesFrequencyFigure(Strain)(Route)CHRONIC EXPOSURESystemic38Rat 103 wkad lib(Fischer- 344)(W)SystemRespCardioGastroMusc/skelHepaticRenalEndocrDermalBd WtLOAELNOAEL(mg/kg/day)Less Serious(mg/kg/day)Serious(mg/kg/day)ReferenceChemical FormComments721 FNCI 1980NOAELs are for organweight andhistopathology.721 F721 F721 F721 F721 F721 F721 Fc322 M (about 12% decrease inbody weight associatedwith a 20% decrease inwater intake)721 F(about 17% decrease inbody weight associatedwith a 10% decrease inwater intake)2121204120412041204120412041204120412042077212131204208721Table 3-2 Levels of Significant Exposure to Phenol - Oral(continued)Exposure/Duration/aKey toSpeciesFrequencyFigure(Strain)(Route)39Mouse103 wk(B6C3F1)ad lib(W)Immuno/ Lymphoret40Rat 103 wkad lib(Fischer- 344)(W)41Mouse103 wk(B6C3F1)ad lib(W)Neurological42Rat 103 wkad lib(Fischer- 344)(W)SystemRespCardioGastroMusc/skelHepaticRenalEndocrDermalBd WtLOAELNOAEL(mg/kg/day)Less Serious(mg/kg/day)Serious(mg/kg/day)ReferenceChemical FormComments1204 FNCI 1980NOAELs are for organweight andhistopathology.1204 F1204 F1204 F1204 F1204 F1204 F1204 F1204 F721 FNCI 1980NOAEL is for weightand histopathology oflymphoreticular organsand tissues.1204 FNCI 1980NOAEL is for weightand histopathology oflymphoreticular organs.Immuno competencewas not evaluated.721 FNCI 1980NOAEL is for weightand histopathology ofthe brain.21412042097212151204Table 3-2 Levels of Significant Exposure to Phenol - Oral(continued)aKey toFigureSpecies(Strain)Exposure/Duration/Frequency(Route)SystemNOAEL(mg/kg/day)Less Serious(mg/kg/day)LOAELSerious(mg/kg/day)ReferenceChemical FormComments43Mouse(B6C3F1)103 wkad lib(W)1204 FNCI 1980NOAEL is for weightand histopathology ofthe brain.Reproductive44Rat(Fischer- 344)103 wkad lib(W)721 FNCI 1980NOAEL is for weightand histopathology ofreproductive organs ofmales and females.Fertility was notassessed.45Mouse(B6C3F1)103 wkad lib(W)1204 FNCI 1980NOAEL is for weightand histopathology ofreproductive organs ofmales and females.Fertility was notassessed.a The number corresponds to entries in Figure 3-2.b Used to derive an acute-duration oral MRL of 1 mg/kg/day; the MRL was derived by dividing the BMDL of 125 mg/kg/day by an uncertainty factor of 100 (10 for animal to humanextrapolation and 10 for human variability).c Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-2. Where such differences exist, only the levels of effect for themost sensitive gender are presented.ad lib = ad libitum; Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = Female; (G) = gavage; Gastro = gastrointestinal; gd = gestational day; gen =generation; Gn pig = guinea pig; (GO) = gavage in oil; (GW) = gavage in water; Hemato = hematological; hr = hour(s); Immuno = immunological; LD50 = lethal dose, 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; RBC = red bloodcell; Resp = respiratory; SRBC = sheep red blood cells; x = time(s); (W) = drinking water; wk = week(s); yr = year(s)Death Respiratory Hematological Hepatic Renal Endocrine Body Weight Immuno/Lymphor Neurological Developmental

1000 

### Figure 3-2 Levels of Significant Exposure to Phenol - Oral

Acute (≤14 days)

Systemic

mg/kg/day

8h 4r 2r 24r 7m 6m 15m 15m 21m 25m
9r 14m 9r 9r 9r 16r 18r 1 15m 21m 25m 5r 3r 12r 9r 9r 12r 13r 16r 19r 23r 24r 100

21m 13r 23r 22r

11r 10r 10r 10r 10r 11r 17r 19r 20r 22r

10r 20r 10

1

0.1

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50 Minimal Risk Level for effects other than CancerRespiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Endocrine Dermal Body Weight Immuno/Lymphor Neurological Reproductive Developmental

10000 Renal 

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

Intermediate (15-364 days)

Systemic

mg/kg/day

29m 29m 29m 29m 29m 29m 29m 29m 29m 36m

26r 26r 26r 26r 26r 26r 26r 26r 26r 26r 34r

1000

29m

26r

32r 27r 27r 27r 30r 37r 35r

32r 100 37r

28m 28m 28m 28m 28m

10

31m

28m 31m 33m

1

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50 Minimal Risk Level for effects other than CancerRespiratory Cardiovascular Gastrointestinal Musculoskeletal Hepatic Endocrine Dermal Body Weight Immuno/Lymphor Neurological Reproductive Renal 

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

Chronic (≥365 days)

Systemic

mg/kg/day

10000

39m 39m 39m 39m 39m 39m 39m 39m 39m 41m 43m 45m

1000

38r 38r 38r 38r 38r 38r 38r 38r 40r 42r 44r

38r

100

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50

for effects other than Cancer Minimal Risk LevelPHENOL 61

3. HEALTH EFFECTS

the 795 mg/kg dose, and five of five animals died within 2 hours following 1,580 mg/kg dose. F rom

these data, the investigators estimated an oral LD 50 of 650 mg/kg.

No effect on survival was observed in mice treated with phenol in the drinking water at doses up to

33.6 mg/kg/day for 28 days (Hsieh et al. 1992). Survival was not affected in rats and mice treated with

phenol in drinking water for 13 or 103 weeks (NCI 1980). Both species were treated with drinking water

concentrations up to 10,000 mg/L in the 13-week study (maximum doses in mg/kg/day: 1,694 for female

rats, 1,556 for male rats; 2,6 43 for female mice, 2,468 for male mice), and up to 5,000 mg/L in the

103-week study (maximum doses in mg/kg/day: 721 for female rats, 645 for male rats; 1,204 for female

mice, 1,180 for female mice).

In most studies, a specific cause of death was not re ported, but common signs preceding death included

convulsions, coma, and respiratory arrest. The LD 50 values and doses resulting in death from each

reliable study in each species in the acute

- duration category are recorded in Table 3-2 and plotted in

Figu re 3-2.

3.2.2.2 Systemic Effects

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

species and duration category are recorded in Table 3-2 and plotted in Figure 3-2.

Respiratory Effects. Stajduhar-Caric (1968) reported on a case in which a woman who ingested

approximately 10–20 g of phenol, became comatose and died within a matter of hours. During the course

of the poisoning and treatment, initially an in crease in respiration was observed, then irregularities in

breathing, and finally cessation of respiration. An autopsy revealed marked hyperemia of the tracheal and

bronchial mucous membranes, as well as pulmonary edema. According to Deichmann and Keplin ger

(1981), the progression of impacts on the respiratory system summarized above are typical of oral

poisonings in humans, although often the intermediate stages are characterized by a decrease in

respiration rate and magnitude. According to these author s, in acute intoxication, death usually results

from respiratory failure. Pulmonary congestion and edema were reported in a man who died following

phenol poisoning (Soares and Tift 1982). In another case of fatal ingestion of phenol, autopsy reported

whi te froth in the nostrils, upper airway, trachea, and bronchi as well as edema and fluid in the lungs (Lo

Dico et al. 1989). Inflammatory changes in the lungs also were observed in a more recent fatal case of

ingestion of phenol (Tanaka et al. 1998).PHENOL 62

3. HEALTH EFFECTS

Dys pnea and rales were observed in pregnant rats treated by gavage with phenol in water on GDs 6– 19

(Narotsky and Kavlock 1995). The respiratory effects were observed at both 40 and 53.3 mg/kg/day.

Gross pathological examinations did not reveal any adverse changes in the lungs of mice treated with

phenol in drinking water at doses of 1.8, 6.2, or 33.6 mg/kg/day for 28 days (Hsieh et al. 1992).

In a study reported by the National Cancer Institute (NCI 1980), rats exposed to 16–1,694 mg/kg/day

(100–10,000 mg /L) and mice exposed to 25–2,642 mg/kg/day (100–10,000 mg/L) phenol in drinking

water exhibited no indication of histopathological effects on the respiratory system after 13 weeks of

exposure. No histological abnormalities of the respiratory tract were ob served in rats or mice exposed to

2,500 or 5,000 ppm phenol in drinking water for 103 weeks (mg/kg/day doses: 322 or 645 for male rats;

360 or 721 for female rats; 590 or 1,180 for male mice; 602 or 1,204 for female mice) (NCI 1980).

Cardiovascular Effec ts. In a recent report on the clinical treatment of phenol poisoning, Langford

et al. (1998) provide a summary of a case report in which a woman accidentally consumed an ounce of

89% phenol that had mistakenly been given to her in preparation for an in- office procedure. Her

immediate reaction upon consuming the phenol was to clutch her throat and collapse, and within

30 minutes, she was comatose and had gone into respiratory arrest. Treatment was initiated with an

endotracheal intubation. Ventilation with a bag and mask led to the detection of a lamp oil odor. Within

an hour, she developed ventricular tachycardia, which responded to cardioversion; however, she

subsequently developed (in the first 24 hours) supraventricular and ventricular dysrhythmia s, metabolic

acidosis, and experienced a grand mal seizure. After a 15

- day hospital stay, she was completely

recovered with no evidence of impaired motility or compromised gastrointestinal or cardiovascular

systems.

Gross pathological examinations did no t reveal any adverse changes in the hearts of mice treated with

phenol in drinking water at doses of 1.8, 6.2, or 33.6 mg/kg/day for 28 days (Hsieh et al. 1992). In a

study reported by the NCI (1980), rats exposed to 16–1,694 mg/kg/day (100–10,000 ppm) an d mice

exposed to 25 –2,642 mg/kg/day (100–10,000 ppm) phenol in drinking water exhibited no indication of

histopathological effects on the heart after 13 weeks of exposure. Histological abnormalities of the heart

were not evident in rats after 103 weeks o f exposure to 322 or 645 mg/kg/day for males or 360 or

721 mg/kg/day for females (2,500 or 5,000 ppm) or in mice after exposure to 590 or 1,180 mg/kg/day for

males or 602 or 1,204 mg/kg/day for females (2,500 or 5,000 ppm). Cardiovascular function was not

evaluated in these studies.PHENOL 63

3. HEALTH EFFECTS

Gastrointestinal Effects. In a study on the clinical treatment of phenol poisoning, Langford et al.

(1998) provide a summary of a case report in which a woman accidentally consumed an ounce of 89%

phenol that had mistakenly been given to her in preparation for an in- office procedure. Her immediate

reaction upon consuming the phenol was to clutch her throat and collapse, and within 30 minutes, she was

comatose and had gone into respiratory arrest. Treatment was initiated wi th an endotracheal intubation,

which revealed her mouth and hypopharynx to be white. Esophagitis and upper gastrointestinal bleeding

occurred in the first week, and an examination of the esophagus on day 8 revealed hyperkeratosis,

erythema, and a friable mucosa. After a 15-day hospital stay, she was completely recovered with no

evidence of impaired motility or compromised gastrointestinal system. A male who ingested a solution

containing phenol and cresol and eventually died did not show macroscopic lesi ons of the esophagus and

stomach, but histological examination revealed exfoliation of the mucosa of the esophagus and

coagulative necrosis of the gastric mucosa (Boatto et al. 2004). Coagulation of the gastric mucosa was

also reported in a fatal case of poisoning with phenol (Soares and Tift 1982). Erosive duodenal gastritis

was also observed in a woman who ingested about 70 mL of a 42–52% phenol solution (Kamijo et al.

1999). Other fatal cases have described m ucous changes in the digestive organs (Tana ka et al. 1998) and

crusted corrugated appearance of the stomach (Lo Dico et al. 1989).

In a retrospective study of 158 persons exposed to phenol in drinking water for several weeks following

an accidental spill of phenol, significantly (p<0.01) increased gastrointestinal symptoms (mouth sores,

nausea, diarrhea) were reported by 17 of the 39 most highly-exposed individuals (Baker et al. 1978).

Exposure concentrations for the most highly-exposed group were >0.1 mg/L, and the study authors

estimated phenol intake during this period as 10–240 mg/person/day (0.14–3.4 mg/kg/day assuming a

70-kg body weight). Symptom rates were not increased among 61 persons exposed to concentrations of

≤0.1 mg/L (0.003 mg/kg/day assuming 2 L water per day and a 70 -kg body weight). Dermal exposure

was not considered in these estimates of dose. A similar study was conducted by Jarvis et al. (1985)

among 344 English households whose drinking water contaminated with phenol. An unexposed group

(250 households) served as control. The day of the contamination incident, the concentration of phenol in

a high -exposure area (250 households) was estimated to be 10 μg/L, whereas in a low -exposure area

(94 househol ds), the concentration was 4.7 μg/L. The day after the incident, the phenol concen tration in

the water from both areas was 4.7 μg/L, and 2 days after the incident, it was 0.9 μg/L. Chlorophenols,

which formed upon chlorination of the water, were detected at a higher concentration of phenol and

followed a similar pattern as phenol. Since the concentration of phenol and chlorophenols were similar in

the two exposed areas, the two exposed areas were combined in the analysis. Exposed individuals hadPHENOL 64

3. HEALTH EFFECTS

signi ficantly higher incidences of gastrointestinal illness (i.e., diarrhea, nausea, vomiting, and abdominal

pain) than the unexposed group, and the onset of symptoms coincided with the period of elevated

concentrations of phenol in the drinking water. Moreove r, stronger associations were observed among

those who reported drinking the water in the exposed areas than among those who reported not drinking

the water in the same areas. The specific contribution of phenol to the adverse signs and symptoms

reported is difficult to determine.

A case control study of 6,913 individuals living near a Korean river contaminated with 30 tons of 100%

phenol found nausea, vomiting, diarrhea, and abdominal pain among 1,824 exposed subjects compared to

1,064 unexposed subjects (Kim et al. 1994). The level of phenol measured in the two reservoirs that

served the community was 0.05 mg/L after the spill, while that in the chlorinated tap water was

0.0084 mg/L.

In a study reported by the NCI (1980), rats exposed up to 1,694 mg/ kg/day and mice exposed up to

2,642 mg/kg/day phenol in drinking water exhibited no indication of histopathological effects on the

gastrointestinal system after 13 weeks of exposure. No histological abnormalities of the gastrointestinal

tract were observe d in rats or mice exposed to phenol in drinking water that provided doses of

approximately 720 and 1,200 mg/kg/day, respectively, for 103 weeks (NCI 1980).

Hematological Effects. No studies were located regarding hematological effects in humans

following oral exposure to phenol.

A 30 –60% decrease in the ratio of polychromatic to normochromatic erythrocytes was observed in the

bone marrow of pregnant mice treated by gavage with a single dose of 265 mg/kg phenol in water on

GD 13 (Ciranni et al. 1988). Dose- related and significant decreases in red blood cell counts were

observed in mice treated with phenol in the drinking water at doses of 1.8, 6.2, or 33.6 mg/kg/day for

28 days (Hsieh et al. 1992). Red blood cell counts in cells x10 6 /mm 3 were 7.17 in controls, 4.9 at the low

dose, 4.64 at the middle dose, and 3.23 at the high dose. A significant decrease in hematocrit was only

observed at the high dose (48% control, 44.1% high dose), and no changes were observed in leucocyte

numbe rs or leucocyte differentials.

No significant alterations in hematology parameters were observed in male or female rats dosed with up

to 301 or 321 mg phenol/kg/day in the drinking water, respectively, for 10 weeks (Ryan et al. 2001).PHENOL 65

3. HEALTH EFFECTS

Musculoskeletal Eff ects. No studies were located regarding musculoskeletal effects in humans

following oral exposure to phenol.

Rats exposed up to 1,694 mg/kg/day and mice exposed up to 2,642 mg/kg/day phenol in drinking water

exhibited no histological abnormalities of t he bone after 13 weeks of exposure (NCI 1980). No

histological abnormalities of the bone were observed in rats or mice up to 721 or 1,204 mg/kg/day,

respectively, of phenol in drinking water for 103 weeks. (NCI 1980).

Hepatic Effects. Serum markers of liver effects, bilirubin, glucose, cholesterol, and AST activity

were not affected in 39 persons exposed to phenol in the drinking water at an estimated dose of 0.14–

3.4 mg/kg/day for several weeks (Baker et al. 1978). Because these examinations were com pleted

7 months after the spill, this study does not provide conclusive evidence that there was no reversible liver

damage. Autopsy of a fatal case of ingestion of phenol revealed substantial toxic changes in the liver

including extension of sinusoid lume ns and an increase in centrilobular increase of cytoplasmic

eosinophility (Tanaka et al. 1998).

Serum markers of liver effects (lactic dehydrogenase, alkaline phosphatase, ALT, bilirubin) and

histopathological changes in the liver were observed in rats gi ven single gavage doses of 224 mg/kg or

14 daily gavage doses of 40 mg phenol/kg in water (Berman et al. 1995). Changes in liver weight were

not observed in pregnant rats treated by gavage with 120 mg/kg/day of phenol in water on GDs 6– 15

(NTP 1983a), or in pregnant mice treated by gavage with 280 mg/kg/day phenol in water on GDs 6– 15

(NTP 1983b).

Gross pathological examinations did not reveal any lesions in mice treated with phenol in the drinking

water at a dose of 33.6 mg/kg/day for 28 days (Hsieh et a l. 1992).

In a study sponsored by the National Cancer Institute (NCI 1980), rats exposed up to 1,694 mg/kg/day

and mice exposed up to 2,642 mg/kg/day phenol in drinking water exhibited no histological abnormalities

of the liver after 13 weeks of exposure. Similar observations were made in rats dosed with up to 301–

321 mg phenol/kg/day in the drinking water for 10 weeks (Ryan et al. 2001). No histological

abnormalities of the liver were observed in rats or mice exposed up to 721 or 1,204 mg/kg/day

respect ively, of phenol in drinking water for 103 weeks (NCI 1980).PHENOL 66

3. HEALTH EFFECTS

Renal Effects. Although not adverse, dark urine (as a result of oxidation products of phenol or a

result of hemoglobin or its breakdown products in the urine) is a common symptom observed in humans

exposed to phenol. In persons exposed to about 0.14–3.4 mg/kg/day phenol in drinking water for several

weeks after an accidental spill, dark urine was reported by 17.9% of the most highly- exposed individuals,

while only 3.4% of the controls reported the effect (Baker et al. 1978). This difference was not

statistically significant. A 3.3

- fold increase in the prevalence of dark urine was reported by persons

exposed to unspecified doses of phenol after an accidental spill in Korea (Kim et al. 1994). Autopsy of an

individual who ingested phenol showed interstitial edema and renal tubular hemorrhage (Tanaka et al.

1998). Extensive renal autolysis was also observed in a fatal case of poisoning with phenol (Soares and

Tift 1982).

Renal tubular necrosis, protein casts, and papillary hemorrhage were not observed in rats treated with a

single gavage dose of 120 mg/kg phenol in water, but were seen in 60% of animals examined at the next

highest dose of 224 mg/kg (Berman et al. 1995). No histopathological changes in the kidney were

observed after 14 daily doses of 12 mg/kg/day, but were observed in 3 of 8 animals given 14 daily doses

of 40 mg/kg/day (Berman et al. 1995).

Gross pathological examinations did not reveal any adverse changes in the kidneys of mice treated with

phenol in drinking water at doses of 1.8, 6.2, or 33.6 mg/kg/day for 28 days (Hsieh et al. 1992).

Rats exposed up to 1,694 mg/kg/day and mice exposed up to 2,642 mg/kg/day of phenol in drinking water

exhibited no ind ication of histopathological effects on the kidney after 13 weeks of exposure (NCI 1980).

Rats exposed to up to 301–321 mg phenol/kg/day in the drinking water for 10 weeks showed no

significant histopathological effects in the kidneys (Ryan et al. 2001).

No compound-related histological changes in the kidneys were observed in rats or mice exposed up to

721 or 1,204 mg/kg/day, respectively, of phenol in drinking water for 103 weeks (NCI 1980). A higher

incidence of inflammation of the kidney was reporte d in male rats exposed to 624 mg/kg/day (96%) than

in controls (74%); however, because of the high incidence of inflammation in the controls, it is impossible

to ascertain whether this was related to the exposure to phenol (NCI 1980). A high age- related i ncidence

of inflammation is expected in male rats of the Fischer -344 strain used in this study. Kidney function,

including glomerular filtration rate and glomerular sieving, however, was not evaluated in this study.

Furthermore, histological examination was limited to standard light microscopic examinations whichPHENOL 67

3. HEALTH EFFECTS

would not have detected functionally significant glomerular abnormalities like disruption of the

glomerular basement membrane or immune complex deposition.

Endocrine Effects. Autopsy of a subject who died following ingestion of a solution containing

phenol showed interstitial hemorrhage in the pancreas and adrenal glands (Tanaka et al. 1998). No

further information regarding effects of phenol on endocrine-related end poi nts was located.

Unspecified microscopic changes were observed in the adrenal glands of rats given a single gavage dose

of 224 mg/kg phenol in water, but no changes were described in rats treated si milarly with doses

≤120 mg/kg/day (Berman et al. 1995). No adrenal gland effects were observed in rats 14 daily gavage

doses of 4, 12, or 40 mg/kg (Berman et al. 1995).

Rats exposed up to 1,694 mg/kg/day and mice exposed up to 2,642 mg/kg/day phenol in d rinking water

exhibited no histopathological changes in the pancreas, pituitary, adrenal glands, thyroid, or parathyroid

after 13 weeks of exposure (NCI 1980). Exposure- related histopathological changes in the pancreas,

pituitary, adrenal glands, thyroid, or parathyroid were also not observed in rats and mice exposed to

2,500 or 5,000 ppm phenol in drinking water for 103 weeks (NCI 1980). Estimated mg/kg/day doses

were 322 or 645 for male rats, 360 or 721 for female rats, 590 or 1,180 for male mice, and 6 02 or

1,204 for female mice.

Dermal Effects. Skin rash and mouth sores were reported in persons living near a site with

contaminated well water resulting from an overturned tanker car carrying 37,900 L of 100% phenol

(Baker et al. 1978). The level of phenol in the drinking water of this cohort was >0.1 mg/L, and while

substantial oral exposure probably occurred, dermal exposure cannot be ruled out. Increases in the

prevalence of skin rashes and sore throats were reported by perso ns drinking water from a river

contaminated by an accidental spill of phenol (Kim et al. 1994). Because the water was chlorinated

before use, the effect may also have been a result of exposure to chlorophenol. Perioral c hemical burns

from phenol were observed in a woman who ingested approximately 70 mL of a 42

– 52% phenol solution

(Kamijo et al. 1999). Spiller et al. (1993) also reported oral and esophageal burns in 17 out of 52 patients

following ingestion of a disinfectant containing 26% phenol.

Rats exposed up to 1,694 mg/kg/day and mice exposed up to 2,642 mg/kg/day phenol in drinking water

exhibited no histopathological changes in the skin after 13 weeks of exposure (NCI 1980). Exposure­PHENOL 68

3. HEALTH EFFECTS

related histopathological changes in the skin were also not o bserved in rats and mice exposed up to 721 or

1,204 mg/kg/day, respectively, phenol in drinking water for 103 weeks (NCI 1980).

Ocular Effects. No studies were located regarding ocular effects in humans or animals following oral

exposure to phenol.

Bo dy Weight Effects. No effects on body weight were observed in rats treated with a single gavage

dose of 224 mg/kg phenol in water or 14 daily gavage doses of 40 mg/kg (Berman et al. 1995; Moser et

al. 1995). Maternal body weight gain was approximately 20% lower in rats treated by gavage with 40 or

53.3 mg/kg/day phenol in water on GDs 6–19 (Narotsky and Kavlock 1995). Maternal body weight gain

was 67% lower than controls in mice treated by gavage with 280 mg/kg/day phenol in water on GDs 6–

15, with no effects on body weight gain observed at 140 mg/kg/day (NTP 1983b). Body weight gain was

not affected in pregnant rats treated by gavage with 120 mg/kg/day phenol in water on GDs 6– 15 (NTP

1983a). Body weight gain was significantly reduced in pregnant rat s dosed with 120 mg phenol/kg/day

on GDs 6

– 15 (11% for GDs 6 –16 and 19% for GDs 12–16) (York 1997). Doses of 360 mg/kg/day

caused a reduction in body weight gain of 38% for GDs 6– 16; the NOAEL for maternal weight gain in

this study was 60 mg/kg/day. The reduction in maternal body weight gain in rats during pregnancy

reported in the York (1997) study was used as the basis for derivation of an acute-duration oral MRL for

phenol.

Body weight was not affected in mice treated with phenol in drinking water at a dose of 33.6 mg/kg/day

for 28 days (Hsieh et al. 1992). During 13-week studies in rats and mice treated with phenol in drinking

water, decreased body weight gain was associated with dose

- related decreases in water intake,

presumably due to taste aversio n (NCI 1980). In rats provided with the highest concentration

(10,000 ppm), body weight gain was decreased by 26% in females at 1,694 mg/kg/day, and by 16% in

males at 1,556 mg/kg/day. An effect on body weight gain was not observed in rats at 3,000 ppm

(467 mg/kg/day for males, 508 mg/kg/day for females). In mice provided with the highest concentration

(10,000 ppm), body weight gain was decreased by 33% in females at 2,642 mg/kg/day, and by 80% in

males at 2,468 mg/kg/day. An effect on body weight gain was not observed in mice at 3,000 ppm

(741 mg/kg/day for males, 793 mg/kg/day for females). A significant decrease in body weight gain

associated with a significant decrease in water consumption was also observed in male and female rats

dosed with 301–321 mg/kg/day phenol in the drinking water for 10 weeks (Ryan et al. 2001).PHENOL 69

3. HEALTH EFFECTS

Decreased mean body weight associated with decreased water intake was also observed in rats in a

103-week study (NCI 1980). At the high concentration (5,000 ppm), body weight was 19 % lower than

controls in males (645 mg/kg/day) and 17% lower than controls in females (721 mg/kg/day). At the low

concentration (2,500 ppm), body weight was 12% lower than controls in males (322 mg/kg/day) and

within 10% of controls in females (360 mg/kg/ day). Body weight was not affected in mice treated with

phenol in drinking water for 103 weeks at doses up to 1,180 for males and up to 1,204 mg/kg/day for

females (NCI 1980).

3.2.2.3 Immunological and Lymphoreticular Effects

No studies were located regarding immunological or lymphoreticular effects in humans following oral

exposure to phenol.

Necrosis or atrophy of the spleen or thymus was observed in four of six rats given a single gavage dose of

224 mg/kg of phenol in water, and one of seven rats given 120 mg/kg/day (Berman et al. 1995). Based on

this effect, which was not further described, the study authors considered 224 mg/kg to be a LOAEL for

immunological effects. One of eight animals given 12 mg/kg/day, and two of eig ht given 40 mg/kg/day

for 14 days showed these same effects.

Hsieh et al. (1992) conducted a 28-day study of the immunotoxicologic impact of phenol in which

CD -1 mice were given drinking water that provided doses of phenol of approximately 0, 1.8, 6.2, or

33.6 mg/kg/day. When challenged with sheep red blood cells (SRBC), a significant decrease was

observed in the splenic concentration of anti -erythrocyte antibody- forming cells and in the anti

erythrocyte antibody titer at the two highest doses, while a significant decrease in the absolute number of

anti

- erythrocyte antibody -forming cells present in the spleen was observed only at the top dose. In

contrast to the results of Hsieh et al. (1992), Ryan et al. (2001) reported no immunologic alterations in

male rats in a drinking water study. Rats were dosed for 10 weeks with up to 301 mg phenol/kg/day and

then immunized intravenously with sheep red blood cells. Eighteen hours later, splenocytes were

prepared in cell culture medium for enumeration of plaque- fo rming cells. Treatment with phenol had no

significant effect on antibody

- forming cells, and there were no significant effects on spleen or thymus

weight, spleen cellularity, or spleen and thymus histology.

Rats exposed up to 1,694 mg/kg/day and mice ex posed up to 2,642 mg/kg/day phenol in drinking water

exhibited no histopathological changes in the bone marrow, spleen, or lymph nodes after 13 weeks ofPHENOL 70

3. HEALTH EFFECTS

exposure (NCI 1980). Exposure-related histopathological changes in the bone marrow, spleen, or lymph

nodes were also not observed in rats or mice exposed to estimated doses of up to 721 or 1,204 mg/kg/day,

respectively, for 103 weeks (NCI 1980).

The highest NOAEL values and all LOAEL values from each reliable study for immunological and

lymphoreticular ef fects in each species and duration category are recorded in Table 3-2 and plotted in

Figure 3-2.

3.2.2.4 Neurological Effects

Headaches were reported 6 times more frequently by persons using drinking water contaminated with

phenol than by controls (Kim et al. 1994). The water was used after chlorination; therefore, chlorophenol

may have contributed to the observed effects. Fine, rapid, rhythmic, perioral movements, as well as signs

of Parkinson’s syndrome were observed in a woman who ingested approximately 70 mL of a 42– 52%

solution of phenol (Kamijo et al. 1999). Central nervous system depression was described in 11 out of

52 patients who ingested amounts ranging from 2 to 90 mL of a disinfectant solution containing 26%

phenol (Spiller et al. 1993).

Acute oral phenol poisoning in rabbits and rats was characterized by muscular tremors in the head region,

which eventually spread to other regions of the body, with the lower extremities being the last affected.

Loss of coordination and convulsions preceded death at doses of 300–940 mg/kg (Deichmann and

Witherup 1944). Liao and Oehme (1981) described tremors of the muscles around the eyes, followed by

convulsions and coma, in rats after a sublethal oral dose of 207 mg/kg phenol. M ild

- to

- severe whole

body tremors and decreased motor activity were reported in rats given a single gavage dose of 120 mg/kg

phenol in water (Moser et al. 1995). A dose of 40 mg/kg resulted in no neurological effects following a

single dose, while increase d rearing was reported following 14 daily doses (Moser et al. 1995). Pregnant

mice treated by gavage with phenol in water on GDs 6–15 exhibited tremors and ataxia at 280 mg/kg/day,

mild tremors on the first 3 days of dosing at 140 mg/kg/day, and no advers e neurological effects at

70 mg/kg/day (NTP 1983b).

In contrast with results from oral gavage studies, phenol administered in the drinking water was much less

toxic. For example, male rats exposed to up to 309 mg phenol/kg/day in the drinking water for 13 weeks

showed no significant alterations in tests of motor activity or a functional observation battery conducted

throughout the exposure period (Beyrouty 1998). However, females dosed with 360 mg phenol/kg/dayPHENOL 71

3. HEALTH EFFECTS

showed a significant reduction in motor activity on week 4 of the study; no significant alterations were

seen in females at 107 mg/kg/day. Gross and microscopic evaluation of the brain, spinal cord, and

peripheral nerves was unremarkable (Beyrouty 1998).

Mice exposed for 28 days to phenol in dr inking water exhibited a significant reduction in dopamine level

in the corpus striatum at the 1.8 mg/kg/day dose, and significantly decreased levels of norepinephrine,

serotonin, and 5-hydroxyindoleacetic acid in the hypothalamus at the 6.2 mg/kg/day dose (Hsieh et al.

1992). Levels of neurotransmitters in other brain regions were also significantly altere d at higher doses of

phenol.

Rats exposed to 16–1,694 mg/kg/day and mice exposed to 25–2,642 mg/kg/day phenol in drinking water

exhibited no abnormal histology of the brain after 13 weeks of exposure (NCI 1980). Histopatho logical

changes in the brain were not evident after 103 weeks of exposure to 322 or 645 mg/kg/day in male rats,

360 or 721 mg/kg/day in female rats, 590 or 1,180 mg/kg/day in male mic e, and 602 or 1,204 mg/kg/day

in female mice (NCI 1980). However, this study did not include tests for neurological impairment or

histopathological examinations of tissues in the nervous system other than the brain.

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

each species and duration category are recorded in Table 3-2 and plotted in Figure 3-2.

3.2.2.5 Reproductive Effects

No studies were located regarding reproductive effe cts in humans following oral exposure to phenol.

No evidence of impaired reproduction was found in rats exposed to phenol in drinking water at

<5,000 ppm (estimated 571 mg/kg/day) for three generations or at <1,000 ppm (estimated

114 mg/kg/day) for five generations (Heller and Pursell 1938). Data regarding breeding habits, controls,

and the methods used to evaluate the rats for reproductive impairment were not reported in sufficient

detail to establish reliable NOAELs or LOAELs for presentation in Table 3-2 and Figure 3-2.

Rats exposed up to 1,694 mg/kg/day and mice exposed up to 2,642 mg/kg/day of phenol in drinking water

exhibited no histopathological changes in the prostate, testes, uterus, or ovaries after 13 weeks of

exposure (NCI 1980). Exposure- re lated histopathological changes in the prostate, testes, uterus, orPHENOL 72

3. HEALTH EFFECTS

ovaries were also not observed in rats or mice exposed up to 721 or 1,204 mg/kg/day, respectively, phenol

in drinking water for 103 weeks (NCI 1980).

In a two

- generation study in which r ats were administered phenol in the drinking water (up to 301–

321 mg/kg/day), there was a significant decrease in absolute seminal vesicle weight in parental males at

301 mg/kg/day and in absolute ovaries weight in parental females at 321 mg/kg/day, but we re no

significant alterations in gross or microscopic appearance of the reproductive organs of males and females

from the parental and F 1 generations (Ryan et al. 2001). In addition, there were no significant effects on

estrus frequency, testicular sperm count, or sperm motility or morphology. Significant reductions in

prostate and uterine weights in all F 1 treated groups were not considered adverse effects of phenol by

Ryan et al. (2001) on the basis of the absence of histological alterations and functio nal reproductive

effects, and based on the fact that only a few animals had organ weights outside the range of concurrent

control values.

Information on the effects of exposure to phenol on the genetic material of germinal cells is presented in

Section 3.3, Genotoxicity.

The highest NOAEL values from each reliable study for reproductive effects in each species and duration

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

3.2.2.6 Developmental Effects

No studies were located regarding developmental effects in humans following oral exposure to phenol.

In a multi-generational study of the effect of various levels of phenol administered orally in water, Heller

and Pursell (1938) saw no effect on growth, reproduction, and normal rearing of young over 5 generations

of rats given concentrations of ≈1,000 mg/L phenol in drinking water (estimated dose of 114 mg/kg/day)

nor over three generations of rats given concentrations of ≈5,000 ppm (estimated dose 571 mg/kg/day).

Phe nol in water was administered to pregnant rats by gavage (5 mL/kg) at dose levels of 0, 30, 60, or

120 mg/kg/day on GDs 6–15 (NTP 1983a). A dose- related decrease in fetal body weight with increasing

dose was observed, with 60 mg/kg/day established as the NOAEL and 120 mg/kg/day as the LOAEL.

The mean reduction in fetal body weight relative to controls was approximately 7%. Concurrent controls

provide the most appropriate comparison for experimental data; however, it is worth noting that thePHENOL 73

3. HEALTH EFFECTS

weights of co ntrol fetuses in this study were 22% higher than those of historical controls. As litter size is

known to influence fetal weight, it is possible that a larger litter size in the high -dose group may have

contributed to the smaller fetal weights in that gro up. The data were not specifically analyzed for that

potential effect. Teratogenic effects were not observed and no signs of maternal toxicity were observed at

any dose level. In a preliminary range -finding study conducted by NTP (1983a), a decrease in maternal

weight gain and an increased incidence of maternal mortality were observed at >160 mg/kg. Tremors, a

typical symptom of phenol toxicity, were also observed.

In a study of the developmental toxicity of phenol and structurally

- related chemicals, K avlock (1990)

examined the effects of 0, 100, 333, 667 and 1,000 mg/kg phenol given by gavage on day 11 of gestation.

Phenol was administered in a 4:4:1:1 mixture of water, Tween 20, propylene glycol, and ethanol.

Five variables were examined: maternal weight change (at 24 and 72 hours postdosing), litter size

(postnatal day [PND] 1 and 6), perinatal loss, pup weight (on PND 1 and 6), and litter biomass (in g on

PND 1 and 6).

Within these five parameters, a significant decrease in maternal weight gain was seen at the two highest

doses. At these same doses, malformations involving the limbs and tail were seen. At a dose of

667 mg/kg, pups in 21% of the litters were affected. At a dose of 1,000 mg/kg, pups in 27% of the litters

were affected. The effe ct on tails was one of shortening or crimping (i.e., ‘kinky’ tails). The hindlimb

effect consisted of paralysis and/or palsy. In animals with palsy, the limb function would alternate

between normal strides and several, second -long period of tetany. Because limb function matures

postnatally, this effect was not evident in the newborn but required 7–10 days to become obvious.

In a subsequent study, Narotsky and Kavlock (1995) found a significant decrease in the number of

liveborn pups associated with se vere respiratory effects in pregnant rats treated by gavage with

53.3 mg/kg/day phenol in water on GDs 6–19. In addition, in one high-dose litter, two of four surviving

pups had kinked tails; this finding was not analyzed for significance but was consiste nt with earlier

observations (Kavlock 1990). Developmental effects were not significant at 40 mg/kg/day.

Phenol in water was administered to pregnant mice by gavage (10 mL/kg) at dose levels of 0, 70, 140, or

280 mg/kg/day on GDs 6–15 (NTP 1983b). Decre ased maternal weight gain, tremors, and increased

maternal mortality were observed at 280 mg/kg/day. In the fetuses, growth retardation, decreased

prenatal viability, abnormal structural development, and an increased incidence of cleft palate were

observed at 280 mg/kg/day. Developmental effects were not observed at 140 mg/kg/day. In pregnantPHENOL 74

3. HEALTH EFFECTS

mice that received 265 mg/kg phenol by gavage on GD 13, Ciranni et al. (1988) found no evidence of

fetal cellular toxicity, as measured by a ratio polychromatic ery throcyte/normochromatic erythrocyte.

York (1997) conducted a study in which phenol was administered in three daily gavage doses in water to

Sprague-Dawley pregnant rats in dosing volumes of 10 mL/kg on GDs 6 –15. The total daily doses were

0, 60, 120, or 360 mg phenol/kg/day. Maternal end points evaluated included clinical signs, body weight,

and food consumption. Dams were also observed for abortions and premature deliveries. Dams were

sacrificed on GD 20 and a gross necropsy was conducted. The uterus was examined for pregnancy,

number and distribution of implantations, live and dead fetuses, and early and late resorptions. Fetuses

were weighed and examined for sex and gross external alterations. Half of the fetuses were examined for

soft tissue alterations and the remaining fetuses were examined for skeletal alterations . In the mid-dose

group, maternal body weight gain was reduced 11% for GDs 6–16 and 19% for GDs 12–16, whereas in

the high -dose group, body weight gain was reduced 38% for GDs 6–16. Maternal final body weight in

the high -dose group was reduced, but <10% relative to controls. Dose- related decreases in food

consumption were also observed during the dosing period. Mean fetal weight in the high-dose group was

reduced 5– 7% relative to co ntrols. In addition, there was a significant decrease in ossification sites on the

hindlimb metatarsals in the high -dose group, which the investigators considered of minimal biological

significance. At the mid - and high- dose levels, there were increases in litters with fetuses with “any

alteration” and with “any variation”, but neither reached statistical significance and there were no clear

dose- response relationships. No significant effects were seen regarding corpora lutea, implantations, litter

sizes, live fetuses, early and late resorptions, and percent resorbed conceptuses. Based on the reduced

fetal weight and delayed ossification in the high-dose group, the dose of 360 mg/kg/day is a

developmental LOAEL; the developmental NOAEL is 120 mg/kg/day. Based on the reduction in body

weight gain, the maternal LOAEL is 120 mg/kg/day and the NOAEL is 60 mg/kg/day.

In a two -generation reproduction study, administration of phenol in the drinking water to the parental

generation (301

– 321 mg/kg/day) resulted in a significant reduction in F 1 pup weight (30% by PND 21

relative to controls) and F 2 pup weight (37% by PND 21 relative to controls) (Ryan et al. 2001). There

was also a decrease in percent live pups on day 4 in both generations and for days 7 –21 in t he F 2
generation at the high -dose level. In addition, preputial separation and vaginal patency were significantly

delayed at the high dose in F 1 males and females, respectively. In this study, water consumption was

significantly reduced at the high dose, including in females during gestation and lactation, and this was

accompanied by reduced food consumption and body weight gain. A LOAEL of 321 mg/kg/day can bePHENOL 75

3. HEALTH EFFECTS

defined in this study for developmental toxicity; the NOAEL for developmental toxicity was

93 mg/kg/day.

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

each species in the acute

- duration category are recorded in Table 3-2 and plotted in Figure 3-2.

3.2.2.7 Cancer

No s tudies were located regarding carcinogenicity in humans following oral exposure to phenol.

The carcinogenicity of orally administered phenol was examined in rats and mice in a study reported by

the NCI (1980). Rats and mice received 0, 2,500, or 5,000 ppm in drinking water for 103 weeks.

Calculated intakes for rats were 322 and 645 mg/kg/day for males and 360 and 721 mg/kg/day for

females. Calculated intakes for mice were 590 and 1,180 mg/kg/day for males and 602 and

1,204 mg/kg/day for females. Statis tically significant increased incidences of pheochromocytomas of the

adrenal gland and leukemia or lymphomas were observed in male rats exposed to 322 mg/kg/day

(2,500 ppm), but not in male rats exposed to 645 mg/kg/day (5,000 ppm). No significant effects were

seen in female rats or mice of either sex exposed to either exposure level. Since cancer occurred only in

males of one of the two species tested and a positive dose -response relationship could not be established,

these results are inconclusive regar ding the carcinogenic potential of orally administered phenol.

3.2.3 Dermal Exposure

3.2.3.1 Death

Application of phenol to the skin can be lethal. Death occurred within 10 minutes after ≈25% of an

individual's body surface was exposed to liquid phenol (Griffiths 1973). The cause of death was reported

to be respiratory depression and cardiac arrest. In another report, an individual died after being painted

with a brush that had been soaked in a solution of phenol and thoroughly washed before use (Lewin and

Cleary 1982). In neither case was the dose known with sufficient accuracy to establish a lethal dose.

A 10

- year -old boy who was hospitalized with serious burns was treated dermally with 7.5 L of an

antiseptic solution containing 2% phenol for 2.5 days. During this period his urine became dark and his

respiration became labored, fell into a coma, and died. Postmortem analysis of urine showed the presence

of 200 mg/L of conjugated phenol (Cronin and Brauer 1949). Soares and Tift (1982) described two fatalPHENOL 76

3. HEALTH EFFECTS

cases attributed to absorption of phenol through intact skin. One was a 17- year -old male who died within

30 minutes of splattering a solution containing 30% phenol over portions of his face, neck, and right

trunk. The other case was a 4

- week -old female who was mistakenly treated with undiluted Castellani’s

paint (a mixture of phenol, basic fuchsin, resorcinol, acetone, ethanol, and water) to treat seborrheic

dermatitis and died 5 hours later.

Lethality associated with dermal exposure to phenol is greatly influenced by the surface area exposed as

well as the concentration of the applied solution. Mortality can vary depending on concentration; a dose

of 100% phenol may be less toxic than the same dose of phenol given as a diluted solution. When an

undiluted dose of 0.5 mL/kg was applied to the shaved backs of groups of five rats; one rat died, a

1/3 dilution killed three rats, a 1/2 dilution killed four rats, and a 2/3 dilution killed all five rats (Conning

and Hayes 1970). Conning and Hayes (1970) speculated that an undiluted solution may produce a

coagulative necrosis, which would slow further penetration of phenol resulting in a smaller number of

deaths than with more diluted solutions. In rats treated with 3,000 mg/kg phenol in a 6% solution over

1/6 of the total body surface, all 22 treated animals died (Deichmann and Witherup 1944). Incr eased

lethality with decreased concentration has also been observed in rabbits treated dermally with

2,000 mg/kg; 95% phenol resulted in the death of 53% of treated rabbits, while 10% phenol in water

resulted in the death of 100% of treated rabbits (Deichm ann and Witherup 1944). The cause of death was

not stated in these studies.

In rats given a single treatment of 5% phenol in water to achieve a dose of 3,000 mg/kg, 10-day-old rats

were more sensitive than 5

- week -old rats or adult rats (Deichmann and Witherup 1944). Within 2–

14 hours after dosing, 13 of 20 10-day- old rats died; 5 of 20 5- week

- old rats died 2 –3 hours after dosing,

and 9 of 20 adult rats died 30–180 minutes after dosing.

The dermal LD 50 of undiluted phenol in rats was reported to be 669 mg/kg (Conning and Hayes 1970).

The LD 50 of an unspecified concentration of phenol in rabbits was reported to be 1,400 mg/kg (Vernot et

al. 1977). Flickinger (1976) determined a dermal LD 50 by exposing male albino rabbits to 0, 252, 500,

1,000, or 2,000 mg/kg phenol which was placed “in contact” with “abraded and intact skin for a

maximum period of 24 hours.” No animals died in the 0, 252, or 500 mg/kg groups whereas three of

four in the 1,000 mg/kg group and all in the 2,000 mg/kg group died the first day following dosing. From

these data, the authors estimated a “single dose skin penetration LD 50 " of 850 mg/kg.PHENOL 77

3. HEALTH EFFECTS

Among pigs treated with a single dose of 500 mg/kg of undiluted phenol on 35– 40% of the total body

surface (about 1,136 cm 2 ; 0.44 mg/cm 2 /kg), t wo of three died (Pullin et al. 1978). The study authors

reported that a general state of lethargy, cyanosis, convulsions, and coma were observed 5–7 minutes

before death.

No effects on survival were observed in mice treated dermally with an unspecified volume of 5% phenol

(3 times/week) or 10% phenol (2 times/week) in acetone for 12 months (Wynder and Hoffmann 1961).

Pretreatment with a single dose of 7,12-dimethylbenz[a]anthracene (7,12-DMBA) followed by phenol

resulted in increased skin tumors and de creased survival.

All LOAEL and LD 50 values from each reliable study are recorded in Table 3-3.

3.2.3.2 Systemic Effects

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

species and duration category are recorded in Table 3-3.

Respiratory Effects. Pulmonary edema was observed in two fatal cases of dermal poisoning with

phenol (Soares and Tift 1982). A 79- year -old man who mistakenly instilled into his no se 0.5 –10 mL of a

89% phenol solution (approximately 0.4–9 g) showed erythema and sloughing of the nasal mucosa 3 days

after the accident (Durback -Morris and Scharman 1999). No further relevant information was located

regarding respiratory effects in huma ns following dermal exposure to phenol.

Dyspnea was reported in pigs treated with a single dose of 500 mg/kg of undiluted phenol over 35–40%

of the total body surface area (0.44 mg/cm 2 /kg) (Pullin et al. 1978). This treatment resulted in the death

of two of the three treated pigs.

Cardiovascular Effects. There have been several reports of cardiac arrhythmias associated with

application of phenol solutions to the skin in connection with the surgical procedure of skin peeling

(Gross 1984; Truppman and Ellenby 1979; Warner and Harper 1985). In this procedure, a mixture of

phenol ( ≈50% w/v), hexachlorophene, and croton oil is applied to the skin while the patient is under

anesthesia. In a series of 54 patients in which the whole face was peeled in 1 day, cardiac arrhythmias

were reported in 39%, whi le in a series of patients in which half the face was treated on 1 day, and the

second half was treated 24 hours later, cardiac arrhythmias were reported in 22% (Gross 1984). The141mg/cm2/d141151mg/cm2/d151087mg/cm2/d087219mg/cm2/d219072mg/cm2/d072Table 3-3 Levels of Significant Exposure to Phenol - DermalSpecies(Strain)Exposure/Duration/Frequency(Route)ACUTE EXPOSUREDeath(Alderly Park)Rat24 hrSystemNOAELLess SeriousLOAEL669.4 Fmg/cm2/dSerious(LD50)ReferenceChemical FormConning and Hayes 1970Comments(Wistar)Ratonce3000mg/cm2/d(13/20 deaths10-day-old, 5/20 deaths5-week-old, 9/20 deathsadult)Deichmann and Witherup 1944(NewZealand)RabbitNS1400 Fmg/cm2/d(LD50)Vernot et al. 1977(Mixed breed)Pig24 hr0.44 Fmg/cm2/d(2/3 died)Pullin et al. 1978SystemicHuman1 hrCardio75 Mmg/cm2/d(cardiac arrhythmia)Warner and Harper 1985142mg/cm2/d142mg/cm2/d258mg/kg258041mg/cm2/dmg/cm2/d041238mg/cm2/d238Table 3-3 Levels of Significant Exposure to Phenol - Dermal(continued)Exposure/LOAELDuration/FrequencyReferenceSpecies(Route)(Strain)System NOAEL Less SeriousSeriousChemical FormComments(Alderly Park)Rat24 hrRenal107.1 Fmg/cm2/d(severe hemoglobinuria,hematin casts in thetubules)Conning and Hayes 1970Dermal107.1 Fmg/cm2/d(severe edema,coagulative necrosis,erythema)(B6C3F1)Mouse(ICR)Mouse(NS)onceonceDermalDermal12 Fmg/cm2/d329 Fmg/kg15 Fmg/cm2/d(skin inflammation)(skin irritation indicatedby thickening of treatedear)Murray et al. 2007Patrick et al. 1985(NS)RabbitonceCardio23.8 Mmg/cm2/d(cardiac arrhythmias,ventricular tachycardia)Wexler et al. 1984220mg/cm2/d220mg/cm2/d143mg/cm2/d143221mg/cm2/d221Table 3-3 Levels of Significant Exposure to Phenol - Dermal(continued)Exposure/LOAELDuration/FrequencyReferenceSpecies(Route)(Strain)System NOAEL Less SeriousSeriousChemical FormComments(Mixed breed)Pig24 hrResp0.44 Fmg/cm2/d(dyspnea)Pullin et al. 1978Dermal0.44 Fmg/cm2/d(necrosis of the skin)Neurological(Alderly Park)Rat24 hr107.1 Fmg/cm2/d(severe muscle tremors,marked twitching,generalized convulsions,loss of consciousnessand prostration)Conning and Hayes 1970(Mixed breed)Pig24 hr0.44 Fmg/cm2/d(twitching, tremors)Pullin et al. 1978Cardio = cardiovascular; d = day(s); F = Female; hr = hour(s); LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL =no-observed-adverse-effect level; NS = not specified; Resp = respiratoryPHENOL 81

3. HEALTH EFFECTS

study author also indicated that the arrhythmias were less severe in th e patients treated over a longer

period of time.

Cardiac arrhythmia and bradycardia were reported in a man that splashed an unspecified concentration of

a phenol-water solution over his face, chest wall, hand, and both arms (Horch et al. 1994). The cardi ac

effects were noted during the first 6 hours after exposure. The serum levels of phenol in μg/L were

11,400 after 1 hour, 17,400 after 4 hours, and 6,000 after 8 hours. Premature heartbeats and arterial

fibrillation were reported in a male who experien ced a 4.5 -hour occlusive exposure to 90% phenol

(Bentur et al. 1998); the concentration of phenol in serum reached a peak of 21.6 mg/L.

Cardiac arrhythmia has also been noted in rabbits treated with 2 mL of a 50% phenol solution on a

15- cm 2 area (23.8 mg/ cm 2 /kg) (Wexler et al. 1984). Reducing plasma concentrations of phenol by forced

diuresis or a longer application time reduced the cardiac effects.

Gastrointestinal Effects. During the first few days after a man splashed a phenol

- water solution

(concentration not stated) on his face, chest wall, hand, and both arms, he complained of nausea and

vomited twice (Horch et al. 1994). A worker who was partially immersed for only a few seconds in a

shallow vat containing a mixture of 40% phenol in dichloromethane, collapsed after showering and was

taken to a hospital where he was found to have burns over 50% of his body. Initial observations were

stable; however, after drinking fluids, he developed nausea and vomiting (Foxall et al. 1989).

No studies were located regarding gastrointestinal effects in animals following dermal exposure to

phenol.

Hematological Effects. No studies were located regarding hematological effects in humans

following dermal exposure to phenol.

Hemoglobinuria and hematin casts were reported in the renal tubules of rats treated dermally with

108 mg/kg phenol (Conning and Hayes 1970). These observations are indicative of red blood cell

hemolysis; however, this was not confirmed with hematological examinations.

Musculoskeletal Effects. Muscle pain in the arms and legs was reported in a case of chronic phenol

poisoning (Merliss 1972). The man worked in a laboratory for 13.5 years where he distilled phenolPHENOL 82

3. HEALTH EFFECTS

several times a day. During the process, heavy odors were detectable, phenol was often spilled on his

clothes, and he noted skin irritation. The man recovered after 2–3 months away from the exposure.

No studies were located regarding musculoskeletal effects in animals following dermal exposure to

phenol.

Hepatic Effects. Two days after a man was splashed with a phenol

- water solution over his face, chest

wall, hand, and both arms, serum bilirubin increased 2-fold (Horch et al. 1994). After 5 days, serum

bilirubin returned to normal . An enlarged and tender liver and increased liver transaminase activity in the

serum were reported in a case of chronic phenol poisoning (Merliss 1972). Lactate dehydrogenase was

about 2 -fold greater than normal, AST was about 21-fold greater than norma l, and ALT was about

100-fold greater than normal. The man worked in a laboratory for 13.5 years where he distilled phenol

several times a day. During the process, heavy odors were detectable, phenol was often spilled on his

clothes, and he noted skin ir ritation.

No studies were located regarding hepatic effects in animals following dermal exposure to phenol.

Renal Effects. Renal tubule cell vacuolization was described in a fatal case of dermal poisoning with

phenol (Soares and Tift 1982). A case of acute renal failure was reported by Foxall et al. (1989) in a

worker who accidentally fell into a shallow vat containing a mixture of phenol (40%) in dichloromethane.

The worker was partially immersed for only a few seconds and avoi ded ingesting any of the solution. He

showered immediately, subsequently collapsed and was admitted to the hospital with surface burns over

50% of his body (involving the face, chest, genitals, and both legs). Following admission he became

anuric and pla sma creatinine levels rose. He was transferred to the regional renal unit where he was

diagnosed with phenol - induced burns, acute tubular necrosis, and fluid overload. For the first 2 weeks,

the patient demonstrated amino aciduria, glycosuria, and lacti c aciduria consistent with renal cortical

necrosis. This was followed by a period of polyuria revealing a biochemical pattern consistent with renal

papillary damage. Treatment consisted of administration of a diuretic intravenously and hemodialysis

daily for a week followed by an additional 18 days of hemodialysis at gradually increasing intervals. The

patient was discharged 42 days after admission once renal clinical chemistry values had return to normal,

although nuclear magnetic resonance (NMR) spectroscopic analysis still revealed abnormalities consistent

with renal papillary damage. One year after the incident, the patient was still polyuric.PHENOL 83

3. HEALTH EFFECTS

Dark urine was reported in a case of chronic phenol poisoning (Merliss 1972). The man worked in a

laborato ry for 13.5 years where he distilled phenol several times a day. During the process, heavy odors

were detectable, phenol was often spilled on his clothes, and he noted skin irritation. The study authors

indicated that the urine was so dark that it suggested hemoglobinuria. Glucose was present in the urine,

although the urine was negative for homogentistic acid (a substance whose presence can cause urine to

darken upon standing) and urobilinogen. The urine cleared 2–3 months after the subject was removed

from phenol exposure. Dark urine was also observed in a man who spilled 90% phenol over an occluded

area of the skin and kept the area unattended for 4.5 hours (Bentur et al. 1998).

Hemoglobinuria and hematin casts in the distal convoluted tubules and tubular lumens located in the

medulla and papilla were reported in rats after a single dermal exposure to 107 mg/kg liquid phenol

(Conning and Hayes 1970). These phenomena are probably related to red blood cell lysis and increased

glomerular filtration of hemoglobin. Hemoglobinuria is characteristic of lethal or near- lethal exposures

by the dermal route.

Dermal Effects. Application of phenol to the skin of humans results in dermal inflammation and

necrosis (Horch et al. 1994; Merliss 1972; Truppman and Ellenby 1979). Data concerning minimal

effective exposure levels in humans were not found. NIOSH (1983) conducted a survey in an Oregon

hospital in response to concerns about respiratory problems and contact dermatitis in house keeping staff

members who were exposed frequently to germicidal solutions containing phenol and other solvents

(formaldehyde, cellosolve, ethanolamine). The housekeeping staff reported significantly more symptoms

of cough, itching, sinus problems, and dermatitis than did other employees. Air concentrations of phenol

in the work areas were below the limit of detection (<0.01 ppm). Urinary phenol levels in the

housekeeping staff members were not significantly different from those of the other employees. T hus,

while it is likely that the employees came into contact with irritants, the cause of the reported symptoms

could not be attributed to phenol or any other specific substance in the work environment. Therefore, this

study is not recorded in Table 3 -3.

Application of 0.1 mL of molten phenol/kg ( ≈100 mg/kg) (Brown et al. 1975) or 107 mg/kg (Conning and

Hayes 1970) to the skin of rats for 24 hours (surface area not reported) produced severe edema, erythema,

and necrosis. In pigs, application of 500 mg/kg molten phenol to 35– 40% of the body surface

(0.44 mg/cm 2 /kg) resulted in skin discoloration after 20–30 minutes of exposure and severe necrosis after

8 hours of exposure. Two of three pigs died within 95 minutes after exposure (Pullin et al. 1978).

Necro sis, hyperemia of superficial dermal vessels, and dense perivascular infiltration of lymphocytes andPHENOL 84

3. HEALTH EFFECTS

neutrophils were noted in the skin of pigs treated dermally with an unspecified amount of 89% phenol

(Hunter et al. 1992). The dose- effect relationship an d time course for skin irritation and inflammation

have been studied in mice (Patrick et al. 1985). The end point examined was swelling (increased

thickness) of the ear after dermal applica tion to the ear pinna. Application of 12 mg/cm 2 /kg of phenol to

the ear resulted in swelling in four of nine mice within 1 hour after application. Severity of skin irritation

increased as the concentration of the applied phenol solution increased. Swelling persisted for 6 weeks

after applica tion of 18 mg/cm 2 /kg. Swelling was observed in only one of eight mice treated with

12 mg/cm 2 /kg phenol. Application of 3.5 mM phenol/kg to a 3- cm 2 shaved dorsal area from mice

resulted in inflammation, as evidenced by an increase in skin bi -fold thickness and recruitment of

infl ammatory cells (Murray et al. 2007). This was accompanied by oxidation of glutathione and protein

thiols and decreased vitamin E and total antioxidant reserves in the skin. Application of an unspecified

amount of a 1:6 or 1:9 phenol:water solution to the skin of guinea pigs for 1 minute resulted in erythema

and increased skin vascular permeability indicated by dye permeability (Steele and Wilhelm 1966).

Skin crusts were reported on mice exposed repeatedly to 5 mg phenol as a 5% (w/v) solution for

32 we eks, whereas skin ulceration was observed in mice exposed to 5 mg phenol as a 20% (w/v) solution

(Salaman and Glendenning 1957). The skin ulceration healed in 4 weeks after the end of the exposure.

In a 52-week study, mice were exposed 2 times each week to 42 or 83 mg/kg of phenol in a 5 or 10%

solution in benzene (Boutwell and Bosch 1959). Severe skin damage was reported after 36 weeks in the

mice exposed to 83 mg/kg. Skin papillomas were reported in mice exposed at 42 mg/kg. Because phenol

was applied in benzene which is also a skin irritant, this study is not presented in Table 3-3.

Direct application of phenol to the inner ear of rats has resulted in external otitis, inner ear damage

(Schmidt et al. 1990), and inflammation of the tympanic membrane (Schmidt and Hellström 1993).

These studies were conducted because phenol has been used as a topical anesthetic in infected ears.

Ocular Effects. No studies were located regarding ocular effects in humans following dermal

exposure to phenol.

A modified Draize test was used to assess ocular damage resulting from application of 5% phenol to the

center of the cornea in New Zealand rabbits (Murphy et al. 1982). The eyes of one group of rabbits were

irrigated with water 30 seconds after exposure, while t he eyes of another group were unirrigated.

Conjunctivitis developed in all treated groups and lasted through the 7 days of observation. Corneal

opacities became apparent in four of nine rabbits 24 hours after phenol application in unirrigated eyes, butPHENOL 85

3. HEALTH EFFECTS

o nly 1 hour after application in four of nine rabbits receiving irrigation. The opacities lasted through the

7-day observation period in the unirrigated eyes, but were cleared by day 7 in the irrigated eyes. Based

on these observations, phenol was designa ted as a severe eye irritant in unirrigated eyes, and as a

moderate eye irritant in irrigated eyes (Murphy et al. 1982).

Body Weight Effects. A man chronically exposed to phenol at a laboratory where he distilled it

several times a day was 71.5 inches tall, weighed 135 pounds, and was described as emaciated (Merliss

1972). Loss of appetite and a slow weight loss were symptoms that the subject reported during the

13.5 years he worked at the laboratory. During the distillation proc ess, heavy odors were detectable,

phenol was often spilled on his clothes, and he noted skin irritation.

No studies were located regarding body weight effects in animals following dermal exposure to phenol.

3.2.3.3 Immunological and Lymphoreticular Eff ects

No studies were located regarding immunological or lymphoreticular effects in humans or animals

following dermal exposure to phenol.

3.2.3.4 Neurological Effects

Fatal dermal exposure to an 80% phenol solution in a 24- year -old man being treated for skin rash was

characterized by severe convulsions prior to death (Lewin and Cleary 1982). A child who suffered

accidental dermal poisoning with phenol became listless and developed seizures before death (So ares and

Tift 1982). Seizures were also reported in a young adult who splattered a solution containing 30% of

phenol over portions of his face, neck, and right trunk and later died (Soares and Tift 1982). A man who

spilled 90% phenol over his foot and shoe had hypalgesia and hypoesthesia of the affected area in

addition to confusion, vertigo, and faintness (Bentur et al. 1998).

Muscle tremors and convulsions are characteristic effects of acute dermal phenol toxicity in laboratory

animals. Tremors that d eveloped into convulsions and prostration were reported in rats exposed to

107 mg/kg liquid phenol; application surface areas were not reported (Conning and Hayes 1970). In pigs,

application of 500 mg/kg over 35

– 40% of the body surface (0.44 mg/cm 2 /kg) re sulted in muscular

tremors in the head region within 3–5 minutes of exposure (Pullin et al. 1978). This was followed by

dilation of the pupils, loss of coordination, and excess salivation and nasal discharge within 5 minutes of

exposure. It was followed by convulsions, coma, and death 5–7 minutes after exposure in two of threePHENOL 86

3. HEALTH EFFECTS

pigs. Direct application of a dose of 38 mg/kg phenol to the inner ear resulted in a reduced threshold for

auditory brainstem response (Schmidt et al. 1990).

No studies were locat ed regarding the following health effects in humans or animals after dermal

exposure to phenol:

3.2.3.5 Reproductive Effects

3.2.3.6 Developmental Effects

3.2.3.7 Cancer

No studies were located regarding cancer in humans f ollowing dermal exposure to phenol.

In a study of the promoting effects of phenol, mice were exposed to 9,10-dimethyl-1,2- benzanthracene

(9,10- DMBA) (300 μg) followed by weekly dermal exposure to 5 mg phenol in either a 5 or 20% phenol

solution in acetone for 32 weeks (Salaman and Glendennin g 1957). Exposure to 9,10- DMBA followed

by phenol (5 or 20%) resulted in a significantly greater incidence of tumors, including carcinomas, than

exposure to 20% phenol alone; tumors, but no carcinomas, resulted from exposure to 20% phenol, and no

tumors resulted from exposure to 5% phenol. Application of 5% phenol alone resulted in skin "crusting"

at the site of application, whereas 20% phenol resulted in skin ulceration. The study authors concluded

that phenol was an effective tumor promoter after a single application of 9,10-DMBA. Although this

study did not include a group of animals that had been exposed to 9,10- DMBA alone, the authors

indicated that previous work done in their laboratory provided the data from such animals and that it was

thus the c omparison between such historical information and the information from this study which led to

their conclusion about the promotional effects of phenol.

A similar promoting activity was observed when an unspecified volume of 10% phenol in acetone was

placed on the backs of mice 2 times/week for 12 months and when 5% phenol in acetone was placed on

the backs of mice 3 times/week for 12 months (Wynder and Hoffmann 1961).

Additional studies indicate that phenol applied to the skin is a cancer promoter and possibly a complete

carcinogen (i.e., promoter and initiator) in mice. Boutwell and Bosch (1959) examined the carcinogenic

effects of phenol in several strains of mice. Mice were exposed to a single dermal application of

9,10- DMBA (75 mg) followed by rep eated dermal applications of a 5 or 10% phenol solution in benzenePHENOL 87

3. HEALTH EFFECTS

(42 or 83 mg/kg/treatment), twice each week for 52 weeks. Two other experimental groups of mice were

exposed to 9,10

- DMBA alone or phenol alone. Severe skin damage, decreased body weight, and

increased mortality were observed in phenol

- treated animals. Sutter strain mice (inbred for

three generations for susceptibility to the initiator 9,10-DMBA) treated with 9,10-DMBA followed by

10% phenol developed papillomas (95% in 13 weeks) and carc inomas (43% in 42 weeks) at a much

higher incidence than mice treated with 9,10- DMBA alone (14% with papillomas at 42 weeks; no

carcinomas), or phenol alone (36% with papillomas at 52 weeks; no carcinomas). One fibrosarcoma was

observed after 52 weeks of exposure to phenol alone. An elevated incidence of papilloma was also

observed in CAF1, C3H, and Holtzmann mice exposed to 9,10-DMBA followed by phenol, and in

Holtzmann mice exposed to 10% phenol alone. The promoting effect of phenol was dose related;

application of 5% phenol (41.7 mg/kg) following 9,10- DMBA treatment resulted in fewer tumors than a

similar protocol using 9,10-DMBA followed by 10% phenol (83.3 mg/kg). Phenol elicits skin tumors in

mice even without treatment with 9,10-DMBA. Ten out of 30 albino mice treated twice weekly for

12 weeks with a 20% phenol solution in dioxane developed papilloma of the skin; also, 8 out of 30 mice

treated with 10% phenol solution in benzene for 15 weeks developed papilloma, and 3 developed

carcinoma of the sk in (Boutwell and Bosch 1959). Because the phenol was administered in benzene or

dioxane, both of which are skin irritants and/or de-fatting agents, this study is not presented in Table 3-3.

The effect of phenol on benzo[a]pyrene (B[a]P) carcinogenicity has been examined (Van Duuren and

Goldschmidt 1976; Van Duuren et al. 1971, 1973). Dermal application of 3 mg phenol in acetone

simultaneously with 5 μg B[a]P resulted in significantly fewer tumors than application of B[a]P alone.

Application surface area s were not reported and could not be estimated from the description of the

application procedure. Mice treated dermally with B[a]P followed by dermal application of brewed tea

on alternate days over a period of 55 days developed epithelial cell carcinoma or exhibited various stages

of squamous cell tumors (Kaiser 1967). The brewed tea contained an unspecified level of phenol, the

presumed cancer promoter in this experiment, as well as cresols and dimethylphenols.

3.3 GENOTOXICITY

Phenol has been evaluated for genotoxicity in both in vivo (Table 3-4) and in vitro (Table 3- 5) test

systems. End points evaluated in in vivo mammalian test systems include chromosomal aberrations,

micronucleus, and deoxyribonuclei c acid (DNA) synthesis. Several different cell types have been

monitored, including bone marrow, liver, and renal cell. Both positive and negative results have been

reported for in vivo genotoxicity tests. In vitro studies have been conducted in prokary otic and eukaryoticPHENOL 88

3. HEALTH EFFECTS



### Table 3

- 4. Genotoxicity of Phenol **In Vivo**

Species (test system) End point Results Reference

Mammalian cells:

Mouse bone marrow Chromosomal aberration – Barale et al. 1990; Chen and Eastmond 1995a; Pashin et al.

1987

Mou se bone marrow Chromosomal aberration + Shelby and Witt 1995

Mouse spermatocytes Chromosomal aberration + Bulsiewicz 1977
Bone marrow from pregnant Micronucleus + Ciranni et al. 1988

mice

Mouse fetal liver cells Micronucleus – Ciranni et al. 1988

M ouse bone marrow Micronucleus + Li et al. 2005; Shelby and Witt

1995

Mouse bone marrow Micronucleus – Barale et al. 1990; Gocke et al.

1981

Mouse tubular renal and liver DNA synthesis + Amlacher and Rudolph 1981 epithelial

Rat testes DNA synthesis – Skare and Schrotel 1984

Rat liver DNA synthesis – Miyagawa et al. 1995

Insects:

Drosophila Micronucleus – Gocke et al. 1981; Sturtevant

1952

+ = positive response; – = negative response; DNA = deoxyribonucleic acidPHENOL 89

3. HEALTH EFFECTS



### Table 3

- 5. Genotoxicity of Phenol **In Vitro**

Results

With Without Species (test system) End point activation activation Reference

Prokaryotic organisms:
Salmonella typhimurium

S. typhimurium

Escherichia coli

E. coli

Eukaryotic organisms:

Aspergillus

V79 Chinese hamster

cells
Chinese hamster ovary

cells
Chinese hamster ovary cells (DNA strand breaks)

Crucian (goldfish) erythrocytes
Mouse lymphoma (DNA strand breaks)

Mouse spermatocytes

Rat liver mitochondria
Syrian hamster embryo

cells
Syrian hamster embryo

cells
Syrian hamster embryo

cells
Syrian hamster embryo

cells

Human lymphocytes

Human lymphocytes

Human lymphocytes

Human lymphocytes Gene mutation

Gene mutation

Gene mutation

Gene mutation

Chromosomal

aberration

Gene mutation

Micronuclei

Chromosomal

aberration

DNA damage

Chromosomal

aberration

DNA damage

DNA synthesi s

Gene mutation

Chromosomal

aberration

Sister chromatid exchanges

Unscheduled DNA synthesis

Sister chromatid exchanges

Sister chromatid exchanges

Sister chromatid exchanges

DNA damage –

+

–
No data

No data

+

+

No data

No data

No data

No data

No data

No data

No data

No data

No data

+

No da ta

No data

No data –

–

–

+

+

–

+

–

+

–

+

–

+

+

+

+

+

–

+

+ Florin et al. 1980; Haworth et al. 1983; Kubo et al. 2002; Pool

and L in 1982

Gocke et al. 1981

Nagel et al. 1982

Demerec et al. 1951

Crebelli et al. 1987

Paschin and Bahitova

1982

Miller et al. 1995

Sze et al. 1996

Li et al. 2005

Pellack

- Walker and

Blumer 1986

Li et al. 2005

Schwartz et al. 1985

Tsutsui et al. 1997

Tsutsui et al. 1997

Tsutsui et al. 1997

Tsutsui et al. 1997

Morimoto and Wolff 1980; Morimoto et al.

1983

Jansson et al. 1986

Erexson et al. 1985

Li et al. 2005PHENOL 90

3. HEALTH EFFECTS



### Table 3

- 5. Genotoxicity of Phenol **In Vitro**

Species (test system) End point

Human diploid fibroblasts DNA synthesis

HeLa cells DNA synthesis Results

With

activation Without

activation

No data +

+ No data Reference

Poirier et al. 1975

Painter and Howard

1982

+ = positive response; – = negative response; DNA = deoxyribonucleic acidPHENOL 91

3. HEALTH EFFECTS

test systems. Results for various end points (gene mutation, chromosomal aberration, micronuclei, DNA

damage, sister chromatid exchanges, and unscheduled DNA synthesis) have been both positive and

negative. The mixed results in both the in vivo and in vitro assays indicate that under certain conditions,

especially at higher doses, phenol has the potential to be genotoxic. However, at the expo sure levels

likely to occur near hazardous waste sites, phenol is not anticipated to be genotoxic.

Positive and negative results have been reported for phenol in in vivo chromosomal aberration tests.

Increases in chromosomal aberrations have been reporte d in bone marrow (Shelby and Witt 1995) and in

spermatocytes (Bulsiewicz 1977) from mice treated with phenol. Chromosomal aberrations were

reported in the bone marrow of male B6C3F 1 mice exposed to phenol through intraperitoneal injection

(Shelby and Witt 1995). Bulsiewicz (1977) also reported results of a five-generation study with Porton

strain inbred mice. Chromosomal aberrations were monitored in spermatogonia and spermatocytes of

gavage treated mice. Dose dependent increases in aberrations were obs erved with succeeding

generations. The investigator attributed the observed chromosomal effects to interactions of phenol with

the spindle apparatus. Other studies have not observed chromosomal aberrations in bone marrow from

mice treated with phenol (Barale et al. 1990; Chen and Eastmond 1995a; Pashin et al. 1987). In tests of

feeding and injection exposures of Drosophila to phenol , results were negative in sex

- linked recessive

lethal assays (Gocke et al. 1981; Sturtevant 1952).

Positive (Ciranni e t al. 1988; Li et al. 2005; Shelby and Witt 1995) and negative (Barale et al. 1990;

Gocke et al. 1981) results were reported for in vivo micronucleus assays in bone marrow isolated from

mice treated with phenol. Bone marrow micronucleus tests were positive for male B6C3F 1 mice exposed

to phenol through intraperitoneal injection (Shelby and Witt 1995). In a study of pregnant CD- 1 mice

receiving doses of phenol, maternal bone marrow micronuclei were studied. Pregnant mice were treated

by gavage with a sing le dose of 265 mg/kg of phenol on GD 13. Observed effects included an increase in

bone marrow micronuclei and cytotoxicity. Micronuclei were not observed in fetal liver tissue (Ciranni et

al. 1988). Bone marrow of Kunming mice exposed to concentrations of 20, 40, or 80 mg/kg of phenol

through intraperitoneal injection showed increased frequency of micronuclei at dose levels of 40 and

80 mg/kg (Li et al. 2005). However, exposures of male CD- 1 mice to maximum intraperitoneal injections

of 160 mg/kg result ed in negative micronucleus tests (Barale et al. 1990). Results were also negative for

micronucleus assays in male and female NMRI mice dosed twice by intraperitoneal injections of

188 mg/kg of phenol (Gocke et al. 1981).PHENOL 92

3. HEALTH EFFECTS

Phenol increased DNA synthesis in tubular renal and liver epithelial cells from mice (Amlacher and

Rudolph 1981). Skare and Schrotel (1984) reported the results of experiments where Sprague- Dawley

rats were dosed with single intraperitoneal injections of 79 mg/kg or five daily intraperitoneal injections

of 39.5 mg/kg/day. Single strand breaks were not observed in testicular cells. A DNA synthesis test in

male B6C3F 1 mice dosed by gavage with concentrations of 0, 300, and 600 mg/kg of phenol also was

negative (Miyagawa et al. 1995).

I n vitro tests with phenol for gene mutations in microorganisms have yielded both negative (Florin et al.

1980; Haworth et al. 1983; Kubo et al. 2002; Nagel et al. 1982; Pool and Lin 1982) and positive

(Demerec et al. 1951; Gocke et al. 1981) results. Nega tive results have been reported in Salmonella

typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 with and without S9 activation

(Haworth et al. 1983; Kubo et al. 2002; Pool and Lin 1982). However, increased mutagenicity was

observed in S. typhimu rium TA98, with S9 activation (Gocke et al. 1981). Paschin and Bahitova (1982)

also reported positive results at the HGPRT locus of V79 for mutagenicity studies involving exposures of

Chinese hamster ovary (CHO) cells, with S9 activation. Studies of Syrian hamster embryos (SHE) were

also positive for mutagenicity (Tsutsui et al. 1997).

In vitro studies regarding chromosomal aberrations in eukaryotic cells have been positive in Aspergillus

(Crebelli et al. 1987), and in SHE cells (Tsutsui et al. 1997), and negative in mouse lymphoma cells

(Pellack -Walker and Blumer 1986) and CHO cells (Sze et al. 1996). Tsutsui et al. (1997) reported dosedependent increases in the frequencies of chromosome aberrations in SHE cells exposed to phenol.

Single strand breaks were not observed in mouse lymphoma L5178YS cells (Pellack- Walker and Blumer

1986).

The report of an in vitro micronucleus study with CHO cells was positive with and without S9 activation,

with stronger results observed with S9 activation (Miller et al . 1995).

Results of in vitro sister chromatid exchange tests were reported as positive and negative. Phenol

produced dose-related increases in sister chromatid exchanges in human lymphocytes at doses of

≥500 μM (Erexson et al. 1985). In contrast, sister chromatid exchanges were not observed in human

lymphocytes incubated with 0–2,000 μM phenol (Jansson et al. 1986). Incubation of human lymphocytes

with 1,000,000 μM, but not 200,000 μM phenol for 72 hours resulted in an increase in sister chromatid

exchanges (Morimoto and Wolff 1980 ). Exposures of human lymphocytes to 3,000 μM phenol with S9PHENOL 93

3. HEALTH EFFECTS

activation also resulted in an increase in sister chromatid exchanges (Morimoto et al. 1983). Phenol

induced sister chromatid exchanges in SHE cells at doses of 1,000 and 3,000 μM (Tsutsui et a l. 1997).

In vitro assays for DNA synthesis have been negative in rat liver mitochondria (Schwartz et al. 1985), and

positive in human fibroblasts (Poirier et al. 1975) and HeLa cells (Painter and Howard 1982). However,

unscheduled DNA synthesis was induced to the same degree in SHE cells incubated with phenol in

concentrations ranging from 1 to 30 μM (Tsutsui et al. 1997).

An in vitro study of DNA damage using the comet assay indicated that phenol induced DNA damage in

human lymphocytes, mouse spermatocytes, and crucian erythrocytes. In these tissues, amounts of DNA

damage increased in conjunction with increasing doses. Observed DNA damage to mouse spermatocytes

and crucian erythrocytes was more significant than DNA damage to human lymphocytes (Li et al. 2005).

3.4 TOXICOKINETICS

Phenol is readily absorbed and widely distributed following inhalation, oral, and dermal exposure. The

distribution of phenol is thought to be dependent on blood flow. Conjugates with glucuron ic acid and

sulfate are the major metabolites of phenol, although small amounts of the hydroxylation products

catechol and hydroquinone are also produced. Sulfotransferase and glucuronyltransferases are present in

most tissues, although the major sites of phenol conjugation are the gastrointestinal tract, liver, lung, and

kidney. Because of the large capacity of the intestines and liver to conjugate phenol, the fact that the

first -pass effect occurs following oral exposure but not following dermal exposure may contribute to the

greater potential for phenol to result in adverse effects following dermal exposure. Phenol and its

conjugates are predominantly excreted in the urine.

3.4.1 Absorption

3.4.1.1 Inhalation Exposure

Phen ol is absorbed readily after inhalation exposure. Eight subjects were exposed to phenol vapors (1.6–

5.2 ppm) for 8 hours (Piotrowski 1971). Subjects were exposed through a face mask in order to eliminate

the possibility of percutaneous absorption. The concentration of phenol in inhaled and exhaled air was

determined, and urine was analyzed for total phenol (phenol and phenol conjugates). Steady- state

appeared to be achieved within 3 hours after initiating exposure; steady- state retention was 60 –88%.PHENOL 94

3. HEALTH EFFECTS

Ur inary recovery of phenol that had been retained in the lungs was 99±8% within 24 hours after initiating

exposure.

Total urinary phenol was determined at about 7 hours into an 8

- hour shift in Bakelite workers exposed to

airborne phenol at 0.16–32 ppm (Ohtsuji and Ikeda 1972). Daily urinary excretion of total phenol was

99% of the estimated amount inhaled indicating that phenol is readily absorbed. However, lung retention

was not measured, and the contribution of percutaneous absorption to urinary phenol could not be

evaluated in this study.

Rats exposed by intratracheal instillation to [ 14 C] -labeled phenol also demonstrated rapid absorption

kinetics, with most of the radioactivity being excreted within 72 hours (Hughes and Hall 1995). Rats

exposed for 6 hours nose -only to 25 ppm [ 14 C] -labeled phenol demonstrated rapid absorption. Greater

than 90% of phenol- derived radioactivity was measured in the urine 30 minutes after initiation of

exposure (Hiser et al. 1994).

3.4.1.2 Oral Exposure

Based on the rapid excretion of phenol and its metabolites in urine, it has been concluded that phenol is

readily absorbed by the oral route in humans (Capel et al. 1972) and a variety of mammalian species

including monkeys (Capel et al. 1972), rodents (Capel et al. 1972; Edwards et al. 1986; Hughes and Hall

1995; Kao et al. 1979; Kenyon et al. 1995), dogs (Capel et al. 1972), rabbits (Capel et al. 1972), cats

(Capel et al. 1972; French et al. 1974), and pigs (Capel et al. 1972; Kao et al. 1979).

In three men given a single oral dose of 0.01 mg/kg [ 14 C] -labeled phenol in food or drink, about 90%

(range 85–98%) of the dose was excreted in the urine in 14 hours (Capel et al. 1972). In this same study,

urinary recovery of orally administered [ 14 C] -labeled phenol was determined in 18 other mammalian

species; mean 24

- hour recoveries of 14 C ranged from 95% in the rat to 31% in the squirrel monkey. Rats

exposed orally to radiolabeled phenol demonstrated rapid absorption and excretion, with most of the

radioactivity being excreted within 72 hours (Hughes and Hall 1995). The gastrointestinal absorption of

phenol has also been studied in rats with in situ preparations. The absorption kinetics of [ 14 C]

- labeled

phenol administered directly into the small intestines of rats were described as first -order, with a rate

constant for intestinal absorption of 0.127±0.003 minute -1 (or half-life of 5.5±0.5 minutes from

t1⁄2=0.693k) (Humphrey et al. 1980). Two hours after [ 14 C]

- labeled phenol was injected into the sm allPHENOL 95

3. HEALTH EFFECTS

intestines of anesthetized rats, recoveries in the urine were 77.9±2% after a 12.5 -mg/kg dose, and

76.9±5.8% after a 25-mg/kg dose (Kao et al. 1979).

Hiser et al. (1994) reported results of the kinetics of oral doses of phenol in rats. Exposures in cluded

single and multiple bolus and drinking water doses of different concentrations. Peak blood concentrations

of free phenol of 0.02 μg/g blood in rats receiving 1.5 mg/kg bolus dose were reached 1–3 minutes after

receiving the dose. A terminal half -l ife of about 8 minutes was calculated for phenol following low

doses. Peak blood concentrations of phenol of 46.4 μg/g blood in rats receiving 150 mg/kg bolus dose

were reached 1 minute after receiving the dose. Since the doses were separated by only a f actor of

100 and the blood peak concentration by a factor of 2,320, these results suggest saturated absorption or

saturated metabolism and excretion. After 24 hours, concentrations of administered [ 14 C]

- radioactivity

were >90% in the urine, regardless of the dosing method or concentration.

3.4.1.3 Dermal Exposure

Phenol is r eadily absorbed through the skin, and the skin is considered the primary route of entry during

occupational exposure (ACGIH 2005). Whole-body skin exposures studies were conducted in volunteers

lightly clothed and unclothed (Piotrowski 1971). The subjects were exposed to phenol vapor (35%

humidity, 26 °C) at concentrations of 1.3, 2.6, or 6.5 ppm for 6 hours. Fresh air was supplied to the

subjects through a face mask in order to prevent absorption of phenol through the lungs. The total

amount of phenol excreted in urine during and after exposure (minus baseline excretion) was used as a

measure of absorption. Absorption increased proportionately with exposure level. Percutaneous

clearance (mg phenol absorbed through the skin per hour/mg phenol per m 3 of air) was estimated to be

0.35 m 3 /hour. Thus, an amount of phenol equivalent to that contained in 0.35 m 3 of air was absorbed

through the skin each hour.

Th e data reported by Piotrowski (1971) provide a basis for comparing the relative contributions of lung

and percutaneous absorption during exposures to phenol vapor. Assuming a ventilation rate for the

human of 0.8 m 3 /hour (EPA 1986a) and a steady- state lun g retention of inhaled phenol of 0.7 m 3 /hour

(Piotrowski 1971), clearance of airborne phenol through the lung is ≈0.6 m 3 /hour. Thus, an amount of

phenol equivalent to that contained in 0.6 m 3 of air was absorbed through the lungs each hour. It can be

concluded that at any given exposure level within the range of 5–25 mg/m 3 (1.3– 6.4 ppm), percutaneous

absorption (0.35 m 3 /hour) will be about half that of absorption through the lungs (0.6 m 3 /hour).PHENOL 96

3. HEALTH EFFECTS

Percutaneous absorption of phenol applied in solution direc tly to the forearm (15.6 cm 2 ) of volunteers has

been measured (Baranowska -Dutkiewicz 1981). Absorption rate from a 2- mL reservoir of an aqueous

phenol solution (2.5, 5.0, or 10.0 g/L) was constant for 60 minutes (0.08 mg/cm 2 /hour) and increased

proportionately with applied concentration. Approximately 13% of the applied dose was absorbed in

30 minutes, of which 80% (range 58–98%) was recovered in the urine within 24 hours.

When human skin was treated in vitro with 0.0013 –0.0027 mg/cm 2 [ 14 C] -labeled pheno l and left

unoccluded, 20% of the radioactivity was absorbed when analyzed 72 hours later, while 7% remained on

the skin surface (Hotchkiss et al. 1992). Covering the skin with a teflon cap resulted in the absorption of

47%, with 3% recovered in the skin. When rat skin was subjected to the same exposure regime in this

study, 72 hours later, 24% of the radioactivity was absorbed with 22% recovered in the skin when the skin

was unoccluded, and 36% was absorbed with 3–4% recovered in the skin when the skin w as occluded.

In rats in which a 0.03-mg/kg dose of [ 14 C] -labeled phenol was placed on the skin, only 1– 5% of the dose

remained in the body 72 hours later (Hughes and Hall 1995). The dermal absorption of phenol was also

studied in three pigs in which undiluted phenol was placed on the skin for 1 minute, and the peak plasma

level was determined (Pullin et al. 1978). Plasma levels were not measurable in one pig treated with a

dose of 90 mg/kg over a surface area of 91.6 cm 2 . In pigs treated with a dose of 500 mg/kg over surface

areas of 91.6 and 1,135.5 cm 2 , peak plasma levels of 0.9 and 30.5 ppm were reported, respectively.

Permeability coefficients for phenol in isolated skin patches from nude mice have been determined (Behl

et al. 1983). The permeability coefficient increased as the concentration of the applied aqueous phenol

solution increased; doubling the concentration from 20 to 40 g/L resulted in a 12

- fold increase in mean

permeability coefficient (0.007–0.085 cm/hour). The value obtained for the permeability coefficient

when 60 g/L was applied to the skin patch (0.169 cm/hour) was similar to that obtained for skin patches

in which the stratum corneum had been removed. It was concluded that phenol concentrations exceeding

20 g/L may destroy a diff usion barrier normally provided by the intact stratum corneum, permitting

increased percutaneous absorption.

Dermal absorption of phenol in the presence of various types of soil was measured in vitro using skin

patches from pigs (Skowronski et al. 1994). Maximum phenol penetration occurred between 2 and

4 hours after treatment in all cases. Compared to samples with no soil present, the presence of sandy soil

reduced the peak penetration by one-half, and the presence of clay soil reduced peak penetration by two

thirds.PHENOL 97

3. HEALTH EFFECTS

3.4.1.4 Other Routes of Exposure

Nomoto et al. (1987) studied the absorption of phenol after injection into 20 patients as part of lumbar or

thoracic sympathetic blockades. Patients were injected with 5 –10 mL 7% phenol. The concentrations of

unconjugated and conjugated phenol (sulfate esters and glucuronic esters) were monitored in blood and

urine samples. Unconjugated phenol reached a mean peak concentration in blood of 3.01±0.28 μg/mL

18.8±2.5 minutes after the injection. The mean peak concentration of conjugated phenol in the blood was

4.15±0.25 μg/mL 54.9±4.5 minutes after the injection. The authors concluded that uptake times indicated

rapid absorption of phenol after injection. The lag time of unconjugated phenol was 5.3±1.6 minutes,

indicating that phenol remained at the injection site before being taken up into the blood. The lag time of

conjugated phenol was 9.9±5.9 minutes.

There is also indirect evidence of phenol being absorbed following phenol injection sclerotherapy for

hemorrhoids. Suppiah and Perry (2005) reported the case of a 43- year -old man who developed jaundice

after an unspecified number of injections of 2 mL of a 5% solution of phenol at hemorrhoidal tissue

during several months. Liver function tests returned to normal after 6 months.

3.4.2 Distribution

3.4.2.1 Inhalation Exposure

No studies were found regarding tissue distribution of phenol in humans after inhal ation exposure.

Rats exposed by intratracheal instillation to radiolabeled phenol were sacrificed 72 hours later and

analyzed for tissue distribution of the radioactivity (Hughes and Hall 1995). Of the radioactivity

remaining in the body (1– 5%), a majori ty was distributed in the lungs (0.13%), skin (0.13%), blood

(0.07%), muscle (0.03%), fat (0.02%), and liver (0.02%).

No information was found on the placental transfer and distribution of phenol; however, Ghantous and

Danielsson (1986) examined this question for benzene, the principal metabolite of which is phenol. Mice,

at GDs 11, 14, and 17, were exposed by inhalation to [ 14 C]-benzene and the distribution of benzene and

its volatile and nonvolatile metabolites was examined using whole -body autoradiogra phy and assessment

of tissue concentrations of 14 C (day 17 only). The authors indicated that the exposure regimen (50 μCi of

[ 14 C] -benzene in maize oil, volatilized by gentle heating) would theoretically produce 2,000 ppm in thePHENOL 98

3. HEALTH EFFECTS

inhalation chamber. Measu rements of the difference between the amount added to the chamber and the

amount inhaled by the animals indicated an uptake of 90% (i.e., 45 μCi). These authors did not

specifically characterize the metabolites, but were able to show that the [ 14 C]

- labele d volatile and

nonvolatile activity crossed the placental barrier. There was no evidence of preferential accumulation.

Indeed, the concentration of volatile and nonvolatile radioactivity in fetal tissues was much lower than

that observed in the correspon ding maternal tissues. As a metric of the relative accumulation, the authors

noted that compared to maternal brain tissue, fetal uptake of benzene was only 8%.

In a study conducted by Hiser et al. (1994), rats were exposed 6 hours nose-only to 25 ppm [ 14 C] -phenol

for either 1 or 8 days. Mean percent of administered dose/g were reported for several tissues.

Radioactivity was quantified in blood, bone, brain, fat, heart, kidney, liver, lung, muscle, skin, spleen,

testes, ovaries, and carcass 24 hours afte r exposure. No single tissue seemed to preferentially accumulate

phenol- derived radioactivity and, in all cases, concentrations were <0.02% administered dose/g tissue.

No significant differences were seen between the 1 - and 8- day exposure experiments.

3 .4.2.2 Oral Exposure

Limited information in humans is available from cases of accidental or intentional ingestion of phenol

that resulted in fatalities. One case involved ingestion of a mixture of phenol and cresol. The

concentrations of phenol measu red in the blood, urine, and stomach content were 58.3, 3.3, and

115 μg/mL, respectively (Boatto et al. 2004). Another case involved ingestion of a mixture of phenol and

chloroform. Phenol was measured at 60 μg/mL in the blood and 208 μg/mL in the urine. Concentrations

in the brain, lungs, liver, and kidney were 106, 116, 166, and 874 μg/g, respectively (Tanaka et al. 1998).

The third case involved ingestion of phenol, which resulted in the following tissue concentrations of

phenol: blood, 130 μg/mL; u rine, 47 μg/mL; bile, 187 μg/mL; brain, 486 μg/g; kidney, 331 μg/g; muscle,

204 μg/g; liver, 228 μg/g; and stomach content, 668 mg (Lo Dico et al. 1989).

In animals, information is available for rabbits (Deichmann 1944) and rats ( Hiser et al. 1994; Hughe s and

Hall 1995; Liao and Oehme 1981). In rabbits, distribution is rapid, with peak tissue concentrations

achieved in most tissues within 1 hour after dosing. The highest peak concentrations and fraction of

administered dose are found in the liver; >90% of the administered dose is eliminated from tissues within

24 hours.PHENOL 99

3. HEALTH EFFECTS

The levels of phenol in various tissues of five rabbits given a lethal (LD 50 ) oral dose of phenol

(500 mg/kg) were determined (Deichmann 1944). The rabbits were killed within 1–3 minute s after

dosing when twitching, the first sign of systemic toxicity, appeared. The highest concentrations of total

phenol (free plus conjugates) were found in the liver (20.9–30.4 mg/100 g tissue), lungs (5.1–

17.1 mg/100 g), blood (6.1–12.6 mg/100 g), brai n and spinal cord (3.1 –10.4 mg/100 g), and kidneys (2.3–

7.1 mg/100 g).

The kinetics of tissue distribution of [ 14 C] -labeled phenol in rats given 207 mg/kg of [ 14 C] -labeled phenol,

a subleth al ( ≈0.5xLD 50 ) oral dose, were studied (Liao and Oehme 1981). Although all rats survived for

16 hours, signs of systemic toxicity were observed including twitching of muscles around the eyes and

ears, convulsions, and coma persisting for 15–30 minutes. T hirty minutes after dosing, 28.4% of

administered 14 C was recovered in tissues (liver, kidney, adrenal, thyroid, spleen, blood, lung, thymus,

brain, testes, heart, muscle, and fat). Sixteen hours after dosing, 0.3% of the administered dose was

recovered i n tissues. Concentrations of 14 C were highest in all tissues 30 minutes after dosing, with the

exception of the thyroid gland, in which peak concentrations were achieved after 2 hours. The highest

concentration and fraction of administered dose were foun d in the liver; 42% (range 29

– 56%) of the

administered dose was recovered in the liver 30 minutes after dosing. Approximately 67– 85% of the 14 C

in blood was present in the plasma fraction, of which 41–50% was bound to plasma proteins or other

macromolecul es. The elimination half

- time for 14 C was <4 hours. Based on their results, the study

authors suggested that blood flow determines the tissue uptake of the radiolabel from phenol.

Rats exposed orally to radiolabeled phenol were sacrificed 72 hours later and analyzed for tissue

distribution of the radioactivity (Hughes and Hall 1995). Of the radioactivity remaining in the body, a

majority was distributed in the muscle (0.08%), skin (0.07%), fat (0.02%), liver (0.02%), and blood

(0.02%).

No evidence of exposure-related DNA adduct formation in femur bone marrow, Zymbal gland, liver, or

spleen was seen in rats treated orally with 75 mg/kg/day phenol for 4 days (Reddy et al. 1990). In this

study, concurrent in vitro exposures of these tissues did produce ad ducts, suggesting that efficient

detoxification and excretion mechanisms may be operating in vivo

.

In a study conducted by Hiser et al. (1994), rats were exposed to [ 14 C]

- phenol via single gavage doses of

1.5, 15, or 150 mg/kg, multiple gavage doses of 1.5 mg/kg/day, 5,000 ppm in drinking water for 1 day, or

5,000 ppm in drinking water for 8 days. In all cases, phenol -derived radioactivity was detected in blood,PHENOL 100

3. HEALTH EFFECTS

bone, brain, fat, heart, kidney, liver, lungs, skin, spleen, testes, ovaries, and carcass 24 h ours after

exposures. Regardless of the dosing method or dose level, no single tissue seemed to accumulate

radioactivity, with all measured concentrations being <0.02% of the administered dose/g tissue.

3.4.2.3 Dermal Exposure

Limited information i s available in humans from a fatal case. Tissue samples (liver, blood, lung, urine,

and stomach contents) from an individual who was painted with benzyl benzoate with a brush that had

been soaked in 80% phenol were analyzed for phenol. The blood containe d 4.7 μg/mL phenol and

unhydrolyzed and hydrolyzed liver samples contained 3.3 and 7.1 μg/g phenol, respectively. Phenol was

not detected in the lung, urine, or stomach contents (Lewin and Cleary 1982).

Rats exposed dermally to radiolabeled phenol were s acrificed 72 hours later and analyzed for tissue

distribution of the radioactivity (Hughes and Hall 1995). Of the radioactivity remaining in the body (1–

5%), a majority was distributed in the skin (0.021%), muscle (0.02%), fat (0.03%), liver (0.01%), and

blood (0.02%).

3.4.2.4 Other Routes of Exposure

No studies were located regarding distribution of phenol in humans after exposure by other routes.

Microdialysis sampling has been used in rats infused with phenol (0.181 nmol/min ute for 90 minutes) to

study excretion into the bile (Scott and Lunte 1993). For all phenol metabolites, bile concentrations were

higher than liver concentrations indicating that the metabolites are actively excreted in the bile.

The distribution of phen ol in the liver has been studied in mice treated intravenously with 31.4 mg/kg

phenol (Davies and Lunte 1996). Microdialysis probes used to monitor the distribution of phenol

metabolites in three regions of the liver (anterior, median, posterior) indicate d that phenol -glucuronide

was the most prevalent metabolite in all three regions, but the level was significantly lower in the anterior

region compared to the other regions. When phenol was delivered to the liver through microdialysis

probes, no regional differences in the delivery of phenol or metabolite formation were observed,

indicating that clearance of phenol from the liver is dominated by blood flow rather than metabolism.PHENOL 101

3. HEALTH EFFECTS

3.4.3 Metabolism

Figure 3

- 3 shows the general meta bolic pathways that transform phenol prior to its excretion in the urine.

Three different enzymes systems catalyze the reactions that transform phenol. Cytosolic phenol

sulfotransferases catalyze the transfer of inorganic sulfur from the activated 3' -phosphoadenosine- 5'

­
phosphosulfate donor molecule to the hydroxyl group on phenol. Microsomal membrane- located uridine

diphosphate (UDP) glucuronosyltransferases catalyze the transfer of an activated glucuronic acid

molecule to the hydroxyl moiety of phenol to form an O- glucuronide conjugate. Cytochrome P4502E1,

also microsomally located, catalyzes the hydroxylation of phenol to form hydroquinone (and to a much

lesser extent, catechol), which is then acted upon by the phase II enzymes ( Buxton 2006; Campbell et al.

1987; Gut et al. 1996; Koop et al. 1989; McFadden 1996; Powley and Carlson 2001; Snyder et al. 1993).

Hydroquinone can, in turn, form conjugates, undergo peroxidation to form benzoquinone, or undergo

further oxidation to form trihydroxybenzene. Al l three enzyme systems that metabolize phenol are found

in multiple tissues and there is competition among them not only for phenol, but also for subsequent

oxidative products, like hydroquinone. As a consequence, the relative amount of the products formed can

vary based on species, dose and route of administration.

Cytochromes other than CYP2E1 also seem to be involved in the metabolism of phenol as demonstrated

by Powley and Carlson (2001) in experiments utilizing chemical inhibitors of CYP2E1, CYP2B,

CYP2F2, and CYP2E1 knockout mice. The investigators found that CYP2E1 was responsible for only

approximately 50% of phenol metabolism in liver, suggesting the participation of other cytochromes.

Experiments in pulmonary microsomes showed that both CYP2E1 and CYP2F2 played important roles in

the metabolism of phenol.

Phenol can also undergo peroxidation to form 4,4’ -biphenol and diphenoquinone. This has been

demonstrated in studies that used in vitro cell preparations with high peroxidase activity (Ea stmond et al.

1986; Post et al. 1986), purified peroxidase enzymes (Smart and Zannoni 1984; Subrahmanyam and

O'Brien 1985), or cell lines that have high myeloperoxidase activity (Kolachana et al. 1993). Thus far,

there is no direct evidence that these per oxidation reactions occur in vivo

.

In vivo, the gastrointestinal tract, liver, lung, and kidney appear to be the major sites of phenol sulfate and

glucuronide conjugation of simple phenols (Cassidy and Houston 1984; Powell et al. 1974; Quebbemann

and Anders 1973; Tremaine et al. 1984). Experiments conducted by Cassidy and Houston (1984) in rats

injected intra -arterially, intravenously, or intraduodenally (doses ranged from 0.5 to 15 mg/kg) allowedPHENOL 102

3. HEALTH EFFECTS



### Figure 3

- 3. Metabolism of Phenol

Biphenyl polymers

Glutathione O O conjugate OH HO
peroxidase

Biphenol* Diphenylquinone*

peroxidase

OH

Sulfate conjugate conjugate UGT Glucuronide PST

Phenol CYP2E1 OH

OH PST CYP2E1

Sulfate and glucuronide conjugation OH UGT PST

UGT OH Hydroquinone Catechol peroxidase

O CYP2E1 CYP2E1 Sulfate and glucuronide conjugates

OH Glutathione conjugate
OH PST Sulfate and glucuronide conjugates UGT O

Benzoquinone*
OH

Trihydroxybenzene*

PST = phenol sulfotransferase; UGT = UDP-dependent glucuronosyl transferase

*Indicates metabolites identified in vitro only

Source: EPA 2002PHENOL 103

3. HEALTH EFFECTS

them to evaluate the first

- pass metabolism by different tissues. It was assumed that phenol that was

systemically available had not been conjugated or metabolized and, therefore, the doses at which this

occurred reflected the doses at which metabolic reactions were saturated. The investigators found that

metabolism became nearly saturated in the liver at doses 10 times lower than in the endothelial lung,

whereas metabolism in the gut was not saturated even at the highest dose tested. They also obse rved that

the endothelial lung had a much lower affinity for phenol than the liver and gut. However, caution should

be exercised when interpreting the results of the metabolic capacity of the lung because normal exposure

results in exposure of the epithelial respiratory tract rather than the endothelial surface, as occurred in this

study.

Four principal metabolites have been identified in mammals: two phenol and two hydroquinone

conjugates (of sulfate and glucuronide) (Capel et a l. 1972; Hoffmann et al. 1999; Kenyon et al. 1995;

Wheldrake et al. 1978). In humans, rats, and mice given low doses of phenol orally, sulfate conjugates of

phenol were found to predominate. However, in guinea pigs, pigs, and fruit bats, the glucuronide

conjugates were dominant (Capel et al. 1972). In humans given an oral dose of 0.01 mg/kg, 77% of the

urinary 14 C was identified as phenyl sulfate, 16% as phenyl glucuronide, and trace amounts (<1%) as the

sulfate and glucuronide conjugates of hydroquinone (Capel et al. 1972).

In mice, phenyl sulfate was the predominant urinary metabolite for low doses (1

– 21 mg/kg) of phenol

administered either by gavage and intravenously; however, as the dose increased, a decrease in phenol

sulfation and a concomitant inc rease in glucuronidation of both phenol and hydroquinone was seen

suggesting saturation of the sulfation pathway (Kenyon et al. 1995). The degree of saturation appeared to

be slightly greater following gavage administration, and intravenous administration resulted in higher

proportions of the products of oxidative metabolism, with male mice being more prone than female mice.

These latter observations suggest that the oxidative pathway become more prominent when phenol is

introduced directly into the circulation, bypassing an initial intestinal sulfate conjugation process, and also

suggests that the sulfate conjugation process saturates at a lower concentration in males than in females.

Similarly, in the rat, the ratio of phenyl sulfate/glucuronide conju gates in urine decreased from 2.6 to

0.7 when the intravenous dose level is increased from 1.2 to 25 mg/kg (Weitering et al. 1979). This

phenomenon appears to be, at least in part, the result of differences in K

m in the two pathways, in relation

to their respective V

max (Koster et al. 1981; Weitering et al. 1979). The range of substrate concentrations

over which the reaction rate remains a linear function of concentration narrows as V

max /K

m decreases. A

shift toward glucuronide formation as a function of dose would be expected in V

max /K

m , for the sulfationPHENOL 104

3. HEALTH EFFECTS

pathway was less significant than the glucuronide pathway. Treatment of rats with an intraperitoneal dose

of phenol (23

– 188 mg/kg) has also been shown to result in dose- dependent decreases in hepatic

3'-phosphoadeonsine 5'-phospho sulfate (PAPS), the co

- substrate for the sulfate conjugation of phenol, as

well as sulfate (Kim et al. 1995). The depletion of PAPS may also contribute to the saturation of sulfation

at high doses of phenol. In another study of rats exposed to single and multiple bolus and drinking water

doses of different concentrations, metabolites in the urine were primarily conjugates of phenol, showing

dose-dependant concentrations (Hiser et al. 1994). For bolus doses, the ratios of glu curonide to sulfate

phenol conjugates were 0.61 for 1.5 and 15 mg/kg doses and 1.16 for 150 mg/kg doses. Drinking water

exposures resulted in a similar ratio of glucuronide to sulfate as observed for the 150 mg/kg bolus dose,

with a ratio of 0.60. For inhalation exposures, ratios ranged from 0.24 to 0.39. Small amounts of an

unidentified metabolite (2

– 4% total urinary radioactivity) were also detected.

All three enzyme systems involved in phenol metabolism have other substrates, which can competitively

inhibit the metabolism of phenol, thereby changing the balance among metabolites. Inhibition of phenol

sulfotransferase with chlorinated phenols (e.g., pentachlorophenol) results in increased glucuronide

conjugation of simple phenols (Mulder and Scholtens 1977). Similarly, benzene is metabolized by

CYP2E1; thus, high exposures to benzene may competitively inhibit phenol metabolism, resulting in

decreasing hydroquinone production (and its corresponding sulfate and glucuronide conjugates)

(Medinsky et al. 1 995; Schlosser et al. 1993). Further information regarding the shift between sulfation,

glucuronidation, and oxidation reactions is presented in Section 3.5.1, Pharmacokinetics Mechanisms.

Age

- and sex

- related changes in phenol sulfoconjugation were stud ied in hepatic cytosolic preparations

from fetal, newborn, and adult rats (Iwasaki et al. 1993). Phenol sulfoconjugation activity was higher in

adult males (1.94±0.1 nmol/mg/minute) than females (1.07±0.03 nmol/mg/minute), although there were

no sex- relat ed differences in the younger rats. Activity in fetal rats was very low

( 0.04±0.01 nmol/mg/minute). Activity at 2 days after birth was half that in adult females and a quarter of

that in adult males, and remained constant until 25 days after birth. At 2 years of age, activity was

intermediate between young adult male and female activities, and there were no sex

- related differences.

Heaton and Renwick (1991) found that young rats have a higher production of oxidative metabolism than

adult rats. If this were the case in humans, children might be potentially more sensitive to the systemic

effects of phenol, if a reactive intermediate is responsible for phenol toxicity. However, since

glucuronidation does not appear to be limited in the young, production o f oxidative products may be a

smaller risk than anticipated. Caution should be exercised when extrapolating from adolescent rats toPHENOL 105

3. HEALTH EFFECTS

children, since rodents are well known to undergo a number of changes in xenobiotic- metabolizing

enzymes during sexual development (Waxman et al. 1985).

3.4.4 Elimination and Excretion

Phenol, in its free and conjugated forms, is a normal constituent of human urine. Piotrowski (1971)

reported 8.7±2.0 mg/day as the daily excretion rate of total phen ol (free plus conjugates) in human

subjects with no known exposure to phenol. Others have reported a range of values. In a study of

workers employed in the distillation of high- temperature phenolic fractions of tar, mean values of phenol

in the urine of 13.8 mg/L in 26 male non-exposed workers and 67.8 mg/L in 89 exposed workers were

reported (Bieniek 1994). The highest concentration was found 2 hours after the end of the work shift.

Quint et al. (1998) evaluated the urinary phenol concentration before and after using phenol to chemically

cauterize the lesion created by excision of chrondroblastoma in 11 patients. Preoperatively, the average

urinary concentration of phenol was 5.1 mg/L. Ling and Hanninen (1991) studied the effect of phenol on

serum and urinary concentrations in patients who switched from a conventional diet to an uncooked

“vegan” diet. Patients were tested at week 0, were on the vegan diet for 4 weeks, and then were on the

regular diet for the second month. Urinary and serum levels of phenol were measured at weeks 0, 2, 4,

and 9. A significant decrease in both urinary and serum concentrations of phenol was seen within

2 weeks of adopting the vegan diet. At 2 weeks, the serum concentration had dropped from about 0.75 to

0.5 mg/L (abou t 30%), and levels in urine had dropped from about 7 mg/L to about 3 mg/L (about 60%).

These data indicate that phenol is a natural product of metabolism that may vary significantly depending

at least on diet, but probably also due to other factors.

Horc h et al. (1994) make the statement “urine phenol concentrations should be monitored in exposed

persons to determine if they are within normal range (0.5–81 mg/L),” but they provide no citation for the

range given. It should be noted that as late as 1980, gas chromatographic analyses of urine used to

determine phenol levels showed fairly large interlaboratory variation (Van Roosmalen et al. 1981). Thus,

the range of values given above, if derived from multiple references including the older literature, may be

artificially broad.

3.4.4.1 Inhalation Exposure

Phenol absorbed through the lungs is excreted rapidly in urine in its free and conjugated forms. Within

24 hours after human subjects inhaled phenol at concentrations of 6– 20 m g/m 3 (1.5–5.1 ppm), 99±8% of

the phenol retained in the lungs was excreted (Piotrowski 1971). The urinary excretion of phenol wasPHENOL 106

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studied in 106 men occupationally exposed to phenol, cresols, xylenols, and other phenolic derivatives,

and 26 unexposed cont rols (Bieniek 1994). Urine samples were taken after 4 hours at work, and in

16 workers every 2 hours for 24 hours after an 8-hour shift. The mean level of phenol in urine of the

exposed workers was 87.3 mg/L, compared to 11.7 mg/L in controls. The highe st phenol concentra tions

were recorded between 8 and 10 hours after the beginning of the exposure. Exposure concentrations were

not reported in this study.

A study of workers in a Bakelite factory reported a linear correlation between concentrations of phenol in

the air (up to 12.5 mg/m 3 or 3.25 ppm) and urinary excretion of total phenol (free plus conjugated)

(Ohtsuji and Ikeda 1972). However, the urinary concentration of free phenol seemed to be independent of

the environmental phenol, suggesting that under the exposure conditions, the maximum capacity to

conjugate phenol had not been reached.

Urinary excretion of total phenol (free and conjugates) is considered a biomarker of exposure for phenol.

The biological exposure index (BEI) for phenol, for exposure to 5 ppm in air, is 250 mg/g creatinine when

measured at the end of the shift (ACGIH 2001).

In rats exposed by intratracheal instillation to radiolabeled phenol, elimination was 95% complete after

72 hours, with the primary elimination route being through the urine (Hughes and Hall 1995). Fecal

elimination was slower and accounted for less overall.

In a study conducted by Hiser et al. (1994), rats were exposed via nose-only inhalation for 6 hours to

25 ppm 14 C-phenol for either 1 or 8 days. Th irty hours after initiation of exposure, mean percentages of

phenol- derived radioactivity were measured in urine and feces. In rats exposed for 1 day, values in urine

were 94.48% (males) and 90.92% (females). In rats exposed for 8 days, values in urine were 97.40%

(males). In rats exposed for 1 day, values in feces were 3.33% (males) and 2.02% (females). In rats

exposed for 8 days, values in feces were 0.81% (males). Less than 1% remained in tissues and carcass.

These results indicate rapid eliminatio n of phenol in urine after inhalation exposure.

3.4.4.2 Oral Exposure

Phenol absorbed from the gastrointestinal tract is excreted rapidly in urine as free phenol or conjugates

(Capel et al. 1972; Deichmann 1944; Edwards et al. 1986; French et al. 1974; Kao et al. 1979; Kenyon et

al. 1995; Liao and Oehme 1981). In three human subjects who received a single oral dose of 0.01 mg/kgPHENOL 107

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[ 14 C] -labeled phenol, the mean 24-hour urinary recovery of 14 C was 90% (range 85 –90%) of the

administered dose (Capel et al. 1972). In this same study, urinary recovery of orally administered

[ 14 C] -labeled phenol was determined in 18 other mammalian species; the mean 24

- hour recoveries of 14 C

ranged from 95% in the rat to 31% in the squirrel monkey. In t hree separate fatal cases of ingestion of

phenol at unknown quantities, phenol was detected in the urine at concentrations of 3.3 μg/mL (Boatto et

al. 2004), 208 μg/mL (Tanaka et al. 1998), and 47 μg/mL (Lo Dico et al. 1989).

Both urinary and fecal excretion of 14 C was determined in rats administered an oral dose of 1.2 mg/kg of

[ 14 C] -labeled phenol (Edwards et al. 1986). Rats excreted 80.3±11.2% in the urine and 1.8±1.6% in the

feces in 24 hours. In rats exposed orally to radiolabeled phenol, eliminatio n was 95% complete after

72 hours, with the primary elimination route being through the urine (Hughes and Hall 1995). Fecal

elimination was slower and less overall.

Hiser et al. (1994) reported results of rats exposed to single and multiple bolus and dri nking water doses

of different concentrations of [ 14 C] -phenol. After 24 hours, concentrations of administered 14 C

radioactivity were >90% in the urine, regardless of the dose method or concentration. Less than 1%

remained in tissues and carcass. This in dicates rapid elimination of phenol in urine after oral exposure.

3.4.4.3 Dermal Exposure

Phenol absorbed through the skin is rapidly excreted in urine as free phenol or conjugates. A 4.5-hour

occlusive exposure of one foot of a n adult male to 90% phenol resulted in an elimination half- life of

13.86 hours. When admitted to the hospital, the phenol urine concentration was 7,909 mg/g in creatine.

Over the next 12, 20, 43, 58, and 82 hours, phenol concentrations in the urine were measured at 13,416,

721, 80, 62.8, and 35.7 mg/g creatine, respectively (Bentur et al. 1998). Following an industrial accident

in which a phenol- water solution was splashed over a man's face, chest wall, hand, and both arms, phenol

in the urine decreased from 566 mg/L after 4 hours to 0.75 mg/L 46 hours after the exposure (Horch et al.

1994). Subjects exposed to dermally applied reservoirs containing phenol solutions (2.5–10 mg/L)

excreted 80% (range 58–98%) of the absorbed phenol in the urine within 24 h ours (Baranowska

Dutkiewicz 1981). Another study in which both clothed and unclothed human subjects were dermally

exposed for 7 hours to phenol vapors while breathing clean air to avoid inhalation exposure, found that

almost 100% of the absorbed phenol was excreted in the urine within 1 day, with clothing providing no

apparent protection (Piotrowski 1971).PHENOL 108

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In rats exposed dermally to radiolabeled phenol, elimination was 95% complete after 72 hours, with the

primary elimination route being through the urine (Hughes and Hall 1995). Fecal elimination was slower

and less overall.

3.4.4.4 Other Routes of Exposure

Observations of elimination of phenol (5–10 mL 7%) after injection into 20 patients were carried out as

part lumbar of lumbar and thoracic sympat hetic blockade treatments. Apparent elimination half

- lives

were 30.3±2.8 minutes for unconjugated phenol and 64.0±7.3 minutes for conjugated phenol. Urinary

excretion of conjugated phenol was 52±5% after 8 hours (Nomoto et al. 1987).

3.4.5 Physiologic ally 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 critic al biological

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based

pharmacodynamic (PBPD) models use mathematical descriptions of the dose -response function to

quantitatively describe the relationship between target tissue dose and toxic end points.

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to

delineate and characterize the relationships between: (1 ) the external/exposure concentration and target

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from

route to route, between species, and between subpopulations within a species. The biological basis of

PBPK models results in more meaningful extrapolations than those generated with the more conventional

use of uncertainty factors.

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model

representation, (2) model parameterization, (3) model simulation, and (4) model va lidation (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 AndersenPHENOL 109

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1994; Leung 1993). PBPK models for a parti cular 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 algebraic

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations

provides the predictions of tissue dose. Computers then provide process simulations based on these

solutions.

The structure and mat hematical expressions used in PBPK models significantly simplify the true

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are

adequately described, however, this simplification is desirable because data are o ften unavailable for

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of

PBPK models in risk assessm ent.

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994).

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste

sites) based on the results of studies where doses were higher or were administered in different species.

Figure 3- 4 shows a conceptualized representation of a PBPK model.

If PBPK models for phenol 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.

3.4.5.1 Summary of PBPK Models

A PBPK model simulating phenol disposition has been developed as part of the attempt to understand the

toxicity of benzene, of which phenol is the primary metabolite (Bois et al. 1991). Human exposure to

benzene is widespread, and much of the toxicity of benzene is due to the action of its metabolites. Thus,

while no studies were located involving PBPK models developed specifically for phenol exposure, the

benzene model of Bois et al. (1991) is capable of predicting the pharmacokinetics of phenol and is

appropriate to this discussion.PHENOL 110

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### Figure 3

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

Hypothetical Chemical Substance

Inhaled chemical Exhaled chemical

Ingestion

Chemicals in air

contacting skin Lungs

Liver

Fat

Slowly perfused

tissues

Richly perfused

tissues

Kidney

Skin V

E

N

O

U

S

B

L

O

O

D A

R

T

E

R

I

A

L

B

L

O

O

D V

max K

m GI

Tract

Feces

Urine

Sou rce: adapted from Krishnan et al. 1994

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by ingestion, metabolized in the liver, and excreted in the urine or by exhalation.PHENOL 111

3. HEALTH EFFECTS

Two empirical compartmental models for benzene have also been developed, which predict the

production and subsequent metabolism of phenol. A two-compartment model for quantifying benzene

hepatic metabolism to phenol and other metabolites in an in vitro microsome system was developed by

Schlosser et al. (1993) and enhanced by Medinsky et al. (1995). This model does not predict benzene (or

phenol) absorption, disposition, or excretion from the body of animals or humans. A one- compartment

model of phenol in humans was developed for assessing the variability of worker biomarkers related to

occupational exposures (Pierrehumbert et al. 2002). Methods for model calibratio n and validation data

were not reported. Both of these models are limited for use in phenol risk assessment since they do not

reduce uncertainties associated with extrapolation animal internal dosimetry to humans or high exposure

levels to low levels.

3. 4.5.2 Discussion of Models

The Bois et al. (1991) Model

A PBPK model for benzene and phenol was developed by Bois et al. (1991) to explore differences in

metabolite formation and distribution from benzene or phenol exposures to clarify why benzene, bu t not

phenol, is carcinogenic in rats and humans.

Description of the model. The model represents the male rat as a series of flow

- limited

compartments interconnected by arterial and alveolar blood flow. The disposition of benzene and phenol

was predicted in the liver, fat, bone marrow, and well- and poorly-perfused tissues. In addition, phenol

distribution to the gut and lung was included. Routes of exposure included oral gavage dosing,

inhalation, and intravenous injection of both compounds. Elimination of benzene was accomplished by

exhalation and metabolism in the liver and bone marrow. Additionally, phenol was conjugated in the

liver, lung, and gut. Hepatic and bone marrow metabolism of benzene to phenol was described by

Michaelis

- Menten genera tion of benzene oxide followed by first-order production of phenol. MichaelisMenten kinetics described the transformation of benzene oxide to diols or glutathione conjugates and

phenol to hydroquinone and sulfo - and glucurono- conjugates. Physiological f low and metabolic rates and

constants were allometrically scaled to body weight. Instead of using point estimates of physiological and

metabolic parameters values, uniform or log-uniform distributions (e.g., ranges) of parameter values were

defined for al l 64 model parameters. The model was executed using Monte Carlo techniques, in which

individual random values were sampled from each parameter distribution during iterative model runs to

produce distributions of model outputs rather than single values. T his was done to accommodatePHENOL 112

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variability and uncertainty in the parameter values. The parameter distributions were taken from the

literature.

The model was calibrated to rat data for gavage (Sabourin et al. 1987, 1989) or inhalation (Sabourin et al.

1987, 1989) of benzene and intravenous, intra- arterial, intra -duodenal, and hepatic portal injection of

phenol (Cassidy and Houston 1984) by adjusting the bounds of alveolar ventilation and other

nonspecified parameter distributions. Different compartments per taining to separate metabolic systems

were assessed by selective injection as follows: jugular vein to assess first

- pass metabolism across lung,

hepatic portal vein to assess hepatic first

- pass metabolism, duodenum to assess intestinal mucosa

metabolism, and carotid artery to assess immediate tissues distribution.

Validation of the model. Validation of this model against empirical data was not done, introducing

uncertainty into the ability of the model to predict other data. Of particular interest is the prediction that

hydroquinone production is greater following phenol administration as compared to benzene

administration. This is in opposition to the prediction of Medinsky et al. (1995).

Target tissues. The target tissues were blood and bone marrow. The expected levels of phenol in

blood and bone marrow, and total hydroquinone were substantially higher after phenol administration

than after benzene administration.

Species extrapolation. Extrapolation of this model from rats to other animals or humans has not

been done.

Interroute extrapolation. The model included parameter values for intestinal absorption and

pulmonary partitioning of phenol, which enable simulation of oral and inhalation exposures, respectively.

However, calibration and validation of these routes was not performed against empirical data. Predictions

of phenol metabolism and distribution following injection into various sites were used to illustrate

possible consequences of first- pass metabolism following oral exposure t o phenol.

Risk assessment. This model has not been applied to a quantitative risk assessment of benzene or

phenol. The predicted blood and bone marrow phenol and total hydroquinone levels were substantially

higher after phenol administration than after benzene administration. This finding is counter to the

hypothesis that phenol or hydroquinone plays a direct role in the carcinogenicity of benzene, suggesting

that other metabolites must be involved. The study authors suggest that catechol, a potentia lly genotoxicPHENOL 113

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oxidation metabolite produced in much larger amounts following benzene, as opposed to phenol

administration, may contribute to benzene's carcinogenicity.

3.5 MECHANISMS OF ACTION

3.5.1 Pharmacokinetic Mechanisms

Absorption of phenol occurs fairly rapidly via the inhalation (Hughes and Hall 1995; Ohtsuji and Ikeda

1972; Piotrowski 1971), oral (Capel et al. 1972; Edwards et al. 1986; French et al. 1974; Hughes and Hall

1995; Kao et al. 1979; Kenyon et al. 1995), and dermal (Baranowska -Dutkiewicz 1981; Hughes and Hall

1995; Piotrowski 1971) routes. Because it is an irritant, tissue damage, inflammation, or other irritation

effects may occur at the sites of absorption. Because of its high pK

a , ionization will not occu r within the

acid environment of the gut. The action of gut microflora on phenol breakdown is not expected to be

significant.

When it is absorbed through the lungs, gut, or skin, phenol conjugated at the portal -of- entry and free

phenol enter the bloodstream where it can then be distributed throughout the body (if the conjugation

capacity of the tissue has been saturated by a high dose). The dilution of phenol in water enhances the

dermal absorption of phenol, as indicated by the greater toxicity of a wat er -phenol solution compared to

neat phenol (Conning and Hayes 1970). Conning and Hayes (1970) speculated that an undiluted solution

may produce a coagulative necrosis, which would slow further penetration of phenol resulting in less

phenol absorbed than w ith more diluted solutions.

As described in Section 3.4.3, Metabolism, conjugation with glucuronic acid and conjugation with sulfate

are the main routes of detoxification of phenol. In most species tested, including humans, sulfation

predominates at lo wer doses. As doses increase, glucuronidation increases, as does the formation of

oxidative metabolites. Some have suggested that the shift from sulfation to glucuronidation is caused by

a reduction in the availability of co

- substrates in conjugation rea ction and/or reduction in the sulfate pool

(Kim et al. 1995) or due to a difference in K

m of the two pathways in relation to their respective V

max (Weitering et al. 1979). An alternative explanation for the dose- dependent metabolic profiles for phenol

is that the activities of metabolizing enzymes vary across areas of the liver (Medinsky et al. 1995). As

blood flows into the liver from the periphery of the lobule towards the central vein, it encounters first a

zone in which both sulfotransferases and glucuronosyltransferases are present (periportal zone 1), the

former predominating. Glucuronosyltransferases predominate in zone 2, whereas both glucuronosyltranferases and monooxygenases are present in pericentral zone 3. In this zonal arrangement, phenolPHENOL 114

3. HEALTH EFFECTS

would be metabolized first by sulfotransferases, and at low doses, little free phenol would be available for

glucuronide conjugation and oxidation. However, at increasing phenol doses, unconjugated phenol that

reaches zone 2 is available for glucuronidati on. At even higher doses that exceed the conjugation

capacities of zones 1 and 2, oxidative metabolites are generated (Kenyon et al. 1995). Studies in isolated

perfused liver from rats (Ballinger et al. 1995) and mice (Hoffmann et al. 1999) have validate d the

‘enzyme zonation’ model.

The influence of enzyme localization on intestinal metabolism of phenol has also been studied (Kothare

and Zimmerman 2002). In an in situ perfused intestine preparation from rat, the investigators showed that

sulfation was the predominant metabolic pathway after vascular administration of phenol, whereas

luminal dosing produced greater glucuronidation. These results were consistent with the sulfotransferases

being cytosolic enzymes (Burchell and Coughtrie 1997) and glucuro nyltransferase being located between

the nuclear and apical membrane of the epithelial cell (Inoue et al. 1999) and showing a decreasing

expressional gradient from the villus to the crypt (Chowdhury et al. 1985).

Phenol that is absorbed is rapidly excret ed in the urine as free phenol or conjugates (BaranowskaDutkiewicz 1981; Capel et al. 1972; Deichmann 1944; Edwards et al. 1986; French et al. 1974; Hughes

and Hall 1995; Kao et al. 1979; Kenyon et al. 1995; Liao and Oehme 1981; Piotrowski 1971).

3.5.2 Mechanisms of Toxicity

Limited information is available regarding the mechanism(s) of toxicity of phenol. Phenol is irritating

and corrosive at high concentrations as evidenced by numerous cases of accidental dermal exposure or

intentional or accidental ingestion of phenol. Phenol impairs the stratum corneum and produces

coagulation necrosis by denaturing and precipitating proteins. Studies in mice suggest that dermal

application of phenol increases the formation of free radicals in the skin, and that the redox cycling of

these radicals reduces antioxidant capacity, leading to significant oxidative damage of protein, DNA, and

lipids (Murray et al. 2007).

Phenol is a hydroxylated metabolite of benzene and it further undergoes oxidative metabolism to produce

other compounds; however, it is still unknown with certainty whether the parent compound or a

metabolite(s) is responsible for phenol’s systemic toxicity. The major tissues in which metabolism

appears to occur are the liver, gut, lung, and kidney (Cassidy and Houston 1984; Powell et al. 1974;

Quebbemann and Anders 1973; Tremaine et al. 1984). A study by Chapman et al. (1994) provided somePHENOL 115

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insight on a possible toxic entity. These investigators found that incubation of whole rat conceptus in

vitro with phenol resulted in minor dysmorphogenic and embryotoxic effect. However, addition of

exogenous hepatic bioactivation system greatly increased the toxicity of phenol. The major metabolites

formed were hydroquinone, catechol, and benzoquinone and these three metabolites exhibited similar

potency. Chapman et al. (1994) also found that adding together phenol and hydroquinone resulted in

more -than-additive embryotoxicity which, according to the investigators, suggested the involvement of a

peroxidative mechanism for phenol bioactivation.

Several studies in animals have reported tremors following exposure by oral gavage (Moser et al. 1995;

NTP 1983b). The mechanism by which phenol or metabolites exert this effect is unknown. Ther e is little

indication from studies in animals or from fatal poisoning cases in humans that phenol distributes

preferentially to the brain, although tremors also may be caused by actions at the periphery. Injections of

phenol (2–3%) have been used to block nerve conduction in a number of neurological disorders (i.e.,

spasticity in cerebral palsy, cervical dystonia) or to relieve pain in certain cancers. This occurs by phenol

physically interrupting the continuity of axons and inducing axonal degeneration. How this may be

related to tremors caused by gavage dosing of phenol, if at all, is unknown. It has been suggested that

phenol exposure results in cardiac effects because it blocks the cardiac sodium channel subtype, with little

effect on sodium channels in skeletal muscle (Zamponi et al. 1994). A preferential block by phenol of

sodium channels in inhibitory pathways would be consistent with a net result of increased activity or even

tremors, but there is no experimental support for this hypothesis.

3. 5.3 Animal

- to

- Human Extrapolations

Although mammals all metabolize phenol to the same metabolites, the amounts of each metabolite vary

between species. For example, in the old world monkeys and prosimians, sulfation is the major phenol

conjugation pathway, while in the new world monkeys, glucuronidation predominates (Mehta et al.

1978). Cats and pigs have low activities of phenol glucuronyltransferase, and metabolize phenol to

phenyl sulfate nearly exclusively (Capel et al. 1972; French et al. 1974; Miller et al. 1976). Because

humans have a greater capacity to glucuronidate phenol, cats and pigs would not be good models for the

metabolism of phenol by humans.

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine

system because of the ability of these chemicals to mimic or block endogenous hormones. ChemicalsPHENOL 116

3. HEALTH EFFECTS

with this type of activity are most commonly referred to as e ndocrine disruptors . However, appropriate

terminology to describe such effects remains controversial. The terminology endocrine disruptors

, initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to

develop a scr eening program for “...certain substances [which] may have an effect produced by a

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a

panel called the Endocrine Disruptors Screening and Testing Adviso ry 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 hormo nally active agents . The terminology endocrine modulators has also been used to

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to

the health of humans, aquatic animals, and wildlife. However, others think that endocrine- active

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are

similar in structure and action to endogenous estrogen. Although the public health significance and

descriptive terminology of substances capable of affecting the endocrine system remains controversial,

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction,

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering,

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994;

Giwerc man et al. 1993; Hoel et al. 1992).

Based on the available information, there is no clear evidence that phenol is an endocrine disruptor in

humans or in animals. Long-term studies in rats and mice treated with phenol in the drinking water did

not report alterations in the gross or microscopic appearance of the reproductive organs (NCI 1980). In

the 13-week experiment, rats and mice received approximately up to 1,700 and 2,700 mg phenol/kg/day,

respectively. In the 2

- year study, rats received estimated d oses of phenol of up to 600–700 mg/kg/day

and mice received 1,100–1,200 mg/kg/day. Similar observations were made in a more recent

two -generation reproductive study in rats (Ryan et al. 2001). In the latter study, the highest doses of

phenol, 301– 321 mg/ kg/day, had no significant effect on fertility, estrus frequency, testicular sperm

count, or sperm motility or morphology. Significant reductions in prostate and uterine weights in all F 1PHENOL 117

3. HEALTH EFFECTS

treated groups were not considered adverse effects of phenol by Ryan et al. (2001) on the basis of the

absence of histological alterations and functional reproductive effects, and based on the fact that only a

few animals had organ weights outside the range of concurrent control values.

In standard developmental toxicity studies in rats and mice, with one exception, fetotoxicity has only been

reported at doses that were also toxic to the mothers (Narotsky and Kavlock 1995; NTP 1983b; Ryan et

al. 2001; York 1997). In the study by NTP (1983a) in rats, a 7% decrease in feta l body weight was

reported at the high -dose level, 120 mg/kg/day, without any evidence of maternal toxicity. However,

historical control data showed that the concurrent control fetal weight for the CD rat was much higher

(22%) than the historical control weight. In addition, a larger litter size in the high-dose group may have

contributed to the smaller fetal weight in the high -dose group.

Only two reports were located with relevant information from assays in vitro . In one of them, phenol

tested negative for estrogenic activity in a reporter gene expression assay using yeast cells (Nishihara et

al. 2000). A substance was considered positive when its activity was >10% of the activity of 10 -7 M 17β

estradiol. For phenol, that concentration was >1x10 -3 M. The other study found that phenol had very

weak binding affinity to a purified recombinant human estrogen receptor (Hu and Aizawa 2003).

3.7 CHILDREN’S SUSCEPTIBILITY

This section discus ses potential health effects from exposures during the period from conception to

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation.

Relevant animal and in vitro models are also discussed.

Children are not small adults. They differ from adults in their exposures and may differ in their

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children.

Children someti mes differ from adults in their susceptibility to hazardous chemicals, but whether there is

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less

susceptible than adults to health effects, and the relationship may change with developmental age

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There arePHENOL 118

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critical periods of structural and functional development during both prenatal and postnatal life, and a

particular structu re or function will be most sensitive to disruption during its critical period(s). Damage

may not be evident until a later stage of development. There are often differences in pharmacokinetics

and metabolism between children and adults. For example, absorption may be different in neonates

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example,

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek

1966; Widdowson and Dickerson 1964). The infant also has an immature blood- brain barrier (Adinolfi

1985; Johanson 1980) and probably an immature blood- testis barrier (Setchell and Waites 1975). Many

xenobiot ic 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 stag es (Komori et al. 1990; Leeder and

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of

the parent compound to its toxic form or in detoxification. There may also be differences in excretion,

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948).

Children and adults may differ in their capacity to repair damage from chemical insults. Children also

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly

relevant to cancer.

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others

may decrease susceptibility to the same chemical. For example, although infants breathe more air per

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar

absorption (NRC 1993).

Based on a very limited data set, it is likely that most of the effects of phenol exposure, including cardiac

arrhythmias and central nervous system depression, observed in adults after exposure to high amounts of

phenol will be observed in children if exposures are comparable. The data are insu fficient to determine

whether children will be especially sensitive to such effects, however.PHENOL 119

3. HEALTH EFFECTS

IARC (1989), citing Hinkel and Kintzel (1968), indicated that a newborn infant whose umbilicus had

been bound with a bandage containing 2% phenol, died after 11 hours. Another newborn whose skin

ulcer was treated with a solution of 30% phenol/60% camphor developed circulatory failure, cerebral

intoxication, and methemoglobinemia, but recovered after a blood transfusion. Rogers et al. (1978)

evaluated the percuta neous absorption of phenol in 16 infants, aged 2 –5 months, who were treated for

seborrhoeic eczema with Magenta Paint B.P.C., a medicine containing 4% phenol. The treatment

consisted of twice daily painting of the napkin and skin folds (representing about 11–15% of the body

surface) with the Magenta paint over 48 hours, with an average of 32 mL of paint (approximately

1,300 mg of phenol) applied to each child. Phenol was detected in the urine of four of the infants;

however, no information on concentration was presented. Liver function tests run on 8 of the 16 treated

infants showed no abnormalities. The study was initiated because of the observation of signs of central

nervous system depression in a 6 -month-old who had been treated over a much larger ar ea (all of the body

except the face).

A study of 2,075 infants exposed to phenolic disinfectants used to clean hospital nursery surfaces reported

a significant increase in mean third -day microbilirubin level and an increase in the proportion of infants

wi th a microbilirubin level >10 mg/dL (Doan et al. 1979). However, no cases of severe jaundice were

observed. Since infants did not come into direct contact with the cleaned surfaces, exposure was assumed

to have occurred by inhalation of fumes.

In a 5 -year (1987–1991) retrospective review of acute exposures to a phenol -containing disinfectant

(Creolin DisinfectantTM [26% phenol]) reported to a regional poison control center, Spiller et al. (1993)

identified 96 patients, 16 of which were lost to follow -up. There were 60 oral -only exposures, 7 dermal

only exposures, 12 oral/dermal exposures, and 1 inhalation exposure. Sixty (75%) of the patients were

under 5 years of age. It was not possible to determine from the information presented the degree of

concordance between the 60 patients with oral -only exposures and the 60 under the age of 5, but it is clear

that oral exposure of young children is the predominant characteristic of this population of exposed

individuals. In this regard, children have clearly been demonstrated to be at greater risk of exposure to

phenol via the accidental ingestion of phenol- containing disinfectants. Vomiting and lethargy were the

main signs of toxicity observed in the children.

Warner and Harper (1985) reported the case of a 10

- year

- old male developed cardiac arrh ythmias

following a chemical peeling procedure initiated to remove a 12x17 cm hairy nevus of the left scapula

and nape. An hour into the procedure, which involved the application of a solution of phenol (60%PHENOL 1 20

3. HEALTH EFFECTS

phenol, 0.8% croton oil in hexachlorophene soap and water) to the entire surface of the nevus, multifocal

and coupled premature ventricular complexes developed in the electrocardiogram, but subsided after

infusion of bretylium sulfate. Although this was a severe reaction, it is difficult to determine, based on

just one case, whether it reflects a special sensitivity based on age. A 10

- year -old boy who was

hospitalized with serious burns was treated dermally with 7.5 L of an antiseptic solution containing

2% phenol for 2.5 days. During this period, hi s urine became dark, his respiration became labored, he fell

into a coma, and he died. Postmortem analysis of urine revealed 200 mg/L of conjugated phenol (Cronin

and Brauer 1949).

In a review of the use of phenol as a neurolytic agent, Wood (1978) summarized the results of a number

of studies including one in which children with cerebral palsy were given nerve blocks with 3% phenol in

water as a treatment for spasticity. Out of 150 blocks on 46 children, 9 were associated with

complications, 8 with musc le weakness, and 1 with painful paresthesia. This degree of complication was

twice that reported by another group who reported on 98 blocks, presumably in adults, with a

complication rate of 3% with all complica tions being transient paresthesia. The first group concluded that

in children the risk was too great for the benefit of the procedure. These two studies in combination

suggest that children may be especially sensitive to phenol given by injection. Interestingly, a later study

(Morrison et al. 19 91) involving 24 pediatric patients similarly treated for spasticity with injections of 5%

phenol in water at the motor point of insertion during halothane anesthesia concluded that there was no

increase in the incidence of complications. In this study the complications of concern were cardiac

arrhythmias and the incidence was 19%, yet the authors concluded that the procedure appeared

“appropriate to perform in the day- surgery context.” The difference in these studies is likely due to the

fact that the earlier study evaluated the incidence of delayed complications, whereas the Morrison et al.

(1991) work evaluated the incidence of an immediate complication, e.g., cardiac arrhythmias. There was

no indication in the Morrison et al. (1991) study that delayed complications such as subsequent muscle

weakness or paresthesia were evaluated.

Only one study in animals was located that compared the age -dependency toxicity of phenol. Deichmann

and Witherup (1944) administered phenol orally and subcutaneously to thr ee age groups of rats: 10 days

old, 5 weeks old, and adults. At a dose of 600 mg/kg orally, death occurred in 90% of 10-day- old rats, in

30% of 5- week -old rats, and in 60% of adult rats. Similarly, 3,000 mg/kg administered subcutaneously

caused death in 65% of 10 -day-old rats, 25% of 5- week

- old rats, and 45% of adult animals. These results

suggested that neonates are more sensitive than adults, and that adults are more sensitive than young rats,

but these findings have not been confirmed.PHENOL 121

3. HEALTH EFFECTS

Extremely l imited data regarding possible adverse developmental effects in humans exposed to phenol

provide no evidence for effects. As mentioned in Section 3.6, standard developmental toxicity studies in

rats and mice, with one exception (NTP 1983a), have reported fetotoxicity at doses that were also toxic to

the mothers (Narotsky and Kavlock 1995; NTP 1983b; Ryan et al. 2001; York 1997). Results from some

studies in vivo and in vitro suggest that phenol potentially could affect the germ cells, opening the

possibility that parental exposure would result in adverse childhood development or cancer (Bulsiewicz

1977; Li et al. 2005). However, the results of a well- conducted two -generation reproduction study do not

support that possibility (Ryan et al. 2001).

There i s no information regarding pharmacokinetics of phenol in children. As discussed in Section 3.4.3,

phenol is metabolized by CYP2E1 isozymes and also forms sulfate and glucuronide conjugates. To the

extent that the enzymes involved in the metabolism of phenol are developmentally regulated, the

metabolism, and consequently the toxicity of phenol, in immature humans may be different than in adults.

If microsomal oxidation transforms phenol into a toxic metabolite, a reduced CYP2E1 activity, as it

seems to oc cur in neonates, would result in decreased toxicity. However, the ability of the liver to

sulfonate phenol, and consequently facilitate elimination, also develops with age (Iwasaki et al. 1993).

Thus, a lower ability to conjugate could result in more phenol available for oxidative metabolism. Heaton

and Renwick (1991) found that young rats have a higher production of oxidative metabolism than adult

rats. If this were the case in humans, children might be potentially more sensitive to the systemic effects

of phenol. Glucuronide conjugation reactions also are considerably reduced in the young and reach adult

values only after the age of 3 in humans. This would play a role at high doses where the glucuronide

metabolites of phenol predominate. As previously mentioned, caution should be exercised when

extrapolating from adolescent rats to children, since rodents are known to undergo a number of changes in

xenobiotic-metabolizing enzymes during sexual development (Waxman et al. 1985).

It is not known whet her phenol can cross the placenta and there are no reports on levels of phenol in

maternal milk.

There are no biomarkers of exposure or effects for phenol that have been validated in children or in adults

exposed as children. No relevant studies were loc ated regarding interactions of phenol with other

chemicals in children or adults.PHENOL 122

3. HEALTH EFFECTS

3.8 BIOMARKERS OF EXPOSURE AND EFFECT

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have

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

1989).

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers

as tools of exposure in the general population is very limited. A biom arker of exposure is a xenobiotic

substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target

molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The

preferred biomarkers of exposure are generally the substance itself, substance

- specific metabolites in

readily obtainable body fluid(s), or excreta. However, several factors can confound the use and

interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures

from more than one source. The substance being measured may be a metabolite of another xenobiotic

substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic

compounds). Depending o n 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 iden tify 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 phenol are discussed in Section 3.8.1.

Biomarkers of eff ect are defined as any measurable biochemical, physiologic, or other alteration within an

organism that, depending on magnitude, can be recognized as an established or potential health

impairment or disease (NAS/NRC 1989). This definition encompasses bioc hemical or cellular signals of

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung

capacity. Note that these markers are not often substance specific. They also may not be directly

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused

by phenol are discussed in Section 3.8.2.

A biomarker of suscep tibility is an indicator of an inherent or acquired limitation of an organism's ability

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in thePHENOL 123

3. HEALTH EFFECTS

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are

discussed in Section 3.10, Populations That Are Unusually Susceptible.

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Phenol

Biological monitoring for exposure to phenol is possible by measuring blood or urine levels of the parent

compound. However, it should be noted that phenol and metabolites of phenol may also come from other

sources. For example, phenol is a metabolite of benzene and of protein metabolism. Urine samples taken

from male workers employed in the distillation of high- temperature phenolic fractions of tar revealed a

phenol excretion rate of 4.20 mg/hour compared to a control rate of 0.53 mg/hour for non -exposed

workers (Bieniek 1994). Samples were taken 4 hours into the workers' workday, but the worker exposure

levels were not reported. A study of workers in a Bakelite factory reported a linear correlation between

concentrations of phenol in the air (up to 12.5 mg/m 3 or 3.25 ppm) and urinary excretion of total phenol

(free plus conjugated) (Ohtsuji and Ikeda 1972). However, the urinary concentration of free phenol

seemed to be independent of the environmental phenol, suggesting that under the exposure conditions, the

maximum capacity to conjugate phenol had not been reached.

The biological exposure index (BEI) for occupational exposure to 5 ppm phenol is 250 mg total phenol in

urine/g creat inine (ACGIH 2005). The urine should be collected at the end of the 8-hour work shift. The

sample can be stored in the refrigerator for 4 days or frozen for at least 3 months before analysis. ACGIH

(2005) warns that the test is nonspecific and should not be used when workers are exposed to benzene or

to household products or medications that contain phenol. Dermal exposure may result in overestimation

of inhalation exposure.

Phenol can also be measured in the urine after oral exposure, although a dose- response relationship

between oral exposure to phenol and phenol in the urine has not been established. In persons not exposed

to phenol or benzene, the total phenol concentration in the urine does not exceed 20 mg/L and is usually

<10 mg/L (ACGIH 2005 ).

3.8.2 Biomarkers Used to Characterize Effects Caused by Phenol

Specific biomarkers used to characterize effects caused by phenol have not been identified. Dark urine

has been reported in persons exposed to phenol (orally, dermally, or by inhalation) (Baker et al. 1978;

Bentur et al. 1998; Cronin and Brauer 1949; Kim et al. 1994; Merliss 1972). The dark urine may be a

result of an oxidation product of phenol or hemoglobin or hemoglobin breakdown products. FurtherPHENOL 124

3. HEALTH EFFECTS

research is req uired to identify the cause of the dark urine. If it is the result of an oxidation product of

phenol, it should be considered a biomarker of exposure.

For more information on biomarkers for renal and hepatic effects of chemicals see ATSDR/CDC

Subcommittee Report on Biological Indicators of Organ Damage (Agency for Toxic Substances and

Disease Registry 1990) and for information on biomarkers for neurological effects see OTA (1990).

3.9 INTERACTIONS WITH OTHER CHEMICALS

Phenol is a tumor promoter in laboratory animals. In mice, dermal exposure to phenol in benzene

(Boutwell and Bosch 1959) or in acetone (Salaman and Glendenning 1957; Wynder and Hoffmann 1961)

increased the incidence of tumors resulting from dermal exposure to the tumor initiator, 9,10- DMBA.

The mechanism of phenol promotion activity is not known, but may be related to the dermal damage that

it causes and subsequent rapid cell division that may take place to repair the damage. When injected with

mixtures of phenol and hydroquinone, a hydroxylated metabolite of phenol, mice exhibited significantly

depressed bone marrow erythropoiesis compared to injection with phenol alone (Chen and Eastmond

1995a). The involvement of peripheral acetylcholine in phenol- induced tre mors was implicated by

studies in which mice were injected with phenol and pentobarbital, an inhibitor of acetylcholine release

(Itoh 1995).

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

A susceptible population will exhibit a different or enhanced response to phenol than will most persons

exposed to the same level of phenol 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 res ult in reduced detoxification or excretion of phenol, or compromised function of organs

affected by phenol. Populations who are at greater risk due to their unusually high exposure to phenol are

discussed in Section 6.7, Populations with Potentially High Exposures.

Potentially, individuals with low activities of the enzymes phenol sulfotransferase and glucuronyltransferase may be more susceptible to phenol toxicity. Persons with ulcerative colitis may have an

impaired capacity to s ulfate phenol (Ramakrishna et al. 1991), which may increase the amount of

unchanged phenol that is absorbed following oral exposure. Neonates may also be more susceptible to

toxicity from dermally-applied phenol because of increased skin permeability and proportionately greater

surface area. A study in which 10 -day- old rats were more sensitive to lethality following oral exposure toPHENOL 125

3. HEALTH EFFECTS

phenol than 5- week -old or adult rats (Deichmann and Witherup 1944) further suggests that the young

may be more sensitive to phenol. For a more detailed discussion, please see Section 3.7. Because phenol

is a vesicant, individuals with sensitive skin or pulmonary incapacity may be more sensitive to phenol.

Individuals with kidney or liver diseases that impair metabolism or ex cretion of phenol and phenol

metabolites may be more susceptible to phenol.

3.11 METHODS FOR REDUCING TOXIC EFFECTS

This section will describe clinical practice and research concerning methods for reducing toxic effects of

exposure to phenol. 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 phenol. 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

phenol:

Goldfrank LR, Flomenbaum NE, Lewin NA, et al. 2002. Goldfrank’s toxicologic emergencies. 7th ed. New York, NY: McGraw

- Hil l.

Haddad LM, Shannon MW, Winchester JF. 1998. Clinical management of poisoning and drug overdose. 3rd ed. Philadelphia, PA: WB Saunders Company.

Viccellio P. 1998. Emergency toxicology. 2nd ed. Philadelphia, PA: Lippinco tt -Raven Publishers.

3.11.1 Reducing Peak Absorption Following Exposure

Human exposure to phenol may occur by inhalation, ingestion, or dermal contact. Mitigation methods for

reducing exposure to phenol include the general recommendation of separating contaminated food, water,

air, and clothing from the exposed individual. Externally, phenol can produce mild irritation; acute

exposure may produce dermatitis and abnormal pigmentation (HSDB 2008). Dermal exposure to

relatively l ow concentrations of phenol (5– 6%) over a sufficient surface area can result in death.

Therefore, speed in removing phenol from the s kin is important (HSDB 2008). A study was conducted to

assess the efficacy of 10 different strategies to decontaminate the skin of anesthetized pigs that were

exposed to 89% aqueous phenol for 1 minute (Monteiro -Riviere et al. 2001). The treatment included

plain water washes for different periods of time, as well as soap, polyethylene glycol, and isopropanol

solutions. Th e evaluation was based on scoring of erythema, edema, and histological parameters of the

skin. The result showed polyethylene glycol (PEG 400) and 70% isopropanol were superior to the other

treatments and equally effective in reducing skin damage. The st udy also found that PEG 400, 70%PHENOL 126

3. HEALTH EFFECTS

isopropanol, and 15

- minute water treatments significantly reduced phenol absorption in the isolated

porcine skin flap relative to no treatment.

Emesis is not recommended following oral ingestion of phenol because of phenol ’s corrosive effects and

potential for seizures and rapid central nervous system depression. Instead, in the absence of esophageal

injury, repeated gastric lavage is recommended followed by administration of olive oil or vegetable oil to

remove surface ph enol and prevent deeper penetration. This can be followed by administration of a

cathartic such as castor oil, sorbitol, or saline. Lavage is contraindicated if esophageal injury is suspected.

3.11.2 Reducing Body Burden

Pheno l is excreted in the breath, urine, and feces. Mitigation strategies to increase urinary output and

dilute the chemical once it is in the bloodstream may be useful. One method for this may be increased

hydration of the individual in order to stimulate di uresis. Hemodialysis is not effective in removing

phenol. Information on the distribution of phenol is limited and provides little insight on how distribution

might be altered to facilitate any attempts at mitigation of effects.

3.11.3 Interfering wit h the Mechanism of Action for Toxic Effects

The mechanism of action of phenol in the body is not well understood. Reports of cardiac arrhythmias

resulting from phenol exposure are not uncommon (Gross 1984; Horch et al. 1994; Truppman and

Ellenby 1979; Warner and Harper 1985). Specific methods to interfere with the mechanism of action for

phenol were not identified. Treatment of phenol toxicity is essentially supportive. Patients exposed by

inhalation should be removed from the contaminated area and given 100% humidified oxygen and

ventilatory assistance. Cardiovascular support includes the use of intravenous saline and vasopressors to

support the blood pressure. Lidocaine can be used to treat ventricular dysrhythmias and bretilium for

lidocaine -refractory arrhythmias. Administration of sodium bicarbonate intravenously may rapidly

reverse central nervous system depression in the presence of metabolic acidosis. Also, if

methemoglobinemia is >30%, ingestion of methylene blue may be warranted.

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

adequat e information on the health effects of phenol is available. Where adequate information is notPHENOL 127

3. HEALTH EFFECTS

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

initiation of a program of research designed to determine the health effects (and techniques for developing

methods to determine such health effects) of phenol.

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 substa nce -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 nee ds will be

evaluated and prioritized, and a substance- specific research agenda will be proposed.

3.12.1 Existing Information on Health Effects of Phenol

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to

phenol are summarized in Figure 3-5. The purpose of this figure is to illustrate the existing information

concerning the health effects of phenol. Each dot in the figure indicates that one or more studies provide

information associated with that part icular 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 Substan ce -Specific Data

Needs Related to Toxicological Profiles (Agency for Toxic Substances and Disease Registry 1989), is

substance- specific information necessary to conduct comprehensive public health assessments.

Generally, ATSDR defines a data gap more broa dly as any substance

- specific information missing from

the scientific literature.

The existing information on the health effects of phenol in humans comes from case reports of people

who accidentally or intentionally swallowed phenol-containing substances or whose skin came in contact

with phenol, subjects exposed to phenol (and possibly to other substances at the same time) at work, and

populations whose drinking water was contaminated with phenol (and other substances). Acute oral and

dermal exposure to high amounts of phenol caused serious systemic effects and even death in humans due

phenol’s irritant and corrosive properties.

Acute

- and intermediate

- duration inhalation studies in animals are available, but only one of these stud ies

can be considered a modern study. Inhalation studies in animals showed adverse respiratory,

cardiovascular, liver, renal, and neurological effects. Phenol administered by oral gavage is much more

toxic than in drinking water; this is related to diffe rences in toxicokinetics between the two means ofPHENOL 128

3. HEALTH EFFECTS



### Figure 3

- 5. Existing Information on Health Effects of Phenol

D

e a t h A c u t e

I n t e

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i a t e

C

h

r o

n i c

I m

m

u n o l o g i c / L y

m

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o

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N

e

u r o l o g i c

R

e

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u c t i v e

D

e v e l o

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e n t a l

G

e n o t o x i c

C

a n c e

r Systemic

Inhalation

Oral

Dermal

Human

D

e a t h A c u t e

I n t e

r m

e d

i a t e

C

h

r o

n i c

I m

m

u n o l o g i c / L

y m

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o r e t i c

N

e

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e

p r o d

u c t i v e

D

e v e l o

p m

e

n t a l

G

e

n o t o x i c

C

a

n c e r Systemic

Inhalation

Oral

Dermal

Animal

Existing StudiesPHENOL 129

3. HEALTH EFFECTS

administration. Phenol exhibited relatively little toxicity in drinking water studies, including studies of

reproductive and developmental end points. Of special interest is a study that reported hematological,

immunological, and neurological effects in mice exposed to low concentrations of phenol in the drinking

water for 28 days. Longer

- term studies examined mostly systemic end points. Data are extensive

regarding genotoxicity of phenol in bacterial systems and mammalian systems. Data regarding the oral

carcinogenicity of phenol in rats and mice are available, as well as data on the dermal carcinogenicity,

and tumor-promoting and tumor- inhibiting activities of phenol.

3.12.2 Identification of Data Needs

Acute

- Duration Exposure. Case reports of humans exposed to high doses of phenol, either orally or

dermally, have provided acute toxicity information. Both ingestion of phenol (Boatto et al. 2004; Soares

and Tift 1982; Stajduhar-Caric 1968; Tanaka et al. 1998) and contact of phenol with a significant area of

the skin (Cronin and Brauer 1949; Griffiths 1973; Soares and Tift 1982) have caused deaths in humans.

The cardiovascular system also might be considered a target for acute phenol toxicity. Supraventricular

and ventricular dysrhythmias were reported in a case of acute ingestion of phenol (Langford et al. 1998)

and cardiac arrhythmia and bradycardia wer e reported following acute dermal exposure to phenol (Gross

1984; Horch et al. 1994; Truppman and Ellenby 1979; Warner and Harper 1985). Two acute-duration

inhalation studies in animals of limited scope indicated that the respiratory tract and the nervous system

are targets for phenol toxicity (De Ceaurriz et al. 1981; Flickinger 1976). A more recent well-conducted

study that used modern methodology to evaluate a number of relevant end points, including upper and

lower respiratory tract histology, defined a study NOAEL of 25 ppm, the highest exposure level tested

(Hoffman et al. 2001). Because no adverse effects were reported in that study, it was considered an

unsuitable basis for an MRL. Therefore, additional studies may be necessary to establish NOAEL s and

LOAELs that can be used to construct dose

- response relationships for acute exposure to phenol.

Acute -duration oral gavage studies in animals provided information on lethal doses (Berman et al. 1995;

Deichmann and Witherup 1944; Flickinger 1976; von Oettingen and Sharpless 1946) and other effects,

including renal (Berman et al. 1995), hematological (Ciranni et al. 1988), neurological (Moser et al.

1995), and developmental effects (Narotsky and Kavlock 1995; NTP 1983a, 1983b). A study in which

pregn ant rats were administered phenol by oral gavage, but divided in three daily doses and in a relatively

high volume to minimize the effects of a bolus dose of phenol, reported a significant reduction in body

weight gain in the dams at ≥120 mg/kg/day, but no significant developmental effects were reported at this

dose level (York 1997). The maternal NOAEL was 60 mg/kg/day. Decreased fetal weight and decreasedPHENOL 130

3. HEALTH EFFECTS

ossification sites were only seen at the highest dose level, 360 mg/kg/day. The reduction in maternal

weight gain during pregnancy was used as the basis for the derivation of an acute -duration oral MRL of

1 mg/kg/day for phenol. A need for additional acute- duration oral studies is not apparent at this time.

Phenol i s a well known skin irritant and further acute

- duration dermal studies in animals are unlikely to

provide new key information.

Intermediate

- Duration Exposure. Limited information exists regarding effects of phenol in

humans exposed for intermediate durations. A study of office workers exposed to vapors of a liquid

wood preservative containing phenol, among a number of other chlorinated compounds, reported adverse

respiratory, hematological, hepatic, and ocular effects, but the specific role of phenol, if any, could not be

ascertained (Baj et al. 1994). Studies of populations whose drinking water was contaminated with phenol

found increased incidences of nausea and diarrhea, but exposure to chloro phenols may have also occurred

(Baker et al. 1978; Jarvis et al. 1985; Kim et al. 1994). Only three studies were identified that exposed

animals to airborne phenol for intermediate durations (Dalin and Kristoffersson 1974; Deichmann et al.

1944; U.S. Air Force 1961). These studies provided evidence of respiratory, heart, liver, kidney, and

neurological effects, but had numerous limitations including poor control of exposure levels, unclear

scope of the evaluations, and limited reporting, and were inadequate for MRL derivation. Therefore, a

well -conducted 90-day inhalation study that examines a comprehensive number of end points would

provide valuable information for dose-response analyses and possibly MRL derivation. Since phenol is

well absorbed through the skin, a nose -only exposure protocol may be considered.

Several studies provided information on the effects of phenol following intermediate-duration oral

exposure and all of them used drinking water to administer phenol. A 13-week drinking water study in

rats and mice evaluated clinical signs and gross a nd microscopic appearance of a number of organs and

tissues and found little evidence of toxicity (NCI 1980). A two- generation reproduction study found no

evidence of reproductive effects in male or female rats, but reported decreased pup weight and reduc ed

viability (Ryan et al. 2001). A specialized 13 -week neurotoxicity study reported decreased motor activity

in female rats (Beyrouty 1998). In these three studies, the doses tested were higher than doses tested in

acute -duration oral studies. The most significant findings in the intermediate

- duration oral database were

those of Hsieh et al. (1992) who reported hematological, neurochemical, and immunological effects in

mice at dose levels much lower than those used in other studies that tested similar en d points. The Hsieh

et al. (1992) study was not used for derivation of an intermediate- duration oral MRL largely due to the

unconfirmed nature of findings and because only five mice comprised each dose group. Replication of

Hsieh’s findings seems necessary before using the data for risk assessment. Skin ulcerations werePHENOL 131

3. HEALTH EFFECTS

reported in mice treated dermally with 20% phenol in acetone once each week for 24 –32 weeks (Salaman

and Glendenning 1957). Because humans are more likely to be dermally exposed to phenol in water, and

phenol is readily absorbed through the skin, additional intermediate-duration studies examining the

effects of dermal exposure to different concentrations of phenol in water may fill a data gap.

Chronic

- Duration Exposure and Cancer. The re is limited information on health effects in

humans exposed chronically to phenol. Neither morbidity nor mortality was significantly increased in

workers in five companies that used formaldehyde and phenol (Dosemeci et al. 1991). In another study

of wo rkers in the rubber industry, exposure to phenol was associated with an increased incidence of

cardiovascular disease, independently of being associated with exposure to other solvents such as carbon

disulfide (Wilcosky and Tyroler 1983). Liver effects, a s judged by increased serum activities of ALT and

AST, were reported in a case of prolonged inhalation exposure to phenol (Merliss 1972) and in workers in

an oil-refining plant (Shamy et al. 1994), but exposure to other solvents could not be ruled out in t he latter

case. The lack of exposure data and simultaneous exposure to other chemicals precluded using the human

data for derivation of a chronic-duration inhalation MRL for phenol. No chronic- duration inhalation

studies in animals were identified. This constitutes a data gap that may need to be filled.

The only chronic-duration animal studies are the NCI (1980) 103- week studies in rats and mice. NCI

(1980) evaluated clinical signs, organ weights, and gross and microscopic appearance of organs and

tissues. Under the conditions of the study, phenol showed essentially no systemic toxicity. A chronicduration oral drinking water study with emphasis on immunological end points may be necessary if the

intermediate -duration immunotoxicity study that NTP is currently conducting confirms that

immunocompetence is the most sensitive end point for phenol toxicity. Since, as previously mentioned,

phenol is readily absorbed through the skin and the possibility exists of dermal exposure via contaminated

water (b athing or showering) at or near waste sites, a chronic-duration dermal study of phenol in water

may be considered if the results of a shorter

- term study suggest that adverse effects might happen.

A study of phenol-exposed wood industry workers reported a small, nonsignificant excess of respiratory

cancers (Kauppinen et al. 1986) and a study of phenol production workers reported a small,

nonsignificant excess of Hodgkin’s disease and of lung, esophageal, and kidney cancers (Dosemeci et al.

1991). However, the interpretation of these findings is complicated due to lack of dose-response and

potential for confounding. Phenol has been tested for carcinogenicity in long- term drinking water

bioassays in rats and mice (NCI 1980). Statistically significant incre ased incidences of

pheochromocytomas of the adrenal gland and leukemia or lymphomas were observed in male ratsPHENOL 132

3. HEALTH EFFECTS

exposed to the low dose of phenol, but not to the high dose of phenol. No significant effects were seen in

female rats or in mice. Additional b ioassays do not seem necessary at this time.

Genotoxicity. Phenol has been tested extensively for genotoxicity in a variety of in vivo (Amlacher

and Rudolph 1981; Barale et al. 1990; Bulsiewicz 1977; Chen and Eastmond 1995a; Ciranni et al. 1988;

Gocke et al. 1981; Li et al. 2005; Miyagawa et al. 1995; Pashin et al. 1987; Shelby and Witt 1995; Skare

and Schrotel 1984; Sturtevant 1952) and in vitro (Crebelli et al. 1987; Demerec et al. 1951; Erexson et al.

1985; Florin et al. 1980; Gocke et al. 1981; Haworth et al. 1983; Jansson et al. 1986; Kubo et al. 2002; Li

et al. 2005; Miller et al. 1995; Morimoto and Wolff 1980; Morimoto et al. 1983; Nagel et al. 1982;

Painter and Howard 1982; Paschin and Bahitova 1982; Pellack-Walker and Blumer 1986; Poirier et al.

1975; Pool and Lin 1982; Schwartz et al. 1985; Sze et al. 1996; Tsutsui et al. 1997) tests. The results of

these assays have been equivocal. Phenol appears to be potentially genotoxic, although this may be more

a result of the action of its metabolites than the parent compound. Additional genotoxi city studies of

phenol do not seem to be necessary.

Reproductive Toxicity. Extremely limited data regarding possible adverse reproductive effects in

humans following exposure to phenol provide no evidence for effects (Axelsson et al. 1984). Histopathological changes in reproductive organs were not observed in rats or mice treated with phenol in the

drinking water for 13 or 103 weeks (NCI 1980). In a two-generation study in which rat s were

administered phenol in the drinking water, there were no significant alterations in gross or microscopic

appearance of the reproductive organs of males and females from the parental and F 1 generations (Ryan et

al. 2001). In addition, there were no significant effects on estrus frequency, testicular sperm count, or

sperm motility or morphology. Significant reductions in prostate and uterine weights in all F 1 treated

groups were not considered adverse effects of phenol by Ryan et al. (2001) on the basis of the absence of

histological alterations and functional reproductive effects, and based on the fact that only a few animals

had organ weights outside the range of concurrent control values. Additional reproductive toxicity

studies by the oral route do not seem necessary. Studies by the inhalation or dermal route also do not

seem necessary since there is no indication that reproductive effects would be route -dependent.

Developmental Toxicity. Extremely limited data regarding possible adverse dev elopmental effects

in humans following exposure to phenol provide no evidence for effects (Axelsson et al. 1984). Phenol

has been evaluated for developmental effects in rats and mice exposed by oral gavage ( Ciranni et al.

1988; Kavlock 1990; Narotsky and Kavlock 1995; NTP 1983a, 1983b; York 1997) and in rats dosed

through the drinking water in a two-generation reproduction study (Ryan et al. 2001). These studiesPHENOL 133

3. HEALTH EFFECTS

indicated that fetotoxicity occurs only at dose levels that are also toxic to the mother. The study by York

(1997) was used to derive an acute- duration oral MRL of 1.0 mg/kg/day for phenol. Additional

developmental studies by the oral route of exposure do not seem necessary at this time. Also, studies by

the inhalation or dermal route also do no t seem necessary since there is no indication that developmental

effects would be route-dependent.

Immunotoxicity. Immunological effects were reported in workers exposed for 6 months to a mixture

of phenol, formaldehyde, and organic chlorohydrocarbons, although there is some question whether the

exposure was due to phenol or a substituted phenol (Baj et al. 1994). Increased susceptibility to bacteria

was not observed in mice exposed by inhalation to phenol (Aranyi et al. 1986). Necrosis or atrophy o f the

spleen or thymus, which was not described further, was observed in rats given a single dose of phenol by

oral gavage (Berman et al. 1995). Effects on the spleen or thymus were not observed in rats given

14 daily doses of phenol (Berman et al. 1995). Decreased antibody production in response to

immunization with SRBC was observed in mice treated with relatively low doses of phenol in the

drinking water for 28 days (Hsieh et al. 1992). Ryan et al. (2001) conducted similar tests in rats in the

two

- gen eration reproductive study and found no significant effects of phenol. It would be useful to try to

replicate Hsieh’s findings before the results can be used for risk assessment. In longer

- term studies,

histopathologic changes in the spleen or thymus were not observed in rats or mice exposed to phenol in

the drinking water for 13 or 103 weeks, but immunocompetence was not assessed (NCI 1980). Studies by

the inhalation and dermal routes are not necessary since there is no evidence of route -dependency.

Ne urotoxicity. An increase in the number of headaches was reported by persons exposed to phenol in

drinking water following an accident, but chlorophenols may have contributed to the observed effects

(Kim et al. 1994). As reported in a retrospective revi ew (Spiller et al. 1993), 11 patients with oral

exposures to phenol -based disinfectants experienced rapid central nervous system depression, but no

seizures occurred. Neurological effects (muscle tremor, loss of coordination) have been reported in

laborat ory animals after single exposures to high concentrations of phenol in the air (Flickinger 1976),

continuous exposure in the air (Dalin and Kristoffersson 1974), repeated intermittent exposures in the air

(Deichmann et al. 1944), and oral gavage dosing (Deichmann and Witherup 1944; Liao and Oehme 1981;

Moser et al. 1995; NTP 1983b). In contrast, no such effects were observed in rats and mice in drinking

water studies of longer durations and with higher doses of phenol ( Beyrouty 1998; NCI 1980). These

neurological effects correlate with peak blood concentrations of phenol achieved during gavage dosing.

Drinking water studies suggest that the nervous system is not a sensitive target for phenol toxicity by thisPHENOL 134

3. HEALTH EFFECTS

route of exposure. A need to conduct additional toxicity studies is not apparent, but studies aimed at

elucidating the mechanism(s) of phenol neurotoxicity are needed

.

Epidemiological and Human Dosimetry Studies. As previously mentioned, information about

the health effects o f phenol in humans is derived from studies of workers and members of the general

population following inhalation, oral, and dermal exposure. Specific effects and references are mentioned

in previous sections. Doses were generally not available, but Deich mann and Keplinger (1981) estimated

that an oral dose as low as 1 g could be fatal in humans, but also pointed out that patients occasionally

survived doses as high as 65 g. Other than the skin and mucosal membranes, the liver and cardiovascular

system mi ght by considered targets for phenol toxicity. Wilcosky and Tyroler 1983 studied workers in

the rubber industry and found that exposure to phenol was associated with an increased incidence of

cardiovascular disease, independently of being associated with exposure to other solvents such as carbon

disulfide. Cardiac arrhythmia and bradycardia were reported following acute dermal exposure to phenol

(Gross 1984; Horch et al. 1994; Truppman and Ellenby 1979; Warner and Harper 1985) and

supraventricular and ven tricular dysrhythmias were reported in a case of acute ingestion of phenol

(Langford et al. 1998). Liver effects were reported in a case of prolonged inhalation exposure to phenol

(Merliss 1972) and in workers in an oil-refining plant (Shamy et al. 1994), but exposure to other solvents

could not be ruled out in the latter case. Prolonged exposure to low levels of phenol may occur at or near

waste sites via contaminated water. Since such contamination may lead to inhalation exposure

(evaporation of phenol when bathing or showering, particularly if the water is acidic), dermal exposure

(absorption through the skin), and oral exposure (ingestion of water or cooking with contaminated water),

a dosimetric model that predicts total exposure and intake of phenol from contaminated water would be

valuable. The specific end points that should be monitored under such exposure scenario (prolonged low

level) are not immediately apparent. Phenol administered in the drinking water to rats and mice for

2 years showed al most no systemic toxicity (NCI 1980).

Biomarkers of Exposure and Effect.

Exposure. Measurement of total phenol in the urine is the most useful biomarker following inhalation

exposure to phenol (ACGIH 2001). The test is nonspecific and should not be used when workers are

exposed to benzene, to household products, or to medications containing phenol. Dermal exposure may

also result in overestimation of inhalation exposure. In persons not exposed to phenol or benzene, the

total phenol concentration in the urine does not exceed 20 mg/L and the mean is usually <10 mg/L

(ACGIH 2001). Phenol can also be measured in the urine after oral exposure, although a dose- responsePHENOL 135

3. HEALTH EFFECTS

relationship between oral exposure to phenol and phenol in the urine has not been established. Benzene

metabolism yields not only phenol, 1,4 -dihydroxybenzene, and their sulfates and glucuronides, but also

the benzene- specific t,t -muconic acid. For both t,t -muconic acid and S -phenylmercapturic acid,

significant corr elations were shown with benzene concentrations in air and in blood (Popp et al. 1994;

Stommel et al. 1989). Thus, determination of urinary concentrations of these metabolites allows

delineation of the portion of metabolites stemming from phenols and the portion derived from benzene

exposure. Further research on the relationship between exposure doses and urinary levels of phenol is

needed.

Effect. Specific biomarkers used to characterize effects caused by phenol have not been identified. Dark

urine has been reported in persons occupationally exposed to phenol (inhalation, dermal) (ACGIH 2001;

Merliss 1972), and following oral exposure (Baker et al. 1978; Kim et al. 1994). The dark urine may be a

result of an oxidation product of phenol or hemoglobin. Further research is required to identify the cause

of the dark urine.

Absorption, Distribution, Metabolism, and Excretion. The toxicokinetics of phenol have been

studied extensively in laboratory animals and humans. Phenol is readily absorbed from the lungs,

gastrointestinal tract, and skin. A study that examined the absorption of phenol vapor through the skin

indicates that it is readily absorbed and clothing does not serve as a barrier (Piotrowski 1971). Dermal

absorption is considered the primary route of entry for vapor, liquid, and solid phenol (ACGIH 2001).

Conjugation of phenol with glucuronic acid and sulfate are the main detoxification pathways.

Conjugation occurs predominantly in the lungs, gastrointestinal tract, li ver, and kidneys. The skin has

relatively low potential to detoxify phenol. Therefore, absorption through the skin may represent the

greatest hazard from phenol because it readily passes through the skin and because there is no first

- pass

metabolic effec t as is observed following oral exposure. Further studies regarding the metabolism of

phenol following dermal exposure are needed. In vitro studies of phenol metabolism have demonstrated

that reactive intermediates are produced during the metabolism of p henol (Chapman et al. 1994;

Eastmond et al. 1986; Lunte and Kissinger 1983; Subrahmanyam and O'Brien 1985). These reactive

compounds may be involved in mediating phenol toxicity. Further investigation of these compounds in

tissues suspected of being targets for phenol toxicity (i.e., the lungs, skin, liver, kidney, and heart) are

needed to provide information for extrapolating from animals to humans.

There is no PBPK model specifically designed for phenol, although phenol, as a major metabolite of

benzene, has been considered in a PBPK model of benzene discussed in this profile (Bois et al. 1991).PHENOL 136

3. HEALTH EFFECTS

The model does not adequately explain the differences in carcinogenicity observed between benzene and

phenol, and needs additional refinements in order to inco rporate all the observations and be validated.

Additional efforts to develop a PBPK model for phenol are needed

.

Comparative Toxicokinetics. The metabolism and excretion of orally administered phenol in

18 animal species have been compared to metaboli sm and excretion in humans (Capel et al. 1972). The

rat was the most similar to the human with respect to the fraction of administered dose excreted in urine

in 24 hours (95%) and the number and relative abundance of the four principal metabolites excrete d in

urine (sulfate and glucuronide conjugates of phenol and 1,4-dihydroxybenzene). The rat excreted a larger

fraction of the orally administered dose than the guinea pig or the rabbit (Capel et al. 1972) and appears to

be the least susceptible of the three species to respiratory, cardiovascular, hepatic, renal, and neurological

effects of inhaled phenol (Deichmann et al. 1944). More rapid metabolism and excretion of absorbed

phenol may account for the lower sensitivity of the rat to systemic effects of p henol. More information

on the relative rates of metabolism of phenol in various species is needed to identify the most appropriate

animal model for studying potential health effects in humans.

Methods for Reducing Toxic Effects. Removing a person from phenol exposure is the most

important method for reducing toxic effects of phenol. This is especially important following dermal

exposure, after which speed in removing phenol from the skin is important (HSDB 2008 ). Because a

study has shown that dilut ion in water increases the dermal absorption of phenol (Conning and Hayes

1970), it has been recommended that polyethylene be used to remove dermal contamination with phenol

(Viccellio 1998 ). Because water is readily available, others believe that its use is more appropriate for the

decontamination of skin following phenol exposure (Pullin et al. 1978). A study is available that

evaluated several strategies to decontaminate the skin of pigs following acute dermal exposure to phenol

(Monteiro

- Riviere et al . 2001). The study showed that polyethylene glycol (PEG 400) and 70%

isopropanol were superior to other treatments and equal effective in reducing skin damage induced by

phenol. The general recommendations for reducing the absorption of phenol following acute oral

exposure are well established and have a proven efficiency (HSDB 2008 ). No additional investigations

are considered necessary at this time.

No clinical treatments, other than supportive measures, are currently available to enhance elimination of

phenol following exposure. Studies designed to assess the potential risks or benefits of increasing

ventilation to enhance pulmonary elimination or of stimulating excretion of phenol and its metabolic

products are needed.PHENOL 137

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.

Deichmann and Witherup (1944) found that 10 -day- old rats were more sensitive to lethality following

oral exposure to phenol than 5- week -old or adult rats; however, this work has never been repeated and

there was little other information evaluating the toxicity of phenol at various ages. Such studies need to

be conducted in order to follow up this earlier observation. However, caution should be exercised when

extrapolating from adolescent rats to children, since rodents are known to undergo a number of changes in

xenobiotic- meta bolizing enzymes during sexual development (Waxman et al. 1985).

Studies that specifically evaluated age

- related changes in the phase I and phase II metabolic

transformations of phenol are not available. However, in general, it is known that there is a reduced

capacity to metabolize xenobiotics in the first 15 days of life, and that the different enzyme systems have

different time courses of development thereafter (Morselli et al. 1980). For example, glucuronide

conjugation reactions are considerably r educed in young humans, and reach adult values only after the

age of 3, whereas sulfate conjugations and oxidative reactions catalyzed by the cytochrome

P450 enzymes apparently develop more rapidly ( Buxton 2006; Morselli et al. 1980). Thus, there could be

age

- related differences in the balance among metabolites, particularly at high doses where the glucuronide

metabolites begin to dominate. While there is agreement that conjugation reactions represent a

detoxification mechanism for phenol, it is still unknown whether parent compound or an oxidation

product(s) is the entity responsible for the systemic toxicity of phenol in vivo . Studies are needed to

examine how age affects the metabolism of phenol, and particularly how age changes the balance

between phase I and phase II metabolism at either high or low doses.

There was no information found on the placental transfer of phenol or on the concentrations of phenol

present in breast milk. There is evidence that benzene and its (not specifically identified) m etabolites do

cross the placenta, although there is no evidence of selective accumulation (Ghantous and Danielsson

1986). Additional studies of this issue are needed to determine if phenol and its metabolites are among

the metabolites of benzene that cros s the placenta, and if so whether phenol behaves like benzene in the

lack of accumulation. Information is also needed on the content of phenol in breast milk under various

conditions (e.g, smoking versus nonsmoking mothers) in order to determine if breast milk could ever be a

source of phenol exposure for children.PHENOL 138

3. HEALTH EFFECTS

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs:

Exposures of Children.

3.12.3 Ongoing Studies

No ongoing studies pertaining to p henol were identified in the Federal Research in Progress database

(FEDRIP 2006).PHENOL 139



### 4. CHEMICAL AND PHYSICAL INFORMATION

4.1 CHEMICAL IDENTITY

Information regarding the chemical identity of phenol is located in Table 4-1.

4.2 PHYSICAL AND CHEMICAL PROPERTIES

Information regarding the physical and chemical properties of phenol is located in Table 4-2.PHENOL 140

4. CHEMICAL AND PHYSICAL INFORMATION



### Table 4

- 1. Chemical Identity of Phenol

Characteristic Information Reference

Chemical name Pheno l Lide 2005
Synonym(s) Benzenol, hydroxylbenzene, Lewis 2000 monophenol, oxybenzene, phenyl alcohol, phenyl hydrate, phenyl hydroxide, phenylic acid, phenylic

alcohol
Registered trade name(s) Carbolic acid, phenic acid, phenic Gardner et al. 1978

alcohol

Chemical formula C 6 H 6 O Lide 2005

Chemical structure 

### OH Budavari et al. 1989

Identification numbers:
CAS registry 108

- 95

- 2 HSDB 200 8

NIOSH RTECS SJ3325000 RTECS 2006

EPA hazardous waste U188 EPA 1998; HSDB 2008

DO T/UN/NA/IMCO shipping UN 1671 (solid) HSDB 2008
UN 2312 (molten)

UN 2821 (solution)
IMO 6.1 (solid, molten, solution)

HSDB 113 HSDB 2008

NCI C50124 Lewis 200 0

CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency;

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; RTE CS=Registry of Toxic Effects of Chemical SubstancesPHENOL 141

4. CHEMICAL AND PHYSICAL INFORMATION



### Table 4

- 2. Physical and Chemical Properties of Phenol

Property Information Reference

Molecular weight 94.11 1 Lide 2005

Color Colorless to light pink HSDB 2008

Physical state Crystalline solid li quid (w/ 8% H 2 O)

Melting point 40.89 °C Lide 2005

Boiling point 181.87 °C Lide 2005
Density at 20 °C/4 °C 1.0545 at 45 °C/4 °C Lide 2005

Vapor density 3.24 Lewis 200 0

Odor Distinct aromatic, somewhat sickening, sweet HSDB 2008

and acrid odor

Odor th reshold:

Water 7.9 ppm (w/v) Amoore and Hautala 1983
1 ppm (w/v) Baker et al. 1978

Air 0.040 ppm (v/v) Amoore and Hautala 1983
Solubility:

Water at 2 5 °C 8 .28x10 4 m g/L Southworth and Keller 1986
Organic solvent(s) Soluble in water a nd ethanol, very soluble in Lide 2005 ether, miscible with acetone and benzene

Partition coefficients:

Log K
ow 1.46 HSDB 2008
Log K
oc 1.21

– 1.96 Artiola

- Fortuny and Fuller 1982; Boyd 1982; Briggs 1981; Sacan and Balcioglu 1996; Scott et al. 1983
Vapor pressure at 25 °C 0.35 mmHg HSDB 2008

Henry's law constant 3.0 x10 7 atms m 3

- mol Gaffney et al. 1987

Autoignition temperature 715 °C Lewis 200 0

Flashpoint, open cup 85 °C HSDB 2008

Flashpoint, closed cup 79 °C HSDB 2008
Flammability limits (in ai r, 1.7

– 8.6% HSDB 2008 by % v)

Conversion factors:
ppm (v/v) to mg/m 3 in ppm (v/v)x3.92=mg/m 3
air (25 °C)
mg/m 3 to ppm (v/v) in mg/m 3 x0.225=ppm (v/v) air (25 °C)

atm = atmosphere; v = volume; w = weightPHENOL 142

4. CHEMICAL AND PHYSICAL INFORMATION



### This page is intentionally blank.PHENOL 143



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

5.1 PRODUCTION

Table 5- 1 lists the number of facilities in each state that manufacture or process phenol, the intended use,

and the range of maximum amounts of phenol that are stored onsite. The data listed in Table 5- 1 are

derived from the Toxics Release Inventory (TRI) (TRI05 2007). Only certain types of facilities were

required to report. Therefore, this is not an e xhaustive list.

Phenol has been obtained by distillation from petroleum and synthesis by oxidation of cumene or toluene,

and by vapor-phase hydrolysis of chlorobenzene ( Wallace 1998). In 2004, nearly 98% of U.S. phenol

production was based on oxidation of cumene except at one company that used toluene oxidation and a

few companies that distilled phenol from petroleum (CMR 2005). In 2004, the total annual capacity of

phenol production approached 6.6 billion pounds (CMR 2005). A list of current U.S. produ cers of phenol

is found in Table 5 -2.

5.2 IMPORT/EXPORT

According to the National Trade Data Bank (USITC 2008), exports of phenol were 503 million kg

(1,110 million pounds) (USITC 2008). The major importer of phenol from the Uni ted States was Canada,

with an import value of 117 million kg during 2007. The total amount of phenol imported to the United

States was 1.3 million kg ( 2.8 million pounds) in 2005. The largest exporter of phenol to the United

States was South Africa, whi ch exported 1 million kg of phenol (USITC 2008 ).

5.3 USE

The two major uses of phenol in 2004 were the production of bisphenol-A (48%) and the production of

phenolic resins (25%) (CMR 2005). The largest use for bisphenol- A is as an intermediate in the

production of epoxy resins (Thurman 1982). Phenol- formaldehyde resins comprise over 95% of this

market (Thurman 1982). Other major uses of phenol include the production of caprolactam (11%),

aniline (2%), alkylphenols (4%), xyleno ls (4%), and miscellaneous uses (6%) (CMR 2005). Phenol is

used as a slimicide (a chemical toxic to bacteria and fungi characteristic of aqueous slimes) and as a

general disinfectant in solution or mixed with slaked lime for toilets, stables, cesspools, f loors, drains, and

other areas (Budavari et al. 1989; Hawley 1981).PHENOL 144

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



### Table 5

- 1. Facilities that Produce, Process, or Use Phenol

Minimum Maximum
Number of amount on site amount on site
State a facilities in pounds b in pounds b Activities and uses c

AK 1 1 00 999 1, 13

AL 93 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

AR 39 0 49,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

AZ 17 0 9,999,999 1, 5, 6, 7, 8, 11, 12

CA 122 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

CO 6 0 99,999 1, 2, 5, 6, 9, 10, 11

CT 24 0 999,999 2, 3, 6, 7, 8, 10, 11, 12, 14

DE 10 1,000 999,999 1, 3, 5, 6, 7, 12, 13

FL 27 0 9,999,999 1, 5, 6, 7, 8, 11, 12, 13

GA 68 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14

GU 2 0 9,999 9

IA 31 0 999 ,999 2, 3, 5, 6, 7, 8, 10, 11, 12

ID 6 0 9,999 1, 2, 3, 5, 7, 11, 13

IL 105 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

IN 126 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

KS 36 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 1 2, 13

KY 51 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13

LA 100 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

MA 38 0 499,999,999 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13

MD 19 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 11, 13

ME 23 0 999,999 1, 2, 3, 5, 6, 7, 8, 10, 12, 13, 14

MI 88 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

MN 41 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13

MO 42 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12

MS 49 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

MT 15 0 9,999,999 1, 2, 3, 5, 6, 9, 13, 14

NC 69 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

ND 3 0 99,999 1, 5, 7

NE 9 100 999,999 1, 3, 5, 6, 8, 11, 12

NH 11 0 999,999 1, 2, 3, 5, 7, 8, 10, 11, 12, 13

NJ 47 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

NM 3 10,000 999,999 1, 2, 3, 7, 10, 12, 13

NV 2 1,000 99,999 7

NY 62 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

OH 122 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

OK 45 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

OR 50 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13

PA 108 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13PHENOL 145

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



### Table 5

- 1. Facilities that Produce, Process, or Use Phenol

Minimum Maximum
Number of amount on site amount on site
State a facilities in pounds b in pounds b Activities and uses c

PR 15 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13

RI 5 1 00 99,999 6, 7, 8

SC 53 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

SD 1 1,000 9,999 3, 6, 10, 11

TN 72 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

TX 155 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

UT 2 5 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13

VA 41 0 49,999,999 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 14

VI 4 100 999,999 1, 2, 3, 4, 5, 6, 7, 9

VT 6 1,000 9,999 2, 3, 6, 8, 10

WA 58 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

WI 60 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13

WV 27 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13

WY 13 0 999,999 1, 3, 4, 5, 6, 7, 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/Othe r Uses

4. Sale/Distribution 9. Article Component 14. Process Impurity

5. Byproduct 10. Repackaging

Source: TRI05 2007 (Data are from 2005)PHENOL 146

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



### Table 5

- 2. Current U.S. Producers of Phenol

Capacity Company Location (millions of pounds)

Dakota Gasification Company Beulah, North Dakota 35
The Dow Chemical Company Oyste r Creek, Texas 650
General Electric Company, GE Advanced Mount Vernon, Indiana 750

Materials Plastics
Georgia Gulf Corporation Pasadena, Texas 160
Georgia Gulf Corporation Plaquemine, Louisiana 500

INOES Phenol Inc. Theodore, Alabama 1200

JLM Chemical s Blue Island, Illinois 100

Merisol USA LLC Houston, Texas 25

Noveon Inc. Kalama, Washington 75
Shell Chemical Company Deer Park, Texas 1,180

Sunoco Inc. Haverhill, Ohio 1,000

Sunoco Inc. Philadelphia, Pennsylvania 1,115

Source: Derived from SRI 20 06PHENOL 147

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

5.4 DISPOSAL

Phenol is listed as a toxic substance under Section 313 of the Emergency Planning and Community Right

to Know Act (EPCRA) under Title III of the Superfund Amendments and Reauthorization Act (SARA)

(EPA 1998c). Disposal of wastes containing phenol is controlled by a number of federal regulations (see

Chapter 8).PHENOL 148

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



### This page is intentionally blank.PHENOL 149



### 6. POTENTIAL FOR HUMAN EXPOSURE

6.1 OVERVIEW

Phenol has been identified in at least 5 95 of the 1,678 hazardous waste sites that have been proposed for

inclusion on the EPA National Priorities List (NPL) (HazDat 2006). However, the number of sites

evaluated for phenol is not known. The frequency of these sites can be seen in Figure 6-1. Of these sites,

589 are located within the United States and 4 are located in the Commonwealth of Puerto Rico (not

shown) and 2 are located in the Virgin Islands (not shown).

Phenol is released to the air and water as a result of its manufacture, its use in phenolic resins, and organic

synthesis (Wallace et al. 1996). Phenol is found in petroleum products such as coal tar, and creosote and

can be released by combustion of wood and auto exhaust (Wallace et al. 1996). Phenol is also produced

by the natural degradation of organic wastes including benzene. Phenol is a major metabolite of benzene

(Rothman et al. 1998), which is found extensively in the environment (Agency for Toxic Substances and

Disease Registry 2006), therefore, phenol may be formed in the environment as a result of the natural

degradation of benzene.

Phenol mainly enters the water from industrial effluent discharges. Phenol is degraded rapidly in air by

gas -phase hydroxyl radical reaction (estimated half-life 14.6 hours), but may persist in water for a

somewhat longer period. Half- lives for biodegradation range from <1 day in samples of lake water to

9 days in estuarine water; a typical half -life for photooxidation by photochemically produced peroxyl

radicals is appr oximately 19 hours. In soil, phenol will generally biodegrade rapidly; however,

biodegradation of phenol in water or soil may be hindered or precluded by the presence of high, toxic

concentrations of phenol or other chemicals, or by other factors such as a lack of nutrients or

microorganisms capable of degrading phenol. If biodegradation is sufficiently slow, phenol in sunlit

water will undergo photooxidation with photochemically produced peroxyl radicals, and phenol in soil

will leach to groundwater. Ph enol may remain in air, water, and soil for much longer periods if it is

continually or consistently released to these media from point sources. Since plants can metabolize

phenol readily, exposure through eating food derived from plants grown in phenol-c ontaining soil is

probably minimal.

Phenol has been measured in effluents (up to 53 ppm), ambient water (1.5–>100 ppb), drinking water (not

quantified), groundwater (1.9–>10 ppb), rain (0.075

– 1.2 ppb), sediment (>10 ppb), and ambient air (0.03–

44 ppb). Occupational exposures occur through inhalation and dermal exposure; air concentrationsPHENOL 151

6. POTENTIAL FOR HUMAN EXPOSURE

monitored in various workplaces range from 0.1 to 12.5 mg/m 3 (0.03–32 ppm). Occupational as well a s

consumer exposure may also occur through dermal contact with phenol or phenol-containing products.

6.2 RELEASES TO THE ENVIRONMENT

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of

facilities are requi red 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 pr oduces,

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI

chemical in a calendar year (EPA 2005).

6.2.1 Air

Estimated releases of 7.6 million pounds (~3,480 metric tons) of phenol to the atmosphere from

677 domestic manufacturing and processing facilities in 2004, accounted for about 64% of the estimated

total environmental releases from facilities required to report to the TRI (TRI05 2007). These releases are

summarized in Table 6 -1.

During manufacturing, phenol is released primarily to the atmosphere from storage tank vents and during

transport loading (EPA 1979c). Other major sources of release to the atmosphere are residential wood

burning and automobile exhaust (EPA 1981a). Volatilization from environmental waters and soils has

been shown to be a slow process (see Section 6.3.1) and is not expected to be a significant source of

atmospheric phenol. Phenol is released into the atmosphere from industrial combustion processes. For

example, phenol has been detected at a concentration of 0.36 ppb in the emissions of a waste incinerator

plant in Germany (Jay and Stieglitz 1995). In Brazil, an estimated 64 kg/year of phenol is released to the

urban areas located near coal

- fired pow er stations, indicating that people who live near coal-fired power

stations may have an increased risk of exposure to phenol (Moreira dos Santos et al. 2004). Phenol is alsoPHENOL 152

6. POTENTIAL FOR HUMAN EXPOSURE



### Table 6

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

Use Phenol a

Reported amounts released in pounds per year b

Total release

On

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

- site j Off

- site k off

- site

AL 33 407,745 278 0 8,213 0 408,261 7,975 416,236

AR 15 53,803 136 0 4 ,781 0 54,241 4,479 58,720

AZ 2 5,499 No data 0 100 0 5,499 100 5,599

CA 33 100,135 1,974 0 5,544 305 102,117 5,841 107,958

CO 2 32 No data 0 0 0 32 0 32

CT 4 5,631 No data 0 649 728 5,631 1,377 7,008

DE 2 160 44,595 0 0 0 44,755 0 44,755

FL 12 114,2 30 950 0 91 0 115,272 0 115,272

GA 25 146,687 518 0 1,468 2,102 147,242 3,533 150,775

IA 5 17,126 36 0 100,501 0 17,162 100,501 117,663

ID 2 1,005 5 0 4,428 0 1,010 4,428 5,438

IL 28 614,954 602 0 50,925 251 616,526 50,206 666,732

IN 32 391,396 3,660 100,000 35,975 5 495,190 35,845 531,035

KS 7 76,565 54 0 5,869 1,829 76,637 7,680 84,317

KY 13 108,867 809 0 56,542 0 109,676 56,542 166,218

LA 36 124,638 15,173 150,002 10,660 120 295,401 5,192 300,593

MA 6 15,108 No data 0 803 0 15,108 803 15,911

MD 2 13,004 No data 0 0 0 13,004 0 13,004

ME 5 25,852 15 0 906 0 25,893 880 26,773

MI 29 121,520 660 19 78,038 44,762 122,188 122,810 244,998

MN 8 55,892 150 0 98 3 56,117 26 56,143

MO 9 15,024 0 0 0 0 15,024 0 15,024

MS 12 67,983 207 0 1,238 0 68,190 1 ,238 69,428

MT 5 3,724 25 0 23 0 3,772 0 3,772

NC 23 186,812 311 0 164,098 0 187,269 163,952 351,221

ND 1 220 49 2,100 0 0 2,369 0 2,369

NE 4 888 No data 0 147 0 896 139 1,035

NH 2 6,203 No data 0 1 0 6,203 1 6,204

NJ 10 6,218 1,828 0 10,327 0 16,022 2,351 18,373

NM 1 1,078 No data 0 0 0 1,078 0 1,078

NY 23 57,689 62 0 22,704 56,518 57,777 79,196 136,973

OH 45 522,126 1,219 34 119,210 807 528,880 114,516 643,397

OK 10 21,713 558 0 17,557 4,855 38,249 6,434 44,683

OR 22 186,431 189 0 12,935 3,453 187,736 15,272 203,008

PA 29 424,309 9,699 0 4,994 2,093 434,776 6,319 441,096

PR 3 4,974 No data 0 4,561 0 4,974 4,561 9,535

RI 1 724 No data 0 0 0 724 0 724PHENOL 153

6. POTENTIAL FOR HUMAN EXPOSURE



### Table 6

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

Use Phenol a

Reported amounts released in pounds per year b

Total release

On

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

- site j Off

- site k off

- site

SC 20 93,387 1,284 0 148,473 0 115,489 127,656 243,145

TN 15 81,725 305 0 2,006 45 82,439 1, 642 84,081

TX 75 233,116 7,659 1,225,465 99,083 118 1,416,533 148,909 1,565,442

UT 3 31,100 No data 0 7,600 0 38,700 0 38,700

VA 12 56,625 299 0 31,225 750 87,264 1,635 88,899

VI 1 78,848 612 0 1 0 79,460 1 79,461

WA 19 127,933 5,382 0 427 181 133,355 568 133,923

WI 23 305,630 55 0 27,762 30 305,685 27,792 333,477

WV 6 20,279 188 0 69 44 20,475 105 20,580

WY 2 750 No data 0 0 0 750 0 750

Total 677 4,935,360 99,546 1,477,621 1,040,033 118,999 6,561,054 1,110,505 7,671,559

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 use d.

d Number of reporting facilities.

e The sum of fugitive and point source releases are included in releases to air by a given facility.

f Surface water discharges, waste water treatment

- (metals only), and publicly owned treatment works ( POTWs) (metal

and me tal compounds).

g Class I wells, Class II

- V wells, and underground injection.

h Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on

- site landfills, land treatment, surface impoundments, other land disposal, other landfills.

i Storage only, solidification/stabilization (metals only), other off

- site management, transfers to waste broker for disposal, unknown
j The sum of all releases of the chemical to air, land, water, and underground injection wells.

k Total amount of chemical transferred off

- site, including to POTWs.

RF = reporting facilities; UI = underground injection

Source: TRI05 2007 (Data are from 2005)PHENOL 154

6. POTENTIAL FOR HUMAN EXPOSURE

found in cigarette smoke and in plastics (Graedel 1978), but no data are available to determine the extent

of exposure to p henol from these sources.

6.2.2 Water

Estimated releases of 99,546 pounds (~45 metric tons) of phenol to surface water from 677 domestic

manufacturing and processing facilities in 2005, accounted for about 0.1% of the estimated total

environmental rel eases from facilities required to report to the TRI (TRI05 2007). These releases are

summarized in Table 6 -1.

The most common anthropogenic sources of phenol in natural water include coal tar (Thurman 1982) and

waste water from manu facturing industries such as resins, plastics, fibers, adhesives, iron, steel,

aluminum, leather, rubber (EPA 1981b), and effluents from synthetic fuel manufacturing (Parkhurst et al.

1979). Phenol is also released from paper pulp mills (Keith 1976) and w ood treatment facilities (Goerlitz

et al. 1985). Other releases of phenol result from commercial use of phenol and phenol-containing

products, including slimicides, general disinfectants (Budavari et al. 1989; Hawley 1981), and medicinal

preparations such as throat lozenges, mouthwashes, gargles, and antiseptic lotions (Darisimall 2006).

Two natural sources of phenol in aquatic media are animal wastes and decomposition of organic wastes

(EPA 1980). As a metabolite of benzene, phenol may be released from publicly owned treatment works

(POTWs) and sewage overflow. For example, it has been estimated that 3.8 kg/day of phenol are released

to Newark Bay, in New Jersey, from municipal treatment facilities (Crawford et al. 1995). Phenol was

detected in 2% of t he effluent samples from New York City sewage waste facilities collected during 1989

to 1993 at concentrations of 6–310 g/L (Stubin et al. 1996). Because it is a metabolite, phenol is likely to

be found in other sewage and POTWs facilities. No data are available to determine the extent of exposure

from these sources.

Estimated releases of 85,700 pounds (~39 metric tons) of phenol to surface water from 689 domestic

manufacturing and processing facilities in 2004, accounted for about 0.1% of the estimated total

environmental releases from facilities required to report to the TRI (TRI0 5 2007 ). These releases are

summarized in Table 6 -1.

The most common anthropogenic sources of phenol in natural water include coal tar (Thurman 1982) and

waste water from manufacturing industries such as resins, plastics, fibers, adhesives, iron, steel,

aluminum, leather, rubber (EPA 1981b), and effluents from synthetic fuel manufacturing (Parkhurst et al.PHENOL 155

6. POTENTIAL FOR HUMAN EXPOSURE

1979). Phenol is also released from paper pulp mills (Keith 1976) and wood treatment facilities (Goerlitz

et al. 1985). Other releases of phenol result from commercial use of phenol and phenol-containing

products, including slimicides, general disinfectants (Budavari et al. 1989; Hawley 1981), and medi cinal

preparations such as throat lozenges, mouthwashes, gargles, and antisep tic lotions (Darisimall 2006).

6.2.3 Soil

Estimated releases of 1 million pounds (~472 metric tons) of phenol to soils from 689 domestic

manufacturing and processing faciliti es in 2005, accounted for about 14% of the estimated total

environmental releases from facilities required to report to the TRI (TRI05 2007). An additional

1.5 million pounds (~670 metric tons), constituting about 19% of the total environmental emissions, were

released via underground injection (TRI05 2007). These releases are summarized in Table 6-1.

Phenol may be released to the soil during its manufacturing process, when spills occur during loading and

transport, and when it leac hes from hazardous waste sites and landfills (Xing et al. 1994). Generally, data

on concentrations of phenol found in soil at sites other than hazardous waste sites are lacking. This may

be due in part to a rapid rate of biodegradation and leaching (see Sections 6.3.1 and 6.3.2.3). Phenol can

be expected to be found in soils that receive continuous or consistent releases from a point source. Phenol

that leaches through soil to groundwater spends at least some time in that soil as it travels to the

groundwater. Phenol has been found in groundwater, mainly at or near hazardous waste sites.

6.3 ENVIRONMENTAL FATE

6.3.1 Transport and Partitioning

Phenol is released into the air and discharged into water from both manufacturing and use. Based on its

high water solubility (see Table 4 -2) and the fact that it has been detected in rainwater, some phenol may

wash out of the atmosphere; however, it is probable that only limited amounts wash out because of the

short atmospheric half-life of phenol. During the day, when photochemically produced hydroxyl radical

concentrations are highest in the atmosphere, very little atmospheric transport of phenol is likely to occur.

In water, neither volatilization nor sorption to sediments and sus pended particulates are expected to be

important transport mechanisms. Using the Henry's Law constant of 3x10 -7 atm m 3 /mol ( Gaffney et al.

1987 ), a volatilization half

- life of 88 days was calculated for phenol evaporation from a model river 1 m

deep with a current of 1 m/second, and wind velocity of 3 m/second (Lyman et al. 1982). The biologicalPHENOL 156

6. POTENTIAL FOR HUMAN EXPOSURE

treatment of waste water containing phenol has shown that <1% of phenol is removed by stripping

(Kincannon et al. 1983; Petrasek et al. 1983).

Phenol has been re ported in sediments at levels as high as 608 ppm dry weight; however, it is not known

whether the location of the site where this concentration was reported is at or near a point source of

release, such as a hazardous waste dump. The concentrations of the overlying waters were not reported.

The moderately low soil sorption partition coefficient (1.21– 1.96) suggests that sorption to sediment is

not an important transport process. There is very little sorption of phenol onto aquifer materials (Ehrlich

et a l. 1982), suggesting that phenol sorption to sediments may also be minimal. Based on the soil

adsorption coefficient, phenol is expected to leach to groundwater; however, the rate of phenol

biodegradation in the soil may be so rapid, except in cases of la rge releases such as spills or continuous

releases such as leaching from landfill sites, that the probability of groundwater contamination may be

low (Ehrlich et al. 1982). Phenol has been detected in groundwater as a result of leaching through soil

from a spill of phenol (Delfino and Dube 1976), from landfill sites (Clark and Piskin 1977), and from

hazardous waste sites (Plumb 1987). The sorption coefficient for phenol by soils increases with

increasing soil organic matter which may indicate that soil organic matter may be the primary phenol

sorbent in soil (Xing et al. 1994).

Phenol is not expected to bioconcentrate significantly in aquatic organisms. Reported log bioconcentration factors (BCF) in fish for phenol include 0.28 for goldfish, (Kobayashi et al. 1979) and 1.3 for golden

orfe (Freitag et al. 1984). The highest mean level of phenol detected in bottom fish from Commencement

Bay in Tacoma, Washington, was 0.14 ppm (Nicola et al. 1987). The levels of phenol in the water or

sediments were not s tated.

The pKa of phenol is 10 (O’Neil 2001), indicating that phenol will primarily exist as the protonated acid

at environmental pH values. In alkaline soils and water, phenol will partially exist as an anion, which can

affect its fate and transport pro cesses.

Although it has been shown that plants readily uptake phenol (DOE 1987), bioaccumulation does not take

place due to a high rate of respiratory decomposition of phenol to CO 2

.PHENOL 157

6. POTENTIAL FOR HUMAN EXPOSURE

6.3.2 Transformation and Degradation

6.3.2.1 Air

The gas -phase reaction of phenol with photochemically produced hydroxyl radicals is probably a major

removal mechanism in the atmosphere. An estimated half -life for phenol for this reaction is 0.61 days

(EPA 1979a). The reaction of phenol with nit rate radicals during the night may constitute a significant

removal process. This is based on a rate constant of 3.8x10 -12 cm 3 /molecule second for this reaction,

corresponding to a half- life of 15 minutes at an atmospheric concentration of 2x10 8 nitrate r adicals per

cm 3 (Atkinson et al. 1987). The reaction of phenol with nitrate radicals present in the atmosphere during

smog episodes may decrease the half -life of phenol in polluted atmospheres. The above data indicate that

phenol has a short half- life in the atmosphere, probably <1 day. Phenol does not absorb light in the

region of 290– 330 nm (Lide and Milne 1994); therefore, it should not photodegrade directly in the

atmosphere.

6.3.2.2 Water

Although phenol does not absorb light at wavelengths >290, phenols react rapidly to sunlit natural water

via an indirect reaction with photochemically produced hydroxyl radicals and peroxyl radicals; typical

half-lives for hydroxyl and peroxyl radical reactions are on the order of 100 an d 19.2 hours of sunlight,

respectively (Canonica et al. 1995; Mill and Mabey 1985). These reactions require dissolved natural

organic materials that function as photosensitizers (Canonica et al. 1995). The estimated half- life for the

reaction of phenol with photochemically produced singlet oxygen in sunlit surface waters contaminated

by humic substances is 83 days (assuming Switzerland summer sunlight and a singlet oxygen

concentration of 4x10 -14 molar [M]) (Scully and Hoigne 1987).

Phenol is readily b iodegradable in natural water, provided the concentration is not high enough to cause

significant inhibition through microbial toxicity. Complete degradation in <1 day has been reported in

water from three lakes; the rates of degradation were affected by the concentration of organic and

inorganic nutrients in the water (Rubin and Alexander 1983). Complete removal of phenol in river water

has been reported after 2 days at 20 °C and after 4 days at 4 °C (Ludzack and Ettinger 1960). The

degradation of pheno l is somewhat slower in salt water, and a half -life of 9 days has been reported in an

estuarine river (EPA 1979b). Rapid degradation of phenol also has been reported in various sewage and

water treatment processes. Removal in aerobic activated sludge rea ctors is frequently >90% with a

retention time of 8 hours (Stover and Kincannon 1983). In aerobic reactors using municipal seedPHENOL 158

6. POTENTIAL FOR HUMAN EXPOSURE

(conventional activated sludge organisms) and in reactors using an industrial seed (mixture of organisms),

it was noted that co ncentrations as low as 50 mg/L inhibited organism respiration rates, but complete

inhibition was not observed at concentrations as high as 200 mg/L (Davis et al. 1981). Utilization is also

very high in anaerobic reactors, although acclimation periods are longer and degradation usually takes

about 2 weeks (Boyd et al. 1983; Healy and Young 1978). One method of phenol breakdown is

accomplished by the bacterium Pseudomonas sp. CF600, which uses a set of enzymes encoded by the

plasmid dmp operon (Powlowski and Shingler 1994). The use of sequence batch reactors (SBR) in

treating sludge contaminated with phenolic compounds has proven effective in breaking down the

compounds biologically with no evidence of phenol volatility (Al- Harazin et al. 1991). Levels as high as

a one- time treatment of 1,600 mg/L can be broken down by 75% with a 1-day retention time. Lower

concentrations as high as 800 mg/L can be broken down to <0.5 mg/L with a 1

- day retention time. The

alga Ochromonas danica has also been shown to degrade phenol (Semple and Cain 1996). When grown

in the dark with 0.1–1 mM phenol as the sole carbon source, phenol was removed within 3 days. Because

of the rapid rate of biodegradation, groundwater is generally free of phenol even though it is highly

mobile in soil. However, monitoring data in Section 6.4.2 contain groundwater concentrations in areas of

large phenol releases.

While the evidence presented in the literature cited above suggests that phenol can be rapidly and

virtually completely degraded u nder both natural water and sewage treatment plant conditions,

monitoring data presented in Section 6.4 below indicate that phenol, despite this apparent

biodegradability, is still present in the environment. This suggests that the exact conditions under which

phenol is rapidly degraded are not present in all instances. In some situations, the concentration of phenol

may be too high or the populations of microorganisms may not be present in sufficient concentration for

significant biodegradation to occur.

6.3.2.3 Sediment and Soil

Available data indicate that phenol biodegrades in soil under both aerobic and anaerobic soil conditions.

The half

- life of phenol in soil is generally <5 days (Baker and Mayfield 1980), but acidic soil s and some

surface soils may have half-lives of up to 23 days (Shiu et al. 1994). Mineralization in an alkaline, parabrown soil under aerobic conditions was 45.5, 48, and 65% after 3, 7, and 70 days, respectively (Haider et

al. 1974). Half- lives for deg radation of low concentrations of phenol in two silt loam soils were 2.70 and

3.51 hours (Scott et al. 1983). Plants have been shown to be capable of metabolizing phenol readily

(DOE 1987).PHENOL 159

6. POTENTIAL FOR HUMAN EXPOSURE

While degradation is slower under anaerobic conditions, evidence presented in the literature suggests that

phenol can be rapidly and virtually completely degraded in soil under both aerobic and anaerobic

conditions (Baker and Mayfield 1980).

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

Reliable evaluation of the potential for human exposure to phenol depends in part on the reliability of

supporting analytical data from environmental samples and biological specimens. Concentrations of

phenol 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 phenol levels monitored or estimated in the

environment, it should also be noted that the amount of chemical identified analytically is not necessarily

equivalent to the amount that is bioavailable. The analytical methods available for monitoring phenol in a

variety of environmental media are detailed in Chapter 7.

6.4.1 Air

There are very few monitoring data concerning the presence of phenol in ambient air. Phenol was found

at a median concentration of 30 parts per trillion (ppt) in 7 samples from 1 U.S. urban/suburban site in

1974 and at an overall median concentration of 5,000 ppt in 83 samples from 7 source-dominated sites

between 1974 and 1978 (EPA 1982). The individual medians of the seven source sites ranged from

520 to 44,000 ppt (EPA 1982). Phenol was detected, but not quantified, in air above the Niagara River in

September of 1982 (Hoff and Chan 1987). Phenol concentrations in two ur ban areas ranged from 13 to

91 ppt and from <5 to 75 ppb with 50% of all measurements <8 ppb (EPA 1981a). Phenol was found at

approximately 1 ppb in the ambient air near a fishmeal factory in Japan (Hoshika et al. 1981). In a study

to determine contaminants in the air of agricultural areas, phenol was found in 42 out of 53 air samples

taken from 8 farms at an average concentration of 10 μg/m 3 (Sunesson et al. 2001). Phenol was detected

in indoor and outdoor air in the city of Ottawa, Canada at concentrat ion ranges of 0.01 –5.16 and 0.01–

1.41 μg/m 3 , respectively (Zhu et al. 2005).

In a study of various air samples from Helsinki, Finland, 92% of outdoor air and 86% of indoor air did

not have detectible quantities of phenol (Edwards et al. 2001). Workplac e and personal exposure samples

also had low relative percentages of phenol with only 12 and 11% of the samples above the limits of

detection, respectively (Edwards et al. 2001).PHENOL 160

6. POTENTIAL FOR HUMAN EXPOSURE

Higher phenol concentrations may occur when there is smog or in highly con taminated air. During a

smog episode in West Covina, California, in July of 1973, phenol concentrations ranged from 16 to

91 ppt, with a mean concentration of 60 ppt (Cronn et al. 1977). During a haze episode in 1998 in Brunei,

Syria, phenol was found in 8 out of 15 sites tested in concentrations ranging from 0.07 to 0.41 μg/m 3 ; of

these sites, 4 were near a hospital (Muraleedharan et al. 2000).

Phenol and other volatile organic compounds were measured in the air of 50 homes or apartments in

Finland (Kostiainen 1995). The average concentration was 0.23 ppb, with a range of 0–0.77 ppb. Phenol

levels were not significantly higher in houses in which people complained of symptoms that resembled

those of a sick building syndrome.

Phenol has been detecte d in the ash phase of burning pine, oak, and eucalyptus in concentrations of 524,

300, and 434 mg/kg, respectively (Schauer et al. 2001). Phenol has also been identified in the combustion

of soft fireplace wood, hard fireplace wood, stove wood, and synthetic wood at concentrations of 158,

247, 142, and 8.58 mg/kg, respectively (McDonald et al. 2000).

Phenol is released to the atmosphere from burning coal. In a study of three urban sites in Brazil near

coal -fired power stations, phenol was detected in all three locations with concentrations ranging from

0.98 to 1.60 μg/m 3 (Moreira dos Santos et al. 2004). This indicates that families living near coal- fired

power stations may be exposed to higher concentrations of phenol.

6.4.2 Water

Phenol has been detected in surface waters, rainwater, sed iments, drinking water, groundwater, industrial

effluents, urban runoff, and at hazardous waste sites. Background levels of phenol from relatively pristine

sites can be as high as 1 ppb for unpolluted groundwater and have been reported to range from 0.01 to

1 ppb in unpolluted rivers (Thurman 1985). Phenol has been detected in Lake Huron water at 3–24 ppb

(Konasewich et al. 1978) and industrial rivers in the United States at 0–5 ppb (Sheldon and Hites 1978,

1979). The annual mean concentration of phenol in water from the lower Mississippi River was 1.5 ppb

(EPA 1980). River water in an unspecified location in the United States was reported to contain 10–

100 ppb of phenol (Jungclaus et al. 1978). Phenol was detected, but not quantified, in a Niagara Rive r

watershed (Elder et al. 1981) and in 2 of 110 raw water samples analyzed during the National Organic

Monitoring Survey (EPA 1980).PHENOL 161

6. POTENTIAL FOR HUMAN EXPOSURE

In a study of 95 organic waste components from 139 streams in 30 states from 1999 to 2000, phenol was

detected in 85 sampl es with a median concentration of 0.7 μg/L (Kolpin et al. 2002). Phenol has been

detected in China in water samples taken near the Huanchao River water factory, in the Tanking River,

and near the Tanking River water factory at concentrations of 0.053, 0.0 44, and 0.033 μg/L, respectively

(Huang et al. 2003).

Each year about 30 million m 3 of mine water is pumped into the Samara River in the Ukraine. Phenol

was detected in the surface water in the Samara River from 1987 to 1990 with concentrations ranging

from 1.5 to 8.3 μg/L (Goncharuk and Milyukin 1999). In a study of organic contaminants in the

groundwater from creosote contaminated sites in Denmark, phenol was detected in all 11 sites tested with

concentrations ranging from 11 to 249 μg/L (Johansen et a l. 1997).

In general, higher levels of phenol appear to be found in lakes and rivers that serve as water sources and

discharge receivers for industrial and population centers, probably as a result of industrial activity and

commercial use of phenol -containing products. For example, the presence of higher levels of phenol in

the Delaware River near Philadelphia is the result of industrial effluents discharged into the sewer system

(Sheldon and Hites 1979). Phenol was detected in 23% of samples of influent of waste water from New

York City during 1989 to 1993 at concentrations ranging from 8 to 490 g/L; phenol was detected in 2% of

effluent samples at concentrations ranging from 6 to 310 g/L during the same period (Stubin et al. 1996).

The presence of phen ol in drinking water probably results from using contaminated surface water or

groundwater as a source. Its presence in groundwater is probably the result of release to soil, often

industrial releases or leachate from waste dumps, and the subsequent leach ing of phenol through the soil

to the groundwater. Phenol has been detected, but not quantified, in drinking water from 5 of 14 drinking

water treatment plants between July 1977 and June 1979 in one of three sites (groundwater source), in

three out of ten (surface water source) as well as water source used after distribution (Fielding et al.

1981). Phenol levels in tap water, spring water, and mineral water in Italy were 0.58, 0.051, and

0.161 μ g/L, respectively (Achilli et al. 1995). Phenol was detected at a maximum concentration of

1,130 ppm in ninewells in Wisconsin after a spill, and was detected for at least 1.5 years after the spill

(Delfino and Dube 1976). I t was found at concentrations up to 10.4 ppm in groundwater from a sand

aquifer adjacent to waste ponds at a wood-preserving facility in Florida (Goerlitz et al. 1985), and was

detected at 6.510,000 ppb in two aquifers 15 months after the completion of a c oal gasification project

(Stuermer et al. 1982). Phenol was detected at a maximum concentration of 1.9 ppm in leachates from

landfill sites in Illinois (Clark and Piskin 1977). Near a landfill in central Florida, phenol was found inPHENOL 162

6. POTENTIAL FOR HUMAN EXPOSURE

groundwater and surface water at about 17and 15 ppb, respectively (Chen and Zoltek 1995). Phenol was

detected, but not quantified, in the groundwater at 13.6% of 178 CERCLA hazardous waste sites (Plumb

1987).

Phenol was detected during seven rain events in Portland, Oregon, between February and April of 1984.

Concentrations in rain ranged from >75 to 1,200 ppt, and averaged above 280 ppt. Gas- phase

concentrations ranged from 220 (56.1 ppt) to 410 ng/m 3 (105 ppt) and averaged 320 ng/m 3 (82 ppt)

(Leuenberger et al. 1985).

Phenol can also be transported in snow and rain. In Germany, phenol has also been detected in clouds at

Mount Brocken in June 1994 and during April to May in Great Dun Fell with mean concentrations of

3.0 μg/L and 5 .4 μg/L, respectively (L üttke 1999). Snow from Neulaniemi, Muonio, and Levi, Finland,

contained phenol in concentrations of 0.16, 0.04, and 0.02 μg/kg, respectively (Poliakova et al. 2000). In

Russia, phenol was detected in snow samples at concentrations of 0.02, 0.21, and 1.3 μg/kg in Butovo,

Moscow State University, and Shosse Entuzoastov (a heavily industrial district in Moscow), respectively

(Poliakova et al. 2000).

Phenol has been detected in the effluent discharges of a variety of industries. It was found in petroleum

refinery waste wat er at concentrations of 33.5 ppm (Pfeffer 1979) and 100 ppb (Paterson et al. 1996), in

the treated and untreated effluent from a coal conversion plant at 4 and 4,780 ppm, respectively

(Parkhurst et al. 1979), and in shale oil waste water at a maximum of 4.5 ppm (Hawthorne and Sievers

1984). It has also been detected in the effluent from a chemical specialties manufacturing plant at 0.01–

0.30 ppm (Jungclaus et al. 1978), in effluent from paper mills at 5–8 ppb (Keith 1976; Paterson et al.

1996), and at 0.3 ppm in a 24-hour composite sample from a plant on the Delaware River, 2 and 4 miles

downriver from a sewage treatment plant (Sheldon and Hites 1979).

A study of the seasonal effects on the concentration of pesticides as well as other contaminants in Gulf of

Gdansk in the Baltic Sea from autumn 2001 to spring 2003 showed only 1 out of 14 samples taken in

autumn to have a detectable level of phenol with a concentration of 2.3 μg/L (Kot -Wasik et al. 2004). In

the spring, phenol was detected in 11 of the 14 s amples at concentration s ranging from 0.3 to 0.8 μg/L

(Kot

- Wasik et al. 2004).

Phenol has also been found in the primary and secondary effluent from the Los Angeles City Treatment

Plant at concentrations of 32 and <10 ppb, respectively (Young et al. 1983). It was found in 3 ofPHENOL 163

6. POTENTIAL FOR HUMAN EXPOSURE

86 samples of runoff from 2 of 15 cities at 3

– 10 ppb by the U.S. Nationwide Urban Runoff Program as of

July of 1982 (Cole et al. 1984).

6.4.3 Sediment and Soil

Very few data concerning the presence of p henol in soils were found. Phenol generally does not adsorb

very strongly to soils and tends to leach rapidly through soil, which may account for the lack of

monitoring data, since any phenol released to soils is likely to leach to groundwater. Moreover, phenol is

readily degraded in the environment, which is expected to attenuate its levels in soil.

Sediment collected 6 km northwest of the Los Angeles County waste- water treatment plant discharge

zone at Palos Verdes, California, contained 10 ppb (dry we ight) phenol (Gossett et al. 1983).

In a study of contaminants in stream bed sediments across the United States, phenol was detected at

536 sites at a maximum concentration o f 210 μg/kg (Lopes and Furlong 2001).

6.4.4 Other Environmental Media

Phenol has been reported at concentrations of 7 and 28.6 ppm in smoked summer sausage and smoked

pork belly, respectively (EPA 1980), and was identified but not quantified in mountain cheese (Dumont

and Adda 1978), fried bacon (Ho et al. 1983), fried chicken (Tang et al. 1983), and black fermented tea

(Kaiser 1967). Phenol has also been found in honey at concentrations ranging from 0 (detection limit

0.1 ppm) to 19 ppm (Sporns 1981). It was present each time the honey was collected with phenol- treated

boards. Phenol has been reported in three different types of fermented soybe an curds at concentrations

ranging from 450 to 6,000 μg/kg (Chung 1999).

Phenol has been found in bottomfish from five sites in Commencement Bay in Tacoma, Washington, at a

highest maximum average and overall maximum concentration of 0.14 and 0.22 ppm, re spectively

(Nicola et al. 1987). Phenol has been reported to be a natural component of animal matter; it has been

found at 0 –1.6 ppm in rabbit muscle tissue (EPA 1980).

Phenol has been detected in the eggs of birds in the Lake Baikal Region of Italy in c oncentrations ranging

from 840 to <20 μg/kg dry weight (Lebedev et al. 1998).PHENOL 164

6. POTENTIAL FOR HUMAN EXPOSURE

Phenol is also found in medicinal preparations including throat lozenges, mouthwashes, gargles, and

antiseptic lotions (Darisimall 2006). Commercial antiseptic lotions may contain up to 1.4% phenol

(Darisimall 2006). Package labeling information indicates that commercial throat lozenges contain up to

29 mg of phenol per lozenge (Darisimall 2006). Other consumer products such as disinfectants and

cleaners may contain phenol (O’Neil 2001).. It has been found that the smoke of 1 nonfilter cigarette

contains 60– 140 μg of phenol, 19 –35 μg for a filter -tipped cigarette, and 24–107 μg in cigars (IARC

1986; NCI 1998). Using a testing method developed by the U.S. Federal Trade Commission (FTC),

analysis of the smoke from several different brands and types of cigarettes found phenol in concentrations

ranging from 0.3 to 68 μg/cigarette (Roemer et al. 2004). The lowest concentration came from an

electrically heated prototype cigarette, while most of the commercial brands we re within a range of 2.6

–

23.4 μg/cigarette (Roemer et al. 2004).

While not detected in topsoil from Holy Cross Mountain Park, Poland, and surrounding area, phenol was

detected in 4 out of the 12 pine needle samples taken from the same area (Migaszewski 19 99).

Phenol was detected in 303 of 389 samples of settled dust from indoor residences in Sweden; the mean

concentration of phenol was 4 μg/g dust (Nilsson et al. 2005).

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

Data conce rning concentrations of phenol in ambient air are insufficient to estimate the potential for

exposure by inhalation. However, smoke from a single nonfilter cigarette was observed to contain 60–

140 μg phenol, while levels of phenol range from 19 to 35 μg i n the smoke of filter-tipped cigarettes, and

from 24 to 107 μg in the smoke of cigars (IARC 1986; NCI 1998). Therefore, indoor environments

polluted w ith tobacco smoke are likely to contain measurable amounts of phenol (Guerin et al. 1992).

Nonsmokers wh o live with smokers are thought to be exposed to as much as 1.1 μg/m 3 . This would

account for a daily inhalation of 6–14 μg/day (Nazaroff and Singer 2004).

Phenol concentrations in surface and drinking waters are expected to vary with location and proxim ity to

varying industrial and municipal discharges. Considering the lack of quantitative, current monitoring data

and the probable seasonal, spatial, and temporal variations in the concentrations of phenol at these

sources, it is not possible to estimate accurately a potential daily dose of phenol from drinking

contaminated water or from dermal exposure to contaminated water. Nonetheless, it is probable that only

those systems that receive their water from contaminated surface water and groundwater contai n phenol.PHENOL 165

6. POTENTIAL FOR HUMAN EXPOSURE

Although phenol has been identified in various food products, a quantitative estimate regarding the intake

of phenol from the ingestion of food has not been estimated.

Few data concerning occupational exposures to phenol were located. The average airborne

concentrations of phenol to which workers were exposed at three locations within two wood creosote

impregnation plants ranged from 0.03 to 0.5 ppm (Heikkila et al. 1987). A phenol concentration of

approximately 0.5 ppm was measured in the wor kroom air at a casting factory in Osaka City, Japan

(Kuwata et al. 1980), and concentrations as high as 3.2 ppm were measured in Japanese Bakelite factories

(Ohtsuji and Ikeda 1972). Considering the lack of quantitative monitoring data for phenol in occup ational

atmospheres, it is not possible to estimate the potential for occupational exposure to phenol. The data,

however, do show that exposure to phenol through breathing and dermal contact with contaminated

workroom atmospheres is possible. The National Occupational Exposure Survey (NOES) conducted by

NIOSH estimated that 584, 372 workers were exposed to phenol in the United States (NIO SH 1990). The

NOES database does not contain information on the frequency, concentration, or duration of exposures.

Th e survey provides only estimates of workers potentially exposed to chemicals in the workplace.

Other occupations that may have increased exposure risk include laboratory workers, morticians, and

house cleaners. Phenol is a common solvent used in labora tory research as well as a component of

embalming fluid. The general population may be exposed to phenol found in consumer products such as

general disinfectants used to clean toilets, floors, drains, and other areas (Lewis 200 1; O’Neil 2001).

House cleaners and people who work with these products daily are likely to have increased exposure.

Exposure to phenol also occurs through the use and subsequent ingestion of phenol-containing products,

including mouthwashes, gargles, and throat sprays (Darisimall 2006). The concentration of phenol in

throat sprays ranged from 0.5 to 1.4% phenol. Determining actual dosage from these sprays would be

difficult as the delivery method is not precise. Cepastat ® lozenges, a readily available remedy for sore

throats, contains 14.5–29 mg phenol/lozenge (Darisimall 2006). If a patient (adults and children over 6)

takes the maximum recommended daily number of 18 lozenges, this would result in approximate doses of

270–520 mg phenol/day. There is no control over the intake of non-prescription drugs and therefore,

some individuals may consume considerably higher doses of phenol.

The estimated relative contributions of the various exposure routes and sources of total phenol exposure

cannot be estimated using the available dat a. Nonetheless, for persons not exposed to phenol in the

workplace, exposure will most likely result from: inhalation of contaminated ambient air, primarily in thePHENOL 166

6. POTENTIAL FOR HUMAN EXPOSURE

vicinity of industries and municipalities that release significant amounts of phenol into the atmosphere;

ingestion of drinking water from contaminated surface waters or groundwaters; ingestion of phenolcontaining products; and dermal exposure to contaminated water and to phenol-containing products.

Dermal contact with phenol or ingestion of phenol-containing products probably constitutes the largest

consumer exposure, although this exposure may occur on an acute basis. Inhalation and dermal

exposures appear to be most significant in occupational settings. Total phenol exposure for workers

exposed to phenol in the workplace is probably substantially higher than for those not exposed in the

workplace.

Exposure to benzene is likely to increase phenol exposure because phenol is a metabolite of benzene and

is often used to detect benzene expos ure. Major releases of benzene include cigarette smoke, auto

exhaust, and gasoline fumes.

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 h azardous substances are discussed in Section 3.7, Children’s Susceptibility.

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways.

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults.

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk

or formula to the di et of older children who eat more of certain types of foods than adults. A child’s

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths,

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993).

Oral, dermal, and combined oral- dermal exposures are the most likely routes by which child ren will be

exposed to phenol. Oral exposure to low levels of phenol among children is likely because many

consumer products contain phenol, particularly in medicines such as gargles, throat lozenges, and others

(Darisimall 2006). Products other than medicines that contain phenols include general disinfectants,

cleaners, and epoxies.PHENOL 167

6. POTENTIAL FOR HUMAN EXPOSURE

Some foods containing phenol have been identified (see Section 6.4.4) and ingestion of these could result

in low levels of phenol exposure in children. In addition, phenol is produced endogenously as a

breakdown product of protein metabolism; normal concentrations in urine generally do not exceed

20 mg/L (ACGIH 2001).

Since phenol can be readily absorbed through the skin (ACGIH 2001), children may be more susceptible

to l ow levels of phenol exposure since they have a higher skin

- surface -area to weight ratio. Since young

children are more likely to come in contact with the floor and other low- lying areas, they may be exposed

to phenol found in consumer products such as gen eral disinfectants used to clean toilets, floors, drains,

and other areas ( Lewis 2001 ; O’Neil 2001 ).

Exposure to phenol through inhalation is a less probable route than oral and dermal. It is known that both

cigarettes and cigars contain small amounts (1 9– 140 μg) of phenol (IARC 1986; NCI 1998), and smoking

these products indoors produces a measurable amount of phenol (Guerin et al. 1992). If children are

present in indoor environments polluted with tobacco smoke, they may be exposed to low levels of

phen ol.

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

Populations with potentially high exposure to phenol generally include those who are exposed to

relatively highly contaminated environments over long periods of time. These include populations

exposed to both identified and unidentified phenol- containing waste disposal sites and landfills.

Populations residing in the vicinity of industries that manufacture or use phenol and large population

centers may be exposed to potentially high levels of phenol. Persons who work at establishments that

manufacture or use phenol have a risk for high exposure to phenol. Populations that regularly ingest food

contaminated with phenol or that regularly ingest or come in contact with phenol-containing products are

at risk for high exposure to phenol. Populations that live near a phenol spill site, especially those whose

water supply sources are near the spill sites, have a risk for high exposure to phenol. Relatively high

exposure may also res ult from exposure to emissions from municipal waste incinerators and cigarette

smoke, although no quantitative data concerning phenol emission from these sources were located. Low

income communities and minority populations are more likely to live adjacen t to waste disposal sites and

landfills where phenol is present.PHENOL 168

6. POTENTIAL FOR HUMAN EXPOSURE

THE NOES conducted by NIOSH estimated that 584,372 workers were exposed to phenol in the United

States (CDC Website). Workers in the petroleum industry, as well as workers in industries tha t

manufacture of caprolactam (nylon manufacture), bisphenol A (epoxy resin and polycarbonate

manufacture), herbicides, wood preservatives, hydraulic fluids, heavy- duty surfactants, lube

- oil additives,

tank linings and coatings, and intermediates for plasti cizers and other specialty chemicals, may be

exposed to phenol. Phenol is also used in throat lozenges, disinfectants, and ointments. It is also used for

facial skin peels and to cause nerve block (Gingell et al. 2001). A list of estimated work induced

exposure events for 19 different industries is presented in Table 6

- 2 (Brandorff et al. 1995).

People who are exposed to large amounts of benzene are also likely to be exposed to large amounts of

phenol, a metabolite of benzene. Elevated levels of phenol have been detected in workers occupationally

exposed to benzene. Workers exposed to 0.8– 25.1 or 33.1 –331.7 ppm for 2.5–3 hours during an 8-hour

workday had median urinary phenol levels of 55.6 and 351 ng/g creatine, respectively (Rothman et al.

1998). Control workers who were not exposed to benzene at the workplace had urinary phenol levels of

17.3 ng/g creatine (Rothman et al. 1998).

6.8 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether

adequate information on the health effects of phenol is available. Where adequate information is not

available, ATSDR, in conjunction with NTP, i s 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 phenol.

6.8.1 Identification of Data Needs

Physical and Chemical Properti es. Knowledge of physical and chemical properties is essential for

estimating the partitioning of a chemical in the environment. Information about the physical and

chemical properties of phenol is available (Hawley 1981; HSDB 2008; IARC 1989), and the database is

adequate for the input requirements of environmental models that predict the behavior of a chemical

under specific conditions.

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 requiredPHENOL 169

6. POTENTIAL FOR HUMAN EXPOSURE



### Table 6

- 2. Estimated Exposure To Phenol At Various Industry Sites

Estimated number of Estimated weight used in Industry exposure events tonnes of substance

Manuf acture of basic metals 180 1.7
Manufacture of fabricated metal products 8,200 27

Electrical machinery and apparatus 1,400 0.0012
Manufacture of transport equipment 700 40

Painters and carpenters 440 0.021

Construction 4,300 11

Wholesale trade 840 16

Manufacture of textiles and leather 2,600 1

Manufacture of wood and furniture 670 1.2

Manufacture of chemicals 580 0.85

Manufacture of non

- metallic mineral 1,300 4,100 products

Manufacture of precision and optical 1,300 0.0023

instruments

Manufacture of plastic and boat building 840 <0.0001 repair

Personal services, cleaning, and hair 260 0.0002 dressing
Sewage and refuse disposal 210 0.0009
Agricultural, hunting, and forestry 550 0.65

Health sciences and pharmacies 1,200 0.25

Source: Brandorff et al. 1995PHENOL 170

6. POTENTIAL FOR HUMAN EXPOSURE

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 producti on facilities and emissions.

Additional production data are available from the Chemical Marketing Reporter (CMR 2005), and

import/export data for phenol are available on the U.S. International Trade Commission website ( USITC

2008). Additional data are not needed at this time.

Environmental Fate. Based on the physical properties of phenol, volatilization and sorption of

phenol to sediments are not expected to be important transport mechanisms (Lyman et al. 19 82). The

adsorption of phenol to soils has been shown to increase with increasing organic matter (Xing et al.

1994). Photochemical degradation of phenol is thought to be an important process both in air (EPA

1979a) and water (Scully and Hoigne 1987). Ph enol is also readily biodegradable (Ludzack and Ettinger

1960; Rubin and Alexander 1983; Scott et al. 1983; Stover and Kincannon 1983). Soil sorption data are

available ( Artiola -Fortuny and Fuller 1982; Boyd 1982; Briggs 1981; Sacan and Balcioglu 1996; Sc ott et

al. 1983). Additional data are not needed at this time.

Bioavailability from Environmental Media. Data from monitoring studies indicate that phenol is

present in the environment ( EPA 1981a, 1982; Gossett et al. 1983; Hoff and Chan 1987; Konasewich et

al. 1978; Sheldon and Hites 1978, 1979; Thurman 1985) as well as in environmental organisms (Nicola et

al. 1987). Exposure to phenol is most likely to be highest in areas at or near industrial centers and

population centers where drinking and bathing water, ambient air, and certain foods, such as fish, are

obtained from sources contaminated with phenol. Reliable data on the bioavailability of phenol from

inhaled air and from skin exposed to phenol vapor have been reported for humans (Piotrowski 1971).

Studies of bioavailability of phenol from ingested soil and foods and dermal contact with contaminated

water are needed for evaluating the hazards posed by ingesting materials that have been contaminated

with phenol.

Food Chain Bioaccumulation. No studies were located regarding the food chain bioaccumulation

of phenol from environmental media. Data from monitoring studies indicate that phenol is present in the

environment as well as in environmental organisms (Nicola et al. 1 987). The available bioaccumulation

studies are concerned only with exposure of fish to aqueous concentrations of phenol. Although the

results of these studies indicate a low potential for bioaccumulation (see Section 6.3.1), the detection of

phenol in f ish (see Section 6.4.4) indicates that phenol can be found in aquatic organisms; it is possiblePHENOL 171

6. POTENTIAL FOR HUMAN EXPOSURE

that food chain bioaccumulation may occur. A clearer understanding of the potential for bioaccumulation

would aid in determining how levels in the environment affect the food chain and potentially impact

human exposure levels. A study examining phenol levels in organisms from several trophic levels is

needed.

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of phenol in

contaminated media at hazardous waste sites are needed so that the information obtained on levels of

phenol in the environment can be used in combination with the known body burden of phenol to assess

the potential risk of adverse health effects in populations l iving in the vicinity of hazardous waste sites.

Phenol has been measured in air (Cronn et al. 1977; EPA 1981a, 1982), water (EPA 1980; Sheldon and

Hites 1978, 1979; Thurman 1985), and sediments (Gossett et al. 1983). Additional more recent

monitoring data would help to estimate human exposure to phenol.

Exposure Levels in Humans. Data concerning exposure levels in humans are incomplete and not

current (Heikkila et al. 1987; Kuwata et al. 1980; Ohtsuji and Ikeda 1972). A detailed recent database of

exposure would be helpful in determining the current exposure levels, thereby allowing the estimation of

the average daily dose associated with various scenarios such as living near a hazardous waste site or

landfi ll, or with drinking water containing phenol. An environmental media monitoring program would

provide the necessary information for estimating environmental exposures, while a detailed examination

of the uses of phenol and the kinds of potential exposure in addition to workplace monitoring would

probably provide adequate workplace information. The environmental media that would provide the most

useful information are air, groundwater, and surface and drinking water in urban and industrial locations,

and air, groundwater, and surface water at hazardous waste sites. Performing the monitoring over a

1- year period would allow estimation of seasonal variations.

This information is necessary for assessing the need to conduct health studies on these populations.

Exposures of Children. Children are likely to be exposed to low levels of phenol from the use of

many consumer products including medicines and cleaning agents (Budavari et al. 1989; Douglas 1972;

EPA 1980; Hawley 1981). There are no known data that quantify the level of exposure to phenol in

children. It is likely that young children may be exposed to low levels of phenol because they come into

contact with the floor and other areas where disinfectants containing phenol might be used. More studies

are needed to assess whether children differ in their weight -adjusted intake of phenol, as little or noPHENOL 172

6. POTENTIAL FOR HUMAN EXPOSURE

information is known. Studies are needed to measure the baseline phenol level in children’s urine in

order to use phenol levels in urine as a biomarker of exposure.

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 phenol were located. Thi s substance is not

currently one of the compounds for which a sub- registry has been established in the National Exposure

Registry. The substance will be considered in the future when chemical selection is made for sub

registries to be established. The in formation that is amassed in the National Exposure Registry facilitates

the epidemiological research needed to assess adverse health outcomes that may be related to exposure to

this substance.

6.8.2 Ongoing Studies

The Federal Research in Progress (FE DRIP 2006) database provides additional information obtainable

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. The only

study pertaining to the potential for human exposure found in this database was an expo sure assessment

study done at Mount Sinai School of Medicine at New York University and supported by National

Institute of Environmental Health Sciences. Part of this research is to design new approaches to assess

and quantify the levels of exposures to known toxicants in children and infants.PHENOL 173



### 7. ANALYTICAL METHODS

The purpose of this chapter is to describe the analytical methods that are available for detecting,

measuring, and/or monitoring phenol, its metabolites, and other bioma rkers of exposure and effect to

phenol. 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 group s such as the Association of

Official Analytical Chemists (AOAC) and the American Public Health Association (APHA).

Additionally, analytical methods are included that modify previously used methods to obtain lower

detection limits and/or to improve accura cy and precision.

7.1 BIOLOGICAL MATERIALS

Analytical methods for the detection of phenol in biological materials are summarized in Table 7 -1.

Phenol is expected to be present in blood and urine in its free acid and conjugated f orms (glucuronide and

sulfate). The average urinary phenol concentration in unexposed individuals is 9.5±3.6 mg/L when

corrected to a standard specific gravity of 1.024 (Piotrowski 1971). In exposed individuals, the urinary

phenol level may vary from 10 to 200 mg/L (Tesarova and Packova 1983). The two common methods

for quantifying conjugated phenol are chemical and enzymatic hydrolysis of the conjugate to the free

phenol form. The chemical method uses acidic hydrolysis (Baldwin et al. 1981; Needham et al. 1984).

Both the nature of the acid (sulfuric versus perchloric) and the temperature should be controlled carefully

to obtain a quantitative yield and to avoid thermal decomposition of other phenolic or related compounds

that may interfere with phenol quantification (Baldwin et al. 1981; Rick et al. 1982). The best available

method appears to be specific enzyme hydrolysis or hydrolysis at ambient temperature with sulfuric acid.

Enzymatic hydrolysis with an extract of Helix pomatia has also been used t o liberate phenol from its

conjugates (Ahmed and Hale 1994).

High

- performance liquid chromatographic separation with electrochemical detection may provide the best

sensitivity for phenol quantification in biological samples (Tesarova and Packova 1983). The use of gas

chromatography with a flame ionization detector may be a more versatile method, if other non-ionic

pollutants must be quantified. The advantages and disadvantages of different methods available for the

quantification of phenol and metabolites in biological and environmental samples have been discussed by

Tesarova and Packova (1983).PHENOL 174

7. ANALYTICAL METHODS



### Table 7

- 1. Analytical Methods for Determining Phenol in Biological Samples

Sample Analytical d etection Percent Sample matrix Preparation method method limit recovery Reference

Whole blood Sample extracted with ethyl acetate, extract concentrated and analyzed (for free phenol), pack ed blood cells previously extracted for free phenol incubated with β

- glucuronidase containing sulfatase at 37 °C, extracted with ethyl acetate

after addition of normal saline solution, and extract concentrated and analyzed (for conjugated phenol)

Whole blood Sample with spiked internal standard extracted with ethyl

acetate and extract concentrated and analyzed

Urine Sample mixed with phosphoric acid, passed through a pre

column at 165 °C for hydrolysis of conjugates (for free and conjugated phenol), and analyzed

Urine Sample heated under reflux
with HClO 4 , solvent extracted, concentrated, and separated by TLC; spot developed by

p

- nitro

- benzenediazonium fluoroborate, removed quantitatively and solvent extracted (for free and conjugated phenol), and analyzed

Urine Acidified sample stream distilled, reacted with ammonia,

N

- chloro

- succinimide, and sodium nitroprusside at basic pH (method probably for free phenol), and analyzed

Urine Sample incubat ed with glucuronidase and sulfatase at pH 5 and 3.7 °C, H 2 SO 4 added and steam distilled (total phenol) and analyzed

Urine Sample hydrolyzed at room temperature and extract ed with methyl tert

- butyl ether (total phenol) and analyzed GC

- FID <1 mg/mL

GC

- FID 0.1 mg/L

GC

- FID NG

Spectro

- NG photometry

Spectro

- 0.3 mg/L photometry

HPLC

- 2 ng/

electro

- inection

chemical

detector

GC

- FID NG 97% (free O’Grodnick et phenol); 103% al. 1983 (conjugated phenol)

>90% at Handson an d

concentrations Hanrahan 1983 above 0.5 mg/L

89% (for Baldwin et al. conjugates) 1981

NG Bienick and

Wi lczok 1986

>95% Amlathe et al.

1987

95

– 107% Schaltenbrand
and Coburn

1985

NG Rick et al. 1982PHENOL 175

7. ANALYTICAL METHODS



### Table 7

- 1. Analytical Methods for Determining Phenol in Biological Samples

Sample Analytical d etection Percent Sample matrix Preparation method method limit recovery Reference

Urine Sample spiked with internal GC

- FID NG 93

– 97% at 20 – Needham et al. standard, hydrolyzed with 70 mg/L 1984

H 2 SO 4 , and extracted with ethyl acetate (free and conjugated) and analyzed

Urine Sample spiked with internal GC

- FID 0.1 mg/L 99% at Van standard, distilled with H 2 SO 4 5.9 mg/L Roosmalen et in a special apparatus, distillate al. 1981 directly injected into GC (free and conjugated)

Urine Two spot urine sample s GC

- FID 0.5 μg/mL 94

– 95 % NIOSH 1994 a (before and after exposure), (Method hydrolyzed with HCl or 8305) perchloric acid, extracted with diethyl ether, and directly injected into GC

FID = flame ionization detector; GC = gas chromatography; H 2 SO 4 = sulfuric acid; HCl = hydrochloric acid;
HClO 4 = perchloric acid; HPLC = high performance liquid chromatography; NG = not given; TLC = thin layer chromatographyPHENOL 176

7. ANALYTICAL METHODS

The level of phenol detected in blood or urine may not accurately reflect actual phenol exposure because

phenol may also appear as a metabolite of benzene or other drugs. It has been shown that under certain

acidic conditions used for the hydrolysis of c onjugated phenols, acetyl salicylic acid (aspirin) may

produce phenol (Baldwin et al. 1981) and yield spuriously higher values for phenol in blood and urine.

For occupational exposure, it is recommended that urine samples be collected at the end of an 8 -hour

work shift (ACGIH 2001). Small amounts of thymol can be used as a preservative, and the urine can be

stored for 4 days if refrigerated, or at least 3 months if frozen.

7.2 ENVIRONMENTAL SAMPLES

Analytical methods for detecti ng phenol in environmental samples are summarized in Table 7 -2. The

accuracy and sensitivity of phenol determination in environmental samples depends on sample preconcentration and pretreatment and the analytical method employed. The recovery of phenol from air and

water by the various preconcentration methods is usually low for samples containing low levels of phenol.

The two preconcentration methods commonly used for phenols in water are adsorption on XAD resin and

adsorption on carbon. Both can give low recoveries, as shown by Van Rossum and Webb (1978).

Solvent extraction at acidic pH with subsequent solvent concentration also gives unsatisfactory recovery

for phenol. Even during carefully controlled conditions, phenol losses of up to 60% may occur during

solvent evaporation (Handson and Hanrahan 1983). The in situ acetylation with subsequent solvent

extraction as developed by Sithole et al. (1986) is probably one of the most promising methods.

Capillary columns may provide the best method for the separation of phenols prior to their quantification

(Eichelberger et al. 1983; Shafer et al. 1981; Sithole et al. 1986). Of the various methods available for

detection, the two commonly used methods that are most sensitive are ma ss spectrometry and flame

ionization detection. Although electron capture detectors provide good sensitivities for higher chlorinesubstituted phenols, they are poor for phenol itself (Sithole et al. 1986). The best method for the

quantification of pheno l may be mass spectrometric detection in the selected ion mode, but the loss of

qualitative information may be significant (Eichelberger et al. 1983).

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 phenol is available. Where adequate information is notPHENOL 177

7. ANALYTICAL METHODS



### Table 7

- 2. Analytical Meth ods for Determining Phenol in Environmental Samples

Sample Analytical Sample Percent

matrix Preparation method method detection limit recovery Reference

Urban air

Air

Occupational

air

Occupational

air

Occupational

air

Total particulate

matter in cigarette

smoke

Industrial emission, auto exhaust,

and tobacco

smoke

Drinking
water, waste water, and

natural water

Waste water

and natural

water

Water Sample collected in bubbler containing NaOH, derivatized as nitrobenzeneazo compound

Sample collected on a solid sorbent tube, desorbed using

methanol
Sorption on activated carbon, desorption by solvent and derivatized to trimethylsilyl product
Sorption on XAD

- 2, desorption by acetonitrile and concentrated if necessary

Sample collected with a thermal desorption tube using a sorbent capable of capturing a
C 6 organic compound

Extract particulate matter with NaOH, buffer to pH 4.6

Sample collected in NaOH

bubbler and derivatized to

p

- nitrobenzene

- diazonium

tetrafluoroborate

Direct distillation of solvent

cleaned sample (if necessary) at acidic pH, react with

4- amino

- antipyrine and potassium ferricyanide at pH 8,

extract in chloroform

None

1

- L sample acidified and extracted with methylene

chloride HPLC

- UV

GC

- FID (Method 2546)

GC

- FID

HPLC

electro

chemical

detector and
HPLC

- UV

GC

- MS ( Method 2549)

HPLC

fluorescence spectrophoto

meter

HPLC

- UV

Spectrophoto

metric (Method 5530c)

GC

- FID (Method 6420b)

GC

- FID (Method 604) Kuwata et al.

1980

NIOSH 1994b

Yrjanheikki

1987

Nieminen and

Heikkila 1986

NIOSH 199 6

Tomkins et al.

1984

Kuwata et al

. 1980

APHA 19 98a

APHA 19 98b

EPA 2001a 0.05 ppb for

150

- L sample;

58

– 60% at

0.33

– 0.5 μg phenol

1

– 3 μg/sample ND 72.3% at

10

– 50 μg phenol

0.5 mg/m 3
(0.13 ppm)

8 μg/m 3
(2.04 ppb) with

12 L air (electro

chemical);

0.16 mg/m 3
(0.04 ppm) with 12 L air (UV)
100 ng/tube or

less

0.3 mg/L

0.05 ppb for

150

- L sample

1 μg/L for

500

- mL sample

<1 mg/L

0.14 μg/L 96

– 102%

at 2.5 – 100 mg/m 3

ND

NA

91% at 20 – 30 μg

ND

ND

ND

44%PHENOL 178

7. ANALYTICAL METHODS



### Table 7

- 2. Analytical Meth ods for Determining Phenol in Environmental Samples

Sample Analytical Sample Percent

matrix Preparation method method detection limit recovery Reference

Water

Water, waste

water

Water, waste

water

Water

Water

Waste water

Potable water

and raw

source water

Drinking

water 1

- L sample is adjuste d to pH

>11 and extracted with methylene chloride

Acidified sample extract with solvent, concentrated or derivatized to pentafluoro

benzylbromide product

Sample extracted in acidic pH,

extract concentrated

Sample passed through graphitized carbon black, eluted with methylene chloride

Sample passed through a

mixed XAD

- 4/8 column, solvent

eluted and concentrated

Distillation of acidified solution, reacted with ammonia,

N

- chloro

- su ccinimide, and

sodium nitro

- prusside at basic pH
Sample acetylated in situ by addition of acetic anhydride,

solvent extracted and concentrated; alternativ ely, extracted acidic sample derivatized by pentafluorobenzyl bromide and cleaned up by column chromatography

1

- L sample is extracted using a solid phase extraction cartridge GC

- MS (Method 635)

GC

- FID; GC

ECD (for

derivatized

EPA Met hod 604)

GC

- MS (EPA Method 625);
HRGC

- MS (EPA Method 625.1)

Ion

suppression;

reversed phase LC

with UV

detection

GC

- MS

Spectrophoto

metric

HRGC

- ECD (for pentafluoro

benzyl derivative);
HRGC

- MS (for acetyl derivative)

GC

- MS (Method 528) 1.5 μg/L

0.14 μg/L (FID); 2.2 μg/L (ECD)

1.5 μ g/L (GC

MS); 1

– 10 μ g/L (HRGC

- MS)

50

– 100 ng/L

ND

<0.3 mg/L

<50 ng/L (pentafluoro

benzyl);

<50 ng/L (acetyl derivative)

0.026 μg/L 56%

41% (FID); ND (ECD)

36% (GC

MS) at 10 – 1,500 μ g/L; 25% (GC

MS) at

8.3 μg/L;

42% (HRGC

MS) at

20 μg/L

91

– 97%

46

- 70% (distilled water); 9% (tap water)

96.7% at

3 mg/L

10

– 64% ( penta

fluoro

benzyl derivative);

70

– 132% (acetyl derivative)

85 EPA 2001c

EPA 1982

Eichelberger et al. 1983;

EPA 1982

Di Corci a et
al. 1996

Van Rossum

and Webb

1978

Amlathe et al.

1987

Sithole et al.

1986

EPA 2000aPHENOL 179

7. ANALYTICAL METHODS



### Table 7

- 2. Analytical Meth ods for Determining Phenol in Environmental Samples

Sample Analytical Sample Percent

matrix Preparation method method detection limit recovery Reference

Water The sample is extracted at pH

12

– 13, then at pH <2 with methylene chloride using

continuous extraction techniques; the extract is dried

over sodium sulfate and

concentrated to a volume of

1 mL

Drinking

water Water samples collected and analyzed via GC

- MS

Aqueous samples Samples extracted and cleaned up (according to sample matrix) and the solvent appropriatel y exchanged; the phenols are

then determined with or without

derivatization

Sediment Homogenized sample solvent extracted at acidic pH, fractionated by GPC and

fractions concentrated

Groundwater Solvent extraction in acidic pH,

extract concentrated

Soil, sediment Sample mixed with anhydrous powdered Na 2 SO 4 , solvent extracted ultrasonically, extract subjecte d to GPC if necessary,

extract concentrated

Water and Phenols separated on a Nova

waste water Pak Phenyl column eluted with

ammonium acetate:acetonitrile

Groundwater Solvent extraction, column chromatographic cleanup,

concentration of extract

Bottom Wet sediment samples dried

sediment and compounds extracted using dich loromethane

Water Water samples filtered using glass fiber filters; samples extracted using SPE cartridges
Soil, sludge, Extracted by soxhlet or

or solid waste sonication, extract subjected t o column chromatographic cleanup and concentrated GC

- MS (Method 1625)

GC

- MS (Method
OM100R

GC

- MS (Method

8041A

HRGC

- MS

GC

- MS (EPA

CLP Method)

GC

- MS (EPA

CLP Method

LC

- ED

GC

- MS (EPA

Method 8250A)

GC

- MS (Method 0

­ 5130

- 95)

GC

- MS (Method 0

­ 1433

- 01)

GC

- MS (EPA

Method 8250A) Not applicable

Not applicable

Not applicable

ND

10 μg/L

330 μg/kg

0.5 mg/L

1.5 mg/L

23.5 μg/kg

0.11 μg/L

1.5 mg/kg N ot applicable

Not applicable

93%

112

– 128%

a t 400 ng/g

ND

ND

91

– 100%

0.43c+ 1.26)/cx

100 where

c is the

actual

concentra

tion

84

93

ND EPA 2001b

DOE 1997

EPA 2000b

Lopez

- Avila

et al. 1983

EPA 1987

EPA 1987

Paterson et

al. 1996

EPA 1994b

USGS 1995

USGS 2002

EPA 1994bPHENOL 180

7. ANALYTICAL METHODS



### Table 7

- 2. Analytical Meth ods for Determining Phenol in Environmental Samples

Sample

matrix Preparation method Analytical

method Sample

detection limit Percent

recovery Reference

Aqueous and

nonaqueous samples Samples are extracted; extracts are cleaned up, as necessary, and the solvent exchanged to one that is compatible with the
GC detector to be used EPA Method

8041A ND 93% EPA 2007

Soil, air,
water, Soxhlet extraction with
acetone/hexane GC

- MS (Method 8270D) 10 μg/L 46% EPA 1998

Honey Sample dissolved in water, steam distilled; distillate cleaned up by column chromatography HPLC

- UP 0.1 ppm (for

10

- g sample 98% at

111 μg added phenol Sporns 1981

C 6 = 6 carbon; ECD = electron capture detector; ED = electrochemical detection; FID = flame ionization detector;
GC = gas chromatography; GPC = gel permeation chromatography; HPLC = high performance liquid chromatography; HRGC = high resolution gas chromatography; LC = liquid chromatography; MS = mass spectrometry; Na 2 SO 4 = sodium sulfate; NaOH = sodium hydroxide; ND = no data ; SPE = solid

- phase extraction;

UV = ultraviolet detectionPHENOL 181

7. ANALYTICAL METHODS

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research

designed to determine the h ealth effects (and techniques for developing methods to determine such health

effects) of phenol.

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 w ill 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

. Measurement of total phenol in urine serves as a biomarker of exposure for persons

occupationally exposed to phenol (ACGIH 2001).

Effect. Specific biomarkers used to characterize effects caused by phenol have not been identified. Dark

urine has been reported in persons occupationally exposed to phenol (inhalation, dermal) (ACGIH 2001;

Merliss 1972) and following oral exposure (Baker et al. 1978; Kim et al. 1994). The dark urine may be a

result of an oxidation product of phenol, or hemoglobin and hemoglobin breakdown products. Further

research is required to identify the cause of the dark urine and relate it to exposure concentration.

Methods for Determining Parent Compounds and Degradation Products in Environmental

Media. The analytical methods availab le (Amlathe et al. 1987; Baldwin et al. 1981; Bieniek and

Wilczok 1986; Handson and Hanrahan 1983; Needham et al. 1984; O'Grodnick et al. 1983; Rick et al.

1982; Schaltenbrand and Coburn 1985; Van Roosmalen et al. 1981) are adequate for the quantification of

phenol and its conjugates in biological samples. The study of the levels of parent compound in human

blood, urine, or other biological matrices can be useful in deriving a correlation between the levels of this

compound found in the environment and those found in human tissue or body fluid.

The changes in metabolite concentrations in human blood, urine, or other appropriate biological media

over time may be useful in estimating phenol's rate of metabolism in humans. In some instances, the

quantification of metabolites may be useful in correlating the exposure doses to the human body burden.PHENOL 182

7. ANALYTICAL METHODS

Studies that correlate phenol exposure with levels of metabolites in human biological matrices are not

available for this compound, although analytical methods for the quantification of the metabolites are

available.

Methods for Determining Parent Compounds and Degradation Products in Environ mental

Media. The analytical methods available (Eichelberger et al. 1983; EPA 1982, 1986b, 1986c, 1987;

Kuwata et al. 1980; Nieminen and Heikkila 1986; NIOSH 1994a, 1994b, 1996; Sithole et al. 1986;

Tomkins et al. 1984; Van Rossum and Webb 1978; Yrjanheikki 1978) are adequate for the quantification

of phenol in environmental materials. Knowledge of the levels of this compound in environmental media,

such as air, water, and food, can be used to indicate exposure of humans to this compound through the

inhalation of air and ingestion of drinking water and foods containing phenol.

Although the products of environmental biotic and abiotic degradation of phenol have been identified

adequately, no systematic study measuring the concentrations of the degradation products in the

environment was found. Analytical methods are available for determining the levels of the degradation

products such as hydroxylated phenol. Knowledge of the levels of degradation products would allow the

development of a monitoring program designed to assess the ambient concentrations of phenol

degradation products in the environment. Such a program could provide information concerning both

human and environmental exposure to phenol since it might allow an estimation of the concentration of

phenol in the environment prior to degradation.

7.3.2 Ongoing Studies

The Federal Research i n Progress (FEDRIP 2006) database provides additional information obtainable

from a few ongoing studies that may fill in some of the data needs identified in Section 7.3.1. Two

studies pertaining to analytical procedures for phenol detection were found in this database. Research

being done at Mount Sinai School of Medicine at New York University and supported by National

Institute of Environmental Health Sciences is looking into more accurate methods for quantitative

detection to toxicants in children and infants. A study from A.D. Grosso sponsored by the Center for

Biologics and Evaluation—Quality Control is looking at chromatographic determination of phenol used

as an antimicrobial preservative in vaccines and allergenic extracts.

The Environmental Health Laboratory Sciences Division of the National Center for Environmental

Health, Centers for Disease Control and Prevention, is developing methods for the analysis of phenol andPHENOL 183

7. ANALYTICAL METHODS

other volatile organic compounds in blood. These methods use purge and trap methodology, highresolution gas chromatography, and magnetic sector mass spectrometry, which give detection limits in the

low parts per trillion (ppt) range.

The Environmental Health Laboratory Sciences Division of the National Center for Environmental

Health, Centers for Disease Control and Prevention, is developing methods for the analysis of phenol and

other phenolic compounds in urine. These methods use high-resolution gas chromatography and

magnetic sector mass spectrometry, which give detection li mits in the low parts per trillion (ppt) range.PHENOL 184

7. ANALYTICAL METHODS



### This page is intentionally blank.PHENOL 185



### 8. REGULATIONS AND ADVISORIES

International and national regulations and guidelines pertinent to human exposure to phenol are

summarized in Table 8-1.

ATSDR has derived an acute -duration oral MRL of 1.0 mg/kg/day based on a BMDL of 125 mg/kg/day

for changes in body weight gain in pregnant rats exposed to phenol by gavage using divided dosing

during GDs 6–15 (York 1997). An uncertainty factor of 100 was used (10 for animal to human

extrapolation and 10 for human variability).

EPA (IRIS 2006) derived an oral reference dose (RfD) of 0.3 mg/kg/day for phenol based on a BMDL of

93 mg/kg/day for decreased maternal weight gain observed in Sprague

- Dawley rats dosed with phenol

during gestation (York 1997).

The IARC classification for phenol is Group 3, not classifiable with regard to its carcinogenicity to

humans (IARC 2004). The EPA cancer classification for phenol is D, not classifiable as to human

carcinogenicity (IRIS 2006). The National Toxicology Program has not classified phenol for human

carcinogenicity (NTP 200 5 ). The American Conference of Governmental Industrial Hygienists (ACGIH)

has classified phenol as an A4 carcinogen ( not classifiable as a human carcinogen ) (ACGIH 2005).

OSHA has required employers of workers who are occupationally exposed to phenol to institute

engineering controls and work practices to reduce and maintain employee exposure at or below

permissible exposure limits (PE Ls) (OSHA 2005a). The employer must use engineering and work

practice controls to reduce exposures to or below an 8

- hour time

- weighted average (TWA) of 5 ppm for

phenol (OSHA 2005a). ACGIH (2005) and NIOSH (2005) also recommend a TWA exposure limit of

5 ppm for occupational exposure.

Phenol is regulated by the Clean Water Effluent Guidelines for the following industrial point sources:

electroplating, organic chemicals, steam electric, asbestos, timber products processing, metal finishing,

paving and roofing, paint formulating, ink formulating, gum and wood, carbon black, metal molding and

casting, aluminum forming, and electrical and electronic components; see the electronic Code of Federal

Regulations for a complete listing (NARA 2006).PHENOL 186

8. REGULATIONS AND ADVISORIES



### Table 8

- 1. R egulations and Guidelines Applicable to Phenol

Agency Description Information Reference

INTERNATIONAL

Guidelines:

IARC Carcinogenicity classification Group 3 a IARC 2004

WHO Air quality guidelines No data WHO 2000 Drinking water quality guid elines No data WHO 2004

NATIONAL Regulations and
Guidelines:

a. Air

ACGIH TLV (8

- hour TWA) b 5 ppm ACGIH 2005

EPA AEGL

- 1 c,d EPA 2006a

10 minutes 19 ppm
30 minutes 19 ppm
60 minutes 15 ppm
4 hours 9.5 ppm
8 hours 6.3 ppm
AEGL

- 2 c,d

10 minutes 29 ppm
30 minutes 29 ppm
60 minutes 23 ppm
4 hours 15 ppm
8 hours 12 ppm
AEGL

- 3 c,d Not recommended due
to insufficient data
Hazardous air pollutant Yes EPA 2006d
42 USC 7412

NIOSH REL (10

- hour T WA) e 5 ppm NIOSH 2005 Ceiling limit (15

- minute TWA) 15.6 ppm

IDLH 250 ppm
OSHA PEL (8

- hour TWA) for general industry f 5 ppm OSHA 2005c

29 CFR 1910.1000 PEL (8

- hour TWA) for construction industry f 5 ppm OSHA 2005b

29 CFR 1926.55, Appendix A

PEL (8

- hour TWA) for shipyard industry f 5 ppm OSHA 2005a

29 CFR 1915.1000

b. Water

EPA Designated as a hazardous substances Yes EPA 2006b
in accordance with Section 311(b)(2)(A) 40 CFR 116.4
of the Clean Water Act Designated as a toxic pollutant in Yes EPA 2006c

ac cordance with Section 307(a)(1) of 40 CFR 401.15
the Federal Water Pollution Control ActPHENOL 187

8. REGULATIONS AND ADVISORIES



### Table 8

- 1. R egulations and Guidelines Applicable to Phenol

Agency Description Information Reference

NATIONAL (cont.)

EPA Drinking water standards and health EPA 2004

advisories

1

- day health advisory for a 10

- kg 6 mg/L

child

10

- day health advisory for a 10

- kg 6 mg/L

child

DWEL 11 mg/L

Lifetime 2 mg/L
National primary drinking water No data EPA 2003

standards Reportable quantities of hazardous 1,000 pounds EPA 2006g substances designated pursuant to 40 CFR 117.3
Section 311 of the Clean Water Act

Toxics criteria for those states not EPA 2006m complying with Clean Water Act 40 CFR 131.36
Section 303(c)(2)(B) for human health (10 -6 risk for carcinogens) for consumption of: Water + organism 21 mg/L Organism only 4,600 mg/ L Water quality criteria for human health EPA 2006f consumption of: Water + organism 21 mg/L Organism only 1,700 mg/L

c. Food

EPA Exemptions from the requirement of a Yes EPA 2006k tolerance as an inert ingredient (as a 40 CFR 180.920 solvent) when used pre

- harvest Exemptions from the requirement of a Yes EPA 2006l tolerance as an inert ingredients (as a 40 CFR 180.930 solvent) when applied to animals

FDA Bottled drinking water 0.001 mg/L FDA 2005 Included on the “Everything Added to Yes FDA 2006
Foods in the United States” List

d. Other

ACGIH Carcinogenicity classification A4 g ACGIH 2005 Biological exposure indices (end of 250 mg/g creatinine shift) for total phenol in urine

CPSC Substance named in the Federal ≤ 5% CPSC 2005
Caustic Poison Act; phenol and any preparation containing phenol in a

concentration

EPA Carcinogenicity classification Group D h IRIS 2006 Oral slope factor Not applicable

Inhalation unit risk Not applicablePHENOL 188

8. REGULATIONS AND ADVISORIES



### Table 8

- 1. R egulations and Guidelines Applicable to Phenol

Agency Description Information Reference

NATIONAL (cont.)

RfC Not ap plicable i IRIS 2006

RfD 0.3 mg/kg/day Identification and listing of hazardous U188 EPA 2006e waste; hazardous waste number 40 CFR 261, Appendix VIII Superfund, emergency planning, and community right

- to

- know Designated CERCLA hazardous Yes EPA 2006h

substanc e 40 CFR 302.4 Reportable quantity 1,000 pounds

Effective date of toxic chemical 01/01/87 EPA 2006j release reporting 40 CFR 372.65 Extremely hazardous substances 500/10,000 pounds EPA 2006i and their threshold planning 40 CFR 355, quantities Appendix A

NTP Carcinogenicity classification No data NTP 200 5

a Group 3: not classifiable as to carcinogenicity to humans

b Skin notation: refers to the potential significant contribution to the overall exposure by the cutaneous route,

inc luding mucous membranes and the eyes, either by contact with vapors, liquids, or solids.

c AEGL- 1 is the airborne concentration of a substance above which it is predicted that the general population, including susceptible individuals, could experience notab le discomfort, irritation, or certain asymptomatic nonsensory
effects. 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 s erious, long

- lasting adverse health effects or an impaired ability to escape. 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.

d Level of distinct odor awareness = 0.25 ppm

e Skin designation: indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices, gloves, coveralls, goggles, and other appropriate equipment.

f Skin designation

g A4: not classifiable as a human carcinogen

h Group D: not classifiable as to human carcinogenicity

i Not applicable: no adequate inhalation exposure studies exist from which an inhalation RfC may be derived

. A

route

- to

- route extrapolation is not appropriate, because phenol can be a direct contact irritant, and so portal

- of

- entry effects are a potential concern.

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = Acute Exposure Guideline Level;
CERCLA = Comprehensive Environmetnal Response, Compensation, and Liability Act; CFR = Code of Federal Regulations; CPSC = Consumer Product Safety Commission; DWEL = drinking water equivalent level;

EPA = Environmental Protection Agency; FDA = Foo d and Drug Administration; IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information System;
NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicolo gy Program;
OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; REL = recommended exposure limit; RfC = inhalation reference concentration; RfD = oral reference dose; TLV = threshold limit values;

TWA = time

- weighted ave rage; USC = United States Code; WHO = World Health OrganizationPHENOL 189

8. REGULATIONS AND ADVISORIES

EPA regulates phenol under the Clean Water Act (CWA) and the Clean Air Act (CAA) and has

designated it as a hazardous substance and a hazardous air pollutant (HAP) (EPA 2006b, 2006c). Phen ol

is on the list of chemicals appearing in “Toxic Chemicals Subject to Section 313 of the Emergency

Planning and Community Right- to -Know Act of 1986" (EPA 2006j) and has been assigned a reportable

quantity (RQ) limit of 1,000 pounds (EPA 2006h). The RQ r epresents the amount of a designated

hazardous substance which, when released to the environment, must be reported to the appropriate

authority. Phenol is also considered to be an extremely hazardous substance (EPA 2006i).PHENOL 190

8. REGULATIONS AND ADVISORIES



### This page is intentionally blank._______________________ PHENOL 191



### 9. REFERENCES

ACGIH. 2001. Documentation of the threshold limit values and biological exposure indices. Phenol. 7th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

ACGIH. 2005. Threshold limit values for chemical substances and physical agents and biological indices. Cincinnati, OH: American Conference of Government Industrial Hygienists.

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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.

A dsorption

— The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the surfaces of solid bodies or liquids with which they are in contact.

Adsorption Coefficient (K

oc )— The ratio of the amount of a chemical adsorbed per un it weight of organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd)

— The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or

sediment.

Benchmark Dose (BMD)

— Usually defined as the lower confidence limit on the dose that produces a specified magnitude of changes in a specified adverse response. For example, a 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 b y modeling the dose response curve in the region of the dose response relationship where biologically observable data are feasible.

Benchmark Dose Model

— A statistical dose

- response model applied to either experimental toxicological or epidemiological d ata 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 low est 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 St udy

— 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 an d 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.PHENOL 222

10. GLOSSARY

Ceiling Value

— A concentrat ion of a substance that should not be exceeded, even instantaneously.

Chronic Exposure

— Exposure to a chemical for 365 days or more, as specified in the Toxicological

Profiles.

Cohort Study

— A type of epidemiological study of a specific group or groups of people who have had a common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are followed forward from exposure to outcome. At least one exposed group is compared to one unexposed

group.

Cross

- sectional Study

— A ty pe of epidemiological study of a group or groups of people that examines the relationship between exposure and outcome to a chemical or to chemicals at one point in time.

Data Needs

— Substance-specific informational needs that if met would reduce the uncertainties of human

health assessment.

Developmental Toxicity— The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the ti me of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism.

Dose

- Response Relationship

— The quantitative relationship between the amount of exposure to a

toxicant and the incidence of the adverse effects.

Embryotoxicity and Fetotoxicity

— Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurs. The terms, as used here , include malformations and variations, altered growth, and in utero
death.

Environmental Protection Agency (EPA) Health Advisory— An estimate of acceptable drinking water

levels for a chemical substance based on health effects information. A health advis ory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials.

Epidemiology

— Refers to the investigation of factors that determine the frequency and distribution of

disease or other health -related conditions within a defined human population during a specified period.

Genotoxicity

— A specific adverse effect on the genome of living cells that, upon the duplication of affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific alteration of the molecular structure of the genome.

Half

- life

— A measure of rate for the time required to eliminate one half of a quantity of a chemical from the body or environmental media.

Immediately Dangerous to Life or Health (IDLH)

— The maximum environmental concentration of a contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or

irreversible health effects.

Immunologic Toxicity— The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals.PHENOL 223

10. GLOSSARY

Immunological Effects

— Functional changes in the immune response.

Incidence

— The ratio of individuals in a population who develop a specified condition to the total number of individuals in that population who could have developed that condition in a specified time period.

Intermediate Exposure

— Exposure to a chemical for a duration of 15– 364 days, as specified in the Toxicological Profiles.

In Vitro

— Isolated from the living organism and artificially maintained, as in a test tube.

In Vivo

— Occurring within the living organism.

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

to have caused death in humans or animals.

Letha l 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 defined 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 population.

Lowest

- Observed

- Adverse

- Effect Level (LOAEL)

— The lowest exposure level of chemi cal in a study, or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control.

Lymphoreticular Effects

— Represent morphological effects involving lymphatic tissues such as the lymph nodes, spleen, and thymus.

Malformations— Permanent structural changes that may adversely affect survival, development, or

function.

Minimal Risk Level (MRL)

— An estimate of daily human exposure to a ha zardous substance that is likely to be without an appreciable risk of adverse noncancer health effects over a specified route and duration of exposure.

Modifying Factor (MF)

— A value (greater than zero) that is applied to the derivation of a Minimal Risk

L evel (MRL) to reflect additional concerns about the database that are not covered by the uncertainty

factors. The default value for a MF is 1.

Morbidity

— State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific population.

Mortality— Death; mortality rate is a measure of the number of deaths in a population during a specified

interval of time.PHENOL 224

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 t o birth defects, miscarriages, or cancer.

Necropsy

— The gross examination of the organs and tissues of a dead body to determine the cause of death or pathological conditions.

Neurotoxicity— The occurrence of adverse effects on the nervous system following exposure to a
chemical.

No

- Observed

- Adverse

- Effect Level (NOAEL)

— The dose of a chemical at which there were no statistically or biologically significant increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not

considered to be adverse.

Octanol- Water Partition Coefficient (K

ow )— The equilibrium ratio of the concentrations of a chemical

in n -octanol and water, in dilute solution.

Odds Ratio (OR)

— A means of measuring the association between an exposure (such as toxic substances and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence among subjects exposed to a particular risk factor divi ded 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 p hosphorus-containing organic compound and especially a pesticide that acts by inhibiting cholinesterase.

Permissible Exposure Limit (PEL)

— An Occupational Safety and Health Administration (OSHA) allowable exposure level in workplace air averaged over an 8 -hour shift of a 40-hour workweek.

Pesticide

— General classification of chemicals specifically developed and produced for use in the control of agricultural and public health pests.

Pharmacokinetics

— The dynamic behavior of a material in the body, used to p redict the fate (disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body.

Pharmacokinetic Model

— A set of equations that can be used to describe the time course of a parent chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data

- based and physiologically-based. A data- based model divides the animal system into a series of compartments, which, in general, do not represent real, identifiable anatomic regions of the body, whereas the physiologically-based model compartments represent real anatomic regions of the body.

Physiologically Based Pharmacodynamic (PBPD) Model

— A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end points. These models advance the importance of physiologically based models in that they clearly describe the biological effect (response) produced by the system following exposure to an exogenous

substance.

Physiologically Based Pharmacokinetic (PBPK) Model

— Comprised of a series of compartments representing organs or tissue groups with realistic weights and blood flo ws. These models require aPHENOL 225

10. GLOSSARY

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical information, such as air/ blood partition coefficients, and metabolic parameters. PBPK models are also called biologically based tissue dosimetry models.

Prevalence

— The number of cases of a disease or condition in a population at one point in time.

Prospective Study

— A type of c ohort 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 proced ure. 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 for 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 exposu res 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 exposure of the human population to a potential hazard that is likely to be without risk o f deleterious effects during a lifetime. The RfD is operationally derived from the no

- observed

- adverse

- effect level (NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to

nonthreshold effects such as cancer.

Reportable Quantity (RQ)

— The quantity of a hazardous substan ce 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 CE RCLA 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

t his system.

Retrospective Study

— A type of cohort study based on a group of persons known to have been exposed at some time in the past. Data are collected from routinely recorded events, up to the time the study is undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing records and/or examining survivors of the cohort.

Risk

— The possibility or chance that some adverse effect will result from a given exposure to a chemical.PHENOL 226

10. GLOSSARY

Risk Factor

— An aspect of personal b ehavior or lifestyle, an environmental exposure, or an inborn or

inherited characteristic that is associated with an increased occurrence of disease or other health

- related

event or condition.

Risk Ratio

— The ratio of the risk among persons with specific risk factors compared to the risk among persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed group compared to the unexposed group.

Short

- Term Exposure Limit (STEL)

— The American Conference of Governmen tal 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 Threshol d 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 b road range of adverse effects on target organs or physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical.

Teratogen

— A chemical that causes structural defects that affect the development of an organism.

Threshold Limit Value (TLV)

— An American Conference of Governmental Industrial Hygienists (ACGIH) concentration of a substance to which most workers can be exposed without adverse effect.

T he TLV may be expressed as a Time Weighted Average (TWA), as a Short -Term Exposure Limit (STEL), or as a ceiling limit (CL).

Time

- Weighted Average (TWA)

— An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour workweek.

Toxic Dose (50) (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 experimental animal population.

Toxicokinetic

— The absorption, distribution, and elimination of toxic compounds in the living organism.

Uncertainty Factor (UF)

— A factor used in operationally deriving the Minimal Risk Level (MRL) or Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating fromdata 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 red uced UF of 3 may be used on a case -by- case basis, 3 being the approximate logarithmic average of 10 and 1.

Xenobiotic

— Any chemical that is foreign to the biological system.PHENOL A-1



### APPENDIX A. ATSDR MINIMAL RISK LEVEL S 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 Substa nces and Disease Registry (ATSDR) develop jointly with

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicologica l

profiles for each substance included on the priority list of hazardous substances; and assure the initiation

of a research program to fill identified data needs associated with the substances.

The toxicological profiles include an examination, summary, and interpretation of available toxicological

information and epidemiologic evaluations of a hazardous substance. During the development of

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to

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

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of

cancer effects. These substance

- specific estimates, which are intended to serve as screening levels, are

used by ATSDR health assessors to identify contaminants and potential health effects that may be of

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean -up or

action levels.

MRLs are derived for hazardous substances using the no

- observed

- adverse

- effect level/uncertainty factor

approach. They are below levels that might cause adverse health effects in the people most sensitive to

such chemical

- induced effects. MRLs are derived for acute (1

– 14 days), int ermediate (15 –364 days), and

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently,

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical -induced end

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level

above the MRL does not mean that adverse health effects will occur.

MRLs are intended only to serve as a screening tool to help public health professionals decide where to

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

APPENDIX A

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

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants,

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes

that humans are more sensitive to the effects of hazardous substance than animals a nd that certain persons

may be particularly sensitive. Thus, the resulting MRL may be as much as 100

- fold below levels that

have been shown to be nontoxic in laboratory animals.

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency- wide MRL

Workgroup reviews, with participation from other federal agencies and comments from the public. They

are subject to change as new infor mation becomes available concomitant with updating the toxicological

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels.

For additional information regarding MRLs, please contact the Division of Toxicology and

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE,

Mailstop F-32, Atlanta, Georgia 30333.PHENOL A-3

APPENDIX A



### MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Phenol

CAS Numbers: 108-95-2

Date: July 2008

Profile Status: Draft 3 Post-Public

Route: [ ] Inhalation [x] Oral

Duration: [x] Acute [ ] Intermediate [ ] Chronic Graph Key: 13 Species: Rat

Minimal Risk Level : 1 [x] mg/kg/day [ ] ppm

Reference : York. 1997. Oral (gavage) developmental toxicity study of phenol in rats. Procter & Gamble Co. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D.

OTS0573686.

Experimental design : Groups of pregnant Sprague- Dawley rats (25/dose group) were dosed 3 times daily with 0, 20, 40, or 120 mg phenol/kg (total daily doses of 0, 60, 120, and 360 mg/kg) by gavage in water on gestation days (GDs) 6 –15; the dosing volume was 10 mL/kg. Maternal end points evaluated included clinical signs, body weight, and food consumption. Dams were also observed for abortions and premature deliveries. Dams were sacrificed on GD 20 and a gross necropsy was conducted. The uterus was examined for pregnancy, number and distribution of implantations, live and dead fetuses, and early and late resorptions. Fetuses were weighed and examined for sex and gross external alterations. Half of the fetuses were examined for soft tissue alterations and the remaining fetuses were examined for skeletal

alterations.

Effect noted in study and corresponding doses : One d am in the 360 mg/kg/day group died on GD 11 and the death was attributed to phenol treatment. Clinical signs considered treatment

- related included excess salivation and tachypnea in rats exposed to 360 mg/kg/day. Gross necropsy of the dams did not reveal

any treatment -related alterations. In the 120 mg/kg/day group, maternal body weight gain was significantly reduced for GDs 6 –16 (11%) and for GDs 12– 16 (19%), whereas in the 360 mg/kg/day group, body weight gain was reduced 38% for gestation days 6–16. Maternal final body weight in the 360 mg/kg/day group was reduced, but <10% relative to controls. Food consumption was reduced in the 360 mg/kg/day group by 16% for GDs 6–20 and by 15% for GDs 0–20; in the 120 mg/kg/day group, food consumption for GDs 6–16 was reduced 11%. Fetal body weight at the 360 mg/kg/day level was reduced

5– 7% relative to controls. There was a significant decrease in ossification sites on the hindlimb metatarsals in the 360 mg/kg/day group. At the 120 and 360 mg/kg/day dose level s, there were increases in litters with fetuses with "any alteration" and with "any variation", but neither reached statistical significance and there were no clear dose

- response relationships. There were no significant effects on corpora lutea, implantat ions, litter sizes, live fetuses, early and late resorptions, and percent resorbed conceptuses. Based on decreased fetal body weight and delayed ossification, the dose of 360 mg/kg/day is a LOAEL for developmental effects; the NOAEL is 120 mg/kg/day. Bas ed on decreased weight gain during gestation, the dose of 120 mg/kg/day is a LOAEL for decreased maternal body weight gain; the NOAEL is 60 mg/kg/day.

Data from York (1997) were analyzed using the BMD approach for MRL derivation. BMD models in the

EPA Benchmark Dose Software (BMDS version 2.0) (linear, polynomial, power, and Hill models) were fit to the maternal body weight gain data to determine potential points of departure for the MRL. The linear model with homogeneous variance, which is the simples t model and the model that provided the best fit for the data, was selected. In the absence of a clear criteria as to what level of change in weightPHENOL A-4

APPENDIX A

gain during pregnancy should be considered adverse, the benchmark response (BMR) was defined as a change i n mean body weight gain equal to one standard deviation from the control mean (EPA 2000c). The corresponding BMD was 152 mg/kg/day; the corresponding benchmark dose limit (BMDL) was 125 mg/kg/day. Applying an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability) to the BMDL results in an acute -duration oral MRL of 1 mg/kg/day.

Dose and end point used for MRL derivation : BMDL of 125 mg/kg/day for decreased maternal weight gain.

[ ] NOAEL [ ] LOAEL [x] BMDL

Uncertainty Factors used in MRL derivation :

[x] 10 for extrapolation from animals to humans
[x] 10 for human variability

Was a conversion factor used from ppm in food or water to a mg/body weight dose ? Not applicable.

If an inhalation study in animals, list conversion factors used in determining human equivalent dose : Not applicable.

Was a conversion used from intermittent to continuous exposure ? Not applicable.

Other additional studies or pertinent information that lend support to this MRL : In another developmental study, rats were gavaged with phenol in doses of 0, 30, 60, and 120 mg/kg/day in a dosing volume of 5 mL/kg during GDs 6–15 (NTP 1983a). There was no maternal toxicity, but mean fetal body weight at this dose level was approximate ly 7% lower than controls. However, since historical control data showed that the concurrent control fetal weight for the CD rat was much higher (22%) than the historical control weight and a larger litter size in the high -dose group may have contributed to the smaller fetal weight in the high -dose group, the dose of 120 mg/kg/day can be considered an equivocal LOAEL for developmental effects; the NOAEL was 60 mg/kg/day and supports the NOAEL of 60 mg/kg/day identified in the York (1997) study.

As discuss ed in Section 2.3, effects of phenol administered to animals by oral gavage are different than those observed in drinking water studies. Phenol administered by gavage is much more toxic than administered in the drinking water and this is related to the pharmacokinetics of phenol. Furthermore, it has been shown that the volume of administration is important; the smaller the volume, the greater the toxicity of a given amount of phenol (NTP 1983a). Studies have shown that the toxicity of phenol is

correlate d with peak blood concentration rather than with total dose, such as the area under the phenol blood concentration curve (AUC) (Hiser et al. 1994). In general, NOAELs in oral gavage studies were 5–

10 times lower than in drinking water studies. The York ( 1997) study was considered an appropriate study for MRL derivation because it used a divided dosing protocol that resembles more closely a potential environmental exposure scenario to phenol.

Agency Contacts (Chemical Managers) : Jewel Crawford; Obaid Far oon; Jewell WilsonPHENOL A-5

APPENDIX A

BENCHMARK MODELING OF MATERNAL WEIGHT GAIN IN RATS

Benchmark dose models in the EPA Benchmark Dose Sof tware (BMDS version 2.0) (linear, polynomial, power, and Hill models) were fit to the maternal body weight gain data (see Tables A-1, and A-2, and Figure A -1) to determine potential points of departure for the MRL. The linear model with homogeneous variance (which was identical to the power model), was selected because it was the simplest model and provided the best fit. In the absenc e of a clear criteria as to what level of change in weight gain during pregnancy should be considered adverse, the BMR was defined as a change in mean body weight gain equal to one standard deviation from the control mean (EPA 2000c).



### Table A

- 1. Data f or the Change in Body Weight Gain in Pregnant Rats Exposed to Phenol on Gestation Days 6

– 15

Dose (mg/kg/day) Number of animals tested Body weight gain (g) Standard deviation

0 23 64 10.7

60 25 58 9.4

120 23 56.8 10.8

360 25 39.8 9.5

Source: York 1997

The corresponding BMD was 152.1 mg/kg/day; the corresponding BMDL was 124.6 mg/kg/day. Applying an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability) to the BMDL results in an acute -duration oral MRL of 1 mg/kg/day.



### Table A

- 2. Model Predictions for Changes in Body Weight Gain in Pregnant Rats Exposed to Phenol on Gestation Days 6

– 15

Model BMD 1stddev (mg/kg/day) BMDL 1stddev (mg/kg/day) p

- value a AIC

- fitted

Linear b,c 152.1 124.6 0.6055 542.79

2

- degree p olynomial c 157.0 124.6 0.3191 544.78

Power b 152.1 124.6 0.6055 542.79

Hill 151.2 123.7 0.3156 544.79

a Values <0.05 fail to meet conventional goodness

- of

- fit criteria.

b Best- fitting models

c The polynomial coefficients are restricted to be negative.

A IC = Akaike’s Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the benchmark dose; NA = not applicable; p = p value from the Chi

- squared test

Source: York 1997PHENOL A-6

APPENDIX A



### Figure A

- 1. Changes in Body Weight Gain in Pregnant Rats Exposed to Phenol on Gestation Days 6

– 15*

Linear Model with 0.95 Confidence Level

Linear 70Mean Response 65

60

55

50

45

40

35 BMD BMDL

0 50 100 150 200 250 300 350

dose 09:09 07/18 2008

*BMDs and BMDLs indicated are for a change of 1 standard deviation and are in units of mg/kg/day.

Source: York 1997

The homogeneous variance linear model form of the response function for the change in maternal body weight gain is:

Y[dose] = beta_0 + beta_1*dose + beta_2*dose^2 + ...

Linear Model Parameter Estimates for the Change in Maternal Body Weight Gain:

Variable Estimate Standard Error

alpha 98.6 14.2

beta_0 63.4 1.4

beta_1

- 0.07 0.007PHENOL 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 peopl e living in the vicinity of a hazardous waste site or chemical release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the chemical.

The major headings i n the Public Health Statement are useful to find specific topics of concern. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters in the profile that will provide more information on the given topic.

Chapter 2

Relevance to Public Health

This chapter provides a health effects summary based on evaluations of existing toxicologic,epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions:

1. What effects are known to occur in humans?

2. What effects observed in animals are likely to be of concern to humans?

3. What exposure con ditions 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 can cer 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 th e relevance to public health are identified in the Chapter 3 Data Needs section.

Interpretation of Minimal Risk Levels

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not meant to support regulatory action, but to acquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans.PHENOL B-2

APPENDIX B

MRLs should help physicians and public health officials determine the safety of a community living near a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on toxicological studies in animals and on re ports of human occupational

exposure.

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, "Relevance to Public Health," contains basic information known about the substance. Other sections such as Chapt er 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are Unusually Susceptible" provide important supplemental information.

MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure.

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential systemic, neurological, and developmental effects. If this information and reliable quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest no

- observed

- adverse

- effect level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a

lowest

- observed

- adverse

- effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor (UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The product is then divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a sub stance

- 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 fig ures 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.PHENOL 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 t wo 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 Fig ure 3-1) and oral (LSE Figure 3- 2) routes. Not all substances will have data on each route of exposure and will not, therefore, have all five of the tables and figures.

(2) Exposure Period . Three exposure periods— acute (less than 15 days), intermediate (15– 364 days), and chronic (365 days or more)— are presented within each relevant route of exposure. In this example, an inhalation study of intermediate exposure duration is reported. For quick reference to health effects occurring from a known length of exposure, locate the applicable exposure period within the LSE table and figure.

(3) Health Effect . The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table (see key number 18).

(4) Key to Figure . Each key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example, the study represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL (also see the two "18r" data point s in sample Figure 3 -1).

(5) Species . The test species, whether animal or human, are identified in this column. Chapter 2, "Relevance to Public Health," covers the relevance of animal data to human toxicity and

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent

human doses to derive an MRL.

(6) Exposure Frequency/Duration . The duration of the study and the weekly and daily exposure regimens are provided in this column. This permits comparison of NOAELs and LOAELs from different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation for 6 hours/day, 5 days/week, for 13 weeks. For a m ore complete review of the dosing regimen, refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 1981).

(7) System . This column further defines the systemic effects. These systems include respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In the example of key number 18, one systemic effect (respiratory) was investigated.

(8) NOAEL . A NOAEL is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see

footnote "b").PHENOL B-4

APPENDIX B

(9) LOAEL . A LOAEL is the lowest dose used in the study that caused a harmful health effect. LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific end point used to quantify the adverse effect accompanies the LOAEL. The respiratory eff ect reported in key number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from

Serious LOAELs.

(10) Reference . The complete reference citation is given in Chapter 9 of the profile.

(11) CEL . A CEL is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses not causing

measurable cancer increases.

(12) Footnotes . Explanations of abbreviations or reference notes for data in the LSE tables are found

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to

derive an MRL of 0.005 ppm.

LEGEND See Sample Figure 3

- 1 (page B

- 7)

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure concentrations for particular exposure periods.

(13) Exposure Period . The same exposure periods appear as in the LSE table. In this example, health effects observed within the acute and intermediate exposure periods are illustrated.

(14) Health Effect . These are the categories of health effects for which reliable quan titative data exists. The same health effects appear in the LSE table.

(15) Levels of Exposure . Concentrations or doses for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log scale "y" axis. Inhalation exposure is reported in mg/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 exposure MRL is based. The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of

0.005 ppm (see footnote "b" in the LSE table).

(17) CEL . Key number 38m is one of three studies for which CELs were derived. The diamond symbol refers to a CEL for the test species -mouse. The number 38 corresponds to the entry in the

LSE table.PHENOL B-5

APPENDIX B

(18) Estimated Upper -Bound Human C ancer 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.SAMPLE1**→**Table 3-1. Levels of Significant Exposure to [Chemical x]–InhalationLOAEL (effect)ExposureKey tofrequency/NOAELLess serious Serious (ppm)figureaSpecies durationSystem(ppm)(ppm)Reference234**→**INTERMEDIATE EXPOSURE5678910**→**Systemic**↓ ↓** **↓ ↓ ↓** **↓**18Rat13 wkResp3b10 (hyperplasia)**→**5 d/wkNitschke et al. 19816 hr/dCHRONIC EXPOSURECancer11**↓**38Rat18 mo20(CEL, multipleWong et al. 19825 d/wkorgans)7 hr/d39Rat89–104 wk10(CEL,lung tumors, NTP 19825 d/wknasal tumors)6 hr/d40Mouse79–103 wk10(CEL, lung tumors,NTP 19825 d/wkhemangiosarcomas)6 hr/d12**→**aThe 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). PHENOL B-6

APPENDIX BPHENOL B-7

APPENDIX BPHENOL B-8

APPENDIX B



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



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

ACGIH American Co nference of Governmental Industrial Hygienists

ACOEM American College of Occupational and Environmental Medicine

ADI acceptable daily intake

ADME absorption, distribution, metabolism, and excretion

AED atomic emission detection

AFID alkali flame ionization detector

AFOSH Air Force Office of Safety and Health

ALT alanine aminotransferase

AML acute myeloid leukemia

AOAC Association of Official Analytical Chemists

AOEC Association of Occupational and Environmental Clinics

AP alkaline phosphatase

APHA American Public Health Association

AST aspartate aminotransferase

atm atmosphere

ATSDR Agency for Toxic Substances and Disease Registry AWQC Ambient Water Quality Criteria

BAT best available technology

BCF bioconcentration factor

BEI Biological Exposure Index

BMD benchmark dose

BMR benchmark response

BSC Board of Scientific Counselors

C centigrade

CAA Clean Air Act

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency

CAS Chemical Abstract Services

CDC Centers for Disease Control and Prevention

CEL cancer effect level

CELDS Computer- Environmental Legislative Data System

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act

CFR Code of Federal Regulations

Ci curie

CI confidence interval

CL ceiling limit value

CLP Contract Labor atory Program

cm centimeter

CML chronic myeloid leukemia

CPSC Consumer Products Safety Commission

CWA Clean Water Act

DHEW Department of Health, Education, and Welfare

DHHS Department of Health and Human Services

DNA deoxyribonucleic acid

DOD Department of Defense

DOE Department of Energy

DOL Department of Labor

DOT Department of Transportation

DOT/UN/ Department of Transportation/United Nations/

NA/IMCO North America/Intergovernmental Maritime Dangerous Goods CodePHENOL C-2

APPENDIX C

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 Insecticide, Fungicide, and Rodenticide Act

FPD flame photometric detection fpm feet per minute

FR Federal Register

FSH follicle stimulating hormone

g gram GC gas ch romatography 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 o n Cancer

IDLH immediately dangerous to life and health

ILO International Labor Organization

IRIS Integrated Risk Information System

Kd adsorption ratio kg kilogram kkg metric ton

K

oc organic carbon partition coefficient

K

ow octanol- water partition coeffi cient

L liter

LC liquid chromatography

LC 50 lethal concentration, 50% kill

LC Lo lethal concentration, 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 maximum allowable level

mCi millicurie

MCL maximum contaminant level

MCLG maximum contaminant level goal

MF modifying factorPHENOL C-3

APPENDIX C

MFO mixed function oxidase

mg milligram

mL milliliter

mm millimeter mmHg millimeters of mercury

mmol millimole mppcf millions of particles per cubic foot

MRL Minimal Risk Level

MS mass spectrometry NAAQS National Ambient Air Quality Standard

NAS National Academy of Science

NATICH National Air T oxics Information Clearinghouse

NATO North Atlantic Treaty Organization

NCE normochromatic erythrocytes

NCEH National Center for Environmental Health

NCI National Cancer Institute

ND not detected

NFPA National Fire Protection Association

ng nanogram NHANES National Health and Nutrition Examination Survey

NIEHS National Institute of Environmental Health Sciences

NIOSH National Institute for Occupational Safety and Health

NIOSHTIC NIOSH's Computerized Information Retrieval System

NLM National Library of Medic ine

nm nanometer
nmol nanomole

NOAEL no- observed

- adverse

- effect level

NOES National Occupational Exposure Survey

NOHS National Occupational Hazard Survey

NPD nitrogen phosphorus detection

NPDES National Pollutant Discharge Elimination System

NPL National Priorities List

NR not reported

NRC National Research Council

NS not specified

NSPS New Source Performance Standards

NTIS National Technical Information Service

NTP National Toxicology Program

ODW Office of Drinking Water, EPA

OERR Office of Emergency and R emedial 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 r atio

OSHA Occupational Safety and Health Administration

OSW Office of Solid Waste, EPA

OTS Office of Toxic Substances

OW Office of Water

OWRS Office of Water Regulations and Standards, EPA

PAH polycyclic aromatic hydrocarbonPHENOL C-4

APPENDIX C

PBPD physiologically based pharmacodynamic

PBPK physiologically based pharmacokinetic

PCE polychromatic erythrocytes

PEL permissible exposure limit

pg picogram

PHS Public Health Service

PID photo ionization detector pmol picomole

PMR proportionate mortality ratio ppb parts per billion ppm parts per million

ppt parts per trillion

PSNS pretreatment standards for new sources

RBC red blood cell

REL recommended exposure level/limit

RfC reference concentration

RfD reference dose

RNA ribonucleic acid RQ reportable quantity

RTECS Registry of T oxic Effects of Chemical Substances

SARA Superfund Amendments and Reauthorization Act

SCE sister chromatid exchange

SGOT serum glutamic oxaloacetic transaminase

SGPT serum glutamic pyruvic transaminase

SIC standard industrial classification

SIM selected io n 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, 5 0% specific toxic effect

TLV threshold limit value

TOC total organic carbon TPQ threshold planning quantity

TRI Toxics Release Inventory

TSCA Toxic Substances Control Act

TWA time

- weighted average

UF uncertainty factor

U.S. United States

USDA United States Department of Agriculture

USGS United States Geological Survey

VOC volatile organic compound

WBC white blood cell

WHO World Health OrganizationPHENOL 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 resultPHENOL C-6

APPENDIX C



### This page is intentionally blank.PHENOL D-1



### APPENDIX D. INDEX

absorbed dose............................................................................................................................................122 acetylcholine .............................................................................................................................................124 adrenal gland ........................................................................................................................... 14, 67, 75, 131 adsorption.................................................................................................................................. 156, 170, 176

aerobic

................................................................................................ ................................... 9, 157, 158, 159

alanine aminotransferase (see ALT) ..................................................................................................... 10, 36

ALT (see alanine aminotransferase ) ........................................................................... 10, 36, 37, 65, 82, 131

ambient air ................................................................................................................ 149, 159, 164, 165, 170 anaerobic....................................................................................................................................... 9, 158, 159 aspartate aminotransferase (see AST) ................................................................................................... 35, 36

AST (see aspartate aminotransferase )......................................................................... 10, 36, 37, 65, 82, 131 bioaccumulation................................................................................................................................ 156, 170 bioavailability

................................................................................................ ...........................................170

bioconcentration factor .............................................................................................................................156 biodegradation............................................................................................................. 10, 149, 155, 156, 158 biomarker .................................................................. 106, 111, 121, 122, 123, 124, 134, 135, 172, 173, 181

blood cell count

................................................................................................ ............................... 12, 36, 64 body weight effects......................................................................................................................... 39, 68, 85

breast milk

................................................................................................ ............................... 5, 10, 137, 166

cancer ...................................................................................................... 4, 22, 44, 75, 86, 87, 118, 121, 185 carcinogen

................................................................................................ ................................... 86, 185, 188 carcinogenic ...................................................................................................................... 14, 21, 75, 86, 111 carcinogenicity ............................................................................ 4, 14, 75, 87, 112, 129, 131, 136, 185, 188 carcinoma.............................................................................................................................................. 86, 87 cardiac arrhythmia ........................................................................................ 12, 77, 118, 119, 120, 126, 129

cardiovascular ............................................................................... 4, 10, 23, 34, 62, 127, 129, 131, 134, 136

cardiovascular e ffects ...................................................................................................................... 34, 62, 77

catechol

................................................................................................ ............................... 93, 101, 112, 115 chromosomal aberrations................................................................................................................ 87, 91, 92

clearance

................................................................................................ ............................................. 95, 100 consumer products ............................................................................................ 1, 9, 164, 165, 166, 167, 171

death .......................................... 4, 11, 18, 21, 22, 23, 35, 43, 44, 61, 70, 75, 76, 77, 85, 120, 125, 127, 188 deoxyribonucleic acid (see DNA) ................................................................................................... 87, 88, 90

dermal e ffects ............................................................................................................................ 38, 39, 67, 83 disinfectant.................................................................................................................... 1, 5, 67, 70, 119, 143

DNA (see deoxyribonucleic acid)..................................................... 87, 88, 89, 90, 91, 92, 93, 99, 114, 122 dopamine............................................................................................................................................... 20, 71

elimination half

- time

................................................................................................ ...................................99 endocrine..................................................................................................................................... 67, 115, 116

endocrine e ffects

................................................................................................ .........................................67 erythema ............................................................................................................................ 11, 63, 77, 83, 125

estrogen receptor

................................................................................................ .......................................117 estrogenic

................................................................................................ ..................................................117

fetal tissue

................................................................................................ ...................................................98

fetus

................................................................................................ ...........................................................117 gastrointestinal effects .............................................................................................................. 34, 35, 63, 81 general population ..................................................................................... 10, 22, 35, 44, 122, 134, 165, 188 genotoxic............................................................................................................................... 21, 91, 112, 132 genotoxicity................................................................................................................................. 87, 129, 132PHENOL D-2

APPENDIX D

germinal cell

................................................................................................ ................................................72 glucuronide ............................................................................... 100, 101, 103, 104, 114, 121, 136, 137, 173 groundwater ...................................................................... 2, 9, 149, 155, 156, 158, 160, 161, 163, 164, 171 growth retardation.......................................................................................................................................73

half- life .............................................................................................. 9, 94, 95, 107, 122, 149, 155, 157, 158 hematological effects ...................................................................................................................... 35, 64, 81 hematopoietic..............................................................................................................................................35 hepatic effects ......................................................................................................................... 36, 65, 82, 124 hydrolysis.......................................................................................................................... 143, 173, 174, 176 hydroquinone ...................................................................................... 93, 101, 103, 104, 111, 112, 115, 124 hydroxyl radical ........................................................................................................................ 149, 155, 157 immune system

................................................................................................ ...........................................40 immunological .............................................................. 12, 13, 19, 21, 35, 40, 41, 69, 70, 85, 129, 130, 131 immunological effects................................................................................................................... 19, 69, 130

K

ow ................................................................................................ ............................................................141

LD 50

................................................................................................ ..................................... 45, 61, 76, 77, 99

leukemia

................................................................................................ ........................................ 14, 75, 131 lympho reticular ............................................................................................................. 13, 20, 41, 69, 70, 85

metabolic effects

................................................................................................ .........................................40

micronuclei .................................................................................................................................................91

milk

................................................................................................ ............................................... 5, 121, 137

musculoskeletal effects ............................................................................................................. 36, 65, 81, 82

neurobehavioral.........................................................................................................................................116

neurochemical

................................................................................................ ............................... 12, 19, 130 norepinephrine ...................................................................................................................................... 20, 71 nuclear................................................................................................................................................. 82, 114

ocular effects

................................................................................................ ................................. 68, 84, 130

odds ratio.....................................................................................................................................................44 pharmacodynamic.....................................................................................................................................108 pharmacokinetic........................................................................................................ 108, 109, 110, 118, 121 placenta ............................................................................................................................................. 121, 137 placental barrier

................................................................................................ ..........................................98

rate constant

................................................................................................ ........................................ 94, 157

renal e ffects

................................................................................................ ..................................... 38, 66, 82

retention

................................................................................................ .................................. 93, 94, 95, 157

salivation

................................................................................................ ............................................... 18, 85 solubility

................................................................................................ ...................................................155 spermatogonia.............................................................................................................................................91

sulfate .................................... 93, 97, 101, 103, 104, 113, 115, 120, 121, 124, 135, 136, 137, 173, 179, 180 thyroid................................................................................................................................................... 67, 99 toxicokinetic.................................................................................................................... 12, 16, 21, 127, 135

tremors .............................................................................. 4, 11, 12, 14, 15, 16, 40, 42, 70, 73, 85, 115, 124 tumors ..................................................................................................................................... 77, 86, 87, 124 volatility

................................................................................................ ....................................................158

volatilization

................................................................................................ ..................................... 155, 170